Treatment Of Bile Duct Cancer Research Articles

Investigation of the usefulness of a bile duct biopsy and bile cytology using a hyperspectral camera and machine learning.

To improve the efficiency of pathological diagnoses, the development of automatic pathological diagnostic systems using artificial intelligence (AI) is progressing; however, problems include the low interpretability of AI technology and the need for large amounts of data. We herein report the usefulness of a general-purpose method that combines a hyperspectral camera with machine learning. As a result of analyzing bile duct biopsy and bile cytology specimens, which are especially difficult to determine as benign or malignant, using multiple machine learning models, both were able to identify benign or malignant cells with an accuracy rate of more than 80% (93.3% for bile duct biopsy specimens and 83.2% for bile cytology specimens). This method has the potential to contribute to the diagnosis and treatment of bile duct cancer and is expected to be widely applied and utilized in general pathological diagnoses.

Disparities in the Diagnosis and Treatment of Bile Duct Cancer in People with Disabilities: A National Cohort Study in South Korea.

We aimed to evaluate the impacts of disability on the diagnosis, treatment, and prognosis of bile duct cancer (BDC) according to the severity and type of disability. Patients diagnosed with BDC were selected from an age- and sex-matched population (1:3 ratio) with or without disabilities from the National Disability Database, the Korean Central Cancer Registry, and the Korean National Health Insurance claims database. The cohort included 15,065 patients with BDC, with a significantly lower rate in those with severe disabilities than in people without or with mild disabilities (110.6 vs. 136.5 vs. 147.6 per 105 persons, respectively). People with severe disabilities were diagnosed with BDC at an earlier age but were less likely to undergo surgery (adjusted odds ratio (aOR) = 0.52, 95% confidence interval (CI): 0.45-0.61) or chemotherapy (aOR = 0.76, 95% CI: 0.61-0.95) compared to those without disabilities. This trend was more evident in patients with mental disabilities. The overall and cancer-specific mortality rates were higher in patients (especially women) with disabilities than in those without. There needs systemic approach to ensure equal access to quality cancer care for people with disabilities.

Tumour Budding as an Independent Prognostic Factor for Survival in Patients With Distal Bile Duct Cancer

Surgical resection is the standard treatment for bile duct cancer. However, even when surgical resection is possible, the 5-year survival rate is reportedly 25.0-55.0%. Therefore, bile duct cancer is associated with poor prognoses. We conducted a clinicopathological investigation, focusing on the histological phenomenon of tumour budding, which has previously been reported to be correlated with the survival of patients with a variety of cancers. To investigate the significance of tumour budding in distal bile duct cancer, we recruited 65 patients who underwent pancreatoduodenectomy at our institution between 1995 and 2011. Tumour budding was observed and evaluated using the 'hot spot method'. The 'low' budding group comprised 0-4 cell clusters and the 'high' budding group ≥5 cell clusters. Additionally, immunostaining was performed in high-budding areas. Tumour budding and stage were confirmed using a Cox proportional hazards model as independent prognostic factors for overall survival (p<0.05) in all patients. There was a significant association between budding and zinc finger E-box binding homeobox 1 expression, an endothelial-mesenchymal transition-induced transcription factor. In stage II cases, the prognosis was significantly worse in the 'high' budding group compared to that in the 'low' budding group. The budding phenomenon is an independent prognostic factor for patients with distal bile duct cancer. Understanding the mechanisms underlying tumour budding in distal bile duct cancer and its relationship with poor prognoses may be useful for the development of novel treatments for this disease.

Gambogic Acid and Piperine Synergistically Induce Apoptosis in Human Cholangiocarcinoma Cell via Caspase and Mitochondria-Mediated Pathway.

Most cholangiocarcinoma (CCA) patients undergo chemotherapy as a therapeutic approach due to the disease's frequently late diagnosis. However, because CCA is resistant to currently available treatments, the prognosis for this cancer is still quite poor. Combination therapy has emerged as a novel and promising strategy in cancer treatment, as monotherapy frequently results in tumor recurrence and drug resistance. Gambogic acid has been shown to have a synergism with other compounds in combating certain cancer cells. Moreover, piperine has been shown to improve the efficacy of numerous chemotherapy drugs and other anticancer natural substances. However, no research has been done on the combination of these two compounds in the treatment of bile duct cancer. In this study, the cytotoxic activity was determined by using the MTT assay, and then, the combined effect was assessed by using the combination index (CI). We found that the combination of gambogic acid and piperine inhibited cell viability more effectively than either treatment alone, and it also demonstrated a synergistically cytotoxic effect against CCA cells. Interestingly, the findings allowed the use of lower concentrations of gambogic acid in cancer treatment when combined with piperine, which could reduce its adverse effect on normal cholangiocytes. Furthermore, the combination of the two compounds increased CCA cell death by inducing apoptosis via both the extrinsic and intrinsic or mitochondria-mediated pathways, as determined by caspase-3, -8, and -9 activity and the reduction of mitochondrial transmembrane potential (ΔΨm). It is possible that the use of these two natural compounds together could be a promising strategy for the treatment of bile duct cancer.

Highly Specific L-Type Amino Acid Transporter 1 Inhibition by JPH203 as a Potential Pan-Cancer Treatment

Accelerated cancer cell growth requires a massive intake of amino acids. Overexpression of L-type (large) amino acid transporter 1 (LAT1) on the cancer cell membrane facilitates such a demand, which is limited in normal organs. Therefore, LAT1 overexpression is ideal as a molecular cancer therapeutic target. JPH203, a LAT1-selective non-transportable blocker, had demonstrated LAT1 inhibition in &lt;10 µM IC50 values and effectively suppressed cancer cell growth in studies involving several types of cancer cell lines and tumor xenograft models. A limited phase I clinical trial was performed on five different solid tumors and showed that JPH203 is well-tolerated and has a promising activity for the treatment of bile duct cancer. This review details the development and prospect of JPH203 as a LAT1-targeting cancer therapy.

54 Disparities in the Diagnosis and Treatment of Bile Duct Cancer Among People With Disability: A National Cohort Study in the Republic of Korea

INTRODUCTION: This study aimed to evaluate the disparity of diagnosis, treatment and prognosis of bile duct cancer (BDC) by the presence, severity and type of disability. METHODS: Patients diagnosed with BDC were selected from a cohort, consisted with 1:3 ratio of age- and sex-matched population with or without disability from the National Disability Database, the Korean Central Cancer Registry, and the Korean National Health Insurance claims database. We evaluated the demographics, socioeconomic status, stages, treatment, and survival rates of BDC patients depending on the presence, severity and type of disability. RESULTS: The cohort included 15,065 patients with BDC, with a significantly lower rate among people with severe disabilities than people without or with mild disabilities (110.6 vs. 136.5 or 147.6 per 105 persons, respectively). Patients with disabilities had higher Charlson comorbidity index (1.43 vs. 2.00) and more below poverty line (6.0% vs. 11.9%) than those without disabilities. People with severe disabilities were diagnosed BDC at earlier age, but less likely to undergo surgery (adjusted odds ratio 0.52, 95% confidence interval 0.45–0.61) or chemotherapy (0.55, 0.45–0.67) than those without disabilities. This trend was more evident in patients with mental disorders. The overall and cancer specific mortality rates were higher in patients with disabilities than those without disabilities. CONCLUSION: In Korea, people with disabilities have a lower rate of BDC diagnosis, receive less surgery or chemotherapy, and have a lower survival rate than people without disabilities. This trend was more evident in patient with severe disabilities and with mental disorders.

Development of bile duct cancer as a long-term complication of biliary-enteric anastomosis for benign diseases: a report of five patients

Objective To study the association, clinical presentation, and diagnosis and treatment of bile duct cancer as a late complication of biliary-enteric anastomoses for benign diseases. Methods A retrospective study was carried out on 5 patients and the medical literature was reviewed. Results They were 3 males and 2 females. The average age was (66.0±0.7) years. The average time period was (14.0±6.1) years after biliary-enteric anastomosis. The clinical presentations included right upper quadrant pain, fever, chills and jaundice. CA19-9, CT and MRI were valuable in diagnosis. There were two patients with distal and three patients with perihilar cholangiocarcinomas (type IIIa, n=2, and type IV, n=1). Local resection with lymphadenectomy was carried out in one patient. Another patient underwent pancreaticoduodenectomy. The remaining three patients only underwent percutaneous transhepatic cholangial drainage (PTCD). The 2 patients who underwent surgery died of progressive tumor disease at 8 and 13 months postoperatively. The other three patients who underwent palliative biliary drainage died within 6 months of PTCD. There was no significant difference between the two types of treatment (P>0.05). Conclusions Chronic cholangitis caused by reflux and bacterial infection was properly a predisposing factor leading to late development of bile duct cancer after biliary-enteric anastomosis for benign diseases. Patients treated with biliary-enteric anastomosis should be closely monitored for late development of cholangiocarcinoma. Some procedures such as choledochoduodenostomy and jejunum interposition choledochoduodenostomy should be abandoned because of their poor outcomes and severe complications. Proper indications of biliary-enteric anastomosis should strictly be followed and the Oddi's sphincter should be protected if possible to prevent late development of bile duct cancer. Key words: Biliary tract diseases; Biliary tract surgical procedures; Bile duct neoplasms; Biliary-enteric anastomosis; Postoperative complication; Treatment outcome

Surgical Technique of Pancreatic Parenchyma Transection-Delayed Approach (PPTDA) in Hepatopancreatoduodenectomy for Hilar Cholangiocarcinoma

BackgroundThe combination of major hepatectomy and pancreatoduodenectomy (PD), that is, a hepatopancreatoduodenectomy (HPD), is the only curative treatment for bile duct cancer with extensive horizontal tumor spread invading both the hepatic hilum and the intrapancreatic bile duct. However, this aggressive procedure remains controversial with regard to the balance between the survival benefit and high risk of mortality and morbidity, especially the risk for postoperative hepatic failure and postoperative pancreatic fistula. Here, we describe the efficacy of a novel modified technique of HPD with delayed division of the pancreatic parenchyma for hilar cholangiocarcinoma, and focus on the surgical technique and the short-term outcomes, with a representative case. Technical PresentationThis new surgical technique involves dissection of the pancreatic parenchyma and relevant mesoduodenum at the final step after dissecting the required parts on the inferior side and superior side of the tumor, enabling excision of the resected specimen. This technique described herein can prevent saponification of the resected surface of the pancreas by dissecting the pancreatic parenchyma toward the latter half of the surgical procedure as much as possible. The results suggest that there may also be a relationship between this technique and the prevention of postoperative pancreatic fistula. ConclusionThis new surgical technique of HPD may be able to prevent postoperative pancreatic fistula by performing intraoperative dissection of the pancreatic parenchyma as late as possible, which in turn, may improve the safety of HPD.

Brachytherapy in the treatment of bile duct cancer - a tough challenge.

The majority of patients with bile duct cancer are diagnosed with clinically advanced disease. Most of these patients have a short life expectancy and are treated with palliative aim. Most patients present with locally advanced or metastatic disease, which is not amenable to surgical resection, resulting in poor survival. Adjuvant or definitive radiotherapy, with or without chemotherapy, is therefore used in many centers worldwide for better local control, and with the expectation that it will have a favorable effect on survival. However, the lack of appropriate prospective trials, as well as the small size of the published series and their retrospective nature, has produced insufficient evidence for the best treatment for these patients. Intraluminal brachytherapy is an important component in the multimodality approach to bile duct cancers. The objective of this treatment is to deliver a high local dose of radiation to the tumor while sparing surrounding healthy tissues. The treatment can be safely adapted for right and left hepatic duct, and for common bile duct lesions. Brachytherapy plays a limited but specific role in definitive treatment with curative intent in selected cases of early disease, as well as in the postoperative treatment of small residual disease. Depending on the location of the lesion, in some cases, brachytherapy is a treatment of choice. Clinical indications, different techniques, results, and complications are discussed in this work.

Multidisciplinary treatment for bile duct cancer

Multidisciplinary treatment for bile duct cancer

Biliary Excretion of Curcumin Is Mediated by Multidrug Resistance-Associated Protein 2

Curcumin has a wide spectrum of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. Recently, its potential as effective chemoprevention against cholangiocarcinoma, a highly malignant tumor of the bile duct with limited therapeutic options, was reported. The purpose of the present study was to investigate the contribution of multidrug resistance-associated protein 2 (Mrp2) to the biliary excretion of curcumin using Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic rats (EHBR). After intravenous administration of curcumin with a loading dose of 4.5 mg/kg, followed by a constant infusion of 18 mg/kg/h to the SDR and EHBR, the pharmacokinetic parameters of curcumin were estimated. In EHBR, the total area under the bile concentration-time curve from 0 to 80 min following curcumin administration was dramatically decreased (0.094%) compared to that in SDR. In addition, the plasma-to-bile and liver-to-bile clearances were both significantly decreased compared to SDR. These results provide the first evidence that Mrp2 mediates the biliary excretion of curcumin and thus may be a major factor in the control of exposure of curcumin to the bile duct. This study may be helpful to the potential use of curcumin as a treatment for bile duct cancer, and to understanding the genetic polymorphism of Mrp2 for clinical trials of curcumin.

Surgical strategy for bile duct cancer: Advances and current limitations

The aim of this review is to describe recent advances and topics in the surgical management of bile duct cancer. Radical resection with a microscopically negative margin (R0) is the only way to cure cholangiocarcinoma and is associated with marked survival advantages compared to margin-positive resections. Complete resection of the tumor is the surgeon's ultimate aim, and several advances in the surgical treatment for bile duct cancer have been made within the last two decades. Multidetector row computed tomography has emerged as an indispensable diagnostic modality for the precise preoperative evaluation of bile duct cancer, in terms of both longitudinal and vertical tumor invasion. Many meticulous operative procedures have been established, especially extended hepatectomy for hilar cholangiocarcinoma, to achieve a negative resection margin, which is the only prognostic factor under the control of the surgeon. A complete caudate lobectomy and resection of the inferior part of Couinaud's segment IV coupled with right or left hemihepatectomy has become the standard surgical procedure for hilar cholangiocarcinoma, and pylorus-preserving pancreaticoduodenectomy is the first choice for distal bile duct cancer. Limited resection for middle bile duct cancer is indicated for only strictly selected cases. Preoperative treatments including biliary drainage and portal vein embolization are also indicated for only selected patients, especially jaundiced patients anticipating major hepatectomy. Liver transplantation seems ideal for complete resection of bile duct cancer, but the high recurrence rate and decreased patient survival after liver transplant preclude it from being considered standard treatment. Adjuvant chemotherapy and radiotherapy have a potentially crucial role in prolonging survival and controlling local recurrence, but no definite regimen has been established to date. Further evidence is needed to fully define the role of liver transplantation and adjuvant chemo-radiotherapy.

Significance of positive ductal margin and prognostic factors of surgical resection in middle and distal bile duct carcinoma

To discuss the significance of a positive ductal margin and evaluate the prognostic factors related to surgical resection for middle and distal bile duct carcinoma. A retrospective clinicopathological analysis of 79 patients who had undergone surgical resection for middle or distal bile ductal cancer between January 1990 and December 2006 was conducted. The surgical procedures consisted of pancreatoduodenectomy in 46 patients, bile duct resection in 25 patients, bile duct resection plus hepatectomy in 6 patients, and bile duct resection with partial resection of portal vein in 2 patients. In 74 patients, 5 patients were excluded because they died after surgery without being discharged from the hospital, 15 clinicopathologic factors were evaluated using univariate and multivariate analysis. The overall 5-year survival rate and the median survival time was 30.7% and 36 months, respectively. Sixteen of 74 patients (20.3%) were determined to have positive ductal margins on the final pathological examination. As a result, hepatic-side ductal margin, duodenal-side ductal margin and both was found to be positive in 6, 3 and 2 patients, respectively. Five patients had positive radial margins. The 5-year survival rate was 34.4% in 58 patients without microscopic residual disease (R0), and 15.5% in 16 patients with microscopic residual tumor (R1). The ductal recurrence rate of 16 patients with R1 resection was higher than 58 patients with R0 resection (62.5% vs. 17.2%, chi(2) = 13.024, P < 0.01). The 1-, 3-, and 5-year survival rates were better in the patients with R0 (92.5%, 56.7%, and 34.4%, respectively) than those in the patients with R1 resection (75.0%, 23.2%, and 15.5%, respectively) (P < 0.05). Twelve patients received postoperative adjuvant therapy. The 5-year survival rate was not significantly different between patients with postoperative adjuvant therapy and those without (18.2% vs. 31.8%, P = 0.221). The preoperative serum level of hemoglobin, pathological differentiation grade, the depth of neoplastic invasion, lymph node metastasis, R1 resection, and TNM stage were significant prognostic factors on the univariate analysis. Multivariate analysis revealed that lymph node metastasis and R1 resection were the independent prognostic factors. In the treatment of middle and distal bile duct cancer, radical resection should be made to obtain a tumor-free margin. An aggressive surgical approach may improve the survival for middle bile duct cancer. Adjuvant therapy needs to be further developed.

Current surgical treatment for bile duct cancer.

Since extrahepatic bile duct cancer is difficult to diagnose and to cure, a safe and radical surgical strategy is needed. In this review, the modes of infiltration and spread of extrahepatic bile duct cancer and surgical strategy are discussed. Extended hemihepatectomy, with or without pancreatoduodenectomy (PD), plus extrahepatic bile duct resection and regional lymphadenectomy has recently been recognized as the standard curative treatment for hilar bile duct cancer. On the other hand, PD is the choice of treatment for middle and distal bile duct cancer. Major hepatectomy concomitant with PD (hepatopancreatoduodenectomy) has been applied to selected patients with widespread tumors. Preoperative biliary drainage (BD) followed by portal vein embolization (PVE) enables major hepatectomy in patients with hilar bile duct cancer without mortality. BD should be performed considering the surgical procedure, especially, in patients with separated intrahepatic bile ducts caused by hilar bile duct cancer. Right or left trisectoriectomy are indicated according to the tumor spread and biliary anatomy. As a result, extended radical resection offers a chance for cure of hilar bile duct cancer with improved resectability, curability, and a 5-year survival rate of 40%. A 5-year survival rate has ranged from 24% to 39% after PD for middle and distal bile duct cancer.

Diagnosis and treatment of bile duct cancer -from the viewpoint of physician-

Diagnosis and treatment of bile duct cancer -from the viewpoint of physician-

Surgical and endoscopic management of bile duct cancer

There is still considerable controversy regarding the value of surgical versus nonsurgical treatment for bile duct cancer. Therapeutic modalities vary from total hepatectomy and liver transplantation to percutaneous or endoscopic stent insertion. The aim of this study was to assess the results of the treatment of 118 patients presented with bile duct cancer in the Department of Surgery, University of Szeged, during the time period 1990-2002. The age, male/female ratio, postoperative morbidity and mortality were analyzed. The resectability rate was 18% (21/118). The mortality rate was 23.8% (5/21) after radical operations and 7% or 12.5% after the palliative procedures. 67 patients had palliative surgery following unsuccessful or recurrent jaundice after non-surgical palliation. The previously applied palliative methods have been transpapillary stenting, endoscopic pig-tail drainage, percutaneous transhepatic drainage or dilatation. Palliative surgery for jaundice caused by extrahepatic bile duct cancer is justified in cases with an unsuccessful attempt for endoscopic stenting or occlusion of endoscopically placed endoprothesis. Bilio-enteric bypass with a Roux-Y jejunal loop is superior than external drainage respecting desicterization, postoperative recovery, mortality, complication rate and quality of life.

Photodynamic therapy with 5-aminolevulinic acid is not effective in bile duct cancer

Background: The results of preliminary studies of photodynamic therapy (PDT) for palliation of patients with bile duct cancer with hematoporphyrin derivative have been good. Rapid elimination of a photosensitizer could potentially shorten the time requirement for shielding from light. This would enhance the benefit of this form of palliative treatment. Therefore the feasibility of PDT was investigated for nonresectable bile duct cancer by using 5-aminolevulinic acid. Methods: Four patients with nonresectable bile duct cancer underwent cholangiography, cholangioscopy, and intraductal US before PDT. Light activation was performed 5 to 7 hours after oral administration of 5-aminolevulinic acid. All patients had an endoprosthesis placed in the bile duct after PDT. Results: Cholangioscopy 72 hours after PDT revealed superficial fibrinoid necrosis. However, 4 weeks after PDT there was no significant reduction in bile duct stenoses. Two patients had infectious complications develop, but phototoxicity was not observed. Conclusions: Although superficial tumor necrosis was evident, PDT with 5-aminolevulinic acid failed to significantly reduce malignant bile duct obstruction. Therefore 5-aminolevulinic acid-PDT cannot be recommended for the palliative treatment of bile duct cancer.

Radiotherapy as a component of multidisciplinary treatment of bile duct cancer: a surgeon's perspective

Surgery is the only curative treatment for bile duct cancer (BDC). However, because of frequent loco-regional recurrence, radical surgery during advanced stages of the disease is often unsuccessful. Despite recent evidence of improvement in patient survival and quality of life, alternatives such as radiation therapy have not been fully developed and remain controversial. This article reviews current publications that deal with various irradiation procedures for the treatment of BDC, with particular attention to adjuvants to surgical resection, including liver transplantation, as a component of treatment of BDC. Specialized boost techniques, including conformal external beam irradiation (EBRT), brachytherapy via transhepatic catheters or a retrograde endoscopic stent, or intraoperative irradiation with electrons (IOERT), are summarized in relation to patient survival.

Photodynamic therapy with 5-aminolevulinic acid is not effective in bile duct cancer

Background: The results of preliminary studies of photodynamic therapy (PDT) for palliation of patients with bile duct cancer with hematoporphyrin derivative have been good. Rapid elimination of a photosensitizer could potentially shorten the time requirement for shielding from light. This would enhance the benefit of this form of palliative treatment. Therefore the feasibility of PDT was investigated for nonresectable bile duct cancer by using 5-aminolevulinic acid. Methods: Four patients with nonresectable bile duct cancer underwent cholangiography, cholangioscopy, and intraductal US before PDT. Light activation was performed 5 to 7 hours after oral administration of 5-aminolevulinic acid. All patients had an endoprosthesis placed in the bile duct after PDT. Results: Cholangioscopy 72 hours after PDT revealed superficial fibrinoid necrosis. However, 4 weeks after PDT there was no significant reduction in bile duct stenoses. Two patients had infectious complications develop, but phototoxicity was not observed. Conclusions: Although superficial tumor necrosis was evident, PDT with 5-aminolevulinic acid failed to significantly reduce malignant bile duct obstruction. Therefore 5-aminolevulinic acid-PDT cannot be recommended for the palliative treatment of bile duct cancer.

Surgical possibilities for bile duct cancer: Standard surgical treatment

There is no consensus on the surgical treatment of bile duct cancer, which varies from total nihilism to an extremely aggressive resectional policy. This paper describes the adoption of a 'middle road' approach to these difficult cancers, and suggests that selective use of stenting, bypass and resection with judicious application of adjunctive chemotherapy is an appropriate attitude until controlled studies of the alternatives are available. The main aims of treatment are (a) relief of obstructive jaundice, (b) prevention and treatment of future recurrent obstruction and cholangitis, and (c) eradication of tumour when possible. Local resection carries a low morbidity and mortality and is always a reasonable option in patients fit for surgery, but the relative value of non-radical resection and stenting with chemotherapy remains to be determined. Extended resections, including major hepatectomy and radical lymph node dissection, are only justified when the intent is curative, and some patients may not be suitable for such extensive surgery. In patients who are explored and determined to be unsuitable for major resection, surgical bypass is an option, but there is little evidence that this produces better palliation or quality of survival than optimal percutaneous or endoscopic stenting. Of 76 patients referred to the author over 7 years, 27 (35%) underwent surgical resection, and 23 (30%) had no operation. In patients followed up for more than 1 year, median survival following curative resection (9 patients) was 26 months, and after palliative resection (15 patients) it was 11 months. Median survivals after palliative biliary-enteric bypass (11), exploration alone (9), or no operation (20) were 2, 4, and 5 months respectively. A cautious and selective approach to surgery for these tumours is advocated.