Severe Adverse Events Research Articles

Assessment of renal response in Tunisian patients with proliferative lupus nephritis under three different induction immunosuppressive agents: A prognostic retrospective study.

The aim of our study was to evaluate the renal response (RR) of three immunosuppressive protocols in the induction treatment of proliferative lupus nephritis (PLN) in a Tunisian population. We performed a retrospective prognostic cohort study in the Internal Medicine Department of the Habib Thameur University Hospital in Tunis from January 2000 to December 2023, and included kidney biopsy proven proliferative lupus nephritis patients. Three induction treatments were compared: High CYP regimen: glucocorticoids (GC) + IV cyclophosphamide (CYP) in monthly pulses of 0.7g/m2 for 6 months; Low CYP regimen: GC + IV CYP in biweekly pulses of 500mg for 3 months; and MMF regimen: GC + oral MMF 1.5g twice daily for 6 months. The primary endpoint was the incidence of RR (complete and partial remission) at one year post-diagnosis. The additional outcomes were end-stage kidney disease (ESKD), severe adverse events (AEs) and death. Our study included 78 PLN patients (High CYP: 17, Low CYP: 40, MMF: 21). The study found that 94.1% of patients receiving High CYP achieved the primary endpoint, RR, compared to 67.5% of those receiving Low CYP and 61.9% in the MMF group. For the additional outcomes, there were 3 cases of ESKD, all in the Low CYP group, 5 cases of death (4 in the Low CYP group and 1 in the MMF group), and 20 cases of severe AEs, all of which were severe infections (5 in the High CYP group, 12 in the Low CYP group, and 3 in the MMF group). Multivariate analysis showed that the High CYP regimen was more associated with RR than the MMF regimen, with an adjusted OR of 9.846 (95% CI: 1.087-98.210); p = 0.042. Multivariate analysis did not show statistically significant differences between the High CYP regimen and the Low CYP regimen in terms of RR. As an induction treatment for PLN, the High CYP regimen was strongly associated with a higher rate of RR than the MMF regimen. There were no statistically significant differences between the High CYP regimen and the Low CYP regimen in terms of RR.

Tolerability Assessment of Tyrosine Kinase Inhibitors in Patients With Solid Tumor Malignancies and Hypoalbuminemia.

Hypoalbuminemia is common in patients with advanced solid tumor malignancies. However, despite the increased use of highly protein-bound tyrosine kinase inhibitors (TKIs) in cancer treatments, the tolerability of these agents in patients with hypoalbuminemia is not fully known. Our aim is to assess whether patients on oral TKIs with hypoalbuminemia are at higher risk for experiencing medication-related adverse events, therefore requiring careful considerations. This is a single-center, retrospective study including patients ≥18 years of age with a solid tumor malignancy who had taken at least one dose of oral TKIs with a protein binding of ≥90% between June 1, 2016, and June 1, 2021. The primary outcome was to compare time to TKI discontinuation due to adverse events between patients with and without hypoalbuminemia. Key secondary outcomes include TKI discontinuation and dose reduction rates, time to TKI dose reduction, and severity of adverse events. Out of 282 included patients, 134 (48%) patients had hypoalbuminemia and 148 (52%) had normal albumin levels. Compared with patients without hypoalbuminemia, patients with hypoalbuminemia had shorter median time on treatment at 2.8 months (95% CI = 2.3-4.5 months) versus 4.3 months (95% CI = 2.8-6.4 months; P = 0.003). In patients who had TKI discontinuation, dose reduction was associated with longer time on treatment in patients in the normal albumin group compared with patients in the hypoalbuminemia group or patients without dose reduction (P < 0.0001). Patients in the hypoalbuminemia group experienced significantly more grade 3/4 adverse events compared with those in the normal albumin group (73% vs 27%, P < 0.0001). Hypoalbuminemia is a risk factor for both shorter time on treatment and more severe adverse events in patients with solid tumor malignancies taking highly protein-bound oral TKIs. This study highlights the need for closer monitoring of this patient population by health care providers.

Prognostic implications of CK19 positivity in patients with early recurrent hepatocellular carcinoma after hepatic resection undergoing transarterial chemoembolization

BackgroundThis study aimed to compare the survival outcomes of transarterial chemoembolization (TACE) between patients with early recurrent hepatocellular carcinoma (rHCC) after hepatic resection, stratified by cytokeratin (CK) 19 expression.MethodsA retrospective analysis was conducted on 63 patients with early rHCC after hepatic resection who underwent TACE between January 2017 and December 2021. Patients were divided into two groups based on CK19 expression: CK19-negative (n=31) and CK19-positive (n=32). Overall survival (OS) and progression-free survival (PFS) were compared between the two groups using the Kaplan-Meier method and log-rank test. Cox regression analysis was performed to identify independent risk factors for OS and PFS.ResultsThe CK19-negative group demonstrated a significantly longer median OS compared to the CK19-positive group (635 days vs. 432 days, p=0.013). Similarly, the CK19-negative group had a longer median PFS than the CK19-positive group (291 days vs. 117 days, p=0.014). Multivariate Cox analysis identified Child-Pugh A grade, CK19-negative expression, and increased TACE sessions as protective factors for OS. No severe TACE-related adverse events were observed.ConclusionIn patients with early rHCC after hepatic resection, those with CK19-positive expression had poorer survival outcomes following TACE compared to CK19-negative patients. These findings suggest the need for additional therapies to improve survival in CK19-positive individuals.

B-179 Comparative Evaluation of Cisplatin Release from Alginate Hydrogels with Embedded Silver Nanoparticles: An HPLC and Colorimetric Spectrophotometry Study

Abstract Background Cisplatin [cis-dichlorodiamine platinum (II)], is a well-recognized chemotherapeutical drug. Cisplatin has been employed in treating a wide range of human cancers, such as those of the breast, bladder, lung, ovarian, and testicular cancers. Its therapeutic action is attributed to its capacity to form crosslinks with the DNA's purine bases, disrupting DNA repair processes, causing DNA damage, and ultimately leading to apoptosis in cancerous cells. Nonetheless, the application of cisplatin is constrained by the development of multidrug resistance and the occurrence of severe adverse effects, including nephrotoxicity, bone marrow suppression, hearing loss, allergic responses, nerve damage, and low magnesium levels in the blood. Numerous strategies have been explored to enhance the anticancer effectiveness of cisplatin while minimizing its associated toxicities. These strategies include combination therapies that incorporate nanoparticles, liposomes, and polymer micelles. In this project, cisplatin was embedded into alginate hydrogels loaded with silver nanoparticles and in vitro cisplatin release study using HPLC and UV-Vis spectrophotometry were studied. Methods We developed a novel nanocomplex by integrating silver nanoparticles (AgNPs) with alginate hydrogel coating to create a versatile platform for drug delivery. To incorporate the chemotherapeutic agent, cisplatin (150 ppm) was introduced into the AgNPs-alginate mixture utilizing rapid stirring to ensure uniform distribution and encapsulation of cisplatin within the nanocomplex. A range of analytical methods, such as UV-Vis, FTIR, SEM/EDX, and Zeta potential analysis, were employed to characterize the nanocomplex. To evaluate cisplatin release kinetics from the nanocomplex, we employed an in vitro dialysis method for monitoring its sustained release. High-performance liquid chromatography (HPLC) was used for precise cisplatin release quantification, then validated by colorimetric spectrophotometry. This dual-method approach ensured accurate insights into the nanocomplex’s release dynamics, substantiating its potential in enhancing targeted cancer therapy through advanced drug delivery systems. Results The analysis through UV-Vis revealed an absorption spectrum around 410 nm, indicative of the characteristic plasmon resonance associated with silver nanoparticles. TEM provided high-resolution imagery, revealing that the size of the silver nanoparticles varied between 4 and 30 nm, averaging at 13 nm with a standard deviation of 5 nm specifically for the alginate-coated AgNPs. SEM images confirmed the anticipated spherical distribution of silver nanoparticles within the alginate hydrogel framework. EDX spectroscopy analysis further verified the incorporation of silver nanoparticles and platinum within the complex. The cisplatin release studies from this newly developed nanocomplex illustrated a prolonged, slow, and consistent release pattern, extending over days, in stark contrast to the rapid and complete release of cisplatin from its unbound state, which achieved peak release within an hour. Conclusions In this study, we successfully developed and validated an innovative, multifunctional nanoplatform for drug delivery, comprising alginate hydrogel synergistically co-loaded with silver nanoparticles (AgNPs) and cisplatin. This novel drug carrier system demonstrated a marked enhancement in the controlled delivery of cisplatin, evidenced by the slow and sustained release profile observed over three days. The slow and sustained release of cisplatin from the alginate complex, compared to the free form, highlights the efficacy of the nanoplatform in modulating the drug’s release kinetics.

Comprehensive audit of gastrointestinal endoscopy adverse events: Emphasizing quality indicators and economic impact with the AIG-AGREE modification.

Background and study aims: This study aimed to conduct a clinical audit of adverse events (AEs) arising from gastrointestinal endoscopy, utilizing the AGREE classification for AEs and establishing its correlation with the ASGE classification. This study further integrated the economic repercussions of AEs into the AGREE classification through the AIG-AGREE modification. Patients and methods: A prospective observational study was conducted at the Asian Institute of Gastroenterology, Hyderabad, India, from July 1, 2021, to December 31, 2021. The study included all patients who underwent diagnostic or therapeutic endoscopic procedures. AEs were categorized using the American Society of Gastrointestinal Endoscopy (ASGE) and AGREE classifications. A quality indicator questionnaire containing 15 questions was graded based on the latest ASGE and European Society of Gastrointestinal Endoscopy guidelines. The grading scale ranged from 1 to 3 (poor), 4 to 6 (average), 7 to 9 (excellent), to 10 (outstanding). In addition, the AIG-AGREE modification divided the economic impact into five scales (α, β, γ, δ, and ε) based on multiples of the baseline amount. (ClinicalTrials.gov Identifier: NCT05228353) Results: Over the 6-month study period, a total of 42,471 endoscopic procedures were performed, identifying 220 AEs. Analysis revealed a significant positive correlation (Pearson correlation coefficient = 0.79; P < 0.001) between the grades of AEs in the AGREE and ASGE classifications. The median score for all quality indicators was 8, indicating excellent services based on feedback from 13,042 surveyed patients. Notably, patients with more severe AEs (AGREE III-V) exhibited higher economic impact categories (β, γ, δ, ε) compared with those with less severe AEs (AGREE I-II). Conclusions: The AIG-AGREE modification stands as a pioneering effort that highlights the importance of considering economic factors in the evaluation of AEs in gastrointestinal endoscopy.

Safety, pharmacokinetics, and food-effect of pivmecillinam after single- and multiple-dose in healthy Chinese subjects: a phase I study.

Urinary tract infection (UTI) is one of the most prevalent bacterial infectious diseases worldwide. However, the resistance of urinary pathogens to other UTI antibiotics such as trimethoprim and trimethoprim/sulphamethoxazole increased. Pivmecillinam is a prodrug of mecillinam, which is effective for the treatment of urinary tract infections. The purpose of this study was to assess the safety, and pharmacokinetics of pivmecillinam and mecillinam after single- and multiple-dose oral administration of pivmecillinam tablets in healthy Chinese subjects. The study also investigated the profile of urinary excretion of mecillinam, as well as the effect of food and gender on the pharmacokinetics of pivmecillinam and mecillinam. This study was a single-center, open-label phase I study carried out in three groups. In total, 34 subjects were included in the study: group 1-food effect study with pivmecillinam 200mg (n = 12); group 2-single- and multiple-dose study with pivmecillinam 400mg (n = 12); group 3-single dose study with pivmecillinam 600mg (n = 10). The plasma and urine concentrations of pivmecillinam and mecillinam were measured, and their pharmacokinetics were calculated. Treatment-emergent adverse events were evaluated and recorded in safety assessments for three groups. No severe adverse events were found in this study. After a single dose of pivmecillinam was taken orally, the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of pivmecillinam increased in a dose-proportional manner, nor did mecillinam. Food had significant effects on Cmax and AUC0-t of pivmecillinam and Cmax of mecillinam. The mean cumulative percentage of urine excretion of mecillinam at 0 to 24h ranged from 35.5 to 44.0%. Urinary cumulative excretion is relative to the drug dose, but the diet and multiple-dose administration did not affect the urinary cumulative excretion rate. The safety and pharmacokinetics of pivmecillinam and mecillinam after single- (200/400/600mg) or multiple-dose (400mg) administration were demonstrated in healthy Chinese subjects. Food affected the pharmacokinetics of pivmecillinam and mecillinam.

Patients with fibromyalgia have increased risk of 90-day postoperative adverse events following arthroscopic rotator cuff repair

BackgroundArthroscopic rotator cuff repair (RCR) is a common surgical intervention for symptomatic rotator cuff tears when conservative management fails. Understanding the potential correlation of short- and longer-term outcomes associated with defined comorbidities can help with patient selection, counseling, and related care pathways. The association of fibromyalgia, one potential comorbidity, with outcomes following RCR has not been reported in the literature. MethodsPatients with and without fibromyalgia diagnosed prior to undergoing RCR were identified from the PearlDiver Mariner161 database between 2016 and April 30, 2022, using Current Procedural Terminology (CPT) codes. Exclusion criteria were age less than 18 years, a diagnosis of neoplasm, trauma, or infection within 90 days prior to surgery, and postoperative records of fewer than 90 days. Patients with and without fibromyalgia were matched 1:4 based on age, sex, and Elixhauser Comorbidity Index (ECI).Ninety-day adverse events were assessed. Severe adverse events were defined as the occurrence of sepsis, surgical site infection, cardiac events, deep vein thrombosis, or pulmonary embolism. Minor adverse events were defined as the occurrence of wound dehiscence, urinary tract infection, pneumonia, transfusion, hematoma, or acute kidney injury. Also identified was the occurrence of any adverse event, emergency department (ED) visits, and readmission. These outcomes were compared with multivariate analysis. One-year revisions were assessed with Kaplan-Meier curves and compared with the log-rank test. ResultsIn total, 295,169 RCR patients were identified, of which fibromyalgia was noted for 12,366 (4.2%). Following matching, the final cohort sizes for those with and without fibromyalgia were 11,387 and 45,354 respectively.Diagnosis of fibromyalgia was independently associated with increased risk of all individual adverse events as well as aggregated incidence of severe, minor, and any adverse events (p<0.0001 for all). Additionally, patients with fibromyalgia had independently 90-day increased odds of ED utilization (p<0.0001). There was no statistically significant difference in reoperation between the cohorts within 1 year of surgery. Discussion and ConclusionFibromyalgia was associated with significantly increased 90-day postoperative adverse events and ED visits. These findings are relevant in surgical planning but are also balanced by a lack of difference in one-year revisions.

S3520 Incarcerated Colonoscope: An Uncommon but Severe Adverse Event

S3520 Incarcerated Colonoscope: An Uncommon but Severe Adverse Event

Online Mindfulness-Based Intervention (eMBI) in management of dyspnea in patients with interstitial lung disease: A randomized clinical trial

Dyspnea and cough are frequent symptoms in ILD patients. The management of these symptoms is challenging, and evidence-based therapies are lacking. To evaluate the effect of an online Mindfulness-Based Intervention (eMBI) on reducing dyspnea in patients affected by different ILDs. This study was a prospective, open-label, controlled trial that included patients ≥18 years and a modified Medical Research Council (mMRC) dyspnea scale score of ≥ 1. Patients were randomized into either the eMBI or the control group (CG) for 8 weeks. The primary outcome was the change in the dyspnea mMRC scale. The Leicester Cough Questionnaire (LCQ), King's Brief Interstitial Lung Disease (K-BILD) questionnaire, and Depression, Anxiety, and Stress Scale (DASS-21) were performed before and after the eight weeks. All analyses were conducted on an intention-to-treat basis. The study was registered at the Brazilian Registry of Clinical Trials (ReBEC), RBR-3s4mf9y. 24 patients in the eMBI and 25 in the CG completed the intervention. In the eMBI group, compared to the control group, there was a greater proportion of patients with a reduction in dyspnea according to the mMRC scale score (48.9% versus 15.4%, p = 0.001). There was no significant difference between the groups in the LCQ (p = 0.666), or in the K-BILD (p = 0.108), depression (p = 0.08), or anxiety (p = 0.869 or stress (p = 0.789). No moderate or severe adverse events were observed in either group. Eight weeks eMBI is a potentially viable and safe approach, that can help manage dyspnea in ILD patients.

Long-term immunogenicity of the SA14-14-2 Japanese encephalitis (JE) vaccine (CD.JEVAX®) booster following chimeric JE (IMOJEV®) vaccine priming in Thai children

ABSTRACT Japanese encephalitis (JE) is a significant public health concern in Asia, particularly in children, where vaccination plays a crucial role in prevention. In this study, we investigated the immunogenicity and safety of two different live-attenuated JE vaccines used as primary and booster doses. Fifty healthy participants aged 1–3 years, who were primed with the chimeric JE vaccine IMOJEV® a year earlier, received a booster dose of the SA14-14-2 JE vaccine CD.JEVAX®. To evaluate the immune response, JE-neutralizing antibody titers were assessed on day 0 (pre-booster), day 30, and annually from 1 to 5 years post-booster using the 50% plaque reduction neutralization test (JEPRNT50). The assessment revealed strong immunogenicity 30 d post-booster, with a geometric mean titer of 2092.4 [95% confidence interval (CI): 1473.9–2970.5] and a seroprotection rate of 100%, which gradually decreased to 97.5% at 5 years post-booster. No severe adverse events were observed. The most common reaction within 7 d of vaccination was fever (20%; 95% CI: 10.7–32.3). These results indicate that a booster dose of CD.JEVAX® elicits a strong immune response in children previously vaccinated with IMOJEV® while maintaining a good safety profile, thus supporting the interchangeability of these two live-attenuated JE vaccines. Registered at www.thaiclinicaltrials.org (TCTR ID: TCTR20221102003), our study suggests that CD.JEVAX® can be a viable option for booster vaccination in JE prevention programs, potentially enhancing vaccine flexibility and accessibility.

Infliximab for parenchymal neuro-Behçet's syndrome: case series and meta-analysis.

This study aims to evaluate the efficacy and safety of infliximab (IFX) in patients with parenchymal neuro-Behçet's syndrome (p-NBS). We retrospectively analysed eleven p-NBS patients treated with IFX at our institution and combined them with studies from database searches for a meta-analysis. Pooled estimates of clinical response (complete and partial remission) and MRI improvement at months 3, 6, and 12 were calculated. One patient achieved CR and the other ten patients achieved PR at our institution. 8 studies (77 patients) were included in the meta-analysis. At 3, 6, and 12 months, 97% (95%CI 61.9-100%), 89.6% (95%CI 45.9-100%), 100% (95%CI 96.0-100%) of patients showed clinical response and 100% (95%CI 89.7-100%), 89.1% (95% CI 26.3-100%), 99.5% (95% CI 96.0-100%) of patients showed radiological improvement, respectively. Severe adverse events were observed in 7 patients. IFX was effective and relatively safe for p-NBS. Patients should be re-evaluated after 3 months of IFX to determine further therapy.

A Meta-Analysis of Efficacy and Safety of Neoadjuvant Immunotherapy Plus Chemotherapy for Resectable Non-Small Cell Lung Cancer.

Neoadjuvant immunotherapy plus chemotherapy has ushered in a new era for surgical treatment for patients with NSCLC. This study aimed to examine the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy in NSCLC. Eligible studies were identified from PubMed, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and conference meeting abstracts. The endpoints included major pathological response (MPR), complete pathological response (pCR), surgical resection rate, R0 resection, treatment-related adverse events (TRAEs), severe adverse events (SAEs), surgical complications, treatment discontinuation, surgical delay, and treatment-related death. Stata 18 software was used for statistical analysis, and p < 0.05 was considered statistically significant. Twenty-two studies including a total of 1108 patients were eligible for this study. Among the patients who received neoadjuvant immunotherapy plus chemotherapy, the pooled MPR rate was 51% (95% CI [0.44-0.58]), and pCR rate was 34% (95% CI [0.28-0.40]). The pooled surgical resection rate was 85% (95% CI [0.81-0.89]), and the pooled R0 rate was 94% (95% CI [0.91-0.96]). The pooled rate of pathological tumor downstaging was 84% (95% CI [0.79-0.88]), and the pooled rate of pathological nodal downstaging was 38% (95% CI [0.23-0.57]). During the treatment of neoadjuvant immunotherapy plus chemotherapy with or without surgery, the pooled rate of TRAEs (any grade) was 84% (95% CI [0.73-0.91]), and the pooled rate of SAEs was 29% (95% CI [0.21-0.38]). Surgical complications pooled rate was 25% (95% CI [0.14-0.41]). The pooled rate of treatment discontinuation (11%, 95% CI [0.09-0.13]), surgical delay (3%, 95% CI [0.02-0.05]), and treatment-related death (2%, 95% CI [0.02-0.03]) were conducted. Neoadjuvant immunotherapy plus chemotherapy provides a high pathological response, surgical resection rate, R0 resection rate, and pathological downstage rate and has a low risk of increasing the incidence of SAEs, surgical complications, treatment discontinuation, surgical delay, and treatment-related death. The validation of prospective and large sample studies is needed to confirm this conclusion.

Efficacy of a single dose of cryopreserved human umbilical cord mesenchymal stromal cells for the treatment of knee osteoarthritis:a randomized, controlled, double-blind pilot study

BackgroundKnee osteoarthritis (OA) is the most prevalent degenerative musculoskeletal disorder, which is particularly common in older population. While conventional treatments have limited effectiveness, the development of more effective therapeutic strategies is necessary to address this primary source of pain and disability. Umbilical cord mesenchymal stromal cells (UC-MSCs) offer a promising therapeutic approach for treating knee OA. AimThis randomized, prospective, double-blind and controlled pilot study was carried out to evaluate and compare the safety and therapeutic efficacy of a single intra-articular injection of a standardized product CellistemOA (5 × 106 ± 5 × 105 UC-MSCs), vs. triamcinolone (a synthetic corticosteroid) (10 mg/mL) in thirty patients with symptomatic knee OA (Kellgren–Lawrence grade II or III). MethodsThe outcomes included changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores based on a Likert scale, numerical rating score (NRS) for pain, Magnetic Resonance Imaging (MRI), and quality of life (SF-36 questionnaire), from baseline and throughout 12-months of follow-up. ResultsPatients treated with CellistemOA showed significant improvement in WOMAC score (including the three subscale scores (pain, stiffness and function), NRS in pain, and SF-36 profile from baseline to 12 months (p < 0.05) compared to the triamcinolone group, and no severe adverse events were reported. There were no significant differences in MRI WORMS scores between the two groups. However, patients who received the cellular treatment experienced a significant improvement in their SF-36 profile (p < 0.05). ConclusionsThis pilot study revealed that a single dose of CellistemOA is safe and superior to the active comparator in knee OA at 1-year of follow-up, making it a compelling therapeutic alternative to treat symptomatic OA patients.

Analysis of emergent reoperations after bariatric surgery: an important metric for safe same-day surgery

BackgroundEarly reoperation after sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) is a severe adverse event that may increase the risk of perioperative mortality if there is a delay in care. However, it is unclear what proportion of reoperations occur within 24 hours of surgery and who is at greater risk, which may impact the safety of performing safe same-day surgery. ObjectivesTo evaluate the incidence of reoperation in the first 24 hours after primary SG and RYGB. SettingMichigan Bariatric Surgery Collaborative, Ann Arbor, Michigan. MethodsUsing a statewide bariatric surgery data registry, patients undergoing primary SG (n = 49,848) and RYGB (n = 11,267) cases were analyzed. Patients who had a subsequent reoperation were identified and reasons for reoperation were compared between those occurring <24 hours versus >24 hours. In addition, patients who underwent a reoperation <24 hours were compared with patients who underwent primary SG or RYGB and did not experience any complications. ResultsThe overall rate of reoperation was .72% for SG and 2.1% for RYGB. Reoperation <24 hours of index procedure was 32.0% after SG and 24.2%, after gastric bypass, with the most common reason being hemorrhage (86.15%% and 55.4% respectively). Older age, hypertension, liver disease, and longer operative times were associated with reoperation <24 hours after SG, whereas longer operative times were associated with reoperation <24 hours after RYGB. Concurrent hiatal hernia repair was not associated with increased risk. ConclusionsReoperation after primary bariatric surgery is rare but occurs within 24 hours in approximately one third of the cases after SG and one quarter of cases after RYGB. Older patients with significant comorbidities are at increased risk and should be considered poor candidates for same-day surgery given the possibility of an early life-threatening event.

Feasibility of Percutaneous Radiofrequency Ablation for Abdominal Wall Endometriosis: A Prospective Pilot Study

Study ObjectiveTo assess the feasibility of percutaneous radiofrequency ablation (PRFA) of anterior abdominal wall endometriosis (AWE) lesions and to describe its efficacy on clinical symptoms and on the volume of the lesion. DesignInterventional, prospective, non-comparative, phase 1 clinical trial. SettingPatients consulting at the multidisciplinary endometriosis expert center at Croix Rousse University Hospital (Hospices Civils de Lyon). PatientsTen patients with 1 to 3 AWE lesions treated by PRFA with 6 months follow-up. InterventionsPRFA of AWE lesions were performed under ultrasound guidance. Initial power ranged from 3 to 10 W, with progressive increases in power. The thermal effect in the ablation zone was monitored in real time (appearance of hyperechoic signals). A contrast-enhanced ultrasound check was also carried out. We used multiShot technique until the entire nodule was covered by the hyperechogenic cloud. Measurements and Main ResultsTen patients (12 nodules) were positively treated from 25/06/2020 to 27/07/2022, 8 under local anesthesia and 2 under general anesthesia, which represented 100% feasibility. Nine patients had previous caesarean section.At 6 months the nodule pain at palpation disappeared for 9 patients (90%), mean cyclic pain VAS significantly decreased from 5.7 points (0.9 SD 0.9 VS 6.6 SD 3.2 p=.03) and non-cyclic pain from 3.8 points (0.8 SD 1.3 vs 4.6 SD 3.3 p=.02). Patients reported a significant improvement of their quality of life at 6 months (SF36 total score increase by 218 points p<.01). We observed a significant reduction of 78% in the volume of the nodule at 6 months on MRI (1.2cm3 SD 1.3 vs 5.4cm3 SD 8.2 p<.01); 11/12 treated nodules were non-vascularized/enhanced on post-procedure MRI.All Patients were treated on an outpatient basis.We report one severe adverse event (incisional hernia). ConclusionPRFA is feasible and may be a clinically effective treatment for AWE.https://clinicaltrials.gov/study/NCT04333017Clinical trial registry number: NCT04333017

Long-term efficacy and safety of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): extended follow-up of an open-label, multicentre, randomised, non-inferiority trial

STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks. We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda). Participants were randomly assigned 1:2:2:2 (via permuted blocks and stratified by site and HIV status plus CD4 cell count) to the 2011 WHO long regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of an injectable antituberculous drug. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome, reported previously, was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable) at week 76. Here we report efficacy outcomes at week 132, analysed in the modified intention-to-treat (mITT) population. Safety assessments continued to 132 weeks and were in all participants who received at least one dose of the study regimen. All comparisons used concurrently randomised participants. This trial is registered on ISRCTN (ISRCTN18148631) and is now completed. Between March 28, 2016, and Jan 28, 2020, 588 participants were randomly assigned to the long (n=32), control (n=202), oral (n=211), or 6-month (n=143) treatment regimens; 352 (60%) were male and 236 (40%) were female. Of the 556 participants on the three shorter regimens, 517 were included in the mITT population (187 in control group, 196 in oral group, and 134 in 6-month group) and 465 in the per-protocol analyses. Six additional participants had an unfavourable outcome that occurred between week 76 and the end of efficacy follow-up (one in control group, four in oral group, one in 6-month group). In the mITT population, the proportion of patients with an unfavourable outcome at the end of follow-up was 19·6% (95% CI 14·3 to 24·9) in the oral group and 29·3% (23·3 to 36·5) in the control group (-9·7 percentage points difference [95% CI -18·7 to -1·8]; psuperiority=0·024). An estimated 9·8% (95% CI 4·6 to 14·9) of participants on the 6-month regimen had an unfavourable outcome, which was significantly lower than for those concurrently on the control regimen (32·5% [23·7 to 40·2]; psuperiority<0·0001) or the oral regimen (23·8% [16·9 to 31·1]; psuperiority=0·013). Few serious or severe adverse events were reported after week 76, with no indication of a difference between the regimens. At week 132, treatment-emergent hearing loss was recorded in significantly fewer participants on the oral regimen (7/205; 3%) than the control regimen (16/198; 8%; p=0.041); there was no significant difference in severe hearing loss between the oral regimen (6/139; 4%) and the 6-month regimen (5/143; 4%; p=0·72). Death rates were low: 1·01 (95% CI 0·48 to 2·12) per 100 person-years in participants allocated to bedaquiline (ie, oral and 6-month regimen, n=287) compared with 1·52 (0·63 to 3·66) in participants on the control regimen (n=140; p=0·49). Both of the bedaquiline-containing regimens maintained superiority to the control regimen, without evidence of increased mortality, providing two additional evidence-based treatment options for patients; previous mortality concerns for bedaquiline were not substantiated. US Agency for International Development and Janssen Research & Development.

Allogeneic CD5-specific CAR-T therapy for relapsed/refractory T-ALL: a phase 1 trial.

Refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL) patients have poor prognoses, due to the lack of effective salvage therapies. Recently, CD7-targeting chimeric antigen receptor (CAR)-T therapies show efficacy in patients with r/r T-ALL, but relapse with CD7 loss is common. This study evaluates a CD5-gene-edited CAR-T cell therapy targeting CD5 in 19 r/r T-ALL patients, most of whom had previously failed CD7 CAR-T interventions. CAR-T products were derived from previous transplant donors (Cohort A) or newly matched donors (Cohort B). Primary endpoints were dose-limiting toxicity at 21 days and adverse events within 30 days. Secondary endpoints were responses, pharmacokinetics and severe adverse events after 30 days. A total of 16 received infusions, 10 at target dose of 1 × 106 kg-1. All encountered grade 3-4 cytopenias and one had a grade 3 infection within 30 days. All patients (100%) achieved complete remission or complete remission with incomplete blood count recovery by day 30. At a median follow-up of 14.3 months, four received transplantation; three were in remission and one died of infection. Of 12 untransplanted patients, 2 were in remission, 3 relapsed, 5 died of infection and 2 of thrombotic microangiopathy. CAR-T cells persisted and cleared CD5+ T cells. CD5- T cells, mostly CD5-gene-edited, increased but remained below normal levels. These results suggest this CD5-specific CAR-T intervention has a high remission rate for T-ALL patients. Evidence also suggests the risk of late-onset severe infection may be mitigated with consolidative transplantation. This study provides insights that could help to optimize this promising intervention. ClinicalTrials.gov registration: NCT05032599 .

The impact of acyl-CoA:cholesterol transferase (ACAT) inhibitors on biophysical membrane properties depends on membrane lipid composition

Acyl-coenzyme A: cholesterol acyltransferases are enzymes which are involved in the homeostasis of cholesterol. Impaired enzyme activity is associated with the occurrence of various diseases like Alzheimer’s disease, atherosclerosis, and cancers. At present, mitotane is the only inhibitor of this class of enzymes in clinical use for the treatment of adrenocortical carcinoma but associated with common and severe adverse effects. The therapeutic effect of mitotane depends on its interaction with cellular membranes. The search for less toxic but equally effective compounds is hampered by an incomplete understanding of these biophysical properties. In the present study, the interaction of the three ACAT inhibitors nevanimibe, Sandoz 58-035, and AZD 3988 with membranes has been investigated using lipid model membranes in conjunction with biophysical experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches. The data show, that the drugs (i) incorporate into lipid membranes, (ii) differently influence the structure of lipid membranes; (iii) affect membrane structure depending on the lipid composition; and (iv) do not cause hemolysis of red blood cells. The results are discussed with regard to the use of the drugs, in particular to better understand their efficacy and possible side effects.

Real world experience with cladribine tablets in the management of relapsing multiple sclerosis in Qatar

ObjectivesTo study the 30-month safety and effectiveness of Cladribine tablets (CladT) in relapsing multiple sclerosis (RMS) months in a real-world setting. MethodsRetrospective single-centre observational study in Qatar (January 2018–Feb 2023). Clinical and MRI data, lymphocyte counts and adverse events (AE) were recorded for patients with RMS who received at least one course of CladT. ResultsForty-six patients were included (mean follow-up 22 months); 34 (74%) were female, 22 (48%) were disease-modifying therapy (DMT) naïve, 16 (35%) had switched from platform DMT and 8 (17%) from high efficacy (HE) DMD. Mean age was 26.7±7.2y, mean disease duration was 7.2±6.0y. Common reasons for treatment with CladT were MS activity (91%), pregnancy planning (17%), AE (20%), compliance (9%). 44/46 ( 96%) received the year 2 course of CladT. Annualised relapse rate (ARR) fell from 1.02 (baseline) to 0.1, 0, 0.1, 0.1 and 0.1 for years 1–5 post-treatment, respectively; 87.5–100% were free of relapses at these times, vs. 21% at baseline. There were no relapses in year 2; 78%, 100%, 84%, 80% and 100%, respectively, were free of GD+ MRI lesions at years 1–5, vs. 31% at baseline. Most clinical AE were mild (1 moderate, no severe AE); 12 contracted Covid-19 (no hospitalisations). Grade 3 lymphopenia occurred in 5 patients. ConclusionsCladT appeared to be effective and safe in our retrospective study, irrespective of prior treatments, consistent with other real world data that support the early use of CladT in the management of RRMS.

Including the bowel within the iceball during cryoablation: a retrospective single-center review of adverse events

To evaluate the safety of including bowel in the ice-ball during cryoablation. 43 patients who underwent 50 cryoablations between 1/1/2012 and 2/1/2023 were retrospectively reviewed and compared to a control cohort of those undergoing cryoablation without bowel involvement (n=86). Adverse events (AEs) were stratified by the Society of Interventional Radiology Adverse Events classification system, 2017 (1). Adverse events occurring within 12 months and factors that may affect the AE rate, such as degree of bowel involvement and portion of bowel involved, were reviewed. Fourteen AEs occurred in 13 patients (13/43, 30.2%). This included 7 grade 1 AEs (7/43,16.3%), 3 grade 2 (3/43,7.0%) and 4 grade 3 (4/43,9.3%). Of them 1 grade 3 AE was judged to be related to bowel involvement (1/43,2.3%). When comparing AEs by degree of bowel wall involvement, there were more injuries with the full thickness bowel wall cases (6/9,66.7%), compared with partial thickness, but the findings were not statistically significant (p=0.140). When looking at AEs by portion of the intestine involved, it was found that 7 (7/14,50%), 10 (10/17,58.8%), and 4 (4/19, 21.1%,p=0.055) were found when stomach, small bowel or large bowel was involved respectively. No significant difference in AEs (13/43,30.2% vs 31/86,36%,p=0.511) or severe AEs (4/43, 9.3% vs 9/86, 10.5%, p=0.836) was found between the study and control cohorts. Findings from this single center retrospective experience suggest that bowel wall involvement by the ice ball during cryoablation resulted in a lower-than-expected rate of adverse events for bowel-related injuries.