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Background: Neoadjuvant therapy (NAT) emerged as the standard of care for patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgery; however, surgery is morbid, and tools to predict resection margin status (RMS) and prognosis in the preoperative setting are needed. Radiomic models, specifically delta radiomic features (DRFs), may provide insight into treatment dynamics to improve preoperative predictions., Methods: We retrospectively collected clinical, pathological, and surgical data (patients with resectable, borderline, locally advanced, and metastatic disease), and pre/post-NAT contrast-enhanced computed tomography (CT) scans from PDAC patients at the University of Texas Southwestern Medical Center (UTSW; discovery) and Humanitas Hospital (validation cohort). Gross tumor volume was contoured from CT scans, and 257 radiomics features were extracted. DRFs were calculated by direct subtraction of pre/post-NAT radiomic features. Cox proportional models and binary prediction models, including/excluding clinical variables, were constructed to predict overall survival (OS), disease-free survival (DFS), and RMS., Results: The discovery and validation cohorts comprised 58 and 31 patients, respectively. Both cohorts had similar clinical characteristics, apart from differences in NAT (FOLFIRINOX vs. gemcitabine/nab-paclitaxel; p < 0.05) and type of surgery resections (pancreatoduodenectomy, distal or total pancreatectomy; p < 0.05). The model that combined clinical variables (pre-NAT carbohydrate antigen (CA) 19-9, the change in CA19-9 after NAT (∆CA19-9), and resectability status) and DRFs outperformed the clinical feature-based models and other radiomics feature-based models in predicting OS (UTSW: 0.73; Humanitas: 0.66), DFS (UTSW: 0.75; Humanitas: 0.64), and RMS (UTSW 0.73; Humanitas: 0.69)., Conclusions: Our externally validated, predictive/prognostic delta-radiomics models, which incorporate clinical variables, show promise in predicting the risk of predicting RMS in NAT-treated PDAC patients and their OS or DFS., (© 2023. The Author(s).)

Introduction: There is a well-established positive correlation between improved physician wellness and patient care outcomes. Mental fitness is a component of wellness that is understudied in academic medicine. We piloted a structured mental fitness Positive Intelligence (PQ) training program for academic surgeons, hypothesizing this would be associated with improvements in PQ scores, wellness, sleep, and trainee evaluations., Methods: This is a single-institution, prospective, mixed-methods pilot study. All active Burn/Trauma/Acute & Critical Care Surgical faculty and fellows in our division were offered the PQ program and the option to participate in this research study. The 6-wk program consists of daily exercises on a smartphone application, weekly readings, and small-group meetings with a trained mindfulness coach. Study outcomes included changes in pretraining versus post-training PQ scores, sleep hygiene, wellness, and teaching scores. A Net Promoter Score was calculated to measure user overall experience (range -100 to 100; positive scores being supportive). For secondary analysis, participants were stratified into high versus low user groups by "muscle" scores, which were calculated by program use over time. A postintervention focus group was also held to evaluate perceptions of wellness and experience with the PQ program., Results: Data were analyzed for 15 participants who provided consent. The participants were primarily White (73.3%), Assistant Professors (66.7%) with Surgical Critical Care fellowship training (86.7%), and a slight female predominance (53.3%). Comparison of scores pretraining versus post-training demonstrated statistically significant increases in PQ (59 versus 65, P = 0.004), but no significant differences for sleep (24.0 versus 29.0, P = 0.33) or well-being (89.0 versus 94.0, P = 0.10). Additionally, there was no significant difference in teaching evaluations for both residents (9.1 versus 9.3, P = 0.33) and medical students (8.3 versus 8.5, P = 0.77). High versus low user groups were defined by the median muscle score (166 [Interquartile range 95.5-298.5]). High users demonstrated a statistically higher proportion of ongoing usage (75% versus 14%, P < 0.05). The final Net Promoter Score score was 25, which demonstrates program support within this group. Focus group content analysis established eight major categories: current approaches to wellness, preknowledge, reasons for participation, expected gains, program strengths, suggestions for improvement, recommendations for approaches, and sustainability., Conclusions: Our pilot study highlighted certain benefits of a structured mental fitness program for academic acute care surgeons. Our mixed-methods data demonstrate significant improvement in PQ scores, ongoing usage in high user participants, as well as interpersonal benefits such as improved connectedness and creation of a shared language within participants. Future work should evaluate this program on a higher-powered scale, with a focus on intentionality in wellness efforts, increased exposure to mental fitness, and recruitment of trainees and other health-care providers, as well as identifying the potential implications for patient outcomes., (Published by Elsevier Inc.)

Importance: Robotic-assisted nipple-sparing mastectomies with multiport robots have been described in the US since 2015; however, significant hurdles to multiport robotic surgery exist in breast surgery., Objective: To demonstrate that the single-port da Vinci SP (Intuitive Surgical) robotic system is feasible in patients undergoing robotic nipple-sparing mastectomy (rNSM)., Design, Setting, and Participants: An initial case series of 20 patients at a large university hospital underwent bilateral single-port robotic nipple-sparing mastectomies (SPrNSM) with tissue expander reconstruction from February 1, 2020, through January 4, 2023. Participants included women who met surgical criteria for nipple-sparing mastectomies, per standard of care., Intervention: Surgery using a single-port robot and the surgical technique of the authors., Main Outcomes and Measures: Age, indication, body mass index, breast size, operative time, conversion to open surgery, systemic complications, postoperative skin necrosis, and reported skin and nipple areolar complex (NAC) sensation., Results: Twenty women aged 29 to 63 years (median, 40 years) underwent bilateral SPrNSM. Eleven patients completed prophylactic surgery due to a high risk for breast cancer (more than 20% lifetime risk) and 9 patients had breast cancer. Breast size ranged from A through D cup with median B cup and a body mass index range of 19.7 through 27.8 (median 24.4). The total duration of the procedure from incision to skin closure for both sides ranged from 205 minutes to 351 minutes (median, 277). The median robotic time for bilateral SPrNSM was 116 minutes and varied by cup size (A cup, 95 minutes; B cup, 140 minutes; C cup, 118 minutes; D cup, 114 minutes) with no inflection point in learning curve. No cases were converted to open and no immediate complications, such as hematoma, positive margins, or recurrence, were seen. In the first 10 patients prior to routine sensation testing, 20 resected breasts had measurable NAC sensation at a range from 4 to 36 months post-index resection (65%). In the second 10 patients of the cohort, measurable NAC was preserved in 13 of 20 resected breasts 2 weeks following the index operation (65%)., Conclusion and Relevance: In this case series, SPrNSM with immediate reconstruction was feasible and performed safely by an experienced breast surgeon with limited previous robotic training. Further studies confirming the preliminary data demonstrating improved NAC and skin sensation following SPrNSM are warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT05245812.

Background: Large-scale evaluation of surgical safety checklist performance has been limited by the need for direct observation. The operating room (OR) Black Box is a multichannel surgical data capture platform that may allow for the holistic evaluation of checklist performance at scale., Study Design: In this retrospective cohort study, data from 7 North American academic medical centers using the OR Black Box were collected between August 2020 and January 2022. All cases captured during this period were analyzed. Measures of checklist compliance, team engagement, and quality of checklist content review were investigated., Results: Data from 7,243 surgical procedures were evaluated. A time-out was performed during most surgical procedures (98.4%, n = 7,127), whereas a debrief was performed during 62.3% (n = 4,510) of procedures. The mean percentage of OR staff who paused and participated during the time-out and debrief was 75.5% (SD 25.1%) and 54.6% (SD 36.4%), respectively. A team introduction (performed 42.6% of the time) was associated with more prompts completed (31.3% vs 18.7%, p < 0.001), a higher engagement score (0.90 vs 0.86, p < 0.001), and a higher percentage of team members who ceased other activities (80.3% vs 72%, p < 0.001) during the time-out., Conclusions: Remote assessment using OR Black Box data provides useful insight into surgical safety checklist performance. Many items included in the time-out and debrief were not routinely discussed. Completion of a team introduction was associated with improved time-out performance. There is potential to use OR Black Box metrics to improve intraoperative process measures., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: The learning curve of robotic surgical skills is poorly understood. There is a lack of data on the transferability of skills from open and laparoscopic training to robotic surgery. In this retrospective cohort study, we investigated the impact of training acquired during intern year on the development of robotic skills in general surgery residents, prior to formal robotic training., Methods: Between 2019 and 2021, novice general surgery residents underwent robotic skill assessment using 3 validated inanimate drills before starting intern year. After completing basic open and laparoscopic proficiency-based curricula, they completed an identical robotic skill assessment at the end of intern year. Pre and post intern year robotic performances were recorded and analyzed by 2 blinded graders. Video-based assessment included completion time, errors, and the modified Objective Structured Assessment of Technical Skills (mOSATS) score., Results: The total time needed to complete all 3 robotic drills decreased from a mean of 26 to 17 minutes after intern year (p < 0.001). The number of errors decreased from a mean of 2.16 to 0.56 errors per subject (p < 0.001). The aggregated mOSATS score increased by an average of 41% (p < 0.001), with a greater increase in technical skill domains compared to the knowledge-based domain. The interrater intraclass correlation coefficient was 0.91., Conclusions: Baseline robotic surgical skills are limited without formal training. Our findings suggest that acquiring basic open and laparoscopic skills, such as knot tying, needle driving, and tissue handling results in improved performance on the robotic platform, prior to formal robotic training. Therefore, requiring trainees to complete fundamental open and laparoscopic training prior to robotic training may be an efficient and effective strategy within a surgical residency curriculum., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Recent development of methods to discover and engineer therapeutic T-cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that TCR-based agents will be similarly important contributors to the treatment of a variety of medical conditions, especially cancers. TCR engineered cells, soluble TCRs and their derivatives, TCR-mimic antibodies, and TCR-based CAR T cells promise the possibility of highly specific drugs that can expand the scope of immunologic agents to recognize intracellular targets, including mutated proteins and undruggable transcription factors, not accessible by traditional antibodies. Hurdles exist regarding discovery, specificity, pharmacokinetics, and best modality of use that will need to be overcome before the full potential of TCR-based agents is achieved. HLA restriction may limit each agent to patient subpopulations and off-target reactivities remain important barriers to widespread development and use of these new agents. In this review we discuss the unique opportunities for these new classes of drugs, describe their unique antigenic targets, compare them to traditional antibody therapeutics and CAR T cells, and review the various obstacles that must be overcome before full application of these drugs can be realized., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts., Background and Aims: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results., Methods: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data., Results: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity., Conclusions: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines., Competing Interests: A.D.S. has received an honorarium from Foundation Medicine Inc. M.N.N. and Y.E.N. own intellectual property related to the PancreaSeq technology and receive royalties from University of Pittsburgh. R.H.H. has the potential to receive royalty payments from Thrive Earlier Detection for the GNAS invention in an arrangement reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. The remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: The COVID-19 pandemic rapidly altered the landscape of medical education, particularly disrupting the residency application process and highlighting the need for structured mentorship programs. This prompted our institution to develop a virtual mentoring program to provide tailored, one-on-one mentoring to medical students applying to general surgery residency. The aim of this study was to examine general surgery applicant perception of a pilot virtual mentoring curriculum., Design: The mentorship program included student-tailored mentoring and advising in 5 domains: resume editing, personal statement composition, requesting letters of recommendation, interview skills, and residency program ranking. Electronic surveys were administered following ERAS application submission to participating applicants. The surveys were distributed and collected via a REDCap database., Results: Eighteen out of 19 participants completed the survey. Confidence in a competitive resume (p = 0.006), interview skills (p < 0.001), obtaining letters of recommendation (p = 0.002), personal statement drafting (p < 0.001), and ranking residency programs (p < 0.001) were all significantly improved following completion of the program. Overall utility of the curriculum and likelihood to participate again and recommend the program to others was rated a median 5/5 on the Likert scale (5 [IQR 4-5]). Confidence in the matching carried a premedian 66.5 (50-65) and a postmedian 84 (75-91) (p = 0.004)., Conclusion: Following the completion of the virtual mentoring program, participants were found to be more confident in all 5 targeted domains. In addition, they were more confident in their overall ability to match. General Surgery applicants find tailored virtual mentoring programs to be a useful tool allowing for continued program development and expansion., (Copyright © 2023 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Importance: Advocates of laparoscopic surgery argue that all inguinal hernias, including initial and unilateral ones, should be repaired laparoscopically. Prior work suggests outcomes of open repair are improved by using local rather than general anesthesia, but no prior studies have compared laparoscopic surgery with open repair under local anesthesia., Objective: To evaluate postoperative outcomes of open inguinal hernia repair under general or local anesthesia compared with laparoscopic repair., Design, Setting, and Participants: This retrospective cohort study identified 107 073 patients in the Veterans Affairs Surgical Quality Improvement Program database who underwent unilateral initial inguinal hernia repair from 1998 to 2019. Data were analyzed from October 2021 to March 2022., Exposures: Patients were divided into 3 groups for comparison: (1) open repair with local anesthesia (n = 22 333), (2) open repair with general anesthesia (n = 75 104), and (3) laparoscopic repair with general anesthesia (n = 9636)., Main Outcomes and Measures: Operative time and postoperative morbidity were compared using quantile regression and inverse probability propensity weighting. A 2-stage least-squares regression and probabilistic sensitivity analysis was used to quantify and address bias from unmeasured confounding in this observational study., Results: Of 107 073 included patients, 106 529 (99.5%) were men, and the median (IQR) age was 63 (55-71) years. Compared with open repair with general anesthesia, laparoscopic repair was associated with a nonsignificant 0.15% (95% CI, -0.39 to 0.09; P = .22) reduction in postoperative complications. There was no significant difference in complications between laparoscopic surgery and open repair with local anesthesia (-0.05%; 95% CI, -0.34 to 0.28; P = .70). Operative time was similar for the laparoscopic and open general anesthesia groups (4.31 minutes; 95% CI, 0.45-8.57; P = .048), but operative times were significantly longer for laparoscopic compared with open repair under local anesthesia (10.42 minutes; 95% CI, 5.80-15.05; P < .001). Sensitivity analysis and 2-stage least-squares regression demonstrated that these findings were robust to bias from unmeasured confounding., Conclusions and Relevance: In this study, laparoscopic and open repair with local anesthesia were reasonable options for patients with initial unilateral inguinal hernias, and the decision should be made considering both patient and surgeon factors.

Background & Aims: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time., Methods: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens., Results: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations., Conclusions: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Target identification for chimeric antigen receptor (CAR) T-cell therapies remains challenging due to the limited repertoire of tumor-specific surface proteins. Intracellular proteins presented in the context of cell surface HLA provide a wide pool of potential antigens targetable through T-cell receptor mimic antibodies. Mass spectrometry (MS) of HLA ligands from 8 hematologic and nonhematologic cancer cell lines identified a shared, non-immunogenic, HLA-A*02-restricted ligand (ALNEQIARL) derived from the kinetochore-associated NDC80 gene. CAR T cells directed against the ALNEQIARL:HLA-A*02 complex exhibited high sensitivity and specificity for recognition and killing of multiple cancer types, especially those of hematologic origin, and were efficacious in mouse models against a human leukemia and a solid tumor. In contrast, no toxicities toward resting or activated healthy leukocytes as well as hematopoietic stem cells were observed. This shows how MS can inform the design of broadly reactive therapeutic T-cell receptor mimic CAR T-cell therapies that can target multiple cancer types currently not druggable by small molecules, conventional CAR T cells, T cells, or antibodies., (© 2022 by The American Society of Hematology.)

Purpose: In 2003, randomized trials demonstrated potentially improved outcomes when local instead of general anesthesia is used for inguinal hernia repair. Our study aimed to evaluate how the use of local anesthesia for this procedure changed over time following the publication of the trials' level 1 evidence., Methods: We used the 1998-2018 Veterans Affairs Surgical Quality Improvement Program database to identify adults who underwent open, unilateral inguinal hernia repair under local or general anesthesia. Our primary outcome was the percentage of cases performed under local anesthesia. We used a time-series design to examine the trend and rate of change of the use of local anesthesia., Results: We included 97,437 veterans, of which 22,333 (22.9%) had hernia surgery under local anesthesia. The median age of veterans receiving local anesthesia remained stable at 64-67 years over time. The use of local anesthesia decreased steadily, from 38.2% at the beginning year to 15.1% in the final year (P < 0.0001). The publication of results from randomized trials (in 2003) did not appear to increase the overall use or change the rate of decline in the use of local anesthesia. Overall, we found that the use of local anesthesia decreased by about 1.5% per year., Conclusion: The utilization of local anesthesia for inguinal hernia repair in the VA has steadily declined over the last 20 + years, despite data showing equivalence or superiority to general anesthesia. Future studies should explore barriers to the use of local anesthesia for hernia repair., (© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Wounds continue to be of a global concern. Therefore, a more focussed, evidence-based approach to wound assessment and management is required. The WOUND COMPASS™ Clinical Support App (CSA) is designed to support the health care professional with wound assessment and management at the point of care. This real-world pilot study aimed to determine the utility of the CSA during routine wound management, in multiple care settings. A non-interventional, real-world pilot programme of the CSA was conducted at four sites. Patients received routine wound management. The CSA was programmed to replicate the site's formulary for evidence-based wound management. Anonymised pre- and post-pilot clinician opinion surveys on useability and impact of the CSA were collected and reported. Wound Specialists (n = 7 [100%]) and Non-Wound Specialists (NWS) (n = 58 [82%]) indicated that competence and confidence in wound assessment were enhanced with use of the CSA (100%; 82%). Furthermore, practice variation was reduced because of a greater compliance to their local formulary (n = 7 [100%]; 79% [54%]). This real-world pilot shows the positive impact of the CSA, and the improvements that can be potentially realised via reduction in practice variation, improvement in NWSs confidence when managing wounds and increased formulary compliance., (© 2022 Smith and Nephew. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Exploring the repertoire of peptides presented on major histocompatibility complexes (MHCs) helps identify targets for immunotherapy in many hematologic malignancies. However, there is a paucity of such data for diffuse large B-cell lymphomas (DLBCLs), which might be explained by the profound downregulation of MHC expression in many DLBCLs, and in particular in the enhancer of zeste homolog 2 (EZH2)-mutated subgroup. Epigenetic drug treatment, especially in the context of interferon-γ (IFN-γ), restored MHC expression in DLBCL. In DLBCL, peptides presented on MHCs were identified via mass spectrometry after treatment with tazemetostat or decitabine alone or in combination with IFN-γ. Such treatment synergistically increased the expression of MHC class I surface proteins up to 50-fold and the expression of class II surface proteins up to threefold. Peptides presented on MHCs increased to a similar extent for both class I and class II MHCs. Overall, these treatments restored the diversity of the immunopeptidome to levels described in healthy B cells for 2 of 3 cell lines and allowed the systematic search for new targets for immunotherapy. Consequently, we identified multiple MHC ligands from the regulator of G protein signaling 13 (RGS13) and E2F transcription factor 8 (E2F8) on different MHC alleles, none of which have been described in healthy tissues and therefore represent tumor-specific MHC ligands that are unmasked only after drug treatment. Overall, our results show that EZH2 inhibition in combination with decitabine and IFN-γ can expand the repertoire of MHC ligands presented on DLBCLs by revealing suppressed epitopes, thus allowing the systematic analysis and identification of new potential immunotherapy targets., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Introduction: Despite advances, readmission and mortality rates for surgical patients with colon cancer remain high. Prediction models using regression techniques allows for risk stratification to aid periprocedural care. Technological advances have enabled large data to be analyzed using machine learning (ML) algorithms. A national database of colon cancer patients was selected to determine whether ML methods better predict outcomes following surgery compared to conventional methods., Methods: Surgical colon cancer patients were identified using the 2013 National Cancer Database (NCDB). The negative outcome was defined as a composite of 30-d unplanned readmission and 30- and 90-d mortality. ML models, including Random Forest and XGBoost, were built and compared with conventional logistic regression. For the accounting of unbalanced outcomes, a synthetic minority oversampling technique (SMOTE) was implemented and applied using XGBoost., Results: Analysis included 528,060 patients. The negative outcome occurred in 11.6% of patients. Model building utilized 30 variables. The primary metric for model comparison was area under the curve (AUC). In comparison to logistic regression (AUC 0.730, 95% CI: 0.725-0.735), AUC's for ML algorithms ranged between 0.748 and 0.757, with the Random Forest model (AUC 0.757, 95% CI: 0.752-0.762) outperforming XGBoost (AUC 0.756, 95% CI: 0.751-0.761) and XGBoost using SMOTE data (AUC 0.748, 95% CI: 0.743-0.753)., Conclusions: We show that a large registry of surgical colon cancer patients can be utilized to build ML models to improve outcome prediction with differential discriminative ability. These results reveal the potential of these methods to enhance risk prediction, leading to improved strategies to mitigate those risks., (Copyright © 2022 Elsevier Inc. All rights reserved.)

It has been shown that intraoperative stress can have a negative effect on surgeon surgical skills during laparoscopic procedures. For novice surgeons, stressful conditions can lead to significantly higher velocity, acceleration, and jerk of the surgical instrument tips, resulting in faster but less smooth movements. However, it is still not clear which of these kinematic features (velocity, acceleration, or jerk) is the best marker for identifying the normal and stressed conditions. Therefore, in order to find the most significant kinematic feature that is affected by intraoperative stress, we implemented a spatial attention-based Long-Short-Term-Memory (LSTM) classifier. In a prior IRB approved experiment, we collected data from medical students performing an extended peg transfer task who were randomized into a control group and a group performing the task under external psychological stresses. In our prior work, we obtained "representative" normal or stressed movements from this dataset using kinematic data as the input. In this study, a spatial attention mechanism is used to describe the contribution of each kinematic feature to the classification of normal/stressed movements. We tested our classifier under Leave-One-User-Out (LOUO) cross-validation, and the classifier reached an overall accuracy of 77.11% for classifying "representative" normal and stressed movements using kinematic features as the input. More importantly, we also studied the spatial attention extracted from the proposed classifier. Velocity and acceleration on both sides had significantly higher attention for classifying a normal movement ( p <= 0.0001); Velocity ( p <= 0.015) and jerk ( p <= 0.001) on non-dominant hand had significant higher attention for classifying a stressed movement, and it is worthy noting that the attention of jerk on non-dominant hand side had the largest increment when moving from describing normal movements to stressed movements ( p = 0.0000). In general, we found that the jerk on non-dominant hand side can be used for characterizing the stressed movements for novice surgeons more effectively., Competing Interests: Disclosure The authors declared that they have no conflict of interest.

Objective: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown., Design: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS)., Results: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%)., Conclusions: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Excessive stress experienced by the surgeon can have a negative effect on the surgeon's technical skills. The goal of this study is to evaluate and validate a deep learning framework for real-time detection of stressed surgical movements using kinematic data., Methods: 30 medical students were recruited as the subjects to perform a modified peg transfer task and were randomized into two groups, a control group (n=15) and a stressed group (n=15) that completed the task under deteriorating, simulated stressful conditions. To classify stressed movements, we first developed an attention-based Long-Short-Term-Memory recurrent neural network (LSTM) trained to classify normal/stressed trials and obtain the contribution of each data frame to the stress level classification. Next, we extracted the important frames from each trial and used another LSTM network to implement the frame-wise classification of normal and stressed movements., Results: The classification between normal and stressed trials using attention-based LSTM model reached an overall accuracy of 75.86% under Leave-One-User-Out (LOUO) cross-validation. The second LSTM classifier was able to distinguish between the typical normal and stressed movement with an accuracy of 74.96% with an 8-second observation under LOUO. Finally, the normal and stressed movements in stressed trials could be classified with the accuracy of 68.18% with a 16-second observation under LOUO., Conclusion: In this study, we extracted the movements which are more likely to be affected by stress and validated the feasibility of using LSTM and kinematic data for frame-wise detection of stress level during laparoscopic training. The proposed classifier could be potentially be integrated with robot-assisted surgery platforms for stress management purposes., (© 2022. CARS.)

Despite the success of immune checkpoint blockade therapy, few strategies sufficiently overcome immunosuppression within the tumor microenvironment (TME). Targeting regulatory T cells (T regs ) is challenging, because perturbing intratumoral T reg function must be specific enough to avoid systemic inflammatory side effects. Thus, no T reg -targeted agents have proven both safe and efficacious in patients with cancer. Neuropilin-1 (NRP1) is recognized for its role in supporting intratumoral T reg function while being dispensable for peripheral homeostasis. Nonetheless, little is known about the biology of human NRP1 + T regs and the signals that regulate NRP1 expression. Here, we report that NRP1 is preferentially expressed on intratumoral T regs across six distinct cancer types compared to healthy donor peripheral blood [peripheral blood lymphocyte (PBL)] and site-matched, noncancer tissue. Furthermore, NRP1 + T reg prevalence is associated with reduced progression-free survival in head and neck cancer. Human NRP1 + T regs have broad activation programs and elevated suppressive function. Unlike mouse T regs , we demonstrate that NRP1 identifies a transient activation state of human T regs driven by continuous T cell receptor (TCR) signaling through the mitogen-activated protein kinase pathway and interleukin-2 exposure. The prevalence of NRP1 + T regs in patient PBL correlates with the intratumoral abundance of NRP1 + T regs and may indicate higher disease burden. These findings support further clinical evaluation of NRP1 as a suitable therapeutic target to enhance antitumor immunity by inhibiting T reg function in the TME.

Increased levels of stress can impair surgeon performance and patient safety during surgery. The aim of this study is to investigate the effect of short term stressors on laparoscopic performance through analysis of kinematic data. Thirty subjects were randomly assigned into two groups in this IRB-approved study. The control group was required to finish an extended-duration peg transfer task (6 minutes) using the FLS trainer while listening to normal simulated vital signs and while being observed by a silent moderator. The stressed group finished the same task but listened to a period of progressively deteriorating simulated patient vitals, as well as critical verbal feedback from the moderator, which culminated in 30 seconds of cardiac arrest and expiration of the simulated patient. For all subjects, video and position data using electromagnetic trackers mounted on the handles of the laparoscopic instruments were recorded. A statistical analysis comparing time-series velocity, acceleration, and jerk data, as well as path length and economy of volume was conducted. Clinical stressors lead to significantly higher velocity, acceleration, jerk, and path length as well as lower economy of volume. An objective evaluation score using a modified OSATS technique was also significantly worse for the stressed group than the control group. This study shows the potential feasibility and advantages of using the time-series kinematic data to identify the stressful conditions during laparoscopic surgery in near-real-time. This data could be useful in the design of future robot-assisted algorithms to reduce the unwanted effects of stress on surgical performance.

Oncogenic KRAS mutation-driven pancreatic ductal adenocarcinoma is currently the fourth-leading cause of cancer-related deaths in the United States. Macroautophagy (hereafter "autophagy") is one of the lysosome-dependent degradation systems that can remove abnormal proteins, damaged organelles, or invading pathogens by activating dynamic membrane structures (e.g., phagophores, autophagosomes, and autolysosomes). Impaired autophagy (including excessive activation and defects) is a pathological feature of human diseases, including pancreatic cancer. However, dysfunctional autophagy has many types and plays a complex role in pancreatic tumor biology, depending on various factors, such as tumor stage, microenvironment, immunometabolic state, and death signals. As a modulator connecting various cellular events, pharmacological targeting of nonselective autophagy may lead to both good and bad therapeutic effects. In contrast, targeting selective autophagy could reduce potential side effects of the drugs used. In this review, we describe the advances and challenges of autophagy in the development and therapy of pancreatic cancer. Abbreviations : AMPK: AMP-activated protein kinase; CQ: chloroquine; csc: cancer stem cells; DAMP: danger/damage-associated molecular pattern; EMT: epithelial-mesenchymal transition; lncRNA: long noncoding RNA; MIR: microRNA; PanIN: pancreatic intraepithelial neoplasia; PDAC: pancreatic ductal adenocarcinoma; PtdIns3K: phosphatidylinositol 3-kinase; SNARE: soluble NSF attachment protein receptor; UPS: ubiquitin-proteasome system.

Macroautophagy (hereafter referred to as "autophagy") is a lysosome-mediated degradation process that plays a complex role in cellular stress, either promoting survival or triggering death. Early studies suggest that ferroptosis, an iron-dependent form of regulated cell death, is not related to autophagy. Conversely, recent evidence indicates that the molecular machinery of autophagy facilitates ferroptosis through the selective degradation of anti-ferroptosis regulators. However, the mechanism of autophagy-dependent ferroptosis remains incompletely understood. Here, we examine the early dynamic change in protein expression of autophagic (e.g., MAP1LC3B and SQSTM1) or ferroptotic (e.g., SLC7A11 and GPX4) regulators in 60 human cancer cell lines in response to two classical ferroptosis activators (erastin and RSL3) in the absence or presence of the lysosomal inhibitor chloroquine. Compared to erastin, RSL3 exhibits wider and stronger activity in the upregulation of MAP1LC3B-II or downregulation of SQSTM1 in 80% (48/60) or 63% (38/60) of cell lines, respectively. Both RSL3 and erastin failed to affect SLC7A11 expression, but they led to GPX4 downregulation in 12% (7/60) and 3% (2/60) of cell lines, respectively. Additionally, the intracellular iron exporter SLC40A1/ferroportin-1 was identified as a new substrate for autophagic elimination, and its degradation by SQSTM1 promoted ferroptosis in vitro and in xenograft tumor mouse models. Together, these findings show tumor heterogeneity in autophagy-dependent ferroptosis, which might have different biological behaviors with regard to the dynamic characteristics of cell death. Abbreviations: ATG: Autophagy-related; CQ: Chloroquine; GPX4: Glutathione peroxidase 4; MAP1LC3B/LC3: Microtubule-associated protein 1 light chain 3 beta: NCOA4: Nuclear Receptor Coactivator 4; ROS: Reactive Oxygen Species; SLC40A1/ferroportin-1: Solute Carrier family 40 Member 1; SLC7A11: Solute Carrier Family 7 Member 11; SQSTM1/p62: Sequestosome 1.

Background: The optimal anesthesia modality for umbilical hernia repair is unclear. We hypothesized that using local rather than general anesthesia would be associated with improved outcomes, especially for frail patients., Methods: We utilized the 1998-2018 Veterans Affairs Surgical Quality Improvement Program to identify patients who underwent elective, open umbilical hernia repair under general or local anesthesia. We used the Risk Analysis Index to measure frailty. Outcomes included complications and operative time., Results: There were 4958 Veterans (13%) whose hernias were repaired under local anesthesia. Compared to general anesthesia, local was associated with a 12%-24% faster operative time for all patients, and an 86% lower (OR 0.14, 95%CI 0.03-0.72) complication rate for frail patients., Conclusions: Local anesthesia may reduce the operative time for all patients and complications for frail patients having umbilical hernia repair., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Many studies have identified racial disparities in healthcare, but few have described disparities in the use of anesthesia modalities. We examined racial disparities in the use of local versus general anesthesia for inguinal hernia repair. We hypothesized that African American and Hispanic patients would be less likely than Caucasians to receive local anesthesia for inguinal hernia repair., Materials and Methods: We included 78,766 patients aged ≥ 18 years in the Veterans Affairs Surgical Quality Improvement Program database who underwent elective, unilateral, open inguinal hernia repair under general or local anesthesia from 1998-2018. We used multiple logistic regression to compare use of local versus general anesthesia and 30-day postoperative complications by race/ethnicity., Results: In total, 17,892 (23%) patients received local anesthesia. Caucasian patients more frequently received local anesthesia (15,009; 24%), compared to African Americans (2353; 17%) and Hispanics (530; 19%), P < 0.05. After adjusting for covariates, we found that African Americans (OR 0.82, 95% CI 0.77-0.86) and Hispanics (OR 0.77, 95% CI 0.69-0.87) were significantly less likely to have hernia surgery under local anesthesia compared to Caucasians. Additionally, local anesthesia was associated with fewer postoperative complications for African American patients (OR 0.46, 95% CI 0.27-0.77)., Conclusions: Although local anesthesia was associated with enhanced recovery for African American patients, they were less likely to have inguinal hernias repaired under local than Caucasians. Addressing this disparity requires a better understanding of how surgeons, anesthesiologists, and patient-related factors may affect the choice of anesthesia modality for hernia repair., (Copyright © 2021. Published by Elsevier Inc.)

Objective: During the initial wave of the COVID-19 pandemic, organ transplantation was classified a CMS Tier 3b procedure which should not be postponed. The differential impact of the pandemic on access to liver transplantation was assessed., Summary Background Data: Disparities in organ access and transplant outcomes among vulnerable populations have served as obstacles in liver transplantation., Methods: Using UNOS STARfile data, adult waitlisted candidates were identified from March 1, 2020 to November 30, 2020 (n = 21,702 pandemic) and March 1, 2019 to November 30, 2019 (n = 22,797 pre-pandemic), and further categorized and analyzed by time periods: March to May (Period 1), June to August (Period 2), and September to November (Period 3). Comparisons between pandemic and pre-pandemic groups included: Minority status, demographics, diagnosis, MELD, insurance type, and transplant center characteristics. Liver transplant centers (n = 113) were divided into tertiles by volume (small, medium, large) for further analyses. Multivariable logistic regression was fitted to assess odds of transplant. Competing risk regression was used to predict probability of removal from the waitlist due to transplantation or death and sickness. Additional temporal analyses were performed to assess changes in outcomes over the course of the pandemic., Results: During Period 1 of the pandemic, Minorities showed greater reduction in both listing (-14% vs -12% Whites), and transplant (-15% vs -7% Whites), despite a higher median MELD at transplant (23 vs 20 Whites, P < 0.001). Of candidates with public insurance, Minorities demonstrated an 18.5% decrease in transplants during Period 1 (vs -8% Whites). Although large programs increased transplants during Period 1, accounting for 61.5% of liver transplants versus 53.4% pre-pandemic (P < 0.001), Minorities constituted significantly fewer transplants at these programs during this time period (27.7% pandemic vs 31.7% pre-pandemic, P = 0.04). Although improvements in disparities in candidate listings, removals, and transplants were observed during Periods 2 and 3, the adjusted odds ratio of transplant for Minorities was 0.89 (95% CI 0.83-0.96, P = 0.001) over the entire pandemic period., Conclusions: COVID-19's effect on access to liver transplantation has been ubiquitous. However, Minorities, especially those with public insurance, have been disproportionately affected. Importantly, despite the uncertainty and challenges, our systems have remarkable resiliency, as demonstrated by the temporal improvements observed during Periods 2 and 3. As the pandemic persists, and the aftermath ensues, health care systems must consciously strive to identify and equitably serve vulnerable populations., Competing Interests: Conflict of interest: Raymond Lynch receives research support from the Mid-America Transplant Foundation. The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Frailty predisposes patients to poor postoperative outcomes. We evaluated whether using local rather than general anesthesia for hernia repair could mitigate effects of frailty., Methods: We used the Risk Analysis Index (RAI) to identify 8,038 frail patients in the 1998-2018 Veterans Affairs Surgical Quality Improvement Program database who underwent elective, open unilateral inguinal hernia repair under local or general anesthesia. Our outcome of interest was the incidence of postoperative complications., Results: In total, 5,188 (65%) patients received general anesthesia and 2,850 (35%) received local. Local anesthesia was associated with a 48% reduction in complications (OR 0.52, 95%CI 0.38-0.72). Among the frailest patients (RAI≥70), predicted probability of a postoperative complication ranged from 22 to 33% with general anesthesia, compared to 13-21% with local., Conclusions: Local anesthesia was associated with a ∼50% reduction in postoperative complications in frail Veterans. Given the paucity of interventions for frail patients, there is an urgent need for a randomized trial comparing effects of anesthesia modality on postoperative complications in this vulnerable population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Neoadjuvant therapy is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). It is unknown whether neoadjuvant chemoradiotherapy is more effective than chemotherapy (NCRT vs. NAC). We aim to compare pathological and survival outcomes of NCRT and NAC in patients with PDAC., Patients and Methods: Single-center analysis of PDAC patients treated with NCRT or NAC followed by resection between December 2008 and December 2018 was performed. Average treatment effect (ATE) was estimated after case-control matching using Mahalanobis distance nearest-neighbor matching. Inverse probability weighted estimates (IPWE)-based ATE was estimated for disease-free survival (DFS) and overall survival (OS)., Results: Among the 418 patients (mean age 66.8 years, 51% female) included in the study, 327 received NAC and 91 received NCRT. NCRT patients had higher rates of locally advanced disease, number of neoadjuvant chemotherapy cycles, more chemotherapy regimen crossover (gemcitabine and 5-FU based), and were more likely to undergo open surgical procedures and/or vascular resection (all p < 0.05). After matched analysis, NCRT was associated with a significant reduction in lymph node positive disease [ATE = (-)0.24, p = 0.007] and lymphovascular invasion [ATE = (-)0.20, p = 0.02]. While NCRT was associated with significantly improved DFS by 9.5 months (p = 0.006), it did not affect OS by IPWE-based ATE after adjusting for adjuvant therapy (ATE = 5.5 months; p = 0.32)., Conclusion: Compared with NAC alone, NCRT is associated with improved pathologic surrogates and disease-free survival, but not overall survival in patients with PDAC.