Cholangiocellular Cancer Research Articles

Coagulological disorders during liver resections in patients with malignant tumors

The purpose of the study. To study the coagulation profile of patients undergoing liver resections using laboratory tests and thromboelastography. Materials and methods. The results of observation of coagulological changes in 45 patients were studied: with colorectal liver metastases - 24 (53.3%) cases, with hepatocellular cancer - 14 (31.1%), with cholangiocellular cancer - 7 (15.6%). Right-sided hemihepatectomy was performed in 22 (48.9%) patients, right-sided extended hemihepatectomy - in 7 (15.6%), left-sided hemihepatectomy - in 8 (17.8%), resection of the left sector - in 8 (17.8%). Laboratory diagnostics included standard conventional coagulation tests and thromboelastography. Results. The concentrations of total bilirubin and alkaline phosphatase significantly increased up to 3 days of the postoperative period inclusive. The international normalized ratio increased significantly after liver resection immediately after surgery, as well as after 1, 3 and 5 days of observation. The level of fibrinogen in the first day after surgery decreases, and then increased to the initial value. Thromboelastometric parameters indicated a stable and normal coagulation function with a short ability to hypercoagulate immediately after liver resection. Conclusion. Although standard routine laboratory tests such as activated partial thromboplastin time and international normalized ratio may remain within normal limits or indicate hypocoagulation, the patient may be at risk for thrombosis. Thromboelastography measures the rate of formation, stabilization, and lysis of a clot using whole blood, which gives a more complete picture of coagulation status. Thus, routine laboratory parameters alone should not be used to decide whether to delay thromboembolic prophylaxis after liver resection.

Radiomics and radiogenomics in intrahepatic cholangiocarcinoma

Purpose of the study. Analytical review and analysis of available literature on texture analysis of computed tomgraphy (CT) and magnetic resonance imaging (MRI) in noninvasive diagnosis of ICC and correlation with molecular genetic features and tumor immunophenotype.Materials and methods. The scientific publications and clinical guidelines in the information- analytical systems PubMed, Scopus for 2012–2022 were carried out using the keywords: "mri", "radiomics", "texture analysis", "radiogenomics", "intrahepatic cholangiocarcinoma", "molecular". 49 articles were selected for analysis after excluding studies dealing with technical aspects of radiomics and describing individual clinical observations.Results. The presented review demonstrated the broad possibilities and prospects of application of CT and MRI texture analysis in the study of cholangiocellular cancer, including the first results in the study of molecular features (signatures) of this tumor. Correlation of texture features with the expression of immunotherapy target genes KRAS/NRAS/BRAF as well as IDH1/2 mutation was shown. Texture scores were the predominant independent predictor of microvascular invasion, which was a major independent risk factor for postoperative recurrence.Conclusion. The use of texture analysis undoubtedly demonstrates promising possibilities both in noninvasive assessment of the HCC histological differentiation grade, as well as in differential diagnosis with hepatocellular carcinoma, metastases, and requires further study for systematization and standardization of the obtained data.

Presentation of Metastatic Cholangiocellular Cancer with Orbital Metastasis

Presentation of Metastatic Cholangiocellular Cancer with Orbital Metastasis

Resection interventions in the treatment of hepatocellular cancer in a specialized surgery center

Background. The relevance of the treatment of hepatocellular cancer (HCC) is determined by a significant increase in the incidence rate and its high prevalence among primary malignant hepatic tumors.The aim of the study. To summarize the experience of providing specialized medical care to patients with hepatocellular cancer.Methods. We studied the direct results of treatment of patients with primary hepatic cancer treated at the Kuzbass Regional Hepatological Center for the period from January 2015 to August 2022. The materials for the study were medical records of patients with an established diagnosis of primary hepatic cancer, surgical records, results of pathohistologic examination. The exclusion criterion was diagnosed cholangiocellular carcinoma.Results. During the period from 2015 to 2022, 59 patients with primary hepatic cancer were treated at the Kuzbass Regional Hepatological Center. Among them, hepatocellular cancer was diagnosed in 48 cases, cholangiocellular cancer – in 11 cases; radical surgery was performed in 12 patients with hepatocellular cancer; fatal outcome was noted in 1 (2.1 %) patient, complications in the postoperative period developed in 5 (41.7 %) cases and were ranked as I-3, IIIb-1 and IVb-1 according to Clavien – Dindo classification.Conclusion. The degree of risk of severe post-resection hepatic failure should be considered one of the main criteria in choosing a strategy for radical surgical treatment. New surgical approaches (laparoscopic vascular isolation of the portal blood flow, using temporary hemostasis in laparoscopic hepatic resections and the device for its implementation) in resection surgery of primary hepatic cancer can improve the immediate results of treatment.

A Rare Case of Cholangiocellular Liver Cancer with Hematogenous Metastases and Organ Changes in the Generalization of the Process

Introduction. Cholangiocellular cancer is a malignant tumor from the epithelium of the bile ducts. Intravital diagnosis is often difficult to make due to the absence of any definitive signs of cancer and problems with detecting the first signs. Following the relevance of the problem, a case of cholangiocellular liver cancer with generalized metastases is presented.Materials and methods. The analysis of the received supporting medical documentation and the description of macroand micropreparations using histological (hematoxylin and eosin staining) and immunohistochemical methods were carried out.Results and discussion. Patient L.M., 60 years old, died at home, was referred by a general practitioner to the pathology department for autopsy examination. During the forensic autopsy, the macroscopic examination revealed dense liver substance, a «tree-like» mass of gray-yellow-brown color on the sections around the portal vein and intrahepatic bile ducts, with involvement of the right and left liver lobes and multiple gray nodules located throughout the liver parenchyma. The intrahepatic bile ducts malfunction due to expanding tumor tissue. Histological examination revealed a moderately differentiated tumor growth of cholangiocellular carcinoma, consisting of polymorphic cells separated by layers of fibrous tissue with areas of necrosis, foci of cholestasis. Immunohistochemical analysis of the tumor tissue of the lungs, liver: cytokeratins CAM 5.2 (+). All groups of lymph nodes of hepatoduodenal ligament, along vesicular and common bile ducts, hepatic artery and portal vein, surrounding left gastric and common hepatic artery, as well as lymph nodes of posterior pancreaticoduodenal group and distant lymph nodes are celiac; upper mesenteric and paraaortic zones appear unremarkable. Cerebral edema, pulmonary edema and necronephrosis were reported.Conclusion. The presented case is of particular interest to practitioners owing to the absence of the characteristic lymph node metastases and presence of hematogenous metastases and development of multiple organ failure.

The role of molecular genetic factors in the development of cholangiocellular cancer: A review

This article highlights the main inducers of cholangiocarcinogenesis. Data are presented on the study of gene mutations, the variations of which depending on the localization of biliary cancer may be different (FGFR2 in intrahepatic PRKACA, PRKACB cholangiocarcinoma in extrahepatic cholangiocarcinoma). Mutations in the KRAS, TP53, ARIAD1A genes are common in extrahepatic bile duct cancer. Epigenetic events such as DNA hypermethylation, histone modifications, chromatin remodeling, and disturbances in miRNA expression are considered. A number of epigenetic features, such as the presence of a TP53 gene mutation with hypermethylation of p14ARF, DAPK, and/or ASC, correlate with a more aggressive course of the disease. The role of the SOX17 gene in the development of drug resistance is highlighted. The study of molecular genetic features of extrahepatic bile duct cancer is an important aspect in understanding the pathogenesis of this type of tumor, reveals new prognostic and diagnostic markers of the disease. It is possible that in the future, as knowledge is accumulated, this will make it possible to individualize approaches to the treatment of this category of patients.

Sensitivity of [18F]FDG PET/CT and classification of the primary tumor site in patients with carcinoma of unknown primary.

The aim of this study is to find the sensitivity of the [18F]FDG PET/CT and the classification of the primary sites of carcinoma of unknown primary (CUP) as a single-center experience. Sixty-eight patients with a mean age of 62.43 ± 12.78 years were included in this study retrospectively. Sixty-five patients had biopsy or surgery after PET/CT, which revealed pathological diagnoses of malign primary tumors, while primary tumor site could not be detected in three patients with histopathological examination. We evaluated the primary site of CUP with [18F]FDG PET/CT. Primary sites of three patients were not determined by histopathological examination. Malign lesions indicating the primary site of tumor were identified in 52 of 68 patients with PET/CT correctly. The primary tumor was lung cancer in 14 patients, cholangiocellular cancer in 9 patients, lymphoma in 9 patients, pancreas cancer in 6 patients, gastric cancer in 4 patients, ovary cancer in 4 patients, colon cancer in 4 patients, breast cancer in 3 patients, hepatocellular cancer in 2 patients, rectal cancer in 2 patients, sarcoma in 2 patients, esophagus, renal cell cancer, squamous cell cancer, endometrium cancer, malign melanoma, and multiple myeloma in 1 patient with histopathological examination. PET/CT was false positive in one patient. There were 13 patients in whom primary tumor could not be localized by PET/CT, but was diagnosed by histopathological evaluation. PET/CT should be the first-line diagnostic tool for CUP, other diagnostic imaging tools should be applied after a negative whole-body PET/CT.

Comparison of the Capabilities of Spectroscopic and Quantitative Video Analysis of Fluorescence for the Diagnosis and Photodynamic Therapy Control of Cholangiocellular Cancer

Cholangiocellular cancer (CCC) is a malignant neoplasm of the hepatobiliary system that is difficult to diagnose and treat. Currently, the most effective treatment of CCC is demonstrated under the control by fluorescent diagnosis. Photodynamic therapy (PDT) has also shown good results in the treatment of this disease, and fluorescence analysis of the photosensitizer is a good approach to control PDT. This article presents the results of a comparison of spectroscopic and quantitative video-fluorescent analysis of chlorin e6 photosensitizer fluorescence in vivo during cholangiocellular cancer surgery. Spectroscopic analysis provides accurate information about the concentration of the photosensitizer in the tumor, while the video-fluorescence method is convenient for visualizing tumor margins. A direct correlation is shown between these two methods when comparing the fluorescence signals before and after PDT. The applied paired Student’s t-test shows a significant difference between fluorescence signal before and after PDT in both diagnostic methods. In this regard, video-fluorescence navigation is not inferior in accuracy, sensitivity, or efficiency to spectroscopic methods.

Imbalanced immunobiological reactivity, infection and mutagenesis factors in the hepatobiliary system affected by a natural focal habitat factor — a trematode invasion by <i>Opisthorchis felineus</i>

An interaction between decreasing host anti-infective defense due to long-term invasion with Opisthorchis felineus in the hepatobiliary system, duct bile colonization by microflora and revealing the endogenous mutagenesis (carcinogenesis) factor in bile — secondary bile acids — is considered in the article. The role of organism genotype in pathogen-related immune response to Opisthorchis felineus trematode and helminth development in the hepatobiliary system has been shown. The role of dysregulated mechanisms of tissue homeostasis in induction of compensatory chronic homeostatic proliferation and somatic cell oncogenesis is discussed. The study results evidence that disturbed functioning of regulatory T cells, inhibition of the NK cell effector function and very high functional activity of memory B cells are of great importance in imbalanced host immunobiological reactivity, caused by chronic opistorchis invasion. Decreased host anti-infective protection causes intrahepatic bile duct infection with different bacterial species. Presence of secondary bile acids in hepatobiliary system was associated with biliary bacterial strains inhabiting intestinal tract: Proteus vulgaris, Proteus mirabilis, Citrobacter freundii, Bacteroides alcaligues faecalis, Clostridium, Streptococcus faecalis, Еscherichia coli — gut microflora agents. Participation of microbiota in bile acid biotransformation immediately in the duct bile has been confirmed in experiments in vitro. Experimental methods on Drosophila melanogaster and Salmonella typhimurium strains: TA100, TA98 allowed to find out that bile from chronic opistorchiasis patients exerts higher mutagenic activity compared to control groups. Mutational events in somatic and bacterial cells depend on the presence of secondary bile acids (deoxycholic, lithocholic) in duct bile, as well as the level of total bile acid concentration. The study data confirm the concept by Professor A.A. Shain about the presence of endogenous risk factor for developing primary cholangiocellular liver cancer such as secondary bile acids in the bile of chronic opistorchiasis patients. A concept of cholangiocarcinogenesis, based on mutational events, is added up with disturbance of generative cycle in tissue cells and their differentiation due to decreased chalone factor activity, as well as sensitivity threshold to it. Level of investigation and understanding of mechanisms underlying cholangiocarcinogenesis during chronic opisthorchis invasion will allow to develop pathogenetic approaches to correct homeostasis regulation and prevention of cholangiocarcinomas.

The PLATON pilot-study “Platform for analyzing targetable tumor mutations”: A PLATON network study.

TPS6598 Background: PLATON Network is designed as a platform to improve personalized therapy based on genomic profiles in gastrointestinal cancer patients. PLATON’s study-design focuses on patient’s molecular profiling and will provide a network web application for interlinking PLATON investigators which integrates information of the participating centers, their patients, the molecular profiles and available clinical trials at PLATON`s study-sites. Methods: The PLATON Network is designed as a permanent open, multicenter, prospective, cohort study with biobanking, with a shared platform infrastructure for associated sub-studies. In a first approach the PLATON Network enrolls within its pilot-study 200 patients in Germany of both sexes and ages over 18 at 40 study sites (NCT04484636) with signed informed consent. All patients of the pilot-study are diagnosed with hepatocellular cancer (HCC), intra- and extrahepatic cholangiocellular carcinoma (CCA), gallbladder carcinoma (GBCA), pancreatic cancer (PDCA) or esophagogastric cancer (EC/GC). At the time of enrolment, patients are within their first-line therapy and no local curative therapy is available. Molecular profiling will be performed with the Foundation Medicine Assays FoundationOne CDx and FoundationOne Liquid CDx. Investigators may use the platform for searching clinical trials matching the individual molecular profile of their patients or may identify a patient, who may be eligible for a study or other treatment options available at the corresponding centers of the PLATON network. The interactive network web application will comprise a dashboard and a moderated chat room to interact for example in a virtual Molecular Tumor Board. The first patient was included on the 25th of November 2020. Up to 12th of February 2021, a total of 36 patients HCC (N = 1), CCA (N = 6), PDCA (N = 12), GBCA (N = 0) and EC/GC (N = 16) were enrolled at 11 study-sites and the results of 29 genetic analyses were completed. All cohorts of the pilot-study are open for recruitments up to a maximum of 40 individuals per diagnostic group. Clinical trial information: NCT04484636.

The Using of Cryodestruction Methods in the Treatment of Primary Liver Cancer

Objective: to improve treatment outcomes, quality and life expectancy in patients with primary liver cancer. Materials and methods: Since 2012, cryodestruction (CD) was performed in 14 patients with primary liver cancer, in 6 patients with hepatocellular cancer (HCR) and 8 patients with cholangiocellular cancer (CCR), 5 women and 8 men. The size of the lesions in the liver was 2-8 cm, the number of lesions was 1-8 (3±2). The exposure time was 3-5 min, the exposure temperature was -186С. CD in combination with RFA was performed in 5 patients, CD+liver resection-in 2 patients, a CD+RFA+liver resection - in 2 patients. All patients were subsequently given adjuvant chemotherapy. Results: Severe life-threatening complications were observed in 2 (7.1%) operated patients: - 1 (7.1%) intra-abdominal bleeding, 1 - death due to progression of multiple organ failure during sepsis after application of CD in combination with liver resection and RFA. Survival in patients after the use of cryodestruction in combination with other methods of local destruction was 20.5±5 months, after cryodestruction - 12.56±3 months. (p < 0.05). Survival in patients after the use of cryodestruction in combination with other methods of local destruction with CCR was 9.2±4.5 months (p < 0.05), with cryodestruction - 7 + 2.5 months. (p < 0.05). Conclusion: Cryodestruction in combination with other methods of local destruction in primary liver cancer in unresectable patients is an intervention that significantly improves the quality of life of cancer patients. When using adjuvant chemotherapy, there is also a slight improvement in survival rates.

New approaches to diagnostics and treatment of cholangiocellular cancer based on photonics methods.

Cholangiocellular cancer (CCC) is an oncological disease of the bile ducts characterized by a high mortality rate. To date, the use of standard methods for the diagnosis and treatment of CCC has not been able to reduce mortality from this disease. This work presents the results of fluorescence diagnostics (FD), which consists in using a modified optical fiber and photodynamic therapy (PDT) using a therapeutic laser instead of a low-intensity laser. This technique was tested on 43 patients in a clinical setting. The results obtained indicate a direct correlation between spectroscopic and video FD methods. Furthermore, a direct correlation was found between the photobleaching of a chlorin e6-based photosensitizer, with the commercial names of Photolon Radachlorin and Photoran and stricture regression. Our findings demonstrate the possibility of using a therapeutic laser with a wavelength of 660 nm for both diagnosis and treatment of bile ducts cancer, which results in a significant reduction of the operation time without decreasing its effectiveness.

Study of photobiomodulation effects with violet-blue and red light in experimental oncogenesis

Introduction. There is still an open question about the limits of medical use of low-intensity electromagnetic radiation of the optical range in tumor growth due to the risk of increased proliferation of tumor cells. The conditions under which the tumor process is stimulated, as well as the mechanisms of photobiomodulation in oncological pathology, remain unclear. The aim of the study - in vitro evaluation and comparison of the effect of low-intensity electromagnetic radiation with wavelengths of 400, 460 and 660 nm on the activity of free-radical processes in tumor tissue and blood in normal and growing experimental neoplasia. Materials and methods. The study was conducted on biological material obtained from white non-linear rats intact and with subcutaneously transplanted cholangiocellular cancer MS-1. The sources of low-intensity radiation with wavelengths of 400, 460 and 660 nm were led generators. The content of hemoglobin, the activity of superoxide dismutase and catalase, changes in the overall level of free radical processes and antioxidant activity by induced chemiluminescence, and DNA damage by the method of DNA comets were studied. Data analysis was performed using nonparametric statistics methods. Results. The multidirectional effect of radiation with wavelengths of 400, 460 and 660 nm on free-radical homeostasis indicators at the early and late stages of tumor growth, as well as the dependence of biological effects on the wavelength of radiation, was found. Conclusions. The results obtained allow making a number of assumptions about the mechanisms of action of the optical electromagnetic waves on tumor growth, modulating free radical processes in the tumor-bearing organism.

Photodynamic therapy in combined treatment of cholangiocellular carcinoma (case report)

In this article a case report of an effective combined treatment of a patient with locally advanced cholangiocellular cancer who underwent neoadjuvant regional chemotherapy, extended surgery, adjuvant regional chemotherapy, as well as a set of minimally invasive endoscopic and percutaneous endobiliary techniques, which allowed the progression of the disease, including to increase the patients survival rate is presented. (5 figs, bibliography: 5 refs).

Association between cholangiocarcinoma and liver flukes: review of epidemiological studies

According to official medical statistics, liver fluke infections caused by Opisthorchis felineus , Opisthorchis viverrini and Clonorchis sinensis , are reported annually in the Southeast Asia, European countries and the Russian Federation. These infections are the main cause of digestive system diseases in the population of endemic regions. The aim of the review is to analyze the findings of epidemiological studies and to assess the relationship between liver and bile duct cancer and Opisthorchiidae liver fluke infections. Materials and methods. The authors reviewed original studies published in 1974–2019 via the MEDLINE databases and the eLIBRARY scientific digital library. Results . The studies have shown that cholangiocarcinoma is a significant medical and social problem in the trematode-endemic areas of Southeast Asia due to the absence of specific symptoms, long asymptomatic course, resistance to therapy and high mortality of patients. Long-term infection caused by trematodes Opisthorchis viverrini and Clonorchis sinensis is associated with a significant risk of developing cholangiocellular cancer. An epidemiological multicenter study is required to establish the relationship between the Opisthorchis felineus infection and cholangiocarcinoma in the population of endemic regions in the Russian Federation.

Frequency and effects of mutations in the KRAS gene on the survival of patients after surgical treatment of intrahepatic cholangiocarcinoma

Aim. To study the effect of mutations in the KRAS gene on the clinical course of intrahepatic cholangiocellular cancer (ICC) after surgical treatment in the Russian population.Materials and methods. A molecular genetic study of tumour tissue samples from 33 patients with intrahepatic cholangiocellular cancer obtained after surgical treatment was carried out using real-time polymerase chain reaction.Results. In the Russian population, the frequency of mutations in the KRAS gene in ICC was 27%, mainly in 12 (78%), 13 (33%), 61 (55%), 117 (44%) and 146 (44%) codons of 2, 3, 4 exons. In terms of KRAS gene mutations, intrahepatic cholangiocellular cancer is characterised by a pronounced heterogeneity. As a rule, the KRAS gene demonstrates multiple mutations at several loci and co-mutations in other genes, in particular, in IDH1/IDH2, PIK3CA, NRAS and BRAF genes. KRAS gene mutations in ICC were found to be significantly more common in women. The overall survival rate was significantly higher in patients with a KRAS mutation as compared to those with the wild type of the gene. Regarding the relapse-free survival rate in the groups of patients with the mutant and wild type of the KRAS gene, no significant differences were found.Conclusion. In the Russian population, no negative association between mutations in the KRAS gene and clinical outcomes was observed.

Two-stage liver resection for intrahepatic cholangiocarcinoma

The small remnant liver volume remains an urgent problem in liver resection surgery. The use of the method of twostage liver resection – the Associated Liver Partition and Portal vein ligation for Staged hepatectomy in most cases allows to solve this problem. However, this method is associated with a number of complications and limitations. The presented clinical observation shows the effectiveness of an alternative version of this technology – radiofrequency ablation of the liver parenchyma in the plane of the proposed resection with ligation of the right branch of the portal vein to increase the volume of the estimated liver remnant in intrahepatic cholangiocellular cancer.

Combinative Treatment of Nonresectable Cholangiocellular Cancer Complicated by Obstructive Jaundice.

Combinative Treatment of Nonresectable Cholangiocellular Cancer Complicated by Obstructive Jaundice.

Long-term results of surgical treatment of intrahepatic cholangiocarcinoma

To evaluate the long-term outcomes of surgical treatment of intrahepatic cholangiocarcinoma depending tumor dimensions, vascular invasion, lymph node metastases, cellular differentiation and quality of resection. There were 46 patients with intrahepatic cholangiocellular cancer. Extended hemihepatectomy was made in 14 patients (30.4%), resection of two and three liver segments - in 17 cases (36.9%), standard hemihepatectomy - in 15 patients (32.6%). Liver resection was combined with extrahepatic bile duct resection in 5 (10.9%) patients. Liver resection was followed by biopsy of specimens. Dimension and number of tumors, differentiation grade, resection margin, liver capsule invasion, vascular invasion and regional lymph node metastases were analyzed. Forty-four (95.6%) patients were followed-up in long-term postoperative period. Statistical analysis was performed using Statistica 13.2 (Dell Inc., USA) and IBM SPSS Statistics v.25 (IBM Corp., USA) software package. Survival was analyzed using the Kaplan-Meier method. Overall 1-, 3- and 5-year survival rates with two-sided 95% confidence intervals (95% CI) were calculated using IBM SPSS Statistics v.25 software. Median survival was 37 months, 1-year - 75.9% (60.9-90.9%), 3-year - 57.6% (35.5-79.6%), 5-year - 36% (8.2-63.7%). Median survival after R1 resection was 37 months, R2 resection - 12 months. Median survival was not achieved in R0 group. We found significant differences in overall survival depending on quality of resection. Tumor dimension over 5 cm, low-grade adenocarcinoma, microvascular invasion and lymph node metastases were associated with impaired postoperative survival. However, differences were not significant. The main surgical strategy in patients with intrahepatic cholangiocarcinoma should be ensuring microscopically negative resection margin.

Combined treatment for locally advanced cholangiocellular liver cancer - the case report

Liver resection is the standard in the treatment of patients with the local uncomplicated intrahepatic bile duct cancer. Systemic chemotherapy is prescribed in the presence of distant metastases. Difficulties in a choice of the treatment method come up when one or several factors are revealed: the tumor spread towards the surrounding structures, multiple liver lesions, lymph nodes involvement signs. The complications presence manages treatment strategy too. The case describes the possibilities of an individual multimodal approach in a treatment strategy for the patient with locally advanced liver cholangiocarcinoma complicated by obstructive jaundice, cholangitis, cholangiogenic abscesses. The surgical approach was approved as the main one. Methods of interventional radiology, chemotherapy, radiation therapy were applied when necessary. The mentioned above treatment strategy allowed us to achieve good results in this difficult clinical case. The patient is alive for more than four years from the time of surgery, signs of progression are not currently defined.