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Background: Liver resection represents the first choice of treatment for primary and secondary liver malignancies, offering the patient the best chance of long-term survival. The extensive use of major hepatectomy increases the risk of post-hepatectomy liver failure (PHLF), which is associated with a high frequency of postoperative complications, mortality and increased length of hospital stay. Aims: The aim of this review is to investigate the different risk factors related to the occurrence of PHLF and to identify the limits for a safe liver resection in patients with normal liver and injured liver (cirrhosis, cholestasis, steatosis and post-chemotherapy liver injury). Methods: A literature search was undertaken in PubMed and related search engines, looking for articles relating to hepatic failure following hepatectomy in normal liver or injured liver. Results: In spite of improvements in surgical and postoperative management, the parameters determining how much liver can be resected are still largely undefined. A number of preoperative, intraoperative and postoperative factors all contribute to the likelihood of liver failure after surgery. The safe limits for liver resection can be estimated from the data of the literature for patients with normal liver and for those with different types of liver injury. Conclusions: Preoperative assessment that includes evaluation of liver volume and function of the remnant liver is a mandatory prerequisite before major hepatectomy. The critical residual liver volume for patients able to predict PHLF is mainly related to the presence of pre-existing liver disease and liver function. Among patients with normal liver, the limit for safe resection ranges from 20 to 30% future remnant liver of total liver volume. In patients with injured liver (cirrhosis, cholestasis or steatosis), preoperative assessment of the risk of PHLF should include future remnant liver volumetry and accurate liver function evaluation, including different dynamic liver function tests.

Increasing evidence advocates the prognostic role of RDW in various tumours. We analysed 591 patients to assess whether RDW is a prognostic factor for overall (OS) and cancer-related survival (CRS) for patients with colorectal cancer (CRC). The data were retrieved from a retrospective database. The optimal cut-off value for RDW was set at 14.1%; accordingly, two groups were considered: those with a value equal or lower than 14.1% (L-RDW), and those with a value higher than 14.1% (H-RDW). The mean value of RDW rose from pT1 to pT4 tumours. H-RDW correlated with age above the mean, colonic location of the lesion, pT and TNM stage. Finally, H-RDW was significantly associated with the intent of surgery: almost 50% of patients who underwent a non-curative resection presented H-RDW, compared to 19.3% in R0 resections. OS was significantly lower in patients with H-RDW. CRS was similar in the two groups. Stratifying patients according to TNM stage worse OS was associated with H-RDW only in early stages, whereas there was no difference for stages II-IV. Multivariate analysis confirmed that H-RDW was not an independent prognostic factor. Although H-RDW correlated with some negative clinical-pathological factors, it did not seem to independently influence OS and CRS.

Background Cholangiocarcinoma can be classified in intrahepatic cholangiocarcinoma (ICC) and perihilar cholangiocarcinoma (PCC). Moreover, PCC includes two different forms: extrahepatic (EH) PCC, which arises from the perihilar EH large ducts, and intrahepatic (IH) PCC, in which a significant liver mass invades the perihilar bile ducts. In this study, we investigated the molecular profile and molecular prognostic factors in EH-PCC, IH-PCC, and ICC submitted to curative surgery. Methods Ninety-one patients with cholangiocarcinoma (38 EH-PCC, 18 IH-PCC, and 35 ICC), who underwent curative surgery in a single tertiary hepatobiliary surgery referral center were assessed for mutational status in 56 cancer-related genes. Results The most frequently mutated genes in EH-PCC were KRAS (47.4 %), TP53 (23.7 %) and ARID1A (15.8 %); in IH-PCC were KRAS (22.2 %), PBRM1 (16.7 %), and PIK3CA (16.7 %); and in ICC were IDH1 (17.1 %), NRAS (17.1 %), and BAP1 (14.3 %). The presence of mutations in ALK , IDH1 , and TP53 genes was significantly associated with poor prognosis in patients with EH-PCC ( p  < 0.001, p  = 0.043, and p  = 0.019, respectively). Mutation of the TP53 gene was significantly associated with poor prognosis in patients with IH-PCC ( p  = 0.049). The presence of mutations in ARID1A , PIK3C2G , STK11 , TGFBR2 , and TP53 genes was significantly associated with poor prognosis in patients with ICC ( p  = 0.012, p  = 0.030, p  = 0.030, p  = 0.011, and p  = 0.011, respectively). Conclusions Mutational gene profiling identified different gene mutations in EH-PCC, IH-PCC, and ICC. Moreover, our study reported specific prognostic genes that can identify patients with poor prognosis after curative surgery who may benefit from traditional or target adjuvant treatments.

PurposeTo investigate the effectiveness of percutaneous approaches to treat bile leak and to propose an anatomical classification of biliary fistula to guide the most appropriate percutaneous approach.Materials and MethodsFifty-six patients with bile leakage after hepatobiliary surgery were included. Based on preoperative images and postoperative fistulogram images, three categories of bile leakage were defined. Every category was treated with non-surgical approaches (internal–external percutaneous drainage, percutaneous/endoscopic biliodigestive anastomosis with rendez-vous technique and biliodigestive percutaneous anastomosis with totally radiologic rendez-vous).ResultsIn 44/56 (78%) patients, anatomical conformation was “direct communication” (bile ducts upstream from the leak present a direct communication with downstream ducts) and their treatment was conventional percutaneous drainage. In 5/56 (9%), anatomical conformation was “indirect communication” (bile ducts upstream from the leak communicate with downstream ducts through a bile collection) and treatment was percutaneous/endoscopic rendez-vous technique. In 7/56 (12%), anatomical conformation was “no communication” (ducts upstream from the leak are completely excluded from ducts downstream) and treatment was totally radiologic rendez-vous. In 54/56 (96%) during the follow-up, cholangiography revealed complete resolution of the leak without residual stenosis and drains were removed. Complications occurred in 12/56 (21%). Procedure-related mortality was 0%. Ten patients, after > 6 months from resolution of their fistula and drain removal, died due to cancer recurrence. Currently, 44/56 patients (77%) at long-term follow-up (> 12 months) are alive, without bile leak.ConclusionOur classification helps to choose the most proper percutaneous approach in all kinds of bile leakage, even in severe cases; these are safe techniques with a high success rate.

Background: Biliary tract cancer (BTC) is an aggressive malignancy often diagnosed at an advanced stage and is associated with a poor prognosis. Non-invasive approaches can facilitate the early detection and identification of biomarkers to inform treatment strategies. Liquid biopsy, particularly through the analysis of circulating tumor DNA (ctDNA), has recently emerged as a valuable clinical and prognostic tool for guiding BTC management. Methods: The PubMed, Cochrane Library, and Wiley databases were searched for terms related to BTC and ctDNA, aiming to include studies evaluating the value of ctDNA as a predictor of overall (OS), progression-free (PFS), disease (DFS), and recurrence-free survival (RFS). Results: Twelve studies encompassing 2374 patients were considered eligible. The detection of ctDNA was associated with higher mortality and progression risk (HR 2.61, 95%CI 2.19–3.11 and HR 2.69, 95%CI 1.82–3.98, respectively), regardless of the ctDNA sampling time. The variant allele frequency (VAF) emerged as a valuable predictive marker, with higher VAF values being associated with higher mortality and progression risk (HR 2.37, 95%CI 1.83–3.06, and HR 2.22, 95%CI 1.40–3.53, respectively) compared with low levels of VAF. This association was observed regardless of chemotherapy administration, suggesting that VAF may serve as a potential marker of treatment resistance. Conclusions: This review underscores the clinical relevance of ctDNA status and related markers, such as VAF, in the management and prognostic evaluation of BTC. The findings support the integration of liquid biopsy into clinical practice to improve risk stratification, enable the early detection of relapse, and inform personalized treatment strategies, ultimately contributing to more precise and effective patient care in BTC.

BackgroundHepatopancreatoduodenectomy is performed to achieve curative resection of malignant biliary tumors.1 However, the morbidity and mortality associated with this challenging surgical procedure remain high, and optimal indications remain unclear.2–4 Biliary papillomatosis (BP) is a precursor lesion of cholangiocarcinoma. This video shows hepatopancreatoduodenecomy for multifocal cholangiocarcinoma in the setting of BP.PatientA 75-year-old man with a medical history of cholecystectomy presented with obstructive jaundice. Magnetic resonance colangiopancreatography and computed tomography scan showed diffuse biliary dilation with mild enhancing nodularities in the whole extrahepatic bile duct. Cholangioscopy with biopsies proved cholangiocarcinoma arising from BP at the prepapillary common bile duct (CBD) and the biliary confluence. The second-order right ducts were free of disease. The patient underwent nasobiliary drainage and was considered for hepatopancreatoduodenecomy.TechniqueA right subcostal incision was performed. Intraoperative ultrasound showed BP of the intrapancreatic CBD spreading only to the left bile duct. En bloc resection of the left liver, caudate lobe, and CBD was performed together with pylorus-preserving pancreatoduodenectomy. The reconstruction phase was performed on a single-loop by duct-to-mucosa pancreatojejunostomy, two-duct biliojejunostomy with mucosa-to-mucosa alignment, and duodenojejunostomy. Transanastomotic external stents were used for biliary and pancreatic drainage. Histopathologic examination confirmed foci of cholangiocarcinoma arising from BP. Resection margins were negative. Lymph node metastasis, microvascular invasion, perineural invasion, and mucin secretion were absent. The patient was discharged on postoperative day 14 without complications. At the 2-year follow-up assessment, he was alive and free of disease.ConclusionCholangiocarcinoma arising from BP is a proper indication for hepatopancreatoduodenectomy. The long-term oncologic benefits might outweigh the possible perioperative complications.5,6

Introduction The prognostic significance of lymph node dissection (LND), the number and status of harvested lymph nodes (LNs), and the lymph node ratio (LNR) are still under debate in intrahepatic (ICC) and perihilar (PCC) cholangiocarcinoma. The aims of this study were to evaluate the prognostic value of the extent of LN dissection, the number of positive LNs, the distribution of positive LNs along different LN stations, and the LNR in a cohort of patients with ICC and PCC who underwent surgical resection and to compare the different prognostic values of lymph node involvement. Material and Methods A retrospective analysis was done evaluating extent of LND, number, status, and location of harvested LNs in a cohort of 145 patients with cholangiocarcinoma submitted to surgical resection with curative intent from 1990 to 2012. Results Seventy patients had ICC and 75 had PCC. The median survival times of patients with N0 and N+ tumors were 42 and 19 months in ICC patients ( p  = 0.05) and 42 and 22 months in PCC patients ( p  = 0.01). In patients without LN metastases, the median survival times of patients with up to three LNs retrieved and with more than three LNs retrieved were 38 and 69 months in ICC patients ( p  = 0.05) and 18 and 43 months in PCC patients ( p  = 0.04), respectively. In N+ patients, the location of positive LNs (hepatoduodenal ligament or other regional stations) did not influence overall survival in ICC or PCC patients ( p  = 0.6). The median survival times of patients with LNRs of 0 and >0.25 were 43 and 19 months in ICC patients ( p  = 0.01); the 0–0.25 group did not reach the value. In PCC patients, median survival of 0, 0–0.25, and >0.25 groups of patients were 42, 23, and 11 months ( p  = 0.01), respectively. Conclusions LN metastasis is a major prognostic factor after surgical resection of cholangiocarcinoma. The number of harvested LNs and the LNR showed a high prognostic value in ICC and PCC.

The incidence and mortality rates of intrahepatic cholangiocarcinoma have been rising worldwide. Few patients present an early-stage disease that is amenable to curative surgery and after resection, high recurrence rates persist. To identify new independent marker related to aggressive behaviour, two prognostic groups of patient were selected and divided according to prognostic performance. All patients alive at 36 months were included in good prognostic performers, while all patients died due to disease within 36 months in poor prognostic performers. Using high-coverage target sequencing we analysed principal genetic alterations in two groups and compared results to clinical data. In the 33 cases included in poor prognosis group, TP53 was most mutated gene ( p  = 0.011) and exclusively present in these cases. Similarly, ARID1A was exclusive of this group ( p  = 0.024). TP53 and ARID1A are mutually exclusive in this study. Statistical analysis showed mutations in TP53 and ARID1A genes and amplification of MET gene as independent predictors of poor prognosis ( TP53 , p  = 0.0031, ARID1A , p  = 0.0007, MET , p  = 0.0003 in Cox analysis). LOH in PTEN was also identified as marker of disease recurrence ( p  = 0.04) in univariate analysis. This work improves our understanding of aggressiveness related to this tumour type and has identified novel prognostic markers of clinical outcome.

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation. The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation.

Background and Aims The role of lymph node dissection (LND) in patients with small intrahepatic cholangiocarcinoma (ICC) is still under debate. The aims of this study were to compare the lymph node (LN) status and its correlation with survival among patients with ICC stratified by tumor size. Methods A retrospective analysis of a multi-institutional series of 259 patients undergoing curative-intent surgery was carried out. Patients were stratified into Small-ICC (≤ 3 cm) and Large-ICC (> 3 cm) based on tumor size. Results There were 53 and 206 patients in Small-ICC and Large-ICC groups, respectively. The incidence of LND was 62% among Small-ICC patients and 78% among Large-ICC patients ( p  = 0.016). LN metastases were identified in 30.3% and 38.5% of Small-ICC and Large-ICC patients, respectively ( p  = 0.37). No differences in terms of number of harvested LN and LN metastases were identified comparing Small- and Large-ICC patients. The 5-year overall survival (OS) was 52.6% for Small-ICC and 36.2% for Large-ICC ( p  = 0.024). The 5-year OS according to the LN status (N0 vs N+) was 84.8% and 36.0% ( p  = 0.032) in Small-ICC, and 45.7% and 12.1% in Large-ICC ( p  < 0.001), respectively. Conclusion While Small-ICC patients with no LN metastasis had a good long-term survival, the LN resulted in an important variable associated with survival also for patients in this group. Moreover, the incidence of LN metastasis did not differ when comparing Small-ICC and Large-ICC patients, suggesting that LND is mandatory in the surgical treatment of ICC regardless of tumor size.