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Pancreatic Neoplasms: HELP
Articles by Bohuslav Melichar
Based on 12 articles published since 2010
(Why 12 articles?)

Between 2010 and 2020, B. Melichar wrote the following 12 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Review Biomarkers and pathways of chemoresistance and chemosensitivity for personalized treatment of pancreatic adenocarcinoma. 2019

Zemanek, Tomas / Melichar, Bohuslav / Lovecek, Martin / Soucek, Pavel / Mohelnikova-Duchonova, Beatrice. ·Department of Oncology, Faculty of Medicine & Dentistry, Palacky University Olomouc, University Hospital Olomouc, Czech Republic. · Institute of Molecular & Translational Medicine, Faculty of Medicine & Dentistry, Palacky University, Olomouc, Czech Republic. · Department of Surgery I, Faculty of Medicine & Dentistry, Palacky University, Olomouc, University Hospital Olomouc, Czech Republic. · Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic. ·Pharmacogenomics · Pubmed #30539680.

ABSTRACT: Pancreatic carcinoma is usually diagnosed late when treatment options are limited and is considered a chemo-resistant malignancy. However, early stage, good performance status and specific patient subgroup are thought to have a more favorable prognosis. Search for novel molecular biomarkers, which could predict treatment resistance, represents a major opportunity, but also a challenge in further research. This review summarizes most aspects of individualized therapy of pancreatic cancer including promising biomarkers, BRCA-deficient pancreatic cancer and its etiology. It may be estimated that nearly a third of metastatic pancreatic ductal adenocarcinoma patients could benefit from treatment other than gold standard chemotherapy. Thus, other aspects of an individualized approach concerning the main factors for the choice of the best therapy for individual pancreatic cancer patient (surgery and chemotherapy), as well as the future directions (target therapy and immunotherapy), are also addressed.

2 Review Different clinical presentations of metachronous pulmonary metastases after resection of pancreatic ductal adenocarcinoma: Retrospective study and review of the literature. 2017

Lovecek, Martin / Skalicky, Pavel / Chudacek, Josef / Szkorupa, Marek / Svebisova, Hana / Lemstrova, Radmila / Ehrmann, Jiri / Melichar, Bohuslav / Yogeswara, Tharani / Klos, Dusan / Vrba, Radek / Havlik, Roman / Mohelnikova-Duchonova, Beatrice. ·Department of Surgery I, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, 77520 Olomouc, Czech Republic. · Department of Oncology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University, 77520 Olomouc, Czech Republic. · Department of Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, 77520 Olomouc, Czech Republic. · Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, University Hospital Olomouc, 77520 Olomouc, Czech Republic. · Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University, 775220 Olomouc, Czech Republic. ·World J Gastroenterol · Pubmed #29085191.

ABSTRACT: AIM: To analyze pancreatic cancer patients who developed metachronous pulmonary metastases (MPM) as a first site of recurrence after the curative-intent surgery. METHODS: One-hundred-fifty-nine consecutive pancreatic ductal adenocarcinoma (PDAC) patients who underwent radical pancreatic surgery between 2006 and 2013 were included in this retrospective analysis. The clinical data including age, sex, grade, primary tumor location, pTNM stage, lymph node infiltration, microangioinvasion, perineural invasion, lymphovascular invasion, the therapy administered, and follow-up were all obtained from medical records. Further analysis covered only patients with metachronous metastases. Clinical and histopathological data (age, sex, grade, primary tumor location, pTNM stage, lymph node infiltration, microangioinvasion, perineural invasion, lymphovascular invasion, the therapy administered and follow-up) of patients with metachronous non-pulmonary metastases and patients with metachronous pulmonary metastases were statistically assessed. Disease-free survival (DFS) from pancreas resection until metastases onset and overall survival (OS) were calculated. Wilcoxon test, χ RESULTS: Metachronous pulmonary metastases were observed in 20 (16.9%) and were operable in 3 (2.5%) of PDAC patients after a prior curative-intent surgery. Patients with isolated pulmonary metastases (oligometastases and multiple metastases) had estimated prior DFS and OS of 35.4 and 81.4 mo, respectively, and those with metachronous pulmonary metastases accompanied by other metastases had prior DFS and OS of 17.3 and 23.4 mo, respectively. Patients with non-pulmonary metastases had prior DFS and OS of 9.4 and 15.8 mo, respectively. Different clinical scenarios according to the presentation of MPM were observed and patients could be divided to three subgroups with different prognosis which could be used for the selection of treatment strategy: isolated pulmonary oligometastases, isolated multiple pulmonary metastases and pulmonary metastases accompanied by other metastases. CONCLUSION: Surgery should be considered for all patients with isolated pulmonary oligometastases, but the risk of intervention has to be individually weighted for each patient.

3 Review Therapeutic potential of taxanes in the treatment of metastatic pancreatic cancer. 2016

Lemstrova, Radmila / Melichar, Bohuslav / Mohelnikova-Duchonova, Beatrice. ·Department of Oncology, Palacky University Medical School and Teaching Hospital, IP Pavlova 6, 775 20, Olomouc, Czech Republic. · Department of Oncology, Palacky University Medical School and Teaching Hospital, IP Pavlova 6, 775 20, Olomouc, Czech Republic. mohelnikova@szu.cz. · Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic. mohelnikova@szu.cz. ·Cancer Chemother Pharmacol · Pubmed #27250969.

ABSTRACT: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease with very poor prognosis. Chemotherapy is the primary treatment modality for patients with locally advanced and metastatic PDAC, but the efficacy of currently available regimens is limited. Taxanes are widely used in many primary cancers including breast, ovarian and lung cancers. The activity of combined regimen of taxanes plus nucleoside analogue or platinum derivate in terms of response rate ranges between 20 and 57 % in PDAC and may prolong overall survival. Since 2013 nab-paclitaxel (paclitaxel-albumin-bound particles) became a new treatment option for patients with metastatic pancreatic cancer based on the results of MPACT trial. Moreover, encouraging activity in PDAC of the combination regimen of paclitaxel and carboplatin that is being widely used in other solid tumors has been reported recently. Biomarkers, including biomarkers predictive of taxane resistance, could allow individualized tailored therapy. BRCA mutation status could serve as predictor of better chemotherapy treatment outcome in PDAC. The present review summarizes the principal clinical trials evaluating the efficacy of taxanes both as monotherapy and in combination in view of the potential use in the treatment of PDAC.

4 Review Role of solute carrier transporters in pancreatic cancer: a review. 2014

Lemstrová, Radmila / Souček, Pavel / Melichar, Bohuslav / Mohelnikova-Duchonova, Beatrice. ·Department of Oncology, Palacky University Medical School & Teaching Hospital, Olomouc, Czech Republic. ·Pharmacogenomics · Pubmed #25084206.

ABSTRACT: Nucleoside analogs such as gemcitabine and 5-fluorouracil are currently the cornerstone of chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). Decreased drug transport into tumor cells that may be caused by low expression of membrane proteins, such as solute carrier transporters, represents one of the principal mechanisms of chemotherapy resistance. Individual diversity of multidrug resistance is the major challenge limiting the success of anticancer treatment. Novel biomarkers and pharmacogenomic approaches could further optimize treatment algorithms leading to better survival and lower treatment toxicity in PDAC patients. In this review, the most promising predictive biomarkers from the solute carrier transporter family of membrane transporters and the potential applications for PDAC therapy with nucleoside analogues are summarized.

5 Clinical Trial Phase 2 placebo-controlled, double-blind trial of dasatinib added to gemcitabine for patients with locally-advanced pancreatic cancer. 2017

Evans, T R J / Van Cutsem, E / Moore, M J / Bazin, I S / Rosemurgy, A / Bodoky, G / Deplanque, G / Harrison, M / Melichar, B / Pezet, D / Elekes, A / Rock, E / Lin, C / Strauss, L / O'Dwyer, P J. ·Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK. · Department of Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. · Princess Margaret Cancer, Toronto, Canada. · Federal State Budgetary Institution, Dubna, Russia. · Surgery, Florida Hospital, Tampa, Tampa, USA. · Oncology, St.László Teaching Hospital, Budapest, Hungary. · Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. · East and North Hertfordshire NHS Trust, Northwood, Middlesex, UK. · Department of Oncology, Lekarska Fakulta Univerzity Palackeho a Fakultni Nemocnice, Olomouc, Czech Republic. · CHU Estaing, Clermont-Ferrand, France. · Otsuka Pharmaceutical Development and Commercialization, Princeton. · Bristol-Myers Squibb Company, Princeton. · Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA. ·Ann Oncol · Pubmed #27998964.

ABSTRACT: Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate with limited treatment options. Gemcitabine provides a marginal survival benefit for patients with advanced PDAC. Dasatinib is a competitive inhibitor of Src kinase, which is overexpressed in PDAC tumors. Dasatinib and gemcitabine were combined in a phase 1 clinical trial where stable disease was achieved in two of eight patients with gemcitabine-refractory PDAC. Patients and methods: This placebo-controlled, randomized, double-blind, phase II study compared the combination of gemcitabine plus dasatinib to gemcitabine plus placebo in patients with locally advanced, non-metastatic PDAC. Patients received gemcitabine 1000 mg/m2 (30-min IV infusion) on days 1, 8, 15 of a 28-day cycle combined with either 100 mg oral dasatinib or placebo tablets daily. The primary objective was overall survival (OS), with safety and progression-free survival (PFS) as secondary objectives. Exploratory endpoints included overall response rate, freedom from distant metastasis, pain and fatigue progression and response rate, and CA19-9 response rate. Results: There was no statistically significant difference in OS between the two treatment groups (HR = 1.16; 95% confidence interval [CI]: 0.81-1.65; P = 0.5656). Secondary and exploratory endpoint analyses also showed no statistically significant differences. The burden of toxicity was higher in the dasatinib arm. Conclusions: Dasatinib failed to show increased OS or PFS in patients with locally advanced PDAC. Alternative combinations or trial designs may show a role for src inhibition in PDAC treatment.

6 Clinical Trial Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer. 2017

Van Laethem, Jean-Luc / Riess, Hanno / Jassem, Jacek / Haas, Michael / Martens, Uwe M / Weekes, Colin / Peeters, Marc / Ross, Paul / Bridgewater, John / Melichar, Bohuslav / Cascinu, Stefano / Saramak, Piotr / Michl, Patrick / Van Brummelen, David / Zaniboni, Alberto / Schmiegel, Wollf / Dueland, Svein / Giurescu, Marius / Garosi, Vittorio L / Roth, Katrin / Schulz, Anke / Seidel, Henrik / Rajagopalan, Prabhu / Teufel, Michael / Childs, Barrett H. ·Department of Gastroenterology, Erasme University Hospital, CP 572/10, route de Lennik 808, 1070, Brussels, Belgium. JL.VanLaethem@erasme.ulb.ac.be. · Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charity Hospital, Virchow-Klinikum Campus, Augustenburger Platz 1, 13353, Berlin, Germany. · Department of Oncology and Radiotherapy, Medical University of Gdansk, M. Skłodowskiej-Curie 3a Street, Gdansk, 80-210, Poland. · Department of Hematology and Oncology, University of Munich Medical Center, Marchioninistraße 15, 81366, Munich, Germany. · Department of Hematology and Oncology, Cancer Center Heilbronn-Franken, Am Gesundbrunnen 20-26, 74078, Heilbronn, Germany. · Division of Medical Oncology, University of Colorado Cancer Center, 1665 Aurora Ct, Aurora, CO, 80045, USA. · Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium. · Department of Medical Oncology, Guy's & St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK. · Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6DD, UK. · Department of Oncology, Palacky University Medical School and University Hospital Olomouc, Křížkovského 8, 771 47, Olomouc, Czech Republic. · Department of Medical Oncology, A.O.U. United Hospitals, Polytechnic University of Marche, Piazza Roma, 22, Ancona, Italy. · Department of Oncological Gastroenterology, Maria Skłodowska-Curie Memorial Cancer Center, ul. W.K. Roentgena 5, 02-781, Warsaw, Poland. · Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital of Giessen and Marburg, Baldingerstraße, 35043, Marburg, Germany. · Universitätsklinikum Halle - University Hospital Halle (Saale), Ernst-Grube-Straße 40, 06120, Halle (Saale), Germany. · Department of Radiotherapy, UZ Brussels, Avenue du Laerbeek 101, 1090, Brussels, Belgium. · Department of Medical Oncology, Poliambulanza Foundation Hospital Institute, Via Bissolati, 57, Brescia, Italy. · Department of Gastroenterology and Hepatology, Medical University Hospital Bochum, Alexandrinenstraße 1, Bochum, 44791, Germany. · Department of Oncology, Oslo University Radium Hospital, Trondheimsveien 235, Bjerke, 0514, Oslo, Norway. · Bayer Pharma AG, Müllerstraße 178, 13353, Berlin, Germany. · Bayer S.p.A., Viale Certosa 126-130, 20156, Milan, Italy. · Bayer HealthCare Pharmaceuticals, Inc., 100 Bayer Blvd, Whippany, NJ, 07981, USA. ·Target Oncol · Pubmed #27975152.

ABSTRACT: BACKGROUND: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. METHODS: Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. RESULTS: Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m CONCLUSION: Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.

7 Clinical Trial A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer. 2015

Deplanque, G / Demarchi, M / Hebbar, M / Flynn, P / Melichar, B / Atkins, J / Nowara, E / Moyé, L / Piquemal, D / Ritter, D / Dubreuil, P / Mansfield, C D / Acin, Y / Moussy, A / Hermine, O / Hammel, P. ·Department of Medical Oncology, Saint Joseph Hospital, Paris gdeplanque@hpsj.fr. · Department of Medical Oncology, University Hospital of Besançon, Besançon. · Department of Medical Oncology, University Hospital, Lille, France. · Metro-Minnesota Community Clinical Oncology Program, Park Nicollet Institute, Minneapolis, USA. · Department of Oncology, Palacký University Medical School & Teaching Hospital, Olomouc, Czech Republic. · Southeastern Medical Oncology Center, Goldsboro, USA. · Department of Clinical and Experimental Oncology, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland. · Department of Biostatistics, University of Texas School of Public Health, Houston, USA. · Clinical Development, Acobiom, Montpellier. · Signaling, Hematopoiesis and Mechanism of Oncogenesis, Inserm U1068, CRCM, Marseille Institut Paoli-Calmettes, Marseille Aix-Marseille University, UM 105, Marseille CNRS, UMR7258, CRCM, Marseille Clinical Development, AB Science, Paris. · Clinical Development, AB Science, Paris. · Clinical Development, AB Science, Paris Department of Clinical Hematology, Necker Hospital, Paris INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Paris Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris CNRS ERL 8254, Paris Laboratory of Excellence GR-Ex, Paris National Reference Center on Mastocytosis (CEREMAST), Paris. · Department of Gastroenterology, Hôpital Beaujon, Clichy, France. ·Ann Oncol · Pubmed #25858497.

ABSTRACT: BACKGROUND: Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. RESULTS: Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. CONCLUSIONS: The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00789633.

8 Clinical Trial A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. 2015

Fuchs, C S / Azevedo, S / Okusaka, T / Van Laethem, J-L / Lipton, L R / Riess, H / Szczylik, C / Moore, M J / Peeters, M / Bodoky, G / Ikeda, M / Melichar, B / Nemecek, R / Ohkawa, S / Świeboda-Sadlej, A / Tjulandin, S A / Van Cutsem, E / Loberg, R / Haddad, V / Gansert, J L / Bach, B A / Carrato, A. ·Department of Medical Oncology/Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston, USA charles_fuchs@dfci.harvard.edu. · Oncology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan. · Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium. · Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia. · Department of Hematology, Oncology, and Tumor Immunology, Charité University, Berlin, Germany. · Department of Oncology, Military Institute of Health Services, Warsaw, Poland. · Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Oncology, Antwerp University Hospital, Edegum, Belgium. · Department of Oncology, St László Hospital, Budapest, Hungary. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan. · Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc. · Department of Oncology, Masaryk University Medical School and Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan. · Department of Haematology, Oncology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland. · Department of Clinical Pharmacology and Chemotherapy, Russian Cancer Research Center, Moscow, Russia. · Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium. · Medical Sciences, Amgen Inc., Thousand Oaks, USA. · Global Biostatistical Science, Amgen Ltd, Cambridge, UK. · Global Development, Thousand Oaks. · Development Oncology Therapeutics, Amgen Inc., Thousand Oaks, USA. · Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain. ·Ann Oncol · Pubmed #25609246.

ABSTRACT: BACKGROUND: This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer. PATIENTS AND METHODS: Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers. RESULTS: Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months [95% confidence interval (CI), 6.3-8.2] in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm [hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494], and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77-1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed [insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3] were not associated with a treatment effect on OS or PFS by ganitumab. CONCLUSION: Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01231347.

9 Article Clinical Impact of Pancreatic Metastases from Renal Cell Carcinoma: A Multicenter Retrospective Analysis. 2016

Grassi, Paolo / Doucet, Ludovic / Giglione, Palma / Grünwald, Viktor / Melichar, Bohuslav / Galli, Luca / De Giorgi, Ugo / Sabbatini, Roberto / Ortega, Cinzia / Santoni, Matteo / Bamias, Aristotelis / Verzoni, Elena / Derosa, Lisa / Studentova, Hana / Pacifici, Monica / Coppa, Jorgelina / Mazzaferro, Vincenzo / de Braud, Filippo / Porta, Camillo / Escudier, Bernard / Procopio, Giuseppe. ·Medical Oncology 1, Fondazione IRCCS Istituto Nazionale Tumori, via G. Venezian 1, 20133, Milano, Italy. · Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · Medical Oncology, IRCCS San Matteo University Hospital Foundation, Viale Camillo Golgi, 19, 27100, Pavia, Italy. · Clinic for Haematology, Hemostasis, Oncology and Stemcelltransplantation, Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany. · Dept of Oncology, Palacký University Medical School and Teaching Hospital, I.P. Pavlova 6, 775 20, Olomouc, Czech Republic. · Medical Oncology 2, A.O.U.P., Istituto Toscano Tumori, via Roma 67, 56126, Pisa, Italy. · Dept of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, via P. Maroncelli 40, 47014, Meldola, Italy. · Dept of Oncology and Haematology and Respiratory Disease, University Hospital, Via del Pozzo 71, 41124, Modena, Italy. · Medical Oncology 1 - Candiolo Cancer Institute-FPO, IRCCS, Strada Provinciale, 142 km 3,95, 10060, Candiolo, Italy. · Medical Oncology, AOU Ospedali Riuniti, Università Politecnica delle Marche, Via Conca, 71, 60126, Ancona, Italy. · Dept of Clinical Therapeutics, Alexandra General Hospital, V. Sofias and Lourou 1 11528, Athens, Greece. · Medical Statistics, Trial Center, Fondazione IRCCS Istituto Nazionale Tumori, via G. Venezian 1, 20133, Milano, Italy. · Gastrointestinal Surgery and Liver Transplantation Unit, Fondazione IRCCS Istituto Nazionale Tumori, via G. Venezian 1, 20133, Milano, Italy. ·PLoS One · Pubmed #27064898.

ABSTRACT: Pancreatic metastases from renal cell carcinoma are uncommon and their prognostic significance is not well defined. In this analysis we evaluated the outcome of patients with pancreatic metastases treated with either targeted therapies or local treatment to the pancreas. Patients with pancreatic metastases from renal cell carcinoma treated between 1993 and 2014 were identified from 11 European centers. Clinical records were retrospectively reviewed. Kaplan-Meier method and log-rank test were used to evaluate progression-free survival and overall survival. Cox's proportional hazard models were used for survival analysis. In total, 276 PM patients were evaluated, including 77 (28%) patients treated by either surgery or radiotherapy to the pancreas, and 256 (93%) who received systemic therapy. Median time from nephrectomy to diagnosis of pancreatic metastases was 91 months (IQR 54-142). Disease control rate after first-line TTs was 84%, with a median progression-free survival of 12 months (95% CI 10-14). Median overall survival was 73 months (95% CI 61-86) with a 5-year OS of 58%. Median OS of patients treated with local treatment was 106 months (95% CI 78-204) with a 5-year overall survival of 75%. On multivariable analysis, nephrectomy (HR 5.31; 95%CI 2.36-11.92; p<0.0001), Memorial Sloan Kettering/International Metastatic RCC Database Consortium prognostic score (HR 1.45, 95% CI 0.94-2.23 for intermediate vs good vs risk; HR 2.76 95%, CI 1.43-5.35 for poor vs good risk p = 0.0099) and pancreatic local treatment (HR 0.48; 95%CI 0.30-0.78 p = 0.0029) were associated with overall survival. Difference in median OS between patients with PM and that reported in a matched-control group of mRCC patients with extrapancreatic metastases was statistically significant (p < .0001). Pancreatic metastases from renal cell carcinoma usually occur years after nephrectomy, are associated with an indolent behavior and a prolonged survival. Targeted therapies and locoregional approaches are active and achieve high disease control rate.

10 Article Human equilibrative nucleoside transporter 1 (hENT1): do we really have a new predictive biomarker of chemotherapy outcome in pancreatic cancer patients? 2013

Mohelnikova-Duchonova, Beatrice / Melichar, Bohuslav. ·Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic; Biomedical Centre, Faculty of Medicine in Plzen, Charles University in Prague, Plzen, Czech Republic. Electronic address: beatrice.mohelnikova@gmail.com. ·Pancreatology · Pubmed #24280569.

ABSTRACT: Although systemic chemotherapy significantly improves the overall survival of pancreatic cancer patients, the prognosis remains extremely poor. The development of a drug resistance, either de novo or induced resistance, significantly limits the effectiveness of chemotherapy. SLC29A1 gene encodes human equilibrative nucleoside transporter 1 (hENT1) protein that is mediating the transport of nucleotides, both purines and pyrimidines, into the tumor cells. The aim of this mini-review is to summarize the current information concerning the prognostic and predictive role of SLC29A1 transporter (hENT1) expression in pancreatic cancer. Increased expression of SLC29A1 in vitro has been described as a potential critical factor determining the sensitivity of pancreatic cancer cells to gemcitabine and 5-fluorouracil, the principal cytotoxic agents used in the treatment of pancreatic cancer. The reports on the relationship between SLC29A1 expression and prognosis of patients with pancreatic cancer are currently rather conflicting. However, majority of studies on patients with resected pancreatic cancer have suggested that high SLC29A1expression may be predictive of improved survival in patients treated with gemcitabine. SLC29A1 has not been shown to represent a predictive biomarker for patients treated by 5-fluorouracil. In conclusion, potential prognostic and predictive role of SLC29A1 has been demonstrated for selected subset of patients.

11 Article The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer. 2013

Mohelnikova-Duchonova, Beatrice / Brynychova, Veronika / Hlavac, Viktor / Kocik, Matej / Oliverius, Martin / Hlavsa, Jan / Honsova, Eva / Mazanec, Jan / Kala, Zdenek / Melichar, Bohuslav / Soucek, Pavel. ·Toxicogenomics Unit, National Institute of Public Health, Srobarova 48, Prague 10, Czech Republic. D.Beatrice@seznam.cz ·Cancer Chemother Pharmacol · Pubmed #23934321.

ABSTRACT: OBJECTIVES: The aim of this study was to investigate the prognostic significance of fourteen anticancer drug-relevant solute carrier transporters (SLCs) in pancreatic cancer in the context of clinical-pathological characteristics and the KRAS mutation status of tumors. METHODS: Tumors and non-neoplastic pancreatic tissues were obtained from 32 histologically verified patients with pancreatic ductal adenocarcinoma. The transcript profile of SLCs was assessed using quantitative real-time PCR. KRAS mutations in exon 2 were assessed by high-resolution melting analysis and confirmed by sequencing. RESULTS: SLC22A3 and SLC22A18 were upregulated and SLC22A1, SLC22A2, SLC22A11, SLC28A1, SLC28A3 and SLC29A1 were downregulated when compared with non-neoplastic pancreatic tissues. Moreover, significantly lower levels of SLC22A1, SLC22A11 and SLC29A1 were found in tumors with angioinvasion. There was also a significantly higher transcript level of SLC28A1 in tumors with regional lymph nodes affected by metastasis. The study found that a high expression of SLC28A1 was significantly associated with poor overall survival in unselected patients. In contrast, a high expression of SLC22A3 or SLC29A3 was significantly associated with longer overall survival in patients treated with nucleoside analogs. Protein expression of SLC22A1, SLC22A3 and SLC29A3 in tumor tissues of patients with pancreatic carcinoma was observed by immunoblotting for the first time. Finally, SLC levels were not found to be associated with KRAS mutation status in exon 2. CONCLUSIONS: This study identified a number of associations of transcript levels of SLCs with prognosis of pancreatic cancer patients.

12 Article [Pancreatic cancer surgery at Ist Surgical Clinic of the Olomouc Faculty Hospital (FN Olomouc)]. 2010

Lovecek, M / Neoral, C / Klos, D / Skalický, P / Kysucan, J / Vrba, R / Melichar, B / Svébisová, H / Tozzi di Angelo, I / Kliment, M / Havlík, R. ·I. Chirurgická klinika LF UP a FN Olomouc. ·Rozhl Chir · Pubmed #21404512.

ABSTRACT: INTRODUCTION: Surgical treatment plays a key role in the efforts to improve prognosis of patients with pancreatic cancer. The pancreatic cancer incidence rates are on increase and so does the number of patients undergoing potentially curative resection procedures. However, despite all diagnostic advancements and treatments adjusted to specific patient's needs, the outcomes are not satisfactory enough. The aim of the surgical procedure is to radically remove the tumor, including the regional lymph nodes, to promote early and uncomplicated healing and to facilitate early initiation of oncological treatment. AIM: The aim of the study was to assess current potential of diagnostic and surgical treatment in pancreatic cancer when all currently available diagnostic methods are emloyed and to present the university clinic's outcomes. METHODS AND PATIENT GROUP: From 2006 to IX 2010, a total of 177 pancreatic resections and 123 right-sided pancreatoduodenectomies for malignant disorders were performed at the authors' clinic. 76 pancreatoduodenectomies were performed for ductal carcinoma of the pancreatic head. The study group included 51 males and 25 females, the mean age of 62.9 years. Based on the TNM classification (UICC), 11% of the subjects presented with stage I, 78% with stage II and 3% with stage III diseases. The procedures radicality was the following: R0 in 59 subjects, R1 in 5 subjects while in 12 subjects, the radicality was undetected by the authors. Histopatological grading in this patient group was as follows: G1 in 20%, G2 in 34% and G3 in 46% of the subjects. Perineural invasion, invasion into lymphatic vessels or other vessels was not detected in 21 subjects (27.6%). The authors assessed complication rates based on the DeOliveira classification and survival rates in individual disease stages. OUTCOMES: Complications occurred in 44.7% of the operated subjects. Serious complications requiring reintervention were reported in 13 subjects (17.1%), including reinterventions in general anesthesia in 10 subjects (13.1%). Two patients died: a 79-year old female died from multiorgan failure as a result of aspiration, and a 76-year old male died from multiorgan failure following completion of pancreatectomy due to pancreaticojejunal anastomosis insufficiency. The thirty- and sixty-day mortality rate was 2.6%, however, it was null over the past three years. The mean survival time was 17.1 months, with the median of 13.5 months. The patient group's overall 3-, 6-, 9-, 12, 15- and 18- month survival following radical resections was 95.6%, 90.3%, 76.3%, 62.7%, 52.3% and 45%, respectively. 82%, 52%, 35% and 35% of the operated stage I patients survived 1, 2, 3 and 4 years, respectively. The mean hospitalization duration was 16.8 days (10-45). CONCLUSION: Although the procedures are extremely demanding, especially in the reconstruction phase, the outcomes have improved significantly due to ongoing experience, improvements in the surgical technique and in the complex postoperative care. At specialized clinics, the mortality rate has dropped below 5%, the morbidity rate below 40% and the postoperative dehiscence rates below 10%. During the past three years, the authors' clinic has reached null 30- and 60-day mortality rate following the pancreatic head resections, the complication rate following pancreaticoduodenal anastomosis is slightly above 5% (6.5%) and the morbidity rate is slightly above 40% (44.7%). The authors consider the procedure safe at their clinic and all indicated patients are expected to benefit from it.