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In prior work, Friends of Cancer Research convened multiple data partners to establish standardized definitions for oncology real-world end points derived from electronic health records (EHRs) and claims data. Here, we assessed the performance of real-world overall survival (rwOS) from data sets sourced from EHRs by evaluating the ability of the end point to reflect expected differences from a previous randomized controlled trial across five data sources, after applying inclusion/exclusion criteria. The KEYNOTE-189 clinical trial protocol of platinum doublet chemotherapy (chemotherapy) vs. programmed cell death protein 1 (PD-1) in combination with platinum doublet chemotherapy (PD-1 combination) in first-line nonsquamous metastatic non-small cell lung cancer guided retrospective cohort selection. The Kaplan-Meier product limit estimator was used to calculate 12-month rwOS with 95% confidence intervals (CIs) in each data source. Cox proportional hazards models estimated hazard ratios (HRs) and associated 95% CIs, controlled for prognostic factors. Once the inclusion/exclusion criteria were applied, the five resulting data sets included 155 to 1,501 patients in the chemotherapy cohort and 36 to 405 patients in the PD-1 combination cohort. Twelve-month rwOS ranged from 45% to 58% in the chemotherapy cohort and 44% to 68% in the PD-1 combination cohort. The adjusted HR for death ranged from 0.80 (95% CI: 0.69, 0.93) to 1.15 (95% CI: 0.71, 1.85), controlling for age, gender, performance status, and smoking status. This study yielded insights regarding data capture, including ability of real-world data to precisely identify patient populations and the impact of criteria on end points. Sensitivity analyses could elucidate data set-specific factors that drive results.

Objective To characterize the interventional clinical trials in infertility and to assess whether trial location or industry sponsorship was associated with trial noncompletion. Design Retrospective review of trials registered with ClinicalTrials.gov . Setting None. Patient(s) None. Intervention(s) None. Main Outcome Measure(s) Descriptive statistics characterizing the attributes of the clinical trials including intervention type, topic, population, completion status, size, location, sponsor, and results. The effects of the sponsor and trial location on trial noncompletion were assessed via logistic regression. Result(s) In total, 505 trials initiated between 2010 and 2020 were included in our analysis. Drug interventions were the most commonly studied (45%); ovarian stimulation trials accounted for 27% of the studies. Live birth was tracked as an outcome by 20% of the studies; 3% of the trials included mental health outcomes. Few trials (15%) enrolled male participants. Only 11% of the trials reported results, and 4% of the trials reported the race or ethnicity of the participants. Most trials (82%) were conducted outside the United States. Overall, 18% of the trials were not completed, most often because of lack of accrual (47%). United States trials had over twice the odds of noncompletion in univariate analysis (odds ratio = 2.48, 95% confidence interval = [1.47, 4.17]); however, this relationship lost significance after adjusting for potential confounders (odds ratio = 0.95, 95% confidence interval = [0.42, 2.14]). Trial sponsorship was not associated with trial noncompletion. Conclusion(s) Infertility trials predominantly investigated drug interventions, particularly ovarian stimulation. Live birth was an infrequent outcome despite its relevance to patients. Clinical trials should aim to address the unmet needs in fertility care and be inclusive of underserved populations affected by infertility.

Objective and design The aim of this double-blind, placebo-controlled, phase III CORONA clinical trial was to evaluate the efficacy and safety of IL-6 receptor inhibitor levilimab (LVL) in subjects with severe COVID-19. Subjects The study included 217 patients. The eligible were men and non-pregnant women aged 18 years or older, hospitalized for severe COVID-19 pneumonia. Treatment 206 subjects were randomized (1:1) to receive single subcutaneous administration of LVL 324 mg or placebo, both in combination with standard of care (SOC). 204 patients received allocated therapy. After the LVL/placebo administration in case of deterioration of symptoms, the investigator could perform a single open-label LVL 324 mg administration as the rescue therapy. Methods The primary efficacy endpoint was the proportion of patients with sustained clinical improvement on the 7-category ordinal scale on Day 14. All efficacy data obtained after rescue therapy administration were considered missing. For primary efficacy analysis, all subjects with missing data were considered non-responders. Results 63.1% and 42.7% of patients in the LVL and in the placebo groups, respectively, achieved sustained clinical improvement on Day 14 (P = .0017). The frequency of adverse drug reactions was comparable between the groups. Conclusion In patients with radiologically confirmed SARS-CoV-2 pneumonia, requiring or not oxygen therapy (but not ventilation) with no signs of other active infection administration of LVL + SOC results in an increase of sustained clinical improvement rate. Trail registration The trial is registered at the US National Institutes of Health (ClinicalTrials.gov; NCT04397562).

Aims The risk of hemoglobin decline induced by low‐dose aspirin in glucose‐6‐phosphate dehydrogenase (G6PD) deficiency remains unknown, and its influence on stroke outcome remains to be investigated. This study aimed to evaluate the effect of G6PD deficiency on hemoglobin level during aspirin treatment and its association with outcome after acute ischemic stroke. Methods In total, 279 patients (40 G6PD‐deficient and 239 G6PD‐normal) with acute ischemic stroke treated with aspirin 100 mg/day from a cohort study were examined. The primary safety endpoint was a hemoglobin decline ≥25 g/L or 25% from baseline within 14 days after aspirin treatment. Poor outcomes were defined as a modified Rankin Scale score ≥2 at 3 months. The χ 2 test was used to compare stroke outcomes, and multivariate logistic regression analyses were performed to analyze the association between hemoglobin level and outcomes. Results The G6PD‐deficient group had lower baseline hemoglobin and tended to develop comorbid pulmonary infection more frequently (p, Hemoglobin decrease with bilirubin increase after aspirin treatment in patients with G6PD deficiency suggests hemolysis, which may influence stroke prognosis. The risk of hemoglobin decline should be carefully monitored in G6PD‐deficient stroke patients taking aspirin.

The clinical efficacy of ticagrelor versus clopidogrel has not been replicated in East Asian populations. The pronounced bleeding risk with ticagrelor was of concern given the increased bleeding tendency in Asian populations. This study evaluated efficacy and safety of ticagrelor versus clopidogrel in patients with non-ST-elevation myocardial infarction (NSTEMI) in the entire Taiwan. We used the Taiwan National Health Insurance Research Database to identify 6203 patients aged ≥ 20 years with NSTEMI hospitalization and prescription of dual antiplatelets at discharge between January 2014 and December 2014. Cohorts of ticagrelor and clopidogrel were matched 1:1 based on propensity score matching to balance baseline covariates. The primary composite efficacy endpoints included death from any cause, non-fatal myocardial infarction, and non-fatal stroke. The secondary efficacy endpoints were the individual components. The primary safety endpoint was major bleeding requiring hospitalization. The incidence of primary efficacy endpoint was 20.3% in the ticagrelor users and 20.7% in the clopidogrel users (adjusted HR 0.94; 95% CI 0.73–1.22), with the median (interquartile range, IQR) follow-up period of 5.2 (2.3–8.5) months. The incidence of primary safety endpoint was 2.3% in the ticagrelor users and 3.2% in the clopidogrel users (adjusted HR 0.67; 95% CI 0.33–1.35). Regarding the secondary efficacy endpoint, patients treated with ticagrelor had significantly lower incidence of stroke (adjusted HR 0.44; 95% CI 0.21–0.94; p = 0.033). In this nationwide Taiwanese cohort of NSTEMI, treatment with ticagrelor after discharge, as compared to clopidogrel, had similar rates of ischemic composite events and major bleeding. Nevertheless, the median follow-up time was only 5.2 months, and the reduced stroke events with ticagrelor compared to clopidogrel needs further verification.

Long-term data on neurological and radiological outcome after aneurysmal subarachnoid hemorrhage (aSAH) are scarce. The aim of this study was to report neurological and radiological outcome15 years after aSAH.Patients with aSAH who were randomly assigned to endovascular treatment (EVT) or microsurgical treatment (MST) during 1997-2001 were included. Main end points were neurological outcome assessed by modified Rankin Scale, fatigue assessed by mental fatigue scale, and radiological outcome assessed by magnetic resonance angiography. Results for mental fatigue scale were compared with a control group.After 15-21 years, 46 (62.2%) of the 74 survivors replied to a questionnaire. Of these patients, 18 received MST, and 28 received EVT. Modified Rankin Scale score of 0-2 was found in 100% of patients in the EVT group and 88.8% of patients in the MST group. Moderate or severe mental fatigue was found in 7/28 patients (25%) in the EVT group and 7/18 patients (38.8%) in the MST group (P0.05), whereas moderate or severe mental fatigue was observed in 3/34 patients (8.9%) in the control group. Magnetic resonance angiography was performed in 29 patients. In the EVT group, new neck remnants were found in 2/16 patients (12.5%), and de novo aneurysm was found in 2/16 patients (12.5%). In the MST group, de novo aneurysm was found in 1/13 patients (7.7%).Neurological outcome at long-term follow-up after aSAH was good; however, mental fatigue was overrepresented in patients compared with healthy control subjects regardless of treatment modality. Residual or de novo aneurysm was found in 17% of patients warranting radiological long-term follow-up.

We aimed to evaluate the feasibility of multidomain intervention (MI) tailored to the Korean context. In an outcome assessor-blinded, randomized controlled trial, participants without dementia and with one or more modifiable dementia risk factors, aged 60-79 years, were randomly assigned to the facility-based MI (FMI; n=51), the home-based MI (HMI; n=51), or the control group receiving general health advice (n=50). The 24-week intervention comprised vascular risk management, cognitive training, social activity, physical exercise, nutrition guidance, and motivational enhancement. The FMI participants performed all intervention programs at a facility three times a week. The HMI participants performed some programs at a facility once every 1-2 weeks and performed others at home. The primary outcome was feasibility measured through retention, adherence, and at least no differences from the control group in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In the FMI and HMI groups, the retention rates were 88.2% and 96.1%, and adherence to the intervention was 94.5% and 96.8%, respectively. The RBANS total scale index score improved significantly in the FMI (5.46 ± 7.50, P = 0.004) and HMI (5.50 ± 8.14, P = 0.004) groups compared to the control group (-0.74 ± 11.51). The FMI and HMI are feasible and there are indicators of efficacy.

Background Left ventricular assist device (LVAD) candidacy screening includes evaluation for peripheral arterial disease (PVD). However, given current evidence, the impact of PAD on post-LVAD complications remains unknown. Methods The National Inpatient Sample (NIS) database (2002-2017) was utilized to identify all LVAD cases. The in-hospital safety endpoints included major cardiovascular adverse events and its components. A propensity-matched analysis was used to obtain adjusted odds ratios (aOR). A subgroup analysis of patients with diabetes mellitus (DM) with PAD was also performed. Results A total of 27424 patients with LVAD implantation [PAD: 516 (1.8%) and no-PAD 26908 (98.2%)] were included. There were significant intergroup differences in the demographics and baseline comorbidities. A weighted sample of 1053 (no-PAD 537, PAD 516) propensity-matched population was selected. The adjusted odds for in-hospital mortality (aOR 1.7; 95% CI, 1.2-2.44, P=0.004) were found to be significantly higher for LVAD-patients with PAD. There was no significant difference in the adjusted odds of MACE (aOR 1.16, 95% CI 0.87-1.5), post-procedure bleeding (aOR 0.88, 95% CI 0.62-1.26, P=0.54) and risk of pneumonia (aOR 0.67, 95% CI 0.44-1.15, P=0.63) between the two groups. A selected cohort of DM-only population (7339) consistently showed a higher adjusted mortality rate in PAD patients with LVAD implantation (aOR 2.3, 95% CI 1.2-4.47, p=0.01). The rate of MACE (p=0.17), myocardial infarction (p=0.12), stroke (p=0.60), post-procedural (0.10) and major bleeding (p=0.51) remained identical between patients with PAD and those with no-PAD. Conclusion PAD confers an increased risk of in-hospital all-cause mortality in patients undergoing LVAD implantation. This risk increases further in patients with a concomitant diagnosis of DM.

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been linked to thrombotic complications and endothelial dysfunction. We assessed the prognostic implications of endothelial activation through measurement of endothelin-I precursor peptide (proET-1), the stable precursor protein of Endothelin-1, in a well-defined cohort of patients hospitalized with COVID-19.MethodsWe measured proET-1 in 74 consecutively admitted adult patients with confirmed COVID-19 and compared its prognostic accuracy to that of patients with community-acquired pneumonia (n = 876) and viral bronchitis (n = 371) from a previous study by means of logistic regression analysis. The primary endpoint was all-cause 30-day mortality.ResultsOverall, median admission proET-1 levels were lower in COVID-19 patients compared to those with pneumonia and exacerbated bronchitis, respectively (57.0 pmol/l vs. 113.0 pmol/l vs. 96.0 pmol/l, p ConclusionsCompared to other types of pulmonary infection, COVID-19 shows only a mild activation of the endothelium as assessed through measurement of proET-1. Therefore, the high mortality associated with COVID-19 may not be attributed to endothelial dysfunction by the surrogate marker proET-1.

Aim: Two peptide cocktail vaccines using glypican-3, WD-repeat-containing protein up-regulated in hepatocellular carcinoma (HCC) and nei endonuclease VIII-like three epitopes were evaluated in advanced HCC in two Phase I studies. Patients & methods: Study 1 evaluated dose-limiting toxicities (DLTs) of peptides 1–3 (HLA-A24-restricted) and study 2 evaluated DLTs of peptides 1–6 (HLA-A24 or A02-restricted). Results: Overall, 18 and 14 patients were enrolled in studies 1 and 2, respectively. No DLTs were observed up to 7.1 mg of the vaccine cocktail. No complete response/partial response was observed. Stable disease was reported in nine and five patients with a disease control rate of 52.9% and 35.7% in studies 1 and 2, respectively. Conclusion: Both vaccines showed good tolerability and potential usefulness against HCC. Clinical trial registration: JapicCTI-121933 ; JapicCTI-142477

AIMS The aim of this study was to explore the utility of 18F-FDG PET/CT in the assessment of response to antitubercular treatment (ATT) and identification of treatment endpoint. PATIENTS AND METHODS Forty patients (mean age, 35.3 years; 27 men) with clinically, radiologically, and histopathologically proven joint tuberculosis prospectively underwent clinical, biochemical, and PET/CT evaluation at baseline and after ~6, 12, and 18 months of ATT. Two patients were lost to follow-up, and 1 defaulted treatment. The remaining 37 were followed up until complete response (CR) was achieved. Images were visually and quantitatively (SUVmax ratio and metabolically active disease volume [MV]) evaluated by 2 experienced nuclear medicine physicians. RESULTS Knee (n = 18) and ankle (n = 7) were the most frequently involved sites. The median MV and SUVmax ratio at baseline were 85.10 mL and 7.21, respectively. Five patients had noncontiguous vertebral involvement, 12 had pulmonary lesions, 2 had abscesses, 6 had mediastinal, and 30 had local lymph nodal involvement. Complete response was seen in 1/39, 11/37, and 30/37 patients after 6, 12, and 18 months of ATT. Significant reductions in visual analog scale score, tenderness, joint swelling, SUVmax ratios, and MVs (Friedman test, P < 0.001) were seen after each follow-up. The median time-to-CR in skeletal lesions was significantly longer than extraskeletal lesions (591 vs 409 days; Wilcoxon signed-rank test, P < 0.001). Time-to-CR in joint lesions positively correlated with MV at first follow-up (Pearson = 0.452, P = 0.005) and negatively correlated with percentage change in MV (first follow-up from baseline) (Pearson = -0.620, P < 0.001). ROC analysis yielded a cutoff of ≤71% reduction in MV at first follow-up (80.8% sensitivity, 81.8% specificity) to predict extension of ATT beyond 12 months. Using ROC analysis at second follow-up, a cutoff of ≤12.67 mL (for CR) was derived and was validated in patients at the third follow-up, with an accuracy of 84.4%. Patients with CR in PET/CT maintained disease-free state during a mean follow-up of 271 days. CONCLUSIONS 18F-FDG PET/CT is an excellent tool in estimating total disease burden, assessing response to ATT and identification of treatment endpoint in joint tuberculosis.

Although there is a strong biological rationale for early decompression of the injured spinal cord, the influence of the timing of surgical decompression for acute spinal cord injury (SCI) remains debated, with substantial variability in clinical practice. We aimed to objectively evaluate the effect of timing of decompressive surgery for acute SCI on long-term neurological outcomes.We did a pooled analysis of individual patient data derived from four independent, prospective, multicentre data sources, including data from December, 1991, to March, 2017. Three of these studies had been published; of these, only one study previously specifically analysed the effect of the timing of surgical decompression. These four datasets were selected because they were among the highest quality acute SCI datasets available and contained highly granular data. Individual patient data were obtained by request from study authors. All patients who underwent decompressive surgery for acute SCI within these datasets were included. Patients were stratified into early (24 h after spinal injury) and late (≥24 h after spinal injury) decompression groups. Neurological outcomes were assessed by American Spinal Injury Association (ASIA), or International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), examination. The primary endpoint was change in total motor score from baseline to 1 year after spinal injury. Secondary endpoints were ASIA Impairment Scale (AIS) grade and change in upper-extremity motor, lower-extremity motor, light touch, and pin prick scores after 1 year. One-stage meta-analyses were done by hierarchical mixed-effects regression adjusting for baseline score, age, mechanism of injury, AIS grade, level of injury, and administration of methylprednisolone. Effect sizes were summarised by mean difference (MD) for sensorimotor scores and common odds ratio (cOR) for AIS grade, with corresponding 95% CIs. As a secondary analysis, change in total motor score was regressed against time to surgical decompression (h) as a continuous variable, using a restricted cubic spline with adjustment for the same covariates as in the primary analysis.We identified 1548 eligible patients from the four datasets. Outcome data at 1 year after spinal injury were available for 1031 patients (66·6%). Patients who underwent early surgical decompression (n=528) experienced greater recovery than patients who had late decompression surgery (n=1020) at 1 year after spinal injury; total motor scores improved by 23·7 points (95% CI 19·2-28·2) in the early surgery group versus 19·7 points (15·3-24·0) in the late surgery group (MD 4·0 points [1·7-6·3]; p=0·0006), light touch scores improved by 19·0 points (15·1-23·0) vs 14·8 points (11·2-18·4; MD 4·3 [1·6-7·0]; p=0·0021), and pin prick scores improved by 18·3 points (13·7-22·9) versus 14·2 points (9·8-18·6; MD 4·0 [1·5-6·6]; p=0·0020). Patients who had early decompression also had better AIS grades at 1 year after surgery, indicating less severe impairment, compared with patients who had late surgery (cOR 1·48 [95% CI 1·16-1·89]; p=0·0019). When time to surgical decompression was modelled as a continuous variable, there was a steep decline in change in total motor score with increasing time during the first 24-36 h after injury (p0·0001); and after 36 h, change in total motor score plateaued.Surgical decompression within 24 h of acute SCI is associated with improved sensorimotor recovery. The first 24-36 h after injury appears to represent a crucial time window to achieve optimal neurological recovery with decompressive surgery following acute SCI.None.

To compare the treatment outcome and severe late adverse effects (AEs) between conventional volume and dose (CVD) and simultaneously reduced volume and dose (SRVD) of clinical target volume treatments in patients with nasopharyngeal carcinoma.This retrospective cohort study enrolled patients with nonmetastatic stage II to IV nasopharyngeal cancer from a single institute. Survival endpoints and severe (≥grade 3) late AEs and comorbidity were compared between groups. The correlation of severe late AEs, comorbidity, and overall survival (OS) were evaluated using Kaplan-Meier and Cox regression methods.From January 2012 to June 2017, this study enrolled 178 patients, 64 in the CVD group and 114 in the SRVD group. The 2 groups did not differ significantly in patient characteristics except for mean follow-up time (37.6 vs 48.8 months; P = .01). The SRVD group did not significantly differ from the CVD group in local control survival (82.0% vs 78.4%; P = .85), regional control survival (89.9% vs 86.0%; P = .62), or disease-free survival (76.4% vs 66.9%; P = .67). The SRVD group had significantly better OS (93.9% vs 67.0%; P.001) and salvage survival (79.3% vs 20.7%; P.01) and a significantly lower ratio of severe lung infection (1 of 113 vs 5 of 59; P = .02). The SRVD group had a significantly lower risk of mortality (hazard ratio [HR], 0.3; P = .03). The factors associated with a significantly higher risk of mortality were N3 (regional lymph node stage status of N3) (HR, 3.0; P = .02); comorbidities of diabetes, coronary artery disease, or chronic kidney disease (grades 2-3) (HR, 3.8; P = .009), and severe lung infection (HR, 6.3; P = .007).Simultaneously reduced volume and dose of clinical target volumes did not impair locoregional control or disease-free survival. The benefits of SRVD treatment may include significant reduction in severe late AEs, particularly lung infection, dysphagia, and xerostomia. However, additional studies with longer patient follow-up are required to confirm these benefits.

To understand the growing needs of an aging human population, there is demand for scalable and reproducible approaches to study animal models of aging and to test novel therapeutic interventions. We investigated the sensitivity and utility of a continuous monitoring platform and its digital biomarkers (motion, breathing rate, and wheel running) to evaluate behavioral and physiological differences between “young” (12 weeks) and “old” (23 months) male C57BL/6J mice with or without running wheels in the home cage. Compared to young mice, old mice showed marked reductions in motion and breathing rate, as well as altered circadian rhythms. Mice without running wheels possessed lower breathing rates compared to their counterparts with running wheels. Digital biomarkers showed age-dependent changes in response to routine procedures (cage changes and blood sampling) and alterations in subjects that unexpectedly reached endpoint. Continuous collection of digital biomarkers in the home cage can enhance current approaches by providing unbiased longitudinal monitoring for large-scale aging studies.

Background: No randomized trial has compared the yield of the ProCore needle, a novel needle for endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA), with standard needle...

Purpose To investigate if radiographic imaging changes defined as necrosis correlate with regions in the brain with elevated linear energy transfer (LET) for proton radiation therapy treatments with partial brain involvement in central nervous system and patients with head and neck cancer. Methods and Materials Fifty patients with head and neck, skull base, or intracranial tumors who underwent proton therapy between 2004 to 2016 with a minimum prescription dose of 59.4 Gy (relative biological effectiveness) and with magnetic resonance imaging changes indicative of brain necrosis after radiation therapy were retrospectively reviewed. Each treatment plan was recalculated using Monte Carlo simulations to provide accurate dose distributions as well as 3-dimensional distributions of LET. To assess the effect of LET on radiographic imaging changes several voxel-based analyses were performed. Results In this patient cohort, LET adjusted for dose was not found to be associated with risk of brain necrosis. Conclusions A voxel-based analysis of brain necrosis as an endpoint is difficult owing to uncertainties in the origin of necrosis, timing of imaging, variability in patient specific radiosensitivity, and the simultaneous effect of dose and LET. Even though it is expected that the LET and thus relative biological effectiveness increases at the end of range, effects in patients might be small compared with interpatient variability of radiosensitivity and might be obscured by other confounding factors.

In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0–6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P

Expression of the mu-opioid receptor (MOR) is associated with poor long-term outcomes in various types of cancer. The association between MOR expression and clinical outcomes in laryngeal squamous cell carcinoma (LSCC) is not clear.This retrospective study included patients who underwent laryngectomy for LSCC. The expression pattern of the MOR protein and OPRM1 gene in tumours and corresponding adjacent non-carcinoma specimens was measured. Propensity score matching was used to minimise bias. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were intraoperative sufentanil consumption, grade of surgical complications according to the Clavien-Dindo classification, and hospital length of stay.A total of 207 LSCC patients were enrolled. After propensity score matching, there was a significant difference in DFS between groups at 1, 3, and 5 yr (60.2% vs 81.2%, P=0.019; 39.4% vs 50.2%, P=0.026; 37.5% vs 42.5%, P=0.023, respectively) in patients with high MOR expression. The OS rates at 1, 3, and 5 yr were significantly lower in the high MOR expression group (81.2% vs 93.2%, P=0.027; 57.7% vs 78.3%, P0.001; 42.5% vs 60.3%, P0.001, respectively). The multivariate analysis indicated that high MOR expression was associated with worse DFS and OS (hazard ratio: 1.52, 95% confidence interval: 1.07, 2.25, P=0.034; hazard ratio: 1.42, 95% confidence interval: 1.17, 2.34, P=0.032).High MOR expression may be associated with poor prognosis in patients with LSCC, suggesting that MOR could be used as a valuable molecular biomarker to predict prognosis of LSCC patients.

This prospective multicenter non-randomized phase III study aims to evaluate the long-term outcome of sentinel node navigation surgery for early gastric cancer compared with conventional distal or total gastrectomy. Clinically diagnosed primary T1N0M0 gastric cancer patients with a single lesion (≤40 mm) and without previous endoscopic treatment will be enrolled in this study. Sentinel nodes are identified by dye and radioisotope tracers and are subjected to intraoperative rapid pathology. For patients with negative sentinel node metastasis, individualized surgery consisting of limited stomach resection and sentinel node basin dissection is performed, while standard gastrectomy with D2 lymph node dissection is employed for the positive sentinel node patients. A total of 225 patients will be accrued from 13 hospitals that have experience in sentinel node mapping. The primary endpoint is 5-year relapse-free survival. The secondary endpoints are overall survival, sentinel node detection rate, diagnostic accuracy for sentinel node, distribution of sentinel nodes and metastatic sentinel node/non-sentinel node, and postoperative quality of life.

Purpose Patients with a first attack of acute pancreatitis (AP) can develop recurrent acute pancreatitis (RAP). Hence, this study aimed to investigate the clinical features of the disease and the risk factors for RAP. Methods We performed a retrospective study of 522 patients from Jan 1 to Dec 31, 2006. All patients with AP were followed for 36 months. The primary end point was the rate of RAP. The secondary end points were the risk factors that were evaluated by Cox regression analysis. The cumulative risk of RAP was assessed using Kaplan-Meier analysis. Results 56 of the 522 patients (10.7%) developed RAP. Among those RAP patients, 37 (7.1%) experienced one relapse, 10 (1.9%) experienced two relapses, and 9 (1.7%) experienced three or more relapses. Univariate analysis indicated that age (p = 0.016), male sex, etiology of AP (p = 0.001), local complications (p = 0.001) and Length of stay (LOS) (p = 0.007) were associated with RAP. Multivariate analysis with the Cox proportional hazards model showed that male sex (HR = 2.486, 95% CI, 0.169–0.960, p = 0.04), HTG-associated etiology (HR = 5.690, 95% CI, 2.138–15.146, p = 0.001), alcohol-associated etiology (HR = 5.867, 95% CI, 1.446–23.803, p = 0.013) and current local complications at index admission (HR = 8.917, 95% CI, 3.650–21.789, p = 0.001) were significant independent risk factors for RAP. Conclusions A first attack of AP led to RAP in 10.7% of patients within 3 years. Male sex was significantly associated with RAP. The etiologies of alcohol and HTG and local complications were the strongest risk factors for recurrent disease. Patients with these characteristics should be given special attention and followed-up closely.

Introduction/aim Pancreatic necrosis occurs in a quarter of patients with acute pancreatitis, many of whom form an acute necrotic collection (ANC). The current standard treatment is to defer percutaneous catheter drainage (PCD) until the latter becomes “walled off,” which takes approximately four weeks. The majority of patients that develop persistent organ failure (POF), the primary determinant of mortality, do so within four weeks. To defer PCD until after four weeks may result in a worse outcome because of a missed opportunity to treat early infection and thereby reduce the severity and/or duration of POF. This study is aimed to compare the clinical outcome of the current standard approach with early on-demand PCD in acute necrotizing pancreatitis (ANP) patients with ANC and POF. Methods/design This is an open-label, multi-center, parallel, randomized, controlled trial. All patients with ANP who develop POF during the first week of onset will be screened for eligibility. In total, 120 study subjects will be randomized to either early on-demand PCD or standard care. Patients assigned to the former will receive PCD when they show signs of decompensation like new-onset OF, aggravation of pre-existent OF, and persistent OF for more than a week. The primary composite endpoint is major complication and/or death. Patients will be followed until discharge or death with an additional follow-up 90 days after randomization. Discussion This study challenges the standard 4-week delay before PCD and will answer the question whether early on-demand PCD is associated with a lower incidence of major complications and/or death.

Multimorbidity is common in patients with cardiovascular disease. Clinical trials in cardiovascular medicine mostly enroll patients who are younger, healthier, and more affluent than average patients with the condition of interest. These trials rarely account for patient-level multimorbidity in a systematic fashion. Further, treatment effect heterogeneity is usually tested across subgroups of patients based on the presence or absence of individual variables, not on the basis of summative risk scores that account for multimorbidity. Thus, the impact of multimorbidity on treatment effects is poorly understood. In this study, we performed a multimorbidity-based risk-stratified reanalysis of the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial. Our objectives were to describe the distribution of multimorbidity using a modified version of the Charlson Comorbidity Index (mCCI), scale 0–14, and to assess its impact on the original primary endpoint of all-cause mortality. The majority of patients in the AFFIRM trial had an mCCI score of ≤ 4 (55.5%), and there was no statistically significant difference in the risk of death for rate versus rhythm control in these patients (7.9 vs. 8.8%; p = 0.44). However, for patients with an mCCI ≥ 5 (44.5%), there was a strong trend toward a reduction in death with rate control that nearly reached statistical significance despite being underpowered (24.5 vs. 28.3%; p = 0.07). This proof-of-concept study supports the idea that clinical trials in cardiovascular medicine should systematically assess for multimorbidity and investigate its potential impact on treatment effects.

Background Information on characteristics and outcomes of intensive care unit (ICU) patients with COVID‐19 remains limited. We examined characteristics, clinical course and early outcomes of patients with COVID‐19 admitted to ICU. Methods We included all 260 patients with COVID‐19 admitted to nine ICUs at the Karolinska University Hospital (Stockholm, Sweden) between 9 March and 20 April 2020. Primary outcome was in‐hospital mortality among patients with definite outcomes (discharged from ICU or death), as of 30 April 2020 (study end point). Secondary outcomes included ICU length of stay, the proportion of patients receiving mechanical ventilation and renal replacement therapy, and hospital discharge destination. Results Of 260 ICU patients with COVID‐19, 208 (80.0%) were men, the median age was 59 (IQR 51‐65) years, 154 (59.2%) had at least one comorbidity, and the median duration of symptoms preceding ICU admission was 11 (IQR 8‐14) days. Sixty‐two (23.8%) patients remained in ICU at study end point. Among the 198 patients with definite outcomes, ICU length of stay was 12 (IQR, 6‐18) days, 163 (82.3%) received mechanical ventilation, 28 (14.1%) received renal replacement therapy, 60 (30.3%) died, 62 (31.3%) were discharged home, 47 (23.7%) were discharged to ward, and 29 (14.6%) were discharged to another health care facility. On multivariable logistic regression analysis, older age and admission from the emergency department was associated with higher mortality. Conclusion This study presents detailed data on clinical characteristics and early outcomes of consecutive patients with COVID‐19 admitted to ICU in a large tertiary hospital in Sweden.

PURPOSE: This prospective, nonrandomized, interventional phase 1-2 study investigated the individualization of elective node irradiation in clinically N0 head and neck squamous cell carcinoma by sentinel lymph node (SLN) mapping with single-photon emission computed tomography/computed tomography (SPECT/CT) and its impact on tumor control and radiation-related toxicity.METHODS AND MATERIALS: Forty-four patients with clinically N0 head and neck squamous cell carcinoma treated with definitive (chemo-)radiation therapy were imaged with SPECT/CT after 99mTc nanocolloid injection around the tumor. The neck levels containing up to the 4 hottest SLNs were selected for prophylactic irradiation. A comparative virtual planning was performed with the selection of neck levels based on the current international guidelines. Regional control was monitored as a function of the selected volume. Dosimetric data for the organs at risk were compared between the plans. Normal tissue complication probability (NTCP) rates were derived for xerostomia, dysphagia, and hypothyroidism to predict the clinical benefit and correlated to quality-of-life (QoL) assessments at 6 months. RESULTS: Sixteen percent of patients presented unpredicted lymphatic drainage, and 48% drained unilaterally. The nodal clinical target volume based on lymphoscintigraphy was smaller than the nodal clinical target volume based on international guidelines by a factor of 2 (P < .0001). After a median follow-up of 46 months, only 1 patient experienced a regional relapse in a nonirradiated area. Significant median dose reductions to organs at risk were observed, particularly to contralateral salivary glands in patients with unilateral drainage (14.6-28.1 Gy) and to the thyroid gland in all patients (22.4-48.9 Gy). Median NTCP reductions were observed for xerostomia (0.3% to 13.7%), dysphagia (1.7% to 10.8%), and hypothyroidism (14.0% to 36.1%). QoL at 6 months was improved, particularly in patients irradiated unilaterally.CONCLUSIONS: Neck SLN mapping with SPECT/CT individualizes and reduces the elective nodal target volumes without compromising the regional control. The NTCP rates were reduced and favorable QoL were observed in all patients, particularly in the case of unilateral irradiation.

Background: The ICH E9(R1) addendum states that the strategy to account for intercurrent events should be included when defining an estimand, the treatment effect to be estimated based on the study objective. The estimator used to assess the treatment effect needs to be aligned with the estimand that accounted for intercurrent events. Regardless of the strategy, missing data resulting from patient premature withdrawal could undermine the robustness of the study results. Informative censoring due to dropouts in an events-based study is one such example. Sensitivity analyses using imputation methods are useful to examine the uncertainty due to informative censoring and address the robustness and strength of the study results. Methods: We assessed the effect of premature patient withdrawal in the PRECISION study, a randomized non-inferiority clinical trial of patients with chronic arthritic pain that compared the cardiovascular safety of three nonsteroidal anti-inflammatory drugs–based treatment policies or paradigms. The protocol-defined use of concomitant or rescue medications was permitted since changes in pain medications due to insufficient analgesia were expected in patients in this long-term study. Anticipating that premature study discontinuations could potentially lead to informative censoring, a supplementary analysis was pre-specified in which censored outcomes due to the premature study discontinuation were imputed based on adverse events that were clinically associated with the primary endpoint (cardiovascular outcome based on the Antiplatelet Trialists Collaboration composite endpoint). Furthermore, tipping point analyses were conducted to test the robustness of the primary analysis results by assuming data censored not at random. The level of increase at which the primary study conclusion would change was estimated. Results: For the analysis of time to first primary endpoint event through 30 months, 4065 out of the 24,081 enrolled patients were lost to follow-up, withdrew consent, or were no longer willing to participate in the study. These withdrawals occurred gradually and resulted in a cumulative total of 5893 censored patient-years of observation (10.2%). The rate of discontinuation and the baseline characteristics of the discontinued patients were similar across the three treatment groups. The non-inferiority conclusion from the primary analysis was confirmed in the supplementary analysis incorporating relevant adverse events. Furthermore, tipping point analyses demonstrated that in order to lose non-inferiority in the primary analysis, the risk of primary endpoint events during the censored observation time would have to increase by more than 2.7-fold in the celecoxib group while remaining constant in the other nonsteroidal anti-inflammatory drugs groups, demonstrating that the scenarios where the study results are invalid appear not plausible. Conclusions: Supplementary and sensitivity analyses presented to address informative censoring in PRECISION helped to further interpret and strengthen the study results.

Summary Background & aims Chronic intestinal failure (IF) in children is a rare and heterogeneous disease requiring treatment with parenteral nutrition. A uniform definition for chronic IF and standardized outcome measures to compare therapeutic trials in these children are lacking. Therefore, the aim of this study is to systematically assess how definitions and outcome measures are defined in therapeutic trials of children with chronic IF. Methods MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception till August 2018. No language restriction was used. Results A total of 1766 articles was found of which 70 studies fulfilled our inclusion criteria. 54 studies (76%) did not report any definition of IF. Of the 16 studies (23%) which reported a definition of IF, 7 different definitions were found. The two most frequently used definitions were: (1) the inability to absorb adequate nutrients to maintain body weight or normal growth and development (n = 5), and (2) the dependence upon parenteral nutrition to maintain minimal energy requirements for growth and development (n = 5). A total of 117 different outcomes were reported. The three most reported outcome measures were: mortality (n = 27), liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl trans peptidase) (n = 27), and growth (n = 23). Quality of reporting was considered fair to poor in most studies. Conclusion There is a lack of reported definitions in studies concerning pediatric IF. Heterogeneity exists in outcome reporting in research concerning pediatric chronic IF. Therefore, we recommend the development of a core outcome set.

In reproductive medicine, the needs and desires of infertility patients drive future research, with the most important outcome being live birth of a baby. Large, multicenter, randomized clinical trials are considered the best research tool to evaluate the effectiveness of medical interventions, but they can often take a long time to find definitive answers. Advances in individual participant data (IPD) and network meta-analysis have enabled research questions to be answered more quickly, but better planning could streamline this process further. To harmonize research findings that are taking place globally in this way, it is crucial that the same outcomes are collected in clinical trials conducted in reproductive medicine. Furthermore, the conduct of clinical trials often requires collaboration on an international scale; however, individual countries have their own processes for research prioritization and delivery. We describe the perspective of high- and low-resourced settings and industry as well as the mechanisms of prioritization and coordination that are in place in different settings. In addition, we discuss the importance of the patient perspective, which can help shape the research question, clinical trial design, and the logistical operations of trial delivery. The need for increased global collaboration and coalitions within and between stakeholders is evident for the research community to accelerate advances and maximize benefits in reproductive medicine.