The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Decolonizing drug-resistant E. coli with phage and probiotics: breaking the frequency-dependent dominance of residents.

Widespread antibiotic resistance in commensal bacteria creates a persistent challenge for human health. Resident drug-resistant microbes can prevent clinical interventions, colonize wounds post-surgery, pass resistance traits to pathogens or move to more harmful niches following routine interventions such as catheterization. Accelerating the removal of resistant bacteria or actively decolonizing particular lineages from hosts could therefore have a number of long-term benefits. However, removing resident bacteria via competition with probiotics, for example, poses a number of ecological challenges. Resident microbes are likely to have physiological and numerical advantages and competition based on bacteriocins or other secreted antagonists is expected to give advantages to the dominant partner, via positive frequency dependence. Since a narrow range of Escherichia coli genotypes (primarily those belonging to the clonal group ST131) cause a significant proportion of multidrug-resistant infections, this group presents a promising target for decolonization with bacteriophage, as narrow-host-range viral predation could lead to selective removal of particular genotypes. In this study we tested how a combination of an ST131-specific phage and competition from the well-known probiotic E. coli Nissle strain could displace E. coli ST131 under aerobic and anaerobic growth conditions in vitro. We showed that the addition of phage was able to break the frequency-dependent advantage of a numerically dominant ST131 isolate. Moreover, the addition of competing E. coli Nissle could improve the ability of phage to suppress ST131 by two orders of magnitude. Low-cost phage resistance evolved readily in these experiments and was not inhibited by the presence of a probiotic competitor. Nevertheless, combinations of phage and probiotic produced stable long-term suppression of ST131 over multiple transfers and under both aerobic and anaerobic growth conditions. Combinations of phage and probiotic therefore have real potential for accelerating the removal of drug-resistant commensal targets.

Evaluating an alcohol harm-reduction campaign advising drinkers of the alcohol-cancer link.

INTRODUCTION: Public awareness of the alcohol-cancer link is low. Provision of this information could reduce alcohol consumption and related harms. The Spread campaign is a multi-media education campaign implemented in Western Australia to inform people about the carcinogenic properties of alcohol and associated harms. The aims of the present study were to (i) examine attitudinal and behavioural outcomes of the Spread campaign and (ii) identify demographic and drinking status factors associated with enactment of harm-reduction behaviours resulting from exposure. METHOD: A cross sectional survey of Western Australian drinkers (consumed alcohol at least a few times in the previous 12 months, n = 760) examined campaign recognition, campaign perceptions, and behaviours resulting from campaign exposure. Chi-square analyses and a generalised linear model were used to identify demographic and alcohol-related factors associated with behavioural outcomes. RESULTS: Around two-thirds of respondents recognised the campaign (65%), and of these, 22% reported successfully reducing how often or how much they drank due to seeing the campaign. Three quarters (73%) of all respondents considered the campaign message about the alcohol-cancer link to be believable. Respondents drinking at levels above the Australian guideline were less likely to have positive perceptions of the campaign than those complying with the guideline, but were more likely to report enacting the assessed harm-reduction behaviours as a result of campaign exposure. DISCUSSION AND CONCLUSION: The results suggest that provision of information about the alcohol-cancer link has the potential to motivate reduced alcohol consumption. Implementing such campaigns could constitute an effective alcohol harm-reduction strategy.

"They're sleek, stylish and sexy:" selling e-cigarettes online.

OBJECTIVE: We examined the product range, marketing strategies, access and marketing claims made by Australian and New Zealand (NZ) online e-cigarette retailers. METHODS: Twenty Australian (n=10) and NZ (n=10) e-cigarette retail websites were identified via Google using a combination of keywords nominated by an expert panel and identified via a literature review: 'e-cigarette', 'e-cigs', 'vape', and 'vaping', combined with 'Australia', 'AU', 'New Zealand' and 'NZ' and then examined. RESULTS: Products were extensive (disposable, pod-based, reusable, replacement parts), 95% (n=19) offered 'Starter Kits,' flavoured e-liquid (n=1,032), most containing nicotine (70%, n=14). Most retailers (85%, n=17) offered price discounts and free delivery. There were unsubstantiated health claims (80%, n=16), cessation claims (65%, n=13) and cost-benefit claims (50%, n=10) promoting e-cigarette use. Most (n=14) website age verification features simply required the purchaser to indicate they were aged 18 years. CONCLUSIONS: Although e-cigarette regulations are different in Australia and NZ, the online product range, marketing strategies, access and marketing claims were similar and sold e-liquid containing nicotine. The health and cessation e-cigarette marketing claims were outlandish and unsubstantiated. IMPLICATIONS FOR PUBLIC HEALTH: Most purchasing of e-cigarettes occurs online. Regulations and enforcement to limit access and stop unsubstantiated marketing claims must be a public health priority.

The emergence of e-cigarette retail shops in a regulated tobacco control environment.

ISSUE ADDRESSED: E-cigarettes are of growing concern. We aimed to determine the location and characteristics of retail shops selling e-cigarette products in Perth, Western Australia. METHODS: Two phase study: (i) identifying all e-cigarette retailers in the Greater Capital City Statistical Area of Perth; (ii) audit at the point-of-sale to assess products, promotions and shop characteristics (n = 41). RESULTS: Ninety-eight retailers selling e-cigarette products were identified: 43 tobacconists (44%), 21 vape shops (21% - up from one shop in 2017), 14 supermarkets (14%), 12 service stations (12%) and 8 smoke shops (8%). The most common e-cigarette product was non-nicotine e-liquid, available at 38 (93%) stores audited. Most stores sold parts of e-cigarette devices (n = 25, 61%). Front counter displays were the most frequent form of promotion (n = 40, 98%). Vape shops differed from other retailers, having bar-style layouts (n = 15, 71%), lounge areas (n = 7, 33%) and free e-liquid samples (n = 17, 89%). CONCLUSION: The availability of e-cigarette products from retail shops and particularly vape shops is increasing. E-cigarette retailers are using traditional promotional techniques including point-of-sale displays to market their products, while vape shops are extending their appeal through bar style, lounge layouts and free trials. IMPLICATIONS FOR PUBLIC HEALTH: Understanding the e-cigarette retail store environment is essential for identifying emergent trends, potential regulations and future research. SO WHAT?: The e-cigarette retail market in the Perth is growing, shops using traditional and new promotional techniques to market e-cigarette products. Our findings identify a need for public health surveillance, regulations and legislation.

Rapid and specific degradation of endogenous proteins in mouse models using auxin-inducible degrons.

Auxin-inducible degrons are a chemical genetic tool for targeted protein degradation and are widely used to study protein function in cultured mammalian cells. Here, we develop CRISPR-engineered mouse lines that enable rapid and highly specific degradation of tagged endogenous proteins in vivo. Most but not all cell types are competent for degradation. By combining ligand titrations with genetic crosses to generate animals with different allelic combinations, we show that degradation kinetics depend upon the dose of the tagged protein, ligand, and the E3 ligase substrate receptor TIR1. Rapid degradation of condensin I and II - two essential regulators of mitotic chromosome structure - revealed that both complexes are individually required for cell division in precursor lymphocytes, but not in their differentiated peripheral lymphocyte derivatives. This generalisable approach provides unprecedented temporal control over the dose of endogenous proteins in mouse models, with implications for studying essential biological pathways and modelling drug activity in mammalian tissues.

Using the transtheoretical model of behaviour change to analyse the impact of stopping exercise: a reflection.

This article is an analytical reflection of the personal health journey of a first-year nursing student that was undertaken as part of a first-year unit of study. Focusing on social, physical and psychological aspects of health, it explores the impact of the cessation of exercise on her emotional and physical health and wellbeing. This is relevant to current practice as a result of COVID-19, which reduced opportunities for exercise for many people, whether because of self-isolation and lockdown restrictions on leisure facilities or increased workload and caring responsibilities, all of which affect health and wellbeing. The article is presented in the first person, reflecting the personal analysis it captures.

Interannual monsoon wind variability as a key driver of East African small pelagic fisheries.

Small pelagic fisheries provide food security, livelihood support and economic stability for East African coastal communities-a region of least developed countries. Using remotely- sensed and field observations together with modelling, we address the biophysical drivers of this important resource. We show that annual variations of fisheries yield parallel those of chlorophyll-a (an index of phytoplankton biomass). While enhanced phytoplankton biomass during the Northeast monsoon is triggered by wind-driven upwelling, during the Southeast monsoon, it is driven by two current induced mechanisms: coastal "dynamic uplift" upwelling; and westward advection of nutrients. This biological response to the Southeast monsoon is greater than that to the Northeast monsoon. For years unaffected by strong El-Niño/La-Niña events, the Southeast monsoon wind strength over the south tropical Indian Ocean is the main driver of year-to-year variability. This has important implications for the predictability of fisheries yield, its response to climate change, policy and resource management.

Strong Environment-Genotype Interactions Determine the Fitness Costs of Antibiotic Resistance In Vitro and in an Insect Model of Infection.

The acquisition of antibiotic resistance commonly imposes fitness costs, a reduction in the fitness of bacteria in the absence of drugs. These costs have been quantified primarily using in vitro experiments and a small number of in vivo studies in mice, and it is commonly assumed that these diverse methods are consistent. Here, we used an insect model of infection to compare the fitness costs of antibiotic resistance in vivo to those in vitro Experiments explored diverse mechanisms of resistance in a Gram-positive pathogen, Bacillus thuringiensis, and a Gram-negative intestinal symbiont, Enterobacter cloacae Rifampin resistance in B. thuringiensis showed fitness costs that were typically elevated in vivo, although these were modulated by genotype-environment interactions. In contrast, resistance to cefotaxime via derepression of AmpC ß-lactamase in E. cloacae resulted in no detectable costs in vivo or in vitro, while spontaneous resistance to nalidixic acid, and carriage of the IncP plasmid RP4, imposed costs that increased in vivo Overall, fitness costs in vitro were a poor predictor of fitness costs in vivo because of strong genotype-environment interactions throughout this study. Insect infections provide a cheap and accessible means of assessing the fitness consequences of resistance mutations, data that are important for understanding the evolution and spread of resistance. This study emphasizes that the fitness costs imposed by particular mutations or different modes of resistance are extremely variable and that only a subset of these mutations is likely to be prevalent outside the laboratory.

Plasma N-acetyl-glucosaminidase in advanced gastro-intestinal adenocarcinoma correlates with age, stage and outcome.

BACKGROUND: N-acetyl-glucosaminidase (NAG) is a potential marker of genotoxicity. We retrospectively analyzed plasma NAG and clinico-pathologic features in advanced gastrointestinal adenocarcinoma patients. METHODS: Plasma from 118 patients and 51 healthy volunteers was analyzed for associations between NAG levels and age, disease presence, stage, treatment responses and survival. RESULTS: Pretreatment NAG correlated with age but was independently increased in metastatic versus locally advanced disease, particularly in gastric/esophageal patients. NAG was also associated with reduced overall survival. In subgroup analysis, increased NAG activity between day 1 and 2 of chemotherapy cycle 1 correlated with treatment response. CONCLUSION: We demonstrated that NAG correlates with gastrointestinal cancer outcomes. Further studies are required to determine if plasma markers of genotoxicity can be useful for disease monitoring.

Raf kinase inhibitor protein expression combined with peritoneal involvement and lymphovascular invasion predicts prognosis in Dukes' B colorectal cancer patients.

AIMS: There is controversy regarding the use of adjuvant therapy in patients with Dukes' B colorectal cancer (CRC). New markers, identifying high-risk Dukes' B patients, are needed. Here, we examine the utility of Raf kinase inhibitor protein (RKIP) as such a marker and promoter methylation as a mechanism of RKIP down-regulation. METHODS AND RESULTS: We used a tissue microarray of 220 patients with Dukes' B CRC to examine the effect of RKIP expression on survival. Pyrosequencing was used to assess RKIP promoter methylation status.RKIP expression correlated inversely with disease-specific survival in this cohort. In multivariate analysis, RKIP was found to be an independent prognostic indicator, along with peritoneal invasion and lymphovascular invasion (LVI). RKIP promoter hypermethylation was seen in only one of 29 tumours analysed by pyrosequencing. CONCLUSIONS: Raf kinase inhibitor protein, peritoneal invasion and LVI provide independent prognostic information in this cohort of Dukes' B CRC patients.This demonstrates the potential utility of RKIP in identifying 'high-risk' Dukes' B patients. It is this high-risk group which is most likely to benefit from close postoperative monitoring and may derive the most benefit from adjuvant therapy.

A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation.

PURPOSE: poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma. METHODS: Patients with chemotherapy naïve measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. RESULTS: Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. CONCLUSIONS: This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.

Raf kinase inhibitor protein expression in a survival analysis of colorectal cancer patients.

PURPOSE: Raf kinase inhibitor protein (RKIP) inhibits the Raf and nuclear factor kappa B signaling pathways, and suppresses metastasis in animal models. We examined whether RKIP expression in primary colorectal cancers (CRCs) correlates with the risk of metastasis and overall survival. PATIENTS AND METHODS: RKIP expression was examined immunohistochemically in three separate cohorts: a tissue microarray containing 276 samples from human tumors and normal tissues, and retrospective studies of 268 CRC patients and 65 early-stage CRCs. Overall and metastasis-free survival rates were measured. RESULTS: RKIP was expressed in normal epithelia but was reduced in metastatic tumors. RKIP expression in primary CRC was an independent prognostic marker for survival using multivariate Cox regression analysis (hazard ratio, 2.808; 95% CI, 1.58 to 4.96; P = .0002), independent of Dukes' stage. Patients with Dukes' C RKIP-positive tumors had similar 5-year survival rates as early-stage patients if tumors had equivalent RKIP expression levels. An independent study of early-stage CRCs confirmed that reduced RKIP expression predicted metastatic recurrence and reduced disease-free survival (hazard ratio, 4.5; 95% CI, 1.7 to 12.3; P = .003). RKIP expression was independent of sex, age, mitotic index, lymphatic and vascular invasion, depth of invasion, and tumor site, but correlated positively with apoptotic index (P = .024). Weak or loss of RKIP expression was the most significant and independent prognostic marker using a multivariate regression equation (hazard ratio, 4.5; 95% CI, 1.7 to 12.3; P = .003). CONCLUSION: RKIP expression in primary CRCs correlates with overall and disease-free survival, and can be useful for identifying early-stage CRC patients at risk of relapse.

Management of Skin Toxicity Related to the Use of Imatinib Mesylate (STI571, Glivectrade mark) for Advanced Stage Gastrointestinal Stromal Tumours.

Skin toxicity is a common side-effect of treatment with imatinib mesylate (STI571, Glivectrade mark) in advanced gastrointestinal stromal tumours (GIST) and chronic myeloid leukaemia. The optimal duration of treatment with imatinib mesylate in GIST has not yet been established, as durable remissions have been observed in patients. It is, therefore, important to develop strategies to deal with common side-effects of what may be a long-term treatment. Here we report the case of a patient with advanced GIST who developed a cutaneous drug reaction secondary to imatinib mesylate and the various management options that may be employed depending upon the severity of the toxicity. The case and literature are discussed.

Emerging drugs in colorectal cancer.

A raft of novel agents with different modes of action is finally challenging the position of 5-fluorouracil (5-FU) as the gold standard treatment for colorectal cancer. Oral fluoropyrimidines, topoisomerase I inhibitors and new generation platinum compounds are all currently being investigated. There is also increasing interest in the development and use of biological therapies, which may allow treatments to become tailored to individual patients and cause less toxicity than conventional cytotoxics. It is hoped that with the development of these new drugs, the response rates and survival for patients with colorectal cancer will improve from the poor prognosis that many face at present.