Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer.

Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7-97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1-2 vomiting OR 1.87 [95% CI 1.37-2.56] and OR 2.27 [95% CI 1.59-3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3-4 diarrhea OR 118.06 [95% CI 7.28-1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3-4 infections. Abemaciclib had significantly less grade 3-4 transaminitis and grade 3-4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.

Modifiable risk factors for prostate cancer in low- and lower-middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Most of the epidemiological data on prostate cancer risk factors come from high-income countries (HIC). Reducing exposure to prostate cancer modifiable risk factors may significantly lower PCa morbidity and mortality in LIC and MIC. The objective of this study was to summarize the evidence on modifiable risk factors (RFs) for PCa in LIC and lower-middle-income countries (LMIC). METHODS: We conducted a systematic search on MEDLINE, EMBASE, and Global Health databases. We selected case-control and cohort studies from 2010 onwards that studied modifiable RFs for PCa in LIC and LMIC with a population of 30 million or more, as defined by the World Bank in January 2021. Risk of bias was assessed by the Ottawa-Newcastle tool. Individual study estimates were pooled when estimates were available for at least two studies. RESULTS: 5740 studies were initially identified; 16 studies met inclusion criteria. All were case-control studies except one retrospective cohort study. Higher fat intake was associated with a higher risk of PCa incidence with an odds ratio (OR) of 3.13 (95% CI 1.33-7.33). Higher vegetable intake (OR 0.48, 95% CI 0.24-0.97) and tea consumption (OR 0.51, 95% CI 0.32-0.83) were associated with a lower risk for PCa. There was no association between fruits, fish, and chicken consumption and risk of PCa. Alcohol consumption, smoking, red meat intake, and a BMI ≥ 25-30 kg/m2 showed a trend towards an increased risk, although these were not statistically significant. CONCLUSIONS: In LIC and LMIC, high fat intake was associated with higher risk of PCa while a diet rich in vegetables and tea intake was associated with a lower risk. Future prospective studies will be important to elucidate whether other modifiable risk factors for PCa specific to LIC and LMIC can be identified to inform impactful and cost-effective preventive strategies in these countries.

Cardiac Monitoring and Heart Failure in Advanced Breast Cancer Patients Treated With Trastuzumab in Ontario, Canada.

Background: Trastuzumab has improved patient outcomes in HER2 + breast cancer (BC) but carries a risk of cardiotoxicity. Routine cardiac imaging is recommended for advanced breast cancer (aBC) patients during trastuzumab treatment despite a lack of evidence that this improves patient outcomes. This study was conducted to understand predictive factors for cardiac events and determine the impact of cardiovascular monitoring in aBC. Methods: This retrospective population-based cohort study included aBC patients treated with trastuzumab (all lines), in Ontario, Canada from 2007 to 2017. The overall cohort was divided into two groups; those who developed a cardiac event (CE) vs. those who did not. Patients with pre-existing heart disease were excluded. Logistic regression was performed to identify patient characteristics associated with an increased risk of CE. Results: Of 2,284 patients with HER2 + aBC treated with trastuzumab, 167 (7.3%) developed a CE. Median age at first dose of trastuzumab was 57 (IQR 49-66); 61 (IQR 51-70) for patients with a CE. Median number of cycles was 16 (IQR 7-32); 21 (IQR 8-45) for patients with a CE (p < 0.01). Twelve (0.5%) patients died of cardiac causes; all had a prior CE. Increased risk of CEs was associated with age > 60 (OR 5.21, 95% CI 1.83-14.84, p = 0.05) and higher number cycles of trastuzumab (OR 1.01; 95% CI 1-101, p = 0.028). Conclusion: This is the first population-based study to report on CEs and cardiac monitoring in HER2 + aBC patients during trastuzumab-based therapy. Older age and longer treatment with trastuzumab were associated with an increased risk of a CE.

Internal jugular vein ultrasound for the diagnosis of hypovolemia and hypervolemia in acutely ill adults: a systematic review and meta-analysis.

Accurate volume status assessments allow physicians to rapidly implement therapeutic measures in acutely unwell patients. However, existing bedside diagnostic tools are often unreliable for assessing intravascular volume. We searched PUBMED, EMBASE, CENTRAL, and Web of Science for English language articles without date restrictions on January 20, 2022. Studies reporting the diagnostic accuracy of IJV-US for hypovolemia and/or hypervolemia in an acute care setting were screened for inclusion. We included studies using any method of IJV-US assessment as the index test, compared against any reference standard. We fitted hierarchical summary receiver operating characteristic (HSROC) models for meta-analysis of diagnostic test accuracy, separately for hypovolemia and hypervolemia. Two reviewers independently extracted data and assessed risk of bias using QUADAS-2. We assessed certainty of evidence using the GRADE approach. A total of 26 studies were included, of which 19 studies (956 patients) examined IJV-US for hypovolemia and 13 studies (672 patients) examined IJV-US for hypervolemia. For the diagnosis of hypovolemia, IJV-US had a pooled sensitivity of 0.82 (95% CI 0.76 to 0.87; moderate-certainty evidence) and specificity of 0.82 (95% CI 0.73 to 0.88; moderate-certainty evidence). Measurement of IJV collapsibility indices had higher diagnostic accuracy (sensitivity 0.85, 95% CI 0.80 to 0.89; specificity 0.78, 95% CI 0.64 to 0.88) than static IJV indices (sensitivity 0.73, 95% CI 0.60 to 0.82; specificity 0.70, 95% CI 0.48 to 0.86). For the diagnosis of hypervolemia, IJV-US had a pooled sensitivity of 0.84 (95% CI 0.70 to 0.92; moderate-certainty evidence) and specificity of 0.70 (95% CI 0.55 to 0.82; very low-certainty evidence). IJV-US has moderate sensitivity and specificity for the diagnosis of hypervolemia and hypovolemia. Randomized controlled trials are needed to determine the role of IJV-US for guiding therapeutic interventions aimed at optimizing volume status.

Pursuing Connectivity in Cardio-Oncology Care-The Future of Telemedicine and Artificial Intelligence in Providing Equity and Access to Rural Communities.

The aim of this review is to discuss the current health disparities in rural communities and to explore the potential role of telehealth and artificial intelligence in providing cardio-oncology care to underserviced communities. With advancements in early detection and cancer treatment, survivorship has increased. The interplay between cancer and cardiovascular disease, which are the leading causes of morbidity and mortality in this population, has been increasingly recognized. Worldwide, cardio-oncology clinics (COCs) have emerged to deliver a multidisciplinary approach to the care of patients with cancer to mitigate cardiovascular risks while minimizing interruptions in cancer treatment. Despite the value of COCs, the accessibility gap between urban and rural communities in both oncology and cardio-oncology contributes to health care disparities and may be an underrecognized determinant of health globally. Telehealth and artificial intelligence offer opportunities to provide timely care irrespective of rurality. We therefore explore current developments within this sphere and propose a novel model of care to address the disparity in urban vs. rural cardio-oncology using the experience in Canada, a geographically large country with many rural communities.

Piloting 'Virtual Ward': a novel platform for delivering medical student education by residents.

BACKGROUND: Clinical experiences lie at the heart of undergraduate medical education (UGME). COVID-19 related disruptions in Medical Education impacted medical students substantially. As educators, efforts directed at developing new mediums to educate our medical students in the face of these new limitations were vital. The Virtual Ward (VW) pilot was an inaugural resident-driven, virtual educational opportunity aimed at supplement the learning of core internal medicine skills for undergraduate medical students. METHODS: Interested medical students were paired in groups of 5-6 with an internal medicine resident tutor. The McMaster University UGME core internal medicine topic list was provided to resident tutors to teach in an open, morning-report format in which students directed content selection. Following completion of the VW series, we distributed an online anonymous survey using a 5-point Likert scale to gauge the efficacy of the intervention and compare it to existing learning modalities offered by the UGME. RESULTS: In total, 166 medical students and 27 internal medicine resident tutors participated in the VW pilot. 46 (28%) medical students responded to the survey and 96% of survey respondents rated the sessions as being helpful to their learning. The majority rated VW superior to existing learning modalities and 94% thought VW should continue after COVID-related restrictions abate. CONCLUSIONS: VW is a novel educational platform that was very well received by learners. We propose VW may have a continued supplemental role post-pandemic to help with translation of knowledge to clinical skills and provide an additional avenue of mentorship for students.

Point-of-care ultrasound training for respiratory therapists: A scoping review.

Introduction: Point-of-care ultrasound (POCUS), although commonly used in clinical practice, is not currently included in training programs for respiratory therapists (RTs). In fact, given its ubiquity and clinical utility, RTs in Ontario, Canada, are changing their mandate to incorporate POCUS into their daily patient assessment. Therefore, we conducted a scoping review of the literature, aiming to describe the current evidence of POCUS training and methods of curriculum delivery for RTs to inform an evidence-based program design. Method: We systematically searched MEDLINE, EMBASE, CINAHL, and Web of Science from inception to 8 July 2020. We included all studies reporting on RT training in POCUS. Documents included English language, full-text reports of all study designs. Title and abstract screening, full-text review, and data abstraction were done independently and in duplicate. Results: Seven studies met our inclusion criteria, including four full texts and three abstracts; all were prospective and single-center studies, except one multicenter study. Reports were from nine different countries. Studies described cardiac, lung, and procedural ultrasonography use. The majority used a combination of educational methods; didactic talks, hands-on sessions, and practical assessments being the most common methods. There was a median of 11 participants enrolled in a training session. The instructors were physicians from various specialties such as critical care, pulmonology, and radiology. Conclusions: This scoping review identified seven papers that explored different methods of a POCUS curriculum delivery for RTs. From the interventions outlined, teaching POCUS skills to RTs seems feasible. However, further work needs to be done to solidify a POCUS curriculum specific to RTs and examine the impact on patient-related outcomes.

Comprehensive genomic profiling of treatment resistant metastatic castrate sensitive prostate cancer reveals high frequency of potential therapeutic targets.

INTRODUCTION: While comprehensive genomic profiling (CGP) data is becoming increasingly important in the management of prostate cancer, it remains under-utilized in the setting of metastatic castrate sensitive prostate cancer (mCSPC). We aimed to explore the feasibility and potential utility of CGP in mCSPC. PATIENTS AND METHODS: Patients with mCSPC were prospectively recruited at the Princess Margaret Cancer Centre to the OCTANE trial (NCT02906943). The objective was to assess the feasibility of profiling archival standard diagnostic tumor tissue using next generation sequencing with a custom hybridization capture DNA-based or a targeted DNA/RNA amplicon-based panel. Clinical data were extracted from electronic health records. RESULTS: Among 39 mCSPC patients enrolled, 21 (54%) had sufficient archival tissue for CGP. Most had high volume (71%) or de novo (71%) mCSPC, with the majority being androgen deprivation therapy (ADT) naïve. In total, 62% of patients had a pathogenic and/or a likely pathogenic variant, many of which involved DNA damage repair (DDR, 19%), cell cycle (24%), and Androgen Receptor (AR, 10%) pathways. After median follow-up of 32.1 months, 18 of 21 patients progressed, with median time to mCRPC of 14.3 months (95% CI 10.2-21.0). Patients with AR and DDR variants seemed to have shorter median time to mCRPC; 10.2 (95% CI 9.50-NR) and 10.3 months (95% CI 6.6-14.3) respectively. CONCLUSION: In this cohort of highly treatment resistant mCSPC, most of which were ADT-naïve, CGP using archival tumor tissue was feasible for over half of patients, and 62% of patients profiled had a pathogenic and/or a likely pathogenic variant. The presence of de novo variants provides biological basis for evaluating intensification strategies of systemic therapy. This highlights the potential role of routine CGP in biomarker development and clinical trial design in the setting of mCSPC.

ALK inhibitor-induced bradycardia: A systematic-review and meta-analysis.

INTRODUCTION: Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC. MATERIALS AND METHODS: We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, National clinical trial registry, and Web of Science Core Collection. We included all randomized controlled trials in which an ALK-inhibitor was compared with another ALK-inhibitor or standard chemotherapy. Meta-analyses were conducted to evaluate the pooled incidence rates of bradycardia and dizziness using fixed effect models. RESULTS: The pooled incidence of bradycardia among 1737 individuals prescribed ALK inhibitors was 8% during a mean follow-up of 1.26 years. Crizotinib led to more bradycardia than standard chemotherapy (relative risk, RR 24.68, 95% CI 7.11-85.), while no difference was seen between crizotinib and alectinib (RR 1.12, 95% CI 0.79-1.59). The next-generation ALK inhibitors alectinib, brigatinib and lorlatinib combined resulted in a similar rate of bradycardia when compared to crizotinib (RR 0.77, 95% CI 0.57-1.04). All ALK inhibitors (as an aggregate) caused more dizziness (as a potential symptom of bradycardia) than standard chemotherapy (RR 1.88, 95% CI 1.44-2.44). CONCLUSION: Crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors.

Cardiogenic shock in the context of newly diagnosed anomalous origin of the right coronary artery originating from the pulmonary artery: a case report.

BACKGROUND: Anomalous right coronary artery (RCA) from the pulmonary artery (ARCAPA) is a rare congenital heart abnormality with varying clinical presentations, for which multiple imaging modalities are often required for diagnosis. CASE SUMMARY: We present a case of a 76-year-old female presenting with 2 weeks of palpitations and shortness of breath who was found to be in rapid atrial fibrillation (AF) with congestive heart failure. Despite initial medical management, the patient developed cardiogenic shock with anuric renal failure. Emergent right and left heart catheterization did not demonstrate any significant obstructive coronary artery disease but showed severe right ventricular (RV) failure and raised the possibility of an ARCAPA. This diagnosis was further corroborated by findings on a subsequent transoesophageal echocardiogram. In view of profound decline and limited anticipated improvement, the patient ultimately decided to pursue comfort measures in a hospice setting. DISCUSSION: We postulate that the underlying aetiology of our patient's shock state was multifactorial, notably progressive RCA-territory ischaemia and RV failure, sepsis, and new-onset uncontrolled AF. In adults, unrecognized congenital heart disease can uncommonly cause cardiogenic shock. In our case, echocardiography and invasive angiography were integrated for the diagnosis of ARCAPA given the clinical circumstances that limited the use of cardiac computed tomography angiography.

A survey of Canadian breast health professionals' recommendations for high-risk benign breast disease

Summary: The management of high-risk benign breast disease (BBD) is changing because of improvements in radiological and pathological analysis. We sought to determine the current practice recommendations of breast health professionals in managing patients with high-risk BBD. We surveyed members of the Canadian Society of Surgical Oncology, Canadian Association of General Surgeons and Canadian Association of Radiologists. The survey contained demographic and case-based questions concerning management of high-risk benign breast lesions. Participants were asked for their recommendations and opinions regarding future risk of breast cancer as well as the role of chemoprevention. There was no consistency among the 41 respondents in the treatment recommendations for any of the high-risk benign conditions, and the lifetime risk associated with classic lobular carcinoma in situ was vastly underestimated. Education and evidenced-based guidelines are urgently needed to ensure more uniform practice nationally.

A pilot validation study of crowdsourcing systematic reviews: update of a searchable database of pediatric clinical trials of high-dose vitamin D.

BACKGROUND: Completing large systematic reviews and maintaining them up to date poses significant challenges. This is mainly due to the toll required of a small group of experts to screen and extract potentially eligible citations. Automated approaches have failed so far in providing an accessible and adaptable tool to the research community. Over the past decade, crowdsourcing has become attractive in the scientific field, and implementing it in citation screening could save the investigative team significant work and decrease the time to publication. METHODS: Citations from the 2015 update of a pediatrics vitamin D systematic review were uploaded to an online platform designed for crowdsourcing the screening process (http://www.CHEORI.org/en/CrowdScreenOverview). Three sets of exclusion criteria were used for screening, with a review of abstracts at level one, and full-text eligibility determined through two screening stages. Two trained reviewers, who participated in the initial systematic review, established citation eligibility. In parallel, each citation received four independent assessments from an untrained crowd with a medical background. Citations were retained or excluded if they received three congruent assessments. Otherwise, they were reviewed by the principal investigator. Measured outcomes included sensitivity of the crowd to retain eligible studies, and potential work saved defined as citations sorted by the crowd (excluded or retained) without involvement of the principal investigator. RESULTS: A total of 148 citations for screening were identified, of which 20 met eligibility criteria (true positives). The four reviewers from the crowd agreed completely on 63% (95% CI: 57-69%) of assessments, and achieved a sensitivity of 100% (95% CI: 88-100%) and a specificity of 99% (95% CI: 96-100%). Potential work saved to the research team was 84% (95% CI: 77-89%) at the abstract screening stage, and 73% (95% CI: 67-79%) through all three levels. In addition, different thresholds for citation retention and exclusion were assessed. With an algorithm favoring sensitivity (citation excluded only if all four reviewers agree), sensitivity was maintained at 100%, with a decrease of potential work saved to 66% (95% CI: 59-71%). In contrast, increasing the threshold required for retention (exclude all citations not obtaining 3/4 retain assessments) decreased sensitivity to 85% (95% CI: 65-96%), while improving potential workload saved to 92% (95% CI: 88-95%). CONCLUSIONS: This study demonstrates the accuracy of crowdsourcing for systematic review citations screening, with retention of all eligible articles and a significant reduction in the work required from the investigative team. Together, these two findings suggest that crowdsourcing could represent a significant advancement in the area of systematic review. Future directions include further study to assess validity across medical fields and determination of the capacity of a non-medical crowd.