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Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0–40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults. Clinical and molecular data were collected from a population-based cohort of children, adolescents, and young adults with gliomas from Toronto (TOR-Ped, age 0–18 years, collected Jan 1, 2000, to Dec 31, 2021; and TOR-AYA, age 18–40 years, collected Jan 1, 2000, to June 30, 2019). Additional validation paediatric cohorts from St Jude Children's Research Hospital (0–18 years, 2015–21) and the Children's Brain Tumor Network (0–18 years, 1981–2021) were used. Functional genomic tools were applied with the primary aim of assessing primary MMRD prevalence among glioma subgroups and germline impact. To evaluate the effect of primary MMRD on therapy and overall survival, Kaplan–Meier estimates were used on an additional cohort of patients with primary MMRD gliomas treated with immunotherapy. 1389 gliomas were included in the study. The prevalence of primary MMRD ranged between 3·7% and 12·4% in high-grade gliomas (overall 30 of 483; 6·2%, 95% CI 4·2–8·7) and less than 1% in low-grade gliomas (four of 899; 0·4%, 0·1–1·1; p<0·0001 by χ2 test). Specific molecular analysis for all gliomas showed that primary MMRD was absent among oligodendrogliomas (none of 67) and uncommon in BRAFV600E gliomas (one of 110) and histone mutant-driven gliomas (one of 150). In the paediatric age group (<18 years), primary MMRD was common in IDHWT and H3WT gliomas harbouring pathogenic TP53 variants (21 of 61; 34·4%, 22·7–47·7) and in malignant IDHmut gliomas (five of eight; 62·5%, 24·5–91·5). Germline aetiology accounted for 33 (94·3%) of 35 primary MMRD gliomas, including children, adolescents, and young adults with previously unrecognised Lynch syndrome. Survival was poor for patients with primary MMRD gliomas. Particularly poor survival was observed for those with IDHmut astrocytomas with primary MMRD when compared with those with mismatch repair-proficient gliomas (HR 12·6, 95% CI 2·8–57·5; p=0·0011 by multivariable Cox regression). Immune checkpoint blockade was associated with improved survival for patients with primary MMRD gliomas compared with conventional chemoradiotherapy regimens (HR 0·4, 0·3–0·7; p=0·0017 by multivariable Cox regression), regardless of age or germline status. Primary MMRD is more common than previously reported in gliomas in children, adolescents, and young adults, is enriched in specific molecular subgroups, and is associated with poor outcomes. Accurate detection, genetic testing, early diagnosis through surveillance, and implementation of immunotherapy might improve survival for these patients. The Canadian Institutes for Health Research, Stand Up to Cancer—Bristol Myers Squibb Catalyst, US National Institutes of Health, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Canada's Immunotherapy Network, Harry and Agnieszka Hall, Meagan's Hug, BRAINchild Canada, and the LivWise Foundation.

BACKGROUND: Comorbid mood disorders affect the prognosis of obsessive-compulsive disorder (OCD) negatively. Affective temperaments are assumed to be subsyndromal symptoms and precursors of mood disorders, but its effects on OCD outcome still remain unclear. There is a body of evidence, which supports the association between circadian rhythm disturbances and mood disorders in the literature. In contrast, there is limited data concerning the effects of chronobiological differences among the patients with OCD and OCD comorbid mood disorders. The main objective of this present study was to examine the clinical effects of affective temperaments and chronotype differences in patients with OCD. METHODS: The study participants were 76 patients with OCD, who have been under treatment at least for 12 weeks, and 55 healthy controls. The participants were administered the Yale-Brown Obsessive Compulsive Scale, Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Auto-questionnaire, Morningness and Eveningness Questionnaire, Hamilton Depression Rating Scale, and Hamilton Anxiety Scale. RESULTS: OCD patients scored higher in depressive, cyclothymic, irritable, and anxious temperament scores compared to the healthy controls. There were significant differences between patients with remission and not remission in depressive, cyclothymic, irritable, and anxious temperaments. Eveningness chronotype was more frequent in OCD patients; however, the difference was not statistically significant. CONCLUSIONS: Understanding the effects of affective temperaments and chronotype differences on the outcome of patients with OCD might provide valuable insights in developing new treatment approaches especially in treatment-resistant OCD cases.