Androgen Deprivation Therapy/Androgen Receptor Signaling Inhibitor Treatments for Prostate Cancer: Pathophysiology and Review of Effects on Cardiovascular Disease.

Androgen deprivation therapy is the cornerstone of systemic management for prostate cancer but is associated with multiple adverse effects that must be considered during treatment. These effects occur because of the profound hypogonadism that is induced from lack of testosterone or due to the medications used in the treatment or in combination with androgen receptor signaling inhibitors. This article critically reviews the associations between androgen deprivation therapy, androgen receptor signaling inhibitors, and cardiovascular complications such as prolonged QT interval, atrial fibrillation, heart failure, atherosclerosis, coronary heart disease, venous thromboembolism, and peripheral arterial occlusive disease. These unfavorable outcomes reinforce the need for regular cardiovascular screening of patients undergoing androgen deprivation for the management of prostate cancer.

PoCUS identification of distal biceps tendon rupture: a case report.

BACKGROUND: In the Emergency Department (ED), patients may present with various injuries that damage muscles, tendons, ligaments, and bony structures. Fractures, joint dislocations, strains, and sprains are prevalent among them. However, distal biceps tendon ruptures are uncommon. CASE REPORT: Here, we report a case of a young man presented to the ED with a complaint of left arm pain following a martial arts activity. The diagnosis of distal biceps tendon rupture was made using a point-of-care ultrasound (PoCUS), and an early referral to the orthopedic service was provided. CONCLUSION: This case highlights the utility of point-of-care ultrasound in assessing musculoskeletal injuries in the ED. Early incorporation of PoCUS into routine clinical practice can potentially improve the overall care of musculoskeletal injuries.

From compression to diagnosis: identification of superior vena cava syndrome using point-of-care ultrasound in the emergency department.

BACKGROUND: Superior vena cava (SVC) syndrome is an urgent condition arising from restricted blood flow through the SVC, often linked to factors like malignancy, thrombosis, or infections. Typically, confirmation of the diagnosis involves computed tomography. However, many patients experience respiratory distress and cannot lie supine. Given the increasing integration of point-of-care ultrasound in emergency medicine, it is important to be familiar with findings that are suggestive of this important condition. CASE REPORT: In this case report, we highlight a young patient presenting to the emergency department with superior vena cava syndrome symptoms, successfully diagnosed using point-of-care ultrasound. CONCLUSION: This case highlights the utility of point-of-care ultrasound based diagnosis of SVC syndrome and upper arm deep venous thrombosis in a patient with underlying malignancy which ultimately led to early involvement of relevant speciality for initiation of treatment.

PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19).

PURPOSE: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.

Durable and dramatic response to checkpoint inhibition combined with COX-2 inhibitor celecoxib in a patient with p16+ metastatic sinonasal undifferentiated carcinoma: A case study.

BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is an exceedingly rare head and neck malignancy. No consensus exists on treatment for metastatic disease. CASE: A 56-year-old female was diagnosed with SNUC after endorsing sinus congestion, diplopia, and right orbital pain. Initially treated with surgery and radiation, she later developed significant metastatic disease. She demonstrated progression of her hepatic metastases under pembrolizumab therapy. However, the addition of ipilimumab and a COX-2 inhibitor resulted in significant improvement in her lesions as well as an ongoing durable response. Her regimen was complicated by immune-related adverse events successfully treated with steroids. CONCLUSION: Dual checkpoint inhibition deserves consideration when treating metastatic SNUC, especially after single agent therapy has failed. The positive effect of this treatment may be augmented by IDO1 inhibition.

The Host-specific Microbiota is Required for Diet-Specific Metabolic Homeostasis.

In complex mammals, the importance and host-specificity of microbial communities have been demonstrated through their positive effects on host immune fitness or performance. However, whether host metabolic physiology homeostasis depends on a specific bacterial community exclusive to the host remains unclear. Here, we show that the coevolved host-specific microbiota is required to maintain diet-specific flexible and sufficient metabolic homeostasis through a high colonization rate, modulating gut metabolites, and related targets. Using germ-free (GF) mice, we tested whether the fitness benefiting the host metabolic phenotype of microbiota was host-specific. We demonstrated that GF mice associated with exogenous microbiota (human microbiota (HM)), which exhibited different and reduced gut microbial species diversity, significantly elevated metabolic rate, and exhibited metabolic insufficiency, all characteristics of GF mice. Strikingly, the absence of the host-specific microbiome attenuated high-fat diet-specific metabolism features. Different diets caused different metabolic changes in only host-specific microbiota-associated mice, not the host-microbiota mismatched mice. While RNA sequencing revealed subtle changes in the expression of genes in the liver, GF mice and HM mice showed considerably altered expression of genes associated with metabolic physiology compared to GF mice associated with host-specific microbiota. The effect of diet outweighed microbiota in the liver transcriptome. These changes occurred in the setting of decreased luminal short-chain fatty acids (SCFAs) and the secondary bile acid (BAs) pool and downstream gut signaling targets in HM and GF mice, which affects whole-body metabolism. These data indicate that a foreign microbial community provides little metabolic benefit to the host when compared to a host-specific microbiome, due to the colonization selection pressure and microbiota-derived metabolites dysfunction. Overall, microbiome fitness effects on the host metabolic phenotype were host-specific. Understanding the impact of the host-specificity of the microbiome on metabolic homeostasis may provide important insights for building a better probiotic. Highlights: Microbiome fitness effects on the host metabolic phenotype were host-specific in mammals.Human microbiota-associated mice exhibited lower host metabolic fitness or performance, and similar functional costs in GF mice.Different diets cause different metabolic changes only in host-specific microbiota-associated mice, not the host-microbiota mismatched mice.The defective gut microbiota in host-specific microbiota, microbial metabolites and related targets likely drive the metabolic homeostasis.

Gut microbes and the liver circadian clock partition glucose and lipid metabolism.

Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours.

Factors associated with regular dental attendance by aged adults: A systematic review.

OBJECTIVES: To determine factors influencing regular dental attendance in aged adults 65 and over according to Andersen's Behavioural Model. BACKGROUND: Regular attendance for dental visits is vital to improve and maintain oral health, quality of life and general well-being. Aged adults 65 years and older experience barriers to regular dental attendance, which in turn leads to an increased risk for oral diseases. MATERIALS AND METHODS: An electronic search was undertaken in April 2021 in Cochrane, Embase, Medline, Cinahl, Dentistry & Oral Science Source via EBSCOhost and Embase for papers on factors influencing the frequency of attendance by older people. Risk of bias was assessed according to the Newcastle-Ottawa Scale for cohort and case-control studies, and with modified version of this tool for cross-sectional studies. Frequency effect size was calculated for factors described in Andersen's Behavioural Model (predisposing, enabling and needs-related). RESULTS: Twenty-one studies were eligible for inclusion. Factors frequently investigated affecting regular dental attendance included: age, gender, education (predisposing); income, and social support (enabling); and remaining teeth, pain, perceived health (needs-related). Income was the only factors with a 100% positive association with regular dental attendance. CONCLUSIONS: This systematic review confirms the complex interconnectedness of several factors and dental attendance in older adults. A number of factors were identified which warrant further investigation to improve access to dental care to socio-economically vulnerable older populations.

Combination treatment of bilateral periocular sebaceous carcinomas with microsatellite instability with neoadjuvant pembrolizumab and Mohs surgery.

This case highlights the successful use of pembrolizumab for neoadjuvant treatment of MMR-deficient sebaceous carcinoma of bilateral eyelids to reduce tumour burden allowing smaller defect post-Mohs surgery and better reconstructive outcome. Microsatellite stability, tumour mutational burden and PD-L1 expression are important prognostic factors to be considered for the use of neoadjuvant pembrolizumab. Further studies are needed to determine if neoadjuvant pembrolizumab consistently improves surgical and cosmetic outcomes and reduces local recurrence and metastasis.

The association of phosphodiesterase-5 inhibitors with the biochemical recurrence-free and overall survival of patients with prostate cancer following radical prostatectomy.

PURPOSE: To determine whether phosphodiesterase-5 inhibitor documentation is associated with biochemical relapse-free and overall survival of patients with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: We undertook a retrospective cohort analysis of 3,100 patients with prostate cancer treated with radical prostatectomy between 2003 and 2015. The patients were categorized as a phosphodiesterase- 5- inhibitor user or non-user. The biochemical relapse-free and overall survival at 5-years and 10-years were determined. RESULTS: Of the patients, 1,372 reported phosphodiesterase-5 inhibitor documentation, and 1,728 did not. The biochemical recurrence-free survival for non-users at 5- and 10-years follow-up was 87.6% and 85.3%, respectively, and the overall survival at these time intervals was 97.9% and 94.5%. The biochemical recurrence-free survival for phosphodiesterase-5 inhibitor users was 94.3% and 93.2% at 5- and 10-years follow-up, respectively, and overall survival was 99.2% and 95.8% at these intervals. The hazard ratio for biochemical recurrence-free survival was 0.44 (CI 0.34-0.56) and for overall survival was 0.65 (CI 0.45-0.94). On the multivariate analysis, phosphodiesterase-5 inhibitor documentation was associated with a lower risk of biochemical recurrence and death when corrected for the other variables. Age at surgery and Gleason scores >8 was associated with a higher risk of death. Higher pathological stage, higher Gleason score, presence of lymph node metastases, and nonwhite race were associated with a higher risk of recurrence. CONCLUSION: This retrospective analysis revealed a significant association of postoperative phosphodiesterase-5 inhibitor documentation with biochemical recurrence-free- and overall survival in patients with localized prostate cancer treated with radical prostatectomy. Larger scale studies are warranted to investigate the clinical significance of this association.

Phase I study protocol: NKTR-255 as monotherapy or combined with daratumumab or rituximab in hematologic malignancies.

NKTR-255 is an investigational polyethylene glycol-modified recombinant human IL-15 (rhIL-15) receptor agonist, designed to improve the immunotherapeutic and anti-cancer benefit observed with rhIL-15 while circumventing the toxicities associated with this therapy. In preclinical studies, NKTR-255 has demonstrated enhanced proliferation and function of CD8+ T cells and natural killer cells, as well as enhanced anti-tumor activity and survival both as monotherapy and in combination with monoclonal antibodies in multiple cancer models. Here, we describe the rationale and design of the first-in-human Phase I, dose-escalation and dose-expansion study of NKTR-255 alone and in combination with daratumumab or rituximab in adults with relapsed/refractory multiple myeloma or non-Hodgkin's lymphoma that will determine the maximum tolerated dose and recommended Phase II dose for NKTR-255.

Lay abstract Interleukin-15 (IL-15) is a protein that helps the body's natural immune system to defend itself against infections and diseases like cancer. This article discusses a clinical trial in patients with multiple myeloma or non-Hodgkin's lymphoma that evaluates a new investigational medicine, NKTR-255, a polymer-modified form of IL-15 that has been engineered to improve its ability to provide a sustained anti-tumor immune response. The trial will explore different doses of NKTR-255 to determine patient side effects and to find the highest acceptable dose that patients can tolerate. Based on this, a dose will be chosen that offers an optimal balance between having a positive anti-cancer effect and minimizing side effects. This dose will be tested further in patients who have had different treatments in the past. If the side effects are acceptable, this dose will be tested in a new trial in a large number of patients. Clinical Trial Registration: NCT04136756 (ClinicalTrials.gov).

A review of staging chest CT in trunk and extremity soft tissue sarcoma.

OBJECTIVES: To determine the incidence of pulmonary metastases on chest CT in trunk and extremity soft tissue sarcoma based on two size criteria, and to identify factors associated with metastases. METHODS: Retrospective review of chest CT studies in patients with trunk and extremity soft tissue sarcoma over an 18-month period. Data collected included patient age/sex, tumour location, size and relationship to fascia. All chest CTs were reviewed for the presence of metastases which were diagnosed according to two size criteria: multiple nodules > 5 mm in size or multiple nodules > 10 mm in size. Follow-up CT studies were reviewed in cases initially considered indeterminate. RESULTS: 127 males and 73 females were included (mean age 57.1 years; range 10-90 years). 147 (73.5%) tumours were deep to the fascia and 53 (26.5%) superficial. Tumour size classified according to the 12 AJCC 2019 criteria was: T1 = 52, T2 = 76, T3 = 39, T4 = 33. Based on nodule size >5 mm, 73 (36.5%) patients had no metastases, 42 (21%) had metastases, while 85 (42.5%) studies were indeterminate. Based on nodule size >10 mm, 73 (36.5%) patients had no metastases, 28 (14%) had metastases, while 99 (49.5%) studies were indeterminate. Larger maximum dimension of the primary tumour was a risk factor for pulmonary metastases using both size criteria. CONCLUSION: The incidence of pulmonary metastases at presentation in trunk and extremity soft tissue sarcoma is 14-21%. 42.5-49.5% of chest CTs were indeterminate. ADVANCES IN KNOWLEDGE: The incidence of pulmonary metastases at presentation in trunk and extremity soft tissue sarcoma is 14-21%. Indeterminate pulmonary nodules are also very common.

Robotic surgery: disruptive innovation or unfulfilled promise? A systematic review and meta-analysis of the first 30 years.

BACKGROUND: Robotic surgery has been in existence for 30 years. This study aimed to evaluate the overall perioperative outcomes of robotic surgery compared with open surgery (OS) and conventional minimally invasive surgery (MIS) across various surgical procedures. METHODS: MEDLINE, EMBASE, PsycINFO, and ClinicalTrials.gov were searched from 1990 up to October 2013 with no language restriction. Relevant review articles were hand-searched for remaining studies. Randomised controlled trials (RCTs) and prospective comparative studies (PROs) on perioperative outcomes, regardless of patient age and sex, were included. Primary outcomes were blood loss, blood transfusion rate, operative time, length of hospital stay, and 30-day overall complication rate. RESULTS: We identified 99 relevant articles (108 studies, 14,448 patients). For robotic versus OS, 50 studies (11 RCTs, 39 PROs) demonstrated reduction in blood loss [ratio of means (RoM) 0.505, 95 % confidence interval (CI) 0.408-0.602], transfusion rate [risk ratio (RR) 0.272, 95 % CI 0.165-0.449], length of hospital stay (RoM 0.695, 0.615-0.774), and 30-day overall complication rate (RR 0.637, 0.483-0.838) in favour of robotic surgery. For robotic versus MIS, 58 studies (21 RCTs, 37 PROs) demonstrated reduced blood loss (RoM 0.853, 0.736-0.969) and transfusion rate (RR 0.621, 0.390-0.988) in favour of robotic surgery but similar length of hospital stay (RoM 0.982, 0.936-1.027) and 30-day overall complication rate (RR 0.988, 0.822-1.188). In both comparisons, robotic surgery prolonged operative time (OS: RoM 1.073, 1.022-1.124; MIS: RoM 1.135, 1.096-1.173). The benefits of robotic surgery lacked robustness on RCT-sensitivity analyses. However, many studies, including the relatively few available RCTs, suffered from high risk of bias and inadequate statistical power. CONCLUSIONS: Our results showed that robotic surgery contributed positively to some perioperative outcomes but longer operative times remained a shortcoming. Better quality evidence is needed to guide surgical decision making regarding the precise clinical targets of this innovation in the next generation of its use.

Bariatric Surgery or Non-Surgical Weight Loss for Obstructive Sleep Apnoea? A Systematic Review and Comparison of Meta-analyses.

BACKGROUND: Obstructive sleep apnoea (OSA) is a well-recognised complication of obesity. Non-surgical weight loss (medical, behavioural and lifestyle interventions) may improve OSA outcomes, although long-term weight control remains challenging. Bariatric surgery offers a successful strategy for long-term weight loss and symptom resolution. OBJECTIVES: To comparatively appraise bariatric surgery vs. non-surgical weight loss interventions in OSA treatment utilising body mass index (BMI) and apnoea-hypopnoea index (AHI) as objective measures of weight loss and apnoea severity. METHODS: A systematic literature review revealed 19 surgical (n = 525) and 20 non-surgical (n = 825) studies reporting the primary endpoints of BMI and AHI before and after intervention. Data were meta-analysed using random effects modelling. Subgroup analysis, quality scoring and risk of bias were assessed. RESULTS: Surgical patients had a mean pre-intervention BMI of 51.3 and achieved a significant 14 kg/m(2) weighted decrease in BMI (95%CI [11.91, 16.44]), with a 29/h weighted decrease in AHI (95%CI [22.41, 36.74]). Non-surgical patients had a mean pre-intervention BMI of 38.3 and achieved a significant weighted decrease in BMI of 3.1 kg/m(2) (95%CI [2.42, 3.79]), with a weighted decrease in AHI of 11/h (95%CI [7.81, 14.98]). Heterogeneity was high across all outcomes. CONCLUSIONS: Both bariatric surgery and non-surgical weight loss may have significant beneficial effects on OSA through BMI and AHI reduction. However, bariatric surgery may offer markedly greater improvement in BMI and AHI than non-surgical alternatives. Future studies must address the lack of randomised controlled and comparative trials in order to confirm the exact relationship between metabolic surgery and non-surgical weight loss interventions in OSA resolution.

Pulmonary embolism mimicking left-ventricular hypertrophy on ECG.

Patients with pulmonary embolism (PE) can show changes on the ECG. Here, we report the case of a 48-year-old man who initially presented with calf discomfort and swelling. He was discharged with no anticoagulation after a negative complex duplex venous ultrasonography for deep vein thrombosis (DVT). He presented 4 days later with shortness of breath and pleuritic chest pain. Multiple pulmonary emboli were found on CT pulmonary angiogram. His ECGs showed left-ventricular strain which is unusual for PE. He was anticoagulated and discharged. Despite presenting 2 days later with PE-related complications, he eventually recovered well.

BRISK--research-oriented storage kit for biology-related data.

MOTIVATION: In genetic science, large-scale international research collaborations represent a growing trend. These collaborations have demanding and challenging database, storage, retrieval and communication needs. These studies typically involve demographic and clinical data, in addition to the results from numerous genomic studies (omics studies) such as gene expression, eQTL, genome-wide association and methylation studies, which present numerous challenges, thus the need for data integration platforms that can handle these complex data structures. Inefficient methods of data transfer and access control still plague research collaboration. As science becomes more and more collaborative in nature, the need for a system that adequately manages data sharing becomes paramount. RESULTS: Biology-Related Information Storage Kit (BRISK) is a package of several web-based data management tools that provide a cohesive data integration and management platform. It was specifically designed to provide the architecture necessary to promote collaboration and expedite data sharing between scientists. AVAILABILITY AND IMPLEMENTATION: The software, documentation, Java source code and demo are available at http://genapha.icapture.ubc.ca/brisk/index.jsp. BRISK was developed in Java, and tested on an Apache Tomcat 6 server with a MySQL database. CONTACT: denise.daley@hli.ubc.ca.

An investigation of community noise in high-rise residential environments.

High-rise dwellers in Singapore are often subjected to several community noise sources in close proximity. These include food center, children playground, soccer playground, basketball playground, waste disposal truck, etc. A scientific and reliable approach is required for evaluation of the community noise and its impact on high-rise dwellers. A comprehensive noise survey by a cluster sampling technique, conducted among 522 households in five residential towns in Singapore, showed that community noise was one of the prime sources of noise in a high-rise residential environment. From a subjective noise survey, undertaken concurrent with objective noise measurements, a mean outdoor noise level of 59 dBA was established as an acceptable noise level in the indoor environment. To investigate the level of noise exposure from different community noise sources, software modeling and simulations were carried out. The predicted results were validated with field measured data at five 16 story residential buildings. Analysis of noise exposure data showed that except for waste disposal truck, noise exposure due to other community noise sources (building distance of 15 m) were within the established acceptable noise level. A factor analysis of the survey data identified the key factors related to the disturbance due to community noise sources.

Spontaneous bilateral pneumothorax in metastatic renal cell carcinoma on sunitinib therapy.

Bilateral spontaneous pneumothorax is a rare occurrence in patients with both primary and metastatic lung cancer. Pneumothorax occurring as a complication of vascular endothelial growth factor receptor (VEGFR) inhibitor therapy has not been previously described in the medical literature. Sunitinib malate is a VEGFR inhibitor approved for the treatment of advanced renal cell carcinoma. We present a patient with metastatic renal cell carcinoma manifested as bilateral pulmonary nodules who developed a bilateral spontaneous pneumothorax 3 weeks after initiation of sunitinib therapy. We believe that sunitinib therapy resulted in necrosis of multiple pleural-based pulmonary nodules with central cavernization and ultimately rupture with bronchopleural fistula formation. Based on this experience, we advise that practitioners exercise caution when prescribing anti-VEGFR therapy in patients with pleural-based pulmonary metastases and recognize that the efficacy and toxicity of these agents may be closely linked.