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SHARED RESEARCH

RESOURCES

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scientific report 2012

cardiology

respiratory pathophysiology

clinical psychology

Medical statistics, Biometry, and Bioinformatics

tissue Bank

functional Genomics

cancer proteomics

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Shared Research Resources

HEADPatrizia Piotti, MD

CLINICAL RESEARCH STAFFPatrizia Greco, MDCostanza Mantovani, MDCarlo Materazzo, MDEnzo Viggiano, MD

POSTDOCTORAL FELLOWIryna Arendar, MD

NURSESSabrina Barrotta, Graziella Borlenghi, Maria N. Depetro, Rosella Murru, Luisa Sala

ADMINISTRATIVE PERSONNELMaria Grazia Marchetti, Rosanna Villani

cardioloGy

The Cardiology Unit is mainly concerned with the preoperative evaluation of surgical patients. Working in tight collaboration with anesthesiologists and thoracic and abdominal surgeons, the Units aims to reduce preoperative risk and manage complications. The Unit also provides evaluations and consultations for patients from the Fondazione IRCCS Istituto Neurologico C. Besta. Among the main duties of the Cardiology Unit are evaluation of the general cardiac status of all candidates for chemo-radiotherapy treatment to monitor potential cardiovascular toxicity related to antineoplastic treatments from early recognition to diagnosis and therapy. All of the Phase I, II, and III clinical studies carried out at INT require regular cardiologic surveillance to assess the cardiotoxicity of new experimental drugs (monoclonal antibodies, receptor tyrosine kinase inhibitors, BRAF inhibitors, MEK inhibitors).Keywords: preoperative evaluation, cardiotoxicity, experimental drugs

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respiratory patHopHysioloGy

HEADRoberto Boffi, MD

CLINICAL RESEARCH STAFFAlessandra Busia, MD

POSTDOCTORAL FELLOWSPaolo Pozzi, MD

Elena Munarini, Psy DChiara Marabelli, Psy D

TECHNICIANSMaria Chiricosta, Simona Montalti,

Fabio Valente

HEALTHCARE ASSISTANTSara Santoro

ADMINISTRATIVES PERSONNELMaria Grazia Marchetti, Rosanna Villani

The Unit provides a broad range of respiratory consultations as well as pulmonary function tests such as:• Spirometry• Body plethysmography• Lung transfer of carbon monoxide (TLCO)• Cardiopulmonary excercise test (CPET)• Pulse Oximetry The inpatient activity is mainly focused on:• Preoperative evaluation of patients planned for thoracic surgery

(lobectomy, bilobectomy, pneumonectomy, wedge resections, thoracectomy, mediastinoscopy)

• Short- and long-term follow-up of pulmonary toxicities due to chemotherapy (especially bleomycin) and/or radiotherapy

• Pharmacological aid to smoker inpatients• Healthcare associated pneumonia and/or pulmonary graft-versus-host diseaseThe outpatient activity is focused on:• Asthma and COPD patients• Interstitial lung diseases and evaluation of sarcoidosis• Smoker outpatients with a dedicated anti-tobacco clinic.The clinical research activity stems from productive collaborations with different cooperative groups:• Department of Predictive and Preventive Medicine (pharmacogenetic of

smoking cessation drugs)• Thoracic Surgery (smoking cessation within a lung cancer screening trial)• Clinical Psycology (smoking cessation counselling for inpatient smokers)• Società Italiana di Medicina Generale (indoor and outdoor pollution

from cigarette smoke).In 2012, the Unit carried out 4539 inpatient and 8320 outpatient pneumological visits and pulmonary function tests.Keywords: pulmonary function tests, anti-tobacco clinic, pulmonary toxicity

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clinical psycHoloGyThe mission of the Clinical Psychology Unit is to support patients living with life-threatening illness, along with their families. The Unit aims to improve their quality of life and well-being, and relieve mental suffering throughout the course of illness and survivorship. Psycho-Oncology covers the whole range of mental and emotional difficulties related to cancer, stimulates research, and develops training so that psychosocial care may be integrated with clinical oncology specialties for holistic patient care. The clinical activity includes: psychological assessment, individual psychological counseling, short psychotherapies, family therapies, and psycho-educational groups. During 2012, our psychologists treated over 4500 outpatients. The following psycho-educational initiatives were run: a) the Ulysses program, which involves patients and their relatives in educational and psychological support groups; b) stress management training and relaxation imagery groups; c) touch therapy groups; d) meaning oriented groups. The “Ambulatorio Giocoparola”, created with the aim to give ill parents support in communicating with their children about the disease, continued its activity. Collaboration with other clinical units on specific issues included: • Multidisciplinary clinical project to support cancer patients undergoing

liver transplant surgery in collaboration with the Liver Transplantation Unit. • Multidisciplinary clinical project to support decision-making in BRCA1/2

carriers in collaboration with the Medical Genetics Unit • Clinical decision making counseling, psychological support, and psycho-

sexual counseling for prostate cancer patients in collaboration with the Prostate Program

• The multidisciplinary smoking cessation project for inpatients in collaboration with the Tobacco Control Laboratory.

Our research aims to assess the subjective impact of cancer and cancer treatments on patients’ quality of life and the psychosocial aspects related to the various phases of the oncological disease.Keywords: psycho-oncology, psychosocial support, quality of life

HEADClaudia Borreani, Psy D

CLINICAL RESEARCH STAFFSilvia Bettega, Social WorkerMarco Bosisio, Psy DLaura Gangeri, PsycoPedagogistMargherita Greco, Psy DMicaela B. Lina, Psy DLuciana Murru, Psy DPatrizia Trimigno, Psy D

FELLOWElisabetta Bianchi, PsyD

STATISTICIANCinzia Brunelli

ADMINISTRATIVE PERSONNELTeresa M. Cariglia

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HEADAdriano Decarli, PhD

RESEARCH STAFFElia Biganzoli, PhD

Sara Pizzamiglio, MScPaolo Verderio, Biol Sci D, PhD

POSTDOCTORAL FELLOWSIlaria Ardoino, PhD

Matteo Malvezzi, PhD

PHD STUDENTSNicola BassaniAnnalisa Orenti

FELLOWChiara M. Ciniselli, MSc

ADMINISTRATIVE PERSONNELMaria C. Piano

Medical statistics, BioMetry, and BioinforMatics

The Medical Statistics, Biometry, and Bioinformatics Unit (MSBB) provides quantitative support to research activity across various Departments at INT. Moreover, MSBB maintains collaborative relationships with other national or international research groups. The INT group activity is governed by a convention with the University of Milan. Biostatistics for Oriented Basic Research and Quality Control (Paolo Verderio) The team applies statistical methods to different phases of the biomarker development process in oncology. Specifically, it provides implementation and statistical analysis of quality control studies for tumor biomarkers and in vitro diagnostic tools; studies for the evaluation of inherited diseases in oncology; studies for setting up and validation of biological

assays; studies for preclinical pharmacology and testing new molecular detection strategies based on innovative technologies. As partner of the FP7 EU Project SPIDIA (standardization and improvement of generic pre-analytical tools and procedures for in vitro diagnostics), the team is currently involved in the planning, implementation, and statistical analysis of ring trials, and also contributes to the setup and validation of biological assays and testing new molecular detection strategies based on innovative technologies.Biostatistics for Bioinformatics and Translational Research (Elia M. Biganzoli) In the context of analytical molecular epidemiology, the team supports the transfer of basic preclinical research to clinics, using quantitative approaches to assess the impact of new technologies in oncology according to cost-benefit principles and sustainability perspectives. Within the framework of collaborative projects, our teams are involved in research concerning the assessment of high-throughput and next generation sequencing platforms for DNA and RNA analysis, qRT-PCR, and high-throughput assays in cancer. Statistical bioinformatics research also supports the design and analysis of NGS experiments. Studies on follow-up data with reference to the analysis of risk patterns related to metastatic dormancy are conducted in cooperation with clinical units. Elia M. Biganzoli is the PI of the 2012 AIRC project “Statistical Tools for Prognosis and Prediction in Cancer: Assessments and Application to a Sarcoma Case Series”.Keywords: quality control, tumor biomarkers, biological assays, risk prediction methods,

high dimensional data methods

CliniCal EpidEmiology and Trial organizaTion

In 2012, the Unit provided statistical support to 129 research projects (mainly in the areas of surgical, medical or hematological oncology), 96 of which were launched in 2012. A total of 15 articles were published.Keywords: biostatistics, study design, data analysis

HEADLuigi Mariani, MD, PhD

RESEARCH STAFFRosalba Miceli, PhD

TECHNICIANSalvatore LoVullo, BSc

ADMINISTRATIVE PERSONNELMaria C. Piano

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Since 2002, the Tissue Bank Facility of INT has been dedicated to the collection and distribution of neoplastic, preneoplastic, and normal tissues from human subjects for research projects. This resource is a project of INT Scientific Directorate, with day-to-day staff supervision provided by personnel from the Departments of Pathology and Experimental Oncology & Molecular Medicine. The activities are overseen by an interdepartmental advisory committee, which also evaluates and approves research projects depending on the availability of tissue specimens. Adopting TUBAFROST procedures, although slightly modified to comply with local conditions, the INT Tissue Bank stores frozen samples (primary and metastatic lesions, with corresponding normal tissues) and contributes specimens to a large number of specific research projects dealing with almost all tumor types.All patients/subjects sign an informed consent document (approved by the Independent Ethics Committee and filed in the patients’ record) to donate leftover tissue/biological specimens from diagnostic procedures to the INT Tissue Bank for future studies. It is a one-time general consent with a two-step decision process that allows patients to control the use of their samples and foster important research. At the time of surgical and/or medical procedures, patients are told how samples and health information will be obtained, what risks future research can pose to them, and whether the research will have any impact on their clinical care. They can choose whether their samples and associated information may or may not be used for future research, relying on an Independent Ethics Committee for the approval of biologically and/or clinically relevant studies. Alternatively, patients are contacted repeatedly and asked for study specific authorization for the use of biological samples and associated personal information. Guidelines have been proposed to define responsibilities for Tissue Bank management, policies, and procedures to protect patient confidentiality and privacy, and establish priorities for specimen distribution. A survey carried out on about 4000 informed consent forms showed that reliable and consistent responses were obtained in 80% of cases: 95% of patients support future research use of their biological samples, with a request to be repeatedly contacted in only 3% of cases.In 2012, the INT Tissue Bank stored frozen specimens from 1256 new cases (including 94 benign lesions), and in parallel the collection of blood specimens (stored as whole blood, serum, plasma, and buffy coats) was started. Dr Daidone was involved by the Lombardy Region in the technical group developing regulatory guidelines for research biobanks and by the AIOM-SIAPEC (the Italian Association of Medical Oncologists and the Italian Society of Pathology and Diagnostic Cytology) for the collaborative drawing-up of a national-policy document dealing with different items related to research biobanking for oncology (i.e. definitions, aims, governance, infrastructure and technical requirements, informed consent, privacy, and access rules).

DIRECTORSGiuseppe Pelosi, MDMaria Grazia Daidone, Biol Sci D, PhD

RESEARCH STAFFSilvia Veneroni, Biol Sci D

TECHNICIANSAntonio ScavoFrancesco PastoreGloria Morandi

tissue Bank

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HEAD Silvana Canevari, Bio Sci D

RESEARCH STAFF Marina Bagnoli, Biol Sci DVera Cappelletti, Biol Sci DLoris De Cecco, Biol Sci DRosaria Orlandi, Biol Sci D

Maria Luisa Sensi, Biol Sci D

POSTDOCTORAL FELLOWSMaurizio Callari, Biotech D, Bioinformatician

Gaetano De Feo, Biol Sci DMatteo Dugo, Biotech D, Bioinformatician

Patrizia Pinciroli, Biol Sci D

TECHNICIANSEdoardo Marchesi

Donata Penso

functional GenoMics and BioinforMaticsThe activities of the Functional Genomics and Bioinformatics core facility are conducted using the following instruments: QIAcube for nucleic acid purification; Agilent Bioanalyzer, Nanodrop, Qubit for quantity and quality control of nucleic acids; Illumina and Agilent platforms for microarray analysis of mRNA expression, miRNA and lncRNA expression, ChIP-on-chip, DNA methylation, CGH and CNV, SNPs; Quantstudio 12K for quantitative real-time PCR; automated liquid handling MultiProbe II; Next Generation Sequencing SOLiD™ 5500xl Wildfire and 3130 Sequencer for Sanger Sequencing; dedicated servers, work-stations, and up-to-date software, hardware and web-based databases. The research group comprises full time personnel involved in wet analyses and personnel dedicating part of their institutional activity to computational analysis of wet and in silico data.The core facility performs: study design; RNA and DNA extraction and quality controls; all the labeling and hybridization methodologies required for high quality analysis; data processing and statistical analysis. Full computational analyses are performed using open-source software (such as R-Bioconductor, BRB, GSEA, MAGIA, Cytoscape) and dedicated licenses (such as IPA for candidate protein interactions and Gene Spring). Identification and bio-functional interpretation of promising biomarkers are based on differential expression analysis, pathway analysis with over-representation or gene set enrichment approaches (GO and GSEA), and integration of different kinds of data. This facility also provides certification of identity of cell lines adhering to ATCC guidelines and processing samples on a 3130 capillary genetic analyzer.During 2012, more than 2500 samples from experimental and clinical studies were analyzed for: whole genome expression; Illumina DASL assay (cDNA-mediated annealing, selection, extension and ligation); miRNA whole expression. Other ongoing activities in collaboration with

different research INT Units and with the support of the Statistics Unit include: establishment of specific methodologies for gene and miRNA expression and next generation sequencing; definition of computational methodologies for miRNA expression normalization and time course analyses; information and formation of INT personnel through dedicated seminars.Keywords: next generation sequencing,

RNA and DNA analysis

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cancer proteoMics The laboratory uses proteomics to analyze cell lines, tissue biopsies, and biofluid samples. A combination of proteomics profiling - aimed to characterize as many proteins as possible from cell line secretomes, body fluids, or extracts - and bioinformatic analyses allow us to reveal critical biological information. Our studies suggest new tumor classification strategies and lines of therapeutic intervention. • A large number of low-abundance proteins were identified in cerebrospinal

fluids from pediatric patients with a central nervous system tumor using highly sensitive mass spectrometry-based methods (in collaboration with the Pediatric Unit, the Unit of Medical Statistics and Biometry and the Center for Applied Proteomics and Molecular Medicine, GMU, Manassas, Virginia, US). In addition to cataloging proteins, the analytical approach and statistical workflow we created has the potential to improve the accuracy of patient classification.

• An iron metabolism-related biomarker in plasma useful for breast tumor classification was detected in collaboration with the Biomarkers and Molecular Targets Units at DOSMM and the Medical Statistics and Biometry Unit. The study also suggested that mass-spectrometry-based protein profiling may be an important tool for identifying breast cancer biosignatures in plasma.

• A strategy for multidimensional data integration was devised to produce genotype-phenotype relationships in Wilms’ tumors (in collaboration with the Pediatric Unit and the Molecular Bases of Genetic Risk and Genetic Testing Unit). These studies aim to better understand pathway-related genes and proteins associated with poor prognosis.

• The effects of targeting MIF/CD74 signaling axis in thyroid cancer have been studied in collaboration with the Department of Diagnostic Pathology and Molecular Medicine at the INT. The results clearly indicated that MIF/CD74 is an important pro-survival axis that sustains the activation of ERK1/2.

Keywords: mass spectrometry, cancer biomarkers, human fluids,

signaling pathways, targeted therapy

HEADItalia Bongarzone, Biol Sci D

POSTDOCTORAL FELLOWSDario Caccia, Biotech Med D, PhDRuben Magni, Biotech Med D, PhD

TECHNICIANSMaida De Bortoli

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