Incidence Of Severe Adverse Events Research Articles

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.

68Ga-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. Ex-vivo biodistribution of 68Ga-Trivehexin (90min p.i.) and 177Lu-D0301 (90min and 24h p.i.) was determined in healthy C57BL/6N and H2009 (human lung adenocarcinoma) xenografted CB17-SCID mice without and with co-infusion of 100µL 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. 30min before and after the radiopharmaceutical, or i.v. 2min before the radiopharmaceutical. Gelo was administered either i.v. 2min prior activity, or pre-mixed and injected together with the radiopharmaceutical (n = 5 per group). C57BL/6N mice were furthermore imaged by PET (90min p.i.) and SPECT (24h p.i.). Kidney 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.), 90min 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.) 24h 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% (90min p.i.) and 85% (24h p.i.) in H2009 bearing SCID mice. Since tumor uptake was not (90min p.i.) or only slightly reduced (15%, 24h p.i.), the tumor/kidney ratio was improved by factors of 3.3 (90min p.i.) and 2.6 (24h p.i.). Reduction of kidney uptake was demonstrated by SPECT, which also showed that the remaining activity was located in the cortex. The 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.

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.

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.

Efficacy and safety of gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel in treatment-naïve advanced pancreatic ductal adenocarcinoma.

Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.

Is acupuncture safe in the ICU? A systematic review and meta-analysis.

The safety of interventions for critically ill patients is a crucial issue. In recent years, several studies have treated critically ill patients with acupuncture. However, the safety of acupuncture in this setting remains to be systematically measured. In May 2022, the electronic databases of PubMed and the Cochrane Library were searched for studies comparing acupuncture interventions to control interventions in critically ill patients. Study outcomes examined the incidence of severe adverse events (AEs), minor AEs, adverse reactions, ICU stays, and 28-day mortality. A total of 31 articles were analyzed, and no serious AEs related to acupuncture treatment were identified. No significant differences were found between the groups in the meta-analysis of minor AEs (risk ratio [RR] 5.69 [0.34, 96.60], P = 0.23, I2 = 76%). A reduced risk in the incidence of adverse reactions following acupuncture intervention was evidenced (RR 0.33 [0.22, 0.50], P = 0.00001, I2 = 44%). The patients in the acupuncture arm spent significantly less time in the intensive care unit (ICU) (Mean difference -1.45 [-11.94, -10.97], P = 0.00001, I2 = 56%) and also exhibited lower 28-day mortality rates (odds ratio 0.61 [0.48, 0.78], P = 0.0001, I2 = 0%). There is no evidence to indicate a higher risk of severe or minor AEs in patients who receive acupuncture. Acupuncture demonstrated favorable results in both ICU stay and 28-day mortality measurements, in addition to presenting with fewer adverse reactions compared to routine ICU care. However, the low certainty of the evidence resulting from a high risk of bias in the included studies merits substantial consideration, and further research is still warranted. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=142131, identifier: CRD42020142131.

Percutaneous paravalvular leak closure after transcatheter aortic valve implantation: the international PLUGinTAVI Registry.

Data regarding the safety and long-term effectiveness of percutaneous closure of paravalvular leak (PVL) after transcatheter aortic valve implantation (TAVI) are scarce. This study aims to present alarge multicentre international experience of percutaneous post-TAVI PVL closure. All patients who underwent percutaneous post-TAVI PVL closure in 14 hospitals across Europe and North America between January 2018 and October 2022 were included. Overall, 45 patients (64% male) were enrolled. The median age was 80 years (75-84). Among them, 67% and 33% had self-expanding and balloon-expandable valve implantations, respectively. Baseline post-TAVI PVL was severe in 67% of cases and moderate in the rest. The time from index TAVI to PVL closure procedure was 16.1 (8.7-34.8) months. Most patients were in NYHA Class III and IV (73%) before the procedure, and 40% had referred hospitalisations for heart failure between TAVI and the PVL closure procedure. Successful PVL closure was achieved in 94%, reducing regurgitation to ≤mild in 91% and moderate in the rest. The Amplatzer Valvular Plug III was the most frequently used device (27 cases), followed by the Amplatzer Valvular Plug 4. The incidence of severe adverse events was 11%. None of the patients died during the index hospitalisation. During long-term follow-up (21.7±16.2 months), the all-cause mortality rate was 14%, and patients presented improvement in functional status and asignificant reduction in the rate of hospitalisation for heart failure (from 40% to 6%). Percutaneous PVL closure is afeasible and safe option for treating post-TAVI leaks. Successful PVL reduction to mild or less could be associated with acute and long-lasting improvements in clinical outcomes.

Assessing the Optimal Regimen: A Systematic Review and Network Meta-Analysis of the Efficacy and Safety of Long-Acting Granulocyte Colony-Stimulating Factors in Patients with Breast Cancer.

Patients with breast cancer undergoing chemotherapy are susceptible to prolonged and severe neutropenia. Multiple biosimilars of long-acting granulocyte colony-stimulating factors (LA-G-CSFs) have been newly developed to prevent this disease. Nonetheless, which LA-G-CSF regimen has the optimal balance of efficacy and safety remains controversial. Moreover, there is a lack of evidence supporting clinical decisions on LA-G-CSF dose escalation in poor conditions. PubMed, Embase, Cochrane Library, Web of Science, and several Chinese databases were searched (December 2022) to collect randomized controlled trials (RCTs) about LA-G-CSFs preventing chemotherapy-induced neutropenia in breast cancer patients. No restrictions were imposed on language. A Bayesian network meta-analysis was performed. We assessed the incidence of severe neutropenia (SN) and febrile neutropenia (FN), the duration of SN (DSN), and the absolute neutrophil account recovery time (ANCrt) for efficacy, while the incidence of severe adverse events (SAE) was assessed for safety. The study was registered in PROSPERO (CRD42022361606). A total of 33 RCTs were included. Our network meta-analysis demonstrated that lipegfilgrastim 6 mg and eflapegrastim 13.2 mg outperformed other LA-G-CSFs with high efficacy rates and few safety concerns (SUCRA of lipegfilgrastim 6 mg: ANC rt 95.2%, FN 97.4%; eflapegrastim 13.2 mg: FN 87%, SN 89.3%). Additionally, 3.6 mg, 4.5 mg, 6 mg, and 13.2 mg dosages all performed significantly better than 1.8 mg in reducing the duration of SN (3.6 mg: DSN, SMD -0.68 [-1.13, -0.22; moderate]; 4.5 mg: -0.87 [-1.57, -0.17; low]; 6 mg: -0.89 [-1.49, -0.29; moderate]; 13.2 mg: -1.02 [1.63, -0.41; high]). Increasing the dosage from the guideline-recommended 6 mg to 13.2 mg can reduce both the duration and incidence of SN (SMD -0.13 [-0.24 to -0.03], RR 0.65 [0.43 to 0.96], respectively), with no significant difference in SAE. For patients with breast cancer, lipegfilgrastim 6 mg and eflapegrastim 13.2 mg might be the most effective regimen among LA-G-CSFs. Higher doses of LA-G-CSF may enhance efficacy without causing additional SAEs.

First-line osimertinib for patients with EGFR-mutated advanced non-small cell lung cancer: efficacy and safety during the COVID-19 pandemic.

The FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease 2019 (COVID-19) pandemic. Patients diagnosed with EGFR-mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models. The cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged ≥75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1-26.2] and 25.4 months (95% CI: 20.3-not reached), respectively. On multivariable analysis, age ≥75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), programmed death ligand 1 (PD-L1) expression ≥50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. A proportion of 16.5% of the cohort developed grade ≥3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94-7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19. In a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS ≥2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.

A Comparison of the Outcomes of Transarterial Chemoembolization and Transarterial Radioembolization in the Management of Neuroendocrine Liver Metastases in Adults: A Systematic Review.

The purpose of this article is to review the existing English scientific literature and determine the superior modality between transarterial chemoembolization (TACE) and radioembolization (TARE) in the treatment of neuroendocrine liver metastases (NELMs). To that end, we followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to search PubMed, the Cochrane Library, and Google Scholar. We identified 14 observational studies and no randomized controlled trials (RCTs) investigating the use of TACE or TARE to treat NELM. We used the Newcastle-Ottawa Scale to assess the risk of bias in these studies. We concluded that TACE and TARE appeared to have similar outcomes when comparing overall survival, progression-free survival, radiological response, symptomatic response, and the incidence of severe adverse events. Further large-scale RCTs are needed to identify the superior modality conclusively. We also identified several unique prognostic factors for overall survival, such as the neutrophil-lymphocyte ratio, volumetric multiparametric magnetic resonance imaging, serum albumin, alkaline phosphatase, and pancreastatin.

Endoscopic submucosal dissection for early cancers or precancerous lesions of the upper gastrointestinal tract in cirrhotic patients with esophagogastric varices: Ten-year experience from a large tertiary center in China.

Treatment strategies for early cancers or precancerous lesions of the upper gastrointestinal tract in cirrhotic patients with esophagogastric varices (EGV) are complicated and risky. We aimed to assess the efficacy and safety of endoscopic submucosal dissection (ESD) in the treatment of such patients and explore optimal treatment strategies. We retrospectively enrolled 15 cirrhotic patients with EGV who underwent ESD for early cancers or precancerous lesions of the upper gastrointestinal tract from January 2012 to December 2021 at our center. Clinical features, endoscopic findings, treatment methods, adverse events and follow-up data were analyzed. Of the 15 patients, 1 had a platelet count <30×1000/mm3. Five were untreated for EGV, 1 was treated after ESD, 6 were treated before ESD, 1 was treated before and during ESD, and 2 were treated during ESD. The R0 resection rate was 100%. Of the 16 mucosal lesions, 15 were ERB-0 or ERB-c1, and 1 was ERB-c2. No patient experienced deterioration in liver function. The only adverse events were fever in 2 patients and postoperative bleeding (PB) in 2 patients. During a median follow-up of 27 months, 1 patient's esophageal HGD recurred at 19 months. No death resulted from the ESD procedure, liver function injury or gastrointestinal tumor itself. ESD is an effective and safe treatment for early cancers or precancerous lesions of the upper gastrointestinal tract in cirrhotic patients with EGV. The incidence of severe adverse events is very low due to the development of individualized clinical treatment strategies.

Real-world effectiveness and safety of multiple myeloma treatments based on thalidomide and bortezomib: A retrospective cohort study from 2009 to 2020 in a Brazilian metropolis

BackgroundMultiple myeloma (MM) is an incurable cancer of plasma cells; the survival of which has improved over the years with the emergence of new treatments. In Brazil, the availability of treatment-regimens is different from developed countries. Real-world evidence with Brazilian patients is lacking. ObjectivesOur aim was to evaluate the effectiveness and the safety of MM treatments in a Brazilian metropolis. MethodsThis was a retrospective cohort study with MM patients, beginning MM treatment from 2009 to 2020 (i.e., before bortezomib became available in public health services). Patients’ medical records were revised to obtain clinical variables. The primary outcomes were Overall Survival (OS) and Progression Free Survival (PFS, measured as time to next treatment), and the secondary outcomes were Adverse Events (AE). Kaplan-Meier curves were obtained and the Cox proportional hazards model was performed for univariate and multivariate analyses. The incidence of AE was estimated and the chi-squared test was performed to evaluate the association between AE and MM regimens. ResultsIn total, 278 patients participated in the study with median age of 64 years; 50.4 % were females, 55.8 % attended a private clinic, 34.9 % received autologous stem cell transplantation (ASCT) and 32.4 % were on polypharmacy. Most patients from public services used thalidomide-based regimens (40.3 %) and at private clinics used bortezomib-based regimens (38.1 %) as first-line treatment. Patients had a median OS of 99 months. Patients had median PFS of 28 months in first-line treatment, which was significantly different for age (p = 0.0055), polypharmacy (p = 0.0094) and ASCT (p < 0.0001). PFS was independently associated to polypharmacy and ASCT. The incidence of peripheral neuropathy (39.6 %) was high. In contrast, the incidence of severe AE was low. We found significant difference between first-line T + B-based regimens and leukopenia (p = 0.012). ConclusionOur study showed that patients on polypharmacy and who did not receive ASCT had worse PFS. Similar to other Latin countries, most patients used thalidomide- and bortezomib-based regimens as first-line treatments having similar OS and PFS. Treatments were considered relatively safe, especially regarding serious AE.

Performance and Safety of EUS Ablation Techniques for Pancreatic Cystic Lesions: A Systematic Review and Meta-Analysis.

Pancreatic cystic lesions (PCL) represent an increasingly diagnosed condition with significant burden to patients' lives and medical resources. Endoscopic ultrasound (EUS) ablation techniques have been utilized to treat focal pancreatic lesions. This systematic review with meta-analysis aims to assess the efficacy of EUS ablation on PCL in terms of complete or partial response and safety. A systematic search in Medline, Cochrane and Scopus databases was performed in April 2023 for studies assessing the performance of the various EUS ablation techniques. The primary outcome was complete cyst resolution, defined as cyst disappearance in follow-up imaging. Secondary outcomes included partial resolution (reduction in PCL size), and adverse events rate. A subgroup analysis was planned to evaluate the impact of the available ablation techniques (ethanol, ethanol/paclitaxel, radiofrequency ablation (RFA), and lauromacrogol) on the results. Meta-analyses using a random effects model were conducted and the results were reported as percentages with 95% confidence intervals (95%CI). Fifteen studies (840 patients) were eligible for analysis. Complete cyst resolution after EUS ablation was achieved in 44% of cases (95%CI: 31-57; 352/767; I2 = 93.7%), and the respective partial response rate was 30% (95%CI: 20-39; 206/767; I2 = 86.1%). Adverse events were recorded in 14% (95%CI: 8-20; 164/840; I2 = 87.2%) of cases, rated as mild in 10% (95%CI: 5-15; 128/840; I2 = 86.7%), and severe in 4% (95%CI: 3-5; 36/840; I2 = 0%). The subgroup analysis for the primary outcome revealed rates of 70% (95%CI: 64-76; I2 = 42.3%) for ethanol/paclitaxel, 44% (95%CI: 33-54; I2= 0%) for lauromacrogol, 32% (95%CI: 27-36; I2 = 88.4%) for ethanol, and 13% (95%CI: 4-22; I2 = 95.8%) for RFA. Considering adverse events, the ethanol-based subgroup rated the highest percentage (16%; 95%CI: 13-20; I2 = 91.0%). EUS ablation of pancreatic cysts provides acceptable rates of complete resolution and a low incidence of severe adverse events, with chemoablative agents yielding higher performance rates.