Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.

External validation and application of the Diabetes Population Risk Tool (DPoRT) for prediction of type 2 diabetes onset in the US population.

INTRODUCTION: Characterizing diabetes risk in the population is important for population health assessment and diabetes prevention planning. We aimed to externally validate an existing 10-year population risk model for type 2 diabetes in the USA and model the population benefit of diabetes prevention approaches using population survey data. RESEARCH DESIGN AND METHODS: The Diabetes Population Risk Tool (DPoRT), originally derived and validated in Canada, was applied to an external validation cohort of 23 477 adults from the 2009 National Health Interview Survey (NHIS). We assessed predictive performance for discrimination (C-statistic) and calibration plots against observed incident diabetes cases identified from the NHIS 2009-2018 cycles. We applied DPoRT to the 2018 NHIS cohort (n=21 187) to generate 10-year risk prediction estimates and characterize the preventive benefit of three diabetes prevention scenarios: (1) community-wide strategy; (2) high-risk strategy and (3) combined approach. RESULTS: DPoRT demonstrated good discrimination (C-statistic=0.778 (males); 0.787 (females)) and good calibration across the range of risk. We predicted a baseline risk of 10.2% and 21 076 000 new cases of diabetes in the USA from 2018 to 2028. The community-wide strategy and high-risk strategy estimated diabetes risk reductions of 0.2% and 0.3%, respectively. The combined approach estimated a 0.4% risk reduction and 843 000 diabetes cases averted in 10 years. CONCLUSIONS: DPoRT has transportability for predicting population-level diabetes risk in the USA using routinely collected survey data. We demonstrate the model's applicability for population health assessment and diabetes prevention planning. Our modeling predicted that the combination of community-wide and targeted prevention approaches for those at highest risk are needed to reduce diabetes burden in the USA.

Pathophysiology of Hepatic Encephalopathy: A Framework for Clinicians.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that is observed primarily in patients with liver disease. The pathophysiology is complex and involves many factors including ammonia toxicity, dysregulation of central nervous system activity, and excess inflammatory cytokines. Symptoms of HE range from subclinical to debilitating. HE can be difficult to treat and represents a large burden to patients, their caregivers, and the health-care system because of associated resource utilization. This review article provides an overview of the current understanding of the pathophysiology behind HE and where the current research and treatments are pointing toward.

CSF1R Inhibition in Patients With Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase 1 Study of Vimseltinib.

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. PATIENTS AND METHODS: This first-in-human, multicenter, open-label, phase 1/2 study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase 2 dose (RP2D), and characterize the pharmacokinetics (PK); exploratory objectives included pharmacodynamics and efficacy. RESULTS: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were grade 1/2. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The RP2D was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7 to 46.9), and the objective response rate as assessed by independent radiological review using Response Evaluation Criteria in Solid Tumors version 1.1 was 72%. CONCLUSIONS: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT whose disease is not amenable to surgery.

Early-Onset Colorectal Cancer: Prevalence, Risk Factors, and Clinical Features Among Commercially Insured Adults in the United States.

BACKGROUND:  The incidence of colorectal cancer (CRC) in patients younger than 50 has been rising over the last several decades, accounting for up to 25% of total cases. Despite the screening age recently being lowered to 45, a significant proportion of cases would still arise at younger ages prior to screening. Nonfamilial early-onset CRC remains a particular concern. Identification of risk factors and clinical features in this age group is needed to improve detection. METHODS: In this retrospective cohort analysis using claims data from the Truven Health MarketScan® Commercial Claims insurance database from 2007 to 2017, patients were identified with colon and rectal cancer, compared across three age groups (ages 18-40, 40-50, and >50), and analyzed for risk factors and clinical features. RESULTS: Female sex was more prevalent in the younger age group compared to age >50 (54% and 51.9% vs. 49.6%), with little change noted between rectal cancer age groups by sex. A higher percentage of younger patients were in the obese age groups compared with older groups for colon cancer, particularly the morbidly obese with BMI >40 (24.94%, 25.75%, and 21.34% in the three age groups). Abdominal pain was a common presenting symptom identified in the age groups <50 compared with age >50 (25% and 19% vs. 14%), along with hematochezia, weight loss, and anemia. CONCLUSIONS: Morbid obesity and female sex may be important risk factors among patients with early-onset CRC. The presence of abdominal pain was more common among the early-onset CRC cohort.

Circadian Rhythms, the Gut Microbiome, and Metabolic Disorders.

The circadian clock and gut microbiome play integral roles in preserving metabolic homeostasis. Circadian rhythms represent an endogenous time-keeping system that regulates cell and organ functions and synchronizes physiology with external cues to establish metabolic homeostasis. A variety of functions throughout the gastrointestinal tract and liver are under circadian control, including nutrient transport, processing, and detoxification. The gut microbiota also plays an essential role in host metabolism, regulating processes such as digestion, inflammatory modulation, and bile acid metabolism. Both the circadian clock and the gut microbiota influence each other in a reciprocal fashion, as gut dysbiosis can precipitate circadian asynchrony, and vice-versa. Disruption of either system impacts homeostasis in a bidirectional manner and can contribute to metabolic dysfunction. Evidence suggests such disruptions can lead to the development of metabolic diseases, including obesity, diabetes, nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. This review will provide a basic overview of the circadian and gut microbial systems, how they are intertwined, and their impact on the liver and gastrointestinal tract and in the development of metabolic disease. Particular areas of discussion include epigenetic regulation of circadian pathways as well as a mechanistic overview of microbial dysbiosis. In addition, therapeutic targets of these systems, including dietary modifications, behavioral modifications, and microbial-directed therapies, will be explored.

The Role of Race, Sex, and Age in Circadian Disruption and Metabolic Disorders.

Circadian rhythms are 24-hour internal biological cycles that play an important role in metabolism, and their disruption has been implicated in the development of diseases such as diabetes mellitus type 2, obesity, coronary artery disease, hypertension, and metabolic syndrome. This phenomenon is illustrated by increased rates of risk factors for cardiovascular disease in night shift workers. Race, sex, and age are factors that play a role in circadian rhythms and metabolic disorders. The focus of this review article is to assess the link between circadian rhythm physiology and metabolic disorders from a race, sex, and age perspective. Black Americans were noted to have shorter free-running circadian periods, or tau, increased cortisol levels, and poorer sleep habits compared to white Americans, possibly contributing to increased rates of obesity, hypertension, and hyperlipidemia. Women were also noted to have shorter tau, increased levels of proinflammatory gut bacteria, and reduced sleep quality compared to men, possibly leading to higher rates of obesity, metabolic syndrome, hypertension (in postmenopausal women), and nonalcoholic fatty liver disease. Older people were noted to have decreased expression of anti-inflammatory clock genes compared to younger people, possibly leading to increased rates of obesity, diabetes, hyperlipidemia, and hypertension. Groups that are at a higher risk for metabolic disorders such as black Americans, women, and the elderly may have internal time keeping systems that place them at a higher risk for developing abnormal hormonal and/or inflammatory pathways.