Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial.

BACKGROUND: Dynamic changes in circulating tumour DNA (ctDNA) levels may predict long-term outcome. We utilised samples from a phase I/II randomised trial (BEECH) to assess ctDNA dynamics as a surrogate for progression-free survival (PFS) and early predictor of drug efficacy. PATIENTS AND METHODS: Patients with estrogen receptor-positive advanced metastatic breast cancer (ER+ mBC) in the BEECH study, paclitaxel plus placebo versus paclitaxel plus AKT inhibitor capivasertib, had plasma samples collected for ctDNA analysis at baseline and at multiple time points in the development cohort (safety run-in, part A) and validation cohort (randomised, part B). Baseline sample ctDNA sequencing identified mutations for longitudinal analysis and mutation-specific digital droplet PCR (ddPCR) assays were utilised to assess change in ctDNA abundance (allele fraction) between baseline and 872 on-treatment samples. Primary objective was to assess whether early suppression of ctDNA, based on pre-defined criteria from the development cohort, independently predicted outcome in the validation cohort. RESULTS: In the development cohort, suppression of ctDNA was apparent after 8 days of treatment (P = 0.014), with cycle 2 day 1 (4 weeks) identified as the optimal time point to predict PFS from early ctDNA dynamics. In the validation cohort, median PFS was 11.1 months in patients with suppressed ctDNA at 4 weeks and 6.4 months in patients with high ctDNA (hazard ratio = 0.20, 95% confidence interval 0.083-0.50, P < 0.0001). There was no difference in the level of ctDNA suppression between patients randomised to capivasertib or placebo overall (P = 0.904) nor in the PIK3CA mutant subpopulation (P = 0.071). Clonal haematopoiesis of indeterminate potential (CHIP) was evident in 30% (18/59) baseline samples, although CHIP had no effect on tolerance of chemotherapy nor on PFS. CONCLUSION: Early on-treatment ctDNA dynamics are a surrogate for PFS. Dynamic ctDNA assessment has the potential to substantially enhance early drug development. CLINICAL REGISTRATION NUMBER: NCT01625286.

Chemsex and the city: sexualised substance use in gay bisexual and other men who have sex with men attending sexual health clinics.

The objective of this study was to analyse associations between sexualised substance use (chemsex), STI diagnoses and sexual behaviour among gay bisexual and other men who have sex with men accessing sexual health clinics to better inform clinical pathways. A retrospective case notes review was undertaken following the introduction of more detailed and holistic profomas for all gay bisexual and other men who have sex with men attending two London sexual health clinics between 1 June 2014 and 31 January 2015. Chemsex status was documented for 655/818. Overall, 30% disclosed recreational drug use of whom 113 (57%) disclosed chemsex and 27 (13.5%) injecting drugs. HIV-positive gay bisexual and other men who have sex with men were more likely to disclose chemsex (AOR 6.68; 95% CI 3.91-11.42; p < 0.001). Those disclosing chemsex had a higher incidence of acute bacterial STIs (AOR 2.83 CI 1.79-4.47; p < 0.001), rectal STIs (AOR 3.10 CI 1.81-5.32; p < 0.001) or hepatitis C (AOR 15.41 CI 1.50-158.17; p = 0.021). HIV incidence in the study period was 1.8% (chemsex) vs. 0.9% (no chemsex) (p = 0.61). Chemsex was associated with having more sexual partners, transactional sex, group sex, fisting, sharing sex toys, injecting drug use, higher alcohol consumption and the use of 'bareback' sexual networking applications (p < 0.004). Chemsex participants were also more likely to have accessed post-exposure prophylaxis for HIV in the study period and report sex with a discordant HIV or hepatitis C-infected partner (p < 0.001). Chemsex disclosure is associated with higher risk-taking behaviours, acute bacterial STIs, rectal STIs and hepatitis C incidence. HIV incidence was higher but not significantly so in the study period. Chemsex disclosure in sexual health clinics should prompt an opportunity for prevention, health promotion and wellbeing interventions.

Malnutrition in children with food allergies in the UK.

BACKGROUND: The mainstay of dietary management of food allergies remains the elimination diet. However, the removal of major food groups may predispose children to an inadequate nutrient intake. We therefore set out to establish growth status in food allergic children receiving dietetic input in the UK. METHODS: Dietitians were approached via the Food Allergy and Intolerance Specialist Group from the British Dietetic Association and asked to submit anthropometrical data for children with food allergies. Data collected related to the systems involved and number of foods excluded. Malnutrition was defined according to World Health Organization standards. RESULTS: Data from 13 different centres yielded 97 patients (51 male and 46 female) of which 66 excluded ≤2 foods and 31 excluded ≥3 foods. Data indicated that 8.5% had a weight for age ≤ -2 Z-score and, conversely, 8.5% were ≥2 Z-score. For height for age, 11.1% were ≤ -2 Z-score and, for weight for height, 3.7% were ≤ -2 Z-score and 7.5% ≥2 Z-score. Type of allergy, system involved and specific food elimination did not impact on the level of malnutrition. However, the elimination of ≥3 foods significantly impacted on weight for age (P = 0.044). CONCLUSIONS: The present study demonstrates that children with food allergies are more underweight than the general UK population, which appears to be linked to the number of foods excluded. However, the impact of the disease process itself should not be disregarded. Additionally, obesity can also occur in this population despite dietary elimination.

Evolution of surface area-to-volume ratio for a water meniscus evaporating between contacting silica spheres.

An experimental investigation was performed under isothermal conditions to quantify the rate of evaporation of water from a receding pendular meniscus connecting two silica spheres. Optically based measurements were used to determine the relevant meniscus dimensions, and the meniscus was modeled using a toroidal approximation. The rate of change of meniscus surface area and volume was then predicted using mathematical modeling software. The results demonstrated that once the meniscus transitioned from a relatively flat surface to one with an increasing radius of curvature, the rate of change of the ratio of surface area-to-volume was relatively constant over the range of water contents that were observable using the optical investigation techniques implemented in this study. Comparison of the flux of water from the meniscus surface demonstrated that the evaporation of bound water was four orders of magnitude slower than evaporation from a free water surface.

Issues inherent in the multicultural feminist couple treatment of African-American, same-gender loving female adult survivors of child sexual abuse.

This manuscript focuses on four potential stumbling blocks in the multicultural feminist couple treatment of African-American, same-gender loving female adult child sexual abuse survivors: (1) gender roles; (2) "coming out" to self, family, and the community; (3) lesbian couple relationships; and (4) the expression of lesbian sexuality. These four potential barriers to therapeutic outcome within the context of multicultural feminist couple treatment needs to be systematically addressed during the provision of culturally-informed clinical services to African-American, same-gender loving female adult child sexual abuse survivors. The nature and impact of feminism on the family, as an institution, served as the framework for this discussion.