PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.

Heart transplantation in end-stage heart failure secondary to cardiac sarcoidosis: an updated systematic review.

The prevalence of cardiac sarcoidosis is increasing with improved cardiac imaging and may lead to severe heart failure, cardiomyopathy, and arrhythmias that warrant heart transplant consideration. This study aimed to evaluate the outcomes of heart transplantation in sarcoidosis. We systematically searched PubMed/MEDLINE, EMBASE and Cochrane Library following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. We identified 15 articles that examined patients with cardiac sarcoidosis. The study aimed to evaluate the outcomes of heart transplantation in cardiac sarcoidosis. We systematically searched EMBASE, PubMed/MEDLINE, and Cochrane Library following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We identified 15 studies that examined 1075 patients with cardiac sarcoidosis who underwent heart transplantation. A total of five studies reported individual patient data. Forty-two patients have been pooled for further analysis. There were 22 male patients, 14 female patients, and 7 patients whose gender was not reported. Among these patients, 10 patients had concomitant pulmonary sarcoidosis at the time of diagnosis. The mean survival was reported for all 42 patients. The mean survival in months was 71.4 months, with a range of 2 days to 288 months. Three patients died of graft failure, 2 patients from septic shock, 2 patients from pneumonia, 1 patient from cervical cancer, and 1 patient from sudden cardiac death. One patient developed a malignant arrythmia in the setting of CMV myocarditis post-heart transplant. Sarcoidosis recurrence after heart transplant was reported in 3 of 30 patients..Patients with cardiac sarcoidosis have shown to have favorable outcomes after heart transplant. Despite these outcomes, some centers still hesitate to pursue heart transplant for CS patients. Carefully selected patients with advanced-stage heart failure due to cardiac sarcoidosis have encouraging outcomes after transplantation. Further studies will be needed to evaluate the outcomes of heart transplantation in sarcoidosis.

A Cavitary Lesion in a Patient with Antineutrophilic Cytoplasmic Antibody (ANCA) Associated Vasculitis: A Case Report and Review of the Literature.

Patients with antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis who were on immunosuppressive therapy with corticosteroids may be susceptible to cavitary lesions.1 Only a few cases have been reported in the literature to date. Immunosuppression was shown to improve prognosis in patients with vasculitis. However, adverse therapy events and the risk of opportunistic infections become a major cause of morbidity and mortality in this specific patient population. We present a case of a 75-year-old female who was diagnosed and treated in our hospital for ANCA-associated vasculitis and returned within a few weeks of medical therapy and was found to have developed cavitation concerning for worsening vasculitis or an opportunistic fungal infection or combination of both. Given the risk of severe complications from opportunistic fungal infections, close monitoring and prophylactic antifungal therapy should be considered. Further studies are needed to evaluate the benefit of prophylaxis in this patient population.

Outcomes of heart transplantation in cardiac amyloidosis: an updated systematic review.

Cardiac amyloidosis is one of the most common infiltrative cardiomyopathies that is characterized by the extracellular deposition of misfolded fibrillar protein. Several studies have previously found that patients with amyloid in the past have performed poorly after heart transplantation. Recent advancements in treatments have been made that have significantly improved outcomes in these patients. The study aimed to evaluate the outcomes of heart transplantation in cardiac amyloidosis. We systematically searched EMBASE, PubMed/MEDLINE, and Cochrane Library databases on 30 December 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We identified 22 studies that examined 42,951 patients with cardiac amyloidosis of which only 1,329 patients underwent isolated heart transplantation. Seven studies reported individual patient data. The results of 123 patients have been pooled for analysis. There were 70 male patients, 45 female patients, and eight patients who did not report their gender. Among the types of amyloids, 63 (51%) patients were found to have light chain amyloidosis (AL) and 33 (27%) patients had transthyretin amyloidosis (ATTR). Only 41 patients (33.3%) reported a monoclonal component. There were 30 patients with AL that underwent autologous hematopoietic stem cell transplant (ASCT). The mean survival of 24 out of 30 patients was 4.33 years. In addition, the reported data include 13 patients requiring intra-aortic balloon pump (IABP), six with cardiac resynchronization therapy (CRT), and four with implantable cardioverter defibrillator (ICD). With the current advancements in treatments in combination with a multidisciplinary approach and careful patient selection, patients undergoing heart transplantation for amyloidosis may have encouraging results in the current era. Further studies will be needed to evaluate the outcomes of heart transplantation in amyloidosis patients now that several advances have been made in the field.

Full decongestion in acute heart failure therapy.

Incomplete decongestion is the main cause of readmission in the early post-discharge period of a hospitalization for acute heart failure. Recent heart failure guidelines have highlighted initiation and rapid up-titration of quadruple therapy with angiotensin receptor neprilysin inhibitor, beta adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor to prevent hospitalizations for heart failure with reduced ejection fraction. However, full decongestion remains the foremost therapeutic goal of hospitalization for heart failure. While early addition of sodium glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists may be helpful, the value of the other therapeutics comes after decongestion is complete.

Meta-Analysis Comparing Outcomes of Remote Hemodynamic Assessment Versus Standard Care in Patients With Heart Failure.

In patients with congestive heart failure (CHF), remote hemodynamic monitoring can reduce heart failure exacerbation and mortality. In this study, we compared the effectiveness of remote hemodynamic monitoring with that of standard care in the management of patients with CHF. The remote monitoring group included 7,733 patients, and the control group included 7,567 patients. Chi-square test and I-square statistics were used to assess heterogeneity. Risk ratios (RRs) were calculated using fixed-effects and random-effects methods to determine the risk of all-cause hospitalization and CHF-related hospitalization (primary outcomes) and all-cause mortality and device outcomes (secondary outcomes). Pooled findings indicated a 7% lower risk of all-cause hospitalization in the remote monitoring group than that in the control group (RR 0.93, 95% confidence interval [CI] 0.89 to 0.98, p = 0.004). The results also revealed a 32% lower risk of CHF-related hospitalization in the remote monitoring group than that in the control group (RR 0.68, 95% CI 0.65 to 0.71, p <0.001). No statistically significant differences were noted between the groups in terms of all-cause mortality (RR 0.97, 95% CI 0.87 to 1.07, p = 0.53) and device outcomes (RR 1.23 95% CI 0.92 to 1.65, p = 0.16). These results provided evidence regarding the comparable effectiveness of remote CHF monitoring and routine care. The current evidence is insufficient to introduce remote hemodynamic CHF monitoring; however, our results suggest that the integration of telemonitoring systems with routine medical management may improve heart failure care.

Cabozantinib-Induced Severe Cardiac Dysfunction: A Case Report and a Systematic Review of the Literature.

Cabozantinib is a novel multitargeted receptor tyrosine kinase inhibitor commonly used to treat advanced renal cell carcinoma. Cardiotoxicity is not a previously well-described adverse effect of cabozantinib. We present a rare case of a 74-year-old male with a history of renal cell carcinoma who underwent partial nephrectomy. The patient had been recently started on cabozantinib for advanced metastatic renal cell carcinoma. He developed acute onset of heart failure and subclinical hypothyroidism within nine months of treatment. Our case report postulates a causal relationship between cabozantinib and the development of non-ischemic cardiomyopathy.

Outcomes With Left Ventricular Assist Device in End-Stage Renal Disease: A Systematic Review.

Renal dysfunction is a common comorbidity in patients with advanced heart failure who may benefit from mechanical circulatory support (MCS). Unfortunately, renal function may result after left ventricular assist device (LVAD) implantation. The purpose of this study is to examine the outcomes of advanced heart failure patients with end-stage renal disease (ESRD) requiring mechanical circulatory support as a bridge to transplant (BTT) or destination therapy (DT). We searched Medline, Embase, and Cochrane in September 2021. The following keywords were used: left ventricular assist device or LVAD and end-stage renal disease or ESRD. Our study included case reports, case series, descriptive studies, and randomized control trials. Review articles, guidelines, systematic reviews, and meta-analyses were excluded. We also excluded pediatric cases. We identified 278 articles; 92 were duplicated, 186 articles entered the screening phase, and 133 articles were excluded by title and abstract. After the full-text screening, 40 articles were excluded. This systematic review included 13 articles. Among the contraindications to LVAD implantation, a general contraindication is for patients found to have stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR): <30 mL/minute/1.73 m2), while those on dialysis are an absolute contraindication LVAD implantation. Despite the limited data and publications on LVADs in patients with ESRD, LVAD implantation as a bridge to transplantation or destination therapy may be considered in selected patients without increasing morbidity and mortality. Therefore, shared decision-making around the treatment of advanced heart failure with these patients and the care team is essential.

New onset hypertension after transplantation.

It has been reported that up to 90% of organ transplant recipients have suboptimal blood pressure control. Uncontrolled hypertension is a well-known culprit of cardiovascular and overall morbidity and mortality. In addition, rigorous control of hypertension after organ transplantation is a crucial factor in prolonging graft survival. Nevertheless, hypertension after organ transplantation encompasses a broader range of causes than those identified in non-organ transplant patients. Hence, specific management awareness of those factors is mandated. An in-depth understanding of hypertension after organ transplantation remains a debatable issue that necessitates further clarification. This article provides a comprehensive review of the prevalence, risk factors, etiology, complications, prevention, and management of hypertension after organ transplantation.

BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.

Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44-CD40- B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.

The Appearance of an Underrecognized Congenital Heart Disease in a Patient With COVID-19 Pneumonia.

A 60-year-old woman presented to the emergency department with worsening shortness of breath and non-productive cough for 1 week, which was preceding a recent COVID-19 infection. At the time the patient thought this was part of the constellation of symptoms of COVID-19, so she stayed home until her symptoms worsened to the point of needing hospitalization. The patient was found to have a rare and complex congenital heart disease that led her to develop acute heart failure precipitated by COVID-19 pneumonia. Medical management and surgical repair were essential in this patient given the late presentation.

Thrombocytopenia Secondary to Herpes Simplex Virus-2 Infection Successfully Treated by Acyclovir.

Thrombocytopenia is a common clinical condition associated with a wide variety of clinical conditions including infections, malignancy, medications, liver disorder, and autoimmune conditions, etc. The association between thrombocytopenia and herpes simplex virus (HSV) is reported only once in a case report dating back to 1978. We report a case of a 66-year-old female with generalized weakness, mechanical fall, genital ulcerations, and breast fold and genital area skin redness, warmth, and mild tenderness. Initial labs showed mild leukocytosis, normal platelet count, mild lactic acidosis, and urine analysis suggestive of urinary tract infection. The patient was started on broad-spectrum antibiotics. During the course of hospitalization, the patient developed severe thrombocytopenia with platelet counts dropping less than 40000/µL (normal range: 150,000-450,000/µL), and genital pain and ulceration worsened. The genital swab was sent which came back positive for the HSV-2 virus. Soon after the start of acyclovir for HSV-2 infection, the genital pain and ulceration improved and platelet counts gradually increased to 157,000/µL. Other causes of thrombocytopenia such as sepsis, heparin-induced thrombocytopenia, consumptive coagulopathy, medication-induced thrombocytopenia, immune thrombocytopenia, and thrombotic thrombocytopenic purpura were ruled out.

Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma.

The drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-ß, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103- DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.