Pembrolizumab efficacy in a tumor mutation burden-high glioblastoma patient: A case study and implications for precision oncology.

A glioblastoma (GBM) patient with a high tumor mutation burden (TMB-high) and mismatch repair deficiency (dMMR) exhibited a significant response to pembrolizumab, an immune checkpoint inhibitor (ICI), despite prior treatment with temozolomide (TMZ), known to induce hypermutation and potential resistance to ICIs. The rapid disease progression, indicated by 80% Ki67 positivity, was markedly countered by the positive outcome of pembrolizumab treatment. This case challenges traditional GBM treatment paradigms, demonstrating the potential of precision oncology in patients with significant TMB and dMMR, and underscores the importance of comprehensive genomic profiling in guiding clinical decisions in GBM management.

Comparison of two families with and without ataxia harboring novel variants in PRKCG.

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant SCA caused by variants of the PRKCG encoding protein kinase C gamma (PKCγ). Although the toxic gain-of-function mechanism is the main cause of SCA14, its molecular pathophysiology remains unclear. To elucidate the molecular pathogenesis of SCA14, we analyzed two families with the variants in PRKCG.

Real-world safety and effectiveness of ledipasvir/sofosbuvir for the treatment of chronic hepatitis C virus genotype 1 in Japan.

As patients with chronic hepatitis C virus (HCV) tend to be older and/or have advanced liver disease in Japan, real-world data are needed to evaluate safe and effective treatment options. The study aim was to assess safety and effectiveness of ledipasvir/sofosbuvir (LDV/SOF) in a real-world cohort of Japanese patients with HCV genotype (GT) 1 infection overall and by patient subgroups: elderly, compensated cirrhotic, advanced fibrotic and those with hepatocellular carcinoma (HCC). A large prospective observational study was conducted, enrolling adult patients treated for HCV GT1 infection with LDV/SOF at clinical sites across Japan.

Germline mutation landscape of multiple endocrine neoplasia type 1 using full gene next-generation sequencing.

Background Loss-of-function germline MEN1 gene mutations account for 75-95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated. Objective To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile.

[A case of Parkinson's disease following restless genial sensation].

A 62-year-old woman experienced uncomfortable genial sensation in 2010. Her uncomfortable sensation was exacerbated during rest at night and improved by walking. She exhibited short-stepped gait with postural disturbance and was diagnosed as suffering from Parkinson's disease (PD) in 2013.

Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility.

Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project.

Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation.

Context: The phenotype of familial pheochromocytoma (PHEO) associated with germline TMEM127 mutations (TMEM127-related PHEO) has not been clearly defined.

Objective: This study aimed to investigate the penetrance, full phenotypic spectrum and effectiveness of clinical/genetic screening in TMEM127-related PHEO.

Design, Setting, And Participants: Clinical and genetic screening, and genetic counseling were offered to 151 individuals from a six-generation family carrying a TMEM127 germline mutation in a referral center.

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations.

Objective: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for.

Design: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.

p27 variant and corticotropinoma susceptibility: a genetic and in vitro study.

Germline mutations in p27(kip1) are associated with increased susceptibility to multiple endocrine neoplasias (MEN) both in rats and humans; however, the potential role of common polymorphisms of this gene in endocrine tumor susceptibility and tumorigenesis remains mostly unrecognized. To assess the risk associated with polymorphism rs2066827 (p27-V109G), we genotyped a large cohort of Brazilian patients with sporadic endocrine tumors (pituitary adenomas, n=252; pheochromocytomas, n=125; medullary thyroid carcinoma, n=51; and parathyroid adenomas, n=19) and 885 population-matched healthy controls and determined the odds ratios and 95% CIs. Significant associations were found for the group of patients with pituitary adenomas (P=0.

Penetrance of functioning and nonfunctioning pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 in the second decade of life.

Context: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. A potential positive correlation between tumor size and malignancy (2-3 cm, 18%; >3 cm, 43%) has greatly influenced the management of MEN1 adults with NF-PETs.

Objective: The aim of the study was to estimate the penetrance of NF-PETs, insulinomas, and gastrinomas in young MEN1 carriers.

Polymorphisms in the p27kip-1 and prohibitin genes denote novel genes associated with melanoma risk in Brazil, a high ultraviolet index region.

Ultraviolet (UV) radiation is a major environmental risk factor to the development of cutaneous melanoma as it induces pyrimidine dimers in DNA. Genes that exert their function by arresting the cell cycle are critical to avoid carcinogenic mutations, allowing the processing of DNA repair systems. This study was carried out to evaluate the role of polymorphisms in cell cycle genes such as TP53, p27, CDKN2A, prohibitin, and GADD153 in melanoma risk as well as their influence on known risk factors in a high UV index region.

RET haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family.

Hirschsprung disease is a congenital form of aganglionic megacolon that results from cristopathy. Hirschsprung disease usually occurs as a sporadic disease, although it may be associated with several inherited conditions, such as multiple endocrine neoplasia type 2. The rearranged during transfection (RET) proto-oncogene is the major susceptibility gene for Hirschsprung disease, and germline mutations in RET have been reported in up to 50% of the inherited forms of Hirschsprung disease and in 15-20% of sporadic cases of Hirschsprung disease.

Narrowing the gap of personalized medicine in emerging countries: the case of multiple endocrine neoplasias in Brazil.

The finished version of the human genome sequence was completed in 2003, and this event initiated a revolution in medical practice, which is usually referred to as the age of genomic or personalized medicine. Genomic medicine aims to be predictive, personalized, preventive, and also participative (4Ps). It offers a new approach to several pathological conditions, although its impact so far has been more evident in mendelian diseases.

Somatotroph pituitary adenoma with acromegaly and autosomal dominant polycystic kidney disease: SSTR5 polymorphism and PKD1 mutation.

A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior.