Clinically significant germline pathogenic variants are missed by tumor genomic sequencing.

A germline pathogenic variant may be present even if the results of tumor genomic sequencing do not suggest one. There are key differences in the assay design and reporting of variants between germline and somatic laboratories. When appropriate, both tests should be completed to aid in therapy decisions and determining optimal screening and risk-reduction interventions.

Identification of germline cancer predisposition variants during clinical ctDNA testing.

Next-generation sequencing of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. ctDNA variant allele frequency (VAF) is commonly reported and may aid in discerning whether a variant is germline or somatic. We report on the fidelity of VAF in ctDNA as a predictor for germline variant carriage. Two patient cohorts were studied. Cohort 1 included patients with known germline variants. Cohort 2 included patients with any variant detected by the ctDNA assay with VAF of 40-60%. In cohort 1, 36 of 91 (40%) known germline variants were identified through ctDNA analysis with a VAF of 39-87.6%. In cohort 2, 111 of 160 (69%) variants identified by ctDNA analysis with a VAF between 40 and 60% were found to be germline. Therefore, variants with a VAF between 40 and 60% should induce suspicion for germline status but should not be used as a replacement for germline testing.

Found in translation: navigating uncertainty to save a child's heart. Paediatric cardiac surgery in Cape Town, South Africa.

This medical humanities paper describes our qualitative research into pathways to care and informed consent for 10 children who had cardiac surgery in the Red Cross War Memorial Children's Hospital, Cape Town, South Africa. Our multidisciplinary team consists of cardiologists, anthropologists, a social scientist and a general practitioner in two sites, South Africa and Australia. This paper builds on our first publication in a specialist cardiology journal on a 'qualitative snapshot' of these children's life stories from 2011 to 2016 but turns to the medical humanities to explore a concept of 'uncertainty'. Data analysis revealed that for the children's parents and doctors, 'uncertainty' underscored procedures. Indeed, the literature review showed that 'uncertainty' is intrinsic to heart surgery and was integral to Barnard's first heart transplant in Cape Town in 1967. We demonstrate that in meeting the challenges inherent in the 'uncertainty dimension', doctors established greater 'medical certainty'about each operation. This happened as they encountered the difficult clinical and biopsychosocial factors that were fundamental to the diagnosis of children's cardiac defects. It was doctors' translation of these decision-making processes that informed parental decisions and described why, despite feelings of uncertainty, parents signed consent. To visually describe heart surgery in this locality we asked the South African photographer, Guy Neveling to record some children undergoing echocardiograms and surgery. These photographs qualitatively demonstrate what medical certainty entails, and parents' trust in doctors and surgeons, whom they knew had 'reasonable certainty' that their child's 'heart is worth saving'.

Precision Prevention: The Current State and Future of Genomically Guided Cancer Prevention.

The identification of cancer-predisposing germline variants has potentially substantial clinical impact for patients and their families. Although management guidelines have been proposed for some genes, guidelines for other genes are lacking. This review focuses on the current surveillance and management guidelines for the most common hereditary cancer syndromes and discusses some of the most pivotal studies supporting the available guidelines. We also highlight the gaps in the identification of germline carriers, the cascade testing of at-risk relatives, and the challenges impeding the proper follow-up and optimal management of pathogenic germline carriers. The anticipated surge in the number of identified germline carriers, deficient management guidelines, poor cascade testing uptake, and long-term follow-up necessitate the development of multidisciplinary clinics as an obligatory step toward the improvement of cancer prevention.

Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy.

PURPOSE: Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS: A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS: Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION: The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common.

A first qualitative snapshot: cardiac surgery and recovery in 10 children in the Red Cross War Memorial Children's Hospital, Cape Town, South Africa (2011-2016).

This article describes our qualitative research on the follow-up of 10 children, 5 years into recovery after cardiac surgery. The research was driven by a multi-disciplinary team of medical anthropologists, cardiologists, and an intensive care specialist and was based at the Red Cross War Memorial Children's Hospital where they underwent surgeries. The research sought to answer two questions; first, could we successfully maintain contact with and follow up the children; the second - which will be answered in future papers - asked what life was like for them and their families during surgery and later recovery. The results are presented as a discussion on the themes that arose in our engagement and analysis and not as clinical evidence. These showed that elective surgery although significantly delayed was successful, and all children were followed up at their medical appointments. The researchers, however, were unable to establish follow-up with all families over the duration of the study. In the final round of interviews in the respondents' homes, of 10 children, we remained in contact with seven. The discussion argues that effective communication and access to these children was often compromised by their coming from the poorer communities in the Cape Town metropolitan region, making them even more vulnerable during their recovery periods.

Access to mental health care in El Salvador: a case study of progress toward decentralization / Acceso a la atención de salud mental en El Salvador: un estudio de caso de progreso hacia la descentralización / Acesso à saúde mental em El Salvador: um estudo de caso sobre o progresso em direção à descentralização

ABSTRACT Objective To assess the need for decentralization of psychiatric services in El Salvador, based on country-specific evidence, and to generate baseline measures the government and researchers could use to monitor and measure future progress toward decentralization. Methods Observations were made and psychiatric outpatients and their families/caregivers (n = 453) surveyed with a cross-sectional instrument at the National Psychiatric Hospital (Hospital Nacional General y de Psiquiatría "Dr. José Molina Martínez") in the capital city of San Salvador. Findings were compared with national census data to determine barriers to psychiatric care in a largely centralized system. The following data were collected: department of origin, travel time to hospital, time in hospital, costs, and qualitative comments about accessing services. Descriptive statistics and regression were used to assess the data. Government reports on all psychiatric outpatient consultations provided nationwide in 2015 (n = 61 010) at 10 regional hospitals were also reviewed and compared to population data to determine the proportion of the population of each hospital service area (department or group of departments) that received a psychiatric outpatient consultation. Results Households from the half of the country (7 out of 14 departments) farthest away from the National Psychiatric Hospital (42% of the general population) spent twice as much time and three times as much money to access the hospital's psychiatric outpatient services, resulting in severe hardship on both patients and families/caregivers. Conclusions This report estimates that 45% of those with mental health needs in the seven departments farthest away from the National Psychiatric Hospital departments are still not accessing services compared to the seven departments nearest the hospital. The results of this study support the World Health Organization's call for governments to fully implement community-based mental health systems. This is the first study to assess progress toward decentralization of psychiatric services in El Salvador.

RESUMEN Objetivo Evaluar la necesidad de la descentralización de los servicios psiquiátricos en El Salvador con base en la evidencia específica del país y generar medidas de referencia que podrían ser utilizadas por el gobierno y los investigadores para monitorear y medir el progreso futuro hacia la descentralización. Métodos Se realizaron observaciones, y se encuestaron pacientes psiquiátricos ambulatorios y sus familiares/cuidadores (n = 453) con un instrumento de corte transversal en el Hospital Nacional Psiquiátrico (Hospital Nacional General y de Psiquiatría "Dr. José Molina Martínez") en la capital, San Salvador. Los hallazgos se compararon con los datos del censo nacional para determinar las barreras en el acceso a la atención psiquiátrica en un sistema en gran medida centralizado. Se recopilaron los siguientes datos: departamento de origen, tiempo de viaje al hospital, tiempo en el hospital, costos y comentarios cualitativos sobre el acceso a los servicios. Se usaron estadísticas descriptivas y regresión para evaluar los datos. También se revisaron informes gubernamentales sobre todas las consultas psiquiátricas ambulatorias proporcionados a nivel nacional en 2015 (n = 61 010) en 10 hospitales regionales, y estos se compararon con datos poblacionales para determinar la proporción de la población de cada área de servicio hospitalario (departamento o grupo de departamentos) que efectuó una consulta psiquiátrica ambulatoria. Resultados Los hogares de la mitad del país (7 de los 14 departamentos) más alejados del Hospital Psiquiátrico Nacional (42% de la población general) gastaron el doble de tiempo y tres veces más dinero para acceder a los servicios psiquiátricos ambulatorios del hospital, lo que resultó en dificultades económicas severas tanto para los pacientes como para sus familias/cuidadores. Conclusiones Este informe estimó que el 45% de las personas con necesidades de salud mental en los 7 departamentos más alejados del Hospital Nacional Psiquiátrico aún no tienen acceso a los servicios en comparación con los 7 departamentos más cercanos al hospital. Los resultados de este estudio respaldan el llamado de la Organización Mundial de la Salud para que los gobiernos implementen por completo sistemas de salud mental basados en la comunidad. Este es el primer estudio en evaluar el progreso hacia la descentralización de los servicios psiquiátricos en El Salvador.

RESUMO Objetivo Avaliar a necessidade de descentralização dos serviços psiquiátricos em El Salvador com base em provas específicas do país e gerar medições de referência que poderiam ser usados pelo governo e pesquisadores para monitorar e medir o progresso futuro no sentido da descentralização. Métodos Observações foram feitas, e foram pesquisados pacientes psiquiátricos ambulatoriais e suas famílias/cuidadores (n = 453) com uma ferramentas de seção transversal no Hospital Psiquiátrico Nacional (National Hospital Geral e Psiquiatria "Dr. Jose Molina Martinez") na capital, São Salvador. Os resultados foram comparados com dados do censo nacional para determinar as barreiras ao acesso à assistência psiquiátrica em um sistema amplamente centralizado. Os seguintes dados foram coletados: departamento de origem, tempo de deslocamento para o hospital, tempo no hospital, custos e comentários qualitativos sobre o acesso aos serviços. Para avaliar os dados foram utilizadas estatística descritiva e regressão. Também foram analisados relatórios do governo sobre todas as consultas psiquiátricas ambulatoriais a nível nacional em 2015 (n = 61 010) em 10 hospitais regionais, e comparados com os dados da população para determinar a proporção da população de cada área de serviço hospitalar (departamento ou grupo de departamentos) que recebeu uma consulta psiquiátrica para pacientes ambulatoriais. Resultados As pessoas da metade do país (7 dos 14 departamentos) mais afastada do Hospital Psiquiátrico Nacional (42% da população geral) gastaram o dobro do tempo e três vezes mais dinheiro para acessar os serviços psiquiátricos ambulatoriais do hospital, o que resultou em privação severa para pacientes e familiares/cuidadores. Conclusões Este relatório estimou que 45% das pessoas com necessidades de saúde mental nos 7 departamentos mais distantes do Hospital Psiquiátrico Nacional ainda não têm acesso aos serviços em comparação com os 7 departamentos mais próximos do hospital. Os resultados deste estudo apoiam o apelo da Organização Mundial de Saúde para que os governos implementem totalmente os sistemas de saúde mental baseados na comunidade. Este é o primeiro estudo a avaliar o progresso em direção à descentralização dos serviços psiquiátricos em El Salvador.