scholarly journals Use of a rare disease registry for establishing phenotypic classification of previously unassigned GLA variants: a consensus classification system by a multispecialty Fabry disease genotype–phenotype workgroup

2020 ◽  
Vol 57 (8) ◽  
pp. 542-551 ◽  
Author(s):  
Dominique P Germain ◽  
João Paulo Oliveira ◽  
Daniel G Bichet ◽  
Han-Wook Yoo ◽  
Robert J Hopkin ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Clinical Care ◽  
Clinical Event ◽  
Iterative System ◽  
Kaplan Meier ◽  
Pathogenicity Prediction ◽  
Uncertain Significance ◽  
Rare Disease Registry ◽  
Consensus Classification ◽  
Phenotypic Classification

BackgroundFabry disease (α-galactosidase deficiency) is an X-linked genetic disease caused by a variety of pathogenic GLA variants. The phenotypic heterogeneity is considerable, with two major forms, classic and later-onset disease, but adjudication of clinical phenotype is currently lacking for many variants. We aimed to determine consensus phenotypic classification for previously unclassified GLA variants from the GLA-specific fabry-database.org database.MethodsA Fabry disease genotype–phenotype workgroup developed a five-stage iterative system based on expert clinical assessment, published literature and clinical evidence of pathogenicity using a 2-point scoring system based on clinical hallmarks of classic disease. Kaplan–Meier (KM) analysis of severe clinical event-free survival was used as final validation. Results were compared with those from web-based disease databases and in silico pathogenicity prediction programmes.ResultsFinal consensus on classifications of ‘pathogenic’ was achieved for 32 of 33 GLA variants (26 ‘classic’ phenotype, 171 males; 6 ‘later-onset’ phenotype, 57 males). One variant remained of uncertain significance. KM curves were similar for the known fabry-database.org database phenotypes and when workgroup consensus classifications were added, and the curves retained the same separation between ‘classic’ and ‘later-onset’ phenotypes.ConclusionThe iterative system implemented by a Fabry disease genotype–phenotype workgroup achieved phenotypic classifications for variants that were previously unclassified. Clinical pathogenicity associated with a particular GLA variant defined in affected males appears to have predictive value and also generally correlates with risk for affected females. The newly established classifications can be of benefit to the clinical care of Fabry patients harbouring these variants.

Edoxaban treatment of elderly patients with atrial fibrillation in routine clinical practice: 1-year results of the non-interventional Global ETNA-AF program

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Yamashita ◽  
C.C Wang ◽  
Y.-H Kim ◽  
R De Caterina ◽  
P Kirchhof ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Practice ◽  
Major Bleeding ◽  
Intracranial Haemorrhage ◽  
Clinical Care ◽  
Oral Anticoagulants ◽  
Clinical Event ◽  
Funding Source ◽  
Private Company ◽  
All Cause Mortality

Abstract Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

P0067PREDICTORS OF LONG-TERM OUTCOME IN A SPANISH COHORT OF PATIENTS WITH FABRY DISEASE ON ENZYME REPLACEMENT THERAPY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Marian Goicoechea ◽  
Francisco Gomez-Preciado ◽  
Silvia Benito ◽  
Joan Torras ◽  
Roser Torra ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Left Ventricular ◽  
Response To Therapy ◽  
Clinical Event ◽  
Enzyme Replacement ◽  
Clinical Events ◽  
The Impact

Abstract Background and Aims Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in Fabry disease patients on ERT. Method Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). Results In 69 patients (42 males, 27 females, mean age 44.6 ±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242 to 128 mg/g (p = 0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR ≤60 ml/min/1.73 m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043), being these differences more relevant in females (log Rank 18.514, p<0.001) than males (logRank: 3.442, p=0.064). Lower baseline eGFR was associated with a 3- to 7-fold increase in the risk of clinical events in different Cox models. Conclusion GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. For the first time, we show that initiation of ERT in women before renal function deteriorates has a similar or even larger impact as in Fabry males to prevent clinical events.

Application of the International Germ Cell Consensus Classification (IGCCC) to the Nova Scotia population of patients with germ cell tumors (GCT)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14625-14625
Author(s):  
E. Maydanski Murphy ◽  
J. Douglas ◽  
K. Thompson ◽  
L. A. Wood
Keyword(s):  
Nova Scotia ◽  
Germ Cell ◽  
Germ Cell Tumors ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Population Based ◽  
Similar Distribution ◽  
Kaplan Meier ◽  
Visceral Metastases ◽  
Consensus Classification

14625 Background: The IGCCC is the internationally accepted, clinically based, prognostic classification used to aid in the management of GCT. The goal of this study was to determine if the IGCCC is applicable to a population based cohort. Methods: A retrospective chart review of all patients diagnosed with GCT in NS between 1984–2004 was completed, and IGCCC classification (good, intermediate, poor) was assigned to each patient based on the site of the primary lesion, the presence or absence of non-pulmonary visceral metastases and pre-chemotherapy tumor marker values. Kaplan-Meier estimates of five year progression free survival (PFS) and overall survival (OS) were calculated for each IGCCC group, for both non-seminomatous GCT and seminomatous GCT. Results: The distribution, PFS and OS are shown below. Conclusions: The IGCCC seems applicable to a population-based cohort, with similar distribution of categories, as well as clear prognostic ability. This project was funded by a Norah Stephen Oncology Scholars Summer Studentship Grant from Cancer Care Nova Scotia. [Table: see text] [Table: see text]

scholarly journals A Combined Prospective and Retrospective Comparison of Long-Term Functional Outcomes Suggests Delayed Loss of Ambulation and Pulmonary Decline with Long-Term Eteplirsen Treatment

2021 ◽  
pp. 1-14 ◽  
Author(s):  
Olga Mitelman ◽  
Hoda Z. Abdel-Hamid ◽  
Barry J. Byrne ◽  
Anne M. Connolly ◽  
Peter Heydemann ◽  
...  
Keyword(s):  
Natural History ◽  
Repeated Measures ◽  
Proportional Hazards ◽  
Clinical Care ◽  
Standard Of Care ◽  
Cox Proportional Hazards ◽  
Kaplan Meier ◽  
Cox Proportional Hazards Models

Background: Studies 4658-201/202 (201/202) evaluated treatment effects of eteplirsen over 4 years in patients with Duchenne muscular dystrophy and confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405) further followed these patients while receiving eteplirsen during usual clinical care. Objective: To compare long-term clinical outcomes of eteplirsen-treated patients from Studies 201/202/405 with those of external controls. Methods: Median total follow-up time was approximately 6 years of eteplirsen treatment. Outcomes included loss of ambulation (LOA) and percent-predicted forced vital capacity (FVC%p). Time to LOA was compared between eteplirsen-treated patients and standard of care (SOC) external controls and was measured from eteplirsen initiation in 201/202 or, in the SOC group, from the first study visit. Comparisons were conducted using univariate Kaplan-Meier analyses and log-rank tests, and multivariate Cox proportional hazards models with regression adjustment for baseline characteristics. Annual change in FVC%p was compared between eteplirsen-treated patients and natural history study patients using linear mixed models with repeated measures. Results: Data were included from all 12 patients in Studies 201/202 and the 10 patients with available data from 405. Median age at LOA was 15.16 years. Eteplirsen-treated patients experienced a statistically significant longer median time to LOA by 2.09 years (5.09 vs. 3.00 years, p < 0.01) and significantly attenuated rates of pulmonary decline vs. natural history patients (FVC%p change: –3.3 vs. –6.0 percentage points annually, p < 0.0001). Conclusions: Study 405 highlights the functional benefits of eteplirsen on ambulatory and pulmonary function outcomes up to 7 years of follow-up in comparison to external controls.

Three-year survival outcomes in a prospective cohort evaluating a prognostic 31-gene expression profile (31-GEP) test for cutaneous melanoma (CM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9519-9519 ◽  
Author(s):  
Eddy C. Hsueh ◽  
James R. DeBloom ◽  
Robert W. Cook ◽  
Kelly McMasters
Keyword(s):  
High Risk ◽  
Cox Regression ◽  
Clinical Care ◽  
Positive Sentinel Lymph Node ◽  
Clinical Registry ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Class 1 ◽  
Data Censoring

9519 Background: A 31-GEP test is a validated prognostic tool for predicting the risk of metastasis in CM, classifying patients (pts) as Class 1 (low risk) or Class 2 (high risk). Here we report updated survival analysis from two clinical registry studies (NCT02355574/NCT02355587) designed to prospectively evaluate outcomes in patients for whom the GEP test was part of their clinical care. Methods: Eleven US dermatologic and surgical centers participated using IRB-approved protocols. Participants were CM pts ≥16 years old who had successful 31-GEP test results. Recurrence-free (RFS), distant metastasis-free (DMFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox regression analysis. Results: At data censoring, 340 pts were accrued who had completed at least one follow-up visit. Median age was 58 years (range 18-87), 53.5% were male, median Breslow thickness was 1.2mm (range 0.2-12mm), 18.2% (62/340) were ulcerated, and 11.2% (38/340) had a positive sentinel lymph node (SLN). Median follow-up was 3.2 years for pts without an event. Six percent (16/265) of Class 1 pts had a recurrence compared to 33% (25/75) of Class 2 pts (p < 0.001). Three-year RFS was 96%, 91%, 80%, and 62% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Three-year DMFS was 97%, 93%, 84%, and 80% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Three-year OS was 98%, 90%, 96%, and 74% for Class 1A, 1B, 2A, and 2B, respectively (p < 0.001). Class 2 was an independent predictor of RFS and OS in multivariate analysis (respective HRs: 2.28 and 3.70, p < 0.05). Conclusions: Consistent with results from previous studies, this analysis demonstrates that the GEP test complements conventional staging and improves the ability to identify high-risk CM pts. These results support use of the test for guiding decisions related to follow-up, surveillance, and treatment in CM pts. Clinical trial information: NCT02355574/NCT02355587.

scholarly journals S-CAP extends clinical-grade pathogenicity prediction to genetic variants that affect RNA splicing

2018 ◽  
Author(s):  
Karthik A. Jagadeesh ◽  
Joseph M. Paggi ◽  
James S. Ye ◽  
Peter D. Stenson ◽  
David N. Cooper ◽  
...  
Keyword(s):  
Genetic Variants ◽  
In Silico ◽  
Rna Splicing ◽  
Clinical Grade ◽  
Inherited Disease ◽  
Variants Of Uncertain Significance ◽  
Pathogenicity Prediction ◽  
Uncertain Significance ◽  
Human Inherited Disease

AbstractThere are over 15,000 known variants that cause human inherited disease by disrupting RNA splicing. While several in silico methods such as CADD, EIGEN and LINSIGHT are commonly used to predict the pathogenicity of noncoding variants, we introduce S-CAP, a tool developed specially for splicing which is better able to effectively distinguish pathogenic splicing-relevant variants from benign variants. S-CAP is a novel splicing pathogenicity predictor that reduces the number of splicing-relevant variants of uncertain significance in patient exomes by 41%, a nearly 3-fold improvement over existing noncoding pathogenicity measures while correctly classifying known pathogenic splicing-relevant variants with a clinical-grade 95% sensitivity.

Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care

2021 ◽  
pp. 577-584
Author(s):  
Jianbang Chiang ◽  
Tze Hao Chia ◽  
Jeanette Yuen ◽  
Tarryn Shaw ◽  
Shao-Tzu Li ◽  
...  
Keyword(s):  
Cancer Genetics ◽  
Clinical Care ◽  
Asian Country ◽  
Pathogenic Variant ◽  
Cancer Predisposition ◽  
Variant Of Uncertain Significance ◽  
Variants Of Uncertain Significance ◽  
Predisposition Genes ◽  
Uncertain Significance ◽  
The Impact

PURPOSE Genetic testing has clinical utility in the management of patients with hereditary cancer syndromes. However, the increased likelihood of encountering a variant of uncertain significance in individuals of non-European descent such as Asians may be challenging to both clinicians and patients. This study aims to evaluate the impact of variant reclassification in an Asian country with variants of uncertain significance reported in cancer predisposition genes. METHODS A retrospective analysis of patients seen at the Cancer Genetics Service at the National Cancer Centre Singapore between February 2014 and March 2020 was conducted. The frequency, direction, and time to variant reclassification were evaluated by comparing the reclassified report against the original report. RESULTS A total of 1,412 variants of uncertain significance were reported in 49.9% (845 of 1,695) of patients. Over 6 years, 6.7% (94 of 1,412) of variants were reclassified. Most variants of uncertain significance (94.1%, 80 of 85) were downgraded to benign or likely benign variant, with a smaller proportion of variants of uncertain significance (5.9%, 5 of 85) upgraded to pathogenic or likely pathogenic variant. Actionable variants of uncertain significance upgrades and pathogenic or likely pathogenic variant downgrades, which resulted in management changes, happened in 31.0% (39 of 126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s), respectively. CONCLUSION We propose a clinical guideline to standardize management of patients reported to have variants of uncertain significance. Management should be based on the patient’s personal history, family history, and variant interpretation. For clinically relevant or suspicious variants of uncertain significance, follow-up is recommended every 2 years, as actionable reclassifications may happen during this period.

Variant reclassification and its impact on clinical care in an Asian cancer center.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10583-10583
Author(s):  
Jianbang Chiang ◽  
Tze Hao Chia ◽  
Sock Hoai Chan ◽  
Joanne YY Ngeow
Keyword(s):  
Cancer Genetics ◽  
Clinical Care ◽  
Asian Country ◽  
Pathogenic Variant ◽  
Cancer Center ◽  
Variant Of Uncertain Significance ◽  
Patients With Cancer ◽  
Uncertain Significance ◽  
Original Report ◽  
Management Changes

10583 Background: Genetic testing has demonstrated clinical utility in the identification and subsequent surveillance of patients with cancer predisposition syndromes. However, the increased likelihood of encountering a variant of uncertain significance (VUS) in individuals of non-European descent such as Asians may be challenging to both clinicians and patients in interpretation and management. VUS can be reclassified as more data becomes available. VUS reclassification is important, as it may have implications for surveillance and treatment. This study aims to evaluate the prevalence and patterns of variant reclassification in an Asian country and its impact on patient management. Methods: A prospective cohort of patients seen at the Cancer Genetics Service at the National Cancer Center Singapore between February 2014 to March 2020 was evaluated. The frequency, direction and time to variant reclassification was assessed by comparing the reclassified report against the original report. Results: A total of 1412 VUS were reported in 49.9% (845/1695) of patients. Over six-years, 6.7% (94/1412) of variants were reclassified. Most VUS (94.1%; 80/85) were downgraded to benign/likely benign variant, with a smaller proportion of VUS (5.9%; 5/85) upgraded to pathogenic/likely pathogenic variant. Actionable VUS upgrades and pathogenic/likely pathogenic variant downgrades, that resulted in management changes, happened in 31.0% (39/126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s) respectively. Conclusions: Clinicians need to put in place a system for review of variants, as variant reclassification can lead to changes in management in nearly 1/3 of patients. Management should be based on the patient’s personal history, family history and variant interpretation. We propose a clinical guideline to standardize management of patients with VUS. For clinically relevant or suspicious VUS, follow-up is recommended every two years, as actionable reclassifications may happen during this period.

scholarly journals Gastrointestinal Involvement in Anderson-Fabry Disease: A Narrative Review

2021 ◽  
Vol 18 (6) ◽  
pp. 3320
Author(s):  
Fabio Caputo ◽  
Lisa Lungaro ◽  
Adriana Galdi ◽  
Eleonora Zoli ◽  
Fiorella Giancola ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Clinical Manifestations ◽  
Rare Condition ◽  
Narrative Review ◽  
Diagnostic Tools ◽  
Lysosomal Storage ◽  
Variant Of Uncertain Significance ◽  
Gi Symptoms ◽  
Uncertain Significance ◽  
Gla Gene

Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder leading to a wide array of clinical manifestations. Among these, gastrointestinal (GI) symptoms such as abdominal pain, bloating, and diarrhea affect about half of the FD adults and more than half of FD children. GI symptoms could be the first manifestation of FD; however, being non-specific, they overlap with the clinical picture of other conditions, such as irritable bowel syndrome and inflammatory bowel disease. This common overlap is the main reason why FD patients are often unrecognized and diagnosis is delayed for many years. The present narrative review is aimed to promote awareness of the GI manifestations of FD amongst general practitioners and specialists and highlight the latest findings of this rare condition including diagnostic tools and therapies. Finally, we will discuss some preliminary data on a patient presenting with GI symptoms who turned to be affected by a variant of uncertain significance of alpha-galactosidase (GLA) gene.

scholarly journals Bone metastases and skeletal-related events from neuroendocrine tumors

2015 ◽  
Vol 4 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Katherine Van Loon ◽  
Li Zhang ◽  
Jennifer Keiser ◽  
Cendy Carrasco ◽  
Katherine Glass ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Neuroendocrine Tumors ◽  
Clinical Care ◽  
Cord Compression ◽  
Time To Event ◽  
Time To Event Data ◽  
Kaplan Meier ◽  
Number Of Patients ◽  
Skeletal Related Events ◽  
Neuroendocrine Carcinomas

Neuroendocrine tumors (NETs) metastasize to bone; however, a multi-institution evaluation of the natural history and complications of bone metastases across multiple NET subtypes has not, to our knowledge, previously been conducted. At two tertiary academic centers, we identified patients with bone metastases from databases of patients with a diagnosis of NET between 2004 and 2008. Detection of bone metastases, occurrence of skeletal-related events (SREs), and interventions were analyzed using summary statistics and categorical methods. Time-to-event data were assessed using Kaplan–Meier estimates and log-rank tests. Between 2004 and 2008, 82 out of 691 NET patients (12%) were reported to have bone metastases. Of the 82 patients with bone metastases, 55% were men and their median age was 49. Bone metastases occurred in 25% of pheochromocytomas and paragangliomas, 20% of high-grade neuroendocrine carcinomas, 9% of carcinoid tumors, and 8% of pancreatic NETs. At time of detection of bone metastases, 60% reported symptoms, including pain; 10% developed cord compression, 9% suffered a pathological fracture, and 4% developed hypercalcemia. Occurrence of SREs did not differ significantly with regard to tumor histology. Of patients with bone metastases, 67 (82%) received at least one form of bone-directed treatment, 50% received radiation, 45% received a bisphosphonate, 18% underwent surgery, 11% received 131I-MIBG, 5% received denosumab, and 46% were treated with more than one treatment modality. Bone metastases occur in a substantial number of patients diagnosed with NETs. Patients are often symptomatic and many develop SREs. Given the recent therapeutic advances and increasing life expectancy of patients with NETs, development of guidelines for surveillance and clinical care of bone metastases from NETs is needed.

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