Higher Adverse Events Research Articles

First report of the randomized phase III study of bi-weekly trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) vs. FTD/TPI monotherapy for chemorefractory metastatic colorectal cancer (mCRC): JCOG2014 (ROBiTS).

118 Background: FTD/TPI has been widely used as one of the standard therapies in the late-line treatment for patients with mCRC, and the efficacy of FTD/TPI plus BEV combination was also recently reported in the SUNLIGHT trial. However, the combination of FTD/TPI plus BEV increased the frequency of hematologic toxicity. On the other hand, several phase II studies suggested that modifying the FTD/TPI schedule in combination with BEV from 4-week intervals (2 weeks-on, 2 weeks-off) to bi-weekly dosing (1 week-on, 1 week-off) reduced hematologic toxicities without reducing efficacy. Therefore, we commenced a phase III study to confirm the superiority of bi-weekly FTD/TPI plus BEV to 4-week intervals FTD/TPI monotherapy. Methods: This study is an open-label, multicenter, phase III trial conducted in Colorectal Cancer Study Group of Japan Clinical Oncology Group. We randomly assigned, in a 1:1 ratio, patients who were refractory or intolerant to fluoropyrimidine, oxaliplatin, irinotecan, angiogenesis inhibitor, anti-EGFR antibody (if RAS-wild type), BRAF inhibitor and anti-EGFR antibody (if BRAF V600E-mutant), and immune check point inhibitor (if dMMR/MSI-H) to the treatment of mCRC to receive 4-week intervals FTD/TPI 70mg/m2/day monotherapy (arm A) or bi-weekly FTD/TPI plus bevacizumab 5mg/kg (arm B). The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response rate (RR), disease control rate (DCR), and safety. Results: In consideration of the results of the SUNLIGHT trial, this study was prematurely terminated. Between January 2022 and February 2023, a total of 152 patients were randomized (75 in the arm A and 77 in the arm B). Patient backgrounds between the two arms were well balanced. At the data cut-off date, all enrolled patients discontinued protocol treatment due to disease progression (69.3% vs. 59.7%) and treatment-related adverse events (6.7% vs. 2.6%). With a median follow-up of 8.3 months for surviving patients (OS events, 45% vs. 40%), the median OS was 12.2 vs. 11.8 months (hazard ratio [HR], 0.905; 95% confidence interval [CI], 0.556 to 1.473) and the median PFS was 2.4 vs. 4.0 months (HR, 0.607; 95% CI, 0.426 to 0.865). RR was 1.3% vs. 5.3% and DCR was 45.3% vs. 53.3%. The most common Grade 3 or higher adverse events in each group were neutropenia (46.6% vs. 24.0%), anemia (15.1% vs. 4.0%), fatigue (2.7% vs. 8.0%), anorexia (5.5% vs. 5.3%), nausea (5.5% vs. 5.3%) and febrile neutropenia (4.1% vs. 0%). Conclusions: Although this study was terminated early, the bi-weekly FTD/TPI plus BEV combination in late-line chemotherapy for patients with mCRC resulted in prolonged PFS and reduced hematologic toxicity compared to 4-week intervals FTD/TPI monotherapy. Long-term results including OS are currently under follow-up. Clinical trial information: jRCTs031210544 .

Efficacy and safety of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy in locally advanced esophageal cancer: An updated meta-analysis.

Currently, the optimal treatment for neoadjuvant therapy for locally advanced esophageal cancer is not clear, and there is no evidence that neoadjuvant chemoradiotherapy (nCRT) is superior to neoadjuvant chemotherapy (nCT). Due to the publication of new clinical trials and defects in previous meta-analyses, we conducted an updated meta-analysis to evaluate the efficacy and safety of nCRT and nCT. The following databases were searched for studies: PubMed, EMBASE, and Cochrane library (updated to April 22, 2023). All randomized trials comparing nCRT with nCT in locally advanced esophageal cancer met the inclusion criteria. Data were analyzed using Review Manager 5.4.1 (Cochrane collaboration software). Primary outcomes assessed from the trials included overall survival (OS), progression-free survival (PFS), pathological complete response (pCR), R0 resection rate, postoperative complications, postoperative mortality, and grade 3 or higher adverse events (3 + AEs). This systematic review and meta-analysis included 7 randomized controlled studies involving 1372 patients (686 receiving nCRT and 686 receiving nCT). Compared with nCT, nCRT significantly improved OS (HR = 0.80; 95% CI: 0.68-0.94), PFS (HR = 0.78; 95% CI: 0.66-0.93), pCR (OR = 13.00; 95% CI: 7.82-21.61) and R0 resection (OR = 1.84; 95% CI: 1.32-2.57), but was associated with higher postoperative mortality (OR = 2.31; 95% CI: 1.26-4.25) and grade 3 + AEs (OR = 2.21; 95% CI: 1.36-3.58). There was no significant difference in postoperative complications between nCRT and nCT (OR = 1.15; 95% CI: 0.82-1.61). Subgroup analysis showed significant survival benefit in squamous cell carcinoma (HR = 0.80; 95% CI: 0.68-0.98), but not in adenocarcinoma (HR = 0.80; 95% CI: 0.63-1.08). Our meta-analysis found superior efficacy associated with nCRT compared with nCT in both tumor regression and prolonged survival, but increased the risk of postoperative mortality and grade 3 + AEs. Esophageal squamous cell carcinoma was more likely to benefit from nCRT than esophageal adenocarcinoma in the term of OS.

Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non–Small Cell Lung Cancer

Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. ClinicalTrials.gov Identifier: NCT04158440.

First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane β-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

PAZEC: a Dutch Gynaecological Oncology Group open-label, multicenter, phase II study of pazopanib in metastatic and locally advanced hormone-resistant endometrial cancer

ObjectiveThere is a continued need for improvement of second-line systemic treatment for metastatic and/or recurrent endometrial cancer.MethodsIn this phase II, open-label study, eligible patients had histologically or cytologically confirmed endometrial...

Feasibility of Intraoperative Radiotherapy Tumor Bed Boost in Patients with Breast Cancer after Neoadjuvant Chemotherapy.

This study aimed to assess the feasibility and safety of administering intraoperative radiotherapy (IORT) as a boost during breast-conserving surgery (BCS) following neoadjuvant chemotherapy for patients at high risk of breast cancer recurrence. Patients who underwent neoadjuvant chemotherapy received a single 20-Gy dose of IORT during BCS, followed by external beam radiotherapy 4-6 weeks after surgery. The median follow-up duration was 31.0 months (range, 18.0-59.0 months). Initial tumor sizes had a median of 2.6 cm (range: 0.8-5.3 cm), reducing to 0.3 cm (range: 0-4.0 cm) after neoadjuvant chemotherapy. The most common neoadjuvant chemotherapy regimen was doxorubicin and cyclophosphamide, followed by paclitaxel (n=42, 73.7%). Among 57 patients who received neoadjuvant chemotherapy before BCS and IORT, 2 patients (3.5%) required secondary surgery to achieve negative resection margins due to initially positive margins. Regional lymph node irradiation was performed in 37 (64.9%) patients. There was no grade 3 or higher adverse events, with 4 patients (7.0%) experiencing grade 2 acute radiation dermatitis and 3 (5.3%) having less than grade 2 breast edema. Binary correlation analysis did not reveal statistically significant associations between applicator size or radiation therapy modality and the risk of treatment-related toxicity. Furthermore, chi-square analysis showed that the grade of treatment-related toxicity was not associated with the fractionated regimen (p=0.375). Most patients successfully received IORT as a tumor bed boost after neoadjuvant chemotherapy. Thus, IORT may be a safe and feasible option for patients with advanced-stage breast cancer receiving neoadjuvant chemotherapy.

Neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer.

This study aimed to explore the efficacy of neoadjuvant chemotherapy plus programmed death-1 (PD-1) inhibitor camrelizumab for the treatment of locally advanced esophageal cancer. This was a retrospective analysis. 87 patients with locally advanced esophageal cancer were included who received neoadjuvant chemotherapy plus immunotherapy between June 2018 and April 2021 in our oncology department. The postoperative clinical outcomes and varying expressions of PD-1 were evaluated in all enrolled patients. The post-treatment disease control rate (DCR) was 83.91%, and the objective response rate (ORR) was 59.77%. Cancer tissues were categorized based on PD-1 expression into PD-1 negative (39 cases) and PD-1 positive (33 cases), with a PD-1 positive rate of 45.83%. Patients with PD-1-positive tumors exhibited a significantly higher ORR compared to those with PD-1-negative tumors, although DCRs did not differ significantly between the groups. The 12-month progression-free survival rate was significantly higher in PD-1-positive patients. In contrast, no significant difference was found in the 12-month overall survival rate between the two groups. The incidence of grade III adverse events was 10.34%, and no grade IV or higher adverse events were observed. In patients with locally advanced esophageal cancer, neoadjuvant chemotherapy plus immunotherapy demonstrates good efficacy and safety, especially for PD-1-positive patients, and significantly improves prognosis.

Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. A multicenter, randomized, double-blind, placebo-controlled, phase II study. Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. ClinicalTrials.gov identifier: NCT03976882.

Safety, Efficacy, and Pharmacokinetics of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies BMS-986414 (C135-LS) and BMS-986413 (C144-LS) Administered Subcutaneously in Non-Hospitalized Persons with COVID-19 in a Phase 2 Trial.

Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration. ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days. A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA <LLoQ at day 3 (risk ratio [RR] for BMS mAbs versus placebo: 1.03; 95%CI: 0.80, 1.32), at day 7 (RR: 1.04; 95%CI: 0.94, 1.15), or at day 14 (RR: 1.00; 95%CI: 0.90, 1.12). Fewer grade 3 TEAEs were reported for the BMS mAbs arm than placebo (RR: 0.58 [95%CI: 0.25, 1.32]). Through day 28, there were no deaths, and there were 4 hospitalizations in the BMS mAbs arm versus 3 in the placebo arm. Higher early plasma mAb concentrations were associated with more favorable outcomes. While safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.

Clinical efficacy and adverse reactions analysis of PD-1/PD-L1 inhibitors in advanced esophageal squamous cell carcinoma.

The aim of this study was to investigate the clinical efficacy and associated adverse reactions of Programmed Death Receptor-1 (PD-1)/PD-L1 inhibitors in the management of patients with advanced esophageal squamous cell carcinoma (ESCC). In this retrospective study, 54 patients with advanced ESCC treated with PD-1/PD-L1 inhibitors in our hospital from January 2021 to January 2023 were identified as the research subjects. Using propensity score matching at a 1:1 ratio, patients only receiving chemotherapy were recruited as controls. The clinical effectiveness of PD-1/PD-L1 was evaluated by comparing the objective response rate (ORR) and disease control rate (DCR). Progression-free survival (PFS) and overall survival (OS) were analyzed for treatment outcome assessments. Adverse events (AEs) between the two groups were recorded and compared. Patients treated with PD-1/PD-L1 inhibitors had a higher rate of ORR (33.33%) and disease control (85.19%), compared to controls with an objective response rate of 20.37% and a disease control rate of 59.26%. The two groups showed similar ORR results, while the incorporation of PD-1/PD-L1 inhibitors resulted in significantly increased DCR when compared to the controls. The median OS was 22 months (95% CI: 1,629 months) for the control group and 31 months (95% CI: 28NA) for the study group, suggesting OS benefits offered by PD-1/PD-L1 inhibitor treatment (HR=0.479, 95% CI: 0.284, 0.809). The median PFS was 15 months (95% CI: 1,223 months) for the control group and 23 months (95% CI: 1,926) for the study group, indicating more PFS benefits provided by PD-1/PD-L1 inhibitors (HR=0.662, 95% CI: 0.436, 1.005). Adverse events and their severity were recorded during patient follow-up, and no grade 5 adverse events were reported in either group. The incidence of grade 3 or higher adverse events between the two groups was similar, while PD-1/PD-L1 inhibitors appeared to significantly reduce the incidence of gastrointestinal reactions in patients. PD-1/PD-L1 inhibitors integrated with chemotherapy provide significant benefits in the management of patients with advanced ESCC without increasing adverse events.

Efficacy and safety of low-dose cyclophosphamide combined with lenvatinib, pembrolizumab and TACE for unresectable hepatocellular carcinoma: A single-center, prospective, single-arm clinical trial.

Unresectable hepatocellular carcinoma (uHCC) continues to pose effective treatment options. The objective of this study was to assess the efficacy and safety of combining low-dose cyclophosphamide with lenvatinib, pembrolizumab and transarterial chemoembolization (TACE) for the treatment of uHCC. From February 2022 to November 2023, a total of 40 patients diagnosed with uHCC were enrolled in this small-dose, single-center, single-arm, prospective study. They received a combined treatment of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE. Study endpoints included progression-free survival (PFS), objective response rate (ORR), and safety assessment. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), while survival analysis was conducted through Kaplan-Meier curve analysis for overall survival (OS) and PFS. Adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). A total of 34 patients were included in the study. The median follow-up duration was 11.2 [95% confidence interval (95% CI), 5.3-14.6] months, and the median PFS (mPFS) was 15.5 (95% CI, 5.4-NA) months. Median OS (mOS) was not attained during the study period. The ORR was 55.9%, and the disease control rate (DCR) was 70.6%. AEs were reported in 27 (79.4%) patients. The most frequently reported AEs (with an incidence rate >10%) included abnormal liver function (52.9%), abdominal pain (44.1%), abdominal distension and constipation (29.4%), hypertension (20.6%), leukopenia (17.6%), constipation (17.6%), ascites (14.7%), and insomnia (14.7%). Abnormal liver function (14.7%) had the most common grade 3 or higher AEs. A combination of low-dose cyclophosphamide with lenvatinib, pembrolizumab, and TACE is safe and effective for uHCC, showcasing a promising therapeutic strategy for managing uHCC.

A randomized clinical trial comparing internal and external pessaries in the treatment of pelvic organ prolapse in postmenopausal women: A pilot study

Introduction and hypothesisInternal vaginal pessary is among the leading treatments for pelvic organ prolapse (POP); however, it has a high adverse event rate. An external pessary was recently developed as an alternative. The study's objective was to compare the efficacy of external and internal pessaries in treating POP in postmenopausal women. MethodsThis parallel randomized (1:1 ratio) open-blind study included 40 symptomatic women with stage 2 or 3 POP. They were randomized into two groups: group 1 (internal pessary) and group 2 (external pessary) (n = 20 in each); and evaluated at the start of and 3 months after the treatment. Statistical analysis was performed to compare the results within and between the groups before and after the 3-month treatment. ResultsThe groups were homogeneous, except for the variables previous pregnancies (p = 0.030) and POP-Q score of apical prolapse (p = 0.023) whose values were higher in group 2. A significant improvement in quality of life was observed in both groups after 3 months of follow-up; however, internal pessaries were found to be more effective (p < 0.001). In group 1 there were differences between the initial and final POP-Q scores of anterior (0.004) and apical prolapse (p = 0.005). The complication rate associated with internal pessary use was high (p = 0.044). ConclusionsThe present data suggested that external pessaries have a similar effect to internal ones for the treatment of POP and improvement of the quality of life of postmenopausal women.

Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas

AbstractDespite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.

Orlando Protocol for single session ductal clearance of common bile duct stones at endosopic retrograde cholangiopancreatography.

Approach to management of common bile duct stones (CBDS) by endoscopic retrograde cholangiopancreatography (ERCP) is not standardized. We examined outcomes by applying predetermined protocol for CBDS management. When standard extraction techniques failed at ERCP, presence of tapered bile duct and stone-duct ratio were calculated. Large balloon sphincteroplasty (LBS) and/or mechanical/single-operator cholangioscopy-guided lithotripsy was performed based on presence of tapered bile duct and stone-duct mismatch. Primary outcome was single-session ductal clearance. Secondary outcome was adverse events. Of 409 patients treated over 16 months, 321 (78.5%) had no tapered bile duct or stone-duct mismatch, and single-session ductal clearance was achieved using standard techniques in 99.7% over median duration of 14 min (interquartile range [IQR] 9-21 min). Of 88 (21.5%) patients with difficult CBDS, tapered duct was seen in 79 (89.8%) and/or stone-duct mismatch in 36 (40.9%). Single-session ductal clearance was achieved in all 88 patients (100%) by LBS in 79 (89.8%), mechanical lithotripsy in 20 (22.7%), and single-operator cholangioscopy-guided lithotripsy in 16 (18.2%) over a median duration of 29 min (IQR 17-47 min). Overall, single-session ductal clearance was achieved in 99.8% with adverse events in 17 (4.2%) that included perforation in two, postsphincterotomy bleeding in one, and mild/moderate post-ERCP pancreatitis in 14 patients. A predetermined protocol optimized outcomes by enabling single-session ductal clearance of CBDS with high technical success and low adverse events.

Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial

Relapsed/refractory aggressive large B cell lymphoma (LBCL) remains an area of unmet need. Here we report the primary analysis of a phase 1b/2 trial of outpatient mosunetuzumab (a CD20xCD3 T-cell-engaging bispecific antibody) plus polatuzumab vedotin (an anti-CD79B antibody–drug conjugate) in relapsed/refractory LBCL. The phase 2 component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate. Secondary endpoints included investigator-assessed overall response rate, complete response, duration of response, progression-free survival and overall survival. At data cutoff, 120 patients were enrolled (22 dose escalation, 98 dose expansion). The primary endpoint was met during dose expansion, with IRC-assessed best overall response rate and complete response rates of 59.2% (58/98; 95% confidence interval (CI): 48.8–69.0) and 45.9% (45/98; 95% CI: 35.8–56.3), respectively (median follow-up, 23.9 months). Median duration of complete was not reached (95% CI: 20.5–not estimable (NE)). Median progression-free survival was 11.4 months (95% CI: 6.2–18.7). Median overall survival was 23.3 months (95% CI: 14.8–NE). Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%, 30/120) and fatigue (6.7%, 8/120). Any-grade cytokine release syndrome occurred in 16.7% of patients. These data demonstrate that mosunetuzumab plus polatuzumab vedotin has a favorable safety profile with highly durable responses suitable as second-line therapy in transplant-ineligible relapsed/refractory LBCL. ClinicalTrials.gov identifier: NCT03671018.

Human factors in pelvic exenteration: themes in high-performing teams.

The aim of this study was to investigate the role of human factors in pelvic exenteration and how team performance is optimized in the preoperative, intraoperative and postoperative phases. Qualitative analysis of focus groups was used to capture authentic human interactions that reflect real-world multiprofessional performance. Theatre teams were treated as clusters, with a particular focus group containing participants who worked together regularly. Three focus groups were conducted. Four themes emerged - driving force, technical skills, nontechnical skills and operational aspects - with a total of 16 subthemes. Saturation was reached by group 2, with no new subthemes emerging after this. There was some interaction between the themes and the subthemes. Broadly speaking, driving force led to the development of specialised technical skills and nontechnical skills, which were operationalized into successful service through operational aspects. This study of teams performing pelvic exenteration is the first in the field using this methodology. It has generated rich qualitative data with authentic insights into the pragmatic aspects of developing and delivering a service. In addition, it shows how the themes are connected or 'coupled' in a network, for example technical and non-technical skills. In a complex system, 'tight coupling' leads to both high performance and adverse events. In this paper, we report the qualitative aspects of high performance by pelvic exenteration teams in a complex sociotechnical system, which depends on tight coupling of several themes.

High Mannose Correlates With Surrogate Indexes of Insulin Resistance and Is Associated With an Increased Risk of Cardiovascular Events Independently of Glycemic Status and Traditional Risk Factors.

To explore the associations among mannose, indexes of insulin resistance (IR) and secretion, and long-term cardiovascular outcomes. Fasting mannose was assayed in 1,403 participants, one-half of which had a first myocardial infarction (MI) with either normal glucose tolerance (n = 1,045) or newly detected dysglycemia (i.e., impaired glucose tolerance or type 2 diabetes; n = 358). Regression models were used to explore mannose associations with surrogate indexes of IR/insulin secretion. Multivariate Cox models were used to investigate the independent association between high (higher quartile) versus low (lower three quartiles) mannose and major adverse cardiac events (MACE) (n = 163) during the 10-year follow-up. Mannose was independently associated with IR indexes (all P ≤ 0.001). High versus low mannose was independently associated with MACE (hazard ratio 1.54, 95% CI 1.07-2.20) in the overall population. Mannose might represent a new biomarker able to track early, potentially detrimental glucometabolic alterations independently of glycemic state.

Treatment Responses to Integrase Strand-transfer Inhibitor-containing Antiretroviral Regimens in Combination With Short-course Rifapentine-based Regimens for Latent Tuberculosis Infection Among People With HIV.

Real-world experience with combinations of short-course rifapentine-based regimens and integrase strand-transfer inhibitor-containing antiretroviral therapy (ART) in management of latent tuberculous infection (LTBI) is limited among people with human immunodeficiency virus (PWH). From August 2019 to October 2022, PWH receiving 3 months of weekly rifapentine plus isoniazid (3HP) or 1 month of daily rifapentine plus isoniazid (1HP) in combination with ART were included. The primary outcome was virologic response within 12 months after LTBI treatment; secondary outcomes included treatment completion rate and safety of LTBI regimens. During the study period, 479 PWH (94.6% male; median age, 43 years) were included: 142 received 1HP and bictegravir (BIC)-containing regimens (1HP/BIC group), 46 1HP and dolutegravir (DTG)-containing regimens (1HP/DTG group), 38 3HP and BIC-containing regimens (3HP/BIC group), 214 3HP and DTG-containing regimens (3HP/DTG group), 17 1HP and other ART regimens (1HP/others group), and 22 3HP/other ART regimens (3HP/others group). In the intention-to-treat analysis, the proportions of PWH maintaining plasma HIV-1 RNA <200 copies/mL within 12 months after LTBI treatment completion were 96.5% (1HP/BIC), 100% (1HP/DTG), 100% (3HP/BIC), 95.8% (3HP/DTG), 100% (1HP/others), and 100% (3HP/others). The overall completion rates were >80% for all treatment groups, whereas >50% of the included PWH experienced any adverse event. LTBI regimens and ART combinations were not associated with virologic response and completion rate. Combinations of short-course rifapentine-based regimens and integrase strand-transfer inhibitor-containing ART maintained viral suppression for most PWH within 12 months of LTBI treatment completion with low rates of grade 3 or higher adverse events.

High risks adverse events associated with usage of aspirin in chronic obstructive pulmonary disease

ABSTRACT Background Despite potential benefits and widespread prescription of aspirin among chronic obstructive pulmonary disease (COPD) patients, limited research has investigated its adverse effects (AEs) in COPD population. Methods We conducted a retrospective analysis of adverse drug events (ADEs) reported in the US Food and Drug Administration Adverse Event Reporting System (FAERS) between Q1 2013 and Q2 2022. COPD patients were categorized into two groups based on aspirin use. ADEs related to aspirin use were identified using combined reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) methods. Results A total of 56,660 ADEs reports associated with COPD patients were included in the study. Among these reports, 144 adverse events were linked to aspirin use in COPD patients, including fatigue (4.12%), diarrhea (3.13%), dyspnea exertional (2.03%), rhinorrhea (1.99%), weight increased (1.89%) and vomiting (1.84%), muscle spasms (1.79%), cardiac disorder (1.74%), heart rate increased (1.69%) and peripheral swelling (1.59%). Subgroup analysis indicates that age and gender might affect the AEs frequency in COPD patients using aspirin. Conclusions Our findings identify 10 most frequently reported ADEs associated with aspirin use in COPD patients, thus offer valuable insights into the AEs of aspirin for safer clinical utilization in COPD management.

Letter-only discharge process for virtual fracture clinic, a safe alternative to telephone discharge, outcomes and 12 month follow up for 1140 patients

Telephone consult has become the accepted discharge method for virtual fracture clinic (VFC) within the United Kingdom. Telephone consultations are time consuming; many orthopaedic units lack the resources and staff to deliver large numbers of daily telephone consultations which may block the development of an effective VFC. Our study aim was to validate a letter only VFC discharge process for safety and efficacy. A letter only discharge VFC was instigated in response to the COVID-19 pandemic (April 2020). No ethical approval was required, the protocol was designed as a phased service evaluation and improvement project after change in practice. After smaller pilot audits, a comprehensive review of discharges outcomes from the VFC August-September 2021 (Phase 1) and January-March 2022 (Phase 2) was completed. Electronic letters, AE (accident and emergency) attendances and PACS database images (radiography and scans) taken over a 12 month follow up were analysed for failed discharges and adverse outcomes. Of 4810 patients reviewed in VFC, 1140 were discharged (24%). Mean patient age; 35 years (range 2–98), two thirds of patients were adults (>16 years). 116 (10%) returned with symptoms related to their initial presentation usually within the first few weeks via contact with the VFC helpline. Of the returning patients 65 were discharged again with the same advice, 48 underwent further imaging (CT/ MRI/ US scanning). 6 patients (0.5%) underwent surgery for problems relating to the initial injury; 2 knee meniscal repair/debridement, 1 ACL reconstruction, 1 fixation fifth metatarsal non-union, 2 shoulder arthroscopy. All surgeries were performed on elective timescales between 4 and 12 months after injury. Discharging letters detailed rehabilitation and symptom resolution timeframes. Our approach did not result in high return rates or adverse events (unexpected operations) in comparison to published traditional telephone discharge VFC. Units with limited staffing resources wishing to implement a VFC could safely adopt this approach as an alternative to telephone discharge.