Short-term Endpoints Research Articles

Efficacy and safety of high-power short duration atrial fibrillation ablation in elderly patients.

Data about atrial fibrillation (AF) ablation using high-power short duration (HPSD) radiofrequency ablation in the elderly population is still scarce. The aim of our study was to investigate the efficacy and safety of HPSD ablation in patients over 75 years compared to younger patients. Consecutive patients older than 75 years with paroxysmal or persistent AF undergoing a first-time AF ablation using 50 W HPSD ablation approach were analyzed in this retrospective observational analysis and compared to a control group <75 years. Short-term endpoints included intraprocedural reconnection of at least one pulmonary vein(PV)and intrahospital and AF recurrence during 3 months blanking period, as well as a long-term endpoint of freedom from atrial arrhythmias of antiarrhythmic drugs after 12 months. A total of 540 patients underwent a first AF ablation with HPSD (66 ± 10 years; 58% male; 47% paroxysmal AF). Mean age was 78 ± 2.4 and 63 ± 6.3 years (p < .001), respectively. Elderly patients were significantly more often women (p < .001).The procedure, fluoroscopy, and ablation were comparable. Elderly patients revealed significantly more often extra-PV low-voltage areas requiring additional left atrial ablations (p < .001). Overall complication rates were low; however, elderly patients revealed higher major complication rates mainly due to unmasking sick sinus syndrome (p = .003). Freedom from arrhythmia recurrences was comparable (68% vs. 76%, log-rank p = .087). Only in the subgroup of paroxysmal AF, AF recurrences were more common after 12 months (69% vs. 82%; log-rank p = .040; hazard ratio: 1.462, p = .044) in the elderly patients. In multivariable Cox regression analysis of the whole cohort persistent AF, female gender, diabetes mellitus and presence of left atrium low-voltage areas, but not age >75 years were associated with AF recurrences. HPSD AF ablation of patients >75 years in experienced centers is safe and effective. Therefore, age alone should not be the reason to withhold AF ablation from vital elderly patients due to only a slightly worse outcome and safety profile. In paroxysmal AF, elderly patients have more recurrences compared to the younger control group.

A randomized group sequential enrichment design for immunotherapy and targeted therapy

In targeted therapy or immunotherapy, it is common that only a subpopulation of patients are sensitive to and thus may benefit from the therapy. In practice, based on pre-clinical data, it is often assumed that the sensitive subpopulation is known. Subsequent clinical trial data, however, often show that this assumptions is false. We propose a randomized, group sequential enrichment (GSE) design to evaluate an experimental treatment against a control. The GSE design starts by enrolling patients under broad eligibility criteria and then alters the entry criteria to restrict enrollment to treatment-sensitive patients based on accumulating data of short-term and long-term survival endpoints. The short-term endpoint is used to facilitate enrichment when a limited number of survival events are observed, while the final determination of treatment efficacy and sensitive subpopulation is based on the survival. The group sequential approach is adopted to implement the adaptive enrichment strategy. The proposed design simultaneously achieves two primary goals of precision medicine: to determine whether the experimental drug is superior to the control and to identify the target population that is sensitive to the treatment. A simulation study shows that the proposed design well controls the type I error rate and yields substantially higher power than the conventional group sequential design and existing two-stage enrichment design.

Short-term safety outcomes of mastectomy and immediate prepectoral implant-based breast reconstruction: Pre-BRA prospective multicentre cohort study.

Prepectoral breast reconstruction (PPBR) has recently been introduced to reduce postoperative pain and improve cosmetic outcomes in women having implant-based procedures. High-quality evidence to support the practice of PPBR, however, is lacking. Pre-BRA is an IDEAL stage 2a/2b study that aimed to establish the safety, effectiveness, and stability of PPBR before definitive evaluation in an RCT. The short-term safety endpoints at 3 months after surgery are reported here. Consecutive patients electing to undergo immediate PPBR at participating UK centres between July 2019 and December 2020 were invited to participate. Demographic, operative, oncology, and complication data were collected. The primary outcome was implant loss at 3 months. Other outcomes of interest included readmission, reoperation, and infection. Some 347 women underwent 424 immediate implant-based reconstructions at 40 centres. Most were single-stage direct-to-implant (357, 84.2 per cent) biological mesh-assisted (341, 80.4 per cent) procedures. Conversion to subpectoral reconstruction was necessary in four patients (0.9 per cent) owing to poor skin-flap quality. Of the 343 women who underwent PPBR, 144 (42.0 per cent) experienced at least one postoperative complication. Implant loss occurred in 28 women (8.2 per cent), 67 (19.5 per cent) experienced an infection, 60 (17.5 per cent) were readmitted for a complication, and 55 (16.0 per cent) required reoperation within 3 months of reconstruction. Complication rates following PPBR are high and implant loss is comparable to that associated with subpectoral mesh-assisted implant-based techniques. These findings support the need for a well-designed RCT comparing prepectoral and subpectoral reconstruction to establish best practice for implant-based breast reconstruction.

TAVI in patients with low-flow low-gradient aortic stenosis–short-term and long-term outcomes

ObjectivesThe study objective was to characterize different groups of low-flow low-gradient (LFLG) aortic stenosis (AS) and determine short-term outcomes and long-term mortality according to Valve Academic Research Consortium-3 (VARC-3) endpoint definitions.BackgroundCharacteristics and outcomes of patients with LFLG AS undergoing transcatheter aortic valve implantation (TAVI) are poorly understood.MethodsAll patients undergoing TAVI at our center between 2013 and 2019 were screened. Patients were divided into three groups according to mean pressure gradient (dPmean), ejection fraction (LVEF), and stroke volume index (SVi): high gradient (HG) AS (dPmean ≥ 40 mmHg), classical LFLG (cLFLG) AS (dPmean < 40 mmHg, LVEF < 50%), and paradoxical LFLG (pLFLG) AS (dPmean < 40 mmHg, LVEF ≥ 50%, SVi ≤ 35 ml/m2).ResultsWe included 1776 patients (956 HG, 447 cLFLG, and 373 pLFLG patients). Most baseline characteristics differed significantly. Median Society of Thoracic Surgeons (STS) score was highest in cLFLG, followed by pLFLG and HG patients (5.0, 3.9 and 3.0, respectively, p < 0.01). Compared to HG patients, odds ratios for the short-term VARC-3 composite endpoints, technical failure (cLFLG, 0.76 [95% confidence interval, 0.40–1.36], pLFLG, 1.37 [0.79–2.31]) and device failure (cLFLG, 1.06 [0.74–1.49], pLFLG, 0.97 [0.66–1.41]) were similar, without relevant differences within LFLG patients. NYHA classes improved equally in all groups. Compared to HG, LFLG patients had a higher 3-year all-cause mortality (STS score-adjusted hazard ratios, cLFLG 2.16 [1.77–2.64], pLFLG 1.53 [1.22–193]), as well as cardiovascular mortality (cLFLG, 2.88 [2.15–3.84], pLFLG, 2.08 [1.50–2.87]).ConclusionsWhile 3-year mortality remains high after TAVI in LFLG compared to HG patients, symptoms improve in all subsets after TAVI.Graphical abstract

Treatment and clinical endpoints in polycythemia vera: seeking the best obtainable version of the truth

AbstractPolycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm driven by the JAK2 V617F (or rarely exon 12) mutation. Its natural history can extend over a few decades, and therefore treatment planning is predicated on continual reassessment of traditional risk features (age, prior thrombosis) to evaluate the need for cytoreduction besides foundational therapy with low-dose aspirin and stringent phlebotomy. Shorter- and longer-term patient goals should be considered in light of several variables such as comorbid conditions (especially cardiovascular risk factors), disease symptoms, and the risk-benefit profile of available drugs. While hydroxyurea has been the pro forma choice of cytoreduction for many practitioners over the last half-century, the more recent regulatory approvals of ruxolitinib and ropeginterferon-alfa-2b, based on phase 3 randomized trials, highlight an expanding portfolio of active drugs. Obtaining high-level evidence for short-term clinical trial endpoints such as hematocrit control, symptom burden/quality of life, splenomegaly, and JAK2 V617F allele burden lies within the timeline of most studies. However, in many cases, it may not be possible to adequately power trials to capture significant differences in the typically low event rates of thrombosis as well as longer-horizon endpoints such as evolution to myelofibrosis and acute myeloid leukemia and survival. This Perspective highlights the challenges of addressing these data gaps and outstanding questions in the emerging treatment landscape of PV.

Effect of Prehabilitation Before Total Knee Replacement for Knee Osteoarthritis on Functional Outcomes

Multidisciplinary prehabilitation before total knee replacement (TKR) for osteoarthritis may improve outcomes in the postoperative period. To compare multidisciplinary prehabilitation with usual care before TKR for osteoarthritis in terms of functional independence and activity limitations after surgery. This prospective, open-label randomized clinical trial recruited participants 50 to 85 years of age with knee osteoarthritis according to the American College of Rheumatology criteria for whom a TKR was scheduled at 3 French tertiary care centers. Recruitment started on October 4, 2012, with follow-up completed on November 29, 2017. Statistical analyses were conducted from March 29, 2018, to March 6, 2019. Four supervised sessions of multidisciplinary rehabilitation and education (2 sessions per week, at least 2 months before TKR, delivered to groups of 4-6 participants at each investigating center; session duration was 90 minutes and included 30 minutes of education followed by 60 minutes of exercise therapy) or usual care (information booklet and standard advice by the orthopedic surgeon) before TKR. The short-term primary end point was the proportion of participants achieving functional independence a mean (SD) of 4 (1) days after surgery defined as level 3 on the 4 functional tests. The midterm primary end point was activity limitations within 6 months after TKR assessed by the area under the receiver operating characteristic curve of the self-administered Western Ontario Questionnaire and McMaster Universities Osteoarthritis Index function subscale. A total of 262 patients (mean [SD] age, 68.6 [8.0] years; 178 women [68%]) were randomized (131 to each group). A mean (SD) of 4 (1) days after surgery, 34 of 101 (34%) in the experimental group vs 26 of 95 (27%) in the control group achieved functional independence (risk ratio, 1.4; 97.5% CI, 0.9-2.1; P = .15). At 6 months, the mean (SD) area under the curve for the Western Ontario Questionnaire and McMaster Universities Osteoarthritis Index function subscale was 38.1 (16.5) mm2 in the experimental group vs 40.6 (17.8) mm2 in the control group (absolute difference, -2.8 mm2; 97.5% CI, -7.8 to 2.3; P = .31 after multiple imputation). No differences were found in secondary outcomes. This randomized clinical trial found no evidence that multidisciplinary prehabilitation before TKR for osteoarthritis improves short-term functional independence or reduces midterm activity limitations after surgery. ClinicalTrials.gov Identifier: NCT01671917.

Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): Short-term outcomes of a multicenter randomized controlled trial.

14 Background: Robotic surgery for rectal cancer is gaining popularity, but persuasive evidence on long-term oncological outcomes is lacking. This multicenter randomized controlled trial compared robotic and conventional laparoscopic surgery regarding surgical quality and long-term oncological outcomes among patients with middle and low rectal cancer. Methods: This superiority trial was undertaken at 11 hospitals in 8 Chinese provinces. Patients with middle (&gt; 7–12 cm from anal verge) or low (0–7 cm from anal verge) rectal adenocarcinoma, cT1–T3 N0–1 or ycT1–T3 Nx after preoperative radio-/chemoradiotherapy, and no evidence of distant metastasis were enrolled and randomly assigned in a 1:1 ratio to receive robotic or conventional laparoscopic surgery. Secondary (short-term) end points (surgical quality, pathological radicality, and postoperative recovery) were compared using modified intention-to-treat (mITT) analysis. Three-year locoregional recurrence rate as the primary endpoint is expected by the end of 2023. This trial was registered with ClinicalTrials.gov (NCT02817126). Results: Between July 2016 and December 2020, 1240 patients were enrolled; 1180 were included in the mITT analysis (591 in robotic and 589 in laparoscopic group). There were significantly more sphincter-preserving surgeries (low anterior resections) performed in the robotic group (83.1% vs. 76.9%, p = 0.008). With more macroscopic complete resections (95.4% vs. 91.9%, p = 0.012), robotic surgery had better integrity of the mesorectal fascia, and had lower circumferential resection margin positivity rate (4.0% vs. 7.1%, difference = -3.1%, 95% confidence interval = -6.0% to -0.5%, p = 0.023) and more lymph nodes harvested (median, 15.0 vs. 14.0, p = 0.004). Robotic surgery also reduced the open conversion rate (1.7% vs. 3.9%, p = 0.021), estimated blood loss (median, 40.0 ml vs. 50.0 ml, p &lt; 0.001), intraoperative complication rate (5.4% vs. 8.7%, p = 0.029), and 30-day postoperative complication rate (Clavien-Dindo grade II or higher, 16.1% vs. 22.9%, p = 0.003), leading to better postoperative recovery and shorter postoperative hospital stay (median, 7.0 days vs. 8.0 days, p &lt; 0.001). The 30-day postoperative mortality was similar between the two groups (0.2% vs. 0.2%, p &gt; 0.999). Conclusions: Robotic surgery for middle and low rectal cancer significantly reduced surgical injury, improved oncological radicality, and promoted postoperative recovery compared with conventional laparoscopic surgery. Clinical trial information: NCT02817126.

Using Surrogate Endpoints in Adaptive Designs with Delayed Treatment Effect

Delayed treatment effects have been commonly observed in clinical trials, which bring more challenges to the interim decision making particularly in adaptive designs setting. An improper interim analysis (IA) may falsely stop a promising study based on the traditional conditional power (CP) approach assuming the observed treatment effect will carry over for the entire study. For such scenario, a short-term surrogate endpoint which is predictive of the primary long-term outcome can be extremely useful for a more accurate CP calculation and adaptative decision. In this article, we propose using a surrogate endpoint in the IA to improve the CP calculation in designing an adaptive sample size reestimation or event size reestimation study. Through theoretical derivation and extensive simulations, we show that our proposed approach demonstrates the practical feasibility and benefits of using a surrogate endpoint for adaptive designs with delayed treatment effects. The average overall power is shown to be significantly higher than conventional event size reestimation and group sequential design when there is a delayed treatment effect in primary survival endpoint. We also demonstrate proposed approach in a case study of Phase III non-small cell lung cancer (NSCLC) trial with delayed treatment effect. Finally, we give recommendations on how this method could be implemented in confirmatory clinical trials.

The impact of neoadjuvant concurrent chemoradiation on exosomal markers (CD63 and CD9) expression and their prognostic significance in patients with rectal adenocarcinoma.

Introduction: Exosomes have pivotal roles in cancer development. The impact of neoadjuvant concurrent chemoradiation (NCCR) on exosomal markers (CD63 and CD9) expression and their prognostic significance in patients with rectal adenocarcinoma are yet to be explored.Materials and Methods: Between 2015 and 2018, 33 patients had rectal adenocarcinoma treated with NCCR and had pre-NCCR biopsy and post-NCCR resected rectum. CD63 and CD9 expression was assessed by immunohistochemistry (IHC). The short-term surrogate endpoint neoadjuvant rectal (NAR) score was used for assessment of prognostic significance. Un-Paired t-test was used for statistical analysis.Results: The mean tumor CD63 and CD9 scores in pre-NCCR biopsy vs. post-NCCR resected rectum were 106 vs. 165 (P = 0.0022) and 136 vs. 215 (P < 0.0001) respectively. The mean tumor CD63 and CD9 scores respectively in pre-NCCR biopsy was 99 and 130 in patients with low-intermediate NAR score compared to 117 and 144 in patients with high NAR score (P = 0.4934) (P = 0.5519). The mean tumor CD63 and CD9 scores respectively in post-NCCR resected rectum was 155 and 205 in patients with low-intermediate NAR score compared to 180 and 230 in patients with high NAR score (P = 0.3793) (P = 0.2837).Conclusions: The expression of the exosomal markers (CD63 and CD9) increased in patients with rectal adenocarcinoma after treatment with NCCR. The exosomal markers (CD63 and CD9) may have a prognostic significance. There was a trend for higher CD63 and CD9 expression in patients with high NAR score compared with low-intermediate NAR scores. The lack of statistical significance is likely due to the small sample size.

Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

Genomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation. We examine whether the current evidence base reflects public tolerance for uncertainty for genomics to diagnose rare childhood genetic disease. We conducted focus groups with general population parents in Vancouver, Canada, and Oxford, United Kingdom, to discuss expectations and concerns related to genomic testing to diagnose rare childhood genetic disease. Applying a purposive sampling technique, recruitment continued until thematic saturation was reached. Transcripts were analysed using thematic analysis. Thirty-three parents participated across four focus groups. Participants valued causal diagnoses alongside management strategies to improve patient health and wellbeing. Further, participants valued expanding the evidence base to reduce evidentiary uncertainty while ensuring security of information. Willingness to pay out of pocket for testing reflected perceived familial health benefit. Diagnostic yield fails to fully capture valued outcomes, and efforts to resolve uncertainty better reflect public priorities. Evaluations of genomic testing that fully integrate valued endpoints are necessary to ensure consistency with best practices and public willingness to accept the uncertain familial benefit.

Systolic blood pressure and outcome in patients admitted with acute heart failure: a pooled analysis from 4 randomized clinical trials

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Danish Heart Foundation Background In acute heart failure (AHF), low systolic blood pressure (SBP) has been associated with poor outcome. Less is known of the risk related to normal versus elevated SBP and interaction with left ventricular ejection fraction. Purpose The aim of the present study was to assess the association between baseline SBP and short- and long-term outcome in a large cohort of AHF-patients. Methods A pooled cohort of four randomized controlled trials investigating the vasodilator serelaxin versus placebo in patients admitted with AHF and an SBP from 125 to 180 mmHg. Endpoints were 180-day all-cause mortality and a short-term composite endpoint (worsening heart failure, all-cause mortality or hospital readmission for HF through Day 14). Left ventricular ejection fraction (LVEF) was categorized into HFrEF (&amp;lt;40%) and HFpEF (= &amp;gt;40%). Multivariable Cox regression was used and adjusted for age, sex, baseline body mass index, HFrEF, serum estimated glomerular filtration rate, allocated treatment (placebo/serelaxin), diabetes mellitus, ischemic heart disease, and atrial fibrillation/flutter. Measurements and Main Results A total of 10.533 patients with a mean age of 73 (±12) years and median SBP of 140 (130-150) mmHg were included within mean 8.2 hours from admission. LVEF was assessed in 8493 (81%), and of these, 4294 (51%) had HFrEF. Increasing SBP as a continuous variable was inversely associated with 180-day mortality (HRadjusted: 0.93 [0.88-0.98], p = 0.004 per 10 mmHg increase) and with the composite endpoint (HRadjusted: 0.90 [0.85-0.95], p &amp;lt; 0.0001 per 10 mmHg increase). A significant interaction was observed regarding LVEF, revealing that SBP was not associated with mortality in patients with HFpEF (HRadjusted: 1.01 [0.94-1.09], p = 0.83 per 10 mmHg increase), but SBP was associated with increased mortality in HFrEF (HRadjusted: 0.80 [0.73-0.88], p &amp;lt; 0.001 per 10 mmHg increase) (Figure). Conclusions Elevated SBP is independently associated with favorable short- and long-term outcome in AHF-patients. The association between SBP and mortality was, however, not present in patients with preserved LVEF. Abstract Figure. Survival plots by SBP and LVEF

Prognostic importance of circumferential resection margin in the era of evolving surgical and multidisciplinary treatment of rectal cancer: A systematic review and meta-analysis

BackgroundCircumferential resection margin is considered an important prognostic parameter after rectal cancer surgery, but its impact might have changed because of improved surgical quality and tailored multimodality treatment. The aim of this systematic review was to determine the prognostic importance of circumferential resection margin involvement based on the most recent literature. MethodsA systematic literature search of MEDLINE, Embase, and the Cochrane Library was performed for studies published between January 2006 and May 2019. Studies were included if 3- or 5-year oncological outcomes were reported depending on circumferential resection margin status. Outcome parameters were local recurrence, overall survival, disease-free survival, and distant metastasis rate. The Newcastle Ottawa Scale and Jadad score were used for quality assessment of the studies. Meta-analysis was performed using a random effects model and reported as a pooled odds ratio or hazard ratio with 95% confidence interval. ResultsSeventy-five studies were included, comprising a total of 85,048 rectal cancer patients. Significant associations between circumferential resection margin involvement and all long-term outcome parameters were uniformly found, with varying odds ratios and hazard ratios depending on circumferential resection margin definition (<1 mm, ≤1 mm, otherwise), neoadjuvant treatment, study period, and geographical origin of the studies. ConclusionCircumferential resection margin involvement has remained an independent, poor prognostic factor for local recurrence and survival in most recent literature, indicating that circumferential resection margin status can still be used as a short-term surrogate endpoint.

English spoken stress recognition based on natural language processing and endpoint detection algorithm

Nowadays, there are more and more researches on the application of natural language processing technology in computer-aided language system, which can provide a good assistant role for foreign language learners. However, in the research of computer-aided language system, there are still some deficiencies in the recognition of English spoken stress nodes, which cannot be well recognized. Based on this, this paper proposes a method of English spoken accent recognition based on natural language processing and endpoint detection algorithm, which aims to promote the accuracy of accent recognition in the computer-aided language system and improve the performance of the computer-aided language system. In order to avoid the interference of background noise, this paper proposes a short-term time-frequency endpoint detection algorithm which can accurately judge the beginning and end of speech in complex environment. Then, on the basis of traditional speech feature extraction and fractal dimension theory, a nonlinear fractal dimension speech feature is extracted. Finally, RankNet is used to process the extracted features to realize the recognition of English spoken stress nodes. In the simulation analysis, the application effect of the short-term time-frequency endpoint detection algorithm proposed in this paper in the complex background noise and the effect of non-linear fractal dimension speech features on the recognition of English spoken stress nodes are verified. Finally, the performance and good application effect of the method designed in this paper are illustrated.

Early versus late tracheotomy in ICU patients: A meta-analysis of randomized controlled trials.

This study aimed to quantitatively analyze the available randomized controlled trials (RCTs) and investigate whether early tracheotomy can improve clinical endpoints compared with late tracheotomy in critically ill patients undergoing mechanical ventilation. The electronic databases of PubMed, Embase, and the Cochrane library were systematically searched in August 2019. The investigated outcomes were calculated using relative risks (RRs) and standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) through the random-effects model for categories and continuous data, respectively. The electronic searches yielded 2289 records, including 15 RCTs comprising a total of 3003 patients and found to be relevant for the final quantitative analysis. The summary RRs that indicated early versus late tracheotomy were not associated with the risk of short-term mortality (RR: 0.87; 95% CI: 0.74-1.03; P = .114) and ventilator-associated pneumonia (RR: 0.90; 95% CI: 0.78-1.04; P = .156). Moreover, early tracheotomy was associated with shorter intensive care unit (ICU) stay (SMD: -1.81; 95% CI: -2.64 to -0.99; P < .001) and mechanical ventilation duration (SMD: -1.17; 95% CI: -2.10 to -0.24; P = .014). Finally, no significant difference was observed between early and late tracheotomy for hospital stay (SMD: -0.42; 95% CI: -1.36-0.52; P = .377). The present meta-analysis suggests that early tracheotomy can reduce the length of ICU stay and mechanical ventilation duration, but the timing of the tracheotomy was not associated with the short-term clinical endpoints in critically ill patients undergoing mechanical ventilation.

Minimally Invasive Versus open AbdominoThoracic Esophagectomy for esophageal carcinoma (MIVATE)\xa0\u2014\xa0study protocol for a randomized controlled trial DRKS00016773

BackgroundThe only curative treatment for most esophageal cancers is radical esophagectomy. Minimally invasive esophagectomy (MIE) aims to reduce postoperative morbidity, but is not yet widely established. Linear stapled anastomosis is a promising technique for MIE because it is quite feasible even without robotic assistance. The aim of the present study is to compare total MIE with linear stapled anastomosis to open esophagectomy (OE) with circular stapled anastomosis with special regard to postoperative morbidity in an expertise-based randomized controlled trial (RCT).Methods/designThis superiority RCT compares MIE with linear stapled anastomosis (intervention) to OE with circular stapled anastomosis (control) for Ivor-Lewis esophagectomy. It was initiated in February 2019, and recruitment is expected to last for 3 years. For inclusion, patients must be 18 years of age or more with a resectable primary malignancy in the distal esophagus. Participants with tumor localizations above the azygos vein, metastasis, or infiltration into adjacent tissue will be excluded. In an expertise-based approach, the allocated treatment will only be carried out by the single most experienced surgeon of the surgical center for each respective technique. The sample size was calculated with 20 participants per group for the primary endpoint postoperative morbidity according to comprehensive complication index (CCI) within 30 postoperative days. Secondary endpoints include anastomotic insufficiency, pulmonary complications, other intra- and postoperative outcome parameters such as estimated blood loss, operative time, length of stay, short-term oncologic endpoints, adherence to a standardized fast-track protocol, postoperative pain, and postoperative recovery (QoR-15). Quality of life (SF-36, CAT EORTC QLQ-C30, CAT EORTC QLQ-OES18) and oncological outcomes are evaluated with 60 months follow-up.DiscussionMIVATE is the first RCT to compare OE with circular stapled anastomosis to total MIE with linear stapled anastomosis exclusively for intrathoracic anastomosis. The expertise-based approach limits bias due to heterogeneity of surgical expertise. The use of a dedicated fast-track protocol in both OE and MIE will shed light on the role of the access strategy alone in this setting. The findings of this study will serve to define which approach has the best perioperative outcome for patients requiring esophagectomy.Trial registrationGerman Clinical Trials Register DRKS00016773. Registered on 18 February 2019.

Conspicuity of prostate cancer on multiparametric magnetic resonance imaging: A cross-disciplinary translational hypothesis.

Pre‐biopsy multiparametric magnetic resonance imaging (mpMRI) has transformed the risk stratification and diagnostic approach for suspected prostate cancer. The majority of clinically significant prostate cancers are visible on pre‐biopsy mpMRI, however, there are a subset of significant tumors that are not detected by mpMRI. The radiobiological mechanisms underpinning mpMRI‐visibility and invisibility of these cancers remain uncertain. Emerging evidence suggests that mpMRI‐visible tumors are enriched with molecular features associated with increased disease aggressivity and poor clinical prognosis, which is supported by short‐term endpoints, such as biochemical recurrence following surgery. Furthermore, at the histopathological level, mpMRI‐visible tumors appear to exhibit increased architectural and vascular density compared to mpMRI‐invisible disease. It seems probable that the genomic, pathological, radiological, and clinical features of mpMRI‐visible and mpMRI‐invisible prostate cancers are interrelated. Here, we propose a novel cross‐disciplinary theory that links genomic and molecular evidence with cellular and histopathological appearances, elucidating both the mpMRI visibility and clinical status of significant prostate cancer.

Prognostic Significance of Neoadjuvant Rectal Scores in Preoperative Short-Course Radiotherapy and Long-Course Concurrent Chemoradiotherapy for Patients with Locally Advanced Rectal Cancer.

This study aimed to investigate the prognostic factors and the utility of the neoadjuvant rectal (NAR) score for patients who have locally advanced rectal cancer (LARC) treated with preoperative short-course radiotherapy (SRT) or long-course concurrent chemoradiotherapy (CRT). Of 314 consecutive stage 2 or 3 rectal cancer patients enrolled from January 2006 to December 2017, 205 underwent preoperative SRT (2500cGy/5 fractions), and 109 underwent preoperative CRT (4200-5080cGy/21-28 fractions) after total mesorectal excision (TME). The study calculated NAR scores using the following equation: [5 pN - 3(cT - pT) + 12]2/9.61. The multivariate analysis showed that age above 65years, pT4, pN2, NAR scores higher than 16, and distance from anal verges (< 8cm) were significant prognostic factors for overall survival (OS), whereas, pN2, NAR scores lower than 16, and distance from anal verges (< 8cm) were significant prognostic factors for disease-free survival (DFS) and distant metastasis (DM). The patients with an NAR score higher than 16, had a 5-year OS rate of 67.6%, a DFS rate of 56.9%, a locoregional recurrence (LRR) rate of 7.7%, and a DM rate of 35% compared with corresponding rates of 87.6%, 76.7%, 5.4%, and 7.2% for the patients with an NAR score of 16 or lower (p < 0.001 for OS, < 0.001 for DFS, 0.25 for LRR, and < 0.001 for DM). For patients who undergo SRT or CRT for LARC, a higher NAR score is associated with worse OS and DFS and higher DM rates at 5years. The NAR score could be used as a short-term surrogate end point after neoadjuvant therapy for LARC.

Optimal decision-making in oncology development programs based on probability of success for phase III utilizing phase II/III data on response and overall survival.

In clinical development, there is a trade-off between investment and level of confidence in the potential of the drug before going into phase III. Reduced investment requires the use of short-term endpoints. On new compounds, only limited information about the relationship between treatment effects of short- and long-term endpoints is usually available. Therefore, decision-making solely based on short-term endpoints does not seem desirable. Our goal is to plan an efficient development program, which uses short- and long-term endpoints data for decision-making. We found that with limited prior information and restrictions on maximum sample size, decision-making after phase II cannot be substantially improved. We follow the concept of a "phase 2+" design where after a go-to-phase-III-decision, further follow-up data from phase II are employed to make interim decisions on phase III. The program will be stopped early when additional phase II and/or available phase III data lead to a low probability of success (PoS). We utilize information from a multi-categorical short-term endpoint (response status) and a long-term endpoint (overall survival (OS)) to determine the PoS in phase III with OS as the primary endpoint. Optimal combinations of decision boundaries and time points are demonstrated in a simulation study. Our results show that the proposed second look using additional follow-up data from phase II/III improves PoS estimates compared to the first look, especially when prior data about the control arm is available. The proposed planning strategy allows a customized compromise between the quality of decision-making and program duration.

Usefulness of Restaging Pelvis Magnetic Resonance Imaging After Neoadjuvant Concurrent Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

IntroductionIn patients with locally advanced rectal cancer, restaging pelvis magnetic resonance imaging (MRI) after neoadjuvant concurrent chemoradiotherapy is recommended despite its limited accuracy in predicting pathologic T (ypT) and N (ypN) stage. Neoadjuvant rectal (NAR) score is a novel short-term surrogate endpoint for disease-free survival (DFS) and overall survival (OS). We tested the agreement between restaging MRI T (yT) and N (yN) with ypT and ypN stages, respectively, and explored the prognostic significance of restaging MRI NAR (mNAR) score. Patients and MethodsBetween 2014 and 2018, 43 patients with locally advanced rectal cancer completed neoadjuvant concurrent chemoradiotherapy, had a restaging MRI, and underwent surgery. Weighted kappa was used to test the agreement between yT and yN with ypT and ypN, respectively. A kappa value of less than 0.5 was deemed unacceptable. Paired t test was used to compare NAR and mNAR mean scores. Survival was estimated by Kaplan-Meier curves. ResultsRestaging MRI could not predict ypT stage (slight agreement, κ = 0.111) or ypN stage (fair agreement, κ = 0.278). The mean mNAR score was higher than the mean NAR score (20 vs. 16, P = .0079). The median DFS for patients with low-intermediate NAR and high NAR was not reached vs. 30 months (P = .0063). The median OS for patients with low-intermediate NAR and high NAR was not reached vs. 40 months (P = .0056). There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores (not reached in both groups, P = .058) compared to patients with high mNAR scores (not reached in both groups, P = .15). ConclusionRestaging MRI could not predict ypT and ypN stage. The mean mNAR score was higher than the mean NAR score. There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores compared to patients with high mNAR scores.

Highlights From the AASLD/EASL ALD Endpoints Conference 2019.

Watch a video presentation of this article Watch an interview with the author.