Citations

Objective: The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Background: Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking. Methods: The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines. Results: Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population (https://rediscover.unipi.it/). Conclusions: The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population.

Abstract Aims Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. Methods and results In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF] <35%). During a median follow-up of 6 years (interquartile range 1.6–12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. Conclusion In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.

Abstract The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Background Resting coronary flow velocity (CFV) in the mid‐distal left anterior descending coronary artery can be easily assessed with transthoracic echocardiography. In this observational study, the authors sought to assess the relationship between resting CFV, CFV reserve (CFVR), and outcome in patients with chronic coronary syndromes. Methods and Results In a prospective multicenter study design, the authors retrospectively analyzed 7576 patients (age, 66±11 years; 4312 men) with chronic coronary syndromes and left ventricular ejection fraction ≥50% referred for dipyridamole stress echocardiography. Recruitment (years 2003–2021) involved 7 accredited laboratories, with interobserver variability <10% for CFV measurement at study entry. Baseline peak diastolic CFV was obtained by pulsed‐wave Doppler in the mid‐distal left anterior descending coronary artery. CFVR (abnormal value ≤2.0) was assessed with dipyridamole. All‐cause death was the only end point. The mean CFV of the left anterior descending coronary artery was 31±12 cm/s. The mean CFVR was 2.32±0.60. During a median follow‐up of 5.9±4.3 years, 1121 (15%) patients died. At multivariable analysis, resting CFV ≥32 cm/s was identified by a receiver operating curve as the best cutoff and was independently associated with mortality (hazard ratio [HR], 1.24 [95% CI, 1.10–1.40]; P <0.0001) together with CFVR ≤2.0 (HR, 1.78 [95% CI, 1.57–2.02]; P <0.0001), age, diabetes, history of coronary surgery, and left ventricular ejection fraction. When both CFV and CFVR were considered, the mortality rate was highest in patients with resting CFV ≥32 cm/s and CFVR ≤2.0 and lowest in patients with resting CFV <32 cm/s and CFVR >2.0. Conclusions High resting CFV is associated with worse survival in patients with chronic coronary syndromes and left ventricular ejection fraction ≥50%. The value is independent and additive to CFVR. The combination of high resting CFV and low CFVR is associated with the worst survival.

ImportanceArginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma.ObjectiveTo determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor.Design, Setting, and ParticipantsThis was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months’ follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023.InterventionPatients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months.Main Outcomes and MeasuresThe primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only.ResultsAmong 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo).Conclusions and RelevanceIn this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology.Trial RegistrationClinicalTrials.gov Identifier: NCT02709512

Objective We describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL‐PAN). Methods Patients with PAN were recruited between 1990 and 2020 from observational cohorts of nine countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency classification algorithm. Patients with PAN related to hepatitis B virus (n = 12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n = 16) or familial Mediterranean fever (n = 11), were excluded. Data regarding organ involvement, relapse, disease‐related damage, and survival were analyzed. Results Three hundred fifty‐eight patients (female:male ratio 174:184), including those with systemic PAN (sPAN, n = 282) and cutaneous PAN (n = 76), were included. Twenty‐five were pediatric onset. Mean ± SD age at diagnosis was 44.3 ± 18.1 years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (interquartile range) 59.6 (99.5) months of follow‐up, relapse occurred in 48.5% of patients. One, 5‐ and 10‐year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of death for sPAN included age ≥65 years at diagnosis, serum creatinine at diagnosis >140 μmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement. Conclusion The spectrum of PAN remains a complex, multifaceted disease. Relapse is common. Age ≥65 years and serum creatinine >140 μmol/L at diagnosis, as well as gastrointestinal and CNS involvement, are independent predictors of death in sPAN. image

516 Background: Based on only smaller retrospective cohort studies, current guidelines recommend primary retroperitoneal lymph node dissection (RPLND) for men with marker-negative stage 2a non-seminomatous germ cell tumor (NSGCT). We aimed to reassess the role of primary RPLND in marker negative stage 2a, explore results in stages 2b/c and/or marker-positive disease, and evaluate surgical methods, recurrence, and adjuvant chemotherapy indications. Methods: Data from 17 institutions were collected, comprising 305 men who underwent primary RPLND for stage 2 NSGCT. Regression analyses were conducted to predict histology in the RPLND specimen and progression-free survival (PFS). Results: A larger retroperitoneal lymph node diameter was associated with pure teratoma in the RPLND specimen (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.09, p-value = 0.02), but it did not correlate with PFS. The 5-year PFS rates were 85% for men with pure teratoma, 94% for men with viable cancer who received adjuvant chemotherapy, and 72% for men with viable cancer who did not receive adjuvant chemotherapy. The number of adjuvant chemotherapy cycles did not significantly affect PFS. Conclusions: Our study suggests considering primary RPLND not only in marker negative clinical stage 2a but also marker negative clinical stage 2b. Further research should identify the efficacy in men in other stages (2C or marker positive) and which patients may benefit from adjuvant chemotherapy and the optimal cycle number.

Abstract Background Colorectal surgery in patients with inflammatory bowel disease (IBD) and cirrhosis is associated with high morbidity related to portal hypertension. Thought to reduce surgical risk, transjugular intrahepatic portosystemic shunt (TIPS) may be used to decrease portal pressures. In this study, we aimed to characterize surgical outcomes of patients with IBD and cirrhosis who underwent preoperative TIPS at a large tertiary care center. Methods We retrospectively identified patients with IBD and cirrhosis who had undergone TIPS between 2010-2023 for portal decompression prior to colorectal surgery. All other indications for TIPS led to patient exclusion. Demographic and medical data was collected, including surgical indication and portal pressure measurement. Data on surgical outcomes were compiled through chart review. Results We identified 10 patients (60% male) with IBD and history of decompensated cirrhosis who underwent preoperative TIPS for portal decompression (Table 1). Surgical indications were colonic dysplasia (50%), refractory IBD (50%), and stenosis or stricture (30%). All patients were deemed nonsurgical candidates due to significant surgical risk from portal hypertension. Following multidisciplinary coordination, patients underwent TIPS for portal decompression at a median of 47 days (IQR 34-80) prior to colorectal surgery. TIPS was associated with significant reduction in portal pressure (22.5 vs 18.5mmHg, p&lt;0.01) and portosystemic gradient (12.5 vs 5.5mmHg, p&lt;0.01) in all patients. Of 10 patients, 30% had TIPS-related complications (transient fluid overload and encephalopathy). In terms of surgical complications, 40% of patients required intraoperative blood transfusion (range: 1-4 units). Postoperatively, 30% of patients had surgical site bleeding and 10% had wound dehiscence, although none required reoperation. Systemic complications occurred in 30% of patients, with systemic signs of infection being the most common. Transaminitis (50%) and coagulopathy (40%) were also common. Median hospital stay was 7 days (IQR 5.5-9.3), with 40% of patients being readmitted within 30 days. Most common cause of readmission was systemic infection (75%), abdominal abscess (50%), or electrolyte abnormality (50%), with one patient requiring reoperation for wound dehiscence. Ninety-day and 1-year survival was 100% and 90% respectively. Conclusion In our series of patients with IBD and cirrhosis requiring surgery but deemed nonsurgical candidates, preoperative TIPS lead to portal decompression and facilitated successful surgical intervention despite heightened risk. Nevertheless, significant operative and postoperative complications were noted. Future studies are needed to determine optimal surgical timing following TIPS placement.

Ever since its introduction as a diagnostic imaging tool the potential of magnetic resonance imaging (MRI) in radiation therapy (RT) treatment simulation and planning has been recognized. Recent technical advances have addressed many of the impediments to use of this technology and as a result have resulted in rapid and growing adoption of MRI in RT. The purpose of this article is to provide a broad review of the multiple uses of MR in the RT treatment simulation and planning process, identify several of the most used clinical scenarios in which MR is integral to the simulation and planning process, highlight existing limitations and provide multiple unmet needs thereby highlighting opportunities for the diagnostic MR imaging community to contribute and collaborate with our oncology colleagues.Evidence Level5Technical EfficacyStage 5

Abstract Aims The determinants and relevance of right ventricular (RV) mechanical dyssynchrony in heart failure with reduced ejection fraction (HFrEF) are poorly understood. We hypothesized that increased afterload may adversely affect the synchrony of RV contraction. Methods and results A total of 148 patients with HFrEF and 36 controls underwent echocardiography, right heart catheterization, and gated single-photon emission computed tomography to measure RV chamber volumes and mechanical dyssynchrony (phase standard deviation of systolic displacement timing). Exams were repeated after preload (N = 135) and afterload (N = 15) modulation. Patients with HFrEF showed higher RV dyssynchrony compared with controls (40.6 ± 17.5° vs. 27.8 ± 9.1°, P &lt; 0.001). The magnitude of RV dyssynchrony in HFrEF correlated with larger RV and left ventricular (LV) volumes, lower RV ejection fraction (RVEF) and LV ejection fraction, reduced intrinsic contractility, increased heart rate, higher pulmonary artery (PA) load, and impaired RV–PA coupling (all P ≤ 0.01). Low RVEF was the strongest predictor of RV dyssynchrony. Left bundle branch block (BBB) was associated with greater RV dyssynchrony than right BBB, regardless of QRS duration. RV afterload reduction by sildenafil improved RV dyssynchrony (P = 0.004), whereas preload change with passive leg raise had modest effect. Patients in the highest tertiles of RV dyssynchrony had an increased risk of adverse clinical events compared with those in the lower tertile [T2/T3 vs. T1: hazard ratio 1.98 (95% confidence interval 1.20–3.24), P = 0.007]. Conclusions RV dyssynchrony is associated with RV remodelling, dysfunction, adverse haemodynamics, and greater risk for adverse clinical events. RV dyssynchrony is mitigated by acute RV afterload reduction and could be a potential therapeutic target to improve RV performance in HFrEF.