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Background: Risk factors for in-hospital mortality related to gastrointestinal complications requiring operative intervention after cardiovascular surgery have not been previously described., Methods: Adult patients who underwent cardiovascular surgery followed by gastrointestinal surgery during the same admission between January 2010 and June 2023 were included. Multivariable logistic regression was used to identify predictors of in-hospital mortality. Kaplan-Meier survival analysis was performed to assess overall survival based on identified risk factors., Results: Gastrointestinal complications requiring operative intervention after cardiac surgery occurred in 151 patients, with an overall in-hospital mortality of 35.76% (n = 54). The most common diagnosis was bowel ischemia (50.33%). On multivariable logistic regression, the history of cirrhosis (odds ratio: 37.96, 95% confidence interval: 3.57-543.90) and the clinical condition at the time of emergency general surgery consultation, described by elevated lactate (odds ratio: 5.76, 95% confidence interval: 1.71-22.82), platelets <50 × 10 9 /L (odds ratio: 11.34, 95% confidence interval: 1.60-162.37), ≥3 vasoactive medications (odds ratio: 4.93, 95% CI: 1.29-20.14), and the need for renal replacement therapy (odds ratio: 5.18, 95% confidence interval: 1.46-20.79) were predictive of in-hospital mortality. In-hospital mortality was low when none of the risk factors identified on multivariable analysis were present (2.38%, n = 1 of 42), but in-hospital mortality was universal among patients with 4-5 risk factors (100%, n = 8 of 8)., Conclusions: Gastrointestinal complications after cardiac surgery are disastrous when patient illness becomes severe. Clinicians should maintain a high index of suspicion for gastrointestinal complications to promote early involvement of general surgery. Knowledge of these risk factors could help guide discussions among the multidisciplinary care team, patients, and their families., Competing Interests: Conflict of Interest/Disclosure The authors have no related conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Study findings showing an association between nonsteroidal anti-inflammatory drug use and marginal ulcer, a significant cause of morbidity after gastrojejunostomy, have been inconsistent. This study aimed to evaluate this relationship in large cohort., Methods: This retrospective cohort included adult patients with a history of gastrojejunostomy documented between 2004 and 2023. The electronic medical record was queried for nonsteroidal anti-inflammatory drug prescriptions, marginal ulcer diagnosis, and comorbidities. Multivariable logistic regression was performed to assess the association between marginal ulcer and nonsteroidal anti-inflammatory drug exposures, controlling for smoking, Helicobacter pylori history, acid-suppressing therapy, diabetes, age, and sex., Results: During the study period, 6,888 patients with a history of gastrojejunostomy were identified, of whom 45.2% (n = 3,115) of patients were exposed to an nonsteroidal anti-inflammatory drug and 10.12% (n = 697) developed a marginal ulcer. On multivariable analysis, the risk of marginal ulcer was found to be dose-dependent, with increasing odds of marginal ulcer with an increasing number of nonsteroidal anti-inflammatory drug exposures from odds ratio 1.67 (95% confidence interval, 1.37-2.02) with 1-2 nonsteroidal anti-inflammatory drug exposures to odds ratio 2.42 (95% confidence interval, 1.79-3.24) with >8 nonsteroidal anti-inflammatory drug exposures. Acid-suppressing therapy was found to be protective (odds ratio, 0.61; 95% confidence interval, 0.52-0.73). Over the last decade, the number of nonsteroidal anti-inflammatory drugs prescribed to patients with gastrojejunostomy has significantly increased from 15.87 prescriptions per 1,000 patients per year to 531.02 per 1,000 patients per year (R 2  = 0.91, P < .001)., Conclusion: Marginal ulcer after gastrojejunostomy is associated with nonsteroidal anti-inflammatory drug prescriptions in a dose-dependent manner. Although acid-suppressing therapy appears protective for marginal ulcer, quality improvement efforts should focus on diminishing nonsteroidal anti-inflammatory drug prescribing in this population., Competing Interests: Conflicts of Interest/Disclosures The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Kirsten rat sarcoma mutation was reported to adversely affect local tumor control after percutaneous ablation of colorectal liver metastasis. Nevertheless, the effect of Kirsten rat sarcoma mutation on surgical ablation has not been investigated in the literature. The aim of this study is to analyze the impact of Kirsten rat sarcoma mutation on local recurrence after surgical ablation of colorectal liver metastasis., Methods: This was an institutional review board-approved study of patients who underwent surgical ablation of colorectal liver metastasis between 2005 and 2023 at a single center and underwent Kirsten rat sarcoma testing with ≥1 year follow-up. Local recurrence was analyzed using univariate Kaplan-Meier and multivariate Cox hazard models., Results: A total of 163 patients with 424 lesions fulfilled inclusion criteria. Fifty (30.7%) patients received radiofrequency ablation and 113 (69.3%) patients received microwave ablation. Fifty-seven patients (32.2%) with 177 lesions were found to have a Kirsten rat sarcoma mutation. Patients with Kirsten rat sarcoma mutation had a larger number of tumors, percentage of posteriorly located tumors, and tumor burden score compared with those with wild-type Kirsten rat sarcoma. Nevertheless, there was no difference between the groups regarding local recurrence per lesion (15% vs 17%, respectively, P = not significant). Independent predictors of local recurrence included tumor size, ablation margin, and blood vessel proximity for radiofrequency ablation compared with tumor size and ablation margin for microwave ablation., Conclusion: There was no effect of Kirsten rat sarcoma mutations on local recurrence after surgical radiofrequency ablation or microwave ablation of colorectal liver metastasis in this study. Tumor size and ablation margin remained as independent predictors., Competing Interests: Conflicts of Interest/Disclosure Dr Eren Berber has consulting agreements with Medtronic, Ethicon, and Fluoptics. He has received honoraria for consulting work. The other authors have no potential conflicts to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To assess factors affecting the cumulative lifespan of a transplanted liver., Background: Liver aging is different from other solid organs. It is unknown how old a liver can actually get after liver transplantation., Methods: Deceased donor liver transplants from 1988 to 2021 were queried from the United States UNOS registry. Cumulative liver age was calculated as donor age + recipient graft survival., Results: In total, 184,515 livers were included. Most were donation after brain death donors (n = 175,343). The percentage of livers achieving >70, 80, 90, and 100 years cumulative age was 7.8% (n = 14,392), 1.9% (n = 3576), 0.3% (n = 528), and 0.01% (n = 21), respectively. The youngest donor age contributing to a cumulative liver age >90 years was 59 years, with posttransplant survival of 34 years. In pediatric recipients, 736 (4.4%) and 282 livers (1.7%) survived >50 and 60 years overall, respectively. Transplanted livers achieved cumulative age >90 years in 2.86 per 1000 and >100 years in 0.1 per 1000. The U.S. population at large has a cumulative "liver age" >90 years in 5.35 per 1000 persons, and >100 years in 0.2 per 1000. Livers aged >60 years at transplant experienced both improved cumulative survival ( P < 0.0001) and interestingly improved survival after transplantation ( P < 0.0001). Recipient warm ischemia time of >30 minutes was most predictive of reduced cumulative liver survival overall (n = 184,515, hazard ratio = 1.126, P < 0.001) and excluding patients with mortality in the first 6 months (n = 151,884, hazard ratio = 0.973, P < 0.001)., Conclusions: In summary, transplanted livers frequently get as old as those in the average population despite ischemic-reperfusion-injury and immunosuppression. The presented results justify using older donor livers regardless of donation type, even in sicker recipients with limited options., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Subtotal cholecystectomy provides a safe, bail-out alternative for difficult gallbladders. However, long-term outcomes comparing fenestrating and reconstituting subtotal cholecystectomy subtypes remain underexplored., Methods: This retrospective cohort included patients who underwent subtotal cholecystectomy between 2010 and 2020 within a single hospital system. Subtotal cholecystectomy was identified by parsing operative notes for keywords. Demographic and clinical variables were collected by manual review. Patient-reported outcomes were collected via phone using an abbreviated Gastrointestinal Quality-of-Life Index., Results: We identified 218 subtotal cholecystectomies, with 113 (51.8%) fenestrating subtotal cholecystectomy and 105 (48.2%) reconstituting subtotal cholecystectomy and a median follow-up of 63 months (interquartile range 27-106). Rates of bile duct injury (0.9% vs 1.0%; P > .99), bile leak (10.6% vs 9.5%; P > .99), and 30-day readmission (7.6% vs 8.0%; P > .99) did not differ between fenestrating and reconstituting subtotal cholecystectomy. For fenestrating subtotal cholecystectomy, the postoperative bile leak rate decreased fourfold when cystic duct closure was achieved (6.0% vs 24.1%; P = .012). Subtotal cholecystectomies completed laparoscopically had fewer postoperative bile leaks (2.9% vs 16.8%; P = .001), fewer wound complications (4.8% vs 13.3%; P = .035), and decreased length of stay (7.00 ± 9.07 vs 10.15 ± 13.50 days; P < .001) compared with open operations. The survey response rate was 38.9% (n = 51/131); 47 patients (92.2%) did not report recurrent biliary pain or postprandial nausea or vomiting, but 19 patients (37.2%) reported dietary restriction. Long-term completion cholecystectomy rate was 0.9%., Conclusion: Given no notable difference in postoperative or quality of life outcomes between subtotal cholecystectomy subtypes, consideration of technique depends on intraoperative conditions. Cystic duct closure during fenestrating subtotal cholecystectomy and laparoscopic completion of subtotal cholecystectomy are associated with improved postoperative outcomes., Competing Interests: Conflict of Interest/Disclosure The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Histotripsy is a novel, noninvasive, nonionizing, and nonthermal approach that uses focused ultrasound waves to treat liver tumors. This technology received a de novo Food and Drug Administration grant in late 2023. This study aimed to provide the first report on post-trial real-world clinical safety data., Methods: Safety outcomes within 30 days of histotripsy were collected after obtaining Food and Drug Administration clearance (December 22, 2023 to July 26, 2024). All centers that performed histotripsy were invited to participate in this study. Complications requiring treatment were graded using the Clavien-Dindo classification and Comprehensive Complication Index (CCI)., Results: A total of 295 patients underwent histotripsy for 510 tumors at 18 centers. The treated liver tumor types included colorectal metastases (n = 140), neuroendocrine tumors (n = 46), hepatocellular carcinomas (n = 31), pancreatic tumors (n = 30), and breast metastases (n = 26). The most common numbers of tumors treated per procedure were 1 (n = 170), 2 (n = 69), and 3 (n = 37). All 8 liver segments were treated for tumors. Safety data were available for 230 patients from 9 centers. Of note, 12 of 230 patients (5.2%) experienced complications of any grade. Most patients (9 [75%]) had minor cases (Clavien-Dindo grade ≤ II). The median and mean CCIs were 0.00 (IQR, 0.00-0.00) and 0.00 (95% CI, 0.00-0.75). All 3 major complications (Clavien-Dindo grade > II [1.3%]) were death due to disease progression. All 3 patients underwent histotripsy with palliative intent for known advanced intra- and extrahepatic diseases., Conclusion: To the best of our knowledge, this is the first study to report on the real-world therapeutic use of histotripsy for liver tumors. Histotripsy was well tolerated, with few overall complications and rare serious complications, indicating a safety profile that compares favorably with that of other liver-directed and surgical therapies for the treatment of liver tumors. Long-term follow-up data, including oncologic outcomes, were collected., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: There is sparse literature on whether routine cholangiography (RC) vs selective cholangiography (SC) during cholecystectomy is associated with improved perioperative outcomes, regardless of whether an intraoperative cholangiogram (IOC) is performed., Objective: To compare perioperative outcomes of cholecystectomy between surgeons who routinely vs selectively perform IOC., Design, Setting, and Participants: This retrospective cohort study was conducted from January 2015 through June 2023 and took place within the Cleveland Clinic Enterprise, which includes 18 hospitals and 9 ambulatory surgery centers in 2 states (Ohio and Florida). Participants included adult patients who underwent cholecystectomy for benign biliary disease. Data analysis was conducted between July 2023 and August 2024., Exposure: Routine cholangiography, defined as more than 70% of cholecystectomies performed with IOC per surgeon over the study period., Main Outcome(s) and Measure(s): The primary outcome was major bile duct injury (BDI). Hierarchical mixed-effects models with patients nested in hospitals adjusted for individual- and surgeon-level characteristics were used to assess the odds of major BDI and secondary outcomes (minor BDI, operative duration, and perioperative endoscopic retrograde cholangiopancreatography [ERCP])., Results: A total of 134 surgeons performed 28 212 cholecystectomies with 10 244 in the RC cohort (mean age, 52.71 [SD, 17.78] years; 7102 female participants [69.33%]) and 17 968 in the SC cohort (mean age, 52.33 [SD, 17.72] years; 12 135 female participants [67.54%]). Overall, 26 major BDIs (0.09%) and 105 minor BDIs (0.34%) were identified. Controlling for patient and surgeon characteristics nested in hospitals, RC was associated with decreased odds of major BDI (odds ratio [OR], 0.16; 95% CI, 0.15-0.18) and minor BDI (OR, 0.83; 95% CI, 0.77-0.89) compared with SC. Major BDIs were recognized intraoperatively more often in the RC cohort than the SC cohort (76.9% vs 23.0%; difference, 53.8%; 95% CI, 15.9%-80.2%). Lastly, RC was not significantly associated with increased perioperative ERCP utilization (OR, 1.01; 95% CI, 0.90-1.14) or negative ERCP rate (RC, 27 of 844 [3.2%] vs SC, 57 of 1570 [3.6%]; difference, -0.3%; 95% CI, -1.9% to 1.0%)., Conclusions and Relevance: In this study, RC was associated with decreased odds of major and minor BDI, as well as increased intraoperative recognition of major BDI when it occurred. RC could be considered as a health systems strategy to minimize BDI, acknowledging the overall low prevalence but high morbidity from these injuries.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) of the body/tail is notably different than PDAC in the head of the pancreas. Surgery plus chemotherapy is known to improve outcomes for all PDAC. The sequence of this therapy is well studied in head cancers yet has never been evaluated systematically in relation to distal pancreatectomy (DP)., Methods: Patients receiving DP for PDAC and who received chemotherapy were included. Patients were compared receiving neoadjuvant systemic therapy (NAST) only, adjuvant (AST) only, both NAST + AST, and who received total neoadjuvant therapy (TNT), defined as > 24 weeks NAST before DP. PSM was performed 1:1 between AST and each other group creating quadruplets of patients for analysis. Matching factors were determined by multivariate cox-regression analysis of factors independently affecting survival. Survival was considered from diagnosis and from surgery to account for potential biases., Results: In total, 4677 patients were selected with 400 (8.6%) receiving TNT, 536 (11.5%) NAST, 3235 (69.2%) AST, and 506 (10.8%) NAST + AST. A total of 341 quadruplets were selected after PSM. There were no differences in comorbidities, T/N-stage, retrieved or positive lymph nodes, and margin status after matching. Kaplan-Meier analysis showed no difference in median OS between the matched treatment groups (33.71 ± 2.07 vs. 35.22 ± 1.62 vs. 32.53 ± 3.31 vs. 37.88 ± 1.90, respectively; log-rank p = 0.464). Five-year OS was not different between the groups (21% vs. 18% vs. 20% vs. 25%, respectively; p = 0.501)., Conclusion: The sequence of chemotherapy and surgery did not impact survival in distal PDAC. Providers should tailor an individualized approach designed to maximize the chance of completing both treatments., (© 2025 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs) are increasingly recognized with the increasing use of high-fidelity cross-sectional imaging, particularly subcentimeter (<1 cm) lesions. Data regarding the risk of progression in subcentimeter cysts are absent. This study aimed to define the risk associated with subcentimeter SB-IPMNs and to propose a surveillance strategy based on this cohort., Methods: A prospectively maintained database was queried for patients with SB-IPMN who underwent nonoperative surveillance with ≥2 cross-sectional imaging studies performed >6 months apart. Clinically relevant (CR) progression has been previously defined as the development of symptoms, worrisome/high-risk stigmata, or invasive cancer (IC). Growth of ≥5 mm in 2 years is considered CR progression, whereas size of ≥3 cm alone is not., Results: A total of 1000 patients were included in the study, of whom 291 (29.1%) had SB-IPMN of <1 cm. The median follow-up times from diagnosis were 7.1 years (IQR, 3.2-10.4) in subcentimeter cysts and 6.4 years (IQR, 2.8-10.0) in cysts of ≥1 cm (P =.090). CR progression was less common in the subcentimeter cyst group than in the larger cyst group (7.2% vs 19.0%, respectively; log-rank P <.001). Cysts that progressed did so at similar time intervals (median: 3.7 years in the subcentimeter cyst group vs 3.3 years in the larger cyst group; P =.707). The subcentimeter cyst group developed IC (1.4% in the subcentimeter cyst group vs 1.8% in the larger cyst group; log-rank; P =.608) and high-risk pathology (high-grade dysplasia [HGD]/IC) at a similar rate as the larger cyst group (P =.198). Of 547 patients with cysts that were initially stable for 5 years of surveillance, 25 (4.7%) developed high-risk pathology. This was not different by initial cyst size (log-rank P =.116). Spline curves demonstrated consistently low risk of HGD/IC across increasing cyst size despite a higher rate of CR progression. The CR progression criteria best discriminated high-risk pathology in subcentimeter cysts. The rate of size growth did not correlate with high-risk pathology (hazards ratio, 1.14; 95% CI, 0.88-1.50)., Conclusion: Subcentimeter SB-IPMNs develop malignant potential as frequently as their larger counterparts and do so at similar time courses. Often incidental, subcentimeter-presumed SB-IPMNs are diagnosed at arbitrary points in the disease course and require similar surveillance duration as their larger counterparts. The rate of growth is not predictive of high-risk pathology. These cysts do not develop CR progression as frequently. However, such features better discriminate high-risk pathology in subcentimeter cysts, making the development of such features more concerning when they occur., (Copyright © 2025. Published by Elsevier Inc.)

Solid-organ malignancies represent a significant disease burden and remain one of the leading causes of death globally. In the past few decades, the rapid evolution of imaging modalities has shifted the paradigm towards image-based precision medicine, especially in the care of patients with solid-organ malignancies. Metabolic tumor volume (MTV) is one such semi-quantitative parameter obtained from positron emission tomography (PET) imaging with 18 F-fluorodeoxyglucose (FDG) that has been shown to have significant implications in the clinical oncology setting. Across various solid tumor malignancies, including lung cancer, head and neck cancer, breast cancer, esophageal cancer, and colorectal cancer, the current literature has demonstrated an association between MTV and various clinical outcomes. MTV may be used in conjunction with several existing and established clinical parameters to help inform risk stratification and treatment strategies and predict outcomes in cancer. Optimizing such volumetric parameters is paramount for advancing efforts to advance cancer care for our patients. While such advancements are made, it is important to investigate and address the limitations of MTV, including variability in terms of measurement methods, a lack of standardized cut-off values, and the impact of inherent tumor heterogeneity. Despite these limitations, which can precipitate challenges in standardization, MTV as a prognostic factor has great potential and opens an avenue for the future integration of technology into an image-based precision medicine model of care for cancer patients. This article serves as a narrative review and explores the utility and limitations of PET-MTV in various settings of solid-organ malignancy.

Competing Interests: Disclosure: Gonzalo Sapisochin received grant support from Bayer and Roche; he was also a consultant for Novartis, Integra, Roche®, AstraZeneca, Chiesi, Eisai, HepaRegeniX, and Stryker. Research collaborations with AstraZeneca, HepaRegeniX, Stryker, and Natera are reported.

Background: This study compares selection criteria for liver transplant (LT) for hepatocellular carcinoma (HCC) for inclusivity and predictive ability to identify the most permissive criteria that maintain patient outcomes., Methods: The Scientific Registry of Transplant Recipients (SRTR) database was queried for deceased donor LT's for HCC (2003-2020) with 3-y follow-up; these data were compared with a 2-center experience. Milan, University of California, San Francisco (UCSF), 5-5-500, Up-to-seven (U7), HALT-HCC, and Metroticket 2.0 scores were calculated., Results: Nationally, 26 409 patients were included, and 547 at the 2 institutions. Median SRTR-follow-up was 6.8 y (interquartile range 3.9-10.1). Three criteria allowed the expansion of candidacy versus Milan: UCSF (7.7%, n = 1898), Metroticket 2.0 (4.2%, n = 1037), and U7 (3.5%, n = 828). The absolute difference in 3-y overall survival (OS) between scores was 1.5%. HALT-HCC (area under the curve [AUC] = 0.559, 0.551-0.567) best predicted 3-y OS although AUC was notably similar between criteria (0.506 < AUC < 0.527, Mila n = 0.513, UCSF = 0.506, 5-5-500 = 0.522, U7 = 0.511, HALT-HCC = 0.559, and Metroticket 2.0 = 0.520), as was Harrall's c-statistic (0.507 < c-statistic < 0.532). All scores predicted survival to P  < 0.001 on competing risk analysis. Median follow-up in our enterprise was 9.8 y (interquartile range 7.1-13.3). U7 (13.0%, n = 58), UCSF (11.1%, n = 50), HALT-HCC (6.4%, n = 29), and Metroticket 2.0 (6.3%, n = 28) allowed candidate expansion. HALT-HCC (AUC = 0.768, 0.713-0.823) and Metroticket 2.0 (AUC = 0.739, 0.677-0.801) were the most predictive of recurrence. All scores predicted recurrence and survival to P  < 0.001 using competing risk analysis., Conclusions: Less restrictive criteria such as Metroticket 2.0, UCSF, or U7 allow broader application of transplants for HCC without sacrificing outcomes. Thus, the criteria for Model for End-stage Liver Disease-exception points for HCC should be expanded to allow more patients to receive life-saving transplantation., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Pancreatic acinar cell carcinoma (pACC) is a rare malignancy with unique clinical and molecular features. The role of chemotherapy in pACC management is not well established., Methods: The National Cancer Database (NCDB) for pACC was used. Cox regression was used in resected pACC patients to identify significant overall survival (OS) predictors. Patients were then divided based on these risk factors into propensity-matched group of surgery versus surgery + chemotherapy and Kaplan-Meier analysis was performed with log-rank tests to compare OS., Results: The NCDB 2004-2020 included 1592 pACC patients, 1553 were selected. Median age was 66 and 1090 (70.2%) were males. 622 (40.1%) received chemotherapy only, 257 (16.5%) had surgery only, and 365 (23.5%) had both. 189 Patients who received surgery were only matched to peers who had surgery + chemotherapy. The median OS for surgery only was 57.8 ± 6.0 versus 54.2 ± 9.9 months for surgery + chemotherapy (p = 0.836). Cox regression identified nodal and margin status as independent predictors of OS. Therefore, subgroups of patients with node-negative, node-positive, margin-negative, and margin-positive resections were similarly matched 1:1 for the receipt of surgery only versus surgery + chemotherapy. Only patients with node-positive disease had a significant OS benefit with the addition of chemotherapy (44.2 ± 7.3 vs. 27.5 ± 10.5 months; p = 0.036)., Conclusion: Our analysis suggests that surgical resection remains the cornerstone of therapy for pACC. Node status and margin status are the primary prognosticators. The addition of chemotherapy provides an OS benefit only in node-positive disease., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Background: Liver transplantation (LT) is the treatment of choice for end-stage liver disease and certain malignancies such as hepatocellular carcinoma (HCC). Data on the surgical management of de novo or recurrent tumors that develop in the transplanted allograft are limited. This study aimed to investigate the perioperative and long-term outcomes for patients undergoing hepatic resection for de novo or recurrent tumors after liver transplantation., Methods: The study enrolled adult and pediatric patients from 12 centers across North America who underwent hepatic resection for the treatment of a solid tumor after LT. Perioperative outcomes were assessed as well as recurrence free survival (RFS) and overall survival (OS) for those undergoing resection for HCC., Results: Between 2003 and 2023, 54 patients underwent hepatic resection of solid tumors after LT. For 50 patients (92.6 %), resection of malignant lesions was performed. The most common lesion was HCC (n = 35, 64.8 %), followed by cholangiocarcinoma (n = 6, 11.1 %) and colorectal liver metastases (n = 6, 11.1 %). The majority of the 35 patients underwent resection of HCC did not receive any preoperative therapy (82.9 %) or adjuvant therapy (71.4 %), with resection their only treatment method for HCC. During a median follow-up period of 50.7 months, the median RFS was 21.5 months, and the median OS was 49.6 months., Conclusion: Hepatic resection following OLT is safe and associated with morbidity and mortality rates that are comparable to those reported for patients undergoing resection in native livers. Hepatic resection as the primary and often only treatment modality for HCC following LT is associated with acceptable RFS and OS and should be considered in well selected patients., (© 2024. Society of Surgical Oncology.)

We describe a novel pre-liver transplant (LT) approach in colorectal liver metastasis, allowing for improved monitoring of tumor biology and reduction of disease burden before committing a patient to transplantation. Patients undergoing LT for colorectal liver metastasis at Cleveland Clinic were included. The described protocol involves intensive locoregional therapy with systemic chemotherapy, aiming to reach minimal disease burden revealed by positron emission tomography scan and carcinoembryonic Ag. Patients with no detectable disease or irreversible treatment-induced liver injury undergo transplant. Nine patients received liver transplant out of 27 who were evaluated (33.3%). The median follow-up was 700 days. Seven patients (77.8%) received a living donor LT. Five had no detectable disease, and 4 had treatment-induced cirrhosis. Pretransplant management included chemotherapy (n = 9) +/- bevacizumab (n = 6) and/or anti-EGFR (n = 6). The median number of pre-LT cycles of chemotherapy was 16 (range 10-40). Liver-directed therapy included Yttrium-90 (n = 5), ablation (n = 4), resection (n = 4), and hepatic artery infusion pump (n = 3). Three patients recurred after LT. Actuarial 1- and 2-year recurrence-free survival were 75% (n = 6/8) and 60% (n = 3/5). Recurrence occurred in the lungs (n = 1), liver graft (n = 1), and lungs+para-aortic nodes (n = 1). Patients with pre-LT detectable disease had reduced RFS ( p = 0.04). All patients with recurrence had histologically viable tumors in the liver explant. Patients treated in our protocol (n = 16) demonstrated improved survival versus those who were not candidates (n = 11) regardless of transplant status ( p = 0.01). A protocol defined by aggressive pretransplant liver-directed treatment and transplant for patients with the undetectable disease or treatment-induced liver injury may help prevent tumor recurrence., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Liver transplantation (LT) is a key treatment for primary and secondary liver cancers, reducing tumor burden with concurrent improvement of liver function. While significant improvement in survival is noted with LT, cancer recurrence rates remain high. Mitochondrial dysfunction caused by ischemia-reperfusion injury (IRI) is known to drive tumor recurrence by creating a favorable microenvironment rich in pro-inflammatory and angiogenic factors. Therefore, strategies that decrease reperfusion injury and mitochondrial dysfunction may also decrease cancer recurrence following LT. Machine perfusion techniques are increasingly used in routine clinical practice of LT with improved post-transplant outcomes and increased use of marginal grafts. Normothermic (NMP) and hypothermic oxygenated machine perfusion (HOPE) provide oxygen to ischemic tissues, and impact IRI and potential cancer recurrence through different mechanisms. This article discussed the link between IRI-associated inflammation and tumor recurrence after LT. The current literature was screened for the role of machine perfusion as a strategy to mitigate the risk of cancer recurrence. Upfront NMP ("ischemia free organ transplantation") and end-ischemic HOPE were shown to reduce hepatocellular carcinoma recurrence in retrospective studies. Three prospective randomized controlled trials are ongoing in Europe to provide robust evidence on the impact of HOPE on cancer recurrence in LT.

Liver transplantation is associated with a high risk of postoperative complications due to the complexity of the surgical procedure, recipient disease severity and the wide range of graft quality, which remains somewhat unpredictable. However, survival rates after transplantation continue to improve and the focus has thus turned to other clinically relevant endpoints including post-transplant complications, patient quality of life and costs. Procedures like liver transplantation offer the entire spectrum of post-surgical events, even in donor-recipient constellations deemed of low risk within recently defined benchmark criteria. The Clavien-Dindo classification and the CCI (comprehensive complication index) were established to assess postoperative morbidity and are widely utilised across surgical specialties. These scores depend on the number and grade of complications, which reflect the interventions required, and are frequently used to assess specific donor-recipient risk profiles and new approaches, such as machine perfusion. However, these scores are associated with inter-observer variability when used in practice, mainly due to the lack of uniform definitions. The concept of benchmarking was recently introduced in surgery and transplantation as a mechanism of standardising expected donor/recipient risk with outcomes within the first year after surgery. However, the management of complications differs significantly worldwide, as does the rating scale assigned to various complications. This may lead to inhomogeneous interpretation of study results, leading to difficulty in assessing the clinical effects of novel preservation technologies and other therapeutics in liver transplantation. This article critically discusses frequent challenges associated with risk and outcome assessment following liver transplantation., Competing Interests: Conflict of interest PAC developed the Clavien-Dindo classification and the comprehensive complication index (CCI). All other authors have nothing to disclose. Views expressed by the authors are entirely their own and may not reflect those of any company. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Disclosure: The authors declare that they have nothing to disclose.

Liver transplant (LT) for colorectal cancer liver metastases (CRLM) is increasingly popular, yet the ideal selection criteria remain unknown. Pretransplant positron emission tomography (PET) metabolic tumor volume (MTV) has been described as predicting recurrence, with a proposed cutoff of MTV ≥70 cm 3 . This approach has not been validated. Patients undergoing LT for CRLM at 2 academic transplant centers (January 1, 2017, to December 1, 2023) were included. PET-MTV was calculated by a staff radiologist from the most recent PET-scan before LT using the published protocol. Twenty-six patients were included. Median follow-up was 609 days (IQR 320-1069) and from PET to LT was 1.9 months (1.3-2.6). Nearly all (n=24, 92.3%) received living donor transplantation. Absolute recurrence rate was 30.8% (n=8). Actuarial unadjusted 1- and 2-year recurrence-free survival (RFS) were 83% (n=15/18) and 62% (n=8/13); 1- and 2-year overall survival were 100% (n=18/18) and 85% (n=11/13). The incidence of recurrence-per-year follow-up was 0.35 when MTV ≥70 cm 3 versus 0.10 if MTV <70 cm 3 ( P <0.001). Median RFS using Kaplan-Meier product-estimate was 0.83 years (95% CI: 0.43-1.23) in MTV≥70 cm 3 versus 4.1 years (95% CI: 2.90-5.22) when MTV<70 cm 3 ( p <0.001); this was also associated with improved overall survival ( p =0.003). MTV>70 cm 3 demonstrated HR=2.42 (95% CI: 2.2-62.2, p =0.006) for association with RFS on univariate Cox-proportional hazards analysis, and an AUC=0.771 (95% CI: 0.560-0.981) for predicting recurrence ( p =0.030). Nineteen patients (69.2%) had histologically viable tumors, which were associated with recurrence (43% vs. 0%, p =0.039) and reduced RFS (log-rank p =0.019). PET-MTV was associated with the presence of histologically viable tumor (AUC=0.763, 95% CI: 0.583-0.944). PET-MTV ≥70 cm 3 was associated with reduced RFS and overall survival after LT for CRLM, confirming findings from the Norway group. This is likely due to its ability to identify residual viable tumors, which are independently associated with recurrence. PET-MTV should be a key selection criterion prior to LT for CRLM., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) are becoming more prevalent with advanced medical imaging and account for most of pancreatic cystic neoplasms (PCNs). Most incidental lesions should be surveyed, with resection reserved for specific, high-risk cases. Solid organ transplantation candidates may be high risk of resection before transplant and will require systemic immunosuppression after transplant, which has been theorized to alter the natural history of the IPMN. We aimed to describe the progression in surveilled cysts after solid organ transplantation., Methods: A prospectively maintained database of PCNs was queried for patients with IPMN. Patients who had received a previous solid organ transplantation and with ≥2 imaging studies >6 months apart after transplantation were included. Clinically relevant (CR) progression was defined as symptoms, worrisome/high-risk stigmata, or invasive carcinoma (IC). Growth ≥5 mm in 2 years is considered CR progression; size ≥3 cm alone is not., Results: Between 1997 and 2023, 252 patients received solid organ transplantation (liver, 86; kidney, 113; and lung, 54) and were diagnosed as having an IPMN. This cohort was compared with a set of 770 patients surveilled for IPMN who did not have previous transplantation. Median follow-up period was 3.7 years (IQR, 1.6-6.8). Moreover, 2 transplant patients (0.8%) developed IC, and 4 developed (1.6%) high-grade dysplasia (HGD). Both were less common in transplant patients than the nontransplant population (IC, 3.3%; HGD, 2.9%), although this was not significant on time-to-event analysis (IC, P = .152; HGD, P = .352). The rate of CR progression was high in the transplant cohort (n = 118; 47%). Features of CR progression included size growth (n = 79; 67%), other worrisome/high-risk stigmata (n = 25; 21%), and new main duct involvement (n = 14; 12%). Compared with the nontransplant (n = 128; 17%), transplant patients had a higher rate of CR progression (P < .001), which was mostly explained by a more frequent size growth (31% vs 9%; P < .001). However, no transplant patients with size growth CR progression developed IC. Moreover, 17 (6.7%) required pancreatic surgery for CR progression after transplant vs 58 (7.5%) in the nontransplant population. Furthermore, 6 resected cysts (35%) harbored high-risk pathology after transplant (IC, 2; HGD, 4) vs 40 (69%) in the general population (P < .001; IC, 29; HGD, 11)., Conclusion: Malignant transformation of BD-IPMNs is rare despite systemic immunosuppression in solid organ transplant patients. This supports transplantation in patients with IPMN without fear of worsening their risk of pancreatic cancer, although it was associated with a higher risk of disease progression. Patients with IPMNs should be surveilled with yearly scans after transplant, with pancreatic resection reserved for only high-risk features as we continue to define the optimal criteria for those with CR progression., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined the predictive value of Flavin Mononucleotide (FMN) levels in the flush solution used during cold storage of donor livers on outcomes post-transplantation., Background: Static cold storage for liver grafts induces hypoxia with subsequent impaired mitochondrial function and Flavin Mononucleotide (FMN) release upon reperfusion., Methods: This study enrolled 62 recipients who received whole liver grafts from donation after brain death (n=50) and circulatory death donors (n=12) between June 2022 and July 2023. FMN concentrations were measured in flush solutions on the back-table. ROC-curve analysis identified an FMN level cut-off for graft survival. Post-transplant outcomes were examined according to FMN levels., Results: FMN level was significantly associated with graft survival, with an area-under-the-curve (AUC) of 0.858 (95%CI: 0.754-0.963, P<0.001), outperforming the donor risk index (AUC 0.571, 95%CI: 0.227-0.915, P=0.686). The study cohort was divided into low-FMN (<37.5 ng/mL, n=40) and high-FMN groups (≥37.5 ng/mL, n=22). The low-FMN group had superior one-year graft survival compared with the high-FMN group (100% vs. 77%, P=0.003). Levels of transaminases within 7 days post-transplant were significantly higher in the high-FMN group (P=0.003). The high-FMN group developed acute rejections (41% vs. 15%, P=0.023) and early allograft dysfunction (50% vs. 20%, P=0.014) more frequently. Median comprehensive complication index in the high-FMN group was significantly higher (54 [interquartile range, 40-78] vs. 42 [interquartile range, 28-52], P=0.017)., Conclusion: The FMN level measured in donor livers' cold storage flush solution is a valid biomarker to predict post-transplant outcomes. Liver grafts with high FMN levels may benefit from machine perfusion to improve outcomes., Competing Interests: Conflict of interest statement: All authors declare they have no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Takotsubo cardiomyopathy (TCM) is an acute, stress-mediated, reversible cardiomyopathy that occurs in the absence of hemodynamically significant coronary artery disease. We aimed to investigate the characteristics and outcomes of patients who developed TCM following liver transplantation (LT) in a multicenter study. Adult patients from 6 centers across the United States who developed TCM according to Mayo Clinic criteria following LT between 2008 and 2023 were included. Demographics, perioperative and long-term outcomes, and treatment modalities were assessed. Fifty-five patients were included. The center incidence of TCM ranged from 0.1% to 0.5%. The majority were female (54.5%) and Caucasian (87.2%), and the median age at transplant was 59 years. The primary etiologies for LT were alcohol-associated cirrhosis (49.1%) and metabolic dysfunction-associated steatotic liver disease cirrhosis (21.8%). The median time from LT to TCM diagnosis was 4 days. TCM was associated with a 60.9% reduction in left ventricular ejection fraction (LVEF) from a pretransplant median LVEF of 64.0%-25.0%. The most common treatment for TCM was diuretics (67.3%) and afterload reduction (54.5%), with only 27.3% of patients requiring vasopressor support. At a median follow-up of 31.5 months, 1-year and 3-year overall survivals (OSs) were 86.3% and 69.4%, respectively. A repeat echocardiogram performed at a median of 84 days demonstrated that 45/55 patients (81.8%) had recovered LVEF ≥50%. Patients with LVEF recovery to ≥50% had significantly improved OS compared to those without LVEF recovery >50% (106.4 vs. 12.2 mo, p = 0.001). TCM following LT is associated with a significant reduction in LVEF; however, the majority of patients recover LVEF to >50% with minimal perioperative mortality. Importantly, follow-up assessment of LVEF has significant implications as lack of recovery is associated with worse OS., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Open offers (OOs) in liver transplantation (LT) result from bypassing the traditional allocation system. Little is known about the trends of OOs or the differences in donor/recipient characteristics compared to traditionally placed organs. We aim to quantify modern practices regarding OOs and understand NMP's impact, focusing on social determinants of health (SDH), cost, and graft-associated risk., Methods: LTs from 1/1/2018 to 12/31/2023 at a single center were included. NMP was implemented on 10/1/2022. The CDC (centers for disease control)-validated social vulnerability index (SVI) and donor risk index (DRI) were calculated. Comprehensive complications index (CCI), Clavien-Dindo grades, patient and graft survival, and costs of transplantation were included., Results: 1162 LTs were performed; 193 (16.8%) from OOs. OOs were more common in the post-NMP era (26.5% vs. 13.3%, p < 0.001). Pre-NMP, patients receiving OOs had longer waitlist times (118 vs. 69 days, p < 0.001), lower MELDs (17 vs. 25 points, p < 0.001), and riskier grafts (DRI = 1.8 vs. 1.6, p = 0.004) compared to standard offers. Post-NMP, recipients receiving OOs demonstrated no difference in waitlist time (27 vs. 20 days, p = 0.21) or graft risk (DRI = 2.03 vs. 2.23, p = 0.17). OO recipient MELD remained lower (16 vs. 22, p < 0.001). OO recipients were more socially vulnerable (SVI), pre-NMP (0.41 vs. 0.36, p = 0.004), but less vulnerable after NMP (0.23 vs. 0.36, p = 0.019). Despite increased graft risk, pre-NMP OO-LTs were less expensive in the 90-day global period ($154 939 vs. $178 970, p = 0.002) and the 180-days pre-/post-LT ($208 807 vs. $228 091, p = 0.021). Cost trends remained similar with NMP., Conclusion: OOs are increasingly utilized and may be appealing due to demonstrated cost reductions even with NMP. Although most OO-related metrics in our center remain similar before and after machine perfusion, programs should take caution that increasing use does not worsen organ access for socially vulnerable populations., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Objective: To quantify the rate of progression in surveilled cysts and assess what factors should indicate delayed resection., Background: Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs) are increasingly discovered, making it challenging to identify which patients require resection, thus avoiding inappropriate treatment. Most incidental lesions are surveyed, yet the consequences of that decision remain uncertain., Methods: A prospectively maintained database of pancreatic cystic neoplasms was queried for patients with SB-IPMN. Patients with ≥2 imaging studies >6 months apart were included. Clinically relevant progression (CR-progression) was defined by symptoms, worrisome/high-risk stigmata, or invasive cancer (IC). Growth ≥5 mm in 2 years is considered CR-progression; size ≥3 cm alone is not., Results: Between 1997 and 2023, 1337 patients were diagnosed with SB-IPMN. Thirty-seven (2.7%) underwent up-front surgery; 1000 (75.0%) had >6 months of surveillance.The rate of CR-progression was 15.3% (n = 153) based on size increase (n = 63, 6.3%), main-duct involvement (n = 48, 4.8%), symptoms (n = 8, 5.0%), or other criteria (n = 34, 3.4%). At a median follow-up of 6.6 years (interquartile range: 3.0-10.26), 17 patients (1.7%) developed IC. Those with CR-progression developed IC in 11.1% (n = 17) and high-grade dysplasia (HGD) in 6.5% (n = 10). Nearly half of the cancers were not contiguous with the surveyed SB-IPMN.Size ≥3 cm was not associated with HGD/IC ( P = 0.232). HGD/IC was least common in CR-progression determined by size growth (6.3%) versus main-duct involvement (24%) or other (43%, P < 0.001)Patients with CR-progression demonstrated improved survival (overall survival) with resection on time-to-event ( P < 0.001) and multivariate Cox regression (hazard ratio = 0.205, 0.096-0.439, P < 0.001) analyses. Overall survival was not improved with resection in all patients ( P = 0.244)., Conclusions: CR-progression for SB-IPMNs is uncommon, with the development of cancer anywhere in the pancreas being rare. Initial size should not drive resection. Long-term and consistent nonoperative surveillance is warranted, with surgery currently reserved for CR-progression, knowing that the majority of these still harbor low-grade pathology., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The frequency of minimally invasive distal pancreatectomy is gradually exceeding that of the open approach. Our study aims to compare short-term outcomes of robotic (RDP) and laparoscopic (LDP) distal pancreatectomies for pancreatic ductal adenocarcinoma (PDAC) using a national database., Methods: The National Cancer Database was utilized to identify patients with PDAC who underwent distal pancreatectomy from 2010-2020. Short-term technical and oncologic outcomes such as margin status and nodal harvest were included. Propensity-score matching (PSM) was performed comparing LDP and RDP cohorts. Multivariate logistic-regression models were then used to assess the impact of institutional volume on the MIDP surgical and technical oncologic outcomes., Results: 1537 patients underwent MIDP with curative intent. Most cases were laparoscopic (74.4%, n = 1144), with a gradual increase in robotic utilization, from 8.7% in 2010 to 32.0% of MIDP cases ten years later. For PSM, 698 LDP patients were matched with 349 RDP. The odds of conversion to an open case were 58% less in RDP (12.6%) compared to LDP (25.5%) with no statistically significant difference in technical oncologic results. There was no difference in length of stay (OR = 1.0[0.7-1.4]), 30-day mortality (OR = 0.5[0.2-2.0]) or 90-day mortality (OR = 1.1[0.5-2.4]) between RDP and LDP, although there was a higher 30-day readmission rate with RDP (OR = 1.71[1.1-2.7]). There were statistically significant differences in technical oncologic outcomes (nodal harvest, margin status, initiation of adjuvant therapy) based on MIDP volume quartiles., Conclusion: Laparoscopic and robotic distal pancreatectomy have similar peri- and post-operative surgical and oncologic outcomes, with a higher rate of conversion to open in the laparoscopic cohort., (© 2024. The Author(s).)

Background: Ablation is an alternative treatment modality for selected patients with colorectal liver metastases (CRLMs). Although initially widely performed via radiofrequency ablation (RFA), more recently, microwave ablation (MWA) is being preferred due to its perceived superiority in creating the ablation zones. The aim of this study is to compare the long-term efficacy of these two modalities performed surgically., Methods: Patients undergoing surgical liver ablation from 2005-2023 at a tertiary center by a single surgeon for CRLM were included in a retrospective institutional review board-approved study. Outcomes were compared using Wilcoxon, Chi-square, Kaplan-Meier, and Cox multivariate regression analyses. Continuous data are presented as median (interquartile range)., Results: There were a total of 242 patients. Laparoscopic RFA was done in 121 patients with 303 lesions and laparoscopic MWA in 121 patients with 300 lesions. There was no difference between the groups regarding operative time (161 vs. 147 minutes, respectively, P=0.4), perioperative morbidity (3% vs. 8%, respectively, P=0.2) or hospital stay (1 vs. 1 day, P=0.05). Local recurrence (LR) per lesion with at least 1 year of imaging follow-up was 29% in the RFA and 13% in the MWA group (P<0.001). Based on univariate survival analysis, tumor size, blood vessel proximity, ablation margin, and ablation modality were independent predictors of LR. To control these variables, direct matching was performed. Each cohort included 189 lesions. Kaplan-Meier analysis of these cohorts showed increased LR-free survival in the MWA group vs. the RFA group (P=0.005)., Conclusions: This large study confirms our initial observation that local tumor control rate is better after MWA vs . RFA., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-677/coif). E.B. reports consulting fees for consulting work from Medtronic, Ethicon and Fluoptics. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

The comparison of outcomes in liver transplantation (LT) is hampered by using clinically nonrelevant surrogate endpoints and considerable variability in reported relevant posttransplant outcomes. Such variability stems from nonstandard outcome measures across studies, variable definitions of the same complication, and different timing of reporting. The Clavien-Dindo classification was established to improve the rigor of outcome reporting but is nonspecific to an intervention, and there are unsolved dilemmas specifically related to LT. Core outcome sets (COSs) have been used in other specialties to standardize outcomes research, but have not been defined for LT. Thus, we use the 5 major benchmarking studies published to date to define a 10-measure COS for LT using previously validated metrics. We further provide standard definitions for each of the 10 measures that may be used in international research on the topic. These definitions also include standard time points for recording to facilitate between-study comparisons and future meta-analysis. These 10 outcomes are paired with 3 validated, procedure-independent metrics, including the Clavien-Dindo Classification and the Comprehensive Complications Index. The Clavien scale and Comprehensive Complications Index are specifically reviewed to enhance their utility in LT, and their use, along with the COS, is explored. We encourage future studies to employ this COS along with the Clavien-Dindo grading system and Comprehensive Complications Index to improve the reproducibility and generalizability of research concerning LT., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.

Chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC), continue to be a global health burden with a rise in incidence and mortality, necessitating a need for the discovery of novel biomarkers for HCC detection. This study aimed to identify novel non-invasive biomarkers for these different liver disease states. We performed untargeted metabolomics in plasma (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 34) and saliva samples (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 22) to test for significant metabolite associations with each disease state. Additionally, we identified enriched biochemical pathways and analyzed correlations of metabolites between, and within, the two biofluids. We identified two salivary metabolites and 28 plasma metabolites significantly associated with at least one liver disease state. No metabolites were significantly correlated between biofluids, but we did identify numerous metabolites correlated within saliva and plasma, respectively. Pathway analysis revealed significant pathways enriched within plasma metabolites for several disease states. Our work provides a detailed analysis of the altered metabolome at various stages of liver disease while providing some context to altered pathways and relationships between metabolites.

Objective: Describe the utility of circulating tumor DNA in the postoperative surveillance of hepatocellular carcinoma (HCC)., Background: Current biomarkers for HCC like alpha-fetoprotein (AFP) are lacking. Circulating tumor DNA (ctDNA) has shown promise in colorectal and lung cancers, but its utility in HCC remains relatively unknown., Methods: Patients with HCC undergoing curative-intent resection from November 1, 2020, to July 1, 2023, received ctDNA testing using the Guardant360 platform. Tumor mutational burden (TMB) is calculated as the number of somatic mutations-per-megabase of genomic material identified., Results: Forty-seven patients had postoperative ctDNA testing. The mean follow-up was 27 months, and the maximum was 43.2 months. Twelve patients (26%) experienced recurrence. Most (n=41/47, 87.2%) had identifiable ctDNA postoperatively; 55.3% (n=26) were TMB-not detected versus 45.7% (n=21) TMB-detectable. Postoperative identifiable ctDNA was not associated with RFS ( P =0.518). Detectable TMB was associated with reduced RFS (6.9 vs 14.7 mo, P =0.049). There was a higher rate of recurrence in patients with TMB (n=9/21, 42.9%, vs n=3/26, 11.5%, P =0.02). Area under the curve for TMB-prediction of recurrence was 0.752 versus 0.550 for AFP. ROC analysis established a TMB cutoff of 4.8mut/mB for predicting post-operative recurrence ( P =0.002) and RFS ( P =0.025). AFP was not correlated with RFS using the lab-normal cutoff (<11 ng/mL, P =0.682) or the cutoff established by ROC analysis (≥4.6 ng/mL, P =0.494). TMB-high was associated with poorer RFS on cox-regression analysis (hazard ratio=5.386, 95% CI: 1.109-26.160, P =0.037), while microvascular invasion ( P =0.853) and AFP ( P =0.439) were not., Conclusions: Identifiable TMB on postoperative ctDNA predicts HCC recurrence and outperformed AFP in this cohort. Perioperative ctDNA may be a useful surveillance tool following curative-intent hepatectomy. Larger-scale studies are needed to confirm this utility and investigate additional applications in HCC patients, including the potential for prophylactic treatment in patients with residual TMB after resection., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Immunotherapy is emerging as a promising option for certain locally advanced and metastatic cutaneous malignancies. However, the role of neoadjuvant immunotherapy (NIO) in Merkel cell carcinoma (MCC) with clinically detected regional lymph node metastasis (CDRLNM) has not been fully elucidated., Methods: For this study, MCC patients with CDRLNM who underwent surgical excision were selected from the National Cancer Database (NCDB). Those who received NIO were propensity-matched with those who did not, and Kaplan-Meier analysis was used to compare overall survival (OS)., Results: Of the 1809 selected patients, 356 (19.7%) received NIO followed by wide excision (n = 352, 98.9%) or amputation (n = 4, 1.1%). The rate of complete pathologic response for the primary tumor (ypT0) was 45.2%. Only 223 patents (63.4%) also underwent lymph node dissection (LND). The complete pathologic nodal response (ypN0) rate for these patients was 17.9%. A pathologic complete response of both the primary tumor and the nodal basin (ypT0 ypN0) was seen in 16 of the 223 patients who underwent both primary tumor surgery and LND. Subsequently, 151 pairs were matched between the NIO and no-NIO groups (including only patients with LND). Kaplan-Meier analysis demonstrated a significant OS improvement with NIO (median not reached vs. 35.0 ± 8.0 months; p = 0.025). The 5-year OS was 57% in the NIO group versus 44% in no-NIO group (p = 0.021)., Conclusion: The study suggests that NIO in MCC with CDRLNM provides improved OS in addition to promising rates of primary complete response, which could change the profile of surgical resection. This supports ongoing clinical trials exploring the use of NIO in MCC., (© 2024. The Author(s).)

Background: Neoadjuvant systemic therapy (NAST) is a treatment option for intrahepatic cholangiocarcinoma (iCCA), though its impact on short-term oncologic outcomes and long-term survival remains relatively unknown., Methods: The National Cancer Database (NCDB) between 2004 and 2019 was queried for patients with reportedly resectable (Stage I-IIIB) iCCA who received curative-intent resection with lymphadenectomy. Propensity matching was performed between groups based on the use of NAST and groups were compared for overall survival (OS) and oncologic outcomes, including nodal harvest, rate of node positivity, rate of positive margins, and administration of adjuvant therapy., Results: Two thousand and five hundred ninety-six patients met inclusion criteria; 364 (14%) received NAST versus 1763 (68%) up-front resection. After matching, 332 pairs of patients were matched between NAST and no NAST. Patients receiving NAST had a greater nodal harvest (OR = 1.26 [1.09-1.88]; p < 0.001) and a lower rate of node positivity (OR = 0.67 [0.49-0.63]; p < 0.001). Patients without NAST were more likely to complete adjuvant systemic therapy (OR = 0.45 [0.33-0.62]; p < 0.001). However, patients receiving NAST had no OS benefit after resection compared to those who did not receive NAST (median OS 48.3 ± 5.3 vs. 38.8 ± 3.7 months; p = 0.160). Node-positive disease (OR = 2.10 [1.78-2.45]; p < 0.001) conferred the greatest risk for reduced OS followed by positive-margin resection (OR = 1.42 [1.21-1.47]; p < 0.001) and increasing T-stage (OR = 1.34 [1.21-1.47]; p < 0.001)., Conclusion: NAST for iCCA was associated with improved quality of oncologic resection but did not confer an OS benefit versus up-front resection., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The gut microbiome has been implicated in outcomes for HCC, and gut microbe-derived products may serve as potential non-invasive indices for early HCC detection. This study evaluated differences in plasma concentrations of gut microbiota-derived metabolites., Methods: Forty-one patients with HCC and 96 healthy controls were enrolled from surgical clinics at the Cleveland Clinic from 2016 to 2020. Gut microbiota-derived circulating metabolites detectable in plasma were compared between patients with HCC and healthy controls. Hierarchical clustering was performed for generating heatmaps based on circulating metabolite concentrations using ClustVis, with Euclidean and Ward settings and significant differences between metabolite concentrations were tested using a binary logistic regression model., Results: In patients with HCC, 25 (61%) had histologically confirmed cirrhosis. Trimethylamine (TMA)-related metabolites were found at higher concentrations in those with HCC, including choline ( p < 0.001), betaine ( p < 0.001), carnitine ( p = 0.007), TMA ( p < 0.001) and trimethylamine N-oxide (TMAO, p < 0.001). Notably, concentrations of P-cresol glucuronide ( p < 0.001), indole-lactic acid ( p = 0.038), 5-hydroxyindoleacetic acid ( p < 0.0001) and 4-hydroxyphenyllactic acid ( p < 0.001) were also increased in those with HCC compared to healthy controls. Hierarchical clustering of the metabolite panel separated patients based on the presence of HCC ( p < 0.001), but was not able to distinguish between patients with HCC based on the presence of cirrhosis ( p = 0.42)., Conclusions: Gut microbiota-derived metabolites were differentially abundant in patients with HCC versus healthy controls. The observed perturbations of the TMAO pathway in HCC seem particularly promising as a target of future research and may have both diagnostic and therapeutic implications.

Secondary liver malignancies are a serious and challenging global health concern. Secondary metastasis to the liver is most commonly from colorectal cancer that has metastatically spread through splanchnic circulation. Metastatic diseases can portend poor prognosis due to the progressive nature typically found on detection. Improvements in detection of disease, monitoring therapy response, and monitoring for recurrence are crucial to the improvement in the management of secondary liver malignancies. Assessment of ctDNA in these patient populations poses an opportunity to impact the management of secondary liver malignancies. In this review, we aim to discuss ctDNA, the current literature, and future directions of this technology within secondary liver malignancies., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Primary liver malignancies are a serious and challenging global health concern. The most common primary tumors are hepatocellular carcinoma and cholangiocarcinoma. These diseases portend poor prognosis when presenting with progressive, extensive disease. There is a critical need for improved diagnosis, therapeutic intervention, and monitoring surveillance in liver-related malignancies. Liquid biopsy using ctDNA provides an opportunity for growth within these domains for liver-related malignancy. However, ctDNA is relatively understudied in this field compared with other solid tumor types, possibly due to the complex nature of the pathology. In this review, we aim to discuss ctDNA, the current literature, and future directions of this technology within primary liver malignancies., (© 2024 The Author(s). Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Liver transplantation is known to generate significant inflammation in the entire organ based on the metabolic profile and the tissue's ability to recover from the ischemia-reperfusion injury (IRI). This cascade contributes to post-transplant complications, affecting both the synthetic liver function (immediate) and the scar development in the biliary tree. The new occurrence of biliary strictures, and the recurrence of malignant and benign liver diseases, such as cholangiocarcinoma (CCA) and primary sclerosing cholangitis (PSC), are direct consequences linked to this inflammation. The accumulation of toxic metabolites, such as succinate, causes undirected electron flows, triggering the releases of reactive oxygen species (ROS) from a severely dysfunctional mitochondrial complex 1. This initiates the inflammatory IRI cascade, with subsequent ischemic biliary stricturing, and the upregulation of pro-tumorigenic signaling. Such inflammation is both local and systemic, promoting an immunocompromised status that can lead to the recurrence of underlying liver disease, both malignant and benign in nature. The traditional treatment for CCA was resection, when possible, followed by cytotoxic chemotherapy. Liver transplant oncology is increasingly recognized as a potentially curative approach for patients with intrahepatic (iCCA) and perihilar (pCCA) cholangiocarcinoma. The link between IRI and disease recurrence is increasingly recognized in transplant oncology for hepatocellular carcinoma. However, smaller numbers have prevented similar analyses for CCA. The mechanistic link may be even more critical in this disease, as IRI causes the most profound damage to the intrahepatic bile ducts. This article reviews the underlying mechanisms associated with biliary inflammation and biliary pathology after liver transplantation. One main focus is on the link between transplant-related IRI-associated inflammation and the recurrence of cholangiocarcinoma and benign liver diseases of the biliary tree. Risk factors and protective strategies are highlighted., Competing Interests: The authors declare no conflicts of interest.

Purpose of Review: Machine perfusion has been adopted into clinical practice in Europe since the mid-2010s and, more recently, in the United States (US) following approval of normothermic machine perfusion (NMP). We aim to review recent advances, provide discussion of potential future directions, and summarize challenges currently facing the field., Recent Findings: Both NMP and hypothermic-oxygenated perfusion (HOPE) improve overall outcomes after liver transplantation versus traditional static cold storage (SCS) and offer improved logistical flexibility. HOPE offers additional protection to the biliary system stemming from its' protection of mitochondria and lessening of ischemia-reperfusion injury. Normothermic regional perfusion (NRP) is touted to offer similar protective effects on the biliary system, though this has not been studied prospectively.The most critical question remaining is the optimal use cases for each of the three techniques (NMP, HOPE, and NRP), particularly as HOPE and NRP become more available in the US. There are additional questions regarding the most effective criteria for viability assessment and the true economic impact of these techniques. Finally, with each technique purported to allow well tolerated use of riskier grafts, there is an urgent need to define terminology for graft risk, as baseline population differences make comparison of current data challenging., Summary: Machine perfusion is now widely available in all western countries and has become an essential tool in liver transplantation. Identification of the ideal technique for each graft, optimization of viability assessment, cost-effectiveness analyses, and proper definition of graft risk are the next steps to maximizing the utility of these powerful tools., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Assess cost and complication outcomes after liver transplantation (LT) using normothermic machine perfusion (NMP)., Background: End-ischemic NMP is often used to aid logistics, yet its impact on outcomes after LT remains unclear, as does its true impact on costs associated with transplantation., Methods: Deceased donor liver recipients at 2 centers (January 1, 2019, to June 30, 2023) were included. Retransplants, splits, and combined grafts were excluded. End-ischemic NMP (OrganOx-Metra) was implemented in October 2022 for extended-criteria donation after brain death (DBDs), all donations after circulatory deaths (DCDs), and logistics. NMP cases were matched 1:2 with static cold storage controls (SCS) using the Balance-of-Risk [donation after brain death (DBD)-grafts] and UK-DCD Score (DCD-grafts)., Results: Overall, 803 transplantations were included, 174 (21.7%) receiving NMP. Matching was achieved between 118 NMP-DBDs with 236 SCS; and 37 NMP-DCD with 74 corresponding SCS. For both graft types, median inpatient comprehensive complications index values were comparable between groups. DCD-NMP grafts experienced reduced cumulative 90-day comprehensive complications index (27.6 vs 41.9, P =0.028). NMP also reduced the need for early relaparotomy and renal replacement therapy, with subsequently less frequent major complications (Clavien-Dindo ≥IVa). This effect was more pronounced in DCD transplants. NMP had no protective effect on early biliary complications. Organ acquisition/preservation costs were higher with NMP, yet NMP-treated grafts had lower 90-day pretransplant costs in the context of shorter waiting list times. Overall costs were comparable for both cohorts., Conclusions: This is the first risk-adjusted outcome and cost analysis comparing NMP and SCS. In addition to logistical benefits, NMP was associated with a reduction in relaparotomy and bleeding in DBD grafts, and overall complications and post-LT renal replacement for DCDs. While organ acquisition/preservation was more costly with NMP, overall 90-day health care costs-per-transplantation were comparable., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Background & Aims: Liver cancer-related deaths are projected to exceed one million annually by 2030. Existing therapies have significant limitations, including severe side effects and inconsistent efficacy. Innovative therapeutic approaches to address primary liver cancer (PLC) have led to the ongoing development of tumor-derived organoids. These are sophisticated three-dimensional structures capable of mimicking native tissue architecture and function in vitro , improving our ability to model in vivo homeostasis and disease., Methods: This systematic review consolidates known literature on human and mouse liver organoids across all PLC subtypes, emphasizing diagnostic precision, disease modeling, and drug screening capabilities., Results: Across all 39 included studies, organoids were most frequently patient-derived, closely followed by cancer cell line-derived. The literature concentrated on hepatocellular carcinoma and intrahepatic cholangiocarcinoma, while exploration of other subtypes was limited. These studies demonstrate a valuable role for PLC organoid cultures in biomarker discovery, disease modeling, and therapeutic exploration., Conclusions: Encouraging advances such as organoid-on-a-chip and co-culturing systems hold promise for advancing treatment regimens for PLC. Standardizing in vitro protocols is crucial to integrate research breakthroughs into practical treatment strategies for PLC., Impact and Implications: This study provides an overview of the current understanding of tumor-derived organoids in primary liver cancers, emphasizing their potential in diagnostics, disease modeling, and drug screening. The scientific foundation rests on the organoids' ability to replicate the tumor microenvironment and genetic landscape, opening new avenues for personalized therapies. These insights are crucial for both researchers and clinicians, as patient-derived organoids can help identify biomarkers and therapeutic targets. Physicians and policymakers can harness these advances to drive progress in precision medicine, while recognizing the challenges involved in standardizing organoid models for clinical implementation., (© 2024 The Authors.)

Purpose: Postoperative pancreatic fistula (POPF) remains a devastating complication of pancreatoduodenectomy (PD). Minimally invasive PD (MIPD), including laparoscopic (LPD) and robotic (RPD) approaches, have comparable POPF rates to open PD (OPD). However, we hypothesize that the likelihood of having a more severe POPF, as defined as clinically relevant POPF (CR-POPF), would be higher in an MIPD relative to OPD., Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) targeted pancreatectomy dataset (2014-2020) was reviewed for any POPF after OPD. Propensity score matching (PSM) compared MIPD to OPD, and then RPD to LPD., Results: Among 3,083 patients who developed a POPF, 2,843 (92.2%) underwent OPD and 240 (7.8%) MIPD; of these, 25.0% were LPD (n = 60) and 75.0% RPD (n = 180). Grade B POPF was observed in 45.4% (n = 1,400), and grade C in 6.0% (n = 185). After PSM, MIPD patients had higher rates of CR-POPF (47.3% OPD vs. 54.4% MIPD, p = 0.037), as well as higher reoperation (9.1% vs. 15.3%, p = 0.006), delayed gastric emptying (29.2% vs. 35.8%, p = 0.041), and readmission rates (28.2% vs. 35.1%, p = 0.032). However, CR-POPF rates were comparable between LPD and RPD (56.8% vs. 49.3%, p = 0.408)., Conclusion: The impact of POPF is more clinically pronounced after MIPD than OPD with a more complex postoperative course. The difference appears to be attributed to the minimally invasive environment itself as no difference was noted between LPD and RPD. A clear biological explanation of this clinical observation remains missing. Further studies are warranted.