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Objectives: Inflammatory joint disease (IJD) is associated with an increased risk of developing cardiovascular disease (CVD). Arterial stiffness is both a risk factor and a surrogate marker for CVD. This study aims to compare arterial stiffness across patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and, by extension, to explore the relationship between arterial stiffness and the estimated CVD risk by the Systematic COronary Risk Evaluation (SCORE) algorithm. Method: During the study period, from April 2017 to June 2018, 196 patients with IJD visited the Preventive Cardio-Rheuma Clinic in Oslo, Norway. A CVD risk stratification was performed, including the assessment of traditional risk factors and the measurement of arterial stiffness. Results: Thirty-six patients (18.4%) had elevated aortic pulse wave velocity (aPWV) (≥ 10 m/s). After adjustment for age and heart rate, arterial stiffness was comparable across the IJD entities (p = 0.69). Associated factors, revealed by regression analysis, were age, blood pressure, heart rate, presence of carotid plaques, establis hed CVD, non-steroidal anti-inflammatory drugs, and statin use. Furthermore, aPWV was positively correlated with estimated CVD risk (r = 0.7, p < 0.001) and patients with a very high predicted CVD risk (SCORE ≥ 10%) had significantly higher aPWV than patients at lower CVD risk (9.2 vs 7.5 m/s, p < 0.001). Conclusion: The degree of arterial stiffness was comparable across the IJD entities and was highly associated with the estimated CVD risk. Our findings support the need for an increased focus on prevention of CVD in all patients with IJD.

Aim: The triglyceride-glucose index (TyG index) is proposed as a surrogate parameter for insulin resistance (IR) and, when elevated, is related to increased cardiovascular risks. Whether the TyG index is of great value in predicting adverse prognosis for individuals diagnosed with non-ST-segment elevation acute coronary syndrome (NSTE-ACS), who received elective percutaneous coronary intervention (PCI), and without recognized diabetes remains unclear. Methods: Overall, 1,510 subjects diagnosed with NSTE-ACS, who received elective PCI, and without recognized diabetes were enrolled in the current study. All participants received a routine follow-up after discharge. The TyG index was obtained from the following equation: napierian logarithmic (ln) [fasting triglyceride (TG, mg/dL)×fasting blood glucose (FBG, mg/dL)/2]. Adverse cardiovascular events included all-cause death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke, and ischemia-driven revascularization, composite of which was defined as the primary endpoint. Results: Overall, 316 (20.9%) endpoint events were documented during a 48-month follow-up. Despite adjusting for confounding variates, the TyG index remains to be a significant risk predictor for the primary endpoint, with a hazard ratio (HR) [95% confidence interval (CI)] of 2.433 (1.853-3.196) ( P ＜0.001). A significant enhancement on the predictive performance for the primary endpoint emerged when adding the TyG index into a baseline model [area under the receiver-operating characteristic (ROC) curve (AUC), 0.835 for baseline model vs. 0.853 for baseline model＋TyG index, P ＜0.001; net reclassification improvement (NRI), 0.194, P ＜0.001; integrated discrimination improvement (IDI), 0.023, P =0.007]. Conclusions: The TyG index is an independent risk predictor for adverse cardiovascular events in nondiabetic subjects diagnosed with NSTE-ACS and who received elective PCI. Further prospective studies are needed to verify these findings.

Correlations among survival endpoints are important for exploring surrogate endpoints of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms. In this article, we reconsider the definition of Kendall's concordance measure (tau) in the context of individual patient data meta-analyses of randomized controlled trials. According to our new definition of Kendall's tau, its value depends on the treatment arms. We then suggest extending the existing copula (and frailty) models so that their Kendall's tau can vary across treatment arms. Our newly proposed model, a joint frailty-conditional copula model, is the implementation of the new definition of Kendall's tau in meta-analyses. In order to facilitate our approach, we develop an original R function condCox.reg(.) and make it available in the R package joint.Cox ( https://CRAN.R-project.org/package=joint.Cox ). We apply the proposed method to a gastric cancer dataset (3288 patients in 14 randomized trials from the GASTRIC group). This data analysis concludes that Kendall's tau has different values between the surgical treatment arm and the adjuvant chemotherapy arm ( p-value

INTRODUCTION: We aimed to evaluate the trajectory of two surrogates of fluid overload -antigen carbohydrate 125 (CA125) and amino-terminal pro-brain natriuretic peptide (NT-proBNP)- after the addition of oral empagliflozin to usual care in a cohort of patients with chronic heart failure (CHF) and type 2 diabetes (T2D). METHODS AND RESULTS: From October 2015 to February 2019, 60 ambulatory patients with CHF and T2D were retrospectively included. The primary endpoint was to assess the longitudinal trajectory of plasma levels of CA125 and NT-proBNP after empagliflozin initiation. Changes in quantitative variables were evaluated using linear mixed regression. Median CA125 and NT-proBNP at baseline were 17 (11-75) U/mL and 1662 (647-4230) pg/mL, respectively. A total of 510 outpatient visits were recorded [median (interquartile range) of visits per patient: 6 (4-11)] during a median of 1.78 years. We found a significant and steady decrease in the log of CA125 after empagliflozin initiation (p < 0.001). Conversely, the log of NT-proBNP predicted trajectory did not significantly change (p = 0.425). CONCLUSION: In this cohort of patients with CHF and T2D, empagliflozin initiation was associated with a significant decrease in CA125 levels without modifying the trajectory of NT-proBNP. Considering that CA125 has emerged as a surrogate marker of tissue congestion, we hypothesize that empagliflozin might predominantly promote extravascular decongestion.

Background High-molecular-weight (MW) oat β-glucan (OBG), consumed at 3-4 g/d, in solid foods reduces LDL cholesterol by a median of ∼6.5%. Objectives We evaluated the effect of a beverage providing 3 g/d high-MW OBG on reduction of LDL cholesterol (primary endpoint) when compared with placebo. Methods We performed a parallel-design, randomized clinical trial at a contract research organization; participants, caregivers, and outcome assessors were blinded to treatment allocation. Participants with LDL cholesterol between 3.0 and 5.0 mmol/L, inclusive [n = 538 screened, n = 260 ineligible, n = 23 lost, n = 48 withdrawn (product safety); n = 207 randomly assigned, n = 7 dropped out, n = 9 withdrawn (protocol violation); n = 191 analyzed; n = 72 (37.7%) male, mean ± SD age: 43.3 ± 14.3 y, BMI: 29.7 ± 5.2 kg/m2], were randomly assigned to consume, 3 times daily for 4 wk, 1 g OBG (n = 104, n = 96 analyzed) or rice powder (Control, n = 103, n = 95 analyzed) mixed into 250 mL water. Treatment effects were assessed as change from baseline and differences analyzed using a 2-sided t test via ANOVA with baseline characteristics as covariates. Results After 4 wk, change from baseline least-squares-mean LDL cholesterol on OBG (-0.195 mmol/L) was less than on Control (0.012 mmol/L) by mean: 0.207 mmol/L (95% CI: 0.318, 0.096 mmol/L; P = 0.0003); the following secondary endpoints were also reduced as follows: total cholesterol (TC) (0.226 mmol/L; 95% CI: 0.361, 0.091 mmol/L; P = 0.001), TC:HDL cholesterol ratio (0.147; 95% CI: 0.284, 0.010; P = 0.036), non-HDL cholesterol (0.194 mmol/L; 95% CI: 0.314, 0.073 mmol/L; P = 0.002), and Framingham cardiovascular disease (CVD) risk (0.474; 95% CI: 0.900, 0.049, P = 0.029). Changes in HDL cholesterol, triglycerides, glucose, and insulin did not differ between treatment groups (P > 0.05). Lipid treatment effects were not significantly modified by age, sex, BMI, or hypertension treatment. There were no major adverse events, but both treatments transiently increased gastrointestinal symptoms. Conclusions Consuming a beverage containing 1 g high-MW OBG 3 times daily for 4 wk significantly reduced LDL cholesterol by ∼6% and CVD risk by ∼8% in healthy adults with LDL cholesterol between 3 and 5 mmol/L.This trial was registered at clinicaltrials.gov as NCT03911427.

Liver-limited metastatic colorectal cancer is a potentially curable disease. Pathologic response (pR) to preoperative chemotherapy (CT) for colorectal liver metastases (CLM) is a surrogate endpoint for overall survival (OS). We conducted the first meta-analysis of observational studies to estimate the overall effect of bevacizumab on pR in preoperative systemic therapy for CLM.We systematically searched PubMed, Cochrane Library, CINAHL, Web of Science, Embase, and LILACS for studies published between January 2004 and August 2019 that compared the pR of CT plus bevacizumab to CT alone as preoperative therapy for CLM. The primary endpoint was pathologic complete response (pCR). Secondary endpoints were pathologic major (pMaR) and minor (pMiR) response. Overall effects were expressed by odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model.Of the 1,452 studies yielded by the search, 9 were eligible, totaling 1,202 patients (516 CT plus bevacizumab and 686 CT alone). The addition of bevacizumab to CT increased the pCR rate without reaching statistical significance (OR: 1.24, 95% CI 0.81 to 1.92, P = .32). However, pMaR was significantly higher (OR: 2.45, 95% CI 1.85 to 3.25, P.001), and pMiR was significantly lower (OR: 0.41, 95% CI 0.31 to 0.54, P.001), in the bevacizumab group. The analyses showed a low level of heterogeneity (IThis meta-analysis demonstrates that bevacizumab plus preoperative CT is associated with higher rates of pR in CLM. Antiangiogenics might improve the OS of CLM patients and should be evaluated in randomized clinical trials.The benefit of perioperative chemotherapy for colorectal liver metastases (CLM) is uncertain, but pathologic response (pR) to preoperative chemotherapy is a strong prognostic factor. Our meta-analysis of observational studies compared the pR of bevacizumab plus chemotherapy to chemotherapy alone as preoperative systemic therapy in the management of CLM. The addition of bevacizumab was associated with significantly higher rates of pR.

BackgroundWhite matter hyperintensities (WMHs) are a highly prevalent MRI marker of cerebral small vessel disease (SVD), which predict stroke and dementia risk, and are being increasingly used as a surrogate marker in clinical trials. However, the influence of study population selection on WMH progression rate has not been studied and the effect of individual patient factors for WMH growth are not fully understood.MethodsWe performed a systematic review and meta-analysis of the literature on progression of WMHs in longitudinal studies to determine rates of WMH growth, and how these varied according to population characteristics and cardiovascular risk factors. We used these data to calculate necessary sample sizes for clinical trials using WMH as an endpoint.ResultsWMH growth rate was highest in SVD (2.50cc/year), intermediate in unselected stroke patients (1.29cc/year) and lower in patients with non-stroke cardiovascular disease, and with cognitive impairment. Age was significantly associated with progression (correlation coefficient 0.15cc/year, 95% CI 0.02 to 0.28cc/year) as was baseline lesion volume (0.6cc/year, 95% CI 0.13 to 1.06 cc/year). Both hypertension (OR 1.72, 95% CI 1.19 to 2.46) and current smoking (OR 1.48, 95% CI 1.02 to 2.16) were associated with WMH growth. Sample sizes for a clinical trial varied greatly with patient population selection and baseline lesion volume; estimates are provided.ConclusionsWMH progression varies markedly according to the characteristics of the population being studied and this will have a major impact on sample sizes required in a clinical trial. Our sample size estimates provide data for planning clinical trials using WMH as an outcome measure.PROSPERO registration numberCRD42020191781.

Introduction Major pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the significance of pathologic response in lymph nodes harboring metastatic tumors in such patients remains uncertain. Therefore, we studied the effect of neoadjuvant chemotherapy on resected positive lymph nodes and determined if the degree of pathologic response in the lymph nodes alone (LN-MPR) or in combination with that of the primary tumor (PT-MPR) was able to predict the outcome. Methods A total of 75 patients with NSCLC who underwent neoadjuvant chemotherapy and completed surgical resection were included in this study. Tissue specimens were retrospectively evaluated by two pathologists blinded to the patients' treatments and outcomes. Specimens were reviewed for the degree of pathologic response in the primary tumor and in any involved lymph nodes. The prognostic performance of LN-MPR alone or in combination with PT-MPR with respect to overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression model. Results LN-MPR was significantly predictive of long-term OS after neoadjuvant chemotherapy. A combination of PT-MPR with LN-MPR was significantly associated with outcome and allowed stratification of patients into three prognostic groups (p = 0.001). Conclusions LN-MPR in isolation is a reliable predictor of OS in patients with NSCLC receiving neoadjuvant chemotherapy. A combination of LN-MPR with PT-MPR seems to correlate well with the outcome and can be used to predict prognosis in this patient population.

Background: Neutralizing antibodies (NAbs) are important for protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection. In this study, two assays that are correlated with NAbs were compared: the haemagglutination test (HAT) and the surrogate virus neutralization test (sVNT). Methods: The specificity of the HAT was compared with the sVNT, and the sensitivity and persistence of antibodies in patients with varying severity of illness was assessed in a cohort of 71 patients at 4–6 weeks and 13–16 weeks. The kinetics were assessed in the first, second, and third weeks in patients with varying severity of acute illness. Results: The specificity of the HAT was >99%, and sensitivity was similar to the sVNT. The levels of HAT were significantly and positively correlated with those of the sVNT (Spearman's r = 0.78, P < 0.0001). Patients with moderate and severe illness had higher HAT titres when compared to those with mild illness. Six of seven patients with severe illness had a titre of >1:640 during the second week of illness, whereas only five of 31 patients with a mild illness had a titre of >1:160 in the second week of illness. Conclusions: Since the HAT is a simple and very cheap assay to perform, it would be ideal to use as an indicator of NAbs in resource-poor settings.

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV‐status is assessed routinely in clinical practice. Paradoxically, while the oral cavity seems the predilection site for productive HPV‐infections, figures on HPV‐attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. Major obstacles are the lack of reproducible assays to detect HPV in nonoropharyngeal cancers, the relatively small cohorts studied and consequently the shortfall of convincing data. In our study, we used a validated, nucleic acid‐based workflow to assess HPV‐prevalence in a consecutive cohort of 1016 OCSCCs, and investigated its prognostic impact. In parallel, we analyzed p16‐immunohistochemistry (p16‐IHC) as surrogate marker for transforming HPV‐infection and independent prognosticator. All OCSCC‐patients diagnosed between 2008 and 2014 at two Dutch university medical centers were included (N = 1069). Formalin‐fixed, paraffin‐embedded (FFPE)‐samples of 1016 OCSCCs could be retrieved. Punch biopsies were taken from the tumor area in the FFPE‐blocks and tested for HPV. P16‐IHC was performed on 580 OCSCCs, including all HPV‐positive tumors. From 940 samples (92.5%), nucleic acids were of sufficient quality for HPV‐testing. In total, 21 (2.2%) OCSCCs were HPV DNA‐positive. All HPV DNA‐positive tumors were E6 mRNA‐positive and considered as true HPV‐positive. There was no difference in survival between HPV‐positive and HPV‐negative OCSCCs. In total, 46 of 580 (7.9%) OCSCCs were p16‐immunopositive, including all HPV‐positive tumors. Survival was comparable in p16‐positive and p16‐negative OCSCCs. To conclude, HPV‐prevalence is very low in OCSCC and neither HPV‐status nor p16‐status affects outcome. Based on these data, determining HPV‐status in OCSCC seems irrelevant for clinical management., What's new? While human papillomavirus (HPV)‐infection is prognostic for oropharyngeal squamous cell carcinoma (OCSCC), its role and prognostic impact in OCSCC remain uncertain. In the present study, nucleic acid‐based HPV‐testing of a cohort of 1016 tumor samples collected from OCSCC patients diagnosed between 2008 and 2014 reveals very low HPV‐prevalence in OCSCC. In addition, no difference was found in survival between HPV‐positive and HPV‐negative tumors. The findings indicate that HPV is uncommon in OCSCC and, when present, has no impact on survival, providing new and important insight into the ongoing debate regarding the role of HPV in OCSCC.

Objective Sarcopenia (especially muscle mass assessed using gold standard techniques) has been suggested as a poorer predictor of mortality than muscle function in patients undergoing hemodialysis. Appropriate methods to estimate muscle mass for use as a good predictor of clinical outcomes remain to be established. We investigated whether the modified creatinine index (mCI), which is a surrogate marker of muscle mass, could predict mortality and cardiovascular (CV) hospitalizations independent of muscle function and other confounders in patients on hemodialysis. Design and Methods In this retrospective study, outpatients (n = 542; mean age, 65.3 years; 60% men; median dialysis vintage, 29 months; mean BMI, 22.0 kg/m2) undergoing hemodialysis were investigated. The mCI, handgrip strength, and gait speed were assessed and related to all-cause mortality and a composite of CV hospitalizations and all-cause mortality. Cox proportional and mixed-effects negative binomial models were fit for mortality and the composite outcomes. Results Patients were followed up for a median 3 years (interquartile range: 1.5-5.7). Each per SD increase of mCI (HR:0.63, 95% CI:0.62-0.65), handgrip strength (HR:0.51, 95% CI:0.48-0.54), and gait speed (HR:0.60, 95% CI:0.56-0.64) were significantly associated with lower all-cause mortality rates after adjusting for covariates. The mCI was consistently found to be an independent predictor of mortality after additional adjustment for handgrip strength or gait speed. Furthermore, sarcopenic conditions [i.e., lower mCI, and lower handgrip strength (HR:3.79, 95% CI:2.09-6.87) or slower gait speed (HR:4.20, 95% CI:2.38-7.41)] were significantly associated with a higher risk of mortality after adjusting for covariates. Associations of mCI with multiple CV hospitalizations and mortality were similar to those between mCI and mortality. Conclusion The mCI was a good predictor of clinical outcomes and was comparable to muscle function, including handgrip strength and gait speed. The mCI is likely to provide additional diagnostic and prognostic values for sarcopenia in patients on hemodialysis.

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti‐cancer drugs in Japan were established in 1991 and amended in 2006 after molecular‐targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti‐cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti‐cancer drugs in Japan. To promote global development of anti‐cancer drugs involving Japan, the guidelines have been translated into English., Recent progress in development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti‐cancer drugs. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study with monitoring possible ethnic differences. Because of these changes, we have revised the guidelines for the clinical evaluation of anti‐cancer drugs in Japan.

There is no universally accepted instrument to use as a validated surrogate endpoint for overall survival in phase 2 and phase 3 multimodal rectal cancer trials using chemoradiotherapy. Efforts are hampered by the inaccuracy of clinical TNM staging, the variability of indications for neoadjuvant treatment, and diverse definitions of tumour regression grade. Pathological complete response is commonly used, but fails to capture information from the majority of patients. The neoadjuvant rectal score categorises response and downstaging from the entire trial population to identify whether or not a novel treatment group in a chemoradiation trial is superior by predicting overall survival outcomes. Additionally, the neoadjuvant rectal score assesses the difference between initial clinical and pathological T stage and the presence or absence of nodal involvement after treatment. The neoadjuvant rectal score has been conceptually, but incompletely, statistically validated by two independent trial datasets. However, a fundamental weakness of the score is that no preoperative phase 3 trials in locally advanced rectal cancer in the past 20 years have provided a significant benefit in overall survival to statistically validate the neoadjuvant rectal score as a surrogate endpoint for overall survival. We review the robustness, practical value, applicability, generalisability, advantages, and disadvantages of the neoadjuvant rectal score as a surrogate endpoint for overall survival and recommend how this score could be improved and be acceptable as a standard endpoint in studies investigating neoadjuvant chemotherapy and chemoradiation in patients with rectal cancer.

OBJECTIVES: To evaluate the factors associated with response to neoadjuvant chemotherapy (NACT) and the ability to undergo interval tumor reductive surgery (iTRS) in patients with advanced ovarian cancer. METHODS: We performed a retrospective review from April 2013 to March 2019 of patients with advanced stage ovarian cancer triaged to NACT based on our standard triage algorithm. Clinicopathologic and treatment data were analyzed for factors associated with response to NACT, outcomes at iTRS, and their impact on progression-free survival (PFS). RESULTS: 562 patients met inclusion criteria and triaged to NACT following laparoscopy (n=132) or without laparoscopy (n=430). 413 patients underwent iTRS (74%). Factors that correlated with a patient reaching iTRS included increasing age (p1cm, p

Background In the recent years, an increasing number of patients with multiple comorbidities (e.g. coronary artery disease, diabetes, hypertension) presents to the operating room. The clinical risk factors are accompanied by underlying vascular-endothelial dysfunction, which impairs microcirculation and may predispose to end-organ dysfunction and impaired postoperative outcome. Whether preoperative endothelial dysfunction identifies patients at risk of postoperative complications remains unclear. In this prospective observational study, we tested the hypothesis that impaired flow-mediated dilation (FMD), a non-invasive surrogate marker of endothelial function, correlates with Days at Home within 30 days after surgery (DAH30). DAH30 is a patient-centric metric that captures postoperative complications and importantly also hospital re-admissions. Methods Seventy-one patients scheduled for major abdominal surgery were enrolled. FMD was performed pre-operatively prior to major abdominal surgery and patients were dichotomised at a threshold value of 10%. FMD was then correlated with DAH30 (primary endpoint) and postoperative complications (secondary endpoints). Results DAH30 did not differ between patients with reduced FMD and normal FMD (14 (4) (median (IQR)) vs. 15 (8), P = 0.8). Similary, no differences between both groups were found for CCI (normal FMD: 21 (30) (median (IQR)), reduced FMD: 26 (38), P = 0.4) or frequency of major complications (normal FMD: 7 (19%) (n (%)), reduced FMD: 12 (35%), P = 0.12). The regression analyses revealed that FMD in combination with ASA status and surgery duration had no additional significant predictive effect for DAH30, CCI or Clavien-Dindo score. Conclusion FMD does not add predictive value with regards to DAH30, CCI or Clavien-Dindo score within our study cohort of patients undergoing abdominal surgery. Trial registration The study was registered in the German Clinical Trials Register (DRKS00005472), prospectively registered on 25/11/2013.

Background Sodium valproate (VPA) has been associated with a reduced risk of head and neck cancer development. The potential protective mechanism of action is believed to be via inhibition of histone deacetylase and subsequent epigenetic reprogramming. SAVER is a phase IIb open-label, randomised control trial of VPA as a chemopreventive agent in patients with high-risk oral epithelial dysplasia (OED). The aim of the trial is to gather preliminary evidence of the clinical and biological effects of VPA upon OED and assess the feasibility and acceptability of such a trial, with a view to inform a future definitive phase III study. Methods One hundred and ten patients with high-risk OED will be recruited from up to 10 secondary care sites in the UK and randomised into either VPA or observation only for 4 months. Women of childbearing potential will be excluded due to the teratogenic properties of VPA. Tissue and blood samples will be collected prior to randomisation and on the last day of the intervention/observation-only period (end of 4 months). Clinical measurement and additional safety bloods will be taken at multiple time points during the trial. The primary outcome will be a composite, surrogate endpoint of change in lesion size, change in grade of dysplasia and change in LOH profile at 8 key microsatellite regions. Feasibility outcomes will include recruitment targets, compliance with the study protocol and adverse effects. A qualitative sub-study will explore patient experience and perception of the trial. Discussion The current management options for patients with high-risk OED are limited and mostly include surgical resection and clinical surveillance. However, there remains little evidence whether surgery can effectively lead to a notable reduction in the risk of oral cancer development. Similarly, surveillance is associated with concerns regarding delayed diagnosis of OED progressing to malignancy. The SAVER trial provides an opportunity to investigate the effects of a repurposed, inexpensive and well-tolerated medication as a potential chemopreventive strategy for patients with high-risk OED. The clinical and biological findings of SAVER will inform the appropriateness, design and feasibility of a definitive phase III trial. Trial registration The trial is registered with the European Clinical Trials Database (Eudra-CT 2018-000197-30). (http://www.isrctn.com/ISRCTN12448611). The trial was prospectively registered on 24/04/2018.

AIM The aim was to investigate the influence of distal resection margin and extent of mesorectal excision on long-term oncological outcomes. METHOD Consecutive patients with upper and middle third rectal cancer from June 2006 to February 2016 were reviewed. Patients were divided into four groups depending on the distal margin considered as a surrogate marker of the extension of mesorectal excision (Q1 ≤10 mm, Q2 11-20 mm, Q3 21-30 mm, Q4 ≥31 mm). Local-recurrence-free survival (LRFS), disease-free survival (DFS) and overall survival (OS) were estimated. Cox regression models were used to investigate the influence of surgical and clinicopathological variables on prognosis by adjusting for confounding factors. RESULTS Two hundred and eleven patients with mid (125) and upper (86) rectal cancer underwent wide mesorectal excision. The median follow-up was 48.64 months (interquartile range 28-63). 17.5% patients developed recurrence. The 5-year LRFS, DFS and OS for all patients were 93.20%, 83.89% and 80.1%, respectively, with no statistically significant differences between groups (LRFS, P = 0.601; DFS, P = 0.487; OS, P = 0.468). In the multivariable analysis the recurrences and survival were associated with the quality of the mesorectum (LRFS, hazard ratio 10.629, 95% CI 2.324-48.610, P = 0.002; DFS, hazard ratio 2.789, 95% CI 1.314-5.922, P = 0.008). CONCLUSION A wide anatomical resection with partial mesorectal excision and shorter distal resection margin does not jeopardize the oncological outcomes.

IntroductionEvidence suggests that cigarette smokers who switch to electronic nicotine delivery systems (ENDS) reduce their exposure to harmful toxicants and carcinogens. It is unclear if dual-use is associated with decreases in exposure to toxicants.MethodsThis parallel-group confinement study assessed changes in biomarkers of exposure (BOEs) over six days among healthy adult smokers who were randomized into 1 of 11 study groups: eight JUUL-brand System (JUUL) groups (4 JUUL flavors [Virginia Tobacco, Menthol, Mint, Mango] × 2 nicotine concentrations [5.0% or 3.0% by weight]); Dual-Use group used preferred JUUL flavor (5.0% nicotine) and ≤50% usual brand (UB) cigarettes/day; UB Cigarette group and one group abstained from all tobacco/nicotine product use (Abstinence group). Urine and blood analysis assessed changes in primary BOE endpoints (NNAL, 3-HPMA, MHBMA, S-PMA COHb) and secondary BOE endpoints (NNN, HMPMA, CEMA, 1-OHP, O-toluidine, 2-NA, 4-ABP) among 279 adult smokers.ResultsIn JUUL groups, median percent reductions in primary BOEs (Day 6–Baseline) were 90%–≥100% of Abstinence; there were no significant differences between JUUL groups and Abstinence. All reductions in JUUL groups were substantially and statistically significantly greater than reductions in the UB Cigarette group (ps < 0.025). Median reductions in primary BOEs in the Dual-Use group were 43%–55% of Abstinence. Similar results were observed for secondary BOEs.ConclusionThis study suggests that the use of JUUL as a complete or partial substitute (i.e., dual-use with ≥50% reduction in cigarette consumption) for combustible cigarettes can substantially reduce exposure to multiple toxins associated with cigarette smoking.ImplicationsThis study adds to the growing body of evidence supporting the utility of ENDS products as potentially reduced-harm alternatives to cigarettes for adult smokers. Adult smokers who switched completely from cigarette smoking to use of the JUUL System (“JUUL”) in two nicotine concentrations (5.0% and 3.0%) and four flavors significantly reduced their exposure to multiple classes of cigarette-related toxicants. Additionally, smokers who used JUUL and continued smoking but reduced their daily cigarette consumption by ≥50% (dual users) also significantly reduced their toxicant exposure compared to cigarette smoking.

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival (PFS). Obinutuzumab was superior to rituximab for PFS in the GALLIUM study, although the benefit was small and required more drug. Chemotherapy platforms have changed in the past decade, as bendamustine combined with rituximab has become commonly utilized frontline strategy in North America and parts of Europe, although there is certainly no one standard treatment. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, the development of novel combinations, and strategies to reduce the risk of transformation. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate endpoints, so that novel agents can be tested (and adopted, if appropriate) efficiently.

Pseudomelanosis coli is historically associated with anthraquinone laxatives and is often used as a surrogate marker for chronic laxative use. The opioid epidemic has seen an increase in laxative use for chronic constipation. Anthraquinone laxatives have demonstrated tumorigenic potential in animal studies due to their apoptotic effects on colonic epithelial cells. Colorectal cancer is associated with significant mortality and morbidity worldwide. Human studies have not shown a significant correlation between anthraquinone laxative use, pseudomelanosis coli, and colorectal carcinoma. The characteristic pigmentation of pseudomelanosis also appears to be absent macroscopically and on histology of neoplastic epithelium. However, there appears to be a slightly higher risk of adenoma development. This has been attributed to a higher polyp detection rate during endoscopy on account of the color contrast between the polyp against a darker background of pseudomelanosis., Pseudomelanosis coli may have tumorigenic potential from chronic laxative use and is associated with a higher polyp detection rate.

Although electrolyte abnormalities are related to worse clinical outcomes in patients with acute myocardial infarction (AMI), little is known about the association between admission serum magnesium level and adverse events in AMI patients complicated by out-of-hospital cardiac arrest presenting with malignant ventricular arrhythmias (OHCA-MVA). We investigated the prognostic value of serum magnesium level on admission in these patients.We retrospectively analyzed the data of 165 consecutive reperfused AMI patients complicated with OHCA-MVA between April 2007 and February 2020 in our university hospital. Serum magnesium concentration was measured on admission. The primary outcome was in-hospital death.Fifty-four patients (33%) died during hospitalization. Higher serum magnesium level was significantly related to in-hospital death (FineGray's test; p 0.001). In multivariable logistic regression analyses, serum magnesium level on admission was independently associated with in-hospital death (hazard ratio 2.68, 95% confidence interval 1.24-5.80) even after adjustment for covariates. Furthermore, the incidences of cardiogenic shock necessitating an intra-aortic balloon pump (p = 0.005) or extracorporeal membrane oxygenation (p 0.001), tracheal intubation (p 0.001) and persistent vegetative state (p = 0.002) were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level.In reperfused AMI patients complicated by OHCA-MVA, admission serum magnesium level might be a potential surrogate marker for predicting in-hospital death.

Background IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although most IgAN cases are sporadic, few show a familial aggregation. However, the prevalence and prognosis of IgAN individuals with positive familial history (FH) of renal disorders remains uncertain. To address these issues, we conducted a longitudinal observational study on a single-institution cohort of patients with biopsy-proven IgAN. Methods A total of 467 IgAN patients who underwent renal biopsy during 1994 to 2019 were ascertained to have positive- or negative-FH by history taking and were followed for an average of 8.9 years. We compared the clinical and pathological features of the two subgroups. The primary outcome, a composite of a hard endpoint (end-stage renal disease [ESRD]) and surrogate endpoint (a 50% or more reduction in the estimated glomerular filtration rate [eGFR] from baseline), was evaluated. To estimate the risk for progression to ESRD, a Cox proportional hazards analysis was performed for a subset of patients who underwent follow-up for > 2 years and had an eGFR > 30 mL/min/1.73 m2 at baseline (n = 389; observation, 8.7 years). Results Positive-FH subtype accounted for 11.6% (n = 54) of all IgAN patients. At baseline, there were no significant differences between the positive- and negative-FH subgroups regarding age, sex, comorbid disease, MEST-C score, observation period, and therapeutic interventions. However, the eGFR value at baselines was significantly lower in the positive-FH subgroup than in the negative-FH subgroup (P P = 0.03), after adjusting for confounding factors. eGFR at follow-up was significantly lower in the positive-FH subgroup than in the negative-FH subgroup after adjustment for age and observation period. Conclusions Positive-FH was found in 11.6% of all IgAN patients, consistent with the incidence seen in previous literature. A significantly lower eGFR at baseline and last follow-up and unfavorable renal outcomes in the positive-FH subgroup suggest that certain genetic risk factors predisposing to renal failure may exist in a fraction of our IgAN cohort. (331 words).

Background Patients with non-left-main coronary bifurcation lesions are usually best treated with a stepwise provisional approach. However, patients with true left main stem bifurcation lesions have been shown in one dedicated randomized study to benefit from systematic dual stent implantation. Methods and results Four hundred and sixty-seven patients with true left main stem bifurcation lesions requiring intervention were recruited to the EBC MAIN study in 11 European countries. Patients were aged 71 ± 10 years; 77% were male. Patients were randomly allocated to a stepwise layered provisional strategy (n = 230) or a systematic dual stent approach (n = 237). The primary endpoint (a composite of death, myocardial infarction, and target lesion revascularization at 12 months) occurred in 14.7% of the stepwise provisional group vs. 17.7% of the systematic dual stent group (hazard ratio 0.8, 95% confidence interval 0.5–1.3; P = 0.34). Secondary endpoints were death (3.0% vs. 4.2%, P = 0.48), myocardial infarction (10.0% vs. 10.1%, P = 0.91), target lesion revascularization (6.1% vs. 9.3%, P = 0.16), and stent thrombosis (1.7% vs. 1.3%, P = 0.90), respectively. Procedure time, X-ray dose and consumables favoured the stepwise provisional approach. Symptomatic improvement was excellent and equal in each group. Conclusions Among patients with true bifurcation left main stem stenosis requiring intervention, fewer major adverse cardiac events occurred with a stepwise layered provisional approach than with planned dual stenting, although the difference was not statistically significant. The stepwise provisional strategy should remain the default for distal left main stem bifurcation intervention. Study registration http://clinicaltrials.gov NCT02497014.

Aims Contemporary 2nd-generation thin-strut drug-eluting stents (DES) are considered standard of care for revascularization of patients undergoing percutaneous coronary intervention. A previous meta-analysis of 10 randomized controlled trials (RCTs) with 11 658 patients demonstrated a 16% reduction in the 1-year risk of target lesion failure (TLF) with ultrathin-strut DES compared with conventional 2nd-generation thin-strut DES. Whether this benefit is sustained longer term is not known, and newer trial data may inform these relative outcomes. We therefore sought to perform an updated systematic review and meta-analysis of RCTs comparing clinical outcomes with ultrathin-strut DES (≤70 µm strut thickness) with conventional 2nd-generation thin-strut DES. Methods and results We performed a random-effects meta-analysis of all RCTs comparing ultrathin-strut DES to conventional 2nd-generation thin-strut DES. The pre-specified primary endpoint was long-term TLF, a composite of cardiac death, myocardial infarction (MI), or clinically driven target lesion revascularization (CD-TLR). Secondary endpoints included the components of TLF, stent thrombosis (ST), and all-cause death. There were 16 eligible trials in which 20 701 patients were randomized. The weighted mean follow-up duration was 2.5 years. Ultrathin-strut DES were associated with a 15% reduction in long-term TLF compared with conventional 2nd-generation thin-strut DES [relative risk (RR) 0.85, 95% confidence interval (CI) 0.76–0.96, P = 0.008] driven by a 25% reduction in CD-TLR (RR 0.75, 95% CI 0.62–0.92, P = 0.005). There were no significant differences between stent types in the risks of MI, ST, cardiac death, or all-cause mortality. Conclusions At a mean follow-up of 2.5 years, ultrathin-strut DES reduced the risk of TLF, driven by less CD-TLR compared with conventional 2nd-generation thin-strut DES, with similar risks of MI, ST, cardiac death, and all-cause mortality.

AIMS Oropharyngeal squamous cell carcinomas (OPSCC) related to human papillomavirus (HPV) infection have a better prognosis than those without HPV infection. Although p16INK4a overexpression is used as a surrogate marker for HPV infection, 5-20% of p16-positive OPSCC are described as being unrelated to HPV infection, with worse overall survival compared to OPSCC-related HPV. There is therefore a risk of undertreating a proportion of OPSCC patients falsely considered to be HPV-driven because of p16 positivity. TP53 mutations are highly prevalent in OPSCC driven by mutagens in tobacco and alcohol. We describe herein a combined p16/p53 algorithm to predict HPV tumour status in OPSCC. METHODS AND RESULTS A total of 110 OPSCC were identified in the database of the pathology department and were studied using p16 and p53 immunohistochemistry. For p16-positive or p16-negative/wild-type patterns-p53 (WT-p53) cases (n = 63), DNA in-situ hybridisation for high-risk HPV was performed, and if negative the HPV status was controlled by HPV DNA polymerase chain reaction (PCR) (n = 19). A significant association between TP53 mutation and pattern of p53 expression was found (WT-p53, seven of 16, P

AIMS p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC), but it is not sufficient in all clinical settings. METHODS AND RESULTS We examined the p16 and Rb expression status in 177 OPSCC cases by immunohistochemistry and the presence of transcriptionally active HR-HPV infection by mRNA in-situ hybridisation. The 177 cases were divided into p16+ /HPV+ (n = 105, 59.3%), p16+ /HPV- (n = 8, 4.5%) and p16- /HPV- (n = 64, 36.2%) groups. The p16+ /HPV- and p16- /HPV- groups had a trend towards worse overall survival (OS) or significantly worse OS than the p16+ /HPV+ group (n = 105) (P = 0.0610, P = 0.0004, respectively). We divided the Rb status into preserved expression (> 90%, n = 68), partial loss (PL) (10-90%, n = 97) and complete loss (CL) (

Objective To prospectively determine the value of optical coherence tomography (OCT) as a surrogate outcome measure for the progression of myelopathy in males with adrenoleukodystrophy. Methods Retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thickness were measured at baseline, 1‐ and 2‐year follow‐up in patients and age‐matched controls. We assessed the severity of myelopathy with clinical parameters: Expanded Disability Status Scale (EDSS), Severity Scoring system for Progressive Myelopathy (SSPROM), and timed up‐and‐go. Linear mixed model analysis was used to compare changes in retinal layer thickness of patients to controls. In addition, we correlated changes in retinal layer thickness with changes in clinical parameters. Results Longitudinal data were available for 28 patients and 29 controls. Peripapillary RNFL (pRNFL) thickness decreased significantly in patients compared to controls (−1.75µm, p = 0.001), whereas change in macular GCL and RNFL was not different between groups. Analysis of the symptomatic subgroup showed that, apart from a similar decrease in pRNFL thickness, GCL thickness decreased significantly (−0.55 µm, p = 0.014). There were moderately strong correlations between changes in retinal layer thickness and changes in clinical parameters of severity of myelopathy. Interpretation This prospective study demonstrates the potential of OCT‐measured retinal neurodegeneration as a surrogate outcome measure for the progression of myelopathy in adrenoleukodystrophy. As differences were small, our findings need to be confirmed with longer follow‐up and/or in a larger patient sample.

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.

Copeptin is a surrogate marker of arginine vasopressin release with better stability and simplicity of measurement. Postoperative copeptin levels may guide clinicians in stratifying patients who need close monitoring of fluid balance. The objective is to determine whether copeptin is a predictive marker of postoperative diabetes insipidus (DI).This is a prospective diagnostic study. Patients who underwent neurosurgical intervention of the sellar-suprasellar regions were recruited. Serum copeptin levels were measured before and after surgery, within 24 hours. Logistic regression analysis and diagnostic performance measures were calculated to determine the relationship between postoperative copeptin levels and DI.Of 82 patients, 26 (31.7%) developed postoperative DI, with 7 patients (8.5%) having permanent DI. The samples for copeptin measurement were taken at 13 ± 2.1 hours postoperatively. From the receiver operating characteristic analysis, low postoperative copeptin levels (2.5 pmol/L) demonstrated an acceptable ability to predict DI (area under the curve, 0.72; 95% CI, 0.60-0.84). Discriminative power was stronger in the permanent DI group (area under the curve, 0.82; 95% CI, 0.64-1.00). Postoperative copeptin levels2.5 pmol/L were associated with DI (specificity91%). However, postoperative copeptin levels20 pmol/L were rarely associated with DI, with a negative predictive value of 100%.In patients undergoing sellar-suprasellar interventions, low postoperative copeptin levels within the first postoperative day predict postoperative DI, whereas high levels exclude it. Copeptin measurement should be applied in the clinical practice of postoperative care in patients following hypothalamic-pituitary surgery. This study may expand the potential use of copeptin, including in the Asian population.

Heavy menstrual bleeding is common and debilitating but the causes remain ill defined. Rates of obesity in women are increasing and its impact on menstrual blood loss (MBL) is unknown. Therefore, we quantified BMI and MBL in women not taking hormones and with regular menstrual cycles and revealed a positive correlation. In a mouse model of simulated menstruation, diet-induced obesity also resulted in delayed endometrial repair, a surrogate marker for MBL. BrdU staining of mouse uterine tissue revealed decreased proliferation during menstruation in the luminal epithelium of mice on a high-fat diet. Menstruation is known to initiate local endometrial inflammation and endometrial hypoxia; hence, the impact of body weight on these processes was investigated. A panel of hypoxia-regulated genes (VEGF, ADM, LDHA, SLC2A1) showed consistently higher mean values in the endometrium of women with obesity and in uteri of mice with increased weight vs normal controls, although statistical significance was not reached. The inflammatory mediators, Tnf and Il6 were significantly increased in the uterus of mice on a high-fat diet, consistent with a pro-inflammatory local endometrial environment in these mice. In conclusion, obesity was associated with increased MBL in women. Mice given a high-fat diet had delayed endometrial repair at menstruation and provided a model in which to study the influence of obesity on menstrual physiology. Our results indicate that obesity results in a more pro-inflammatory local endometrial environment at menstruation, which may delay endometrial repair and increase menstrual blood loss.

Purpose Postoperative Ileus (POI) remains an important complication for patients after abdominal surgery with an incidence of 10–27% representing an everyday issue for abdominal surgeons. It accounts for patients’ discomfort, increased morbidity, prolonged hospital stays, and a high economic burden. This review outlines the current understanding of POI pathophysiology and focuses on preventive treatments that have proven to be effective or at least show promising effects. Methods Pathophysiology and recommendations for POI treatment are summarized on the basis of a selective literature review. Results While a lot of therapies have been researched over the past decades, many of them failed to prove successful in meta-analyses. To date, there is no evidence-based treatment once POI has manifested. In the era of enhanced recovery after surgery or fast track regimes, a few approaches show a beneficial effect in preventing POI: multimodal, opioid-sparing analgesia with placement of epidural catheters or transverse abdominis plane block; μ-opioid-receptor antagonists; and goal-directed fluid therapy and in general the use of minimally invasive surgery. Conclusion The results of different studies are often contradictory, as a concise definition of POI and reliable surrogate endpoints are still absent. These will be needed to advance POI research and provide clinicians with consistent data to improve the treatment strategies.

Sarcopenia is a clinical syndrome that features muscle atrophy and weakness, and has been associated with cardiovascular events and poor clinical outcomes. Recently, the sarcopenia index (SI) was developed as a simple screening tool based upon the serum creatinine to cystatin C (CysC) ratio. We investigated the association between SI and the prevalence of major adverse cardiovascular events (MACE) in patients with obstructive CAD.Between January 2010 and December 2018, patients with angina pectoris and obstructive CAD requiring coronary artery intervention were enrolled. Serum levels of CysC and other biomarkers were assessed. Patients were divided into two groups according to the SI ([Cr/CysC] x 100). Demographic characteristics and clinical outcomes of the two groups were evaluated. A total of 427 patients (79.6% men, mean age 69.55 ± 12.04 years) were enrolled. Patients with SI 120 (n = 214, 28%) were older, more likely to be of the female gender, and to have more hypertension and congestive heart failure (all p 0.05). The prevalence of major adverse cardiovascular events (MACE) composed of myocardial infarction, stroke, and all-cause mortality was higher in patients with lower SI (p = 0.026). After adjusting for potential confounding factors, multivariate Cox regression (hazard ratio 2.08, p = 0.045) and Kaplan-Meier analyses (log-rank p = 0.0371) revealed that lower SI was significantly associated with a higher prevalence of MACE.Serum creatinine to cystatin C ratio (SI) may be a useful surrogate marker to predict the future prevalence of MACE in patients with obstructive CAD.

Myosteatosis is gathering attention as a feasible indicator for sarcopenia and increased risk of morbidity. However, the prognostic value of intramuscular adipose tissue content (IMAC) as an assessment method for myosteatosis remains controversial. The objectives of this study are to compare the prognostic value of intramuscular adipose tissue content (IMAC) with our newly-developed modified IMAC (mIMAC), and to assess the clinical significance of mIMAC in colorectal cancer (CRC) and gastric cancer (GC).We evaluated 892 patients with CRC or GC, and assessed preoperative IMAC and mIMAC to compare their prognostic and predictive values for postoperative infectious complications in both cohorts.Both preoperative IMAC and mIMAC were sex- and disease-dependent, and positively or negatively correlated with age in CRC and GC patients (IMAC: CRC: r = 0.33, P 0.0001; GC: r = 0.304, P 0.0001; mIMAC: CRC: r = -0.364, P 0.0001; GC: r = -0.263, P 0.0001). In contrast to IMAC, lower preoperative mIMAC was significantly associated with disease-development factors, and was an independent prognostic factor for both overall survival (OS) and disease-free survival (DFS) in both CRC (OS: hazard ratio (HR): 1.95, 95% confidence interval (CI): 1.25-3.03, p = 0.003; DFS: HR: 1.93, 95% CI: 1.22-3.04, p = 0.005) and GC patients (OS: HR: 2.11, 95% CI: 1.22-3.68, P = 0.008; DFS: HR: 2.03, 95% CI: 1.18-3.5, P = 0.011). Patients with postoperative remote infections had a poorer prognosis compared with those without in both cohorts (CRC: HR: 2.67, 95% CI: 1.46-4.89, P = 0.002; GC: HR: 3.01, 95% CI: 1.47-6.19, P = 0.003), and low mIMAC was an independent risk factor for postoperative remote infection in both cancers (CRC: odds ratio (OR): 2.56, 95% CI: 1.06-6.23, P = 0.038; GC: OR: 2.8, 95% CI: 1.03-7.58, P = 0.043). Finally, we assessed the correlation between IMAC or mIMAC and the representative frailty markers body mass index (BMI), serum albumin, and prognostic nutritional index (PNI). We found a positive correlation between preoperative mIMAC and all of these markers in both cohorts (CRC: BMI: r = 0.193, P 0.0001; serum albumin: r = 0.42, P 0.0001; PNI: r = 0.39, P 0.0001; GC: BMI: r = 0.22, P 0.0001; serum albumin: r = 0.212, P 0.0001; PNI: r = 0.287, P 0.0001).Preoperative mIMAC could be useful for perioperative and postoperative management in CRC and GC.

Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM). The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR 3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses. The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03). A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.

Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL’s end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation. These trials were registered at www.clinicaltrials.gov as #NCT02708108 (IDEAL trial) and #NCT01317940 (historical control).

Introduction: The Neoadjuvant rectal (NAR) score is a new surrogate endpoint to be used in clinical trials for early determination of treatment response to different preoperative therapies. The aim is to further validate the NAR-score, primarily developed using chemoradiotherapy (CRT) with a delay to surgery 6-8 weeks, and explore its value using other schedules. Materials and Methods: The study included all 9978 patients diagnosed with non-metastasized RC in 2007-2015 that had undergone surgery and was registered in the Swedish Colorectal Cancer Registry. The patients of interest had either short-course radiotherapy (scRT)/CRT + delayed surgery, longcourse radiotherapy (RT) + delayed surgery, (C)RT + additional chemotherapy, primary surgery, or scRT + immediate surgery. The scRT/CRT + delayed surgery groups were further divided based on time to surgery. Results: Mean NAR-score differed significantly (p < 0.0001) between different treatments. (C) RT + additional chemotherapy had the lowest mean score of 16.3 and CRT + delayed surgery had 17.7. There was a significant difference (p < 0.05) in overall survival (OS) and time to recurrence (TTR) of patients with a Low NAR-score (16) for both CRT- and scRT, with a stronger correlation for CRT-patients. C-index for the NAR-score model (0.623) was not superior to when only pathological T- and N-stage was used (0.646). Conclusions: The NAR-score is prognostic, but it is not better than pT- and pN-stage. However, the NARscore can still discriminate between two treatments that have different cell killing effect and may still be of value in clinical trials as an easier method than pT- and N-stage.

Surrogate endpoints are being used more frequently in randomized controlled trials, even though they do not consistently corelate with patient outcomes. We systemically evaluated the use of surrogate endpoints in multiple myeloma randomized controlled trials over the past 15 years. We searched three databases (Pubmed, Embase, Cochrane) for multiple myeloma randomized controlled trials from January 1, 2005 to December 30, 2019. The primary outcome of our study was the proportion of randomized controlled trials that used overall survival as their primary endpoint. Secondary outcomes included the use of surrogate endpoints, and trends over time, and whether they differed based on study sponsorship. We included 151 randomized controlled trials in our analysis. The primary endpoint was overall survival (OS) in 17 (11.3%) of studies, progression free survival (PFS) or event-defined endpoints in 91 studies (60.3%) and response-based endpoints in 44 studies (29.1%). Quality of life was a primary endpoint in only three studies (2%). The use of OS as a primary endpoint decreased from 28.5% of trials from 2005 to 2009 to 5.5% from 2015 to 2019. There has been a decrease in the clinically meaningful endpoint of OS over the past 15 years in multiple myeloma randomized controlled trials. Use of quality of life as a primary endpoint remains exceedingly low. It remains paramount to recognize that the use of surrogate endpoints is imperfect, and care based upon them requires constant physician and patient re-analysis.

Background Application of advanced body composition measurement methods is not practical in developing countries context due to cost and unavailability of facilities. This study generated ethnic specific body fat percent prediction equation for Ethiopian adults using appropriate data. Methods A cross-sectional study was carried ifrom February to April 2015 among 704 randomly selected adult employees of Jimma University. Ethnic specific Ethiopian body fat percent (BF%) prediction equation was developed using a multivariable linear regression model with measured BF% as dependent variable and age, sex, and body mass index as predictor variables. Agreement between fat percent measured using air displacement plethysmography and body fat percent estimated using Caucasian prediction equations was determined using Bland Altman plot. Results Comparison of ADP measured and predicted BF% showed that Caucasian prediction equation underestimated body fat percent among Ethiopian adults by 6.78% (P Conclusion The Caucasian prediction equation significantly underestimates body fat percent among Ethiopian adults regardless of ethnicity. Ethiopian ethnic-specific prediction equation can be used as a very simple, cheap, and cost-effective alternative for estimating body fat percent among Ethiopian adults for health care provision in the prevention of obesity and related morbidities and for research purposes.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a well-established biomarker in heart failure (HF) but controversially discussed as a potential surrogate marker in HF trials. We analyzed the NT-proBNP/mortality relationship in real-world data (RWD) of 108,330 HF patients from the IBM Watson Health Explorys database and compared it with the NT-proBNP / clinical event end-point relationship in 20 clinical HF studies. With a hierarchical statistical model, we quantified the functional relationship and interstudy variability. To independently qualify the model, we predicted outcome hazard ratios in five phase III HF studies solely based on NT-proBNP measured early in the respective study. In RWD and clinical studies, the relationship between NT-proBNP and clinical outcome is well described by an Emax model. The NT-proBNP independent baseline risk (R0 , RWD/studies median (interstudy interquartile range): 5.5%/3.0% (1.7-4.9%)) is very low compared with the potential NT-proBNP-associated maximum risk (Rmax : 55.2%/79.4% (61.5-89.0%)). The NT-proBNP concentration associated with the half-maximal risk is comparable in RWD and across clinical studies (EC50 : 3,880/2,414 pg/mL (1,460-4,355 pg/mL)). Model-based predictions of phase III outcomes, relying on short-term NT-proBNP data only, match final trial results with comparable confidence intervals. Our analysis qualifies NT-proBNP as a surrogate for clinical outcome in HF trials. NT-proBNP levels after short treatment durations of less than 10 weeks quantitatively predict hazard ratios with confidence levels comparable to final trial readout. Early NT-proBNP measurement can therefore enable shorter and smaller but still reliable HF trials.

The standard treatment for pathological N2 Stage III non-small cell lung cancer with negative surgical margins in Japan is cisplatin-based adjuvant chemotherapy. However, recent studies suggest that the addition of thoracic radiotherapy after adjuvant chemotherapy prolongs survival. While thoracic radiotherapy is considered to prolong survival by improving locoregional control, it is known to increase radiation-induced adverse events. We began a randomized controlled trial in January 2021 in Japan to confirm the superiority of radiotherapy over observation after adjuvant chemotherapy in pathological N2 Stage III non-small cell lung cancer patients with negative surgical margins. We aim to accrue 330 patients from 47 institutions over 5 years. The primary endpoint is relapse-free survival; the secondary endpoints are overall survival, proportion of patients completing radiotherapy in the radiotherapy arm, early adverse events, late adverse events in the radiotherapy arm, serious adverse events and local recurrence.

The study aimed to establish the benefits of using spleen stiffness values measured by two elastography techniques as noninvasive markers for predicting varices needing treatment and comparing their performances. A prospective study was performed, including 107 subjects with compensated liver cirrhosis, who underwent upper digestive endoscopy, as well as spleen stiffness measurements by means of two elastography techniques: pSWE (point shear wave elastography using Virtual Touch Quantification-Siemens Acuson S2000) and 2D-SWE (2D-shear wave elastography-LOGIQ E9, General Electric). Reliable spleen stiffness measurements were obtained in 96.2% (103/107) patients by means of 2D-SWE and in 94.4% (101/107) subjects with pSWE; therefore, 98 subjects were included in the final analysis, of which 40.8% (40/98) had varices needing treatment. The optimal spleen stiffness cut-off value by 2D-SWE for predicting varices needing treatment was 13.2 kPa (AUROC 0.84), while for pSWE, it was 2.91 m/s (AUROC 0.90). Based on AUROC comparison, no difference between the performance of the two techniques for predicting varices needing treatment was found ( p = 0.1606 ). In conclusion, spleen stiffness measured by either 2D-SWE or pSWE is a reliable surrogate marker, with good feasibility, applicability, and predictive accuracy for varices needing treatment, with no significant difference between techniques.

Introduction Oropharyngeal dysphagia is a clinical hallmark of idiopathic inflammatory myopathy (IIM). This study investigated predictors, outcome, and characteristics of oropharyngeal dysphagia in patients with different types of IIM. Methods Flexible endoscopic evaluation of swallowing (FEES) videos of 71 IIM patients were retrospectively analysed for bolus spillage, penetration, aspiration, and pharyngeal residue. Based on these findings, dysphagia severity was rated. Regression analyses were performed to investigate demographic and disease-specific predictors of dysphagia severity and pneumonia as outcome-relevant complications of dysphagia. A score was developed to rate the quality of the endoscopic white-out as a surrogate marker for pharyngeal muscle weakness with consecutive residue. Results Our analysis revealed no independent predictors of dysphagia severity. Dysphagia severity, however, was an independent predictor for pneumonia, which occurred in 24% of patients. Pharyngeal residue with risk of postdeglutitive aspiration was the most common dysphagia pattern. Attenuation of the endoscopic white-out was related to residue severity. Discussion Dysphagia in IIM assessed with FEES is associated with relevant complications such as aspiration pneumonia and must be considered independently of peripheral muscle weakness and disease duration. Swallowing impairment mainly presents with pharyngeal residue. The quality of the white-out may serve as a semi-quantitative surrogate marker for pharyngeal contractility. This article is protected by copyright. All rights reserved.

Trial design This is a phase III, double-blind, randomized, controlled trial. Methods In this trial, patients with laparoscopic colectomy were assigned to either low pressure (LP: 7 mmHg) or standard pressure (SP: 12 mmHg) at a ratio of 1 : 1. The aim of this trial was to assess the impact of low-pressure pneumoperitoneum during laparoscopic colectomy on postoperative recovery. The primary endpoint was the duration of hospital stay. The main secondary endpoints were postoperative pain, consumption of analgesics and postoperative morbidity. Results Some 138 patients were enrolled, of whom 11 were excluded and 127 were analysed: 62 with LP and 65 with SP. Duration of hospital stay (3 versus 4 days; P = 0.010), visual analog scale (0.5 versus 2.0; P = 0.008) and analgesic consumption (level II: 73 versus 88 per cent; P = 0.032; level III: 10 versus 23 per cent; P = 0.042) were lower with LP. Morbidity was not significantly different between the two groups (10 versus 17 per cent; P = 0.231). Conclusion Using low-pressure pneumoperitoneum in laparoscopic colonic resection improves postoperative recovery, shortening the duration of hospitalization and decreasing postoperative pain and analgesic consumption. This suggests that low pressure should become the standard of care for laparoscopic colectomy. Trial registration NCT03813797

Introduction Efficient evaluation with an early surrogate endpoint, taking into account the process of disease evolution, may not only clarify inconsistent or underpowered results but also provide a new insight into the exploration of a new antiviral therapy for treating COVID-19 patients. Methods We assessed the dynamics of COVID-19 disease spectrum, commencing from low-risk (no or low oxygen supplement), medium-risk (non-invasive ventilator or high oxygen supplement), and high-risk (extracorporeal membrane oxygenation or invasive ventilator) risk state on enrollment, and then the subsequent progression and regression of risk states until discharge or death. The efficacy of antiviral therapy in altering the dynamics was assessed by using the high-risk state as a surrogate endpoint based on the data retrieved from the two-arm Adaptive Covid-19 Treatment Trial. Results Using the high-risk state as a surrogate endpoint, remdesivir treatment led to a decrease in the high-risk COVID-19 state by 34.8% (95% CI 26.7–42.0%) for a 14-day period and 29.3% (95% CI 28.8–29.8%) up to 28 days, which were consistent with a statistically significant reduction of death by 30.5% (95% CI 6.6, 50.9%) up to a 28-day period. The estimates of numbers needed to be treated were 100.9 (95% CI 88.1, 115.7) for using the high-risk COVID-19 state as a surrogate endpoint for a 14-day period and 133.3 (95% CI 112.5, 158.0) were required for averting one death from COVID-19 up to 28 days. Conclusions We demonstrate the expedient use of the high-risk COVID-19 disease status as a surrogate endpoint for evaluating the primary outcome of the earliest death. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00431-9.

We aimed to evaluate whether changes in the noninvasively assessed urinary N-terminal fragment of titin (U-titin) concentration may be associated with those of serum creatine kinase (CK) activity, transverse relaxation time (T

Purpose: To study the dynamic changes in plasma Epstein–Barr virus (pEBV) DNA after radiotherapy in nasopharyngeal cancer (NPC). Experimental Design: We conducted a randomized controlled trial of adjuvant chemotherapy versus observation in patients with NPC who had detectable pEBV DNA at 6 weeks post-radiotherapy. Randomized patients had a second pEBV DNA checked at 6 months post-randomization. The primary endpoint was progression-free survival (PFS). Results: We prospectively enrolled 789 patients. Baseline post-radiotherapy pEBV DNA was undetectable in 573 (72.6%) patients, and detectable in 216 (27.4%) patients, of whom 104 (13.2%) patients were eligible for randomization to adjuvant chemotherapy (n = 52) versus observation (n = 52). The first post-radiotherapy pEBV DNA had a sensitivity of 0.48, specificity of 0.81, area under receiver-operator characteristics curve (AUC) of 0.65, false positive (FP) rate of 13.8%, and false negative (FN) rate of 14.4% for disease progression. The second post-radiotherapy pEBV DNA had improved sensitivity of 0.81, specificity of 0.75, AUC of 0.78, FP rate of 14.3%, and FN rate of 8.1%. Patients with complete clearance of post-radiotherapy pEBV DNA (51%) had survival superior to that of patients without post-radiotherapy pEBV DNA clearance (5-year PFS, 85.5% vs. 23.3%; HR, 9.6; P < 0.0001), comparable with patients with initially undetectable post-radiotherapy pEBV DNA (5-year PFS, 77.1%), irrespective of adjuvant chemotherapy or observation. Conclusions: Patients with NPC with detectable post-radiotherapy pEBV DNA who experienced subsequent pEBV DNA clearance had superior survival comparable with patients with initially undetectable post-radiotherapy pEBV DNA. Post-radiotherapy pEBV DNA clearance may serve as an early surrogate endpoint for long-term survival in NPC.

TCR and BCR repertoire diversity plays a critical role in tumor immunity. Thus, analysis of TCR and BCR repertoires might help predict the clinical efficacy of anti-PD-1 treatment. Blood samples from 30 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibody were collected before and six weeks after treatment initiation. The clinical significance of TCR and BCR repertoire diversity in peripheral blood was evaluated in all the enrolled patients (n = 30) or in the subset with (n = 10) or without (n = 20) EGFR/ALK mutation. TCR and BCR diversity was significantly correlated at baseline (R = 0.65; P = 1.6 × 10–4) and on treatment (R = 0.72; P = 1.2 × 10–5). Compared to non-responders (SD or PD), responders (PR) showed significantly decreased TCR and BCR diversity after treatment in the EGFR/ALK wild-type subset (P = 0.0014 and P = 0.034, respectively), but not in all the enrolled patients. The post-treatment reduction in TCR and BCR repertoire diversity was also significantly associated with the occurrence of adverse events in the EGFR/ALK wild-type subset (P = 0.022 and P = 0.014, respectively). Patients with more reduced TCR diversity showed better progression-free survival (PFS) in the EGFR/ALK wild-type subset (P = 0.011) but not in the mutant subset. These findings suggest the clinical significance of changes in peripheral TCR and BCR repertoire diversity after anti-PD-1 treatment in patients with NSCLC without EGFR/ALK mutation. Monitoring of the peripheral TCR and BCR repertoires may serve as a surrogate marker for the early detection of EGFR/ALK wild-type NSCLC patients who would benefit from anti-PD-1 treatment.

Background: Carotid intima-media thickness test is a surrogate marker of subclinical atherosclerosis. Epicardial fat thickness is an early marker of coronary artery disease. Several studies have noted that psoriasis patients have an increased risk of coronary artery disease. In the present study, we attempted to see any variation in carotid intima-media thickness and epicardial fat thickness in psoriasis patients when compared to controls. Aims: 1) To determine the carotid intima-media thickness and epicardial fat thickness in psoriatic patients and healthy controls. 2) To evaluate the association between carotid intima-media thickness and epicardial fat thickness in psoriasis patients. Methods: A hospital-based study with 100 subjects (50 with psoriasis and 50 healthy controls) was conducted in the Dermatology Outpatient Department of Justice KS Hegde Charitable Hospital, a unit of KS Hegde Medical Academy affiliated to NITTE (Deemed to be University) Mangaluru. A detailed history and examination including body mass index, psoriasis area and severity index were done. Carotid ultrasound was done to measure carotid intima-media thickness and transthoracic echocardiography was done to assess epicardial fat thickness in both cases and controls. Independent sample t-test, Pearson rank correlation (r) coefficient were used for statistical analysis. P-value Results: Mean carotid intima-media thickness in the right carotid ([0.51 ± 0.1mm vs 0.47 ± 0.1 mm] [P = 0.038]) and left carotid ([0.53 ± 0.12 mm vs 0.48 ± 0.1 mm] [P = 0.041]) were significantly increased in psoriasis patients than in controls. Mean epicardial fat thickness was significantly increased ([1.76 ± 0.66 mm vs. 1.49 ± 0.47 mm] ([P = 0.020]) in patients with psoriasis when compared with the controls. Epicardial fat thickness was positively correlated with carotid intima-media thickness in patients with psoriasis. Limitations: The cross-sectional design of the study, smoking among study subjects, inter and intraobserver variability of measurement of epicardial fat thickness and carotid intima-media thickness. Conclusion: Carotid intima-media thickness and epicardial fat thickness were increased in psoriasis patients when compared with healthy controls. Epicardial fat thickness was positively correlated with carotid intima-media thickness in cases.

Background Laxity of the submental area is a common cosmetic complaint of the aging population. Objectives The aim of this study was to determine the safety and effectiveness of a temperature-controlled, minimally invasive percutaneous monopolar radiofrequency device to improve dermal laxity and achieve lift. Methods A total of 72 subjects (35-65 years old) with mild to moderate skin laxity in the submental area were included in this single-center prospective study. All subjects received 1 treatment at baseline with an average subdermal temperature of 63°C. The primary endpoint was the proportion of subjects with at least a 20-mm2 decrease in surface area at Day 90 based on 3-dimensional photography. Secondary endpoints included skin elasticity measured by Cutometer, assessment by a blinded physician panel from 2-dimensional photographs, and physician- and subject-reported outcomes. Results At Day 90, 72.1% (95% CI: 62.2%-84.0%; P < 0.001) of subjects achieved at least a 20-mm2 lift of the submental area. All Cutometer-measured skin elasticity values (R2, R5, R7) showed significant improvement by 180 days. The independent panel graded 74.2% of subjects as “improved” at 90 days (95% CI: 62.0%-84.2%; P < 0.001). The treatment was well tolerated, and only 1 possibly related serious adverse event was reported (pharyngeal inflammation). Conclusions Treatment with temperature-controlled monopolar radiofrequency alone is a safe and effective treatment to achieve submental lift for at least 6 months. Level of Evidence: 4

INTRODUCTION: Fractional flow reserve (FFR) measured after percutaneous coronary intervention (PCI) has been identified as a surrogate marker for vessel related adverse events. FFR can be derived from standard coronary computed tomography angiography (CTA). Moreover, the FFR derived from coronary CTA (FFRCT ) Planner is a tool that simulates PCI providing modeled FFRCT values after stenosis opening. AIM: To validate the accuracy of the FFRCT Planner in predicting FFR after PCI with invasive FFR as a reference standard. METHODS: Prospective, international and multicenter study of patients with chronic coronary syndromes undergoing PCI. Patients will undergo coronary CTA with FFRCT prior to PCI. Combined morphological and functional evaluations with motorized FFR hyperemic pullbacks, and optical coherence tomography (OCT) will be performed before and after PCI. The FFRCT Planner will be applied by an independent core laboratory blinded to invasive data, replicating the invasive procedure. The primary objective is to assess the agreement between the predicted FFRCT post-PCI derived from the Planner and invasive FFR. A total of 127 patients will be included in the study. RESULTS: Patient enrollment started in February 2019. Until December 2020, 100 patients have been included. Mean age was 64.1 ± 9.03, 76% were males and 24% diabetics. The target vessels for PCI were LAD 83%, LCX 6%, and RCA 11%. The final results are expected in 2021. CONCLUSION: This study will determine the accuracy and precision of the FFRCT Planner to predict post-PCI FFR in patients with chronic coronary syndromes undergoing percutaneous revascularization. ispartof: CLINICAL CARDIOLOGY vol:44 issue:4 pages:446-454 ispartof: location:United States status: published