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 Purpose: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. Experimental Design: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. Results: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. Conclusions: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. Significance: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Abstract Purpose The aim of this study was to characterize a second‐generation wide‐detector dual‐layer spectral computed tomography (CT) system for material quantification accuracy, acquisition parameter and patient size dependencies, and tissue characterization capabilities. Methods A phantom with multiple tissue‐mimicking and material‐specific inserts was scanned with a dual‐layer spectral detector CT using different tube voltages, collimation widths, radiation dose levels, and size configurations. Accuracy of iodine density maps and virtual monoenergetic images (MonoE) were investigated. Additionally, differences between conventional and MonoE 70 keV images were calculated to evaluate acquisition parameter and patient size dependencies. To demonstrate material quantification and differentiation, liver‐mimicking inserts with adipose and iron were analyzed with a two‐base decomposition utilizing MonoE 50 and 150 keV, and root mean square error (RMSE) for adipose and iron content was reported. Results Measured inserts exhibited quantitative accuracy across a wide range of MonoE levels. MonoE 70 keV images demonstrated reduced dependence compared to conventional images for phantom size (1 vs. 27 HU) and acquisition parameters, particularly tube voltage (4 vs. 37 HU). Iodine density quantification was successful with errors ranging from ‐0.58 to 0.44 mg/mL. Similarly, inserts with different amounts of adipose and iron were differentiated, and the small deviation in values within inserts corresponded to a RMSE of 3.49 ± 1.76% and 1.67 ± 0.84 mg/mL for adipose and iron content, respectively. Conclusion The second‐generation dual‐layer CT enables acquisition of quantitatively accurate spectral data without compromises from differences in patient size and acquisition parameters.

Background and Aims: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). Approach and Results: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP, rs9842969, (0.51, [0.40–0.65]); 5p15.33, TERT, rs2242652, (0.70, (0.62–0.79]); 19q13.11, TM6SF2, rs58542926, (1.49, [1.29–1.72]); 19p13.11 MAU2, rs58489806, (1.53, (1.33–1.75]); and 22q13.31, PNPLA3, rs738409, (1.66, [1.51–1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74–0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. Conclusions: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.

Abstract Aims Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population. Methods and results We assessed two-dimensional speckle-tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON-HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS <16%. Impaired GLS was significantly associated with higher values of circulating baseline N-terminal pro-B-type-natriuretic peptide. After a median follow-up of 3.0 years, there were 407 total HF hospitalizations and cardiovascular deaths. After multivariable adjustment, worse GLS was associated with a greater risk for the primary composite outcome (adjusted hazard ratio per 1% decrease: 1.06; 95% confidence interval 1.02–1.11; p = 0.008). GLS did not modify the treatment effect of sacubitril/valsartan compared with valsartan for the composite outcome (p for interaction >0.1). Conclusions In a large HFpEF population, impaired LV function was observed even among patients with preserved ejection fraction, and was associated with an increased risk of total HF hospitalizations or cardiovascular death, accounting for clinical confounders. These findings highlight the key role of subtle LV systolic impairment in the pathophysiology of HFpEF.

AbstractVenetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real‐world data published on HMAs plus VEN have been either single‐center studies or using community‐based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real‐world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85–13.5), with OS significantly worse among patients with TP53‐mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30‐day and 60‐day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE‐A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Abstract Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.

Abstract Background Efficient and accurate delineation of organs at risk (OARs) is a critical procedure for treatment planning and dose evaluation. Deep learning‐based auto‐segmentation of OARs has shown promising results and is increasingly being used in radiation therapy. However, existing deep learning‐based auto‐segmentation approaches face two challenges in clinical practice: generalizability and human‐AI interaction. A generalizable and promptable auto‐segmentation model, which segments OARs of multiple disease sites simultaneously and supports on‐the‐fly human‐AI interaction, can significantly enhance the efficiency of radiation therapy treatment planning. Purpose Meta's segment anything model (SAM) was proposed as a generalizable and promptable model for next‐generation natural image segmentation. We further evaluated the performance of SAM in radiotherapy segmentation. Methods Computed tomography (CT) images of clinical cases from four disease sites at our institute were collected: prostate, lung, gastrointestinal, and head & neck. For each case, we selected the OARs important in radiotherapy treatment planning. We then compared both the Dice coefficients and Jaccard indices derived from three distinct methods: manual delineation (ground truth), automatic segmentation using SAM's ’segment anything’ mode, and automatic segmentation using SAM's ‘box prompt’ mode that implements manual interaction via live prompts during segmentation. Results Our results indicate that SAM's segment anything mode can achieve clinically acceptable segmentation results in most OARs with Dice scores higher than 0.7. SAM's box prompt mode further improves Dice scores by 0.1∼0.5. Similar results were observed for Jaccard indices. The results show that SAM performs better for prostate and lung, but worse for gastrointestinal and head & neck. When considering the size of organs and the distinctiveness of their boundaries, SAM shows better performance for large organs with distinct boundaries, such as lung and liver, and worse for smaller organs with less distinct boundaries, like parotid and cochlea. Conclusions Our results demonstrate SAM's robust generalizability with consistent accuracy in automatic segmentation for radiotherapy. Furthermore, the advanced box‐prompt method enables the users to augment auto‐segmentation interactively and dynamically, leading to patient‐specific auto‐segmentation in radiation therapy. SAM's generalizability across different disease sites and different modalities makes it feasible to develop a generic auto‐segmentation model in radiotherapy.

Background: Eyelid ptosis may present with upper lid dermatochalasis and brow ptosis. When indicated, ptosis correction (PC) is advocated during upper blepharoplasty (UB). In this study, the authors aimed to report their outcomes following UB and PC. Methods: A retrospective review of patients who underwent UB from November of 2018 to March of 2020 was performed. Patient demographics, clinical characteristics, and revisions were recorded. Cox regression was performed to assess predictors of revision. Results: Overall, 278 patients with 533 UB were included. The mean patient age was 67.3 years. The mean follow-up was 8.3 months. In 169 cases (31.7%), a brow lift was performed. UB and PC were performed in 109 cases (20.5%), of which 60 (55%) involved Müller muscle conjunctival resection and 49 (45%) were levator repairs. New dry eye symptoms lasting 3 months or longer occurred in 4 cases (0.8%), all of which resolved. The revision rate was 3.8% after UB (residual skin [ n = 11], hypertrophic scar [ n = 4], and Herring law–related ptosis [ n = 1]) versus 9.2% after UB and PC (overcorrection [ n = 4], residual skin [ n = 4], and asymmetry [ n = 2]). Multivariable analysis demonstrated increased revision rates after UB and PC ( P = 0.008). There was no difference in revision rates between different techniques of PC. Conclusions: In this study of 278 patients presenting for dermatochalasis, up to 21% of cases required ptosis correction in addition to upper blepharoplasty. Ptosis correction is a safe procedure when combined with upper blepharoplasty, regardless of technique used. The revision rate in our series was 9.2% after the combined procedure, which is greater than the revision rate of upper blepharoplasty only but comparable to that in the literature. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Background: Premature ventricular contractions (PVCs) are associated with an increased risk of implanting implantable cardioverter defibrillator (ICD). Therefore, our study aimed to predict the risk factors for implantable cardioverter defibrillator in patients with premature ventricular contractions. Methods: A total of 309 patients (male 57%, mean age 66.73±16.12) in Olmstate Countywho had premature ventricular contractions and received a 24-hour electrocardiography monitoring were included between January 1994 and September 2010 at Mayo Clinic, Rochester, Minnesota. All these patients were continuously followed o Jun 2015. Student’s t-test, Chi-square, univariate and multivariate Logistic regression models were used to estimate the relationship between the risk factors and the incidence of implanting implantable cardioverter defibrillator (ICD) in PVCs patients. Kaplan–Meier curve of survival in PVCs patients with ICD or free-ICD. Results: The average follow-up time was 9.3±3.9 years, in which 43 (13.9%) patients died and 24 (7.8%) patients had received ICD therapy. Sex, age, pulse pressure, early repolarization syndrome (ERS), heart rate, PVC coupling interval, QRS duration, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD), diabetes were significantly associated with the mortality and the incidence of implanting ICD. Using a multivariate logistic regression model adjusted for potential confounders, showed that LVEF (OR=0.916, 95% CI:0.881 to 0.953, p<0.001) and pulse pressure (OR=1.032, 95% CI:1.001-1.064, p=0.045) were independent factors for ICD implant in PVCs patients. Moreover, implantation of ICD may not reduce mortality in patients with ventricular premature. Conclusions: Increased pulse pressure was associated a higher incidence of ICD in PVCs patients, among many electrocardiographic and clinical variables studied. We also showed that PVs patients with ICD were at high risk of death, and the great pulse pressure was linked with higher morality in PVCs patients.