Cholangiocarcinogenesis and targeted therapy for cholangiocarcinoma

Cholangiocarcinoma includes a highly heterogeneous group of malignant tumors of the biliary tract, developing from the epithelium of the intra- and extrahepatic bile ducts. The incidence of cholangiocarcinoma is growing worldwide and currently accounts for about 15% of all primary neoplastic diseases of the liver and up to 3% of malignant neoplasms of the gastrointestinal tract. The asymptomatic course of these tumors in combination with a very aggressive course and low sensitivity to cytotoxic therapy contributes to a fairly high mortality rate from this disease, amounting to up to 2% in the structure of cancer mortality in the world. The high heterogeneity of cholangiocarcinoma at the genomic, epigenetic and molecular levels significantly reduces the effectiveness of the available treatments. In recent decades, new diagnostic tools and treatment methods have been developed to improve the results of treatment of patients with cholangiocarcinoma. The prevalence of BRAF gene mutations is associated with the occurrence of various tumors, including cholangiocarcinoma. Currently, more than 30 mutations in the BRAF gene with oncogenic potential have been registered. Basically, the V600 codon is affected, an amino acid change occurs, which ultimately leads to the fact that the BRAF protein becomes constantly active, even in the absence of growth factors. Dabrafenib is an inhibitor of the BRAF protein, which is permanently overactive in mutated cells. The use of dabrafenib as monotherapy leads to the development of resistance after 6–7 months. Dabrafenib is used with trametinib, a MEK inhibitor that also blocks the Ras-Raf-MEK-MAPK kinase pathway, to prevent the resistance.

T-Bet Deficiency Attenuates Bile Duct Injury in Experimental Biliary Atresia

Biliary atresia (BA) is an obstructive neonatal cholangiopathy leading to liver cirrhosis and end stage liver disease. A Kasai portoenterostomy may restore biliary drainage, but most patients ultimately require liver transplantation for survival. At diagnosis, immune cells within the liver of patients with BA demonstrate a T-helper 1 (Th1) inflammatory profile similar to rhesus rotavirus (RRV)-infected mice livers developing BA. The transcription factor Tbx21 (T-bet) is essential for induction of a Th1 immune response in both the adaptive and innate immune system. Here we used animals with targeted deletion of the T-bet gene to determine its role in the progression of BA. Infection of newborn T-bet knockout (KO) pups with RRV resulted in a decreased Th1 inflammatory chemokine/cytokine profile when compared to infected wild-type mice. Analysis of the mononuclear cells profile from T-bet KO mice revealed both a significant decrease in the total number of CD3, CD4, and CD8 T cells and their effector molecules granzyme A, perforin, and FasL. Even though the percentage of T-bet KO mice displaying symptoms of an obstructive cholangiopathy and overall mortality rate was not different compared to wild-type mice, the extrahepatic bile ducts of T-bet KO mice remained patent.

Efemp1 modulates elastic fiber formation and mechanics of the extrahepatic bile duct

EGF-Containing Fibulin Extracellular Matrix Protein 1 (EFEMP1, also called fibulin 3) is an extracellular matrix protein linked in a genome-wide association study to biliary atresia, a fibro-inflammatory disease of the neonatal extrahepatic bile duct. EFEMP1 is expressed in most tissues and Efemp1 null mice have decreased elastic fibers in visceral fascia; however, in contrast to other short fibulins (fibulins 4 and 5), EFEMP1 does not have a role in the development of large elastic fibers, and its overall function remains unclear. We demonstrated that EFEMP1 is expressed in the submucosa of both neonatal and adult mouse and human extrahepatic bile ducts and that, in adult Efemp1+/- mice, elastin organization into fibers is decreased. We used pressure myography, a technique developed to study the mechanics of the vasculature, to show that Efemp1+/- extrahepatic bile ducts are more compliant to luminal pressure, leading to increased circumferential stretch. We conclude that EFEMP1 has an important role in the formation of elastic fibers and mechanical properties of the extrahepatic bile duct. These data suggest that altered expression of EFEMP1 in the extrahepatic bile duct leads to an abnormal response to mechanical stress such as obstruction, potentially explaining the role of EFEMP1 in biliary atresia.

Ultrasound Еxamination of the Еxtrahepatic Bile Ducts in Children (Literature Review with our own Clinical Observations)

To study the normal sonographic anatomy of extrahepatic bile ducts, a polypositional ultrasound examination of 120 children aged 0 to 17 years was conducted. The technique of hepatoduodenal ligament ultrasound examination is described. The main sonographic visual indicators for studying the anatomical and topographic structure of extrahepatic bile ducts in children are denoted. The normative parameters of the common bile and common hepatic ducts in children of different age groups are presented.

Iatrogenic hepatic damage as a problem of modern surgery (literature review)

Iatrogenic damage to the extrahepatic bile ducts occurs in a fairly large number of observations, despite constant work aimed at improving surgical interventions. The most optimal chosen therapeutic tactics, as well as the timing of the revealed damage to the bile ducts, determine the effectiveness and quality of care provided to this category of patients. We also have to state that, to date, in the Russian Federation there is no unambiguously generally accepted and approved therapeutic and diagnostic algorithm for iatrogenic damage to the extrahepatic bile ducts. One of the main aspects of the effectiveness of the applied treatment tactics is the level of quality of life of patients who underwent surgical treatment. Treatment and management of patients with iatrogenic damage to the extrahepatic bile ducts still have a fairly large number of controversial issues, the solution of which should improve the immediate results of surgical treatment of this category of patients.

On the question of primary malignant neoplasms of ductus hepatici

Among the neoplasms of large extrahepatic bile ducts, cancers occupy the first place in terms of frequency and importance, and the common bile duct, especially its beginning the place where it flows into the duodenum (papilla Vateri), is the most frequent site of cancer localization.

Sclerosing Extramedullary Hematopoietic Tumor (SEHT) Mimicking a Malignant Bile Duct Tumor-Case Report and Literature Review

Introduction: Sclerosing Extramedullary Hematopoietic Tumor (SEHT) is a very rare lesion associated with chronic myeloproliferative disorders (CMPD). SEHT can mimic morphologically, both macroscopically and microscopically, a wide variety of tumors/lesions. Case presentation: We present the case of a female patient diagnosed with gallstones for which surgery was decided. Intraoperatively, a malignant tumor of extrahepatic bile ducts was suspected. A frozen section examination raised the suspicion of a mesenchymal tumor or an inflammatory pseudotumor. The histological evaluation of the permanent sections, supplemented with an immunohistochemical investigation (IHC), was the one that established the diagnosis of SEHT, based on the presence of areas of sclerosis, atypical CD31+ megakaryocytes, myeloid and erythroid elements. Conclusions: The authors present the difficulties of a morphological diagnosis on the frozen section and on permanent sections in the absence of relevant clinical information and make a review of the literature data dedicated to the subject.

Peculiarities of tactics and surgical intervention in fresh iatrogenic damage of the common liver duct

The aim of the study was to select the most optimal method for completing the operation in case of "fresh" iatrogenic damage to the common hepatic duct, which ensures a favorable course of the postoperative period and preparation for the subsequent reconstructive operation. Material and methods. The study was based on the analysis of the results of surgical treatment of 58 patients with iatrogenic damage to the extrahepatic bile ducts (EPBD) for the period from 1998 to 2018. All patients had complete "fresh" transverse transection or clamping (clipping, ligation) of the common hepatic duct during cholecystectomy. In the first group (40 patients), the operation was completed by drainage of the common hepatic duct with a "free" position of the drainage under the liver and drainage of the subhepatic region; in the second group (18 patients), the drainage of the bile duct was fixed in the bed of the gallbladder, with the formation of a Maidl-type jejunostoma to return bile. Research results and their discussion. All patients (58 people) were initially operated on in hospitals in the Tyumen region and the city of Tyumen. 32 patients (55%) underwent open cholecystectomy, 26 (45%) – laparoscopic. The operation was performed in 13 patients (22%) as planned, in 45 (78%) as an emergency. In 40 (69%) operated patients, when the gallbladder was removed, the common hepatic duct was cut, in 18 (31%) it was clipped (ligated). Out of 40 patients (first group), bile duct transection occurred with open cholecystectomy in 29 (72.5%) people, in 11 (27.5%) with laparoscopic intervention. In all, the trauma of the hepatic duct was noticed by the operating surgeon during the operation. In accordance with the adopted tactics, the surgeon through the CMH contacted the experienced surgeon on duty at the Regional Hospital (GBUZ TO "OKB № 1"), with whom he agreed on the method of completing the operation. Conclusion. The lack of experience of hospital surgeons both in solving a tactical problem, when crossing an AKI or clipping it, and in performing a reconstructive operation after an injury is detected, we consider it expedient to introduce drainage into the proximal section of the intersected duct and transport the patient to a hospital department where there are specialists with such experience. operations. Fixation of the drainage of the common hepatic duct in the bed of the gallbladder, the formation of a Maidl-type jejunostoma with a complete return of bile to the intestine can effectively prepare the patient for reconstructive surgery, improve the technical conditions for its implementation.