12 research outputs found
Global Retinoblastoma Presentation and Analysis by National Income Level
Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4) were female. Most patients (n = 3685 84.7%) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 62.8%), followed by strabismus (n = 429 10.2%) and proptosis (n = 309 7.4%). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 95% CI, 12.94-24.80, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 95% CI, 4.30-7.68). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs. © 2020 American Medical Association. All rights reserved
cDNA cloning and assignment to chromosome 21 of IFI-78K gene, the human equivalent of murine Mx gene.
Recently we have purified to homogeneity and characterized an interferon-induced human protein (p78 protein) which is the equivalent of the interferon-induced murine Mx protein responsible for a specific antiviral state against influenza virus infection. A cDNA library was constructed using mRNAs from interferon-induced human diploid fibroblasts. cDNA clones coding for the human p78 protein were identified and used to determine the chromosomal location of the corresponding gene (termed IFI-78K gene) by hybridization to DNA from a panel of human x rodent somatic cell hybrids. The newly identified gene is located on chromosome 21. This has been confirmed by the observation of a gene dosage effect using chromosome 21 trisomic cells (fibroblasts derived from Down's syndrome patients). Among all interferon-inducible genes mapped so far, the IFI-78K gene is the only one located on chromosome 21, together with the gene for the receptor of type I interferon. Our results also provide further evidence for homology between human chromosome 21 and mouse chromosome 16, since the gene encoding the mouse Mx protein (the presumed mouse homolog protein of human p78 protein) has been assigned to chromosome 16.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe
Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.
We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences
Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow
Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 × 108/kg with a median of 2.7 × 108/kg. The PB cell dose ranged from 0.02 to 77 × 10 8/kg with a median of 9.3 × 108/kg. The median dose for patients receiving BM (2.7 × 108/kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0. 92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. © 2003 by The American Society of Hematology
Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow
PubMed ID: 12829583Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 × 10 8 /kg with a median of 2.7 × 10 8 /kg. The PB cell dose ranged from 0.02 to 77 × 10 8 /kg with a median of 9.3 × 10 8 /kg. The median dose for patients receiving BM (2.7 × 10 8 /kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0. 92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. © 2003 by The American Society of Hematology
Global Retinoblastoma Presentation and Analysis by National Income Level
This cross-sectional analysis reports the retinoblastoma stage at
diagnosis across the world during a single year, investigates
associations between clinical variables and national income level, and
investigates risk factors for advanced disease at diagnosis.
Key PointsQuestionIs the income level of a country of residence
associated with the clinical stage of presentation of patients with
retinoblastoma? FindingsIn this cross-sectional analysis that included
4351 patients with newly diagnosed retinoblastoma, approximately half of
all new retinoblastoma cases worldwide in 2017, 49.1\% of patients from
low-income countries had extraocular tumor at time of diagnosis compared
with 1.5\% of patients from high-income countries. MeaningThe clinical
stage of presentation of retinoblastoma, which has a major influence on
survival, significantly differs among patients from low-income and
high-income countries, which may warrant intervention on national and
international levels.
ImportanceEarly diagnosis of retinoblastoma, the most common intraocular
cancer, can save both a child's life and vision. However, anecdotal
evidence suggests that many children across the world are diagnosed
late. To our knowledge, the clinical presentation of retinoblastoma has
never been assessed on a global scale. ObjectivesTo report the
retinoblastoma stage at diagnosis in patients across the world during a
single year, to investigate associations between clinical variables and
national income level, and to investigate risk factors for advanced
disease at diagnosis. Design, Setting, and ParticipantsA total of 278
retinoblastoma treatment centers were recruited from June 2017 through
December 2018 to participate in a cross-sectional analysis of
treatment-naive patients with retinoblastoma who were diagnosed in 2017.
Main Outcomes and MeasuresAge at presentation, proportion of familial
history of retinoblastoma, and tumor stage and metastasis. ResultsThe
cohort included 4351 new patients from 153 countries; the median age at
diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976
patients (45.4\%) were female. Most patients (n=3685 {[}84.7\%]) were
from low- and middle-income countries (LMICs). Globally, the most common
indication for referral was leukocoria (n=2638 {[}62.8\%]), followed by
strabismus (n=429 {[}10.2\%]) and proptosis (n=309 {[}7.4\%]). Patients
from high-income countries (HICs) were diagnosed at a median age of 14.1
months, with 656 of 666 (98.5\%) patients having intraocular
retinoblastoma and 2 (0.3\%) having metastasis. Patients from low-income
countries were diagnosed at a median age of 30.5 months, with 256 of 521
(49.1\%) having extraocular retinoblastoma and 94 of 498 (18.9\%) having
metastasis. Lower national income level was associated with older
presentation age, higher proportion of locally advanced disease and
distant metastasis, and smaller proportion of familial history of
retinoblastoma. Advanced disease at diagnosis was more common in LMICs
even after adjusting for age (odds ratio for low-income countries vs
upper-middle-income countries and HICs, 17.92 {[}95\% CI, 12.94-24.80],
and for lower-middle-income countries vs upper-middle-income countries
and HICs, 5.74 {[}95\% CI, 4.30-7.68]). Conclusions and RelevanceThis
study is estimated to have included more than half of all new
retinoblastoma cases worldwide in 2017. Children from LMICs, where the
main global retinoblastoma burden lies, presented at an older age with
more advanced disease and demonstrated a smaller proportion of familial
history of retinoblastoma, likely because many do not reach a
childbearing age. Given that retinoblastoma is curable, these data are
concerning and mandate intervention at national and international
levels. Further studies are needed to investigate factors, other than
age at presentation, that may be associated with advanced disease in
LMICs
Anticoagulant selection in relation to the SAMe-TT2R2 score in patients with atrial fibrillation: The GLORIA-AF registry
Aim: The SAMe-TT2R2 score helps identify patients with atrial fibrillation (AF) likely to have poor anticoagulation control during anticoagulation with vitamin K antagonists (VKA) and those with scores >2 might be better managed with a target-specific oral anticoagulant (NOAC). We hypothesized that in clinical practice, VKAs may be prescribed less frequently to patients with AF and SAMe-TT2R2 scores >2 than to patients with lower scores. Methods and results: We analyzed the Phase III dataset of the Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF), a large, global, prospective global registry of patients with newly diagnosed AF and ≥1 stroke risk factor. We compared baseline clinical characteristics and antithrombotic prescriptions to determine the probability of the VKA prescription among anticoagulated patients with the baseline SAMe-TT2R2 score >2 and ≤ 2. Among 17,465 anticoagulated patients with AF, 4,828 (27.6%) patients were prescribed VKA and 12,637 (72.4%) patients an NOAC: 11,884 (68.0%) patients had SAMe-TT2R2 scores 0-2 and 5,581 (32.0%) patients had scores >2. The proportion of patients prescribed VKA was 28.0% among patients with SAMe-TT2R2 scores >2 and 27.5% in those with scores ≤2. Conclusions: The lack of a clear association between the SAMe-TT2R2 score and anticoagulant selection may be attributed to the relative efficacy and safety profiles between NOACs and VKAs as well as to the absence of trial evidence that an SAMe-TT2R2-guided strategy for the selection of the type of anticoagulation in NVAF patients has an impact on clinical outcomes of efficacy and safety. The latter hypothesis is currently being tested in a randomized controlled trial. Clinical trial registration: URL: https://www.clinicaltrials.gov//Unique identifier: NCT01937377, NCT01468701, and NCT01671007. © 2020 Hellenic Society of Cardiolog