The immune microenvironment features and response to immunotherapy in EBV-associated lymphoepithelioma-like cholangiocarcinoma.

BACKGROUND AND AIMS: Limited data are available for tumor immune microenvironment (TIME) in Epstein-Barr virus (EBV)-associated lymphoepithelioma-like cholangiocarcinoma (EBV-LELCC), a rare subtype of intrahepatic cholangiocarcinoma (IHCC). We aimed to investigate TIME features in EBV-LELCC and the correlation between the components of TIME and the clinical outcomes. METHODS: Tumor tissues from five EBV-LELCC cases confirmed through EBER in situ hybridization and five stage-matched conventional IHCC (non-EBV IHCC) cases were collected. These samples were used to evaluate genetic alterations, TIME composition, and PD-L1 expression through ion AmpliSeq comprehensive cancer panel, PanCancer immune profiling panel, immunohistochemistry, and immunofluorescence staining. The correlation between clinical outcomes and TIME components was analyzed in the two EBV-LELCC cases receiving anti-PD-1 treatment. RESULTS: The genetic mutations identified in EBV-LELCC were BARD1, CD19, CD79B, EPHA5, KDM5A, MUC6, MUC16, PTEN, RECQL4, TET1, and TNFAIP3. Both CD79B and TNFAIP3 mutations were involved in the NF-κB signaling pathway. PD-L1 was highly expressed in tumor-infiltrating immune cells, especially the T cells and macrophages. The TIME of EBV-LELCC displayed abundant immune cell infiltration with a stronger adaptive immune response. Increased Th1 cells, NK CD56dim cells, and M1 macrophages, decreased M2 macrophages, exhausted CD8 T cell infiltration, and increased T cell activation signatures in TIME were associated with longer survival. Two patients with metastatic EBV-LELCC had good disease control after anti-PD-1 antibody treatment. A significantly larger TIME component made EBV-LELCCs more sensitive to immune checkpoint blockade (ICB). CONCLUSION: A better understanding of the composition of TIME in EBV-LELCC is critical for predicting the clinical outcomes of ICB treatment.

Discovering proteins for chemoprevention and chemotherapy by curcumin in liver fluke infection-induced bile duct cancer.

Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.

Distribution of tumor stage and initial treatment modality in patients with primary hepatocellular carcinoma

Objective. This study reviewed the distribution of each tumor stage and each type of initial treatment modality among patients with primary hepatocellular carcinoma (HCC) treated at a tertiary tumor hospital between January 2003 and October 2013. Methods. Baseline data of patients with primary hepatocellular carcinoma treated between January 2003 and October 2013 were retrospectively collected. Tumor stage was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system and Hong Kong Clinic Liver Cancer (HKLC) staging system. Results. A total of 6241 patients with primary hepatocellular carcinoma were included in the analysis. In accordance with the BCLC, 28.9% of patients were in stage 0/A, 16.2% in stage B, 53.6% in stage C, and 1.3% in stage D. According to the HKLC stage system, 8.4% patients were in stage I, 1.5% in stage IIa, 29.0% in stage IIb, 10.0% in stage IIIa, 33.6% in stage IIIb, 3.4% in stage IVa, 2.5% in stage IVb, 0.2% in stage Va, and 11.4% in stage Vb. Treatment modalities applied to this patient group were as follows: 33.3% of patients underwent hepatic resection, 36.7% underwent transarterial chemoembolization (TACE), 2.2% underwent radiotherapy, 0.9% underwent local ablated therapy, 8.8% underwent systemic chemotherapy, 4.2% underwent traditional herbal medicine therapy, 0.1% underwent targeted drug therapy, and 13.8% received no treatment. Hepatic resection was the most frequent therapy for patients with BCLC 0/A/B disease, and TACE was the initial therapy for patients with BCLC C disease. In the Hong Kong Clinic Liver Cancer staging system, the main treatments for HKLC I to IIIb disease is hepatic resection and TACE. Systemic chemotherapy was the initial therapy for patients with HKLC IVa/IVb disease. Most HKLC Va/Vb patients received traditional Chinese medicine treatment. Conclusion. Prevalence of stage BCLC B and C disease was high among our hepatocellular carcinoma patients. In Hong Kong Clinic Liver Cancer staging system, HKLC I to IIIb disease was high among our HCC patients. Hepatic resection and TACE are initial therapies (AU)

No disponible

A combination of praziquantel and the traditional medicinal plant Thunbergia laurifolia on Opisthorchis viverrini infection and cholangiocarcinoma in a hamster model.

Cholangiocarcinoma (CCA) associated by Opisthorchis viverrini remains a health problem in Southeast Asia including Thailand. At present, there is still no efficient treatment for CCA. Thunbergia laurifolia is a traditionally used medicinal plant; its aqueous leave extract possesses the antioxidant activity and anti-inflammatory on hamster opisthorchiasis had been reported previously. Here, we demonstrate the combined effects of the T. laurifolia extract plus antihelminthic drug, praziquantel (PZ) on hamsters with opisthorchiasis and hamsters with opisthorchiasis related-cholangiocarcinoma through light microscopic observations of histopathological changes, as well as liver function tests for alanine transaminase (ALT) and alkaline phosphatase, and kidney function tests for blood urea nitrogen and creatinine. Results showed T. laurifolia extract combined with praziquantel reduced inflammatory cell aggregation and inhibiting CCA development, which were correlated to the serum ALT level. These present studies suggest that administration of T. laurifolia after praziquantel treatment clearly improve the hepatobiliary system and could reduce the risk of subsequent CCA development in human.

Transhepatic anterograde biliary drainage using a self-expandable metallic stent: a therapeutic alternative after hepaticojejunostomy with Roux-en-Y reconstruction / Drenaje biliar transhepático anterógrado usando una prótesis metálica autoexpandible: Una alternativa terapéutica tras la hepaticoyeyunostomía con reconstrucción en Y en Roux

Endoscopic drainage is the procedure of choice in cases of obstructive jaundice. However, in patients with a surgical biliary reconstruction, this technique cannot be often satisfactorily used. In these cases, the best alternative has usually been the percutaneous biliary drainage. Since the introduction of endoscopic ultrasoundguided therapy, some new techniques have been proposed to solve these technical problems related to postsurgical disturbed anatomy. In this case report, we describe our successful experience in the performance of a transhepatic anterograde biliary drainage using a self-expandable metallic stent in the context of a patient who previously had undergone a hepaticojejunostomy with Roux-en-Y reconstruction because of a resected hilar cholangiocarcinoma (AU)

Hepatectomía derecha extendida por colangiocarcinoma intrahepático en un paciente con síndrome de Dubin-Johnson / Hepatectomy for cholangiocarcinoma in one patient with Dubin Johnson syndrome

Dubin-Johnson syndrome (SDJ) is a rare benign autosomal recessive congenital disease that causes jaundice. We report a 71 years old male with a Dubin Jonson syndrome diagnosed at the age of 40. On a ultrasound examination and magnetic resonance imaging, a liver tumor was found, that was excised. The pathology report showed a cholangiocarcinoma. During the postoperative period, the patient had a hyperbilirubinemia that subsided slowly. There are reports of hyperbilirubinemia of difficult management after hepatectomy in patients with Dubin-Johnson syndrome.

El síndrome de Dubin-Johnson (SDJ) es una patología benigna, familiar, con carácter autosómico recesivo y de aparición poco frecuente. Consiste en un defecto en la excreción hepática de la bilirrubina conjugada que permite su entrada al canalículo biliar, manifestando un cuadro clínico de ictericia silente. La asociación de esta enfermedad con colangiocarcinoma intrahepático es excepcional, siendo difícil la sospecha precoz de este diagnóstico y también el manejo de la ictericia postoperatoria. El objetivo de este trabajo es describir un caso clínico con estas características y revisión de la literatura existente. Se presenta a un paciente de sexo masculino de 71 años de edad, con antecedente de síndrome de Dubin-Johnson diagnosticado a los 40 años. Asintomático, en exámenes de rutina se encuentra un tumor hepático en la ecotomografía abdominal, que luego se corrobora en la TAC y RNM, mide aproximadamente 10 cm de diámetro, de ubicación central y derecho. Resto de estudio no muestra diseminación. Se realiza laparoscopia diagnóstica y ecografía intraoperatoria confirmando lo visto por imágenes, y se decide convertir a laparotomía para efectuar hepatectomía derecha extendida. Biopsia rápida y diferida informan colangiocarcinoma. Evoluciona favorablemente en el postoperatorio, con hiperbilirrubinemia sostenida de lenta resolución. La asociación de hepatectomía con síndrome de Dubin-Johnson es de muy baja frecuencia, existiendo poca literatura al respecto. Se ha descrito que la hiperbilirrubinemia en el postoperatorio es de difícil manejo, sin embargo, en este caso el paciente evolucionó favorablemente sin necesidad de alguna terapia específica.

External lymphatic fistula after intra-abdominal lymphadenectomy for cancer. Treatment with total parenteral nutrition and somatostatin.

OBJECTIVE: External lymphatic fistula or chyloperitoneum after intra-abdominal lymphadenectomy may present challenging problems. In the absence of definite guidelines the choice of treatment is often empirical, with unpredictable effectiveness, and the reporting of new cases may broaden the available experience. METHODS: We describe two cases. One patient had high-output external fistula (1300 mL/d) after para-aortic lymphadenectomy for metastatic lymph nodes. The fistula became fully evident at postoperative day 4, with resumption of an oral diet, on the basis of a 1300-mL/d output of white milky fluid from an abdominal drainage. Oral feeding was interrupted and total parenteral nutrition was started; this was transiently associated with octreotide administration, subsequently replaced by somatostatin. The second patient had a low-output fistula (350 mL/d) after liver resection and lymphadenectomy for cholangiocarcinoma and underwent treatment with total parenteral nutrition and somatostatin. RESULTS: In the first case the lymphatic fistula healed in just less than 3 wk, with the patient constantly remaining in very good condition, without secondary complications. In the second case the low-output fistula healed more rapidly. CONCLUSION: Interruption of oral feeding with total parenteral nutrition and continuous somatostatin infusion was an effective treatment in both patients with an intra-abdominal lymphatic leak.

Acute renal failure induced by a Brazilian variety of propolis.

Propolis is a resinous substance collected by honeybees and used in hive construction and maintenance. Cumulative evidence suggests that propolis may have anti-inflammatory, antibiotic, antioxidant, antihepatotoxic, and antitumor properties. In addition to topical applications, products containing propolis have been used increasingly as dietary supplements. Although reports of allergic reactions are not uncommon, propolis is reputed to be relatively nontoxic. Its systemic toxicity is rarely reported and hence may be underestimated. This is the first report of propolis-induced acute renal failure. A 59-year-old man required hemodialysis for acute renal failure. The patient had cholangiocarcinoma and had ingested propolis for 2 weeks before presentation. Renal function improved after propolis withdrawal, deteriorated again after reexposure, and then returned to a normal level after the second propolis withdrawal. This case indicates that propolis can induce acute renal failure and emphasizes the need for vigilance and care when propolis is used as a medicine or dietary supplement.

Results of treatment of primary liver cancer at Kaunas University of Medicine Hospital.

Though the results of treatment of primary liver cancer depend on many circumstances, the opportunity to perform a curative liver resection remains the main point in prognosis on survival. The aim of the study was to examine our first experience in the treatment of liver cancer. From 1996 to 2001 we observed 54 patients with liver cancer: 46 hepatocellular and 6 cholangiocellular carcinomas, 1 malignant carcinoid, and 1 carcinosarcoma. In presence of liver cirrhosis (21 patients, 38.8%) hepatic function was evaluated using Child Pugh classification. Lesions were multiple in 28 cases and single in 26 cases. Ten patients (18.5%) were radically resected, 12 patients (22.2%) were managed by laparotomy and biopsy, 2 by percutaneous ethanol injections, 1 by trans-ileocolic portal vein embolization + hepatic artery embolization. There were 7 deaths (28%) and 18 complications (72%) after the surgical treatment. The survival results of patients who underwent resection were better (median 240 days) compared with palliative treatment group (median 113.3 days); by Log-Rank test p=0.208. CONCLUSION. The use of liver resections in patients affected by single or monolateral liver cancer is effective and potentially radical treatment. Mortality and morbidity rate is high. Alternative therapies can be conveniently considered in case of multicentric Child B-C patients.

Severe reversible bone marrow suppression induced by Selaginella doederleinii.

CASE REPORT: We report a 52-year-old female patient with cholangiocarcinoma who developed severe bone marrow suppression after taking Selaginella doederleinii as an alternative anticancer treatment. She developed severe pancytopenia with initial presentations of skin ecchymosis, itching, and gum bleeding 2 weeks after taking Selaginella doederleinii daily. Bone marrow smear and biopsy showed severe hypocellularity with no malignant cell infiltration. Approximately 1 week after stopping Selaginella doederleinii, her hemogram returned to previous levels. Selaginella doederleinii, a popular anticancer herb, may contain an as yet unidentified substance that contributes to reversible bone marrow suppression.

Inhibition of nitrosation.

Humans are exposed through ingestion or inhalation to preformed N-nitroso compounds (NOC) in the environment and through the endogenous nitrosation of amino precursors in the body. Activated macrophages and bacterial strains isolated from human infections can enzymatically produce nitrosating agents and NOC from precursors at neutral pH. As a consequence, endogenous nitrosation may occur at various sites of the body, such as the oral cavity, stomach, urinary bladder, and at other sites of infection or inflammation. Numerous substances to which humans are exposed have been identified and shown to inhibit formation of NOC. Such inhibitors include vitamins C and E, certain phenolic compounds, and complex mixtures such as fruit and vegetable juices or other plant extracts. Nitrosation inhibitors normally destroy the nitrosating agents and, thus, act as competitors for the amino compound that serves as substrate for the nitrosating species. Independently, epidemiological studies have already established that fresh fruits and vegetables that are sources of vitamin C, other vitamins, and polyphenols have a protective effect against cancers at various sites and in particular gastric cancer. This article briefly reviews (a) the chemistry of NOC formation and inhibition; (b) the studies in experimental animals that showed that inhibition of endogenous NOC synthesis leads to a reduction of toxic, mutagenic, and carcinogenic effects; (c) recent studies in humans where the degree of inhibition of endogenous NOC synthesis was directly quantified; and (d) the possible contribution of nitrosation inhibitors to human cancer prevention.