Cardiotoxic profiles of CAR-T therapy and bispecific T-cell engagers in hematological cancers.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager). METHODS: Safety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab. RESULTS: Tisagenlecleucel is associated with cardiac failure (IC025 = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28-5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66]. CONCLUSIONS: Tisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities.

Chimeric antigen receptor (CAR) T-cell therapy and blinatumomab are two new types of cancer therapies used to treat blood cancers that fail to respond to conventional chemotherapy. Our goal is to study if there are major differences in how these treatments affect the heart. We analyzed a large, global database of patients who had these treatments. We find that in a blood cancer called diffuse large B-cell lymphoma, two CAR-T cell therapies are linked to heart failure and low blood pressure. In another type of cancer, acute lymphocytic leukemia, CAR-T cell therapy is associated with heart failure and cardiac arrest. The study suggests that given the frequency and severity of these side effects, clinical care should involve an interdisciplinary team experienced in managing these serious side effects.

Clinicoradiological parameters predicting operative difficulty in laparoscopic partial nephrectomy for renal tumors.

Introduction: The number of renal tumors amenable to laparoscopic surgery is rising, both, due early detection by improved imaging techniques and due to progressive improvements in minimal access surgery. Conversion to open surgery, which is a significant event, can be minimized by proper case selection. We assessed the pre-operative factors that can predict the operative difficulty and can help in case selection, thus avoiding complications and reducing the chances of conversion to open. Methods: One hundred and sixteen patients (73 males and 43 females) with the mean age of 50.78 ± 14.2 years, meeting the inclusion criteria underwent transperitoneal laparoscopic partial nephrectomy (LPN). Various clinical, anthropometric, radiological, and pathological parameters were recorded. Intraoperative difficulty was assessed and graded on a scale of 1 (easiest) to 4 (most difficult or open conversion) by an independent observer to calculate the difficulty score, which along with the other parameters of operative difficulty, was used to calculate the difficulty scale. Significant parameters on the univariate analysis, were subjected to a multivariate analysis, to find parameters that can predict the operative difficulty. Results: The mean age was 52 ± 14.29 years, mean size was 4 ± 1.04 cm, male:female ratio was 1.6:1, most of the tumors were exophytic (60%) and anteriorly located (62%) and had a mean perinephric fat surface density (PnFSD) of 6446.026 ± 2244 surface density pixel units (SDPU). On the univariate analysis, age >60 years, Eastern Cooperative Oncology Group performance score >1, presence of perinephric fat stranding, increased PnFSD (>10,000 SDPU), large tumor size (>4 cm), hilar/posterior location, endophytic tumors and higher clinical stage were significantly associated with intraoperative difficulty. However, on the multivariate analysis, no single factor could independently predict intraoperative difficulty in LPN for Renal tumors. Conclusion: It is difficult to predict the intra-operative difficulty during LPN. Feasibility of LPN should be based on multiple factors rather than a single factor.

Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management.

Since their invention in the early 2000s, tyrosine kinase inhibitors (TKIs) have gained prominence as the most effective pathway-directed anti-cancer agents. TKIs have shown significant utility in the treatment of multiple hematological malignancies and solid tumors, including chronic myelogenous leukemia, non-small cell lung cancers, gastrointestinal stromal tumors, and HER2-positive breast cancers. Given their widespread applications, an increasing frequency of TKI-induced adverse effects has been reported. Although TKIs are known to affect multiple organs in the body including the lungs, liver, gastrointestinal tract, kidneys, thyroid, blood, and skin, cardiac involvement accounts for some of the most serious complications. The most frequently reported cardiovascular side effects range from hypertension, atrial fibrillation, reduced cardiac function, and heart failure to sudden death. The potential mechanisms of these side effects are unclear, leading to critical knowledge gaps in the development of effective therapy and treatment guidelines. There are limited data to infer the best clinical approaches for the early detection and therapeutic modulation of TKI-induced side effects, and universal consensus regarding various management guidelines is yet to be reached. In this state-of-the-art review, we examine multiple pre-clinical and clinical studies and curate evidence on the pathophysiology, mechanisms, and clinical management of these adverse reactions. We expect that this review will provide researchers and allied healthcare providers with the most up-to-date information on the pathophysiology, natural history, risk stratification, and management of emerging TKI-induced side effects in cancer patients.

Giant right hydronephrosis with underlying double malignancy: a case report.

Giant hydronephrosis is mostly caused by ureteropelvic junction obstruction (UPJO). Giant hydronephrosis with concurrent malignancy is less common clinically and is easily misdiagnosed. We report a 77-year-old male who presented with sudden onset progressive abdominal distension in the last month. Abdominal computed tomography showed a right severe hydronephrotic kidney with loss of parenchymal thinning. Cystoscopy showed a 1x1cm papillary lesion protruding from the right ureteric orifice. He underwent a right radical nephroureterectomy with bladder cuff excision with lymph node dissection. Histopathology showed low-grade urothelial carcinoma of the ureter and incidental pleomorphic rhabdomyosarcoma in the right kidney. The patient refused chemotherapy and died 6 months later due to lung metastasis. Incidental pathologic finding of renal rhabdomyosarcoma in adults with giant hydronephrosis and urothelial carcinoma is a rare occurrence with diverse clinical presentations, prognoses, and outcomes.

Primary malignant melanoma of prostate: a case report.

While primary genitourinary melanomas account for less than 1% of all melanoma cases, prostatic melanoma is extremely uncommon. These patients are challenging to identify, with a dismal prognosis. We reported a 52-year-old male patient who presented with lower urinary tract symptoms in the last one and a half months. The patient underwent Holmium laser enucleation of the prostate, and the histopathology result of the resected specimen showed prostatic melanoma. Investigations for systemic melanoma evaluation were negative, and the patient underwent radical cystoprostatectomy, urethrectomy, and bilateral lymph node dissection. The patient refused chemotherapy, developed lung metastasis shortly after surgery at three months, and succumbed to the metastatic disease with overall survival of 6 months. In conclusion, primary malignant melanoma of the prostate is a very rare disease. The most logical therapeutic strategy is aggressive surgical resection, followed immediately by adjuvant therapy.

Left atrial appendage volume as a prognostic Indicator of long-term mortality in Cancer survivors treated with thoracic radiation.

BACKGROUND: Cancer survivors with prior chest radiation therapy (CXRT) frequently present with atrial fibrillation, heart failure, and have higher overall long-term mortality. There are no data examining the utility of left atrial (LA) and LA appendage (LAA) volume-indices to predict clinical outcomes in these patients. OBJECTIVES: We examined the prognostic value of cardiac phase-dependent 3-D volume-rendered cardiac computerized tomography (CT)-derived LA and LAA volume-indices to predict mortality and major adverse cardiac events (MACE) in cancer survivors treated with thoracic irradiation. METHOD: We screened 625 consecutive patients with severe aortic stenosis who had undergone transcatheter aortic valve replacement from 2012 to 2017. Based on the gated cardiac CT image quality, we included 184 patients (CXRT:43, non-CXRT:141) for further analysis. We utilized multiplane-3D-reconstructed cardiac CT images to calculate LA and LAA volume-indices, and examined the prognostic role of CCT-derived LA and LAA volume-indices in predicting the all-cause mortality, cardiovascular (CV) mortality, and MACE. We used multivariate cox-proportional hazard analysis to identify the clinical predictors of survival. RESULTS: Overall, the CXRT group had significantly elevated LAA volume-index compared to non-CXRT group (CXRT:11.2 ± 8.9 ml/m2; non-CXRT:8.6 ± 4.5 ml/m2, p = 0.03). On multivariate cox-proportional hazard analysis, the elevated LAA volume and LAA volume-index were the strongest predictors of reduced survival in CXRT group compared to non-CXRT group (LAA volume: RR = 1.03,95% CI 1.0-1.01, p = 0.01; and LAA volume index: RR = 1.05, 95% CI 1.0-1.01, p = 0.03). LAA volume > 21.9 ml was associated with increased mortality. In contrast, LA volume was not a significant predictor of mortality. CONCLUSION: We describe a novel technique to assess LA and LAA volume using 3-D volume-rendered cardiac CT. This study shows enlarged LAA volume rather than LA volume carries a poor prognosis in cancer-survivors treated with prior CXRT. Compared to conventionally reported markers, LAA volume of > 21.9 ml was incremental to that of other risk factors.

Clinical Significance of Galectin-3 Expression in Squamous Cell Carcinoma of Lung.

Squamous cell carcinoma of lung is an aggressive disease with a poor a prognosis. While majority of these patients do not survive longer than five years, a minor proportion of patients go on to live longer without disease progression. Identification of biomarkers using easily available immunohistochemical assays could improve risk-stratification in lung cancer patients. Galectin-3, a lectin binding protein, expression has been linked to cancer progression and metastasis. We examined the prognostic impact of tumoral galectin-3 expression in 236 patients with completely resected squamous cell carcinoma of the lung and matching normal tissue using tissue microarray samples. In normal lung, galectin-3 staining is present in alveolar macrophages. Galectin-3 expression is detected in 87% of lung squamous cell carcinoma with a mean galectin-3 score of 2 (range 0-3). There was a significant association between galectin-3 expression and pathological stage (p=0.012) and nodal metastasis (p= 0.013). Galectin-3 expression level, however, was not associated with survival outcome. In conclusion, galectin-3 is expression is seen in alveolar macrophages and close to 90% of lung squamous cell carcinoma. Galectin-3 expression is not associated with survival outcome in North American cohort.

Rare metastatic sites of renal cell carcinoma: a case series.

Renal Cell Carcinoma (RCC) is a lethal cancer with a propensity for wide metastasis. The patterns of metastases are not clearly defined, and patients can present with metastasis to unusual sites at the time of diagnosis of the primary tumor or years after radical nephrectomy. Individual diagnostic and surgical approaches are needed to achieve complete resection with disease-free margins, even in the presence of unusual metastatic sites, multifocality, or history of previous metastasectomy. This provides palliation for symptoms and an opportunity for meaningful disease-free and overall survival. Here we present five cases of RCC with metastasis to unusual sites (scalp, jaw, forearm, parotid, breast, and skeletal muscle). Patients were treated with cytoreductive nephrectomy and/or metastasectomy wherever feasible and/or targeted therapy. In conclusion, a high index of suspicion and accurate diagnosis is important as metastasis to unusual sites presents with atypical manifestations and may masquerade as local pathology, misleading the clinician and directly affecting prognosis and survival.

Echocardiographic and Cardiac MRI Comparison of Longitudinal Strain and Strain Rate in Cancer Patients Treated with Immune Checkpoint Inhibitors.

Background: Immune checkpoint inhibitor (ICI)-induced cardiac side effects in cancer patients are increasingly being recognized and can be fatal. There is no standardized cardiac imaging test to examine the effects of ICIs in myocardial morphology and function. Objective: To study the utility of echocardiography and cardiac MRI in examining regional and global changes arising from ICI-induced myocarditis and cardiomyopathy in high-risk subjects suspected to have developed ICI cardiomyopathy. Methods: We studied eight consecutive patients referred for cardiac MRI (CMR) from a comprehensive cancer center for suspected ICI-induced myocarditis and compared the data with sixteen age-matched controls. Using newly developed strain analysis algorithms, we measured myocardial strain and strain rates using echocardiography and CMR. Then, we compared the mean longitudinal strain and strain rates derived from echocardiography and CMR in the same ICI-treated cohort of patients (n = 8). They underwent both of these imaging studies with images taken 24−48 h apart and followed up prospectively within the same hospital course. Results: All our cases had preserved ejection fraction (EF) > 50%. Echocardiogram showed reduced mean systolic longitudinal strain (LS, %) (ICI: −12.381 ± 4.161; control: −19.761 ± 1.925; p < 0.001), peak systolic strain rate (SRS, s−1) (ICI: −0.597 ± 0.218; control: −0.947 ± 0.135; p = 0.002) and early diastolic strain rate (SRE, s−1) (ICI: 0.562 ± 0.295; control: 1.073 ± 0.228; p = 0.002) in ICI-treated cases. Direct comparison between the echocardiogram vs. CMR obtained within the same hospital course demonstrated strong a correlation of LS scores (r = 0.83, p = 0.012) and SRS scores (r = 0.71, p = 0.048). The Bland−Altman plots showed that 95% of the data points fitted within the ±1.96 SD of the mean difference, suggesting an agreement among these two imaging modalities. Conclusion: In this feasibility cohort study, both echocardiography- and CMR-based strain indices illustrate changes in myocardial contractility and relaxation suggestive of ICI-induced cardiomyopathy. Our data, after validation in a larger cohort, can form the basis of myocardial imaging in cancer patients treated with ICIs.

Manipulating adrenergic stress receptor signalling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants.

BACKGROUND: Vascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non-life-threatening conditions. Here we tested whether we could suppress anti-graft immune activity by using a safe ß2 -adrenergic receptor (AR) agonist, terbutaline, to mimic the natural immune suppression generated by nervous system-induced signalling through AR. METHODS: A heterotopic hind limb transplantation model was used with C57BL/6 (H-2b) as recipients and BALB/c (H-2d) mice as donors. To test the modulation of the immune response, graft survival was investigated after daily intraperitoneal injection of ß2 -AR agonist with and without tacrolimus. Analyses of immune compositions and quantification of pro-inflammatory cytokines were performed to gauge functional immunomodulation. The contributions to allograft survival of ß2 -AR signalling in donor and recipient tissue were investigated with ß2 -AR-/- strains. RESULTS: Treatment with the ß2 -AR agonist delayed VCA rejection, even with a subtherapeutic dose of tacrolimus. ß2 -AR agonist decreased T-cell infiltration into the transplanted grafts and decreased memory T-cell populations in recipient's circulation. In addition, decreased levels of inflammatory cytokines (IFN-γ, IL-6, TNF-α, CXCL-1/10 and CCL3/4/5/7) were detected following ß2 -AR agonist treatment, and there was a decreased expression of ICAM-1 and vascular cell adhesion molecule-1 in donor stromal cells. CONCLUSIONS: ß2 -AR agonist can be used safely to mimic the natural suppression of immune responses, which occurs during adrenergic stress-signalling and thereby can be used in combination regimens to reduce the dose needed of toxic immunosuppressive drugs such as tacrolimus. This strategy can be further evaluated for feasibility in the clinic.

Right Atrial Dose Is Associated with Worse Outcome in Patients Undergoing Definitive Stereotactic Body Radiation Therapy for Central Lung Tumors.

The consequence of cardiac substructure irradiation in patients receiving stereotactic body radiation therapy (SBRT) is not well characterized. We reviewed the charts of patients with central lung tumors managed by definitive SBRT from June 2010-April 2019. All patients were treated with five fractions, typically either 5000 cGy (44.6%) or 5500 cGy (42.2%). Via a multi-patient atlas, fourteen cardiac substructures were autosegmented, manually reviewed and analyzed using dosimetric parameters. A total of 83 patients were included with a median follow up of 33.4 months. Univariate Cox regression analysis identified a D45% dose to the right atria and ventricle for further study. Sequential log-rank testing evaluating an association between non-cancer associated survival and D45% dose to the right atria or ventricle and association was employed, identifying candidate cutoff values of 890.3 cGy and 564.4 cGy, respectively. Kaplan-Meier analysis using the reported cutoff values found the D45% right atria constraint to be significantly associated with non-cancer associated (p ≤ 0.001) and overall survival (p ≤ 0.001) but not the right ventricle constraint. Within a multivariate model, the proposed right atria D45% cutoff remained significantly correlated with non-cancer associated survival (Hazard's Ratio (HR) ≤ 8.5, 95% confidence interval (CI) 1.1-64.5, p ≤ 0.04) and OS (HR ≤ 6.1, 95% CI 1.0-36.8, p ≤ 0.04). In conclusion, a dose to D45% of the right atria significantly correlated with outcome and the candidate constraint of 890 cGy stratified non-cancer associated and OS. The inclusion of these findings with previously characterized relationships between proximal airway constraints and survival enhances our understanding of why centrally located tumors are high risk and potentially identifies key constraints in organ at risk prioritization.

Quantitative analysis of International Health Regulations Annual Reports to identify global disparities in the preparedness for radiation emergencies.

OBJECTIVES: Radiation emergencies are rare but can have minor confined effects to catastrophic consequences across the large geographical territories. Geographical disparities in the preparedness for radiation emergencies can negatively impact public-safety and delay protective actions. We examined such disparities using the global and regional radiation preparedness data from the revised annual International Health Regulations (IHR) data sets. SETTINGS: We used IHR State Party Annual Reporting (SPAR) tool and its associated health indicators developed to mitigate public health risk from radiation emergencies. Using the most recent (2019) SPAR database developed for radiation emergencies, along with 12 other cross-sector indicators, we examined the disparities among WHO state and region-wide capacity scores for operational preparedness. RESULTS: Based on the analysis of the 2019 annual reporting data sets from 171 countries, radiation emergency was one of the top three global challenges with an average global preparedness capacity of 55%. Radiation emergency preparedness capacity scores showed highest dispersion score among all 13 capacities suggesting higher disparities for preparedness across the globe. Only 38% of the countries had advanced functional capacity with ≥80% operational readiness, with 28% countries having low to very low operational readiness. No geographical regions had ≥80% operational readiness for radiation emergencies, with 4/6 geographical regions showing limited capacity or effectiveness. Global data from 171 countries showed that the capacity to respond to radiation emergencies correlated with the capacity for chemical events with a correlation coefficient (ρ) of 0.70 (CI 0.61 to 0.77). CONCLUSION: We found major global disparities for the operational preparedness against radiation emergencies. Collaborative approaches involving the public health officials and policymakers at the regional and state levels are needed to develop additional guidance to adapt emergency preparedness plans for radiation incidents.

Role of 68Ga-PSMA-PET/CT for the detection of primary prostate cancer prior to biopsy: a prospective study.

INTRODUCTION: Prostate-specific membrane antigen (PSMA) positron emission tomography/ computed tomography (PET-CT) is widely used as a staging tool for patients with prostate cancer (PCa). The objective of the study is to assess the diagnostic accuracy of 68Ga-PSMA-PET/CT for PCa, which may help us avoid unnecessary biopsies in patients with intermediate prostate-specific antigen (PSA) levels. MATERIAL AND METHODS: In this prospective study, 81 patients suspected of PCa, with either raised PSA between 4-20 ng/ml or abnormal digital rectal examination (DRE) findings were included. 68Ga-PSMA-PET/CT was performed for all patients followed by transrectal ultrasound (TRUS) guided prostate biopsy. SUVmax (maximum standardized uptake value) was measured and correlated with biopsy results. RESULTS: Out of 81 patients, 31 (38.3%) patients were found to have malignancy on biopsy. Median SUVmax of biopsy positive patients was 10.4 (IQR 6.5-16.1) and biopsy negative patients (n=50) was 3.5 (IQR 1-4.9), (p <0.001). At a cut-off of 6.15, 68GA-PSMA-PET/CT demonstrated sensitivity of 84%, specificity of 80%, positive predictive value of 72.2%, negative predictive value of 88.9% and accuracy of 81.5% with an AUC of 0.876 (95% CI: 0.799-0.953, p <0.001). CONCLUSIONS: The 68Ga-PSMA-PET/CT helps to localize suspicious lesions and improving the detection of primary prostate cancer. Our findings indicate a significant correlation of SUVmax values with biopsy results. We were also able to determine a cut-off value of SUVmax below which prostate biopsy can be avoided in selected patients.

Biventricular Strain Imaging with Cardiac MRI in Genotyped and Histology Validated Amyloid Cardiomyopathy.

Cardiac amyloidosis (CA) is a common and potentially fatal infiltrative cardiomyopathy. Contrast-enhanced cardiac MRI (CMR) is used as a diagnostic tool. However, utility of CMR for the comprehensive analysis of biventricular strains and strain rates is not reported as extensively as echocardiography. In addition, RV strain analysis using CMR has not been described previously. OBJECTIVES: We sought to study the global and regional indices of biventricular strain and strain rates in endomyocardial biopsy (EMB)-proven, genotyped cases of CA. METHODS: A database of 80 EMBs was curated from 2012 to 2019 based on histology. A total of 19 EMBs positive for CA were subjected to further tissue-characterization with histology, and compared with four normal biopsy specimens. Samples were genotyped for ATTR- or AL-subtypes. Five patients, with both echocardiography and contrast-enhanced CMR performed 72-h apart, were subjected to comprehensive analysis of biventricular strain and strain-rates. RESULTS: Histology confirmed that the selected samples were indeed positive for cardiac amyloid. Echocardiography showed reduced global and regional left-ventricular (LV) longitudinal strain indices. CMR with tissue-characterization of LV showed global reductions in circumferential, radial and longitudinal strains and strain-rates, following a general trend with the echocardiographic findings. The basal right-ventricular (RV) segments had reduced circumferential strains with no changes in longitudinal strain. CONCLUSIONS: In addition to providing a clinical diagnosis of CA based on contrast clearance-dynamics, CMR can be a potent tool for accurate functional assessment of global and regional changes in strain and strain-rates involving both LV and RV. Further studies are warranted to validate and curate the strain imaging capacity of CMR in CA.

Small Endogeneous Peptide Mitigates Myocardial Remodeling in a Mouse Model of Cardioselective Galectin-3 Overexpression.

BACKGROUND: Myocardial Gal3 (galectin-3) expression is associated with cardiac inflammation and fibrosis. Increased Gal3 portends susceptibility to heart failure and death. There are no data reporting the causative role of Gal3 to mediate cardiac fibro-inflammatory response and heart failure. METHODS: We developed a cardioselective Gal3 gain-of-function mouse (Gal3+/+) using α-myosin heavy chain promotor. We confirmed Gal3-transgene expression with real-time polymerase chain reaction and quantified cardiac/circulating Gal3 with Western blot and immunoassays. We used echocardiogram and cardiac magnetic resonance imaging to measure cardiac volumes, function, and myocardial velocities. Ex vivo, we studied myocardial inflammation/fibrosis and downstream TGF (transforming growth factor) ß1-mRNA expression. We examined the effects of acute myocardial ischemia in presence of excess Gal3 by inducing acute myocardial infarction in mice. Two subsets of mice including mice treated with N-acetyl-seryl-aspartyl-lysyl-proline (a Gal3-inhibitor) and mice with genetic Gal3 loss-of-function (Gal3-/-) were studied for comparative analysis of Gal3 function. RESULTS: Gal3+/+ mice had increased cardiac/circulating Gal3. Gal3+/+ mice showed excess pericardial fat pad, dilated ventricles and cardiac dysfunction, which was partly normalized by N-acetyl-seryl-aspartyl-lysyl-proline. Cardiac magnetic resonance imaging showed reduced myocardial contractile velocities in Gal3+/+. The majority of Gal3+/+ mice did not survive acute myocardial infarction, and the survivors had profound cardiac dysfunction. Myocardial histology of Gal3+/+ mice showed macrophage/mast-cell infiltration, fibrosis and higher TGFß1-mRNA expression, which were mitigated by both Gal3 gene deletion and N-acetyl-seryl-aspartyl-lysyl-proline administration. CONCLUSIONS: Our study shows that cardioselective Gal3 overexpression leads to multiple cardiac phenotypic defects including ventricular dilation and cardiac dysfunction. Pharmacological Gal3 inhibition conferred protective effects with reduction of inflammation and fibrosis. Our study highlights the importance of translational studies to counteract Gal3 function and prevent cardiac dysfunction.

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs. METHODS: We retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors. RESULTS: Among patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes. CONCLUSIONS: Routine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.

Extraction and Characterization of Sesbania cannabina (Retz.) Pers. (Dhaincha) Seed Oil for Potential Engineering Applications.

Sesbania cannabina (Retz.) Pers. (Dhaincha) is a member of family Fabaceae spread over several countries in tropical and subtropical regions of the world. Sesbania aculeata, Sesbania drummondii, Sesbania grandiflora, Sesbania rostrata, Sesbania sesban, and Sesbania speciosa are other members of this family. The agricultural, nutritional and pharmaceutical applications of Sesbania species are known to farmers, villagers, and the tribes since ages and are well studied by researchers. However, the significance of Sesbania as an industrial crop has not been recognized till now. The objective of this study was extraction and characterization of Sesbania cannabina seed oil (SCSO) for potential engineering applications. The seed oil was extracted with hexane in a Soxhlet extractor. Yield was only 2.32% w/w due to long storage at high temperature in seed house. Sesbania cannabina seed oil methyl ester (SCSOME) was prepared via esterification and transesterification for analysis of fatty acid composition of extracted oil. SCSO has high iodine value (118 g I2/100 g) and high saponification value (185.79 mg KOH/g) making the oil suitable for use as candle stocks or in soap making. However, these applications were ruled out on account of being insignificant for oil available in limited quantity. The oil has high viscosity index (174.19), high onset (382°C) and offset (450°C) decomposition temperatures, endothermic nature, and shear rate thickening behaviour. These properties make SCSO a good candidate for application as specialty lubricant required under severe operating conditions of high temperature and high shear rate or as insulating and cooling transformer oil.

Critical Analysis of Outcome Between Ventral and Dorsal Onlay Urethroplasty In Female Urethral Stricture.

OBJECTIVES: To evaluate and compare the 2 surgical approaches of urethral reconstruction for management of refractory female urethral strictures (FUS) in a prospective randomized setting. Early surgical reconstruction is becoming the preferred management strategy for recurrent FUS. Reconstructive techniques have been described as using either dorsal (12-o'clock) or ventral approach (6-o'clock), each with their own advantages. To our best knowledge, a direct comparison between the 2 techniques to prospectively compare outcomes hasn't been made. METHODS: We performed a prospective randomized study in a single tertiary care center on a total of 24 patients, randomizing them into 2 groups of 12 patients each. One group underwent dorsal onlay and other underwent ventral onlay urethroplasty. Preoperative, intraoperative and postoperative outcomes were evaluated and compared for the 2 approaches. RESULTS: There was high success rate (91%) with significant but comparable improvements in flow rates, post void residue and symptomatic outcomes without any major complication. There was 1 recurrence of stricture each in both groups. Important technical differences were noted with easier meatus preservation, lesser bleeding and wider operative field in the ventral approach, while the dorsal approach proving better in distal urethral strictures requiring meatal reconstruction. CONCLUSION: Both approaches of urethroplasty present a very promising modality of management of FUS with comparable outcomes but with important technical differences which must be considered to best tailor the approach for each patient.

CBR3 V244M is associated with LVEF reduction in breast cancer patients treated with doxorubicin.

BACKGROUND: The CBR3 V244M single nucleotide polymorphism has been linked to the risk of anthracycline-related cardiomyopathy in survivors of childhood cancer. There have been limited prospective studies examining the impact of CBR3 V244M on the risk for anthracycline-related cardiotoxicity in adult cohorts. OBJECTIVES: This study evaluated the presence of associations between CBR3 V244M genotype status and changes in echocardiographic parameters in breast cancer patients undergoing doxorubicin treatment. METHODS: We recruited 155 patients with breast cancer receiving treatment with doxorubicin (DOX) at Roswell Park Comprehensive Care Center (Buffalo, NY) to a prospective single arm observational pharmacogenetic study. Patients were genotyped for the CBR3 V244M variant. 92 patients received an echocardiogram at baseline (t0 month) and at 6 months (t6 months) of follow up after DOX treatment. Apical two-chamber and four-chamber echocardiographic images were used to calculate volumes and left ventricular ejection fraction (LVEF) using Simpson's biplane rule by investigators blinded to all patient data. Volumetric indices were evaluated by normalizing the cardiac volumes to the body surface area (BSA). RESULTS: Breast cancer patients with CBR3 GG and AG genotypes both experienced a statistically significant reduction in LVEF at 6 months following initiation of DOX treatment for breast cancer compared with their pre-DOX baseline study. Patients homozygous for the CBR3 V244M G allele (CBR3 V244) exhibited a further statistically significant decrease in LVEF at 6 months following DOX therapy in comparison with patients with heterozygous AG genotype. We found no differences in age, pre-existing cardiac diseases associated with myocardial injury, cumulative DOX dose, or concurrent use of cardioprotective medication between CBR3 genotype groups. CONCLUSIONS: CBR3 V244M genotype status is associated with changes in echocardiographic parameters suggestive of early anthracycline-related cardiomyopathy in subjects undergoing chemotherapy for breast cancer.

Coronary revascularization in patients with stable coronary disease and diabetes mellitus.

PURPOSE OF STUDY: Diabetes mellitus accelerates the development of atherosclerosis. Patients with diabetes mellitus have higher incidence and mortality rates from cardiovascular disease and undergo a disproportionately higher number of coronary interventions compared to the general population. Proper selection of treatment modalities is thus paramount. Treatment strategies include medical management and interventional approaches including coronary artery bypass graft (CABG) surgery and percutaneous coronary interventions (PCI). The purpose of this review is to assimilate emerging evidence comparing CABG to PCI in patients with diabetes and present an outlook on the latest advances in percutaneous interventions, in addition to the optimal medical therapies in patients with diabetes. KEY METHODS: A systematic search of PubMed, Web of Science and EMBASE was performed to identify prospective, randomized trials comparing outcomes of CABG and PCI, and also PCI with different generations of stents used in patients with diabetes. Additional review of bibliography of selected studies was also performed. MAIN CONCLUSIONS: Most of the trials discussed above demonstrate a survival advantage of CABG over PCI in patients with diabetes. However, recent advances in PCI technology are starting to challenge this narrative. Superior stent designs, use of specific drug-eluting stents, image-guided stent deployment, and the use of contemporary antiplatelet and lipid-lowering therapies are continuing to improve the PCI outcomes. Prospective data for such emerging interventional technologies in diabetes is however lacking currently and is the need of the hour.