Immune Checkpoint Inhibitor-Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases.

BACKGROUND: The development of immune checkpoint inhibitors (ICIs) represents a paradigm shift in the treatment of cancers. Despite showing remarkable efficacy, these agents can be associated with life-threatening immune-related adverse events. In recent years, several cases of myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS) have been reported. However, given the rarity, the clinical features and outcomes of these cases remain poorly understood. We, therefore, attempted to systematically review and summarize all cases of IM3OS reported in the literature. MATERIALS AND METHODS: Studies reporting IM3OS were identified in Embase and MEDLINE. Only case reports and case series published in journals or presented at conferences were included. We conducted a systematic review according to the PRISMA Harms guidelines. RESULTS: A total of 60 cases were eligible. The patients' median age was 71 years, and the majority (67%) were males; melanoma was the most common indication for ICIs (38%). The most-reported symptoms were fatigue (80%) and muscle weakness (78%). The median number of doses to the development of IM3OS was one. The average creatine kinase level was 9,645 IU/L. Cardiac arrhythmias occurred in 67% of patients, and 18% had depressed ejection fraction. Initial treatment consisted of immunosuppression with high-dose steroids and supportive therapies. Sixty percent of the patients died in hospital because of acute complications. CONCLUSION: IM3OS can be associated with significant mortality and morbidity. Prospective studies are needed to understand the optimal approach to diagnose and manage these patients and to develop biomarkers to predict the occurrence and severity of this rare but serious condition. IMPLICATIONS FOR PRACTICE: Clinicians should suspect coexisting myositis and/or myasthenia gravis in all patients with immune checkpoint inhibitor-induced myocarditis, given their propensity to occur together. Early recognition and prompt treatment with the help of a multidisciplinary team might help improve the outcomes of this life-threatening condition.

Venous Thromboembolism in COVID-19: Towards an Ideal Approach to Thromboprophylaxis, Screening, and Treatment.

PURPOSE OF REVIEW: Novel coronavirus disease 2019 (COVID-19) has been associated with an increased risk of arterial and venous thromboembolic (VTE) diseases. However, there is a limited amount of data regarding the prevention and management of VTE in severe hospitalized COVID-19 patients. RECENT FINDINGS: In this article, we review currently available clinical data, and mechanisms for COVID-associated coagulopathy, and propose algorithms for screening, prevention (including extended-duration prophylaxis), and treatment of these patients. Although these recommendations are subject to change given rapidly evolving data, we provide a framework that can guide clinicians in managing thrombotic complications in this challenging condition.

A Systematic Review of Breast Implant-Associated Squamous Cell Carcinoma.

Breast augmentation is considered safe, but rare cases of breast implant-associated squamous cell carcinoma (BIA-SCC) have been reported. This study aimed to systematically review published cases of BIA-SCC, providing valuable clinical data. The review included 14 articles and 18 cases of BIA-SCC. An increasing trend in reported BIA-SCC cases was observed, with four cases in the 1990s and 14 cases since 2010. The mean age of affected patients was 56 years, and symptoms typically appeared around 21 years after breast augmentation. Silicone implants used in cosmetic procedures were most commonly associated with BIA-SCC. Implant removal was necessary in all cases, and some patients required a mastectomy. Treatment approaches varied, with the selective use of chemotherapy and/or radiotherapy. The estimated 6-month mortality rate was 11.1%, while the 12-month mortality rate was 23.8%. The estimated 6-month mortality rate should be cautiously interpreted due to the limited sample size. It appears lower than the rate reported by the American Society of Plastic Surgeons, without clear reasons for this discrepancy. This study highlights the importance of enhanced monitoring and information sharing to improve detection and management of BIA-SCC. Healthcare providers should maintain vigilance during the long-term follow-up of breast augmentation patients.

Factor XIII Deficiency Associated With Noonan Syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder with multisystem involvement. NS can be associated with bleeding disorders due to defects in platelet function or coagulation factors and diagnosis can be challenging. Factor XIII (FXIII) deficiency is uncommon in patients with NS. We present a case of NS who presented with bleeding in both thighs and was diagnosed to have deficiency in FXIII.

Efficacy and Safety of Direct Oral Anticoagulants in Venous Thromboembolism Compared to Traditional Anticoagulants in Morbidly Obese Patients: A Systematic Review and Meta-Analysis.

Background Randomized clinical trials comparing the efficacy and safety of direct oral anticoagulants (DOAC) with vitamin K antagonist (VKA) or low molecular weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) generally exclude patients who are morbidly obese (body mass index ≥ 40 kg/m2 or weight ≥ 120 kg). Recently, smaller studies have compared DOACs with warfarin or low molecular weight heparin (LMWH) in morbidly obese patients with VTE. We aim to systematically review and do a meta-analysis of the studies that directly compared DOACs with VKAs or LMWH in morbidly obese patients. Methods Studies comparing DOAC with warfarin or LMWH in patients with acute VTE were identified through electronic literature searches of MEDLINE, EMBASE, Scopus, clinicaltrials.gov, and the Cochrane Library up to March 2020. The primary efficacy outcome was recurrent VTE and the primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) guidelines. Study-specific odds ratios (OR) were calculated and combined using a random-effects model meta-analysis. Result Five studies were identified. Recurrent VTE occurred in 95 of 3207 (2.96%) patients in the DOAC group and 81 of 3181 (2.54%) patients in the VKA and LMWH group (OR: 1.17; 95% CI 0.87 to 1.59, p=.30). Major bleeding occurred in 63 of 3316 (1.89%) patients in the DOAC group, and 83 of 3259(2.54%) patients in the VKA or LMWH group (OR: 0.74; 95% CI: 0.53 to 1.03, p=.08). Sensitivity analysis comparing factor Xa inhibitors apixaban and rivaroxaban to warfarin also yielded consistent findings. Conclusion DOACs showed similar efficacy and safety in the prevention of recurrent VTE risk and major bleeding events in morbidly obese patients when compared to warfarin/LMWH. Our study underscores the need for further modifications of therapy to reduce the high VTE recurrence rate irrespective of whether the patient is on a DOAC or VKA. This might be possible through a very large multi-institutional randomized clinical trial.

Pharmacotherapies in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) causes significant cardiovascular morbidity and mortality. It is a growing problem in the developed world, especially, in the aging population. There is a paucity of data on the treatment of patients with HFpEF. We aimed to identify pharmacotherapies that improve peak oxygen consumption (peak VO2), cardiovascular mortality, and HF hospitalizations in patients with HFpEF. METHODS: We conducted a systematic literature search for English studies in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Scopus, and Google scholar. We searched databases using terms relating to or describing HFpEF, stage C HFpEF, and diastolic HF and included only randomized controlled trials (RCTs). RevMan 5.4 (The Cochrane Collaboration, 2020, London, UK) was used for data analysis, and two independent investigators performed literature retrieval and data-extraction. We used PRISMA guidelines to report the outcomes. We included 14 articles in our systematic review and six studies in meta-analysis. RESULTS: We calculated the pooled mean difference (MD) of peak VO2 between placebo and pharmacotherapies. Our meta-analysis showed that the peak VO2 was comparable between pharmacotherapies and placebo in HFpEF (MD = 0.09, 95% CI: -0.11, 0.30, I2 =28%). Our systematic review highlights that statins and spironolactone use should be further studied in larger RCTs due to their potential beneficial effect on all-cause mortality and hospitalizations, respectively. CONCLUSION: Compared to placebo, none of the pharmacotherapies significantly improved peak VO2 in HFpEF except ivabradine. In our meta-analysis, the pooled improvement in peak VO2 is non-significant. This needs validation with larger studies. We are lacking larger studies on pharmacotherapies that improve peak VO2 in HFpEF. Statin and spironolactone should be further studied in patients with HFpEF as few trials have shown improvement in all-cause mortality and reduction in HF hospitalizations in selected patients, respectively.

Effectiveness of intravenous immunoglobulin use in heparin-induced thrombocytopenia.

: Heparin-induced thrombocytopenia (HIT) syndrome is an immune-mediated disorder producing thrombocytopenia and thrombosis, with or without prior exposure to heparin. Although avoidance of heparin products and nonheparin anticoagulants are used, immune-based therapies including intravenous immunoglobulin (IVIg) have been tried when the thrombocytopenia persists or there is breakthrough thrombosis. We sought to systematically review and analyze the published literature on use of IVIg in the treatment of HIT. A systematic search of PubMed, Google Scholar, EMBASE and SCOPUS for all study designs and reports were carried out from inception until April 2019. Statistical analysis was done using Microsoft Excel and Stata version 13. In 34 patients with HIT, the mean age was 60 years. About 70% cases were by unfractionated heparin exposure and 30% by low-molecular weight heparin. The most common precipitant in the patients without heparin exposure was recent surgery. Average nadir platelet count for which IVIg was used was 28 000/µl. Time from resolution of the thrombocytopenia after IVIg treatment was 3 days with average platelet count recovery to 159 000/µl. Mean time from diagnosis to administration of IVIg was day 18. Thrombosis was identified in 32% of patients. About 77% patients improved (platelet count >100 000/µl or cessation of thrombosis) following use of IVIg. Logistic regression did not identify any factors that predicted IVIg response (P > 0.05). No thrombotic events or other adverse events were noted with use of IVIg. IVIg appears to be a safe and effective treatment option for HIT-related thrombocytopenia and for refractory thrombosis.

Systematic review and meta-analysis of the efficacy and safety of apixaban compared to rivaroxaban in acute VTE in the real world.

Both apixaban and rivaroxaban have been approved for use in acute venous thromboembolism (VTE). Although indirect comparison through network meta-analyses of randomized trials have been performed to compare the efficacy and safety of these agents, further comparison between these agents was lacking until recently. We sought to systematically review and carry out a meta-analysis of studies to further compare apixaban with rivaroxaban from multiple studies done in the real-world settings. Studies comparing rivaroxaban with apixaban in patients with acute VTE were identified through electronic literature searches of MEDLINE, EMBASE, Scopus, and the Cochrane library up to May 2019. Study-specific risk ratios (RRs) were calculated and combined using a random-effects model meta-analysis. In an analysis involving 24 041 patients, recurrent VTE within 6 months occurred in 56 of 4897 patients (1.14%) in the apixaban group and 258 of 19 144 patients (1.35%) in the rivaroxaban group (RR, 0.89; 95% confidence interval [CI], 0.67-1.19; P = .45). Clinically relevant major bleeding occurred in 85 of 11 559 patients (0.74%) in the apixaban group and 350 of 33 909 patients (1.03%) in the rivaroxaban group (RR, 0.73; 95% CI, 0.58-0.93; P = .01). Clinically relevant nonmajor bleeding occurred in 169 of 3417 patients (4.95%) in the apixaban group and 1094 of 12 475 patients (8.77%) in the rivaroxaban group (RR, 0.59; 95% CI, 0.50-0.70; P < .01). Apixaban shows equivalent efficacy in prevention of recurrent VTE but decreased risk of major and minor bleeding events compared with rivaroxaban.