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  2. 2. The Department of Diagnostic Imaging and Radiotherapy is made up of seven Divisions and a number special units have been established within these Divisions: the Magnetic Resonance Unit in Diagnostic Radiology 1, the Computed Tomography Unit and the Intralesional Treatment Unit in Diagnostic Radiology 2, the Breast Imaging Unit and the Diagnostic and Interventional Gastroenterology Unit in Diagnostic Radiology 3, the Clinical PET Unit and the Radiometabolic Therapy and Endocrinology Unit in Nuclear Medicine. The technologies in the area of diagnostic imaging (diagnostic radiology and nuclear medicine) provide not only morphologic information but also functional parameters. The daily activity related to cancer patients is structured in different steps: diagnosis of primary cancer, characterization, staging and restaging, treatment monitoring, and posttreatment follow-up. Besides diagnostic procedures, a large part of the activity of the Department is dedicated to cancer treatment. MRI research is carried out in different fields: monitoring response to therapy, investigating patients with a high genetic risk of cancer, and developing software for imaging elaboration and quantitation. Interventional radiology is an essential component of the scientific culture of INT and several trials are dedicated to central venous catheter placement, embolization and chemoembolization for regional cancer treatment, and new approaches with radiofrequency ablation. A multi- institutional lung cancer screening program with low-dose spiral CT has involved Diagnostic Radiology Division. The Breast Imaging Unit is conducting studies on the surveillance of young women who previously underwent radiation therapy and on the early diagnosis of breast cancer in women with a genetic predisposition. New diagnostic modalities such as elastosonography, a novel noninvasive technique, are under evaluation. The Interventional Gastroenterology Unit performs procedures such as percutaneous gastrojejunostomy, transluminal drainage of fluid collection, balloon HEADS OF DIVISION AND UNIT Daniele Vergnaghi, MD Radiology and Diagnostic Imaging 1 & Magnetic Resonance Unit Alfonso Marchianò, MD Radiology and Diagnostic Imaging 2 & Computed Tomography Unit Francesco Garbagnati, MD Intralesional Treatment Unit Silvana Bergonzi, MD Radiology and Diagnostic Imaging 3 & Breast Imaging Unit Guido Cozzi, MD Diagnostic and Interventional Gastroenterology Unit Emilio Bombardieri, MD Nuclear Medicine Ettore Seregni, MD Nuclear Medicine Therapy and Endocrinology Unit Flavio Crippa, MD Clinical PET Unit Patrizia Olmi, MD Radiotherapy 1 Carlo Fallai, MD Radiotherapy 2 Renato Marchesini, Physics D Medical Physics DIAGNOSTIC IMAGING & RADIOTHERAPY 169 DIRECTOR OF DEPARTMENT Emilio Bombardieri, MD phone number: +39 02 2390 2220 e-mail: emilio.bombardieri@istitutotumori.mi.it
  3. 3. SCIENTIFIC REPORT 2008170 dilatation of stenoses, and palliative stenting. The Nuclear Medicine Division contributes to research activity with high technology modalities like PET/CT to image and better characterize cancer and develop new radiopharmaceuticals (positron- emitting products and radiolabeled peptides and antibodies). These radiopharmaceuticals are selective for tumor targeting and also for delivering “killer” radiation energy to the tumor mass by the administration of high activities of specific radioactive bullets. Dosimetric studies are of major interest in this area since the final goal of these efforts is to provide physicians with quantitative data about the absorbed dose to healthy organs (dose sparing) and tumor lesions (dose optimization to the target). External beam radiation therapy is focused on organ and function preservation, with the aim to deliver a higher total dose to the tumor and spare normal tissues as much as possible. In the Radiation Therapy Division this is obtained by techniques like 3D-conformal stereotactic intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), and brachytherapy with low and high dose rates. The newly acquired linear accelerators permit both online and offline treatment verification, which is especially needed for sophisticated techniques like IMRT and IGRT. High dose rate brachytherapy is also used in uterine cancer, biliary tract cancer and breast cancer. Several trials are addressing pediatric tumors. Research is ongoing on patients with bone metastases and solid tumors (thyroid cancer, rectal cancer, prostate cancer, soft tissue sarcomas, head and neck cancer). The Medical Physics group carries out studies on natural fluorescence spectroscopy of human blood plasma for cancer detection, and simulation of skin and melanocytic lesions with a melanoma-like phantom, mimicking the clinical decision-making related to pigmented skin lesions and implementation of the brachytherapy facility. This summary demonstrates that multidisciplinary interests continue to stimulate clinical studies and basic research, and this is due to the heterogeneity and interaction of the many components of the Department.
  4. 4. DIAGNOSTIC IMAGING & RADIOTHERAPY 171 In 2008 RD1 carried out 10,956 MRI scans and 36,529 conventional radiologic examinations (chest, general bone, contrast radiology of kidney and urinary system). MRI was used for the diagnosis of primary cancer, tumor staging, treatment monitoring, and follow-up. The following new methodologies were improved: - DCE-MRI (dynamic contrast-enhancement magnetic imaging) - Diffusion technology - Perfusion technology - Spectroscopy of prostate cancer and of breast cancer - Magnetic resonance urography and magnetic resonance cholangiopancreatography and new technologies were established: - Total body imaging - MRI-guided breast biopsy. The research activity was focused on several institutional projects on: • Multicenter surveillance of women with a high genetic or familial risk of breast cancer (in collaboration with the Istituto Superiore Sanità, Rome); • Prostate project on the study of patients by means of diffusion and DCE-MRI evaluation and spectroscopy performed with endocoil; • DCE-MRI applied to the evaluation of tumor response to specific treatments carried out in some of the clinical Units. RD1 continued its collaboration with the Department of Biomedical Engineering of the Polytechnic of Milan aimed at developing software for image elaboration. In detail, a project to evaluate the accuracy of both DCE-MRI and diffusion MRI for the diagnosis of rectal cancer relapse was developed. The project on prostate DCE-MRI achieved a high level of development. RD1 collaborated with several clinical Units of the Institute in order to integrate diagnostic imaging with clinical information and to monitor the response of primary cancer to traditional and novel treatment strategies. The radiologists worked in close RADIOLOGY AND DIAGNOSTIC IMAGING 1 THE DIVISION OF DIAGNOSTIC RADIOLOGY 1 (RD1) INCLUDES THE UNIT OF MAGNETIC RESONANCE IMAGING (MRI). THE DIRECTOR OF DIAGNOSTIC RADIOLOGY IS ALSO THE HEAD OF THE MRI UNIT. HEAD OF DIVISION Daniele Vergnaghi, MD STAFF MEMBERS Alberto Laffranchi, MD; Paolo Potepan, MD; Giovanna Trecate, MD; Antonella Messina, MD; Davide Scaramuzza, MD RADIOLOGY TECHNICIANS Valeria Tosi, RT; Carmelina Pannone, RT; Cinzia Fossaceca, RT; Tina Mastrostefano; Antonella Laturra, RT; Nicola Pulerà, RT; Maurizio Zattoni, RT; Annunziata Gaetano, RT; Luca Musumeci, RT
  5. 5. SCIENTIFIC REPORT 2008172 cooperation with the physicians of the Soft Tissue Sarcoma Unit, Pediatric Oncology Unit, Colorectal Surgery Unit, and Head and Neck Unit. The most relevant interest of the Division lies in the area of breast disease, with more than 650 breast MRI examinations performed each year. An experience spanning nearly 20 years makes the Division a national reference center for breast cancer. Important results were obtained in patients at high genetic risk for breast cancer and in patients previously submitted to plastic and reconstructive surgery. FIGURE 1 Total Body Imaging a) T1 W image b) T2 W fat sat c) Fusion image between T1 morfological e diffusion images. Arrows point pathologic tissue due a myeloma disease.
  6. 6. DIAGNOSTIC IMAGING & RADIOTHERAPY 173 RD2 makes use of ultrasonography (US), computed tomography (CT), multifunctional fluoroscopy and digital angiography. Diagnostic oncology and interventionally-oriented radiology represent the daily activity. Inpatients and outpatients with cancer undergo a diagnostic workup, including the different steps of patient management: primary diagnosis, staging, follow-up and monitoring after surgical, chemotherapeutic and/or radiotherapeutic treatment. The interventional radiology activity includes long-term central venous catheter placement, infusion chemotherapy, nutritional support, and infusional support. The selection and follow-up of candidates for liver transplantation are on the way, including perioperative standby for emergency diagnostic procedures related to transplant salvage. All kinds of percutaneous biopsies are currently carried out. During 2008, 1,133 diagnostic vascular procedures, 313 interventional vascular procedures, about 500 long-term central venous catheter placements, 254 nonvascular interventional procedures, and a total of 495 percutaneous biopsies in various body districts were performed. A total of 7,500 US examinations were carried out. Two CT scanners are available, both with fast multislice scanning capacity. About 22,000 diagnostic examinations per year and a substantial number of interventional radiologic procedures are carried out. The Division has set up a study on percutaneous cryoablation in selected patients with small renal masses. The initial results in about 20 patients show a very good tolerability of the procedure and excellent preliminary responses. RD2 has developed several protocols dealing with embolization and chemoembolization for regional cancer treatment. The main fields of interest are primary liver cancer, liver metastases, and head and neck cancer. An international RADIOLOGY AND DIAGNOSTIC IMAGING 2 WITHIN THE DIVISION OF DIAGNOSTIC RADIOLOGY 2 (RD2), TWO SPECIAL UNITS FOR SPECIFIC ACTIVITIES HAVE BEEN ESTABLISHED: THE UNIT OF COMPUTED TOMOGRAPHY AND THE UNIT OF INTRALESIONAL TREATMENT WITH RADIOFREQUENCY. THE DIRECTOR OF THE RD2 DIVISION ALSO LEADS THE UNIT OF COMPUTED TOMOGRAPHY. HEAD OF DIVISION Alfonso Marchianò, MD STAFF MEMBERS Francesco Garbagnati, MD; Enrico Civelli, MD; Giuseppe Di Tolla, MD; Laura F. Frigerio, MD; Rodolfo Lanocita, MD; Carlo Morosi, MD; Carlo Spreafico, MD CONSULTANTS Bruno Damascelli, MD Gianluigi Patelli, MD RADIOLOGY TECHNICIANS Pietro Basile; Marilena Barbiero; Maria Ferrarello; Roberto Gallo; Giuseppina Gentile; Ester Mazzarella; Roberto Nioi; Geremia Porcelli (Radiogy Technicians' Coordinator); Salvatore Romaniello; Luciana Tanzini
  7. 7. SCIENTIFIC REPORT 2008174 multicenter study on the treatment of inoperable hepatocellular carcinoma with intraarterial injection of radiolabeled microspheres is ongoing in collaboration with the Divisions of Nuclear Medicine and Gastrointestinal and Hepatopancreatobiliary Surgery & Liver Transplantation. Over 50 patients have been successfully treated with microspheres. Alternative approaches with radiofrequency ablation and intraarterial chemotherapy are proposed for primary and secondary liver cancer when other conventional treatments are not possible. An innovative approach to control recurrence of glioblastoma using intraarterial infusion of liposomal doxorubicin has been approved and launched by INT and the Carlo Besta Neurologic Institute of Milan. A multicenter observational clinical project with retrievable vena cava filters for pulmonary embolism control in cancer patients is ongoing. RD2 staff offers teaching courses and practical demonstrations to medical and nursing staff. A study of central vein high-flow contrast injection through implanted infusional devices in cancer patients has been activated. The aim of this clinical study is to exploit the use of implanted central venous catheters or ports (currently used only for chemotherapy and intravenous systemic support), thereby improving CT image quality for cancer detection and staging, and treatment monitoring. The lung cancer screening program (MILD) with low-dose spiral CT continued in 2008. We performed over 5,000 low-dose spiral CT scans and are testing the prerelease of a commercial system for computer-aided detection (CAD) of pulmonary nodules. We have published a first report in Radiology on the assessment of in vivo precision volumetric analysis and the estimation of the growth rate of small pulmonary nodules. We are going to compare the performance of radiologists with or without the aid of the CAD system for pulmonary nodule detection. A new screening program is planned for the early detection of kidney cancer. Screening will be done with noninvasive techniques such as ultrasonography. People in the 50- to 60-year age group living in the Lombardy region will be enrolled. Intralesional Treatment (Head of Unit: F. Garbagnati) In 1989 we started a research project to evaluate the possibility to treat inoperable liver tumors with minimally invasive thermoablation procedures. To date we have treated about 770 patients, most of whom suffering from inoperable liver tumors and some having kidney, lung or bone neoplasms. FIGURE 2 Improving CT imaging in oncology. High flow contrast medium injection through implantable infusional devices. Illustrative example. Right small-cell lung cancer. Superior vena cava injection at 5 mL/sec through PowerPort allows 3 dimensional (3D) volume rendering (VR) reconstruction.
  8. 8. DIAGNOSTIC IMAGING & RADIOTHERAPY 175 FIGURE 3 8 cm HCC treated in one session RFTA during arterial stop flow with embolization. The pictures demonstrate TC evaluation of the HCC pre treatment (first image), the stop flow angiographic procedures, TC evaluation during 3 years follow with the complete necrosis of the HCC reduced in volume. After colecistectomy (calcolotic colecistitis) it has been resected also the hepatic residual nodule (last picture) with the anatomopathological evidence of a complete necrosis. In 2008 we used intralesional radiofrequency therapy, simple or combined with arterial stop flow, in one treatment session in 70 patients with hepatocellular carinomas with a maximum diameter of 10 cm. We are collaborating with the Universities of Milan and Pavia to evaluate new procedures and new technical possibilities. The combination of intralesional radiofrequency therapy and arterial stop flow in large hepatocellular carcinomas is very effective and in one session it is possible to treat tumors with a 10- cm diameter during a one-day hospitalization (Figure 3). Being part of RD2, the Intralesional Treatment Unit can benefit from the experience of the interventional radiology staff and collaborate with all clinical and surgical Units to treat unresectable tumors in the best way possible. The Intralesional Treatment Unit also has the capacity to evaluate clinical results by means of radiodiagnostic procedures with a highly precise intralesional approach utilizing radiologic guidance. Ultrasound, CT and angiography procedures in association with intralesional thermoablation techniques can significantly improve treatment results. With the Department of Biomedical Physics of the Milan Polytechnic we are evaluating the quantitative assessment of radiofrequency ablation of liver lesions by means of dedicated software using CT image processing.
  9. 9. SCIENTIFIC REPORT 2008176 Diagnostic oncology and interventional radiology represent the daily activities of the staff members. In 2008 about 39,000 diagnostic and interventional procedures were performed. The two units share their technologists, while each unit has its own radiologists with specific qualifications and expertise. The activity of the Breast Imaging Unit consists mostly of clinical mammography and breast ultrasound studies in symptomatic or treated patients; the same examinations are carried out in asymptomatic women for screening and prevention. In all cases patients are subjected to clinical examination by the radiologist. During 2008, 14,800 mammographic examinations and 8,360 breast ultrasound studies were performed and 460 second opinions released. Moreover, conventional radiodiagnostic procedures were also performed on inpatients. In the same period, numerous interventional procedures were carried out on patients with suspicious clinical or imaging findings detected in INT or other diagnostic centers. These examinations included 658 instances of preoperative targeting of nonpalpable breast lesions and about 900 percutaneous breast biopsies. In comparison with the previous year, there was a further increase in the number of breast biopsies (+12.5%), especially vacuum-assisted procedures – both stereotactic and ultrasound-guided (+34.7%). These methods show several advantages over automated core biopsy, including sampling of numerous larger specimens. Moreover, they reduce the rate of repeat biopsies and enable more accurate histologic characterization. The goal of the diagnostic workup and breast biopsy is to find primary or recurrent breast cancer (BC) at a preclinical stage, and distinguish benign from malignant findings so that unnecessary surgery can be avoided. Biopsy of nonpalpable breast lesions is a basic part of a multidisciplinary approach aimed at providing also the biochemical parameters that are needed for surgical planning. RADIOLOGY AND DIAGNOSTIC IMAGING 3 WITHIN THE DIVISION OF DIAGNOSTIC RADIOLOGY 3 (RD3) TWO UNITS FOR SPECIFIC ACTIVITIES HAVE BEEN CREATED, THE BREAST IMAGING UNIT AND DIAGNOSTIC AND INTERVENTIONAL GASTROENTEROLOGY UNIT. THE DIRECTOR OF RD3 IS ALSO IN CHARGE OF THE BREAST IMAGING UNIT. HEAD OF DIVISION Silvana Bergonzi, MD STAFF MEMBERS Guido Cozzi, MD; Claudio Ferranti, MD; Monica Marchesini, MD; Marco Milella, MD; Monica Salvetti, MD; Gianfranco Scaperrotta, MD; Laura Suman, MD RESEARCH MEMBER Claudia Costa, MD POSTDOCTORAL FELLOWS SvetlanaTelyatnikova, MD Aristeidis Livanos, MD RADIOLOGY TECHNICIANS Luisa Colombo; Luciana Dedei; Enrico Depedri; Cristina Folini (Radiology Technologists Coordinator); Maria Pia Mannella; Stefania Sala; Anna Tavola
  10. 10. DIAGNOSTIC IMAGING & RADIOTHERAPY 177 With regard to research programs, the Unit is still engaged in the program of surveillance and early diagnosis in women with a genetic predisposition (BRCA1 or BRCA2) or a marked family history of BC, and a study is still ongoing in collaboration with the Unit of Genetics and the Unit of Nuclear Magnetic Resonance. The Unit actively participated in the ISS Italian Network for women at high BC risk. The surveillance of young women submitted to radiation therapy of the thorax at prepuberal or puberal age is ongoing in cooperation with the Pediatric Oncology Division; this study is aimed at assessing the risk of such women developing BC. Another collaborative study is being carried out with the Medical Oncology 1 Division for the staging and follow-up of patients with BC accrued in different randomized trials of neoadjuvant therapies. In this subset, ultrasound-guided breast biopsies are also performed to provide a histologic diagnosis and prognostic parameters as required by the trials, after failure of core-needle biopsy on palpable lesions. US evaluation of lymphedema of the arm after mastectomy has been started with the aim to provide detailed information about the characteristics of lymphedema and to ascertain whether there is agreement between US imaging and clinical data.
  11. 11. SCIENTIFIC REPORT 2008178 Diagnostic and Interventional Gastroenterology (Head of Unit: G. Cozzi) The clinical activity of the Unit is mostly oriented towards diagnostic and interventional radiology of the digestive and biliary tracts and towards diagnostic and interventional US applications. Moreover, at the beginning of the year a new field of diagnostic application to the urinary tract was started. Interventional US procedures are mainly performed in thyroid disease. In 2008, 2,734 examinations were performed by the staff of the Unit. Double contrast examinations were carried out when diagnostic problems occurred concerning the upper and lower gastrointestinal tract. Water-soluble contrast examinations were performed in early postsurgical checkups. Interventional procedures were performed in patients with different biliopancreatic diseases; not only palliative definitive biliary drains and stents were positioned, but curative procedures such as dilatation of cicatricial stenoses, drainage of postsurgical fistulas, and stone removal were successfully carried out. A peculiarity of the Unit are gastrointestinal interventional procedures like percutaneous gastrojejunostomy, transluminal drainage of fluid collection, balloon dilatation of cicatricial stenoses, and palliative stenting of inoperable colonic lesions; all these procedures can be used as alternatives to the endoscopic approach. Overall, during 2008, 738 interventional procedures were performed in the Unit, with an increase of 5.3% with respect to the previous year. Among the large number (5,793) of US examinations, thyroid disease represents a prominent field of interest. In the context of the INT “Progetto Tiroide”, in cooperation with the multidisciplinary outpatient service of thyroid disease, 1,682 (+11.2%) neck US examinations for the monitoring of thyroid nodules were performed. In 154 of these patients, because of the clinical and/or radiologic suspicion of malignancy, US- guided percutaneous biopsies were performed. In view of the high rate of nondiagnostic results with fine-needle aspiration biopsy according to the literature, Tru-Cut biopsies with 18-20-gauge needles have been used without any serious complications. Figure 4 Right: on conventional B-mode image, the lesion was suspicious (BI-RADS 4) Left: totally blue Sonoelastographic image coherent with malignancy. Histology: ductal infiltrating carcinoma.
  12. 12. DIAGNOSTIC IMAGING & RADIOTHERAPY 179 The Division of Nuclear Medicine (NM) works is subdivided into different areas: 1) a diagnostic unit for planar and tomographic scintigraphy (SPECT); 2) a PET unit for clinical PET with a 17 MeV cyclotron and two PET scanners; 3) radiochemistry laboratories for γ and β radiopharmaceuticals to be used for diagnosis and therapy; 4) a biochemical laboratory for immunoradiometric assays; 5) a protected ward for radiometabolic therapy; 6) a clinic for outpatients. The NM clinical activity in 2008 amounted to 5,706 tests of traditional diagnostic imaging, 3,517 PET examinations, 294 radiometabolic treatments, more than 80,000 in vitro tests, and 2,665 medical examinations. The research activities of the Division cover many issues: a) measurement of biochemical marker changes associated with tumor response and evaluation of bone metabolism parameters in patients with bone metastases; b) development of original approaches for lymphoscintigraphy with intraoperative sentinel node detection in cancer patients; c) radioreceptor scintigraphy of neuroendocrine tumors; d) studies on clinical PET and validation of PET applications; e) development of new PET radiopharmaceuticals; f) new radiometabolic therapy approaches to thyroid cancer, neuroblastoma, ovarian cancer and lymphoma; g) dosimetric studies to optimize the dose to the tumor for achieving the best efficacy. All these studies have been carried out and developed in the two units belonging to the NM: the Nuclear Medicine Therapy and Endocrinology Unit and the Clinical PET Unit. They are described in the pertaining sections. In addition, studies on sentinel node detection in endometrial cancer and gastric cancer were carried out in a large series of patients. The first study was aimed at evaluating the distribution of 99mTc-nanocolloid in the lymphatic network to detect pelvic and lumbo-aortic metastases. In the majority of patients with early stage cancer, this procedure may avoid unnecessary radical pelvic lymphadenectomy. This research, NUCLEAR MEDICINE HEAD OF DIVISION Emilio Bombardieri, MD STAFF MEMBERS Flavio Crippa, MD; Ettore Seregni, MD; Maria Rita Castellani, MD; Marco Maccauro, MD; Gianluca Serafini, MD; Gianluca Aliberti, MD; Orunesu Eva MD; Alessandra Alessi, MD; Claudio Pascali, Chemist; Carlo Chiesa, Physigist; Vinicio De Sanctis, Engineer; Anna Bogni, Biol Sci RESEARCH ASSOCIATES Angela Coliva, Chemist; Federica Pallotti, MD; Crispu Ornella, Chemist RADIOLOGY TECHNICIANS Monica Testoni (Radiology Technologists Coordinator), Grazia Aprigliano, Elena Fraigola, Rossana Pavesi, Sergio Bavusi, Lidia Spano, Roberto Segreti, Stefano Vola, Matteo Ragazzoni LABORATORY TECHNICIANS Gianenrico Cucchetti, Rita Filieri, Giovanni Nido, Biagio Perrone, Pietro Di Nuzzi, Danilo Baratella THE PHYSICIANS OF THIS DIVISION ARE NUCLEAR MEDICINE SPECIALISTS; SOME OF THEM ARE SPECIALIZED ALSO IN ENDOCRINOLOGY AND ONCOLOGY. OTHER PROFESSIONALS INCLUDE PHYSICISTS, RADIOLOGISTS, RADIOCHEMISTS, ENGINEERS, AND BIOLOGISTS, WORKING TOGETHER IN A MULTIDISCIPLINARY TEAM.
  13. 13. SCIENTIFIC REPORT 2008180 in collaboration with the Unit of Gynecologic Surgery, has become an Italian multicenter trial. The second study aims to evaluate sentinel node lymphoscintigraphy with 99mTc-nanocolloid for guiding lymphadenectomy in gastric cancer patients. This technique proved feasible in T1-T2 cancer, with high sensitivity and a high negative predictive value. A multicenter Italian trial on the use of 111In-pentetreotide in nonfunctioning neuroendocrine tumors is ongoing. The study assesses its diagnostic value in comparison with other conventional radiologic modalities and, above all, aims to demonstrate the potential prognostic value of somatostatin receptor positivity. In the area of radiometabolic therapy other studies are ongoing on the use of high doses of radiopharmaceuticals (131I and 131I-MIBG) for the treatment of advanced thyroid and neuroendocrine tumors. This approach is possible only when adequate pretreatment dosimetric evaluations are available. In NM an important field of research and development concerns clinical dosimetry in nuclear medicine treatments with a view to provide quantitative data on the absorbed dose to cancer lesions and healthy organs. In metastatic thyroid cancer a recent dosimetric study on patients treated with the usual fixed activity confirmed that in all patients the injected activity could have been significantly higher in subsequent treatments, if necessary. Our posttreatment dosimetry drastically changed the ensuing therapeutic strategy in patients in whom the tumor doses proved insufficient (even considering a factor of 2 or 3 of inaccuracy). More than 40 patients with liver carcinomas were treated with intraarterial radioembolization by means of glass microspheres loaded with 90Yttrium. Each treatment was preceded by 99mTc-MAA dosimetry. Median injected activity was in the range of 1-4.9 GBq, corresponding to an average absorbed dose in the treated lobe of more than 100 Gy. In several cases it was possible to evaluate the tumor dose on planar scans, which proved to be around 390 Gy (median). The extraordinarily high tumor dose, never observed in other therapeutic applications, gave in some cases excellent responses, i.e., complete disappearance of the lesion within 6 months. Clinical PET (Head of Unit: F. Crippa) The PET Unit is involved in 1) the production of radioisotopes by cyclotron; 2) the synthesis of PET radiopharmaceuticals, 3) PET imaging. The activity of the cyclotron can be summarized as follows: a) production of 11C and 18F for research and routine procedures of the radiochemistry laboratory; b) surveillance of cyclotron functioning to collect data about its reliability and productivity; c) design and development of an improved loading system of 18F targets;
  14. 14. DIAGNOSTIC IMAGING & RADIOTHERAPY 181 d) development of 18F targets with higher productivity than the current ones. Some results have been obtained in terms of yield and performance of production. The radiochemistry laboratory activity is dedicated to the synthesis of molecules labeled with positron-emitting nuclides such as 18F and 11C. The research activity can be summarized as: 1) development of an innovative and simplified procedure for the synthesis of [18F]FLT (fluorothymidine), for which a patent has been filed; 2) implementation of this synthesis in one of the existing modules; 3) development of an analytic method by HPLC for the evaluation of the chemical and radiochemical purity of the produced [18F]FLT; 4) implementation of the synthesis of [11C]choline in the same module employed for the routine production of [11C]methionine and testing of the reaction conditions. The PET Unit is equipped to study patients with virtually all types of human malignancies for staging and follow-up. In 2008 more than 3,500 PET scans were performed in patients with lymphoma, breast cancer, colon cancer, melanoma, GIST tumors, ovarian cancer, head and neck cancer, and brain tumors – both for tumor detection and to evaluate the response to therapy. This routine activity provided valuable information for patient management, changing therapeutic decisions in more than 30% of cases. As regards clinical research, the most important ongoing programs include: • the use of FDG-PET and CT for the follow-up of asymptomatic melanoma patients with a high risk of metastases. The goal of this research is the early detection of metastases with potential for surgerical treatment; • the use FDG-PET for early chemosensitivity evaluation in lymphoma patients. We are participating in a multicenter study designed and coordinated by the GITIL (Gruppo Italiano Terapie Innovative Linfomi); • the use of FDG-PET to study sarcomas, with particular reference to GISTs and chordomas. Our PET Unit provides imaging support to several clinical research programs carried out by the Sarcoma Group of INT; • the use of [11C]methionine to study brain tumors, in particular low-grade gliomas, where FDG-PET lacks sensitivity as an imaging modality. FIGURE 5 PET provides metabolic images, since the uptake and the distribution of the radipharmaceutical depends on tumour metabolism and the backround activity. The same brain tumour is differently visualized according to fluorodeoxyglucose (FDG) and methionine (MET) pathways.
  15. 15. Nuclear Medicine Therapy and Endocrinology (Head of Unit: E. Seregni) The Unit is part of the NM and its activity covers three main areas: nuclear medicine therapy, a radioisotope laboratory, and an endocrinology outpatient clinic. Each area is involved in routine and experimental procedures. More than 200 patients affected by different diseases including thyroid cancer, neuroendocrine tumors and bone metastasis were hospitalized in 2008 and treated with the appropriate radiopharmaceuticals. Many other patients underwent experimental therapies with new radiopharmaceuticals in clinical trials. At present three protocols are active: • efficacy of myeloablative therapy with 90Y-Zevalin, an anti-CD20 murine monoclonal antibody, in patients with non-Hodgkin’s lymphoma (11 patients treated in 2008); • efficacy of tandem treatment with the somatostatin analogs 90Y-DOTA-TATE and 177Lu-DOTA-TATE of neuroendocrine tumors refractory to conventional therapies. The protocol prescribes four treatment cycles in which the two radiopharmaceuticals are alternated. In 2008 seven patients were treated with one or more cycles. • efficacy of endoarterial treatment with 90Y-TheraSphere microspheres in hepatocellular carcinoma. Up to now 47 patients with unresectable hepatocellular carcinoma have been evaluated for 90Y radioembolization. Thirty-seven patients entered the study and were treated with standard lobar activity of 90Y TheraSpheres. The therapeutic activity was calculated so as to reach a fixed absorbed dose of 120 Gy to the target lobe. Median follow-up was 10 months and, according to RECIST, WHO or EASL criteria, complete or partial responses were obtained in 19-28% of patients, while the overall response rate (SD, PR, CR) was 63-60%. In the Radioisotopes Laboratory a wide panel of analytes consisting of tumor markers, hormones and bone metabolism markers is routinely measured. During 2008 more than 80,000 examinations were performed in hospitalized patients and outpatients. The research activity of the laboratory is mainly performed in collaboration with the Experimental Oncology Department and deals with different areas, including the study of new bone metabolism parameters in patients with skeletal cancer. In this context the biologic and clinical significance of two different isoforms (alpha and beta) of the C- terminal peptide of type I collagen (CTX-1) is assessed in patients treated with zoledronic acid. Other important ongoing studies are focused on the analysis of calcitonin in transgenic mice bearing the RET C634R gene for the mapping of genetic modulators of tumor progression in medullary thyroid cancer; and on the characterization of primary thyrocyte cultures by measuring thyroglobulin and calcitonin to clarify the molecular mechanisms of thyroid carcinogenesis. Also under evaluation is the course of a panel of biomarkers including angiogenic factors, adhesion molecules and growth factors in patients affected by advanced colorectal cancer treated with antiangiogenic drugs. In the endocrinology area, patients affected by thyroid and parathyroid disease, neuroendocrine tumors, pituitary disease, osteoporosis and multiple endocrine neoplasia (MEN2 and MEN1) are currently in active follow-up. We also evaluate and correct endocrine sequelae in pediatric patients affected by neoplastic disease. The research activity is mainly focused on pediatric patients and two studies are currently ongoing: on the evaluation of the biologic and clinical effects of growth hormone replacement in pediatric patients with brain tumors, and on the incidence of metabolic syndrome and insulin resistance in pediatric patients as a consequence of chemotherapy or other anticancer therapies. More than 70 patients have entered the latter study. 182 SCIENTIFIC REPORT 2008 FIGURE 6 Planar total body scintigraphy of a patient affected by ileal neuroendocrine carcinoma with hepatic and lymph-nodal metastasis. Images were acquired 72 hours post injection of a) 90Y-DOTA-TATE (images were acquired exploiting bremsstrahlung of 90-yttrium) and b) 177Lu-DOTA-TATE.
  16. 16. DIAGNOSTIC IMAGING & RADIOTHERAPY 183 HEAD OF DIVISION Patrizia Olmi, MD STAFF MEMBERS Nice Bedini, MD; Anna Di Russo, MD; Vittorio Fossati, MD; Lorenza Gandola, MD; Laura Lozza, MD; Ester Orlandi, MD; Mauro Palazzi, MD; Fulvia Soncini, MD; Silvia Tana, MD; Francesca Valvo, MD; Sergio Villa, MD RESIDENTS Barbara Avuzzi, MD; Serena Berretta, MD; Marzia Franceschini, MD; Sara Morlino, MD; Patrizia Pittoni, MD POSTDOCTORAL FELLOWS Simona Fantini; Emilia Pecori, MD RADIOLOGIC TECHNOLOGISTS Pintaudi Ciro (Radiology Technicians Coordinator), Cosimo Attolino, Arianna Bianchini, Giuseppina Bonanno, Alberto Buzzetti, Carmelo Campolo, Pasquale Contessa, Paolo D'Agnese, Daniele D'Alessio, Carmelo Di Marco, Lucio Donatone, Rosa Fortunato, Sara Frasca, Piera Fusar Poli, Franca Gaetano, Manuela Gatti, Manuela Guerra, Daniela Pierograndi, Carla Valenti Three linacs have internal multileaf collimators and are suited to deliver IMRT. The new machines permit both online and offline treatment verification, which is especially needed for currently used sophisticated techniques such as IMRT and IGRT. The fourth linac is equipped with a dynamic multileaf collimator accessory that makes it possible to deliver stereotactic treatment. The Xio planning system has been upgraded and has led to a more frequent use of image fusion. This technique was applied in 118 patients during the planning phase. A high dose rate brachytherapy facility is available; it is equipped with a Selectron machine for all types of brachytherapy and allows to treat patients on an outpatient basis. A Plato treatment planning system specifically devised for brachytherapy is available. In 2008, 357 brachytherapy treatments were performed in 73 patients with gynecologic, biliary duct and breast cancer. Overall, the RT1 Division has provided care for 1,699 patients, one third of whom (506) were aged 70 years or over. CT simulation was performed in 1810 cases (>1/patient). 3D treatment planning was performed in 2134 cases and IMRT planning in 162 patients. Patient setup was customized by preparing 556 positioning/immobilization devices. IGRT was given in 288 cases, mainly using the fiducial marker system in prostate cancer. The research activity was mainly focused on clinical trials (see section “Ongoing Clinical Studies”, page 221) on: pediatric tumors (medulloblastoma, ependymomas, high-grade gliomas, high-risk neuroblastoma, Wilms’tumor, soft-tissue sarcomas, bone tumors, Ewing's family tumors and late effects such as thyroid neoplasms after irradiation for childhood cancer) and tumors in adult patients (soft tissue sarcomas, head and neck cancer). A ISS cooperative study: a position paper on 3D-CRT was issued in 2008. A new study on the welfare-related issues of the elderly oncologic patient: 40 patients were enrolled in 2008. RADIOTHERAPY 1 THE RADIOTHERAPY 1 (RT1) DIVISION IS EQUIPPED WITH FIVE LINEAR ACCELERATORS AND ONE COBALT UNIT.
  17. 17. SCIENTIFIC REPORT 2008184 Its facilities include eight beds in four shielded rooms, one operating room and one office, for inpatient preparatory procedures and outpatient follow-up, respectively. In addition to external beam radiotherapy, the RT2 administers high dose rate brachytherapy. Brachytherapy is given as endocavitary treatment in uterine cancers, as endoluminal brachytherapy in biliary tract cancers, and as interstitial brachytherapy in breast cancer with high dose rate equipment (Selectron®). High dose rate treatment is generally delivered in the outpatient setting. During 2008, 73 patients were treated with 357 fractions and 216 treatment plans. Combination chemoradiotherapy treatment is also provided, mainly in gynecologic, anorectal and head and neck cancers. Two hundred and fifty cycles of chemotherapy were given during 2008. Supportive care for acute and, less frequently, late radiotherapy-related complications is given as well. RT2 cooperates with the Diagnostic Radiology Divisions in the care of patients undergoing chemoembolization, intraarterial chemotherapy, and other oncologically targeted interventional procedures requiring hospitalization. Overall, 376 patients were referred to RT2 during 2008; their mean hospital stay was 6.1 days. RT2 cooperates with RT1 in the planning and delivery of external beam radiation treatments to outpatients, mainly for breast cancer, gynecologic malignancies, head and neck cancer and soft tissue sarcomas, and in patients with metastatic tumors or patients needing palliative care. The staff members participate actively in the head and neck, breast, and gynecologic cancer groups; they collaborate with the multidisciplinary outpatient clinic for head and neck cancer together with RT1, the Otolaryngology Division, Maxillofacial Division, and Medical Oncology (Head & Neck Unit). RT2 is involved in special techniques of treatment delivery such as cranial and extracranial (body) stereotactic radiotherapy. RADIOTHERAPY 2 RADIATION THERAPY 2 (RT2) IS THE INPATIENT SECTION OF THE DEPARTMENT OF DIAGNOSTIC IMAGING AND RADIOTHERAPY. HEAD OF DIVISION Carlo Fallai, MD STAFF MEMBERS Annamaria Cerrotta, MD POSTDOCTORAL FELLOW Monica Alicia Garcia, MD
  18. 18. DIAGNOSTIC IMAGING & RADIOTHERAPY 185 RT2 has taken part in the general accreditation process, and has contributed to the updating of several guidelines for radiation treatment (IMRT in head and neck cancer, multidisciplinary clinic’s guidelines for head and neck cancer; thyroid cancer). Clinical research projects are on: head and neck cancer (activities in this field have been carried out in collaboration with the Division of Medical Oncology and RT1); gynecologic cancer (in October 2008 PORTEC-3 was started in collaboration with the Gynecology Department. This is a randomized prospective multicenter phase III trial comparing concurrent chemoradiation and adjuvant chemotherapy with pelvic radiation alone in high-risk and advanced-stage endometrial carcinoma. The study is led by the Dutch Cooperative Gynecologic Oncology Group and aims to establish the overall survival, failure-free survival, pelvic and distant recurrence rates and to compare treatment-related toxicity and quality of life in the different treatment arms).
  19. 19. SCIENTIFIC REPORT 2008186 In cooperation with the Radiotherapy Divisions, the Physics Department of the University of Milan, and the Nuclear Engineering Department of the Milan Polytechnic, gel-layer dosimeters are currently under study as a reliable alternative to films, semiconductor arrays or thermoluminescent dosimeters (TLD). Among various experiments, we evaluated the reliability of Fricke gel-layer dosimeters (FGLD) for the measurement of the in-phantom dose distribution produced by a 192Ir brachytherapy source. To this aim, a series of measurements of the same irradiation setup composed of a tissue-equivalent phantom were performed with FGLD and TLD and compared with the dose distributions obtained by means of the treatment planning system. The use of Fricke gel-layer dosimetry shows promise for high dose rate brachytherapy applications, offering three-dimensional dose information with good spatial resolution. In vivo characterization of melanin in melanocytic lesions by means of reflectance spectroscopy. The aim of our research, performed in collaboration with the Day Surgery Unit, was to assess the role of both eumelanin and pheomelanin in the various steps of tumor progression from melanocytic lesion to dysplastic nevus to horizontal and vertical growth phase melanoma. A retrospective analysis was performed on 1,671 multispectral images of in vivo pigmented skin lesions, including 288 melanomas. An innovative model was developed to assess the content of eumelanin and pheomelanin in the lesions starting from their absorbance spectra. Analysis of the absorbance spectra in the different groups showed that the levels of eumelanin and pheomelanin increased and decreased, respectively, from dysplastic nevi to invasive melanomas. In both cases, the trend of melanin levels was associated with the progression from dysplastic nevi to vertical growth phase melanomas, reflecting a possible hierarchy in the natural history of the early phases of the disease. Our results suggest that diffuse reflectance spectroscopy to differentiate eumelanin and pheomelanin in in vivo lesions is a promising technique and is useful to develop better strategies for the characterization of the various melanocytic lesions. MEDICAL PHYSICS HEAD OF DIVISION Renato Marchesini, Physics D STAFF MEMBERS Marta Borroni, Physics D; Ugo Cerchiari, Physics D; Valeria Mongioj, Physics D; Emanuele Pignoli, Physics D; Stefano Tomatis, Physics D; Giancarlo Zonca, Physics D RESEARCH MEMBER Manuela Lualdi, Physics D POSTDOCTORAL FELLOW Mauro Carrara, Physics D RADIOLOGY TECHNICIANS Vito Cosentino, Salvatore Manciero (Coordinator), Luca Marrone, Dario Posté, Claudio Stucchi THE MAIN AREAS OF SCIENTIFIC INTEREST OF THE MEDICAL PHYSICS DIVISION ARE: DOSIMETRY IN HIGH DOSE RATE BRACHYTHERAPY.
  20. 20. DIAGNOSTIC IMAGING & RADIOTHERAPY 187 FIGURE 7 Experimental set-up of the 192Ir brachytherapy source and the tissue-equivalent phantom with (a) thermoluminescent dosimeters and (b) Fricke gel-layer dosimeters; (c) superficial dose distribution produced by the source (activity: 285GBq) at 1cm distance, obtained by means of a circular gel dosimeter and a suitably developed software. Hereditary nonpolyposis colorectal cancer (HNPCC) carriers and abnormal oral mucosa light reflectance. Oral light reflectance has been suggested as a new clinical marker in HNPCC carriers, which could be used in first level colorectal cancer (CRC) population screening programs. With the aim to validate this new marker in identifying susceptibility to CRC, additional studies were carried out in cooperation with the Colorectal Cancer Unit. Fifty-six surviving members of various genetically unrelated HNPCC kindreds were enrolled in the study. They were all subjected to HNPCC genetic molecular studies and 42 of them showed HNPCC mutation. In addition, 10 healthy controls were enrolled. For each study subject, spectrophotometric images in 20 different regions of the vestibular oral mucosa were acquired. The mean reflectance spectra in HNPCC carriers and control subjects were evaluated for the entire region and the vessel-free region. In both cases, no evidence of a significant difference between the curves was obtained at any wavelength, in contrast to the findings previously reported. Magnetic resonance in vivo spectroscopy H1. Three-dimensional magnetic resonance spectroscopy is an emerging sensitive tool for the metabolic evaluation of prostate cancer. Choline, creatine, and citrate peaks provide relevant metabolic information for the discrimination of prostate cancer. Resonance for choline, creatine, and citrate occurs at distinct frequencies (approximately 3.2, 3 and 2.6 ppm, respectively) in the spectrum. The spectral trace of prostate cancer is characterized by raised choline (a normal cell membrane constituent, which is elevated in many tumors) and/or reduced citrate (a constituent of normal prostate tissue). In 2008 we were asked to collaborate with magnetic resonance radiologists to tune up the spectra acquisition methodology and the data analysis of spectroscopic imaging of prostate cancer. The ratio of choline and creatine to citrate in regions with normal prostate tissue has been established.