Cardiovascular Adverse Events Associated With Second-generation Bruton Tyrosine Kinase Inhibitor Therapy: A Systematic Review and Meta-analysis.

PURPOSE: Cardiovascular adverse events (CVAEs) are common adverse effects of first-generation Bruton tyrosine kinase inhibitors (BTKis) and limit their use considerably. This led to the development of second-generation BTKis-acalabrutinib and zanubrutinib-which are more selective, potent, and presumed to have better safety profiles than the previous group of medications. However, there have been sporadic reports of CVAEs associated with second-generation BTKis in clinical practice. To address this issue, a comprehensive meta-analysis to pool the documented CVAEs was performed, including major hemorrhage, any bleeding, atrioventricular block, atrial fibrillation/flutter, pericardial effusion, pericarditis, heart failure, cardiac arrest, myocardial infarction, hypertension, hypotension, and stroke. This meta-analysis incorporated 8 studies. Among these, 6 were Phase III trials and 2 were Phase II trials. These studies collectively enrolled a total of 2938 patients. METHODS: Multiple databases, including PubMed, MEDLINE, Cochrane Library, Scopus, and EMBASE, were systematically searched for relevant clinical trials from inception through January 14, 2023. The effect measure used was odds ratio (OR) and 95% CI. FINDINGS: Of a total of 1774 studies identified during the initial database search, 8 were included in the meta-analysis. The incidence of overall and cardiovascular mortality was comparable between the 2 groups. There were no significant differences observed for cardiovascular mortality (OR = 0.36; 95% CI, 0.08-1.65; n = 2588; I2 = 45%; P = 0.19). Similar results were found for all-cause mortality (OR = 0.85; 95% CI, 0.67-1.07), any bleeding (OR = 1.90; 95% CI, 0.88-4.09), major bleeding (OR = 1.07; 95% CI, 0.65-1.76), atrioventricular block (OR = 0.74; 95% CI, 0.15-3.68), atrial fibrillation/flutter (OR = 0.74; 95% CI, 0.37-1.50), and other CVAEs associated with second-generation BTKis. IMPLICATIONS: Based on the available evidence, there is no indication of worse cardiovascular outcomes or superiority of second-generation BTKis compared with standard treatments in terms of safety profile. However, additional large-scale controlled trials are needed to provide robust support for the superior tolerability of new-generation BTKis.

Therapy-related Acute Myeloid Leukemia in Non-Hodgkin Lymphoma Survivors: Risk, Survival Outcomes and Prognostic Factor Analysis.

BACKGROUND: Therapy-related acute myeloid leukemia (tAML) is a serious complication in patients with Non-Hodgkin lymphoma (NHL) exposed to chemotherapy or radiation. This extensive database study aims to quantify the risk of tAML in NHL and determine the impact of tAML on the overall survival (OS) of patients with NHL. MATERIALS AND METHODS: Patients diagnosed with NHL and de novo AML from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results database. Multiple primary standardized incidence ratio (SIR) sessions of the SEER*Stat software were used to calculate SIR and the absolute excess risk of tAML. Overall survival (OS) was evaluated using Kaplan-Meier curves and compared using log-rank tests. Multivariate analysis was used to study the role of each covariate on OS in patients with tAML. RESULTS: The SIR of tAML was 4.89 (95% CI 4.41-5.41), with a higher incidence of tAML observed for age <60 years, NHL prior to 2013 and within 5 years of diagnosis, and those who received chemotherapy. NHL patients with tAML had lower OS than those without tAML (5-year OS 59% vs. 13%, p < 0.001). Patients with tAML showed worse OS than de novo AML in univariate analysis (5-year OS 13% vs. 25%, p = 0.001) but not in multivariate analysis (HR 0.93, 95% CI 0.82-1.04, p = 0.21). Age ≥60 years and lack of chemotherapy were associated with poor OS in tAML subcategory. CONCLUSION: Age, time since NHL diagnosis, and receipt of chemotherapy directly influence the risk of development of tAML in NHL survivors.

Clinical outcomes and prognostic factors in triple-negative invasive lobular carcinoma of the breast.

PURPOSE: Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. METHODS: Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. RESULTS: The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (p < 0.001). There was no significant difference in the OS between TN-ILC and TN-IDC in multivariate analysis (HR 0.96, p = 0.44). Black race and higher TNM stage were associated with worse OS, whereas receipt of chemotherapy or radiation was associated with better OS in TN-ILC. Among women with TN-ILC receiving neoadjuvant chemotherapy, the 5-year OS was 77.3% in women with a complete pathological response (pCR) compared to 39.8% in women without any response. The odds of achieving pCR following neoadjuvant chemotherapy were significantly lower in women with TN-ILC compared to TN-IDC (OR 0.53, p < 0.001). CONCLUSION: Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.

Clinical Outcomes and Prognostic Factors in Triple-Negative Invasive Lobular Carcinoma of the Breast.

Purpose: Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. Methods: Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. Results: The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (p<0.001). There was no significant difference in the OS between TN-ILC and TN-IDC in multivariate analysis (HR 0.96, p=0.44). Black race and higher TNM stage were associated with worse OS, whereas receipt of chemotherapy or radiation was associated with better OS in TN-ILC. Among women with TN-ILC receiving neoadjuvant chemotherapy, the 5-year OS was 77.3% in women with a complete pathological response (pCR) compared to 39.8% in women without any response. The odds of achieving pCR following neoadjuvant chemotherapy were significantly lower in women with TN-ILC compared to TN-IDC (OR 0.53, p<0.001). Conclusion: Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.

Electric Cardioversion vs. Pharmacological with or without Electric Cardioversion for Stable New-Onset Atrial Fibrillation: A Systematic Review and Meta-Analysis.

BACKGROUND: There is no clear consensus on the preference for pharmacological cardioversion (PC) in comparison to electric cardioversion (EC) for hemodynamically stable new-onset atrial fibrillation (NOAF) patients presenting to the emergency department (ED). METHODS: A systematic review and meta-analysis was conducted to assess PC (whether being followed by EC or not) vs. EC in achieving cardioversion for hemodynamically stable NOAF patients. PubMed, PubMed Central, Embase, Scopus, and Cochrane databases were searched to include relevant studies until 7 March 2022. The primary outcome was the successful restoration of sinus rhythm, and secondary outcomes included emergency department (ED) revisits with atrial fibrillation (AF), hospital readmission rate, length of hospital stay, and cardioversion-associated adverse events. RESULTS: A total of three randomized controlled trials (RCTs) and one observational study were included. There was no difference in the rates of successful restoration to sinus rhythm (88.66% vs. 85.25%; OR 1.14, 95% CI 0.35-3.71; n = 868). There was no statistical difference across the two groups for ED revisits with AF, readmission rates, length of hospital stay, and cardioversion-associated adverse effects, with the exception of hypotension, whose incidence was lower in the EC group (OR 0.11, 95% CI 0.04-0.27: n = 727). CONCLUSION: This meta-analysis suggests that there is no difference in successful restoration of sinus rhythm with either modality among patients with hemodynamically stable NOAF.

Thrombophilia Testing in Stroke: A Case Report and Review of Evidence.

Thrombophilia is commonly associated with venous thromboembolism, but its relationship with arterial thrombosis, specifically stroke, is not as clearly established. Several large studies have failed to establish a significant connection between inherited thrombophilia and stroke. While tests for Factor V Leiden mutation, prothrombin mutation, protein C deficiency, protein S deficiency, antithrombin deficiency, and antiphospholipid antibodies are typically done for thrombophilia diagnosis, there appears to be little or no correlation between these markers and stroke. In this article, we discuss a case of a 26-year-old male admitted with right neck pain that developed after playing basketball; he was found to have a right cerebellar infarction. He underwent extensive tests for hypercoagulable disorders, which were negative. We also review current evidence and reassess the value of thrombophilia testing in stroke patients.

Risk of second primary malignancy in patients with primary myelofibrosis: a SEER database study.

Prior studies report a greater incidence of second primary malignancy (SPM) among patients with myeloproliferative neoplasms, although the true risk in primary myelofibrosis (PMF) has not been elucidated. We utilized the Surveillance, Epidemiology, and End Results database to evaluate the risk of SPM in PMF patients and analyzed the effects of sociodemographic factors on the risk of SPM. Out of 5273 patients, 385 patients (7.30%) developed SPM. SPM occurred at SIR of 1.95 (95% CI 1.76-2.15) and AER of 149.01 per 10,000 population. A significantly higher incidence of melanoma (SIR 1.76, 95% CI 1.01-2.86), lymphoma (SIR 3.38, 95% CI 2.28-4.83), and leukemia (SIR 27.19, 95% CI 23.09-31.81) was observed. The risk was significantly higher in patients ≤60 years, males, chemotherapy recipients, within 5 years of PMF diagnosis, and for PMF diagnosed after 2009.

Extracorporeal Membrane Oxygenation (ECMO) Dependent Acute Respiratory Distress Syndrome (ARDS): A Systematic Review and Meta-Analysis.

BACKGROUND:  Extracorporeal membrane oxygenation (ECMO) has emerged as a newer method for managing severe acute respiratory distress syndrome (ARDS) and ARDS refractory to conventional management. However, its current role in the management of ARDS is not clear. Therefore, we conducted this meta-analysis to compare the mortality rates of ECMO over conventional management in ARDS. METHODS:  PubMed, PubMed Central, Embase, and Scopus were searched using appropriate keywords. We selected studies in adults with ARDS that compared the outcomes of patients treated with ECMO vs. conventional management. Cochrane Risk of Bias (RoB) 2.0 and the JBI (Joanna Briggs Institute) quality assessment tools were used for assessing the risk of bias in RCTs and observational studies, respectively. The I2 statistic was used to evaluate heterogeneity, and quantitative synthesis was performed using fixed or random effects to pool studies based on heterogeneities. Meta-analysis was conducted using Revman 5.4. RESULT: Twelve studies were included in this meta-analysis. As compared to the conventional management (mechanical ventilation: MV), patients treated with ECMO had lower odds of 30-days mortality (OR, 0.56; 95% CI, 0.37 to 0.84) and 90 days mortality (OR, 0.59; 95% CI, 0.41 to 0.85). However, there was no significant difference between in-hospital mortality (OR, 0.75; 95% CI, 0.40 to 1.41) and intensive care unit (ICU) mortality (OR, 1.00; 95% CI, 0.36 to 2.79). Similarly, length of hospital stays (LOS) (MD, 3.92; 95% CI, -6.26 to 14.11) did not show statistically significant differences across the two groups. However, the average ICU stay (ICU LOS) was 7.28 days longer in the ECMO group compared with the MV group (MD, 7.28; 95% CI, 2.55 to 12.02). CONCLUSION:  Twenty-eight days and 90-days mortality were decreased in patients managed with ECMO compared with the MV group. Also, ICU LOS was found to be longer in the ECMO group. Furthermore, no statistical difference was found between the two groups for in-hospital mortality and hospital LOS.

Vasopressin versus norepinephrine as the first-line vasopressor in septic shock: A systematic review and meta-analysis.

Background and Aim: Norepinephrine is currently the first-line vasopressor for septic shock. We conducted this meta-analysis to examine the outcomes of adult patients with septic shock who received vasopressin instead of norepinephrine. Methods: We selected studies in adults with septic shock that compared the outcomes of patients treated with vasopressin versus norepinephrine. Cochrane ROB 2.0 and the Joanna Briggs Institute quality assessment tools were used to assess the risk of bias in RCTs and observational studies. Meta-analysis was conducted using RevMan 5.4. Results: Eight studies were included in this meta-analysis. There were no significant differences in 28-day mortality rates (OR, 1.07; CI, 0.80-1.44) and intensive care unit (ICU) mortality (OR, 0.74; CI, 0.21-2.67) between the two groups. Similarly, length of ICU stay, length of hospital stay, mean arterial pressure at 24 h, urine output at 24 h, and serious adverse events also did not differ significantly. However, the odds of renal replacement therapy (RRT) requirement in the vasopressin group were substantially lower than in the norepinephrine group (OR, 0.68; CI, 0.47-0.98). Conclusion: There were no differences in mortality, duration of hospitalization, and adverse effects in adults with septic shock across the two groups. However, the patients treated with vasopressin had lower chances of requiring RRT. Relevance for Patients: Vasopressin use as the first-line vasopressor in septic shock showed a significant reduction in RRT, though there were no significant differences in terms of mortality and other adverse events. Therefore, vasopressin can be considered as a first-line vasopressor in septic shock patients with other risk factors which may contribute to renal failure requiring RRT.

POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, and Skin Changes): A Case Report of a Rare Paraneoplastic Syndrome.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome is a multisystem disorder. Peripheral neuropathy and monoclonal plasma cell disorder are the most common manifestations of POEMS. Although osteosclerotic or mixed sclerotic-lytic lesions are typical, osteolytic lesions are rarely encountered. We present a case of a 39-year-old male with a history of multiple endocrine disorders who presented with paresthesia, edema, and hyperpigmentation and was eventually diagnosed with POEMS syndrome. Patients with unexplained neuropathy should be evaluated for POEMS syndrome, especially when it is associated with other findings like endocrinopathy, organomegaly, skin changes, or edema.

Wild honey poisoning: A case report from western Nepal.

Wild honey has been used for several purposes in South-Asia and Eastern Europe since long ago. One of the commonest is medicinal purposes, especially for gastrointestinal disorders (peptic ulcer disease, dyspepsia, and gastritis), hypertension, and an aphrodisiac (sexual stimulant). However, honey produced from the nectar of few rhododendron species contains a toxin known as grayanotoxin, which acts on the sodium channel and prevents its inactivation leading to vagal activation, causing hypotension and bradycardia. Here, we report a case of 55 years woman who reported to our Emergency Department with complaints of dizziness and vomiting as well as bradycardia and hypotension. Most of the cases of wild honey poisoning resolve within the first 24 h, but in our case, the symptoms persisted for 72 h. So, we must observe patients for 72 h as some cases may last longer. Timely management of the patient can prevent fatal complications.

Hypothermia versus normothermia after out-of-hospital cardiac arrest: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The current guidelines recommend targeted temperature management (TTM) as part of the post-resuscitation care for comatose patients following out-of-hospital cardiac arrest. These recommendations are based on the weak evidence of benefit seen in the early clinical trials. Recent large multicentered trials have failed to show a meaningful clinical benefit of hypothermia, unlike the earlier studies. Thus, to fully appraise the available data, we sought to perform this systematic review and meta-analysis of randomized controlled trials. METHODS: We searched four databases for randomized controlled trials comparing therapeutic hypothermia (32-34 °C) with normothermia (≥36 °C with control of fever) in adult patients resuscitated after out-of-hospital cardiac arrest. Independent reviewers did the title and abstract screening, full-text screening, and extraction. The primary outcome was mortality six months after cardiac arrest, and secondary outcomes were neurological outcomes and adverse effects. RELEVANCE FOR PATIENTS: Six randomized controlled trials were included in this review. There was no significant difference between the hypothermia and normothermia groups in mortality till 6 months follow up after out-of-hospital cardiac arrest (OR 0.88, 95% CI 0.67-1.16; n = 3243; I2 = 51%), or favorable neurological outcome (OR 1.31, 95% CI 0.93-1.84; n = 3091; I2 = 68%). Rates of arrhythmias were notably higher in the hypothermia group than the normothermia group (OR 1.43, 95% CI 1.20-1.71; n = 3029; I2 = 4%). However, odds for development of pneumonia showed no significant differences across two groups (OR 1.13, 95% CI 0.98-1.31; n = 3056; I2 = 22%). Therefore, targeted hypothermia with a target temperature of 32-34 °C does not provide mortality benefit or better neurological outcome in patients resuscitated after the out-of-hospital cardiac arrest when compared with normothermia.

A Case of Advanced Non-Small-Cell Lung Cancer With Response to Alectinib and Favorable Quality of Life.

Lung cancer is the leading cause of cancer death globally and in the United States. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases. A progressive increase in morbidity and mortality is seen with advanced disease. Identifying specific driver mutations, such as anaplastic lymphoma kinase (ALK) mutations and directed therapy, has improved the quality of life and survival in ALK-positive NSCLC patients. Here, we present the case of a 37-year-old female who was diagnosed with stage IV NSCLC (adenocarcinoma) with a positive ALK mutation six years ago. Our case report highlights a rare ALK mutation NSCLC treated with targeted ALK inhibitor therapy. Despite having advanced-stage cancer, the treatment significantly impacted her survival with an improved quality of life.

Valvular Heart Disease Presenting as Sympathetic Crashing Acute Pulmonary Edema (SCAPE) Phenomenon: A Diagnostic and Management Paradigm.

Sympathetic crashing acute pulmonary edema (SCAPE) is an acute decompensated heart failure due to sympathetic overflow. SCAPE is usually triggered by acute insults with an underlying substrate such as long-standing hypertension, chronic heart failure, and valvular heart disease. We present a case of SCAPE in a 91-year-old female due to underlying multivalvular heart disease. Because of severe acute presentation, SCAPE should be identified early, and management should be urgently done to decrease the need for invasive ventilation and prolonged hospitalization.

A Case Report of Acute Transient Encephalopathy Following a Trans-esophageal Echocardiography.

Methemoglobinemia is caused due to an increase in methemoglobin in the blood, impairing oxygen transfer to tissues. Acquired methemoglobinemia is caused by various drugs like local anesthetics, antibiotics, nitrates, nitrites, and food additives. We present a case of a 73-year-old male who presented with cyanosis, altered mental status, and hypoxia following transesophageal echocardiography. Arterial blood gas analysis revealed methemoglobinemia. He had been given topical lidocaine and benzocaine spray before the procedure. He improved after the administration of methylene blue. The case highlights the importance of considering methemoglobinemia in patients presenting with cyanosis, altered mental status, and hypoxia after endoscopic procedures.

Long-Term Favorable Outcome With Nivolumab in a Case of Advanced Non-Small Cell Lung Cancer: A Case Report.

Non-small cell lung cancer (NSCLC) constitutes around 85% of lung cancer cases. Advanced non-small cell lung cancer has a poor prognosis. Immunotherapy plays a pivotal role in managing advanced non-small cell lung cancer not positive for driver mutations. Nivolumab is a monoclonal antibody against programmed death-ligand 1 (PDL1). It is approved as a second-line treatment for patients with advanced non-small cell lung cancer who progress on or after chemotherapy. We present a case of a 71-year-old female with advanced non-small cell lung cancer without any driver mutations diagnosed four years ago. Her disease progressed while on conventional chemotherapy, and she was started on nivolumab three and a half years ago. Her lung nodules resolved, she did not show signs of progression, and her performance status improved while on nivolumab. This case report highlights the current role of nivolumab in the management of NSCLC. Patients whose condition worsens while on conventional chemotherapy can respond very well to modern targeted immunotherapy.

A Narrative Review of Existing Options for COVID-19-Specific Treatments.

The new coronavirus disease 2019 (COVID-19) was declared a global pandemic in early 2020. The ongoing COVID-19 pandemic has affected morbidity and mortality tremendously. Even though multiple drugs are being used throughout the world since the advent of COVID-19, only limited treatment options are available for COVID-19. Therefore, drugs targeting various pathologic aspects of the disease are being explored. Multiple studies have been published to demonstrate their clinical efficacy until now. Based on the current evidence to date, we summarized the mechanism, roles, and side effects of all existing treatment options to target this potentially fatal virus.

Continuous Subcutaneous Apomorphine Infusion in Advanced Parkinson's Disease: A Systematic Review.

Parkinson's disease (PD), a neurodegenerative disorder, is caused due to the loss of dopaminergic neurons in substantia nigra pars compacta, and it mainly affects the motor function of the diseased individual. The most effective treatment for PD to date is levodopa, the precursor molecule for dopamine which ultimately helps overcome the loss of dopamine in the brain. However, long-term levodopa therapy significantly impairs patients' quality of life by causing various disabling motor and non-motor complications. We conducted this study intending to review the available literature that has compared the efficacy and safety of continuous subcutaneous apomorphine infusion (CSAI) with other available treatment options like deep brain stimulation, intestinal levodopa gel, and oral dopaminergic agents. We searched PubMed, Embase, and Scopus databases using the appropriate search strategy. The studies which compared the safety and efficacy of continuous subcutaneous apomorphine infusion to other available treatment options in advanced Parkinson's disease were included in our study. The bias assessment of the studies was done using Cochrane Risk of Bias 2.0 tool for randomized controlled trials, Risk of Bias In Non-Randomized Studies - of Interventions (ROBINS-I) tool for non-randomized interventional studies, and Joanna Briggs Institute Critical Appraisal tools (JBI) for cohort studies. We included eight articles in our systematic review including a randomized controlled trial. None of the included studies had a high risk of bias. We found that in patients with advanced Parkinson's, CSAI demonstrated definite improvement in off-time duration. CSAI has also been shown to improve various non-motor functions, including neuropsychiatric problems in these patients. CSAI has demonstrated safety and efficacy in patients with advanced Parkinson's disease. However, the decision-making is multifactorial. Hence, further studies are required that directly compare the available treatment options with one another and study their overall effects on patients' quality of life.

Behcet's disease in an adult male from Nepal: A case report.

This case report highlights considering Behcet's disease as a diagnosis in orogenital ulcers and uveitis, although its prevalence is unknown in Nepal due to underreporting. Also, collaboration for patient care among relevant specialties is required.

Prevalence of Chronic Kidney Disease, Its Risk Factors and Outcome in Nepal: A Systematic Review and Meta-analysis.

BACKGROUND: Hypertension, diabetes, glomerulonephritis, obesity, and family history of kidney diseases are major risk factors for chronic kidney disease. Due to the paucity of data on a national level regarding the prevalence, risk factors, and complications of chronic kidney disease, we performed this meta-analysis. METHODS: We searched online databases from January 2000 till October 2020. Two reviewers screened articles using Covidence software. Comprehensive Meta-Analysis Software version 3 was used for data analysis. RESULTS: Among chronic kidney disease patients, 35.96% were found to have high LDL, 34.22% had hypercholesterolemia, 39.18% had hypertriglyceridemia, and 42.23% had low HDL. Pigmentary changes were reported in 37.71%, pruritus in 30.96%; and xerosis in 48.55%. Among the reported nail problems, the brown nail was reported in 7.19%, half and half nail in 6.07%, and white nail in 20.65%. CONCLUSIONS: The prevalence of chronic kidney disease among high-risk cohorts in Nepal was significant among risk group with hypertension and diabetes being the most common risk factors. The most common stage of chronic kidney disease was Stage V, and the common complications were skin problems and dyslipidemia.