A Single Institution Experience in the Management of Localized Neuroendocrine Carcinoma of the Bladder.

BACKGROUND: Neuroendocrine carcinoma of the bladder (NEC-bladder) is a rare disease with poor outcomes and variable treatment approaches. MATERIALS AND METHODS: Patients with localized NEC-bladder treated with surgery or radiation between 2001-2021 were retrospectively identified. Rates of pathologic complete response (pCR) and downstaging were evaluated following NAC in surgically-treated patients. Progression-free survival (PFS) and overall survival (OS) were analyzed with univariable (log-rank) and multivariable (MVA; Cox regression) methods. RESULTS: Sixty-five patients were identified having a median age of 73. The tumor histology distribution was small cell (64.6%) or urothelial with NE differentiation (35.4%). Most patients (69.2%) received NAC. Patients received local therapy by surgery (78.5%) or chemoradiation (21.5%). The majority (62.7%) of surgical patients had ≥ pT2 with 37.3% having nodal involvement (pN+). The pCR and downstaging rates were 21.6% and 35.1%, respectively. At a median follow-up of 60 months (m), the median PFS and OS were 16.4m and 25.9m, respectively. NAC improved PFS (p=0.04) and downstaging improved PFS (p=0.012) and OS (p<0.001). Patients receiving NAC with ypN0 vs. ypN+ had median OS of 69.9m vs 15.3m, respectively (p<0.001). MVA identified receipt of NAC and pN as predictors of PFS; pN was predictive of OS. No differences in PFS or OS were seen between histology of primary tumor. The brain metastasis rate was 10.8% with all patients having small cell histology. CONCLUSIONS: Optimized therapy in NEC-bladder includes NAC followed by local consolidation. Ascertainment of ypN0 is associated with long term survival, while pN+ remains associated with poor outcomes.

Linking hearts and minds: understanding the cardiovascular impact of bipolar disorder.

Bipolar disorder is a severe and recurring condition that has become a significant public health issue globally. Studies indicate a heightened risk and earlier onset of cardiovascular diseases among individuals with bipolar disorder, potentially increasing mortality rates. The chronic nature of bipolar disorder leads to disturbances across multiple systems, including autonomic dysfunction, over-activation of the hypothalamic-pituitary-adrenal axis and increased levels of peripheral inflammatory markers. These disruptions cause endothelial damage, the formation of plaques and blood clots, in addition to the medications used to treat bipolar disorder and genetic associations contributing to cardiovascular disease development. Understanding the complex interplay between bipolar disorder and cardiovascular events is essential for the prevention and effective management of cardiovascular conditions in individuals with bipolar disorder.

Bipolar disorder is a mental health condition that affects mood and behavior, significantly impacting the lives of many people around the world. People with this disorder are also at a higher risk for heart diseases, including heart attacks and strokes. Certain lifestyle factors, common among people with bipolar disorder, such as smoking, poor diet and lack of exercise, can cause inflammation and stress, which damage blood vessels and increase the likelihood of heart conditions. The relationship between bipolar disorder and heart disease is complex. The condition affects how the body handles stress and can disrupt normal heart functions. For instance, stress from bipolar disorder can lead to high blood pressure and irregular heartbeats and certain medications taken by those with bipolar disorder can further damage the heart. To better manage these risks, it's important to understand the connection between bipolar disorder and heart disease. Future research should focus on creating guidelines for regular heart health check-ups for people with bipolar disorder and improving overall care to help prevent unfavorable outcomes.

Unwelcome return: analyzing the recent rise of measles cases in the United States.

Measles is a highly contagious viral illness mainly affecting the younger population worldwide despite the availability of a safe and effective vaccine. The disease is caused by measles virus, a member of the Paramyxoviridea family, which is transmitted through aerosols and respiratory droplets. Widespread vaccination has led to a significant decline in morbidity and mortality worldwide; however, recent years have witnessed a resurgence of outbreaks in the United States, highlighting barriers in achieving and sustaining elimination goals. The measles and rubella elimination initiative, under Immunization Agenda 2030, required at least 5 World Health Organization regions to achieve measles elimination by 2020, but none of the regions met these goals. Vaccine hesitancy, virus importation via international travel, and waning immunity are considered contributing factors to the recent surge of measles outbreaks. This review highlights the challenges in the pursuit of measles eradication and the importance of a multidimensional approach involving public health interventions.

Proactive approaches in congestive heart failure: the significance of early goals of care discussion and palliative care.

Congestive Heart Failure (CHF) poses significant challenges to the healthcare system due to its high rates of morbidity and mortality as well as frequent readmissions. All of these factors contribute to increased healthcare delivery costs. Besides the burden on the healthcare system, CHF has far deeper effects on the patient in terms of psychological burden along with debilitating symptoms of dyspnea, all of which reduce quality of life. Prognostic awareness among patients about their disease along with initiating early goals of care discussion by those involved in the care (physicians, nurses, social worker and patient themselves) can help mitigate these challenges. Adopting a proactive approach to address patient preferences, values and end-of-life goals improves patient-centred care, enhances quality of life and reduces the strain on healthcare resources. In this narrative review, studies have been identified using PubMed search to shed knowledge on what is preventing the initiation of goals of care discussions. Some barriers include lack of knowledge about prognosis in both patients and caregivers, inexperience or discomfort in having those conversations and delaying it until CHF becomes too advanced.

Heart disease is the leading cause of death in the United States and by 2030, around 8.5 million people are expected to suffer from heart failure due to increasing rates of obesity, diabetes, smoking, high blood pressure and coronary heart disease. People with heart failure often have severe physical symptoms and emotional distress, which affects their quality of life. Palliative care, which aims to relieve symptoms and provide support, is essential for these patients and their families. It helps improve communication about the disease, reduces hospital readmissions and increases the chances of patients enrolling in hospice care. However, discussions about end-of-life care often do not happen in time or at all for heart failure patients. There are many barriers, including physician's inability to explain the downsides of life-sustaining treatments and patients and families struggling to accept the poor prognosis of the disease. It's important to develop scoring systems, like the Gagne Combined Comorbidity score, to help physicians identify patients at risk of poor outcomes and start end-of-life care discussions early. Signs that a patient might need palliative care include frequent hospital visits, severe ongoing symptoms and advanced treatments. Despite its importance, many heart failure patients do not receive timely palliative care. Early discussions about care preferences, integrating palliative care into regular treatment, and timely hospice referrals can greatly improve the quality of life for these patients and their families.

Understanding the Relationship between the Ketogenic Diet and the Heart: A Novel Therapeutic Potential for Cardiovascular Health.

Obesity and cardiovascular diseases are major health problems worldwide, and weight loss is used as a treatment strategy to enhance various aspects. While there are many weight loss methods, one of the most effective is through a dietary approach. The ketogenic diet (KD), which is characterized by low carbohydrates and high levels of fat and/or protein, is used in obese patients as it is a promising treatment option for weight loss as well as for controlling the risk factors for cardiovascular diseases, as seen in its effects on cardio-metabolic outcomes, particularly in obesity, heart failure, and hypertension. In this review, we summarize the clinical evidence of the efficacy and safety of the KD in controlling risk factors for cardiovascular diseases and discuss the possible mechanisms of action based on recent evidence in understanding the influence of the KD at the cellular and molecular levels.

Critical illness-related corticosteroid insufficiency: latest pathophysiology and management guidelines.

Intensive care unit (ICU) admissions in the United States exceed 5.7 million annually, often leading to complications such as post-intensive care syndrome and high mortality rates. Among these challenges, critical illness-related corticosteroid insufficiency (CIRCI) requires emphasis due to its complex, multiple-cause pathophysiology and varied presentations. CIRCI, characterized by adrenal insufficiency during critical illness, presents in up to 30% of ICU patients and may manifest as an exaggerated inflammatory response. Factors such as dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, altered cortisol metabolism, tissue corticosteroid resistance, and drug-induced suppression contribute to CIRCI. Diagnosis is a complex process, relying on a comprehensive assessment including clinical presentation, laboratory findings, and dynamic stimulatory testing. Treatment involves intensive medical care and exacting glucocorticoid therapy. Recent guidelines advocate for individualized approaches tailored to patient presentation and etiology. Understanding the pathophysiology and treatment of CIRCI is vital for clinicians managing critically ill patients and striving to improve outcomes. This research paper aims to explore the latest developments in the pathophysiology and management of CIRCI.

Beyond the Gut: Exploring Cardiovascular Implications of Celiac Disease.

Celiac disease (CD) is an autoimmune disorder that presents with gastrointestinal symptoms including diarrhea, weight loss, and abdominal bloating due to the inflammation in the small intestine. It has been associated with various extraintestinal manifestations, including mucocutaneous findings such as dermatitis herpetiformis, anemia, dental enamel defects, osteoporosis, and arthritis. Studies have revealed an increasing association between CD and cardiovascular diseases (CVDs), including atherosclerosis, cardiomyopathy, and arrhythmia. Chronic inflammation, nutritional deficiencies from malabsorption, endothelial dysfunction, thrombophilic autoantibodies, thrombocytosis, and protein C and S deficiency have been proposed as the probable mechanisms for the association between the 2 conditions. This article aims to provide a review of the pathophysiological mechanism of celiac disease causing various CVDs and to compare and contrast the existing studies suggesting both favorable and unfavorable CVD outcomes in patients with CD.

Tools for Screening, Predicting, and Evaluating Sepsis and Septic Shock: A Comprehensive Review.

Sepsis is characterized by life-threatening organ dysfunction due to dysregulated host response to infection. It can progress to cause circulatory and cellular/metabolic abnormalities, resulting in septic shock that may significantly increase mortality. The pathophysiology of sepsis involves a complex interplay of invading pathogens and the body's immune defense, causing alteration in normal homeostasis, eventually leading to derangements in the cellular, humoral, circulatory, and metabolic functions. Several scoring systems have been developed to rapidly predict or suspect sepsis, such as Sequential Organ Failure Assessment (SOFA), modified SOFA (mSOFA), quick SOFA (qSOFA), shock index (SI), and modified SI (mSI). Each of these scores has been utilized for triaging patients with sepsis, and as per medical advancements these scoring systems have been modified to include or exclude certain criteria to improve their clinical utility. This review aims to compare the individual scores and their usage for sepsis that may be used for laying the foundation for early recognition and prediction of sepsis and for formulating more precise definitions in the future.

Hearts in the sky: understanding the cardiovascular implications of air travel.

Air travel is widely regarded as the safest mode of transportation, with the United States leading in airline passengers. However, travelers with pre-existing heart conditions face acute cardiovascular risks. Flight pilots and cabin crew are particularly vulnerable to air travel's physiological changes, which can significantly impair their health and performance. Cabin pressure differences and reduced oxygen levels at cruising altitudes of 5000-8000 feet make air travel challenging for individuals with underlying cardiac and pulmonary problems. This, along with dry air, sleep deprivation, missed medication and prolonged sitting, can lead to physiological changes. In-flight and pre-flight stressors contribute to increased health issues, and studies show a rise in medical emergencies during flights. Prolonged exposure to the airplane environment can lead to various health issues for pilots and cabin crew. These changes include impaired judgment, cognitive function and discomfort in the sinuses and ears due to pressure differentials. Therefore, thorough medical screening, skilled instrument use and compliance with safety measures are essential to mitigate these risks. This article reviews the cardiac implications of air travel, discussing the underlying pathophysiology, associated risks and preventive measures to ensure safer flights for individuals with cardiovascular diseases.

This review examines the health risks of air travel for individuals with heart and lung conditions. Changes in cabin pressure and oxygen levels can lower blood oxygen, causing discomfort and health issues. Dry air, sleep problems and prolonged sitting also affect those with existing conditions. Pilots and flight attendants are especially vulnerable due to their continuous exposure.The authors reviewed how air travel impacts heart and lung health and found that in-flight medical emergencies are rising, affecting passengers and flight staff. Common issues include impaired cognitive function and discomfort from pressure changes. The article emphasizes the importance of pre-flight medical check-ups, carrying medical documents and having travel insurance. It also calls for thorough medical screening and skilled instrument use to ensure safety.Results show that current air travel conditions pose significant health risks for those with cardiovascular diseases. The study advocates for improvements in in-flight medical technology, cabin environments and personalized healthcare solutions to enhance safety. These findings suggest that future air travel should focus on reducing cardiovascular complications through advancements in medical support and cabin design.The study provides valuable insights into the physiological effects of flying and recommends measures to make air travel safer for people with heart and lung conditions. It highlights the need for ongoing research and collaboration among healthcare professionals, researchers and aviation authorities to address these health risks effectively.

Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.

PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.

Mast cell-derived BH4 and serotonin are critical mediators of postoperative pain.

Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell-specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P-driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.

TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients With Metastatic Urothelial Cancer Progressing After Previous Checkpoint Inhibitor Therapy.

PURPOSE: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with an SN-38 payload, approved for patients with locally advanced (LA) or metastatic urothelial cancer (mUC) who progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report results from Cohort 2 of TROPHY-U-01 trial, evaluating the efficacy and safety of SG in patients with mUC. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Cohort 2 includes patients with LA or mUC who have had progression or recurrence after a CPI and were cisplatin-ineligible at study initiation. Patients received SG 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end point was objective response rate (ORR) per central review; secondary end points were clinical benefit rate (CBR), duration of response (DOR), and progression-free survival (PFS) per central review and safety. RESULTS: Cohort 2 included 38 patients (61% male; median age 72.5 years; 66% visceral metastases [29% liver]; 50% received previous PT-based chemotherapy as previous [neo]adjuvant therapy]). At a median follow-up of 9.3 months, ORR was 32% (95% CI, 17.5 to 48.7), CBR 42% (95% CI, 26.3 to 59.2), median DOR 5.6 months (95% CI, 2.8 to 13.3), median PFS 5.6 months (95% CI, 4.1 to 8.3), and median overall survival 13.5 months (95% CI, 7.6 to 15.6). Grade ≥3 treatment-emergent adverse events occurred in 87% of patients, most commonly neutropenia (34%), anemia (24%), leukopenia (19%), fatigue (18%), and diarrhea (16%). CONCLUSION: SG monotherapy demonstrated a relatively high ORR with rapid responses; this was feasible with a manageable toxicity profile in cisplatin-ineligible patients who had progression after CPI therapy. Limitations include a moderate sample size and lack of random assignment. These results warrant further evaluation of SG alone and in combinations in patients with LA/mUC.

Navigating the Depths of Cardiovascular Effects on Submariners.

The environment of the submariner is inherently endowed with several health risk factors, namely confinement, inactivity, caloric excess, and circadian disruption, among others, during deployment. Metabolic disturbances, increased cardiovascular risk, and sleep deprivation are associated with interrupting circadian rhythms due to routines contributing to physiological and cognitive abnormalities. Additionally, submariners face vitamin deficits of vitamin D and vitamin B12 due to little exposure to sunlight and poor nutrition. It is associated with cardiovascular dysfunctions, endothelial dysfunctions, metabolic abnormalities, and a greater cardiovascular risk. Moreover, high obesity prevalence has been noted among submariners. Such cases were attributed to leptin resistance, body fat deposits, and lifestyle statistics. Other risk factors to the cardiovascular system, like changes in heart rate variability and heart functions, have been witnessed. These health challenges can be mitigated by adopting proactive steps to address submariners' specific health needs. Such measures should include the prevention of stable circadian rhythms, vitamin intake, lifestyle, and cardiovascular health. By addressing these issues, submariners' well-being will be upheld, and their vulnerability to cardiovascular diseases and other health-related complications will be lessened.

Regenerating the ailing heart: Stem cell therapies for hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart defect (CHD) characterized by a spectrum of underdeveloped left-sided cardiac structures. It is a serious defect and warrants either 3-staged surgical palliation or a heart transplant. Despite numerous surgical advancements, long-term outcomes remain challenging and still have significant morbidity and mortality. There have been notable advancements in stem cell therapy for HLHS, including developments in diverse stem cell origins and methods of administration. Clinical trials have shown safety and potential benefits, including improved ventricular function, reduced heart failure, and fewer adverse events. Younger myocardium seems particularly receptive to stem cell signals, suggesting the importance of early intervention. This review explores the potential of emerging stem cell-based therapies as an adjunctive approach to improve the outcomes for HLHS patients.

An engineered lactate oxidase based electrochemical sensor for continuous detection of biomarker lactic acid in human sweat and serum.

Lactate levels in humans reveal intensity and duration of exertion and provide a critical readout for the severity of life-threatening illnesses such as pediatric sepsis. Using the lactate oxidase enzyme (Lox) from Aerococcus viridians, we demonstrated its functionality for lactate electrochemical sensing in physiological fluids in a lab setting. The structure and dynamics of LOx were validated by crystallography, X-ray scattering, and hydroxyl radical protein footprinting. This provided a validated protein template for understanding and designing an enzyme-based electrochemical sensing elements. Using this template, LOx enzyme variants were generated and compared. Comparison of the variants demonstrates that one exhibits effective lactate sensing at significantly reduced operating voltages. Additionally, we demonstrate that the four hexahistidine-tags on each enzyme tetramer are sufficient for immobilization to create a durable, functional sensor, with no need for a covalent attachment, enabling self-immobilization and eliminating the need for additional immobilization steps. The functionality of the LOx enzyme variants was verified at physiological lactate concentrations in both human serum (0-4 mM) and artificial sweat (0-100 mM) using 3-electrode setups for analysis of the three variants in parallel. Accuracy of measurement in both artificial sweat and human serum were high. Employing a microfluidic flow cell, we successfully monitored varying lactate levels in physiological fluids continuously over a 2h period. Overall, this optimized LOx enzyme, which self-immobilizes onto gold sensing electrodes, facilitates efficient and reliable lactate detection and continuous monitoring at reduced operating voltages suitable for further development towards commercial use.

Feasibility of a Smartphone Application for Education and Symptom Management of Patients With Renal Cell Carcinoma on Combined Tyrosine Kinase and Immune Checkpoint Inhibitors.

PURPOSE: Patients with advanced renal cell carcinoma (RCC) face significant challenges, stemming both from the complexities of the disease itself and the adverse effects of treatments. This study evaluated the feasibility and acceptability of a mobile health (mHealth) application tailored for education and symptom management of patients with advanced RCC receiving combined immune checkpoint inhibitor and tyrosine kinase inhibitor (ICI-TKI) therapy. METHODS: The primary end points were acceptability and feasibility. Acceptability was defined as the proportion of patients approached who consented to participate, setting a benchmark of at least 50% for this metric. Feasibility was gauged by the completion rate of the intervention among the participants; it required at least 50% of participants to fully complete the intervention and at least 70% to finish half of the administered questionnaires. The secondary end points included knowledge assessment and patient-reported outcomes (PROs). PROs were evaluated using validated instruments. To discern the changes between pre- and post-educational module quiz scores, we used the Wilcoxon signed-rank test. Time-course data of PROs were visualized using line plots and then compared using paired t-tests. RESULTS: From November 2022 to July 2023, 20 of 22 (90%) patients approached for the study consented and enrolled. Of the enrolled patients, 60% completed all questionnaires and knowledge assessments at every time point and 75% completed at least half of the surveys and questionnaires. Significant pre/post differences were noted in two of six quizzes in the knowledge assessment. This study population did not experience a significant change in PRO scores after starting therapy. CONCLUSION: The mHealth application designed for education and symptom management in patients with advanced RCC undergoing combination ICI-TKI has proven to be both acceptable and feasible, meeting previous research benchmarks.

Wearable health monitoring: wave of the future or waste of time?

BACKGROUND: Atrial fibrillation is responsible for over 400,000 hospitalizations in the United States (US) each year. This costs the US health system over 4 billion each year. New smartwatches can constantly monitor pulse, oxygen saturation, and even heart rhythm. The FDA has provided clearance for select smartwatches to detect arrhythmias, including atrial fibrillation. FINDINGS: These devices are not currently widely implemented as diagnostic tools. In this review, we delve into the mechanism of how smartwatches work as healthcare tools and how they capture health data. Additionally, we analyze the reliability of the data collected by smartwatches and the accuracy of their sensors in monitoring health parameters. Moreover, we explore the accessibility of smartwatches as healthcare tools and their potential to promote self-care among individuals. Finally, we assess the outcomes of using smartwatches in healthcare, including the limited studies on the clinical effects and barriers to uptake by the community. CONCLUSION: Although smartwatches are accurate for the detection of atrial fibrillation, they still face many hurdles, including access to aging populations and trust in the medical community.

Inherited Germline Variants in Urinary Tract Cancer: A Multicenter Whole-Exome Sequencing Analysis and Correlation With Clinical Features and Tumor Genomics.

PURPOSE: This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV). METHODS: Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted. RESULTS: Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease (P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without (P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways. CONCLUSION: Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Unraveling the Complex Relationship-Atrial Fibrillation and Pulmonary Hypertension.

PURPOSE OF REVIEW: In this article, we underscore the importance of identifying risk factors and monitoring pulmonary hypertension patients for signs of arrhythmias, as this proactive approach can reduce morbidity and mortality. RECENT FINDINGS: Atrial fibrillation is the most prevalent among cardiac arrhythmias and is associated with an increased risk of stroke, morbidity, and mortality. Smoking, obesity, hypertension, a sedentary lifestyle, and diabetes mellitus are some of the modifiable risk factors for atrial fibrillation. Recent studies show that the risk of atrial fibrillation is rising in patients with parenchymal and vascular lung disease. Stretching in the atria and pulmonary veins may lead to the onset of atrial fibrillation in cardiac conditions like hypertension, heart failure, and valvular disease. Atrial fibrillation in patients with pulmonary hypertension (PH) denotes a more advanced disease. Patients with PH are more susceptible to hemodynamic stress caused by tachycardia and an uncoordinated atrioventricular contraction. Therefore, atrial arrhythmias need to be treated because inadequate control of cardiac arrhythmias may result in poor clinical outcomes and lead to disease progression in PH patients. Aside from being a sign of severe disease, AF can also speed up and exacerbate the condition.

Impact of Angiotensin Converting Enzyme Inhibitors on Pathologic Complete Response With Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer.

INTRODUCTION: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. RESULTS: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS. CONCLUSION: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC.