Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

PROPERTIES OF THE BEOSL DOSIMETRY SYSTEM IN THE FRAMEWORK OF A LARGE-SCALE PERSONAL MONITORING SERVICE.

The Individual Monitoring Service of the Helmholtz Zentrum München is currently using the BeOSL dosimetry system for monitoring ∼15 000 persons per month. This dosimetry system has a modular structure and represents a complete new concept on handling dosemeters in a large-scale dosimetry service. It is based on optically stimulated luminescence dosemeters made of beryllium oxide. The dosimetric and operational properties of the system are shown and discussed.

Maternity care in rural Nepal: a health service analysis.

This study assesses the performance of maternity care and its specific service components (preventive interventions in antenatal care, antenatal screening, referral, obstetric care) in Banke District, Nepal, using a set of structure, process, and output/outcome indicators. Data sources included health service documents in 14 first level health units and two hospitals, covering 1378 pregnancies and 1323 deliveries, structured observations, antenatal exit interviews (n = 136) and interviews with maternity users (n = 146). Coverage of antenatal care (28%) and skilled delivery care (16%) was low. In antenatal care, preventive interventions were only partially implemented (effective iron supplementation in 17% of users). On average one minute was spent on individual counselling per consultation. 41% of pregnancies were identified as high risk and 15% received referral advice, which was followed in only 32%. Hospital deliveries accounted for 9.8% of all deliveries. Hospital-based maternal mortality was 6.8/1000 births and the stillbirth rate 70/1000. High rates of stillbirth were observed in breech delivery (258/1000 births), caesarean section (143/1000) and twin delivery (133/1000). The risk of stillbirth was higher for rural women (RR 2.3; 95% CI 1.51-3.50) and appeared to be related to low socio-economic status. Emergency admissions were rare and accounted for 3.4% of hospital deliveries or only 0.4% of all expected deliveries. There was hardly any accumulation of high-risk pregnancies at hospital. The population-based rate of caesarean section was 1.1% (urban 2.3%, rural 0.2%). The estimated unmet obstetric need was high (82 cases or 61% of expected live-threatening maternal conditions did not receive appropriate intervention). The limited effectiveness of maternity care is the result of deficiencies of all service components. We propose a two-pronged approach by starting quality improvement of maternity care from both ends of maternity services: preventive interventions for all women and hospital-based obstetric care. Antenatal screening needs to be rationalized by reducing inflated risk catalogues that result in stereotypical and often rejected referral advice.