Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Use of Social Media as a Platform for Education and Support for People With Diabetes During a Global Pandemic.

BACKGROUND: Patient education is a fundamental aspect of self-management of diabetes. The aim of this study was to understand whether a social media platform is a viable method to deliver education to people with diabetes and understand if people would engage and interact with it. METHODS: Education sessions were provided via 3 platforms in a variety of formats. "Tweetorials" and quizzes were delivered on the diabetes101 Twitter account, a virtual conference via Zoom and video presentations uploaded to YouTube. Audience engagement during and after the sessions were analyzed using social media metrics including impressions and engagement rate using Twitter analytics, Tweepsmap, and YouTube Studio. RESULTS: A total of 22 "tweetorial" sessions and 5 quizzes with a total of 151 polls (both in tweetorial and quiz sessions) receiving a total of 21,269 votes took place. Overall, the 1-h tweetorial sessions gained 1,821,088 impressions with an engagement rate of 6.3%. The sessions received a total of 2,341 retweets, 2,467 replies and 10,060 likes. The quiz days included 113 polls receiving 16,069 votes. The conference covered 8 topics and was attended live by over 100 people on the day. The video presentations on YouTube have received a total of 2,916 views with a watch time of 281 h and 8,847 impressions. CONCLUSION: Despite the limitations of social media, it can be harnessed to provide relevant reliable information and education about diabetes allowing people the time and space to learn at their own pace.

Nursing interventions for people with type 1 diabetes and frequent hypoglycaemia.

Type 1 diabetes is a lifelong condition which affects all age ranges, for reasons unknown, and the UK has one of the highest incidences of this complex condition in the world. Type 1 diabetes is caused by autoimmune damage to the insulin-producing ß-cells found in the pancreatic islet cells, leading to severe insulin deficiency. People with diabetes need to achieve a target glyosylated haemoglobin level to avoid macro- and microvascular complications, but there is the associated risk of hypoglycaemic events. These can vary in severity and consequences but will likely always cause worry for the person living with diabetes. There are many risk factors and reasons to be explored when looking at hypoglycaemia. This case study explores the nursing interventions that can be safely worked through and prioritised, within the community setting, to allow people with diabetes to be safe from severe hypoglycaemia, thus improving their quality of life and safety, as well as reducing costs for the NHS.

Risk Prediction of the Diabetes Missing Million: Identifying Individuals at High Risk of Diabetes and Related Complications.

Early diagnosis and effective management of type 2 diabetes (T2D) are crucial in reducing the risk of developing life-changing complications such as heart failure, stroke, kidney disease, blindness and amputation, which are also associated with significant costs for healthcare providers. However, as T2D symptoms often develop slowly it is not uncommon for people to live with T2D for years without being aware of their condition-commonly known as the undiagnosed missing million. By the time a diagnosis is received, many individuals will have already developed serious complications. While the existence of undiagnosed diabetes has long been recognised, wide-reaching awareness among the general public, clinicians and policymakers is lacking, and there is uncertainty in how best to identify high-risk individuals. In this article we have used consensus expert opinion alongside the available evidence, to provide support for the diabetes healthcare community regarding risk prediction of the missing million. Its purpose is to provide awareness of the risk factors for identifying individuals at high, moderate and low risk of T2D and T2D-related complications. The awareness of risk predictors, particularly in primary care, is important, so that appropriate steps can be taken to reduce the clinical and economic burden of T2D and its complications.