Search

Immune checkpoint inhibitor (ICI) therapy has played an important role in the treatment of several groups of cancers. Although a life prolonging treatment, many side effects have been shown with ICI therapy. This study looked at individual level clinical characteristics and outcomes with ICI therapy in patients who developed ICI-related myocarditis. A comprehensive review of the National Library of Medicine PubMed database was performed. Inclusion criteria were all studies that were composed of case reports and case series of individual patients undergoing ICI therapy that developed myocarditis. To appreciate individual patient level data, observational studies, clinical trials, systematic reviews, and meta-analyses were excluded. Our search yielded 333 results with 71 cases reviewed of ICI therapy-related myocarditis. The findings included an average age of 68 years, higher incidence in men, and pretreatment cardiac history of hypertension. Melanoma was the most prevalent malignancy with nivolumab being the most used ICI therapy. Heart failure was the most prevalent adverse event that was co-prevalent with myocarditis. Corticosteroid therapy alone was the most utilized therapy to treat ICI-related myocarditis. Mortality was seen in nearly half of the patient population. Our study reviewed the preexisting literature of prior reported myocarditis secondary to ICI therapy. Periodic surveillance should be performed by the cardio-oncologist and internist. Due to the expanding role of ICI therapy in treating a variety of cancer patients, appreciation of its impact on the development of myocarditis is needed. Cardiol Res. 2021;12(5):270-278 doi: https://doi.org/10.14740/cr1319

IntroductionHeart Failure disease management clinics have been historically successful in reducing complications, little has been examined in uninsured settings.MethodsThis is a pilot study of HF patients following a recent hospitalization. Uninsured patients were offered enrollment in the disease management clinic during or immediately following hospitalization for a primary HF diagnosis at our institution during 2021. The program included twice-weekly visits with interprofessional support. Patients were scheduled 16 visits (2 months of follow-up) post-hospitalization. Patients who attended two visits were considered enrolled.ResultsOf 59 patients referred, 47(80%) were enrolled. Just 4 patients (8.5%,95%CI:2.5%,20.5%) were readmitted at 30 days, while 4 of 12 (33%,95%CI:13.6%,61.2%) were readmitted at 30 days in those who did not enroll. Program participants were readmitted significantly less frequently than national readmission rate estimates (23%,p=0.02).ConclusionThe CHFC3 program is feasible and holds promise for materially reducing 30-day readmissions for HF complications in the uninsured.

Objective of this retrospective study was to determine if long-term continuous cardiac monitoring with Implantable loop recorder (ILR) in patients with Cryptogenic strokes or TIA is superior at detecting Atrial Fibrillation (AF) than 30-day Event Monitor (EM) and 48-hour Holter Monitor (HM). Furthermore, we aimed to deduce if uncovering AF leads to lower risk of future ischemic strokes, or reduction in mortality. In 20%-30% cases, the cause of stroke remained unexplained after diagnostic workup which has led to coining of the term, Cryptogenic Stroke (CS). Undiagnosed AF is a prime suspect in CS, but guidelines do not recommend initiation of anticoagulation unless AF has formally been detected. IRB approved retrospective study included patients with at least 1 episode of ischemic stroke or TIA without identifiable cause and was monitored with either HM, EM or ILR to diagnose any undiscovered AF. All patients (n = 531) had at least 1 year, and up to 3 years, of follow-up after device placement. Chi-Squared analysis and Multivariable logistic regression demonstrated no statistically significant difference among 3 devices for detection of AF within 1 month of index stroke but a significant difference in AF detection was observed at 6, 12 and 24 months. Cox proportional hazard model showed device type had no significant impact on secondary outcomes: Subsequent ischemic stroke or TIA, Initiation of anticoagulation, Mortality and Incidence of major bleeding. Despite the superiority of AF detection by ILR, it is not superior to HM or EM in lowering the risk of subsequent stroke or TIA, or in reducing mortality.

Infective endocarditis (IE) is a rare but serious disease. Coagulase-negative staphylococci (CoNS) are among the least prevalent causes of IE. Staphylococcus capitis, a species of CoNS, although described in the literature before has only been seen in a few cases. Even with such few cases, complications and mortality have still been demonstrated. In our review, we look at the epidemiology, diagnosis, management, and literature prevalence of CoNS in native and prosthetic valve IE.

Objective To analyze the age-specific temporal trends, in-hospital outcomes and readmissions for acute heart failure (HF). Background There is a paucity of data on the age-specific differences in the trends and outcomes of hospitalizations with acute HF. Methods The National Inpatients Sample database years 2002–2016 and the National Readmissions Database years 2013–2016 were used to identify primary hospitalizations for acute HF. We analyzed the age-specific temporal trends, in-hospital outcomes, and readmissions for acute HF. Results The annual rate of hospitalizations for acute HF declined from 456 per 100,000 people in 2002 to 356 per 100,000 people in 2016 (Ptrend 34 years). Conclusions This nationwide contemporary analysis demonstrated a decline in the annual rates of hospitalizations with acute HF across all age categories except those aged 18–44 years. There was a reduction in rates of in-hospital mortality among middle-aged and older patients, but not in those aged 18–34. In-hospital mortality exhibited a dichotomous relationship with age. There was an inverse relationship between age and 30-days HF readmissions.

Purpose of review Congestive heart failure (CHF) and chronic kidney disease (CKD) often coexist. However, and despite their established benefits, the use of mineralcorticoid receptor antagonists (MRAs) in patients with both comorbidities is inconsistent. This review will focus on the role of aldosterone in CHF, as well as timing, selection, and management of MRAs in CHF patients with CKD. Recent findings Aldosterone in CHF patients contributes to worsening sodium retention, hypokalemia, metabolic alkalosis, cardiac fibrosis, and CKD progression. MRAs are beneficial in CHF patients with CKD despite the adverse events of hyperkalemia and acute kidney injury. MRAs were previously studied in patients with CKD stage III but were recently found to be safe in end-stage kidney disease (ESKD) patients. New nonsteroidal MRAs are more selective for the mineralocorticoid receptor and have a better side effect profile. The use of potassium lowering agents, such as patriomer, helps maintain normokalemia in patients with CKD who are treated with MRAs. Summary It is recommended to use MRAs in CHF patients with normal potassium levels and a glomerular filtration rate of more than 30 ml/min. Their use is also safe in ESKD patients. In nondialysis advanced CKD patients, they may need to be combined to medications such as patiromer. New nonsteroidal MRAs are currently being studied.

Background In-hospital left ventricular (LV) thrombus following acute ST-elevation myocardial infarction (STEMI) has not been evaluated on a national scale and was the focus of this investigation. Methods We used the 2003 to 2013 Nationwide Inpatient Sample database to identify adults ≥18 years old with a principal diagnosis code of ST-elevation myocardial infarction. Patients were divided into two groups defined by the presence or absence of LV thrombus. Clinical characteristics and in-hospital outcomes were studied using relevant statistics. Multiple linear and logistic regression models were conducted to identify factors associated with LV thrombus. Results Of 1,035,888 STEMI patients hospitalized in the U. S from 2003 to 2013, 1982 (0.2%) developed acute in-hospital LV thrombus. Compared to no LV thrombus, patients with LV thrombus were more likely to have in-hospital complications; acute ischemic and hemorrhagic stroke, acute renal failure, gastrointestinal bleed, cardiogenic shock, in-hospital cardiac arrest and mortality. They also had longer mean length of stay and higher hospital charges. Factors associated with LV thrombus included: anterior/anterolateral STEMI, acute or chronic heart failure with reduced ejection fraction, atrial fibrillation, LV aneurysm, Left heart valvular disease, acute or chronic deep venous thrombosis/pulmonary embolism and alcohol abuse. Patients with LV thrombus were less likely to be female [AOR 0.66, 95% CI (0.51–0.84)]. Conclusion The identification of factors associated with early development of LV thrombus following STEMI, will help direct resources for specific high-risk group and prompt cost-effective therapies. Gender variability in LV thrombus development warrants further investigations.

Aspirin is one of the most widely used medications across the global healthcare system and is the foundation in treating ischemic heart disease, as well as secondary prevention for ischemic and valvular heart disease. Challenges arise in treating patients with cardiovascular disease who have concomitant aspirin intolerance. Through an extensive review of the literature, we provide a comprehensive background on the pharmacology of aspirin, the mechanisms behind aspirin intolerance, the importance of aspirin in cardiovascular disease, and the management of aspirin intolerance in both acute coronary syndrome and stable coronary artery disease. Our review includes a multidisciplinary approach from the internist, allergist/immunologist, and cardiologist when evaluating this important patient population.

299 Background: Although epidemiological and clinical differences in gastric cancer (GC) between the US and Japan have been reported, genetic differences have not been clarified. We aimed to characterize molecular differences in GC between the two countries. Methods: We collected data between January 2010 and December 2019 from a prospectively maintained database of GC at our US and Japanese centers. After matching clinicopathological backgrounds, including age, sex, clinical T and N status, and tumor location, the genomic profiles of the primary site were compared for 58 patients in each group undergoing surgical resection and had MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets), a tumor-normal next generation sequencing assay that can detect alterations in exons and select introns of 505 genes. The MSI sensor algorithm was used to assess microsatellite instability. Genomic alterations were filtered for driver variants using OncoKB, and genes were consolidated into pathways using curated pathway templates from the Cancer Genome Atlas. Results: The clinicopathological characteristics were well matched between 58 patients in each cohort. In the entire cohort, the most commonly altered genes were: TP53 (45%), ARID1A (24%), and ERBB2 (17%) in the US cohort, and TP53 (50%), ARID1A (19%), and ERBB2 (17%) in the Japanese cohort. Although KMT2D was more frequently altered in the US cohort (19% vs. 2%), the two cohorts had no significant differences in other altered genes and gene pathways. The tumor with MSI high was found more frequently in the US cohort (22.4% vs. 5.2%, p = 0.01). Among the MSI-normal tumors, the tumor mutational burden (US: 3.5 muts/Mb and Japanese: 4.1 muts/Mb) and the fraction genome altered (US: 0.37 and Japanese: 0.28) did not significantly differ between the two groups. Additionally, no genes or pathways were significantly enriched in either group. Patterns of mutual exclusivity and co-occurrence amongst genes and pathways were also similar between the two groups. Conclusions: In this original genomic comparison of US and Japanese gastric cancers, matching clinicopathological backgrounds, Japanese and US gastric cancers are remarkably similar at the genomic level, with the possible exception of MSI-high tumor that appear to be more frequent in the US.

Coronary microvascular disease or dysfunction (CMVD) has been associated with adverse cardiovascular outcomes. Despite a growing prevalence, guidelines on definitive treatment are lacking. Proposed mechanisms of endothelial dysfunction and resultant inflammation have been demonstrated as the underlying cause. Imaging modalities such as echocardiography, cardiac MRI, PET, and in some instances CT, have been shown to be useful in diagnosing CMVD mainly through assessment of coronary blood flow. Invasive measurements through thermodilution and pressure sensor-guided Doppler microcatheters have also been utilized. Treatment options are directed at targeting inflammatory pathways and angina. In our review, we highlight the current literature on the background of CMVD, diagnostic modalities, and management of this disease.

Heart failure is a leading global pandemic and a cause of economic burden. Although, treatments exist to help symptomatic alleviation, patient compliance and monitoring is the basis of ensuring efficacy. With devices that allow for remote wireless PA pressure monitoring such as CardioMEMS, the inconsistency in patient reporting and factors such as symptoms and hospitalizations can be reduced. A systematic review and meta-analysis utilizing the MEDLINE, Cochrane, and Scopus database was performed to identify randomized and non-randomized clinical trials evaluating baseline characteristics and hospitalizations. Five trials for the systematic review and 2 trials for the meta-analysis meeting the inclusion and exclusion criteria were included. Baseline characteristics included an average age of 64.6 years, male predominance, mean BMI of 29.6, predominance of HFrEF, hypertension the most prevalent comorbidity, and a mean PA pressure of 27.2 mm Hg. The follow-up periods ranged from 90 days to 12 months. There was a total of 64 adverse events, mostly non-serious. Patients who underwent remote PA monitoring were less likely to be hospitalized compared with patients who did not (Odds Ratio: 0.52; 95% Confidence Interval 0.39, 0.69). Remote PA pressure monitoring allows for reduced hospitalizations. With the recent and now resurging SARS-CoV-2 pandemic, devices such as CardioMEMS can allow for heart failure patients to be managed from home to not only reduce hospitalizations but for symptom prevention and management.

Amyloidosis is an infiltrative disease with severe impact on the cardiac anatomy resulting in structural changes 1 . Mitral valve insult from the infiltrative process, although rare, has been known to cause severe mitral regurgitation 4 . Due to underlying comorbidities these patients may not be surgical candidates. 17 , 18 , 19 , 20 The role of percutaneous mitral valve repair in cardiac amyloidosis has been described in a few prior cases. 4 , 15 We review the epidemiology, diagnosis, and treatment of cardiac amyloidosis. We also highlight prior cases described in the literature of cardiac amyloidosis and severe mitral regurgitation, while discussing the role of percutaneous mitral valve repair in these patients.

Soluble guanylate cyclase (sGC) agents have been shown to have possible beneficial effects in heart failure treatment. Unfortunately, the role of sGC in HFpEF has not been shown to be efficacious based on recent trials. The CAPACITY HFpEF and VITALITY-HFpEF trials independently showed that sGC does not improve 6-minute walk test (6MWT) distance or the Kansas City Cardiomyopathy Questionnaire (KCCQ) physical limitation score (PLS). The objective of this study was to analyze current data on the 6MWT and KCCQ PLS score from trials that included patients with HFpEF treated with sGC. Using MEDLINE and Cochrane databases, meta-analysis and systematic review was performed looking at data in the CAPACITY HFpEF and VITALITY-HFpEF trials. For safety analysis we evaluated serious adverse events between the CAPACITY HFpEF, VITALITY-HFpEF, SOCRATES-PRESERVED, and DILATE-1trials. A total of 2 trials were analyzed to assess 6MWT and KCCQ score. The total number of combined patients from both trials assessing 6MWT distance in sGC vs placebo therapy were 620 with 309 in the treatment group and 311 in the placebo group. The total number of combined patients from both trials assessing KCCQ score outcomes were 583 with 280 in the treatment group and 303 in the placebo group. A total of 4 trials were evaluated for safety analysis with a total of 987 patients with 529 in the treatment group and 458 in the placebo group. The analysis did not demonstrate significant difference in 6MWT (P = 0.97), KCCQ PLS (P = 0.83), or serious adverse events (P = 0.67).

3613 Background: Analysis of the IDEA database demonstrates significantly worse disease-free survival in high-risk stage III EO CRC vs AO CRC, regardless of adjuvant therapy intensity or duration. Critically this analysis omits somatic mutational data and germline status. Enrichment of TP53 in EO metastatic CRC (mCRC) is well described and functionality of individual TP53 mutations has been proposed as a potential mechanism of chemotherapy resistance. The prognostic and functional impact of somatic mutations merits analysis in the EO high-risk Stage III cohort. Methods: The Memorial Sloan Kettering MSKCC IMPACT database was queried for MSS Stage III AO CRC (≥50 yrs) and EO CRC ( < 50 yrs) patients(pts); clinico-pathological characteristics, systemic therapies received, and survival outcomes were reviewed. MSI, POLE mutated or hereditary syndrome associated tumors were excluded. We further classified TP53 mutations as GOF (gain of function) versus non GOF/ LOF (loss of function) (Pan M, JCO. 2022, Muller PA, Cancer cell. 2014). Results: 272 pts were included in the analysis (EO = 184, AO = 88). 50% of the EO and 62.5 % of the AO cohorts were male. Tumors were predominantly adenocarcinoma (EO 89% vs AO 91%), moderately differentiated (EO 78% vs AO 74%) and left sided (EO 77% vs AO 48.8%). 87% of the EO and 63.6 % of the AO cohort were TP53mut (p value 0.0003); TP53mut was enriched in the EO cohort regardless of sidedness but there was no significant difference in TP53 mutations between EO high vs low risk. Classifying by 7 putative GOF mutations (R175H, R248Q/W, R249S, R273H/L and R282W) 28.7% of the EO cohort harbored a GOF mutation vs 19.6% of the AO cohort. There was no statistically significant survival difference between pts with TP53mut tumors vs TP53 wild type (TP53wt) in the entire cohort (AO+EO) (p 0.041) or EO or AO cohorts (p 0.049). There was no significant difference in survival outcomes across all cohorts of TP53mut groups, both high and low risk, both GOF and non GOF, treated with 3 vs 6 months of chemotherapy (p 0.67). The EO TP53wt group was enriched relative to the EO TP53mut group for KRAS (60% vs 32%), BRAF (11% vs 4%), and PI3K driver alterations (PIK3CA, 20% vs 13%) and PTEN: (8% vs 3%) In the multivariate survival analysis of EO Stage III CRC BRAFmut status is highly statistically significant (p < 0.001). Conclusions: EO Stage III CRC is enriched for TP53 mutations regardless of sidedness and GOF mutations are identified in a higher proportion of EO CRC than AO CRC. We found no statistically significant difference in survival by TP53mut status across the entire MSS Stage III CRC cohort. There was no interaction between TP53mut status, duration of chemotherapy and overall survival. The functional impact of additional molecular features is being explored and the novel prognostic significance of BRAF demonstrated in this EO Stage III cohort requires further validation.

BACKGROUND There is a paucity of data regarding the outcomes of transcatheter aortic valve replacement (TAVR) versus surgical aortic valve replacement (SAVR) among solid-organ transplant recipients. METHODS Temporal trends in hospitalizations for aortic valve replacement among solid-organ transplant recipients were determined using the National Inpatient Sample database years 2012-2017. Propensity matching was conducted to compare admissions who underwent TAVR versus SAVR. The primary outcome was in-hospital mortality. RESULTS The analysis included 1,730 hospitalizations for isolated AVR; 920 (53.2%) underwent TAVR and 810 (46.7%) underwent SAVR. TAVR was increasingly utilized for solid-organ transplant recipients (Ptrend = 0.01), while there was no change in the number of SAVR procedures (Ptrend = 0.20). The predictors of undergoing TAVR for solid-organ transplant recipients included older age, diabetes, and prior coronary artery bypass surgery, while TAVR was less likely utilized in small-sized hospitals. TAVR was associated with lower in-hospital mortality after matching (0.9 vs. 4.7%, odds ratio [OR] 0.19; 95% confidence interval [CI] 0.11-0.35, p

Background: In-hospital ischemic stroke following acute ST-elevation myocardial infarction (STEMI) has not been evaluated on a national scale in the United States. Methods: We used 2003 to 2014 Nationwide Inpatient Sample data to identify adults with a principal diagnosis of STEMI. Patients were divided into two groups defined by presence or absence of ischemic stroke. Clinical characteristics and in-hospital outcomes were studied using relevant statistics. Multiple linear and logistic regression models identified factors associated with ischemic stroke, national trend of in-hospital stroke incidence and in-hospital mortality. Results: Of 1,842,529 STEMI patients hospitalized from 2003 to 2014, 22,268 (1.2%) developed acute in-hospital ischemic stroke. Those with acute strokes were older (age ≥ 65 years: 70% vs 46%), more likely female (51% vs 33%), and had higher rates of atrial fibrillation (28.9% vs 12.2%) and heart failure (40.5% vs 21.1%). Age and gender adjusted incidence of in-hospital ischemic stroke following STEMI remained stable; 1.4% in 2003 and 1.5% in 2014 (P trend = 0.50). However, age and gender adjusted in-hospital mortality declined in STEMI patients with and without in-hospital ischemic stroke [AOR 0.97 (0.95–0.99) P trend = 0.03, and AOR 0.98 (0.98–0.99) P trend

Aortic stenosis (AS) and arteriovenous malformations (AVM) are a common coexisting pathology in the elderly. When both pathologies are combined, Heyde syndrome is a differential that is widely explored among clinicians. Unfortunately, this may not always be the case. We present a case of an 82-year-old female admitted for acute gastrointestinal (GI) bleeding with a history of AVMs and AS, as well as, an algorithm in diagnosing elderly patients with both pathologies.

Introduction : Cardiovascular injury with SARS-CoV-2 infection is well known. Several studies have outlined baseline characteristics in patients presenting with STEMI and SARS-CoV-2. Paucity in data exists in selective coronary involvement in patients with STEMI and SARS-CoV-2 during the COVID-19 pandemic. Methods : A systematic search and meta-analysis of studies meeting the inclusion and exclusion criteria obtained from MEDLINE, Scopus, and Cochrane databases was performed utilizing PRISMA criteria. The main outcome was likelihood of coronary artery involvement among patients with STEMI and SARS-CoV-2 versus without SARS-CoV-2. The primary adverse outcome measured was in-hospital mortality. Results : The final analysis included 5 observational studies with a total of 2, 266 patients. There was no statistical significance in LM (OR 1.40; 95% CI: 0.68, 2.90), LAD (OR 1.09; 95% CI 0.83, 1.43), LCX (OR 1.17; 95% CI: 0.75, 1.85), or RCA (OR 0.59; 95% Confidence Interval 0.30, 1.17) disease among the two groups. LAD disease was the most prevalent coronary involvement among patients with STEMI and SARS-CoV-2 (49.6%). Higher in-hospital mortality was observed in the STEMI and SARS-CoV-2 group (OR 5.24; 95% Confidence Interval 3.63, 7.56). Discussion : Our analysis demonstrated no statistical significance in selective coronary involvement in patients with STEMI and SARS-CoV-2 during the COVID-19 pandemic. The higher mortality among patients with SARS-CoV-2 and STEMI has been noted in prior studies with concerns being late presentation due to fear of infection, delayed care time, and poor resource allocation. Focus should be placed on identifying and managing comorbidities to reduce mortality.

345 Background: Gastroesophageal junction cancer (GEJC) and gastric cancer (GC) are frequently studied together as one disease. Genomic profiles between the two disease sites have not been well characterized. We aimed to characterize molecular differences between the two disease sites. Methods: We collected data between January 2010 and December 2019 from a prospectively maintained database of GEJC and GC at our center. GEJC was defined according to the Siewert type 1 to 3 classification. Patients who underwent surgical resection and had MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets) sequencing performed on their primary tumor were included in this analysis. Results: Two hundred and seventy-four samples were analyzed; 156 (56.9%) GEJC and 118 (43.1%) GC patients. Regarding molecular subtypes, the GEJC group had a higher frequency of chromosomally instable tumors compared to the GC cohort (55.1% vs. 25.4%, p < 0.001). The fraction of genome altered (FGA) was significantly higher in the GEJC group (p < 0.001). TP53 (75.3% vs. 31.9%, p < 0.001, q < 0.001), CDKN2A (17.1% vs. 4.3%, p = 0.002, q = 0.02), and MDM2 (6.8% vs. 0%, p = 0.007, q = 0.033) were more frequently altered in the GEJC group, whereas CDH1 (2.7% vs. 9.6%, p = 0.037, q = 0.118) and RHOA (0% vs. 6.4%, p = 0.003, q = 0.02) were more frequently altered in the GC group. The GEJC group also had a higher frequency of alterations in the cell cycle pathway compared to the GC patients (36.3% vs. 11.7%, p < 0.001, q < 0.001). Conclusions: There are distinct differences in genomic profiles between GEJC and GC with a higher frequency of mutations in TP53, CDKN2A, MDM2, and cell cycle pathway in the GEJC patients, that may have potential implications in evaluating optimal treatment strategies with targeted therapy.

155 Background: Understanding the role of the tumor microenvironment in the response to chemotherapy and radiation in patients with locally advanced rectal cancer (LARC, stage II-III) can lead to the identification of novel immunologic biomarkers to preselect patients who can avoid surgery and benefit from watch-and-wait strategies. Methods: We performed DNA and RNA sequencing of pre-treatment biopsies from 89 LARC patients who received neoadjuvant therapy, including 5 microsatellite unstable (MSI) and 84 microsatellite stable (MSS) patients. We computed single-sample gene set enrichment analysis (ssGSEA) scores for immune infiltrates and signaling pathways implicated in tumor progression. Immunofluorescence and hematoxylin-eosin staining of tumor slides was performed to confirm significant correlations with RNA-Seq estimates of immune markers. Other genomic variables were also included in the analysis, such as tumor mutational burden (TMB), fraction of genome altered by copy number changes, whole genome duplication events and somatic mutations in rectal cancer driver genes and pathways. Results were largely replicated using an independent cohort of 42 LARC samples with publicly available data from The Cancer Genome Atlas (TCGA). Results: Since MSI tumors are known to have a distinct immunologic profile, we separated them into their own group and performed unsupervised hierarchical clustering on the MSS tumors. We identified a set of immune hot MSS tumors (n = 7) with extensive immune infiltration. These tumors had low TMB and were predominantly classified as CMS4 (5/7). None of the 12 patients in the combined MSI and immune hot MSS groups recurred during the length of our study and they had response rates > 50% (vs. < 25% in the rest of MSS patients). MSI and immune hot MSS tumors had lower frequency of TP53 and APC mutations, and they exhibited increased levels of T cell infiltration. In particular, we observed overexpression of markers for Th1 cells, which produce inflammatory cytokines (e.g., IFN-gamma) and are associated with antitumor immunity. Genes encoding protein targets of immune checkpoint blockade, such as PDCD1 (PD-1), CD274 (PD-L1), CTLA4, HAVCR2 (TIM3) and LAG3, were also overexpressed in the immune hot MSS and - to a lesser extent – the MSI tumors, suggesting that these patients might benefit from the use of immune checkpoint inhibitors. Conclusions: Our results uncover a unique LARC tumor immune profile evident in the pre-treatment setting that could be used to better prognosticate rectal cancer patients and develop novel therapeutic strategies.

In-hospital ischemic stroke following acute ST-elevation myocardial infarction (STEMI) has not been evaluated on a national scale in the United States and was the focus of this investigation. We used the 2003 to 2014 Nationwide Inpatient Sample database to identify adults ≥ 18 years old with a

Introduction In CHF patients, medical therapy optimization (MTO) remains the mainstay of management. However, attaining MTO can be challenging in patients with advanced CHF due to their symptomatic and hemodynamic intolerance. We present a case of a patient with advanced CHF and rectal cancer in whom slowly cautious MTO succeeded in improving cardiac function and candidacy for cancer chemotherapy and surgery. Case A 57-year-old male with a medical history of advanced nonischemic CHF (EF 10-15%), a-fib, and rectal well-differentiated adenocarcinoma stage IIA (diagnosed 1 month ago) with GI bleeding and defecation pain presented with dyspnea on minimal exertion and orthopnea. He also had dizziness with standing due to symptomatic hypotension. SBP was between 100-115 mmHg. MRI pelvis showed T3 rectal mass with no enlargement of lymph nodes. Further imaging showed no distant metastases. Due to his advanced CHF, the patient was considered at high risk for surgery or chemotherapy. Rectal palliative radiation therapy was performed. He agreed on hospice palliative care for symptomatic relief. From Cardiology stand of point, the decision was made to continue MTO aiming for myocardial recovery. Radical adjustment of regimen and initiation of medications at miniscule doses eventually led to myocardial recovery with EF of 51% (figure 1). Patient's SOB and dizziness improved. Cancer progressed to stage IIIb. Due to his improvement, the patient became at lower cardiac risk for other cancer therapy options. As a result, Oncology plan changed to proceed with FOLFOX (5-FU/ Leucovorin/ Oxaliplatin) chemotherapy and surgery. Discussion In our patient, advanced therapy with left ventricular assist device was not possible given his risk of worsening GI bleeding on anticoagulation. Heart transplantation was not an option given the risk of cancer progression on immunosuppressive therapy. In the context of the patient's condition and comorbidities, the best option left was to proceed with cautious MTO with clinical and hemodynamic monitoring. MTO resulted in clinical and cardiac function improvement. This gave the patient the window to become a candidate for other cancer therapy options that were not available for him before. Conclusion Medical therapy optimization in all patients with CHF should always be sought. Despite being challenging under certain circumstances, as seen in our patient, slow and cautious MTO can eventually result in significant improvement in clinical status, cardiac function, and candidacy for other therapy options for other comorbidities.

Superior vena cava (SVC) syndrome is a group of symptoms that result from mechanical obstruction in the superior vena cava. It can result from multiple catheterizations of the venous system or a complication of heart transplant surgery. A 59-year-old male with a history of non-ischemic

Introduction Heart transplant patients are at high risk of organ rejection and require close monitoring with frequent endomyocardial biopsies (EMB), especially during their first post-transplant year. We encountered a hypercellular, atypical endocardial lesion composed of enlarged, pleomorphic cells in a 54-year-old male heart transplant recipient 7.5 months post-transplantation. Our initial impression was post-transplant lymphoproliferative disorder or malignancy. We later identified two additional cases with similar histopathologic findings and hypothesized that these were actually reactive changes or so called epithelial-mesenchymal transition (EMT). EMTs have not been previously reported in EMB from heart transplant recipients and we identified 3 cases in less than a one year time period. Methods For these 3 cases, we further evaluated their clinical history and analyzed the EMB with additional immunostains (CD3, CD68, CD20, PAX-5, Kappa, Lambda, WT1, CK AE1/3, CD34, adenovirus, and EBV) to determine the etiology of the lesions. Right heart EMB are conducted at our institution weekly for the first 8 weeks and then every 3 months thereafter. Results All 3 patients had undergone orthotopic heart transplant replacement 2-7 months prior to having the EMB in which the lesions were observed and received similar induction and immune suppression regimens (MMF and tacrolimus). The IHC stains showed that the atypical-appearing cells were forming a new layer on the endocardial surface and were transitioning from epithelial-like (AE1/3+) to mesenchymal-like (CD34+), and were thus undergoing EMT. Underlying this reactive process was mixed inflammation including macrophages and scattered aggregates of CD3+ T cells; there was no evidence of a lymphoproliferative disorder and EBV was negative. All 3 patients had similar EM findings. Their subsequent biopsies showed similar lesions, although slightly less cellular, with increased fibrosis. Graft function remained normal in all patients. Conclusion The presence of atypical appearing cells on EMB can raise suspicion for rejection or post-transplant lymphoproliferative disorder; however, this appears to often be a reparative process, namely EMT. Similar to reports in kidney transplant patients on tacrolimus, EMT does not seem to play a role in the development of allograft rejection. Due to our small sample size, further investigation is needed.

Infarct healing is dependent on an inflammatory reaction that results in leukocyte infiltration and clearance of the wound from dead cells and matrix debris. However, optimal infarct healing requires timely activation of “stop signals” that suppress inflammatory mediator synthesis and mediate resolution of the inflammatory infiltrate, promoting formation of a scar. A growing body of evidence suggests that interactions involving the transmembrane receptor CD44 may play an important role in resolution of inflammation and migration of fibroblasts in injured tissues. We examined the role of CD44 signaling in infarct healing and cardiac remodeling using a mouse model of reperfused infarction. CD44 expression was markedly induced in the infarcted myocardium and was localized on infiltrating leukocytes, wound myofibroblasts, and vascular cells. In comparison with wild-type mice, CD44−/− animals showed enhanced and prolonged neutrophil and macrophage infiltration and increased expression of proinflammatory cytokines following myocardial infarction. In CD44null infarcts, the enhanced inflammatory phase was followed by decreased fibroblast infiltration, reduced collagen deposition, and diminished proliferative activity. Isolated CD44null cardiac fibroblasts had reduced proliferation upon stimulation with serum and decreased collagen synthesis in response to TGF-β in comparison to wild-type fibroblasts. The healing defects in CD44−/− mice were associated with enhanced dilative remodeling of the infarcted ventricle, without affecting the size of the infarct. Our findings suggest that CD44-mediated interactions are critically involved in infarct healing. CD44 signaling is important for resolution of the postinfarction inflammatory reaction and regulates fibroblast function.

The present study demonstrates the effects of the water-soluble fraction (WSF) of a crude oil, enhanced ultraviolet-B radiation (UVBR: 280 to 320 nm), and the combination of WSF and en- hanced UVBR on a natural plankton assemblage (

In July 1996, bacterial abundance and incorporation of [3H]thymidine (3H-TdR) were determined every 4 h during a mesocosm experiment initially designed to study the effects of different intensities of ultraviolet-B (UVB) radiation on the summer planktonic community of the lower St. Lawrence Estuary. Water was obtained from the quay of the Maurice Lamontagne Institute (Mont-joli, Qué.) and incubated in experimental mesocosms (1500 L total volume, n = 8) with continuous mixing provided by a pumping system. During 72 h, different UVB intensities showed no significant effects on the bacterial incorporation of3H-TdR. This indicates that in the presence of other trophic levels and with continuous mixing, bacterioplankton responses to UVB are substantially different from those reported in axenic bacterial cultures or even whole-water incubations exposed to UVB at fixed depths. In conjunction with this observation,3H-TdR incorporation exhibited a significant periodic variation within all experimental treatments. The periodicity consisted of a 16-h cycle occurring independently of the time of the day. When the3H-TdR incorporation was normalized to cell abundance, the resulting cell-specific thymidine incorporation exhibited the same periodic oscillatory pattern. On the other hand, other factors suspected of inducing such a variability showed no consistent oscillation. In addition to suggesting an endogenously controlled activity of the studied bacterial community, the results of the present study indicate that failure of taking temporal variations of bacterial activity into account may introduce an error of almost 50% in the estimation of the daily thymidine incorporation rates. This represents a considerable error, because several studies rely on this measurement to estimate bacterial carbon production and to establish carbon budgets within different oceanic provinces.Key words: bacterioplankton, [3H]thymidine, ultraviolet-B radiation, periodicity, endogenous cycles, St. Lawrence Estuary.

The proinflammatory cytokine interleukin (IL)-1 signals exclusively through the type I IL-1 receptor (IL-1RI). IL-1 expression is markedly induced in the infarcted heart; however, its role in cardiac injury and repair remains controversial. We examined the effects of disrupted IL-1 signaling on infarct healing and cardiac remodeling using IL-1RI(-/-) mice. After reperfused infarction IL-1RI-null mice exhibited decreased infiltration of the infarcted myocardium with neutrophils and macrophages and reduced chemokine and cytokine expression. In the absence of IL-1 signaling, suppressed inflammation was followed by an attenuated fibrotic response. Infarcted IL-1RI(-/-) mice had decreased myofibroblast infiltration and reduced collagen deposition in the infarcted and remodeling myocardium. IL-1RI deficiency protected against the development of adverse remodeling; however, infarct size was comparable between groups suggesting that the beneficial effects of IL-1RI gene disruption were not attributable to decreased cardiomyocyte injury. Reduced chamber dilation in IL-1RI-null animals was associated with decreased collagen deposition and attenuated matrix metalloproteinase (MMP)-2 and MMP-3 expression in the peri-infarct area, suggesting decreased fibrotic remodeling of the noninfarcted heart. IL-1beta stimulated MMP mRNA synthesis in wild-type, but not in IL-1RI-null cardiac fibroblasts. In conclusion, IL-1 signaling is essential for activation of inflammatory and fibrogenic pathways in the healing infarct, playing an important role in the pathogenesis of remodeling after infarction. Thus, interventional therapeutics targeting the IL-1 system may have great benefits in myocardial infarction.

The five current members of the thrombospondin (TSP) family can be divided in two subgroups according to their molecular architecture. TSP-1 and -2 (subgroup A) are trimeric matricellular proteins that do not contribute directly to tissue integrity, but influence cell function by modulating cell-matrix interactions, whereas TSP-3, -4 and -5 (subgroup B) are pentameric proteins. TSP-1 and TSP-2 are markedly induced in healing wounds and may regulate cellular responses important for tissue repair. TSP-1 is a crucial activator of TGF-beta, whereas both TSP-1 and TSP-2 inhibit angiogenesis. This manuscript reviews our current knowledge on the expression and role of the TSPs in healing myocardial infarcts. In both canine and murine infarcts, TSP-1 shows a strikingly selective localization in the infarct border zone. In the absence of injury, TSP-1 -/- mice exhibit normal cardiac morphology and show no evidence of myocardial inflammation. Infarcted TSP-1 -/- mice have an enhanced and protracted inflammatory response with subsequent expansion of granulation tissue in the non-infarcted area, resulting in myofibroblast infiltration into the viable myocardium neighboring the infarct. Infarcted TSP-1 -/- animals have enhanced left ventricular remodeling compared with their wildtype littermates. We suggest that TSP-1 is a critical component of the protective mechanisms induced in the infarct border zone in order to limit expansion of fibrosis into the non-infarcted myocardium. Localized TSP-1 expression may suppress expansion of the inflammatory process by activating TGF-beta or by inhibiting local angiogenesis. In addition, TSP-1-mediated inhibition of MMP activity may decrease adverse remodeling. TSP-2, on the other hand, appears to be a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading. The expression and potential role of the pentameric TSPs in the infarcted heart remain unknown. Understanding the specific mechanisms responsible for the protective effects of TSP-1 and TSP-2 in healing infarcts may lead to novel therapeutic interventions aiming at attenuating adverse left ventricular remodeling.

The impact of UV-B radiation (UVBR; 280-320 nm) on lower levels of a natural plankton assemblage (bacteria, phytoplankton and microzooplankton) from the St. Lawrence Estuary was studied during 9 days using several immersed outdoor mesocosms. Two exposure treatments were used in triplicate mesocosms: natural UVBR (N treatment, considered as the control treatment) and lamp-enhanced UVBR (H treatment, simulating 60% depletion of the ozone layer). A phytoplankton bloom developed after day 3, but no significant differences were found between treatments during the entire experiment for phytoplankton biomass (chlorophyll a and cell carbon) nor for phytoplankton cell abundances from flow cytometry and optical microscopy of three phytoplankton size classes (picoplankton, nanoplankton and microplankton). In contrast, bacterial abundances showed significantly higher values in the H treatment, attributed to a decrease in predation pressure due to a dramatic reduction in ciliate biomass (approximately 70-80%) in the H treatment relative to the N treatment. The most abundant ciliate species were Strombidinium sp., Prorodon ovum and Tintinnopsis sp.; all showed significantly lower abundances under the H treatment. P. ovum was the less-affected species (50% reduction in the H treatment compared with that of the N control), contrasting with approximately 90% for the other ones. Total specific phytoplanktonic and bacterial production were not affected by enhanced UVBR. However, both the ratio of primary to bacterial biomass and production decreased markedly under the H treatment. In contrast, the ratio of phytoplankton to bacterial plus ciliate carbon biomass showed an opposite trend than the previous results, with higher values in the H treatment at the end of the experiment. These results are explained by the changes in the ciliate biomass and suggest that UVBR can alter the structure of the lower levels of the planktonic community by selectively affecting key species. On the other hand, linearity between particulate organic carbon (POC) and estimated planktonic carbon was lost during the postbloom period in both treatments. On the basis of previous studies, our results can be attributed to the aggregation of carbon released by cells to the water column in the form of transparent exopolymer particles (TEPs) under nutrient limiting conditions. Unexpectedly, POC during such a period was higher in the H treatment than in controls. We hypothesize a decrease in the ingestion of TEPs by ciliates, in coincidence with increased DOC release by phytoplankton cells under enhanced UVBR. The consequences of such results for the carbon cycle in the ocean are discussed.

Objectives This study sought to examine the role of platelet-derived growth factor (PDGF) signaling in healing myocardial infarcts. Background Platelet-derived growth factor isoforms exert potent fibrogenic effects through interactions with PDGF receptor (PDGFR)-α and PDGFR-β. In addition, PDGFR-β signaling mediates coating of developing vessels with mural cells, leading to the formation of a mature vasculature. We hypothesized that PDGFR activation may regulate fibrosis and vascular maturation in healing myocardial infarcts. Methods Mice undergoing reperfused infarction protocols were injected daily with a neutralizing anti–PDGFR-β antibody (APB5), an anti-PDGFR-α antibody (APA5), or control immunoglobulin G, and were killed after 7 days of reperfusion. Results The PDGF-B, PDGFR-α, and PDGFR-β mRNA expression was induced in reperfused mouse infarcts. Perivascular cells expressing phosphorylated PDGFR-β were identified in the infarct after 7 days of reperfusion, indicating activation of the PDGF-BB/PDGFR-β pathway. The PDGFR-β blockade resulted in impaired maturation of the infarct vasculature, enhanced capillary density, and formation of dilated uncoated vessels. Defective vascular maturation in antibody-treated mice was associated with increased and prolonged extravasation of red blood cells and monocyte/macrophages, suggesting increased permeability. These defects resulted in decreased collagen content in the healing infarct. In contrast, PDGFR-α inhibition did not affect vascular maturation, but significantly decreased collagen deposition in the infarct. Conclusions Platelet-derived growth factor signaling critically regulates postinfarction repair. Both PDGFR-β– and PDGFR-α–mediated pathways promote collagen deposition in the infarct. Activation of PDGF-B/PDGFR-β is also involved in recruitment of mural cells by neovessels, regulating maturation of the infarct vasculature. Acquisition of a mural coat and maturation of the vasculature promotes resolution of inflammation and stabilization of the scar.

Mortality due to coronary artery disease is known to increase progressively with age. Older age was associated with a higher risk of in-hospital and post-discharge mortality in the GISSI-2 (Gruppo Italiano per lo Studio della Sopravivenza nell’Infarcto Miocardico 2) trial (1) and was a predictor of death and left ventricular dilation in patients with acute myocardial infarction (MI) enrolled in the SAVE (Survival and Ventricular Enlargement) trial (2). The exponential age-related increase in infarction-related mortality rates was not explained by larger infarcts (1). Although both clinical and experimental studies have demonstrated the adverse effects of senescence on cardiac function and remodeling after MI (2,3), the mechanisms responsible for these effects remain poorly understood. Post-infarction remodeling is closely intertwined with an inflammatory reaction that ultimately results in fibrous tissue deposition and formation of a scar. Inflammatory mediators regulate key cellular interactions in the infarct, modulating deposition and metabolism of extracellular matrix proteins in the wound. These actions have profound effects on the reparative response and ultimately determine the geometric characteristics of the infarcted ventricle by affecting the tensile strength of the scar (4–6). Both clinical studies and experimental investigations demonstrated aging-associated defects in inflammation and tissue repair. Cutaneous wounds heal more slowly in elderly patients as compared with younger patients (7,8) and show diminished expression of endothelial adhesion molecules (9). Furthermore, healing wounds in aged animals demonstrate a defective response to exogenously administered growth factors (10). We hypothesized that aging-associated alterations in inflammatory mediator expression and impaired responsiveness of senescent cells to growth factors might be important mechanisms responsible for defective infarct healing and adverse remodeling in elderly patients. With a mouse model of reperfused infarction, we compared the inflammatory and fibrotic response between young and old animals. Aging was associated with an attenuated post-infarction inflammatory response, delayed phagocytosis of dead cardiomyocytes, and markedly decreased collagen deposition in the infarct. These defects resulted in increased ventricular dilation and hypertrophy. Fibroblasts isolated from senescent animals exhibited a blunted response to transforming growth factor (TGF)-β stimulation, suggesting that impaired responsiveness to growth factors might mediate defective healing in senescent mouse infarcts.

The effects of ultraviolet-B radiation (UVBR) on the bacterivory of a natural marine protozoan community were examined as part of a 7 d experiment designed to study the effects of different UVBR intensities on the summer planktonic assemblage of the lower St. Lawrence Estuary. Quebec, Canada. The experiment was conducted in large containers (mesocosms) subjected to 1 of the following UVBR regimes: excluded UVBR (WWB), natural UVBR (NUVB), and natural UVBR enhanced with either 2 lamps (LUVB) or 3 lamps (HUVB). Incubations with fluorescently labeled bacteria were conducted daily as a tool to understand the interaction between the potential bacterivores (heterotrophic ciliates and nanoflagellates) and bacteria within the studied system. UVBR intensities had no significant effects on the estimated clearance and ingestion rates (CR and IR, respectively) until Day 5 of the experiment. During the following 2 d, characterized by low nutrient concentration, both CR and IR decreased with the increase of the daily UVBR (at 305 and 320 nm) doses received. The maximum difference between treatments was observed on Day 7, where both clearance and ingestion rate values in the NUVB, LUVB and HUVB treatments were significantly lower than the WUVB treatment. Our data suggest that over a 1 d period and under conditions of high nutrient concentrations, protozoan bacterivory is not affected by W B R increases. When nutrient concentrations become low, bacterivores become more susceptible to damaging UVBR effects. We think that the deterioration of food quality, itself resulting from the synergistic action of nutrients and UVBR stresses, is responsible for the increased sensitivity of bacterivores to UVBR. UVBR-induced decreases in bacterivory would represent a considerable loss to the higher tropic levels that feed upon bacterivores.

With the continuing increase of ultraviolet-B radiation (UVBR: 280-320 nm) fluxes toward the Earth's surface, there is concern regarding a possible negative impact on heterotrophic bacterioplankton. The effects of enhanced UVBR on a natural bacterioplankton community were studied during a 7-day experiment conducted in mesocosms (1500 L). Four light regimes were tested: natural light, 280 to 313 nm excluded UVBR, and two levels of UVBR enhancement. During the first 3 days of the experiment characterized by high inorganic nutrient concentrations (nitrates > 1 µmol L-1 and ammonium > 0.1 µmol L-l), UVBR had no effect on both bacterial abundances and activities. From day 4 to the end of the experiment, nitrate concentrations remained low (