Incidence Of Severe Adverse Events Research Articles

Efficacy and safety of sacituzumab govitecan Trop-2-targeted antibody-drug conjugate in solid tumors and UGT1A1*28 polymorphism: a systematic review and meta-analysis.

Sacituzumab govitecan (SG) is a promising Trop-2-targeted antibody-drug conjugate (ADC) approved for the treatment of metastatic triple-negative breast cancer (TNBC). Early phase clinical trials have demonstrated good clinical activity and safety profile of SG in various tumor types, albeit with differing response rates and durations. The aim of this systematic review and meta-analysis was to evaluate the clinical efficacy and toxicity of SG and the influence of UGT1A1*28 genotype in clinical trials involving solid tumors. A systematic review of the literature from publicly available databases was performed on February 15, 2024 whereby studies published till 15 February 2024 were retrieved according to PRISMA guidelines [PROSPERO #CRD42022359943]. Data extracted included tumor type, sample size, demographic information, SG dose, UGT1A1*28 status, toxicity events, duration of follow-up, response, and survival outcomes. Risks of bias analysis was refereed using the Joanna Briggs Institute quality assessment tool for the cohort and RCT studies using 11 and 13 parameters, respectively. Statistical analysis was performed using the DerSimonian and Laird inverse variance methods. Heterogeneity was assessed using the I2 statistic and Χ2 tests. P value < 0.05 was considered as statistical significance. Eleven eligible clinical trials comprised of 1578 patients harboring various tumor types including TNBC, lung, genitourinary and gastrointestinal malignancies were included in the systematic review and meta-analysis. Pooled incidences of severe adverse events were minimal at <10%, with the exception of grade 3-4 neutropenia at 37.4%. The median PFS and OS across all studies were 4.9 (95%CI: 4.0-5.8) months and 9.6 (95%CI: 7.6-11.6) months, respectively. Objective response rate across all studies evaluated was 17.1% (95%CI: 12.0-22.1). Our systematic review and meta-analysis confirmed that SG confers good clinical activity in certain solid tumor types and was tolerable with minimal adverse events. The potential utility of UGT1A1*28 genotyping in predicting clinical response and outcomes could not be determined due to the limited number of studies with available UGT1A1 genotype data.

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.

The efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors combined with statins in patients with hypercholesterolemia: a network meta-analysis.

In recent years, the position of PCSK9 inhibitors as adjuvant therapy to statins in guidelines has further improved. However, there remained a dearth of direct comparative studies among different PCSK9 inhibitors. Therefore, this study aimed to conduct a network meta-analysis to evaluate the efficacy and safety of different PCSK9 inhibitors combined with statins. A comprehensive literature search was conducted from the study's inception to 12 November 2023, encompassing multiple online databases including PubMed, Embase, Cochrane Central, Web of Science, and ClinicalTrials.gov to obtain relevant randomized controlled trials. Frequentist network meta-analysis was employed to compare the efficacy and safety of different PCSK9 inhibitors. The efficacy endpoints were low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) (Lp(a)). The safety endpoints were any adverse events (AE), severe adverse events (SAE), AE leading to treatment discontinuation, and injection-site reaction. Compared with placebo and ezetimibe, all PCSK9 inhibitors demonstrated significant reductions in LDL-C levels. Notably, evolocumab exhibited the most pronounced effect with a treatment difference of -63.67% (-68.47% to -58.87%) compared with placebo. Regarding dosage selection for evolocumab, the regimen of 140 mg Q2W (-69.13%, -74.55% to -63.72%) was superior to 420 mg QM (-61.51%, -65.97% to -57.05%). Based on rankings and P-scores analysis, tafolecimab 150 mg Q2W demonstrated superior efficacy in reducing ApoB levels (-61.70%, -84.38% to -39.02%) and Lp(a) levels (-43%, 30%, -68%, 81% to -17%, 79%). Furthermore, the safety profile of PCSK9 inhibitors was favorable with no increase in the incidence of AE, SAE, or AE leading to treatment discontinuation; however, alirocumab, inclisiran, and tafolecimab may potentially entail a potential risk associated with injection-site reactions. Compared with placebo and ezetimibe, PCSK9 inhibitors can significantly reduce LDL-C, ApoB, and Lp(a) when combined with statins to treat hypercholesterolemia. Furthermore, PCSK9 inhibitors and ezetimibe exhibit similar safety profiles. [PROSPERO], identifier [CRD42023490506].

Efficacy and safety of duodenal-jejunal bypass liner for obesity and type 2 diabetes: A systematic review and meta-analysis.

This study aimed to evaluate the efficacy and safety of duodenal-jejunal bypass liner (DJBL) for obesity and type 2 diabetes mellitus. A comprehensive search of electronic databases was conducted up to September 15, 2022. Thirty studies involving 1751 patients were included. At 12 months post-implantation, the reduction in body mass index (BMI) was 4.8 kg/m2 (95% CI 4.1, 5.5), with an excess weight loss of 41.3% (95% CI 33.4%,49.2%) and a total weight loss of 13.1% (95% CI 10.1%, 16.0%). Significant decrease was observed in HbA1c and fasting glucose, with a standardized mean difference of - 0.72 (95% CI - 0.95, - 0.48) and - 0.62 (95% CI - 0.82, - 0.42), respectively. However, these improvements in weight loss and glycemic control were only partially sustained after explantation. In situ, DJBL significantly improves blood pressure and lipid levels. The pooled early removal rate was 19%, and the incidence of severe adverse events was 17%, including device migration (6%), gastrointestinal hemorrhage (4%), device obstruction (4%), and hepatic abscess (2%). DJBL offers significant improvement in weight loss and glycemic control, as well as cardiovascular parameters while in situ. Further studies are warranted to better understand the long-term efficacy and safety of DJBL. The benefits of DJBL need to be carefully weighed against the risks in clinical decision-making.

Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma.

Pancreatic adenocarcinoma, a malignancy that arises in the cells of the pancreas, is a devastating disease with unclear etiology and often poor prognosis. Locally advanced pancreatic cancer, a stage where the tumor has grown significantly but has not yet spread to distant organs, presents unique challenges in treatment. This article aims to discuss the current strategies, challenges, and future directions in the management of locally advanced pancreatic adenocarcinoma (LAPC). To investigate the feasibility and efficacy of programmed cell death 1 (PD-1) inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC. Eligible patients had LAPC, an Eastern cooperative oncology group performance status of 0 or 1, adequate organ and marrow functions, and no prior anticancer therapy. In the observation group, participants received intravenous sintilimab 200 mg once every 3 wk, and received concurrent chemoradiotherapy (concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-1 40 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression, death, or unacceptable toxicity). In the control group, participants only received concurrent chemoradiotherapy. From April 2020 to November 2021, 64 participants were finally enrolled with 34 in the observation group and 30 in the control group. Thirty-four patients completed the scheduled course of chemoradiotherapy, while 32 (94.1%) received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group. Thirty patients completed the scheduled course of chemoradiotherapy in the control group. Based on the Response Evaluation Criteria in Solid Tumors guidelines, the analysis of the observation group revealed that a partial response was observed in 11 patients (32.4%), stable disease was evident in 19 patients (55.9%), and 4 patients (11.8%) experienced progressive disease; a partial response was observed in 6 (20.0%) patients, stable disease in 18 (60%), and progressive disease in 6 (20%) in the control group. The major toxic effects were leukopenia and nausea. The incidence of severe adverse events (AEs) (grade 3 or 4) was 26.5% (9/34) in the observation group and 23.3% (7/30) in the control group. There were no treatment-related deaths. The observation group demonstrated a significantly longer median overall survival (22.1 mo compared to 15.8 mo) (P < 0.05) and progression-free survival (12.2 mo vs 10.1 mo) (P < 0.05) in comparison to the control group. The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group (P > 0.05). Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients, and warrants further investigation.

Safety and Feasibility of Neoadjuvant-Modified FOLFIRINOX in Elderly Patients with Pancreatic Cancer.

The optimal treatment strategy for neoadjuvant chemotherapy in elderly patients with pancreatic cancer (PC) remains unclear. Hence, this study was aimed at evaluating the safety and feasibility of neoadjuvant-modified FOLFIRINOX (mFOLFIRINOX) in elderly patients with PC. We retrospectively collected data from 62 patients who received neoadjuvant mFOLFIRINOX between May 2015 and October 2023 and comparatively analyzed the clinicopathological data and outcomes between the non-elderly group (age: <75 years) and elderly group (age: >75 years). The non-elderly and elderly groups comprised 39 and 23 patients, respectively. Although elevated levels of aspartate aminotransferase (p = 0.0173) and alanine aminotransferase (p = 0.0378) and nausea (p = 0.0177) were more frequent in the elderly group, the incidence of severe adverse events was similar between the groups. Intergroup differences in resection rate (p = 0.3381), postoperative severe complication rates (p = 0.2450), and postoperative hospital stay (p = 0.3496) were not significant. Furthermore, no significant intergroup differences were found in survival in either the whole or the resection cohorts. The perioperative and postoperative outcomes of elderly patients treated with neoadjuvant mFOLFIRINOX were comparable with those of non-elderly patients. Neoadjuvant mFOLFIRINOX should be considered a feasible option for elderly patients with PC.

Early safety of endoscopic sleeve gastroplasty in super obesity (body mass index > 50)

BackgroundThe prevalence of super obesity (body mass index [BMI] > 50) continues to rise. However, the adoption of bariatric surgery in this population remains very low. There are limited studies evaluating the utility of endoscopic sleeve gastroplasty (ESG) in super obesity. ObjectivesThe purpose of this study is to evaluate the short-term safety profile of ESG in patients with super obesity using data from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database. SettingUnited States. MethodsWe retrospectively analyzed patients who underwent ESG and sleeve gastrectomy (SG) from 2016 to 2021. Patients with BMI >50 who underwent ESG were compared to ESG patients with BMI <50 and also SG patients with BMI >50. Primary outcomes included the incidence of severe adverse events (AEs), hospital readmission, reintervention, and reoperation within 30 days of the primary procedure. Secondary outcomes included procedure time, hospital length of stay, and total body weight loss at 30 days. ResultsThere were no significant differences in AE, reoperations, hospital readmissions, or reinterventions for patients with super obesity undergoing ESG, compared to patients with BMI below 50. Mean total body weight loss was greater in patients with super obesity. There were no significant differences in AEs for patients with super obesity who underwent ESG versus SG, although ESG patients had more hospital readmissions, reinterventions, and reoperations. ConclusionsESG may be performed safely, with comparable safety to SG, in patients with BMI as high as 70. However, further studies are needed to validate the feasibility and long-term efficacy prior to clinical implementation.

Transarterial chemoembolization combined with donafenib or lenvatinib as first-line treatment for unresectable hepatocellular carcinoma: A single-center real-world retrospective study.

e16137 Background: Combined Transarterial chemoembolization (TACE) with tyrosine kinase inhibitor (TKI) treatment has been proven to be beneficial. This study aimed to retrospectively compare the efficacy and safety of Donafenib (DON)-TACE versus Lenvatinib (LEN)-TACE as first-line treatment for unresectable hepatocellular carcinoma (uHCC). Methods: From May 2020 to May 2023, a retrospective analysis was conducted on the clinical data of 93 patients with previously untreated uHCC who underwent treatment at the department of Interventional Radiology of the Third Affiliated Hospital of Sun Yat-sen University. Among them, 49 were in the DON-TACE group and 44 in the LEN-TACE group. The primary endpoint was progression-free survival (PFS) according to mRECIST, and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety outcome. Results: As of the data cut-off date Aug 26, 2023, the median PFS was 221 days (95% CI 141–366) in the DON-TACE group and 173 days (95% CI 108–215) in the LEN-TACE group (HR = 0.783, 95% CI 0.462–1.325, P = 0.362).ORR and DCR of the DON-TACE group were 55.1% (95% CI 40.23–69.33) and 75.51% (95% CI 61.13–86.66), respectively, while those of the LEN-TACE group were 61.36% (95% CI 45.49–75.64) and 81.82% (95% CI 67.29–91.81). No significant difference was observed either in ORR(P = 0.689) or DCR(P = 0.627) between the two groups. The incidence rates of total adverse events for any grade (85.71% vs 100.00%, P = 0.027) and ≥Grade 3 (22.496% vs 45.45%, P = 0.019) were significantly lower in the DON-TACE group. In addition, the incidence rates of AST increased (27.27% vs 56.82%, P = 0.005), diarrhea (6.12% vs 25.00%, P = 0.011), vomiting (0% vs 40.91%, P &lt; 0.001), proteinuria (0% vs 18.18%, P = 0.011), gastrointestinal hemorrhage (0% vs 13.64%, P = 0.048) and hypertension (2.04% vs 36.36%, P &lt; 0.001) for any grade were also significantly lower in the DON-TACE group. Conclusions: DON-TACE and LEN-TACE showed comparable efficacy as first-line therapies for uHCC patients. DON-TACE demonstrated a lower incidence of severe adverse events.

Endoscopy of Low BMI Patients Compared to Normal BMI Patients: A Study From the Aseer Region, Saudi Arabia.

Gastrointestinal (GI) endoscopies are essential for detecting and treating various digestive tract problems. While typically safe, these treatments can entail the risk of severe adverse events (SAEs), especially in individuals with a low body mass index (BMI).The current study aimed to evaluate whether post-endoscopy SAEs are more common in patients with low BMI and find risk factors for serious adverse outcomes in Saudi Arabian patientsfrom Khamis Mushait, Aseer region, Saudi Arabia. The data of 398 adult patients with abdominal endoscopies between April and November 2023 were analyzed. Patients were divided into two groups: low BMI (BMI ≤ 18.5) and control (18.5 ≤ BMI ≤ 30). They were matched for age, gender, comorbidities, endoscopy type, and other pertinent characteristics. Low-BMI patients (Group I, n = 108) were substantially younger and had lower levels of albumin and total protein than the control group (Group II, n = 209). Comorbidities varied between groups, with diabetes mellitus more prevalent in Group II and inflammatory bowel disease (IBD) more commonplace in Group I. Treatment options also differed, with Group I receiving more biological treatments, steroids, and feeding tubes. Endoscopic procedures and indications were comparable among groups, with no significant variations in post-endoscopy complications. The endoscopy results varied from gastritis to colon malignancy, with no SAEs recorded in either group. Unlike earlier findings, this study found no higher incidence of SAEs in low-BMI individuals having abdominal endoscopy. This might be because of the restricted guidelines of different medical authorities, including clear informed consent that illustrates any risks, benefits, alternatives, sedation plan, and potential diagnostic or therapeutic interventions. Also, professional endoscopists and consultants who ensure adequate visualization of the GI mucosa, using mucosal cleansing and insufflation as necessary, should avoid any risk of abdominal hemorrhage. These findings highlight the significance of personalized risk assessment and pre-procedural optimization, including nutritional assistance, in this patient population. More prospective research with larger sample sizes is needed to validate these findings and create targeted techniques for improving outcomes in individuals with a low BMI having endoscopic operations.

Efficacy and safety of different cycles of neoadjuvant immunotherapy in resectable non-small cell lung cancer: A systematic review and meta-analysis

BackgroundThere is no standard consensus on the optimal number of cycles of neoadjuvant immunotherapy prior to surgery for patients with locoregionally advanced non-small cell lung cancer (NSCLC). We carried out a systematic review to evaluate the efficacy and safety of neoadjuvant immunotherapy with different treatment cycles in order to provide valuable information for clinical decision-making. MethodsPubMed, Embase, the Cochrane Library and ClinicalTrials.gov were systematically searched before May 2023. The included studies were categorized based on different treatment cycles of neoadjuvant immunotherapy to assess their respective efficacy and safety in patients with resectable NSCLC. ResultsIncorporating data from 29 studies with 1331 patients, we found major pathological response rates of 43 % (95%CI, 34–52 %) with two cycles and 33 % (95%CI, 22–45 %) with three cycles of neoadjuvant immunotherapy. Radiological response rates were 39 % (95%CI, 28–50 %) and 56 % (95%CI, 44–68 %) for two and three cycles, respectively, with higher incidence rates of severe adverse events (SAEs) in the three-cycle group (32 %; 95%CI, 21–50 %). Despite similar rates of R0 resection between two and three cycles, the latter showed a slightly higher surgical delay rate (1 % vs. 7 %). Neoadjuvant treatment modes significantly affected outcomes, with the combination of immunotherapy and chemotherapy demonstrating superiority in improving pathological and radiological response rates, while the incidence of SAEs in patients receiving combination therapy remained within an acceptable range (23 %; 95%CI, 15–35 %). However, regardless of the treatment mode administered, an increase in the number of treatment cycles did not result in substantial improvement in pathological response rates. ConclusionThere are clear advantages of combining immunotherapy and chemotherapy in neoadjuvant settings. Increasing the number of cycles of neoadjuvant immunotherapy from two to three primarily may not substantially improve the overall efficacy, while increasing the risk of adverse events. Further analysis of the outcomes of four cycles of neoadjuvant immunotherapy is necessary.

Effect of mTOR inhibitors on the mortality and safety of patients with lymphangioleiomyomatosis on the lung transplantation waitlist: A retrospective cohort study

BackgroundAlthough lung transplantation (LTx) is the last resort for patients with end-stage lymphangioleiomyomatosis (LAM), the high waitlist mortality is a source of concern in Japan. Discontinuation of mechanistic target of rapamycin (mTOR) inhibitors prior to LTx is recommended due to the incidence of severe adverse events. Therefore, we hypothesized that mTOR inhibitors may affect the mortality of patients with LAM on the LTx waitlist. MethodsWe retrospectively compared the characteristics of consecutive patients with LAM on the LTx waitlist who were and were not receiving mTOR inhibitors. ResultsTwenty-nine consecutive patients with LAM who listed our center between January 2004 and December 2021 were selected from the database and enrolled in the present study. Seventeen patients (58.6%) were receiving a mTOR inhibitor, sirolimus (treatment group). During a median listing period of 1277 days, 12 patients (41.4%) were hospitalized, six patients (20.7%) died from disease before LTx, and 15 patients underwent LTx. Among the deceased patients, four patients (66.6%) had pneumothoraces. The waitlist mortality in the treatment group was significantly lower than that in the non-treatment group (p = 0.03). Among the six patients who discontinued sirolimus in the treatment group, four patients (66.6%) were hospitalized with respiratory complications after the discontinuation of sirolimus. No mTOR inhibitor-related complications arose in the treatment group undergoing LTx (n = 7), including those on a reduced sirolimus dose. ConclusionsAdministration of an mTOR inhibitor until LTx may decrease waitlist mortality. Due to life-threatening events after discontinuing sirolimus pre-LTx, a reduced dose until LTx is permissible.

Efficiency of succinylated gelatin and amino acid infusions for kidney uptake reduction of radiolabeled αvβ6-integrin targeting peptides: considerations on clinical safety profiles

Purpose68Ga-Trivehexin is an investigational PET radiopharmaceutical (NCT05799274) targeting αvβ6-integrin for PET imaging of carcinomas. 177Lu-D0301 is a structurally related therapeutic peptide tetramer. However, it showed considerable kidney uptake in rodents, impeding clinical applicability. We therefore evaluated the impact of different kidney protection strategies on the biodistribution of both agents in normal and tumor-bearing mice.MethodsEx-vivo biodistribution of 68Ga-Trivehexin (90 min p.i.) and 177Lu-D0301 (90 min and 24 h p.i.) was determined in healthy C57BL/6N and H2009 (human lung adenocarcinoma) xenografted CB17-SCID mice without and with co-infusion of 100 µL of solutions containing 2.5% arginine + 2.5% lysine (Arg/Lys), 4% succinylated gelatin (gelofusine, gelo), or combinations thereof. Arg/Lys was injected either i.p. 30 min before and after the radiopharmaceutical, or i.v. 2 min before the radiopharmaceutical. Gelo was administered either i.v. 2 min prior activity, or pre-mixed and injected together with the radiopharmaceutical (n = 5 per group). C57BL/6N mice were furthermore imaged by PET (90 min p.i.) and SPECT (24 h p.i.).ResultsKidney uptake of 68Ga-Trivehexin in C57BL/6N mice was reduced by 15% (Arg/Lys i.p.), 25% (Arg/Lys i.v.), and 70% (gelo i.v.), 90 min p.i., relative to control. 177Lu-D0301 kidney uptake was reduced by 2% (Arg/Lys i.p.), 41% (Arg/Lys i.v.), 61% (gelo i.v.) and 66% (gelo + Arg/Lys i.v.) 24 h p.i., compared to control. Combination of Arg/Lys and gelo provided no substantial benefit. Gelo furthermore reduced kidney uptake of 177Lu-D0301 by 76% (90 min p.i.) and 85% (24 h p.i.) in H2009 bearing SCID mice. Since tumor uptake was not (90 min p.i.) or only slightly reduced (15%, 24 h p.i.), the tumor/kidney ratio was improved by factors of 3.3 (90 min p.i.) and 2.6 (24 h p.i.). Reduction of kidney uptake was demonstrated by SPECT, which also showed that the remaining activity was located in the cortex.ConclusionsThe kidney uptake of both investigated radiopharmaceuticals was more efficiently reduced by gelofusine (61–85%) than Arg/Lys (25–41%). Gelofusine appears particularly suitable for reducing renal uptake of αvβ6-integrin targeted 177Lu-labeled peptide multimers because its application led to approximately three times higher tumor-to-kidney ratios. Since the incidence of severe adverse events (anaphylaxis) with succinylated gelatin products (reportedly 0.0062–0.038%) is comparable to that of gadolinium-based MRI or iodinated CT contrast agents (0.008% and 0.04%, respectively), clinical use of gelofusine during radioligand therapy appears feasible if similar risk management strategies as for contrast agents are applied.

The efficacy and safety of molidustat for anemia in dialysis-dependent and non-dialysis-dependent chronic kidney disease patients: A systematic review and meta-analysis

ObjectiveMolidustat is a novel agent investigated for the treatment of anemia in both dialysisdependent (DD) and non-dialysis-dependent (NDD) patients. Its efficacy and safety are still unclear. MethodsWe searched five databases to identify randomized controlled trials comparing molidustat to erythropoiesis-stimulating agents (ESAs) or placebo in patients with anemia. ResultsSix studies containing 2025 eligible participants were identified. For NDD patients, the change in Hb levels from baseline (ΔHb) was significantly higher for molidustat than for placebo [mean difference (MD) = 1.47 (95 % CI: 1.18 to 1.75), P < 0.00001] and ΔHb was also significantly higher for molidustat than for ESAs [MD = 0.25 (95 % CI 0.09 to 0.40), P = 0.002]. For NDD patients, Δhepcidin was significantly lower for molidustat than for placebo [MD = −20.66 (95 % CI: −31.67 to −9.66), P = 0.0002] and Δhepcidin was also significantly lower for molidustat than for ESAs [MD = −24.51 (95 % CI: −29.12 to −19.90), P < 0.00001]. For NDD patients, Δiron was significantly lower for molidustat than for ESAs [MD = −11.85 (95 % CI: −15.52 to −8.18), P < 0.00001], and ΔTSAT was also significantly lower for molidustat than for ESAs [MD = −5.29 (95 % CI: −6.81 to −3.78), P < 0.00001]. For NDD patients, Δferritin was significantly lower for molidustat than for placebo [MD = −90.01 (95 % CI: −134.77 to −45.25), P < 0.00001]. However, for DD-CKD patients, molidustat showed an effect similar to that of ESAs on increasing the Hb level [MD = −0.18 (95 % CI: −0.47 to 0.11), P = 0.23], Δiron level [MD = 3.78 (95 % CI: −7.21 to 14.76), P = 0.5], Δferritin level [MD = 25.03 (95 % CI: −34.69 to 84.75), P = 0.41], and Δhepcidin level [MD = 1.20 (95 % CI: −4.36 to 6.76), P = 0.67]. For DD-CKD patients, compared with the placebo or ESA group, molidustat showed a significantly higher level on ΔTSAT[MD = 3.88 (95 % CI: 2.10 to 5.65), P < 0.0001] and a slightly increased level on ΔTIBC level [MD = 1.08 (95 % CI: −0.07 to 2.23), P = 0.07]. There was no significant difference in the incidence of severe adverse events (SAEs), death, and cardio-related adverse events between molidustat and the ESAs groups. ConclusionsMoricizine can effectively improves Hb levels in NDD patients and corrects anemia in DD patients without increasing adverse event incidence.

The Incidence of Postoperative Complications Following Lumbar and Bone Marrow Punctures in Pediatric Anesthesia: Insights From APRICOT.

Bone marrow aspiration and lumbar puncture are procedures frequently performed in pediatric oncology. We aimed at assessing the incidence and risk factors of perioperative complications in children undergoing these procedures under sedation or general anesthesia. Based on the APRICOT study, we performed a secondary analysis, including 893 children undergoing bone marrow aspiration and lumbar puncture. The primary outcome was the incidence of perioperative complications. Secondary outcomes were their risk factors. We analyzed data of 893 children who underwent 915 procedures. The incidence of severe adverse events was 1.7% and of respiratory complications was 1.1%. Prematurity (RR 4.976; 95% CI 1.097-22.568; P = 0.038), intubation (RR: 6.80, 95% CI 1.66-27.7; P =0.008), and emergency situations (RR 3.99; 95% CI 1.14-13.96; P = 0.030) increased the risk for respiratory complications. The incidence of cardiovascular instability was 0.4%, with premedication as risk factor (RR 6.678; 95% CI 1.325-33.644; P =0.021). A low incidence of perioperative adverse events was observed in children undergoing bone marrow aspiration or lumbar puncture under sedation and/or general anesthesia, with respiratory complications being the most frequent. Careful preoperative assessment should be undertaken to identify risk factors associated with an increased risk, allowing for appropriate adjustment of anesthesia management.

P763 Rare and severe adverse events in pediatric inflammatory bowel disease: identification of safety signals through the international prospective PIBD-SETQuality Safety Registry

Abstract Background Rare but severe adverse events (AEs) can occur in pediatric inflammatory bowel disease (PIBD) due to ongoing inflammation, secondary to immunosuppressive drugs or as coincidental finding. These events can lead to significant disability or even death. Limited prospective research hampers the understanding of the incidences, risk factors, and outcomes associated with these events. Methods As part of the ongoing international PIBD-SETQuality Safety Registry, participating pediatric gastroenterologists prospectively reported the occurrence of any of 10 listed rare and severe AEs in their PIBD patient population (&amp;lt;19 years) via monthly electronic surveys since October 2016. Additionally, physicians could report ‘other rare and severe AEs’. Participants received an annual denominator survey, to report the number of PIBD patients under their care. Incidence rates (IRs) were calculated for each AE using Poisson regression models and were compared between countries. Upon reporting AEs, participants received specific follow-up forms to collect patient and IBD characteristics, as well as complication details (diagnosis, risk factors, management, outcome). Results Over a 77-month study period (October 2016 to April 2023), 222 pediatric gastroenterologists from 167 centers across 36 countries actively contributed to the registry, completing 7,975 monthly surveys with a median response rate of 86% [IQR 82%-88%]. On average, participants contributed for 53 months [IQR 25-72]. They covered 30,192 PIBD patients, with 114,528 patient-years (PY) of follow-up. In total, 285 listed complications were reported, alongside 117 uncategorized ‘other rare and severe AEs’. The highest IRs (95%CI) per 10,000 PY were found for VTE (IR 5.50 [2.74-4.99]), renal failure (IR 3.67 [2.67-4.89]), opportunistic infections (IR 2.88 [2.01-3.98]), and cancer (IR 2.71 [1.86-3.77]) (Figure 1). The lowest IRs (95%CI) per 10,000 PY were found for liver failure (IR 0.35 [0.11-0.81]) and HLH (IR 0.52 [0.21-1.06]). Combined IRs of the listed AEs did not differ among the five countries with the highest contribution of PY (p=0.18). Conclusion Through international collaboration among a large network of PIBD specialists, the Safety Registry has confirmed the increased incidence of several AEs in PIBD, including VTE, cancer and renal failure. Clinical characterization of these events may lead to a better understanding of their underlying etiologies and outcomes. This improves patient care by providing guidance for management development, facilitating well informed clinical decision making and may lead to prevention of these rare and severe events.

Brentuximab Vedotin in the Treatment of Cutaneuous T Cell Lymphomas: A Multicenter, Retrospective, Case-Control Study from Italy

Brentuximab Vedotin (BV) is an anti-CD30 monoclonal antibody approved for relapsed/refractory CD30+ cutaneous T-cell lymphomas. The posology recommends its use until disease progression, unbearable toxicity, or completion of 16 cycles. A common side effect of BV is peripheral neuropathy (PN), which may lead to chronic complications and often leads to early treatment interruption. To reduce long-term side effects, clinicians often choose to interrupt BV early when the patient shows an adequate response. However, it remains uncertain whether this approach effectively reduces the incidence of PN. Furthermore, it is unknown whether this reduction in cumulative dose negatively impacts the relapse-free interval (RFI) or the time to next treatment (TTNT). This study aims to investigate whether a reduced BV treatment schedule is beneficial in terms of severe side effects compared to the standard schedule and to compare RFI and TTNT between the two schedules. The study was conducted retrospectively as a multicenter, observational case-control study. Clinical and pathological data from 71 patients (44 males, median age 66 yeas) were analyzed. Various CTCLs subtypes were represented in the study population (43 had MF, 7 had folliculotropic MF, 10 had pc ALCL, 3 had PTCL-NOS, and 8 had SS). The median follow-up duration was 525 days. Of the patients, 11 (15.4%) completed 16 cycles of BV, 21 (29.6%) stopped treatment due to disease progression (PD), 12(16.9%) experienced severe adverse events, 20 (28.1%) stopped treatment due to an adequate response based on the clinician's decision, the remaining patients were still under treatment at the time of data cut-off. Out of the 71 patients, 20 developed PN, with 6 of them experiencing severe (G3) symptoms. At the last follow-up, 7 (35%) cases of PN had resolved, 8 were mild (G1), and 5 remained moderate (G2). No differences were observed in PN incidence or the number of infusions between patients who achieved an adequate clinical response and those who developed PN. No significant differences were observed in the median number of BV infusions between the groups. Age at the time of the first infusion was the only variable associated with an increased risk of toxicity. However, no significant correlation was found between any variable and the incidence of PN. The median RFI for patients receiving all 16 cycles was 882 days (95% CI 461, NA), compared to 357 days (95%CI 313, NA) for those who stopped BV after an adequate response, but this difference was not statistically significant (Pv=0.25). Similarly, the median TTNT in patients receiving all 16 cycles was 814 days (lower 95% CI = 458, upper NA), compared to 502 days in patients who stopped BV after achieving an adequate response (324, NA; pV=0.6). In conclusion, based on the data analyzed, early interruption of BV after achieving an adequate response did not significantly reduce the incidence of severe adverse events or PN. Further data are required to determine if early interruption of BV negatively impacts patients' RFI or TTNT.

Combination Chemotherapy in Patients with Newly Diagnosed Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCN): First Results of a Prospective French Trial (LpDessai)

Introduction Blastic plasmacytoid dendritic cell neoplasms (BPDCN) are now well-characterized diseases clearly referenced in the 5 th edition of the World Health Organization (WHO) Classification of Tumors (2022) 1 but treatment remains a real challenge. There is no consensus on the first line treatment even if CD123 targeted therapies are available in the USA and some European countries. Standard chemotherapy remains largely used as first line treatment with better results of leukemia-based regimens despite a high toxicity rate in this frail population 2,3. To establish a reference chemotherapy scheme, we prospectively evaluated the efficacy and toxicity of a combination chemotherapy (idarubicin, methotrexate, L-asparaginase, and dexamethasone) in newly diagnosed BPDCN patients (pts) in France. Patients and methods This single stage phase II study enrolled consecutive adult pts with suspected BPDCN in participating French centers. BPDCN diagnosis was centrally reviewed for cytology and immunophenotype (IF) (Pr Garnache Ottou F, UMR RIGHT BESANCON) and if needed for histology (Dr Petrella T, Montréal, Canada) according to published recommendations 1,4. After giving their informed consent, patients were evaluated for tumoral involvement by PET-scan, systematic lumbar puncture, and the mSWAT score was calculated for skin extension. Patients then received three 21 days-cycles of Ida/Metho/L-asp/Dex combination, before evaluation. Eligible patients with complete response (CR), complete response with incomplete bone marrow recovery (CRi) or partial response (PR) underwent allogeneic hematopoietic stem cell transplantation (HCT). Those not eligible received consolidation chemotherapy with 28 days cycles of Metho/L-asp/Dex (Figure 1). The primary objective was the proportion of patients with CR after 3 cycles of chemotherapy. Secondary objectives were the proportion of patients with an objective response (ORR) defined as CR, CRi or PR, the minimal residual disease (MRD) in responding patients evaluated by the presence of plasmacytoid dendritic cell blast measured by flow cytometry in the bone marrow, the incidence of severe adverse events and overall survival (OS). The competent ethics committee (Comité de Protection des Personnes Île de France 8) approved the study. The Besançon University hospital promoted the trial, financed by a grant of the French National Cancer Institute (INCa-DGOS_11093). Results Twenty-eight pts, originating from 16 centers, were screened between May 2019 and March 2023. Two patients with a misdiagnosis were screen failures. Two patients did not receive the planned chemotherapy due to clinical deterioration; 24 patients (21 male, 3 female) received at least one chemotherapy cycle and 23 are analyzed with a current end-point on June 30, 2023. Median age was 65y (21-79y). ECOG status was 0-1 in 20 cases, and 2 in 3 cases. A cutaneous involvement was identified in 16 pts (70%) and an extra medullary involvement was present in 13 (62%) pts: spleen, n= 6 (25%); lymph nodes, n= 7 (30%). Twenty-three pts (90%) had a bone marrow infiltration (identified only on IF in 4 cases), and 3 cases (14%) a documented central nervous system involvement. Nine pts had to stop planned treatment due to severe adverse events (3 deaths, 4 acute renal failure and 2 grade 4 febrile neutropenia) and in 4 pts, at least one cycle had to be delayed. Among the 15 pts receiving at least 3 cycles, 12 (80% and 50% of the whole cohort) were in ORR (CR = 8, CRi = 2, PR = 2) after the 3rd cycle of chemotherapy, 2 pts did not respond. Eight of ten (80%) CR/CRi pts had a MRD &amp;lt; 10 -4 without any further relapse. Nine of 12 responding patients (75%) received an allogeneic HCT 1-2 months after the end of the 3 rd cycle. Global OS at 6 months for responding or failing pts were 100% and 37% respectively (Figure 2). Conclusion In selected pts, an adapted chemotherapy could offer high CR rate in pts able to follow the planned treatment but remains toxic in frail pts, with only half of the them achieving a 3 rd cycle of chemotherapy. We confirm that pts achieving ORR and receiving HCT obtain prolonged CR. MRD level seems to correlate with OS and could be a useful tool to manage treatment toxicity in BPDCN frail pts.

Early Outcomes of Interwoven Nitinol Wire Stent Placement versus Endarterectomy for the Treatment of Atherosclerotic Disease of the Common Femoral Artery

PurposeTo compare the clinical outcomes of common femoral artery (CFA) atherosclerotic disease treated with either surgical endarterectomy or an interwoven nitinol wire stent system. Materials and MethodsA retrospective review was conducted of all patients with chronic, de novo atherosclerotic CFA disease treated with surgical endarterectomy (CFAE) or stent placement between July 2019 and March 2022. Outcome measures assessed up to 12 months after procedure included clinical improvement, primary restenosis, target vessel revascularization (TVR), major adverse limb events (MALEs), and all-cause mortality. ResultsThirty-nine stents were deployed in 33 patients, and 56 CFAEs were performed in 55 patients. No differences were noted in the rate of primary patency (95.5% vs 94.4%, P = .618), TVR (2.9% vs 1.8%, P = .777), MALE (5.1% vs 5.4%, P = .949), and all-cause mortality (14.1% vs 3.6%, P = .076) between the stent and CFAE groups up to 12 months after procedure. There was greater improvement in median clinical severity in the stent group than in the CFAE group (Rutherford score change of 3.0 vs 1.5, P = .013). The median length of stay was less for the stent group (3 vs 7 days, P = .002), and there was a lower likelihood of severe or disabling adverse events in the stent group (0 vs 9 cases, P = .010). ConclusionsPatients treated with an interwoven nitinol wire stent had patency rates comparable to those treated with CFAE while having a lower incidence of severe adverse events and a shorter length of hospital stay than those who underwent CFAE.

Treatment of active systemic lupus erythematosus with baricitinib: A meta-analysis of randomized controlled trials.

This study aimed to evaluate the safety and effectiveness of baricitinib in patients with systemic lupus erythematosus (SLE). We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Register to find relevant publications. Using data from randomized controlled trials (RCTs), we performed a meta-analysis to investigate the safety and efficacy of baricitinib in patients with active SLE who did not respond well to standard treatments. A total of 1849 individuals (1235 experimental participants and 614 controls) from three RCTs on baricitinib were included. A reduction of ≥ 4 points from baseline in SLEDAI-2K score in the baricitinib 4mg group was greater than the placebo group's reduction (odds ratio [OR] = 1.407, 95% confidence interval [CI] 1.123-1.763, p = .003). The baricitinib 4mg group significantly outperformed the placebo group in terms of SLEDAI-2K remission of arthritis or rash (OR = 1.327, 95% CI = 1.059-1.663, p = .014). Other effectiveness outcomes such as the SRI4 response did not substantially improve in the baricitinib 4mg group when compared with the placebo group. And there were no significant increase in the efficacy outcomes in the baricitinib 2mg group than in the placebo group. However, there was a substantially higher incidence of severe adverse events (SAE) and serious infections in the baricitinib 4mg group (OR = 1.493, 95% CI = 1.002-2.225, p = .049; OR = 2.303, 95% CI = 1.147-4.622, p = .019) compared to the placebo group. There were no differences between the baricitinib 2mg and placebo groups in any of the safety outcome data. Meta-analysis reveals that baricitinib 4mg is beneficial for treating active SLE in terms of a reduction of ≥ 4 points from baseline in SLEDAI-2K score and SLEDAI-2K remission of arthritis or rash. However, the higher frequency of SAEs and serious infections was observed in the group receiving baricitinib 4mg.

Awake Tracheal Intubation Is Associated with Fewer Adverse Events in Critical Care Patients than Anaesthetised Tracheal Intubation.

Tracheal intubation in critical care is a high-risk procedure requiring significant expertise and airway strategy modification. We hypothesise that awake tracheal intubation is associated with a lower incidence of severe adverse events compared to standard tracheal intubation in critical care patients. Records were acquired for all tracheal intubations performed from 2020 to 2022 for critical care patients at a tertiary hospital. Each awake tracheal intubation case, using a videolaryngoscope with a hyperangulated blade (McGrath® MAC X-Blade), was propensity matched with two controls (1:2 ratio; standard intubation videolaryngoscopy (VL) and direct laryngoscopy (DL) undergoing general anaesthesia). The primary endpoint was the incidence of adverse events, defined as a mean arterial pressure of <55 mmHg (hypotension), SpO2 < 80% (desaturation) after sufficient preoxygenation, or peri-interventional cardiac arrest. Of the 135 tracheal intubations included for analysis, 45 involved the use of an awake tracheal intubation. At least one adverse event occurred after tracheal intubation in 36/135 (27%) of patients, including awake 1/45 (2.2%; 1/1 hypotension), VL 10/45 (22%; 6/10 hypotension and 4/10 desaturation), and DL 25/45 (47%; 10/25 hypotension, 12/25 desaturation, and 3/25 cardiac arrest; p < 0.0001). In this retrospective observational study of intubation practices in critical care patients, awake tracheal intubation was associated with a lower incidence of severe adverse events than anaesthetised tracheal intubation.