Changes in plasma biomarkers following treatment with cabozantinib in metastatic castration-resistant prostate cancer: a post hoc analysis of an extension cohort of a phase II trial

BACKGROUND: Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). METHODS: Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST. RESULTS: A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib. CONCLUSIONS: Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches

Suitability of cohesionless soil as a highway construction material

Major parts of the Eastern and Northern provinces of Sri Lankti are covered with cohesionless soil. Utilization of locally available soil for the construction of the subbase of these roads will optimize the cost and reduce the environmental impact. Recently cracks, settlement and outward movement have been observed in the pavement constructed using the locally available sandy soil. It is suspected that the usage of locally available soil would have caused this failure. Objective of this study is to assess the quality of the cohesionless soil as a highway construction material. Further, the applicability and validity of the currently used specifications for use of cohesionless soil as a highway construction material are also evaluated. To accomplish the above tasks, the experience of the construction industry in this regard WOJ gathered through site visits, case studies, interviews with relevant personals. Based on the collected information a comprehensive laboratory test program was formulated to investigate the interrelationships between the soil properties such as grading, maximum dry density, California Bearing Ratio(CBR) value, plasticity index(PI), and liquid limit by mixing different type of clays with pure coarse sand. Laboratory test results and field data collected from road construction projects were analyzed. Final results were reviewed by the senior consultants at Road Development Authority(RDA) and National Building and Research OrganizationfNBRO)

HIV-Associated Neurocognitive Disorders: The First Longitudinal Follow-Up of a cART-Treated Cohort of Older People in Sub-Saharan Africa

\ua9 2022 Lippincott Williams and Wilkins. All rights reserved. Background: HIV-associated neurocognitive disorders (HAND) are a highly prevalent chronic complication in older people living with HIV (PLWH) in high-income countries. Although sub-Saharan Africa has a newly emergent population of older combination antiretroviral therapy (cART)-treated PLWH, HAND have not been studied longitudinally. We assessed longitudinal prevalence of HAND and have identified possible modifiable factors in a population of PLWH aged 50 years or older, over 3 years of follow-up. Methods: Detailed neuropsychological and clinical assessment was completed annually in the period 2016-2019 in a systematic sample of cART-treated PLWH in Kilimanjaro, Tanzania. A consensus panel defined HAND using American Academy of Neurology criteria for asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. HIV disease severity and other factors associated with HAND progression, improvement, and stability were evaluated in individuals fully assessed at baseline and in 2019.Results:At baseline, 47% of the cohort (n = 253, 72.3% female individuals) met HAND criteria despite good HIV disease control [Y1 59.5% (n = 185), Y2 61.7% (n = 162), and Y3 57.9% (n = 121)]. Of participants fully assessed at baseline and year 3 (n = 121), HAND remained stable in 54% (n = 57), improved in 15% (n = 16), and declined in 31% (n = 33). Older age and lower education level significantly predicted HAND progression, whereas HIV-specific factors did not. Male sex and shorter cART duration were associated with improvement. Conclusions: In this first longitudinal study characterizing clinical course of HAND in older cART-treated PLWH in sub-Saharan Africa, HAND was highly prevalent with variable progression and reversibility. Progression may be more related to cognitive reserve than HIV disease in cART-treated PLWH