Oncological risks associated with the planned watch-and-wait strategy using total neoadjuvant treatment for rectal cancer: A narrative review.

Overall survival benefit of total neoadjuvant treatment (TNT) remains unconfirmed. Thus, in our opinion, the main rationale for using TNT is a planned watch-and-wait (w&w) strategy to improve patients' long-term quality of life through organ preservation. The OPRA randomized trial, which examined a planned w&w strategy using TNT, showed a higher organ preservation rate but also a higher regrowth rate compared to studies on the opportunistic w&w strategy. Higher rates of complete clinical response with TNT did not improve disease-free survival compared to historical controls. Therefore, the gain in organ-sparing capability might not be balanced by the increased oncological risk. The ultimate local failure rate in the intention-to-treat analysis of the OPRA trial was 13% for induction chemotherapy and 16% for consolidation chemotherapy, which seems higher than expected compared to 8% in a meta-analysis of w&w studies or 12% after TNT and surgery in the PRODIGE-23 and RAPIDO trials, which enrolled patients with more advanced cancers than the OPRA trial. Other studies also suggest worse local control when surgery is delayed for radio-chemoresistant cancers. Our review questions the safety of the planned w&w strategy using TNT in unselected patients. To reduce the oncological risk while maintaining high organ preservation rates, we suggest that the planned w&w strategy using TNT requires a two-tier patient selection process: before treatment and after tumor response assessment at the midpoint of consolidation chemotherapy. These robust selections should identify patients who are unlikely to achieve organ preservation with TNT and would be better managed by preoperative chemoradiotherapy (without consolidation chemotherapy) and surgery, or by discontinuing consolidation chemotherapy and proceeding directly to surgery.

Implications of bone metastasis on response to systemic therapy in patients with advanced renal cell carcinoma: A systematic literature review.

INTRODUCTION: Bone metastases negatively affect prognosis in patients with advanced renal cell carcinoma (aRCC). We conducted a systematic literature review to identify clinical trial publications including patients with aRCC with and without bone metastases. METHODS: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta­Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42022355436). MEDLINE and Embase databases were searched (September 2, 2022) to identify publications reporting efficacy and safety outcomes for patients with/without bone metastasis from clinical trials of systemic RCC therapies. Risk of bias was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Of 526 publications screened, 19 were eligible: seven (from five studies) reported phase 3 trials, six reported phase 2 trials, one reported phase 1b/2 trials, and five were pooled analyses. Five publications reported moderate-quality evidence, while 14 were graded as low- or very low-quality evidence, suggesting a high potential for uncertainty. Five studies reported benefits of investigational therapies versus comparators in patients with and without bone metastases; these studies included cabozantinib, nivolumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab treatment arms. Data were also available for nivolumab plus ipilimumab. Bone metastases were consistently associated with poor prognosis in patients with aRCC. Preliminary data support the hypothesis that therapies targeting pathways implicated in the development of bone metastases may be beneficial, and warrant further investigation. However, data to support treatment decision-making are lacking. CONCLUSION: Our findings highlight the need for clinical data to assist in defining the optimal treatment for patients with aRCC and bone metastasis.

Assessing asymmetrical kidney function in living donors: a retrospective cohort study on CT metrics.

BACKGROUND: Live donor kidney transplantation is the preferred kidney replacement therapy for eligible patients but requires thorough donor evaluation to minimise risks. Contemporary guidelines recommend split kidney function measurement in living donors only when there is a significant kidney size discrepancy, yet the evidence for this is poor, and practice varies nationally. This study evaluates the efficacy of CT-derived kidney metrics in detecting significant functional asymmetry. METHODS: We conducted a retrospective cohort analysis of 123 prospective living kidney donors at a regional transplant centre from June 2011 to October 2014, utilising CT to determine kidney and cortical volumes and lengths. Asymmetric kidney function (AKF), defined by > 10% function difference on DMSA scans, was correlated with CT measurements to calculate the diagnostic accuracy of current guidelines. RESULTS: Among the prospective donors, the median age was 42 years, and 59.3% were female. The median split kidney function difference was 4%, with 25 individuals exhibiting > 10% AKF. Kidney length discrepancy proved to be a poor indicator of AKF (sensitivity: 28%, specificity: 84%). While negative predictive values for cortical and kidney volumes were high (96% and 93%, respectively), sensitivity was low, and specificity and positive predictive value did not meet satisfactory thresholds. CONCLUSIONS: CT-derived metrics of kidney length, cortical, and total volume show limited sensitivity and specificity in identifying significant AKF. These findings provide evidence to support revised guideline development in the assessment of living kidney donors.

Plain language summary of the results from the TALAPRO-2 study: Talazoparib plus enzalutamide versus placebo plus enzalutamide for patients with advanced prostate cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?: Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?: TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study. WHAT ARE THE KEY TAKEAWAYS?: A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients).Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).

Healthcare-associated infections and antimicrobial use at a major referral hospital in Papua New Guinea: a point prevalence survey.

Background: Healthcare-associated infections (HAI) and antimicrobial use (AMU) are drivers for antimicrobial resistance, and robust data are required to inform interventions and track changes. We aimed to estimate the prevalence of HAI and AMU at Port Moresby General Hospital (PMGH), the largest hospital in Papua New Guinea. Methods: We did a point prevalence survey (PPS) on HAI and AMU at PMGH in May 2023 using the European Centre for Disease Prevention and Control (ECDC) PPS protocol. We included all critical care patients and randomly sampled half of the patients in other acute-care wards. We calculated weighted HAI and AMU prevalence estimates to account for this sampling strategy. Weighted HAI estimates were also calculated for an expanded definition that included physician diagnosis. Findings: Of 361 patients surveyed in 18 wards, the ECDC protocol identified 28 HAIs in 26 patients, resulting in a weighted HAI prevalence of 6.7% (95% CI: 4.6, 9.8). Surgical site infections (9/28, 32%) were the most common HAI. When adding physician diagnosis to the ECDC definitions, more skin and soft tissue, respiratory, and bloodstream HAIs were detected, and the weighted HAI prevalence was 12.4% (95% CI: 9.4, 16.3). The prevalence of AMU was 66.5% (95%CI: 61.3, 71.2), and 73.2% (263/359) of antibiotics were from the World Health Organization Access group. Interpretation: This is the first reported hospital PPS of HAI and AMU in Papua New Guinea. These results can be used to prioritise interventions, and as a baseline against which future point prevalence surveys can be compared. Funding: Australian Government Department of Foreign Affairs and Trade and Therapeutic Guidelines Limited Australia.

Optimising the use of the prostate- specific antigen blood test in asymptomatic men for early prostate cancer detection in primary care: report from a UK clinical consensus.

BACKGROUND: Screening is not recommended for prostate cancer in the UK. Asymptomatic men aged ≥50 years can request a prostate-specific antigen (PSA) test following counselling on potential harms and benefits. There are areas of clinical uncertainty among GPs, resulting in the content and quality of counselling varying. AIM: To produce a consensus that can influence guidelines for UK primary care on the optimal use of the PSA test in asymptomatic men for early prostate cancer detection. DESIGN AND SETTING: Prostate Cancer UK facilitated a RAND/UCLA consensus. METHOD: Statements covering five topics were developed with a subgroup of experts. A panel of 15 experts in prostate cancer scored (round one) statements on a scale of one (strongly disagree) to nine (strongly agree). Panellists met to discuss statements before rescoring (round two). A lived experience panel of seven men scored a subset of statements with outcomes fed into the main panel. RESULTS: Of the initial 94 statements reviewed by the expert panel, a final 48/85 (56%) achieved consensus. In the absence of screening, there was consensus on proactive approaches to initiate discussions about the PSA test with men who were at higher-than-average risk. CONCLUSION: Improvements in the prostate cancer diagnostic pathway may have reduced some of the harms associated with PSA testing; however, several areas of uncertainty remain in relation to screening, including optimal PSA thresholds for referral and intervals for retesting. There is consensus on proactive approaches to testing in higher-than-average risk groups. This should prompt a review of current guidelines.

Biomarkers associated with survival in patients with platinum-refractory urothelial carcinoma treated with paclitaxel.

BACKGROUND: Taxane- based chemotherapy is widely used in patients with platinum- and immunotherapy refractory, metastatic urothelial carcinoma (mUC). Outcomes are poor and biomarkers associated with outcome are lacking. We aim to identify cancer hallmarks associated with survival in patients receiving paclitaxel. METHODS: Whole-transcriptome profiles were generated for a subset of patients enrolled in a randomised phase II study investigating paclitaxel and pazopanib in platinum refractory mUC (PLUTO, EudraCT 2011-001841-34). Estimates of gene expression were calculated and input into the Almac proprietary analysis pipeline and signature scores were calculated using ClaraT V3.0.0. Ten key gene signatures were assessed: Immuno-Oncology, Epithelial to Mesenchymal Transition, Angiogenesis, Proliferation, Cell Death, Genome Instability, Energetics, Inflammation, Immortality and Evading Growth. Hazard ratios were calculated using Cox regression model and Kaplan-Meier methods were used to estimate progression free survival (PFS) and overall survival (OS). RESULTS: 38 and 45 patients treated with paclitaxel or pazopanib were included. Patients with high genome instability expression treated with paclitaxel had significantly improved survival with a HR of 0.29 (95% CI: 0.14-0.61, p=0.001) and HR 0.34 (95% CI: 0.17-0.69, p=0.003) for PFS and OS, respectively. Similarly, patients with high evading growth suppressor expression treated with paclitaxel had improved PFS and OS with a HR of 0.35 (95% CI: 0.19-0.77, p=0.007) and HR 0.46 (95% CI: 0.23-0.91, p=0.026), respectively. No other gene signatures had significant impact on outcome. In both paclitaxel and pazopanib cohorts, angiogenesis activation was associated with worse PFS and OS, and VEGF targeted therapy did not improve outcomes. CONCLUSION: High Genome-instability and Evading-growth suppressor biologies are associated with improved survival in patients with platinum refractory mUC receiving paclitaxel. These may refine mUC risk stratification and guide treatment decision in the future.

Turmeric-induced Liver Injury.

The use of herbal and dietary supplements has gained an increasing foothold in the United States. While often touted as safer alternatives to more traditional "western" therapeutics, the pharmacology and pharmacokinetics of these substances, their interactions with other medications, their purity, and individual pharmacogenomics, remain unknown. Turmeric is a popular supplement that has been demonstrated to be safe, and even hepatoprotective. Recently, however, there have been several reports of turmeric-induced liver injury. We report a case of drug-induced liver injury due to turmeric that was complicated by acute liver failure and hepatorenal syndrome.

Merck Animal Health Veterinary Team study reveals factors associated with well-being, burnout, and mental health among nonveterinarian practice team members.

OBJECTIVE: To assess the levels of burnout, well-being, and mental health of nonveterinarian employees of veterinary practices and, for context, compare them to veterinarians and the general population by use of validated instruments. METHODS: An online survey of 2,271 nonveterinary practice employees drawn from members of the North American Veterinary Technicians Association, members of the Veterinary Hospital Managers Association, referrals from veterinarian respondents to a companion survey, and a large hospital group that owns several hundred US veterinary practices. The study was fielded from September 11 to October 9, 2023. RESULTS: A majority of practice team members were satisfied with their work in veterinary medicine. However, serious psychological distress was twice as prevalent among team members as among veterinarians and well-being was lower than that of veterinarians. Burnout was similar to veterinarians. Personality played a role: team members on average were more likely to score higher in neuroticism than veterinarians and the general population, and neuroticism was a predictor of low well-being, poor mental health, and burnout. There was also evidence of substantial financial stress among team members. CONCLUSIONS: Serious psychological distress was common among practice team members. Financial stress may play a role. Burnout and low levels of well-being were also common. CLINICAL RELEVANCE: This study provided a useful profile of the psychological conditions that many practice employees may be experiencing.

Mechanisms of sensitivity and resistance to CDK4/CDK6 inhibitors in hormone receptor-positive breast cancer treatment.

Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR+ BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

Dynamic Drop Penetration of Horizontally Oriented Fiber Arrays.

In this experimental study, we combine drop impact into porous media and onto a single fiber to study drop impact into fiber arrays inspired by mammalian fur coats. In our 3D-printed arrays, we vary the packing density, fiber alignment, strand cross-section, and wettability. Drops impact fibers fixed at both ends, penetrating over short periods of time by momentum and laterally spreading throughout the array. Using image analysis, we measure penetration depth and wetted width into the array. Impact Weber number and intrinsic porosity define penetration, retraction, and rebound regimes. On average, at an impact Weber number of ≈80, staggered fibers reduce penetration by 24% in hydrophilic fibers and 34% in hydrophobic fibers, and the penetration reduction percentage is expected to increase with increasing Weber number. Our results indicate that as density grows toward the density of mammalian pelts, penetration will reach a maximum value independent of drop impact velocity, thereby providing an effective rain barrier. Hydrophilicity at the densities we test, 50-150 strands/cm2, aids fiber array resistance to dynamic penetration by impacting drops through the promotion of lateral drop spreading and inhibition of drop fragmentation. Conversely, hydrophobic fibers best resist low-speed wicking. The fraction of a drop that infiltrates hydrophilic and hydrophobic fibers is nearly identical for a fixed Weber number because lateral spreading restricts the penetration depth into hydrophilic fibers but does not restrict mass infiltration. Above a critical Weber number, the entire drop mass penetrates fiber arrays regardless of strand wettability.

Multi-Center Two-Year Patency Outcomes of Endovascular Arteriovenous Fistulas (endoAVF) Created with a 4 French System.

PURPOSE: To assess multicenter two-year patency outcomes of endovascular arteriovenous fistulas (endoAVF) created with the WavelinQ device. MATERIALS AND METHODS: Patients who had fistulas created at three centers from January 2018 to December 2020 were included in this retrospective study. In total, 112 patients underwent endoAVF creation [40 females, 72 males; mean age 60 years (range 18-88)]. Data collected included patient demographics, location of fistula creation, interventions performed, and brachial artery flows pre- and post-creation. Two-year cumulative patency, functional patency, and primary patency were assessed with Kaplan-Meier methodology. Factors affecting patency and maturation were examined using the Cox proportional hazards model. RESULTS: Technical success defined as angiographically successful endoAVF creation was 97.3% (109/112). In 11 patients the fistula did not mature for dialysis use. For 98 patients (87%) with endoAVF maturation, 12- and 24-month cumulative patency was 94.3% and 91.7%. Functional patency (two-needle cannulation) at 12 and 24 months was 95.7% and 92.7%, respectively. Median maturation time is 95 days (IQR 51-231 days). Male gender and brachial vein coiling at the time of endoAVF creation were predictive of maturation. There were 34 censored events (four patients undergoing renal transplantation; 30 patients deceased). Number of reinterventions per patient year was 0.73 where 43 were maturation procedures and 101 were maintenance procedures. One Grade 3 complication occurred of arterial access puncture site pseudoaneurysm. CONCLUSION: A high two-year functional and cumulative patency following endoAVF creation with the WavelinQ device was observed in this multicenter real-world experience Level of Evidence: 3 Level of Evidence III.

Multivariable prognostic modelling to improve prediction of colorectal cancer recurrence: the PROSPeCT trial.

OBJECTIVE: Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. MATERIAL AND METHODS: This multicentre trial (ISRCTN 95037515) recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-node stage, tumour size, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume, transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. RESULTS: Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). CONCLUSION: A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. CLINICAL RELEVANCE STATEMENT: A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. KEY POINTS: Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisation of risk stratification schema will help individualise treatment plans and follow-up schedules.

Toxicities of Novel Agents for the Treatment of Advanced Bladder Cancer.

Enfortumab vedotin and erdafitinib have specific toxicities that need careful management in order to optimise drug exposure while maintaining patients' quality of life. Patient education, meticulous monitoring, and a multidisciplinary approach are key to optimising outcomes so that patients can reap the benefits of these new treatments.

Dormancy of a specialist herbivore, Anthonomus rufipennis (Coleoptera: Curculionidae), in a dry tropical forest.

The life history aspects of dormancy of the weevil Anthonomus rufipennis LeConte (Coleoptera: Curculionidae) were studied a 57-month period in a seasonally dry tropical forest of central Mexico. Weevil populations and their physiological status were monitored on both the reproductive host tree, Senna polyantha (Collad.) H.S: Irwin & Barneby (Fabales: Fabaceae) and the highly favored refuge host, Tillandsia recurvata L. (Poales: Bromeliaceae) or "ball moss." During the dry season, weevils were only found on the refuge host with a mean total density of 1.014 ± 2.532 individuals/ball moss (N = 1,681). Weevil densities on T. recurvata between early and late dry seasons were not significantly different, suggesting that dry season survival was relatively high. Weevils collected during these seasons revealed little reproductive development and relatively high-fat accumulation in both sexes. During 5 of 6 yr, densities of the weevils in T. recurvata dropped significantly during the early rainy seasons, when the reproductive host trees leafed out and began producing oviposition sites (flower buds). At this time, more males than females initially moved to vegetative trees and showed significant signs of reproductive development. Recolonization of ball moss by weevils began during the late rainy season when oviposition sites (flower buds) were still available. A proportion of the weevils remained on the reproductive host, suggesting that A. rufipennis is facultatively multivoltine. The methodologies and results of the study can serve as a model system for future studies of the dormancy of other insects in dry tropical forests and provide insight into the dormancy of other anthonomine weevils of economic importance.

Work-life balance is essential to reducing burnout, improving well-being.

OBJECTIVE: To assess levels of burnout, well-being, and mental health of veterinarians and compare them to those of nonveterinarians by use of validated instruments, and to identify the predictive values of techniques individuals can use to help reduce burnout and/or improve well-being and mental health. SAMPLE: An online survey of 4,636 veterinarians from a random sample of 40,000 US veterinarians provided by the AVMA. METHODS: The study was fielded from September 11 to October 9, 2023. RESULTS: Burnout and well-being of veterinarians were generally consistent with that of employed US adults. Serious psychological distress was more common among veterinarians than in the general population. Veterinarians on average were more likely to score higher in neuroticism than nonveterinarians, and neuroticism was a predictor of low well-being, poor mental health, and burnout. Work-life balance, an effective coping mechanism for stress, and working in a positive clinic culture were among the significant factors that predicted good well-being and mental health and reduced burnout. CLINICAL RELEVANCE: The higher percentage than the norm of veterinarians with serious psychological distress was a concern. Focusing on maintaining a good work-life balance and adopting a reliable coping mechanism can potentially help reduce distress. Veterinary medicine is an inherently stressful profession. The purpose of this study was to identify key factors that contribute to burnout, well-being, and mental health and to determine what behaviors and management techniques help reduce stress and burnout and contribute to well-being and mental health, thus improving job satisfaction and personal fulfillment.

A review of Musca sorbens (Diptera: Muscidae) and Musca domestica behavior and responses to chemical and visual cues.

Musca flies (Diptera: Muscidae) have been found culpable in the mechanical transmission of several infectious agents, including viruses, bacteria, protozoans, and helminths, particularly in low-income settings in tropical regions. In large numbers, these flies can negatively impact the health of communities and their livestock through the transmission of pathogens. In some parts of the world, Musca sorbens is of particular importance because it has been linked with the transmission of trachoma, a leading cause of preventable and irreversible blindness or visual impairment caused by Chlamydia trachomatis, but the contribution these flies make to trachoma transmission has not been quantified and even less is known for other pathogens. Current tools for control and monitoring of house flies remain fairly rudimentary and have focused on the use of environmental management, insecticides, traps, and sticky papers. Given that the behaviors of flies are triggered by chemical cues from their environment, monitoring approaches may be improved by focusing on those activities that are associated with nuisance behaviors or with potential pathogen transmission, and there are opportunities to improve fly control by exploiting behaviors toward semiochemicals that act as attractants or repellents. We review current knowledge on the odor and visual cues that affect the behavior of M. sorbens and Musca domestica, with the aim of better understanding how these can be exploited to support disease monitoring and guide the development of more effective control strategies.

Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial.

BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC.