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.

Photodynamic Therapy: A Prospective Therapeutic Approach for Viral Infections and Induced Neoplasia.

The recent COVID-19 pandemic outbreak and arising complications during treatments have highlighted and demonstrated again the evolving ability of microorganisms, especially viral resistance to treatment as they develop into new and strong strains. The search for novel and effective treatments to counter the effects of ever-changing viruses is undergoing. Although it is an approved procedure for treating cancer, photodynamic therapy (PDT) was first used against bacteria and has now shown potential against viruses and certain induced diseases. PDT is a multi-stage process and uses photosensitizing molecules (PSs) that accumulate in diseased tissues and eradicates them after being light-activated in the presence of oxygen. In this review, studies describing viruses and their roles in disrupting cell regulation mechanisms and signaling pathways and facilitating tumorigenesis were described. With the development of innovative "or smart" PSs through the use of nanoparticles and two-photon excitation, among other strategies, PDT can boost immune responses, inactivate viral infections, and eradicate neoplastic cells. Visualization and monitoring of biological processes can be achieved in real-time with nanomedicines and better tissue penetration strategies. After photodynamic inactivation of viruses, signaling pathways seem to be restored but the underlying mechanisms are still to be elucidated. Light-mediated treatments are suitable to manage both oncogenic viral infections and induced neoplasia.

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.

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.

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.

Efficacy, safety, and immunogenicity of the Shigella sonnei 1790GAHB GMMA candidate vaccine: Results from a phase 2b randomized, placebo-controlled challenge study in adults.

BACKGROUND: Shigellosis accounts for substantial morbidity and mortality worldwide and is the second most common cause of moderate and severe diarrhoea in children. METHODS: This phase 2b study (NCT03527173), conducted between August 2018 and November 2019, evaluated vaccine efficacy (VE), safety, and immunogenicity of a Shigella sonnei GMMA candidate vaccine (1790GAHB) in adults, using a S. sonnei 53 G controlled human infection model. Participants (randomized 1:1) received two doses of 1790GAHB or placebo (GAHB-Placebo), at day (D) 1 and D29, and an oral challenge of S. sonnei 53 G at D57. VE was evaluated using several endpoints, reflecting different case definitions of shigellosis. For the primary endpoint, the success criterion was a lower limit of the 90% confidence interval >0. FINDINGS: Thirty-six and 35 participants received 1790GAHB or placebo, respectively; 33 and 29 were challenged, 15 and 12 developed shigellosis. VE was not demonstrated for any endpoint. Adverse events were more frequent in 1790GAHB versus placebo recipients post-vaccination. Anti-S. sonnei lipopolysaccharide (LPS) IgG responses increased at D29 and remained stable through D57 in group 1790GAHB; no increase was shown in placebo recipients. INTERPRETATION: 1790GAHB had an acceptable safety profile and induced anti-LPS IgG responses but did not demonstrate clinical efficacy against shigellosis. Baseline/pre-challenge antibody levels were higher in participants who did not develop shigellosis post-challenge, suggesting a role of anti-LPS IgG antibodies in clinical protection, although not fully elucidated in this study. For further vaccine development an increased S. sonnei O-antigen content is likely needed to enhance anti-LPS immune responses. FUNDING: GlaxoSmithKline Biologicals SA, Bill and Melinda Gates Foundation.

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.

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.

Booster Vaccination With GVGH Shigella sonnei 1790GAHB GMMA Vaccine Compared to Single Vaccination in Unvaccinated Healthy European Adults: Results From a Phase 1 Clinical Trial.

The investigational Shigella sonnei vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti-S. sonnei lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2-3 years earlier (boosted group), compared to one dose in 28 vaccine-naïve individuals (vaccine-naïve group). Anti-S. sonnei LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day [D]1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naïve group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naïve groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naïve group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naïve participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naïve individuals. Vaccination was well tolerated.

Erratum to: Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA).

[This corrects the article DOI: 10.1186/s13017-016-0089-y.].

A Phase 2a Randomized Study to Evaluate the Safety and Immunogenicity of the 1790GAHB Generalized Modules for Membrane Antigen Vaccine against Shigella sonnei Administered Intramuscularly to Adults from a Shigellosis-Endemic Country.

Shigellosis is a mild-to-severe diarrheal infection, caused by the genus Shigella, and is responsible for significant morbidity and mortality worldwide. We evaluated the safety and immunogenicity of an investigational Shigella sonnei vaccine (1790GAHB) based on generalized modules for membrane antigens (GMMA) in Kenya, a Shigella-endemic country. This phase 2a, observer-blind, controlled randomized study (NCT02676895) enrolled 74 healthy adults aged 18-45 years, of whom 72 were vaccinated. Participants received, in a 1:1:1 ratio, two vaccinations with the 1790GAHB vaccine at doses of either 1.5/25 µg of O antigen (OAg)/protein (group 1.5/25 µg) or 5.9/100 µg (group 5.9/100 µg) at day (D) 1 and D29, or vaccination with a quadrivalent meningococcal vaccine at D1 and tetanus, diphtheria, and acellular pertussis vaccine at D29 (control group). Solicited and unsolicited adverse events (AEs), serious AEs (SAEs), and AEs of special interest (neutropenia and reactive arthritis) were collected. Anti-S. sonnei lipopolysaccharide (LPS) serum immunoglobulin G (IgG) geometric mean concentrations (GMC) were evaluated at D1, D29, and D57 and compared to anti-S. sonnei LPS antibody levels in convalescent patients naturally exposed to S. sonnei. The percentages of participants with seroresponse were also calculated. The most frequently reported solicited local and systemic AEs across all groups were pain and headache, respectively. Only one case of severe systemic reaction was reported (severe headache after first vaccination in group 5.9/100 µg). Seven and three episodes of neutropenia, assessed as probably or possibly related to vaccination respectively, were reported in the investigational and control groups, respectively. No other SAEs were reported. Despite very high baseline anti-S. sonnei LPS serum IgG levels, the 1790GAHB vaccine induced robust antibody responses. At D29, GMC increased 2.10- and 4.43-fold from baseline in groups 1.5/25 and 5.9/100 µg, respectively, whereas no increase was observed in the control group. Antibody titers at D57 were not statistically different from those at D29. Seroresponse was 68% at D29 and 90% at D57 in group 1.5/25 µg, and 96% after each vaccination in group 5.9/100 µg. The 1790GAHB vaccine was well tolerated and highly immunogenic in a population of African adults, regardless of the GMMA OAg/protein content used.

Laparoscopic cholecystectomy due to acute calculous cholecystitis in 16 weeks' in vitro fertilization and embryo transfer pregnancy: report of the first case.

The most common cases of acute abdomen during pregnancy are acute appendicitis followed by acute cholecystitis. The case presented is a 33-year-old patient in 16 weeks' in vitro fertilization and embryo transfer pregnancy who developed acute cholecystitis. Previously there were two unsuccessful cycles, one complicated with ovarian hyperstimulation syndrome. Due to clinical deterioration during intravenous antibiotic therapy laparoscopic cholecystectomy was performed and acute cholecystitis found. The postoperative course was uneventful. During the first 24 h tocolysis with intravenous fenoterol in addition to peroral atenolol 2 Χ 50 mg was administered. Postoperative course was uneventful with further normal pregnancy. Elective cesarean section was made in term pregnancy (39 weeks) with singleton with Apgar 10/10. Current guidelines do not recommend prophylactic tocolysis in pregnant population with acute abdomen but there is no mention of the IVF-ET subpopulation of patients. Also, there are no guidelines for thromboprophylaxis in such patients with increased risk of thromboembolic accidents. To our knowledge this is the first case report of a laparoscopic cholecystectomy during IVF-ET gestation.

Hepatoid adenocarcinoma of the stomach: case report and short notes on immunohistochemical markers.

Hepatoid adenocarcinoma of the stomach is a rare type of gastric carcinoma with an extremely poor prognosis. We describe a 72-year-old man who underwent esophagogastroduodenoscopy which revealed 50 mm exulcerated lesion with a central necrosis on the lesser curvature and the posterior wall of the body of the stomach. Gastric biopsy revealed a poorly differentiated (anaplastic) adenocarcinoma. The serum level of alpha-fetoprotein (AFP) was (3220 ng/mL). After diagnosis of AFP-producing gastric adenocarcinoma, total gastrectomy, with splenectomy, was performed. The tumor showed immunohistochemical positivity for AFP and Hep Par 1. According to these histopathological and immunohistochemical findings, the tumor was diagnosed as hepatoid adenocarcinoma. At 24 months postoperatively the patient is still alive without metastatic disease on repeated abdominal CTs. Because of the poor prognosis for this histological type of tumor, accurate diagnosis of hepatoid adenocarcinoma is important, and long-term follow-up is required.

Calyceal plication with pyeloplasty in the treatment of giant hydronephrosis in children.

The relief of obstruction alone is frequently not sufficient to ensure renal salvage in giant hydronephrosis. We report on our experience with plication of the renal calyces used as an adjunct to dismembered pyeloplasty in patients with giant hydronephrosis. We describe the operative technique and outcomes in ten children after a follow-up period of six months. Ten patients (six girls and four boys) with a mean age of 8.1 years (range 2-14 years) with giant hydronephrosis caused by primary ureteropelvic junction obstruction underwent a dismembered pyeloplasty followed by plication of the dilated renal calyces. The preoperative evaluation included an excretory urography, ultrasonography, 99mTc-DMSA and 99mTc-DTPA scans. The same tests were repeated six months after the operation to evaluate the outcomes. There were no intraoperative or postoperative complications. Excretory urography and ultrasonography performed six months after the operation demonstrated a significant improvement of the morphology of the operated kidneys. The kidneys shrunk in diameter from a mean of 149.5 mm (range 89-224 mm) to 93.6 mm (range 68-121 mm) and the mean diameter of the calyces was reduced from 26.9 mm (range 15-42 mm) to 14.7 mm (range 10-24 mm). Renal 99mTc-DTPA scans showed improved perfusion and renal function after surgery, with the mean elimination rate decreasing from 22.41 min (range 17.84 - 28.22 min) to 11.7 min (range 8.16-13.76 mm). 99mTc-DMSA scans demonstrated no new scars and no deterioration of renal parenchyma after surgery. We believe that plication of the renal calyces is the method of choice to be used as an adjunct to the Anderson-Hynes pyeloplasty in the treatment of paediatric patients with giant hydronephrosis.