The detection of germline and somatic BRCA1/2 genetic variants through parallel testing of patients with high-grade serous ovarian cancer: a national retrospective audit.

OBJECTIVE: To determine the frequency of germline and somatic pathogenic BRCA1 and BRCA2 variants in patients with high-grade serous ovarian cancer tested by next-generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. DESIGN: National retrospective audit. SETTING: The All Wales Medical Genomics Service (AWMGS). POPULATION: Patients with high-grade serous ovarian/fallopian tube/peritoneal cancer referred by oncologists to the AWMGS between February 2015 and February 2021 for germline and/or tumour testing of the BRCA1 and BRCA2 genes by NGS. METHODS: Analysis of NGS data from germline and/or tumour testing. MAIN OUTCOME MEASURES: Frequency of BRCA1 and BRCA2 pathogenic variants. RESULTS: The overall observed germline/somatic pathogenic variant detection rate was 11.6% in the 844 patients included in this study, with a 9.2% (73/791) germline pathogenic variant detection rate. Parallel tumour and germline testing was carried out for 169 patients and the overall pathogenic variant detection rate for this cohort was 14.8%, with 6.5% (11/169) shown to have a somatic pathogenic variant. Two BRCA1 dosage variants were found during germline screens, representing 2.0% (2/98) of patients with a pathogenic variant that would have been missed through tumour testing alone. CONCLUSIONS: Parallel germline and tumour BRCA1 and BRCA2 testing maximises the detection of pathogenic variants in patients with high-grade serous ovarian cancer. TWEETABLE ABSTRACT: Parallel germline and tumour testing maximises BRCA pathogenic variant detection in ovarian cancer.

A Prospective Phase I/II Study of Docetaxel, Cisplatin and Continuous Capecitabine in Advanced Oesophago-Gastric Cancer (NWCOG-3).

AIMS: This open-label prospective phase I/II dose-escalation study determined the maximum tolerated dose (MTD) and then evaluated response, safety and feasibility of a novel combination of docetaxel, cisplatinum and capecitabine (DCC) in chemotherapy-naive patients with advanced oesophago-gastric carcinoma. MATERIALS AND METHODS: Patients with adenocarcinoma or squamous cell carcinoma of the oesophagus or stomach, of good performance status, deemed too advanced for curative treatment, were given systematically increasing doses of 3 weekly DCC to ascertain the MTD. Phase II administered up to six cycles of DCC at the MTD, assessing response and toxicity. RESULTS: Between November 2007 and November 2012, 15 patients were recruited into phase I and 41 into phase II. The MDT was a 21 day cycle of docetaxel 60 mg/m2 IV day 1, cisplatinum 60 mg/m2 IV day 1 and oral capecitabine 1000 mg/m2 daily in two divided doses for days 1-21. The most common phase II grade 3-4 toxicities were neutropenia 88% (10% febrile neutropenia), fatigue 15%, sensory neuropathy 10% and non-neutropenic infection 10%. The overall response rate was 51%, median progression-free survival was 7.4 months (confidence interval 6.7-9.4) and median overall survival was 10.9 months (confidence interval 7.7-13.7). CONCLUSION: DCC was tolerable and feasible with promising efficacy, and may be suitable for future investigation in both first-line metastatic and neoadjuvant settings.

A review of systemic anticancer therapy in disease palliation.

Background: Systemic anticancer therapy (SACT) is a collective term to describe the growing number of differing therapies used in malignancy to achieve palliation. Improving symptoms, quality of life (QOL) and where possible quantity of life are the goals of these treatments. Sources of data: A comprehensive literature review was undertaken using Medline, Embase and the Cochrane database. Areas of agreement: The use of palliative SACT can lead to increases in symptom control, QOL and survival. The breadth of treatable cancers has increased along with the number of therapeutic options. Areas of controversy: The increasing use of SACT in the last weeks of life and the lack of consistency about the terms Supportive Care/Best Supportive Care in the trial setting. Growing points: Integration between oncology and other palliative services leads to better outcomes. Areas timely for developing research: Improved prognostication tools to elucidate which patients will benefit from SACT.

Reducing febrile neutropenia rates in early breast cancer. Experience of two UK cancer centres.

PURPOSE: Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is used in many institutions across the UK due to unacceptable febrile neutropenia (FN) rates with FEC-D (fluorouracil, epirubicin, cyclophosphamide-docetaxel). The resultant reduction in FN rate is thought to maintain dose intensity and improve patient experience. This retrospective study was performed to assess whether the addition of G-CSF primary prophylaxis into daily clinical practice has achieved these aims. METHODS: Collaborative audit performed in two UK cancer centres before and after the integration of G-CSF primary prophylaxis with FEC-D. The primary objective was FN rate. RESULTS: Data from 342 patients were analysed, 151 before routine use of primary G-CSF and 191 after. The FN rates were 30 and 11%, respectively. Despite the 99% adherence to primary G-CSF policy, there were more dose reductions (8 increased to 13%) and dose delays (11 increased to 23%) following the use of G-CSF primary prophylaxis. This appeared to be due to non-FN toxicities. Inpatient days decreased substantially from 93 to 16 and antibiotic courses from 28 to 13 (per hundred patients). CONCLUSIONS: Near universal adherence to the G-CSF policy in FEC-D treatment has led to a reduction in FN rate and inpatient days but has not translated into improved dose intensity. This collaborative audit allows sufficient data to give insight into current practice and generate hypotheses for further investigation.

Quality of hospital care in African American and white patients with ischemic stroke and TIA.

OBJECTIVE: To examine whether differences exist in the in-hospital diagnostic evaluation and treatment of African American and white patients with ischemic stroke (IS) and TIA. METHODS: The authors used a state-wide hospital-based stroke registry prototype designed to measure and track the quality of acute stroke care. Weighted descriptive statistics for each racial group are reported for the following variables, which were deemed to be potential confounders of the association between race and the quality of stroke care: age, gender, insurance status, emergency medical services arrival, functional status on presentation, modified Rankin score at discharge, stroke subtype, neurologist involved in care, and stroke pathway utilization. The magnitude and significance of the associations between race and each quality indicator of in-hospital acute stroke care were determined by separate multiple logistic regression models, adjusting for all potential confounding variables. RESULTS: Among patients admitted with IS and TIA who were alive at discharge (n = 1,837), 340 (18.5%) were African American and 1497 (81.5%) were white. After multivariate analysis, African Americans were less likely to have a door-to-CT time of less than 25 minutes (odds ratio [OR] 0.13 [CI 0.049 to 0.32]), obtain cardiac monitoring (OR 0.54 [CI 0.29 to 1.03]), undergo dysphagia screening (OR 0.69 [CI 0.50 to 0.95]), and receive smoking cessation counseling (OR 0.27 [CI 0.17 to 0.42]). CONCLUSIONS: Quality of hospital care for African American and white patients with acute ischemic stroke and TIA was similar in many respects. However, African Americans were less likely to receive a CT within 25 minutes of arrival, cardiac monitoring, dysphagia screening, and smoking cessation counseling.

IV tissue plasminogen activator use in acute stroke: experience from a statewide registry.

OBJECTIVE: To assess the use of IV recombinant tissue plasminogen activator (rt-PA) in a statewide hospital-based stroke registry and to identify factors associated with its use among eligible patients. METHODS: A modified stratified sampling scheme was used to obtain a representative sample of 16 hospitals. Prospective case ascertainment and data collection were used to identify all acute stroke admissions over a 6-month period. Subjects eligible for IV rt-PA were defined as those who arrived within 3 hours of onset, who had no evidence of hemorrhage on initial brain image, and who had no physician-documented reasons for non-treatment with IV rt-PA. Multivariate logistic regression was used to identify factors associated with IV rt-PA use. RESULTS: Of 2,566 stroke admissions, 330 (12.9%) met the eligibility criteria for rt-PA treatment, and of these 43 (13%) received IV rt-PA treatment. Among 2,236 admissions excluded from consideration, 21% had evidence of hemorrhage on initial imaging, 35% had unknown stroke onset times, 38% had an onset to arrival time >3 hours, and 6% had physician documented contraindications. Among eligible patients, being male, use of emergency medical services, and rapid presentation were associated with increased IV rt-PA use. CONCLUSIONS: Treatment with IV rt-PA was underutilized in this hospital-based stroke registry. The primary reason for nontreatment was delayed presentation. Reducing prehospital and in-hospital response times would help increase IV rt-PA use, as would greater emergency medical services use. Improving the documentation of onset times would help clarify the underlying causes of delayed presentation.