BACKGROUND: Constitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival.
METHODS: In order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus.
RESULTS: The working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia.
CONCLUSIONS: This position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.

The new guidelines of the European Society of Cardiology (ESC) on treatment of adult congenital heart disease (ACHD) were published in August 2020. The previous recommendations from 2010 were adapted to reflect the diagnostic and therapeutic progress made in the past 10 years. The recommendations are nearly exclusively based on an evidence level C (consensus of opinion of experts or knowledge from small studies, retrospective studies or registries). This is not surprising considering the heterogeneous patient population with a multitude of cardiac defects and repair strategies performed in the past. The cohort of ACHD patients is steadily growing in numbers and is becoming older due to reduced perioperative morbidity and mortality and further medical progress. Therefore, the current guidelines do not focus solely on the acute treatment of cardiac problems but also address the importance of a comprehensive longitudinal follow-up for a chronic, lifelong disorder. On a defect-specific level, progress in the past decade in arrhythmia diagnosis and management, percutaneous interventions and the treatment of pulmonary arterial hypertension have led to many revised or new recommendations. Finally, the 2020 guidelines also address for the first time the management of coronary anomalies.
UNASSIGNED: Im August 2020 veröffentlichte die European Society of Cardiology (ESC) neue Leitlinien zur Behandlung von Erwachsenen mit angeborenem Herzfehler („adult congenital heart disease“, ACHD). Die bisherigen Empfehlungen des Jahres 2010 wurden den Entwicklungen der letzten 10 Jahre in Diagnostik und Therapie angepasst. Nach wie vor entsprechen die Empfehlungen aber nahezu ausschließlich einem Evidenzgrad C (Expertenmeinung oder Erkenntnisse aus kleinen respektive retrospektiven Studien oder Registerstudien). Wir sprechen von einer heterogenen Patientenpopulation mit einer Vielzahl von unterschiedlichen Herzfehlern und Korrektureingriffen, die sich dank sinkender perioperativer Mortalität und weiterer medizinischer Fortschritte in konstantem Wachstum befindet und älter wird. Die aktuellen Leitlinien sind dementsprechend nicht nur auf die akute Behandlung kardialer Probleme fokussiert, sondern legen das Augenmerk auf eine gesamtheitliche longitudinale Betreuung. Ergänzt werden diese allgemeinen Aspekte durch defektspezifische Empfehlungen, wobei v. a. Fortschritte bei Arrhythmiediagnose und -behandlung, invasiver Kardiologie sowie pulmonalarterieller Hypertonie zu wesentlichen Anpassungen führten. Erstmalig wird in den Leitlinien 2020 auch die Thematik von Koronaranomalien aufgegriffen.

An estimated 10% of breast and ovarian cancers result from hereditary causes. Current testing guidelines for germ line susceptibility genes in patients with breast carcinoma were developed to identify carriers of BRCA1/ 2 variants and have evolved in the panel-testing era. We evaluated the capability of the National Comprehensive Cancer Network (NCCN) guidelines to identify patients with breast cancer with pathogenic variants in expanded panel testing.
An institutional review board-approved multicenter prospective registry was initiated with 20 community and academic sites experienced in cancer genetic testing and counseling. Eligibility criteria included patients with a previously or newly diagnosed breast cancer who had not undergone either single- or multigene testing. Consecutive patients 18 to 90 years of age were consented and underwent an 80-gene panel test. Health Insurance Portability and Accountability Act-compliant electronic case report forms collected information on patient demographics, diagnoses, phenotypes, and test results.
More than 1,000 patients were enrolled, and data records for 959 patients were analyzed; 49.95% met NCCN criteria, and 50.05% did not. Overall, 8.65% of patients had a pathogenic/likely pathogenic (P/LP) variant. Of patients who met NCCN guidelines with test results, 9.39% had a P/LP variant. Of patients who did not meet guidelines, 7.9% had a P/LP variant. The difference in positive results between these groups was not statistically significant (Fisher\'s exact test P = .4241).
Our results indicate that nearly half of patients with breast cancer with a P/LP variant with clinically actionable and/or management guidelines in development are missed by current testing guidelines. We recommend that all patients with a diagnosis of breast cancer undergo expanded panel testing.

An international panel of experts representing 17 European countries and Israel convened to discuss current needs and future developments in BRCA testing and counselling and to issue consensus recommendations. The experts agreed that, with the increasing availability of high-throughput testing platforms and the registration of poly-ADP-ribose-polymerase inhibitors, the need for genetic counselling and testing will rapidly increase in the near future. Consequently, the already existing shortage of genetic counsellors is expected to worsen and to compromise the quality of care particularly in individuals and families with suspected or proven hereditary breast or ovarian cancer. Increasing educational efforts within the breast cancer caregiver community may alleviate this limitation by enabling all involved specialities to perform genetic counselling. In the therapeutic setting, for patients with a clinical suspicion of genetic susceptibility and if the results may have an immediate impact on the therapeutic strategy, the majority voted that BRCA1/2 testing should be performed after histological diagnosis of breast cancer, regardless of oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status. Experts also agreed that, in the predictive and therapeutic setting, genetic testing should be limited to individuals with a personal or family history suggestive of a BRCA1/2 pathogenic variant and should also include high-risk actionable genes beyond BRCA1/2. Of high-risk actionable genes, all pathological variants (i.e. class IV and V) should be reported; class III variants of unknown significance, should be reported provided that the current lack of clinical utility of the variant is expressly stated. Genetic counselling should always address the possibility that already tested individuals might be re-contacted in case new information on a particular variant results in a re-classification.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease.

暂无摘要。

暂无摘要。