Validation of the RSClin risk calculator in the National Cancer Data Base.

BACKGROUND: Guidelines recommend the use of genomic assays such as OncotypeDx to aid in decisions regarding the use of chemotherapy for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. The RSClin prognostic tool integrates OncotypeDx and clinicopathologic features to predict distant recurrence and chemotherapy benefit, but further validation is needed before broad clinical adoption. METHODS: This study included patients from the National Cancer Data Base (NCDB) who were diagnosed with stage I-III HR+/HER2- breast cancer from 2010 to 2020 and received adjuvant endocrine therapy with or without chemotherapy. RSClin-predicted chemotherapy benefit was stratified into low (<3% reduction in distant recurrence), intermediate (3%-5%), and high (>5%). Cox models were used to model mortality adjusted for age, comorbidity index, insurance, and race/ethnicity. RESULTS: A total of 285,441 patients were identified for inclusion from the NCDB, with an average age of 60 years and a median follow-up of 58 months. Chemotherapy was associated with improved overall survival only for those predicted to have intermediate (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.60-0.79) and high benefit per RSClin (aHR, 0.66; 95% CI, 0.61-0.72). Consistent benefit was seen in the subset with a low OncotypeDx score (<26) and intermediate (aHR, 0.66; 95% CI, 0.53-0.82) or high (aHR, 0.71; 95% CI, 0.58-0.86) RSClin-predicted benefit. No survival benefit with chemotherapy was seen in patients with a high OncotypeDx score (≥26) and low benefit per RSClin (aHR, 1.70; 95% CI, 0.41-6.99). CONCLUSIONS: RSClin may identify high-risk patients who benefit from treatment intensification more accurately than OncotypeDx, and further prospective study is needed.

Psychotherapy for Alcohol Use Disorder Is Associated With Reduced Risk of Incident Alcohol-Associated Liver Disease.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a devastating complication of alcohol use disorder (AUD). Once it develops, ALD is exceedingly difficult to treat; it therefore is critical to identify ways to prevent ALD. By treating the causes of increased alcohol consumption, psychotherapy may offer prophylactic benefit against the development of ALD for patients with AUD. METHODS: In this retrospective cohort study, we used International Classification of Diseases, 9th and 10th revision, codes to identify 9635 patients with AUD in the Mass General Brigham Biobank. The mean follow-up period from AUD diagnosis was 9.2 years. We used Cox regression models to generate hazard ratios (HR) for the development of ALD given the receipt or nonreceipt of psychotherapy, adjusting for a range of other contributors including the receipt of medication-assisted treatment. RESULTS: In our cohort, 60.4% of patients were men, 83.5% of patients were white, the median age was 57.0 years, and 3544 patients (36.8%) received psychotherapy. ALD developed in 1135 patients (11.8%). In multivariable analysis, psychotherapy was associated with a reduced rate of ALD (HR, 0.59; 95% CI, 0.50-0.71; P < .001). This association held for both individual psychotherapy (HR, 0.70; 95% CI, 0.56-0.86; P < .001) and group psychotherapy (HR, 0.76; 95% CI, 0.61-0.94; P = .01). Among patients with cirrhosis, psychotherapy was associated with a lower rate of hepatic decompensation (HR, 0.68; 95% CI, 0.48-0.95; P = .03). CONCLUSIONS: The receipt of psychotherapy in the setting of AUD is associated with reduced incidence and progression of ALD. Given the safety and potential benefit of psychotherapy, clinicians should consider using it to prevent the development of ALD.

Rethinking the role of hydroxychloroquine in the treatment of COVID-19.

There are currently no proven or approved treatments for coronavirus disease 2019 (COVID-19). Early anecdotal reports and limited in vitro data led to the significant uptake of hydroxychloroquine (HCQ), and to lesser extent chloroquine (CQ), for many patients with this disease. As an increasing number of patients with COVID-19 are treated with these agents and more evidence accumulates, there continues to be no high-quality clinical data showing a clear benefit of these agents for this disease. Moreover, these agents have the potential to cause harm, including a broad range of adverse events including serious cardiac side effects when combined with other agents. In addition, the known and potent immunomodulatory effects of these agents which support their use in the treatment of auto-immune conditions, and provided a component in the original rationale for their use in patients with COVID-19, may, in fact, undermine their utility in the context of the treatment of this respiratory viral infection. Specifically, the impact of HCQ on cytokine production and suppression of antigen presentation may have immunologic consequences that hamper innate and adaptive antiviral immune responses for patients with COVID-19. Similarly, the reported in vitro inhibition of viral proliferation is largely derived from the blockade of viral fusion that initiates infection rather than the direct inhibition of viral replication as seen with nucleoside/tide analogs in other viral infections. Given these facts and the growing uncertainty about these agents for the treatment of COVID-19, it is clear that at the very least thoughtful planning and data collection from randomized clinical trials are needed to understand what if any role these agents may have in this disease. In this article, we review the datasets that support or detract from the use of these agents for the treatment of COVID-19 and render a data informed opinion that they should only be used with caution and in the context of carefully thought out clinical trials, or on a case-by-case basis after rigorous consideration of the risks and benefits of this therapeutic approach.

Substance use disorder is associated with alcohol-associated liver disease in patients with alcohol use disorder.

Background and Aims: Substance use disorder (SUD) commonly associates with alcohol use disorder (AUD), and certain substances have independently been shown to drive liver injury. In this work, we sought to determine if co-existing SUD in patients with AUD associated with the presence of alcohol-associated liver disease (ALD). Methods: We performed a cross-sectional analysis using the Mass General Brigham Biobank to identify patients based on ICD-10 codes. We performed multivariate analyses accounting for a wide range of demographic and clinical variables to evaluate the association between SUD and ALD. We subsequently used the same method to evaluate the association between SUD and hepatic decompensation. Results: We identified 2848 patients with a diagnosis of AUD, 9.0% of which had ALD. 25.2% had a history of SUD. In multivariate analyses, patients with SUD were more frequently diagnosed with ALD compared to those without SUD (OR = 1.95, P = 0.001). Furthermore, the number of concurrent SUDs was positively associated with the diagnosis of ALD (OR: 1.33, P < 0.001). Independent of the presence of other SUDs, opioid use disorder in patients with AUD was associated with ALD (OR = 1.902, P = 0.02). In subsequent analyses, we found that sedative use disorder was associated with hepatic decompensation (OR: 2.068, P = 0.03). Conclusions: In patients with AUD, SUD, and in particular opioid use disorder, was independently associated with the diagnosis of ALD.

Incidence and Progression of Alcohol-Associated Liver Disease After Medical Therapy for Alcohol Use Disorder.

Importance: Alcohol-associated liver disease (ALD) is one of the most devastating complications of alcohol use disorder (AUD), an increasingly prevalent condition. Medical addiction therapy for AUD may play a role in protecting against the development and progression of ALD. Objective: To ascertain whether medical addiction therapy was associated with an altered risk of developing ALD in patients with AUD. Design, Setting, and Participants: This retrospective cohort study used the Mass General Brigham Biobank, an ongoing research initiative that had recruited 127 480 patients between its start in 2010 and August 17, 2021, when data for the present study were retrieved. The mean follow-up duration from AUD diagnosis was 9.2 years. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision diagnosis codes were used to identify ALD and AUD diagnoses. Exposures: Medical addiction therapy was defined as the documented use of disulfiram, acamprosate, naltrexone, gabapentin, topiramate, or baclofen. Patients were considered to be treated if they initiated medical addiction therapy before the relevant outcome. Main Outcomes and Measures: Adjusted odds ratios (aORs) for the development of ALD and hepatic decompensation were calculated and adjusted for multiple risk factors. Results: The cohort comprised 9635 patients with AUD, of whom 5821 were male individuals (60.4%), and the mean (SD) age was 54.8 (16.5) years. A total of 1135 patients (11.8%) had ALD and 3906 patients (40.5%) were treated with medical addiction therapy. In multivariable analyses, medical addiction therapy for AUD was associated with decreased incidence of ALD (aOR, 0.37; 95% CI, 0.31-0.43; P < .001). This association was evident for naltrexone (aOR, 0.67; 95% CI, 0.46-0.95; P = .03), gabapentin (aOR, 0.36; 95% CI, 0.30-0.43; P < .001), topiramate (aOR, 0.47; 95% CI, 0.32-0.66; P < .001), and baclofen (aOR, 0.57; 95% CI, 0.36-0.88; P = .01). In addition, pharmacotherapy for AUD was associated with lower incidence of hepatic decompensation in patients with cirrhosis (aOR, 0.35; 95% CI, 0.23-0.53, P < .001), including naltrexone (aOR, 0.27; 95% CI, 0.10-0.64; P = .005) and gabapentin (aOR, 0.36; 95% CI, 0.23-0.56; P < .001). This association persisted even when medical addiction therapy was initiated only after the diagnosis of cirrhosis (aOR, 0.41; 95% CI, 0.23-0.71; P = .002). Conclusions and Relevance: Results of this study showed that receipt of medical addiction therapy for AUD was associated with reduced incidence and progression of ALD. The associations of individual pharmacotherapy with the outcomes of ALD and hepatic decompensation varied widely.

An exploratory analysis of the competing effects of alcohol use and advanced hepatic fibrosis on serum HDL.

While alcohol use has been shown to increase serum HDL, advanced liver disease associates with decreased serum HDL. The combined influence of alcohol consumption and liver fibrosis is poorly defined. In this study, we sought to investigate the competing effects of alcohol use and hepatic fibrosis on serum HDL and to determine if the presence of advanced hepatic fibrosis ablates the reported effect of alcohol consumption on serum HDL. We performed a cross-sectional, exploratory analysis examining the interaction between alcohol use and advanced hepatic fibrosis on serum HDL levels in 10,528 patients from the Partners Biobank. Hepatic fibrosis was assessed using the FIB-4 index. We excluded patients with baseline characteristics that affect serum HDL, independent of alcohol use or the presence or advanced hepatic fibrosis. We observed an incremental correlation between increasing HDL levels and amount of alcohol consumed (P < 0.0001), plateauing in those individuals who drink 1-2 drinks per day, Contrastingly, we found a negative association between the presence of advanced hepatic fibrosis and lower HDL levels, independent of alcohol use (beta coefficient: -0.011075, SEM0.003091, P value: 0.0001). Finally, when comparing subjects with advanced hepatic fibrosis who do not use alcohol to those who do, we observed that alcohol use is associated with increased HDL levels (54.58 mg/dL vs 67.26 mg/dL, p = 0.0009). This HDL-elevating effect of alcohol was more pronounced than that seen in patients without evidence of advanced hepatic fibrosis (60.88 mg/dL vs 67.93 mg/dL, p < 0.0001). Our data suggest that the presence of advanced hepatic fibrosis does not blunt the HDL-elevating effect of alcohol use.

Serum HMGB1 associates with liver disease and predicts readmission and mortality in patients with alcohol use disorder.

Identifying the minority of patients with alcohol use disorder (AUD) who develop the wide spectrum of alcohol-associated liver disease (ALD), and risk-stratifying these patients, is of critical importance. High-Mobility Group Box 1 protein (HMGB1) is an alarmin that has been implicated in the pathogenesis of multiple liver diseases. Its use as a biomarker for liver disease in those with AUD has not been studied. In this report, we investigated the association between serum HMGB1 and the presence, severity, and progression of ALD in two well-characterized cohorts of patients with AUD. In our discovery cohort of 80 patients, we found that patients with AUD and ALD exhibited higher serum HMGB1 levels compared to patients with AUD only (p = 0.0002). Additionally, serum HMGB1 levels were positively associated with liver disease severity (p < 0.0001). We found that index serum HMGB1 levels were associated with liver disease progression, defined by an increase in MELD score at 120 days (p = 0.0397). Serum HMGB1 was notable for its diagnostic and prognostic ability; it proved able to distinguish accurately between severe and non-severe forms of ALD in both our discovery cohort (AUC = 0.8199, p = 0.0003) and an independent validation cohort of 74 patients with AUD (AUC = 0.8818, p < 0.0001). Moreover, serum HMGB1 levels effectively predicted both liver-related readmission (AUC = 0.8849, p < 0.0001) and transplantation/death (AUC = 0.8614, p = 0.0002) at 90 days. The predictive potential of HMGB1 was also validated in an independent cohort of patients with AUD. Taken together, our results suggest that serum HMGB1 shows promise as a biologically relevant biomarker for ALD in patients with AUD.