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http://www.ncbi.nlm.nih.gov/pubmed/28923211 | 1. Semin Oncol. 2017 Apr;44(2):132-135. doi: 10.1053/j.seminoncol.2017.06.007.
Epub 2017 Jul 13.
Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell
death-1 (PD-1) that are interchangeable.
Prasad V(1), Kaestner V(2).
Author information:
(1)Division of Hematology Oncology, Knight Cancer Institute, Oregon Health &
Science University, Portland, OR; Department of Public Health and Preventive
Medicine, Oregon Health & Science University, Portland, OR; Senior Scholar in
the Center for Health Care Ethics, Oregon Health & Science University, Portland,
OR. Electronic address: prasad@ohsu.edu.
(2)Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon
Health & Science University, Portland, OR. Electronic address:
kaestner@ohsu.edu.
Nivolumab (Opdivo, Bristol Meyer Squibb, New York, NY) and pembrolizumab
(Keytruda, Merck, Kenilworth, NJ) are the first two US Food and Drug
Administration (FDA)-approved monoclonal antibodies targeting programmed death-1
(PD-1). Nivolumab and pembrolizumab work by interfering with the interaction
between PD-1 and programmed death ligand-1 (PD-L1), whose unimpeded interaction
downregulates T cells allowing cancer cells to evade immune surveillance. These
drugs have earned a series of FDA approvals for melanoma, non-small cell lung
cancer (NSCLC), head and neck squamous cell cancer (HNSCC), urothelial cancer,
classical Hodgkin lymphoma, and renal cell cancer. In this review we will
summarize the data for efficacy and toxicity for these two agents. We conclude
that they represent two valuable but interchangeable alternatives to target
their approved indications. We will discuss how this can help global payers
seeking to contain the cost of cancer therapeutics that continues to spiral out
of control.
Copyright © 2017. Published by Elsevier Inc.
DOI: 10.1053/j.seminoncol.2017.06.007
PMID: 28923211 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27058852 | 1. Clin Adv Hematol Oncol. 2015 Dec;13(12):858-68.
Programmed death 1 immune checkpoint inhibitors.
Trivedi MS(1), Hoffner B(2), Winkelmann JL(1), Abbott ME(1), Hamid O(2),
Carvajal RD(1).
Author information:
(1)Columbia University Medical Center, New York, New York.
(2)The Angeles Clinic and Research Institute, Los Angeles, California.
Programmed death 1 (PD-1) is an immune checkpoint that provides inhibitory
signals to the immune system in order to modulate the activity of T cells in
peripheral tissues and maintain self-tolerance in the setting of infection and
inflammation. In cancer, the immune checkpoints are exploited so that the tumor
cells are able to evade the immune system. Immune checkpoint inhibitors are a
type of cancer immunotherapy that targets pathways such as PD-1 in order to
reinvigorate and enhance the immune response against tumor cells. The US Food
and Drug Administration (FDA) has approved 2 PD-1 inhibitors, nivolumab and
pembrolizumab, and several others are under investigation. Although PD-1
inhibitors have demonstrated activity in many different types of malignancies,
FDA approval has been granted only in melanoma and in non-small cell lung cancer
(NSCLC). Identifying biomarkers that can predict response to PD-1 inhibitors is
critical to maximizing the benefit of these agents. Future directions for PD-1
inhibitors include investigation of combination therapies, use in malignancies
other than melanoma and NSCLC, and refinement of biomarkers.
PMID: 27058852 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27795534 | 1. Rinsho Ketsueki. 2016;57(10):2224-2231. doi: 10.11406/rinketsu.57.2224.
[Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) in cancer
therapy].
[Article in Japanese]
Hatae R(1), Chamoto K.
Author information:
(1)Department of Immunology and Genomic Medicine, Graduate School of Medicine,
Kyoto University.
Immune checkpoint inhibitors, especially anti-programmed cell death-1 (PD-1)
antibodies, have revolutionized cancer therapy. A PD-1 antibody, nivolumab, was
the first of these agents to be approved by the Pharmaceuticals and Medical
Devices Agency (PMDA) of Japan, as a new cancer drug for melanoma, in July 2014.
While PD-1 mAb therapy has so far been approved only for untreated malignant
melanomas and non-small cell lung cancer, many clinical studies on various types
of cancer have been conducted worldwide. Immune checkpoint inhibitors target
lymphocytes rather than cancer cells, and evoke an anti-tumor immune reaction.
Since the activated lymphocytes recognize various tumor-associated antigens
including a mutated antigen, immune checkpoint inhibitors exhibit continuous
long-term effectiveness, despite the generation of genetic mutations in cancer
cells. As compared with previous cancer treatments, immune checkpoint inhibitors
show superior efficacy against tumors with fewer side effects. Therefore, these
novel immune checkpoint inhibitor agents are anticipated to become a 4th cancer
treatment option following surgery, chemotherapy, and radiation therapy. Herein,
we review the main clinical results of PD-1 mAb cancer immunotherapy obtained to
date and discuss issues relevant to administering this form of treatment.
DOI: 10.11406/rinketsu.57.2224
PMID: 27795534 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30304963 | 1. Expert Rev Anticancer Ther. 2018 Dec;18(12):1169-1175. doi:
10.1080/14737140.2018.1535315. Epub 2018 Oct 22.
Nivolumab for the treatment of hepatocellular carcinoma.
Finkelmeier F(1), Waidmann O(1), Trojan J(1).
Author information:
(1)a Medizinische Klinik 1 , Universitätsklinikum Frankfurt, Goethe-Universität
, Frankfurt/Main , Germany.
T-cell checkpoint inhibition as a cancer treatment approach has been the main
breakthrough in cancer treatment during the last years. Since the approval of
the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of
melanoma, research and drug development in this field has accelerated massively.
In 2014, the US Food and Drug Administration (FDA) approved the first PD-1
targeting agent, namely pembrolizumab, shortly followed by nivolumab. Areas
covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal
antibody which is approved for multiple advanced malignancies, including
melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's lymphoma,
squamous head and neck cancer, and urothelial carcinoma. In September 2017,
nivolumab was approved by the FDA for liver cancer as a second line treatment
after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial
CheckMate-040. This article reviews the concept of immunotherapy in liver cancer
with focus on nivolumab. Expert commentary: Immunotherapy in hepatocellular
carcinoma is safe and is a new treatment option for patients with advanced stage
disease besides sorafenib and regorafenib in the US. Randomized phase III trials
of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono-
or combination-therapy are ongoing.
DOI: 10.1080/14737140.2018.1535315
PMID: 30304963 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33686894 | 1. Expert Opin Emerg Drugs. 2021 Jun;26(2):79-92. doi:
10.1080/14728214.2021.1901884. Epub 2021 Mar 19.
Emerging PD-1/PD-L1 antagonists for the treatment of malignant melanoma.
Vanella V(1), Festino L(1), Vitale MG(1), Alfano B(1), Ascierto PA(1).
Author information:
(1)Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto
Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy.
INTRODUCTION: Increased understanding of the interactive mechanisms between
tumors and the immune system led to the development of immune checkpoint
inhibitors, which have revolutioned the treatment of metastatic melanoma and
subsequently many other tumors. In 2014, nivolumab and pembrolizumab, two
checkpoint inhibitors binding to PD-1, were approved for the treatment of
metastatic melanoma. Since then, a plethora of new molecules have enriched the
armamentarium against melanoma.
AREAS COVERED: This review summarizes the last updates about treatment with
nivolumab and pembrolizumab, data on other PD-1/PDL-1 agents such as
spartalizumab and atezolizumab and emerging compounds, new combinations with
NKTR-214, anti LAG-3, anti IDO-1 and TVEC, new checkpoint inhibitors (e.g. TIM-3
or TIGIT) and other new molecules for the treatment of metastatic melanoma.
EXPERT OPINION: Currently, several ongoing clinical trials are investigating
novel molecules, or immunotherapy combinations, in order to achieve even better
survival outcomes for patients, overcoming resistance mechanisms and improving
toxicity profiles. The challenge in the near future will be to select the most
appropriate treatments according to the specific characteristics of the
patients.
DOI: 10.1080/14728214.2021.1901884
PMID: 33686894 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32863353 | 1. Jpn J Infect Dis. 2021 Mar 24;74(2):102-109. doi: 10.7883/yoken.JJID.2020.444.
Epub 2020 Aug 31.
Growth Characteristics of Rickettsia Species LON Strains Closely Related to
Rickettsia japonica Isolated from Haemaphysalis longicornis Ticks in Mouse
Derived L929 and Human-Derived THP-1 Host Cell Lines.
Tai H(1), Su H(1), Takamoto N(1), Fujita H(1)(2), Takano A(3), Oishi S(4), Abe
F(4), Ando S(5), Ohashi N(1).
Author information:
(1)Graduate Program in Pharmaceutical and Nutritional Sciences, Graduate School
of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka,
Japan.
(2)Mahara Institute of Medical Acarology, Japan.
(3)Department of Veterinary Medicine, Joint Faculty of Veterinary Medicine,
Yamaguchi University, Japan.
(4)Department of Microbiology, Shizuoka Institute of Environment and Hygiene,
Japan.
(5)Department of Virology I, National Institute of Infectious Diseases, Japan.
Non-pathogenic Rickettsia species LON strains closely related to an agent of
Japanese spotted fever (JSF), R. japonica, were isolated in Japan from
Haemaphysalis longicornis ticks in 2001. However, the biological properties of
LONs in mammalian host cells are poorly understood. In this study, microscopic
analysis showed that LONs in a mouse-derived L929 host cell line were rod shaped
with sizes of 0.3-0.5 × 0.5-2.0 μm. Molecular analysis revealed the existence of
a LON-specific disrupted open reading frame in R. japonica-related
group-specific DNA regions. Growth kinetics of LON-2 and LON-13 strains analyzed
by a quantitative real-time PCR showed 100-fold or more increment of LONs
cultured in L929 host cells at 30°C and slightly less increment at 33°C, and
25-fold increment in human-derived THP-1 host cells at 35°C on day 7 (168 h)
post infection. The generation times of the two LON strains cultured in L929 and
THP-1 were estimated to be 9.4-12.9 h and 9.6-10.9 h, respectively. To our
knowledge, this is the first report on the biological characteristics of
Rickettsia sp. LON strains in mammalian cells, which may provide significant
information for the experimental approaches for other rickettsiae.
DOI: 10.7883/yoken.JJID.2020.444
PMID: 32863353 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33808008 | 1. Pharmaceutics. 2021 Mar 5;13(3):341. doi: 10.3390/pharmaceutics13030341.
Dermatillomania: Strategies for Developing Protective Biomaterials/Cloth.
Ravipati P(1), Conti B(1), Chiesa E(1), Andrieux K(2).
Author information:
(1)Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.
(2)Department of Pharmacie, Université Paris Descartes, 75006 Paris, France.
Dermatillomania or skin picking disorder (SPD) is a chronic, recurrent, and
treatment resistant neuropsychiatric disorder with an underestimated prevalence
that has a concerning negative impact on an individual's health and quality of
life. The current treatment strategies focus on behavioral and pharmacological
therapies that are not very effective. Thus, the primary objective of this
review is to provide an introduction to SPD and discuss its current treatment
strategies as well as to propose biomaterial-based physical barrier strategies
as a supporting or alternative treatment. To this end, searches were conducted
within the PubMed database and Google Scholar, and the results obtained were
organized and presented as per the following categories: prevalence, etiology,
consequences, diagnostic criteria, and treatment strategies. Furthermore,
special attention was provided to alternative treatment strategies and
biomaterial-based physical treatment strategies. A total of six products with
the potential to be applied as physical barrier strategies in supporting SPD
treatment were shortlisted and discussed. The results indicated that SPD is a
complex, underestimated, and underemphasized neuropsychiatric disorder that
needs heightened attention, especially with regard to its treatment and care.
Moreover, the high synergistic potential of biomaterials and nanosystems in this
area remains to be explored. Certain strategies that are already being utilized
for wound healing can also be further exploited, particularly as far as the
prevention of infections is concerned.
DOI: 10.3390/pharmaceutics13030341
PMCID: PMC8001957
PMID: 33808008
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36016429 | 1. Viruses. 2022 Aug 18;14(8):1807. doi: 10.3390/v14081807.
Clinical Differentiation of Severe Fever with Thrombocytopenia Syndrome from
Japanese Spotted Fever.
Nakada N(1)(2), Yamamoto K(1), Tanaka M(1), Ashizawa H(1), Yoshida M(3), Umemura
A(3), Fukuda Y(3), Katoh S(4), Sumiyoshi M(5), Mihara S(5), Kobayashi T(6), Ito
Y(1), Ashizawa N(1)(7), Takeda K(1), Ide S(6)(8), Iwanaga N(1), Takazono
T(1)(7), Tashiro M(7), Tanaka T(7), Nakamichi S(2), Morimoto K(9), Ariyoshi
K(9), Morita K(10), Kurihara S(11), Yanagihara K(12), Furumoto A(5)(8),
Izumikawa K(7), Mukae H(1).
Author information:
(1)Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki
852-8102, Japan.
(2)Health Center, Nagasaki University, Nagasaki 852-8521, Japan.
(3)Department of Respiratory Medicine, Sasebo City General Hospital, Sasebo
857-8511, Japan.
(4)Department of General Internal Medicine, Nagasaki Rosai Hospital, Sasebo
857-0134, Japan.
(5)Department of Respiratory Medicine, Isahaya General Hospital, Isahaya
854-8501, Japan.
(6)Department of Respiratory Medicine, Sasebo Chuo Hospital, Sasebo 857-1195,
Japan.
(7)Department of Infection Control and Education Center, Nagasaki University
Hospital, Nagasaki 852-8102, Japan.
(8)Infectious Disease Experts Training Center, Nagasaki University Hospital,
Nagasaki 852-8102, Japan.
(9)Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki
University, Nagasaki 852-8523, Japan.
(10)Department of Virology, Institute of Tropical Medicine, Nagasaki University,
Nagasaki 852-8523, Japan.
(11)Department of Medical Safety, Nagasaki University Hospital, Nagasaki
852-8102, Japan.
(12)Department of Laboratory Medicine, Nagasaki University Hospital, Nagasaki
852-8102, Japan.
Severe fever with thrombocytopenia syndrome (SFTS) and Japanese spotted fever
(JSF; a spotted fever group rickettsiosis) are tick-borne zoonoses that are
becoming a significant public health threat in Japan and East Asia. Strategies
for treatment and infection control differ between the two; therefore, initial
differential diagnosis is important. We aimed to compare the clinical
characteristics of SFTS and JSF based on symptomology, physical examination,
laboratory data, and radiography findings at admission. This retrospective study
included patients with SFTS and JSF treated at five hospitals in Nagasaki
Prefecture, western Japan, between 2013 and 2020. Data from 23 patients with
SFTS and 38 patients with JSF were examined for differentiating factors and were
divided by 7:3 into a training cohort and a validation cohort. Decision tree
analysis revealed leukopenia (white blood cell [WBC] < 4000/μL) and altered
mental status as the best differentiating factors (AUC 1.000) with 100%
sensitivity and 100% specificity. Using only physical examination factors,
absence of skin rash and altered mental status resulted in the best
differentiating factors with AUC 0.871, 71.4% sensitivity, and 90.0%
specificity. When treating patients with suspected tick-borne infection, WBC <
4000/µL, absence of skin rash, and altered mental status are very useful to
differentiate SFTS from JSF.
DOI: 10.3390/v14081807
PMCID: PMC9415593
PMID: 36016429 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35507925 | 1. Trop Biomed. 2022 Mar 1;39(1):55-59. doi: 10.47665/tb.39.1.007.
A new record of Rickettsia japonica in ticks infesting a Burmese ferret-badger
in Thailand.
Hirunkanokpun S(1), Ahantarig A(2), Baimai B(2), Pramual P(3), Trinachartvanit
W(2).
Author information:
(1)Department of Biology, Faculty of Science, Ramkhamhaeng University, Bangkok,
10240, Thailand.
(2)Biodiversity Research Cluster, Department of Biology, Faculty of Science,
Mahidol University, Rama 6 Road, Bangkok, 10400, Thailand.
(3)Department of Biology, Faculty of science, Mahasarakham University, Maha
Sarakham, 44150, Thailand.
Ticks are important vectors of arthropod-borne diseases and they can transmit a
wide variety of zoonotic pathogens to humans, domestic and wild animals.
Rickettsia japonica is a member of SFG rickettsiae causing Japanese spotted
fever (JSF) and can transmit to humans via infected ticks. In this study, we
report the first case of Rickettsia japonica in Haemaphysalis hystricis tick
collected from a roadkill Burmese ferret-badger ( Melogale personata ) in Loei
province, northeastern Thailand. According to the DNA sequences and phylogenetic
analyses of the outer membrane protein A and B genes ( ompA and ompB), the
detected R. japonica was identical to those found in JSF patients in Korea,
Japan, and China, and closely related to Rickettsia detected by ompA in a tick
from Thailand. Further study on the prevalence of R. japonica and diversity of
mammalian reservoir hosts will be useful to gain a better understanding of JSF
epidemiology.
DOI: 10.47665/tb.39.1.007
PMID: 35507925 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35668012 | 1. J Geriatr Oncol. 2022 Sep;13(7):997-1002. doi: 10.1016/j.jgo.2022.05.013. Epub
2022 Jun 3.
Real-life safety of PD-1 and PD-L1 inhibitors in older patients with cancer: An
observational study.
Storm BN(1), Abedian Kalkhoran H(2), Wilms EB(2), Brocken P(3), Codrington H(3),
Houtsma D(4), Portielje JEA(5), de Glas N(5), van der Ziel D(5), van den Bos
F(6), Visser LE(7).
Author information:
(1)Department of Pharmacy, Haga Teaching Hospital, The Hague, the Netherlands.
Electronic address: b.n.storm@hagaziekenhuis.nl.
(2)Department of Pharmacy, Haga Teaching Hospital, The Hague, the Netherlands.
(3)Department of Pulmonary Diseases - Pulmonic Oncology, Haga Teaching Hospital,
The Hague, the Netherlands.
(4)Department of Internal Medicine - Medical Oncology, Haga Teaching Hospital,
The Hague, the Netherlands.
(5)Department of Internal Medicine - Medical Oncology, University Medical Centre
Leiden, Leiden, the Netherlands.
(6)Department of Gerontology & Geriatrics, University Medical Centre Leiden,
Leiden, the Netherlands.
(7)Department of Pharmacy, Haga Teaching Hospital, The Hague, the Netherlands;
Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands.
INTRODUCTION: To compare the real-world safety profile of programmed cell
death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors between
younger and older patients.
MATERIALS AND METHODS: All patients receiving pembrolizumab, nivolumab,
atezolizumab or durvalumab between September 2016 and September 2019 at Haga
Teaching Hospital, The Hague, The Netherlands were included in this
retrospective study. Immune-related adverse drug reactions (irADRs) were
manually retrieved from the electronic patient files. The cumulative incidence
of irADRs were compared between younger (<65 years) and older (≥65 years)
patients using a Pearsons Chi-square test.
RESULTS: We identified 217 patients who were treated with at least one dose of
PD-(L)1 inhibitor. 58% were 65 years or older at the start of immunotherapy. 183
patients (84.3%) received monotherapy PD-(L)1 inhibitors and 34 (15.7%) received
chemo-immunotherapy. A total of 278 irADRs were registered. Cutaneous irADRs
(53.9%), thyroid gland disorders (20.3%), and non-infectious diarrhoea/colitis
(17.5%) were the most frequently reported irADRs. The majority of the irADRs
were mild to moderate and no fatal irADRs were observed. 61 (21.9%) of the
irADRs needed systemic treatment, of which 19 (6.8%) required treatment with
corticosteroids. 18 irADRs (6.5%) were severe and resulted in hospitalisation.
The cumulative incidence of cutaneous irADRs was different between the age
groups: 45.7% of the patients <65 years and in 60.0% of the patients ≥65 years
(p = 0.036). No statistical difference was found in the cumulative incidence of
other irADRs between the two age groups.
DISCUSSION: Advanced age is not associated with immune-related adverse drug
reactions of PD-1 and PD-L1 inhibitors.
Copyright © 2022 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.jgo.2022.05.013
PMID: 35668012 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest None. |
http://www.ncbi.nlm.nih.gov/pubmed/20587542 | 1. Int Immunol. 2010 Aug;22(8):651-60. doi: 10.1093/intimm/dxq049. Epub 2010 Jun
29.
PD-L1 and PD-L2 differ in their molecular mechanisms of interaction with PD-1.
Ghiotto M(1), Gauthier L, Serriari N, Pastor S, Truneh A, Nunès JA, Olive D.
Author information:
(1)Institut National de la Santé et de la Recherche Médicale, Unité 891, Centre
de Recherche en Cancérologie de Marseille, Marseille, France.
The programmed death-1 (PD-1) molecule is involved in peripheral tolerance and
in the immune escape mechanisms during chronic viral infections and cancer. PD-1
interacts with two ligands, PD-L1 and PD-L2. We have investigated the molecular
mechanisms of PD-1 interactions with its ligands by surface plasmon resonance
and cell surface binding as well as the ability of the two ligands to compete
for PD-1 binding. PD-L1 and PD-L2 bound PD-1 with comparable affinities, but
striking differences were observed at the level of the association and
dissociation characteristics. PD-L1, but not PD-L2, had a delayed interaction
reminiscent of a phenomenon of conformational transition. These mechanisms were
confirmed by using PD-L1 mAbs that delayed the dissociation of PD-L1 from PD-1.
This mechanism was not restricted to PD-1 binding since PD-L1 behaved in a
similar manner with its second ligand, CD80. Finally, we could demonstrate that
PD-L1 and PD-L2 competed for PD-1 binding and conversely, an antagonist PD-1 mAb
blocked both PD-L1 and PD-L2 binding to PD-1 and strongly enhanced T-cell
proliferation. These data further emphasize the differential molecular
mechanisms of interaction of PD-L1 and PD-L2 with PD-1, and suggest possible new
approach for the therapy of chronic infection, cancer and transplantation.
DOI: 10.1093/intimm/dxq049
PMCID: PMC3168865
PMID: 20587542 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST The authors declare no
financial or commercial conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/30851544 | 1. Leuk Res. 2019 Apr;79:52-59. doi: 10.1016/j.leukres.2019.02.010. Epub 2019 Feb
28.
Programmed Cell Death Receptor (PD-1) Ligand (PD-L1) expression in Philadelphia
chromosome-negative myeloproliferative neoplasms.
Wang JC(1), Chen C(2), Kundra A(2), Kodali S(2), Pandey A(2), Wong C(2), Cheung
T(2), Gotlieb V(2), Joseph G(2), Tribie S(2).
Author information:
(1)Division of Hematology/Oncology, Brookdale University Hospital Medical
Center, Brooklyn, NY 11212, USA. Electronic address: jcwang0005@gmail.com.
(2)Division of Hematology/Oncology, Brookdale University Hospital Medical
Center, Brooklyn, NY 11212, USA.
Programmed Cell Death Receptor (PD-1) and its Ligand (PD-L1) pathway inhibitor
therapy has been explored in the field of oncology treatment mainly for solid
tumors. In hematologic malignancies, there is limited information except for
Hodgkin's lymphoma, and there is even less information regarding
myeloproliferative neoplasm (MPN). Therefore, we explored this by first
measuring PD-1 and PD-L1 levels (percentage of positive cells) in 63 patients
with Philadelphia chromosome-negative MPN (Ph(-) MPN), including 16 MF (12 PMF,
2 post-PV-MF, 2 post-ET-MF), 29 ET, and 18 PV. We found there was no significant
difference in PD-1 or PD-L1 levels between the different MPN groups but that
there was a significant difference when PV, ET and MF were grouped as MPN and
compared with controls, of all immune cells including CD4+, CD8+, CD14+ and
CD34+ progenitor cells. We further found a higher incidence of higher expression
levels (more than 50% of cells with positive expression) of PD-1 and PD-L1 (20%
and 26%, respectively) in the CD34+ cells; in contrast, we found a low incidence
(0.08-1.8%) in the immune cells in MPN patients. PD-1 and PD-L1 levels were also
measured by MFI methods, and we obtained similar results except the measurements
by percentage appeared to be more sensitive than the MFI methods. We found no
correlation between PD-1 and PD-L1 expression levels and clinical features
including WBC, platelet counts, hemoglobin levels, presence or absence of the
JAK2, MPL, or CALR gene mutation, or splenomegaly. Since MPN represents stem
cell disorders, the presence of elevated expression of PD-1 and PD-L1 in these
cells suggests that the exploration of PD-1 and PD-L1 pathway inhibitor therapy
may be worthwhile in Ph(-) MPN.
Copyright © 2019 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.leukres.2019.02.010
PMID: 30851544 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31436392 | 1. Cancer Med. 2019 Oct;8(13):5969-5978. doi: 10.1002/cam4.2510. Epub 2019 Aug
22.
The effects and safety of PD-1/PD-L1 inhibitors on head and neck cancer: A
systematic review and meta-analysis.
Wang BC(1), Cao RB(1), Li PD(1), Fu C(2).
Author information:
(1)Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan, China.
(2)Department of Dermatology, The First Hospital of Wuhan, Wuhan, China.
BACKGROUND: Inhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1)
have been increasingly used in head and neck cancer therapy and reported to
improve the outcomes with an acceptable safety profile. This systematic review
and meta-analysis was conducted to assess the benefit and risk of PD-1/PD-L1
inhibitors in patients with head and neck cancer.
METHOD: The PubMed, Cochrane Library, EMBASE and Web of Science databases were
systematically searched to find potentially eligible studies up to May 30, 2019.
Primary outcomes were overall survival (OS), progression-free survival (PFS),
objective response rate (ORR), disease control rate (DCR) and adverse events.
RESULTS: Overall, this analysis consisted of nine eligible studies, with two
randomized controlled trials and seven single arm trials. In the treatment of
recurrent or metastatic head and neck cancer, PD-1 inhibitors showed
significantly lower relative risk of death than standard-of-care therapy (odds
ratio [OR] = 0.60, 95% confidence interval [CI]: 0.44-0.82, I2 = 0%, P = .001).
Programmed cell death-1 inhibitors also decreased the risk of disease
progression, however, there was no statistically significant difference of PFS
between the treatments (OR = 0.69, 95% CI: 0.48-1.01, I2 = 0%, P = .05).
Subgroup analysis showed that human papillomavirus (HPV) positive patients had
higher response rates than HPV negative patients in PD-1/PD-L1
inhibitors-treated population (ORR: 18.8% vs 12.2%; DCR: 42.8% vs 34.4%). The
most common any-grade and grade ≥3 treatment-related adverse events were fatigue
(14.7%, 95% CI: 12.3%-17.1%) and aspartate aminotransferase increased (1.6%, 95%
CI: 0.3%-2.9%), respectively.
CONCLUSION: Programmed cell death-1 inhibitors prolonged OS in comparison with
standard-of-care therapy in recurrent or metastatic head and neck cancer
patients. Human papillomavirus positive patients were superior to HPV negative
patients in the treatment of PD-1/PD-L1 inhibitors. More phase III randomized
controlled trials are warranted to confirm our findings.
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
DOI: 10.1002/cam4.2510
PMCID: PMC6792498
PMID: 31436392 [Indexed for MEDLINE]
Conflict of interest statement: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/27903604 | 1. J Exp Med. 2016 Dec 12;213(13):2835-2840. doi: 10.1084/jem.20161462. Epub 2016
Nov 30.
What does PD-L1 positive or negative mean?
Ribas A(1)(2), Hu-Lieskovan S(3)(2).
Author information:
(1)Department of Medicine, Division of Hematology-Oncology, University of
California, Los Angeles (UCLA), Los Angeles, CA 90095 aribas@mednet.ucla.edu.
(2)Jonsson Comprehensive Cancer Center (JCCC), University of California, Los
Angeles (UCLA), Los Angeles, CA 90095.
(3)Department of Medicine, Division of Hematology-Oncology, University of
California, Los Angeles (UCLA), Los Angeles, CA 90095.
Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select
patients and analyze responses to anti-PD-1/L1 antibodies. The expression of
PD-L1 is regulated in different ways, which leads to a different significance of
its presence or absence. PD-L1 positivity may be a result of genetic events
leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1
expression on cancer cells and noncancer cells in response to a T cell
infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate,
which may be reversed with an immune response. Finally, a tumor that is unable
to express PD-L1 because of a genetic event will always be negative for PD-L1 on
cancer cells.
© 2016 Ribas and Hu-Lieskovan.
DOI: 10.1084/jem.20161462
PMCID: PMC5154949
PMID: 27903604 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30519815 | 1. Target Oncol. 2018 Dec;13(6):769-777. doi: 10.1007/s11523-018-0610-1.
PD-1 and PD-L1 Expression in Male Breast Cancer in Comparison with Female Breast
Cancer.
Manson QF(1), Ter Hoeve ND(1), Buerger H(2), Moelans CB(1), van Diest PJ(3).
Author information:
(1)Department of Pathology, University Medical Center Utrecht, PO Box 85500,
3508 GA, Utrecht, The Netherlands.
(2)Institute of Pathology Paderborn/Höxter, Cooperative Breast Center,
Paderborn, Germany.
(3)Department of Pathology, University Medical Center Utrecht, PO Box 85500,
3508 GA, Utrecht, The Netherlands. p.j.vandiest@umcutrecht.nl.
BACKGROUND: Male breast cancer is rare, as it represents less than 1% of all
breast cancer cases. In addition, male breast cancer appears to have a different
biology than female breast cancer. Programmed death-1 (PD-1) and its ligand,
programmed death-ligand 1 (PD-L1), seem to have prognostic and predictive values
in a variety of cancers, including female breast cancer. However, the role of
PD-1 and PD-L1 expression in male breast cancer has not yet been studied.
OBJECTIVES: To compare PD-1 and PD-L1 expression in male breast cancer to female
breast cancer and to evaluate prognostic values in both groups.
PATIENTS AND METHODS: Tissue microarrays from formalin-fixed paraffin-embedded
resection material of 247 female and 164 male breast cancer patients were
stained for PD-1 and PD-L1 by immunohistochemistry.
RESULTS: PD-1 expression on tumor-infiltrating lymphocytes was significantly
less frequent in male than in female cancers (48.9 vs. 65.3%, p = 0.002). In
contrast, PD-L1 expression on tumor and immune cells did not differ between the
two groups. In male breast cancer, PD-1 and tumor PD-L1 were associated with
grade 3 tumors. In female breast cancer, PD-1 and PD-L1 were associated with
comparably worse clinicopathological variables. In a survival analysis, no
prognostic value was observed for PD-1 and PD-L1 in either male and female
breast cancer. In a subgroup analysis, female patients with grade 3/tumor
PD-L1-negative or ER-negative/immune PD-L1-negative tumors had worse overall
survival.
CONCLUSIONS: PD-1 seems to be less often expressed in male breast cancer
compared to female breast cancer. Although PD-1 and PD-L1 are not definite
indicators for good or bad responses, male breast cancer patients may therefore
respond differently to checkpoint immunotherapy with PD-1 inhibitors than female
patients.
DOI: 10.1007/s11523-018-0610-1
PMCID: PMC6297201
PMID: 30519815 [Indexed for MEDLINE]
Conflict of interest statement: Quirine F. Manson, Natalie D. ter Hoeve, Horst
Buerger, Cathy B. Moelans, and Paul J. van Diest, declare that they have no
conflicts of interest that might be relevant to the contents of this manuscript. |
http://www.ncbi.nlm.nih.gov/pubmed/21118528 | 1. Crit Care. 2010;14(6):R220. doi: 10.1186/cc9354. Epub 2010 Nov 30.
PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte
apoptosis and reversing monocyte dysfunction.
Zhang Y(1), Zhou Y, Lou J, Li J, Bo L, Zhu K, Wan X, Deng X, Cai Z.
Author information:
(1)Clinical Research Center, Changhai Hospital, Second Military Medical
University, 168 Changhai Road, Shanghai, 200433, PR China.
INTRODUCTION: Lymphocyte apoptosis and monocyte dysfunction play a pivotal role
in sepsis-induced immunosuppression. Programmed death-1 (PD1) and its ligand
programmed death ligand-1 (PD-L1) exert inhibitory function by regulating the
balance among T cell activation, tolerance, and immunopathology. PD-1 deficiency
or blockade has been shown to improve survival in murine sepsis. However, PD-L1
and PD-1 differ in their expression patterns and the role of PD-L1 in
sepsis-induced immunosuppression is still unknown.
METHODS: Sepsis was induced in adult C57BL/6 male mice via cecal ligation and
puncture (CLP). The expression of PD-1 and PD-L1 expression on peripheral T
cells, B cells and monocytes were measured 24 hours after CLP or sham surgery.
Additionally, the effects of anti-PD-L1 antibody on lymphocyte number, apoptosis
of spleen and thymus, activities of caspase-8 and caspase-9, cytokine
production, bacterial clearance, and survival were determined.
RESULTS: Expression of PD-1 on T cells, B cells and monocytes and PD-L1 on B
cells and monocytes were up-regulated in septic animals compared to
sham-operated controls. PD-L1 blockade significantly improved survival of CLP
mice. Anti-PD-L1 antibody administration prevented sepsis-induced depletion of
lymphocytes, increased tumor necrosis factor (TNF)-α and interleukin (IL)-6
production, decreased IL-10 production, and enhanced bacterial clearance.
CONCLUSIONS: PD-L1 blockade exerts a protective effect on sepsis at least partly
by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction.
Anti-PD-L1 antibody administration may be a promising therapeutic strategy for
sepsis-induced immunosuppression.
DOI: 10.1186/cc9354
PMCID: PMC3220038
PMID: 21118528 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16606670 | 1. J Exp Med. 2006 Apr 17;203(4):883-95. doi: 10.1084/jem.20051776. Epub 2006 Apr
10.
Tissue expression of PD-L1 mediates peripheral T cell tolerance.
Keir ME(1), Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M,
Freeman GJ, Sayegh MH, Sharpe AH.
Author information:
(1)Department of Pathology, Brigham and Women's Hospital and Children's Hospital
Boston, MA 02115, USA.
Comment in
J Exp Med. 2006 Apr 17;203(4):817-20. doi: 10.1084/jem.20060219.
Programmed death 1 (PD-1), an inhibitory receptor expressed on activated
lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1
ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal
cells, including pancreatic islet cells; and PD-L2, which is restricted to
macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have
synergistic or unique roles in regulating T cell activation and tolerance, we
generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2(-/-) mice) and compared them
to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in
inhibiting interleukin-2 and interferon-gamma production during T cell
activation. However, PD-L1 has a unique and critical role in controlling
self-reactive T cells in the pancreas. Our studies with bone marrow chimeras
demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is
insufficient to prevent the early onset diabetes that develops in
PD-L1/PD-L2(-/-) non-obese diabetic mice. PD-L1 expression in islets protects
against immunopathology after transplantation of syngeneic islets into diabetic
recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell-mediated tissue
destruction and effector cytokine production. These data provide evidence that
PD-L1 expression on parenchymal cells rather than hematopoietic cells protects
against autoimmune diabetes and point to a novel role for PD-1-PD-L1
interactions in mediating tissue tolerance.
DOI: 10.1084/jem.20051776
PMCID: PMC2118286
PMID: 16606670 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31876895 | 1. JAMA Oncol. 2020 Mar 1;6(3):375-384. doi: 10.1001/jamaoncol.2019.5367.
Use of Immunotherapy With Programmed Cell Death 1 vs Programmed Cell Death
Ligand 1 Inhibitors in Patients With Cancer: A Systematic Review and
Meta-analysis.
Duan J(1), Cui L(2), Zhao X(2), Bai H(1), Cai S(2), Wang G(2), Zhao Z(2), Zhao
J(2), Chen S(2), Song J(2), Qi C(2), Wang Q(2), Huang M(2), Zhang Y(2), Huang
D(2), Bai Y(2), Sun F(3), Lee JJ(4), Wang Z(1), Wang J(1).
Author information:
(1)State Key Laboratory of Molecular Oncology, Department of Medical Oncology,
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences &
Peking Union Medical College, Beijing, China.
(2)The Medical Department, 3D Medicines Inc, Shanghai, China.
(3)School of Public Health, Department of Epidemiology and Biostatistics, Peking
University Health Science Centre, Beijing, China.
(4)Department of Biostatistics, The University of Texas MD Anderson Cancer
Center, Houston.
Comment in
JAMA Oncol. 2020 Jul 1;6(7):1116-1117. doi: 10.1001/jamaoncol.2020.0646.
JAMA Oncol. 2020 Jul 1;6(7):1115-1116. doi: 10.1001/jamaoncol.2020.0637.
JAMA Oncol. 2020 Jul 1;6(7):1115. doi: 10.1001/jamaoncol.2020.0631.
JAMA Oncol. 2020 Jul 1;6(7):1114-1115. doi: 10.1001/jamaoncol.2020.0628.
JAMA Oncol. 2020 Jul 1;6(7):1113-1114. doi: 10.1001/jamaoncol.2020.0625.
IMPORTANCE: Immune checkpoint inhibitors of programmed cell death 1 (PD-1) and
its ligand (PD-L1) have led to a paradigm shift in cancer treatment.
Understanding the clinical efficacy and safety profile of these drugs is
necessary for treatment strategy in clinical practice.
OBJECTIVE: To assess the differences between anti-PD-1 and anti-PD-L1 regarding
efficacy and safety shown in randomized clinical trials across various tumor
types.
DATA SOURCES: Systematic searches of PubMed, Cochrane CENTRAL, and Embase were
conducted from January 1, 2000, to March 1, 2019. In addition, abstracts and
presentations from all major conference proceedings were reviewed.
STUDY SELECTION: All randomized clinical trials that compared anti-PD-1 and
anti-PD-L1 with standard treatment in patients with cancer were selected as
candidates. Retrospective studies, single-arm phase 1/2 studies, and trials
comparing anti-PD-1 and anti-PD-L1 with other immunotherapies were excluded.
Studies of anti-PD-1 and anti-PD-L1 therapy were screened and paired by the
matching of clinical characteristics as mirror groups.
DATA EXTRACTION AND SYNTHESIS: Three investigators independently extracted data
from each study following the PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-analyses) guideline. Trial names, first author, year of
publication, study design, National Clinical Trial identifier number, blinding
status, study phase, pathologic characteristics, number of patients, patients'
age and sex distribution, Eastern Cooperative Oncology Group Performance Status,
lines of treatment, study drugs, biomarker status, follow-up time, incidence of
adverse events, and hazard ratios (HRs) with 95% CIs for overall survival and
progression-free survival were extracted. A random-effects model was applied for
data analysis.
MAIN OUTCOMES AND MEASURES: Differences in OS between anti-PD-1 and anti-PD-L1
across different cancer types were assessed. An effect size was derived from
each mirror group and then pooled across all groups using a random-effects
model.
RESULTS: Nineteen randomized clinical trials involving 11 379 patients were
included in the meta-analysis. Overall, anti-PD-1 exhibited superior overall
survival (HR, 0.75; 95% CI, 0.65-0.86; P < .001) and progression-free survival
(HR, 0.73; 95% CI, 0.56-0.96; P = .02) compared with anti-PD-L1. No significant
difference was observed in their safety profiles. Sensitivity analysis presented
consistency in the overall estimates across these analyses. Consistent results
were observed through frequentist and bayesian approaches with the same studies.
CONCLUSIONS AND RELEVANCE: Comprehensive analysis suggests that anti-PD-1
exhibited favorable survival outcomes and a safety profile comparable to that of
anti-PD-L1, which may provide a useful guide for clinicians.
DOI: 10.1001/jamaoncol.2019.5367
PMCID: PMC6990765
PMID: 31876895 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: Drs Cui, X.
Zhao, Cai, G. Wang, Z. Zhao, J. Zhao, Chen, Song, Qi, Q. Wang, M. Huang, Zhang,
D. Huang, and Bai are employees of 3D Medicines Inc. No other conflicts were
reported. |
http://www.ncbi.nlm.nih.gov/pubmed/21097698 | 1. J Leukoc Biol. 2011 Apr;89(4):507-15. doi: 10.1189/jlb.0610327. Epub 2010 Nov
19.
Expression of PD-L1 and PD-L2 on human macrophages is up-regulated by HIV-1 and
differentially modulated by IL-10.
Rodríguez-García M(1), Porichis F, de Jong OG, Levi K, Diefenbach TJ, Lifson JD,
Freeman GJ, Walker BD, Kaufmann DE, Kavanagh DG.
Author information:
(1)Ragon Institute of MGH, MIT and Harvard University, 149 13th St.,
Charlestown, MA 02129, USA.
Comment in
J Leukoc Biol. 89:495.
PD-1 plays an important role in T cell exhaustion during HIV infection. PD-1 has
two ligands: PD-L1, expressed on hematopoietic and nonhematopoietic cells, and
PD-L2, limited to DCs and macrophages. Little is known about PD-L1 expression
and regulation in human macrophages. Previous reports have found few immediate
effects of macrophage exposure to HIV, suggesting that macrophages lack PRRs for
this virus. Using quantitative confocal microscopy and a multiplexed cytokine
bead array, we measured induction of PD-L1, PD-L2, and innate response cytokines
in human MDMs in response to chemically inactivated HIV virions. Consistent with
previous reports, no cytokines were induced by HIV virion exposure. Whereas
PD-L1 and PD-L2 had low baseline expression, TLR ligands (LPS and CL097)
up-regulated PD-L1 but not PD-L2. Unlike what we found for cytokine expression,
PD-L1 and PD-L2 were up-regulated in response to exposure with inactivated HIV
virions or with replication-competent HIV. Expression of PD-L1 was
differentially modulated by IL-10, which induced up-regulation of PD-L1 but not
of PD-L2, and IL-10 blockade enhanced only PD-L2 expression. We discuss
implications for innate recognition of HIV by macrophages and potential,
different roles for PD-L1 and PD-L2 in immunity and pathogenesis.
DOI: 10.1189/jlb.0610327
PMCID: PMC3058820
PMID: 21097698 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28960263 | 1. Cancer. 2018 Jan 15;124(2):271-277. doi: 10.1002/cncr.31043. Epub 2017 Sep 28.
Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small
cell lung cancer: A systematic analysis of the literature.
Pillai RN(1), Behera M(1), Owonikoko TK(1), Kamphorst AO(2), Pakkala S(1),
Belani CP(3), Khuri FR(1), Ahmed R(2), Ramalingam SS(1).
Author information:
(1)Department of Hematology and Oncology, Winship Cancer Institute, Emory
University, Atlanta, Georgia.
(2)Emory Vaccine Center, Department of Microbiology and Immunology, Emory
University, Atlanta, Georgia.
(3)Pennsylvania University, Penn State Hershey Cancer Institute, Hershey,
Pennsylvania.
Comment in
J Thorac Dis. 2018 Nov;10(Suppl 33):S4034-S4037. doi:
10.21037/jtd.2018.09.46.
J Thorac Dis. 2018 Nov;10(Suppl 33):S4065-S4068. doi:
10.21037/jtd.2018.09.83.
J Thorac Dis. 2018 Nov;10(Suppl 33):S4069-S4072. doi:
10.21037/jtd.2018.09.102.
J Thorac Dis. 2018 Nov;10(Suppl 33):S4082-S4084. doi:
10.21037/jtd.2018.09.103.
BACKGROUND: Monoclonal antibodies against programmed cell death protein 1 (PD-1)
and programmed death ligand 1 (PD-L1) are effective therapies in patients with
non-small cell lung cancer (NSCLC). Herein, the authors performed a systematic
review investigating differences in the toxicities of PD-1 and PD-L1 inhibitors.
METHODS: An electronic literature search was performed of public databases
(MEDLINE, Excerpta Medica dataBASE [EMBASE], and Cochrane) and conference
proceedings for trials using PD-1 inhibitors (nivolumab and pembrolizumab) and
PD-L1 inhibitors (atezolizumab, durvalumab, and avelumab) in patients with
NSCLC. A formal systematic analysis was conducted with Comprehensive
Meta-Analysis software (version 2.2). Clinical and demographic characteristics,
response, and toxicity data were compared between both groups.
RESULTS: A total of 23 studies reported between 2013 and 2016 were eligible for
analysis. The total number of patients evaluated for toxicities was 3284
patients in the PD-1 group and 2460 patients in the PD-L1 group. The baseline
patient characteristics of the 2 groups were similar, although there was a trend
toward increased squamous histology in the group treated with PD-L1 (32% vs 25%;
P = .6). There was no difference in response rate noted between PD-1 (19%) and
PD-L1 (18.6%) inhibitors (P = .17). The incidence of overall adverse events
(AEs) was comparable between the PD-1 and PD-L1 inhibitors (64% [95% confidence
interval (95% CI), 63%-66%] vs 66% [95% CI, 65%-69%]; P = .8). Fatigue was the
most frequently reported AE with both classes of drugs. Patients treated with
PD-1 inhibitors were found to have a slightly increased rate of immune-related
AEs (16% [95% CI, 14%-17%] vs 11% [95% CI, 10%-13%]; P = .07) and pneumonitis
(4% [95% CI, 3%-5%] vs 2% [95% CI, 1%-3%]; P = .01) compared with patients who
received PD-L1 inhibitors.
CONCLUSIONS: In this systematic review involving 5744 patients with NSCLC, the
toxicity and efficacy profiles of PD-1 and PD-L1 inhibitors appear to be
similar. Cancer 2018;124:271-7. © 2017 American Cancer Society.
© 2017 American Cancer Society.
DOI: 10.1002/cncr.31043
PMCID: PMC5761314
PMID: 28960263 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures: None of the authors have any
conflicts of interest to report. |
http://www.ncbi.nlm.nih.gov/pubmed/17924994 | 1. Am J Transplant. 2007 Dec;7(12):2683-92. doi:
10.1111/j.1600-6143.2007.01999.x. Epub 2007 Oct 9.
Striking dichotomy of PD-L1 and PD-L2 pathways in regulating alloreactive CD4(+)
and CD8(+) T cells in vivo.
Habicht A(1), Kewalaramani R, Vu MD, Demirci G, Blazar BR, Sayegh MH, Li XC.
Author information:
(1)Transplantation Research Center, Brigham and Women's Hospital and the
Children's Hospital of Boston, Boston, MA, USA.
Programmed death-1 (PD-1) is a recently identified coinhibitory molecule that
belongs to the CD28 superfamily. PD-1 has two ligands PD-L1 and PD-L2. There is
some evidence that PD-L1 and PD-L2 serve distinct functions, but their exact
function in alloimmunity remains unclear. In the present study, we used a
GVHD-like model that allows detailed analyses of T-cell activation at a single
cell level in vivo to examine the role of PD-1/PD-L1 and PD-1/PD-L2 interactions
in regulating proliferation of CD4(+) and CD8(+) T cells in response to
alloantigen stimulation. We found that both CD4(+) and CD8(+) T cells
proliferated vigorously in vivo and that PD-L1 and PD-L2 exhibit strikingly
different effect on T-cell proliferation. While blocking PD-L1 did not affect
the in vivo proliferation of CD4(+) and CD8(+) T cells regardless of CD28
costimulation, blocking PD-L2 resulted in a marked increase in the responder
frequency of CD8(+) T-cells in vivo. The effect of PD-L2 on the CD8(+) T-cell
proliferation is regulated by CD28 costimulation and by the CD4(+) T cells. We
conclude that PD-L1 and PD-L2 function differently in regulating alloreactive
T-cell activation in vivo, and PD-L2 is predominant in this model in limiting
alloreactive CD8(+) T-cell proliferation.
DOI: 10.1111/j.1600-6143.2007.01999.x
PMID: 17924994 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30547271 | 1. Clin Exp Metastasis. 2019 Feb;36(1):29-37. doi: 10.1007/s10585-018-9950-6.
Epub 2018 Dec 13.
Frequent discordance in PD-1 and PD-L1 expression between primary breast tumors
and their matched distant metastases.
Manson QF(1), Schrijver WAME(1), Ter Hoeve ND(1), Moelans CB(1), van Diest
PJ(2).
Author information:
(1)Department of Pathology, University Medical Center Utrecht, PO Box 85500,
3508 GA, Utrecht, The Netherlands.
(2)Department of Pathology, University Medical Center Utrecht, PO Box 85500,
3508 GA, Utrecht, The Netherlands. p.j.vandiest@umcutrecht.nl.
Programmed death-1 (PD-1) is an immune checkpoint that is able to inhibit the
immune system by binding to its ligand programmed death-ligand 1 (PD-L1). In
many cancer types, among which breast cancer, prognostic and/or predictive
values have been suggested for both PD-1 and PD-L1. Previous research has
demonstrated discrepancies in PD-L1 expression between primary breast tumors and
distant metastases, however data so far have been scarce. We therefore evaluated
immunohistochemical expression levels of PD-1 and PD-L1 in primary breast tumors
and their paired distant metastases, and evaluated prognostic values. Tissue
microarrays from formalin-fixed paraffin-embedded resection specimens of primary
breast cancers and their matched distant metastases were immunohistochemically
stained for PD-1 and PD-L1. PD-1 was available in both primary tumor and
metastasis in 82 patients, and PD-L1 in 49 patients. PD-1 was discrepant between
primary tumor and metastasis in half of the patients (50%), PD-L1 on tumor cells
was discrepant in 28.5%, and PD-L1 on immune cells in 40.8% of the patients. In
primary tumors there was a correlation between PD-1 positivity and a higher
tumor grade, and between immune PD-L1 and ER negativity. In survival analyses, a
significantly better overall survival was observed for patients with PD-L1
negative primary breast tumors that developed PD-L1 positive distant metastases
(HR 3.013, CI 1.201-7.561, p = 0.019). To conclude, PD-1 and tumor and immune
PD-L1 seem to be discordantly expressed between primary tumors and their matched
distant metastases in about one-third to a half of the breast cancer patients.
Further, gained expression of PD-L1 in metastases seems to indicate better
survival. This illustrates the need of reassessing PD-1 and PD-L1 expression on
biopsies of distant metastases to optimize the usefulness of these biomarkers.
DOI: 10.1007/s10585-018-9950-6
PMCID: PMC6394593
PMID: 30547271 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/12697896 | 1. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5336-41. doi:
10.1073/pnas.0931259100. Epub 2003 Apr 15.
PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells.
Loke P(1), Allison JP.
Author information:
(1)Howard Hughes Medical Institute, University of California, Berkeley, CA
94720, USA.
PD-L1 and PD-L2 are ligands for PD-1, a costimulatory molecule that plays an
inhibitory role in regulating T cell activation in the periphery. We find that
PD-L1 is highly expressed on inflammatory macrophages as compared with resident
peritoneal macrophages but can be induced on resident macrophages by classical
activation stimuli such as lipopolysaccharide, IFN-gamma, and
polyinosinic-polycytidylic acid. Further up-regulation of PD-L1 on inflammatory
macrophages can also be induced by subsequent exposure to lipopolysaccharide and
IFN-gamma. In contrast, PD-L2 is not expressed on inflammatory macrophages but
can be induced by alternative activation via IL-4. Although PD-L1 is highly
inducible on a variety of antigen-presenting cell lines as well as resident
macrophages, PD-L2 is most significantly inducible only on inflammatory
macrophages. PD-L1 up-regulation depends on TLR4 and STAT1, whereas PD-L2
expression depends on IL-4R alpha and STAT6. Consistent with these results, T
helper 1T helper 2 (Th1/Th2) cells also differentially up-regulate PD-L1 and
PD-L2 expression on inflammatory macrophages. Hence, Th1 cells as well as
microbial products can enhance PD-L1 expression on many different macrophage
populations, whereas Th2 cells instruct only inflammatory macrophages to
up-regulate PD-L2. These results suggest that PD-L1 and PD-L2 might have
different functions in regulating type 1 and type 2 responses.
DOI: 10.1073/pnas.0931259100
PMCID: PMC154346
PMID: 12697896 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32770212 | 1. Adv Nutr. 2020 Nov 16;11(6):1405-1413. doi: 10.1093/advances/nmaa089.
The "Virtual Digital Twins" Concept in Precision Nutrition.
Gkouskou K(1)(2), Vlastos I(1), Karkalousos P(3), Chaniotis D(3), Sanoudou
D(4)(5)(6), Eliopoulos AG(1)(5)(6).
Author information:
(1)Department of Biology, School of Medicine, National and Kapodistrian
University of Athens, Athens, Greece.
(2)Embiodiagnostics, Biology Research Company, Heraklion, Crete, Greece.
(3)Department of Biomedical Sciences, University of West Attica, Athens, Greece.
(4)Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal
Medicine, School of Medicine, National and Kapodistrian University of Athens,
Athens, Greece.
(5)Center for New Biotechnologies and Precision Medicine, School of Medicine,
National and Kapodistrian University of Athens, Athens, Greece.
(6)Center of Basic Research, Biomedical Research Foundation of the Academy of
Athens, Athens, Greece.
Nutritional and lifestyle changes remain at the core of healthy aging and
disease prevention. Accumulating evidence underscores the impact of genetic,
metabolic, and host gut microbial factors on individual responses to nutrients,
paving the way for the stratification of nutritional guidelines. However,
technological advances that incorporate biological, nutritional, lifestyle, and
health data at an unprecedented scale and depth conceptualize a future where
preventative dietary interventions will exceed stratification and will be highly
individualized. We herein discuss how genetic information combined with
longitudinal metabolomic, immune, behavioral, and gut microbial parameters, and
bioclinical variables could define a digital replica of oneself, a "virtual
digital twin," which could serve to guide nutrition in a personalized manner.
Such a model may revolutionize the management of obesity and its comorbidities,
and provide a pillar for healthy aging.
Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.
DOI: 10.1093/advances/nmaa089
PMCID: PMC7666894
PMID: 32770212 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34536404 | 1. Lancet Neurol. 2021 Oct;20(10):821-831. doi: 10.1016/S1474-4422(21)00242-8.
Safety and efficacy of oral levosimendan in people with amyotrophic lateral
sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled
phase 3 trial.
Cudkowicz M(1), Genge A(2), Maragakis N(3), Petri S(4), van den Berg L(5), Aho
VV(6), Sarapohja T(6), Kuoppamäki M(6), Garratt C(6), Al-Chalabi A(7); REFALS
investigators.
Collaborators: Kiernan M, Mathers S, Henderson R, Needham M, Schultz D, Löscher
W, Mitrovic N, Rath J, Damme PV, De Bleecker JL, Delstanche S, Johnston W,
Zinman L, O'Connell C, Matte G, Dionne A, Korngut L, Turnbull J, Laaksovirta H,
Jokela M, Tapiola T, Soriani MH, Couratier P, Camu W, Corcia P, Ludolph A,
Großkreutz J, Meyer T, Boentert M, Schrank B, Prudlo J, Untucht R, Hardiman O,
Siciliano G, Chio' A, Mazzini L, Inghilleri M, Caponnetto C, Mora G, Mora
Pardina JS, Farrero Munoz E, Vázquez Costa JF, Aguera Morales E, Varona L,
Andersen P, Ingre C, Johansson R, Radunovic A, Young C, Babu S, Shaibani A,
Staff N, Vu T, Rivner M, Scelsa S, Sivakumar K, Waheed W, Heitzman D, Rana S,
Pattee G, Ajroud-Driss S, Bayat E, Kasarskis E, Lange DJ, Elliott M, Harris B,
Felice K, Pulley MT, Kwan J, Brown M, Ravits J, Burford M, Karam C, Miller T,
Andrews J, Levine T, Locatelli E, Wymer J, Bedlack R, Fee D, Goyal N, Oskarsson
B, McCluskey L, Caress J, Weiss M, Quick A, Bromberg M, Lacomis D, Goutman S,
Rezania K, Guliani G, Goslin K, Katz JS.
Author information:
(1)Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA, USA.
Electronic address: cudkowicz.merit@mgh.harvard.edu.
(2)Clinical Research Unit and ALS clinic, Montreal Neurological Institute and
Hospital, Montreal, QC, Canada.
(3)Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
(4)Medizinische Hochschule Hannover, Hannover, Germany.
(5)Department of Neurology, University Medical Center Utrecht, Utrecht,
Netherlands.
(6)Orion Corporation, Espoo, Finland.
(7)Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical
Neuroscience Institute, and Department of Neurology, King's College Hospital,
King's College London, London, UK.
Comment in
Nat Rev Neurol. 2021 Nov;17(11):660. doi: 10.1038/s41582-021-00569-7.
Comment on
Lancet Neurol. 2021 Oct;20(10):775-777. doi: 10.1016/S1474-4422(21)00255-6.
BACKGROUND: There is an urgent unmet need for new therapies in amyotrophic
lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a
calcium sensitiser, was shown to improve neuromechanical efficiency and
contractile function of the human diaphragm. We aimed to evaluate the safety and
efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with
a focus on respiratory function.
METHODS: The REFALS study is a randomised, double-blind, placebo-controlled
phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14
countries worldwide. People with amyotrophic lateral sclerosis were eligible for
participation if they were at least 18 years of age and had a sitting slow vital
capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by
interactive web-response system to receive either levosimendan or placebo. The
capsules for oral administration were identical in appearance to maintain
blinding of participants and investigators. The primary endpoint was the change
from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted
normal sitting SVC. The key secondary endpoint was the combined assessment of
function and survival (CAFS) up to 48 weeks. Analyses were done in the
intention-to-treat population, comprising all participants who were randomly
assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has
been completed. An extension study (REFALS-ES; NCT03948178) has also been
completed, but will be reported separately.
FINDINGS: Between June 21, 2018, and June 28, 2019, 871 people were screened for
the study, of whom 496 were randomly assigned either levosimendan (n=329) or
placebo (n=167). Participants were followed up between June 27, 2018 and June
26, 2020, for a median duration of 50·1 (IQR 37·5-51·1) weeks. The median
duration of treatment was 47·9 (IQR 26·4-48·1) weeks. Change from baseline in
supine SVC at 12 weeks was -6·73% with levosimendan and -6·99% with placebo,
with no significant difference between the treatments (estimated treatment
difference 0·26%, 95% CI -2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did
not differ between treatment groups (least squares mean change from baseline
10·69, 95% CI -15·74 to 37·12; nominal p value=0·43). The most frequent adverse
events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12
[7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%]
vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants
allocated levosimendan and 20 (12%) assigned placebo died during the trial,
mainly due to respiratory failure or progression of amyotrophic lateral
sclerosis.
INTERPRETATION: Levosimendan was not superior to placebo in maintaining
respiratory function in a broad population with amyotrophic lateral sclerosis.
Although levosimendan was generally well tolerated, increased heart rate and
headache occurred more frequently with levosimendan than with placebo. The
possibility of a clinically relevant subgroup of responsive individuals requires
further evaluation.
FUNDING: Orion Corporation.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(21)00242-8
PMID: 34536404 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests MC reports consultancy
fees from Biohaven Pharmaceuticals, Eli Lilly, Orion Corporation, Revelescio,
Wave Pharmaceuticals, Mitsubishi Tanabe Pharma, Anelixis, Aclipse, Cytokinetics,
Avexis, Sunovian, Disarm, ALS Pharmaceuticals, RRD, Biogen, Takeda, outside the
submitted work. AG reports personal fees from Mitsubishi Tanabe Pharma America,
Sanofi Genzyme, ALS Pharma, AB Sciences, Biogen, Novartis, CSL Behring, Anavex,
Avexis, Alexion, Revalesio, Roche, Cytokinetics, Orion Corporation, and Akcea,
outside the submitted work. NM reports personal fees from Orion Corporation,
during the conduct of the study; personal fees from Massachusetts General
Hospital, Cytokinetics, Amylyx, and Orphazyme, outside the submitted work; and
clinical trial site principle investigator fees from Biogen Idec, Medicinova,
Anelixis, Apellis, and Helixmith. SP reports grants from the German
Neuromuscular Society, Federal Ministry of Education and Research, German
Israeli Foundation for scientific research and development, and EU Joint
Programme for Neurodegenerative Disease Research; and speaker or medical expert
honoraria from Cytokinetics, Desitin Pharma, Biogen, Novartis, Teva
Pharmaceuticals, and Roche, outside of the submitted work. LvdB is on the
advisory board Orion, with no financial compensation. LvdB reports personal fees
from Denali, Calico, Biogen, Ferrer, and Orphazyme; and grants from Takeda,
outside the submitted work. VVA, TS and CG are Employees of Orion Corporation;
MK is an employee of Orion Corporation and owns Orion Corporation stocks. AA-C
reports non-financial support from Orion Corporation, during the conduct of the
study; consultancy fees from Mitsubishi Tanabe Pharma, Biogen Idec,
Cytokinetics, Wave Pharmaceuticals, Apellis, Amylyx, Novartis, and Eli Lilly,
outside the submitted work. |
http://www.ncbi.nlm.nih.gov/pubmed/31315908 | 1. J Neurol Neurosurg Psychiatry. 2019 Oct;90(10):1165-1170. doi:
10.1136/jnnp-2018-320288. Epub 2019 Jul 17.
Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre,
randomised, double-blind, placebo-controlled trial.
Al-Chalabi A(1)(2), Shaw P(3), Leigh PN(4), van den Berg L(5), Hardiman O(6),
Ludolph A(7), Aho VV(8), Sarapohja T(9), Kuoppamäki M(10)(11).
Author information:
(1)Department of Basic and Clinical Neuroscience, King's College London, Maurice
Wohl Clinical Neuroscience Institute, London, UK.
(2)Department of Neurology, King's College Hospital, London, UK.
(3)Sheffield Institute for Translational Neuroscience and NIHR Sheffield
Biomedical Research Centre, University of Sheffield, Sheffield, UK.
(4)Department of Neuroscience Brighton and Sussex Medical School, Trafford
Centre for Biomedical Science, Falmer, Brighton, UK.
(5)Departmentof Neurology, University Medical Center Utrecht, Utrecht, The
Netherlands.
(6)Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity
College Dublin, Dublin, Ireland.
(7)Department of Neurology, University of Ulm, Ulm, Germany.
(8)Orion Pharma, Orion Corporation, Turku, Finland valtteri.aho@orionpharma.com.
(9)Orion Pharma, Orion Corporation, Espoo, Finland.
(10)Orion Pharma, Orion Corporation, Turku, Finland.
(11)Lundbeck, Copenhagen, Denmark.
OBJECTIVE: To evaluate the efficacy and safety of oral levosimendan in patients
with amyotrophic lateral sclerosis (ALS). This phase II, randomised,
double-blind, placebo-controlled, crossover, three-period study with 6 months
open-label follow-up enrolled adults with ALS and sitting slow vital capacity
(SVC) 60%-90 % of predicted from 11 sites in four countries.
METHODS: Patients received levosimendan 1 mg daily, 1 mg two times a day or
placebo during three 14-day crossover periods and levosimendan 1-2 mg daily
during open-label follow-up. Primary endpoint was sitting SVC; secondary
endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R),
tolerability and safety.
RESULTS: Of 66 patients randomised, 59 contributed to the double-blind results
and 50 entered open-label follow-up. Sitting SVC was not significantly different
between the treatments. In post hoc analysis using period-wise baselines, supine
SVC favoured levosimendan over placebo, estimated mean differences from baseline
being -3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38%
on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during
levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002)
and 3.3% during placebo. The respective frequencies for increased heart rate
were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences
between the treatments were seen for other adverse events.
CONCLUSIONS: Levosimendan did not achieve the primary endpoint of improving
sitting SVC in ALS. Headache and increased heart rate were increased on
levosimendan, although it was otherwise well tolerated. A phase III study to
evaluate the longer term effects of oral levosimendan in ALS is ongoing.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.
DOI: 10.1136/jnnp-2018-320288
PMCID: PMC6817985
PMID: 31315908 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: VVA and TS are employees of
Orion Corporation. Other authors have no conflicts to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/24031027 | 1. Carcinogenesis. 2014 Feb;35(2):424-31. doi: 10.1093/carcin/bgt305. Epub 2013
Sep 12.
PD-1 blockage delays murine squamous cell carcinoma development.
Belai EB(1), de Oliveira CE, Gasparoto TH, Ramos RN, Torres SA, Garlet GP,
Cavassani KA, Silva JS, Campanelli AP.
Author information:
(1)Department of Biological Sciences and.
Engagement of programmed death-1 (PD-1) with its two ligands [programmed death
ligand-1 (PD-L1) and PD-L2] has been associated with the suppression of
tumor-reactive T cells; however, the underlying mechanism for this T-cell
dysfunction is not clear. We hypothesized that PD-1 and PD-L1 signals are, in
part, responsible for squamous cell carcinoma (SCC) escape from immune antitumor
regulation by modulation of the tumor environment. In the present study, we used
a multistage model of SCC to examine the role of PD-1/PD-L1 activation during
tumor development. Tumor sites presented an increased percentage of CD4(+) and
CD8(+) T cells expressing PD-1 when compared with non-tumorigenic control mice,
whereas the expression of PD-L1 was particularly increased in F4/80(+)
macrophages in tumor sites. Further, the systemic immune neutralization of PD-1
resulted in a decreased number and delayed incidence rate of papillomas followed
by a differential expression of cytokeratins, suggesting that the PD-1-PD-L1
interaction contributes to the progression of SCC by downregulation of antitumor
responses. In fact, blocking PD-1 increased the percentage of CD8(+) and CD4(+)
T cells, and the levels of interferon-γ in the tumor sites. Our results
indicated involvement of PD-1(+) T cells in SCC development and in the
modulation of the inflammatory immune response.
DOI: 10.1093/carcin/bgt305
PMID: 24031027 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36362876 | 1. Life (Basel). 2022 Oct 27;12(11):1721. doi: 10.3390/life12111721.
Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.
Seker Yilmaz B(1), Baruteau J(1)(2)(3), Arslan N(4), Aydin HI(5), Barth M(6),
Bozaci AE(7), Brassier A(8), Canda E(9), Cano A(10), Chronopoulou E(11),
Connolly GM(12), Damaj L(13), Dawson C(14), Dobbelaere D(15), Douillard C(15),
Eminoglu FT(16), Erdol S(17), Ersoy M(18), Fang S(3), Feillet F(19), Gokcay
G(20), Goksoy E(21), Gorce M(22), Inci A(23), Kadioglu B(24), Kardas F(25),
Kasapkara CS(26), Kilic Yildirim G(27), Kor D(28), Kose M(29), Marelli
C(30)(31), Mundy H(32), O'Sullivan S(33), Ozturk Hismi B(34), Ramachandran
R(35), Roubertie A(30)(31), Sanlilar M(36), Schiff M(8), Sreekantam S(37),
Stepien KM(38), Uzun Unal O(39), Yildiz Y(40), Zubarioglu T(41), Gissen
P(1)(2)(3).
Author information:
(1)Genetics and Genomic Medicine Department, Great Ormond Street Institute of
Child Health, University College London, London WC1N 1EH, UK.
(2)National Institute of Health Research Great Ormond Street Biomedical Research
Centre, London WC1N 1EH, UK.
(3)Metabolic Medicine Department, Great Ormond Street Hospital for Children NHS
Foundation Trust, London WC1N 3JH, UK.
(4)Paediatric Metabolic Medicine Department, Dokuz Eylul University Faculty of
Medicine, Izmir 35340, Turkey.
(5)Paediatric Metabolic Medicine Department, Baskent University Faculty of
Medicine, Ankara 06490, Turkey.
(6)Centre de Référence des Maladies Héréditaires du Métabolisme, CHU Angers, 4
rue Larrey, CEDEX 9, 49933 Angers, France.
(7)Paediatric Metabolic Medicine Department, Diyarbakir Children's Hospital,
Diyarbakir 21100, Turkey.
(8)Reference Center for Inborn Errors of Metabolism, Necker University Hospital,
APHP and University of Paris Cité, 75015 Paris, France.
(9)Paediatric Metabolic Medicine Department, Ege University Faculty of Medicine,
Izmir 35100, Turkey.
(10)Reference Center of Inherited Metabolic Disorders, Timone Enfants Hospital,
264 rue Saint-Pierre, 13005 Marseille, France.
(11)Department of Inherited Metabolic Disease, Division of Women's and
Children's Services, University Hospitals Bristol NHS Foundation Trust, Bristol
BS1 3NU, UK.
(12)Belfast Health and Social Care Trust, Belfast BT9 7AB, UK.
(13)Centre de Compétence Maladies Héréditaires du Métabolisme, CHU Hôpital Sud,
CEDEX 2, 35203 Rennes, France.
(14)Metabolic Medicine Department, University Hospitals Birmingham NHS
Foundation Trust, Birmingham B15 2GW, UK.
(15)Medical Reference Center for Inherited Metabolic Diseases, Jeanne de Flandre
University Hospital and RADEME Research Team for Rare Metabolic and
Developmental Diseases, EA 7364 CHRU Lille, 59000 Lille, France.
(16)Paediatric Metabolic Medicine Department, Ankara University Faculty of
Medicine, Ankara 06080, Turkey.
(17)Paediatric Metabolic Medicine Department, Uludag University Faculty of
Medicine, Bursa 16059, Turkey.
(18)Paediatric Metabolic Medicine Department, Dr Sadi Konuk Reseach & Training
Hospital, Istanbul 34450, Turkey.
(19)Centre de Référence des Maladies Métaboliques de Nancy, CHU Brabois Enfants,
5 Rue du Morvan, 54500 Vandœuvre-lès-Nancy, France.
(20)Paediatric Metabolic Medicine Department, Istanbul University Istanbul
Faculty of Medicine, Istanbul 34093, Turkey.
(21)Paediatric Metabolic Medicine Department, Cengiz Gokcek Children's Hospital,
Gaziantep 27010, Turkey.
(22)Centre de Référence des Maladies Rares du Métabolisme, Hôpital des
Enfants-CHU Toulouse, 330 Avenue de Grande-Bretagne, CEDEX 9, 31059 Toulouse,
France.
(23)Paediatric Metabolic Medicine Department, Gazi University Faculty of
Medicine, Ankara 06500, Turkey.
(24)Paediatric Metabolic Medicine Department, Konya City Hospital, Konya 42020,
Turkey.
(25)Paediatric Metabolic Medicine Department, Erciyes University Faculty of
Medicine, Kayseri 38030, Turkey.
(26)Paediatric Metabolic Medicine Department, Ankara Yildirim Beyazit University
Faculty of Medicine, Ankara 06800, Turkey.
(27)Paediatric Metabolic Medicine Department, Osmangazi University Faculty of
Medicine, Eskisehir 26480, Turkey.
(28)Paediatric Metabolic Medicine Department, Cukurova University Faculty of
Medicine, Adana 01250, Turkey.
(29)Paediatric Metabolic Medicine Department, Faculty of Medicine, Izmir Katip
Celebi University, Izmir 35620, Turkey.
(30)MMDN, University Montpellier, EPHE, INSERM, 34090 Montpellier, France.
(31)Expert Center for Metabolic and Neurogenetic Diseases, Centre Hospitalier
Universitaire (CHU), 34090 Montpellier, France.
(32)Evelina Children's Hospital, Guy's and St Thomas' NHS Foundation Trust,
London SE1 7EH, UK.
(33)Royal Belfast Hospital for Sick Children, Belfast BT12 6BA, UK.
(34)Paediatric Metabolic Medicine Department, Marmara University Faculty of
Medicine, Istanbul 34854, Turkey.
(35)Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.
(36)Paediatric Metabolic Medicine Department, Antalya Training and Research
Hospital, Antalya 07100, Turkey.
(37)Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham
B4 6NH, UK.
(38)Adult Inherited Metabolic Diseases, Salford Royal NHS Foundation Trust,
Salford M6 8HD, UK.
(39)Paediatric Metabolic Medicine Department, Kocaeli University Faculty of
Medicine, Kocaeli 41380, Turkey.
(40)Paediatric Metabolic Medicine Department, Hacettepe University Faculty of
Medicine, Ankara 06230, Turkey.
(41)Paediatric Metabolic Medicine Department, Istanbul University-Cerrahpasa
Faculty of Medicine, Istanbul 34096, Turkey.
X-linked ornithine transcarbamylase deficiency (OTCD) is the most common urea
cycle defect. The disease severity ranges from asymptomatic carrier state to
severe neonatal presentation with hyperammonaemic encephalopathy. We audited the
diagnosis and management of OTCD, using an online 12-question-survey that was
sent to 75 metabolic centres in Turkey, France and the UK. Thirty-nine centres
responded and 495 patients were reported in total. A total of 208 French
patients were reported, including 71 (34%) males, 86 (41%) symptomatic and 51
(25%) asymptomatic females. Eighty-five Turkish patients included 32 (38%)
males, 39 (46%) symptomatic and 14 (16%) asymptomatic females. Out of the 202 UK
patients, 66 (33%) were male, 83 (41%) asymptomatic and 53 (26%) symptomatic
females. A total of 19%, 12% and 7% of the patients presented with a
neonatal-onset phenotype in France, Turkey and the UK, respectively. Vomiting,
altered mental status and encephalopathy were the most common initial symptoms
in all three countries. While 69% in France and 79% in Turkey were receiving
protein restriction, 42% were on a protein-restricted diet in the UK. A total of
76%, 47% and 33% of patients were treated with ammonia scavengers in Turkey,
France and the UK, respectively. The findings of our audit emphasize the
differences and similarities in manifestations and management practices in three
countries.
DOI: 10.3390/life12111721
PMCID: PMC9695856
PMID: 36362876
Conflict of interest statement: PG is an academic co-founder of Bloomsbury
Genetic Therapies, UCL spinout developing a gene programme in OTC deficiency. |
http://www.ncbi.nlm.nih.gov/pubmed/36217298 | 1. Ann Clin Transl Neurol. 2022 Nov;9(11):1715-1726. doi: 10.1002/acn3.51668.
Epub 2022 Oct 10.
Predicting the disease severity in male individuals with ornithine
transcarbamylase deficiency.
Scharre S(#)(1), Posset R(#)(1), Garbade SF(1), Gleich F(1), Seidl MJ(1), Druck
AC(1), Okun JG(1), Gropman AL(2), Nagamani SCS(3), Hoffmann GF(1), Kölker S(1),
Zielonka M(1)(4); Urea Cycle Disorders Consortium (UCDC) and the European
registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia
Study Group.
Collaborators: Ah Mew N, Baumgartner MR, Berry GT, Berry SA, Burrage L, Diaz GA,
Ficicioglu C, Kisin G, Konczal L, Lam C, McCandless SE, Merritt JL, Schulze A,
Walter ME, Wilson A, Wong D, Arnaudo F, Augoustides-Savvopoulou P, Barić I,
Bosch AM, Cano A, Chien YH, Dionisi-Vici C, Dobbelaere D, Eyskens F, Freisinger
P, Garcia-Cazorla A, Honzik T, Karall D, Lund AM, Murphy E, Santer R, Schiff M,
Skouma A, Sykut-Cegielska J, Wijburg FA, Zeman J.
Author information:
(1)Division of Pediatric Neurology and Metabolic Medicine, Center for Child and
Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
(2)Division of Neurodevelopmental Pediatrics and Neurogenetics, Children's
National Health System and The George Washington School of Medicine, Washington,
District of Columbia, USA.
(3)Department of Molecular and Human Genetics, Baylor College of Medicine and
Texas Children's Hospital, Houston, Texas, USA.
(4)Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg,
Germany.
(#)Contributed equally
OBJECTIVE: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked
metabolic disease and the most common urea cycle disorder. Due to high
phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to
moderate symptoms and even asymptomatic individuals, the prediction of the
disease course at an early disease stage is very important to individually
adjust therapies such as medical treatment or liver transplantation. In this
translational study, we developed a severity-adjusted classification system
based on in vitro residual enzymatic OTC activity.
METHODS: Applying a cell-based expression system, residual enzymatic OTC
activities of 71 pathogenic OTC variants were spectrophotometrically determined
and subsequently correlated with clinical and biochemical outcome parameters of
119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD
registries.
RESULTS: Integration of multiple data sources enabled the establishment of a
robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not
only correlates with age at first symptoms, initial peak plasma ammonium
concentration and frequency of metabolic decompensations but also predicts
mortality. The critical threshold of 4.3% residual enzymatic activity
distinguishes a severe from an attenuated phenotype.
INTERPRETATION: Residual enzymatic OTC activity reliably predicts the disease
severity in mOTC-D and could thus serve as a tool for severity-adjusted
evaluation of therapeutic strategies and counselling patients and parents.
© 2022 The Authors. Annals of Clinical and Translational Neurology published by
Wiley Periodicals LLC on behalf of American Neurological Association.
DOI: 10.1002/acn3.51668
PMCID: PMC9639638
PMID: 36217298 [Indexed for MEDLINE]
Conflict of interest statement: SK received EU funding for the European registry
and network for Intoxication type Metabolic Diseases (E‐IMD; CHAFEA agreement
no. 2010 12 01). SK receives funding from Immedica Pharma AB for the European
Post‐Authorization Registry for Ravicti® (glycerol phenylbutyrate) oral liquid
in partnership with the E‐IMD (RRPE) (EU PAS Register no. EUPAS17267;
http://www.encepp.eu/). SK and GFH receive funding from the Dietmar Hopp
Foundation (St. Leon‐Rot, Germany) for a pilot study on extended newborn
screening evaluating the technical feasibility, diagnostic process quality and
health benefits for 28 inherited metabolic diseases including UCDs (NBS 2025,
project no. 1DH1911376, 1DH2011117). GFH received lecture fees from Swedish
Orphan Biovitrum GmbH. RP receives consultancy fees from Immedica Pharma AB. The
sponsors have in no way influenced the design, conductance, analysis and report
of the present study. All other authors declare that they have no conflict of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/3945292 | 1. N Engl J Med. 1986 Feb 27;314(9):541-7. doi: 10.1056/NEJM198602273140903.
Natural history of symptomatic partial ornithine transcarbamylase deficiency.
Rowe PC, Newman SL, Brusilow SW.
We reviewed the natural history and differential diagnosis of ornithine
transcarbamylase deficiency (an X-linked inborn error of urea synthesis) in 13
symptomatic female heterozygotes. The patients presented as early as the first
week of life or as late as the sixth year. The most common symptoms before
diagnosis were nonspecific: episodic extreme irritability (100 percent),
episodic vomiting and lethargy (100 percent), protein avoidance (92 percent),
ataxia (77 percent), Stage II coma (46 percent), delayed physical growth (38
percent), developmental delay (38 percent), and seizures (23 percent). Including
the proband, 42 percent of the female members of the 13 families studied had
symptoms. The median interval between the onset of major symptoms (vomiting and
lethargy, seizures, and coma) and diagnosis was 16 months (range, 1 to 142).
Five patients had IQ scores below 70 at the time of diagnosis. We suggest that
careful evaluation of the family history, the dietary history, the episodic
nature of the nonspecific symptoms, the response of these symptoms to the
withdrawal of protein, and their frequent onset at the time of weaning from
breast milk will permit early diagnosis and might thereby reduce the risk of
death or neurologic impairment in female patients with partial ornithine
transcarbamylase deficiency.
DOI: 10.1056/NEJM198602273140903
PMID: 3945292 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17845164 | 1. Pediatr Dermatol. 2007 Jul-Aug;24(4):394-6. doi:
10.1111/j.1525-1470.2007.00457.x.
Acrodermatitis enteropathica-like dermatosis associated with ornithine
transcarbamylase deficiency.
Pascual JC(1), Matarredona J, Mut J.
Author information:
(1)Department of Dermatology, Hospital General Universitario de Elche, Elche,
Spain. pascual_josram@gva.es
The urea cycle is the major metabolic pathway for excretion of waste nitrogen.
Ornithine transcarbamylase deficiency is the most frequent urea cycle disorder.
It is a hereditary-X-linked disease with over 150 mutations described. Ornithine
transcarbamylase deficiency causes vomiting, lethargy, hyperventilation, and
even death, mainly in the neonatal period. Ammonia, an extremely toxic molecule
for the organism, is generated during protein catabolism and is accumulated in
patients with this deficiency. Part of the treatment consists of a low-protein
diet, to avoid hyperammonemia episodes, which can even have a fatal outcome.
Patients can become deficient in several amino acids, either through the
low-protein diet or directly through the primary enzyme deficiency; this in turn
can cause an acrodermatitis enteropathica-like dermatosis.
DOI: 10.1111/j.1525-1470.2007.00457.x
PMID: 17845164 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36394206 | 1. Clin Transl Med. 2022 Nov;12(11):e1113. doi: 10.1002/ctm2.1113.
Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis
potential of colorectal cancer.
Pan YJ(1), Huo FC(1), Kang MJ(1), Liu BW(2), Wu MD(1), Pei DS(1).
Author information:
(1)Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University,
Xuzhou, China.
(2)Department of General Surgery, Xuzhou Medical University, Xuzhou, China.
BACKGROUND: Dysregulation of alternative splicing (AS) induced by
serine/arginine-rich proteins has recently been linked to cancer metastasis.
Nonetheless, as a member of the serine/arginine-rich protein family, the
involvement of SRSF11 in colorectal cancer (CRC) is unknown.
METHODS: The TCGA dataset and clinical samples were used to assess SRSF11
expression levels in CRC. For SRSF11, functional experiments were conducted both
in vitro and in vivo. RNA-seq technology was used to analyze and screen
SRSF11-triggered AS events, which were then confirmed by in vivo UV crosslinking
and immunoprecipitation (CLIP) and mini-gene reporter assays. Jalview software
was used to determine the preferential binding motif with relation to exon
skipping (ES) events. Furthermore, coimmunoprecipitation (Co-IP) and Phospho-tag
SDS-PAGE experiments were used to investigate PAK5-mediated phosphorylation
regulation on SRSF11, and in vitro kinase experiments validated the interaction.
RESULTS: In CRC, SRSF11 was discovered to be overexpressed and associated with a
poor prognosis. And SRSF11 played a pro-metastatic role in vitro and in vivo. By
screening SRSF11-regulated AS events, we identified the binding motif of
SRSF11-triggered splicing-switching of HSPA12A AS, which specifically regulated
HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the
HSPA12A transcript with exon 2 retention increased N-cadherin expression by
promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated
SRSF11 at serine 287, protecting it from ubiquitination degradation.
CONCLUSIONS: SRSF11 exerts pro-metastatic effects in CRC by inhibiting the AS of
HSPA12A pre-RNA. Our findings point to SRSF11-regulated HSPA12A splicing as a
novel relationship between SRSF11-regulated splicing and CRC metastasis and
suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and
prognostic biomarker in CRC.
© 2022 The Authors. Clinical and Translational Medicine published by John Wiley
& Sons Australia, Ltd on behalf of Shanghai Institute of Clinical
Bioinformatics.
DOI: 10.1002/ctm2.1113
PMCID: PMC9670187
PMID: 36394206 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no potential conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36001712 | 1. N Engl J Med. 2022 Aug 25;387(8):715-726. doi: 10.1056/NEJMoa2201302.
Olokizumab versus Placebo or Adalimumab in Rheumatoid Arthritis.
Smolen JS(1), Feist E(1), Fatenejad S(1), Grishin SA(1), Korneva EV(1), Nasonov
EL(1), Samsonov MY(1), Fleischmann RM(1); CREDO2 Group.
Collaborators: Everding A, Khariouzov A, Koenig R, Kuehne C, Wassenberg S,
Kurthen R, Bortlik L, Dokoupilova E, Horvath R, Lapcikova A, Prochazkova L,
Simkova G, Urbanova Z, Vitek P, Svobodova M, Blahova M, Petrikova A, Sleglova O,
Machkova M, Rosa J, Novosad L, Houzarova A, Stejfova Z, Gollerova V, Dvorak Z,
Drescher E, Nagy M, Simoncsics E, Sulyok G, Somos E, Takacs K, Kovacs A,
Rapolthy I, Scheinberg MA, Cauceglia Melazzi AC, D'Andrea Marcolino FM, Ferreira
Fernandes AM, Bohn JM, Radominski SC, Scafuto Scotton A, Waldemar Keiserman M,
Ximenes AC, da Silva AC, Emerich de Abreu CR, de Vasconcelos V, Lima SM, Martins
de Mello F, Mihaela Ramazan AM, Asnal C, Constanza Subils G, Gulin JP, Del Valle
Lucero E, Mannucci Walter PA, Moreno JLC, Spindler AJ, Testa GA, Venarotti HO,
Velasco Zamora BJ, Kerzberg E, Tate P, Velasco Zamora JL, Gallo R, Carrio J,
Alvarellos AJ, Basijokiene V, Bukauskiene L, Lauciuviene R, Kvedaraviciene R,
Dambrauskiene J, Ranceva J, Chen HA, Liou LB, Chalem Choueka MR, Arbelaez Cortes
A, Velez Sanchez PJ, Jaller Raad JJ, Saaibi Solano DL, Ong V, Pakozdi A,
Williams E, George E, Gwynne C, Batley M, Savi T, Müller R, Ju JH, Lee SS, Park
YB, Kim J, Jung SY, Lim MK, De la Garza Ramos EH, Garcia Valladares I, Jara
Quezada L, Duran Barragan S, Vicente Vicente Gonzalez V, Enriquez Sosa FE, Perez
EMV, Flores Alvarado DE, Rizo Rodriguez JC, Munoz Lopez S, Pacheco Tena C,
Saulite-Kandevica D, Rehman Q, Neuwelt CM, Schnitz W, Kutner M, Diegel R, Najam
S, Sunkureddi P, Waller P, Ayesu K, Bunch T, Wolfe S, Pick M, Mallepalli J,
Mabaquiao A, Paez H, Edgerton C, Churchill M, Forstot J, Chohan S, Bhadbhade P,
Kenney H, Jesus A, Eisenberg M, El-Kadi H, Goddard D, Saadeh C, Goldberger E,
Fraser A, Scoville C, Howell M, Arne ET, Smith K, Mehta C, Gladstein G, Harris
M, Baraf H, Mishra N, Codding C, Lee E, Neal-Kraal R, LaGrone R, Metyas S,
Murphy F, Babajanians A, Antolini C, Cedeno JE, Querubin R, Vasandani J, King C,
Snow D, Iglesias N, Diri E, Firooz N, Karrar A, Brionez T, Shaikh AA, Khan A,
Soloman N, Diaz-Secades L, Kreutz D, Basu D, Rivera T, Zagar K, Kumar V, Su TK,
Javed S, Bognar M, Tsoneva K, Todorov S, Toncheva A, Dimitrov E, Kapandjieva N,
Kopcheva S, Bichovska D, Stoilov R, Penev D, Petranova T, Zielinska A,
Rell-Bakalarska M, Burczynska J, Jeka S, Pawtel A, Dankiewicz-Fares I, Dudek A,
Dworak K, Kolacinski R, Racewicz A, Olechnowicz-Tietz S, Kaminski A, Kuc K,
Strzelecka A, Wojtecka-Grabka M, Rapa A, Malys Brylka A, Rowinska-Osuch A,
Wronisz M, Vezikova N, Gordeev I, Evstigneeva L, Izmozherova N, Kamalova R,
Krechikova D, Matsievskaya G, Plaksina T, Smolyarchuk E, Stanislav M.
Author information:
(1)From the Division of Rheumatology, Department of Medicine 3, Medical
University of Vienna, Vienna (J.S.S.); Helios Fachklinik Vogelsang-Gommern,
Vogelsang-Gommern, Germany (E.F.); SFC Medica, Charlotte, NC (S.F.); R-Pharm
(S.A.G., E.V.K., M.Y.S.), V.A. Nasonova Research Institute of Rheumatology
(E.L.N.), and Sechenov Medical University (M.Y.S.) - all in Moscow; and the
University of Texas Southwestern Medical Center at Dallas and Metroplex Clinical
Research Center - both in Dallas (R.M.F.).
BACKGROUND: The cytokine interleukin-6 is involved in the pathogenesis of
rheumatoid arthritis. Olokizumab, a humanized monoclonal antibody targeting the
interleukin-6 cytokine directly, is being tested for the treatment of rheumatoid
arthritis.
METHODS: In a 24-week, phase 3, multicenter, placebo- and active-controlled
trial, we randomly assigned (in a 2:2:2:1 ratio) patients with rheumatoid
arthritis and an inadequate response to methotrexate to receive subcutaneous
olokizumab at a dose of 64 mg every 2 or 4 weeks, adalimumab (40 mg every 2
weeks), or placebo; all patients continued methotrexate therapy. The primary end
point was an American College of Rheumatology 20 (ACR20) response (≥20% fewer
tender and swollen joints and ≥20% improvement in three of five other domains)
at week 12, with each olokizumab dose tested for superiority to placebo. We also
tested the noninferiority of each olokizumab dose to adalimumab with respect to
the percentage of patients with an ACR20 response (noninferiority margin, -12
percentage points in the lower boundary of the 97.5% confidence interval for the
difference between groups).
RESULTS: A total of 464 patients were assigned to receive olokizumab every 2
weeks, 479 to receive olokizumab every 4 weeks, 462 to receive adalimumab, and
243 to receive placebo. An ACR20 response at week 12 occurred in 44.4% of the
patients receiving placebo, in 70.3% receiving olokizumab every 2 weeks
(difference vs. placebo, 25.9 percentage points; 97.5% confidence interval [CI],
17.1 to 34.1), in 71.4% receiving olokizumab every 4 weeks (difference vs.
placebo, 27.0 percentage points; 97.5% CI, 18.3 to 35.2), and in 66.9% receiving
adalimumab (difference vs. placebo, 22.5 percentage points; 95% CI, 14.8 to
29.8) (P<0.001 for the superiority of each olokizumab dose to placebo). Both
olokizumab doses were noninferior to adalimumab with respect to the percentage
of patients with an ACR20 response at week 12 (difference, 3.4 percentage points
[97.5% CI, -3.5 to 10.2] with olokizumab every 2 weeks and 4.5 percentage points
[97.5% CI, -2.2 to 11.2] with olokizumab every 4 weeks). Adverse events, most
commonly infections, occurred in approximately 70% of the patients who received
olokizumab. Antibodies against olokizumab were detected in 3.8% of the patients
receiving the drug every 2 weeks and in 5.1% of those receiving it every 4
weeks.
CONCLUSIONS: In patients with rheumatoid arthritis who were receiving
maintenance methotrexate, olokizumab was superior to placebo and noninferior to
adalimumab in producing an ACR20 response at 12 weeks. Larger and longer trials
are required to determine the efficacy and safety of olokizumab in patients with
rheumatoid arthritis. (Supported by R-Pharm; CREDO2 ClinicalTrials.gov number,
NCT02760407.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2201302
PMID: 36001712 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29956806 | 1. Mol Med Rep. 2018 Sep;18(3):3020-3026. doi: 10.3892/mmr.2018.9230. Epub 2018
Jun 27.
Decreased expression of TROAP suppresses cellular proliferation, migration and
invasion in gastric cancer.
Jing K(1), Mao Q(1), Ma P(1).
Author information:
(1)Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong
University, Nantong, Jiangsu 226001, P.R. China.
Trophinin associated protein (TROAP) is a cytoplasmic protein required for
spindle assembly and cell invasion; however, its biological function in cancer
remains to be elucidated. In the present study, by analyzing three independent
datasets from the Oncomine database, it was identified that TROAP mRNA
expression was upregulated in gastric cancer (GC) tissues compared with normal
counterparts. Furthermore, elevated expression of TROAP was associated with poor
survival in patients with GC, as predicted using Kaplan‑Meier analysis. TROAP
was knocked down to verify its functional role in gastric cancer cell lines,
SGC‑7901 and MGC80‑3. MTT assay was used to analyze cell proliferation. Cell
cycle progression, and migration and invasion were determined using flow
cytometry and Transwell assay, respectively. In vitro experiments demonstrated
that knockdown of TROAP significantly suppressed cell proliferation, G1 to S
cell cycle transition, and the migration and invasion ability of GC cells. The
results of the present study suggest that TROAP is overexpressed in GC and
serves an oncogenic role in gastric cancer by affecting cell proliferation and
invasion.
DOI: 10.3892/mmr.2018.9230
PMID: 29956806 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34077623 | 1. CNS Neurosci Ther. 2021 Jun 2;27(9):1064-76. doi: 10.1111/cns.13688. Online
ahead of print.
TROAP regulates cell cycle and promotes tumor progression through Wnt/β-Catenin
signaling pathway in glioma cells.
Zhao ZQ(1)(2), Wu XJ(1)(2), Cheng YH(1)(2), Zhou YF(2), Ma XM(2), Zhang J(1)(2),
Heng XY(1)(2), Feng F(1)(2)(3).
Author information:
(1)Department of Neurosurgery, Linyi People's Hospital, Linyi, China.
(2)Institute of Brain Science and Brain-Like Intelligence, Linyi People's
Hospital, Linyi, China.
(3)Institute of Clinical Medicine College, Guangzhou University of Chinese
Medicine, Guangzhou, China.
AIMS: Experimental evidence demonstrated a crucial role of TROAP
(Trophinin-associated protein) in regulating the cell proliferation of multiple
tumors, while TROAP expression and function were largely unknown in glioma. We
aimed to investigate the oncogenic role of TROAP and its potential mechanisms in
gliomagenesis.
METHODS: Four gene expression databases (GEO, TCGA, GTEx and CCLE) were enrolled
in our study and used for TROAP expression and survival analysis. TROAP
expression was quantified by qRT-PCR, western blot and immunohistochemistry
assays in glioma tissues and cell lines. TROAP knockdown and overexpression
vector were constructed and transfected into glioma cells. CCK-8, colony
formation, transwell, and wound healing assays were used to evaluate cell
viability, migration and invasion, flow cytometry to determine cell cycle
arrest. Gene set enrichment analysis (GSEA) was conducted to screen the pathway
involved in TROAP-high phenotype. The expression of cell cycle and Wnt/β-Catenin
signaling proteins were analyzed by immunofluorescence and western blot.
RESULTS: Based on the bioinformatic analysis and a series of functional assays,
we found the TROAP was enriched in glioma tissues and cell lines, its
overexpression was correlated with the clinicopathologic characteristics and
poor prognosis. TROAP knockdown inhibited cell proliferation, migration,
invasion, and G1/S cell cycle arrest compared with control group in glioma.
Mechanism analysis revealed that TROAP activated Wnt/β-Catenin pathway and
upregulated its downstream targets expression, while silencing β-Catenin or
Axin2 could reverse the tumor-promoting effects caused by TROAP, confirming that
TROAP-induced malignant phenotype and tumorigenesis via Wnt/β-Catenin signaling
pathway.
CONCLUSION: The present study found that TROAP accelerated the progression of
gliomagenesis through Wnt/β-Catenin pathway, and TROAP might be considered as a
novel target for glioma therapy.
© 2021 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley &
Sons Ltd.
DOI: 10.1111/cns.13688
PMCID: PMC8339535
PMID: 34077623
Conflict of interest statement: No potential conflicts of interest were
disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/30854102 | 1. J Cancer. 2019 Jan 29;10(4):957-967. doi: 10.7150/jca.26666. eCollection 2019.
The Upregulation of Trophinin-Associated Protein (TROAP) Predicts a Poor
Prognosis in Hepatocellular Carcinoma.
Hu H(1), Xu L(2), Chen Y(3), Luo SJ(1), Wu YZ(3), Xu SH(1), Liu MT(1), Lin F(2),
Mei Y(2), Yang Q(2), Qiang YY(2), Lin YW(1), Deng YJ(1), Lin T(1), Sha YQ(1),
Huang BJ(2), Zhang SJ(1).
Author information:
(1)Department of Chinese Medicine, the First Affiliated Hospital, Sun Yat-sen
University, Guangzhou 510080, Guangdong, P. R. China.
(2)State Key Laboratory of Oncology in South China; Collaborative Innovation
Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou
510060, P. R. China.
(3)Department of Chinese Medicine, the Third Affiliated Hospital, Sun Yat-sen
University, Guangzhou 510630, Guangdong, P. R. China.
Purpose: Trophinin-associated protein (TROAP) is a cytoplasmic protein that
plays a significant role in the processes of embryo transplantation and
microtubule regulation. However, the relevant survival analysis and cancer
progression analysis have not yet been reported. Methods: Eighteen matched pairs
of tumor and adjacent non-tumor samples were evaluated to detect the TROAP mRNA
level. Immunohistochemistry (IHC) was used to evaluate the TROAP expression in
108 hepatocellular carcinoma patients who underwent surgical resection.
Meanwhile, data from the TCGA database was statistically evaluated. Results: In
the present study, we detected a significant increase in the TROAP mRNA level in
tumor tissues when compared with adjacent non-tumor tissues. Moreover, the
upregulation of TROAP was associated with increased serum AFP and GGT; the
greater the tumor number was, the larger the tumor size, differentiation grade,
and cancer embolus in clinical analysis. In HCC patients, elevated TROAP
expression in the primary tumor was positively related to clinical severity,
such as poor overall survival and disease-free survival. In addition, both
univariate and multivariate survival analysis validated that TROAP expression
was a promising independent risk factor for overall survival and disease-free
survival in HCC patients. Furthermore, the results derived from the analysis of
data from the TCGA database were consistent with previous results. Altogether,
our results show that TROAP is a novel crucial regulator of HCC progression and
is a potential therapeutic biomarker for HCC patients. Conclusions: Elevated
TROAP expression predicted a poor prognosis, and TROAP may serve as a potential
biomarker for application in oncotherapy.
DOI: 10.7150/jca.26666
PMCID: PMC6400818
PMID: 30854102
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interest exists. |
http://www.ncbi.nlm.nih.gov/pubmed/30284652 | 1. Dig Dis Sci. 2019 Jan;64(1):137-143. doi: 10.1007/s10620-018-5315-x. Epub 2018
Oct 4.
High Trophinin-Associated Protein Expression Is an Independent Predictor of Poor
Survival in Liver Cancer.
Jiao Y(1), Li Y(2), Lu Z(3), Liu Y(4).
Author information:
(1)Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of
Jilin University, Changchun, 130021, Jilin, People's Republic of China.
(2)Department of Pathophysiology, College of Basic Medical Sciences, Jilin
University, Changchun, 130021, Jilin, People's Republic of China.
(3)Department of General Surgery, The Second Hospital of Jilin University,
Changchun, 130041, Jilin, People's Republic of China.
(4)Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of
Jilin University, Changchun, 130021, Jilin, People's Republic of China.
liuyahui2008@yeah.net.
BACKGROUND: Trophinin-associated protein (TROAP) is a cytoplasmic protein that
functions as an adhesion molecule in processes such as embryo implantation,
spindle formation, and cancer.
OBJECTIVE: To evaluate the relationship of TROAP expression in hepatocellular
carcinoma (HCC) tissue with clinicopathologic parameters and survival time in
liver cancer patients based on an analysis of The Cancer Genome Atlas Liver
Hepatocellular Carcinoma (TCGA-LIHC) data.
METHODS: RNA-sequencing (RNA-Seq) expression data and clinical information were
downloaded for the TCGA-LIHC cohort. Associations between TROAP expression in
HCC tissues and clinical parameters were evaluated by Chi-square tests.
Differences in survival between high and low expression groups (median
expression cutoff) from Cox regression analysis were compared, and P values were
calculated by a log-rank test. Kaplan-Meier curves were compared with the
log-rank test.
RESULTS: Analysis of RNA-Seq gene expression data for 373 patients with primary
tumors revealed overexpression of TROAP in liver cancer. High TROAP expression
was associated with survival status (P = 0.015), T stage (P = 0.049), clinical
stage (P = 0.048), and gender (P = 0.033). Patients with high TROAP-expressing
liver cancers had a shorter median overall survival of 3.83 years compared with
5.80 years for patients with low TROAP-expressing liver cancers (P = 0.00422).
Multivariate analysis identified TROAP expression as an independent prognostic
variable for overall survival in liver cancer patients.
CONCLUSION: TROAP expression is an independent predictor of poor survival in
liver cancer.
DOI: 10.1007/s10620-018-5315-x
PMID: 30284652 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34344706 | 1. Ann Rheum Dis. 2022 Apr;81(4):469-479. doi: 10.1136/annrheumdis-2021-219876.
Epub 2021 Aug 3.
Olokizumab, a monoclonal antibody against interleukin 6, in combination with
methotrexate in patients with rheumatoid arthritis inadequately controlled by
methotrexate: efficacy and safety results of a randomised controlled phase III
study.
Nasonov E(1), Fatenejad S(2), Feist E(3), Ivanova M(4), Korneva E(5), Krechikova
DG(6), Maslyanskiy AL(7), Samsonov M(5), Stoilov R(4), Zonova EV(8), Genovese
M(9).
Author information:
(1)Research Institute of Rheumatology of RAMS, Moskva, Russian Federation.
(2)SFC Medica, Charlotte, North Carolina, USA.
(3)Department for Rheumatology, HELIOS Specialist Hospital Vogelsang/Gommern
Clinic for Rheumatology, Gommern, Germany.
(4)University Hospital St Ivan Rilski Rheumatology Clinic, Sofia, Bulgaria.
(5)Medical, CJSC R-Pharm, Moskow, Russian Federation.
(6)Non-state Healthcare Institution Regional Clinical Hospital at Smolensk
Station, Smolensk, Russian Federation.
(7)Medical Research Centre, Federal Almazov North West Medical Research Centre,
Saint-Petersburg, Russian Federation.
(8)Novosibirsk State Medical University, Novosibirsk, Russian Federation.
(9)Division of Immunology and Rheumatology, Stanford University, Stanford,
California, USA genovese@stanford.edu.
OBJECTIVE: To evaluate the efficacy and safety of olokizumab (OKZ) in patients
with active rheumatoid arthritis despite treatment with methotrexate (MTX).
METHODS: In this 24-week multicentre, placebo-controlled, double-blind study,
patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg
once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The
primary efficacy endpoint was the proportion of patients achieving an American
College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy
endpoints included percentage of subjects achieving Disease Activity Score
28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire
Disability Index at week 12, ACR50 response and Clinical Disease Activity Index
≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study.
RESULTS: A total of 428 patients were randomised. ACR20 responses were more
frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than
placebo (25.9%) (p<0.0001 for both comparisons). There were significant
differences in all secondary efficacy endpoints between OKZ-treated arms and
placebo. Treatment-emergent serious adverse events (TESAEs) were reported by
more patients in the OKZ groups compared with placebo. Infections were the most
common TESAEs. No subjects developed neutralising antidrug antibodies.
CONCLUSIONS: Treatment with OKZ was associated with significant improvement in
signs, symptoms and physical function of rheumatoid arthritis without
discernible differences between the two regimens. Safety was as expected for
this class of agents. Low immunogenicity was observed. Trial registration number
NCT02760368.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No
commercial re-use. See rights and permissions. Published by BMJ.
DOI: 10.1136/annrheumdis-2021-219876
PMCID: PMC8921576
PMID: 34344706 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: EN: speakers’ bureau for
AbbVie, Eli Lilly, Janssen, Novartis, Pfizer. SF: consulting fees from R-Pharm
International, ICON and PPD contract research organisations, shareholder of
Pfizer, INC stocks. EF: research grants from BMS, Eli Lilly, Novartis, Roche;
consulting fees from AbbVie, BMS, Eli Lilly, Gilead Sciences, Galapagos,
Novartis, Roche, Sanofi, Sobi; speakers’ bureau for AbbVie, BMS, Eli Lilly,
Gilead Sciences, Galapagos, Medac, Novartis, Roche, Sanofi, Sobi. MI: speakers’
bureau for AbbVie, Eli Lilly, MSD, Novartis, Pfizer, UCB. EK: employee of
R-Pharm, with no R-Pharm stock. DGK: speakers’ bureau for Bayer, Boehringer
Ingelheim, UCB; research grants from BMS, Eli Lilly, Janssen, Pfizer, R-Pharm.
ALM: consulting fees from R-Pharm; speakers’ bureau for AbbVie, Boehringer
Ingelheim, Novartis, R-Pharm; other activities for AbbVie, Johnson, MSD,
Novartis, Roche, outside the submitted work. MS: employee of R-Pharm, with
R-Pharm stock. RS: speakers’ bureau for AbbVie, Boehringer Ingelheim, Eli Lilly,
Janssen, MSD, Novartis, Pfizer, UCB. EVZ: research grants from AbbVie, Celgene,
Janssen, Novartis, Amgen, Pfizer, speakers’ bureau and consultant for AbbVie,
Celgene, Janssen, Novartis, Pfizer, Sanofi, Boehringer Ingelheim, Bayer, Sandoz.
MG: employee of Gilead Sciences, with Gilead Sciences stock. |
http://www.ncbi.nlm.nih.gov/pubmed/29117881 | 1. Oncol Res. 2018 Jun 11;26(5):691-701. doi: 10.3727/096504017X15101398724809.
Epub 2017 Nov 8.
Downregulated Trophinin-Associated Protein Plays a Critical Role in Human
Hepatocellular Carcinoma Through Upregulation of Tumor Cell Growth and
Migration.
Lian Y(1), Fan W(2), Huang Y(3), Wang H(1), Wang J(1), Zhou L(3), Wu X(3), Deng
M(2), Huang Y(1).
Author information:
(1)Guangdong Province Key Laboratory of Liver Disease Research, The Third
Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China.
(2)Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun
Yat-Sen University, Guangzhou, P.R. China.
(3)Department of Infectious Diseases, The Third Affiliated Hospital of Sun
Yat-Sen University, Guangzhou, P.R. China.
Trophinin-associated protein (TROAP) was a protein first identified to mediate
the process of embryo transplantation and later found to be involved in
microtubule regulation. However, little is known about the role of TROAP in
hepatocellular carcinoma (HCC). In the present study, we reported that both
TROAP mRNA and protein expressions were downregulated in human HCC samples as
well as cell lines. A high level of TROAP was associated with small tumor size
(p < 0.05), minor tumor nodules (p < 0.01), and mild vein invasion (p < 0.05).
We further constructed in vitro TROAP depletion and overexpression HCC cell
models. TROAP depletion significantly enhanced the proliferation and colony
formation abilities, whereas TROAP overexpression had an inhibitory effect on
the growth of HCC cells. The G1/S phase arrest by TROAP overexpression
correlated with increased cell cycle inhibitors p21 and p27, and declined cell
cycle promoting kinase complex CDK6/cyclin D1. Depressed TROAP expression
enhanced the migration ability, while the opposite influence was observed in
TROAP-overexpressed HCC cells. Taken together, these results indicate that TROAP
suppresses cellular growth and migration in HCC. This discovery will further our
understanding of the pathogenic mechanisms of human HCC.
DOI: 10.3727/096504017X15101398724809
PMCID: PMC7844635
PMID: 29117881 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33500384 | 1. Cell Death Dis. 2021 Jan 26;12(1):125. doi: 10.1038/s41419-021-03422-3.
TROAP switches DYRK1 activity to drive hepatocellular carcinoma progression.
Li L(#)(1)(2)(3), Wei JR(#)(4), Song Y(#)(5), Fang S(#)(6), Du Y(#)(6), Li Z(7),
Zeng TT(7), Zhu YH(7), Li Y(7), Guan XY(8)(9)(10).
Author information:
(1)State Key Laboratory of Oncology in South China and Collaborative Innovation
Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060,
Guangzhou, China. lilei728@hku.hk.
(2)Department of Clinical Oncology, State Key Laboratory for Liver Research, The
University of Hong Kong, Hong Kong, China. lilei728@hku.hk.
(3)Department of Clinical Oncology Center, The University of Hongkong-Shenzhen
Hospital, 518053, Shenzhen, China. lilei728@hku.hk.
(4)State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun
Yat-sen University, 510060, Guangzhou, China.
(5)Affiliated Cancer Hospital & Institutes of Guangzhou Medical University,
Guangzhou Key Medical Discipline Construction Project, 510095, Guangzhou, China.
(6)The Seventh Affiliated Hospital, Sun Yat-sen University, 518100, Shenzhen,
China.
(7)State Key Laboratory of Oncology in South China and Collaborative Innovation
Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060,
Guangzhou, China.
(8)State Key Laboratory of Oncology in South China and Collaborative Innovation
Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060,
Guangzhou, China. xyguan@hku.hk.
(9)Department of Clinical Oncology, State Key Laboratory for Liver Research, The
University of Hong Kong, Hong Kong, China. xyguan@hku.hk.
(10)Department of Clinical Oncology Center, The University of Hongkong-Shenzhen
Hospital, 518053, Shenzhen, China. xyguan@hku.hk.
(#)Contributed equally
Hepatocellular carcinoma (HCC) is one of the common malignancy and lacks
effective therapeutic targets. Here, we demonstrated that ectopic expression of
trophinin-associated protein (TROAP) dramatically drove HCC cell growth assessed
by foci formation in monolayer culture, colony formation in soft agar and
orthotopic liver transplantation in nude mice. Inversely, silencing TROAP
expression with short-hairpin RNA attenuated the malignant proliferation of HCC
cells in vitro and in vivo. Next, mechanistic investigation revealed that TROAP
directly bound to dual specificity tyrosine phosphorylation regulated kinase
1A/B (DYRK1A/B), resulting in the cytoplasmic retention of proteins DYRK1A/B and
promoting cell cycle process via activation of Akt/GSK-3β signaling. Combination
of cisplatin with an inhibitor of DYRK1 AZ191 effectively inhibited tumor growth
in mouse model for HCC cells with high level of TROAP. Clinically, TROAP was
significantly upregulated by miR-142-5p in HCC tissues, which predicted the poor
survival of patients with HCC. Therefore, TROAP/DYRK1/Akt axis may be a
promising therapeutic target and prognostic indicator for patients with HCC.
DOI: 10.1038/s41419-021-03422-3
PMCID: PMC7838256
PMID: 33500384 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/31198787 | 1. Biomed Res Int. 2019 May 6;2019:6140951. doi: 10.1155/2019/6140951.
eCollection 2019.
TROAP Promotes Breast Cancer Proliferation and Metastasis.
Li K(1), Zhang R(2), Wei M(3), Zhao L(1), Wang Y(4), Feng X(5), Yang Y(5), Yang
S(6), Zhang L(5).
Author information:
(1)Department of Oncology I, Shengjing Hospital of China Medical University,
Shenyang, China.
(2)Shuwen Biotech Co. Ltd., Deqing, China.
(3)School of Pharmacy, China Medical University, Shenyang, China.
(4)The 4 Affiliated Hospital of Harbin Medical University, Harbin, China.
(5)Department of Pathology, Harbin Medical University, Harbin, China.
(6)Department of Anatomy, Basic Medical Science College, Harbin Medical
University, Harbin, China.
Trophinin-associated protein (TROAP) is a cytoplasmic protein required for
microtubular cytoskeleton regulation and spindle assembly, and its expression
plays a critical role in the initiation and progression of various types of
cancer. However, little is known about the role of TROAP in breast cancer (BC).
TROAP mRNA expression levels and clinical data from Gene Expression Omnibus
(GEO) datasets (GSE42568, 104 BC patients; GSE1456, 159 BC patients; and
GSE21653, 266 BC patients) were analyzed by the R2: Genomics Analysis and
Visualization Platform to estimate overall survival (OS). We also analyzed the
genes correlated with TROAP by gene ontology (GO) enrichment analysis and Kyoto
Encyclopedia of Genes and Genomes (KEGG) analysis to predict potential
relationships between TROAP and other genes in BC. Our study verified that both
TROAP mRNA and protein expression levels were upregulated in human BC samples
and cell lines. In vitro experiments demonstrated that TROAP knockdown
significantly inhibited cell proliferation, the G1 to S phase transition, and
the migration and invasion abilities of BC cells. The present study suggests
that TROAP plays an important role in promoting the proliferation, invasion, and
metastasis of BC.
DOI: 10.1155/2019/6140951
PMCID: PMC6526557
PMID: 31198787 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30431120 | 1. Oncol Rep. 2019 Feb;41(2):1169-1179. doi: 10.3892/or.2018.6854. Epub 2018 Nov
9.
TROAP regulates prostate cancer progression via the WNT3/survivin signalling
pathways.
Ye J(1), Chu C(1), Chen M(2), Shi Z(3), Gan S(1), Qu F(1), Pan X(1), Yang Q(1),
Tian Y(1), Wang L(1), Yang W(1), Cui X(1).
Author information:
(1)Department of Urology, Third Affiliated Hospital, The Second Military Medical
University, Shanghai 201805, P.R. China.
(2)Department of Urology, Affiliated Changzheng Hospital, The Second Military
Medical University, Shanghai 200003, P.R. China.
(3)Department of Urology, Taizhou First People's Hospital, Taizhou, Zhejiang
318020, P.R. China.
Prostate cancer (PCa) is one of the most commonly diagnosed malignancies, and
90% of advanced prostate cancer patients relapse after therapy. Trophinin
associated protein (TROAP) is essential for centrosome integrity and proper
bipolar organisation of spindle assembly during mitosis and plays an essential
role in proliferation. We found that TROAP expression correlates with patient
survival and speculated that it may be involved in PCa progression. The Oncomine
database tool (http://www.oncomine.org) was used to analyse TROAP mRNA
expression from microarray data, and patient survival analysis for target genes
was performed using the PROGgeneV2 Database (http://watson.compbio.iupui.edu).
Gene interference with lentivirus was used to silence TROAP expression in PCa
cells and knockdown efficiency was detected by qRT-PCR and western blot
analysis. Cell viability, colony formation, cell cycle and apoptosis were then
assessed to determine the function of TROAP in PCa cells. Markers of cell cycle
and apoptosis were tested by western blotting. The correlation between WNT3 or
survivin expression and TROAP transcripts in prostate cancer tissues was
analysed using GEPIA (http://gepia.cancer-pku.cn) and validated by western
blotting. The in vivo role of TROAP was investigated using xenografts. This
protein was overexpressed in PCa, and exhibited relatively higher expression in
PCa cell lines, DU145 and 22Rv1. Importantly, analysing human cancer databases
available from PROGgeneV2 showed that higher expression of TROAP is associated
with shorter overall survival in prostate cancer patients. TROAP knockdown
inhibited cell proliferation and led to cell cycle arrest at S phase in 22Rv1
and DU145 cells. Cell cycle arrest resulted in apoptosis in both cell lines via
the cyclin A2-cyclin B1-caspase pathway. WNT3 and survivin expression levels
were found to correlate with TROAP in PCa, and in vivo xenograft assays revealed
that silencing of TROAP inhibited PCa tumour growth. Therefore, TROAP might
represent a novel predictive marker to guide therapeutic intervention.
DOI: 10.3892/or.2018.6854
PMID: 30431120 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31285897 | 1. J Thorac Dis. 2019 May;11(5):2043-2050. doi: 10.21037/jtd.2019.04.86.
Trophinin-associated protein expression is an independent prognostic biomarker
in lung adenocarcinoma.
Chen Z(1), Zhou Y(1), Luo R(1), Liu K(1), Chen Z(1).
Author information:
(1)Department of Thoracic Surgery, Sir Run Run Shaw Hospital, School of
Medicine, Zhejiang University, Hangzhou 310016, China.
BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide,
with lung adenocarcinoma (LAC) representing the most common subtype.
Trophinin-associated protein (TROAP) is a cytoplasmic protein first identified
to mediate the process of embryo transplantation, which has been recently found
to be involved in microtubule regulation. However, limited information about the
role of TROAP in LAC is available.
METHODS: We evaluated the relationship of TROAP expression in LAC tissues with
clinical pathologic parameters and the survival time in LAC patients based on a
statistical analysis of The Cancer Genome Atlas (TCGA) lung cancer data (N=528).
Differences in survival between high and low expression groups (median
expression cutoff) from the Cox univariate/multivariate regression analysis were
then compared.
RESULTS: According to the Chi-square tests, we found high TROAP expression
correlated with younger age (≤60) (P=0.047), male sex (P<0.005), an earlier
T-stage (P=0.011), N-stage (P=0.017), M-stage (P=0.022), TNM (P=0.007), and a
longer smoking history (>30 pack-year) (P<0.001). A Kaplan-Meier analysis
demonstrated that high TROAP expression may correspond with poor overall
survival of LAC patients in T3 stage (P=0.0013), N0 stage (P=0.014), and M0
stage (P=0.0023). Multivariate analysis confirmed that TROAP expression was
related to overall survival in LAC patients independently [hazard ratio (HR):
1.784, 95% confidence interval (CI): 1.072-2.968, P=0.026].
CONCLUSIONS: Our results suggested that TROAP is an independent prognostic
biomarker of poor survival in LAC.
DOI: 10.21037/jtd.2019.04.86
PMCID: PMC6588746
PMID: 31285897
Conflict of interest statement: Conflicts of Interest: The authors have no
conflicts of interest to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/33692939 | 1. Front Oncol. 2021 Feb 22;10:592239. doi: 10.3389/fonc.2020.592239. eCollection
2020.
EZH2-TROAP Pathway Promotes Prostate Cancer Progression Via TWIST Signals.
Jin L(1), Zhou Y(1), Chen G(2), Dai G(1), Fu K(1), Yang D(1), Zhu J(1).
Author information:
(1)Department of Urology, Second Affiliated Hospital of Soochow University,
Suzhou, China.
(2)Department of Radiology, Second Affiliated Hospital of Soochow University,
Suzhou, China.
Trophinin-associated protein (TROAP) has been shown to be overexpressed and
promotes tumor progression in some tumors. We performed this study to assess the
biological and clinical significance of TROAP in prostate cancer. We downloaded
TROAP mRNA expression data from TCGA and GEO databases. We analyzed expressions
of TROAP and other genes in prostate cancer tumors at different stages and
assessed Gleason scores. We used Celigo image, Transwell, and rescue assays, and
flow cytometry detection to assess growth, apoptosis, proliferation, migration,
and invasion of the prostate cancer cells. We identified and validated up- and
down-stream genes in the TROAP pathway. The mRNA data suggested that TROAP
expression was markedly upregulated in prostate cancer compared with its
expression in normal tissues, especially in cancers with high stages and Gleason
scores. Moreover, a high TROAP expression was associated with poor patient
survival. Results of our in vitro assay showed that TROAP knockdown inhibited
DU145 and PC3 cell proliferation and viability via cell apoptosis and S phase
cycle arrest. The Transwell assay showed that TROAP knockdown inhibited cell
migration and invasion, probably through MMP-9 and E-Cadherin modulation.
Overexpression of TWIST partially abrogated the inhibitory effects of TROAP
knockdown on prostate cancer cells. Our integrative mechanism dissection
revealed that TROAP is in a pathway downstream of EZH2 and that it activates the
TWIST/c-Myc pathway to regulate prostate cancer progression. In all, we
identified TROAP as a driver of prostate cancer development and progression,
providing a novel target for prostate cancer treatments.
Copyright © 2021 Jin, Zhou, Chen, Dai, Fu, Yang and Zhu.
DOI: 10.3389/fonc.2020.592239
PMCID: PMC7938320
PMID: 33692939
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35708862 | 1. Mol Biol Rep. 2022 Aug;49(8):7899-7909. doi: 10.1007/s11033-022-07622-8. Epub
2022 Jun 16.
Trophinin-associated protein expression correlates with shorter survival of
patients with glioma: a study based on multiple data fusion analysis.
Sun Y(#)(1), Liu ZD(#)(2), Liu RZ(#)(2), Lian XY(#)(2), Cheng XB(2), Jia YL(3),
Liu BF(2), Gao YZ(4), Wang X(5).
Author information:
(1)Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou
University, Zhengzhou, Henan, China.
(2)Department of Surgery of Spine and Spinal Cord, People's Hospital of
Zhengzhou University, Henan Provincial People's Hospital; People's Hospital of
Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan,
China.
(3)Department of Neurosurgery, Henan Provincial People's Hospital, People's
Hospital of Henan University, People's Hospital of Zhengzhou University, No. 7,
Weiwu Road, Zhengzhou, 450003, Henan, China.
(4)Department of Surgery of Spine and Spinal Cord, People's Hospital of
Zhengzhou University, Henan Provincial People's Hospital; People's Hospital of
Henan University, No. 7, Weiwu Road, Jinshui District, Zhengzhou, 450003, Henan,
China. yanzhenggaohn@163.com.
(5)Department of Neurosurgery, The Fifth Affiliated Hospital of Zhengzhou
University, Zhengzhou, Henan, China. xinjunwangpaper@163.com.
(#)Contributed equally
BACKGROUND: Trophinin-associated protein (TROAP) mediates embryonic transfer,
regulates microtubules, and is associated with the biological behavior of
various cancers. However, there is limited information on the role of TROAP in
glioma.
METHODS AND RESULTS: We obtained clinical information on 1948 patients with
glioma from The Cancer Genome Atlas, Gene Expression Omnibus and the Chinese
Glioma Genome Atlas. Basal assays were used to measure changes in TROAP
expression levels in high-grade glioma cell lines and in normal human
astrocytes. Quantitative reverse transcription polymerase chain reaction assays
showed that TROAP expression was higher in glioma cell lines than in normal
astrocytes. The expression level of TROAP in 749 glioma was significantly higher
than that in 228 normal brain tissues using Student's t test. The expression of
TROAP has a positive relationship with the clinical characteristics of poor
prognosis, such as WHO grade, age and has negatively correlated with the
indicators of beneficial prognosis, such as IDH mutation and 1p19q co-deletion.
Kaplan-Meier survival curves, single multifactor analysis were used to analyze
correlations between TROAP and clinical features and prognosis of gliomas. In
addition, TROAP overexpression was an independent risk factor for glioma and was
associated with reduced overall survival of patients with glioma particularly in
patients with WHO grade III and grade IV glioma. Gene set enrichment analysis
showed that homologous recombination, cell cycle, and p53 signaling pathways
were enriched in samples overexpressing TROAP.
CONCLUSION: TROAP is a potential risk factor associated with poor prognosis in
patients with glioma and may act as a highly specific biomarker, offering the
possibility of individualized glioma treatment.
© 2022. The Author(s), under exclusive licence to Springer Nature B.V.
DOI: 10.1007/s11033-022-07622-8
PMID: 35708862 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34287099 | 1. Cell Cycle. 2021 Aug;20(16):1578-1588. doi: 10.1080/15384101.2021.1953767.
Epub 2021 Jul 21.
MiR-532-3p suppresses cell viability, migration and invasion of clear cell renal
cell carcinoma through targeting TROAP.
Gao B(1), Wang L(1), Zhang Y(1), Zhang N(1), Han M(1), Liu H(1), Sun D(1), Liu
Y(1).
Author information:
(1)Department of Urology, Tangshan Central Hospital, Tangshan, Hebei, P.R.
China.
Clear cell renal cell carcinoma (ccRCC) is a subtype of renal cell cancer with
the highest mortality, infiltration, and metastasis rate, threatening human
health. Despite oncogenic role of TROAP in various cancers, its function in
ccRCC remains to be unraveled. The differentially expressed mRNAs (DEmRNAs) and
miRNAs (DEmiRNAs) were obtained by analyzing the related data sets of ccRCC in
TCGA. The expression levels of mRNAs and miRNAs in the cell were detected by
qRT-PCR, while the protein levels were characterized by western blot. The
viability, migratory and invasive abilities of ccRCC cells were determined by
MTT, wound healing and cell invasion assays. The combination of miRNA target
site prediction and dual-luciferase reporter gene assay verified the binding
relationship between miR-532-3p and TROAP. Research on ccRCC displayed that
TROAP expression was upregulated, while miR-532-3p was down-regulated. Besides,
upregulation of TROAP could accelerate viability, migratory and invasive
potentials of ccRCC cells. On the contrary, miR-532-3p could downregulate TROAP
level, but TROAP upregulation reversed the viability, migration, and invasion of
ccRCC cells. MiR-532-3p could attenuate the viability, migration and invasion of
ccRCC cells by targeting TROAP. This may generate novel insights into molecular
therapeutic targets for ccRCC.
DOI: 10.1080/15384101.2021.1953767
PMCID: PMC8409774
PMID: 34287099 [Indexed for MEDLINE]
Conflict of interest statement: No potential conflict of interest was reported
by the author(s). |
http://www.ncbi.nlm.nih.gov/pubmed/36394206 | 1. Clin Transl Med. 2022 Nov;12(11):e1113. doi: 10.1002/ctm2.1113.
Alternative splicing of HSPA12A pre-RNA by SRSF11 contributes to metastasis
potential of colorectal cancer.
Pan YJ(1), Huo FC(1), Kang MJ(1), Liu BW(2), Wu MD(1), Pei DS(1).
Author information:
(1)Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University,
Xuzhou, China.
(2)Department of General Surgery, Xuzhou Medical University, Xuzhou, China.
BACKGROUND: Dysregulation of alternative splicing (AS) induced by
serine/arginine-rich proteins has recently been linked to cancer metastasis.
Nonetheless, as a member of the serine/arginine-rich protein family, the
involvement of SRSF11 in colorectal cancer (CRC) is unknown.
METHODS: The TCGA dataset and clinical samples were used to assess SRSF11
expression levels in CRC. For SRSF11, functional experiments were conducted both
in vitro and in vivo. RNA-seq technology was used to analyze and screen
SRSF11-triggered AS events, which were then confirmed by in vivo UV crosslinking
and immunoprecipitation (CLIP) and mini-gene reporter assays. Jalview software
was used to determine the preferential binding motif with relation to exon
skipping (ES) events. Furthermore, coimmunoprecipitation (Co-IP) and Phospho-tag
SDS-PAGE experiments were used to investigate PAK5-mediated phosphorylation
regulation on SRSF11, and in vitro kinase experiments validated the interaction.
RESULTS: In CRC, SRSF11 was discovered to be overexpressed and associated with a
poor prognosis. And SRSF11 played a pro-metastatic role in vitro and in vivo. By
screening SRSF11-regulated AS events, we identified the binding motif of
SRSF11-triggered splicing-switching of HSPA12A AS, which specifically regulated
HSPA12A AS by directly binding to a motif in exon 2. Mechanistically, the
HSPA12A transcript with exon 2 retention increased N-cadherin expression by
promoting RNA stability. Furthermore, the oncogenic kinase PAK5 phosphorylated
SRSF11 at serine 287, protecting it from ubiquitination degradation.
CONCLUSIONS: SRSF11 exerts pro-metastatic effects in CRC by inhibiting the AS of
HSPA12A pre-RNA. Our findings point to SRSF11-regulated HSPA12A splicing as a
novel relationship between SRSF11-regulated splicing and CRC metastasis and
suggest a PAK5/SRSF11/HSPA12A axis as a potential therapeutic target and
prognostic biomarker in CRC.
© 2022 The Authors. Clinical and Translational Medicine published by John Wiley
& Sons Australia, Ltd on behalf of Shanghai Institute of Clinical
Bioinformatics.
DOI: 10.1002/ctm2.1113
PMCID: PMC9670187
PMID: 36394206 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no potential conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36190128 | 1. mBio. 2022 Oct 26;13(5):e0180422. doi: 10.1128/mbio.01804-22. Epub 2022 Oct 3.
Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor
Lenacapavir.
Bester SM(1), Adu-Ampratwum D(2), Annamalai AS(1), Wei G(1), Briganti L(1),
Murphy BC(1), Haney R(1), Fuchs JR(2), Kvaratskhelia M(1).
Author information:
(1)Division of Infectious Diseases, Anschutz Medical Campus, University of
Colorado School of Medicine, Aurora, Colorado, USA.
(2)Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The
Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.
Lenacapavir (LEN) is a long-acting, highly potent HIV-1 capsid (CA) inhibitor.
The evolution of viral variants under the genetic pressure of LEN identified
Q67H, N74D, and Q67H/N74D CA substitutions as the main resistance associated
mutations (RAMs). Here, we determined high-resolution structures of CA hexamers
containing these RAMs in the absence and presence of LEN. Our findings reveal
that the Q67H change induces a conformational switch, which adversely affects
the inhibitor binding. In the unliganded protein, the His67 side chain adopts
the closed conformation by projecting into the inhibitor binding pocket and
thereby creating steric hindrance with respect to LEN. Upon the inhibitor
binding, the His67 side chain repositions to the open conformation that closely
resembles the Gln67 side chain in the WT protein. We propose that the switch
from the closed conformation to the open conformation, which is needed to
accommodate LEN, accounts for the reduced inhibitor potency with respect to the
Q67H CA variant. The N74D CA change results in the loss of a direct hydrogen
bond and in induced electrostatic repulsions between CA and LEN. The double
Q67H/N74D substitutions exhibited cumulative effects of respective single amino
acid changes. An examination of LEN binding kinetics to CA hexamers revealed
that Q67H and N74D CA changes adversely influenced the inhibitor binding
affinity (KD) by primarily affecting the dissociation rate constant (koff). We
used these structural and mechanistic findings to rationally modify LEN. The
resulting analog exhibited increased potency against the Q67H/N74D viral
variant. Thus, our studies provide a means for the development of
second-generation inhibitors with enhanced barriers to resistance. IMPORTANCE
LEN is an investigational long-acting agent for future HIV-1 treatment regimens.
While ongoing clinical trials have highlighted a largely beneficial profile of
LEN for the treatment of HIV-1 infected people with limited therapy options, one
notable shortcoming is a relatively low barrier of viral resistance to the
inhibitor. Cell culture-based viral breakthrough assays identified N74D, Q67H,
and N74D/Q67H capsid changes as the main resistance associated mutations (RAMs).
N74D and Q67H capsid substitutions have also emerged in clinical trials in some
patients who received subcutaneous LEN. Understanding the structural basis
behind viral resistance to LEN is expected to aid in the rational development of
improved inhibitors with enhanced barriers to resistance. Here, we report high
resolution structures of the main drug resistant capsid variants, which provide
mechanistic insight into the viral resistance to LEN. We used these findings to
develop an improved inhibitor, which exhibited enhanced activity against the
viral Q67H/N74D capsid phenotype compared with that of parental LEN.
DOI: 10.1128/mbio.01804-22
PMCID: PMC9600929
PMID: 36190128 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36202818 | 1. Nat Commun. 2022 Oct 6;13(1):5879. doi: 10.1038/s41467-022-33662-6.
Prion-like low complexity regions enable avid virus-host interactions during
HIV-1 infection.
Wei G(1), Iqbal N(2), Courouble VV(3), Francis AC(4)(5), Singh PK(6)(7), Hudait
A(8), Annamalai AS(1), Bester S(1), Huang SW(1)(9), Shkriabai N(1), Briganti
L(1), Haney R(1), KewalRamani VN(9), Voth GA(8), Engelman AN(6)(7), Melikyan
GB(5), Griffin PR(3), Asturias F(2), Kvaratskhelia M(10).
Author information:
(1)Division of Infectious Diseases, Anschutz Medical Campus, University of
Colorado School of Medicine, Aurora, CO, 80045, USA.
(2)Department of Biochemistry & Molecular Genetics, Anschutz Medical Campus,
University of Colorado School of Medicine, Aurora, CO, 80045, USA.
(3)Department of Molecular Medicine, The Scripps Research Institute, Jupiter,
FL, 33458, USA.
(4)Institute of Molecular Biophysics, Department of Biological Sciences, Florida
State University, Tallahassee, FL, 32306, USA.
(5)Department of Pediatrics, Emory University, Atlanta, GA, 30322, USA.
(6)Department of Cancer Immunology & Virology, Dana-Farber Cancer Institute,
Boston, MA, 02215, USA.
(7)Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
(8)Department of Chemistry, Chicago Center for Theoretical Chemistry, Institute
for Biophysical Dynamics, and James Franck Institute, The University of Chicago,
Chicago, IL, 60637, USA.
(9)Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702,
USA.
(10)Division of Infectious Diseases, Anschutz Medical Campus, University of
Colorado School of Medicine, Aurora, CO, 80045, USA.
mamuka.kvaratskhelia@cuanschutz.edu.
Cellular proteins CPSF6, NUP153 and SEC24C play crucial roles in HIV-1
infection. While weak interactions of short phenylalanine-glycine (FG)
containing peptides with isolated capsid hexamers have been characterized, how
these cellular factors functionally engage with biologically relevant mature
HIV-1 capsid lattices is unknown. Here we show that prion-like low complexity
regions (LCRs) enable avid CPSF6, NUP153 and SEC24C binding to capsid lattices.
Structural studies revealed that multivalent CPSF6 assembly is mediated by
LCR-LCR interactions, which are templated by binding of CPSF6 FG peptides to a
subset of hydrophobic capsid pockets positioned along adjoining hexamers. In
infected cells, avid CPSF6 LCR-mediated binding to HIV-1 cores is essential for
functional virus-host interactions. The investigational drug lenacapavir
accesses unoccupied hydrophobic pockets in the complex to potently impair HIV-1
inside the nucleus without displacing the tightly bound cellular cofactor from
virus cores. These results establish previously undescribed mechanisms of
virus-host interactions and antiviral action.
© 2022. The Author(s).
DOI: 10.1038/s41467-022-33662-6
PMCID: PMC9537594
PMID: 36202818 [Indexed for MEDLINE]
Conflict of interest statement: A.N.E. has received compensation from ViiV
Healthcare Co. for work unrelated to this study. No other authors have potential
competing interests to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/36272024 | 1. Drugs. 2022 Sep;82(14):1499-1504. doi: 10.1007/s40265-022-01786-0.
Lenacapavir: First Approval.
Paik J(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. dru@adis.com.
Erratum in
Drugs. 2023 Jul;83(11):1061. doi: 10.1007/s40265-023-01908-2.
Lenacapavir (Sunlenca®) is a long-acting capsid inhibitor of human
immunodeficiency virus type 1 (HIV-1) being developed by Gilead Sciences Inc. It
is available as an oral tablet and injectable solution, with the latter being a
slow-release formulation to allow bi-annual subcutaneous administration. In
August 2022, lenacapavir received its first approval in the EU for use in
combination with other antiretroviral(s) in adults with multi-drug resistant HIV
infection, for whom it is otherwise not possible to construct a suppressive
anti-viral regimen. This article summarizes the milestones in the development of
lenacapavir leading to this first approval for the treatment of HIV-1 infection.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01786-0
PMCID: PMC10267266
PMID: 36272024 [Indexed for MEDLINE]
Conflict of interest statement: During the peer review process the manufacturer
of the agent under review was offered an opportunity to comment on the article.
Changes resulting from any comments received were made by the authors on the
basis of scientific completeness and accuracy. Julia Paik is a salaried employee
of Adis International Ltd/Springer Nature, and declares no relevant conflicts of
interest. All authors contributed to the review and are responsible for the
article content. |
http://www.ncbi.nlm.nih.gov/pubmed/34871187 | 1. Curr Opin HIV AIDS. 2022 Jan 1;17(1):15-21. doi: 10.1097/COH.0000000000000713.
Lenacapavir: a first-in-class HIV-1 capsid inhibitor.
Dvory-Sobol H(1), Shaik N, Callebaut C, Rhee MS.
Author information:
(1)Gilead Sciences, Foster City, California, USA.
PURPOSE OF REVIEW: This review summarizes available data for lenacapavir, an
investigational first-in-class agent that disrupts functioning of HIV capsid
protein across multiple steps in the viral life cycle.
RECENT FINDINGS: Lenacapavir demonstrated picomolar potency in vitro with no
cross resistance to existing antiretroviral classes and potent antiviral
activity in persons with HIV-1. In persons with HIV-1, there was no preexisting
resistance to lenacapavir regardless of treatment history. Lenacapavir can be
administered orally either daily or weekly and subcutaneously up to every
6 months. In heavily treatment-experienced persons with multidrug-resistant
HIV-1 and in treatment-naive persons with HIV-1, lenacapavir in combination with
other antiretroviral agents led to high rates of virologic suppression and was
well tolerated.
SUMMARY: Ongoing studies are evaluating long-acting dosing of lenacapavir for
treating HIV-1 in combination with other antiretrovirals and preventing HIV-1 as
a single agent.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/COH.0000000000000713
PMID: 34871187 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36166211 | 1. Nefrologia (Engl Ed). 2021 Mar-Apr;41(2):123-136. doi:
10.1016/j.nefroe.2020.11.011. Epub 2021 May 11.
Iron replacement therapy in the management of anaemia in non-dialysis Chronic
kidney disease patients: Perspective of the Spanish Nephrology Society Anaemia
Group.
Cases A(1), Puchades MJ(2), de Sequera P(3), Quiroga B(4), Martin-Rodriguez
L(5), Gorriz JL(6), Portolés J(5); en representación del Grupode Anemia de la
S.E.N..
Author information:
(1)Universitat de Barcelona, IDIBAPS, Spain.
(2)Servicio de Nefrología, Hospital Clínico, INCLIVA, Universidad de Valencia,
Valencia, Spain.
(3)Servicio de Nefrología, Hospital Universitario Infanta Leonor, Madrid, Spain.
(4)Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid,
Servicio de Nefrología, Hospital Clínico, Valencia, INCLIVA, Universidad de
Valencia, Spain.
(5)Servicio de Nefrología, Hospital Universitario Puerta de Hierro Majadahonda,
REDInREN ISCiii 016/009/009 RETYC, Majadahonda, Madrid, Spain.
(6)Servicio de Nefrología, Hospital Clínico, INCLIVA, Universidad de Valencia,
Valencia, Spain. Electronic address: jlgorriz@senefro.org.
This work presents an update on the management of iron deficiency in patients
with chronic kidney disease (CKD), either with or without anaemia. A review is
made of the recommendations of the guidelines for the treatment of iron
deficiency in CKD. It also presents new studies on iron deficiency in patients
with CKD, as well as new findings about iron therapy and its impact on clinical
outcomes. Anaemia is a common complication of CRF, and is associated with a
decrease in the quality of life of the patients, as well as an increase in
morbidity and mortality. Iron deficiency (absolute or functional) is common in
non-dialysis chronic kidney disease patients, and may cause anaemia or a low
response to erythropoiesis-stimulating agents. For this reason, the clinical
guidelines for the treatment of the anaemia in Nephrology indicate the
correction of the deficiency in the presence of anaemia. Iron replacement
therapy is indicated in patients with CKD and anaemia (Hb < 12 g/dl) in
accordance with the guidelines. There is no unanimity in the indication of iron
replacement therapy in patients with Hb > 12 g/dl, regardless of whether they
have an absolute or functional iron deficiency. Intravenous iron replacement
therapy is safe, more efficient and rapid than oral therapy for achieving an
increase haemoglobin lels and reducing the dose of erythropoiesis-stimulating
agents. For the administration of intravenous iron in non-dialysis chronic renal
failure patients a strategy of high doses and low frequency would be preferred
on being more convenient for the patient, preserves better the venous capital,
and is safe and cost-effective. Iron plays an essential role in energy
metabolism and other body functions beyond the synthesis of haemoglobin, for
which the iron deficiency, even in the absence of anaemia, could have harmful
effects in patients with CKD. The correction of the iron deficiency, in the
absence of anaemia is associated with functional improvement in patients with
heart failure, and in muscle function or fatigue in patients without CKD.
Despite the evidence of benefits in the correction of iron deficiency in
patients with CKD, more studies are required to evaluate the impact of the
correction of the iron deficiency in the absence of anaemia on morbidity and
mortality, quality of life and physical capacity, as well as the long-term
effect of oral and intravenous iron replacement therapy in this population.
Copyright © 2020 Sociedad Española de Nefrología. Published by Elsevier España,
S.L.U. All rights reserved.
DOI: 10.1016/j.nefroe.2020.11.011
PMID: 36166211 |
http://www.ncbi.nlm.nih.gov/pubmed/28153964 | 1. Perit Dial Int. 2017 1-2;37(1):6-13. doi: 10.3747/pdi.2016.00193.
Anemia in Peritoneal Dialysis Patients; Iron Repletion, Current and Future
Therapies.
Zeidan A(1), Bhandari S(2).
Author information:
(1)Department of Academic Renal Research, Hull and East Yorkshire Hospital Trust
and Hull York Medical School, Kingston Upon Hull, UK.
(2)Department of Academic Renal Research, Hull and East Yorkshire Hospital Trust
and Hull York Medical School, Kingston Upon Hull, UK sunil.bhandari@hey.nhs.uk.
Iron deficiency, both functional and absolute, is common in patients with
chronic kidney disease (CKD), especially those requiring dialysis. Guidelines
advocate treatment of iron-deficiency anemia in patients with CKD and those on
peritoneal dialysis (PD). Oral iron is often insufficient and slow to improve
hemoglobin concentrations because of high hepcidin levels causing impaired
absorption and mobilization, while intravenous (IV) supplementation replenishes
and maintains iron stores more effectively and is now standard practice (Kidney
Disease Improving Global Outcomes [KDIGO] 2012 guidelines). However, there still
remain concerns about the effects of labile iron and possible increased risk of
infections for this group of patients.To date, the majority of published studies
have focused on hemodialysis (HD) patients; very limited data are available
regarding patients on PD. This review summarizes the rationale for iron therapy,
methods of treatment, potential adverse effects, and long-term concerns in PD
patients. In addition we highlight some interesting potential future therapies
under study.
Copyright © 2017 International Society for Peritoneal Dialysis.
DOI: 10.3747/pdi.2016.00193
PMID: 28153964 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29533917 | 1. Wiad Lek. 2017;70(6 pt 2):1215-1218.
[Iron supplementation in chronic kidney disease].
[Article in Polish]
Graczyk M(1), Dylewska M(1).
Author information:
(1)Katedra i Klinika Nefrologii, Dializoterapii i Chorób Wewnętrznych,
Warszawski Uniwersytet Medyczny, Warszawa, Polska.
Treatment with iron preparations remains one of the main directions in the
treatment of anemia in patients with chronic kidney disease. Intravenous agents,
although effective, may have serious adverse effects, while oral iron
supplementation may be ineffective due to malabsorption and gastrointestinal
side effects. The solution may be modern drugs such as ferric pyrophosphate
added to dialysis fluid or liposomal iron without gastrointestinal adverse
effects.
PMID: 29533917 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33516607 | 1. Nefrologia (Engl Ed). 2021 Mar-Apr;41(2):123-136. doi:
10.1016/j.nefro.2020.11.003. Epub 2021 Jan 28.
Iron replacement therapy in the management of anaemia in non-dialysis chronic
renal failure patients: Perspective of the Spanish Nephrology Society Anaemia
Group.
[Article in English, Spanish]
Cases A(1), Puchades MJ(2), de Sequera P(3), Quiroga B(4), Martin-Rodriguez
L(5), Gorriz JL(6), Portolés J(5); en representación del Grupo de Anemia de la
S.E.N..
Author information:
(1)Universitat de Barcelona, IDIBAPS, España.
(2)Servicio de Nefrología, Hospital Clínico, INCLIVA, Universidad de Valencia,
Valencia, España.
(3)Servicio de Nefrología, Hospital Universitario Infanta Leonor, Madrid,
España.
(4)Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid,
Servicio de Nefrología, Hospital Clínico, Valencia, INCLIVA, Universidad de
Valencia, España.
(5)Servicio de Nefrología, Hospital Universitario Puerta de Hierro Majadahonda,
REDInREN ISCiii 016/009/009 RETYC, Majadahonda, Madrid, España.
(6)Servicio de Nefrología, Hospital Clínico, INCLIVA, Universidad de Valencia,
Valencia, España. Electronic address: jlgorriz@senefro.org.
Comment in
Nefrologia (Engl Ed). 2022 Nov-Dec;42(6):736-737. doi:
10.1016/j.nefroe.2021.04.016.
This work presents an update on the management of iron deficiency in patients
with chronic renal failure (CRF), either with or without anaemia. A review is
made of the recommendations of the guidelines for the treatment of iron
deficiency in CRF. It also presents new studies on iron deficiency in patients
with CRF, as well as new findings about iron deficiency and its impact on
clinical outcomes. Anaemia is a common complication of CRF, and is associated
with a decrease in the quality of life of the patients, as well as an increase
in morbidity and mortality. Iron deficiency (absolute or functional) is common
in non-dialysis chronic renal failure patients, and may cause anaemia or a low
response to erythropoiesis-stimulating agents. For this reason, the clinical
guidelines for the treatment of the anaemia in Nephrology advise the correction
of the deficiency in the presence of anaemia. Iron replacement therapy is
indicated in patients with CRF and anaemia (Hb < 12 g/dL) in accordance with the
guidelines. There is no unanimity in the indication of iron replacement therapy
in patients with Hb>12 g/dL, regardless of whether they have an absolute or
functional iron deficiency. Intravenous iron replacement therapy is safe, more
efficient and rapid than oral therapy for achieving an increase haemoglobin
levels and reducing the dose of erythropoiesis-stimulating agents. For the
administration of intravenous iron in non-dialysis chronic renal failure
patients a strategy of high doses and low frequency would be preferred on being
more convenient for the patient, better conserving of the venous tree, and on
being safe and cost-effective. Iron plays an essential role in energy metabolism
and other body functions beyond the synthesis of haemoglobin synthesis, for
which the iron deficiency, even in the absence of anaemia, could have a harmful
effect in patients with CRF. The correction of the iron deficiency, in the
absence of anaemia is associated with functional improvement in patients with
heart failure, and in muscle function or fatigue in patients without CRF.
Despite the evidence of benefits in the correction of iron deficiency in
patients with CRF, more studies are required to evaluate the impact of the
correction of the iron deficiency in the absence of anaemia on morbidity and
mortality, quality of life and physical capacity, as well as the long-term
effect of oral and intravenous iron replacement therapy in this population.
Copyright © 2020 Sociedad Española de Nefrología. Published by Elsevier España,
S.L.U. All rights reserved.
DOI: 10.1016/j.nefro.2020.11.003
PMID: 33516607 |
http://www.ncbi.nlm.nih.gov/pubmed/30970355 | 1. Acta Haematol. 2019;142(1):44-50. doi: 10.1159/000496492. Epub 2019 Apr 10.
Iron Deficiency Anemia in Chronic Kidney Disease.
Gafter-Gvili A(1)(2)(3), Schechter A(4), Rozen-Zvi B(5)(6).
Author information:
(1)Department of Medicine A, Rabin Medical Center, Beilinson Campus, Petah
Tikva, Israel, anatga2@clalit.org.il.
(2)Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center,
Beilinson Campus, Petah Tikva, Israel, anatga2@clalit.org.il.
(3)Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel,
anatga2@clalit.org.il.
(4)Department of Medicine A, Rabin Medical Center, Beilinson Campus, Petah
Tikva, Israel.
(5)Nephrology and Hypertension Unit, Rabin Medical Center, Petah Tikva, Israel.
(6)Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Iron deficiency anemia is a common complication of chronic kidney disease (CKD).
CKD patients suffer from both absolute and functional iron deficiency. Absolute
iron deficiency is defined by severely reduced or absent iron stores, while
functional iron deficiency is defined by adequate iron stores but insufficient
iron availability for incorporation into erythroid precursors. This is due to
increased levels of hepcidin. Anemia in CKD is associated with an increased risk
of morbidity and mortality. The association between anemia and mortality may be
related to the severity of anemia. All CKD patients should be screened for
anemia during the initial evaluation for CKD. Criteria used to define iron
deficiency are different among CKD compared to normal renal function. Among CKD
patients, absolute iron deficiency is defined when the transferrin saturation
(TSAT) is ≤20% and the serum ferritin concentration is ≤100 ng/mL among
predialysis and peritoneal dialysis patients or ≤200 ng/mL among hemodialysis
patients. Functional iron deficiency, also known as iron-restricted
erythropoiesis, is characterized by TSAT ≤20% and elevated ferritin levels. Iron
supplementation is recommended for all CKD patients with anemia. There is
general agreement according to guidelines that intravenous (i.v.) iron
supplementation is the preferred method for CKD patients on dialysis (CKD stage
5D) and either i.v. or oral iron is recommended for patients with CKD ND (CKD
stages 3-5). In this review we discuss the evidence base for these
recommendations.
© 2019 S. Karger AG, Basel.
DOI: 10.1159/000496492
PMID: 30970355 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36165109 | 1. Nefrologia (Engl Ed). 2021 Jul-Aug;41(4):403-411. doi:
10.1016/j.nefroe.2021.10.007.
Intravenous iron in heart failure and chronic kidney disease.
Carrilho P(1).
Author information:
(1)Hospital Professor Doutor Fernando Fonseca EPE, Amadora, Portugal. Electronic
address: patricia_carrilho@hotmail.com.
Intravenous iron therapy is increasingly being used worldwide to treat anemia in
chronic kidney disease and more recently iron deficiency in heart failure.
Promising results were obtained in randomized clinical trials in the latter,
showing symptomatic and functional capacity improvement with intravenous iron
therapy. Meanwhile, confirmation of clinical benefit in hard-endpoints such as
mortality and hospitalization is expected in large clinical trials that are
already taking place. In chronic kidney disease, concern about iron overload is
being substituted by claims of direct cardiovascular benefit of iron
supplementation, as suggested by preliminary studies in heart failure. We
discuss the pitfalls of present studies and gaps in knowledge, stressing the
known differences between iron metabolism in heart and renal failure. Systemic
and cellular iron handling and the role of hepcidin are reviewed, as well as the
role of iron in atherosclerosis, especially in view of its relevance to patients
undergoing dialysis. We summarize the evidence available concerning iron
overload, availability and toxicity in CKD, that should be taken into account
before embracing aggressive intravenous iron supplementation.
Copyright © 2020 Sociedad Española de Nefrología. Published by Elsevier España,
S.L.U. All rights reserved.
DOI: 10.1016/j.nefroe.2021.10.007
PMID: 36165109 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31477258 | 1. Adv Chronic Kidney Dis. 2019 Jul;26(4):272-291. doi:
10.1053/j.ackd.2019.05.002.
Novel Oral Iron Therapies for Iron Deficiency Anemia in Chronic Kidney Disease.
Pergola PE(1), Fishbane S(2), Ganz T(3).
Author information:
(1)Renal Associates PA, San Antonio, TX. Electronic address:
ppergola@raparesearch.com.
(2)Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY.
(3)David Geffen School of Medicine, UCLA, Los Angeles, CA.
Iron deficiency anemia (IDA) is a frequent complication of chronic kidney
disease (CKD) and is associated with adverse outcomes in these patients.
Patients with CKD and IDA remain largely undertreated. Conventional oral iron
agents are insufficiently effective due to poor absorption and cause
gastrointestinal side effects; thus, novel oral iron preparations are needed.
This article covers current treatment guidelines for patients with anemia and
CKD and clinical trial data for iron-repletion agents currently in use, as well
as for novel oral iron therapies in development. Ferric citrate, a novel oral
iron-repletion agent approved for patients with non-dialysis-dependent CKD and
IDA, demonstrated improvements in hemoglobin levels and iron parameters, with
good tolerability in patients with non-dialysis-dependent CKD. When used as a
phosphate binder, ferric citrate also improves hemoglobin and iron parameters in
dialysis-dependent CKD, but additional trials are needed to evaluate its
efficacy as an iron-repletion agent in this setting. Other novel oral iron
preparations in development for IDA in patients with CKD include ferric maltol,
which is approved in Europe and the United States for IDA in adult patients, and
sucrosomial iron, which has been evaluated in IDA associated with CKD and
several other clinical settings.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1053/j.ackd.2019.05.002
PMID: 31477258 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28403561 | 1. Hemodial Int. 2017 Jun;21 Suppl 1:S78-S82. doi: 10.1111/hdi.12561. Epub 2017
Apr 12.
Iron deficiency anemia in chronic kidney disease: Uncertainties and cautions.
Agarwal R(1).
Author information:
(1)Department of Medicine, Indiana University School of Medicine and Richard L.
Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA.
Anemia in chronic kidney disease is common and iron deficiency is an important
cause. To repair iron-deficiency anemia, replacement of iron is needed. Iron can
be replaced either by the oral route or by the intravenous route. In a
meta-analysis, 5 of the 6 trials were short-term, 1 to 3 months, and compared to
oral iron, the mean increase in hemoglobin with intravenous iron was only 0.31
g/dL. However, one of the studies included in this meta-analysis was 6 months
long and had a mean decline in hemoglobin of 0.52 g/dL associated with
intravenous iron administration. Given the short duration of most of the
clinical trials comparing oral with intravenous administration of iron the
long-term safety of these modes of administration of supplemental iron could not
be assessed. Replacement of iron by the oral route is associated with mostly
minor complications such as black stools, constipation, and abdominal
discomfort. In contrast, intravenous administration of iron may lead to severe
adverse events such as anaphylaxis and, as a more recent randomized trial has
suggested, delayed complications such as infections and cardiovascular disease.
Delayed complications of repeated intravenous iron use are difficult to
recognize at an individual level therefore inpatients who have had recent
cardiovascular events or are infected, intravenous iron should probably be
avoided. Balancing safety and efficacy would require clinical judgment because 1
size may not fit all till we have better data to support the liberal use of
parenteral iron.
© Published 2017. This article is a U.S. Government work and is in the public
domain in the USA.
DOI: 10.1111/hdi.12561
PMID: 28403561 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28412770 | 1. Pediatr Nephrol. 2018 Feb;33(2):227-238. doi: 10.1007/s00467-017-3663-y. Epub
2017 Apr 15.
Anemia in chronic kidney disease.
Atkinson MA(1), Warady BA(2).
Author information:
(1)Division of Pediatric Nephrology, Johns Hopkins University School of
Medicine, 200 N. Wolfe St, Baltimore, MD, 21287, USA. matkins3@jhmi.edu.
(2)Division of Pediatric Nephrology, Children's Mercy Kansas City, Kansas City,
MO, USA.
Anemia is common and associated with adverse outcomes in children with chronic
kidney disease (CKD). Many factors contribute to declining hemoglobin as CKD
progresses, but impaired production of erythropoietin by failing kidneys is a
central cause. Hepcidin-mediated iron restriction also contributes to anemia by
downregulating both intestinal iron absorption and release of stored iron for
erythropoiesis. The core components of anemia management remain
erythropoiesis-stimulating agents (ESA) and iron supplementation, but despite
these therapies, a substantial number of children remain anemic. Although
escalating ESA dose to target higher hemoglobin has been associated with adverse
outcomes in adults, no trials have investigated this association in children,
and maintaining hemoglobin levels in a narrow range with conservative ESA dosing
is challenging. Judicious use of iron supplementation can enhance the response
to ESAs, but the iron storage markers most commonly used in clinical practice
have limitations in distinguishing which patients will benefit most from
additional iron. Several novel anemia therapies, including hypoxia-inducible
factor stabilizers, prolyl hydroxylase inhibitors, and dialysate-delivered iron
supplements, have been developed and may offer options for alternative anemia
management. However, the safety and efficacy of these agents in children with
CKD has yet to be assessed.
DOI: 10.1007/s00467-017-3663-y
PMID: 28412770 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34514189 | 1. Kidney Int Rep. 2021 Jun 5;6(9):2261-2269. doi: 10.1016/j.ekir.2021.05.020.
eCollection 2021 Sep.
Treatment of Iron Deficiency Anemia in CKD and End-Stage Kidney Disease.
Gutiérrez OM(1).
Author information:
(1)Division of Nephrology, Department of Medicine and Department of
Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Iron deficiency is common in individuals with chronic kidney disease and plays a
major role in the development of anemia. Oral and intravenous iron agents are
both available to replete iron in patients with chronic kidney disease diagnosed
with iron deficiency. The choice of which agent to use is most often dictated by
goals of therapy, tolerability, convenience, and response to prior therapy.
Diminished absorption of iron in the gastrointestinal tract and a high incidence
of gastrointestinal adverse effects can reduce the efficacy of oral iron agents,
necessitating the use of i.v. iron formulations to treat iron deficiency anemia,
particularly in patients requiring kidney replacement therapy. Newer oral agents
may help to overcome these limitations and help treat iron deficiency in those
not requiring kidney replacement therapy. Recent studies have provided new
evidence that more aggressive repletion of iron in patients with chronic kidney
disease requiring kidney replacement therapy may provide benefits with respect
to anemia management and hard clinical outcomes such as cardiovascular disease
and survival.
© 2021 International Society of Nephrology. Published by Elsevier Inc.
DOI: 10.1016/j.ekir.2021.05.020
PMCID: PMC8418942
PMID: 34514189 |
http://www.ncbi.nlm.nih.gov/pubmed/27236129 | 1. Semin Nephrol. 2016 Mar;36(2):94-8. doi: 10.1016/j.semnephrol.2016.02.002.
Diagnosis of Iron-Deficiency Anemia in Chronic Kidney Disease.
Bahrainwala J(1), Berns JS(2).
Author information:
(1)Renal, Electrolyte and Hypertension Division, Hospital of the University of
Pennsylvania, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA. Electronic address: jehan.bahrainwala@uphs.upenn.edu.
(2)Renal, Electrolyte and Hypertension Division, Hospital of the University of
Pennsylvania, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA.
Anemia is a common and clinically important consequence of chronic kidney
disease (CKD). It is most commonly a result of decreased erythropoietin
production by the kidneys and/or iron deficiency. Deciding on the appropriate
treatment for anemia associated with CKD with iron replacement and
erythropoietic-stimulating agents requires an ability to accurately diagnose
iron-deficiency anemia. However, the diagnosis of iron-deficiency anemia in CKD
patients is complicated by the relatively poor predictive ability of easily
obtained routine serum iron indices (eg, ferritin and transferrin saturation)
and more invasive gold standard measures of iron deficiency (eg, bone marrow
iron stores) or erythropoietic response to supplemental iron. In this review, we
discuss the diagnostic utility of currently used serum iron indices and emerging
alternative markers of iron stores.
Copyright © 2016 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.semnephrol.2016.02.002
PMID: 27236129 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35058395 | 1. Wiad Lek. 2021;74(12):3230-3233.
NOVEL IRON BIOMARKERS IN CHRONIC KIDNEY DISEASE.
Zapora-Kurel A(1), Malyszko J(2).
Author information:
(1)HYPERTENSION AND INTERNAL MEDICINE, MEDICAL UNIVERSITY OF BIALYSTOK,
BIALYSTOK, POLAND.
(2)NEPHROLOGY, DIALYSIS AND INTERNAL MEDICINE, WARSAW MEDICAL UNIVERSITY,
WARSAW, POLAND.
CKD is one of the fastest growing causes of death in the world and in 2040, it
is estimated that it will be in the top five causes of death. In order to slow
down this process, it is necessary to improve prevention, inhibit development
and treat complications including anemia. Anemia is one of the common
complication of chronic kidney disease (CKD), which is a significant clinical
problem. It is most often the result of decreased renal production of
erythropoietin and / or iron deficiency. Iron deficiency anemia is one of the
most common problems in CKD that increases mortality. In order to successfully
treat anemia in CKD with erythropoiesis-stimulating agentsand (ESA) and iron
substitution, it is necessary to determine iron iron level. The diagnosis of
iron deficiency anemia in patients with CKD is complicated due to the relatively
low predictive ability of routine serum iron markers (e.g., ferritin and
transferrin saturation) and more invasive measurements such as bone marrow iron
stores. In the review novel biomarkers of iron metabolism are discussed such as
hypoxia-inducible factor, erythroferon, growth differentiation factor 15 etc.
with their possible clinical relevance.
PMID: 35058395 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22303745 | 1. Rev Med Suisse. 2012 Jan 11;8(323):70-3.
[Management of renal anemia in patients with chronic kidney disease: the role of
the general practitioner].
[Article in French]
Ruedin P(1), Dickenmann M, Martin PY, Wüthrich RP.
Author information:
(1)patrick.ruedin@bluewin.ch
The prevalence of chronic kidney disease (CKD) is high and diabetic nephropathy
is a leading cause of CKD. One of the most common complications of CKD is
anemia, the frequency and severity of which increase as kidney failure
progresses. Renal anemia is primarily caused by reduced renal erythropoietin
production. It can also be associated with iron deficiency caused by reduced
iron absorption, occult blood loss and impaired iron mobilization. This work
provides an overview of the management of renal anemia with focus on intravenous
iron therapy, which is more effective than oral iron administration in CKD due
to reduced iron absorption.
PMID: 22303745 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18824288 | 1. Am J Kidney Dis. 2008 Nov;52(5):907-15. doi: 10.1053/j.ajkd.2008.08.001. Epub
2008 Sep 27.
Safety of ferumoxytol in patients with anemia and CKD.
Singh A(1), Patel T, Hertel J, Bernardo M, Kausz A, Brenner L.
Author information:
(1)Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Comment in
Am J Kidney Dis. 2008 Nov;52(5):826-9. doi: 10.1053/j.ajkd.2008.09.006.
BACKGROUND: Iron deficiency anemia is a common complication in patients with
chronic kidney disease (CKD). Currently available intravenous (IV) iron
replacement therapies have either inconvenient regimens of administration or
adverse event profiles that limit their utility in the outpatient setting.
Ferumoxytol is a novel, semisynthetic, carbohydrate-coated, superparamagnetic
iron oxide nanoparticle that is administered IV as an injection. The main
objective of this study was to assess the safety of ferumoxytol for the
treatment of patients with CKD stages 1 to 5 and 5D.
STUDY DESIGN: Phase 3, randomized, double-blind, placebo-controlled, crossover,
multicenter study of a single 510-mg dose of ferumoxytol versus saline as
placebo.
SETTING & PARTICIPANTS: 750 patients with CKD stages 1 to 5 and 5D.
INTERVENTION: An IV injection of either 17 mL of ferumoxytol or saline placebo
over 17 seconds on day 0 and the alternate agent on day 7.
OUTCOMES & MEASUREMENTS: Descriptive comparison of adverse events, laboratory
tests, and vital signs.
RESULTS: Of 750 randomly assigned patients with CKD, 60% were not on dialysis
therapy. 713 patients received ferumoxytol, and 711 received placebo. There were
420 adverse events reported; 242 in 152 patients (21.3%) with ferumoxytol and
178 in 119 patients (16.7%) with placebo. The incidence of related adverse
events was 5.2% with ferumoxytol and 4.5% with placebo. The most common related
adverse events after each treatment included symptoms related to the
injection/infusion site, dizziness, pruritus, headache, fatigue, and nausea.
Serious adverse events occurred in 21 patients (2.9%) after ferumoxytol and 13
patients (1.8%) after placebo. Serious related adverse events were observed in 1
patient (0.1%) after each treatment. There was no meaningful decrease in blood
pressure after administration of ferumoxytol or placebo.
LIMITATIONS: Follow-up was 7 days after each study treatment.
CONCLUSIONS: Ferumoxytol is well tolerated and has a safety profile similar to
placebo in anemic patients with CKD stages 1 to 5 and 5D.
DOI: 10.1053/j.ajkd.2008.08.001
PMID: 18824288 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20126670 | 1. Drugs Today (Barc). 2009 Nov;45(11):779-86. doi:
10.1358/dot.2009.45.11.1420459.
Ferumoxytol for the treatment of anemia in chronic kidney disease.
Rosner MH(1), Bolton WK.
Author information:
(1)Division of Nephrology, Department of Medicine, University of Virginia Health
System, Charlottesville, Virginia, USA.
Iron deficiency anemia is a common occurrence in patients with chronic kidney
disease and many patients do not respond well to supplementation with oral iron.
There are now five intravenous iron preparations available for use in the
chronic kidney disease patient, with ferumoxytol being the most recently
approved agent. As opposed to previously available intravenous irons,
ferumoxytol has the advantage of not needing a test dose, allowing a large dose
of iron (510 mg) to be given in a short period of time by bolus injection, and
no reported cases of anaphylaxis. Ferumoxytol has advantages for use in the
outpatient setting to treat iron deficiency, in patients with chronic kidney
disease not yet on dialysis and in patients on peritoneal dialysis. The use of
ferumoxytol in the hemodialysis population where thrice weekly intravenous
access is the norm is less clear. Cost-effectiveness studies and post-approval
studies on ferumoxytol as well as changes in the cost structure of dialysis
reimbursement will likely have a large impact on the use of this new agent.
Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.
DOI: 10.1358/dot.2009.45.11.1420459
PMID: 20126670 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21684231 | 1. Nephrol Ther. 2012 Feb;8(1):41-6. doi: 10.1016/j.nephro.2011.04.005. Epub 2011
Jun 17.
[Treatment of iron deficiency in predialysis state by low molecular weight iron
dextran high doses intravenously].
[Article in French]
Fievet P(1), Coppin M, Brazier F, Lefèvre M, Stephan R, Demontis R.
Author information:
(1)Service de néphrologie hémodialyse, centre hospitalier Laennec, boulevard
Laennec, 60100 Creil, France. Patrick.FIEVET@ch-creil.fr
Anemia is a common complication of chronic kidney disease (CKD) in predialysis
stage. Iron deficiency is more common than in normal patients and plays a key
role in the genesis of anemia. Its correction avoids the use of erythropoiesis
stimulating agents (ESA) or reduces their dosage. Treatment with oral iron is
often poorly tolerated and ineffective, necessitating the use of intravenous
iron. New forms of injectable iron allow the use of high doses and correct iron
deficiency in a single administration with consequent preservation of venous
capital and lower costs. We studied the effectiveness of iron dextran of low
molecular weight (LMWID) in high doses to correct iron deficiency and treat
anemia in predialysis CKD patients. Twenty-nine doses of 500 to 1600 mg were
administered to 25 patients followed for CKD (GFR between 60 and 10 ml/min per
1.73 m(2)), selected on biological criteria of iron deficiency defined by a
ratio of transferrin saturation (TSAT) <20% and/or serum ferritin of less than
100 μg/L. Patients received treatment by ESA in 16 cases out of 29. One month
after treatment, hemoglobin (Hb) increased significantly (11.4±1.6 vs 10.4±1.4
g/dL, P=0.0003) along with a significant increase in TSAT (21.3±7.3 vs
13.3±3.8%, P=0.000003) and serum ferritin (286±253 vs 91±60 μg/L, P=0.00005).
Six patients had a serum ferritin greater than 500 μg/L after treatment, which
may put them at risk of iron overload. Their serum ferritin was higher than the
rest of the population before treatment, while the TSAT was no different,
reflecting a functional deficiency. Their hemoglobin did not increase after
treatment in contrast to the rest of the population suggesting the
unavailability of iron for erythropoiesis with accumulation in the
reticuloendothelial system. Renal function did not change significantly and
there were no cases of acute renal failure. No immediate side effect was
observed. Three patients presented delayed reactions to such self-limiting
myalgia and arthralgia. No venous inflammatory reaction was noted. The
administration of high doses of LMWID is effective in treating anemia of CKD in
the predialysis stage with a satisfactory tolerance, without affecting kidney
function and helps preserve the venous capital. It should be reserved for
patients whose serum ferritin is less than or equal to 150 μg/L.
Copyright © 2011 Association Société de néphrologie. Published by Elsevier SAS.
All rights reserved.
DOI: 10.1016/j.nephro.2011.04.005
PMID: 21684231 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17106764 | 1. Int Urol Nephrol. 2006;38(3-4):719-23. doi: 10.1007/s11255-006-0035-0.
Iron deficiency in patients with chronic kidney disease: potential role for
intravenous iron therapy independent of erythropoietin.
Post JB(1), Wilkes BM, Michelis MF.
Author information:
(1)Division of Nephrology, Lenox Hill Hospital, 100 East 77th Street, New York,
NY 10021, USA. james.post@med.va.gov
The prevalence of iron deficiency and its contribution to the anemia of end
stage renal disease has been extensively studied, but much less is known about
the role of iron deficiency in the pathogenesis of the anemia of chronic kidney
disease in predialysis patients. All new hemodialysis patients entering a single
hemodialysis unit between July 1999 and April 2002 were included in the study.
The admission laboratory tests and the Health Care Financing Administration
(HCFA) 2728 form were examined to determine the prevalence of erythropoietin
use, anemia (Hb<11 g/dl), and iron deficiency (ferritin<100 ng/ml and
transferrin saturation %<20%). In a second part of the study, the effect of
intravenous iron gluconate replacement in patients with stage III & IV chronic
kidney disease was examined. Anemia was present in 68% of all patients starting
hemodialysis. Iron deficiency was a common feature occurring in 29% of patients
taking erythropoietin (49% of all patients) and 26% of patients without
erythropoietin (51% of all patients). Following the administration of
intravenous iron gluconate to four patients, there was a significant rise in
hemoglobin levels from 10.6+/-0.19 to 11.7+/-g/dl (p=0.02).
CONCLUSION: Iron deficiency is common in predialysis patients. Replenishing iron
stores in anemic patients with chronic kidney disease significantly increases
hemoglobin levels and should be considered as an integral part of the therapy
for treating anemia in the predialysis population.
DOI: 10.1007/s11255-006-0035-0
PMID: 17106764 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29481308 | 1. FASEB J. 2018 Jul;32(7):3752-3764. doi: 10.1096/fj.201700667R. Epub 2018 Feb
26.
Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal
anemia.
Agoro R(1), Montagna A(1), Goetz R(2), Aligbe O(1), Singh G(1), Coe LM(1),
Mohammadi M(2), Rivella S(3), Sitara D(1)(4).
Author information:
(1)Department of Basic Science and Craniofacial Biology, New York University
College of Dentistry, New York, New York, USA.
(2)Department of Biochemistry and Molecular Pharmacology, New York University
School of Medicine, New York, New York, USA.
(3)Division of Hematology, Children's Hospital of Philadelphia, Philadelphia,
Pennsylvania, USA; and.
(4)Department of Medicine, New York University School of Medicine, New York, New
York, USA.
Severe anemia and iron deficiency are common complications in chronic kidney
disease. The cause of renal anemia is multifactorial and includes decreased
erythropoietin (Epo) production, iron deficiency, and inflammation, and it is
currently treated with injections of synthetic Epo. However, the use of
recombinant Epo has several adverse effects. We previously reported that high
fibroblast growth factor 23 (FGF23) levels in mice are associated with decreased
red blood cell production, whereas genetic inactivation of Fgf23 results in
expansion of the erythroid lineage. The present study is the first to show that
high FGF23 levels in a mouse model of renal failure contribute to renal anemia,
and inhibiting FGF23 signaling stimulates erythropoiesis and abolishes anemia
and iron deficiency. Moreover, we show that inhibition of FGF23 signaling
significantly decreases erythroid cell apoptosis and influences the commitment
of hematopoietic stem cells toward the erythroid linage. Furthermore, we show
that blocking FGF23 signaling attenuates inflammation, resulting in increased
serum iron and ferritin levels. Our data clearly demonstrate that elevated FGF23
is a causative factor in the development of renal anemia and iron deficiency,
and importantly, blocking FGF23 signaling represents a novel approach to
stimulate erythropoiesis and possibly improve survival for millions of chronic
kidney disease patients worldwide.-Agoro, R., Montagna, A., Goetz, R., Aligbe,
O., Singh, G., Coe, L. M., Mohammadi, M., Rivella, S., Sitara, D. Inhibition of
fibroblast growth factor 23 (FGF23) signaling rescues renal anemia.
DOI: 10.1096/fj.201700667R
PMCID: PMC5998980
PMID: 29481308 [Indexed for MEDLINE]
Conflict of interest statement: The authors thank M. N. T. Wada (University of
Sao Paulo, Sao Paulo, Brazil and New York University School of Dentistry, New
York, USA) and R. C. Bernstein (New York University College of Dentistry) for
technical assistance. The authors are grateful to W. R. Abrams (New York
University College of Dentistry) for invaluable assistance with the technical
visualization of the data, and M. Gregory and P. Lopez (New York University
School of Medicine) for assistance with flow cytometry and flow data analyses.
This work was supported in part by funds from the American Heart Association
(12SDG12080152) and the U.S. Department of Defense (W81XWH-16-1-0598; to D.S.),
and the U.S. National Institutes of Health, National Institute of Dental and
Craniofacial Research (DE 13686; to M.M.). The authors declare no conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/20630409 | 1. Heart Fail Clin. 2010 Jul;6(3):347-57. doi: 10.1016/j.hfc.2010.02.001.
Anemia in chronic kidney disease: new advances.
Patel TV(1), Singh AK.
Author information:
(1)Renal Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA
02115, USA.
Anemia resulting from iron and erythropoietin deficiencies is a common
complication of advanced chronic kidney disease (CKD). This article covers major
advances in our understanding of anemia in patients with CKD, including newly
discovered regulatory molecules, such as hepcidin, to innovative intravenous
iron therapies. The use of erythropoiesis-stimulating agents (ESA) in the
treatment of anemia has undergone seismic shift in the past 3 years as a result
of adverse outcomes associated with targeting higher hemoglobin levels with
these agents. Potential mechanisms for adverse outcomes, such as higher
mortality, are discussed. Despite the disappointing experience with ESAs, there
is a tremendous interest in other novel agents to treat anemia in CKD. Lastly,
while awaiting updated guidelines, the authors outline their recommendations on
how to best manage patients who are anemic and have CKD.
Copyright 2010. Published by Elsevier Inc.
DOI: 10.1016/j.hfc.2010.02.001
PMID: 20630409 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29336855 | 1. Am J Kidney Dis. 2018 Mar;71(3):423-435. doi: 10.1053/j.ajkd.2017.09.026. Epub
2018 Jan 11.
Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018.
Fishbane S(1), Spinowitz B(2).
Author information:
(1)Division of Nephrology, Department of Medicine, Hofstra Northwell School of
Medicine, Great Neck, NY. Electronic address: sfishbane@northwell.edu.
(2)Division of Nephrology, New York-Presbyterian/Queens, Flushing, NY.
Anemia is a frequent complication during the later stages of chronic kidney
disease. When present, it may cause symptoms such as fatigue and shortness of
breath. The pathogenesis of anemia in chronic kidney disease is complex, but a
central feature is a relative deficit of erythropoietin. New information has
elucidated the critical role of the hypoxia-sensing system in mediating
erythropoietin synthesis and release. Iron deficiency is a second important
factor in the anemia of chronic kidney disease. New insights into the dynamics
of iron metabolism have clarified the role of chronic inflammation and hepcidin
as key mediators of impaired iron utilization. In this article, we review the
epidemiology, pathobiology, clinical evaluation, and treatment of anemia in
chronic kidney disease.
Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1053/j.ajkd.2017.09.026
PMID: 29336855 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28372549 | 1. BMC Nephrol. 2017 Apr 3;18(1):117. doi: 10.1186/s12882-017-0523-8.
The Ferumoxytol for Anemia of CKD Trial (FACT)-a randomized controlled trial of
repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis:
background and rationale.
Macdougall IC(1), Dahl NV(2), Bernard K(2), Li Z(2), Batycky A(2), Strauss
WE(3).
Author information:
(1)Department of Renal Medicine, King's College Hospital, Denmark Hill, London,
UK.
(2)AMAG Pharmaceuticals, Inc., 1100 Winter Street, Waltham, MA, 02451, USA.
(3)AMAG Pharmaceuticals, Inc., 1100 Winter Street, Waltham, MA, 02451, USA.
wstrauss@amagpharma.com.
Erratum in
BMC Nephrol. 2018 Apr 26;19(1):97. doi: 10.1186/s12882-018-0899-0.
BACKGROUND: Iron deficiency anemia (IDA) is a common manifestation of chronic
kidney disease (CKD), affecting most patients on hemodialysis and imposing a
substantial clinical burden. Treatment with iron supplementation increases
hemoglobin levels and can reduce the severity of anemia in patients with CKD.
While correcting anemia in these patients is an important therapeutic goal,
there is a lack of long-term trials directly comparing intravenous iron
therapies in patients with CKD receiving hemodialysis.
METHODS/DESIGN: The Ferumoxytol for Anemia of CKD Trial (FACT) is a 13-month,
open-label, randomized, multicenter, international, prospective study with 2
substudies. Entry criteria for the main study include adults with IDA (defined
as hemoglobin <11.5 g/dL [<115.0 g/L] and a transferrin saturation <30%), serum
ferritin <800 ng/mL (<1798 pmol/L), and receiving hemodialysis for ≥3 months.
Patients are randomized to receive ferumoxytol (1.02 g over 2 doses) or iron
sucrose (1.0 g over 10 doses) during the initial 5-week treatment period. Those
with persistent/recurrent IDA over the 11-month observation period will receive
additional 5-week treatment periods, as appropriate. The primary efficacy
endpoint of the main study is the mean change in hemoglobin from Baseline to
Week 5 for each treatment period. The secondary efficacy endpoints include the
mean change in transferrin saturation from Baseline to Week 5 and the proportion
of patients with a hemoglobin increase of ≥1.0 g/dL at any time from Baseline to
Week 5. Safety will be assessed through an examination of the adverse event
profile over the course of the study. An "oxidative stress" substudy in
approximately 100 patients will assess the effects of treatment on biomarkers of
oxidative stress/inflammation during the initial 5-week treatment period, and a
magnetic resonance imaging substudy in approximately 70 patients will assess the
potential for iron deposition in target tissues over 24 months.
DISCUSSION: FACT fulfills the need for a long-term comparative trial in patients
with IDA and CKD receiving hemodialysis. The efficacy and safety results will
provide useful information for guiding therapy in this population. Two hundred
ninety-six patients have been enrolled, and completion of the main study is
expected soon.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01227616 (registered
October 22, 2010); EudraCT number: 2010-022133-28.
DOI: 10.1186/s12882-017-0523-8
PMCID: PMC5379516
PMID: 28372549 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19776721 | 1. Kidney Int. 2009 Dec;76(11):1137-41. doi: 10.1038/ki.2009.357. Epub 2009 Sep
23.
Iron-refractory iron deficiency anemia: new molecular mechanisms.
Cui Y(1), Wu Q, Zhou Y.
Author information:
(1)Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First
Affiliated Hospital, Soochow University, Suzhou, China.
Iron deficiency anemia is a common complication in end-stage renal disease
(ESRD) and impairs the therapeutic efficacy of recombinant erythropoietin. Oral
or parental iron supplements usually are effective in treating iron deficiency
anemia. Some patients, however, respond poorly to iron supplements and are
diagnosed as having iron-refractory iron deficiency anemia. The condition
exacerbates ESRD but its underlying mechanism was unclear. Hepcidin is a central
player in iron homeostasis. It downregulates the iron exporter ferroportin,
thereby inhibiting iron absorption, release, and recycling. In ESRD, plasma
hepcidin levels are elevated, which contributes to iron deficiency in patients.
Matriptase-2, a liver transmembrane serine protease, has been found to have a
major role in controlling hepcidin gene expression. In mice, defects in the
Tmprss6 gene encoding matriptase-2 result in high hepcidin expression and cause
severe microcytic anemia. Similarly, mutations in the human TMPRSS6 gene have
been identified in patients with iron-refractory iron deficiency. Thus,
matriptase-2 is critical for iron homeostasis and may have an important role in
ESRD.
DOI: 10.1038/ki.2009.357
PMCID: PMC2869468
PMID: 19776721 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25468387 | 1. Am J Kidney Dis. 2015 May;65(5):728-36. doi: 10.1053/j.ajkd.2014.10.014. Epub
2014 Nov 4.
A 12-week, double-blind, placebo-controlled trial of ferric citrate for the
treatment of iron deficiency anemia and reduction of serum phosphate in patients
with CKD Stages 3-5.
Block GA(1), Fishbane S(2), Rodriguez M(3), Smits G(4), Shemesh S(5), Pergola
PE(6), Wolf M(7), Chertow GM(8).
Author information:
(1)Denver Nephrologists PC, Denver, CO. Electronic address:
gablock@dnresearch.org.
(2)Hofstra-North Shore LIJ School of Medicine, Great Neck, NY.
(3)Nephrology Service, IMIBIC, Hospital Universitario, Cordoba, Spain.
(4)Denver Nephrologists PC, Denver, CO.
(5)Keryx Biopharmaceuticals Inc, New York, NY.
(6)Renal Associates PA, San Antonio, TX.
(7)Department of Medicine, Institute for Public Health and Medicine,
Northwestern University, Feinberg School of Medicine, Chicago, IL.
(8)Stanford University School of Medicine, Palo Alto, CA.
BACKGROUND: Iron deficiency anemia and serum phosphate levels > 4.0mg/dL are
relatively common in chronic kidney disease stages 3 to 5 and are associated
with higher risks of progressive loss of kidney function, cardiovascular events,
and mortality.
STUDY DESIGN: Double-blind, placebo-controlled, randomized trial.
SETTING & PARTICIPANTS: 149 patients with estimated glomerular filtration rates
< 60 mL/min/1.73 m(2), iron deficiency anemia (hemoglobin, 9.0-12.0 g/dL;
transferrin saturation [TSAT]≤ 30%, serum ferritin ≤ 300 ng/mL), and serum
phosphate levels ≥ 4.0 to 6.0mg/dL. Use of intravenous iron or
erythropoiesis-stimulating agents was prohibited.
INTERVENTION: Randomization to treatment for 12 weeks with ferric citrate
coordination complex (ferric citrate) or placebo.
OUTCOMES & MEASUREMENTS: Coprimary end points were change in TSAT and serum
phosphate level from baseline to end of study. Secondary outcomes included
change from baseline to end of treatment in values for ferritin, hemoglobin,
intact fibroblast growth factor 23 (FGF-23), urinary phosphate excretion, and
estimated glomerular filtration rate.
RESULTS: Ferric citrate treatment increased mean TSAT from 22% ± 7% (SD) to 32%
± 14% and reduced serum phosphate levels from 4.5 ± 0.6 to 3.9 ± 0.6 mg/dL,
while placebo exerted no effect on TSAT (21% ± 8% to 20% ± 8%) and less effect
on serum phosphate level (4.7 ± 0.6 to 4.4 ± 0.8 mg/dL; between-group P<0.001
for each). Ferric citrate increased hemoglobin levels (from 10.5 ± 0.8 to 11.0 ±
1.0 g/dL; P<0.001 vs placebo), reduced urinary phosphate excretion 39% (P<0.001
vs placebo), and reduced serum intact FGF-23 levels from a median of 159 (IQR,
102-289) to 105 (IQR, 65-187) pg/mL (P=0.02 vs placebo). The incidence and
severity of adverse effects were similar between treatment arms.
LIMITATIONS: The study is limited by relatively small sample size and short
duration and by having biochemical rather than clinical outcomes.
CONCLUSIONS: Short-term use of ferric citrate repletes iron stores, increases
hemoglobin levels, and reduces levels of serum phosphate, urinary phosphate
excretion, and FGF-23 in patients with chronic kidney disease stages 3 to 5.
Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All
rights reserved.
DOI: 10.1053/j.ajkd.2014.10.014
PMID: 25468387 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32556307 | 1. Blood. 2020 Aug 13;136(7):783-789. doi: 10.1182/blood.2019004330.
How I treat renal anemia.
Fishbane S(1), Coyne DW(2).
Author information:
(1)Department of Medicine, Donald and Barbara Zucker School of Medicine at
Hofstra/Northwell, Great Neck, NY; and.
(2)Division of Nephrology, School of Medicine, Washington University, St. Louis,
MO.
Anemia is a frequent complication of kidney disease. When severe, it causes
symptoms that can be debilitating. The course of anemia tends to track the
decline in kidney function, with prevalence increasing in more advanced disease.
Although the most common cause is relative erythropoietin deficiency, other
factors such as reduced iron availability contribute to the pathobiology. In
this review, we use cases to explore the surprising complexity of
decision-making in management of renal anemia.
© 2020 by The American Society of Hematology.
DOI: 10.1182/blood.2019004330
PMID: 32556307 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26342303 | 1. Blood Rev. 2016 Jan;30(1):65-72. doi: 10.1016/j.blre.2015.07.006. Epub 2015
Aug 18.
Iron therapy in chronic kidney disease: Recent changes, benefits and risks.
Ribeiro S(1), Belo L(2), Reis F(3), Santos-Silva A(4).
Author information:
(1)Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department
of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy,
University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Electronic address: sandra.ribeiro870@gmail.com.
(2)Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department
of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy,
University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Electronic address: luisbelo@ff.up.pt.
(3)Laboratory of Pharmacology & Experimental Therapeutics, Institute for
Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of
Coimbra, Unidade 1, Polo 3, Azinhaga de Santa Comba, Celas, 3000-548 Coimbra,
Portugal; Center for Neuroscience and Cell Biology, Institute for Biomedical
Imaging and Life Sciences (CNC.IBILI) Research Unit, University of Coimbra, Polo
1, First floor, Rua Larga, 3004-504 Coimbra, Portugal. Electronic address:
freis@fmed.uc.pt.
(4)Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department
of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy,
University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.
Electronic address: assilva@ff.up.pt.
Anemia is a common complication in patients with chronic kidney disease (CKD),
mainly due to inadequate renal production of erythropoietin. In hemodialysis
(HD) patients this condition may be aggravated by iron deficiency (absolute or
functional). The correction of this anemia is usually achieved by treatment with
erythropoiesis stimulating agents (ESAs) and iron (oral or intravenous). Studies
questioning the safety of ESAs (especially at higher doses) changed the pattern
of anemia treatment in CKD patients. According to the new guidelines, when
transferrin saturation is lower than 30% and ferritin lower than 500 ng/mL, a
trial with iron should be started, to avoid therapy with ESAs or at least to
reduce the doses needed to treat the anemia. Recent reports showed increasing
ferritin levels, towards values above 800 ng/mL, in CKD patients treated
according to the guidelines. In this review we focus on the risks of the
increased iron use to treat CKD anemia, namely, iron overload and toxicity,
increased risk of infections, as well as mortality.
DOI: 10.1016/j.blre.2015.07.006
PMID: 26342303 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19833421 | 1. Blood Rev. 2010 Jan;24(1):39-47. doi: 10.1016/j.blre.2009.09.001. Epub 2009
Oct 14.
Anemia in renal disease: diagnosis and management.
Lankhorst CE(1), Wish JB.
Author information:
(1)Division of Nephrology, University Hospitals Case Medical Center, 11100
Euclid Ave, Cleveland, OH 44106, USA. christina.lankhorst@uhhospitals.org
Chronic kidney disease (CKD) is a widespread health problem in the world and
anemia is a common complication. Anemia conveys significant risk for
cardiovascular disease, faster progression of renal failure and decreased
quality of life. Patients with CKD can have anemia for many reasons, including
but not invariably their renal insufficiency. These patients require a thorough
evaluation to identify and correct causes of anemia other than erythropoietin
deficiency. The mainstay of treatment of anemia secondary to CKD has become
erythropoiesis-stimulating agents (ESAs). The use of ESAs does carry risks and
these agents need to be used judiciously. Iron deficiency often co-exists in
this population and must be evaluated and treated. Correction of iron deficiency
can improve anemia and reduce ESA requirements. Partial, but not complete,
correction of anemia is associated with improved outcomes in patients with CKD.
Copyright 2009 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.blre.2009.09.001
PMID: 19833421 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16470356 | 1. Internist (Berl). 2006 Mar;47(3):233-4, 236-8, 240-1. doi:
10.1007/s00108-006-1576-0.
[Renal anemia - an important secondary disease in renal insufficiency].
[Article in German]
Mayer C(1), Achenbach H, Stumvoll M, Fiedler G.
Author information:
(1)Abteilung für Endokrinologie, Diabetologie und Nephrologie, Medizinische
Klinik und Poliklinik III, Universität Leipzig, Leipzig.
christof.mayer@medizin.uni-leipzig.de
Anemia is as a frequent complication in patients with chronic kidney disease,
which gains in importance in the treatment of patients with renal disease. The
main cause of renal anemia is the inadequately low production of endogenous
erythropoietin. Often the patients develop an additional absolute or functional
iron deficiency, which complicates the diagnostic and therapeutic procedures.
Substitution of recombinant human erythropoietin (r-HuEPO) is the most effective
therapy. The goal is a stable haemoglobin level >11 g/dl. An often additional
existing iron deficiency should be balanced adequately according to the
guidelines. With consequent and early treatment morbidity, mortality, and
quality of life can be effectively improved.
DOI: 10.1007/s00108-006-1576-0
PMID: 16470356 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16949463 | 1. Semin Nephrol. 2006 Jul;26(4):261-8. doi: 10.1016/j.semnephrol.2006.06.001.
Pathogenesis of renal anemia.
Nangaku M(1), Eckardt KU.
Author information:
(1)Division of Nephrology and Endocrinology, University of Tokyo School of
Medicine, Tokyo, Japan. mnangaku-tky@umin.ac.jp
Anemia is a common complication of chronic kidney disease. Although mechanisms
involved in the pathogenesis of renal anemia include chronic inflammation, iron
deficiency, and shortened half-life of erythrocytes, the primary cause is
deficiency of erythropoietin (EPO). Serum EPO levels in patients with chronic
kidney disease are usually within the normal range and thus fail to show an
appropriate increase with decreasing hemoglobin levels, as found in nonrenal
anemias. Studies elucidating the regulation of EPO expression led to the
identification of the hypoxia inducible factor-hypoxia responsive element
system. However, despite much progress in understanding the molecular mechanisms
through which cells can sense oxygen availability and translate this information
into altered gene expression, the reason why EPO production is inappropriately
low in diseased kidneys remains incompletely understood. Both alterations in the
function of EPO-producing cells and perturbations of the oxygen-sensing
mechanism in the kidney may contribute. As with other anemias, the consequences
of renal anemia are a moderate decrease in tissue oxygen tensions and
counterregulatory mechanisms that maintain total oxygen consumption, including a
persistent increase in cardiac output.
DOI: 10.1016/j.semnephrol.2006.06.001
PMID: 16949463 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17804903 | 1. Am J Nephrol. 2007;27(6):565-71. doi: 10.1159/000107927. Epub 2007 Sep 5.
Nonhematological benefits of iron.
Agarwal R(1).
Author information:
(1)Division of Nephrology, Department of Medicine, Indiana University School of
Medicine, and Richard L. Roudebush VA Medical Center, Indianapolis, Indiana,
USA. ragarwal@iupui.edu
Iron deficiency anemia is common in people with chronic kidney disease (CKD) and
its importance in supporting erythropoiesis is unquestioned especially in those
patients treated with erythropoietin. Clinical symptomatology such as
fatigability, cold intolerance, failure to concentrate and poor effort
intolerance is often attributed to anemia or uremia. That iron deficiency, per
se, can cause these symptoms is poorly recognized. Clinical and animal studies
that support the benefits of iron supplementation, independent of increasing
hemoglobin, such as those on immune function, physical performance,
thermoregulation, cognition, and restless leg syndrome and aluminum absorption
is the subject of this narrative review.
(c) 2007 S. Karger AG, Basel.
DOI: 10.1159/000107927
PMID: 17804903 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/28682026 | 1. G Ital Nefrol. 2017 Mar;34(Suppl 69):20-35.
[Clinical management of anemia in patients with CKD].
[Article in Italian]
Rivera RF(1), Alibrandi MTS(2), Di Lullo L(3), Fioccari F(4).
Author information:
(1)U.O. Nefrologia e Dialisi, Ospedale San Gerardo, ASST Monza, Italy.
(2)U.O. Nefrologia, Dialisi e Ipertensione, IRCCS Ospedale San Raffaele, Milan,
Italy.
(3)U.O.C Nefrologia e Dialisi, Ospedale L. Parodi Delfino, Colleferro, Rome,
Italy.
(4)U.O.C. Nefrologia e Dialisi, Ospedale S. Paolo, Civitavecchia, Rome, Italy.
Anemia is a frequent complication in chronic kidney disease (CKD), and it is
often accompanied by various clinical symptoms. The primary cause of anemia in
CKD patients is the reduction in the erythropoietin production, which results in
a decrease of signaling molecule that stimulates red blood cell production.
Other possible causes of anemia in CKD include iron deficiency, inflammation,
and the accumulation of uremic toxin. This chapter focuses the discussion on the
strategy of the management of anemia in patients with CKD.
Erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the
primary treatment for anemia in chronic kidney disease. The introduction of ESAs
into clinical practice was a success goal, mediating an increase in hemoglobin
concentrations without the risk for recurrent blood transfusions and improving
quality of life substantially.
Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.
PMID: 28682026 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19325171 | 1. Clin Med Res. 2008 Dec;6(3-4):93-102. doi: 10.3121/cmr.2008.811.
Safety issues with intravenous iron products in the management of anemia in
chronic kidney disease.
Hayat A(1).
Author information:
(1)SUNY Downstate Medical Center, 710 Parkside Avenue, Brooklyn, NY 11226, USA.
amirhayat6@hotmail.com
Anemia is a very common clinical problem in patients with chronic kidney disease
(CKD) and is associated with increased morbidity and mortality in these
patients. Erythropoietin is a hormone synthesized that is deficient in the
majority of patients with advanced kidney disease, thereby predisposing these
patients to anemia. The other cause of anemia is deficiency of iron. Iron
deficiency anemia is common in people with CKD and its importance in supporting
erythropoiesis is unquestioned, especially in those patients treated with
erythropoietin. Intravenous iron is frequently used to treat anemia in CKD
patients and is very efficacious in increasing hemoglobin but at the same time
there are some safety issues associated with it. The objective of this review is
to assess the frequency of adverse drug events associated with four different
iron formulations: two iron dextran products known as high and low molecular
weight iron dextran, iron sucrose, and sodium ferric gluconate complex. Several
electronic databases were searched. In general, with the exception of high
molecular weight iron dextran, serious or life-threatening adverse events
appeared rare. Iron sucrose has the least reported adverse events and high
molecular weight iron dextran has the highest number of reported adverse events.
Low molecular weight iron dextran and ferric gluconate fall in between these two
for number of adverse drug events.
DOI: 10.3121/cmr.2008.811
PMCID: PMC2670525
PMID: 19325171 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17533016 | 1. Am J Kidney Dis. 2007 Jun;49(6):736-43. doi: 10.1053/j.ajkd.2007.03.007.
Iron management in nondialysis-dependent CKD.
Fishbane S(1).
Author information:
(1)SUNY at Stony Brook School of Medicine, USA. sfishbane@metrorenal.com
Iron deficiency has been studied extensively in patients with chronic kidney
disease on hemodialysis therapy. However, few studies looked at iron treatment
in the nondialysis chronic kidney disease population. Limited data suggest that
iron deficiency is common in patients with chronic kidney disease with anemia;
this lack of iron can hinder the effectiveness of erythropoiesis. The diagnosis
of iron deficiency should involve clinical judgment, with an emphasis on
clinical characteristics of the patient because of the limited amount of
literature examining the interpretation of iron testing results. When iron
deficiency is diagnosed in nondialysis patients with chronic kidney disease, a
search must be initiated for any sources of blood loss. After addressing any
blood loss, the preferred route of iron treatment must be determined. To date,
no clear advantage was shown with intravenous versus oral administration in
nondialysis patients, as shown in the hemodialysis setting. Thus, oral iron
therapy may be a more reasonable option unless oral therapy previously failed.
Additional research is needed to support evidence-based guidelines for the
treatment of iron deficiency in the nondialysis chronic kidney disease
population because this population differs from hemodialysis patients in the
decreased extent of blood loss.
DOI: 10.1053/j.ajkd.2007.03.007
PMID: 17533016 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22935483 | 1. J Am Soc Nephrol. 2012 Oct;23(10):1631-4. doi: 10.1681/ASN.2011111078. Epub
2012 Aug 30.
Mechanisms of anemia in CKD.
Babitt JL(1), Lin HY.
Author information:
(1)Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
babitt.jodie@mgh.harvard.edu
Anemia is a common feature of CKD associated with poor outcomes. The current
management of patients with anemia in CKD is controversial, with recent clinical
trials demonstrating increased morbidity and mortality related to erythropoiesis
stimulating agents. Here, we examine recent insights into the molecular
mechanisms underlying anemia of CKD. These insights hold promise for the
development of new diagnostic tests and therapies that directly target the
pathophysiologic processes underlying this form of anemia.
DOI: 10.1681/ASN.2011111078
PMCID: PMC3458456
PMID: 22935483 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23608591 | 1. Heart Rhythm. 2013 Aug;10(8):1220-8. doi: 10.1016/j.hrthm.2013.04.014. Epub
2013 Apr 19.
Modulation of KCNQ1 alternative splicing regulates cardiac IKs and action
potential repolarization.
Lee HC(1), Rudy Y, Po-Yuan P, Sheu SH, Chang JG, Cui J.
Author information:
(1)Department of Biomedical Engineering, Cardiac Bioelectricity and Arrhythmia
Center, Washington University in St. Louis, St Louis, Missouri 63130-4899, USA.
Comment in
Heart Rhythm. 2013 Aug;10(8):1229-30. doi: 10.1016/j.hrthm.2013.06.017.
Heart Rhythm. 2013 Nov;10(11):e82-3. doi: 10.1016/j.hrthm.2013.09.056.
Heart Rhythm. 2013 Nov;10(11):e83. doi: 10.1016/j.hrthm.2013.09.055.
BACKGROUND: Slow delayed-rectifier potassium current (IKs) channels, made of the
pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining
action potential duration (APD) in cardiac myocytes. The consequences of
drug-induced KCNQ1 splice alteration remain unknown.
OBJECTIVE: To study the modulation of KCNQ1 alternative splicing by amiloride
and the consequent changes in IKs and action potentials (APs) in ventricular
myocytes.
METHODS: Canine endocardial, midmyocardial, and epicardial ventricular myocytes
were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing
factors were quantified by using the reverse transcriptase-polymerase chain
reaction and Western blot. The effect of amiloride-induced changes in the
KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch clamp with
and without isoproterenol.
RESULTS: With 50 μmol/L of amiloride for 6 hours, KCNQ1a at transcriptional and
translational levels increased in midmyocardial myocytes but decreased in endo-
and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial
were opposite to that in endo- and epicardial myocytes. In midmyocardial
myocytes amiloride shortened APD and decreased isoproterenol-induced early
afterdepolarizations significantly. The same amiloride-induced effects were
demonstrated by using human ventricular myocyte model for AP simulations under
beta-adrenergic stimulation. Moreover, amiloride reduced the transmural
dispersion of repolarization in pseudo-electrocardiogram.
CONCLUSIONS: Amiloride regulates IKs and APs with transmural differences and
reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested
that the modulation of KCNQ1 splicing may help prevent arrhythmia.
Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights
reserved.
DOI: 10.1016/j.hrthm.2013.04.014
PMCID: PMC3771516
PMID: 23608591 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICTS OF INTEREST: none |
http://www.ncbi.nlm.nih.gov/pubmed/35268286 | 1. J Clin Med. 2022 Feb 23;11(5):1200. doi: 10.3390/jcm11051200.
Catamenial Pneumothorax as the First Expression of Thoracic Endometriosis
Syndrome and Pelvic Endometriosis.
Ciriaco P(1), Muriana P(1), Carretta A(1), Ottolina J(2), Candiani M(2), Negri
G(1).
Author information:
(1)Department of Thoracic Surgery, Scientific Institute and University
Vita-Salute San Raffaele, Hospital San Raffaele Milano, 20132 Milan, Italy.
(2)Department of Obstetrics and Gynecology, Scientific Institute and University
Vita-Salute San Raffaele, Hospital San Raffaele Milano, 20132 Milan, Italy.
OBJECTIVE: The menstrual-related catamenial pneumothorax (CP) can be the first
expression of thoracic endometriosis syndrome (TES), which is the presence of
endometriotic lesions in the lungs and pleura, and pelvic endometriosis (PE).
This study aims to analyze our experience with this specific correlation
describing our multidisciplinary approach to CP.
METHODS: Hospital records of 32 women, operated for CP at our Department from
January 2001 to December 2021 were reviewed. Surgical treatment consisted of
videothoracoscopy and laparoscopy when indicated.
RESULTS: TES and PE were diagnosed in 13 (40.6%) and 12 (37.5%) women,
respectively. The association of TES and PE was present in 11 cases (34%).
Fifteen patients (46.9%) underwent laparoscopy, of which 11 concurrently with
videothoracoscopy. Most of the patients affected had stage III-IV endometriosis
(40.6%). All patients received hormonal therapy after surgery. Five patients
with PE conceived spontaneously resulting in six live births. The mean follow-up
was 117 ± 71 months (range 8-244). Pneumothorax recurrence occurred in six
patients (18.8%). At present, all women are asymptomatic, with no sign of
pneumothorax recurrence.
CONCLUSIONS: CP might be the first expression of TES and/or PE. A
multidisciplinary approach is advocated for optimal management of the disease.
DOI: 10.3390/jcm11051200
PMCID: PMC8911039
PMID: 35268286
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35286587 | 1. Gen Thorac Cardiovasc Surg. 2022 Sep;70(9):818-824. doi:
10.1007/s11748-022-01802-w. Epub 2022 Mar 14.
The importance of diaphragmatic surgery, chemical pleurodesis and postoperative
hormonal therapy in preventing recurrence in catamenial pneumothorax: a
retrospective cohort study.
Campisi A(#)(1)(2), Ciarrocchi AP(#)(3), Grani G(3), Sanna S(3), Congiu S(3),
Mazzarra S(3), Argnani D(3), Salvi M(3), Stella F(3).
Author information:
(1)Thoracic Surgery Unit, Department of Thoracic Diseases, University of
Bologna, G.B. Morgagni-L. Pierantoni Hospital, 34 Carlo Forlanini Street, 47121,
Forlì, Italy. alessio.campisi88@hotmail.com.
(2)Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong
University, 241 Huai Hai Road, Shanghai, 200030, China.
alessio.campisi88@hotmail.com.
(3)Thoracic Surgery Unit, Department of Thoracic Diseases, University of
Bologna, G.B. Morgagni-L. Pierantoni Hospital, 34 Carlo Forlanini Street, 47121,
Forlì, Italy.
(#)Contributed equally
BACKGROUND: Catamenial pneumothorax (CP) is defined as a recurrent, spontaneous
pneumothorax occurring within a day before or 72 h after the onset of
menstruation. Most first episodes go undiagnosed and treated as primary
spontaneous pneumothorax, and only after recurrence is the clinical suspicion of
CP raised. No gold-standard management approach exists, especially in terms of
managing diaphragmatic involvement.
METHODS: This study is a single-centre cohort retrospective study of 24 female
patients who underwent surgery for pneumothorax due to diaphragmatic
endometriosis between January 2008 and December 2016. Two groups were compared:
a group that underwent pleurodesis alone (8 patients) and a group that underwent
diaphragmatic surgery and pleurodesis (16 patients).
RESULTS: There were differences in BMI and smoking habits between the two
groups. The right diaphragm was involved more often (6vs15, p = 0.190). VATS was
the preferred surgical approach and only one conversion occurred in the
diaphragmatic surgery group (p = 0.470). Diaphragmatic abnormalities were
present in all the patients, brown/violet spots (100%) in the pleurodesis group
and perforations (100%) in the diaphragmatic surgery group (p < 0.001). There
were no differences in days of chest tube removal and length of stay. The
recurrence rate was 100% in the pleurodesis alone group while it was only 12.5%
in the diaphragmatic surgery group (< 0.001).
CONCLUSIONS: In our experience, diaphragmatic surgery and pleurodesis followed
by hormonal therapy was an effective approach in preventing recurrence in
patients with catamenial pneumothorax and diaphragmatic involvement.
© 2022. The Author(s), under exclusive licence to The Japanese Association for
Thoracic Surgery.
DOI: 10.1007/s11748-022-01802-w
PMID: 35286587 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35774053 | 1. Radiol Case Rep. 2022 Jun 25;17(9):3119-3125. doi:
10.1016/j.radcr.2022.06.012. eCollection 2022 Sep.
Catamenial pneumothorax: a rare manifestation of endometriosis.
Lameira P(1), Abecasis M(1), Palma S(1), Leitão J(1).
Author information:
(1)Department of Radiology, Centro Hospitalar Universitário Lisboa Norte,
Serviço de Imagiologia Geral, Av. Prof. Egas Moniz MB, 1649-028 Lisboa,
Portugal.
Endometriosis is a common gynecological disease that primarily affects
premenopausal women. It is mainly found in the pelvis but may be found at
several extrapelvic locations. Thoracic endometriosis is a rare extrapelvic
location of endometriosis and the leading cause of catamenial pneumothorax. We
describe the case of a 35-year-old woman with a background of pelvic pain
presenting to the emergency department with chest pain and dyspnea. The chest
X-ray in the emergency department showed a large right-sided pneumothorax.
Further imaging studies during patient evaluation revealed extensive fibrotic
changes in the pelvis and well-defined solid nodules with high signal on T2 and
T1-weighted images on MRI in abdominal and thoracic locations, rendering the
diagnosis of a catamenial pneumothorax in a patient with pelvic, abdominal and
thoracic endometriosis.
© 2022 The Authors. Published by Elsevier Inc. on behalf of University of
Washington.
DOI: 10.1016/j.radcr.2022.06.012
PMCID: PMC9237952
PMID: 35774053 |
http://www.ncbi.nlm.nih.gov/pubmed/36179536 | 1. Eur J Obstet Gynecol Reprod Biol. 2022 Nov;278:141-147. doi:
10.1016/j.ejogrb.2022.09.019. Epub 2022 Sep 21.
Is hormonal manipulation after surgical treatment of catamenial pneumothorax
effective in reducing the rate of recurrence? A systematic review and
meta-analysis.
Elsayed HH(1), Hassaballa AS(2), Mostafa MH(3), El Ghanam M(2), Ahmed MH(2),
Gumaa M(4), Moharram AA(5).
Author information:
(1)Thoracic Surgery Department, Ain Shams University, Cairo, Egypt. Electronic
address: hanyhassan77@hotmail.com.
(2)Cardiothoracic Surgery Department, Ain Shams University, Cairo, Egypt.
(3)Obstetrics and Gynecology Department, Ain Shams University, Cairo, Egypt.
(4)TRUST Research Centre, Cairo, Egypt.
(5)Department of Anaethesia, Intensive Care and Pain Management, Ain Shams
University, Cairo, Egypt.
OBJECTIVES: Catamenial pneumothorax CP is a rare form of spontaneous
pneumothorax in females forming part of thoracic endometriosis syndrome. Studies
have suggested possible benefit from postoperative hormonal administration. As
this treatment is inconsistent, we aimed at performing the first meta-analysis
to study the efficacy of adding hormonal treatment after surgery to reduce the
chances of recurrent catamenial pneumothorax.
METHODS: CENTRAL, MEDLINE/PubMed, Cochrane Library, and Scopus were
systematically searched from inception up to December 15, 2021. Studies
reporting five or more patients with end point outcome were included. The main
outcome assessed was postoperative recurrence of CP after hormonal manipulation.
Baseline, procedural, outcome, and validity data were systematically appraised
and pooled with random-effect methods. meta- regression for the effect of
patient age and follow up period were tested. Publication bias was examined.
This trial was registered with PROSPERO under registration number
CRD42022325377.
RESULTS: Our electronic search retrieved 644 citations, 48 of which were
selected for full-text review. Eleven studies with a combined population of 111
patients fulfilled the inclusion criteria. All patients reached an endpoint of
follow up for postoperative recurrence of catamenial pneumothorax after
receiving hormonal treatment. Overall study validity was acceptable, with a
median score of 6 on the Newcastle Ottawa scale NOS appraising the quality of
observational studies. CP is almost always a right-side disease
(107/111 = 96.3 %). The risk of postoperative recurrence with hormonal treatment
was 17.3 % (8.9 - 25.8 %) with moderate non-significant heterogeneity
(I2 = 40.85 %; P = 0.076). The cumulative risk of recurrence for all patients
not receiving postoperative hormonal therapy included in our study was 54.2 %
(19/35 patients). Meta regression showed age to be a significant predictor of
postoperative recurrence (p = 0.03). As the age increases one year, the risk of
recurrence decreases by 6 % (0.2 - 3 %). Publication bias was detected by
visualizing the funnel plot of standard error, Egger's test with p < 0.01 and
Begg & Mazumdar test with p < 0.01.
CONCLUSION: The study included the largest number of CP patients with outcome
findings of postoperative recurrence with hormonal treatment despite the small
number of studies, non-randomised fashion and publication bias. Our findings
recommend the use of hormonal manipulation after thoracic surgical intervention
for catamenial pneumothorax unless evident contraindications. Younger patients
are at a higher risk of recurrence after surgery.
Copyright © 2022 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ejogrb.2022.09.019
PMID: 36179536 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/35924495 | 1. Rev Med Liege. 2022 Jul;77(7-8):421-425.
[A catamenial pneumothorax, an unknown entity].
[Article in French; Abstract available in French from the publisher]
Nguyen LD(1), Guérisse F(2).
Author information:
(1)Service des Urgences, CHU Tivoli, La Louvière, Belgique.
(2)Service des Urgences, CHU de Charleroi, Belgique.
A 31-year-old patient is admitted to the emergency room because of an acute
right thoracic pain associated with a dyspnea. The patient reports the stopping
of Decapeptyl®, a treatment taken in regards to an endometriosis, but
interrupted to get pregnant. An x-ray highlights a pneumothorax of 15 mm at the
right apical level. It is a second episode for this patient. Catamenial
pneumothorax is one of the most frequent manifestation in terms of a thoracic
endometriosis syndrome (TES). It concerns a rare pathology, unrecognized and
underdiagnosed. The diagnosis should be invoked on all patients having the
childbearing age who are presenting themselves at the emergencies with a right
thoracic pain. The medical care is multidisciplinary, the association of a
hormonal therapy and then a surgical treatment being the best therapeutical
approach. This case report describes the recurrence of a catamenial pneumotorax
induced by the stopping of the endometriosis treatment and reviews the
physiopathology, the diagnosis and its multidisciplinary management.
Publisher: Une patiente de 31 ans est admise aux urgences pour douleur
thoracique droite apparue brutalement et associée à une dyspnée. La patiente
rapporte l’arrêt du Decapeptyl®, traitement pris dans le cadre d’une
endométriose, mais interrompu pour un désir de grossesse. Une radiographie
mettra en évidence un pneumothorax de 15 mm au niveau apical droit. Il s’agit du
deuxième épisode chez cette patiente. Le pneumothorax cataménial (PC) est l’une
des manifestations les plus fréquentes dans le cadre d’un syndrome
d’endométriose thoracique (SET). Il s’agit d’une pathologie rare, méconnue et
sous-diagnostiquée. Il est à évoquer chez toutes patientes en âge de procréer se
présentant aux urgences avec une douleur thoracique droite. La prise en charge
est multidisciplinaire, l’association d’un traitement hormonal, puis
chirurgical, semble être la meilleure approche thérapeutique. Cet article
rapporte la récidive d’un PC, récidive induite par l’arrêt du traitement de
l’endométriose, et revoit la physiopathologie, le diagnostic et la prise en
charge de celui-ci.
PMID: 35924495 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34375738 | 1. J Minim Invasive Gynecol. 2022 Jan;29(1):41-55. doi:
10.1016/j.jmig.2021.08.005. Epub 2021 Aug 8.
Thoracic Endometriosis: A Review Comparing 480 Patients Based on Catamenial and
Noncatamenial Symptoms.
Topbas Selcuki NF(1), Yilmaz S(2), Kaya C(3), Usta T(4), Kale A(5), Oral E(6).
Author information:
(1)Department of Obstetrics and Gynecology, University of Health Sciences
Turkey, Istanbul Sisli Hamidiye Etfal Training and Research Hospital (Dr. Topbas
Selcuki).
(2)Department of Obstetrics and Gynecology, Acibadem Altunizade Hospital (Dr.
Yilmaz).
(3)Department of Obstetrics and Gynecology, Acibadem Mehmet Ali Aydinlar
University, Acibadem Bakirkoy Hospital (Dr. Kaya).
(4)Department of Obstetrics and Gynecology, Acibadem Mehmet Ali Aydinlar
University, Acibadem Altunizade Hospital (Dr. Usta). Electronic address:
drtanerusta@gmail.com.
(5)Department of Obstetrics and Gynecology, University of Health Sciences
Turkey, Istanbul Kartal Dr. Lutfi Kirdar City Hospital (Dr. Kale).
(6)Department of Obstetrics and Gynecology, Bezmialem Vakif University (Dr.
Oral), Istanbul, Turkey.
OBJECTIVE: This review aimed to categorize thoracic endometriosis syndrome (TES)
according to whether the presenting symptoms were catamenial and to evaluate
whether such a categorization enables a better management strategy.
DATA SOURCES: An electronic search was conducted using the PubMed/Medline
database.
METHODS OF STUDY SELECTION: The following keywords were used in combination with
the Boolean operators AND OR: "thoracic endometriosis syndrome," "thoracic
endometriosis," "diaphragm endometriosis," and "catamenial pneumothorax."
TABULATION, INTEGRATION, AND RESULTS: The initial search yielded 445 articles.
Articles in non-English languages, those whose full texts were unavailable, and
those that did not present the symptomatology clearly were further excluded.
After these exclusions, the review included 240 articles and 480 patients: 61
patients in the noncatamenial group and 419 patients in the catamenial group.
The groups differed significantly in presenting symptoms, surgical treatment
techniques, and observed localization of endometriotic loci (p <.05).
CONCLUSION: This review points out the significant differences between patients
with TES with catamenial and noncatamenial symptoms. Such categorization and
awareness by clinicians of these differences among patients with TES can be
helpful in designing a management strategy. When constructing management
guidelines, these differences between patients with catamenial and noncatamenial
symptoms should be taken into consideration.
Copyright © 2021. Published by Elsevier Inc.
DOI: 10.1016/j.jmig.2021.08.005
PMID: 34375738 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27539547 | 1. Angew Chem Int Ed Engl. 2016 Oct 17;55(43):13408-13421. doi:
10.1002/anie.201601091. Epub 2016 Aug 19.
Targeted Covalent Inhibitors for Drug Design.
Baillie TA(1).
Author information:
(1)Department of Medicinal Chemistry, School of Pharmacy, University of
Washington, Box 357610, Seattle, WA, 98195-7610, USA. tbaillie@uw.edu.
In contrast to the traditional mechanism of drug action that relies on the
reversible, noncovalent interaction of a ligand with its biological target, a
targeted covalent inhibitor (TCI) is designed such that the initial, reversible
association is followed by the formation of a covalent bond between an
electrophile on the ligand and a nucleophilic center in the protein. Although
this approach offers a variety of potential benefits (high potency and extended
duration of action), concerns over the possible toxicological consequences of
protein haptenization have hindered the development of the TCI concept.
Recently, approaches to mitigate the risk of serious adverse reactions to this
new class of agent have emerged, thus stimulating interest in the field and
leading to authorization of the first cadre of TCIs to be marketed. The covalent
inhibitor approach is rapidly gaining acceptance as a valuable tool in drug
discovery, and is poised to make a major impact on the design of enzyme
inhibitors and receptor modulators.
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOI: 10.1002/anie.201601091
PMID: 27539547 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23928507 | 1. Phytomedicine. 2013 Oct 15;20(13):1186-9. doi: 10.1016/j.phymed.2013.07.004.
Epub 2013 Aug 6.
Is green tea a potential trigger for autoimmune hepatitis?
Gallo E(1), Maggini V, Berardi M, Pugi A, Notaro R, Talini G, Vannozzi G,
Bagnoli S, Forte P, Mugelli A, Annese V, Firenzuoli F, Vannacci A.
Author information:
(1)University of Florence, Department of Neuroscience, Psychology, Drug Research
and Child Health (NeuroFarBa), Center of Molecular Medicine (CIMMBA), Florence,
Italy.
A case of autoimmune liver hepatitis is reported: the onset was triggered by
consumption of green tea infusion in a patient taking oral contraceptives and
irbesartan. We hypothesize that our patient, carrying genetic variant of hepatic
metabolism making her particularly susceptible to oxidative stress, developed an
abnormal response to a mild toxic insult, afforded by a combination of agents
(oral contraceptives+irbesartan+green tea) that normally would not be able to
cause damage. Her particular hepatic metabolism further increased the drugs'
concentration, favoring the haptenization of liver proteins, eventually leading
to the development of an autoimmune hepatitis.
Copyright © 2013 Elsevier GmbH. All rights reserved.
DOI: 10.1016/j.phymed.2013.07.004
PMID: 23928507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35037874 | 1. Medicina (B Aires). 2022;82(1):147-150.
[Catamenial pneumothorax].
[Article in Spanish; Abstract available in Spanish from the publisher]
Toffolo Pasquini M(1), Auvieux R(2), Tchercansky A(2), Buero A(2), Chimondeguy
D(2), Mendez J(3).
Author information:
(1)Servicio de Cirugía General, Hospital Británico de Buenos Aires, Argentina.
E-mail: marianatoffolo@gmail.com.
(2)Servicio de Cirugía Torácica, Hospital Británico de Buenos Aires, Argentina.
(3)Servicio de Anatomía Patológica, Hospital Británico de Buenos Aires,
Argentina.
Thoracic endometriosis syndrome (TES) is a rare disorder characterized by the
presence of ectopic endometrial tissue in the chest cavity. The typical clinical
manifestation is a spontaneous pneumothorax, which usually presents with chest
pain, dyspnea, and/or cough. The diagnosis requires a high level of clinical
suspicion and a complete gynecological history. Imaging studies can help with
the diagnosis, although the gold standard is video-assisted thoracoscopic
surgery (VATS). Surgical treatment in combination with at least 6 months of
hormonal medical treatment has been shown to improve the prognosis and reduce
the recurrence of this entity. We present the case of a 40-year-old patient with
a history of pelvic endometriosis and multiple episodes of pneumothorax, who
consulted at our institution for a new episode of spontaneous pneumothorax. A
VATS was performed where nodules in the parietal pleura and diaphragmatic
orifices were identified. In the postoperative period, she continued with
hormonal treatment. At 6 months of follow-up, she reported improvement in pain
and did not present new episodes of pneumothorax.
Publisher: El síndrome de endometriosis torácica (TES) es un trastorno poco
común caracterizado por la presencia de tejido endometrial ectópico en la
cavidad torácica. La manifestación clínica típica es un neumotórax espontáneo,
que generalmente se presenta con dolor torácico, disnea y/o tos. El diagnóstico
requiere un alto nivel de sospecha clínica junto con una historia ginecológica
completa. Los estudios de imágenes pueden ayudar con el diagnóstico, pero el
gold standard es la cirugía toracoscópica videoasistida (VATS). Se ha demostrado
que el tratamiento quirúrgico en combinación con al menos 6 meses de tratamiento
médico hormonal mejora el pronóstico y reduce la recurrencia de esta entidad.
Presentamos el caso de una paciente de 40 años con antecedentes de endometriosis
pélvica y múltiples episodios de neumotórax, que consultó en nuestra institución
por un nuevo episodio de neumotórax espontáneo. Se realizó una VATS donde se
identificaron nódulos en la pleura parietal y orificios diafragmáticos. En el
postoperatorio continuó con tratamiento hormonal. A los 6 meses de seguimiento
refirió mejoría del dolor y no presentó nuevos episodios de neumotórax.
PMID: 35037874 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22613852 | 1. Chem Immunol Allergy. 2012;97:32-46. doi: 10.1159/000335614. Epub 2012 May 3.
Etiology and pathogenesis of adverse drug reactions.
Hausmann O(1), Schnyder B, Pichler WJ.
Author information:
(1)Department of Rheumatology and Clinical Immunology/Allergology, Inselspital,
University of Bern, Bern, Switzerland.
In clinical routine, adverse drug reactions (ADR) are common, and they should be
included in the differential diagnosis in all patients undergoing drug
treatment. Only part of those ADR are immune-mediated hypersensitivity reactions
and thus true drug allergies. Far more common are non-immune-mediated ADR, e.g.
due to the pharmacological properties of the drug or to the individual
predisposition of the patient (enzymopathies, cytokine dysbalance, mast cell
hyperreactivity). In true drug allergiesT cell- and immunoglobulin E
(lgE)-mediated reactions dominate the clinical presentation. T cell-mediated ADR
usually have a delayed appearance and include skin eruptions in most cases.
Nevertheless, it should not be forgotten that they may involve systemic T cell
activation and thus take a severe, sometimes lethal turn. Clinical danger signs
are involvement of mucosal surfaces, blistering within the exanthematous skin
areas and systemic symptoms, e.g. fever or malaise. Drug presentation via
antigen-presenting cells to T cells can either involve the classical pathway of
haptenization of endogenous proteins or be directly mediated via noncovalent
binding to immune receptors (MHC molecules or T cell receptors), the so-called
p-i concept. Flare-up reactions during the acute phase of T cell-mediated ADR
should not be mistaken for true drug allergies, as they only occur in the
setting of a highly activated T cell pool. IgE-mediated ADR are less frequent
and involve mast cells and/or basophils as peripheral effector cells. Recent
data suggest that certain patients with drug allergy have a preexistent
sensitization although they have never been exposed to the culprit drug,
probably due to cross-reactivity. Thus, allergic drug reactions on first
encounter are possible. In general, the extent of cross-reactivity is higher in
IgE-compared to T cell-mediated ADR. Based on a specific ethnic background and
only for severe T cell-mediated ADR to certain drugs, a strong HLA association
has been established recently.
Copyright © 2012 S. Karger AG, Basel.
DOI: 10.1159/000335614
PMID: 22613852 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35118122 | 1. Skin Appendage Disord. 2022 Jan;8(1):1-7. doi: 10.1159/000518191. Epub 2021
Sep 1.
Trichotillomania: What Do We Know So Far?
Melo DF(1), Lima CDS(2)(3), Piraccini BM(4)(5), Tosti A(6).
Author information:
(1)Dermatology Department, University of State of Rio de Janeiro (UERJ), Rio de
Janeiro, Brazil.
(2)Dermatology Department, University of State of Pará (UEPA), Belém, Brazil.
(3)Dermatology Department, University Center of Pará (CESUPA), Belém, Brazil.
(4)Department of Experimental, Diagnostic and Specialty Medicine (DIMES) Alma
Mater Studiorum University of Bologna, Bologna, Italy.
(5)IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
(6)Phillip Frost Department of Dermatology and Cutaneous Surgery, University of
Miami School of Medicine, Miami, Florida, USA.
Trichotillomania is defined as an obsessive-compulsive or related disorder in
which patients recurrently pull out hair from any region of their body. The
disease affects mainly female patients, who often deny the habit, and it usually
presents with a bizarre pattern nonscarring patchy alopecia with short hair and
a negative pull test. Trichoscopy can reveal the abnormalities resulting from
the stretching and fracture of hair shafts, and biopsy can be necessary if the
patient or parents have difficulties in accepting the self-inflicted nature of a
trichotillomania diagnosis. Trichotillomania requires a comprehensive treatment
plan and interdisciplinary approach. Physicians should always have a
nonjudgmental, empathic, and inviting attitude toward the patient. Behavioral
therapy has been used with success in the treatment of trichotillomania, but not
all patients are willing or able to comply with this treatment strategy.
Pharmacotherapy can be necessary, especially in adolescents and adult patients.
Options include tricyclic antidepressants, selective serotonin reuptake
inhibitors, and glutamate-modulating agents. Glutamate-modulating agents such as
N-acetylcysteine are a good first-line option due to significant benefits and
low risk of side effects. Physicians must emphasize that the role of
psychiatry-dermatology liaison is extremely necessary with concurrent support
services for the patient and parents, in case of pediatric patients. In
pediatric cases, parents should be advised and thoroughly educated that negative
feedback and punishment for hair pulling are not going to produce positive
results. Social support is a significant pillar to successful habit reversal
training; therefore, physicians must convey the importance of familial support
to achieving remission. This is a review article that aims to discuss the
literature on trichotillomania, addressing etiology, historical aspects,
clinical and trichoscopic features, main variants, differential diagnosis,
diagnostic clues, and psychological and pharmacological management.
Copyright © 2021 by S. Karger AG, Basel.
DOI: 10.1159/000518191
PMCID: PMC8787581
PMID: 35118122
Conflict of interest statement: Dr. Tosti reports being a consultant − DS
Laboratories, Monat Global, Almirall, Tirthy Madison, Eli Lilly, Bristol Myers
Squibb, and P&G. |
http://www.ncbi.nlm.nih.gov/pubmed/30560020 | 1. Intractable Rare Dis Res. 2018 Nov;7(4):271-274. doi: 10.5582/irdr.2018.01094.
Prune belly syndrome: Approaches to its diagnosis and management.
Achour R(1), Bennour W(2), Ksibi I(2), Cheour M(2), Hamila T(1), Hmid RB(1),
Kacem S(2).
Author information:
(1)Emergency Department of Gynecology and Obstetrics, Maternity and Neonatology
Center, Faculty of Medicine, Tunis-El Manar University, Tunis, Tunisia.
(2)Neonatology Department, Maternity and Neonatology Center, Faculty of
Medicine, Tunis-El Manar University, Tunis, Tunisia.
Prune Belly syndrome (PBS) or Eagle-Barrett syndrome is an anatomo-radiological
syndrome consisting of a complex and rare malformation characterized by the
following triad of symptoms: deficiency of the abdominal muscles, malformations
of the urinary tract, and bilateral cryptorchidism. The exact etiology is
unknown, though PBS predominantly occurs in males. The clinical manifestations
can vary widely, from stillbirth to renal and major respiratory dysplasia to
almost normal children. The current study included a total of 3 patients. The
findings included clinical characteristics, diagnostics, therapy, and clinical
outcomes. All patients were diagnosed with congenital aplasia of the abdominal
wall and a variety of urogenital malformations. Cryptorchidism and a
mega-bladder were observed in 2 patients and distinctive renal malformations,
such as renal dysplasia, were observed in 1 patient. Treatment varies but
usually includes surgical management of symptoms. One patient required urgent
urinary surgery; a vesicotomy was urgently performed due to anuria. These
aspects explain the great diversity of opinions on the approach to this
syndrome, but the severity of renal dysplasia is the main prognostic factor. Two
newborns died a few days later due to severe renal failure. Despite these
concerns, many patients with PBS report being in physical and mental health and
having a good quality of life.
DOI: 10.5582/irdr.2018.01094
PMCID: PMC6290839
PMID: 30560020 |
http://www.ncbi.nlm.nih.gov/pubmed/35526214 | 1. Spec Care Dentist. 2023 Jan;43(1):67-72. doi: 10.1111/scd.12728. Epub 2022 May
8.
Dental treatment of patients with prune belly syndrome.
Quilici G(1), Tolarova MM(1), Quilici M(2), Quilici DL(3).
Author information:
(1)University of the Pacific Arthur A. Dugoni School of Dentistry, San
Francisco, California, USA.
(2)Oakland, California, USA.
(3)Department of Veterans Affairs, California, McClellan, USA.
BACKGROUND: Prune belly syndrome (PBS), also known as Eagle-Barrett syndrome
(EGBRS), is a rare congenital disease characterized by deficiency or absence of
abdominal wall muscles, urological abnormalities, and bilateral cryptorchidism.
TYPES OF STUDIES REVIEWED: A review of literature was done using four search
engines (PubMed, Google Scholar, Scopus, Science Direct) and keywords
(individually and in combinations): prune belly syndrome, PBS, Eagle-Barrett
syndrome, dental manifestation, clinical manifestation, and psychological
aspects. The search was run with no language restrictions and covered the
1965-2021 time period.
RESULTS: The search yielded a large number of articles. The vast majority were
dealing with a variety of treatments. PBS is a multisystem disease with a
variable spectrum ranging from mild cases to infant mortality. Comorbidities of
PBS (63% gastrointestinal, 65% orthopedic, and 49% cardiopulmonary) present
challenges for treatment. PBS affects quality of life of patients and
caregivers. We selected and summarized published information that is relevant to
oral health and dental care.
CONCLUSIONS AND PRACTICAL IMPLICATIONS: Providing information to dental
practitioners will improve their understanding of PBS. It will help them to
better treat patients with PBS and it will encourage more dental providers to
welcome patients with PBS into their dental clinics.
© 2022 The Authors. Special Care in Dentistry Published by Special Care
Dentistry Association and Wiley Periodicals LLC.
DOI: 10.1111/scd.12728
PMCID: PMC10083899
PMID: 35526214 [Indexed for MEDLINE]
Conflict of interest statement: The authors declares no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35429431 | 1. Can J Urol. 2022 Apr;29(2):11116-11118.
Robotic treatment of ureteropelvic junction obstruction in Eagle-Barrett
Syndrome.
Faber LS(1), Riley JM(2).
Author information:
(1)Department of Surgery (Division of Urology), University of New Mexico,
Albuquerque, New Mexico, USA.
(2)Department of Urology at University of Arkansas for Medical Sciences, Little
Rock, Arkansas, USA.
Eagle-Barrett Syndrome (EBS) is a rare congenital condition characterized by the
triad of absent or defective abdominal wall muscles, urinary tract
abnormalities, and bilateral cryptorchidism. Ureteropelvic junction obstruction
(UPJO) is seldom reported in these patients, despite it being a common cause of
childhood obstructive uropathy. We present the case of a patient with EBS who
was subsequently identified as having symptomatic UPJO that was successfully
treated with robotic pyeloplasty.
PMID: 35429431 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32774275 | 1. Case Rep Oncol. 2020 Jul 2;13(2):774-782. doi: 10.1159/000507921. eCollection
2020 May-Aug.
Mantle Cell Lymphoma Presenting as a Subcutaneous Mass of the Right Leg.
Fajardo DA(1), France J(2), Targonska BI(3)(4)(5), Kahlon HB(6), Coppes
MJ(4)(5).
Author information:
(1)University of Nevada Reno School of Medicine, Reno, Nevada, USA.
(2)Sierra Pathology Associates, Reno, Nevada, USA.
(3)Reno Radiological Associates, Reno, Nevada, USA.
(4)Department of Pediatrics, University of Nevada Reno School of Medicine, Reno,
Nevada, USA.
(5)Renown Children's Hospital, Reno, Nevada, USA.
(6)Family Medicine, Renown Medical Group, Reno, Nevada, USA.
Mantle cell lymphoma (MCL) is a relatively rare B-cell non-Hodgkin lymphoma,
typically presenting with extensive lymphadenopathy, bone marrow involvement,
and splenomegaly. Extranodal sites can also be involved. We discuss a
73-year-old man whose MCL presented with a 6-month history of a subdermal mass
of the right upper thigh and no systemic symptoms.
Copyright © 2020 by S. Karger AG, Basel.
DOI: 10.1159/000507921
PMCID: PMC7383204
PMID: 32774275
Conflict of interest statement: The authors declare to have no conflict of
interest. Financial support (all based on employment) is provided under “Funding
Sources.” |