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World Journal of Gastroenterology 2012年第12期18卷 1286-1294页

作者： Marta Herreros-Villanueva Elizabeth Hijona Angel Cosme luis bujanda Schulze Center for Novel Therapeutics Division of Oncology ResearchDepartment of MedicineMayo ClinicRochesterMN 55905United States Department of Gastroenterology Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of the Basque CountryDonostia HospitalSan Sebastian 20014Spain Department of Gastroenterology Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of the Basque CountryDonostia Hospital

Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States,and potent therapeutic options are lacking.Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer,currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed.In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes.In the last few years,several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed.These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer.Genetic alterations such as activating mutations in KRas,or TGFb and/or inactivation of tumoral suppressors such as p53,INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice.These mouse models have a spectrum of pathologic changes,from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system.These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches,chemopreventive and/or anticancer treatments.Here,we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

关键词：小鼠模型胰腺癌胰脏治疗方案肿瘤抑制基因恶性肿瘤分子特征遗传工程

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Spontaneous regression of pancreatic cancer: Real or a misdiagnosis?

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World Journal of Gastroenterology 2012年第23期18卷 2902-2908页

作者： Marta Herreros-Villanueva Elizabeth Hijona Angel Cosme luis bujanda Schulze Center for Novel Therapeutics Division of Oncology Research Department of Medicine Mayo Clinic Rochester MN 55905 United States Department of Gastroenterology Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas University of the Basque Country Donostia Hospital-Biodonostia Institute 20014 San Sebastian Spain

Spontaneous tumor regression has been subject of numerous studies and speculations for many years. This phenomenon is exceptional, but well reported, in some types of tumors, but not in pancreatic cancer. Pancreatic cancer has the worst five-year survival rate of any cancer. Despite numerous molecular studies and clinical approaches, using several mouse models, this cancer responds poorly to the existing chemotherapeutic agents and progress on treatment remains elusive. Although pancreatic cancer tumors seldom undergo spontaneous regression, and some authors take that with skepticism, there are some cases reported in the literature. However, the variability in the description of the reports and technical details could make this process susceptible to misdiagnosis. Distinguishing between different types of pancreatic carcinoma should be taken with caution as they have wide differences in malignant potential. Diseases such as pancreatic benign tumors, insulinomas, or autoimmune pancreatitis could be responsible for this misdiagnosis as a pancreatic cancer. Here we review different cases reported, their clinical characteristics, and possible mechanisms leading to spontaneous regression of pancreatic cancer. We also discuss the possibilities of misdiagnosis.

关键词：胰腺癌误诊回归良性肿瘤实时临床特点分子生物学自身免疫性

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c-Met in pancreatic cancer stem cells: Therapeutic implications

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World Journal of Gastroenterology 2012年第38期18卷 5321-5323页

作者： Marta Herreros-Villanueva Aizpea Zubia-Olascoaga luis bujanda Division of Oncology Research Department of Medicine Schulze Center for Novel Therapeutics Mayo Clinic Rochester MN 55905 United States IkerChem Oncology Therapeutics Department 20009 San Sebastian Spain Department of Gastroenterology Centro de Investigación Biomédica en Red en Enfermedades Hepáticasy Digestivas (CIBERehd) Donostia Hospital-Biodonostia Institute University of the Basque Country 20014 San Sebastian Spain

Pancreatic cancer is the deadliest solid cancer and currently the fourth most frequent cause of cancer-related deaths. Emerging evidence suggests that cancer stem cells (CSCs) play a crucial role in the development and progression of this disease. The identification of CSC markers could lead to the development of new therapeutic targets. In this study, the authors explore the functional role of c-Met in pancreatic CSCs, by analyzing self-renewal with sphere assays and tumorigenicity capacity in NOD SCID mice. They concluded that c-Met is a novel marker for identifying pancreatic CSCs and c-Met high in a higher tumorigenic cancer cell population. Inhibition of c-Met with XL184 blocks self-renewal capacity in pancreatic CSCs. In pancreatic tumors established in NOD SCID mice, c-Met inhibition slowed tumor growth and reduced the population of CSCs, along with preventing the development of metastases.

关键词：胰腺干细胞胰腺癌治疗 SCID小鼠肿瘤发生职能作用自我更新胰腺肿瘤

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Adjuvant and neoadjuvant treatment in pancreatic cancer

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World Journal of Gastroenterology 2012年第14期18卷 1565-1572页

Pancreatic adenocarcinoma is one of the most aggressive human malignancies,ranking 4th among causes for cancer-related death in the Western world including the United States.Surgical resection offers the only chance of cure,but only 15 to 20 percent of cases are potentially resectable at presentation.Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy.Currently there is no consensus around the world on what constitutes"standard"adjuvant therapy for pancreatic cancer.This controversy derives from several studies,each fraught with its own limitations.Standards of care also vary somewhat with regard to geography and economy,for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe.Regardless of the efforts in adjuvant and neoadjuvant improved therapy,the major goal to combat pancreatic cancer is to find diagnostic markers,identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients.In this review,authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients.

关键词：辅助治疗胰腺癌恶性肿瘤癌症治疗手术切除治疗方案化疗标准

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Malignant colorectal polyps

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World Journal of Gastroenterology 2010年第25期16卷 3103-3111页

作者： luis bujanda Angel Cosme Ines Gil Juan I Arenas-Mirave Department of Gastroenterology Donostia Hospital Uni-versity of Basque Country Centro de Investigación Biomédica en Enfermedades Hepáticas y Digestivas 20010 San Sebastián Guipúzcoa Spain University of Basque Country Centro de Investigación Biomédica en Enfermedades Hepáticas y Digestivas 20010 San Sebastián Guipúzcoa Spain

Nowadays, the number of cases in which malignant colorectal polyps are removed is increasing due to colorectal cancer screening programmes. Cancerous polyps are classified into non-invasive high grade neoplasia (NHGN), when the cancer has not reached the muscularis mucosa, and malignant polyps, classed as T1, when they have invaded the submucosa. NHGN is considered cured with polypectomy, while the prognosis for malignant polyps depends on various morphological and histological factors. The prognostic factors include, sessile or pedunculated morphology of the polyp, whether partial or en bloc resection is carried out, the degree of differentiation of the carcinoma, vascular or lymphatic involvement, and whether the polypectomy resection margin is tumor free. A malignant polyp at T1 is considered cured with polypectomy ifit is a pedunculated polyp (Ip of the Paris classification), it has been completely resected, it is not poorly differentiated, the resection edge is not affected by the tumor and there is no vascular or lymphatic involvement. The sessile malignant polyp (Is of the Paris classification) at T1 is considered not cured with polypectomy. Only in some cases (e.g. older people with high surgical risk) local excision(polypectomy or endoscopic submucosal dissection or conventional endoscopic mucosal resection) is considered the definitive treatment.

关键词： Favourable histology Follow-up Malignant polyps Non-invasive high grade neoplasia Treatment

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Biochemical determination of lipid content in hepatic steatosis by the Soxtec method

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World Journal of Gastroenterology 2010年第12期16卷 1495-1499页

作者： Elizabeth Hijona Lander Hijona Mikel Larzabal Cristina Sarasqueta Pablo Aldazabal Juan Arenas luis bujanda Department of Gastroenterology University of the Basque CountryDonostia HospitalCenter for Biomedical Research in Hepatic and Digestive Disease(CIBERehd) Department of Gastroenterology Basurto Hospital Department of Pathology Donostia Hospital Department of Epidemiology CIBERESPDonostia Hospital

AIM:To establish a quantitative method to measure the amount of lipids.METHODS:The livers of 53 male Wistar rats(225 g) with different degrees of hepatic steatosis were studied.This model of hepatic steatosis was based on a high carbohydrate,fat-free modified diet.Biopsies were classified into four grades depending on fat accumulation,using the Kleiner and Brunt classification.Total fat was studied by the Soxtec method(SoxtecTM 2050 Auto Fat Extraction System),and agreement between both assays was assessed by calculating theκ coefficient.RESULTS:According to the histological classification,38% of rats presented grade 0,21% grade 1,22% grade 2 and 20% grade 3.The amount of fat per 100 g tissue was 2.60±0.64 g for grade 0,3.87±1.59 g for grade 1,5.82±1.37 g for grade 2 and 8.68± 2.30 g for grade 3.Statistically significant differences were found between the mean values for each of the histological grades(P<0.05).The correlation for the quantification of fat in the liver between both assays was moderate(κ=0.60).CONCLUSION:The biochemical quantification of fat in liver tissue by the Soxtec method was correlated with the histological classification,although the agreement between the two tests was only moderate.

关键词： Liver steatosis Soxtec method Quantitative analysis Histology Biochemistry

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Colorectal and interval cancers of the Colorectal Cancer Screening Program in the Basque Country (Spain)

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World Journal of Gastroenterology 2017年第15期23卷 2731-2742页

作者： Isabel Portillo Eunate Arana-Arri Isabel Idigoras Isabel Bilbao Lorea Martínez-Indart luis bujanda Inaki Gutierrez-Ibarluzea BioCruces Health Research Institute Colorectal Cancer Screening Programme OsakidetzaBasque Health Service Department of Gastroenterology Hospital Donostia/Instituto BiodonostiaCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y DigestivasUniversidad del País Vasco(UPV/EHU Basque Office for Health Technology Assessment Ministry for HealthBasque Government

AIM To assess proportions, related conditions and survival of interval cancer(IC).METHODS The programme has a linkage with different clinical databases and cancer registers to allow suitable evaluation. This evaluation involves the detection of ICs after a negative faecal inmunochemical test(FIT), interval cancer FIT(IC-FIT) prior to a subsequent invitation, and the detection of ICs after a positive FIT and confirmatory diagnosis without colorectal cancer(CRC) detected and before the following recommended c o l o n o s c o p y, I C-c o l o n o s c o p y. W e c o n d u c t e d a retrospective observational study analyzing from January 2009 to December 2015 1193602 invited people onto the Programme(participation rate of 68.6%).RESULTS Two thousand five hundred and eighteen cancers were diagnosed through the programme, 18 cases of IC-colonoscopy were found before the recommended follow-up(43542 colonoscopies performed) and 186 IC-FIT were identified before the following invitation of the 769200 negative FITs. There was no statistically significant relation between the predictor variables of ICs with sex, age and deprivation index, but there was relation between location and stage. Additionally, it was observed that there was less risk when the location was distal rather than proximal(OR = 0.28, 95%CI: 0.20-0.40, P < 0.0001), with no statistical significance when the location was in the rectum as opposed to proximal. When comparing the screen-detected cancers(SCs) with ICs, significant differences in survival were found(P < 0.001); being the 5-years survival for SCs 91.6% and IC-FIT 77.8%.CONCLUSION These findings in a Population Based CRC Screening Programme indicate the need of population-based studies that continue analyzing related factors to improve their detection and reducing harm.

关键词： Colorectal 癌症人口屏蔽计划间隔癌症排泄物的免疫化学的测试 Colonoscopy 诊断死亡幸存

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Antimicrobial susceptibility testing before first-line treatment for Helicobacter pylori infection in patients with dual or triple antibiotic resistance

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World Journal of Gastroenterology 2017年第18期23卷 3367-3373页

作者： Angel Cosme Milagrosa Montes Begona Ibarra Esther Tamayo Horacio Alonso Usua Mendarte Jacobo Lizasoan Marta Herreros-Villanueva luis bujanda Gastroenterology Department Hospital Universitario Donostia/Instituto BiodonostiaUniversidad del País VascoCentro de Investigación Biomédica en Red de Enfermedades Hepaticas y Digestivas Biomedical Research Center Network for Respiratory Diseases Microbiology Department Hospital Universitario Donostia-Instituto Biodonostia Faculty of Life Sciences Universidad Isabel I

AIM To evaluate the efficacy of antimicrobial susceptibilityguided therapy before first-line treatment for infection in patients with dual or triple antibiotic resistance.METHODS A total of 1034 patients infected by Helicobacter pylori(H. pylori) during 2013-2014 were tested for antimicrobial susceptibility. 157 of 1034(15%) patients showed resistance to two(127/1034; 12%) and to three(30/1034; 3%) antibiotics. Sixty-eight patients with dual H. pylori-resistance(clarithromycin, metronidazole or levofloxacin) were treated for 10 d with triple therapies: OAL(omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and levofloxacin 500 mg b.i.d.) 43cases, OAM(omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and metronidazole 500 mg b.i.d.) 12 cases and OAC(omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and clarithromycin 500 mg b.i.d.) 13 cases based on the antimicrobial susceptibility testing. Twelve patients showed triple H. pylori-resistance(clarithromycin, metronidazole and levofloxacin) and received for 10 d triple therapy with OAR(omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and rifabutin 150 mg b.i.d.). Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. RESULTS Intention-to-treat eradication rates were: OAL(97.6%), OAM(91.6%), OAC(92.3%) and OAR(58.3%). Cure rate was significantly higher in na?ve patients treated with OAR-10 compared to patients who had two or three previous treatment failures(83% vs 33%). Adverse events rates for OAL, OAM, OAC and OAR were 22%, 25%, 23% and 17%, respectively, all of them mild-moderate. CONCLUSION Antimicrobial susceptibility-guided triple therapies during 10 d for first-line treatment leads to an eradication rate superior to 90% in patients with dual antibiotic H. pylori resistance.

关键词： Helicobacter pylori 抵抗根除率抗菌剂危险性治疗

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Patterns of local recurrence in rectal cancer after a multidisciplinary approach

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World Journal of Gastroenterology 2011年第13期17卷 1674-1684页

作者： Jose M Enríquez-Navascués Nerea Borda Aintzane Liz-erazu Carlos Placer Jose L Elosegui Juan P Ciria Adelaida Lacasta luis bujanda Colorectal Cancer Multidisciplinary Unit Donostia Hospital University of the Basque CountryCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas 20010 San Sebastian Spain

Improvements in surgery and the application of combined approaches to fight rectal cancer have succeeded in reducing the local recurrence (LR) rate and when there is LR it tends to appear later and less often in isolation. Moreover, a subtle change in the distribution of LRs with respect to the pelvis has been observed. In general terms, prior to total mesorectal excision the most common LRs were central types (perianastomotic and anterior) while lateral and posterior forms (presa-cral) have become more common since the growth in the use of combined treatments. No differences have been reported in the current pattern of LRs as a function of the type of approach used, that is, neo-adjuvant therapies (short-term or long-course radiotherapy, orchemoradiotherapy versus extended lymphadenectomy, though there is a trend towards posterior or presacral LR in patients in the Western world and lateral LR in Asia. Nevertheless, both may arise from the same mechanism. Moreover, as well as the mode of treatment, the type of LR is related to the height of the initial tumor. Nowadays most LRs are related to the advanced nature of the disease. Involvement of the circumferential radial margin and spillage of residual tumor cells from lymphatic leakage in the pelvic side wall are two plausible mechanisms for the genesis of LR. The patterns of pelvic recurrence itself (pelvic subsites) also have important implications for prognosis and are related to the potential success of salvage curative approach. The re-operability for cure and prognosis are generally better for anastomotic and anterior types than for presacral and lateral recurrences. Overall survival after LR diagnosis is lower with radio or chemoradiotherapy plus optimal surgery approaches, compared to optimal surgery alone.

关键词：复发率直肠癌多学科联合治疗手术方法肿瘤细胞 LRS 辅助疗法

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MicroRNAs in biliary diseases

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World Journal of Gastroenterology 2012年第43期18卷 6189-6196页

作者： Patricia Munoz-Garrido Maite García-Fernández de Barrena Elizabeth Hijona Miguel Carracedo JoséJ G Marín luis bujanda Jesús M Banales Division of Hepatology and Gastroenterology Biodonostia Research InstituteDonostia Universitary Hospital20014 San SebastiánSpain Division of Oncology Research Schulze Center for Novel TherapeuticsMayo ClinicRochesterMN 55905United States Division of Hepatology and Gastroenterology Biodonostia Research InstituteDonostia Universitary Hospital20014 San SebastiánSpains Department of Liver and Gastrointestinal Diseases National Institute for the Study of Liver and Gastrointestinal Diseases(CIBERehdfunded by the Spanish CarlosⅢInstitute)08036 BarcelonaSpain Department of Physiology and Pharmacology Experimental Hepatology and Drug Targeting(HEVEFARM)Biomedical Research Institute of Salamanca(IBSAL)University of Salamanca37008 SalamancaSpain Ikerbasque Basque Foundation for Science48011 BilbaoSpain

Cholangiopathies are a group of diseases primarily or secondarily affecting bile duct cells, and result in cholangiocyte proliferation, regression, and/or transformation. Their etiopathogenesis may be associated with a broad variety of causes of different nature, which includes genetic, neoplastic, immune-associated, infectious, vascular, and drug-induced alterations, or being idiopathic. miRNAs, small non-coding endogenous RNAs that post-transcriptionally regulate gene expres sion, have been associated with pathophysiological processes in different organs and cell types, and are postulated as potential targets for diagnosis and therapy. In the current manuscript, knowledge regarding the role of miRNAs in the development and/or progression of cholangiopathies has been reviewed and the most relevant findings in this promising field of hepatology have been highlighted.

关键词：小分子RNA 疾病 miRNA 胆道细胞类型发病机理免疫相关调控基因

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