BRCA1-specific machine learning model predicts variant pathogenicity with high accuracy.

Identification of novel BRCA1 variants outpaces their clinical annotation which highlights the importance of developing accurate computational methods for risk assessment. Therefore our aim was to develop a BRCA1-specific machine learning model to predict the pathogenicity of all types of BRCA1 variants and to apply this model and our previous BRCA2-specific model to assess BRCA variants of uncertain significance (VUS) among Qatari patients with breast cancer. We developed an XGBoost model that utilizes variant information such as position frequency and consequence as well as prediction scores from numerous in silico tools. We trained and tested the model with BRCA1 variants that were reviewed and classified by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. In addition we tested the model's performance on an independent set of missense variants of uncertain significance with experimentally determined functional scores. The model performed excellently in predicting the pathogenicity of ENIGMA-classified variants (accuracy: 99.9%) and in predicting the functional consequence of the independent set of missense variants (accuracy: 93.4%). Moreover it predicted 2 115 potentially pathogenic variants among the 31 058 unreviewed BRCA1 variants in the BRCA exchange database. Using two BRCA-specific models we did not identify any pathogenic BRCA1 variants among those found in patients in Qatar but predicted four potentially pathogenic BRCA2 variants, which could be prioritized for functional validation.

Pancytopenia And Limbic Encephalopathy Complicating Immunotherapy For Clear Cell Endometrial Cancer With Microsatellite Instability-High (MSI-H).

BACKGROUND: Clear cell carcinoma of the endometrium (CCE) has a tendency to occur in a mismatch repair protein deficient molecular background. Treatment with immunotherapy can predict a favorable response. CASE PRESENTATION: We are presenting a 53-year-old female, diagnosed with CCE 17 years ago, who was treated initially with hysterectomy and left salpingo-oophorectomy, who relapsed a few months later, and was then treated with left pelvic mass excision and sigmoidectomy. Recently, the disease recurred as a retroperitoneal lymphadenopathy, which was resected but then relapsed locally, spread to the lungs, and progressed further after three lines of chemotherapy. On pathological review of the tumor, it was found to harbor loss of nuclear expression of MLH-1 and PMS-2. Based on a strong predictor of response to immunotherapy, pembrolizumab was tried. However, within a few days of the single dose of pembrolizumab, immune thrombocytopenia followed by pancytopenia, recurrent seizures, visual hallucination, and cerebellar signs consistent with limbic encephalitis developed, which were not responding to steroid and intravenous immunoglobulin. CONCLUSION: We are presenting a case of a CCE with deficient mismatch repair that developed two autoimmune side effects, pancytopenia and limbic encephalitis, within a few days of a single injection of pembrolizumab.

Exploring the effectiveness of crisis counseling and psychoeducation in relation to improving mental well-being, quality of life and treatment compliance of breast cancer patients in Qatar.

BACKGROUND: An insufficient number of studies have been carried out in the Middle East to evaluate the role of structured psychotherapeutic interventions in enhancing breast cancer patients' psychological well-being, quality of life and treatment compliance. This study has been designed to address this limitation by exploring the benefit of two structured psychotherapeutic interventions, crisis counseling and psychoeducation, in enhancing breast cancer patients' psychological well-being, quality of life and treatment compliance in Qatar. METHODS: A total of 201 women with early-stage breast cancer from the state of Qatar were recruited and randomized into either the control group or one of the treatment groups (crisis counseling or psychoeducation). Each of the two treatment interventions consisted of a total of six 60- to 90-minute sessions, which were provided over a period of 12 weeks. The short- and long-term benefits of the crisis counseling and psychoeducation interventions were evaluated in terms of improving patients' psychological well-being, quality of life and treatment compliance by asking all the patients to complete the Depression, Anxiety and Stress Scale, 21 item version (DASS-21) and European Organization for Research and Treatment of Cancer Quality of Life scale (QLQ-C30) instruments at different points in time and by monitoring their compliance to chemotherapy and radiotherapy treatment. RESULTS: This study revealed that both of the study interventions, crisis counseling and psychoeducation, were effective in improving women's psychological well-being and quality of life over time in comparison to the control group, but had no significant impact on patients' compliance with treatment. In addition, the study showed that psychoeducation conferred a greater advantage than did the crisis counseling model, especially in improving women's psychological well-being over time. CONCLUSION: This study is considered the first of its kind in Qatar to provide evidence on the benefit of crisis counseling and psychoeducation interventions in improving the psychological well-being and quality of life of women with early-stage breast cancer in Qatar. In addition, this study has provided innovative research that can be used as evidence to propose changes to the psychotherapy services for breast cancer patients in Qatar. This research study aims to provide a first step toward further research in the future, which will hopefully lead to a better health care system for cancer patients in Qatar.