Is surgery justified for elderly patients with extrahepatic cholangiocarcinoma? Reappraisal from a viewpoint of comorbidity and organ function.

PURPOSE: The benefit of surgery for older patients with extrahepatic cholangiocarcinoma (EHCC) has not been established and the differences in the general condition of younger vs. older patients remain unclear. METHODS: Patients who underwent curative surgery for EHCC were divided into two groups according to age: those younger than 75 years old (younger group) and those aged 75 years or older (older group). We analyzed the clinical data of the two groups retrospectively. RESULTS: Among the 116 patients analyzed, 45 (38.8%) were in the older group. Regarding comorbidity, only cardiac disease was significantly more common in the older patients; however, the cardiac function of the two groups was identical. There were no significant differences in the prevalence of kidney and lung disease, but renal function was significantly deteriorated and the incidence of the mixed ventilatory defect was significantly greater in the older group. The overall 5-year survival rates for the younger and older groups were 52.4% vs. 50.4% of all cholangiocarcinoma patients (p = 0.458), 42.4% vs. 51.3% of those with hilar cholangiocarcinoma (p = 0.718), and 69.0% vs. 49.1% of those with distal cholangiocarcinoma (p = 0.534), respectively. CONCLUSIONS: Improved survival after surgery can be expected in well-selected older cholangiocarcinoma patients. Comorbidities were not necessarily reflected in organ function, with precise organ function assessment being more important when selecting surgical candidates.

Quantitative magnetic resonance imaging predicts individual future liver performance after liver resection for cancer.

The risk of poor post-operative outcome and the benefits of surgical resection as a curative therapy require careful assessment by the clinical care team for patients with primary and secondary liver cancer. Advances in surgical techniques have improved patient outcomes but identifying which individual patients are at greatest risk of poor post-operative liver performance remains a challenge. Here we report results from a multicentre observational clinical trial (ClinicalTrials.gov NCT03213314) which aimed to inform personalised pre-operative risk assessment in liver cancer surgery by evaluating liver health using quantitative multiparametric magnetic resonance imaging (MRI). We combined estimation of future liver remnant (FLR) volume with corrected T1 (cT1) of the liver parenchyma as a representation of liver health in 143 patients prior to treatment. Patients with an elevated preoperative liver cT1, indicative of fibroinflammation, had a longer post-operative hospital stay compared to those with a cT1 within the normal range (6.5 vs 5 days; p = 0.0053). A composite score combining FLR and cT1 predicted poor liver performance in the 5 days immediately following surgery (AUROC = 0.78). Furthermore, this composite score correlated with the regenerative performance of the liver in the 3 months following resection. This study highlights the utility of quantitative MRI for identifying patients at increased risk of poor post-operative liver performance and a longer stay in hospital. This approach has the potential to inform the assessment of individualised patient risk as part of the clinical decision-making process for liver cancer surgery.

In Vivo Models for Cholangiocarcinoma-What Can We Learn for Human Disease?

Cholangiocarcinoma (CCA) comprises a heterogeneous group of primary liver tumors. They emerge from different hepatic (progenitor) cell populations, typically via sporadic mutations. Chronic biliary inflammation, as seen in primary sclerosing cholangitis (PSC), may trigger CCA development. Although several efforts were made in the last decade to better understand the complex processes of biliary carcinogenesis, it was only recently that new therapeutic advances have been achieved. Animal models are a crucial bridge between in vitro findings on molecular or genetic alterations, pathophysiological understanding, and new therapeutic strategies for the clinic. Nevertheless, it is inherently difficult to recapitulate simultaneously the stromal microenvironment (e.g., immune-competent cells, cholestasis, inflammation, PSC-like changes, fibrosis) and the tumor biology (e.g., mutational burden, local growth, and metastatic spread) in an animal model, so that it would reflect the full clinical reality of CCA. In this review, we highlight available data on animal models for CCA. We discuss if and how these models reflect human disease and whether they can serve as a tool for understanding the pathogenesis, or for predicting a treatment response in patients. In addition, open issues for future developments will be discussed.

Synchronous Double Bile Duct Cancers with Distinct Genetic Features.

A 69-year-old man was referred to our hospital because of appetite loss. Imaging showed a nodular tumor in the perihilar bile duct and a second flat lesion in the distal bile duct. Right hepatopancreaticoduodenectomy was performed, and the histopathological findings demonstrated that the perihilar and distal lesions were moderately and poorly differentiated adenocarcinoma, respectively, and anatomically separated. Furthermore, the resected specimens showed no pancreaticobiliary maljunction. Histological and TP53 gene analyses in a rare case of synchronous double bile duct cancers suggest that there are various genetic pathways through which bile duct cancer develops, highlighting the complexity of its pathogenesis.

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives.

Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease.

Neuroendocrine Changes in Cholangiocarcinoma Growth.

Cholangiocarcinoma (CCA) is a highly aggressive malignancy that emerges from the biliary tree. There are three major classes of CCA-intrahepatic, hilar (perihilar), or distal (extrahepatic)-according to the location of tumor development. Although CCA tumors are mainly derived from biliary epithelia (i.e., cholangiocytes), CCA can be originated from other cells, such as hepatic progenitor cells and hepatocytes. This heterogeneity of CCA may be responsible for poor survival rates of patients, limited effects of chemotherapy and radiotherapy, and the lack of treatment options and novel therapies. Previous studies have identified a number of neuroendocrine mediators, such as hormones, neuropeptides, and neurotransmitters, as well as corresponding receptors. The mediator/receptor signaling pathways play a vital role in cholangiocyte proliferation, as well as CCA progression and metastases. Agonists or antagonists for candidate pathways may lead to the development of novel therapies for CCA patients. However, effects of mediators may differ between healthy or cancerous cholangiocytes, or between different subtypes of receptors. This review summarizes current understandings of neuroendocrine mediators and their functional roles in CCA.

Cancer-associated fibroblasts in cholangiocarcinoma.

PURPOSE OF REVIEW: To give a state-of-art knowledge regarding cancer-associated fibroblasts (CAF) in cholangiocarcinoma (CCA) based both on direct evidence and studies on other desmoplastic cancers. High contingency of CAF characterizes CCA, a tumor with a biliary epithelial phenotype that can emerge anywhere in the biliary tree. Current treatments are very limited, the surgical resection being the only effective treatment but restricted to a minority of patients, whereas the remaining patients undergo palliative chemotherapy regimens. In cancer, CAF shape the tumor microenvironment, drive cancer growth and progression, and contribute to drug resistance. All these functions are accomplished through an interplay network between CAF and surrounding cells including tumor and other stromal cells, i.e. immune and endothelial cells. RECENT FINDINGS: Several studies have pointed out the existence of CAF sub-populations carrying out several and opposite functions, cancer-promoting or cancer-restraining as shown in pancreatic cancer, another prototypic desmoplastic tumor in which heterogeneity of CAF is well demonstrated. SUMMARY: New CAF functions are now emerging in pancreatic and breast cancers like the modulation of immune responses or tumor metabolism, opening new area for treatments.

IgG4-related Sclerosing Cholangitis Mimicking Cholangiocarcinoma Diagnosed by Endoscopic Ultrasound-guided Fine-needle Aspiration.

A 58-year-old man was referred for obstructive jaundice. Imaging modalities revealed the presence of multiple pancreatic tumors and the stenosis of the middle common bile duct due to a hypoenhanced localized tumor. The multiple pancreatic tumors were histopathologically diagnosed as autoimmune pancreatitis by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). To differentiate between IgG4-related sclerosing cholangitis (IgG4-SC) and cholangiocarcinoma, we diagnosed the biliary tumor as IgG4-SC by EUS-FNA because of insufficient pathological materials obtained in a transpapillary manner. We herein report a case of IgG4-SC diagnosed by EUS-FNA.

The tumour microenvironment and immune milieu of cholangiocarcinoma.

Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour-promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.

Investigation of Factors Affecting the Sensitivity of Bile Duct Brush Cytology.

Objectives While bile duct brush cytology during endoscopic retrograde cholangiopancreatography (ERCP) is a well-established procedure for detecting malignant biliary stricture, its sensitivity is reportedly low. We aimed to determine the pre-ERCP factors affecting brush cytology sensitivity. Methods We retrospectively analyzed 185 patients who underwent brush cytology during the first ERCP for undiagnosed biliary stricture at our institution between January 2014 and December 2016. We analyzed the relationship of age, sex, final diagnosis, stricture location, tumor size, stricture length, total bilirubin level, white blood cell count, and C-reactive protein level with brush cytology sensitivity. Results The following conditions were established as final diagnoses: benign disease, 19 cases (10.3%); intrahepatic cholangiocarcinoma, 10 cases (5.4%); hilar cholangiocarcinoma, 38 cases (20.5%); extrahepatic cholangiocarcinoma, 44 cases (23.8%); pancreatic cancer, 55 cases (29.7%); other malignant tumors, 19 cases (10.3%). The sensitivity and specificity of brush cytology were 60.8% and 94.7%, respectively. The stricture length, total bilirubin level, and white blood cell count in true-positive cases were significantly higher than those in false-negative cases. Furthermore, a stratified analysis of the bilirubin levels demonstrated that sensitivity was highest in patients with moderate jaundice (80% for a total bilirubin level of 10-20 mg/dL), but significantly lower in patients with severe jaundice (total bilirubin level ≥20 mg/dL). Conclusion While the sensitivity of brush cytology increases with bilirubin levels of up to 20 mg/dL, severe jaundice has a negative effect on sensitivity, warranting additional pathological examinations according to the pre-ERCP bilirubin level.

Haemostatic radiation therapy for a bleeding intraductal papillary neoplasm of the biliary tree.

Haemostatic radiation was effectively used as a novel rescue therapy in a 60-year-old man who presented with recurrent melaena refractory to all conventional medical and surgical measures. He needed multiple transfusions and was diagnosed to be bleeding from an intraductal papillary biliary neoplasm which was not amenable to surgical resection in view of the background liver disease. He received conventional radiation therapy (RT) of a dose of 3 Gy per fraction for 3 consecutive days after which he stabilised. After cessation of the RT, he did not require transfusion for the next 2 months. His quality of life improved and it gave us time to evaluate for other definitive measures.

Sarcomatous intrahepatic cholangiocarcinoma: Case report and literature review.

RATIONALE: Sarcomatous intrahepatic cholangiocarcinoma is a rare histological variant of cholangiocarcinoma (ICC). Previous medical literature has not mentioned the prevalence of this kind of disease, but a poorer prognosis than that of ordinary ICC was indicated. The diagnosis of the sarcomatous ICC is established on histopathological and immunohistochemical examinations. In this article, we present a new case of a patient with sarcomatous ICC who had no radiographic sign of intrahepatic tumor preoperatively. PATIENT CONCERNS: A 63-year-old man was noted with cholecystolithiasis and right upper abdominal pain. Liver function was within normal limits, although the gamma-glutamyl transpeptidase level was elevated. Serum carbohydrate antigen 19-9 level was elevated. Radiography showed atrophy of the left lobe of the liver, high-intensity signals on T1 weighted images, and low/high-intensity signals on T2 weighted images in hepatic ducts. DIAGNOSES: The preoperative diagnoses were hepatolithiasis, choledocholithiasis, and cholecystolithiasis. INTERVENTIONS: Exploratory laparotomy, adhesion release, cholecystectomy, choledocholithotomy, and T tube drainage were performed. During the surgery, an ill-defined tumor was detected on the atrophic left lateral lobe of the liver. Hepatic left lateral lobectomy was performed to remove the mass. OUTCOMES: The final diagnosis of sarcomatous ICC was made by histopathology after surgery. No evidence of local recurrence or distant metastasis was noted on imaging during follow-up. LESSONS: Although rare, sarcomatous ICC does exist in patients presented with cholecystolithiasis and liver atrophy. Surgeons should be aware of the existence of sarcomatous ICC due to the poor prognosis. We recommend that multidisciplinary approaches may be key to improve prognosis, including adjuvant chemotherapy or radiotherapy.

The Role of Stroma in Cholangiocarcinoma: The Intriguing Interplay between Fibroblastic Component, Immune Cell Subsets and Tumor Epithelium.

Cholangiocarcinoma (CCA) is a severe and mostly intractable adenocarcinoma of biliary epithelial cells. A typical feature of CCA is its highly desmoplastic microenvironment containing fibrogenic connective tissue and an abundance of immune cells (T lymphocytes, Natural Killer (NK) cells, and macrophages) infiltrating tumor epithelium. This strong desmoplasia is orchestrated by various soluble factors and signals, suggesting a critical role in shaping a tumor growth-permissive microenvironment that is responsible for CCA poor clinical outcome. Indeed stroma not only provides an abundance of factors that facilitate CCA initiation, growth and progression, but also a prejudicial impact on therapeutic outcome. This review will give an overview of tumor-stroma signaling in a microenvironment critically regulating CCA development and progression. Identification of CCA secreted factors by both the fibroblast component and immune cell subsets might provide ample opportunities for pharmacological targeting of this type of cancer.

The Curious Case of Cholangiocarcinoma: Opportunities for Environmental Health Scientists to Learn about a Complex Disease.

Deaths from complex, noncommunicable diseases such as cancer are predicted to continue to increase worldwide, with low- and middle-income countries bearing the brunt of the burden. This problem requires a concentrated global effort to avoid devastating losses of life as well as economic losses. Cholangiocarcinoma (CCA) is a readily studied model of complex, noncommunicable disease, but it receives little attention outside of the scientific community in Southeast Asia. Here, we bring attention to the opportunity to study CCA as a model to understand the role of multiple, complex factors in cancer. These factors include allostatic load, individual genetic susceptibility, and environmental exposures such as chemicals, diet, socioeconomic factors, and psychosocial stress. The study of CCA offers a unique opportunity to make novel observations that could advance progress in prevention and intervention approaches for prevalent diseases that involve complex, multifactorial interactions.

[Intrahepatic cholangiocarcinoma followed by vascular invasion: is surgical treatment justified?] / Vnutripechenochnaia kholangiokartsinoma s invaziei v sosudy: opravdano li khirurgicheskoe lechenie?

Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive tumors associated with poor prognosis. Radical surgery is still the main method of treatment in resectable cases. Certain difficulties are observed in case of locally advanced tumors followed by inferior vena cava (IVC) and portal vein (PV) invasion. AIM: To analyze safety of advanced liver resections combined with great vessels repair for locally advanced large and multiple cholangiocellular carcinoma. MATERIAL AND METHODS: Since January 2014 till April 2017 eighty ICC patients have undergone advanced liver resection. There were 62 patients with portal cholangiocarcinoma and 18 with ICC. 4 ICC patients required vascular repair: IVC replacement in 2 cases (i.e. under venous bypass in 1 of them), tangential and circular resection of portal vein bifurcation - in 2 cases. RESULTS: Postoperative complications Clavien-Dindo IIIa developed in all cases. There were no vascular complications. The length of hospital-stay was 14 - 35 days. There were no lethal outcomes. Annual survival was 50%, 2-year - 25%. Adjuvant chemotherapy was used in all patients. CONCLUSION: Advanced liver resection followed by IVC and PV repair for locally advanced ICC may be safely performed and subsequently allows chemotherapeutic treatment.

Sensory neuronopathy associated with cholangiocarcinoma diagnosed 6 years after symptom onset.

A pure sensory neuronopathy (also referred to as a sensory ganglionopathy) is one of a handful of classical neurological paraneoplastic syndromes. Current guidelines recommend that in cases of sensory neuronopathy, a search for an underlying malignancy be pursued for up to 4 years. We report the case of a 52-year-old woman with a sensory neuronopathy who was eventually diagnosed with a cholangiocarcinoma 6 years after the onset of her disease. A CT fluorodeoxyglucose positron emission tomography (FDG-PET) scan performed 18 and 24 months after disease onset failed to identify an underlying neoplasm. Immunomodulatory treatment with corticosteroids, intravenous immunoglobulins and plasma exchange were ineffective. Investigations for Sjogren's disease were negative. A third FDG-PET performed 6 years after symptom onset identified a cholangiocarcinoma, which was confirmed histologically following open resection. Since the tumour was removed, our patient's condition has not progressed, but there has been no improvement and she remains severely disabled.

Sumoylation in p27kip1 via RanBP2 promotes cancer cell growth in cholangiocarcinoma cell line QBC939.

BACKGROUND: Cholangiocarcinoma is one of the deadly disease with poor 5-year survival and poor response to conventional therapies. Previously, we found that p27kip1 nuclear-cytoplasmic translocation confers proliferation potential to cholangiocarcinoma cell line QBC939 and this process is mediated by crm-1. However, no other post-transcriptional regulation was found in this process including sumoylation in cholangiocarcinoma. RESULTS: In this study, we explored the role of sumoylation in the nuclear-cytoplasmic translocation of p27kip1 and its involvement of QBC939 cells' proliferation. First, we identified K73 as the sumoylation site in p27kip1. By utilizing plasmid flag-p27kip1, HA-RanBP2, GST-RanBP2 and His-p27kip1 and immunoprecipitation assay, we validated that p27kip1 can serve as the sumoylation target of RanBP2 in QBC939. Furthermore, we confirmed crm-1's role in promoting nuclear-cytoplasmic translocation of p27kip1 and found that RanBP2's function relies on crm-1. However, K73R mutated p27kip1 can't be identified by crm-1 or RanBP2 in p27kip1 translocation process, suggesting sumoylation of p27kip1 via K73 site is necessary in this process by RanBP2 and crm-1. Phenotypically, the overexpression of either RanBP2 or crm-1 can partially rescue the anti-proliferative effect brought by p27kip1 overexpression in both the MTS and EdU assay. For the first time, we identified and validated the K73 sumoylation site in p27kip1, which is critical to RanBP2 and crm-1 in p27kip1 nuclear-cytoplasmic translocation process. CONCLUSION: Taken together, targeted inhibition of sumoylation of p27kip1 may serve as a potentially potent therapeutic target in the eradication of cholangiocarcinoma development and relapses.