Search

Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy in the advanced setting with poor prognosis. This narrative review provides an overview of the epidemiology of ACC and its molecular pathogenesis with a summary of the main involved signaling pathways. We then provide an update on the clinical presentation, diagnosis, and current management strategies of both localized and metastatic disease from a multidisciplinary perspective. We highlight the debate around the use of mitotane in the adjuvant setting and review the use of combination chemotherapy with etoposide, doxorubicin, and cisplatin. The review also focuses on emerging data providing hope for the use of immune checkpoint inhibitors and targeted therapies in ACC with a summary of ongoing trials., (© The Author(s) 2024. Published by Oxford University Press.)

Sixteen cycles of Brentuximab vedotin (BV) after autologous stem cell transplant (ASCT) in high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated an improved 2-year progression-free survival (PFS) over placebo. However, most patients are unable to complete all 16 cycles at full dose due to toxicity. This retrospective, multicenter study investigated the effect of cumulative maintenance BV dose on 2-year PFS. Data were collected from patients who received at least one cycle of BV maintenance after ASCT with one of the following high-risk features: primary refractory disease (PRD), extra-nodal disease (END), or relapse <12 months (RL<12) from the end of frontline therapy. Cohort 1 had patients with >75% of the planned total cumulative dose, cohort 2 with 51-75% of dose, and cohort 3 with ≤50% of dose. The primary outcome was 2-year PFS. A total of 118 patients were included. Fifty percent had PRD, 29% had RL<12, and 39% had END. Forty-four percent of patients had prior exposure to BV and 65% were in complete remission before ASCT. Only 14% of patients received the full planned BV dose. Sixty-one percent of patients discontinued maintenance early and majority of those (72%) were due to toxicity. The 2-year PFS for the entire population was 80.7%. The 2-year PFS was 89.2% for cohort 1 (n=39), 86.2% for cohort 2 (n=33), and 77.9% for cohort 3 (n=46) (P=0.70). These data are reassuring for patients who require dose reductions or discontinuation to manage toxicity.

Background: Advances in treatment for patients with Diffuse Large B-Cell Lymphoma (DLBCL) have led to improved patient outcomes but the magnitude of these disparities remains understudied with regards to improved survival outcomes. We sought to describe changes in DLBCL survival trends over time and explore potential differential survival patterns by patients' race/ethnicity and age., Methods: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with DLBCL from 1980 to 009 and determined 5-year survival outcomes for all patients, categorizing patients by year of diagnosis. We used descriptive statistics and logistic regression, adjusting for stage and year of diagnosis, to describe changes in 5-year survival rates over time by race/ethnicity and age., Results: We identified 43,564 patients with DLBCL eligible for this study. Median age was 67 years (ages: 18-64 = 44.2%, 65-79 = 37.1%, 80 + = 18.7%). Most patients were male (53.4%) and had advanced stage III/IV disease (40.0%). Most patients were White race (81.4%), followed by Asian/Pacific Islander (API) (6.3%), Black (6.3%), Hispanic (5.4%), and American Indian/Alaska Native (AIAN) (0.05%). Overall, the 5-year survival rate improved from 35.1% in 1980 to 52.4% in 2009 across all races and age groups (odds ratio [OR] for 5-year survival with increasing year of diagnosis = 1.05, P < .001). Patients in racial/ethnic minority groups (API: OR = 0.86, P < .0001; Black: OR = 0.57, P < .0001; AIAN: OR = 0.51, P = .008; Hispanic: 0.76, P = 0.291) and older adults (ages 65-79: OR = 0.43, P < .0001; ages 80+: OR = 0.13, P < .0001) had lower 5-year survival rates after adjusting for race, age, stage, and diagnosis year. We found consistent improvement in the odds of 5-year survival for year of diagnosis across all race and ethnicity groups (White: OR = 1.05, P < .001; API: OR = 1.04, P < .001; Black: OR = 1.06, p<.001; AIAN: OR = 1.05, P < .001; Hispanic: OR = 1.05, P < .005) and age groups (ages 18-64: OR = 1.06, P < .001; ages 65-79: OR = 1.04, P < .001; ages 80+: OR = 1.04, P < .001)., Conclusion: Patients with DLBCL experienced improvements in 5-year survival rates from 1980 to 2009, despite persistently lower survival among patients in racial/ethnic minority groups and older adults., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hemochromatosis, either hereditary hemochromatosis (HH) or secondary hemochromatosis, consists of the accumulation of iron in the liver, heart, and other organs. It leads to end-organ damage in a proportion of affected subjects. Although liver-related morbidity (cirrhosis and hepatocellular carcinoma [HCC]) and mortality are well established, the frequency of these complications remains controversial. The aim of this study is to examine the rate of hospitalization and the incidence of iron overload-related comorbidities in patients with hemochromatosis between the years of 2002 and 2010. We queried the Nationwide Inpatient Sample (NIS) database from the year 2002 to 2010. We included adults (age ≥18 years) and used the ICD-CM 9 code 275.0x to identify hospitalized patients with a diagnosis of hemochromatosis. Data analysis for this study was generated using SAS software version 9.4. A total of 168,614 hospitalized patients between 2002 and 2010 had a diagnosis of hemochromatosis. The majority were males (57%) with a median age of 54 years (37-68), with a predominance of white patients (63.3%) followed by black (26.8%). The rate of hospitalization among patients with hemochromatosis increased by 79% between the years 2002 and 2010 (34.5/100,000 in 2002 vs 61.4/100,000 in 2010). The main associated diagnoses were diabetes mellitus (20.2%), cardiac disease, including arrhythmias (14%) and cardiomyopathy (dilated 3.8%; peri-, endo-, myocarditis 1.3%), liver cirrhosis (8.6%), HCC (1.6%), and acute liver failure (0.81%). Of note, HCC was associated with cirrhosis in 1188 patients (43% of HCC patients) and male sex (87%). Diagnostic biopsies were performed in 6023 (3.6%) of those patients and liver transplant was performed in 881 (0.5%). In-hospital mortality occurred in 3638 (2.16%) patients. In this large database study, we found a rising trend in hospitalization for hemochromatosis, possibly due to the increased recognition of this entity and billing for the condition. The incidence of cirrhosis in hemochromatosis was found to be similar to other studies (8.6% vs 9%). However, the rate of HCC was lower than previous reports (1.6% vs 2.2%-14.9%), and only 43% of HCC was associated with cirrhosis. This raises important pathophysiologic questions regarding the impact of iron overload in HCC. There has been an increase in the rate of hospitalization for patients with a diagnosis of hemochromatosis. This may be related to an increased recognition of hemochromatosis as the underlying etiology for conditions such as diabetes, cardiomyopathy, cirrhosis, and HCC. Further prospective studies are needed to clarify the burden of liver disease in HH and secondary iron overload., Competing Interests: Conflict of interest: The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).)

Platinum-based chemotherapy has long been the backbone of treatment for urothelial carcinoma. Immune checkpoint inhibitors have revolutionized the treatment paradigm and significantly improved outcomes for many patients. More recently, targeted agents such as erdafitinib and antibody drug conjugates enfortumab vedotin and sacituzumab govitecan have demonstrated robust efficacy after progression on prior chemotherapy and immunotherapy. Many additional agents are currently under investigation in ongoing clinical trials. In this review, we discuss the current treatment landscape, review recent clinical data resulting in approval of novel therapeutic agents and highlight important ongoing studies focusing on the therapeutic landscape beyond immune checkpoint inhibition., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Acute chest syndrome (ACS) accounts for the highest mortality in Sickle cell disease patients. Early diagnosis and timely management of ACS results in better outcomes. However, the effectiveness of most treatment modalities for ACS management has not been established., Areas Covered: To review the treatment modalities management protocols and highlight the effectiveness of each option a literature search was done. Randomized controlled trials that assessed the efficacy of different treatment modalities in ACS management in SCD patients were chosen and reviewed., Expert Opinion: 11 randomized controlled trials were found that evaluated the efficacy of incentive spirometry, positive expiratory pressure device, intravenous dexamethasone, oral vs. intravenous morphine, inhaled nitric oxide, unfractionated heparin, and blood transfusion in the prevention or treatment of ACS. Although there are guidelines for ACS treatment, the available evidence is very limited to delineating the effectiveness of various interventions in ACS management. More high-quality studies and trials with a larger patient population can benefit this area to support the recommendations with stronger evidence.

Systemic inflammation has long been associated with poor outcomes in many types of solid tumors. Peripheral blood biomarkers, such as absolute lymphocyte count (ALC) and the ratio of absolute neutrophil count to absolute lymphocyte count (ANC/ALC), have been shown to be immune-inflammatory parameters highlighting an individual's immune status. The prognostic role of ALC and ANC/ALC on overall survival (OS) was examined in patients with advanced non-small cell lung carcinoma (NSCLC) receiving pembrolizumab. Of a total of 239 patients, 52% were male, with a median age of 67 years (interquartile range [IQR], 59-73). Most patients had a diagnosis of adenocarcinoma (76%), with stage IV disease (82%). PD-L1 expression was >50% in 44% of the patients. The median time on treatment with pembrolizumab was 5.8 months (IQR, 2.9-12.7). An ANC/ALC <5 was associated with improved OS at initiation of pembrolizumab (P = .002), whereas an ALC >1.4 deciliter (dL) trended toward improved OS compared with ALC <1.4 dL (P = .053). After adjusting for potential cofounders with a multivariate analysis, a baseline ANC/ALC of 5 or higher was associated with a significantly increased risk of death (HR, 1.93; 95% CI, 1.27-2.93; P = .002). An ANC/ALC <5 at the time of initiation of treatment with pembrolizumab was associated with improved OS in patients with advanced NSCLC. The median ALC and ANC/ALC were significantly lower after 6 weeks of treatment with pembrolizumab.

Background: The relationship between Helicobacter pylori ( H. pylori ) and hepatocellular carcinoma (HCC) was firstly proposed in 1994 after Ward et al demonstrated the role of Helicobacter hepaticus in the development of HCC in mice. Studies also investigated the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) coexisting with H. pylori in causing HCC. A causal relationship was never confirmed, and the relationship remains controversial. This meta-analysis aimed to summarize the research on this topic and investigate if a relationship exists between H. pylori infection and the development of HCC and if the presence of HCV and HBV along with H. pylori plays a role in liver carcinogenesis., Methods: Following PRISMA guidelines, we performed a systematic review of all relevant studies published in the literature using the keywords " Helicobacter pylori " and "hepatocellular carcinoma" on major literature databases, including PubMed, EMBASE, Web of Science, and Cochrane controlled trials register. A total of 656 research studies were identified between 1994 and 2020. Of those, 26 qualified under our selection criteria. Patients who were positive for HCC were classified as cases and those who did not have HCC were classified as controls. The H. pylori status and HCV status, if available, were identified for both groups. Statistical analysis was carried out by a biostatistician according to the Cochrane reviewer's handbook., Results: Out of the 26 studies included in the final analysis, 13 were retrospective case-control studies, 11 were cross-sectional studies, and two were prospective case-control and cohort studies. Overall, the prevalence of H. pylori infection was 64.78% (561 of 866) amongst HCC cases and 47.92% (1,718 of 3,585) in the non-HCC control group. The summary odds ratio (OR) for the association of H. pylori infection with the risk for HCC (using the random-effects model, which accounted for the heterogeneity across the 26 studies) was determined to be 4.75 (95% confidence interval (CI): 3.06 - 7.37, I 2 = 63%). We also performed a subgroup analysis to determine the odds of developing HCC in the presence of H. pylori and HCV coinfection. The summary OR of it was 12.76 (95% CI: 4.13 - 39.41, I 2 = 78%). The summary OR for the risk of developing HCC in the presence of HCV infection without H. pylori infection was 2.21 (95% CI: 0.70 - 6.94, I 2 = 79%). Whereas, the odds of developing HCC in the presence of only H. pylori infection without HCV was found to be 0.54 (95% CI: 0.11 - 2.63, I 2 = 80%). There was inconsistency in the data presented in some studies regarding HCV infection status. Since data were extracted from different study designs, subgroup analysis by study design was performed which showed no significant difference between the study groups (P = 0.5705)., Conclusion: This meta-analysis demonstrates a positive association between H. pylori infection and the development of HCC. There is a significantly higher risk of developing HCC in the presence of HCV infection along with H. pylori . Further prospective cohort studies are needed to prove the causal relationship, especially in cases of HBV and HCV coinfection, and cirrhotic patients., Competing Interests: None to declare., (Copyright 2021, Madala et al.)

Venous thromboembolism (VTE) is the leading preventable cause of death in hospitalized patients and data consistently show that acutely ill medical patients remain at increased risk for VTE-related morbidity and mortality in the post-hospital discharge period. Prescribing extended thromboprophylaxis for up to 45 days following an acute hospitalization in key patient subgroups that include more than one-quarter of hospitalized medically-ill patients represents a paradigm shift in the way hospital-based physicians think about VTE prevention. Advances in the field of primary thromboprophylaxis in acutely-ill medical patients using validated VTE and bleeding risk assessment models have established key patient subgroups at high risk of VTE and low risk of bleeding that may benefit from both in-hospital and extended thromboprophylaxis. The direct oral anticoagulants betrixaban and rivaroxaban are now U.S. Food and Drug Administration-approved for in-hospital and extended thromboprophylaxis in medically ill patients and provide net clinical benefit in these key subgroups. Coronavirus disease-2019 may predispose patients to VTE due to excessive inflammation, platelet activation, endothelial dysfunction, and hemostasis. The optimum preventive strategy for these patients requires further investigation. This article aims to review the latest concepts in predicting and preventing VTE and discuss the new era of extended thromboprophylaxis in hospitalized medically ill patients., Competing Interests: A.C.S acts as a consultant for Janssen, Bayer, Boehringer Ingelheim, BMS, Portola, and the ATLAS Group and received research funding from Janssen and Boehringer Ingelheim. The other author declares no conflict of interest., (Thieme. All rights reserved.)

Background In the PAUSE (Perioperative Anticoagulant Use for Surgery Evaluation) Study, a simple, standardized, perioperative interruption strategy was provided for patients with nonvalvular atrial fibrillation taking direct oral anticoagulants (DOACs). Our objective was to define the factors associated with perioperative bleeding. Methods and Results We analyzed bleeding as the composite of major and clinically relevant nonmajor bleeding. Putative predictors of bleeding, and preoperative DOAC level were prospectively collected during recruitment. We used stratified logistic regression models for analysis. All statistical analyses were performed in R version 3.6.0. There were 3007 patients requiring perioperative DOAC interruption. More than one third of the included patients underwent a high bleeding risk procedure. The 30-day rates of major and clinically relevant nonmajor bleeding were 3.02% in apixaban (n=1257), 2.84% in dabigatran (n=668), and 4.16% for rivaroxaban (n=1082). Multivariate analysis stratified by region found more bleeding for hypertension (odds ratio [OR], 1.79; 95% CI 1.07-2.99; P =0.027), and prior bleeding (OR, 1.71; 95% CI, 1.08-2.71; P =0.021). Surgical bleed risk classification (high- versus low-risk) as a predictor of bleeding was only significant in the univariate analysis. The prediction model for major and clinically relevant nonmajor bleeding had an area under the curve of 0.71, and the preoperative DOAC level did not improve the area under the curve of the model. Conclusions In patients treated with DOACs who required an elective surgery/procedure and were managed with standardized DOAC interruption and resumption, there we did not find reversible risk factors for bleeding, suggesting that adjustment of the PAUSE management protocol to mitigate against bleeding is not needed.

Introduction  The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) Study assessed a standardized perioperative management strategy in patients with atrial fibrillation who were taking a direct oral anticoagulant (DOAC) and required an elective surgery or procedure. The aim of this substudy is to analyze the safety of this management strategy across different patient subgroups, according to four presurgical variables: (1) DOAC type and dose, (2) surgery/procedure bleed risk, (3) patient renal function, and (4) age. Methods  Clinical outcomes analyzed included major bleeding (MB), arterial thromboembolism, any bleeding, and any thromboembolism. We used descriptive statistics to summarize clinical outcomes, where the frequency, proportion, and 95% confidence interval were reported. Fisher's exact tests were used for testing the null hypothesis of independence between the clinical outcome and patient characteristic, where the test p -values were reported. Results  There were 3,007 patients with atrial fibrillation requiring perioperative DOAC management. There was no significant difference in bleeding or thromboembolic outcomes according to DOAC type/dose regimen, renal function, or patient age. The rate of MB was significantly higher with high bleed risk procedures than low bleed risk procedures in apixaban-treated patients (2.9 vs. 0.59%; p  < 0.01), but not in dabigatran-treated patients (0.88 vs. 0.91%; p  = 1.0) or rivaroxaban-treated patients (2.9 vs. 1.3%; p  = 0.06). The risk for thromboembolism did not differ according to surgery/procedure-related bleed risk. Conclusion  Our results suggest that in DOAC-treated patients who received standardized perioperative management, surgical bleed risk is an important determinant of bleeding but not thromboembolic outcomes, although this finding was not consistent across all DOACs. There were no differences in bleeding and thromboembolism according to DOAC type and dose, renal function, or age., Competing Interests: Conflict of Interest J.D.D.: Consulting fees and/or honoraria from Bayer, BMS, Janssen, Leo Pharma, Pfizer, Portola, Sanofi. A.T.: Grant/Research Support: NIH/ BMS/Doasense/Janssen. Honoraria/Consultation: Recovery Force. S.S.: Research grants from Octapharma and Boehringer-Ingelheim and honoraria from Alnylam, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, and Sanofi. A.C.S.: Grants/Research: Boehringer Ingelheim, Janssen, BMS/Pfizer. Consultant/Advisory Board: Bayer, Janssen, Portola, Boehringer Ingelheim, BMS. The other authors have no conflict of interest to disclose., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Extended thromboprophylaxis given to medically ill patients for up to 45 days following an acute hospitalization remains an emerging topic among many hospital-based health care providers. Recent advancements in the field of extended thromboprophylaxis using risk stratification and careful patient selection criteria have led to an improved safety profile of direct oral anticoagulants (DOACs) and established net clinical benefit when given to key patient subgroups at high risk of venous thromboembolism (VTE) and low risk of bleeding. The Food and Drug Administration (FDA) has now approved the DOACs betrixaban and rivaroxaban for both in-hospital and extended thromboprophylaxis in medically ill patients in these key subgroups, which represents more than one-quarter of hospitalized medically ill patients. This has potential to significantly reduce VTE-related morbidity and mortality for these patients. Emerging data also supports reductions in the risk of arterial thromboembolism in medically ill patients with extended thromboprophylaxis post-hospital discharge using DOACs. This article aims to review the most recent concepts of predicting and preventing VTE and to discuss emerging paradigms of extended thromboprophylaxis in hospitalized medically ill patients utilizing an individualized, risk-adapted approach., Competing Interests: K.M.—None. A.C.S.: Consultant—Janssen, Bayer, Boehringer Ingelheim, BMS, Portola, the ATLAS Group; research funding—Janssen, Boehringer Ingelheim.

Heart failure (HF) represents a significant financial burden to the US health care system, affecting approximately 5.7 million Americans. By 2030, the prevalence of HF is expected to increase by 23%. Clinicians generally evaluate volume status in patients with HF by visualizing jugular venous distension to estimate right atrial pressure; a method with an estimated accuracy of only 50%. Currently, the only endorsed methods for acute HF diagnosis in the 2017 American College of Cardiology (ACC) guidelines are brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP), pre-discharge BNP or NT-proBNP, and myocardial fibrosis markers. However, serial testing of BNP to monitor therapy remains controversial. Moreover, an elevated BNP cannot be attributed solely to a cardiac cause. Given the limitations of the current methods, a robust tool is needed to reliably assess volume status in HF patients. It is now known that hemodynamic congestion from increases in intracardiac pressure occurs days to weeks prior to the onset of typical HF symptoms, such as weight gain and shortness of breath. It has been postulated that assessing the inferior vena cava (IVC) diameter with a portable ultrasound, may be the simple, reliable, and cost-effective method of evaluating right atrial pressure, and thus, the severity of HF. Given this exciting new tool in assessing volume status in patients with HF, we pose the question of whether this imaging modality can be used to risk-stratify patients and guide management. The aim of this paper is to highlight the many benefits of portable ultrasound in assessing volume status in this population, and to discuss whether this imaging modality can help guide physicians in the management of their HF patients., Competing Interests: The authors of this manuscript have no conflict of interest to disclose., (Copyright 2020, Khan et al.)