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Pancreatic Neoplasms: HELP
Articles by Marina Macchini
Based on 13 articles published since 2010
(Why 13 articles?)
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Between 2010 and 2020, Marina Macchini wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives. 2019

Macchini, Marina / Chiaravalli, Marta / Zanon, Silvia / Peretti, Umberto / Mazza, Elena / Gianni, Luca / Reni, Michele. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Electronic address: reni.michele@hsr.it. ·Cancer Treat Rev · Pubmed #30414985.

ABSTRACT: By 2030 70% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) will occur in older adults. Elderly patients, defined by the World Health Organization (WHO) as people older than 65 years, represent a heterogeneous group with different biological and functional characteristics that need personalized anticancer treatments. Since older patients are under-represented in randomized phase III trials, their management is mostly extrapolated from studies performed in younger patients, without robust evidence-based recommendations. However, data from retrospective studies and case-control series show that elderly may benefit from chemotherapy in both the adjuvant and advanced disease settings. Although with discordant results, gemcitabine-based treatment and dose-adapted fluorouracil combination regimens seem to be effective and well tolerated in this subset of patients. A proper balance of potential treatment benefits and side effects represent the crucial point for managing elderly patients with PDAC. Therefore an appropriate patient selection is essential to maximize the therapeutic benefit in the older population: randomized studies aiming to better standardizing fitness parameters and implementing the routine use of comprehensive geriatric assessments are strongly warranted. In this light, the detection of molecular prognostic markers able to detect patients who may benefit more from oncological treatments should be a primary endpoint of age-focused clinical trials. Altogether, the field of geriatric oncology will expand in the next years, and the clinical management of elderly patients affected by PDAC will become a major public health issue.

2 Review State of the art biological therapies in pancreatic cancer. 2016

Di Marco, Mariacristina / Grassi, Elisa / Durante, Sandra / Vecchiarelli, Silvia / Palloni, Andrea / Macchini, Marina / Casadei, Riccardo / Ricci, Claudio / Panzacchi, Riccardo / Santini, Donatella / Biasco, Guido. ·Mariacristina Di Marco, Elisa Grassi, Sandra Durante, Silvia Vecchiarelli, Andrea Palloni, Marina Macchini, Guido Biasco, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy. ·World J Gastrointest Oncol · Pubmed #26798437.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival rate of approximately 5%. Several target agents have been tested in PDAC, but almost all have failed to demonstrate efficacy in late phase clinical trials, despite the better understanding of PDAC molecular biology generated by large cancer sequencing initiatives in the past decade. Eroltinib (a small-molecule tyrosine-kinase inhibitor of epidermal growth factor receptor) plus gemcitabine is the only schedule with a biological agent approved for advanced pancreatic cancer, but it has resulted in a very modest survival benefit in unselected patients. In our work, we report a summary of the main clinical trials (closed and ongoing) that refer to biological therapy evaluation in pancreatic cancer treatment.

3 Review Hedgehog signaling: from the cuirass to the heart of pancreatic cancer. 2012

Di Marco, Mariacristina / Macchini, Marina / Vecchiarelli, Silvia / Sina, Sokol / Biasco, Guido. ·L & A Seràgnoli Department of Hematology and Oncological Sciences, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. ·Pancreatology · Pubmed #22898642.

ABSTRACT: Exocrine pancreatic cancer is the fifth cause of cancer-related death in Europe and carries a very poor prognosis for all disease stages. To date no medical treatment has significantly increased patients' survival. One of the reasons for pancreatic cancer's chemoresistence is the complex tumor architecture: cancer cells are surrounded by a dense desmoplastic stroma that blocks drug delivery. Moreover, pancreatic cancer is characterized by a marked heterogeneity of cells, including cancer stem cells (CSCs) that act as tumor-initiating cells and hierarchically control the differentiated cancer cells. In particular, this subpopulation is resistant to classic cytotoxic therapies, and seems to be responsible for disease renewal. Hedgehog signaling (HH) is implicated in pancreatic gland development during embryogenesis and is reactivated during tumorigenesis and the maintenance of pancreatic cancer. Some studies demonstrated that the Hedgehog-secreted signaling proteins are overexpressed in both the stromal and CSCs pools, implying an abnormal activation of HH in the main compartment of pancreatic cancer. For this reason, the Hedgehog pathway could be an interesting target for clinical trials to increase drug concentration in neoplastic cells and hence deplete the stroma and directly kill tumor-initiating cells.

4 Review Metastatic pancreatic cancer: is gemcitabine still the best standard treatment? (Review). 2010

Di Marco, Mariacristina / Di Cicilia, Roberto / Macchini, Marina / Nobili, Elisabetta / Vecchiarelli, Silvia / Brandi, Giovanni / Biasco, Guido. ·L. e A. Seràgnoli Department of Hematology and Oncological Sciences, S. Orsola-Malpighi Hospital, University of Bologna, I-40138 Bologna, Italy. mariacristina.dimarco@unibo.it ·Oncol Rep · Pubmed #20372829.

ABSTRACT: Pancreatic ductal adenocarcinoma is the fourth cause of death in the Western world. Surgery remains the only treatment offering an advantage in terms of overall survival (5-year survival range, 15-25%), but unfortunately only 10-20% of patients present resectable disease at the time of diagnosis. Hence chemotherapy, possibly combined with radiation therapy, remains the only treatment option aimed at palliation of symptoms and ensuring a better quality of life. Notwithstanding the efforts to find more effective therapies for the treatment of pancreatic cancer, significant results have not yet been achieved. Increasing interest has focused on integrated treatments, i.e. chemotherapy combined with targeted therapies, and a better selection of patients. This study examines the principal clinical trials that will help give clinicians an overview of the progress made in the systemic therapy for advanced pancreatic cancer patients in recent years.

5 Clinical Trial Nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in metastatic pancreatic adenocarcinoma (PACT-19): a randomised phase 2 trial. 2018

Reni, Michele / Zanon, Silvia / Peretti, Umberto / Chiaravalli, Marta / Barone, Diletta / Pircher, Chiara / Balzano, Gianpaolo / Macchini, Marina / Romi, Silvia / Gritti, Elena / Mazza, Elena / Nicoletti, Roberto / Doglioni, Claudio / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Radiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Centre, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. ·Lancet Gastroenterol Hepatol · Pubmed #30220407.

ABSTRACT: BACKGROUND: Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. METHODS: This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18-75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m FINDINGS: Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58-86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31-63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. INTERPRETATION: Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. FUNDING: Celgene.

6 Clinical Trial A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma. 2018

Reni, Michele / Zanon, Silvia / Balzano, Gianpaolo / Passoni, Paolo / Pircher, Chiara / Chiaravalli, Marta / Fugazza, Clara / Ceraulo, Domenica / Nicoletti, Roberto / Arcidiacono, Paolo Giorgio / Macchini, Marina / Peretti, Umberto / Castoldi, Renato / Doglioni, Claudio / Falconi, Massimo / Partelli, Stefano / Gianni, Luca. ·Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Electronic address: reni.michele@hsr.it. · Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Department of Radiotherapy, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Department of Radiology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · Pathology Unit, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; Università Vita e Salute, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy; Università Vita e Salute, Milan, Italy. ·Eur J Cancer · Pubmed #30149366.

ABSTRACT: BACKGROUND: The current trial assessed whether the addition of cisplatin and capecitabine to the nab-paclitaxel-gemcitabine backbone is feasible and active against borderline and locally advanced pancreatic adenocarcinoma (PDAC). METHOD: Fifty-four chemo-naive patients, aged between 18 and 75 years, with a pathological diagnosis of locally advanced or borderline resectable PDAC were randomised to receive either nab-paclitaxel, gemcitabine, cisplatin and oral capecitabine (PAXG; arm A; N = 26) or nab-paclitaxel followed by gemcitabine (AG; arm B; N = 28). The primary end-point was the tumour resection rate. If at least four such resections were performed, the treatment was considered as active. The secondary end-points were progression-free survival (PFS), overall survival (OS), Response Evaluation Criteria in Solid Tumours response rate, Hartman's pathologic response, carbohydrate antigen 19.9 response rate and toxicity. RESULTS: Eight patients (31%) in the PAXG arm and nine (32%) in the AG arm underwent resection. PFS at 1-year was 58% in arm A and 39% in arm B. OS at 18-month was 69% in arm A and 54% in arm B. CONCLUSIONS: In this phase II study, the addition of cisplatin and capecitabine to the AG backbone was feasible and yielded promising results in terms of disease control without detrimental impact on tolerability. The approach warrants further investigation in a phase III study. TRIAL REGISTRATION: NCT01730222.

7 Article Time to CA19-9 nadir: a clue for defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma. 2020

Reni, Michele / Peretti, Umberto / Zanon, Silvia / Macchini, Marina / Balzano, Gianpaolo / Mazza, Elena / Tamburrino, Domenico / Orsi, Giulia / Arcidiacono, Paolo Giorgio / Falconi, Massimo / Gianni, Luca. ·Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy. reni.michele@hsr.it. · Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy. · Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy. · Università "Vita E Salute", Via Olgettina 58, 20132, Milan, Italy. ·Cancer Chemother Pharmacol · Pubmed #32157412.

ABSTRACT: BACKGROUND: Defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma (PDAC) receiving primary chemotherapy is an unmet need. The role of time to CA19-9 nadir and of nadir magnitude was explored in this study. PATIENTS AND METHODS: The databases of our institution's prospective trials were queried to speculate on the time to maximum chemotherapy response. Patients with pathologically proven, metastatic (N = 356) or non-metastatic non-resected (N = 163) PDAC and elevated baseline (> 34 UI/mL) CA19-9 were analyzed. Survival curves were estimated using the Kaplan-Meier method and compared by means of the log-rank test for analyses including at least 45 patients. Multivariable Cox proportional hazards model was used to estimate clinical features for their association with OS. All probability values were from two-sided tests. RESULTS: Time to CA19-9 nadir was ≥ 4 months in 184 of 346 (53%) metastatic and 121 of 163 (74%) non-metastatic patients (p = 0.002). The likelihood of a later nadir was higher with taxane-based chemotherapy as compared to taxane-free combinations (73% versus 56%; p = 0.02). Both metastatic and non-metastatic patients had significantly longer survival when nadir occurred later. Patients with a larger CA19-9 nadir magnitude had significantly longer survival. Metastatic patients with CA19-9 reduced by < 50%, 50-89%, or > 89% and had a median survival of 7.4, 9.8, and 14.7 months, respectively (p ≤ 0.001 for all comparisons). The corresponding figures for non-metastatic patients were 10.6; 17.0; and 18.7 months, respectively (p ≤ 0.02 for < 50% versus 50-89% or > 89%; p = 0.14 for 50-89% versus > 89%). Multivariable analyses showed that time to CA19-9 nadir but not CA19-9 nadir magnitude was independently predictive of survival. CONCLUSION: The present study suggests that a 4-6 months program might be a more suitable candidate for prospective assessment in comparison to shorter pre-defined period in patients who are candidates to surgery after primary chemotherapy.

8 Article Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. 2018

Renz, Bernhard W / Tanaka, Takayuki / Sunagawa, Masaki / Takahashi, Ryota / Jiang, Zhengyu / Macchini, Marina / Dantes, Zahra / Valenti, Giovanni / White, Ruth A / Middelhoff, Moritz A / Ilmer, Matthias / Oberstein, Paul E / Angele, Martin K / Deng, Huan / Hayakawa, Yoku / Westphalen, C Benedikt / Werner, Jens / Remotti, Helen / Reichert, Maximilian / Tailor, Yagnesh H / Nagar, Karan / Friedman, Richard A / Iuga, Alina C / Olive, Kenneth P / Wang, Timothy C. ·Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan. · Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. · Division of Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. · Department of Pathology, and Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. · Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan. · Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. · Biomedical Informatics Shared Resource of the Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, Columbia University Medical Center, New York, New York. · Department of Pathology and Cell Biology and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. · Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. tcw21@columbia.edu. ·Cancer Discov · Pubmed #30185628.

ABSTRACT: In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-

9 Article β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. 2018

Renz, Bernhard W / Takahashi, Ryota / Tanaka, Takayuki / Macchini, Marina / Hayakawa, Yoku / Dantes, Zahra / Maurer, H Carlo / Chen, Xiaowei / Jiang, Zhengyu / Westphalen, C Benedikt / Ilmer, Matthias / Valenti, Giovanni / Mohanta, Sarajo K / Habenicht, Andreas J R / Middelhoff, Moritz / Chu, Timothy / Nagar, Karan / Tailor, Yagnesh / Casadei, Riccardo / Di Marco, Mariacristina / Kleespies, Axel / Friedman, Richard A / Remotti, Helen / Reichert, Maximilian / Worthley, Daniel L / Neumann, Jens / Werner, Jens / Iuga, Alina C / Olive, Kenneth P / Wang, Timothy C. ·Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany; Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. · Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Internal Medicine III, Hospital of the University of Munich, 81377 Munich, Germany. · Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, 81377 Munich, Germany. · Institute for Cardiovascular Prevention, University of Munich, 80336 Munich, Germany. · Department of Internal Medicine and Surgery (DIMEC), Alma Mater Studiorum, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy. · Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Sant'Orsola-Malpighi Hospital, 40138 Bologna, Italy. · Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Medicine, University of Adelaide, Adelaide, SA 5005, Australia. · Department of Pathology, Hospital of the University of Munich, 81377 Munich, Germany. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu. ·Cancer Cell · Pubmed #29249692.

ABSTRACT: Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras

10 Article Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis. 2016

Westphalen, C Benedikt / Takemoto, Yoshihiro / Tanaka, Takayuki / Macchini, Marina / Jiang, Zhengyu / Renz, Bernhard W / Chen, Xiaowei / Ormanns, Steffen / Nagar, Karan / Tailor, Yagnesh / May, Randal / Cho, Youngjin / Asfaha, Samuel / Worthley, Daniel L / Hayakawa, Yoku / Urbanska, Aleksandra M / Quante, Michael / Reichert, Maximilian / Broyde, Joshua / Subramaniam, Prem S / Remotti, Helen / Su, Gloria H / Rustgi, Anil K / Friedman, Richard A / Honig, Barry / Califano, Andrea / Houchen, Courtney W / Olive, Kenneth P / Wang, Timothy C. ·Department of Internal Medicine III, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Experimental, Diagnostic and Specialty Medicine, Bologna University, 40128 Bologna, Italy. · Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich D-81377, Munich, Germany; Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology, Hospital of the University of Munich D-81377, Munich, Germany. · Department of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, OK 73104, USA. · Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar II, Technische Universität München, D-81675 Munich, Germany; Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA. · Division of Gastroenterology, Department of Medicine, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA. · Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Otolaryngology / Head & Neck Surgery, Columbia University Medical Center, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA; Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Center for Computational Biology and Bioinformatics (C2B2), Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. · Department of Digestive and Liver Diseases, Columbia University Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu. ·Cell Stem Cell · Pubmed #27058937.

ABSTRACT: The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer.

11 Article Characterization of pancreatic ductal adenocarcinoma using whole transcriptome sequencing and copy number analysis by single-nucleotide polymorphism array. 2015

Di Marco, Mariacristina / Astolfi, Annalisa / Grassi, Elisa / Vecchiarelli, Silvia / Macchini, Marina / Indio, Valentina / Casadei, Riccardo / Ricci, Claudio / D'Ambra, Marielda / Taffurelli, Giovanni / Serra, Carla / Ercolani, Giorgio / Santini, Donatella / D'Errico, Antonia / Pinna, Antonio Daniele / Minni, Francesco / Durante, Sandra / Martella, Laura Raffaella / Biasco, Guido. ·Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola‑Malpighi Hospital, Bologna I‑40100, Italy. · Interdepartmental Center of Cancer Research, Sant'Orsola‑Malpighi Hospital, Bologna I‑40100, Italy. · Department of Medical and Surgical Sciences, Sant'Orsola‑Malpighi Hospital, Bologna I‑40100, Italy. · Department of Digestive Diseases and Internal Medicine, Sant'Orsola‑Malpighi Hospital, Bologna I‑40100, Italy. · Liver and Multiorgan Transplant Unit, Sant'Orsola‑Malpighi Hospital, Bologna I‑40100, Italy. · Pathology Unit, Sant'Orsola‑Malpighi Hospital, Bologna I‑40100, Italy. ·Mol Med Rep · Pubmed #26397140.

ABSTRACT: The aim of the current study was to implement whole transcriptome massively parallel sequencing (RNASeq) and copy number analysis to investigate the molecular biology of pancreatic ductal adenocarcinoma (PDAC). Samples from 16 patients with PDAC were collected by ultrasound‑guided biopsy or from surgical specimens for DNA and RNA extraction. All samples were analyzed by RNASeq performed at 75x2 base pairs on a HiScanSQ Illumina platform. Single‑nucleotide variants (SNVs) were detected with SNVMix and filtered on dbSNP, 1000 Genomes and Cosmic. Non‑synonymous SNVs were analyzed with SNPs&GO and PROVEAN. A total of 13 samples were analyzed by high resolution copy number analysis on an Affymetrix SNP array 6.0. RNAseq resulted in an average of 264 coding non‑synonymous novel SNVs (ranging from 146‑374) and 16 novel insertions or deletions (In/Dels) (ranging from 6‑24) for each sample, of which a mean of 11.2% were disease‑associated and somatic events, while 34.7% were frameshift somatic In/Dels. From this analysis, alterations in the known oncogenes associated with PDAC were observed, including Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations (93.7%) and inactivation of cyclin‑dependent kinase inhibitor 2A (CDKN2A) (50%), mothers against decapentaplegic homolog 4 (SMAD4) (50%), and tumor protein 53 (TP53) (56%). One case that was negative for KRAS exhibited a G13D neuroblastoma RAS viral oncogene homolog mutation. In addition, gene fusions were detected in 10 samples for a total of 23 different intra‑ or inter‑chromosomal rearrangements, however, a recurrent fusion transcript remains to be identified. SNP arrays identified macroscopic and cryptic cytogenetic alterations in 85% of patients. Gains were observed in the chromosome arms 6p, 12p, 18q and 19q which contain KRAS, GATA binding protein 6, protein kinase B and cyclin D3. Deletions were identified on chromosome arms 1p, 9p, 6p, 18q, 10q, 15q, 17p, 21q and 19q which involve TP53, CDKN2A/B, SMAD4, runt‑related transcription factor 2, AT‑rich interactive domain‑containing protein 1A, phosphatase and tensin homolog and serine/threonine kinase 11. In conclusion, genetic alterations in PDCA were observed to involve numerous pathways including cell migration, transforming growth factor‑β signaling, apoptosis, cell proliferation and DNA damage repair. However, signaling alterations were not observed in all tumors and key mutations appeared to differ between PDAC cases.

12 Article Antiprotease strategy in pancreatic cancer treatment: emergence from a preclinical study. 2014

Brandi, Giovanni / Tavolari, Simona / Guarnieri, Tiziana / Di Marco, Mariacristina / Paterini, Paola / Macchini, Marina / Di Girolamo, Stefania / Papi, Alessio / De Rosa, Francesco / Biasco, Guido. ·From the *Department of Experimental, Diagnostic and Specialty Medicine, †"G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), and ‡Center for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi University Hospital; §Department of Biological, Geological and Environmental Sciences; and ∥Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy. ·Pancreas · Pubmed #24201777.

ABSTRACT: OBJECTIVES: Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells. METHODS: The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated. RESULTS: Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog. CONCLUSIONS: Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.

13 Unspecified Preoperative gemcitabine and oxaliplatin in a patient with ovarian metastasis from pancreatic cystadenocarcinoma. 2012

Di Marco, Mariacristina / Vecchiarelli, Silvia / Macchini, Marina / Pezzilli, Raffaele / Santini, Donatella / Casadei, Riccardo / Calculli, Lucia / Sina, Sokol / Panzacchi, Riccardo / Ricci, Claudio / Grassi, Elisa / Minni, Francesco / Biasco, Guido. ·Department of Hematology and Oncological Sciences 'L. & A. Seràgnoli', University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. ·Case Rep Gastroenterol · Pubmed #22949893.

ABSTRACT: We describe a case of clinical benefit and partial response with gemcitabine and oxaliplatin (GEMOX) in a young patient with ovarian metastasis from cystadenocarcinoma of the pancreas. A young woman complained of abdominal pain and constipation. Computed tomography (CT) and magnetic resonance imaging scans disclosed two bilateral ovarian masses with pancreatic extension. She underwent bilateral ovarian and womb resection. During surgery peritoneal carcinosis, a pancreatic mass and multiple abdominal lesions were found. The final diagnosis was mucinous pancreatic cystadenocarcinoma with ovarian and peritoneal metastases. She started chemotherapy with GEMOX (gemcitabine 1,000 mg/m(2)/d1 and oxaliplatin 100 mg/m(2)/d2 every 2 weeks). After 12 cycles of chemotherapy a CT scan showed reduction of the pancreatic mass. She underwent distal pancreatic resection, regional lymphadenectomy and splenectomy. Pathologic examination documented prominent fibrous tissue and few neoplastic cells with mucin-filled cytoplasm. Chemotherapy was continued with gemcitabine as adjuvant treatment for another 3 cycles. There is currently no evidence of disease. As reported in the literature, GEMOX is associated with an improvement in progression-free survival and clinical benefit in patients with advanced pancreatic cancer. This is an interesting case in whom GEMOX transformed inoperable pancreatic cancer into a resectable tumor.