Real world neoadjuvant immunochemotherapy for locally advanced perihilar cholangiocarcinoma: experience from an 11-Case series

Real world neoadjuvant immunochemotherapy for locally advanced perihilar cholangiocarcinoma: experience from an 11-Case series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real world neoadjuvant immunochemotherapy for locally advanced perihilar cholangiocarcinoma: experience from an 11-Case series Xiangde Shi¹, Yanyang Kuang¹, Huolian Liu², Guangzi Shi³, Yanfang Ye⁴, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9279539/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Purpose: Radical resection remains the main potentially curative treatment for perihilar cholangiocarcinoma (PHC), but many patients are diagnosed at locally advanced stage and are not suitable for curative surgery. This study aimed to investigate the safety and preliminary efficacy of neoadjuvant immunochemotherapy in this population Methods: We retrospectively analyzed patients with locally advanced PHC who received neoadjuvant immunochemotherapy at our center between January 2020 and January 2026. The primary endpoints were the R0 resection rate and major pathological response rate (MPR). Secondary endpoints included the objective response rate (ORR), adverse events during neoadjuvant immunochemotherapy, postoperative complications within 90 days, and the 1-year and 2-year overall survival (OS) rates. Results: Eleven patients with locally advanced PHC were included, each with at least one of the features: Bismuth–Corlette type IV disease, regional lymph node metastasis, tumor invasion of hepatic hilar vessels, or tumor involvement of the intrapancreatic bile duct. All patients completed at least two cycles of neoadjuvant immunochemotherapy. The neoadjuvant regimen mainly consisted of gemcitabine-based chemotherapy combined with a PD-1 inhibitor. Peritoneal tumor seeding was identified in 1 patient during laparotomy, and radical surgery was therefore abandoned; the remaining 10 patients successfully proceeded to tumor resection. The R0 resection rate was 45.5% (5/11; 95% CI, 16.7%–76.6%), and the MPR rate was 30.0% (3/10; 95% CI, 6.7%–65.2%), including 1 patient who achieved a pathological complete response (pCR). Radiologically, 3 patients (27.3%, 3/11) were assessed as having a partial response (PR), corresponding to an ORR of 27.3%. The most common hematologic toxicities during neoadjuvant therapy were neutropenia (54.5%, 6/11), anemia (45.5%, 5/11) and thrombocytopenia (36.4%, 4/11). The most common non-hematologic toxicities were elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels (72.7%, 8/11) and nausea/vomiting (54.5%, 6/11). During the first 90 postoperative days, 3 patients (27.3%, 3/11) experienced Clavien–Dindo grade ≥ III complications, with no perioperative mortality. With a median follow-up of 9.31 months, the 1-year OS rate was 87.5% (95% CI, 67.3%–100%), and the 2-year OS rate was 58.3% (95% CI, 25.1%–100%). Conclusion: Neoadjuvant immunochemotherapy may achieve downstaging in patients with locally advanced PHC and appears safe and manageable. perihilar cholangiocarcinoma locally advanced disease neoadjuvant therapy immunochemotherapy R0 resection Figures Figure 1 Introduction Perihilar cholangiocarcinoma (PHC) is a malignancy arising from the hilar bile ducts, defined as the duct located topologically between the right side of the umbilical portion of the left portal vein and the left side of the origin of the right posterior portal vein[ 1 ]. Radical resection remains the only potentially curative treatment in patients with PHC, although the reported 5-year survival rate after curative surgery is still only approximately 11%–41%[ 2 ]. However, because of the unique anatomical location of the hilar bile ducts and the tendency of these tumors to grow longitudinally and radially along the biliary tree, most patients present with extensive biliary involvement at diagnosis, and the hilar vessels adjacent to the bile ducts are frequently invaded by tumor. Consequently, only a minority of patients are candidates for curative resection and postoperative recurrence rates remain high. Neoadjuvant therapy is intended to reduce tumor burden and eradicate micrometastatic disease[ 3 ], thereby increasing the R0 resection rate, decreasing the risk of recurrence, and ultimately improving long-term outcomes[ 4 ]. However, neoadjuvant treatment strategies for PHC, including chemotherapy, immunotherapy, and targeted therapy, remain in the exploratory stage. Neither the NCCN 2025 guidelines nor the ESMO 2023 guidelines provide specific recommendations for neoadjuvant treatment in patients with PHC[ 5 , 6 ]. The development of neoadjuvant treatment for PHC has been limited by the rarity of the disease, its marked anatomical and surgical complexity, and the absence of guideline-endorsed standard strategies[ 2 , 4 – 6 ]. For locally advanced and metastatic biliary tract cancer, immunochemotherapy, as demonstrated in studies such as TOPAZ-1 and KEYNOTE-966, has shown greater survival benefit than chemotherapy alone. Our previous single-center study showed encouraging survival outcomes with postoperative adjuvant immunochemotherapy in resected PHC patients at high risk of recurrence, providing a clinical rationale for further evaluating this strategy in the neoadjuvant treatment of PHC[ 7 ]. However, the role of neoadjuvant immunochemotherapy in PHC has not yet been clearly defined. In this study, we reviewed 11 patients with PHC who received neoadjuvant immunochemotherapy at our center. The primary endpoints were the R0 resection rate and major pathological response (MPR) rate. Additional endpoints included the objective response rate (ORR) according to RECIST version 1.1, treatment-related toxicity, postoperative morbidity within 90 days, and short-term overall survival. Patients and Methods 1. Study Population and Treatment This retrospective cohort study was conducted at a single center in a real-world clinical setting (approval No. SYSKY-2025-893-01). The study population comprised patients with PHC who received neoadjuvant therapy at the Department of Biliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, between January 2020 and January 2026. Clinical and pathological data, survival status, and adverse event (AE) data were obtained through the electronic medical record system and telephone follow-up. The follow-up was censored on January 31, 2026. The inclusion criteria were as follows: (1) age 18–75 years; (2) preoperative cytological or histological confirmation of PHC; locally advanced disease, defined by the presence of at least one of the following features: Bismuth–Corlette type IV disease, regional lymph node metastasis, tumor invasion of hepatic hilar vessels, or tumor involvement of the intrapancreatic bile duct; (3) receipt of at least two cycles of immunochemotherapy followed by surgical evaluation after neoadjuvant therapy; and (4) availability of complete clinicopathological data and key outcome data. The exclusion criteria were: (1) concomitant second primary malignancy; and (2) Eastern Cooperative Oncology Group (ECOG) performance status score ≥ 2 or American Society of Anesthesiologists (ASA) physical status classification ≥ IV, with inability to tolerate surgery as determined by multidisciplinary evaluation. Neoadjuvant treatment regimens included GEMOX (gemcitabine plus oxaliplatin) combined with a PD-1 inhibitor (sintilimab, camrelizumab, or tislelizumab), GAP (gemcitabine, cisplatin, and nab-paclitaxel) combined with toripalimab. Treatment was administered every 3 weeks. Initial dosing was determined with reference to the NCCN and ESMO guidelines and was adjusted according to individual patient conditions. In the event of severe AEs, modification or treatment delay was allowed until the AE resolved to grade ≤ II. Treatment was discontinued in cases of intolerable toxicity, disease progression, patient refusal, or death. The decision to proceed with surgery after neoadjuvant treatment was made through multidisciplinary team discussion (MDT), based on the patient’s general condition, treatment tolerance, radiologic reassessment, extent of biliary and vascular involvement, future liver remnant adequacy, and the anticipated feasibility of curative-intent resection. Preoperative optimization included biliary drainage for obstructive jaundice, assessment of future liver reserve using the indocyanine green clearance test and CT volumetry in patients considered for major hepatectomy, and portal vein embolization when the future liver remnant was deemed insufficient. In selected patients with tumor involvement of the right hepatic artery who were considered unlikely to undergo safe arterial reconstruction, preoperative embolization of the involved artery was performed to promote collateral arterial flow. The final operative approach was determined individually according to radiologic response, the extent of biliary and vascular involvement, and the anticipated safety of curative-intent resection. Postoperative adjuvant therapy consisted of S-1–based treatment, gemcitabine monotherapy, or combination therapy with a PD-1 inhibitor. Postoperative follow-up was performed every 3 months during the first year and every 6 months thereafter. At each follow-up visit, liver function, serum tumor markers, abdominal ultrasonography, CT, or MRI were assessed. Recurrence or progression was determined primarily based on imaging findings, with pathological confirmation obtained when necessary. Adverse reactions during neoadjuvant treatment were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, and postoperative complications were graded according to the Clavien–Dindo classification. The primary endpoints were the R0 resection rate and major pathological response (MPR) rate. Secondary endpoints included the objective response rate (ORR), adverse events during neoadjuvant treatment, postoperative complications within 90 days, and the 1-year and 2-year overall survival (OS) rates. Radiologic response was evaluated in accordance with RECIST version 1.1, with responses categorized as follows: (1) complete response (CR), disappearance of all target lesions, with any pathological lymph node reduced to a short-axis diameter of < 10 mm; (2) partial response (PR), at least a 30% decrease in the sum of diameters of target lesions relative to baseline; (3) stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), using the smallest sum of diameters recorded during treatment as reference; and (4) progressive disease (PD), at least a 20% increase in the sum of diameters of target lesions relative to the smallest sum recorded during treatment, with an absolute increase of at least 5 mm, or the appearance of one or more new lesions[ 8 ]. Postoperative resection specimens were evaluated by pathologists for treatment response. The proportion of residual viable tumor (RVT) relative to the tumor bed area was estimated with reference to macroscopic findings and the extent of fibrosis and necrosis within the tumor bed. MPR was defined as RVT ≤ 10%, and pathological complete response (pCR) was defined as RVT = 0. Because radiologic response in PHC may not fully reflect treatment-induced tumor regression, postoperative pathologic assessment was included as an additional efficacy measure to complement RECIST-based radiologic evaluation, particularly in patients with limited radiologic change after treatment. 2. Statistical Analysis All statistical analyses were performed using R software (R Foundation for Statistical Computing, Vienna, Austria; version 4.5.1). Given the limited sample size (n = 11), the statistical analysis was primarily descriptive. The R0 resection rate, major pathological response (MPR) rate, and 1- and 2-year overall survival (OS) rates are reported with 95% confidence intervals (CIs). OS was defined as the interval from initiation of neoadjuvant therapy to death from any cause or the last follow-up and was estimated using the Kaplan–Meier method. No formal comparative or multivariable analyses were performed because of the exploratory nature of the study and the small sample size. Results 1. Baseline Characteristics A total of 11 patients with perihilar cholangiocarcinoma were included in this study. The baseline characteristics are summarized in Table 1 . Bismuth–Corlette type III and IV disease accounted for most cases, including 5 patients with type IIIa, 3 with type IIIb, 2 with type IVa, whereas only 1 patient had type I disease. Regional lymph node metastasis was present in 8 patients(72.7%), hilar vascular invasion was present in 10 patients(90.9%), and intrapancreatic bile duct involvement in 3 patients(27.3%). By definition, all patients had at least one high-risk feature, consistent with the locally advanced nature of the cohort. Table 1 Baseline characteristics of 11 patients with perihilar cholangiocarcinoma No. Age Sex preoperative CEA (ng/mL) preoperative CA19-9 (U/mL) Bismuth–Corlette Regional lymph node metastasis Hilar vascular invasion Involvement of the intrapancreatic bile duct Neoadjuvant treatment regimen Case.1 59 Female 1.6 50.5 Ⅲa YES YES NO GEMOX + sintilimab ×6 cycles Case.2 49 Male 1.4 10.8 Ⅲb YES YES NO GEMOX + tislelizumab ×5 cycles Case.3 28 Female 1.8 18.1 Ⅲb YES YES YES GP + sintilimab ×4 cycles Case.4 68 Male 11.1 4656 Ⅲa YES YES NO GEMOX + camrelizumab × 3 cycles Case.5 70 Female 6.9 371 Ⅳa YES NO YES GEM + sintilimab ×4 cycles Case.6 56 Male 24.8 7531 Ⅳb NO YES NO GEM + tislelizumab ×2 cycles Case.7 73 Female 3.1 439 Ⅰ NO YES NO GEMOX + camrelizumab ×5 cycles Case.8 26 Male 3.7 28.9 Ⅲa YES YES NO GAP + toripalimab ×4 cycles Case.9 74 Female 3.6 2.0 Ⅳa YES YES NO GEMOX + tislelizumab ×6 cycles Case.10 67 Female 5.9 18.9 Ⅲb NO YES YES GEMOX + tislelizumab ×3 cycles Case.11 36 Male 2.2 323 Ⅲa NO YES NO FOLFIRINOX + pembrolizumab ×1 cycle; GEMOX + pembrolizumab ×2 cycles Note: GEMOX, gemcitabine plus oxaliplatin; GP, gemcitabine plus cisplatin; GEM, gemcitabine; GAP, gemcitabine, cisplatin, and nab-paclitaxel; FOLFIRINOX, leucovorin, fluorouracil, irinotecan, and oxaliplatin; Neoadjuvant treatment exposure was heterogeneous but was predominantly based on gemcitabine-containing regimens combined with PD-1 inhibitor. Seven patients (63.6%) received a GEMOX-containing regimen, whereas the remaining patients received other gemcitabine-based combinations, including GP, GEM, or GAP. No patient in this group received targeted therapy or regional/locoregional treatment. The median preoperative CEA level was 3.6 ng/mL (range, 1.4–24.8 ng/mL). The median preoperative CA19-9 level was 50.5 U/mL (range, 2.0–7531 U/mL), with marked variability across patients. Taken together, these findings indicate that the present cohort represented a clinically high-risk population with both anatomical complexity and adverse biological features. Rather than reflecting a narrowly selected resectable group, the study population more closely resembled a real-world subset of patients in whom curative-intent surgery remained technically possible but oncologically challenging. 2. Adverse Events and Efficacy After Neoadjuvant Therapy Adverse events (AEs) during neoadjuvant treatment were graded according to CTCAE version 5.0. Details are summarized in Table 2 . The most common hematologic toxicities were neutropenia (54.5%, 6/11), anemia (45.5%, 5/11) and thrombocytopenia (36.4%, 4/11). The most common non-hematologic toxicities were elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels (72.7%, 8/11) and nausea/vomiting (54.5%, 6/11). Three patients (27.3%, 3/11) developed biliary tract infection secondary to biliary stent obstruction and were treated with prompt stent replacement and anti-infective therapy. Among severe (grade III–IV) adverse events, ALT/AST elevation accounted for a relatively high proportion (18.2%, 2/11). These events improved with active symptomatic treatment, including hepatoprotective and nutritional support. Table 2 Adverse events during neoadjuvant treatment in patients with perihilar cholangiocarcinoma Adverse event All grades (Grade ≥ 1), n (%) Grade ≥ 3 n (%) Hematologic toxicities Leukopenia 3(27.3%) 1(9.1%) Neutropenia 6(54.5%) 1(9.1%) Anemia 5(45.5%) 1(9.1%) Thrombocytopenia 4(36.4%) 0(0.0%) Non-hematologic toxicities ALT/AST elevation 8(72.7%) 2(18.2%) Nausea/vomiting 6(54.5%) 1(9.1%) Proteinuria 1(9.1%) 0(0.0%) Hypothyroidism 1(9.1%) 0(0.0%) Gastrointestinal hemorrhage 1(9.1%) 1(9.1%) Fatigue 5(45.5%) 0(0.0%) Abdominal pain 4(36.4%) 1(9.1%) Biliary tract infection 3(27.3%) 3(27.3%) Note: Treatment-related adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Grade 1 indicates mild events; grade 2, moderate; grade 3, severe or medically significant events; grade 4, life-threatening events; and grade 5, death. Recurrent events of the same type in the same patient were counted according to the highest grade observed. 3. Tumor response and surgical outcomes Before treatment, patients with obstructive jaundice received preoperative biliary drainage by percutaneous transhepatic cholangial drainage (PTCD) and/or endoscopic biliary drainage, including endoscopic retrograde biliary drainage (ERBD) with biliary stent placement or endoscopic nasobiliary drainage (ENBD). In the present cohort, all 11 patients required biliary drainage because of obstructive jaundice: 8 underwent PTCD, 1 underwent ERBD alone, 1 underwent PTCD plus ENBD, 1 underwent PTCD plus ERBD and 1 underwent ENBD plus ERBD. For patients requiring major hepatectomy, the serum total bilirubin level (TBIL) was required to decrease to below 34.2 µmol/L. Assessment of future liver reserve was estimated based on the indocyanine green (ICG) clearance test (when TBIL is less than 51.3 µmol/L) and CT volumetry. In patients with a ratio of future liver remnant (FLR) to standard liver volume (SLV) ratio of less than 40%, portal vein embolization (PVE) on the side scheduled for resection was performed once the serum TBIL decreased to below 85.5 µmol/L, to promote compensatory hypertrophy of the future liver remnant, 4 patients underwent PVE. In addition, 4 patients scheduled for left hepatectomy who had involvement of the right hepatic artery by the tumor and were considered unlikely to undergo safe intraoperative arterial reconstruction underwent preoperative extrahepatic embolization of the right hepatic artery to facilitate the formation of collateral circulation around the right liver. During surgery, the involved right hepatic artery was resected without reconstruction, and the ligaments around right lobe were not dissected to keep the intact of collateral inflow artery such as right phrenic artery. These preoperative interventions underscore the complexity of perioperative management in this cohort. In many cases, successful progression to surgery required not only systemic treatment response, but also repeated biliary decompression, liver functional optimization, and procedure-specific preparation for major hepatectomy or vascular resection. After neoadjuvant therapy, all 11 patients underwent surgical exploration. One patient (9.1%) was found to have extensive peritoneal metastases at laparotomy and therefore did not undergo tumor resection, whereas the remaining 10 patients underwent surgical resection. Radiologic response, surgical treatment, pathological outcomes, postoperative morbidity, and survival outcomes are summarized in Tables 3 . According to RECIST version 1.1, 3 of 11 patients (27.3%) achieved a partial response (PR), while 8 (72.7%) had stable disease (SD); no patient developed progressive disease (PD), yielding an objective response rate (ORR) of 27.3% (3/11). One patient was found to have peritoneal implantation metastasis at surgical exploration and therefore did not undergo surgical resection, whereas the remaining 10 patients successfully underwent tumor resection (Table 3 ). The most frequently performed procedure was right hemihepatectomy plus total caudate lobectomy (S15678), which was performed in 3 patients (27.3%, 3/11). Extended right hepatectomy plus total caudate lobectomy (S156784′) was performed in 2 patients (18.2%, 2/11), whereas left trisectionectomy plus total caudate lobectomy (S123458), right anterior sectionectomy plus segment IVb resection plus total caudate lobectomy (S14b58), and left medial sectionectomy plus partial segment V resection plus total caudate lobectomy (S145′) were each performed in 1 patient (9.1%, 1/11). Two patients underwent extrahepatic bile duct resection alone. In Case 2, the preoperative diagnosis was Bismuth–Corlette type IIIb disease with tumor invasion of the right hepatic artery that was considered difficult to reconstruct after resection. After neoadjuvant therapy, the patient achieved a partial response (PR) according to RECIST version 1.1 after neoadjuvant therapy and subsequently achieved pathological complete response (pCR) on postoperative assessment. He also underwent preoperative embolization of the proper hepatic artery and subsequently received extrahepatic bile duct resection combined with resection of the proper hepatic artery, right hepatic artery, and left hepatic artery, followed by Roux-en-Y hepaticojejunostomy to the right and left hepatic ducts. In Case 10, the preoperative diagnosis was Bismuth–Corlette type Ⅲb disease with complete occlusion of the right hepatic artery. After neoadjuvant therapy, imaging assessment showed SD; however, intraoperative exploration revealed involvement of the portal vein, common hepatic artery, and intrapancreatic bile duct, and palliative surgery was therefore performed, consisting of extrahepatic bile duct resection and Roux-en-Y hepaticojejunostomy to the right and left hepatic ducts. Four patients (36.4%, 4/11) underwent combined portal vein resection and reconstruction. Among them, 1 underwent interposition grafting between the right posterior portal vein branch and the superior mesenteric vein using an allogeneic vascular graft; 1 underwent end-to-end anastomosis between the main portal vein and the left portal vein branch; 1 underwent end-to-end anastomosis between the main portal vein and the right posterior portal vein branch; 1 underwent end-to-end anastomosis between the main portal vein and the right portal vein branch. Overall, the operative procedures were highly heterogeneous and frequently extensive, reflecting the marked anatomical complexity of locally advanced PHC after neoadjuvant treatment. Major hepatectomy with caudate lobectomy remained the dominant surgical approach, and a substantial proportion of patients required combined vascular resection and reconstruction, highlighting the technical demands of curative-intent surgery in this setting. The R0 resection rate was 45.5% (5/11; 95% CI, 16.7%–76.6%), and the MPR rate was 30.0% (3/10; 95% CI, 6.7%–65.2%). Case 2, who achieved PR according to RECIST version 1.1, subsequently achieved pathological complete response (pCR). Within 90 days after surgery, postoperative complications were assessed in all 11 patients. Three patients (27.3%, 3/11) experienced Clavien–Dindo grade ≥ III complications. Major complications included intra-abdominal hemorrhage requiring reoperation for hemostasis in 2 patients (18.2%, 2/11) and ascites secondary to hepatic insufficiency in 1 patient (9.1%, 1/11). Infection occurred in 2 patients (18.2%, 2/11). Overall, intra-abdominal hemorrhage occurred in 3 patients (27.3%, 3/11), hepatic insufficiency occurred in 2 patients (18.2%, 2/11), bile fistula occurred in 2 patients (18.2%, 2/11), infection occurred in 2 patients (18.2%, 2/11), pancreatic fistula occurred in 1 patient (9.1%, 1/11), and poor wound healing occurred in 1 patient (9.1%, 1/11). No grade IV or V complications were documented in the available records. The follow-up cutoff date was January 31, 2026. Median OS had not been reached at the time of analysis. The 1-year OS rate was 87.5% (95% CI, 67.3%–100%), and the 2-year OS rate was 58.3% (95% CI, 25.1%–100%). During follow-up, postoperative tumor recurrence or progression was observed in 2 patients. Case 1 (Bismuth–Corlette type IIIa) developed recurrence 7 months after surgery and died 13 months postoperatively. In Case 4 (Bismuth–Corlette type IIIa) peritoneal implantation metastasis was identified at intraoperative exploration and curative resection was not performed; the patient died of metastatic disease 3 months after surgery. At the last follow-up, 9 patients in the cohort were still alive. Table 3 Surgical characteristics of patients with perihilar cholangiocarcinoma No. Preoperative biliary drainage Preoperative portal vein embolization Preoperative right hepatic artery embolization RECIST1.1 Operative procedure Resection margin status Pathologic TNM stage Postoperative complication grade Case.1 PTCD NO NO SD S156784’+EHBDR R0 ⅣB Ⅲa Case.2 PTCD NO YES PR EHBDR +RHAR&PHAR+LHAR R0 pCR* Ⅱa Case.3 ERBD &ENBD RAPV YES SD S123458 + EHBDR +PVR(SMV-RPPV) +RHAR&PHAR R1 ⅣA Ⅲb Case.4 PTCD RPV NO SD Exploration only UR ⅣB Ⅱ Case.5 PTCD RPV NO SD S15678 + EHBDR +PVR(RPV) R2 ⅢB Ⅱ Case.6 PTCD& ENBD NO YES SD S12345’+EHBDR +PVR (MPV–RPV) +RHAR&PHAR R1 ⅢC Ⅱ Case.7 PTCD NO NO SD S14b58 + EHBDR+RHAR R0 ⅢA Ⅲb Case.8 PTCD NO NO SD S15678 + EHBDR R0 Ⅱ Ⅱ Case.9 PTCD NO YES PR S145’+EHBDR (Previous resection of segments II and III) RHAR+PHAR R2 ⅣA Ⅱ Case.10 PTCD NO NO SD EHBDR +RHAR+PHAR R2 ⅢC Ⅱ Case.11 PTCD& ERBD RPV NO PR S15678 + PVR+IVCR (graft) R0 ⅢB Ⅱ Note : 1.PTCD, percutaneous transhepatic biliary drainage; 2.ERBD, endoscopic retrograde biliary drainage; 3.ENBD, endoscopic nasobiliary drainage; 4.pCR, pathologic complete response; 5.RAPV, right anterior portal vein; RPV, right portal vein; 6.EHBDR, extrahepatic bile duct resection; RHAR, right hepatic artery resection; CHAR, common hepatic artery resection; PHAR, proper hepatic artery resection; PVR, portal vein resection; MPV, main portal vein; LPV, left portal vein; RPV, right portal vein; RPPV, right posterior portal vein; SMV, superior mesenteric vein; NE, not evaluable; UR, unresectable; PVR*, sidewall reconstruction of the main portal vein; S1234, left hemihepatectomy plus caudate lobectomy; S123458, left trisectionectomy plus total caudate lobectomy; S15678, right hemihepatectomy plus total caudate lobectomy; S145678, right trisectionectomy plus total caudate lobectomy; S14b58, right anterior sectionectomy plus segment IVb resection plus total caudate lobectomy; S145′, left medial sectionectomy plus partial segment V resection plus total caudate lobectomy; IVCR (graft), inferior vena cava resection with vascular graft reconstruction; S12345′, left hemihepatectomy plus partial segment V resection plus total caudate lobectomy; S156784′, right hemihepatectomy plus partial segment IV resection plus total caudate lobectomy. Discussion Radical surgical resection remains the key to achieving long-term survival in patients with perihilar cholangiocarcinoma (PHC). However, PHC is often diagnosed at an advanced stage, with extensive biliary involvement frequently accompanied by tumor invasion of hepatic hilar vessels adjacent to the bile ducts and lymph node metastasis, making R0 resection difficult and postoperative recurrence highly likely. At present, first-line standard treatment for advanced biliary tract cancer (BTC) has entered the era of immunochemotherapy. The TOPAZ-1 and KEYNOTE-966 trials demonstrated that the addition of immunotherapy to gemcitabine plus cisplatin (GemCis) further improved overall survival. In TOPAZ-1, the median OS for patients with advanced BTC treated with durvalumab plus GemCis was 12.8 months, compared with 11.5 months in the chemotherapy-alone control group, representing an improvement of 1.3 months (HR = 0.80). In KEYNOTE-966, the median OS for patients with advanced BTC treated with pembrolizumab plus GemCis was 12.7 months, compared with 10.9 months in the chemotherapy-alone control group, representing an improvement of 1.8 months (HR = 0.83)[ 6 , 9 – 12 ]. In the present study, we retrospectively included 11 patients with locally advanced PHC at our center who were considered by a multidisciplinary team (MDT) to have the potential for curative resection but were also at high risk of recurrence and treated them with a neoadjuvant immunochemotherapy strategy. After neoadjuvant treatment, the objective response rate (ORR) was 27.3% (3/11). Ultimately, all 11 patients underwent surgical exploration, and 10 proceeded to surgical resection. Of the entire treated cohort, 5 patients achieved R0 resection, corresponding to an overall R0 resection rate of 45.5% (5/11). Adverse events during neoadjuvant treatment included hematologic toxicities, neutropenia (54.5%, 6/11), anemia (45.5%, 5/11) and thrombocytopenia (36.4%, 4/11), as well as non-hematologic toxicities, including elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels (72.7%, 8/11) and nausea/vomiting (54.5%, 6/11). Three patients (27.3%, 3/11) developed biliary tract infection secondary to biliary stent obstruction and were treated with prompt stent replacement and anti-infective therapy. Among severe (grade III–IV) adverse events, ALT/AST elevation accounted for a relatively high proportion (18.2%, 2/11). These events improved with active symptomatic treatment, including hepatoprotective and nutritional support. Within 90 days after surgery, 3 patients (27.3%, 3/11) experienced Clavien-Dindo grade ≥ III complications, and no perioperative deaths were observed. The perioperative and short-term follow-up results suggest that this neoadjuvant immunochemotherapy approach is safe and manageable. This finding is clinically meaningful given the complexity of perioperative management in this population. Patients with locally advanced PHC often require prolonged biliary drainage, repeated reassessment of liver function and remnant volume, and major hepatobiliary resection with or without vascular reconstruction. Under these circumstances, the observation that treatment-related toxicity remained manageable and that severe postoperative morbidity was not excessive suggests that neoadjuvant immunochemotherapy did not appear to compromise subsequent surgical feasibility in appropriately selected patients. Kuriyama et al. investigated neoadjuvant chemotherapy alone and found that, among 11 patients with locally advanced disease, only 6 ultimately underwent curative surgery, of whom 4 achieved R0 resection, corresponding to an overall R0 resection rate of 22.2% (4/18) among all patients who received neoadjuvant therapy. In contrast, all 11 patients included in our study had locally advanced perihilar cholangiocarcinoma, and after neoadjuvant immunochemotherapy, 10 ultimately underwent surgical resection and 5 achieved R0 resection, yielding an R0 resection rate of 45.5%. This rate approaches the 57% R0 resection rate reported for low-risk PHC patients treated at 24 international high-volume centers specializing in the surgical management of PHC[ 13 ]. However, this comparison should be interpreted cautiously because the present cohort was not composed of low-risk resectable PHC, but rather of patients with locally advanced disease characterized by major biliary extension, vascular invasion, regional lymph node metastasis, and/or intrapancreatic bile duct involvement. In addition, our R0 rate was calculated using the entire treated cohort as the denominator, thereby also incorporating patients in whom radical resection could not ultimately be completed. From this perspective, an overall R0 resection rate of 45.5% may still be considered clinically meaningful in such a high-risk population. Neoadjuvant treatment should not only focus on the objective response rate (ORR), but also on the depth of pathological response, particularly major pathological response (MPR). Wu et al. (2025) defined MPR as a residual viable tumor proportion of ≤ 10% and demonstrated that it is an independent prognostic factor for both OS and recurrence-free survival (RFS)[ 14 ]. Matsuyama et al. reported that after neoadjuvant GS chemotherapy, only approximately 17% of resected patients achieved complete, marked, or moderate histological response, whereas most patients showed either no response or only minimal response[ 15 ]. These findings suggest that conventional preoperative chemotherapy can induce substantial pathological regression in only a limited subset of patients. In our study, 3 patients had a residual viable tumor proportion of ≤ 10% on postoperative pathological assessment, corresponding to an MPR rate of 30% (3/10). One patient in our cohort achieved pCR. Case 2 was a 49-year-old man initially diagnosed with PHC (Bismuth–Corlette type IIIb). Exploratory laparotomy revealed involvement of the right hepatic artery, which was considered difficult to reconstruct safely after resection. After pathological confirmation of PHC by biopsy, he received 5 cycles of immunochemotherapy (GEMOX plus tislelizumab) beginning in December 2022. During treatment, he developed neutropenia and elevated ALT/AST levels, both graded as CTCAE grade 1 adverse events, and achieved a partial response according to RECIST 1.1. In June 2023, he underwent reoperation. Both intraoperative and postoperative pathological examinations showed no residual carcinoma in the extrahepatic bile duct, surrounding tissues, or hilar lymph nodes, indicating pCR. He has had no tumor recurrence and remains disease-free 38 months after treatment at the follow-up cutoff. Taken together, judging from the R0 resection rate and MPR rate, neoadjuvant immunochemotherapy may be superior to chemotherapy alone or chemoradiotherapy alone. However, this study has several limitations. First, it is a single-center retrospective analysis with a small sample size. Second, there was heterogeneity in the immunochemotherapy regimens used. Third, the follow-up duration remains relatively short and is insufficient to fully evaluate long-term survival benefit and the risk of rare complications. Future multicenter, prospective, large-scale studies are needed to confirm the safety and efficacy of immunochemotherapy as neoadjuvant treatment for PHC. Further efforts should also focus on the identification of reliable biomarkers predictive of treatment response, pathological regression, and survival benefit, so as to improve patient selection and optimize perioperative treatment strategies. Because the present study was not designed to evaluate the independent contribution of targeted agents, the potential role of targeted therapy in the neoadjuvant setting remains unclear. Future studies may further clarify whether patients with biomarker-defined disease, such as tumors harboring potentially targetable alterations including HER2, could derive additional benefit from tailored combination strategies. Conclusion In this real-world case series, neoadjuvant immunochemotherapy showed manageable toxicity and yielded encouraging rates of tumor response, pathological regression, and R0 resection in selected patients with locally advanced PHC. These findings support further prospective evaluation of this strategy in larger multicenter cohorts. Declarations Acknowledgements The authors sincerely thank the Follow-up Center of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, for support in patient follow-up, and Professor Pei’e Cai for her valuable assistance in language editing and revision of the manuscript. Authors’ contributions XS: Conceptualization, data curation, formal analysis, and manuscript drafting. YK: Data curation, statistical analysis, manuscript drafting, and figure preparation. HL: Pathological review, pathological evaluation, and interpretation of pathological findings. GS: Data collection and critical revision of the manuscript. YY: Statistical analysis and critical revision of the manuscript. QT and XY: Study implementation and manuscript review. CL: Study supervision, manuscript revision, and funding acquisition. All authors read and approved the final manuscript. Funding This study was supported by Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tumors (202201020375), Clinical Major Technology Project of Guangzhou Municipal Health Commission (2023P-ZD17), and Guangzhou Science and Technology Program (2024A04J4776). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. Data availability The datasets generated and/or analyzed during the current study are not publicly available because they contain potentially identifiable patient information, but de-identified data are available from the corresponding author on reasonable request. Ethics approval and consent to participate This study was approved by the Medical Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSKY-2025-893-01), and was conducted in accordance with the Declaration of Helsinki. Informed consent was waived by the Medical Ethics Committee due to the retrospective nature of the study. Consent for publication Written informed consent for publication of the clinical details and accompanying images was obtained from the patient described in Figure 1. Competing interests The authors declare that they have no competing interests. References Nagino M. Perihilar cholangiocarcinoma: a surgeon's perspective. iLIVER. 2022;1(1):12–24. doi: https://doi.org/10.1016/j.iliver.2022.03.004 . Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13(5):261–80. https://doi.org/10.1038/nrgastro.2016.51 . Chong N, Yao L, Wang M, Xu Y. The evolving landscape of bench-to-bedside translation in the era of neoadjuvant platforms: perspectives and opportunities. Holistic Integrative Oncology. 2026;5(1). https://doi.org/10.1007/s44178-025-00219-8 . Hewitt DB, Brown ZJ, Pawlik TM. Current Perspectives on the Surgical Management of Perihilar Cholangiocarcinoma. Cancers (Basel). 2022;14(9). https://doi.org/10.3390/cancers14092208 . Benson AB, 3rd, D'Angelica MI, Abrams T, Ahmed A, Akce M, Anaya DA, et al. Biliary Tract Cancers, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw. 2025;23(9):403–18. https://doi.org/10.6004/jnccn.2025.0042 . Vogel A, Bridgewater J, Edeline J, Kelley RK, Klumpen HJ, Malka D, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(2):127–40. https://doi.org/10.1016/j.annonc.2022.10.506 . Liu Q-q, Shi X-d, Ye Y-f, Tang Q-b, Lin H-m, Yu X-h, et al. Real-world experience of postoperative adjuvant chemoimmunotherapy in patients with perihilar cholangiocarcinoma at high risk of recurrence. Cancer Immunology, Immunotherapy. 2023;72(6):1753–61. https://doi.org/10.1007/s00262-022-03362-7 . Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026 . Li J, Zhou S, Xu X, Zheng Q, Zhang F, Luo C, et al. Sintilimab and anlotinib with gemcitabine plus cisplatin in advanced biliary tract cancer: SAGC a randomized phase 2 trial. Nat Commun. 2025;16(1):5559. https://doi.org/10.1038/s41467-025-60119-3 . Lehrke HD, Heimbach JK, Wu TT, Jenkins SM, Gores GJ, Rosen CB, et al. Prognostic Significance of the Histologic Response of Perihilar Cholangiocarcinoma to Preoperative Neoadjuvant Chemoradiation in Liver Explants. Am J Surg Pathol. 2016;40(4):510–8. https://doi.org/10.1097/pas.0000000000000588 . Knox JJ, McNamara MG, Bazin IS, Oh DY, Zubkov O, Breder V, et al. A phase III randomized study of first-line NUC-1031/cisplatin vs. gemcitabine/cisplatin in advanced biliary tract cancer. J Hepatol. 2025;83(2):358–66. https://doi.org/10.1016/j.jhep.2025.01.040 . Oh DY, Ikeda M, Lee CK, Rojas C, Hsu CH, Kim JW, et al. Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial. Hepatology. 2025;81(3):823–36. https://doi.org/10.1097/HEP.0000000000000965 . Mueller M, Breuer E, Mizuno T, Bartsch F, Ratti F, Benzing C, et al. Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers. Ann Surg. 2021;274(5):780–8. https://doi.org/10.1097/SLA.0000000000005103 . Wu G, Chen X, Luo R, Koh YX, Lim TKH, Chew V, et al. Histopathologic Grading of Residual Tumor Predicts Survival of Intrahepatic Cholangiocarcinoma Patients Treated With Neoadjuvant Therapy. American Journal of Surgical Pathology. 2025;49(6):578–87. https://doi.org/10.1097/pas.0000000000002359 . Matsuyama R, Mori R, Ota Y, Homma Y, Yabusita Y, Hiratani S, et al. Impact of Gemcitabine Plus S1 Neoadjuvant Chemotherapy on Borderline Resectable Perihilar Cholangiocarcinoma. Ann Surg Oncol. 2022;29(4):2393–405. https://doi.org/10.1245/s10434-021-11206-4 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 16 Apr, 2026 Editor assigned by journal 10 Apr, 2026 Submission checks completed at journal 07 Apr, 2026 First submitted to journal 31 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9279539","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":624635719,"identity":"22834e53-d509-4c87-a820-228ad25d93ee","order_by":0,"name":"Xiangde Shi¹","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Xiangde","middleName":"","lastName":"Shi¹","suffix":""},{"id":624635720,"identity":"fd132152-4a33-47fb-92b2-da990ebdd724","order_by":1,"name":"Yanyang Kuang¹","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yanyang","middleName":"","lastName":"Kuang¹","suffix":""},{"id":624635723,"identity":"9d4950ac-25f1-4c7c-8ca6-e206625cdaba","order_by":2,"name":"Huolian Liu²","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Huolian","middleName":"","lastName":"Liu²","suffix":""},{"id":624635724,"identity":"a6971252-7c50-4f74-b1d9-cec8d6b5c1f1","order_by":3,"name":"Guangzi Shi³","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Guangzi","middleName":"","lastName":"Shi³","suffix":""},{"id":624635726,"identity":"20455260-6c2f-4d16-a5e3-b1f32f89d9cc","order_by":4,"name":"Yanfang Ye⁴","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yanfang","middleName":"","lastName":"Ye⁴","suffix":""},{"id":624635729,"identity":"43cf2599-1e62-44e3-b2ef-0090ef1bc33a","order_by":5,"name":"Qibin Tang¹","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Qibin","middleName":"","lastName":"Tang¹","suffix":""},{"id":624635730,"identity":"319e1206-0cf4-47fa-b7d0-19d61f27396d","order_by":6,"name":"Xianhuan Yu¹","email":"","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Xianhuan","middleName":"","lastName":"Yu¹","suffix":""},{"id":624635732,"identity":"54f29356-d22e-4222-81f2-4b036a390727","order_by":7,"name":"Chao Liu¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYBACPmYGBiBisOMHEgcewIR58Ghhg2pJlmwAakkgSgsDRAvjhgNAkjgt7DyGnwtqbJiNrx1+CLSlLnH+jATGB2/bGOTNcTqMx1h6xrE0PrPbaQZALYcTN9xIYDac28ZguLMBpxYzZh62w8xmtxNAWg4kbpBIYJPmbWMAcvFp+XeYcfPs9A8wh7H/JqiFt+0w4wbpHJAtzIkNNxLYmPFrYSuW5u1LS5a4nVNwIMHgsPGGMw+bJeeckzDcgEMLP//hjZ95vtnY8c9O3/zhQ0Wd7Pz25IMf3pTZyOOyBQ0YMDg2MDA2AFkSRKkHA3vilY6CUTAKRsFIAQCXUFSE/8EKlQAAAABJRU5ErkJggg==","orcid":"","institution":"Sun Yat-sen Memorial Hospital, Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Chao","middleName":"","lastName":"Liu¹","suffix":""}],"badges":[],"createdAt":"2026-03-31 12:08:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9279539/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9279539/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107834865,"identity":"900ad55b-db22-4abe-adea-a5f3212bb61a","added_by":"auto","created_at":"2026-04-26 15:49:04","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2052203,"visible":true,"origin":"","legend":"\u003cp\u003eCase 2, a 49-year-old male patient with Bismuth–Corlette type IIIb perihilar cholangiocarcinoma: radiologic imaging before and after neoadjuvant therapy, intraoperative findings, postoperative pathology, and gross specimen images. A–B: Comparison of imaging findings before and after neoadjuvant therapy (Arrows indicate the tumor; the patient achieved PR). C: Intraoperative photograph showing resection of the proper hepatic artery, right hepatic artery, left hepatic artery and extra-hepatic bile duct, followed by Roux-en-Y hepaticojejunostomy to the right and left hepatic ducts. D: Resected extrahepatic bile duct. E: Postoperative pathological findings of the extrahepatic bile duct (pCR, magnification ×200).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9279539/v1/1d9ad567d69fdc981a305187.jpeg"},{"id":108180907,"identity":"9cb8acda-d269-4017-a8c8-95c4abfa2db8","added_by":"auto","created_at":"2026-04-30 08:54:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2425035,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9279539/v1/2b6de1b3-67da-43fe-aff7-18ae303058fc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Real world neoadjuvant immunochemotherapy for locally advanced perihilar cholangiocarcinoma: experience from an 11-Case series","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePerihilar cholangiocarcinoma (PHC) is a malignancy arising from the hilar bile ducts, defined as the duct located topologically between the right side of the umbilical portion of the left portal vein and the left side of the origin of the right posterior portal vein[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. Radical resection remains the only potentially curative treatment in patients with PHC, although the reported 5-year survival rate after curative surgery is still only approximately 11%–41%[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, because of the unique anatomical location of the hilar bile ducts and the tendency of these tumors to grow longitudinally and radially along the biliary tree, most patients present with extensive biliary involvement at diagnosis, and the hilar vessels adjacent to the bile ducts are frequently invaded by tumor. Consequently, only a minority of patients are candidates for curative resection and postoperative recurrence rates remain high.\u003c/p\u003e \u003cp\u003eNeoadjuvant therapy is intended to reduce tumor burden and eradicate micrometastatic disease[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e], thereby increasing the R0 resection rate, decreasing the risk of recurrence, and ultimately improving long-term outcomes[\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, neoadjuvant treatment strategies for PHC, including chemotherapy, immunotherapy, and targeted therapy, remain in the exploratory stage. Neither the NCCN 2025 guidelines nor the ESMO 2023 guidelines provide specific recommendations for neoadjuvant treatment in patients with PHC[\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. The development of neoadjuvant treatment for PHC has been limited by the rarity of the disease, its marked anatomical and surgical complexity, and the absence of guideline-endorsed standard strategies[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e For locally advanced and metastatic biliary tract cancer, immunochemotherapy, as demonstrated in studies such as TOPAZ-1 and KEYNOTE-966, has shown greater survival benefit than chemotherapy alone. Our previous single-center study showed encouraging survival outcomes with postoperative adjuvant immunochemotherapy in resected PHC patients at high risk of recurrence, providing a clinical rationale for further evaluating this strategy in the neoadjuvant treatment of PHC[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, the role of neoadjuvant immunochemotherapy in PHC has not yet been clearly defined. In this study, we reviewed 11 patients with PHC who received neoadjuvant immunochemotherapy at our center. The primary endpoints were the R0 resection rate and major pathological response (MPR) rate. Additional endpoints included the objective response rate (ORR) according to RECIST version 1.1, treatment-related toxicity, postoperative morbidity within 90 days, and short-term overall survival.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003ch3\u003e1. Study Population and Treatment\u003c/h3\u003e\u003cp\u003eThis retrospective cohort study was conducted at a single center in a real-world clinical setting (approval No. SYSKY-2025-893-01). The study population comprised patients with PHC who received neoadjuvant therapy at the Department of Biliary and Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, between January 2020 and January 2026. Clinical and pathological data, survival status, and adverse event (AE) data were obtained through the electronic medical record system and telephone follow-up. The follow-up was censored on January 31, 2026.\u003c/p\u003e\u003cp\u003eThe inclusion criteria were as follows: (1) age 18–75 years; (2) preoperative cytological or histological confirmation of PHC; locally advanced disease, defined by the presence of at least one of the following features: Bismuth–Corlette type IV disease, regional lymph node metastasis, tumor invasion of hepatic hilar vessels, or tumor involvement of the intrapancreatic bile duct; (3) receipt of at least two cycles of immunochemotherapy followed by surgical evaluation after neoadjuvant therapy; and (4) availability of complete clinicopathological data and key outcome data. The exclusion criteria were: (1) concomitant second primary malignancy; and (2) Eastern Cooperative Oncology Group (ECOG) performance status score ≥ 2 or American Society of Anesthesiologists (ASA) physical status classification ≥ IV, with inability to tolerate surgery as determined by multidisciplinary evaluation.\u003c/p\u003e\u003cp\u003eNeoadjuvant treatment regimens included GEMOX (gemcitabine plus oxaliplatin) combined with a PD-1 inhibitor (sintilimab, camrelizumab, or tislelizumab), GAP (gemcitabine, cisplatin, and nab-paclitaxel) combined with toripalimab. Treatment was administered every 3 weeks. Initial dosing was determined with reference to the NCCN and ESMO guidelines and was adjusted according to individual patient conditions. In the event of severe AEs, modification or treatment delay was allowed until the AE resolved to grade ≤ II. Treatment was discontinued in cases of intolerable toxicity, disease progression, patient refusal, or death.\u003c/p\u003e\u003cp\u003eThe decision to proceed with surgery after neoadjuvant treatment was made through multidisciplinary team discussion (MDT), based on the patient’s general condition, treatment tolerance, radiologic reassessment, extent of biliary and vascular involvement, future liver remnant adequacy, and the anticipated feasibility of curative-intent resection. Preoperative optimization included biliary drainage for obstructive jaundice, assessment of future liver reserve using the indocyanine green clearance test and CT volumetry in patients considered for major hepatectomy, and portal vein embolization when the future liver remnant was deemed insufficient. In selected patients with tumor involvement of the right hepatic artery who were considered unlikely to undergo safe arterial reconstruction, preoperative embolization of the involved artery was performed to promote collateral arterial flow. The final operative approach was determined individually according to radiologic response, the extent of biliary and vascular involvement, and the anticipated safety of curative-intent resection. Postoperative adjuvant therapy consisted of S-1–based treatment, gemcitabine monotherapy, or combination therapy with a PD-1 inhibitor.\u003c/p\u003e\u003cp\u003ePostoperative follow-up was performed every 3 months during the first year and every 6 months thereafter. At each follow-up visit, liver function, serum tumor markers, abdominal ultrasonography, CT, or MRI were assessed. Recurrence or progression was determined primarily based on imaging findings, with pathological confirmation obtained when necessary.\u003c/p\u003e\u003cp\u003eAdverse reactions during neoadjuvant treatment were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, and postoperative complications were graded according to the Clavien–Dindo classification. The primary endpoints were the R0 resection rate and major pathological response (MPR) rate. Secondary endpoints included the objective response rate (ORR), adverse events during neoadjuvant treatment, postoperative complications within 90 days, and the 1-year and 2-year overall survival (OS) rates.\u003c/p\u003e\u003cp\u003eRadiologic response was evaluated in accordance with RECIST version 1.1, with responses categorized as follows: (1) complete response (CR), disappearance of all target lesions, with any pathological lymph node reduced to a short-axis diameter of \u0026lt; 10 mm; (2) partial response (PR), at least a 30% decrease in the sum of diameters of target lesions relative to baseline; (3) stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), using the smallest sum of diameters recorded during treatment as reference; and (4) progressive disease (PD), at least a 20% increase in the sum of diameters of target lesions relative to the smallest sum recorded during treatment, with an absolute increase of at least 5 mm, or the appearance of one or more new lesions[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePostoperative resection specimens were evaluated by pathologists for treatment response. The proportion of residual viable tumor (RVT) relative to the tumor bed area was estimated with reference to macroscopic findings and the extent of fibrosis and necrosis within the tumor bed. MPR was defined as RVT ≤ 10%, and pathological complete response (pCR) was defined as RVT = 0. Because radiologic response in PHC may not fully reflect treatment-induced tumor regression, postoperative pathologic assessment was included as an additional efficacy measure to complement RECIST-based radiologic evaluation, particularly in patients with limited radiologic change after treatment.\u003c/p\u003e\u003ch3\u003e2. Statistical Analysis\u003c/h3\u003e\u003cp\u003eAll statistical analyses were performed using R software (R Foundation for Statistical Computing, Vienna, Austria; version 4.5.1). Given the limited sample size (n = 11), the statistical analysis was primarily descriptive. The R0 resection rate, major pathological response (MPR) rate, and 1- and 2-year overall survival (OS) rates are reported with 95% confidence intervals (CIs). OS was defined as the interval from initiation of neoadjuvant therapy to death from any cause or the last follow-up and was estimated using the Kaplan–Meier method. No formal comparative or multivariable analyses were performed because of the exploratory nature of the study and the small sample size.\u003c/p\u003e"},{"header":"Results","content":"\n\u003ch3\u003e1. Baseline Characteristics\u003c/h3\u003e\n\u003cp\u003eA total of 11 patients with perihilar cholangiocarcinoma were included in this study. The baseline characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Bismuth\u0026ndash;Corlette type III and IV disease accounted for most cases, including 5 patients with type IIIa, 3 with type IIIb, 2 with type IVa, whereas only 1 patient had type I disease. Regional lymph node metastasis was present in 8 patients(72.7%), hilar vascular invasion was present in 10 patients(90.9%), and intrapancreatic bile duct involvement in 3 patients(27.3%). By definition, all patients had at least one high-risk feature, consistent with the locally advanced nature of the cohort.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of 11 patients with perihilar cholangiocarcinoma\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003epreoperative CEA\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003epreoperative CA19-9\u003c/p\u003e \u003cp\u003e(U/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBismuth\u0026ndash;Corlette\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRegional lymph node metastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHilar vascular invasion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eInvolvement\u003c/p\u003e \u003cp\u003eof the intrapancreatic bile duct\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNeoadjuvant treatment regimen\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅢa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEMOX\u0026thinsp;+\u0026thinsp;sintilimab\u003c/p\u003e \u003cp\u003e\u0026times;6 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅢb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEMOX\u0026thinsp;+\u0026thinsp;tislelizumab\u003c/p\u003e \u003cp\u003e\u0026times;5 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅢb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGP\u0026thinsp;+\u0026thinsp;sintilimab\u003c/p\u003e \u003cp\u003e\u0026times;4 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4656\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅢa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEMOX\u0026thinsp;+\u0026thinsp;camrelizumab\u003c/p\u003e \u003cp\u003e\u0026times; 3 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e371\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅣa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEM\u0026thinsp;+\u0026thinsp;sintilimab\u003c/p\u003e \u003cp\u003e\u0026times;4 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅣb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEM\u0026thinsp;+\u0026thinsp;tislelizumab\u003c/p\u003e \u003cp\u003e\u0026times;2 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅠ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEMOX\u0026thinsp;+\u0026thinsp;camrelizumab\u003c/p\u003e \u003cp\u003e\u0026times;5 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅢa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGAP\u0026thinsp;+\u0026thinsp;toripalimab\u003c/p\u003e \u003cp\u003e\u0026times;4 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅣa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEMOX\u0026thinsp;+\u0026thinsp;tislelizumab\u003c/p\u003e \u003cp\u003e\u0026times;6 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅢb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eGEMOX\u0026thinsp;+\u0026thinsp;tislelizumab\u003c/p\u003e \u003cp\u003e\u0026times;3 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e323\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅢa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eFOLFIRINOX\u003c/p\u003e \u003cp\u003e+ pembrolizumab\u003c/p\u003e \u003cp\u003e\u0026times;1 cycle; GEMOX\u003c/p\u003e \u003cp\u003e+ pembrolizumab \u0026times;2 cycles\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003cem\u003eNote: GEMOX, gemcitabine plus oxaliplatin; GP, gemcitabine plus cisplatin; GEM, gemcitabine; GAP, gemcitabine, cisplatin, and nab-paclitaxel; FOLFIRINOX, leucovorin, fluorouracil, irinotecan, and oxaliplatin;\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNeoadjuvant treatment exposure was heterogeneous but was predominantly based on gemcitabine-containing regimens combined with PD-1 inhibitor. Seven patients (63.6%) received a GEMOX-containing regimen, whereas the remaining patients received other gemcitabine-based combinations, including GP, GEM, or GAP. No patient in this group received targeted therapy or regional/locoregional treatment.\u003c/p\u003e \u003cp\u003eThe median preoperative CEA level was 3.6 ng/mL (range, 1.4\u0026ndash;24.8 ng/mL). The median preoperative CA19-9 level was 50.5 U/mL (range, 2.0\u0026ndash;7531 U/mL), with marked variability across patients.\u003c/p\u003e \u003cp\u003eTaken together, these findings indicate that the present cohort represented a clinically high-risk population with both anatomical complexity and adverse biological features. Rather than reflecting a narrowly selected resectable group, the study population more closely resembled a real-world subset of patients in whom curative-intent surgery remained technically possible but oncologically challenging.\u003c/p\u003e\n\u003ch3\u003e2. Adverse Events and Efficacy After Neoadjuvant Therapy\u003c/h3\u003e\n\u003cp\u003eAdverse events (AEs) during neoadjuvant treatment were graded according to CTCAE version 5.0. Details are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The most common hematologic toxicities were neutropenia (54.5%, 6/11), anemia (45.5%, 5/11) and thrombocytopenia (36.4%, 4/11). The most common non-hematologic toxicities were elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels (72.7%, 8/11) and nausea/vomiting (54.5%, 6/11). Three patients (27.3%, 3/11) developed biliary tract infection secondary to biliary stent obstruction and were treated with prompt stent replacement and anti-infective therapy. Among severe (grade III\u0026ndash;IV) adverse events, ALT/AST elevation accounted for a relatively high proportion (18.2%, 2/11). These events improved with active symptomatic treatment, including hepatoprotective and nutritional support.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events during neoadjuvant treatment in patients with perihilar cholangiocarcinoma\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll grades\u003c/p\u003e \u003cp\u003e(Grade\u0026thinsp;\u0026ge;\u0026thinsp;1), n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic toxicities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(54.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(45.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(36.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-hematologic toxicities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT/AST elevation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(72.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2(18.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea/vomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(54.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProteinuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal hemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(45.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbdominal pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(36.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(9.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBiliary tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(27.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eNote: Treatment-related adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Grade 1 indicates mild events; grade 2, moderate; grade 3, severe or medically significant events; grade 4, life-threatening events; and grade 5, death. Recurrent events of the same type in the same patient were counted according to the highest grade observed.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003e3. Tumor response and surgical outcomes\u003c/h3\u003e\n\u003cp\u003eBefore treatment, patients with obstructive jaundice received preoperative biliary drainage by percutaneous transhepatic cholangial drainage (PTCD) and/or endoscopic biliary drainage, including endoscopic retrograde biliary drainage (ERBD) with biliary stent placement or endoscopic nasobiliary drainage (ENBD). In the present cohort, all 11 patients required biliary drainage because of obstructive jaundice: 8 underwent PTCD, 1 underwent ERBD alone, 1 underwent PTCD plus ENBD, 1 underwent PTCD plus ERBD and 1 underwent ENBD plus ERBD.\u003c/p\u003e \u003cp\u003eFor patients requiring major hepatectomy, the serum total bilirubin level (TBIL) was required to decrease to below 34.2 \u0026micro;mol/L. Assessment of future liver reserve was estimated based on the indocyanine green (ICG) clearance test (when TBIL is less than 51.3 \u0026micro;mol/L) and CT volumetry. In patients with a ratio of future liver remnant (FLR) to standard liver volume (SLV) ratio of less than 40%, portal vein embolization (PVE) on the side scheduled for resection was performed once the serum TBIL decreased to below 85.5 \u0026micro;mol/L, to promote compensatory hypertrophy of the future liver remnant, 4 patients underwent PVE.\u003c/p\u003e \u003cp\u003eIn addition, 4 patients scheduled for left hepatectomy who had involvement of the right hepatic artery by the tumor and were considered unlikely to undergo safe intraoperative arterial reconstruction underwent preoperative extrahepatic embolization of the right hepatic artery to facilitate the formation of collateral circulation around the right liver. During surgery, the involved right hepatic artery was resected without reconstruction, and the ligaments around right lobe were not dissected to keep the intact of collateral inflow artery such as right phrenic artery.\u003c/p\u003e \u003cp\u003eThese preoperative interventions underscore the complexity of perioperative management in this cohort. In many cases, successful progression to surgery required not only systemic treatment response, but also repeated biliary decompression, liver functional optimization, and procedure-specific preparation for major hepatectomy or vascular resection.\u003c/p\u003e \u003cp\u003eAfter neoadjuvant therapy, all 11 patients underwent surgical exploration. One patient (9.1%) was found to have extensive peritoneal metastases at laparotomy and therefore did not undergo tumor resection, whereas the remaining 10 patients underwent surgical resection.\u003c/p\u003e \u003cp\u003eRadiologic response, surgical treatment, pathological outcomes, postoperative morbidity, and survival outcomes are summarized in Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. According to RECIST version 1.1, 3 of 11 patients (27.3%) achieved a partial response (PR), while 8 (72.7%) had stable disease (SD); no patient developed progressive disease (PD), yielding an objective response rate (ORR) of 27.3% (3/11).\u003c/p\u003e \u003cp\u003eOne patient was found to have peritoneal implantation metastasis at surgical exploration and therefore did not undergo surgical resection, whereas the remaining 10 patients successfully underwent tumor resection (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The most frequently performed procedure was right hemihepatectomy plus total caudate lobectomy (S15678), which was performed in 3 patients (27.3%, 3/11). Extended right hepatectomy plus total caudate lobectomy (S156784\u0026prime;) was performed in 2 patients (18.2%, 2/11), whereas left trisectionectomy plus total caudate lobectomy (S123458), right anterior sectionectomy plus segment IVb resection plus total caudate lobectomy (S14b58), and left medial sectionectomy plus partial segment V resection plus total caudate lobectomy (S145\u0026prime;) were each performed in 1 patient (9.1%, 1/11).\u003c/p\u003e \u003cp\u003eTwo patients underwent extrahepatic bile duct resection alone. In Case 2, the preoperative diagnosis was Bismuth\u0026ndash;Corlette type IIIb disease with tumor invasion of the right hepatic artery that was considered difficult to reconstruct after resection. After neoadjuvant therapy, the patient achieved a partial response (PR) according to RECIST version 1.1 after neoadjuvant therapy and subsequently achieved pathological complete response (pCR) on postoperative assessment. He also underwent preoperative embolization of the proper hepatic artery and subsequently received extrahepatic bile duct resection combined with resection of the proper hepatic artery, right hepatic artery, and left hepatic artery, followed by Roux-en-Y hepaticojejunostomy to the right and left hepatic ducts. In Case 10, the preoperative diagnosis was Bismuth\u0026ndash;Corlette type Ⅲb disease with complete occlusion of the right hepatic artery. After neoadjuvant therapy, imaging assessment showed SD; however, intraoperative exploration revealed involvement of the portal vein, common hepatic artery, and intrapancreatic bile duct, and palliative surgery was therefore performed, consisting of extrahepatic bile duct resection and Roux-en-Y hepaticojejunostomy to the right and left hepatic ducts.\u003c/p\u003e \u003cp\u003eFour patients (36.4%, 4/11) underwent combined portal vein resection and reconstruction. Among them, 1 underwent interposition grafting between the right posterior portal vein branch and the superior mesenteric vein using an allogeneic vascular graft; 1 underwent end-to-end anastomosis between the main portal vein and the left portal vein branch; 1 underwent end-to-end anastomosis between the main portal vein and the right posterior portal vein branch; 1 underwent end-to-end anastomosis between the main portal vein and the right portal vein branch.\u003c/p\u003e \u003cp\u003eOverall, the operative procedures were highly heterogeneous and frequently extensive, reflecting the marked anatomical complexity of locally advanced PHC after neoadjuvant treatment. Major hepatectomy with caudate lobectomy remained the dominant surgical approach, and a substantial proportion of patients required combined vascular resection and reconstruction, highlighting the technical demands of curative-intent surgery in this setting.\u003c/p\u003e \u003cp\u003eThe R0 resection rate was 45.5% (5/11; 95% CI, 16.7%\u0026ndash;76.6%), and the MPR rate was 30.0% (3/10; 95% CI, 6.7%\u0026ndash;65.2%). Case 2, who achieved PR according to RECIST version 1.1, subsequently achieved pathological complete response (pCR).\u003c/p\u003e \u003cp\u003eWithin 90 days after surgery, postoperative complications were assessed in all 11 patients. Three patients (27.3%, 3/11) experienced Clavien\u0026ndash;Dindo grade\u0026thinsp;\u0026ge;\u0026thinsp;III complications. Major complications included intra-abdominal hemorrhage requiring reoperation for hemostasis in 2 patients (18.2%, 2/11) and ascites secondary to hepatic insufficiency in 1 patient (9.1%, 1/11). Infection occurred in 2 patients (18.2%, 2/11). Overall, intra-abdominal hemorrhage occurred in 3 patients (27.3%, 3/11), hepatic insufficiency occurred in 2 patients (18.2%, 2/11), bile fistula occurred in 2 patients (18.2%, 2/11), infection occurred in 2 patients (18.2%, 2/11), pancreatic fistula occurred in 1 patient (9.1%, 1/11), and poor wound healing occurred in 1 patient (9.1%, 1/11). No grade IV or V complications were documented in the available records.\u003c/p\u003e \u003cp\u003eThe follow-up cutoff date was January 31, 2026. Median OS had not been reached at the time of analysis. The 1-year OS rate was 87.5% (95% CI, 67.3%\u0026ndash;100%), and the 2-year OS rate was 58.3% (95% CI, 25.1%\u0026ndash;100%). During follow-up, postoperative tumor recurrence or progression was observed in 2 patients. Case 1 (Bismuth\u0026ndash;Corlette type IIIa) developed recurrence 7 months after surgery and died 13 months postoperatively. In Case 4 (Bismuth\u0026ndash;Corlette type IIIa) peritoneal implantation metastasis was identified at intraoperative exploration and curative resection was not performed; the patient died of metastatic disease 3 months after surgery. At the last follow-up, 9 patients in the cohort were still alive.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurgical characteristics of patients with perihilar cholangiocarcinoma\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePreoperative biliary drainage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePreoperative portal vein embolization\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePreoperative right hepatic artery embolization\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRECIST1.1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOperative procedure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eResection margin status\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePathologic TNM stage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePostoperative complication grade\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS156784\u0026rsquo;+EHBDR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅣB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅢa\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEHBDR\u003c/p\u003e \u003cp\u003e+RHAR\u0026amp;PHAR+LHAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003epCR*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡa\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eERBD\u003c/p\u003e \u003cp\u003e\u0026amp;ENBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRAPV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS123458\u0026thinsp;+\u0026thinsp;EHBDR\u003c/p\u003e \u003cp\u003e+PVR(SMV-RPPV) +RHAR\u0026amp;PHAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅣA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅢb\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRPV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eExploration only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eUR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅣB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRPV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS15678\u0026thinsp;+\u0026thinsp;EHBDR\u003c/p\u003e \u003cp\u003e+PVR(RPV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅢB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u0026amp;\u003c/p\u003e \u003cp\u003eENBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS12345\u0026rsquo;+EHBDR\u003c/p\u003e \u003cp\u003e+PVR (MPV\u0026ndash;RPV)\u003c/p\u003e \u003cp\u003e+RHAR\u0026amp;PHAR\u003c/p\u003e\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅢC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS14b58\u0026thinsp;+\u0026thinsp;EHBDR+RHAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅢA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅢb\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS15678\u0026thinsp;+\u0026thinsp;EHBDR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS145\u0026rsquo;+EHBDR\u003c/p\u003e \u003cp\u003e(Previous resection of segments II and III)\u003c/p\u003e \u003cp\u003eRHAR+PHAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅣA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEHBDR\u003c/p\u003e \u003cp\u003e+RHAR+PHAR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅢC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCD\u0026amp;\u003c/p\u003e \u003cp\u003eERBD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRPV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eS15678\u0026thinsp;+\u0026thinsp;PVR+IVCR (graft)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eⅢB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eⅡ\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cem\u003eNote\u003c/em\u003e:\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003cp\u003e1.PTCD, percutaneous transhepatic biliary drainage;\u003c/p\u003e\n\n\u003cp\u003e2.ERBD, endoscopic retrograde biliary drainage;\u003c/p\u003e\n\n\u003cp\u003e3.ENBD, endoscopic nasobiliary drainage;\u003c/p\u003e\n\n\u003cp\u003e4.pCR, pathologic complete response;\u003c/p\u003e\n\n\u003cp\u003e5.RAPV, right anterior portal vein; RPV, right portal vein;\u003c/p\u003e\n\u003cp\u003e \u003cem\u003e6.EHBDR, extrahepatic bile duct resection; RHAR, right hepatic artery resection; CHAR, common hepatic artery resection; PHAR, proper hepatic artery resection; PVR, portal vein resection; MPV, main portal vein; LPV, left portal vein; RPV, right portal vein; RPPV, right posterior portal vein; SMV, superior mesenteric vein; NE, not evaluable; UR, unresectable; PVR*, sidewall reconstruction of the main portal vein; S1234, left hemihepatectomy plus caudate lobectomy; S123458, left trisectionectomy plus total caudate lobectomy; S15678, right hemihepatectomy plus total caudate lobectomy; S145678, right trisectionectomy plus total caudate lobectomy; S14b58, right anterior sectionectomy plus segment IVb resection plus total caudate lobectomy; S145\u0026prime;, left medial sectionectomy plus partial segment V resection plus total caudate lobectomy; IVCR (graft), inferior vena cava resection with vascular graft reconstruction; S12345\u0026prime;, left hemihepatectomy plus partial segment V resection plus total caudate lobectomy; S156784\u0026prime;, right hemihepatectomy plus partial segment IV resection plus total caudate lobectomy.\u003c/em\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRadical surgical resection remains the key to achieving long-term survival in patients with perihilar cholangiocarcinoma (PHC). However, PHC is often diagnosed at an advanced stage, with extensive biliary involvement frequently accompanied by tumor invasion of hepatic hilar vessels adjacent to the bile ducts and lymph node metastasis, making R0 resection difficult and postoperative recurrence highly likely.\u003c/p\u003e \u003cp\u003eAt present, first-line standard treatment for advanced biliary tract cancer (BTC) has entered the era of immunochemotherapy. The TOPAZ-1 and KEYNOTE-966 trials demonstrated that the addition of immunotherapy to gemcitabine plus cisplatin (GemCis) further improved overall survival. In TOPAZ-1, the median OS for patients with advanced BTC treated with durvalumab plus GemCis was 12.8 months, compared with 11.5 months in the chemotherapy-alone control group, representing an improvement of 1.3 months (HR\u0026thinsp;=\u0026thinsp;0.80). In KEYNOTE-966, the median OS for patients with advanced BTC treated with pembrolizumab plus GemCis was 12.7 months, compared with 10.9 months in the chemotherapy-alone control group, representing an improvement of 1.8 months (HR\u0026thinsp;=\u0026thinsp;0.83)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e In the present study, we retrospectively included 11 patients with locally advanced PHC at our center who were considered by a multidisciplinary team (MDT) to have the potential for curative resection but were also at high risk of recurrence and treated them with a neoadjuvant immunochemotherapy strategy. After neoadjuvant treatment, the objective response rate (ORR) was 27.3% (3/11). Ultimately, all 11 patients underwent surgical exploration, and 10 proceeded to surgical resection. Of the entire treated cohort, 5 patients achieved R0 resection, corresponding to an overall R0 resection rate of 45.5% (5/11). Adverse events during neoadjuvant treatment included hematologic toxicities, neutropenia (54.5%, 6/11), anemia (45.5%, 5/11) and thrombocytopenia (36.4%, 4/11), as well as non-hematologic toxicities, including elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels (72.7%, 8/11) and nausea/vomiting (54.5%, 6/11). Three patients (27.3%, 3/11) developed biliary tract infection secondary to biliary stent obstruction and were treated with prompt stent replacement and anti-infective therapy. Among severe (grade III\u0026ndash;IV) adverse events, ALT/AST elevation accounted for a relatively high proportion (18.2%, 2/11). These events improved with active symptomatic treatment, including hepatoprotective and nutritional support.\u003c/p\u003e \u003cp\u003eWithin 90 days after surgery, 3 patients (27.3%, 3/11) experienced Clavien-Dindo grade\u0026thinsp;\u0026ge;\u0026thinsp;III complications, and no perioperative deaths were observed. The perioperative and short-term follow-up results suggest that this neoadjuvant immunochemotherapy approach is safe and manageable.\u003c/p\u003e \u003cp\u003eThis finding is clinically meaningful given the complexity of perioperative management in this population. Patients with locally advanced PHC often require prolonged biliary drainage, repeated reassessment of liver function and remnant volume, and major hepatobiliary resection with or without vascular reconstruction. Under these circumstances, the observation that treatment-related toxicity remained manageable and that severe postoperative morbidity was not excessive suggests that neoadjuvant immunochemotherapy did not appear to compromise subsequent surgical feasibility in appropriately selected patients.\u003c/p\u003e \u003cp\u003eKuriyama et al. investigated neoadjuvant chemotherapy alone and found that, among 11 patients with locally advanced disease, only 6 ultimately underwent curative surgery, of whom 4 achieved R0 resection, corresponding to an overall R0 resection rate of 22.2% (4/18) among all patients who received neoadjuvant therapy. In contrast, all 11 patients included in our study had locally advanced perihilar cholangiocarcinoma, and after neoadjuvant immunochemotherapy, 10 ultimately underwent surgical resection and 5 achieved R0 resection, yielding an R0 resection rate of 45.5%. This rate approaches the 57% R0 resection rate reported for low-risk PHC patients treated at 24 international high-volume centers specializing in the surgical management of PHC[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, this comparison should be interpreted cautiously because the present cohort was not composed of low-risk resectable PHC, but rather of patients with locally advanced disease characterized by major biliary extension, vascular invasion, regional lymph node metastasis, and/or intrapancreatic bile duct involvement. In addition, our R0 rate was calculated using the entire treated cohort as the denominator, thereby also incorporating patients in whom radical resection could not ultimately be completed. From this perspective, an overall R0 resection rate of 45.5% may still be considered clinically meaningful in such a high-risk population.\u003c/p\u003e \u003cp\u003eNeoadjuvant treatment should not only focus on the objective response rate (ORR), but also on the depth of pathological response, particularly major pathological response (MPR). Wu et al. (2025) defined MPR as a residual viable tumor proportion of \u0026le;\u0026thinsp;10% and demonstrated that it is an independent prognostic factor for both OS and recurrence-free survival (RFS)[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Matsuyama et al. reported that after neoadjuvant GS chemotherapy, only approximately 17% of resected patients achieved complete, marked, or moderate histological response, whereas most patients showed either no response or only minimal response[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These findings suggest that conventional preoperative chemotherapy can induce substantial pathological regression in only a limited subset of patients. In our study, 3 patients had a residual viable tumor proportion of \u0026le;\u0026thinsp;10% on postoperative pathological assessment, corresponding to an MPR rate of 30% (3/10).\u003c/p\u003e \u003cp\u003eOne patient in our cohort achieved pCR. Case 2 was a 49-year-old man initially diagnosed with PHC (Bismuth\u0026ndash;Corlette type IIIb). Exploratory laparotomy revealed involvement of the right hepatic artery, which was considered difficult to reconstruct safely after resection. After pathological confirmation of PHC by biopsy, he received 5 cycles of immunochemotherapy (GEMOX plus tislelizumab) beginning in December 2022. During treatment, he developed neutropenia and elevated ALT/AST levels, both graded as CTCAE grade 1 adverse events, and achieved a partial response according to RECIST 1.1. In June 2023, he underwent reoperation. Both intraoperative and postoperative pathological examinations showed no residual carcinoma in the extrahepatic bile duct, surrounding tissues, or hilar lymph nodes, indicating pCR. He has had no tumor recurrence and remains disease-free 38 months after treatment at the follow-up cutoff.\u003c/p\u003e \u003cp\u003eTaken together, judging from the R0 resection rate and MPR rate, neoadjuvant immunochemotherapy may be superior to chemotherapy alone or chemoradiotherapy alone. However, this study has several limitations. First, it is a single-center retrospective analysis with a small sample size. Second, there was heterogeneity in the immunochemotherapy regimens used. Third, the follow-up duration remains relatively short and is insufficient to fully evaluate long-term survival benefit and the risk of rare complications. Future multicenter, prospective, large-scale studies are needed to confirm the safety and efficacy of immunochemotherapy as neoadjuvant treatment for PHC.\u003c/p\u003e \u003cp\u003eFurther efforts should also focus on the identification of reliable biomarkers predictive of treatment response, pathological regression, and survival benefit, so as to improve patient selection and optimize perioperative treatment strategies. Because the present study was not designed to evaluate the independent contribution of targeted agents, the potential role of targeted therapy in the neoadjuvant setting remains unclear. Future studies may further clarify whether patients with biomarker-defined disease, such as tumors harboring potentially targetable alterations including HER2, could derive additional benefit from tailored combination strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this real-world case series, neoadjuvant immunochemotherapy showed manageable toxicity and yielded encouraging rates of tumor response, pathological regression, and R0 resection in selected patients with locally advanced PHC. These findings support further prospective evaluation of this strategy in larger multicenter cohorts.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003cbr\u003e\u003c/strong\u003eThe authors sincerely thank the Follow-up Center of Sun Yat-sen Memorial Hospital, Sun Yat-sen University, for support in patient follow-up, and Professor Pei\u0026rsquo;e Cai for her valuable assistance in language editing and revision of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXS: Conceptualization, data curation, formal analysis, and manuscript drafting.\u003c/p\u003e\n\u003cp\u003eYK: Data curation, statistical analysis, manuscript drafting, and figure preparation.\u003c/p\u003e\n\u003cp\u003eHL: Pathological review, pathological evaluation, and interpretation of pathological findings.\u003c/p\u003e\n\u003cp\u003eGS: Data collection and critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eYY: Statistical analysis and critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eQT and XY: Study implementation and manuscript review.\u003c/p\u003e\n\u003cp\u003eCL: Study supervision, manuscript revision, and funding acquisition.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Guangzhou Key Laboratory of Precise Diagnosis and Treatment of Biliary Tumors (202201020375), Clinical Major Technology Project of Guangzhou Municipal Health Commission (2023P-ZD17), and Guangzhou Science and Technology Program (2024A04J4776). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available because they contain potentially identifiable patient information, but de-identified data are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Medical Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSKY-2025-893-01), and was conducted in accordance with the Declaration of Helsinki. Informed consent was waived by the Medical Ethics Committee due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of the clinical details and accompanying images was obtained from the patient described in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNagino M. Perihilar cholangiocarcinoma: a surgeon's perspective. iLIVER. 2022;1(1):12\u0026ndash;24. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.iliver.2022.03.004\u003c/span\u003e\u003cspan address=\"10.1016/j.iliver.2022.03.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBanales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13(5):261\u0026ndash;80. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/nrgastro.2016.51\u003c/span\u003e\u003cspan address=\"10.1038/nrgastro.2016.51\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChong N, Yao L, Wang M, Xu Y. The evolving landscape of bench-to-bedside translation in the era of neoadjuvant platforms: perspectives and opportunities. Holistic Integrative Oncology. 2026;5(1). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s44178-025-00219-8\u003c/span\u003e\u003cspan address=\"10.1007/s44178-025-00219-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHewitt DB, Brown ZJ, Pawlik TM. Current Perspectives on the Surgical Management of Perihilar Cholangiocarcinoma. Cancers (Basel). 2022;14(9). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/cancers14092208\u003c/span\u003e\u003cspan address=\"10.3390/cancers14092208\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenson AB, 3rd, D'Angelica MI, Abrams T, Ahmed A, Akce M, Anaya DA, et al. Biliary Tract Cancers, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw. 2025;23(9):403\u0026ndash;18. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.6004/jnccn.2025.0042\u003c/span\u003e\u003cspan address=\"10.6004/jnccn.2025.0042\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVogel A, Bridgewater J, Edeline J, Kelley RK, Klumpen HJ, Malka D, et al. Biliary tract cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(2):127\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.annonc.2022.10.506\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2022.10.506\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Q-q, Shi X-d, Ye Y-f, Tang Q-b, Lin H-m, Yu X-h, et al. Real-world experience of postoperative adjuvant chemoimmunotherapy in patients with perihilar cholangiocarcinoma at high risk of recurrence. Cancer Immunology, Immunotherapy. 2023;72(6):1753\u0026ndash;61. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00262-022-03362-7\u003c/span\u003e\u003cspan address=\"10.1007/s00262-022-03362-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228\u0026ndash;47. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ejca.2008.10.026\u003c/span\u003e\u003cspan address=\"10.1016/j.ejca.2008.10.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi J, Zhou S, Xu X, Zheng Q, Zhang F, Luo C, et al. Sintilimab and anlotinib with gemcitabine plus cisplatin in advanced biliary tract cancer: SAGC a randomized phase 2 trial. Nat Commun. 2025;16(1):5559. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41467-025-60119-3\u003c/span\u003e\u003cspan address=\"10.1038/s41467-025-60119-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLehrke HD, Heimbach JK, Wu TT, Jenkins SM, Gores GJ, Rosen CB, et al. Prognostic Significance of the Histologic Response of Perihilar Cholangiocarcinoma to Preoperative Neoadjuvant Chemoradiation in Liver Explants. Am J Surg Pathol. 2016;40(4):510\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/pas.0000000000000588\u003c/span\u003e\u003cspan address=\"10.1097/pas.0000000000000588\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnox JJ, McNamara MG, Bazin IS, Oh DY, Zubkov O, Breder V, et al. A phase III randomized study of first-line NUC-1031/cisplatin vs. gemcitabine/cisplatin in advanced biliary tract cancer. J Hepatol. 2025;83(2):358\u0026ndash;66. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jhep.2025.01.040\u003c/span\u003e\u003cspan address=\"10.1016/j.jhep.2025.01.040\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOh DY, Ikeda M, Lee CK, Rojas C, Hsu CH, Kim JW, et al. Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial. Hepatology. 2025;81(3):823\u0026ndash;36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/HEP.0000000000000965\u003c/span\u003e\u003cspan address=\"10.1097/HEP.0000000000000965\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMueller M, Breuer E, Mizuno T, Bartsch F, Ratti F, Benzing C, et al. Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers. Ann Surg. 2021;274(5):780\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/SLA.0000000000005103\u003c/span\u003e\u003cspan address=\"10.1097/SLA.0000000000005103\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu G, Chen X, Luo R, Koh YX, Lim TKH, Chew V, et al. Histopathologic Grading of Residual Tumor Predicts Survival of Intrahepatic Cholangiocarcinoma Patients Treated With Neoadjuvant Therapy. American Journal of Surgical Pathology. 2025;49(6):578\u0026ndash;87. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/pas.0000000000002359\u003c/span\u003e\u003cspan address=\"10.1097/pas.0000000000002359\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsuyama R, Mori R, Ota Y, Homma Y, Yabusita Y, Hiratani S, et al. Impact of Gemcitabine Plus S1 Neoadjuvant Chemotherapy on Borderline Resectable Perihilar Cholangiocarcinoma. Ann Surg Oncol. 2022;29(4):2393\u0026ndash;405. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1245/s10434-021-11206-4\u003c/span\u003e\u003cspan address=\"10.1245/s10434-021-11206-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"holistic-integrative-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Holistic Integrative Oncology](https://link.springer.com/journal/44178)","snPcode":"44178","submissionUrl":"https://submission.springernature.com/new-submission/44178/3","title":"Holistic Integrative Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"perihilar cholangiocarcinoma, locally advanced disease, neoadjuvant therapy, immunochemotherapy, R0 resection","lastPublishedDoi":"10.21203/rs.3.rs-9279539/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9279539/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eRadical resection remains the main potentially curative treatment for perihilar cholangiocarcinoma (PHC), but many patients are diagnosed at locally advanced stage and are not suitable for curative surgery. This study aimed to investigate the safety and preliminary efficacy of neoadjuvant immunochemotherapy in this population\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe retrospectively analyzed patients with locally advanced PHC who received neoadjuvant immunochemotherapy at our center between January 2020 and January 2026. The primary endpoints were the R0 resection rate and major pathological response rate (MPR). Secondary endpoints included the objective response rate (ORR), adverse events during neoadjuvant immunochemotherapy, postoperative complications within 90 days, and the 1-year and 2-year overall survival (OS) rates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eEleven patients with locally advanced PHC were included, each with at least one of the features: Bismuth–Corlette type IV disease, regional lymph node metastasis, tumor invasion of hepatic hilar vessels, or tumor involvement of the intrapancreatic bile duct. All patients completed at least two cycles of neoadjuvant immunochemotherapy. The neoadjuvant regimen mainly consisted of gemcitabine-based chemotherapy combined with a PD-1 inhibitor. Peritoneal tumor seeding was identified in 1 patient during laparotomy, and radical surgery was therefore abandoned; the remaining 10 patients successfully proceeded to tumor resection. The R0 resection rate was 45.5% (5/11; 95% CI, 16.7%–76.6%), and the MPR rate was 30.0% (3/10; 95% CI, 6.7%–65.2%), including 1 patient who achieved a pathological complete response (pCR). Radiologically, 3 patients (27.3%, 3/11) were assessed as having a partial response (PR), corresponding to an ORR of 27.3%. The most common hematologic toxicities during neoadjuvant therapy were neutropenia (54.5%, 6/11), anemia (45.5%, 5/11) and thrombocytopenia (36.4%, 4/11). The most common non-hematologic toxicities were elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) levels (72.7%, 8/11) and nausea/vomiting (54.5%, 6/11). During the first 90 postoperative days, 3 patients (27.3%, 3/11) experienced Clavien–Dindo grade ≥ III complications, with no perioperative mortality. With a median follow-up of 9.31 months, the 1-year OS rate was 87.5% (95% CI, 67.3%–100%), and the 2-year OS rate was 58.3% (95% CI, 25.1%–100%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eNeoadjuvant immunochemotherapy may achieve downstaging in patients with locally advanced PHC and appears safe and manageable.\u003c/p\u003e","manuscriptTitle":"Real world neoadjuvant immunochemotherapy for locally advanced perihilar cholangiocarcinoma: experience from an 11-Case series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-26 15:49:01","doi":"10.21203/rs.3.rs-9279539/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-04-17T03:00:07+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-10T09:05:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-07T09:12:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Holistic Integrative Oncology","date":"2026-03-31T11:57:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"holistic-integrative-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Holistic Integrative Oncology](https://link.springer.com/journal/44178)","snPcode":"44178","submissionUrl":"https://submission.springernature.com/new-submission/44178/3","title":"Holistic Integrative Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"98364bd8-9398-4418-93f5-b07d9ce8095f","owner":[],"postedDate":"April 26th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-26T15:49:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-26 15:49:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9279539","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9279539","identity":"rs-9279539","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}