Population Pharmacokinetics and Exposure–Response Analysis for the Phase 3 COSMIC-311 Trial of Cabozantinib for Radioiodine-Refractory Differentiated Thyroid Cancer

Background and Objective In the USA, cabozantinib was approved for the treatment of patients aged ≥ 12 years with radioiodine-refractory differentiated thyroid cancer (DTC) who progressed on prior vascular endothelial growth factor (VEGFR)-targeted therapy based on the Phase 3 COSMIC-311 trial, which evaluated cabozantinib 60 mg/day versus placebo. Approved dosing is 60 mg/day for adults and for pediatric patients aged ≥ 12 years with body surface area (BSA) ≥ 1.2 m2, and 40 mg/day for pediatric patients aged ≥ 12 years with BSA \u3c 1.2 m2. This report describes a population pharmacokinetic (PopPK) and exposure–response analysis of COSMIC-311. Methods A PopPK model was developed using concentration-time data from COSMIC-311 and 6 other cabozantinib studies. The final (full) PopPK model was used to simulate the effect of sex, body weight, race, and patient population. For exposure–response analysis, derived datasets from COSMIC-311 were constructed for time-to-event analyses of progression-free survival (PFS) and safety endpoints. Results The PopPK analysis included 4746 cabozantinib PK samples from 1745 patients and healthy volunteers. Body weight had minimal impact on cabozantinib exposure but increasing body weight was associated with increased apparent volume of distribution. Based on model-based simulation, adolescents \u3c 40 kg had higher maximum plasma concentration at steady state of cabozantinib 60 mg/day compared to adults. Allometric scaling simulation in adolescents \u3c 40 kg demonstrated higher exposure with 60 mg/day relative to adults receiving the same dose, while exposure with 40 mg/day in adolescents \u3c 40 kg was similar to 60 mg/day in adults. The exposure–response analysis included 115 patients. There was no clear relationship between PFS or dose modification and cabozantinib exposure. A statistically significant relationship was demonstrated for cabozantinib exposure and hypertension (Grade ≥ 3) and fatigue/asthenia (Grade ≥ 3). Conclusions These results support the dosing strategy implemented in COSMIC-311 and the BSA-based label recommendations for adolescents. The cabozantinib dose should be reduced to manage adverse events as indicated

Community-based model for the delivery of antiretroviral therapy in Cambodia: a quasi-experimental study protocol.

BACKGROUND: Multi-month dispensing (MMD) is the mainstay mechanism for clinically stable people living with HIV in Cambodia to refill antiretroviral therapy (ART) every 3-6 months. However, less frequent ART dispensing through the community-based ART delivery (CAD) model could further reduce the clients' and health facilities' burden. While community-based services have been recognized as an integral component of HIV response in Cambodia, their role and effectiveness in ART delivery have yet to be systematically assessed. This study aims to evaluate the CAD model's effectiveness on the continuum of care and treatment outcomes for stable people living with HIV in Cambodia. METHODS: We will conduct this quasi-experimental study in 20 ART clinics across the capital city and nine provinces between May 2021 and April 2023. Study sites were purposively selected based on the availability of implementing partners, the number of people living with HIV each clinic serves, and the accessibility of the clinics. In the intervention arm, approximately 2000 stable people living with HIV will receive ART and services from the CAD model. Another 2000 stable people living with HIV in the control arm will receive MMD-a standard care model for stable people living with HIV. The primary outcomes will be retention in care, viral load suppression, and adherence to ART. The secondary endpoints will include health providers' work burden, the model's cost-effectiveness, quality of life, mental health, social support, stigma, and discrimination. We will compare the outcome indicators within each arm at baseline, midline, and endline using descriptive and inferential statistics. We will evaluate the differences between the intervention and control arms using the difference-in-differences method. We will perform economic evaluations to determine if the intervention is cost-effective. DISCUSSION: This study will build the evidence base for future implementation and scale-up of CAD model in Cambodia and other similar settings. Furthermore, it will strengthen engagements with community stakeholders and further improve community mobilization, a vital pillar of the Cambodian HIV response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04766710 . Registered 23 February 2021, Version 1

Non-homogeneous Behaviour of the Spatial Distribution of Macrospicules

In this paper the longitudinal and latitudinal spatial distribution of macrospicules is examined. We found a statistical relationship between the active longitude determined by sunspot groups and the longitudinal distribution of macrospicules. This distribution of macrospicules shows an inhomogeneity and non-axysimmetrical behaviour in the time interval from June 2010 until December 2012 covered by observations of the Solar Dynamic Observatory (SDO) satellite. The enhanced positions of the activity and its time variation has been calculated. The migration of the longitudinal distribution of macrospicules shows a similar behaviour as that of the sunspot groups

Distinct pattern of TP53 mutations in human immunodeficiency virusâ related head and neck squamous cell carcinoma

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142251/1/cncr31063.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142251/2/cncr31063_am.pd

Prevalence and service assessment of cataract in Tibetan areas of Sichuan Province, China: population-based study.

OBJECTIVES: To assess the prevalence of visual impairment (VI) and blindness (BL) due to cataract and cataract surgical outcomes in remote dispersed and high-altitude Tibetan areas of China. DESIGN AND SETTING: A cross-sectional study was conducted among people aged 50 and above in Tibetan Autonomous Prefecture of Kandze (TAPK), China, in 2017. The Rapid Assessment of Avoidable Blindness protocol was followed. PARTICIPANTS: Of 5000 eligible participants, 4764 were examined (response rate 95.3%). PRIMARY AND SECONDARY OUTCOME MEASURES: Cataract VI was defined as lens opacity at visual acuity (VA) levels of <3/60 (Blindness (BL)), ≥3/60 and <6/60 (severe visual impairment (SVI)), ≥6/60 and <6/18 (moderate visual impairment (MVI)), ≥6/18 and <6/12 (early visual impairment (EVI)). RESULTS: The estimated prevalence of cataract BL was 0.61% (95% CI 0.42 to 0.87). With best corrected VA, the estimated prevalence of SVI from cataract was 0.86% (95% CI 0.63 to 1.17); MVI was 2.39% (95% CI 2.00 to 2.87) and EVI was 5.21% (95% CI 4.61 to 5.87). Women in TAPK had a significantly higher prevalence of cataract BL (0.82%, 95% CI 0.54 to 2.15) than men (0.34%, 95% CI 0.16 to 0.70). Women had lower cataract surgical coverage (CSC) by eyes (60.8%, 95% CI 55.5 to 65.8) compared with men (70.1%; 95% CI 63.7 to 75.7). The prevalence of cataract BL was higher among Tibetan (2.28%; 95% CI 1.98 to 2.62) than Han Chinese (1.01%%; 95% CI 0.54% to 1.87%). Overall CSC by person with BL (by better eye) was 82.0% (95% CI 75.2 to 87.6). Among cataract-operated participants, 71.2% had VA equal to or better than 6/18. CONCLUSIONS: The study detected a low prevalence of VI and BL due to cataract with high CSC in the study area compared with many other places in China. Further actions should be taken to improve cataract surgical outcome

Association between RUNX3 promoter methylation and gastric cancer: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>Runt-related transcription factor 3 (RUNX3) is a member of the runt-domain family of transcription factors and has been reported to be a candidate tumor suppressor in gastric cancer. However, the association between RUNX3 promoter methylation and gastric cancer remains unclear.</p> <p>Methods</p> <p>We systematically reviewed studies of RUNX3 promoter methylation and gastric cancer published in English or Chinese from January 2000 to January 2011, and quantified the association between RUNX3 promoter methylation and gastric cancer using meta-analysis methods.</p> <p>Results</p> <p>A total of 1740 samples in 974 participants from seventeen studies were included in the meta-analysis. A significant association was observed between RUNX3 promoter methylation and gastric cancer, with an aggregated odds ratio (OR) of 5.63 (95%CI 3.15, 10.07). There was obvious heterogeneity among studies. Subgroup analyses (including by tissue origin, country and age), meta-regression were performed to determine the source of the heterogeneity. Meta-regression showed that the trend in ORs was inversely correlated with age. No publication bias was detected. The ORs for RUNX3 methylation in well-differentiated <it>vs </it>undifferentiated gastric cancers, and in intestinal-type <it>vs </it>diffuse-type carcinomas were 0.59 (95%CI: 0.30, 1.16) and 2.62 (95%CI: 1.33, 5.14), respectively. There were no significant differences in RUNX3 methylation in cancer tissues in relation to age, gender, TNM stage, invasion of tumors into blood vessel or lymphatic ducts, or tumor stage.</p> <p>Conclusions</p> <p>This meta-analysis identified a strong association between methylation of the RUNX3 promoter and gastric cancer, confirming the role of RUNX3 as a tumor suppressor gene.</p