Publications by authors named "Teresa Serrano"

66 Publications

Intrahepatic cholangiocarcinoma: Prognostic factors for recurrence and survival in a series of 67 patients treated surgically at a single center.

Cir Esp (Engl Ed) 2021 Jul 4. Epub 2021 Jul 4.

Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat (Barcelona), Spain.

Introduction: Intrahepatic cholangiocarcinoma is a primary liver neoplasm whose only curative treatment is surgery. The objective of this study was to determine the prognostic factors for survival of intrahepatic cholangiocarcinoma treated surgically with curative intent.

Methods: Sixty-seven patients who had been treated surgically for this neoplasm were collected at Bellvitge University Hospital between 1996 and 2017. Epidemiological, clinical, surgical, anatomopathological, morbidity, mortality and survival data have been analysed.

Results: Postoperative study reflects our centre's experience in the surgical treatment of intrahepatic cholangiocarcinoma over a period of 21 years. Lymphadenectomy was associated with increased morbidity, and vascular invasion in the pathological study was the most important risk factor in the survival analysis.

Conclusions: This study reflects our centre's experience in the surgical treatment of intrahepatic cholangiocarcinoma over a period of 21 years. Lymphadenectomy was associated with increased morbidity, and vascular invasion in the pathological study was the most important risk factor in the survival analysis.
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http://dx.doi.org/10.1016/j.cireng.2021.06.015DOI Listing
July 2021

Chronic pancreatitis for the clinician. Part 2: Treatment and follow-up. Interdisciplinary Position Paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees.

Gastroenterol Hepatol 2021 Jun 23. Epub 2021 Jun 23.

CIBERehd, Instituto de Salud Carlos III, Madrid, España; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, España; Servei de Gastroenterologia, ICMDiM, Hospital Clínic, Barcelona, España; Gastrointestinal and Pancreatic Oncology Research Group, Hospital Clínic, Barcelona, España.

Chronic pancreatitis is associated with impaired quality of life, high incidence of comorbidities, serious complications and mortality. Healthcare costs are exorbitant. Some medical societies have developed guidelines for treatment based on scientific evidence, but the gathered level of evidence for any individual topic is usually low and, therefore, recommendations tend to be vague or weak. In the present position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 2 of these paper series discuss topics on treatment and follow-up. The therapeutic approach should include assessment of etiological factors, clinical manifestations and complications. The complexity of these patients advocates for detailed evaluation in multidisciplinary committees where conservative, endoscopic, interventional radiology or surgical options are weighed. Specialized multidisciplinary units of Pancreatology should be constituted. Indications for surgery are refractory pain, local complications, and suspicion of malignancy. Enzyme replacement therapy is indicated if evidence of exocrine insufficiency or after pancreatic surgery. Response should be evaluated by nutritional parameters and assessment of symptoms. A follow-up program should be planned for every patient with chronic pancreatitis.
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http://dx.doi.org/10.1016/j.gastrohep.2021.05.016DOI Listing
June 2021

Pancreatitis crónica para el clínico. Parte 1: Etiología y Diagnóstico. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees (versión castellana).

Gastroenterol Hepatol 2021 Jun 19. Epub 2021 Jun 19.

CIBERehd, Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, Pabellón 11, 28029, Madrid, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), Carrer del Rosselló, 149, 08036 Barcelona, Spain; Servei de Gastroenterologia, ICMDiM, Hospital Clínic, C. de Villarroel, 170, 08036 Barcelona, Spain; Gastrointestinal and Pancreatic Oncology Research Group, Hospital Clínic, C. de Villarroel 170, 08036 Barcelona, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.gastrohep.2021.05.017DOI Listing
June 2021

2-[F]FDG PET/CT as a Predictor of Microvascular Invasion and High Histological Grade in Patients with Hepatocellular Carcinoma.

Cancers (Basel) 2021 May 23;13(11). Epub 2021 May 23.

Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.

Hepatocellular carcinoma (HCC) generally presents a low avidity for 2-deoxy-2-[F]fluoro-d-glucose (FDG) in PET/CT although an increased FDG uptake seems to relate to more aggressive biological factors. To define the prognostic value of PET/CT with FDG in patients with an HCC scheduled for a tumor resection, forty-one patients were prospectively studied. The histological factors of a poor prognosis were determined and FDG uptake in the HCC lesions was analyzed semi-quantitatively (lean body mass-corrected standardized uptake value (SUL) and tumor-to-liver ratio (TLR) at different time points). The PET metabolic parameters were related to the histological characteristics of the resected tumors and to the evolution of patients. Microvascular invasion (MVI) and a poor grade of differentiation were significantly related to a worse prognosis. The SULpeak of the lesion 60 min post-FDG injection was the best parameter to predict MVI while the SULpeak of the TLR at 60 min was better for a poor differentiation. Moreover, the latter parameter was also the best preoperative variable available to predict any of these two histological factors. Patients with an increased TLRpeak60 presented a significantly higher incidence of poor prognostic factors than the rest (75% vs. 28.6%, = 0.005) and a significantly higher incidence of recurrence at 12 months (38% vs. 0%, = 0.014). Therefore, a semi-quantitative analysis of certain metabolic parameters on PET/CT can help identify, preoperatively, patients with histological factors of a poor prognosis, allowing an adjustment of the therapeutic strategy for those patients with a higher risk of an early recurrence.
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http://dx.doi.org/10.3390/cancers13112554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196959PMC
May 2021

Sinusoidal obstruction syndrome as a manifestation of acute antibody-mediated rejection after liver transplantation.

Am J Transplant 2021 May 19. Epub 2021 May 19.

Liver Transplant Unit, Department of Surgery, Bellvitge University Hospital, IDIBELL, University of Barcelona, Barcelona, Spain.

Antibody-mediated rejection (AMR) after liver transplantation is uncommon but, when present, manifests as graft dysfunction. We report the case of a 54-year-old woman who developed portal hypertension with pleural effusion and ascites secondary to sinusoidal obstruction syndrome (SOS) due to acute AMR following an ABO-matched liver transplantation for autoimmune cirrhosis and hepatocellular carcinoma. Initial immunosuppression comprised basiliximab, decreasing prednisone, tacrolimus, and mycophenolate mofetil. After 1 month, she presented with the massive pleural effusion, slight ascites, and normal liver tests. After excluding common causes of pleural effusion, we performed a liver biopsy that showed atypical rejection with the involvement of large centrilobular veins partially occluded by marked endotheliitis and lax fibrosis suggestive of SOS. Direct immunofluorescence study of C4d showed diffuse endothelial sinusoidal staining, and de novo donor-specific anti-human leukocyte antigen antibodies were detected in his blood. Thus, we diagnosed AMR focused on centrilobular veins and initiated treatment with defibrotide, steroid pulses, and diuretics. However, this was ineffective, and the pleural effusion only resolved when plasmapheresis and intravenous immunoglobulin were started. This case shows that AMR can cause SOS with portal hypertension and present with a pleural effusion, and as such, it should be suspected after excluding other more common causes of effusion.
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http://dx.doi.org/10.1111/ajt.16689DOI Listing
May 2021

Ectopic Cushing's syndrome due to thymic neuroendocrine tumours: a systematic review.

Rev Endocr Metab Disord 2021 May 7. Epub 2021 May 7.

Department of Endocrinology, Bellvitge University Hospital, Biomedical Research Institute of Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Knowledge of ectopic Cushing's syndrome (CS) due to thymic neuroendocrine tumours (NETs) comes from short series or single cases. Our aim is to perform a systematic review using PubMed, Embase, Scopus, Ovid Medline and Biosis Previews of all cases with ectopic CS due to thymic NETs reported in the last 40 years and describe one illustrative patient attended in our institution. Search of literature: From 162 patients, 58.6% were male and mean age was 34.6 ± 13.9 years-old. Median of symptoms until diagnosis was 6 [2-24] months and 62% had aggressive CS. Imaging was positive in 93.7% (chest X-ray), 97.8% (computed tomography), 80.7% (somatostatin receptor scintigraphy) and median tumour size was 47 [25-68.5] mm. At presentation, 18% had localized disease, 26.2% locally invasive and 55.7% advanced. Eighty-eight present underwent surgery and histological subtypes were atypical (46.7%), typical (30.4%) and carcinoma (21.7%). Tumour persisted or recurred in 70.1%, 63% received radiotherapy and 45.2% chemotherapy. Follow-up median was 26.6 [14.5-57.5] months and mortality was reported in 35.8% with median survival of 38 [19-60] months. MEN-1 mutation was referred in 3.1%. Comparatively, carcinomas had aggressive CS more frequently while atypical showed advanced disease more often. In conclusion, thymic NETs causing ectopic CS are presented as aggressive hypercortisolism in the middle aged population. The disease is commonly extended at diagnosis and persists or recurs after surgery in most patients with a short term high mortality.
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http://dx.doi.org/10.1007/s11154-021-09660-2DOI Listing
May 2021

Intrahepatic cholangiocarcinoma: Prognostic factors for recurrence and survival in a series of 67 patients treated surgically at a single center.

Cir Esp (Engl Ed) 2020 Sep 10. Epub 2020 Sep 10.

Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitari de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat (Barcelona), España.

Introduction: Intrahepatic cholangiocarcinoma is a primary liver neoplasm whose only curative treatment is surgery. The objective of this study was to determine the prognostic factors for survival of intrahepatic cholangiocarcinoma treated surgically with curative intent.

Methods: Sixty-seven patients who had been treated surgically for this neoplasm were collected at Bellvitge University Hospital between 1996 and 2017. Epidemiological, clinical, surgical, anatomopathological, morbidity, mortality and survival data have been analysed.

Results: Postoperative morbidity was 47.76%, and postoperative mortality was 1.5%. Lymphadenectomy was associated with increased morbidity. Overall survival was 91%, 49.2% and 39.8% after 12, 36 and 60 months, respectively, and disease-free survival was 67.2%, 32.8% and 22.4%. Postoperative morbidity (reoperation, vascular invasion, adjuvant chemotherapy) were shown to be factors for a poor prognosis. Vascular invasion in the pathological study was the most important risk factor in the survival analysis.

Conclusions: This study reflects our centre's experience in the surgical treatment of intrahepatic cholangiocarcinoma over a period of 21 years. Lymphadenectomy was associated with increased morbidity, and vascular invasion in the pathological study was the most important risk factor in the survival analysis.
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http://dx.doi.org/10.1016/j.ciresp.2020.07.003DOI Listing
September 2020

Clinical and pathological features of Kaposi sarcoma herpesvirus-associated inflammatory cytokine syndrome.

AIDS 2020 11;34(14):2097-2101

HIV and STI Unit, Department of Infectious Diseases, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.

: Kaposi sarcoma Herpesvirus (KSHV)-associated inflammatory cytokine syndrome (KICS) is an uncommon but aggressive human Kaposi sarcoma herpesvirus associated disorder that is mostly reported in people living with HIV. The diagnosis of KICS is based on clinical criteria, and, in contrast to other KSHV-related malignancies, characteristic pathological features have not yet been described. We report novel clinical and pathological features in an HIV-1 infected patient diagnosed with KICS.
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http://dx.doi.org/10.1097/QAD.0000000000002669DOI Listing
November 2020

Prognostic value and risk stratification of residual disease in patients with incidental gallbladder cancer.

World J Surg Oncol 2020 Jan 24;18(1):18. Epub 2020 Jan 24.

Department of Surgery, IDIBELL, Hospital Universitario de Bellvitge, CIBERehd, Servicio de Cirugía General y Digestiva, Universidad de Barcelona, Av Feixa Llarga s/n, 08907, L'Hospitalet de Llobregat, Barcelona, Spain.

Background And Aim: Given their poor prognosis, patients with residual disease (RD) in the re-resection specimen of an incidental gallbladder carcinoma (IGBC) could benefit from a better selection for surgical treatment. The Gallbladder Cancer Risk Score (GBRS) has been proposed to preoperatively identify RD risk more precisely than T-stage alone. The aim of this study was to assess the prognostic value of RD and to validate the GBRS in a retrospective series of patients.

Material And Methods: A prospectively collected database including 59 patients with IGBC diagnosed from December 1996 to November 2015 was retrospectively analyzed. Three locations of RD were established: local, regional, and distant. The effect of RD on overall survival (OS) was analyzed with the Kaplan-Meier method. To identify variables associated with the presence of RD, characteristics of patients with and without RD were compared using Fisher's exact test. The relative risk of RD associated with clinical and pathologic factors was studied with a univariate logistic regression analysis.

Results: RD was found in 30 patients (50.8%). The presence of RD in any location was associated with worse OS (29% vs. 74.2%, p = 0.0001), even after an R0 resection (37.7% vs 74.2%, p = 0.003). There was no significant difference in survival between patients without RD and with local RD (74.2% vs 64.3%, p = 0.266), nor between patients with regional RD and distant RD (16.1% vs 20%, p = 0.411). After selecting patients in which R0 resection was achieved (n = 44), 5-year survival rate for patients without RD, local RD, and regional RD was, respectively, 74.2%, 75%, and 13.9% (p = 0.0001). The GBRS could be calculated in 25 cases (42.3%), and its usefulness to predict the presence of regional or distant RD (RDRD) was confirmed (80% in high-risk patients and 30% in intermediate risk p = 0.041).

Conclusion: RDRD, but not local RD, represents a negative prognostic factor of OS. The GBRS was useful to preoperatively identify patients with high risk of RDRD. An R0 resection did not improve OS of patients with regional RD.
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http://dx.doi.org/10.1186/s12957-020-1794-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982379PMC
January 2020

Duodenal adenocarcinoma: Surgical results of 27 patients treated at a single center.

Cir Esp (Engl Ed) 2019 Nov 26;97(9):523-530. Epub 2019 Sep 26.

Unidad de Cirugía Hepatobiliar y Pancreática, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, España.

Introduction: Duodenal adenocarcinoma is a rare malignancy. Given the rarity of the disease, there is limited data related to resection results. The objective is to analyze results at our hospital after the curative resection of duodenal adenocarcinoma (DA).

Methods: The variables were retrospectively collected from patients operated on between 1990 and 2017 at our hospital.

Results: A total of 27 patients were treated. Twenty-three patients (85%) underwent pancreaticoduodenectomy, and 4 patients (15%) with tumors located in the third and fourth portions of the duodenum underwent segmental duodenal resection. The overall postoperative morbidity was 67% (18 patients). Postoperative mortality was 7% (2 patients); however, postoperative mortality related to surgery was 4% (1 patient). All patients had negative resection margins. A median of 18 lymph nodes (range, 0-38) were retrieved and evaluated, with a median of 1 involved node (range, 0-8). Median follow up was 23 (9-69.7) months. Actuarial overall survival was 62.2 (25.2-99.1) months. Actuarial disease-free survival was 49 (0-133) months.

Conclusions: The surgical treatment of duodenal adenocarcinoma is associated with a high morbidity, although it achieves considerable survival. Depending on the tumor location and if there is no pancreatic infiltration, segmental duodenal resection with negative margins is an alternative to cephalic pancreaticoduodenectomy.
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http://dx.doi.org/10.1016/j.ciresp.2019.06.014DOI Listing
November 2019

Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer.

J Hepatol 2020 01 25;72(1):125-134. Epub 2019 Sep 25.

Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, 28029 Madrid, Spain; TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Gran Via de L'Hospitalet, 199, 08908 Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, L'Hospitalet, 08907 Barcelona, Spain. Electronic address:

Background & Aims: Upon ligand binding, tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), are recruited into clathrin-coated pits for internalization by endocytosis, which is relevant for signalling and/or receptor degradation. In liver cells, transforming growth factor-β (TGF-β) induces both pro- and anti-apoptotic signals; the latter are mediated by the EGFR pathway. Since EGFR mainly traffics via clathrin-coated vesicles, we aimed to analyse the potential role of clathrin in TGF-β-induced signalling in liver cells and its relevance in liver cancer.

Methods: Real-Time PCR and immunohistochemistry were used to analyse clathrin heavy-chain expression in human (CLTC) and mice (Cltc) liver tumours. Transient knockdown (siRNA) or overexpression of CLTC were used to analyse its role on TGF-β and EGFR signalling in vitro. Bioinformatic analysis was used to determine the effect of CLTC and TGFB1 expression on prognosis and overall survival in patients with hepatocellular carcinoma (HCC).

Results: Clathrin expression increased during liver tumorigenesis in humans and mice. CLTC knockdown cells responded to TGF-β phosphorylating SMADs (canonical signalling) but showed impairment in the anti-apoptotic signals (EGFR transactivation). Experiments of loss or gain of function in HCC cells reveal an essential role for clathrin in inhibiting TGF-β-induced apoptosis and upregulation of its pro-apoptotic target NOX4. Autocrine TGF-β signalling in invasive HCC cells upregulates CLTC expression, switching its role to pro-tumorigenic. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival.

Conclusions: This work describes a novel role for clathrin in liver tumorigenesis, favouring non-canonical pro-tumorigenic TGF-β pathways. CLTC expression in human HCC samples could help select patients that would benefit from TGF-β-targeted therapy.

Lay Summary: Clathrin heavy-chain expression increases during liver tumorigenesis in humans (CLTC) and mice (Cltc), altering the cellular response to TGF-β in favour of anti-apoptotic/pro-tumorigenic signals. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival. CLTC expression in HCC human samples could help select patients that would benefit from therapies targeting TGF-β.
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http://dx.doi.org/10.1016/j.jhep.2019.09.012DOI Listing
January 2020

Downregulation of Epidermal Growth Factor Receptor in hepatocellular carcinoma facilitates Transforming Growth Factor-β-induced epithelial to amoeboid transition.

Cancer Lett 2019 Nov 26;464:15-24. Epub 2019 Aug 26.

TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Oncology Program, CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain; Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Spain. Electronic address:

The Epidermal Growth Factor Receptor (EGFR) and the Transforming Growth Factor-beta (TGF-β) are key regulators of hepatocarcinogenesis. Targeting EGFR was proposed as a promising therapy; however, poor success was obtained in human hepatocellular carcinoma (HCC) clinical trials. Here, we describe how EGFR is frequently downregulated in HCC patients while TGF-β is upregulated. Using 2D/3D cellular models, we show that after EGFR loss, TGF-β is more efficient in its pro-migratory and invasive effects, inducing epithelial to amoeboid transition. EGFR knock-down promotes loss of cell-cell and cell-to-matrix adhesion, favouring TGF-β-induced actomyosin contractility and acquisition of an amoeboid migratory phenotype. Moreover, TGF-β upregulates RHOC and CDC42 after EGFR silencing, promoting Myosin II in amoeboid cells. Importantly, low EGFR combined with high TGFB1 or RHOC/CDC42 levels confer poor patient prognosis. In conclusion, this work reveals a new tumour suppressor function for EGFR counteracting TGF-β-mediated epithelial to amoeboid transitions in HCC, supporting a rational for targeting the TGF-β pathway in patients with low EGFR expression. Our work also highlights the relevance of epithelial to amoeboid transition in human tumours and the need to better target this process in the clinic.
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http://dx.doi.org/10.1016/j.canlet.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853171PMC
November 2019

Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer.

Mol Ther Nucleic Acids 2019 Sep 29;17:491-503. Epub 2019 Jun 29.

Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain; CIBERONC, Centro de Investigación Biomédica en Red en Cáncer, Madrid, Spain. Electronic address:

MicroRNAs from the miR-200 family are commonly associated with the inhibition of the metastatic potential of cancer cells, following inhibition of ZEB transcription factors expression and epithelial-to-mesenchymal transition. However, previous studies performed in pancreatic adenocarcinoma revealed a more complex picture challenging this canonical model. To gain better insights into the role of miR-200 family members in this disease, we analyzed the expression of miR-200a, miR-200b, miR-200c, miR-141, miR-429, and miR-205, and ZEB1, ZEB2, and CDH1 in pancreatic tumors and matching normal adjacent parenchyma and patient-derived xenografts. We found that miR-200a, miR-429, and miR-205 are frequently overexpressed in pancreatic tumors, whereas CDH1 is downregulated, and ZEB1 and ZEB2 levels remain unchanged. Furthermore, we measured a positive correlation between miR-200 family members and CDH1 expression, and a negative correlation between ZEB1 and miR-200c, miR-141, and miR-205 expression, respectively. Interestingly, we identified significant changes in expression of epithelial-to-mesenchymal transition regulators and miR-200 members in patient-derived xenografts. Lastly, functional studies revealed that miR-141 and miR-429 inhibit the tumorigenic potential of pancreatic cancer cells. Taken together, this comprehensive analysis strongly suggests that miRNAs from the miR-200 family, and in particular miR-429, may act as a tumor suppressor gene in pancreatic cancer.
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http://dx.doi.org/10.1016/j.omtn.2019.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656921PMC
September 2019

Epigenetic Deregulation of Protocadherin PCDHGC3 in Pheochromocytomas/Paragangliomas Associated With SDHB Mutations.

J Clin Endocrinol Metab 2019 11;104(11):5673-5692

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota.

Context: SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed.

Objective: This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs.

Design: We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs.

Results: We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion.

Conclusions: Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.
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http://dx.doi.org/10.1210/jc.2018-01471DOI Listing
November 2019

Hepatic Angiosarcoma: A Multi-institutional, International Experience with 44 Cases.

Ann Surg Oncol 2019 Feb 19;26(2):576-582. Epub 2018 Nov 19.

Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Background: Hepatic angiosarcoma is a rare primary liver tumor. The aim of this current study was to evaluate the presentation and treatment outcomes in a modern cohort.

Methods: This was a retrospective, multi-institutional, observational study of patients with histopathologic diagnoses of primary hepatic angiosarcoma from four institutions. Clinicopathologic characteristics, treatments, and patient outcomes were examined.

Results: Forty-four patients with hepatic angiosarcoma were identified. Patients were predominantly Caucasian and presented at a median age of 63.7 years; 81.4% of patients had bilobar disease and 37.2% had metastatic disease at the time of presentation. Only 10 patients underwent surgical resection. Median overall survival for the entire cohort was 5.8 months (interquartile range 1.9-16.4), and 1-, 3-, and 5-year actual survival was 30.0%, 8.1%, and 5.6%, respectively. There were only two 5-year survivors, both of whom presented with localized disease and underwent curative resection.

Conclusion: The prognosis for hepatic angiosarcoma remains quite poor. Surgical resection for localized disease results in the best outcomes. Unfortunately, current imaging modalities are often non- diagnostic, and most patients are unresectable at the time of presentation.
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http://dx.doi.org/10.1245/s10434-018-7062-9DOI Listing
February 2019

Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients.

Oncotarget 2018 Apr 3;9(25):17576-17588. Epub 2018 Apr 3.

Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain.

Introduction: There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients.

Methods: , , , , and expression levels were determined by qRT-PCR. We also analyzed and mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test.

Results: Hierarchical cluster analyses from gene expression data identified two groups: group I had , and overexpression and underexpression and group II had overexpression of and low expression of , and . Group II had a significant worse OS ( 0.013) in all the series, and showed a tendency for worse OS ( 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST ( 0.001). OS was significantly worse in KNGL cases with higher expression of ( 0.028) or ( 0.014).

Conclusions: We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors.
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http://dx.doi.org/10.18632/oncotarget.24799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915139PMC
April 2018

Glutathione depletion: Starting point of brain metabolic stress, neuroinflammation and cognitive impairment in rats.

Brain Res Bull 2018 03 26;137:120-131. Epub 2017 Nov 26.

Neurology at the Medico-Surgical Research Center. 3rd student of Medicine, Faculty of Medical Sciences Victoria de Giron, Playa, Havana CP 11300, Cuba.

Glutathione provides protection from oxidative stress-induced damage through the reduction of reactive oxygen species for the maintenance of oxidant homeostasis. Our purpose was to test the effects of depleting tissue GSH by buthionine sulfoximine on brain oxidative metabolism and cognitive performance in rats. Glutathione depletion induced a compensatory response on antioxidant enzymes and increase of cell damage indicators in all the examined cerebral areas at 24h. The effect of GSH depletion on spatial memory recorded at 24h post-surgery showed significant differences between experimental groups for the escape latency to the platform and percentage of total swim distance spending in the target quadrant. The acquisition of a new spatial condition 24h after GSH depletion revealed differences between experimental groups for latencies, swim distance, swim distance in the target quadrant and percentage of total swim distance spending in the target quadrant. The ability of BSO treated group to maintain a restraining behavior was significantly smaller compared with control group. We founded significant correlation among variables of the behavioral studies and oxidative stress indicators. In conclusion, our model shows how increased ROS production by transitory glutathione depletion constitutes the primary cause to neuronal metabolic stress with alterations in synaptic signaling and cognitive deficits.
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http://dx.doi.org/10.1016/j.brainresbull.2017.11.015DOI Listing
March 2018

The level of caveolin-1 expression determines response to TGF-β as a tumour suppressor in hepatocellular carcinoma cells.

Cell Death Dis 2017 10 12;8(10):e3098. Epub 2017 Oct 12.

Bellvitge Biomedical Research Institute (IDIBELL), Oncobell Program, L'Hospitalet de Llobregat, Barcelona, Spain.

Hepatocellular carcinoma (HCC) is a heterogeneous tumour associated with poor prognostic outcome. Caveolin-1 (CAV1), a membrane protein involved in the formation of caveolae, is frequently overexpressed in HCC. Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine having a dual role in hepatocarcinogenesis: inducer of apoptosis at early phases, but pro-tumourigenic once cells acquire mechanisms to overcome its suppressor effects. Apoptosis induced by TGF-β is mediated by upregulation of the NADPH oxidase NOX4, but counteracted by transactivation of the epidermal growth factor receptor (EGFR) pathway. Previous data suggested that CAV1 is required for the anti-apoptotic signals triggered by TGF-β in hepatocytes. Whether this mechanism is relevant in hepatocarcinogenesis has not been explored yet. Here we analysed the TGF-β response in HCC cell lines that express different levels of CAV1. Accordingly, stable CAV1 knockdown or overexpressing cell lines were generated. We demonstrate that CAV1 is protecting HCC cells from TGF-β-induced apoptosis, which attenuates its suppressive effect on clonogenic growth and increases its effects on cell migration. Downregulation of CAV1 in HLE cells promotes TGF-β-mediated induction of the pro-apoptotic BMF, which correlates with upregulation of NOX4, whereas CAV1 overexpression in Huh7 cells shows the opposite effect. CAV1 silenced HLE cells show attenuation in TGF-β-induced EGFR transactivation and activation of the PI3K/AKT pathway. On the contrary, Huh7 cells, which do not respond to TGF-β activating the EGFR pathway, acquire the capacity to do so when CAV1 is overexpressed. Analyses in samples from HCC patients revealed that tumour tissues presented higher expression levels of CAV1 compared with surrounding non-tumoural areas. Furthermore, a significant positive correlation among the expression of CAV1 and TGFB1 was observed. We conclude that CAV1 has an essential role in switching the response to TGF-β from cytostatic to tumourigenic, which could have clinical meaning in patient stratification.
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http://dx.doi.org/10.1038/cddis.2017.469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680590PMC
October 2017

Initial Experience in the Treatment of "Borderline Resectable" Pancreatic Adenocarcinoma.

Cir Esp 2017 Oct 6;95(8):447-456. Epub 2017 Oct 6.

Unitat de Cirurgia Hepatobiliopancreàtica i Trasplantament Hepàtic, Hospital Universitari de Bellvitge, Barcelona, España.

Introduction: A borderline resectable group (APBR) has recently been defined in adenocarcinoma of the pancreas. The objective of the study is to evaluate the results in the surgical treatment after neoadjuvancy of the APBR.

Method: Between 2010 and 2014, we included patients with APBR in a neoadjuvant and surgery protocol, staged by multidetector computed tomography (MDCT). Treatment with chemotherapy was based on gemcitabine and oxaliplatin. Subsequently, MDCT was performed to rule out progression, and 5-FU infusion and concomitant radiotherapy were given. MDCT and resection were performed in absence of progression. A descriptive statistical study was performed, dividing the series into: surgery group (GR group) and progression group (PROG group).

Results: We indicated neoadjuvant treatment to 22 patients, 11 of them were operated, 9 pancreatoduodenectomies, and 2 distal pancreatectomies. Of the 11 patients, 7 required some type of vascular resection; 5 venous resections, one arterial and one both. No postoperative mortality was recorded, 7 (63%) had any complications, and 4 were reoperated. The median postoperative stay was 17 (7-75) days. The pathological study showed complete response (ypT0) in 27%, and free microscopic margins (R0) in 63%. At study clossure, all patients had died, with a median actuarial survival of 13 months (9,6-16,3). The median actuarial survival of the GR group was higher than the PROG group (25 vs. 9 months; p < 0.0001).

Conclusion: The neoadjuvant treatment of APBR allows us to select a group of patients in whom resection achieves a longer survival to the group in which progression is observed. Post-adjuvant pancreatic resection requires vascular resection in most cases.
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http://dx.doi.org/10.1016/j.ciresp.2017.07.008DOI Listing
October 2017

Transforming growth factor-β-induced plasticity causes a migratory stemness phenotype in hepatocellular carcinoma.

Cancer Lett 2017 04 2;392:39-50. Epub 2017 Feb 2.

Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain; Department of Physiological Sciences, School of Medicine, University of Barcelona, Barcelona, Spain. Electronic address:

As part of its potential pro-tumorigenic actions, Transforming Growth Factor-(TGF)-β induces epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells. Whether EMT induces changes in tumor cell plasticity has not been fully explored yet. Here, we analyze the effects of TGF-β on the EMT and stem-related properties of HCC cells and the potential correlation among those processes. The translational aim of the study was to propose a TGF-β/EMT/stem gene signature that would help in recognizing HCC patients as good candidates for anti-TGF-β therapy. Results indicate that when TGF-β induces EMT in HCC cells, a switch in the expression of stem genes is observed and their stemness potential and migratory/invasive capacity are enhanced. However, TGF-β may induce a partial EMT in some epithelial HCC cells, increasing the expression of mesenchymal genes and CD44, but maintaining epithelial gene expression. Epithelial cells show higher stemness potential than the mesenchymal ones, but respond to TGF-β increasing their migratory and invasive capacity. In HCC patient samples, TGFB1 expression most frequently correlates with a partial EMT, increase in mesenchymal genes and CD44 expression, as well as maintenance or over-expression of epithelial-related genes.
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http://dx.doi.org/10.1016/j.canlet.2017.01.037DOI Listing
April 2017

Surgical treatment of non-functioning pancreatic neuroendocrine tumours based on three clinical scenarios.

Cir Esp 2016 Dec 15;94(10):578-587. Epub 2016 Nov 15.

Servicio de Cirugía General y Digestivo, Hospital Universitari de Bellvitge, l'Hospitalet de Llobregat, Barcelona, España.

Introduction: The treatment of patients with non-functioning pancreatic neuroendocrine tumours (NFPNET) is resection in locally pancreatic disease, or with resectable liver metastases. There is controversy about unresectable liver disease.

Methods: We analysed the perioperative data and survival outcome of 63 patients who underwent resection of NFPNET between 1993 and 2012. They were divided into 3 scenarios: A, pancreatic resection (44patients); B, pancreatic and liver resection in synchronous resectable liver metastases (12patients); and C, pancreatic resection in synchronous unresectable liver metastases (6patients). The prognostic factors for survival and recurrence were studied.

Results: Distal pancreatectomy (51%) and pancreaticoduodenectomy (38%) were more frequently performed. Associated surgery was required in 44% of patients, including synchronous liver resections in 9patients. Two patients received a liver transplant during follow-up. According to the WHO classification they were distributed into G1: 10 (16%), G2: 45 (71%), and G3: 8 (13%). The median hospital stay was 11days. Postoperative morbidity and mortality were 49% and 1.6%, respectively. At the closure of the study, 43 (68%) patients were still alive, with a mean actuarial survival of 9.6years. The WHO classification and tumour recurrence were risk factors of mortality in the multivariate analysis. The median actuarial survival by scenarios was 131months (A), 102months (B), and 75months (C) without statistically significant differences.

Conclusions: Surgical resection is the treatment for NFPNET without distant disease. Resectable liver metastases in well-differentiated tumours must be resected. The resection of the pancreatic tumour with unresectable synchronous liver metastasis must be considered in well-differentiated NFPNET. The WHO classification grade and recurrence are risk factors of long-term mortality.
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http://dx.doi.org/10.1016/j.ciresp.2016.07.008DOI Listing
December 2016

promoter is frequently methylated in pancreatic juice of patients with pancreatic carcinomas or periampullary tumors.

Oncol Lett 2016 Sep 15;12(3):2210-2216. Epub 2016 Jul 15.

Department of General and Digestive Surgery, Bellvitge University Hospital, 08907 Barcelona, Spain.

Early detection of pancreatic and periampullary neoplasms is critical to improve their clinical outcome. The present authors previously demonstrated that DNA hypermethylation of and promoters is frequently detected in pancreatic tumor cells. The aim of the present study was to assess their prevalence in pancreatic juice of carcinomas of the pancreas and periampullary area. A total of 135 pancreatic juices obtained from 85 pancreatic cancer (PC), 26 ampullary carcinoma (AC), 10 intraductal papillary mucinous neoplasm (IPMN) and 14 chronic pancreatitis (CP) patients were analyzed. The methylation status of the and promoters was analyzed using methylation specific-melting curve analysis (MS-MCA). mutations were also tested with allele-specific quantitative polymerase chain reaction amplification. Out of the 5 promoters analyzed, (71%) and (65%) were the most frequently methylated in PC juice. methylation was also detected at a high frequency in AC (76%) and IPMN (80%), but only occasionally observed in CP (7%). methylation had a high sensitivity (71-80%) for all types of cancer analyzed. The panel (where a sample scored as positive when ≥2 markers were methylated) did not outperform as a single marker. Finally, detection in pancreatic juice offered a lower sensitivity (50%) and specificity (71%) for detection of any cancer. hypermethylation in pancreatic juice, as assessed by MS-MCA, is a frequent event of potential clinical usefulness in the diagnosis of pancreatic and periampullary neoplasms.
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http://dx.doi.org/10.3892/ol.2016.4868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998563PMC
September 2016

The influence of steatosis on the short- and long-term results of resection of liver metastases from colorectal carcinoma.

HPB (Oxford) 2016 Apr 29;18(4):389-96. Epub 2016 Jan 29.

Hospital Universitario de Bellvitge, Department of General Surgery, Spain.

Unlabelled: We aimed to establish whether the presence of hepatic steatosis influences outcome after resection of colorectal liver metastases (CLM).

Patients And Methods: Patients operated between 1990 and 2014 were divided into four groups based on the degree of hepatic steatosis. The association between hepatic steatosis and outcome was analyzed, using a multivariate and a propensity score case-match analysis.

Results: No significant differences were observed between patients with and without steatosis in either mortality or morbidity in the complete series or after matching (3.2% vs. 3.5%/p = 0.845) (32.3% vs 31.4%/p = 0.802). Five-year survival in patients with and without steatosis were 56.5% and 46.5% respectively (p = 0.046). The steatosis had a significant protective effect in the univariate analysis (HR (95% CI) = 0.78 (0.62-0.99) p = 0.048), and was close to significance in the multivariate analysis (HR (95%) = 0.81 (0.63-1.03) p = 0.089). No significant differences were seen with regard to liver recurrence.

Conclusions: The presence of steatosis does not predict short-outcome after resection of CLM, but appears to be a favorable prognostic factor for survival. This protective effect does not depend on a decrease in liver recurrence.
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http://dx.doi.org/10.1016/j.hpb.2015.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814618PMC
April 2016

Dissecting the role of epidermal growth factor receptor catalytic activity during liver regeneration and hepatocarcinogenesis.

Hepatology 2016 Feb 10;63(2):604-19. Epub 2015 Oct 10.

Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Unlabelled: Different data support a role for the epidermal growth factor receptor (EGFR) pathway during liver regeneration and hepatocarcinogenesis. However, important issues, such as the precise mechanisms mediating its actions and the unique versus redundant functions, have not been fully defined. Here, we present a novel transgenic mouse model expressing a hepatocyte-specific truncated form of human EGFR, which acts as negative dominant mutant (ΔEGFR) and allows definition of its tyrosine kinase-dependent functions. Results indicate a critical role for EGFR catalytic activity during the early stages of liver regeneration. Thus, after two-thirds partial hepatectomy, ΔEGFR livers displayed lower and delayed proliferation and lower activation of proliferative signals, which correlated with overactivation of the transforming growth factor-β pathway. Altered regenerative response was associated with amplification of cytostatic effects of transforming growth factor-β through induction of cell cycle negative regulators. Interestingly, lipid synthesis was severely inhibited in ΔEGFR livers after partial hepatectomy, revealing a new function for EGFR kinase activity as a lipid metabolism regulator in regenerating hepatocytes. In spite of these profound alterations, ΔEGFR livers were able to recover liver mass by overactivating compensatory signals, such as c-Met. Our results also indicate that EGFR catalytic activity is critical in the early preneoplastic stages of the liver because ΔEGFR mice showed a delay in the appearance of diethyl-nitrosamine-induced tumors, which correlated with decreased proliferation and delay in the diethyl-nitrosamine-induced inflammatory process.

Conclusion: These studies demonstrate that EGFR catalytic activity is critical during the initial phases of both liver regeneration and carcinogenesis and provide key mechanistic insights into how this kinase acts to regulate liver pathophysiology. (Hepatology 2016;63:604-619).
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http://dx.doi.org/10.1002/hep.28134DOI Listing
February 2016

Cross-reactivity of EGFR mutation-specific immunohistochemistry assay in HER2-positive tumors.

Appl Immunohistochem Mol Morphol 2015 Sep;23(8):565-70

*Histopat Laboratoris †BIOPAT. Biopatologia Molecular, Grup Assistencia ‡Hospital de Barcelona, SCIAS, Grup Assistencia, Barcelona, Spain.

The coexpression of HER2 and EGFR L858R in a solitary nodule removed from the lung, whose mutation was not confirmed by molecular techniques, made us think about the possible existence of a cross-reaction between HER2 and the EGFR L858R-specific antibody. Our study was designed to further analyze the existence of this cross-reaction and stress the need to exclude a metastatic breast cancer when dealing with EGFR L858R-positive cases. The series consists of 42 primary breast carcinomas, 22 HER2 positive for overexpression and amplification, and 20 negative for both. EGFR mutations were studied by immunohistochemistry and confirmed using real-time PCR when positive. Immunohistochemistry assay with EGFR L858R was positive in 19 (86%) of the HER2-positive breast carcinomas and negative in all HER2-negative carcinomas. The EGFR L858R antibody gives false-positive results in most of the breast carcinomas with HER2 overexpression/amplification. As a consequence, it is essential to confirm any EGFR L858R-positive cases by molecular methods or at least discard the presence of HER2 overexpression/amplification before rendering a diagnosis. It is also important to consider that HER2 has been described in other carcinomas such as urothelial, gastric or ovarian, as well as lung, although infrequently.
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http://dx.doi.org/10.1097/PAI.0000000000000129DOI Listing
September 2015

A monotonic and prognostic genomic signature from fibroblasts for colorectal cancer initiation, progression, and metastasis.

Mol Cancer Res 2014 Sep 14;12(9):1254-66. Epub 2014 May 14.

Translational Research Laboratory,

Unlabelled: The differential gene expression patterns between normal colonic fibroblasts (NCF), carcinoma-associated fibroblasts from primary tumors (CAF-PT), and CAFs from hepatic metastasis (CAF-LM) are hypothesized to be useful for predicting relapse in primary tumors. A transcriptomic profile of NCF (n = 9), CAF-PT (n = 14), and CAF-LM (n = 11) was derived. Prediction Analysis of Microarrays (PAM) was used to obtain molecular details for each fibroblast class, and differentially expressed transcripts were used to classify patients according to recurrence status. A number of transcripts (n = 277) were common to all three types of fibroblasts and whose expression level was sequentially deregulated according to the transition: NCF→CAF-PT→CAF-LM. Importantly, the gene signature was able to accurately classify patients with primary tumors according to their prognosis. This capacity was exploited to obtain a refined 19-gene classifier that predicted recurrence with high accuracy in two independent datasets of patients with colorectal cancer and correlates with fibroblast migratory potential. The prognostic power of this genomic signature is strong evidence of the link between the tumor-stroma microenvironment and cancer progression. Furthermore, the 19-gene classifier was able to identify low-risk patients very accurately, which is of particular importance for stage II patients, who would benefit from the omission of chemotherapy, especially T4N0 patients, who are clinically classified as being at high risk.

Implications: A defined stromal gene expression signature predicts relapse in patients with colorectal cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-14-0121DOI Listing
September 2014

Overactivation of the TGF-β pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells.

Hepatology 2013 Dec 11;58(6):2032-44. Epub 2013 Oct 11.

Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Unlabelled: Transforming growth factor-beta (TGF-β) is an important regulatory suppressor factor in hepatocytes. However, liver tumor cells develop mechanisms to overcome its suppressor effects and respond to this cytokine by inducing other processes, such as the epithelial-mesenchymal transition (EMT), which contributes to tumor progression and dissemination. Recent studies have placed chemokines and their receptors at the center not only of physiological cell migration but also of pathological processes, such as metastasis in cancer. In particular, CXCR4 and its ligand, stromal cell-derived factor 1α (SDF-1α) / chemokine (C-X-C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we show that autocrine stimulation of TGF-β in human liver tumor cells correlates with a mesenchymal-like phenotype, resistance to TGF-β-induced suppressor effects, and high expression of CXCR4, which is required for TGF-β-induced cell migration. Silencing of the TGF-β receptor1 (TGFBR1), or its specific inhibition, recovered the epithelial phenotype and attenuated CXCR4 expression, inhibiting cell migratory capacity. In an experimental mouse model of hepatocarcinogenesis (diethylnitrosamine-induced), tumors showed increased activation of the TGF-β pathway and enhanced CXCR4 levels. In human hepatocellular carcinoma tumors, high levels of CXCR4 always correlated with activation of the TGF-β pathway, a less differentiated phenotype, and a cirrhotic background. CXCR4 concentrated at the tumor border and perivascular areas, suggesting its potential involvement in tumor cell dissemination.

Conclusion: A crosstalk exists among the TGF-β and CXCR4 pathways in liver tumors, reflecting a novel molecular mechanism that explains the protumorigenic effects of TGF-β and opens new perspectives for tumor therapy.
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http://dx.doi.org/10.1002/hep.26597DOI Listing
December 2013

Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells.

Int J Cancer 2013 Nov 4;133(10):2464-72. Epub 2013 Jun 4.

Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona, Spain.

In this article, the effectiveness of a multi-targeted chemo-switch (C-S) schedule that combines metronomic chemotherapy (MET) after treatment with the maximum tolerated dose (MTD) is reported. This schedule was tested with gemcitabine in two distinct human pancreatic adenocarcinoma orthotopic models and with cyclophosphamide in an orthotopic ovarian cancer model. In both models, the C-S schedule had the most favourable effect, achieving at least 80% tumour growth inhibition without increased toxicity. Moreover, in the pancreatic cancer model, although peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C-S groups. C-S treatment caused a decrease in angiogenesis, and its effect on tumour growth was similar to that produced by the MTD followed by anti-angiogenic DC101 treatment. C-S treatment combined an increase in thrombospondin-1 expression with a decrease in the number of CD133+ cancer cells and triple-positive CD133+/CD44+/CD24+ cancer stem cells (CSCs). These findings confirm that the C-S schedule is a challenging clinical strategy with demonstrable inhibitory effects on tumour dissemination, angiogenesis and CSCs.
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http://dx.doi.org/10.1002/ijc.28259DOI Listing
November 2013

Hippocampal neurotrophins after stimulation of the basolateral amygdala, and memory improvement in lesioned rats.

Restor Neurol Neurosci 2013 ;31(2):189-97

Centro de Neurociencias de Cuba, Playa, La Habana, Cuba.

Purpose: To investigate a possible role of neurotrophins in the memory improving effect of stimulating the basolateral amygdala.

Methods: The BDNF and NGF levels were measured in the hippocampus of fimbria-fornix lesioned male rats after four days of training in the water maze and stimulation of the basolateral amygdala.

Results: The behavioral results confirm that daily post-training stimulation of the amygdala improves the learning abilities of the lesioned animals. BDNF increased in lesioned and trained animals, but stimulating the basolateral amygdala induces a significantly greater increase. NGF showed a slight (but significant) increase in fimbria-fornix lesioned and trained animals, but stimulating the amygdala does not produce a further increase. In separate groups of animals we measured the levels of both neurotrophins in acute experiments, after 2 and 24 hours of stimulating the amygdala. BDNF was significantly increased at both times, while NGF showed again only slight increases (significant at 24 h).

Conclusions: These results suggest that the BDNF response to amygdala stimulation might be of functional importance in the observed learning improvement. The changes in NGF are most likely due to the accumulation of this protein after removal of the septal axons.
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http://dx.doi.org/10.3233/RNN-120265DOI Listing
September 2013

Genetic and epigenetic markers in the evaluation of pancreatic masses.

J Clin Pathol 2013 Mar 7;66(3):192-7. Epub 2012 Nov 7.

Translational Research Laboratory, Hereditary Cancer Program, Institut Català d´Oncologia-IDIBELL, Barcelona, Spain.

Background: Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma. The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with KRAS mutation detection in the evaluation of pancreatic masses.

Experimental Design: Sixty-one fine needle aspirates of pancreatic masses (43 pancreatic adenocarcinomas and 18 chronic pancreatitis) were studied. Methylation status of HRH2, EN1, SPARC, CDH13 and APC were analysed using melting curve analysis after DNA bisulfite treatment. KRAS mutations were also analysed.

Results: The methylation panel had a sensitivity of 73% (27 of 37, CI 95% 56 to 86%) and a specificity of 100% whenever two or more promoters were found hypermethylated. KRAS mutations showed a sensitivity of 77% (33 of 43, CI 95% 62 to 88%) and a specificity of 100%. Both molecular analyses added useful information to cytology by increasing the number of informative cases. When genetic and epigenetic analyses were combined sensitivity was 84% (36 of 43 CI 95% 69 to 93%) maintaining a 100% specificity.

Conclusions: Analysis of hypermethylation status of a panel of genes and KRAS mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses. The combined molecular analysis increases the number of informative cases without diminishing specificity.
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http://dx.doi.org/10.1136/jclinpath-2012-201123DOI Listing
March 2013