Concurrent sexual partnerships among individuals on HAART in South Africa: an opportunity for HIV prevention

Concurrent sexual partnerships, a common form of sexual partnering in much of southern Africa, play an important role in HIV transmission dynamics. This study examines the prevalence of concurrency and condom use among the general population and a sample of HAART patients in Cape Town, South Africa. The prevalence of reported concurrency was relatively high among a sample of HAART patients and in the general population (24% and 18% respectively) and reported consistent condom use was significantly higher among HAART patients compared to the general population (58% versus 20%);? perceived concurrency among the study populations' sexual partners was higher among HAART patients (35% versus 20%). Individuals on HAART report higher and more consistent use of condoms than the general population but the prevalence of concurrent relationships remains worryingly high. Greater programmatic attention should be given to promoting risk awareness of and behaviour change around concurrency both in the general population and amongst people living with HIV

BRAF and NRAS locus-specific variants have different outcomes on survival to colorectal cancer

Purpose: Somatic mutation status at KRAS, BRAF and NRAS is associated with prognosis in patients with advanced colorectal cancer (aCRC); however, it remains unclear whether there are intra-locus, variant-specific differences in survival and other clinicopathological parameters. Experimental design: We profiled 2,157 aCRCs for somatic mutations in KRAS, BRAF and NRAS and determined microsatellite instability status. We sought inter- and intra-locus correlations between mutations, and variant-specific associations with survival and clinicopathology. Results: KRAS mutations were rarely found together and those in codons 12 and 13 conferred poor prognosis (HR 1.44, 95% CI 1.28-1.61, p=6.4e-10 and HR 1.53, 95% CI 1.26-1.86, p=1.5e-05, respectively). For BRAF, more c.1781A>G (p.D594G) CRCs carried RAS mutations (14% [3/21]) compared to c.1799T>A (p.V600E) CRCs (1% [2/178], p=9.0e-03). c.1799T>A (p.V600E) was associated with poor prognosis (HR 2.60, 95% CI 2.06-3.28, p=1.0e-15), whereas c.1781A>G (p.D594G) was not (HR 1.30, 95% CI 0.73-2.31, p=0.37); this intra-locus difference was significant (p=0.04). More c.1799T>A (p.V600E) CRCs were found in the right colon (47% [47/100]), compared to c.1781A>G (p.D594G) CRCs (7% [1/15], p=3.7e-03). For NRAS, 5% (3/60) of codon 61 mutant CRCs had KRAS mutations compared to 44% (10/23) of codons 12 and 13 mutant CRCs (p=7.9e-05). Codon 61 mutations conferred poor prognosis (HR 1.47, 95% CI 1.09-1.99, p=0.01), whereas codons 12 and 13 mutations did not (HR 1.29, 95% CI 0.64-2.58, p=0.48). Conclusions: Our data show considerable intra-locus variation in the outcomes of mutations in BRAF and NRAS. These data need to be considered in patient management and personalised cancer therapy

Laparoscopic Cholecystectomy: Incidental Carcinoma of the Gallbladder with Abdominal Wall and Axillary Node Metastasis

A case report is presented of intra-mural gallbladder carcinoma discovered incidentally after laparoscopic cholecystectomy who subsequently developed abdominal wall recurrence at the epigastric exit port, and axillary lymph node metastases. Possible preventative steps for tumour dissemination and a management plan if incidental carcinoma is diagnosed is discussed. The use of a non-porous retrieval bag, early recognition of the carcinoma and excision of the exit wound are advocated

Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial.

INTRODUCTION: Molecular characterisation of tumours is increasing personalisation of cancer therapy, tailored to an individual and their cancer. FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer. During an initial 16-week period of standard first-line chemotherapy, tumour tissue will undergo several molecular assays, with the results used for cohort allocation, then randomisation. Laboratories in Leeds and Cardiff will perform the molecular testing. The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed. METHODS: Wales Cancer Bank supplied FFPE tumour blocks from 97 mCRC patients with consent for use in further research. Both laboratories processed each sample according to an agreed definitive FOCUS4 laboratory protocol, reporting results directly to the MRC Trial Management Group for independent cross-referencing. RESULTS: Pyrosequencing analysis of mutation status at KRAS codons12/13/61/146, NRAS codons12/13/61, BRAF codon600 and PIK3CA codons542/545/546/1047, generated highly concordant results. Two samples gave discrepant results; in one a PIK3CA mutation was detected only in Leeds, and in the other, a PIK3CA mutation was only detected in Cardiff. pTEN and mismatch repair (MMR) protein expression was assessed by immunohistochemistry (IHC) resulting in 6/97 discordant results for pTEN and 5/388 for MMR, resolved upon joint review. Tumour heterogeneity was likely responsible for pyrosequencing discrepancies. The presence of signet-ring cells, necrosis, mucin, edge-effects and over-counterstaining influenced IHC discrepancies. CONCLUSIONS: Pre-trial assay analytical validation is essential to ensure appropriate selection of patients for targeted therapies. This is feasible for both mutation testing and immunohistochemical assays and must be built into the workup of such trials. TRIAL REGISTRATION NUMBER: ISRCTN90061564

Phenotypic consequences of somatic mutations in the ataxia-telangiectasia mutated gene in non-small cell lung cancer

Mutations in the Ataxia-telangiectasia mutated (ATM) gene are frequently found in human cancers, including non-small cell lung cancer (NSCLC). Loss of ATM function confers sensitivity to ionising radiation (IR) and topoisomerase inhibitors and may thus define a subset of cancer patients that could get increased benefit from these therapies. In this study, we evaluated the phenotypic consequences of ATM missense changes reported in seven NSCLC cell lines with regard to radiosensitivity and functionality of ATM signalling. Our data demonstrate that only 2/7 NSCLC cell lines (H1395 and H23) harbouring ATM missense mutations show a functional impairment of ATM signalling following IR-exposure. In these two cell lines, the missense mutations caused a significant reduction in ATM protein levels, impairment of ATM signalling and marked radiosensitivity. Of note, only cell lines with homozygous mutations in the ATM gene showed significant impairment of ATM function. Based on these observations, we developed an immunohistochemistry-based assay to identify patients with loss or reduction of ATM protein expression in a clinical setting. In a set of 137 NSCLC and 154 colorectal cancer specimens we identified tumoral loss of ATM protein expression in 9.5% and 3.9% of cases, respectively, demonstrating the potential utility of this method

Constraining the Scatter in the Mass-Richness Relation of maxBCG Clusters With Weak Lensing and X-ray Data

We measure the logarithmic scatter in mass at fixed richness for clusters in the maxBCG cluster catalog, an optically selected cluster sample drawn from SDSS imaging data. Our measurement is achieved by demanding consistency between available weak lensing and X-ray measurements of the maxBCG clusters, and the X-ray luminosity--mass relation inferred from the 400d X-ray cluster survey, a flux limited X-ray cluster survey. We find \sigma_{\ln M|N_{200}}=0.45^{+0.20}_{-0.18} (95% CL) at N_{200} ~ 40, where N_{200} is the number of red sequence galaxies in a cluster. As a byproduct of our analysis, we also obtain a constraint on the correlation coefficient between \ln Lx and \ln M at fixed richness, which is best expressed as a lower limit, r_{L,M|N} >= 0.85 (95% CL). This is the first observational constraint placed on a correlation coefficient involving two different cluster mass tracers. We use our results to produce a state of the art estimate of the halo mass function at z=0.23 -- the median redshift of the maxBCG cluster sample -- and find that it is consistent with the WMAP5 cosmology. Both the mass function data and its covariance matrix are presented.Comment: 14 pages, 6 figures, submitted to Ap

Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT

Complex trials with innovative designs are becoming increasingly common and offer the potential to improve patient outcomes in a shorter time frame. There is evidence that patients with colorectal cancer fall into different subgroups with varying responsiveness to therapy, and that this variation is linked to genetic biomarkers. To the best of our knowledge, FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and remains one of the first umbrella trial designs to be launched globally. Objectives To identify novel therapies that improve disease control within the molecular subgroup of metastatic colorectal cancer in which the novel therapies were expected to be most effective. Design This was a Phase II/III molecularly stratified umbrella trial that used adaptive statistical methodology to decide which subtrial should close early; new subtrials were added as protocol amendments. Setting The maintenance setting following 16 weeks of first-line combination chemotherapy. Participants Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified subtrial or the non-stratified FOCUS4-N trial. Interventions Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted subtrials were activated: FOCUS4-B (PIK3CA mutation or PTEN overexpression) – aspirin versus placebo; FOCUS4-C (TP53 and RAS mutation) – adavosertib (AstraZeneca Ltd, Cambridge, UK) versus active monitoring; and FOCUS4-D (BRAF-PIK3CA-RAS wild type) – AZD8931 versus placebo. A non-stratified subtrial was also carried out: FOCUS4-N – capecitabine versus active monitoring. Main outcome measures The main outcome measure was progression-free survival from the time of randomisation to progression, comparing the intervention with active monitoring/placebo. Toxicity and overall survival data were collected in all randomised patients, and quality of life (using EuroQol-5 Dimensions) data were collected in FOCUS4-N only. Results Between January 2014 and October 2020, 1434 patients were registered from 88 hospitals in the UK. Successful biomarker testing was completed in 1291 out of 1382 samples (93%), and 908 out of 1315 patients (69%) completing 16 weeks of first-line therapy were eligible for randomisation, with 361 randomly allocated to a subtrial. FOCUS4-B evaluated aspirin versus placebo in the PIK3CA-mutant/ PTEN -loss subgroup, but recruited only six patients, so was closed for futility. FOCUS4-C evaluated adavosertib versus active monitoring in 67 patients in the RAS + TP53 double-mutant subgroup and met its primary end point, showing an improvement in progression-free survival (median 3.61 vs. 1.87 months; hazard ratio 0.35, 95% confidence interval 0.18 to 0.68; p = 0022). FOCUS4-D evaluated AZD8931 in 32 patients in the BRAF-PIK3CA-RAS wild-type subgroup and showed no benefit, so was discontinued after the first interim analysis. FOCUS4-N evaluated capecitabine monotherapy versus active monitoring in 254 patients and met its primary end point, showing improvement in progression-free survival (hazard ratio 0.40, 95% confidence interval 0.21 to 0.75; p < 0.0001). Limitations FOCUS4-C and FOCUS4-N were closed early owing to COVID-19, so did not accrue their planned recruitment numbers. Conclusions Adaptive stratified medicine studies are feasible in common cancers but present challenges. Capecitabine monotherapy is an effective maintenance therapy. Wee1 inhibition using adavosertib shows significant clinical activity, notably in left-sided colorectal cancer. Trial registration This trial was registered as ISRCTN90061546. Funding This project was jointly funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership, and Cancer Research UK. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 9. See the NIHR Journals Library website for further project information

Longitudinal changes in COVID-19 vaccination intent among South African adults: evidence from the NIDS-CRAM panel survey, February to May 2021

Background COVID-19 vaccine hesitancy has threatened the ability of many countries worldwide to contain the pandemic. Given the severe impact of the pandemic in South Africa and disruptions to the roll-out of the vaccine in early 2021, slower-than-expected uptake is a pressing public health challenge in the country. We examined longitudinal changes in COVID-19 vaccination intent among South African adults, as well as determinants of intent to receive a vaccine. Methods We used longitudinal data from Wave 4 (February/March 2021) and Wave 5 (April/May 2021) of the National Income Dynamics Study: Coronavirus Rapid Mobile Survey (NIDS-CRAM), a national and broadly representative panel survey of adults in South Africa. We conducted cross-sectional analyses on aggregate and between-group variation in vaccination intent, examined individual-level changes between waves, and modeled demographic predictors of intent. Results We analysed data for 5629 (Wave 4; 48% male, mean age 41.5 years) and 5862 (Wave 5; 48% male, mean age 41.6 years) respondents. Willingness to get a COVID-19 vaccine significantly increased from 70.8% (95% CI: 68.5–73.1) in Wave 4 to 76.1% (95% CI: 74.2–77.8) in Wave 5. Individual-level analyses indicated that only 6.6% of respondents remained strongly hesitant between survey waves. Although respondents aged 18–24 years were 8.5 percentage points more likely to report hesitancy, hesitant respondents in this group were 5.6 percentage points more likely to change their minds by Wave 5. Concerns about rushed testing and safety of the vaccines were frequent and strongly-held reasons for hesitancy. Conclusions Willingness to receive a COVID-19 vaccine has increased among adults in South Africa, and those who were entrenched in their reluctance make up a small proportion of the country’s population. Younger adults, those in formal housing, and those who trusted COVID-19 information on social media were more likely to be hesitant. Given that stated vaccination intent may not translate into behaviour, our finding that three-quarters of the population were willing to accept the vaccine may reflect an upper bound. Vaccination promotion campaigns should continue to frame vaccine acceptance as the norm and tailor strategies to different demographic groups