Resection and reconstruction of the largest abdominal vein system (the inferior vena cava, hepatic, and portal vein): a narrative review.

Background and Objective: As tumors invade major abdominal veins, surgical procedures are transformed from simple and basic to complicated and challenging. In this narrative review, we focus on what is currently known and not known regarding the technical aspects of major abdominal venous resection and its reconstruction, patency, and oncologic benefit in a cross-cutting perspective. Methods: A systematic literature search was performed in PubMed and Semantic Scholar from inception up to October 18, 2023. We reviewed 106 papers by title, abstract, and full text regarding resection or reconstruction of the inferior vena cava, hepatic vein confluence, portal vein (PV), and middle hepatic vein (MHV) tributaries in living donor liver transplantation (LDLT) in a cross-cutting perspective. Key Content and Findings: The oncologic benefit of aggressive hepatic vein resection with suitable reconstruction against adenocarcinoma remains unclear, and further studies are required to clarify this point. A superior mesenteric/PV resection is now a universal, indispensable, and effective procedure for pancreatic ductal adenocarcinoma. Although many case series using tailor-made autologous venous grafts have been reported, not only size mismatch but also additional surgical incisions and a longer operation time remain obstacles for venous reconstruction. The use of autologous alternative tissue remains only an alternative procedure because the patency rate of customized tubular conduit type to interpose or replace the resected vein is not known. Unlike arterial replacement, venous replacement using synthetic vascular grafts is still rarely reported and there are several inherent limitations except for reconstruction of tributaries of MHV in LDLT. Conclusions: Various approaches to abdominal vein resection and replacement or reconstruction are technically feasible with satisfactory results. Synthetic vascular grafts may be appropriate but have a certain rate of complications.

Advanced Adenosquamous Carcinoma of the Ampulla of Vater Treated with Adjuvant Chemotherapy after Pancreaticoduodenectomy.

Introduction: Adenosquamous carcinoma (ASC) of the ampulla of Vater (AmV) is rare. The prognosis is generally worse in patients undergoing resection of ASC of the AmV than in those undergoing resection of adenocarcinoma of the AmV because the former shows early recurrence after surgery. A treatment strategy for ASC of the AmV has not been established, and the efficacy of adjuvant chemotherapy after curative resection is unclear. Given the paucity of data, we report a case of ASC of the AmV that was curatively resected and treated with adjuvant chemotherapy. Case Presentation: A 66-year-old man presented with pruritus and anorexia. Contrast-enhanced computed tomography revealed a tumor measuring 1.6 cm in diameter located at the AmV and distal bile duct. Biopsy revealed adenocarcinoma of the AmV. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination contradictorily revealed ASC of the AmV and lymph node metastases. The postoperative course of the patient was uneventful, and he was discharged on day 25. The patient underwent S-1 adjuvant chemotherapy for 6 months and did not exhibit any postoperative recurrence for a follow-up duration of 28 months. Conclusion: Although treatment strategy for ASC of the AmV has not been established, our case shows that surgery followed by S-1 adjuvant chemotherapy could improve prognosis of patients with such tumors. However, further research is required to determine the efficacy of adjuvant chemotherapy and treatment strategies for resectable ASC of the AmV.

Intraductal Papillary Mucinous Neoplasm Surveillance Leads to Early Diagnosis and Better Outcomes of Concomitant Cancer.

OBJECTIVE: To examine whether long-term surveillance of intraductal papillary mucinous neoplasms (IPMNs) leads to early diagnosis and better clinical outcomes of pancreatic ductal adenocarcinomas (PDACs) developing concomitantly with IPMNs. SUMMARY BACKGROUND DATA: Long-term image-based surveillance is recommended for patients with low-risk IPMNs. However, it is unknown whether the surveillance can improve surgical and survival outcomes of patients with concomitant PDACs. METHODS: Using a prospective single-institutional cohort of 4,620 patients with pancreatic cysts including 3,638 IPMN patients, we identified 63 patients who developed concomitant PDAC during long-term surveillance. We compared overall survival (OS) of 46 cases with concomitant PDAC to that of 460 matched cases diagnosed with non-IPMN-associated PDAC at the same institution. Multivariable hazard ratios and 95% confidence intervals (CIs) for overall mortality were computed using the Cox regression model with adjustment for potential confounders. RESULTS: Concomitant PDACs were identified at an earlier cancer stage compared to non-IPMN-associated PDACs with 67% and 38% cases identified at stage 2 or earlier, respectively (P<0.001) and 57% and 21% cases with R0 resection, respectively (P<0.001). Compared to non-IPMN-associated PDACs, concomitant PDACs were associated with longer OS (P=0.034) with a multivariable hazard ratio of 0.61 (95% CI, 0.39-0.96). The 5-year survival rate of patients with concomitant PDAC was higher compared to patients with non-IPMN-associated PDAC (34% vs. 18%, respectively; P=0.018). CONCLUSIONS: The surveillance for patients with IPMNs was associated with early identification of concomitant PDACs and longer survival of patients diagnosed with this malignancy.

Update on the Diagnosis and Treatment of Combined Hepatocellular Cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a unique type of liver tumor that contains both hepatocellular carcinoma and cholangiocarcinoma components within a single tumor. The fifth edition of the World Health Organization classification provides a definition and diagnostic criteria for cHCC-CCA. However, the heterogeneous histomorphology and presentation resulting from variation of the proportion of each component poses challenges for clinical diagnosis and treatment. A diagnosis of cHCC-CCA may be suggested by the synchronous elevation of serum tumor markers for hepatocellular carcinoma and cholangiocarcinoma, a mixed enhancement pattern on imaging, and a discrepancy between the elevation of tumor marker and the imaging enhancement pattern. Histopathological examination using hematoxylin and eosin staining is considered the gold standard for diagnosing cHCC-CCA, and comprehensive examination of resection or biopsy specimens is crucial for an accurate diagnosis. Currently, there is no standard treatment for cHCC-CCA, and surgery is the mainstay. Anatomic hepatectomy with lymphadenectomy is among the recommended surgical procedures. The role of liver transplantation in the management of cHCC-CCA is still uncertain. Transarterial chemoembolization may be effective for unresectable cHCC-CCA, particularly for hypervascular tumors. However, the available evidence does not support systemic therapy for advanced cHCC-CCA. The prognosis of cHCC-CCA is generally poor, and there is no established staging system. Further research is needed to better understand the histogenesis and clinical management of cHCC-CCA. This review provides an overview of the current literature on cHCC-CCA with a focus on its clinical characteristics, pathological diagnosis, and management.

Thick silk fibroin vascular graft: A promising tissue-engineered scaffold material for abdominal vein grafts in middle-sized mammals.

Abdominal vein replacement with synthetic tissue-engineered vascular grafts constructed from silk-based scaffold material has not been reported in middle-sized mammals. Fourteen canines that underwent caudal vena cava replacement with a silk fibroin (SF) vascular graft (15 mm long and 8 mm diameter) prepared with natural silk biocompatible thread were allocated to two groups, thin and thick SF groups, based on the graft wall thickness. The short-term patency rate and histologic reactions were compared. The patency rate at 2 weeks after replacement in the thin and thick SF groups was 50% and 88%, respectively (p = 0.04). CD31-positive endothelial cells covered the luminal surface of both groups at 4 weeks. The elastic modulus of the thick SF graft was significantly better than that of the thin SF graft (0.0210 and 0.0007 N/m2, p < 0.01). Roundness of thick SF groups (o = 0.8 mm) was better than thin SF (o = 2.0 mm). There was significant difference between the groups (p = 0.01). SF vascular grafts are a promising tissue-engineered scaffold material for abdominal venous system replacement in middle-sized mammals, with thick-walled grafts being superior to thin-walled grafts.

Optimal age to discontinue long-term surveillance of intraductal papillary mucinous neoplasms: comparative cost-effectiveness of surveillance by age.

OBJECTIVE: Current guidelines recommend long-term image-based surveillance for patients with low-risk intraductal papillary mucinous neoplasms (IPMNs). This simulation study aimed to examine the comparative cost-effectiveness of continued versus discontinued surveillance at different ages and define the optimal age to stop surveillance. DESIGN: We constructed a Markov model with a lifetime horizon to simulate the clinical course of patients with IPMNs receiving imaging-based surveillance. We calculated incremental cost-effectiveness ratios (ICERs) for continued versus discontinued surveillance at different ages to stop surveillance, stratified by sex and IPMN types (branch-duct vs mixed-type). We determined the optimal age to stop surveillance as the lowest age at which the ICER exceeded the willingness-to-pay threshold of US$100 000 per quality-adjusted life year. To estimate model parameters, we used a clinical cohort of 3000 patients with IPMNs and a national database including 40 166 patients with pancreatic cancer receiving pancreatectomy as well as published data. RESULTS: In male patients, the optimal age to stop surveillance was 76-78 years irrespective of the IPMN types, compared with 70, 73, 81, and 84 years for female patients with branch-duct IPMNs <20 mm, =20-29 mm, ≥30 mm and mixed-type IPMNs, respectively. The suggested ages became younger according to an increasing level of comorbidities. In cases with high comorbidity burden, the ICERs were above the willingness-to-pay threshold irrespective of sex and the size of branch-duct IPMNs. CONCLUSIONS: The cost-effectiveness of long-term IPMN surveillance depended on sex, IPMN types, and comorbidity levels, suggesting the potential to personalise patient management from the health economic perspective.

Metallic Stents for Hepatic Venous Outflow Obstruction After Living-Donor Liver Transplantation and their Therapeutic Effects.

BACKGROUND: Living-donor liver transplantation (LDLT) is established as a standard therapy for end-stage liver disease; however, vessel reconstruction is more demanding due to the short length and small size of the available structures compared with deceased-donor whole liver transplantation. Interventional radiology (IR) has become the first-line treatment for vascular complications after LDLT. Hepatic venous outflow obstruction (HVOO) is a life-threatening complication after LDLT. The aim of this study of 592 adult-to-adult LDLT cases was to investigate the safety and efficacy of stent implantation for HVOO after LDLT. METHODS: Records of patients who developed HVOO requiring any treatment were collected with special reference to the metallic stent implantation. There were 232 left-side grafts and 360 right-side grafts. Sixteen cases developed HVOO after LDLT with an incidence rate of 2.7%, 5 with a left liver graft (2%), and 11 with a right-side graft (3%). The IR was attempted for 14 cases; among those, 8 cases were treated by stent implantation. RESULTS: The technical success rate of the initial stent implantation was 100%. The pressure gradient at the stenotic site significantly improved from 12.2 (range, 10.9-20.4 cm H2O) to 3.9 cm H2O (range, 1.4-8.2 cm H2O; P = .03). The volume of the congested graft liver decreased significantly from 1448 (range, 788-2170 mL) to 1265 mL (range, 748-1665 mL; P = .01), and the serum albumin level improved significantly from 3.3 (range, 1.7-3.7 g/dL) to 3.7 g/dL (range, 2.9-4.1 g/dL; P = .02). No procedure-related complication was noted, and the long-term stent patency was 100%. CONCLUSION: Metallic stent implantation for stenotic venous anastomosis after LDLT is a safe and effective treatment.

The Effect of Renin-Angiotensin System Inhibitors in Patients Undergoing Pancreatic Cancer Resection.

OBJECTIVES: The local renin-angiotensin system promotes angiogenesis and proliferation via vascular endothelial growth factor or epidermal growth factor receptor expression. In this study, we aimed to evaluate the impact of angiotensin system inhibitors (ASIs) on long-term outcomes in patients undergoing surgical resection of pancreatic ductal adenocarcinoma (PDAC). METHODS: A single institutional retrospective analysis was performed using the medical records of patients who underwent pancreatic resection with curative intent for PDAC between January 2005 and December 2018. Patient characteristics and surgical outcomes were compared between patients taking ASIs and those who are not. RESULTS: A total of 272 patients were included in the study and classified into the ASI group (n = 121) and the non-ASI group (n = 151). The median overall survival times in the ASI group and non-ASI group were 38.0 and 34.0 months ( P = 0.250), and the median recurrence-free survival times were 24.0 and 15.0 months ( P = 0.025), respectively. Multivariate analysis for recurrence-free survival identified the use of ASIs ( P = 0.020), CA19-9 level >500 IU/L ( P = 0.010), positive lymph node metastasis ( P < 0.001), and no adjuvant chemotherapy ( P < 0.001) as independent prognostic factors. CONCLUSIONS: The use of ASI may improve long-term outcomes after surgery for PDAC.

Effect of Smoke Evacuator on Reduction of Volatile Organic Compounds and Particles in Surgical Smoke: A Randomized Controlled Trial.

BACKGROUND: Surgical smoke is an occupational health problem and is increasingly recognized as a potential source of virus transmission. Dedicated smoke evacuators are used to protect against surgical smoke exposure. We tested the hypothesis that using smoke evacuators would reduce volatile organic compounds and the number of particles in surgical smoke during the laparotomy procedure. STUDY DESIGN: A randomized, double-blind clinical trial was conducted in patients undergoing laparotomy from June 11, 2021, to March 30, 2022, to compare the effectiveness of smoke evacuators with a control (registration, UMIN000044250). The primary outcome was a change in the acetaldehyde level. Secondary outcomes were changes in the formaldehyde level and particle count assessed by the particle size of 0.3, 0.5, 1.0, and 5.0 nm. RESULTS: A total of 42 patients were randomized and assessed (smoke evacuator group, n = 22 vs control group, n = 20). The acetaldehyde level was significantly lower in the smoke evacuator group than in the control group: mean (95% CI), 10.6 (3.7 to 17.5) vs 47.2 (19.9 to 74.5) µg/m 3 , p < 0.001. Similarly, the formaldehyde level was 72.2% lower in the smoke evacuator group than in the control group. Particle counts by each particle size category were 80% to 95% lower in the smoke evacuator group than in the control group (all, p < 0.001). CONCLUSIONS: Dedicated smoke evacuators reduced the level of acetaldehyde and formaldehyde, and the number of particles in surgical smoke, minimizing the potential exposure to volatile organic compounds and particle matters during surgery.

Evaluation of pancreatic chymotrypsin activity for on-site prediction of clinically relevant postoperative pancreatic fistula.

OBJECTIVES: Although the risk of complications due to postoperative pancreatic fistula (POPF) have been evaluated based on the amylase level in drained ascitic fluid, this method has much room for improvement regarding diagnostic accuracy and facility of the measurement. This study aimed to investigate the clinical value of measuring pancreatic chymotrypsin activity for rapid and accurate prediction of POPF after pancreaticoduodenectomy. METHODS: In 52 consecutive patients undergoing pancreaticoduodenectomy, the chymotrypsin activity in pancreatic juice was measured by calculating the increase in fluorescence intensity during the first 5 min after activation with an enzyme-activatable fluorophore. The predictive value for clinically relevant POPF (CR-POPF) was compared between this technique and the conventional method based on the amylase level. RESULTS: According to receiver operating characteristic analyses, pancreatic chymotrypsin activity on postoperative day (POD) 3 measured with a multiplate reader had the highest predictive value for CR-POPF (area under the curve [AUC], 0.752; P < 0.001), yielding 77.8 % sensitivity and 68.8 % specificity. The AUC and sensitivity/specificity of the amylase level in ascitic fluid on POD 3 were 0.695 (P = 0.053) and 77.8 %/41.2 %, respectively. Multivariable analysis identified high pancreatic chymotrypsin activity on POD 3 as an independent risk factor for CR-POPF. Measurement of pancreatic chymotrypsin activity with a prototype portable fluorescence photometer could significantly predict CR-POPF (AUC, 0.731; P = 0.010). CONCLUSION: Measurement of pancreatic chymotrypsin activity enabled accurate and rapid prediction of CR-POPF after pancreaticoduodenectomy. This can help surgeons to implement appropriate drain management at the patient's bedside without delay.

A data-informed timeline for hospital discharge with a reasonably low risk of unplanned readmission after open and minimally invasive liver resections.

BACKGROUND: Postoperative complications following liver resection remain high, ranging from 20% to 50%. Patients are hospitalized for a certain period of time following liver resection because of the risk of postoperative complications. We hypothesized that the risk of complications decreases with each complication-free postoperative day after open and minimally invasive liver resections and can be stratified using a recently reported three-level complexity classification. METHODS: Patients undergoing first liver resection without concomitant other organ resections between 2006 and 2019 were included. The three-level complexity classification was used to categorize liver resection procedures into grades I-III. We assessed the rate of cumulative postoperative complications from the time of liver resection to the time of post-hepatectomy complications (≥ Clavien-Dindo grade II). RESULTS: Of the 911 patients included, 200 underwent resection of grade I procedures, 185 underwent resection of grade II procedures, and 526 underwent resection of grade III procedures. The risks of post-hepatectomy complications changed over time and were stratified by surgical complexity. For patients at the time of liver resection, the estimated 30-day complication rate was 21.8% for open grade I resection, 26.7% for open grade II resection, 38.4% for open grade III resection, 8.6% for laparoscopic grade I resection, and 12.5% for laparoscopic grade II resection. For patients without complications at 7 days, the estimated 30-day complication rate decreased to 2.1% for open grade I, 9.2% for open grade II, 17.6% for open grade III, 1.3% for laparoscopic grade I, and 4.5% for laparascopic grade II. CONCLUSIONS: The post-hepatectomy complication risks were stratified by surgical complexity, liver resection approach, and the period without complication after liver resection.

Utilizing risk-stratified pathways to personalize post-hepatectomy discharge planning: A contemporary analysis of 1,354 patients.

BACKGROUND: While risk-stratified post-hepatectomy pathways (RSPHPs) reduce length-of-stay, can they stratify hepatectomy patients by risk of early postoperative events. METHODS: 90-day outcomes from consecutive hepatectomies were analyzed (1/1/2017-12/31/2021). Pre/post-pathway analysis was performed for pathways: minimally invasive surgery ("MIS"); non-anatomic resection/left hepatectomy ("low-intermediate risk"); right/extended hepatectomy ("high-risk"); "Combination" operations. Time-to-event (TTE) analyses for readmission and interventional radiology procedures (IRPs) was performed. RESULTS: 1354 patients were included: MIS/n= â€‹119 (9 â€‹%); low-intermediate risk/n= â€‹443 (33 â€‹%); high-risk/n= â€‹328 (24 â€‹%); Combination/n= â€‹464 (34 â€‹%). There was no difference in readmission (pre: 13 â€‹% vs. post:11.5 â€‹%, p â€‹= â€‹0.398). There were fewer readmissions in post-pathway patients amongst MIS, low-intermediate risk, and Combination patients (all p â€‹> â€‹0.1). 114 (8.4 â€‹%) patients required IRPs. Time-to-readmission and time-to-IR-procedure plots demonstrated lower plateaus and flatter slopes for MIS/low-intermediate-risk pathways post-pathway implementation (p â€‹< â€‹0.001). CONCLUSION: RSPHPs can reliably stratify patients by risks of readmission or need for an IR procedure by predicting the most frequent period for these events.

Two-step artificial intelligence algorithm for liver segmentation automates anatomic virtual hepatectomy.

BACKGROUND: Anatomic virtual hepatectomy with precise liver segmentation for hemilivers, sectors, or Couinaud's segments using conventional three-dimensional simulation is not automated and artificial intelligence (AI)-based algorithms have not yet been applied. METHODS: Computed tomography data of 174 living-donor candidates for liver transplantation (training data) were used for developing a new two-step AI algorithm to automate liver segmentation that was validated in another 51 donors (validation data). The Pure-AI (no human intervention) and ground truth (GT, full human intervention) data groups were compared. RESULTS: In the Pure-AI group, the median Dice coefficients of the right and left hemilivers were highly similar, 0.95 and 0.92, respectively; sectors, posterior to lateral: 0.86-0.92, and Couinaud's segments 1-8: 0.71-0.89. Labeling of the first-order branch as hemiliver, right or left portal vein perfectly matched; 92.8% of the second-order (sectors); 91.6% of third-order (segments) matched between the Pure-AI and GT data. CONCLUSIONS: The two-step AI algorithm for liver segmentation automates anatomic virtual hepatectomy. The AI-based algorithm correctly divided all hemilivers, and more than 90% of the sectors and segments.

Incidence of and Risk Factors for Incisional Hernia After Hepatectomy for Colorectal Liver Metastases.

BACKGROUND: Incisional hernia (IH) is common after major abdominal surgery; however, the incidence after hepatectomy for cancer has not been described. We analyzed incidence of and risk factors for IH after hepatectomy for colorectal liver metastases (CLM). METHODS: Patients who underwent open hepatectomy with midline or reverse-L incision for CLM at a single institution between 2010 and 2018 were retrospectively analyzed. Postoperative CT scans were reviewed to identify IH and the time from hepatectomy to hernia. Cumulative IH incidence was calculated using competing risk analysis. Risk factors were assessed using Cox proportional hazards model analysis. The relationship between IH incidence and preoperative body mass index (BMI) was estimated using a generalized additive model. RESULTS: Among 470 patients (median follow-up: 16.9 months), IH rates at 12, 24, and 60 months were 41.5%, 51.0%, and 59.2%, respectively. Factors independently associated with IH were surgical site infection (HR: 1.54, 95% CI 1.16-2.06, P = 0.003) and BMI > 25 kg/m2 (HR: 1.94, 95% CI 1.45-2.61, P < 0.001). IH incidence was similar in patients undergoing midline and reverse-L incisions and patients who received and did not receive a bevacizumab-containing regimen. The 1-year IH rate increased with increasing number of risk factors (zero: 22.2%; one: 46.8%; two: 60.3%; P < 0.001). Estimated IH incidence was 10% for BMI of 15 kg/m2 and 80% for BMI of 40 kg/m2. CONCLUSION: IH is common after open hepatectomy for CLM, particularly in obese patients and patients with surgical site infection. Surgeons should consider risk-mitigation strategies, including alternative fascial closure techniques.

Probe-based confocal laser endomicroscopy for real-time evaluation of colorectal liver metastasis in resected surgical specimens.

Probe-based confocal laser endomicroscopy (pCLE) enables real-time examination of tissue structure. This study investigated pCLE with or without fluorescein sodium for the intraoperative diagnosis of colorectal liver metastasis (CLM) and detection of surgical margins. Thirty-four specimens of CLM and adjacent noncancerous tissue were obtained from 21 patients and examined by pCLE between May 2017 and March 2018. Images were obtained both without and with fluorescein sodium applied to the cut surface and compared with hematoxylin and eosin-stained tissue. Fluorescence intensity (FI) was measured by luminance-analysis software. Without external fluorophores, pCLE visualized 91.2% of CLM tissues as an irregular structure with low autofluorescence and 90.5% of noncancerous liver tissues as a regular structure with high autofluorescence. The median FI was significantly lower in cancer than in benign tissue in patients without chemotherapy [70.4 (51.6-110) vs. 48.3 (39.0-59.4), p = 0.002] and with chemotherapy [67.9 (54.6-89.2) vs. 48.6 (28.8-82.1), p < 0.001]. The border was clearly visible; pCLE with fluorescein sodium clearly showed their morphologies. In summary, our study demonstrated real-time pCLE distinguished CLM and noncancerous tissue by differences in structure and FI regardless of prehepatectomy chemotherapy. Fluorescein spray facilitated clear visualization of differences in the morphology.

Conditional recurrence analysis of intrahepatic cholangiocarcinoma: Changes in recurrence rate and survival after recurrence resection by disease-free interval.

AIM: The prognosis of patients with resected intrahepatic cholangiocarcinoma (ICC) is still unsatisfactory, with a high recurrence rate. We aimed to evaluate risks of recurrence changing over time and the survival benefit of resection for recurrent ICC. METHODS: This study included patients who underwent hepatectomy for ICC during 1995-2020. Risk factors for recurrence-free survival (RFS) in patients undergoing initial resection and overall survival (OS) in patients who developed recurrence after initial resection were analyzed. Conditional cumulative incidence of recurrence was assessed. RESULTS: A total of 169 patients were included in the study and 114 patients (67.5%) developed recurrence. Cumulative analyses showed that the 5-year recurrence rate was 69.3% at the time of initial resection but decreased to 24.8% in patients free from recurrence at 2 years after initial resection and 2.6% in patients free from recurrence at 4 years. Re-resection was carried out in 26 (22.8%) of 114 patients who developed recurrence. Multivariable Cox proportional hazards model analysis indicated re-resection (hazard ratio [HR] 0.19; 95% confidence interval [CI] 0.11-0.40, p < 0.001), microvascular invasion (MVI) (HR 2.39; 95% CI 1.05-5.40, p = 0.037), and disease-free interval (months) (HR 0.97; 95% CI 0.95-1.00, p = 0.067) were significantly associated with longer OS after recurrence. CONCLUSIONS: Although the rate of recurrence remains high, conditional cumulative recurrence rate analysis showed that the rate of recurrence decreased by disease-free interval. Resection of recurrent ICC was associated with improved OS, particularly among patients with longer disease-free interval and absence of MVI after initial hepatectomy.

Post-operative mortality and recurrence patterns in pancreatic cancer according to KRAS mutation and CDKN2A, p53, and SMAD4 expression.

Alterations in KRAS, CDKN2A (p16), TP53, and SMAD4 genes have been major drivers of pancreatic carcinogenesis. The clinical course of patients with pancreatic cancer in relation to these driver alterations has not been fully characterised in large populations. We hypothesised that pancreatic carcinomas with different combinations of KRAS mutation and aberrant expression of CDKN2A, p53, and SMAD4 might show distinctive recurrence patterns and post-operative survival outcomes. To test this hypothesis, we utilised a multi-institutional cohort of 1,146 resected pancreatic carcinomas and assessed KRAS mutations by droplet digital polymerase chain reaction and CDKN2A, p53, and SMAD4 expression by immunohistochemistry. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were computed according to each molecular alteration and the number of altered genes using the Cox regression models. Multivariable competing risks regression analyses were conducted to assess the associations of the number of altered genes with specific patterns of recurrence. Loss of SMAD4 expression was associated with short DFS (multivariable HR, 1.24; 95% CI, 1.09-1.43) and OS times (multivariable HR, 1.27; 95% CI, 1.10-1.46). Compared to cases with 0-2 altered genes, cases with three and four altered genes had multivariable HRs for OS of 1.28 (95% CI, 1.09-1.51) and 1.47 (95% CI, 1.22-1.78), respectively (ptrend < 0.001). Patients with an increasing number of altered genes were more likely to have short DFS time (ptrend = 0.003) and to develop liver metastasis (ptrend = 0.006) rather than recurrence at local or other distant sites. In conclusion, loss of SMAD4 expression and an increasing number of altered genes were associated with unfavourable outcomes in pancreatic cancer patients. This study suggests that the accumulation of the four major driver alterations can confer a high metastatic potential to the liver, thereby impairing post-operative survival among patients with pancreatic cancer.