Large Duct Research Articles

Single-cell transcriptomic analysis suggests two molecularly distinct subtypes of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by performing single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues, we find that S100P and SPP1 are two markers for iCCA perihilar large duct type (iCCAphl) and peripheral small duct type (iCCApps). S100P + SPP1− iCCAphl has significantly reduced levels of infiltrating CD4+ T cells, CD56+ NK cells, and increased CCL18+ macrophages and PD1+CD8+ T cells compared to S100P-SPP1 + iCCApps. The transcription factor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCApps has significantly more SPP1+ macrophage infiltration, less aggressiveness and better survival than S100P + SPP1− iCCAphl. Moreover, S100P-SPP1 + iCCApps harbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3+ stemness. Our study extends the understanding of the diversity of tumor cells in iCCA.

Small duct primary sclerosing cholangitis: A discrete variant or a bridge to large duct disease, a practical review.

The natural history, associations with inflammatory bowel disease (IBD), and long-term outcomes of large duct primary sclerosing cholangitis (ldPSC) have been well documented. Small duct primary sclerosing cholangitis (sdPSC) is a much less common and relatively more benign variant. The natural history of sdPSC has been difficult to characterize given the limited number of studies in the literature especially with regards to the subset of patients who progress to large duct involvement. It has been unclear whether sdPSC represented a subset of ldPSC, an earlier staging of ldPSC, or a completely separate and distinct entity of its own. Strong associations between sdPSC and IBD have been established with suspicion that concurrent sdPSC-IBD may be a key prognostic factor in determining which patients are at risk of progression to ldPSC. Little is known regarding the discrete circumstances that predisposes some patients with sdPSC to progress to ldPSC. It has been suspected that progression to large biliary duct involvement subjects this subset of patients to potentially developing life-threatening complications. Here the authors conducted a thorough review of the published sdPSC literature using Pubmed searches and cross-referencing to compile all accessible studies regarding cohorts of sdPSC patients in order better characterize the subset of sdPSC patients who progress to ldPSC and the associated outcomes.

Acoustical Treatments on Ventilation Ducts through Walls: Experimental Results and Novel Models

Sound reduction is complex to estimate for acoustical treatments on ventilation ducts through walls. Various acoustical treatments are available for ventilation ducts, including internal lining (absorption along the inner perimeter), external lagging (external sound insulation), silencer, and suspended ceilings. Previous studies have examined how silencers and the internal lining affect the sound transmission of ventilation ducts. However, there are few theories to predict the effect of external lagging in combination with ventilation ducts and how the total sound reduction is affected. This article aims to investigate different acoustical treatments and develop theoretical models when external lagging with stone wool is used to reduce flanking sound transmission via the surface area of ventilation ducts. Theoretical models are developed for external lagging and compared with measurement data. Measurements and theory are generally in good agreement over the third-octave band range of 100–5000 Hz. The developed models clarify that the distance closest to the wall has the main impact on sound reduction for a combined system with a wall and a ventilation duct. Suspended ceilings and silencers are found to be enough as acoustical treatments for certain combinations of ventilation ducts and walls. However, external lagging seems to be the only effective solution in offices and schools when a large ventilation duct passes through a wall with high sound reduction.

Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review.

Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).

Correlation of LGR5 expression and clinicopathological features in intrahepatic cholangiocarcinoma

Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a known cancer stem cell marker. However, there are no reported analyses of LGR5 mRNA expression in normal liver and liver cancer tissues. Here, we evaluated LGR5 expression by RNAscope, a newly developed RNA in situ hybridization technique, using a tissue microarray consisting of 25 samples of intrahepatic cholangiocarcinoma (ICC) selected from the medical archives at our hospital. LGR5 expression levels were divided into high and low expression groups by the five-grade scoring system, and clinicopathological features were analyzed. Low LGR5 expression was identified in some normal hepatocytes and bile duct cells. In addition, LGR5 expression was identified in all bile duct cancer samples except one case. Well-differentiated to moderately-differentiated adenocarcinoma tended to show higher LGR5 expression than poorly-differentiated adenocarcinoma (P = 0.0561), and the large duct type showed significantly higher LGR5 expression levels than the small duct type (P = 0.0225). Patients in the high LGR5 expression group tended to have good overall survival (OS) (P = 0.0623). The Cox proportional hazard regression model revealed that the high LGR5 expression group showed independently better OS for ICC (P = 0.0285). High LGR5 expression is possibly a good prognosis factor in ICC. However, the detailed mechanism of LGR5 in this disease remains unclear, and further analysis is warranted.

Comparison of endoscopic papillary large‐balloon dilatation with endoscopic sphincterotomy in clearing large common bile duct stones: A systematic review and meta‐analysis of randomized controlled trials

AbstractThere are three methods to retrieve large common bile duct stones, the first is endoscopic sphincterotomy (EST), the second is endoscopic papillary large‐balloon dilatation (EPLBD), and the third is limited EST plus EPLBD. Although EST is the most popularly used method, it has higher risk of bleeding complication and basket stuck. EPLBD alone without EST demonstrated safe and quick in the clinical practice, but there were only few studies focused on comparing EST or EPLBD alone. Thus, this study aims to compare the efficacy and safety of EPLBD with EST. We searched for PubMed, Embase, and Cochrane Library databases to collect relevant articles until August 31st, 2019. We included randomized controlled trials, common bile duct stones > 10 mm, comparison of endoscopic papillary large‐balloon dilatation with endoscopic sphincterotomy, and patients older than 18. We compare endoscopic papillary large‐balloon dilatation with endoscopic sphincterotomy on the clearance of large common bile duct stones, the adverse events, and the need for mechanical lithotripsy. This systematic review and meta‐analysis was registered on PROSPERO and the registration number is CRD42020150485. Total six studies met inclusion criteria and 762 participants were enrolled. The data revealed that endoscopic papillary large‐balloon dilatation alone was comparable to endoscopic sphincterotomy on the clearance of large common bile duct stones (RR = 1.02, 95% CI: 0.93‐1.12), the adverse events (RR = 1.01, 95% CI: 0.71‐1.43) and the need for mechanical lithotripsy. In the subgroup analysis, the requirement of mechanical lithotripsy decreased in the non‐Chinese group (RR = 0.58, 95% CI: 0.41‐0.84). The efficacy and safety to clean large common bile duct stones are comparable in either EPLBD or EST. In addition, EPLBD alone not only saves the operation time but also reduces the chance of mechanical lithotripsy in the subgroup analysis.

Perihilar cholangiocarcinoma: a surgeon's perspective

Perihilar cholangiocarcinoma (PHC) is defined anatomically as tumors located in the extrahepatic biliary tree proximal to the origin of the cystic duct. However, as the boundary between the extrahepatic and intrahepatic bile ducts is not well defined, PHC potentially includes two types of tumors: one is the extrahepatic type, which arises from the large hilar bile duct, and the other is the intrahepatic type, which has an intrahepatic component with invasion of the hepatic hilus. The new American Joint Commission on Cancer tumor-node-metastasis staging system for PHC was well revised; an important revision is that the Bismuth type IV was removed from T4 stage determinants. Most patients with PHC present with obstructive jaundice, and preoperative biliary drainage is mandatory. Previously, percutaneous transhepatic biliary drainage was used in many centers; however, it has been accepted that endoscopic nasobiliary drainage is the most suitable method for PHC. Recently, inside-stents have also been adopted for biliary drainage, with favorable results. Portal vein embolization is widely performed as presurgical treatment for patients undergoing extended hepatectomy to minimize postoperative liver dysfunction. Surgical resection of PHC is technically demanding and continues to be the most difficult challenge for hepatobiliary surgeons. Because of advances in diagnostic and surgical techniques, surgical outcomes and survival rates after resection have steadily improved. However, survival rates, especially for patients with lymph node metastasis, are unsatisfactory, and establishing a protocol for effective adjuvant chemotherapy is an urgent task. Further synergy of endoscopists, radiologists, oncologists, and surgeons is required to conquer this intractable disease.

Efficacy of extracorporeal shock wave lithotripsy of pancreatic stone in chronic pancreatitis

Background: To study overall outcome of ESWL therapy in large pancreatic duct stone as first line therapy in chronic pancreatitis.Methods: A prospective, observational study which took place in MGM medical college and the patient were admitted in general surgery department. Patients were selected based on the inclusion criteria composed of upper abdominal pain, weight loss, oily stools and presence of pancreatic stones or ductal irregularity/ parenchymal atrophy determined by various radiological investigations.Results: In this study 11 patients with pancreatic stones were recruited in duration of 2 years. Among 11 patients included in this study 63.33% were males and 36.375% were females. The mean age of males and females were 35.57 and 40.50 years respectively. It was observed that all study subjects had abdominal pain and history of pancreatitis. 36% patient had single calculi and 64% patient had multiple calculi. 18% calculi were present in the body of pancreas and 46% calculi in head of pancreas. All these patient had undergone ESWL procedures with minimum number of 400 shocks and maximum number of 4600. Among the patients it was noted that 73% had successful complete clearance of calculi, 18% had partial clearance and 9% had no clearanceConclusions: ESWL is efficient tool for the treatment of pancreatic calculi but can be used alone it is adjunct tool to ERCP. Endoscopy, etc.

A210 HEPATOLITHIASIS IS A FREQUENT AND PROGNOSTIC FINDING IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS

AimsIntrahepatic biliary stones (hepatolithiasis) are not well characterised in patients with primary sclerosing cholangitis (PSC).MethodsChart reviews were conducted on 302 patients with a histologic or radiographic diagnosis of PSC followed at the Toronto Centre for Liver Disease. Radiographic data were collected for patients between the years 2008–2018. Depending on frequency of testing, magnetic resonance imaging (MRI) and ultrasound (US) data was reviewed every 3–5 years. We assessed factors associated with hepatolithiasis based on sex, race, age and phenotype of PSC and inflammatory bowel disease (IBD). Qualitative radiographic findings on image report review, episodes of cholangitis, endoscopic retrograde cholangiopancreatography (ERCP) and occurrence of cholangiocarcinoma (CCA), death and transplant were documented. Data are reported with median and IQR and analysed using χ 2 and Mann-Whitney U tests.Results302 patients were reviewed. The median time to follow-up, defined as from date of diagnosis to last clinic visit or to transplantation date, was 98 months (IQR = 87). The mean age at diagnosis was 38 (SD = 15.1) years; 54% of patients were male. A total of 224 patients had IBD (74%). Of the 302 patients, 80 patients (26%) had evidence of hepatolithiasis on US or MRI. Patients with hepatolithiasis were more likely to be younger (37.4 vs 39.1, p = 0.025), male (65% vs. 50%, p = 0.021), and have large duct disease (99% vs. 88%, p = 0.004). Imaging report review revealed patients with hepatolithiasis were more likely to have intrahepatic biliary thickening (76% vs. 45%, p < 0.001), extrahepatic biliary thickening (69% vs. 50%, p = 0.003), focal biliary dilation (96% vs. 78%, p < 0.001) and disease characterised by more reported strictures on qualitative imaging report review (89% vs 69%, p < 0.001). Concomitant presence of cholelithiasis was greater in the hepatolithiasis vs. the non-hepatolithiasis group (45% vs. 19%, p < 0.001). There was no significant difference in the prevalence of hepatic or portal venous thrombosis in both groups. Patients with hepatolithiasis more likely have experienced acute ascending cholangitis (50% vs. 20%, p < 0.001) and need for ERCP (50% vs. 35%, p = 0.020). CCA was numerically higher in the hepatolithiasis group (8.75% vs. 4%, p = 0.1). Patients with hepatolithiasis received transplant more frequently (26.3% vs 12.2%, p < 0.001) with no significant difference in mortality.ConclusionsHepatolithiasis is common in PSC and associated with an increased clinical and radiologic disease burden. Funding AgenciesNone

Treatment patterns and clinical outcomes among patients with biliary tract cancers in a large commercially insured US population.

398 Background: The American Cancer Society estimates 11,980 new cases of biliary tract cancers (BTCs), including gall bladder and nearby large bile ducts, to occur in the US in 2021. BTCs are characterized by poor prognosis and limited treatment choices. Gemcitabine (GEM) plus platinum chemotherapy is the standard of care. However, there are limited data regarding real-world treatment patterns and clinical outcomes for BTCs patients receiving systemic treatments (ST). Methods: A retrospective cohort study of BTCs patients who received first line (1L) ST, using US private payer Cancer Care Quality Program (CCQP) data and administrative claims from the HealthCore Integrated Research Database (HIRD) between 07/01/2014 - 03/31/2021, was performed. Index date was defined as first claim of ST within 60 days of documented 1L therapy in the CCQP from 01/01/2015 - 09/30/2020. Adult BTCs patients with ≥6 months pre-index enrollment were included. Patients with ampullary cancer, brain/ CNS metastases, other primary cancer before BTCs diagnosis were excluded. Treatment patterns and clinical outcomes were examined. Results: A total of 413 patients [Stage IV (n=315), III (n=44), II/I (n=54)] were identified. The mean (SD) age was 61 (10) years, 55% were female, and there were 67% intrahepatic, 22% gall bladder, and 11% extrahepatic BTCs. There were 150 (36%), 203 (49%), 27 (7%) patients with baseline ECOG scores of 0, 1, 2+, respectively. At pre-index, frequently observed conditions included non-alcoholic liver diseases (75%), hypertension (65%), dyslipidemia (48%), mental health conditions (47%), gallstones (41%), gastrointestinal disorders (39%), and obesity (32%). GEM was commonly used as monotherapy (6%) or in combinations (85%): GEM + Cisplatin (64%), GEM + Oxaliplatin (6%), GEM + Capecitabine (5%), GEM + others (10%). Median overall survival was 11.5 months. The table summarizes clinical outcomes by stage. Conclusions: Most patients with BTCs received 1L GEM-based therapies, experienced poor survival and had high hospitalization rates. These data indicate need for future innovative approaches for management of BTC.[Table: see text]

The Liver Biopsy in Neonatal Cholestasis: Just a Cherry on Top?

Content available: Author Audio Recording.

Intrahepatic cholangiocarcinoma: Tumour heterogeneity and its clinical relevance.

Treatment of intrahepatic cholangiocarcinoma (iCCA) is currently at a significant turning point due to the identification of isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted with currently available therapies. Clinical trials of these targeted therapies have been promising, and the iCCA patients who may benefit from these targeted treatments can be identified by pathological examination prior to molecular investigations. This is because IDH mutations and FGFR fusions are mainly seen in the small duct type iCCA, a subtype of iCCA defined by the 5th World Health Organization classification, which can be recognized by the pathological diagnostic process. Therefore, pathology plays an important role in precision medicine for iCCA, not only in confirming the diagnosis, but also in identifying the iCCA patients who may benefit from targeted treatments. However, caution is advised with the pathological diagnosis, as iCCA shows tumour heterogeneity, making it difficult to distinguish small duct type iCCA from hepatocellular carcinoma (HCC), and combined HCC-CCA. This review focuses on the pathological/molecular features of both subtypes of iCCA (large and small duct types), as well as their diagnostic pitfalls, clinical relevance, and future perspectives.

Endoscopic papillary large balloon dilation with or without sphincterotomy for extraction of large bile duct stones

ObjectivesThis work aimed to evaluate the safety and efficacy of endoscopic papillary large balloon dilatation (EPLBD) with or without endoscopic sphincterotomy (EST) in extraction of large common bile duct stones (CBDSs).BackgroundEST combined with EPLBD has been proposed as an alternative to manage large bile duct stones. However, recent reports indicate that EPLBD alone may be safe and effective in this setting.Patients and methodsFrom July 2019 to December 2021, we prospectively compared EPLBD alone (group I, n=100) with EST+EPLBD (group II, n=100) for the treatment of large CBDSs. CBDS clearance rate, frequency of mechanical lithotripsy usage, total procedure time, and intraendoscopic and postendoscopic complications were analyzed.ResultsStatistical analysis revealed that there were no significant differences between the studied groups regarding the use of mechanical lithotripsy (6 vs. 8%, P=0.579), overall and initial stone clearance rates (92 vs. 88%, P=0.346; and 81 vs. 76%, P=0.389, respectively), procedure-related pancreatitis (3 vs. 1%, P=0.312), or other intraendoscopic and postendoscopic adverse events, but there was a significant difference in terms of total procedure time (41.23±10.6 vs. 36.87±8.06, P=0.001).ConclusionThe therapeutic outcomes and complications of sole EPLBD for the removal of large CBDSs were comparable to those of EPLBD with prior EST.

Uniformity and energy evaluation of equal cross-section ventilation system(ECVS) for long tunnel in underground buildings

Uniform ventilation is important for the safety of long tunnel in underground buildings, it is difficult to install the large size air duct to ensure the centerline of each cross-section of the traditional variable cross-section ventilation system(VCVS) superimposed on the same horizontal axis, which is significant to the ventilation uniformity, energy consumption and installation convenience of the VCVS. On the contrary, each cross-section of the Equal Cross-section Ventilation System (ECVS) has the same horizontal axis, therefore, it is more convenient to manufacture and install the large size air duct in the underground long tunnel and achieve uniform ventilation. This study proposes an ECVS, using computational fluid dynamics(CFD) numerical simulation analyzed the influences of main duct velocity, aspect ratio, and outlet numbers on uniformity and energy consumption per unit air volume(ECPV). It revealed that when each ventilation equalizer's valve Angle β is given, uniformity of air supply decreases slightly with an increase in the inlet velocity. When the air supply main duct aspect ratio increases, the outlet velocity standard deviation range is from 0.22 to 0.34. When outlet numbers N=7~12 and β are constant, air supply uniformity and resistance coefficient ξ also decrease with the decrease of outlet numbers. The outlet number has a significant influence on the uniformity of system air supply, main duct velocity, and aspect ratio are relatively small. ECPV is positively correlated with the main duct velocity and outlet number, and is negatively correlated with aspect ratio.

Invasive papillary carcinoma of the breast – A rare case report

Invasive papillary carcinoma (IPC) of the breast is a rare entity, comprising approximately <1%–2% of all breast cancers. It is most commonly seen in postmenopausal females and rarely seen in males. IPC is arising from the dilated duct or large duct. They are low-grade tumors microscopically consisting of well-circumscribed solid nodules of the neoplastic cells separated by fibrovascular cores. It has excellent prognosis, so exact diagnosis is necessary. We report a case of a 68-year-old postmenopausal female, who came with complaints of a lump in the left breast for the past 2 months, modified radical mastectomy was done, and the specimen was sent for histopathological examination. Immunohistochemistry was done estrogen receptor and progesterone receptor positive with human epidermal growth factor receptor 2 negative. The case is presented due to its rarity.

Development and Validation of a Nomogram Model to Predict the Prognosis of Intrahepatic Cholangiocarcinoma

Background: The effective method for predicting prognosis of ICC is still lack. This study aims to establish and verify an effective prognostic nomogram model for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy. Materials and Methods: A nomogram model was developed in a cohort of 127 patients from January 2015 to December 2019. General clinical characteristics including preoperative physical examination data and postoperative pathological features were obtained. The independent risk factors identified by univariate and multivariate COX proportional hazards regression models were used to construct nomogram model. Predictive accuracy and discriminative ability were determined using a concordance index and a calibration curve. In addition, the clinical significance of postoperative pathological subtypes was analyzed by Kaplan-Meier survival analysis. Results: Univariate analysis and multivariate COX regression analysis revealed that CEA, maximum diameter, tumor number, and large duct type ICC was the independent risk factors. These variables were incorporated into the nomogram and the C-index for one year and three year overall survival prediction was 0.765 (95% CI: 0.672–0.814) and 0.695 (95% CI: 0.672–0.814), respectively. Postoperative pathological analysis showed that the large duct ICC had a distinct clinicopathological features and poor outcome. Conclusion: The proposed nomogram enables a prognostic prediction for patients with ICC and postoperative subclassification of ICC is of great significant to the prognosis of ICC.

Subtype Classification of Intrahepatic Cholangiocarcinoma Using Liver MR Imaging Features and Its Prognostic Value

Introduction: Small-duct (SD) and large-duct (LD) subtypes of cholangiocarcinoma have been investigated for their prognostic factors. This study aimed to evaluate the diagnostic value of liver magnetic resonance imaging (MRI) in differentiating SD and LD types of intrahepatic cholangiocarcinoma (iCCA) and its prognostic value in predicting survival outcomes. Methods: One hundred forty patients with surgically confirmed iCCAs (93 SD type and 47 LD type) who had available preoperative gadoxetic acid-enhanced liver MR images were retrospectively included. MRI features suggestive of the LD type over the SD type were analyzed using multivariate logistic analyses. Postoperative recurrence-free survival (RFS) and overall survival (OS) for 107 patients with available survival data were compared according to MRI features. Results: MRI features suggestive of the LD type included infiltrative contour (odds ratio [OR] 14.2, 95% confidence interval [CI]: 2.5–81.7, p = 0.003), diffuse biliary dilatation (OR 9.7, 95% CI: 1.2–76.9, p = 0.032), no arterial phase hyperenhancement (OR 17.8, 95% CI: 2.7–118.6, p = 0.003), and vascular invasion (OR 4.5, 95% CI: 1.3–15.4, p = 0.018). When two or more features were combined, sensitivity was 59.6% (28/47), and specificity was 95.7% (89/93) in discriminating the LD type. RFS/OS was significantly shorter in patients with two or more MRI features, compared to those with none or one (310 days vs. 529 days, p = 0.011/964 days vs. 2,023 days, p = 0.010). Conclusions: Preoperative liver MRI may help predict the pathological subtype of iCCAs as either the SD type or LD type, allowing preoperative identification of patients with poorer survival outcomes.

Critical Illness Cholangiopathy in COVID-19 Long-haulers

Critical Illness Cholangiopathy in COVID-19 Long-haulers

Síndrome de Caroli em um cão

ABSTRACT: Caroli syndrome is characterized by a combination of intrahepatic biliary ductal ectasia and congenital ductal fibrosis due to the failure of involution of ductal plates and large intrahepatic ducts. This study aims to report Caroli syndrome in a dog, with emphasis on clinical characteristics, complementary examinations, and diagnostic approach. A 1-year-old mixed-breed intact male dog was presented with a 7-day history of acute vomiting and anorexia. Clinical evaluation revealed severe jaundice, abdominal pain, dehydration, lethargy, and abdominal distension. Ultrasonography revealed hepatic cysts filled with fluid. Exploratory laparotomy was performed to clarify the imaging findings; however, the dog died shortly after surgery. Postmortem examination revealed that the liver was reduced in size and had multiple interconnected and distended saccular dilations. The bile ducts were markedly dilated and replaced a large part of the liver parenchyma. Multiple small cysts were also observed in the kidneys. Microscopically, the hepatic lesions were characterized by extensive bridging fibrosis associated with proliferating and ectatic bile ducts contiguous with the biliary tree. Marked fibrosis and small cysts were observed in the kidneys. Therefore, a final diagnosis of Caroli syndrome was made. While uncommon, this syndrome should be considered as a differential diagnosis for young dogs with biliary cysts and hepatic fibrosis.

Driver mutations of intrahepatic cholangiocarcinoma shape clinically relevant genomic clusters with distinct molecular features and therapeutic vulnerabilities.

Purpose: To establish a clinically applicable genomic clustering system, we investigated the interactive landscape of driver mutations in intrahepatic cholangiocarcinoma (ICC).Methods: The genomic data of 1481 ICCs from diverse populations was analyzed to investigate the pair-wise co-occurrences or mutual exclusivities among recurrent driver mutations. Clinicopathological features and outcomes were compared among different clusters. Gene expression and DNA methylation profiling datasets were analyzed to investigate the molecular distinctions among mutational clusters. ICC cell lines with different gene mutation backgrounds were used to evaluate the cluster specific biological behaviors and drug sensitivities.Results: Statistically significant mutation-pairs were identified across 21 combinations of genes. Seven most recurrent driver mutations (TP53, KRAS, SMAD4, IDH1/2, FGFR2-fus and BAP1) showed pair-wise co-occurrences or mutual exclusivities and could aggregate into three genetic clusters: Cluster1: represented by tripartite interaction of KRAS, TP53 and SMAD4 mutations, exhibited large bile duct histological phenotype with high CA19-9 level and dismal prognosis; Cluster2: co-association of IDH/BAP1 or FGFR2-fus/BAP1 mutation, was characterized by small bile duct phenotype, low CA19-9 level and optimal prognosis; Cluster3: mutation-free ICC cases with intermediate clinicopathological features. These clusters showed distinct molecular traits, biological behaviors and responses to therapeutic drugs. Finally, we identified S100P and KRT17 as “cluster-specific”, “lineage-dictating” and “prognosis-related” biomarkers, which in combination with CA19-9 could well stratify Cluster3 ICCs into two biologically and clinically distinct subtypes.Conclusions: This clinically applicable clustering system can be instructive to ICC prognostic stratification, molecular classification, and therapeutic optimization.