BACKGROUND:Despite the theoretical advantages of neoadjuvant therapy (NAT) in intrahepatic cholangiocarcinoma (iCCA), its impact on post-recurrence overall survival (PROS) remains poorly defined. This study investigated the association between NAT and post-recurrence outcomes. METHODS:This single-center retrospective study included consecutive patients with histologically confirmed iCCA who underwent curative-intent liver resection at Mayo Clinic Rochester (2000-2024). Neoadjuvant therapy was administered to selected patients with high-risk features. The association between NAT and PROS was evaluated using Kaplan-Meier analysis and multivariable Cox regression adjusted for relevant covariates. RESULTS:Among 343 patients with iCCA, NAT recipients were younger, more often treated in the contemporary era, and included a higher proportion of major resections. Targetable molecular alterations (IDH1, FGFR2) were markedly enriched in the NAT group (48.2% vs 13.9%). Neoadjuvant therapy was associated with significantly improved PROS (median, 31.9 vs 16.4 months; p = 0.006) and remained an independent predictor of survival on multivariable Cox regression (hazard ratio, 0.506; p = 0.008), even after the study accounted for era-dependent molecular-profiling. In contrast, older age and early recurrence were independently associated with worse PROS. Recurrence patterns, including location, timing, and median time to recurrence, remained comparable over time. After recurrence, NAT recipients more frequently underwent curative-intent local therapies and advanced systemic treatments. CONCLUSIONS:Neoadjuvant therapy was associated with improved PROS for resected iCCA patients, consistent with a potential role in biologic selection. Recipients of NAT showed enriched targetable molecular alterations and better PROS despite stable recurrence patterns. These findings position PROS as a relevant endpoint in NAT-treated iCCA, complementing conventional survival metrics.

BACKGROUND:Intrahepatic cholangiocarcinoma (iCCA) with major vascular involvement is a technically challenging and biologically aggressive clinical scenario. Although vascular resection (VR) can be performed at experienced centers, the oncologic value of this approach depends on appropriate patient selection. We evaluated whether neoadjuvant therapy (NAT) may improve selection and outcomes among patients undergoing hepatectomy with concomitant VR. METHODS:A single-institution cohort study of 349 patients who underwent resection for histologically confirmed iCCA between 2000 and 2024 was performed. Patients were stratified by VR status and, within the VR cohort, by receipt of NAT. Overall survival (OS) and recurrence-free survival (RFS) were analyzed using Kaplan-Meier methods and Cox regression, including an interaction term between NAT and VR. RESULTS:Twenty-eight patients (8.0%) underwent major VR, including 11 who received NAT. Compared with patients without VR, those undergoing VR had higher-risk disease and higher 90-day mortality, but similar long-term survival. Within the VR cohort, NAT-treated patients had more adverse baseline clinicopathologic features, yet recurrence occurred less frequently than after upfront VR (27% vs. 82%; p = 0.006). In adjusted analyses restricted to the VR cohort, NAT was associated with improved RFS (HR 0.21; p = 0.041). In the full cohort, the NAT×VR interaction was borderline significant (HR 0.27; p = 0.050), suggesting a potential concentration of the NAT-associated RFS benefit among patients requiring VR. CONCLUSIONS:In patients with iCCA requiring major vascular resection, NAT may improve biologic selection and may be associated with more favorable recurrence-free outcomes despite adverse baseline disease features. Given the small NAT + VR subgroup, these results should be interpreted as hypothesis-generating and warrant validation in larger prospective multicenter cohorts.

BACKGROUND AND OBJECTIVES:Occult intra-abdominal metastases are identified in approximately 20% of patients with radiographically localized pancreatic ductal adenocarcinoma (PDAC) through staging laparoscopy, as peritoneal cytology is limited in sensitivity. Methylated DNA markers (MDMs) have demonstrated high diagnostic accuracy for PDAC in tumor tissue, blood, and pancreatic secretions. This study assesses the feasibility and diagnostic performance of MDMs in peritoneal lavage fluid collected during staging laparoscopy, comparing their performance to mutant KRAS (mKRAS) detection. METHODS:DNA from peritoneal lavage fluid of PDAC patients was analyzed for mKRAS mutations (codons 12, 13, and 61) using droplet-digital PCR and for 13 MDMs and a reference gene (B3GALT6) using quantitative methylation-specific PCR. An MDM score was generated from the average signal of the 13 MDMs and evaluated for its ability to detect intra-abdominal metastases via receiver operator characteristic (ROC) analysis. RESULTS:Among 48 patients, 15 (31%) had intra-abdominal metastases. The MDM score showed 87% sensitivity and 90% specificity (AUC = 0.98), outperforming mKRAS, which showed 40% sensitivity and 85% specificity (AUC = 0.62; p < 0.0001). CONCLUSIONS:MDMs in peritoneal lavage fluid may enable highly accurate molecular staging of PDAC and warrant validation in larger studies.

Carcinoid heart disease (CHD) is associated with advanced neuroendocrine tumor liver metastases (NETLM) and may preclude surgical cytoreduction. We assessed perioperative and long-term outcomes of hepatectomy in patients with CHD. We retrospectively analyzed 311 patients undergoing cytoreductive hepatectomy for intestinal NETLM: non-functional (n = 163), carcinoid syndrome (CS) without CHD (n = 110), and CHD (n = 38), including patients undergoing pre-hepatectomy valve replacement. CHD patients more frequently had >10 liver metastases (78%) and larger lesions (median 9.5 cm) and required major hepatectomy more often (58%). Major morbidity was higher in CHD (up to 47%), yet 90-day mortality remained low (≤4%). Median overall survival after hepatectomy was comparable across groups (12.5 vs. 9.1 vs. 11.4 years; p = .19), including matched analyses. With optimal cardiac management, cytoreductive hepatectomy in CHD is feasible and provides long-term survival comparable to patients without CHD.

BACKGROUND:A decade of pancreas procedure-targeted NSQIP data can reveal trends in pancreatoduodenectomy (PD) at participating centers. METHODS:The pancreatectomy PUFs 2014-2023 were queried for PDs performed for pancreatic adenocarcinoma (PDAC). Trends in neoadjuvant therapy (NAT), minimally invasive surgical (MIS) approach, vascular resection, positive margins, length of stay (LOS), unplanned conversion, post-operative pancreatic fistula (POPF), delayed gastric emptying (DGE), and 30-day mortality were evaluated across years with Chi-square and Mann-Kendall trend tests. RESULTS:With 24,067 patients identified, NAT and MIS rates doubled 24.0%-50.0% and 6.3%-14.7% respectively, with the latter driven by robotic approach. Unplanned conversion rates remained stable at 24.0% with higher rates in laparoscopic vs. robotic (36.2% vs. 17.0%, p<0.001). Vascular resections increased 23.1%-26.5%. POPF rates improved 13.6%-10.2% (p=0.049). Thirty-day mortality and DGE remained stable at 1.8% and 15.0% respectively. Median LOS decreased from 9 to 7 days. Positive margin rate (available starting in 2021) increased 16.0%-18.1% (p=0.039). Laparoscopic had the highest positive margin rate, 25.4% vs. open 17.2% and robotic 15.4% (p=0.004). CONCLUSION:Over the last decade, NAT, robotic MIS, and vascular resection increased while 30-day mortality and complication rates remained stable for PDAC PDs. Robotic had lower rates of unplanned conversion and positive margins compared to laparoscopic.

BACKGROUND:Length of hospital admission after major oncologic surgery is often highly variable. Although in carefully selected patients, early discharge can be safe, few automated systems exist to prospectively identify eligible patients. We aimed to develop and validate a predictive model to provide dynamic discharge predictions through each postoperative day. METHODS:Electronic medical record data from the day of operation through to postoperative day 3 from adult patients who underwent elective pancreas resections between 2001 and 2021 were used. The final model used tabular prior data fitted networks. Early discharge was defined as length of stay <6 days with 90-day readmission as a counterbalance measure. Models were assessed via 10-fold cross validation in an 80% training and validation set and applied to a 20% hold-out test set. RESULTS:A total of 3,081 consecutive patients (median age 64; 46.5% female) were included. All metrics improved as information accrued from postoperative day 0 to 3, with the tabular prior data fitted network performing best: area under the receiver operating characteristic curve of 0.90 (95% confidence interval 0.89-0.91), average precision of 0.80 (0.77-0.83), and Brier score of 0.12 (0.11-0.13) during cross-validation. The area under the receiver operating characteristic curve was 0.93 (95% confidence interval 0.91-0.94), average precision was 0.84 (0.80-0.89), and Brier score was 0.10 (0.08-0.11) in hold-out testing. Readmission rates were lower in those predicted suitable for early discharging (23.9% vs 34.2%). CONCLUSION:This dynamic predictive model to predict early discharge after major oncologic surgery based on automatically abstractable electronic medical record data is now suitable for prospective evaluation.

BACKGROUND:The role of adjuvant therapy after biliary tract cancer (BTC) resection remains debated, particularly in real-world practice. This study examined determinants of adjuvant therapy receipt and its association with survival. METHODS:Patients undergoing curative-intent resection for intrahepatic (iCCA), perihilar (pCCA), and distal cholangiocarcinoma (dCCA), and gallbladder cancer (GBC) at Mayo Clinic Rochester (2000-2024) were retrospectively analyzed. OS and RFS were assessed by Kaplan-Meier analysis. Adjusted analyses excluded 90-day mortality and included multivariable Cox, time-dependent Cox, and propensity-score-matched sensitivity analyses. RESULTS:Among 770 patients (iCCA, n = 343; pCCA, n = 205; GBC, n = 135; dCCA, n = 87), 341 (44.3%) received adjuvant therapy. Non-receipt was independently associated with older age, longer hospitalization, and surgery-related major complications. After excluding 90-day mortality, adjuvant therapy was not associated with improved OS in the overall cohort (p = 0.978), while subtype-specific effects were heterogeneous. Among high-risk patients (N + , R1, or TNM III-IV), adjuvant therapy was associated with longer OS (37.3 vs 30.1 months; p = 0.015). After harmonization of adjusted analyses to 90-day survivors, capecitabine remained independently associated with improved OS, whereas the gemcitabine-based estimate was attenuated to a non-significant trend. High-risk features remained strongly prognostic, and time-dependent Cox models yielded concordant estimates. CONCLUSION:Major postoperative morbidity was a key determinant of adjuvant therapy non-receipt. After excluding 90-day mortality and harmonizing adjusted analyses, adjuvant therapy was not associated with improved survival in the overall cohort, including in propensity-score-matched analysis. Survival associations were most consistent in risk-enriched subgroups but remain exploratory and require prospective randomized validation.

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous, with grade 2 (G2) tumors encompassing a broad Ki-67 proliferation range from 3

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy with limited effective therapies. Treatment resistance is partly due to activated cancer-associated fibroblasts (CAFs), which induce pro-tumor signaling and formation of a highly fibrotic tumor microenvironment. CAFs exist on a functional spectrum of subtypes and are difficult to target in vivo. Oncolytic viruses (OVs) can destroy pro-tumor CAFs and reduce fibrosis. We hypothesized that OV infection both lyses CAFs and reprograms surviving CAFs toward a less tumorigenic phenotype. Using in vitro models with CAFs from patient-derived xenograft (PDX) and syngeneic tumors, we evaluated the effects of Vaccinia (VV) and vesicular stomatitis viruses (VSV) and found that OVs killed iCCA cells and CAFs, while also reducing pro-tumor CAF signaling. In vivo, subcutaneous PDX and syngeneic models evaluated OV efficacy, tumor architecture, and CAF function. OVs effectively killed iCCA cells and CAFs, alongside a significant reduction of pro-tumorigenic signaling from syngeneic CAFs. Tumor growth abrogation correlated with decreased inflammatory CAF signaling, namely, hepatocyte growth factor (HGF) production. Notably, HGF enhanced OV tropism, while OV infection reduced HGF expression, suggesting a CAF antiviral defense that also limits pro-tumor signaling. These findings suggest a dual cytotoxic and reprogramming role for OVs in the iCCA microenvironment.

The aspartate aminotransferase-to-platelet ratio index + albumin–bilirubin (APRI+ALBI) score reflects hepatic functional reserve and is widely used for risk stratification of posthepatectomy liver failure (PHLF). However, whether baseline hepatic function also predicts long-term survival in biliary tract cancer (BTC) remains unclear. Patients undergoing curative-intent liver resection for BTC (perihilar cholangiocarcinoma [pCCA], intrahepatic cholangiocarcinoma [iCCA], gallbladder cancer [GBC]) at Mayo Clinic Rochester between 2000 and 2024 were analyzed. Patients were stratified into APRI+ALBI high and low groups using the previously published cutoff (− 2.46). To minimize baseline imbalances, 1:1 direct matching based on tumor type, age, sex, and Eastern Cooperative Oncology Group (ECOG) status was performed. OS and RFS were analyzed using Kaplan–Meier methods with log-rank testing and multivariable Cox proportional hazards regression analysis. Among 683 eligible patients, 616 with available APRI+ALBI scores were included in the analysis. High (poor) APRI+ALBI scores were associated with male sex, pCCA, more frequent major hepatectomy and vascular resection, and higher rates of lymph node positivity and advanced tumor stage. This group also experienced increased rates of major postoperative complications, PHLF grade B/C, and 90-day mortality. Correspondingly, median OS and RFS were significantly worse in the high APRI+ALBI group (OS: 39.8 versus 62.9 months, p = 0.004; RFS: 22.2 versus 27.4 months, p = 0.019). These significant differences persisted after direct matching, and APRI+ALBI remained an independent predictor of both outcomes on multivariable Cox regression. Preoperative APRI+ALBI score independently predicts survival after curative-intent resection for BTC, supporting a clinically relevant link between baseline hepatic functional reserve and oncologic outcomes beyond perioperative risk.

Background Regional lymph node involvement impacts prognosis for patients with pancreatic neuroendocrine tumors and may influence management decisions for small tumors. Conventional cross-sectional imaging modalities have low sensitivity in detecting regional lymph node metastases, but the diagnostic performance of somatostatin receptor positron emission tomography for this is unknown. Methods Patients with pancreatic neuroendocrine tumors who underwent preoperative gallium 68 DOTATATE positron emission tomography followed by resection with lymphadenectomy from 2017 to 2022 were reviewed. Preoperative gallium 68 DOTATATE positron emission tomography was retrospectively reviewed by radiologists. The presence of suspicious regional lymph nodes was correlated with pathologic reports to determine diagnostic accuracy. Results Among 130 patients who met inclusion criteria, DOTATATE positron emission tomography detected suspicious lymph nodes in 24%, whereas pathologic evaluation demonstrated lymph node involvement in 42%. Overall, sensitivity was 46% and specificity was 92%, with a positive predictive value of 81% and negative predictive value of 29%. Among patients with lymph node involvement confirmed on pathologic review, 92% of patients with true-positive results had a Krenning score of 4 compared with 59% of patients with false-negative results (P = .013), and 58% of patients with true-positive results had lymph nodes >1 cm on preoperative cross-sectional imaging compared with 8.7% of patients with false-negative results (P < .001). Conclusion Gallium 68 DOTATATE positron emission tomography has limited sensitivity but high specificity for preoperative diagnosis of regional pancreatic neuroendocrine tumor lymph node metastases. Detection rate improves with higher Krenning score and larger lymph node size. This study has important implications for preoperative planning, particularly for patients with small tumors who may be candidates for either observation or resection.

BACKGROUND:Upfront resectable pancreatic ductal adenocarcinoma (PDAC) is defined by the NCCN as disease with ≤180° portomesenteric vein (PMV) abutment. However, the clinical significance of PMV abutment in this cohort remains unexplored, and we sought to investigate its impact. METHODS:This multi-institutional study included patients who underwent pancreatoduodenectomy (PD) for upfront resectable PDAC from 2002 to 2023. Patients with PDAC with ≤180° PMV abutment were compared with those without. Overall survival (OS) was compared and stratified based on whether patients underwent upfront surgery or neoadjuvant therapy (NAT). RESULTS:Among 1,446 patients included, 521 (36.0%) had PMV abutment. Median OS for patients with PMV abutment was 28.8 months compared with 31.2 months for those without (P=.17). In a stratified analysis of patients who underwent upfront surgery, patients with PMV abutment had worse OS (19.2 vs 27.6 months; P<.05) and lower R0 resection rates (63.1% vs 87.2%; P<.05) compared with those without. However, in patients who underwent NAT, this difference in R0 resection rate was not observed (91.4% vs 94.0%, respectively; P=.27). Furthermore, there was no significant difference in median OS with NAT (42.5 vs 51.6 months, respectively; P=.48). CONCLUSIONS:In this largest cohort to date of patients with upfront resectable PDAC, PMV abutment was associated with worse OS compared with no PMV abutment when an upfront resection strategy was used. The use of NAT in patients with PMV abutment mitigated this survival difference with increased R0 resection rates. These findings suggest that patients with upfront resectable PDAC with PMV abutment benefit from a NAT approach for optimal survival outcomes, and that the current criteria guidelines need to be redefined.

Hepatic resection (HR) and liver transplantation (LT) are curative-intent treatments for hepatocellular carcinoma (HCC). Patients without cirrhosis are typically analyzed as a single group, obscuring potentially important differences between those with histologically normal liver and those with non-cirrhotic parenchymal disease. We aimed to characterize long-term outcomes following HR stratified by underlying parenchymal quality, with a contemporary LT cohort as an external benchmark. Retrospective cohort study of 662 adults undergoing curative-intent surgery for HCC at 2 tertiary centers (2010-2024). Resection patients (n=380) were stratified by non-tumor parenchymal histology into HR-Normal (n=84), HR-Diseased non-cirrhotic (n=159), and HR-Cirrhotic (n=137). A total of 282 LT recipients served as an external reference but were not entered into comparative models. Overall survival (OS) was analyzed by Kaplan-Meier and multivariable Cox regression, and recurrence by Fine-Gray competing-risks regression. Ninety-day mortality was low across resection strata (1.2%-3.2%). OS differed significantly across parenchymal groups (log-rank p =0.01), driven by superior outcomes in HR-Normal patients compared with both HR-Cirrhotic ( p =0.008) and HR-Diseased ( p =0.005). HR-Cirrhotic and HR-Diseased did not differ ( p =0.97). Five-year OS was 74.4%, 59.8% and 57.2%, respectively. On multivariable Cox regression, both cirrhosis (HR 2.03, 95% CI 1.16-3.54, p =0.01) and diseased non-cirrhotic parenchyma (HR 2.04, 95% CI 1.21-3.43, p =0.008) independently predicted death versus normal liver. Fine-Gray analysis confirmed higher recurrence risk in cirrhotic (sHR 2.09, p =0.01) and diseased non-cirrhotic (sHR 1.80, p =0.04) groups. The LT benchmark cohort achieved a 5-year OS of 82.4%. Histologically normal liver identifies a distinct HR subgroup with favorable oncologic outcomes. The conventional cirrhotic/non-cirrhotic dichotomy underestimates the prognostic impact of underlying parenchymal disease.

High-risk features (e.g., vascular invasion, lymph node involvement, multifocality, elevated carbohydrate antigen 19-9 [CA19-9], tumor size >5 cm) in intrahepatic cholangiocarcinoma (iCCA) are associated with poor prognosis, leading to increased use of neoadjuvant therapy (NAT). Patients (n = 425) treated in 2000–2024 at Mayo Clinic Rochester were categorized into four groups: (1) high-risk iCCA with NAT (chemotherapy- or chemoimmunotherapy-based regimens) followed by surgery, (2) high-risk iCCA with upfront resection, (3) low-risk iCCA with upfront resection, and (4) high-risk iCCA receiving NAT without surgery (“dropouts”). Outcomes included overall (OS) and recurrence-free survival (RFS). An external cohort of 203 iCCA patients from MD Anderson Cancer Center also was analyzed using identical criteria. Of 425 patients, 342 (80.5

ABSTRACT:Pharmacological plasminogen reduction enhanced liver regeneration experimentally and clinically. Small interfering RNA-induced plasminogen deficiency promoted hepatocyte proliferation after partial hepatectomy in mice, contrasting genetic deficiency models. In the HeLiX trial, tranexamic acid reduced posthepatectomy liver failure odds, suggesting a novel therapeutic strategy.

PET imaging at different time points

Background Cytoreductive hepatectomy for liver metastases from G3 neuroendocrine tumors (NETLM) and neuroendocrine carcinomas (NECLM) remains an issue of controversy, with guidelines recommending surgery for limited metastatic burden from NET G3 and systemic therapy for NEC. We assessed surgical and oncologic outcomes after hepatectomy, and factors associated with overall survival (OS). Methods Patients undergoing liver resections for G3 NETLM (n=27) and NECLM (n=15) between January 2000 to December 2020 were compared, stratified for median OS and opposed to G1 (n=75) and G2 NETLM (n=120). Results Median OS after hepatectomy was 12.5 in NETLM G1 patients, 11.2 in G2, 6.3 in G3 and 2.4 years in NECLM (p<0.001), with progression-free survival of 2.1, 1.3, 0.8 and 0.7 years, respectively (p<0.001). Bilobar lesions (92% vs. 29%; p<0.001) and numbers (p<0.001) were higher in NETLM G3 than in NECLM. Major resections (22% vs. 20%; p=1.000), severe complications (33% vs. 20%; p=0.485), and 90-day mortality (7% vs. 7%; p=1.000) were similarly frequent. NETLM G3 long- survivors did not reach median OS after 7 years and 4 years in NECLM. Lesion diameter and count >10 were associated with survival in NETLM G3, while no patient or tumor characteristics were linked to OS in NECLM. Conclusion Although G3 NETLM and NECLM display significantly worse prognosis after cytoreductive hepatectomy compared to G1 and G2 NETLM, some patients might benefit from surgery. While tumor size and lesion count were linked to OS, identification of factors besides standard clinical characteristics are needed to stratify patients as surgical candidates.