Association between tumour somatic mutations and venous thromboembolism in the 100,000 Genomes Project cancer cohort:A study protocol

Venous thromboembolism (VTE) is a common cause of morbidity and mortality in patients with cancer, and there is evidence that specific aberrations in tumour biology contribute to the pathophysiology of this condition. We plan to examine the association between tumour somatic mutations and VTE in an existing cohort of patients with cancer, who were enrolled to the flagship Genomics England 100,000 Genomes Project. Here, we outline an a-priori analysis plan to address this objective, including details on study cohort selection, exposure and outcome definitions, annotation of genetic variants and planned statistical analyses. We will assess the effect of 1) deleterious somatic DNA variants in each gene; 2) tumour mutational burden and 3) tumour mutational signatures on the rate of VTE (outcome) in a pan-cancer cohort. Sensitivity analyses will be performed to examine the robustness of any associations, including adjustment for potentially correlated co-variates including tumour type, stage and systemic anti-cancer therapy. We hope that results from this study may help to identify key genes which are implicated in the development of cancer associated thrombosis, which may shed light on related mechanistic pathways and/or provide data which can be integrated into genetic risk prediction models for these patients

Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis : a cohort study in the UK Biobank

Background Prostate cancer is highly heritable, with >250 common variants associated in genome-wide association studies. It commonly presents with non-specific lower urinary tract symptoms that are frequently associated with benign conditions. Methods Cohort study using UK Biobank data linked to primary care records. Participants were men with a record showing a general practice consultation for a lower urinary tract symptom. The outcome measure was prostate cancer diagnosis within 2 years of consultation. The predictor was a genetic risk score of 269 genetic variants for prostate cancer. Results A genetic risk score (GRS) is associated with prostate cancer in symptomatic men (OR per SD increase = 2.12 [1.86-2.41] P = 3.5e-30). An integrated risk model including age and GRS applied to symptomatic men predicted prostate cancer (AUC 0.768 [0.739-0.796]). Prostate cancer incidence was 8.1% (6.7-9.7) in the highest risk quintile. In the lowest quintile, prostate cancer incidence was Conclusions This study is the first to apply GRS in primary care to improve the triage of symptomatic patients. Men with the lowest genetic risk of developing prostate cancer could safely avoid invasive investigation, whilst those identified with the greatest risk could be fast-tracked for further investigation. These results show that a GRS has potential application to improve the diagnostic pathway of symptomatic patients in primary care.Peer reviewe

Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19

Importance: Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. // Objective: To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. // Design, Setting, and Participants: The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. // Exposures: SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. // Main Outcomes and Measures: The primary end point was all-cause mortality within the primary hospitalization. // Results: Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19–related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). // Conclusions and Relevance: The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed

Analysis of the structure and function of adenovirus type 5 early region 4 protein

The E4orf4 protein of adenovirus type 5 has been shown to induce p53-independent apoptosis. The only known function of E4orf4 is to bind to the Balpha subunit of protein phosphatase 2A (PP2A). A series of experiments were performed with both wild-type and mutant forms of E4orf4 to examine Balpha subunit binding and cell killing following introduction into p53-deficient cells. Deletion mutant analysis indicated residues 12--18 and 103--114 were not required for cell killing. Point mutant analysis indicated that residues required for Balpha binding and cell killing are dispersed throughout the E4orf4 sequence. Analysis of these results showed that binding to PP2A via its Balpha subunit is essential for induction of p53-independent apoptosis by E4orf4. Binding assays showed that E4orf4 cannot bind B'' subunits of PP2A. In human cells, E4orf4 induces an apoptosic pathway that involves caspase-3 independent cleavage of poly(ADP-ribosyl) polymerase. E4orf4's activity may be controlled through post-translational modification since E4orf4 was found to be phosphorylated on serine residues

Motivation to engage in communication skills training by oncology specialty

29 Background: The present study aimed to assess oncology fellows’ motivation to participate in communication skills training by specialty. Methods: Oncology fellows attending communication skills training were invited to participate in program-evaluation research. Before each workshop, participants provided demographic information and completed subjective communications skills and motivation questionnaires. Following the workshop, the subjective communication skills survey was repeated. Results: Fifty physician trainees participated. Half were female. Most were first-year fellows (81%), White/Caucasian (56%), non-Hispanic (92%). Mean age was 32 years ( SD= 3.63). Motivation for attending the workshop was most commonly external regulation (e.g., required participation; M= 5.66, SD= 1.38), followed by identified regulation (e.g., belief the workshop will be helpful; M= 4.30, SD= 1.26) and intrinsic motivation (e.g., interest in topic; M= 3.76, SD= 1.15). Amotivation was less common ( M= 2.47, SD= 1.35). All scales rated 1-7. A one-way ANOVA revealed significant differences in levels of identified regulation ( F(4,44) = 3.26, p= .020) and external regulation ( F(4,45) = 3.47, p= .015) between fellows of different specialties. Post-hoc comparisons revealed that Hematology Oncology fellows reported significantly lower levels of identified regulation than Hospice & Palliative Medicine fellows ( M difference = -1.35, p= .024). Hematology Oncology ( M difference = 1.60, p= .012) and Surgical Oncology fellows ( M difference = 1.67, p= .043) both reported significantly higher levels of external regulation than Hospice & Palliative Medicine fellows. However, there were no significant differences between specialties with regard to post-workshop preparedness or pre-post change in preparedness ( ps > .05). Conclusions: There is opportunity to create targeted interventions to improve physician motivation to participate in communication skills education by matching messaging to each specialty’s motivation type

Predicting survival in cancer patients with and without 30‐day readmission of an unplanned hospitalization using a deficit accumulation approach

Abstract Background For cancer patients with an unplanned hospitalization, estimating survival has been limited. We examined factors predicting survival and investigated the concept of using a deficit‐accumulation survival index (DASI) in this population. Methods Data were abstracted from medical records of 145 patients who had an unplanned 30‐day readmission between 01/01/16 and 09/30/16. Comparison data were obtained for patients who were admitted as close in time to the date of index admission of a study patient, but who did not experience a readmission within 30 days of their discharge date. Our survival analysis compared those readmitted within 30 days versus those who were not. Scores from 23 medical record elements used in our DASI system categorized patients into low‐, moderate‐, and high‐score groups. Results Thirty‐day readmission was strongly associated with the survival (adjusted hazard ratio [HR] 2.39; 95% confidence interval [CI], 1.46‐3.92). Patients readmitted within 30 days of discharge from index admission had a median survival of 147 days (95% CI, 85‐207) versus patients not readmitted who had not reached median survival by the end of the study (P < .0001). DASI was useful in predicting the survival; median survival time was 78 days (95% CI, 61‐131) for the high score, 318 days (95% CI, 207‐426) for the moderate score, and not reached as of 426 days (95% CI, 251 to undetermined) for the low‐score DASI group (P < .0001). Conclusions Patients readmitted within 30 days of an unplanned hospitalization are at higher risk of mortality than those not readmitted. A novel DASI developed from clinical documentation may help to predict survival in this population