Abstract Background and aims: Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and can exhibit cancer-promoting functions; however, recent studies indicate that CAFs can also inhibit cancer growth and progression. In this study, we identified CAFs that act in an inhibitory manner in biliary tract cancer and elucidated their mechanisms. Materials and Methods: We retrospectively evaluated alpha-smooth muscle actin (αSMA) expression in CAFs from 114 cases of pancreatic ductal carcinoma (PDAC) and 154 cases of biliary tract cancers (BTCs) who underwent surgical treatment at our institution from 1996 to 2017. The BTC cell lines, PDAC cell lines, and CAFs were isolated from resected specimens of BTC and PDAC were used to evaluate the proliferative potential of cancer cells. Conditioned media (CM) were prepared from CAFs (CM-CAF). Protein array analysis of CM-CAFs was conducted to identify candidate factors responsible for growth suppression. Results: PDAC patients with positive αSMA expression showed significantly shorter overall survival and recurrence-free survival than αSMA-negative patients (p = 0.003, p = 0.009, respectively). On the other hands, BTC patients with positive αSMA expression showed better recurrence-free survival than αSMA-negative patients (p = 0.03). CM-CAF suppressed the proliferation of cancer cells only in BTC cancer cell lines, not in PDAC cell lines. Protein arrays of CM-CAFs revealed that IL-6 and IL-8 were key suppressive factors on BTC cancer cell proliferation. The inhibitory effects on BTC cell proliferation were abolished upon neutralization of IL-6 and IL-8. Conclusions: CAFs serve as a favorable prognostic factor in BTC but not in PDAC. We demonstrated the presence of tumor-suppressive CAFs in BTC, which exert their anti-proliferative effects through the secretion of IL-6 and IL-8. These findings suggest a novel, context-dependent role for CAFs in the tumor microenvironment of biliary tract cancers. Citation Format: Ryota Tanaka, Kenjiro Kimura, Naoki Tani, Shimpei Eguchi, Daisuke Inoue, Takuto Yasuda, Changgi Ahn, Koichi Nakanishi, Kosuke Hatta, Shigeaki Kurihara, Jun Tauchi, Sadaaki Nishimura, Masahiko Kinoshita, Kohei Nishio, Hiroji Shinkawa, Takeaki Ishizawa. Different roles of cancer-associated fibroblasts in pancreatic cancer and biliary tract cancers cancer-associated fibroblasts as a tumor suppressor in biliary tract cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6033.

BACKGROUND:This study was conducted to determine the clinical significance of pancreatic stump ischemia (PSI) in predicting late-onset pancreatic fistula (LOPF) following stapled distal pancreatectomy (DP). METHODS:A total of 165 patients who underwent stapled DP between July 2018 and March 2024 were included. PSI was defined as a non-enhancing area between the pancreatic stump and stapler line on postoperative contrast-enhanced computed tomography (CT). LOPF was diagnosed when peripancreatic fluid collection necessitated antibiotics and/or image-guided drainage after drain removal. RESULTS:LOPF developed in 19 patients (11.5%). PSI was detected in 40 patients (24.2%) and was significantly more frequent in those with LOPF (47.4% vs. 21.2%). Receiver operating characteristic curve analysis identified a PSI width of ≥ 1.9 mm as the optimal threshold LOPF prediction. The incidence of LOPF was 26.5% among 81 patients with positive PSI (≥ 1.9 mm) on contrast-enhanced CT within 90 days postoperatively. By contrast, LOPF did not develop beyond 90 days following surgery, even when PSI was present. CONCLUSION:PSI may be interpreted as a radiologic factor associated with LOPF after stapled DP. Conservative drain management and close postoperative follow-up are recommended when an ischemic band ≥ 2 mm along a stapler line is detected on early postoperative CT.

BACKGROUND:Vascular invasion is a major prognostic determinant in hepatocellular carcinoma, yet the impact of its type and extent on recurrence patterns remains unclear. We aimed to clarify the differential effects of portal, hepatic, and bile duct invasion on recurrence and survival after curative resection. METHODS:We retrospectively analyzed 1,320 patients who underwent curative hepatocellular carcinoma resection (1990-2022). Vascular invasion was classified by type and grade according to the Japanese classification system. Multivariate Cox regression analyses were performed to evaluate overall survival, recurrence-free survival, and 2-year intrahepatic and extrahepatic recurrence-free survival. RESULTS:Portal vein invasion was stratified according to its extent. Portal vein invasion 1 was associated with early intrahepatic recurrence (P < .001) but not with early extrahepatic recurrence or overall survival. Portal vein invasion 2 and portal vein invasion 3-4 were associated with early intrahepatic recurrence (portal vein invasion 2: P = .004, portal vein invasion 3-4: P < .001) and worse overall survival (portal vein invasion 2: P < .001, portal vein invasion 3-4: P = .024). Hepatic vein invasion demonstrated a distinct pattern: hepatic vein invasion 1 showed a trend toward early extrahepatic recurrence and was associated with early recurrence but not with overall survival. In contrast, hepatic vein invasion 2-3 was significantly associated with early extrahepatic recurrence (P = .005) and worse overall survival (P = .034). Bile duct invasion was not significantly associated with a poor recurrence-free survival or overall survival. CONCLUSION:Portal vein invasion 2-4 and hepatic vein invasion 2-3 were associated with distinct early recurrence patterns and worse overall survival. These findings underscore the importance of detailed vascular invasion grading for refined risk stratification and may inform tailored postoperative surveillance and adjuvant strategies.

This study assessed whether empagliflozin (EMPA) combined with endurance exercise further improves the soleus muscle in spontaneously diabetic Torii fatty rats, a model of obese type 2 diabetes. Male rats were divided into untreated control, exercise, EMPA, or EMPA + exercise groups. Age-matched Sprague-Dawley rats served as nondiabetic controls. Treadmill training and EMPA (0.03% in chow) were provided from 8 to 16 weeks of age. Both EMPA and the combined intervention improved blood glucose and insulin resistance. Additionally, the combined treatment reduced total cholesterol and triglycerides compared with EMPA alone. The cross-sectional area of type I fibers in the soleus tended to improve with all interventions. Combination treatment significantly enhanced citrate synthase activity, mitochondrial functional protein expression, and autophagic flux. These findings suggest that although EMPA does not adversely affect the soleus muscle, combining it with endurance exercise confers superior benefits via improved mitochondrial status, autophagy, and lipid metabolism.

e16464 Background: In pancreatic ductal adenocarcinoma (PDAC), surgical manipulation may facilitate the intraoperative release of circulating tumor cells (CTCs) into the portal venous circulation. The mesenteric approach has been advocated as a strategy to reduce tumor handling and potential tumor cell dissemination; however, its effect on perioperative CTC-related biomarkers has not been fully elucidated. We evaluated perioperative changes in portal venous circulating tumor cell–derived DNA (CTC DNA) to assess the biological impact of surgical approach. Methods: Portal venous blood samples were collected intraoperatively at two time points—immediately after laparotomy and just before specimen removal—in patients undergoing pancreatectomy for PDAC. A total of 107 patients were included: 52 patients underwent the conventional approach and 55 patients underwent the mesenteric-first approach. CTC DNA copy numbers were quantified, and perioperative changes were compared between surgical approaches. Overall survival (OS) was analyzed according to surgical approach and perioperative CTC DNA dynamics. Results: Baseline clinicopathological characteristics and pathological diagnoses were well balanced between the two groups. The mean CTC DNA copy number immediately after laparotomy was 16.0 ± 16.2 copies in the conventional group and 23.7 ± 28.9 copies in the mesenteric-first group. Just before specimen removal, the mean CTC DNA copy number increased to 26.1 ± 29.3 copies in the conventional group, whereas it decreased to 16.3 ± 17.8 copies in the mesenteric-first group. The mean perioperative change in CTC DNA copy number was significantly different between groups, with an increase of +10.1 ± 2.6 copies in the conventional group and a decrease of –7.3 ± 2.6 copies in the mesenteric-first group (p < 0.0001). Despite these marked biological differences, no significant difference in OS was observed between the conventional and mesenteric-first approaches (HR 0.67, 95% CI 0.39–1.13; p = 0.127). Similarly, OS did not differ significantly between patients with increased versus decreased intraoperative CTC DNA copy numbers (HR 0.77, 95% CI 0.45–1.31; p = 0.331). Conclusions: The mesenteric approach was associated with a significant intraoperative reduction in portal venous CTC DNA copy number, suggesting suppression of CTC release during tumor manipulation. Although these perioperative CTC-related changes did not translate into a survival benefit, CTC DNA dynamics may serve as a sensitive biomarker reflecting the biological impact of surgical handling in pancreatic cancer resection. Clinical trial information: NCT03317886 .

BACKGROUND/AIM:We evaluated the impact of log-transformed serum α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels on early hepatocellular carcinoma (HCC) recurrence after hepatectomy and developed a nomogram for risk stratification. PATIENTS AND METHODS:We examined 993 patients who underwent initial curative hepatectomy. A nomogram was constructed to predict early recurrence within 2 years using a Cox proportional hazards model (five-factor log-marker model) based on five preoperatively assessable oncological factors: log AFP, log DCP, multiple tumors, tumor size >3 cm, and macroscopic vascular invasion (MVI). Its time-dependent area under the curve (AUC) at 2 years was compared with a five-factor raw-marker model (replacing log-transformed AFP/DCP with their raw values) and a three-factor model (multiple tumors, tumor size, MVI). Performance was evaluated by time-dependent AUC, bootstrap calibration (1,000 resamples), and observed outcomes across tertiles (T1-T3) of total nomogram points. RESULTS:The five-factor log-marker model (AUC 0.69) outperformed the five-factor raw-marker model (0.67, p=0.013) and the three-factor model (0.65, p<0.001). The nomogram showed good calibration (slope=0.98). Two-year recurrence rates by tertile were 25% (T1), 38% (T2), and 58% (T3); 2-year extrahepatic recurrence rates were 1.5%, 4.2%, and 11%, respectively. The trend across tertiles was significant (p<0.001). CONCLUSION:The nomogram developed using preoperative oncological factors enabled precise prediction of early recurrence after hepatectomy for HCC by incorporating log-transformed AFP and DCP. Our nomogram may be useful in determining treatment strategies for patients with HCC.

BACKGROUND/OBJECTIVES:Indocyanine green (ICG) fluorescence imaging is widely utilized for visualizing hepatic tumors, hepatic segmentation, and biliary anatomy, improving the safety and curability of cancer surgery. However, its application for perfusion assessment in hepatobiliary and pancreatic (HBP) surgery has been less explored. METHODS:This study evaluated outcomes of patients undergoing HBP surgery with vascular reconstruction from April 2022 to August 2024. During surgery, ICG (1.25-5 mg/body) was administered intravenously to assess the need and quality of vascular reconstruction via fluorescence imaging. RESULTS:Among 30 patients undergoing hepatectomies and/or pancreatectomies, ICG fluorescence imaging was used in 16 cases (53%) to evaluate organ and vascular perfusion. In two hepatectomy cases with consideration of reconstruction of the middle hepatic veins, sufficient fluorescence intensities in drainage areas led to the avoidance of middle hepatic vein reconstruction. In 14 cases requiring vascular reconstruction, fluorescence imaging visualized smooth blood flow through anastomotic sites in 11 cases, while insufficient signals were observed in 3 cases. Despite this, re-do anastomoses were not indicated because the fluorescence signals in the targeted organs were adequate. Postoperative contrast-enhanced computed tomography confirmed satisfactory blood perfusion in all cases. CONCLUSIONS:Real-time blood flow assessment using ICG fluorescence imaging provides valuable information for intraoperative decision-making in HBP surgeries that require vascular reconstruction of major vessels, such as hepatic arteries, veins, and the portal system.

BACKGROUND/AIM:Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and can either promote or suppress tumor growth. This study aimed to identify CAFs that inhibit proliferation in biliary tract cancer (BTC) cell lines and explore the underlying mechanisms. MATERIALS AND METHODS:Three BTC cell lines and one pancreatic cancer cell line were treated with conditioned media (CM) from CAFs isolated from BTC specimens. Cell proliferation was assessed, and cytokine profiles in CM were analyzed using protein arrays. Expression of interleukin-6 (IL-6) pathway proteins was examined via western blot and immunohistochemistry (IHC) in BTC tissues. Survival outcomes were analyzed using Kaplan-Meier curves. RESULTS:Some BTC-derived CAFs suppressed cancer cell growth. IL-6 was identified in the CM as a key inhibitory cytokine. IL-6 treatment significantly reduced BTC cell proliferation, accompanied by increased suppressor of cytokine signaling 3 (SOCS3) and decreased activator of transcription 3 (STAT3) expression. In BTC patient tissues, stromal IL-6 expression correlated with improved relapse-free survival (RFS; 60.8 vs. 18.5 months, p=0.008) and overall survival (OS; 61.6 vs. 33.9 months, p=0.05). Patients with positive expression of IL-6 receptor subunits CD130 and CD126, as well as SOCS3, had significantly longer RFS and/or OS compared to negative cases. For CD130, median RFS and OS were 60.8 vs. 17.4 months (p=0.02) and 60.7 vs. 34.6 months (p=0.05), respectively. For SOCS3, RFS and OS were 60.8 vs. 21.1 months (p=0.05) and 51.6 vs. 34.8 months (p=0.04). CD126 positivity was associated with longer RFS (60.8 vs. 21.1 months, p=0.04), but OS did not differ significantly. CONCLUSION:A subset of CAFs in BTC has tumor-suppressive activity mediated by IL-6, which inhibits cancer cell proliferation via the SOCS3/STAT3 pathway and correlates with better clinical outcomes.

L-type fatty acid-binding protein (L-FABP) in proximal tubules is reported to reduce oxidative stress. This study investigated whether renal L-FABP mitigated rhabdomyolysis (RM)-induced acute kidney injury (AKI). Wild-type (WT) mice, which lack renal L-FABP expression, and human L-FABP (hL-FABP) chromosomal transgenic (Tg) mice, which express hL-FABP in proximal tubules, were divided into RM (WT-RM, Tg-RM) and control (WT-Cont, Tg-Cont) groups. RM was induced via intramuscular injection of 50% glycerol/PBS into the quadriceps, whereas controls received PBS alone. On day 1, the WT-RM and Tg-RM groups exhibited similar increases in serum myoglobin, renal dysfunction, heme oxygenase-1 expression, and tubulointerstitial damage. By day 3, the Tg-RM group demonstrated significant improvements in renal function, attenuation of tubulointerstitial damage, and decrease in macrophage infiltration compared with the WT-RM group. Lipid peroxidation marker 4-hydroxynonenal increased similarly in both RM groups on day 1, but its further elevation on day 3 was significantly suppressed in Tg-RM mice. Solute carrier family 7 member 11 on day 1 and glutathione peroxidase 4 on day 3 were significantly higher in Tg-RM mice than in WT-RM mice, which led to the suppression of ferroptosis. In conclusion, renal hL-FABP may prevent progression of RM-induced AKI through ferroptosis inhibition by antioxidative effects.

Indocyanine green (ICG)-C9, a novel cyanine dye developed by the Center for Biosystems Dynamics Research at RIKEN, provides significant advantages over conventional ICG due to its detectability via shortwave-infrared (SWIR) fluorescence imaging. Unlike standard ICG, ICG-C9 facilitates SWIR imaging and displays therapeutic potential when conjugated with antibodies in vivo, suggesting broader applicability across various cancer types. This study evaluated the efficacy of SWIR fluorescence imaging with ICG-C9 in comparison with existing near-infrared (NIR) imaging techniques. We assessed excretion kinetics and the relationship between excitation and fluorescence wavelengths for ICG-C9 and ICG following intravenous administration in BALB/c-nu mice. Tumor uptake was evaluated using a cell-line-derived subcutaneous tumor model from HuH-7 cells, representing hepatocellular carcinoma. Variables including dose, administration route, and exposure time were optimized for comparison. Maximum fluorescence intensity for ICG-C9 was observed with an excitation wavelength of 915 nm and fluorescence emission wavelengths >950 nm within the SWIR spectrum. Both ICG-C9 and ICG followed similar excretion pathways, involving hepatic uptake and biliary excretion. Tumor uptake of ICG-C9 was confirmed under similar conditions to ICG. ICG-C9 demonstrates promising potential as an alternative to NIR fluorescence imaging with ICG, offering unique properties that may enhance imaging capabilities. However, further research is required to establish its clinical applicability and broader therapeutic utility.

BACKGROUND:Maintaining an independent life after hepatopancreaticobiliary surgery is a major goal of elderly people. This prospective study aimed to identify the risk factors for postoperative loss of independence after hepatopancreaticobiliary surgery in elderly individuals. METHODS:Between February 2023 and December 2023, independently living elderly individuals aged ≥65 years who were scheduled for hepatopancreaticobiliary surgery and approved for preoperative evaluation of frailty at 5 institutions were registered. Frailty was evaluated the "Kihon Checklist," which is a phenotypic frailty index. Postoperative loss of independence was defined as hospitalization, need for nursing care, and/or transfer to a rehabilitation facility at 90 days and/or mortality within 90 days. RESULTS:Of the 201 registered patients, 58 (28.9%) were classified as frail, and 21 (10.4%) developed postoperative loss of independence. Univariate and multivariate analyses indicated that frailty (P =.03), cerebrovascular and/or neurological diseases (P =.04), and open surgery (P =.02) were independent risk factors for postoperative loss of independence after hepatopancreaticobiliary surgery. Among the patients with postoperative loss of independence, 2.8% had no applicable risk factors, and 31.4% had ≥2 of these factors (P <.001). The incidence of postoperative loss of independence was 9.4% in the frail patients who underwent minimally invasive surgery (MIS) and 30.8% in those who underwent open surgery (P = .050). CONCLUSION:Postoperative loss of independence was predictable among elderly patients identified as frail using the Kihon Checklist after hepatopancreaticobiliary surgery. MIS for elderly individuals with frailty may reduce the risk of postoperative loss of independence.

OBJECTIVE:This multicenter randomized controlled trial investigated whether the mesenteric approach, which is an infracolic superior mesenteric artery (SMA)-first approach during pancreatoduodenectomy (PD), can improve survival in patients with pancreatic ductal adenocarcinoma (PDAC), compared with the Kocher-first conventional approach. BACKGROUND:The mesenteric approach might improve surgical outcomes through a nontouch isolation technique for PDAC. METHODS:This trial was conducted in 24 Japanese high-volume centers. Patients who were scheduled to undergo PD for resectable PDAC or borderline resectable PDAC with portal vein invasion (BR-PV PDAC) were randomly assigned (1:1) via a central web-based application to the conventional or mesenteric approach. The primary endpoint was overall survival (OS). We also analyzed circulating tumor cell (CTC) DNA in the PV blood obtained during surgery. This trial is registered with ClinicalTrials.gov. NCT03317886, and UMIN Clinical Trials UMIN000029615. RESULTS:Between 2018 and 2021, 360 patients were randomly assigned to conventional (n=181) and mesenteric groups (n=179). With a median follow-up of 39.3 months, the median OS was comparable between conventional and mesenteric groups (41.7 vs. 39.3 months; HR 1.02, 95% CI: 0.76-1.37, P =0.897). CTC analysis showed that the mean change in CTC DNA copy number in PV obtained at laparotomy and just before removal of the specimen was significantly different between the conventional (10.1±2.7) and mesenteric (-7.3±2.6) groups ( P <0.001). CONCLUSIONS:The mesenteric approach does not improve survival in patients with resectable or BR-PV PDAC, although it might prevent spread of cancer cells via vessels during surgery through the nontouch isolation procedure.

The activation of hepatic stellate cells (HSCs) from a quiescent state is a cause of liver fibrosis and a therapeutic target. HSCs are resident mesenchymal cells located in the space of Disse, exhibiting specialized morphological characteristics such as a stellate shape, large lipid droplets, and direct adhesions to hepatocytes via microprojections called HSC spines. Morphological alterations in HSCs play a crucial role in initiating their activation. However, the mechanisms regulating these changes remain unexplored. In this study, we analyzed the morphological alterations associated with HSC activation in vivo using carbon tetrachloride treatment and identified the key factors regulating these changes in vitro. Following carbon tetrachloride treatment, HSCs exhibited shortened cell processes and HSC spines, adopting an oval shape. Subsequently, the HSCs underwent further morphological changes into two activated forms: flattened and complex shapes. In vitro, activation of cell division cycle 42 (Cdc42) maintained the morphological characteristics of quiescent HSCs. Cdc42 activation in HSC cell lines inhibited the expression of markers associated with activated HSCs. Cdc42 inhibitor treatment in vivo prevented quiescent HSCs from maintaining their morphological characteristics and hindered activated HSCs from reverting to the quiescent state. In addition, HSCs around fibrotic areas in the human liver exhibited morphological alterations indicative of early activation. These findings demonstrate that Cdc42 is a crucial regulator of morphological and molecular alterations associated with HSC activation, identifying it as a novel target for the development of therapeutic agents against liver fibrosis.NEW & NOTEWORTHY The activation of hepatic stellate cells from a quiescent state is a cause and a therapeutic target for liver fibrosis. Morphological alterations in the hepatic stellate cells play a critical role in initiating their activation. However, the mechanisms that regulate these alterations remain unexplored. Our results indicate that cell division cycle 42 is a crucial regulator of hepatic stellate cell activation and a novel target for the development of therapeutic agents against liver fibrosis.

Background/Objectives: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. Although these subclassifications may help determine the appropriate treatment strategy, subclassification diagnosis currently depends on postoperative pathological examinations. This study aimed to establish a nomogram to predict ICC subclassifications. Methods: This study included 126 patients with ICC who underwent liver resection. The participants were divided into small and large duct-type ICC groups. A nomogram to predict large duct-type ICC was developed using four diagnostic imaging findings: rim-type enhancement in the early phase, an absence of tumor enhancement in the early phase, the presence of peripheral biliary dilatation due to tumor invasion, the presence of penetrating Glisson’s vessels in the tumor, and two laboratory test results: serum gamma-glutamyl transpeptidase and carbohydrate antigen 19-9 levels. Nomogram performance was also assessed. Moreover, the bootstrap method and calibration plots were used to assess nomogram validity. Results: Seventy and fifty-six patients were pathologically diagnosed with small and large duct-type ICCs, respectively. The area under the curve of the established nomogram was 0.93 and remained 0.91 after Harrell’s bias correction. The sensitivity and specificity of the nomogram developed using the Youden index were higher than those of any of the characteristic imaging findings. Calibration plots demonstrated a strong association between the nomogram and the actual data. Conclusions: We developed a novel preoperative nomogram to predict large duct-type ICC. This nomogram can be clinically useful for predicting the subclassifications of ICCs and may contribute to the establishment of a more appropriate treatment strategy for ICC.

A 60-year-old male presented with jaundice. He had a history of extended left hepatectomy, cholecystectomy, hepaticojejunostomy for moderately to poorly differentiated hepatocellular carcinoma, and transverse colectomy for transverse colon cancer. Computed tomography showed hepatocellular carcinoma recurrence in the liver, extending from the hepaticojejunostomy site to the elevated jejunum, resulting in obstructive jaundice. Internal biliary drainage using a percutaneous transhepatic approach was planned. However, the guidewire could not pass through the obstruction caused by the tumor at the hepaticojejunostomy site. After performing hepatic arterial infusion chemotherapy, to reduce the tumor volume, transcatheter arterial chemoembolization was performed for hepatocellular carcinoma recurrence. After transcatheter arterial chemoembolization, the catheter was successfully advanced beyond the tumor at the elevated jejunum owing to tumor shrinkage, thus completing internal biliary drainage.

In March 2021, the Japanese TNM Classification for Cancer of the Biliary Tract (JCCB) was revised. This study aimed to validate the 7th edition of JCCB based on long-term outcomes after resection for distal cholangiocarcinoma (DCC). We retrospectively reviewed 107 patients with resected DCC without distant metastasis between 2007 and 2019. Survival curves according to TNM factors were compared between the 6th and 7th editions. The 5-year overall survival (OS) and recurrence-free survival rate (RFS) were 43.4% and 35.5%, respectively. Significant differences in OS were observed between T categories in the 7th edition (T1 vs. T2, p = 0.049; T2 vs. T3, p = 0.027), but not in the 6th. The N classification also showed better prognostic discrimination in both editions, with more refined stratification in the 7th. Stage grouping in the 6th edition failed to show significant OS differences, while the 7th edition demonstrated clear stratification (e.g., Stage I vs. IIA, p = 0.0274; StageⅡA vs. StageⅡB, p = 0.0043; StageⅡB vs. StageⅢA, p = 0.0108). These findings indicate that the revised T and N classifications in the 7th edition more accurately reflect postoperative prognosis for resected DCC. Overall, our results support the clinical validity and improved prognostic utility of the 7th edition compared with the 6th edition.

Background/Objectives: Intrahepatic cholangiocarcinoma (iCCA) is subclassified into small- and large-duct types. Small-duct-type iCCAs are associated with a better prognosis, and each subclassification requires different surgical strategies. The efficacy of chemotherapy, including immune checkpoint inhibitors, may vary between subclassifications. However, there are no reports on tumor immune microenvironment (TIME) analyses based on iCCA subclassifications. This study investigated subclassification-specific TIMEs in iCCAs for the purpose of establishing appropriate pharmacotherapy. Methods: A total of 131 resected iCCA cases were analyzed, comprising 73 tumors classified as small-duct-type and 58 as large-duct-type based on pathological evaluation. Immunohistochemical analyses targeting CD8, PD-1, PD-L1, CTLA-4, and S100 protein (a dendritic cell [DC] marker) were performed to investigate the immune-cell status in each subclassification. Results: Large-duct-type iCCA had a significantly higher CD8 expression in tumor-infiltrating cells than small-duct-type ICC. However, the expression of other molecules did not significantly differ between the two tumor types. The proportion of tumors with a high level of S100 protein expression (DC-high group) in tumor-infiltrating cells was significantly higher in small-duct-type ICCs than in large-duct-type iCCAs (30% vs. 1.7%). In small-duct-type iCCAs, the expression levels of CD8, PD-1, PD-L1, and CTLA-4 were significantly higher in the DC-high group than in the DC-low group. Conclusions: We revealed subclassification-specific TIMEs in iCCAs. A subset of small-duct-type iCCAs exhibited strong DC infiltration. In these patients, the tumors may establish an immunosuppressive TIME to evade antitumor immunity triggered by DC-mediated antigen presentation. These findings may contribute to the development of tailored pharmacotherapy for each iCCA subclassification.

This multicenter randomized controlled trial investigated whether the mesenteric approach, which is an infracolic superior mesenteric artery (SMA)-first approach during pancreatoduodenectomy (PD), can improve survival in patients with pancreatic ductal adenocarcinoma (PDAC), compared to the Kocher-first conventional approach. The mesenteric approach might improve surgical outcomes through a non-touch isolation technique for PDAC. This trial was conducted in 24 Japanese high-volume centers. Patients who were scheduled to undergo PD for resectable PDAC or borderline resectable PDAC with portal vein invasion (BR-PV PDAC) were randomly assigned (1:1) via a central web-based application to the conventional or mesenteric approach. The primary endpoint was overall survival (OS). We also analyzed circulating tumor cell (CTC) DNA in the PV blood obtained during surgery. This trial is registered with ClinicalTrials.gov. NCT03317886, and UMIN Clinical Trials UMIN000029615. Between 2018 and 2021, 360 patients were randomly assigned to conventional (n=181) and mesenteric groups (n=179). With a median follow-up of 39.3 months, the median OS was comparable between conventional and mesenteric groups (41.7 vs. 39.3 months; hazard ratio 1.02, 95% confidence interval: 0.76–1.37, P=0.897). CTC analysis showed that the mean change in CTC DNA copy number in PV obtained at laparotomy and just before removal of the specimen was significantly different between the conventional (10.1±2.7) and mesenteric (-7.3±2.6) groups (P<0.001). The mesenteric approach does not improve survival in patients with resectable or BR-PV PDAC, although it might prevent spread of cancer cells via vessels during surgery through the non-touch isolation procedure.