Valoración de la linfadenectomía en una serie consecutiva de pacientes tratados por cáncer biliar / Evaluation of lymphadenectomy in a consecutive series of patients treated for biliary cancer

Resumen Introducción: Si bien actualmente la 8a edición de la clasificación del AJCC para cáncer biliar, recomienda una linfadenectomía con 6 o más GL, su aplicación es escasa. Objetivo: Analizar la aplicabilidad y los resultados de la linfadenectomía en pacientes resecados con fines curativos por cáncer biliar. Materiales y Método: Análisis retrospectivo de pacientes operados por cáncer biliar de 2001 a 2018. Se analizaron variables perioperatorias referidas a la linfadenectomía (número de GL, GL+, morbilidad), comparando supervivencia en pacientes con < 6 y ≥ 6 GL resecados. Resultados: en 72 pacientes resecados por cáncer biliar (46 CaV, 26 CC), se realizaron 66 (91.7%) linfadenectomías N1. En 62.1% (n = 41) se obtuvieron < 6 GL y en el 37.9% (n = 25) ≥ 6 GL. El promedio de GL resecados fue de 5. En 16 (24,2%) linfadenectomías se hallaron GL+ sin diferencias entre ambos grupos. La morbimortalidad global fue de 30,3%, con una mortalidad del 4.5% sin diferencias. Con un seguimiento de 36.9 meses, la supervivencia a 5 años fue 43,7% (n = 17), 7 pacientes con ≥ 6 GL, y 10 pacientes con < 6 GL (p = NS). La supervivencia media en pacientes con GL+ fue 15 meses (6-34 meses). Conclusión: la linfadenectomía ocupa un rol primordial en la cirugía curativa del cáncer biliar, tanto para definir una estadificación y un pronóstico adecuados como para optimizar los resultados de la resección curativa en esta entidad. Su indicación debe ser sistemática con la obtención de un número adecuado de GL acorde a las recomendaciones actuales.

Introduction: Currently the 8th edition of the AJCC classification recommends the resection of 6 or more lymph nodes (LN) in gallbladder cancer and cholangiocarcinoma. However, its implementation is universally scarce. Aim: The goal is to analyze the applicability and results of lymphadenectomy in patients resected with curative purposes in biliary cancer. Materials and Method: a retrospective analysis of patients with biliary cancer (gallbladder carcinoma, intrahepatic and hilar cholangiocarcinoma) treated by curative resection from 2001 to 2018 was performed. Perioperative variables related to lymphadenectomy (LN number, LN positive, related morbidity) were analyzed, comparing survival in patients with < 6 and ≥ 6 resected LN. Results: 72 patients resected for biliary cancer (46 gallbladder cancer, 26 cholangiocarcinoma) were included with 66 (91.7%) N1 lymphadenectomies corresponding to the hepatoduodenal ligament nodes performed. In 62.1% (n = 41) < 6 LN and in 37.9% (n = 25) ≥ 6 LN were resected. Average LN count was 5. In 16 (24.2%) patients positive LN were found, 7 in the group with ≥ 6 LN (28%) vs. 9 in the group with < 6 LN (22%) (p = NS). Overall morbimortality was 30.3% (n = 20). Average follow-up was 36.9 months. Survival at 5 years was 43.7% (n = 17), 7 patients with lymphadenectomy ≥ 6 LN, and 10 patients with < 6 LN (p = NS). Survival mean in patients who had positive LN was 15 months. Conclusión: Lymphadenectomy has a primary role in the radical resection with curative intention for biliary cancer. Systematic indication of lymphadenectomy should be prioritized, with the achievement of an adequately number of LN according to the actual recommendations. Lymphadenectomy is crucial for an adequate staging and prognosis, as well as to optimize the results of curative resection in this entity.

Surveillance method and imaging characteristics of recurrent biliary cancer after surgical resection

This is a review of the diagnostic imaging techniques and findings of recurrent biliary cancer after surgical resection of the extrahepatic bile duct and gallbladder. Radiological examination plays an important role in diagnosing postoperative recurrence of biliary cancers. Early detection and diagnosis of recurrent cancer is critical in obtaining proper treatment and improves the prognosis. In the surveillance of recurrent biliary cancer, several diagnostic imaging modalities are currently used. Usually CT is the most common method for surveillance of postoperative patients, but MRI and PET/CT scans are also widely used. Recurrent biliary cancer can manifest as local recurrence, liver metastasis, lymph node metastasis, and peritoneal metastasis. Imaging findings of a locally recurrent tumor or metastatic lymph node enlargement overlaps with benign postoperative changes, thus radiologists commonly overlook subtle CT findings or misinterpret them as benign postoperative changes. There are several reports that FDG-PET scan is more effective in the diagnosis of recurrent biliary tract cancer than CT. Multidisciplinary diagnostic approaches using CT, MRI, and FDG-PET as well as clinical information seem to be essential for the precise diagnosis of recurrent tumors.

RAS Mutation is a Local Tumour Event and Not a Field Change in Pancreatobiliary Tumours.

Background: KRAS mutation (KRM) is the earliest, most common mutation in pancreatic cancer. Accurate assessment of tumour KRM status in pancreatobiiary tumours is relevant in an era of targeted molecular therapies. Aim: To assess KRM in tumour and non-tumourous margin tissue in patients undergoing a pancreatic resection. Study Design: Original research, retrospective review of prospectively collected specimens. Place and Duration of Study: Patients who had undergone pancreaticoduodenectomy and distal pancreatic resection at the Royal Adelaide Hospital from 2011-2012 were consented for the study. Methods: Patient demographics, background history and tumour details were collated. Tumour tissue and margin areas were macrodissected from FFPE tissue sections following identification by a pathologist. DNA was prepared from the tissue using the QIAamp FFPE Tissue kit (Qiagen GmbH, Hilden Germany). KRM at codons 12 and 13 was assessed using SNaPShot TM (Applied Biosystems, Warrington UK) in tumour tissue and non-tumourous margin tissue. Fourteen patients were included in the study. The median age of the patients in the study was 68 (range 57-86) years. The M : F ratio was 8 : 6. Results: Twelve patients had adenocarcinomas (5 pancreatic; 4 ampullary, 3 biliary) and two had benign mucinous tumours. Six patients with adenocarcinomas had KRM (5@codon 12 and 1@codon 13). Margin tissue was negative for KRM in all the tested patients (p<0.016 Fisher) particularly, in those with tumour KRM. Tumours with KRM were associated with larger tumours 30(22-65) mm vs 20(15-35) mm [median(range)](p = .045 – MW-U). Nodal disease occurred in 6/6 with KRM vs 2/6 without KRM (p = .61 – Fisher). Conclusions: KRM is a local tumour event and not a field change. This suggests that testing for KRM should be reliant on tumour tissue and not surrounding normal margin tissue. KRM was associated with larger malignant tumours and a trend towards nodal disease.

EUS-guided biliary drainage in distal malignant biliary obstruction: a new tool when ERCP fails / Drenagem biliar ecoguiada no câncer biliar distal: uma nova ferramenta na falha da CPRE

Introduction: most of patients with biliary tract cancer are diagnosed at an advanced stage. EUS-guided biliary drainage (EBD) is an alternative to percutaneous transhepatic or surgical drainage techniques after failure at conventional access by endoscopic retrograde cholangiopancreatography (ERCP). Objectives: to evaluate EBD efficacy and safety in patients with malignant biliary obstruction at the Gastrointestinal Endoscopy Department from Hospital das Clínicas of São Paulo University. Methods: there were included in our study patients that had a clinical history of obstructive jaundice and failure at biliary drainage by ERCP. EBD was performed under radioscopic control. The efficacy was analyzed according to clinical outcome and improvement in quality of life after the procedure, which was assessed by the application of a quality of life measurement test, and an evaluation of laboratory tests, signs, symptoms and procedure-related complications. Results: from April 2010 to September 2011, 32 patients with advanced biliary tract cancer were included in our study. Three (9.4%) patients had technical failure at EBD procedure. Technical success was achieved in 90.6% (29/32) and clinical improvement occurred in 100% (29/29). EUS-guided choledochoduodenostomy was the most common drainage procedure (58.62%). Duodenal self-expandable metallic stents were placed in 7 (21.85%) cases. There were a significant ecrease in bilirubin levels (p <0.001) and patients had improvement in quality of life after the procedure (p < 0.05). Complications occurred in 6 (18.75%) patients and the median survival was 90 days. Conclusion: EBD was an effective and safe procedure with acceptable complication rates, providing significant improvement in quality of life.

Introdução: a maioria dos pacientes com câncer biliar é diagnosticada em estágio avançado. A drenagem biliar ecoguiada é uma alternativa à drenagem percutânea e à cirurgia derivativa. Objetivos: avaliar a eficácia e a segurança do método em pacientes com necessidade de drenagem biliar e falha da CPRE prévia. Método: foram incluídos pacientes com obstrução biliar maligna e falha do acesso por CPRE convencional. A eficácia foi avaliada pelo sucesso clínico e pela avaliação da qualidade de vida. Avaliação laboratorial e clínica foram estudadas e computadas por teste estatístico. Resultados: entre abril e setembro, 32 pacientes foram incluídos no protocolo. Em três verificou-se insucesso do acesso ecoguiado. O sucesso técnico ocorreu em 90,6% (29/32) e o sucesso clínico em 100% dos casos. Coledocoduodenostomia ocorreu em 58,6% e foi o acesso mais frequente da casuística apresentada. A melhora da bilirrubina em 7 dias foi significante (p <0,001) e a qualidade de vida foi melhor no seguimento de 30 dias (p <0,05). Complicações ocorreram em 6 (18,75%) e sobrevida média foi de 90 dias. Conclusões: a drenagem biliar ecoguiada é uma ferramenta importante na falha da CPRE prévia e com índices de complicações aceitáveis.

Comparison of Clinical Outcome and Cost-Effectiveness after Various Preoperative Biliary Drainage Methods in Periampullary Cancer with Obstructive Jaundice

The aim of this study was to compare the clinical outcome and cost-effectiveness of preoperative biliary drainage (BD) methods in periampullary cancer, and to suggest guidelines for selecting the appropriate preoperative BD method. Between October 2004 and August 2010, 211 patients underwent pancreatoduodenectomy after preoperative BD. Clinical outcome and cost-effectiveness of the preoperative BD methods were compared based on the final drainage method used and on intention-to-treat analysis. There was no significant difference in drainage duration between percutaneous transhepatic biliary drainage (PTBD) and endoscopic BD groups (14.2 vs 16.6 days, respectively; P = 0.121) but daily diminution of serum bilirubin level was higher in the PTBD group (0.7 vs 0.6 mg/dL/day, respectively; P = 0.041). Based on intention-to-treat analysis, drainage duration was shorter (13.2 vs 16.5 days, respectively; P = 0.049), daily diminution of serum bilirubin level was higher (0.7 vs 0.6 mg/dL/day, respectively; P = 0.041). Medical care cost was lower (14.2 vs 15.7 x 10(3) USD, respectively; P = 0.040) in the PTBD group than in the endoscopic BD group. When selecting the preoperative BD method, practitioners should consider that PTBD is more cost-effective and safer than endoscopic BD.

Comparison of Clinical Outcome and Cost-Effectiveness after Various Preoperative Biliary Drainage Methods in Periampullary Cancer with Obstructive Jaundice

The aim of this study was to compare the clinical outcome and cost-effectiveness of preoperative biliary drainage (BD) methods in periampullary cancer, and to suggest guidelines for selecting the appropriate preoperative BD method. Between October 2004 and August 2010, 211 patients underwent pancreatoduodenectomy after preoperative BD. Clinical outcome and cost-effectiveness of the preoperative BD methods were compared based on the final drainage method used and on intention-to-treat analysis. There was no significant difference in drainage duration between percutaneous transhepatic biliary drainage (PTBD) and endoscopic BD groups (14.2 vs 16.6 days, respectively; P = 0.121) but daily diminution of serum bilirubin level was higher in the PTBD group (0.7 vs 0.6 mg/dL/day, respectively; P = 0.041). Based on intention-to-treat analysis, drainage duration was shorter (13.2 vs 16.5 days, respectively; P = 0.049), daily diminution of serum bilirubin level was higher (0.7 vs 0.6 mg/dL/day, respectively; P = 0.041). Medical care cost was lower (14.2 vs 15.7 x 10(3) USD, respectively; P = 0.040) in the PTBD group than in the endoscopic BD group. When selecting the preoperative BD method, practitioners should consider that PTBD is more cost-effective and safer than endoscopic BD.

Photodynamic Therapy for Cholangiocarcinoma

Cholangiocarcinoma is the primary malignancy arising from the biliary epithelium, and it presents as jaundice, cholestasis, and cholangitis. Over 50 percent of patients present with advanced-stage disease, and the prognosis is poor with the survival measured in months even after biliary decompression. Palliative management has become the standard of care for unresectable disease, and this involves an endoscopic approach. Photodynamic therapy (PDT) involves the administration of a photosensitizer followed by local irradiation with laser therapy. The use of PDT for palliation of bile-duct tumors has produced promising results. Several studies conducted in Europe and the United States have shown that PDT produces a marked improvement in the symptoms of cholestasis, survival, and quality of life. This chapter summarizes the principle of PDT, the technique employed, and the published experience regarding PDT for cholangiocarcinoma.

EC-18, a Synthetic Monoacetyldiacylglyceride, Inhibits Hematogenous Metastasis of KIGB-5 Biliary Cancer Cell in Hamster Model

EC-18 (monoacetyldiacylglyceride) stimulates T cell production of IL-2, IL-4, IL-12, IFN-gamma, and GM-CSF in vitro. To study the effects of these cytokines stimulated by EC-18 on cancer cells, we applied hamster biliary cancer model, a difficult cancer to treat. Cancer (KIGB-5) cells were given intravenously to produce hematogenous metastatic lung lesions which were treated with EC-18 at 10, 25, and 50 mg/kg/day respectively. The fourth group was untreated control. At 4th, 8th, and 12th week the lungs were examined. EC-18 treated groups showed only a few microscopic lung lesions and no evidence of metastatic lesion with highest dose whereas widespread gross lung lesions were observed in untreated control. To investigate whether the anti-tumor effect of EC-18 is associated with suppression of tumor cell Toll-like receptor 4 (TLR-4) expression in addition to stimulation of the immune cells, KIGB-5 cells were exposed to LPS with or without EC-18. TLR-4 mRNA and protein expression, measured by reverse transcriptase PCR (RT-PCR), real-time quantitative PCR and western blot analysis, showed suppression of TLR-4 expression in KIGB-5 cells treated with EC-18 compared with control. In conclusion, EC-18 has a significant anti-tumor effect in this experimental model of biliary cancer suggesting potential for clinical application to this difficult cancer.

EC-18, a Synthetic Monoacetyldiacylglyceride, Inhibits Hematogenous Metastasis of KIGB-5 Biliary Cancer Cell in Hamster Model

EC-18 (monoacetyldiacylglyceride) stimulates T cell production of IL-2, IL-4, IL-12, IFN-gamma, and GM-CSF in vitro. To study the effects of these cytokines stimulated by EC-18 on cancer cells, we applied hamster biliary cancer model, a difficult cancer to treat. Cancer (KIGB-5) cells were given intravenously to produce hematogenous metastatic lung lesions which were treated with EC-18 at 10, 25, and 50 mg/kg/day respectively. The fourth group was untreated control. At 4th, 8th, and 12th week the lungs were examined. EC-18 treated groups showed only a few microscopic lung lesions and no evidence of metastatic lesion with highest dose whereas widespread gross lung lesions were observed in untreated control. To investigate whether the anti-tumor effect of EC-18 is associated with suppression of tumor cell Toll-like receptor 4 (TLR-4) expression in addition to stimulation of the immune cells, KIGB-5 cells were exposed to LPS with or without EC-18. TLR-4 mRNA and protein expression, measured by reverse transcriptase PCR (RT-PCR), real-time quantitative PCR and western blot analysis, showed suppression of TLR-4 expression in KIGB-5 cells treated with EC-18 compared with control. In conclusion, EC-18 has a significant anti-tumor effect in this experimental model of biliary cancer suggesting potential for clinical application to this difficult cancer.

Effect of doses of three-dimensional conformal radiotherapy for unresectable biliary cancer / 中国癌症杂志

Purpose:To determine the effect of doses of three-dimensional conformal radiotherapy(3D-CRT) for unresectable biliary cancer. Methods:48 patients with localized,unresectable cholangiocarcinoma were treated with 3D-CRT.Patients were grouped according to the radiotherapy dose: 12 patients received a total dose of 33-39Gy(low dose group),23 patients received 40-58Gy(medium dose group),and 13 patients received 59.4-68Gy(high dose group). The low dose group received 3Gy/fraction,medium dose group and high dose group received either 1.8 or 2Gy/fraction,5 fraction/week. Results:The median time to local progression for all patients was 10 months. The median overall survival was 12 months. 24(50%)had radiographic evidence of disease progression. 21 of those patients(87.5%) experienced local recurrence as the first radiographic sign of disease progression. The remaining 3 presented with metastatic disease as the initial sign of progression. The time of local failure(P=0.220) and the median survival(P=0.232) were not statistically different among the three groups. The rate of acute gastrointestinal side effects was not statistically different among the three groups(P= 0.485) . Conclusions:Local progresion was the predominant pattern of disease recurrence in this group of patients with unresectable biliary cancer. Because the power to detect even large difference with small numbers of patients is limited,a benefit from high dose radiotherapy cannot be excluded.

Synchronous Biliary Tract Cancers in a Patient with von Recklinghausen Disease

Von Recklinghausen's disease (VRD) is known to be associated with various neoplasms of both neural crest and nonneural crest origin. Approximately 25% of all patients with VRD have documented gastrointestinal involvement. However, most of these tumors are benign neurofibromas. Less commonly, leiomyomas, sarcomas, ganglioneuromas and carcinoids have been reported. We report two cases of synchronous biliary cancer (gallbladder & ampulla of Vater) in patients with von Recklinghausen Disease with jejunal stromal tumors. One case (F/39) was diagnosed as an adenocarcinoma of Vater's ampulla and adenoma of the gallbladder. She underwent a pancreaticoduodenectomy. Another patient (M/55) was diagnosed as an adenocarcinoma of the Vater's ampulla and squamous cell carcinoma of the gallbladder. He underwent a right lobectomy of the liver and a pancreaticoduodenectomy (HPD).