Number Of Severe Adverse Events Research Articles

Abstract 3560: Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials

Abstract Background: Serious adverse events (SAEs) are a critical determinant of drug toxicity in clinical trials. However the drivers of toxicity may be related to patient factors as much or more than drug related factors. Prior studies have shown that time in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. SAEs are a critical determinant of drug toxicity in clinical trials. However, predicting SAEs using conventional PS scales measurements, such as ECOG is challenging because measurements can vary among observers. Prior studies have used activity trackers to measure physical activity and showed that time spent in non-sedentary activity predicted toxicity in cancer patients receiving highly emetogenic chemotherapy. Here, we sought to extend these findings to early phase clinical trial participants by examining data collected in two single-arm, observational, prospective studies at USC Keck and MD Anderson centers. We explored the use of out-of-clinic wearable sensors as an objective metric of frailty so as to identify patients at risk for therapy complications. Methods: Adult patients diagnosed with cancer and enrolled in early stage clinical trials across USC Keck and MD Anderson centers were included in parallel single-arm, observational, prospective studies. Patients used a consumer grade wearable activity tracker (Fitbit) and the study examined associations between the number of severe adverse events to activity levels measured by metabolic equivalents (METs) and get-up-go times across the first 30 days. Trends were assessed using t-tests. Results: 36 eligible patients were included in METs activity analysis. There was a total of 16 recorded incidences of SAEs within the first 30 study days, with 10 patients experiencing at least one SAE. The median non-sedentary time for patients with no SAEs was 27.5 hours above 1.5 METs per week, compared to 21.5 hours for those with at least one SAE occurrence (p-value=0.0146, r2=0.1629). The median get-up-go times for those without SAEs was 10.0 seconds (n=26) and with SAEs was 9.8 seconds (n=10), (p-value=0.828, r2=0.0014). Conclusions: Non-sedentary time, as an objective measure of activity, can be used to identify those patients who are at greatest risk for SAEs in clinical trials. Widely available and inexpensive consumer grade sensors can be used as a stratification tool. Findings should be confirmed in larger patient cohorts across a wider variety of trial settings. Figure 1: Weekly non-sedentary hours vs. presence of SAE in first 30 days of trial enrollment Citation Format: Eli Tran, Luciano Nocera, Anand Kolatkar, Anthony El-Khoueiry, Jacob Thomas, Peter Kuhn, Andrew Zeng, Megumi Kai, Meghan Karuturi, Jorge Nieva. Quantified kinematics and wearable sensors to predict serious adverse events in patients undergoing cancer therapy trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3560.

Intraventricular Lavage vs External Ventricular Drainage for Intraventricular Hemorrhage

Intraventricular lavage has been proposed as a minimally invasive method to evacuate intraventricular hemorrhage. There is little evidence to support its use. To evaluate the safety and potential efficacy of intraventricular lavage treatment of intraventricular hemorrhage. This single-blinded, controlled, investigator-initiated 1:1 randomized clinical trial was conducted at Aarhus University Hospital and Odense University Hospital in Denmark from January 13, 2022, to November 24, 2022. Follow-up duration was 90 days. The trial was set to include 58 patients with intraventricular hemorrhage. Prespecified interim analysis was performed for the first 20 participants. Data were analyzed from February to April 2023. Participants were randomized to receive either intraventricular lavage or standard drainage. The main outcome was risk of catheter occlusions. Additional safety outcomes were catheter-related infections and procedure time, length of stay at the intensive care unit, duration of treatment, and 30-day mortality. The main outcome of the prespecified interim analysis was risk of severe adverse events. Efficacy outcomes were hematoma clearance, functional outcome, overall survival, and shunt dependency. A total of 21 participants (median [IQR] age, 67 [59-82] years; 14 [66%] male) were enrolled, with 11 participants randomized to intraventricular lavage and 10 participants randomized to standard drainage; 20 participants (95%) had secondary intraventricular hemorrhage. The median (IQR) Graeb score was 9 (5-11), and the median (IQR) Glasgow Coma Scale score was 6.5 (4-8). The study was terminated early due to a significantly increased risk of severe adverse events associated with intraventricular lavage at interim analysis (risk difference for control vs intervention, 0.43; 95% CI, 0.06-0.81; P = .04; incidence rate ratio for control vs intervention, 6.0; 95% CI, 1.38-26.1; P = .01). The rate of catheter occlusion was higher for intraventricular lavage compared with drainage (6 of 16 patients [38%] vs 2 of 13 patients [7%]; hazard ratio, 4.4 [95% CI, 0.6-31.2]; P = .14), which met the prespecified α = .20 level. Median (IQR) procedure time for catheter placement was 53.5 (33-75) minutes for intraventricular lavage vs 12 (4-20) minutes for control (P < .001). This randomized clinical trial of intraventricular lavage vs standard drainage found that intraventricular lavage was encumbered with a significantly increased number of severe adverse events. Caution is recommended when using the device to ensure patient safety. ClinicalTrials.gov Identifier: NCT05204849.

Independent Prognostic Factors Associated With Improved Patient-Reported Outcomes in the Prospective Evaluation of Elderly Deformity Surgery (PEEDS) Study.

Prospective, multicenter, international, observational study. Identify independent prognostic factors associated with achieving the minimal clinically important difference (MCID) in patient reported outcome measures (PROMs) among adult spinal deformity (ASD) patients ≥60years of age undergoing primary reconstructive surgery. Patients ≥60years undergoing primary spinal deformity surgery having ≥5levels fused were recruited for this study. Three approaches were used to assess MCID: (1) absolute change:0.5 point increase in the SRS-22r sub-total score/0.18 point increase in the EQ-5D index; (2) relative change: 15% increase in the SRS-22r sub-total/EQ-5D index; (3) relative change with a cut-off in the outcome at baseline: similar to the relative change with an imposed baseline score of ≤3.2/0.7 for the SRS-22r/EQ-5D, respectively. 171 patients completed the SRS-22r and 170 patients completed the EQ-5D at baseline and at 2years postoperative. Patients who reached MCID in the SRS-22r self-reported more pain and worse health at baseline in both approaches (1) and (2). Lower baseline PROMs ((1) - OR: .01 [.00-.12]; (2)- OR: .00 [.00-.07]) and number of severe adverse events (AEs) ((1) - OR: .48 [.28-.82]; (2)- OR: .39 [.23-.69]) were the only identified risk factors. Patients who reached MCID in the EQ-5D demonstrated similar characteristics regarding pain and health at baseline as the SRS-22r using approaches (1) and (2). Higher baseline ODI ((1) - OR: 1.05 [1.02-1.07]) and number of severe AEs (OR: .58 [.38-.89]) were identified as predictive variables. Patients who reached MCID in the SRS22r experienced worse health at baseline using approach (3). The number of AEs (OR: .44 [.25-.77]) and baseline PROMs (OR: .01 [.00-.22] were the only identified predictive factors. Patients who reached MCID in the EQ-5D experienced less AEs and a lower number of actions taken due to the occurrence of AEs using approach (3). The number of actions taken due to AEs (OR: .50 [.35-.73]) was found to be the only predictive variable factor. No surgical, clinical, or radiographic variables were identified as risk factors using either of the aforementioned approaches. In this large multicenter prospective cohort of elderly patients undergoing primary reconstructive surgery for ASD, baseline health status, AEs, and severity of AEs were predictive of reaching MCID. No clinical, radiological, or surgical parameters were identified as factors that can be prognostic for reaching MCID.

Insertable cardiac monitoring devices versus external cardiac monitoring for detecting atrial fibrillation and preventing the recurrence of stroke: A systematic review and meta-analysis

BackgroundAtrial Fibrillation (AF) is a major risk factor for stroke, which is the second leading cause of death worldwide. It remains uncertain whether insertable cardiac monitors (ICMs) enhance the ability to recognize AF over external cardiac monitoring in patients who have experienced a stroke. AimWe conducted a systematic review and meta-analysis to determine whether ICM devices are more effective than external cardiac monitoring for the detection of AF in stroke patients. MethodsWe included studies that reported an AF detection rate in stroke patients with a follow-up of at least 12 months. We analyzed the data of 1233 patients from 3 randomized control trials (RCTs). ResultsWhen compared to external cardiac monitoring, ICM devices (Medtronic Reveal LINQ and Reveal XT) showed a significantly higher detection rate of AF (RR = 5.04, 95% CI = 2.93–8.68; p < 0.05; ARR = 10.47%, NNT = 10). The ICM arm had significantly higher usage of oral anticoagulants (OAC) as compared to the control arm. (RR = 2.76, 95% CI = 1.89–4.02, p < 0.05). Additionally, ICM usage was associated with a higher incidence of mild to moderate adverse events (RR = 10.52, 95% CI =1.35–82.14; p = 0.02) and a higher number of severe adverse events as compared to the control arm (RR = 7.61, 95% CI = 1.36–42.51; p = 0.02). ConclusionICM devices are associated with better detection rates of AF and higher usage of OAC as compared to external cardiac monitoring in post-stroke patients. However, ICM insertion is associated with a higher incidence of mild/moderate and severe adverse effects.

CTNI-34. PRECISION NEURO-ONCOLOGY - A PILOT ANALYSIS OF PERSONALIZED TREATMENT IN RECURRENT GLIOMA

Abstract PURPOSE When brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse. METHODS We performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic Target of Rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted. RESULTS The investigation included 41 patients of which 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357). CONCLUSIONS These encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider prevalence and persistence of actionable molecular alterations in patient tissue.

Portal Vein Recanalization for Noncirrhotic Portal Vein Cavernous Transformation: Transjugular Intrahepatic Portosystemic Shunt Creation versus Portal Vein Stent Placement

PurposeTo compare the clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) creation versus portal vein stent placement (PVS) in patients with noncirrhotic cavernous transformation of the portal vein (CTPV). Materials and MethodsIn this retrospective study, clinical data from patients with noncirrhotic CTPV who underwent TIPS creation or PVS were compared. A total of 54 patients (mean age, 43.8 years ± 15.8; 31 men and 23 women) were included from January 2013 to January 2021; 29 patients underwent TIPS creation, and 25 patients underwent PVS. Stent occlusion, variceal rebleeding, survival, and postprocedural complications were compared between the 2 groups. ResultsThe mean follow-up time was 40.2 months ± 26.2 in the TIPS group and 35.3 months ± 21.1 in the PVS group. The stent occlusion rate in the PVS group (16%, 4 of 25) was significantly lower than that in the TIPS group (41.4%, 12 of 29) during the follow-up (P = .042). The cumulative variceal rebleeding rates in the TIPS group were significantly higher than those in the PVS group (28% vs 4%; P = .027). The procedural success rate was 69% in the TIPS group and 86% in the PVS group (P = .156). There was a higher number of severe adverse events after TIPS than after PVS (0% vs 24%; P = .012). ConclusionsPortal vein recanalization with PVS may be a preferable alternative to TIPS creation in the treatment of noncirrhotic CTPV because of higher stent patency rates, lower risk of variceal rebleeding, and fewer adverse events.

The CHARTER-Ireland trial: can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial

BackgroundCOVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia.MethodsThis is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1β, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1β/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP.DiscussionThis trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection.Trial registrationClinicalTrials.govNCT04511923. Registered on 13 August 2020.Protocol version 8, 22/12/2021Protocol identifier: NUIG-2020-003EudraCT registration number: 2020-003349-12 9 October 2020

Precision neuro-oncology: a pilot analysis of personalized treatment in recurrent glioma

PurposeWhen brain cancer relapses, treatment options are scarce. The use of molecularly matched targeted therapies may provide a feasible and efficacious way to treat individual patients based on the molecular tumor profile. Since little information is available on this strategy in neuro-oncology, we retrospectively analyzed the clinical course of 41 patients who underwent advanced molecular testing at disease relapse.MethodsWe performed Sanger sequencing, targeted next generation sequencing, and immunohistochemistry for analysis of potential targets, including programmed death ligand 1, cyclin D1, phosphorylated mechanistic target of rapamycin, telomerase reverse transcriptase promoter mutation, cyclin-dependent kinase inhibitor 2A/B deletion, or BRAF-V600E mutation. In selected patients, whole exome sequencing was conducted.ResultsThe investigation included 41 patients, of whom 32 had isocitrate dehydrogenase (IDH) wildtype glioblastoma. Molecular analysis revealed actionable targets in 31 of 41 tested patients and 18 patients were treated accordingly (matched therapy group). Twenty-three patients received molecularly unmatched empiric treatment (unmatched therapy group). In both groups, 16 patients were diagnosed with recurrent IDH wildtype glioblastoma. The number of severe adverse events was comparable between the therapy groups. Regarding the IDH wildtype glioblastoma patients, median progression-free survival (mPFS) and median overall survival (mOS) were longer in the matched therapy group (mPFS: 3.8 versus 2.0 months, p = 0.0057; mOS: 13.0 versus 4.3 months, p = 0.0357).ConclusionThese encouraging data provide a rationale for molecularly matched targeted therapy in glioma patients. For further validation, future study designs need to additionally consider the prevalence and persistence of actionable molecular alterations in patient tissue.

A Pilot Randomized Control Trial of Safety and Feasibility of a Delayed Rewarming Intervention for Infants Following Cardiopulmonary Bypass Surgery

Objective: Investigate safety and feasibility of a 12-hour delayed rewarming intervention on infants following congenital heart disease (CHD) surgery. Study Design: Pilot randomized control trial of infants &lt;6 months old with CHD undergoing cardiopulmonary bypass surgery. Infants were randomized 1:1 to standard of care (SOC) or to delayed rewarming intervention, accomplished by using a commercially available temperature regulating blanket set to gradually rewarm from 35°C to 36.5°C in the 12-hours following surgery. Safety was assessed by comparing the frequency of severe adverse events (SAE) for 48 hours after surgery. Feasibility was assessed by analysis of temperature data. Results: Twelve infants were randomized to SOC and 10 to the intervention group. Eight infants (36%) were female, 6 (27%) had Trisomy 21 and 7 (32%) had surgery in the first two weeks of life. Two SOC and one intervention infant had at least one SAE (p=0.57). Feasibility of the delayed rewarming intervention was demonstrated by a statistically significant difference in temperature over time between groups (p&lt;0.001). Heart rates for infants in the intervention group were slower during and after the intervention, without significant changes in blood pressure. Infants in the intervention group had no evidence of coagulopathy with lower, but not statistically significantly lower, chest tube output at alltime points. Conclusions: There were no differences in the number of SAEs for the delayed rewarming group and the temperature curve indicates that the intervention is feasible. The results of this small study, from a single, small volume center must be interpreted cautiously. (NCT03036072).

Systematic review and meta-analysis of fluid therapy protocols in acute pancreatitis: type, rate and route.

Adequate fluid resuscitation is paramount in the management of acute pancreatitis (AP). The aim of this study is to assess benefits and harms of fluid therapy protocols in patients with AP. MEDLINE, Embase, Science Citation Index and clinical trial registries were searched for randomised clinical trials published before May 2020, assessing types of fluids, routes and rates of administration. A total 15 trials (1073 participants) were included. Age ranged from 38 to 73 years; follow-up period ranged from 0.5 to 6 months. Ringer lactate (RL) showed a reduced number of severe adverse events (SAE) when compared to normal saline (NS) (OR 0.48; 95%CI 0.29-0.81, p=0.006); additionally, NS showed reduced SAE (RR 0.38; 95%IC 0.27-0.54, p<0.001) and organ failure (RR 0.30; 95%CI 0.21-0.44, p<0.001) in comparison with hydroxyethyl starch (HES). High fluid rate fluid infusion showed increased mortality (OR 2.88; 95%CI 1.41-5.88, p=0.004), increased number of SAE (RR 1.42; 95%CI 1.04-1.93, p=0.030) and higher incidence of sepsis (RR 2.80; 95%CI 1.51-5.19, p=0.001) compared to moderate fluid rate infusion. In patients with AP, RL should be preferred over NS and HES should not be recommended. Based on low-certainty evidence, moderate-rate fluid infusion should be preferred over high-rate infusion.

Safety and Effectiveness of Cell Therapy in Neurodegenerative Diseases: Take-Home Messages From a Pilot Feasibility Phase I Study of Progressive Supranuclear Palsy.

Mesenchymal stromal cells (MSCs) are multipotent cells with anti-inflammatory properties. Here we tested the safety of MSCs in patients with progressive supranuclear palsy (PSP; ClinicalTrials.gov: NCT01824121; Eudract No. 2011-004051-39). Seven patients were treated. To improve the safety, protocol adjustments were made during the performance of the study. The objectives of our work were: (1) to assess the safety of MSCs and (2) to identify critical issues in cell therapies for neurodegenerative diseases. Autologous MSCs from the bone marrow of PSP patients were administered through the internal carotid arteries. 1-year survival and number of severe adverse events were considered as safety endpoints. Clinical rating scales, neuropsychological assessments, gait and posture analysis, single-photon emission computed tomography, positron emission tomography, and brain magnetic resonance (BMR) were performed at different follow-up times. Peripheral blood levels of inflammatory cytokines were measured before and after cell infusion. Six of the seven treated patients were living 1 year after cell infusion. Asymptomatic spotty lesions were observed at BMR after 24 h in six of the seven treated patients. The last patient in the preliminary cohort (Case 5) exhibited transiently symptomatic BMR ischemic alterations. No severe adverse events were recorded in the last two treated patients. Interleukin-8 serum concentrations decreased in three patients (Case 2, 3, and 4). An adaptive study design, appropriate and up-to-date efficacy measures, adequate sample size estimation, and, possibly, the use of a cellular and/or allogeneic cell sources may help in performing phase II trials in the field.

A randomised controlled unblinded multicentre non-inferiority trial with activated vitamin D and prednisolone treatment in patients with minimal change nephropathy (ADAPTinMCN)

BackgroundMinimal change nephropathy (MCN) is a common cause of nephrotic syndrome in both adults and children. International guidelines recommend treatment with prednisolone 1 mg/kg/day to adults. This dose is derived from an empirically established dose in children, although children generally attain remission faster and relapse more rapidly than adults. Prednisolone is associated with multiple and serious adverse events. Activated vitamin D has been shown to reduce albuminuria in other glomerular renal diseases with a minimum of adverse events. This study tests the hypothesis that a new treatment regimen in MCN combining reduced dose prednisolone and active vitamin D is as efficient in inducing remission and has fewer and less severe adverse events than standard prednisolone. Furthermore, we aim to establish models allowing for more personalized medicine based on assessment of the individual’s prednisolone metabolism.MethodsA randomised controlled multicentre non-inferior unblinded trial including 96 adult, incident patients with biopsy-proven MCN, albuminuria > 3 g/day, and an estimated glomerular filtration rate (eGFR) > 30 ml/min from renal departments in Denmark. Patients are randomised to standard prednisolone (1 mg/kg/day) or reduced prednisolone (0.5 mg/kg/day) and alfacalcidol (0.5 μg/day). The primary outcome is the rate of remissions after 16 weeks and the time from diagnosis to remission. The study will include a saliva test to characterise prednisolone pharmacokinetics and compare them to genetic variations in specific liver enzymes responsible for prednisolone metabolism.DiscussionReducing the prednisolone dose is expected to reduce the number of severe adverse events. This study will examine if reduced prednisolone dose with active vitamin D but without additional immunosuppression is feasible in the treatment of MCN and will reduce the number of adverse events. The findings can potentially change current guidelines for treatment of MCN in adults. Additional outcomes on inter-individual pharmacokinetic and metabolic variations may allow for a more personalised treatment strategy.Trial registrationEudraCT 2017-001206-16, ClinicalTrials.gov NCT03210688. Registered on June 3, 2017.

Clinical Outcome of a Cross-Sectorial Lung Team Treating Patients with COPD at High Risk of Exacerbation: A Randomized Controlled Trial

In addition to the financial burden, acute exacerbation of chronic obstructive pulmonary disease (AECOPD) also has a negative impact on health status and disease progression for patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the effect of affiliation to a cross-sectorial lung team (CLT) on hospitalization and length of hospital stay for patients with COPD and ≥ one severe or two moderate AECOPD events within a year. We conducted a randomized clinical trial between 2017 and 2020. Participants were randomly assigned 1:1 for one year to CLT or usual care (UC). The CLT was available for telephone calls and home visits day and night on the request from patients, and the CLT could initiate home treatment. In total, 56 patients were affiliated to the CLT (Mean: age 71.6 years, FEV1 37.1%) and 57 patients received UC (Mean: age 71.5 years, FEV1; 33.6%). Patients affiliated to the CLT had on average fewer hospitalizations due to AECOPD than patients receiving UC (CLT: 0.59 (95% CI: 0.35; 0.83 - UC: 1.86 (95% CI: 1.12; 2.20; p = 0.002). Patients affiliated to the CLT also had shorter hospital stay on average due to AECOPD (CLT: 3.27(95% CI: 2.39; 4.15 – UC: 4.47 (95% CI: 3.70; 5.24; (p = 0.045). No significant difference in number of severe adverse events, including death, was observed between groups. Affiliation to the CLT seemed safe and reduced both hospitalizations and length of hospital stay related to AECOPD compared to UC.

Efficacy and safety of treatment modalities across EGFR selected/unselected populations with non-small cell lung cancer and brain metastases: A systematic review and Bayesian network meta-analysis

ObjectiveTo compare the efficacy and safety of treatment modalities across different populations with non-small cell lung cancer and brain metastases. MethodsA comprehensive search for randomized controlled trials was conducted in databases including PubMed, Embase, the Cochrane library, the ClinicalTrials.gov, and major international conferences. The main outcomes of interest were progression-free survival, overall survival, and severe adverse events. Bayesian network meta-analytical techniques were implemented, to compare treatment modalities based on efficacy and safety profiles. The protocol for this study has been registered in the Prospective Register of Systematic Reviews (PROSPERO, CRD42020155330). Results15 randomized controlled trials with a total of 1216 patients were analyzed. Network meta-analysis generated six comparisons both in EGFR positive and EGFR unselected populations. For patients harboring EGFR positive mutations, osimertinib appears to significantly increase progression-free survival, compared to 1st generation EGFR-TKI (HR 0.46, 95 %CI 0.38–0.55), 2nd generation EGFR-TKI (HR: 0.59, 95 %CI 0.34–0.99), conventional chemotherapy (HR 0.30, 95 %CI 0.14–0.66), radiotherapy (HR 0.20, 95 %CI 0.14–0.29), and radiotherapy plus 1st generation TKI (HR 0.21, 95 %CI 0.14–0.32). Osimertinib also appears to increase the likelihood of survival and prolong overall survival. For EGFR unselected patients, combined anti-PD1 monoclonal antibody with conventional chemotherapy appears superior to radiotherapy (HR: 0.20, 95 % CI 0.14–0.29), conventional chemotherapy (HR: 0.42, 95 %CI 0.28–0.68), radiotherapy plus conventional chemotherapy (HR: 0.59, 95 %CI 0.32–0.98), radiotherapy plus 1st generation TKI (HR:0.49, 95 %CI 0.25–0.96), and immune checkpoint inhibitors monotherapy (HR:0.44, 95 %CI 0.28–0.69). However, combination therapies are generally more toxic causing an increased number of severe adverse events, particularly when anti-PD1 monoclonal antibody is combined with conventional chemotherapy. ConclusionsOsimertinib appears to be the most effective and safest treatment in NSCLC patients with brain metastases, harboring EGFR positive mutations. The anti-PD1 monoclonal antibody and conventional chemotherapy combination increases survival for NSCLC patients with brain metastases who were not selected according to EGFR mutation, although this increased benefit positively correlates with an increased number of severe adverse events.

MO040LONG-TERM FOLLOW-UP OF IGA NEPHROPATHY PATIENTS AT HIGH RISK OF PROGRESSION ACCORDING TO THE THERAPEUTIC APPROACH EMPLOYED: A MULTICENTER RETROSPECTIVE STUDY OF 947 PATIENTS

Abstract Background and Aims IgA-nephropathy (IgA-N) is a frequent cause of CKD and ESRD. The optimal therapeutic approach and the role of glucocorticoids and immunosuppression is still debated. Aim of this study was to perform a survey across several Italian centers focusing on the long-term outcome of patients with IgA-N at high risk of progression stratified according to the therapeutic approach employed. Method All the consecutive patients affected by biopsy proven IgA-N, proteinuria &amp;gt;1g/day and a follow-up longer than 24 months have been collected across 48 centers. The population has been divided in three groups according to the therapeutic approach: group-1 received ACEi or ARBs alone, group-2 a six months course of glucocorticoids while group-3 glucocorticoids and immunosuppressive drugs. Primary endpoints have been ESRD free-survival, halving of the eGFR free-survival and rate of non-responders (NR, proteinuria &amp;gt;1 g/day). Secondary endpoints have been assessment of the prognostic role of the time average proteinuria (TAP) as well as of the time average slope of proteinuria (TASP) and rate of severe adverse events (SAEs). Results 947 patients have been included and followed for a median time of 60 months (IQR 24-96). Baseline eGFR and proteinuria in the three groups have been respectively 68.1 (95%CI 63.9-72.4)-67.8 (95%CI 65.3-70.3)-63.3 (95%CI 58.5-68.1) ml/min/1.73m2 (p=0.191) and 2.38 (95%CI 2-2.77)-2.65 (95%CI 2.49-2.82)-3.26 (95%CI 2.89-3.64) g/day (p&amp;lt;0.001). Respectively 76/586 (13%) and 28/167 (17%) of the patients in group-2 and 3 required re-treatment with glucocorticoids alone or in combination with immunosuppressive drugs after a median of 24 months from the first cycle. ESRD free-survival has been longer in the group-2 (p=0.004) (figure, panel A); at subgroup analysis this was restricted to the patients with a eGFR&amp;lt;50 ml/min (p=0.004) (figure, panel B) while only a trend was observed in the ones with eGFR ≥50 ml/min (p=0.0631). The halving of the eGFR free-survival has been longer in group-2 only when limiting the analyses to the subgroup with eGFR&amp;lt;50 ml/min (p=0.026) (figure, panel C). The proportion of NR has been significantly lower in group-2 compared to group-1 throughout the first 36 months of follow-up (figure, panel D); of note being NR during the first 36 months increased the risk of developing ESRD during the follow-up (OR 4 95%CI 2.2-7.3, p&amp;lt;0.0001). The TAP and TASP of the first 24 months have been higher in the patients developing ESRD (respectively, mean 2.48 95%CI 2.14-2.82 and 0.81 95%CI 0.70-0.92) compared to the other patients (mean 1.12 95%CI 1.2-1.32 and 0.59 95%CI 0.56-0.61) (p&amp;lt;0.0001 for both comparisons). Of note the 24 months TASP of group-2 was lower compared to group-1 (respectively mean 0.56 95%CI 0.54-0.59 and 0.79 95%CI 0.71-0.87) (p&amp;lt;0.0001). The rate of patients experiencing SAEs during the first 6 months of therapy in the three groups has been respectively 2%, 7% and 16%; of these withdrawn of the therapeutic approach employed has been necessary in 67%, 21% and 48%. During the whole follow-up the number of SAEs per 100 patients/years has been respectively 1.9-2.7 and 2.5 in the 3 groups. Conclusion In this large multicenter retrospective survey, the use of glucocorticoids in patients with IgA-N at high risk of progression has been associated to longer ESRD free-survival, longer time to the halving of the eGFR in the subgroup with eGFR &amp;lt;50 ml/min, lower rate of non-response during the first 36 months of follow-up as well as lower TASP during the first 24 months. The overall rate of SAEs has been low but higher in the group receiving glucocorticoids alone or in combination with immunosuppressors.

An Analysis of Long-Term Outcomes in Patients Treated by Extensive Bowel Resection Due to Advanced Ovarian Cancer Relative to the Effectiveness of Surgery

Introduction: Surgery for advanced ovarian cancer (AOC) often requires bowel resections. However, the impact of bowel surgery on patient overall survival (OS) has not yet been precisely determined. Objective: The aim of the study was to analyze the OS rates in a group of AOC patients undergoing bowel resection. Methods: We carried out a retrospective analysis of patients who had undergone low anterior resection of the rectum (LAR) during primary or interval debulking surgery for AOC. We divided the patients into 2 groups: Group 1 included 69 patients who underwent only LAR; Group 2 included 66 patients who underwent LAR and additional bowel resection. The control group included 71 AOC patients who did not required bowel resection. Results: In the subgroup of patients with no gross residual disease (NGR), there were no differences in OS between Groups 1 and 2. In the subgroup of “optimally” (tumors <1 cm) debulked patients, Group 1 patients had a higher median OS than Group 2 patients. Additionally, there was no difference between Groups 1 and 2 as far as the number of severe adverse events. Conclusions: Multiple bowel resections seem to improve OS in patients when NGR is achieved but should be avoided when complete resection is not possible.

Comparison of salvage therapies for relapsed or refractory diffuse large B-cell lymphoma (DLBCL): Network meta-analysis.

e19037 Background: Salvage chemotherapy followed by autologous stem cell transplantation(ASCT) is the standard second-line treatment for relapsed or refractory diffuse large b-cell lymphoma(DLBCL). Rituximab plus ifosfamide, carboplatin, and etoposide(R-ICE) and rituximab plus dexamethasone, high dose cytarabine, cisplatin(R-DHAP) are the two widely used regimens worldwide but quest for optimal regimen continues. Our objective is to compare currently available salvage therapies based on complete response and adverse events. Methods: Pubmed, EMBASE and Clinicaltrials.gov were queried for salvage therapies in relapsed or refractory DLBCL. Only randomized clinical trials including phase 2 and 3 trials involving salvage therapies for relapsed or refractory DLBCL were selected. Data was extracted based on meta-analysis guidelines by two independent reviewers. Network meta-analyses of treatment effects and adverse outcomes were calculated with a frequentist approach. Results: Overall, 5 studies(1480 patients) were included. The salvage therapies investigated were rituximab plus ifosfamide, carboplatin, and etoposide(R-ICE), rituximab plus dexamethasone, high dose cytarabine, cisplatin(R-DHAP), rituximab plus gemcitabine, dexamethasone, cisplatin(R-GDP), ofatumumab plus dexamethasone, cytarabine, and cisplatin(O-DHAP), ifosfamide plus ofatumunab, carboplatin, and etoposide(O-ICE), dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide(DR-ICE). Of the 6 regimens in the network, treatment with R-DHAP (OR:0.36,95%CI:0.24-0.54), R-GDP(OR:0.37,95%CI: 0.21-0.65), O-ICE(OR:0.16,95%CI: 0.05-0.53), O-DHAP(OR:0.30,95%CI:0.17-0.52), DR-ICE(OR:0.77,95%CI:0.40-1.49) were not superior against network placebo(R-ICE) in achieving complete response. Higher odds of occurring severe adverse events was observed in R-DHAP(OR:2.02,95%CI: 1.35-3.01) and O-DHAP(OR:2.15,95%CI: 1.24-3.72) salvage regimens when compared to R-ICE. Conclusions: R-DHAP, R-GDP, O-ICE and O-DHAP were found to have no difference in treatment effect in achieving complete response in comparison to R-ICE. R-DHAP and O-DHAP are associated with higher number of severe adverse events in comparison with R-ICE. Outcomes mentioned above should be interpreted in the context of drugs and other factors involved in the disease.

Environmental distribution of certain modified live-virus vaccines with a high safety profile presents a low-risk, high-reward to control zoonotic diseases

Oral vaccines aid immunization of hard to reach animal populations but often contain live-attenuated viruses that pose risks of reversion to virulence or residual pathogenicity. Human risk assessment is crucial prior to vaccine field distribution but there is currently no standardized approach. We mapped exposure pathways by which distribution of oral vaccines may result in inoculation into people and applied a Markov chain to estimate the number of severe adverse events. We simulated three oral rabies vaccination (ORV) campaigns: (1) first generation ORV (SAD-B19) in foxes, (2) SAD-B19 in dogs, and (3) third generation ORV (SPBN GASGAS) in dogs. The risk of SAD-B19-associated human deaths was predicted to be low (0.18 per 10 million baits, 95% CI: 0.08, 0.36) when distributed to foxes, but, consistent with international concern, 19 times greater (3.35 per 10 million baits, 95% CI: 2.83, 3.98) when distributed to dogs. We simulated no deaths from SPBN GAS-GAS. Human deaths during dog campaigns were particularly sensitive to dog bite rate, and during wildlife campaigns to animal consumption rate and human contact rate with unconsumed baits. This model highlights the safety of third generation rabies vaccines and serves as a platform for standardized approaches to inform risk assessments.

What's the Harm? A Risk Model to Quantify Human and Animal Adverse Events From Environmentally Distributed Modified Live-Vaccine Viruses

Background: While oral vaccines aid immunization of hard to reach animal populations, the use of live-attenuated viruses in many oral vaccines, including first generation oral rabies vaccines, pose risks of reversion to virulence or residual pathogenicity. While a detailed human risk assessment is crucial prior to field distribution of live-attenuated vaccines, there is currently no standardized approach. Methods: We mapped exposure pathways by which distribution of oral vaccines targeting wildlife or free-roaming dogs may result in mucosal, transdermal, or severe inoculation into people. We applied a continuous-time Markov chain to estimate the number of severe adverse events. We tested the model using three scenarios of oral rabies vaccination (ORV) campaigns: 1) first generation ORV (SAD-B19) in foxes, 2) SAD-B19 in dogs, and 3) third generation ORV (SPBN GASGAS) in dogs. Findings: A low risk of 0·18 (95% CI: 0·08, 0·36) vaccine-associated human deaths per 10 million baits was simulated for campaigns where SAD-B19 was distributed to foxes. However, consistent with international concern, our model predicts that SAD-B19 distributed to dogs could result in 3·35 (95% CI: 2·83, 3·98) vaccine-associated human deaths per 10 million baits. The model simulated no deaths for SPBN GASGAS. Human deaths during dog campaigns was particularly sensitive to dog bite rate, and human deaths during wildlife campaigns was particularly sensitive to animal uptake rate and human contact rate with unconsumed baits. Interpretation: This model highlights the safety of newer live-attenuated rabies vaccines and serves as a platform for standardized approaches to inform risk assessments. Funding Statement: Time for this study was funded through a co-agreement between the Pubic Health Institute and the Centers for Disease Prevention and Control. The funding source had no role in the study design, analysis, preparation of the manuscript, or decision to publish the manuscript. Declaration of Interests: AV is a full time employee of a pharmaceutical company, IDT Biologika GmbH, which manufactures oral rabies vaccine baits. TM from the FriedrichLoeffler-Institute received funding from IDT Biologika GmbH in the frame of a research cooperation for research into mechanisms of oral rabies vaccination and resulting immunity

Impact of fortified versus unfortified lipid-based supplements on morbidity and nutritional status: A randomised double-blind placebo-controlled trial in ill Gambian children.

BackgroundMultiple micronutrients (MMN) are commonly prescribed in pediatric primary healthcare in sub-Saharan Africa to improve nutritional status and appetite without evidence for their effectiveness or international clinical guidelines. Community-wide MMN supplementation has shown limited and heterogeneous impact on growth and morbidity. Short-term ready-to-use therapeutic foods in acutely sick children in a hospital setting also had limited efficacy regarding subsequent growth. The effectiveness of MMN in improving morbidity or growth in sick children presenting for primary care has not been assessed.Methods and findingsWe undertook a double-blind randomised controlled trial of small-quantity lipid-based nutrient supplements (SQ-LNS) fortified with 23 micronutrients in children aged 6 months (mo) to 5 years (y) presenting with an illness at a rural primary healthcare centre in The Gambia. Primary outcomes were repeat clinic presentations and growth over 24 wk. Participants were randomly assigned to receive 1 of 3 interventions: (1) supplementation with micronutrient-fortified SQ-LNS for 12 wk (MMN-12), (2) supplementation with micronutrient-fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk (MMN-6), or (3) supplementation with unfortified SQ-LNS for 12 wk (MMN-0) to be consumed in daily portions. Treatment masking used 16 letters per 6-wk block in the randomisation process. Blinded intention-to-treat analysis based on a prespecified statistical analysis plan included all participants eligible and correctly enrolled.Between December 2009 and June 2011, 1,101 children (age 6–60 mo, mean 25.5 mo) were enrolled, and 1,085 were assessed (MMN-0 = 361, MMN-6 = 362, MMN-12 = 362). MMN supplementation was associated with a small increase in height-for-age z-scores 24 wk after recruitment (effect size for MMN groups combined: 0.084 SD/24 wk, 95% CI: 0.005, 0.168; p = 0.037; equivalent to 2–5 mm depending on age). No significant difference in frequency of morbidity measured by the number of visits to the clinic within 24 wk follow-up was detected with 0.09 presentations per wk for all groups (MMN-0 versus MMN-6: adjusted incidence rate ratio [IRR] 1.03, 95% CI: 0.92, 1.16; MMN-0 versus MMN-12: 1.05, 95% CI: 0.93, 1.18). In post hoc analysis, clinic visits significantly increased by 43% over the first 3 wk of fortified versus unfortified SQ-LNS (adjusted IRR 1.43; 95% CI: 1.07, 1.92; p = 0.016), with respiratory presentations increasing by 52% with fortified SQ-LNS (adjusted IRR 1.52; 95% CI: 1.01, 2.30; p = 0.046). The number of severe adverse events during supplementation were similar between groups (MMN-0 = 20 [1 death]; MMN-6 = 21 [1 death]; MMN-12 = 20 [0 death]). No participant withdrew due to adverse effects. Study limitations included the lack of supervision of daily supplementation.ConclusionPrescribing micronutrient-fortified SQ-LNS to ill children presenting for primary care in rural Gambia had a very small effect on linear growth and did not reduce morbidity compared to unfortified SQ-LNS. An early increase in repeat visits indicates a need for the establishment of evidence-based guidelines and caution with systematic prescribing of MMN. Future research should be directed at understanding the mechanisms behind the lack of effect of MMN supplementation on morbidity measures and limited effect on growth.Trial registrationISRCTN 73571031.