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INTRODUCTION: In the treatment of upper GI endoscopy-negative patients with heartburn and epigastric pain or burning, antacids, antireflux agents, and mucosal protective agents are widely used, alone or as add-on treatment, to increase response to proton-pump inhibitors, which are not indicated in infancy and pregnancy and account for significant cost expenditure. METHODS: In this randomized, controlled, double-blind, double-dummy, multicenter trial assessing the efficacy and safety of mucosal protective agent Poliprotect (neoBianacid, Sansepolcro, Italy) vs omeprazole in the relief of heartburn and epigastric pain/burning, 275 endoscopy-negative outpatients were given a 4-week treatment with omeprazole (20 mg q.d.) or Poliprotect (5 times a day for the initial 2 weeks and on demand thereafter), followed by an open-label 4-week treatment period with Poliprotect on-demand. Gut microbiota change was assessed. RESULTS: A 2-week treatment with Poliprotect proved noninferior to omeprazole for symptom relief (between-group difference in the change in visual analog scale symptom score: [mean, 95% confidence interval] -5.4, -9.9 to -0.1; -6.2, -10.8 to -1.6; intention-to-treat and per-protocol populations, respectively). Poliprotect's benefit remained unaltered after shifting to on-demand intake, with no gut microbiota variation. The initial benefit of omeprazole was maintained against significantly higher use of rescue medicine sachets (mean, 95% confidence interval: Poliprotect 3.9, 2.8-5.0; omeprazole 8.2, 4.8-11.6) and associated with an increased abundance of oral cavity genera in the intestinal microbiota. No relevant adverse events were reported in either treatment arm. DISCUSSION: Poliprotect proved noninferior to standard-dose omeprazole in symptomatic patients with heartburn/epigastric burning without erosive esophagitis and gastroduodenal lesions. Gut microbiota was not affected by Poliprotect treatment. The study is registered in Clinicaltrial.gov (NCT03238534) and the EudraCT database (2015-005216-15).
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Antiulcerosos , Dispepsia , Esofagite , Úlcera Péptica , Humanos , Omeprazol/uso terapêutico , Azia/tratamento farmacológico , Azia/etiologia , Antiulcerosos/uso terapêutico , Esofagite/induzido quimicamente , Inibidores da Bomba de Prótons/uso terapêutico , Dispepsia/tratamento farmacológico , Úlcera Péptica/complicações , Dor Abdominal/tratamento farmacológico , Resultado do Tratamento , Método Duplo-CegoRESUMO
The "Gut-Liver Axis" refers to the physiological bidirectional interplay between the gut and its microbiota and the liver which, in health, occurs thanks to a condition of immune tolerance. In recent years, several studies have shown that, in case of a change in gut bacterial homeostasis or impairment of intestinal barrier functions, cholangiocytes, which are the epithelial cells lining the bile ducts, activate innate immune responses against gut-derived microorganisms or bacterial products that reach the liver via enterohepatic circulation. Intestinal dysbiosis or impaired intestinal barrier functions cause cholangiocytes to be exposed to an increasing amount of microorganisms that can reactivate inflammatory responses, thus inducing the onset of liver fibrosis. The present review focuses on the role of the gut-liver axis in the pathogenesis of cholangiopathies.
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Cirrose Hepática , Fígado , Humanos , Fígado/patologia , Cirrose Hepática/patologia , Ductos Biliares/patologia , Imunidade Inata , Células Epiteliais/patologia , Disbiose/complicações , Disbiose/patologiaRESUMO
BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is a very aggressive cancer showing the presence of high cancer stem cells (CSCs). Doublecortin-like kinase1 (DCLK1) has been demonstrated as a CSC marker in different gastroenterological solid tumors. Our aim was to evaluate in vitro the expression and the biological function of DCLK1 in intrahepatic CCA (iCCA) and perihilar CCA (pCCA). APPROACH AND RESULTS: Specimens surgically resected of human CCA were enzymatically digested, submitted to immunosorting for specific CSC markers (LGR5 [leucine-rich repeat-containing G protein-coupled receptor], CD [clusters of differentiation] 90, EpCAM [epithelial cell adhesion molecule], CD133, and CD13), and primary cell cultures were prepared. DCLK1 expression was analyzed in CCA cell cultures by real-time quantitative PCR, western blot, and immunofluorescence. Functional studies have been performed by evaluating the effects of selective DCLK1 inhibitor (LRRK2-IN-1) on cell proliferation (MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, cell population doubling time), apoptosis, and colony formation capacity. DCLK1 was investigated in situ by immunohistochemistry and real-time quantitative PCR. DCLK1 serum concentration was analyzed by enzyme-linked immunosorbent assay. We describe DCLK1 in CCA with an increased gene and protein DCLK1 expression in pCCALGR5+ and in iCCACD133+ cells compared with unsorted cells. LRRK2-IN-1 showed an anti-proliferative effect in a dose-dependent manner. LRRK2-IN-1 markedly impaired cell proliferation, induced apoptosis, and decreased colony formation capacity and colony size in both iCCA and pCCA compared with the untreated cells. In situ analysis confirmed that DCLK1 is present only in tumors, and not in healthy tissue. Interestingly, DCLK1 was detected in the human serum samples of patients with iCCA (high), pCCA (high), HCC (low), and cirrhosis (low), but it was almost undetectable in healthy controls. CONCLUSIONS: DCLK1 characterizes a specific CSC subpopulation of iCCACD133+ and pCCALGR5+ , and its inhibition exerts anti-neoplastic effects in primary CCA cell cultures. Human DCLK1 serum might represent a serum biomarker for the early CCA diagnosis.
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Neoplasias dos Ductos Biliares/genética , Biomarcadores Tumorais/biossíntese , Colangiocarcinoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas Serina-Treonina Quinases/biossíntese , Receptores Acoplados a Proteínas G/biossíntese , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/patologia , Quinases Semelhantes a Duplacortina , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células-Tronco Neoplásicas/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
BACKGROUND: Due to significant limitations to the access to orthotropic liver transplantation, cell therapies for liver diseases have gained large interest worldwide. SCOPE OF REVIEW: To revise current literature dealing with cell therapy for liver diseases. We discussed the advantages and pitfalls of the different cell sources tested so far in clinical trials and the rationale underlying the potential benefits of transplantation of human biliary tree stem cells (hBTSCs). MAJOR CONCLUSIONS: Transplantation of adult hepatocytes showed transient benefits but requires immune-suppression that is a major pitfall in patients with advanced liver diseases. Mesenchymal stem cells and hematopoietic stem cells transplanted into patients with liver diseases are not able to replace resident hepatocytes but rather they target autoimmune or inflammatory processes into the liver. Stem cells isolated from fetal or adult liver have been recently proposed as alternative cell sources for advanced liver cirrhosis and metabolic liver disease. We demonstrated the presence of multipotent cells expressing a variety of endodermal stem cell markers in (peri)-biliary glands of bile ducts in fetal or adult human tissues, and in crypts of gallbladder epithelium. In the first cirrhotic patients treated in our center with biliary tree stem cell therapy, we registered no adverse event but significant benefits. GENERAL SIGNIFICANCE: The biliary tree stem cell could represent the ideal cell source for the cell therapy of liver diseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Células-Tronco Adultas/transplante , Ductos Biliares/citologia , Células Epiteliais/transplante , Cirrose Hepática/cirurgia , Transplante de Células-Tronco/métodos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Hepatócitos/transplante , Humanos , Terapia de Imunossupressão/efeitos adversos , Fígado/cirurgia , Transplante de Fígado/efeitos adversos , Transplante de Células-Tronco/tendências , Resultado do TratamentoRESUMO
The association between Inflammatory Bowel Disease (IBD) and Spondyloarthritis (SpA) has been known for years, as has the concept that IBD is associated with an altered intestinal bacterial composition, a condition known as "dysbiosis". Recently, a state of intestinal dysbiosis has also been found in SpA. Dysbiosis in the field of IBD has been well characterized so far, as well as in SpA. The aim of this review is to summarize what is known to date and to emphasize the similarities between the microbiota conditions in these two diseases: particularly, an altered distribution in the gut of Enterobacteriaceae, Streptococcus, Haemophilus, Clostridium, Akkermansia, Ruminococcus, Faecalibacterium Prausnitzii, Bacteroides Vulgatus, Dialister Invisus, and Bifidubacterium Adolescentis is common to both IBD and SpA. At the same time, little is known about intestinal dysbiosis in IBD-related SpA. Only a single recent study has found an increase in Escherichia and Shigella abundances and a decrease in Firmicutes, Ruminococcaceae, and Faecalibacterium abundances in an IBD-related SpA group. Based on what has been discovered so far about the altered distribution of bacteria that unite both pathologies, it is appropriate to carry out further studies aiming to improve the understanding of IBD-related SpA for the purpose of developing new therapeutic strategies.
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Intrahepatic cholangiocarcinoma is the second most frequent primary liver cancer after hepatocellular carcinoma. According to International Classification of Diseases-11 (ICD-11), intrahepatic cholangiocarcinoma is identified by a specific diagnostic code, different with respect to perihilar-CCA or distal-CCA. Intrahepatic cholangiocarcinoma originates from intrahepatic small or large bile ducts including the second-order bile ducts and has a silent presentation that combined with the highly aggressive nature and refractoriness to chemotherapy contributes to the alarming increasing incidence and mortality. Indeed, at the moment of the diagnosis, less than 40% of intrahepatic cholangiocarcinoma are suitable of curative surgical therapy, that is so far the only effective treatment. The main goals of clinicians and researchers are to make an early diagnosis, and to carry out molecular characterization to provide the patient with personalized treatment. Unfortunately, these goals are not easily achievable because of the heterogeneity of this tumor from anatomical, molecular, biological, and clinical perspectives. However, recent progress has been made in molecular characterization, surgical treatment, and management of intrahepatic cholangiocarcinoma and, this article deals with these advances.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Transplante de Fígado , Humanos , Ductos Biliares Intra-Hepáticos/patologia , Fígado/patologia , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/terapiaRESUMO
An important tool to explore personal experience of symptoms, treatment and clinical outcome is stratification of illness perception in patients affected by PBC. AIM: To assess the perception of illness in a cohort of Italian patients with PBC. METHODS: Between June and December 2019, a specific questionnaire was administered to a pool of 210 patients from 7 tertiary Italian centers, in order to identify and assess the patient's past history, symptoms and their impact on the quality of life, follow-up, treatment and perceived satisfaction of patients toward the provided care. RESULTS: Fatigue, pruritus, and abdominal discomfort and sicca syndrome were present in 50.4%, 45%, 30.4% and 28.5% of patients, fatigue having the most impacting the daily-life. After a consultation with a specialist, the diagnosis of PBC was met within 18 months for 143 patients. Patients were mostly concerned about possible health problems that occur and in 25% of cases, symptoms had a negative impact on their life. Eighty percent of patients said they were satisfied with efficacy and tolerability of treatment, while 26% requested an improvement in the relationship with the specialist. CONCLUSIONS: The results highlight the importance of both promoting timely referral to the specialist and facilitating communication between healthcare professionals and patients.
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Colangite , Cirrose Hepática Biliar , Fadiga , Humanos , Motivação , Percepção , Qualidade de VidaRESUMO
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that may develop at any point of the biliary tree. Their incidence is rising worldwide, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent nature of these tumours combined with their high aggressiveness and refractory nature contribute to their alarming mortality rates, representing nowadays ~2% of all cancer-related deaths yearly. In the past decade, increasing efforts have been made in order to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to increase patient's welfare.
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Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias Hepáticas , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patologia , Colangiocarcinoma/terapia , Humanos , Incidência , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapiaRESUMO
The Farnesoid X nuclear receptor (FXR) is a nuclear receptor of bile acids whose activation suppresses the synthesis of bile acids stimulates their excretion in the bile and inhibits its uptake in hepatocytes. FXR is also involved in the regulation of over 250 genes including those responsible for the control of lipid and carbohydrate metabolism. The activation of FXR also induces anti-inflammatory effects and antifibrotics. Over the past 10 years they have been synthesized and studied various FXR agonists which have demonstrated beneficial effects in the treatment of the main pathologies cholestatic diseases including primary biliary cholangitis, cholangitis primary sclerosing and cholangiocarcinoma.
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Colestase , Fígado , Ácidos e Sais Biliares/metabolismo , Colestase/tratamento farmacológico , Colestase/metabolismo , Colestase/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
We report a case of acute-onset, long-lasting cholestasis induced by atorvastatin. This antihyperlipidaemic drug was taken for 40 days by a 72-year-old male as a treatment for his mixed dyslipidaemia. At that point, the patient presented with asthenia, nausea, painless icterus, acholic stools and hyperchromic urine with biochemical analyses showing a dramatic increase in bilirubin (total bilirubin 22 mg/dL; direct bilirubin 21 mg/dL) and alkaline phosphatase (up to 4-fold over the normal level) with less marked increases in transaminases. Liver histology showed a pattern of cholestasis with evident signs of cholangiolitis and damage of the interlobular bile ducts. Serum transaminase and bilirubin levels returned to normal within 5 months after atorvastatin withdrawal while alkaline phosphatase normalized after only 8 months. Scores on both the Maria and Victorino clinical scale for the diagnosis of drug-induced hepatitis and the Naranjo Adverse Drug Reaction Probability Scale indicated that atorvastatin was the probable cause of prolonged cholestasis in this patient. This is a rare case of cholestasis probably caused by atorvastatin and unusually characterized by bile duct damage.
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Anticolesterolemiantes/efeitos adversos , Ductos Biliares/efeitos dos fármacos , Colangite/induzido quimicamente , Colestase/induzido quimicamente , Ácidos Heptanoicos/efeitos adversos , Pirróis/efeitos adversos , Idoso , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Ductos Biliares/patologia , Colagogos e Coleréticos/uso terapêutico , Colangite/tratamento farmacológico , Colestase/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Humanos , Masculino , Pirróis/uso terapêutico , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
There is evidence that chronic hepatitis B virus (HBV) infection is associated with an increased risk of intrahepatic cholangiocarcinoma (ICC) development, and it has been hypothesized an etiological role of HBV in the development of this tumor. Very little is known about occult HBV infection (OBI) in ICC. Aims of the study were to investigate the OBI prevalence and to characterize the HBV molecular status at intrahepatic level in OBI-positive cases with ICC. Frozen liver tumor specimens from 47 HBV surface-antigen-negative patients with ICC and 41 paired non-tumor liver tissues were tested for OBI by 4 different HBV-specific nested PCR. Covalently closed circular HBV DNA (HBV cccDNA) and viral integrations were investigated in OBI-positive cases. HBV DNA was detected in tumor and/or non-tumor specimens from 29/47 (61.7%) ICC patients. HBV cccDNA was found in tissues from 5/17 (34.5%) cases examined. HBV integration was detected in 4/10 (40%) tumor tissues tested and involved HBx and HBV-core gene sequences in 3 and 1 cases, respectively. Viral integration occurred: (a) 9,367 nucleotides upstream of the cat-eye-syndrome critical region protein-5-isoform coding sequence; (b) within the cystinosin isoform-1-precursor gene; (c) within the thromboxane-A-synthase-1 gene; (d) within the ATPase phospholipid transporting 9B gene. Occult HBV infection is highly prevalent in patients with ICC. Both free viral genomes and integrated HBV DNA can be present in these cases. These results suggest an involvement of HBV in the carcinogenic process leading to ICC development even in cases with occult infection.
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The biliary tree consists of mature epithelial cells called cholangiocytes and is subdivided in intra and extrahepatic bile ducts. They facilitate the secretion and modification of the bile constituents and act as transport ducts of bile to the intestine. The alteration of the normal function of cholangiocyte, can lead to the development of multiple biliary diseases, known as cholangiopathies, generally chronic, with a progressive course and which often are lacking of an effective treatment, determining a poor prognosis, even lethal, for the patient. These cholangiopathies have peculiar characteristics both for onset and clinical course. The pathogenetic processes affecting cholangiocytes are not yet fully known. Depending on their nature, these diseases are further subdivided into genetic, idiopathic, which include primary biliary cholangitis, primary sclerosing cholangitis and associated IgG4 cholangitis and malignant such as cholangiocarcinoma or mixed hepato-cholangiocarcinoma. This review is focused on the new insights on the pathophysiological and molecular mechanisms involved in the liver damage cascade which provide the basis of novel therapeutic approaches for these cholangiopathies.
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Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Colangite/patologia , Neoplasias dos Ductos Biliares/terapia , Sistema Biliar/fisiopatologia , Colangiocarcinoma/terapia , Colangite/terapia , Células Epiteliais/citologia , Humanos , Hepatopatias/fisiopatologia , Neoplasias Hepáticas/patologiaRESUMO
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA.
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Cholangiocarcinoma (CCA) and its subtypes (mucin- and mixed-CCA) arise from the neoplastic transformation of cholangiocytes, the epithelial cells lining the biliary tree. CCA has a high mortality rate owing to its aggressiveness, late diagnosis and high resistance to radiotherapy and chemotherapeutics. We have demonstrated that CCA is enriched for cancer stem cells which express epithelial to mesenchymal transition (EMT) traits, with these features being associated with aggressiveness and drug resistance. TGF-ß signaling is upregulated in CCA and involved in EMT. We have recently established primary cell cultures from human mucin- and mixed-intrahepatic CCA. In human CCA primary cultures with different levels of EMT trait expression, we evaluated the anticancer effects of: (i) CX-4945, a casein kinase-2 (CK2) inhibitor that blocks TGF-ß1-induced EMT; and (ii) LY2157299, a TGF-ß receptor I kinase inhibitor. We tested primary cell lines expressing EMT trait markers (vimentin, N-cadherin and nuclear catenin) but negative for epithelial markers, and cell lines expressing epithelial markers (CK19-positive) in association with EMT traits. Cell viability was evaluated by MTS assays, apoptosis by Annexin V FITC and cell migration by wound-healing assay. RESULTS: at a dose of 10 µM, CX4945 significantly decreased cell viability of primary human cell cultures from both mucin and mixed CCA, whereas in CK19-positive cell cultures, the effect of CX4945 on cell viability required higher concentrations (>30µM). At the same concentrations, CX4945 also induced apoptosis (3- fold increase vs controls) which correlated with the expression level of CK2 in the different CCA cell lines (mucin- and mixed-CCA). Indeed, no apoptotic effects were observed in CK19-positive cells expressing lower CK2 levels. The effects of CX4945 on viability and apoptosis were associated with an increased number of γ-H2ax (biomarker for DNA double-strand breaks) foci, suggesting the active role of CK2 as a repair mechanism in CCAs. LY2157299 failed to influence cell proliferation or apoptosis but significantly inhibited cell migration. At a 50 µM concentration, in fact, LY2157299 significantly impaired (at 24, 48 and 120 hrs) the wound-healing of primary cell cultures from both mucin-and mixed-CCA. In conclusion, we demonstrated that CX4945 and LY2157299 exert relevant but distinct anticancer effects against human CCA cells, with CX4945 acting on cell viability and apoptosis, and LY2157299 impairing cell migration. These results suggest that targeting the TGF-ß signaling with a combination of CX-4945 and LY2157299 could have potential benefits in the treatment of human CCA.
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Apoptose , Colangiocarcinoma/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Colangiocarcinoma/patologia , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Humanos , Naftiridinas/química , Células-Tronco Neoplásicas/citologia , Fenazinas , Cultura Primária de Células , Pirazóis/química , Quinolinas/química , Transdução de Sinais , CicatrizaçãoRESUMO
We investigated the sensitivity of intrahepatic cholangiocarcinoma (IHCCA) subtypes to chemotherapeutics and molecular targeted agents. Primary cultures of mucin- and mixed-IHCCA were prepared from surgical specimens (N. 18 IHCCA patients) and evaluated for cell proliferation (MTS assay) and apoptosis (Caspase 3) after incubation (72 hours) with increasing concentrations of different drugs. In vivo, subcutaneous human tumor xenografts were evaluated. Primary cultures of mucin- and mixed-IHCCA were characterized by a different pattern of expression of cancer stem cell markers, and by a different drug sensitivity. Gemcitabine and the Gemcitabine-Cisplatin combination were more active in inhibiting cell proliferation in mixed-IHCCA while Cisplatin or Abraxane were more effective against mucin-IHCCA, where Abraxane also enhances apoptosis. 5-Fluoracil showed a slight inhibitory effect on cell proliferation that was more significant in mixed- than mucin-IHCCA primary cultures and, induced apoptosis only in mucin-IHCCA. Among Hg inhibitors, LY2940680 and Vismodegib showed slight effects on proliferation of both IHCCA subtypes. The tyrosine kinase inhibitors, Imatinib Mesylate and Sorafenib showed significant inhibitory effects on proliferation of both mucin- and mixed-IHCCA. The MEK 1/2 inhibitor, Selumetinib, inhibited proliferation of only mucin-IHCCA while the aminopeptidase-N inhibitor, Bestatin was more active against mixed-IHCCA. The c-erbB2 blocking antibody was more active against mixed-IHCCA while, the Wnt inhibitor, LGK974, similarly inhibited proliferation of mucin- and mixed-IHCCA. Either mucin- or mixed-IHCCA showed high sensitivity to nanomolar concentrations of the dual PI3-kinase/mTOR inhibitor, NVP-BEZ235. In vivo, in subcutaneous xenografts, either NVP-BEZ235 or Abraxane, blocked tumor growth. In conclusion, mucin- and mixed-IHCCA are characterized by a different drug sensitivity. Cisplatin, Abraxane and the MEK 1/2 inhibitor, Selumetinib were more active against mucin-IHCCA while, Gemcitabine, Gemcitabine-Cisplatin combination, the c-erbB2 blocking antibody and bestatin worked better against mixed-IHCCA. Remarkably, we identified a dual PI3-kinase/mTOR inhibitor that both in vitro and in vivo, exerts dramatic antiproliferative effects against both mucin- and mixed-IHCCA.
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Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Idoso , Idoso de 80 Anos ou mais , Paclitaxel Ligado a Albumina/farmacologia , Anilidas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Benzimidazóis/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Proliferação de Células , Colangiocarcinoma/metabolismo , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Fluoruracila/farmacologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mucinas/química , Transplante de Neoplasias , Ftalazinas/farmacologia , Piridinas/farmacologia , GencitabinaRESUMO
Cholangiocarcinoma (CCA) is a very heterogeneous cancer from any point of view, including epidemiology, risk factors, morphology, pathology, molecular pathology, modalities of growth and clinical features. Given this heterogeneity, a uniform classification respecting the epidemiologic, pathologic and clinical needs is currently lacking. In this manuscript we discussed the different proposed classifications of CCA in relation with recent advances in pathophysiology and biology of this cancer.
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BACKGROUND: Very few studies assessed cholangiocarcinoma clinical characteristics. AIM: To evaluate the clinical characteristics of intra-hepatic (IH) and extra-hepatic (EH)-CCA. METHODS: We performed a national survey based on a questionnaire. RESULTS: 218 cholangiocarcinomas were observed (47% EH-CCA, 53% IH-CCA) with an age at the diagnosis higher for EH-CCA. Coexistence of cirrhosis or viral cirrhosis was more frequent in IH-CCA than EH-CCA. An incidental asymptomatic presentation occurred in 28% of IH-CCA vs 4% EH-CCA whilst, 74% EH-CCA vs 28% IH-CCA presented with jaundice. 91% of IH-CCA presented as a single intra-hepatic mass, whilst 50% of EH-CCA was peri-hilar. In the diagnostic work-up, 70% of all cholangiocarcinoma cases received at least 3 different imaging procedures. Tissue-proven diagnosis was obtained in 80% cholangiocarcinoma. Open surgery with curative intent was performed in 45% of IH-CCA and 29% EH-CCA. 18% IH-CCA vs 4% EH-CCA did not received treatment. CONCLUSIONS: In Italy IH-CCA is managed as frequently as EH-CCA. In comparison to EH-CCA, IH-CCA occurs at younger age and is more frequently associated with cirrhosis and with an incidental asymptomatic presentation. In contrast, most EH-CCAs are jaundiced at the diagnosis. Cholangiocarcinoma diagnostic management is cost- and time-consuming with curative surgical treatment applicable more frequently in IH-CCA.
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Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares Extra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/diagnóstico , Dor Abdominal/etiologia , Idoso , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Ductos Biliares Extra-Hepáticos/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Colangiocarcinoma/complicações , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Colangiopancreatografia Retrógrada Endoscópica , Colangiopancreatografia por Ressonância Magnética , Coleta de Dados , Diarreia/etiologia , Fadiga/etiologia , Feminino , Hepatite C/complicações , Humanos , Itália , Icterícia/etiologia , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Tomografia Computadorizada por Raios X , Ultrassonografia , Vômito/etiologia , Redução de PesoRESUMO
BACKGROUND: Very little data exist on the epidemiology of cholangiocarcinoma in Italy. AIM: We focus on the descriptive epidemiology of cholangiocarcinoma in Italy. METHODS: Data on incidence were obtained from the Italian Association of Tumour Registries while mortality data were obtained from the Italian National Institute of Statistics. RESULTS: A progressive increase of incidence with age was seen for extra-hepatic, intra-hepatic and not otherwise specified cholangiocarcinoma. Crude incidence rates were higher for extra-hepatic cholangiocarcinoma than those for intra-hepatic cholangiocarcinoma and in men compared to women. An increasing incidence trend was observed, from 1988 to 2005, for both extra-hepatic- and intra-hepatic cholangiocarcinoma with a 3-6% yearly increase and with a rate of increase higher for men than for women and for intra-hepatic- than for extra-hepatic cholangiocarcinoma. For intra-hepatic cholangiocarcinoma, the mortality rates progressively increased from 0.15 per million in 1980 to 5.9 per million in 2003, when mortality for this cancer surpassed extra-hepatic cholangiocarcinoma. Mortality rates for extra-hepatic cholangiocarcinoma showed an increasing trend from 1980 to 1994 but, in contrast to intra-hepatic cholangiocarcinoma, a stable or slightly decreasing trend from 1995 to 2003 was observed. CONCLUSIONS: In Italy, cholangiocarcinoma showed a progressive increase in incidence and mortality in the last two decades mainly in intra-hepatic cholangiocarcinoma.
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Neoplasias dos Ductos Biliares/mortalidade , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/mortalidade , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Ductos Biliares Extra-Hepáticos , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Distribuição por Sexo , Adulto JovemRESUMO
Cholangiocarcinoma (CCA) is a malignant tumour that arises from biliary epithelium at any portion of the biliary tree. CCA is currently classified as intra-hepatic or extra-hepatic CCA (EH-CCA). Recent evidences suggest that intra-hepatic CCA (IH-CCA) and EH-CCA are biologically different cancers, giving further support to a number of recent epidemiological studies showing large differences in terms of incidence, mortality and risk factors. The purpose of this manuscript is to review recent literature dealing with the descriptive epidemiology and risk factors of CCA with a special effort to compare IH- with EH-CCA.
RESUMO
Cholangiocarcinoma is commonly considered a rare cancer. However, if we consider the hepato-biliary system a single entity, cancers of the gallbladder, intra-hepatic and extra-hepatic biliary tree altogether represent approximately 30% of the total with incidence rates close to that of hepatocellular carcinoma, which is the third most common cause of cancer-related death worldwide. In addition, cholangiocarcinoma is characterized by a very poor prognosis and virtually no response to chemotherapeutics; radical surgery, the only effective treatment, is not frequently applicable because late diagnosis. Biomarkers for screening programs and for follow-up of categories at risk are under investigation, however, currently none of the proposed markers has reached clinical application. For all these considerations, cancers of the biliary tree system should merit much more scientific attention also because a progressive increase in incidence and mortality for these cancers has been reported worldwide. This manuscript deals with the most recent advances in the epidemiology, biology and clinical presentation of cholangiocarcinoma.