DIAGNOSTIC IMAGING

DIAGNOSTIC IMAGING& RADIOTHERAPY

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, MDRadiology and Diagnostic Imaging 1 &Magnetic Resonance Unit

Alfonso Marchianò, MDRadiology and Diagnostic Imaging 2 &Computed Tomography Unit

Francesco Garbagnati, MDIntralesional Treatment Unit

Silvana Bergonzi, MDRadiology and Diagnostic Imaging 3 &Breast Imaging Unit

Guido Cozzi, MDDiagnostic and InterventionalGastroenterology Unit

Emilio Bombardieri, MDNuclear Medicine

Ettore Seregni, MDNuclear Medicine Therapy andEndocrinology Unit

Flavio Crippa, MDClinical PET Unit

Patrizia Olmi, MDRadiotherapy 1

Carlo Fallai, MDRadiotherapy 2

Renato Marchesini, Physics DMedical Physics

DIAGNOSTIC IMAGING & RADIOTHERAPY 169

DIRECTOR OF DEPARTMENT

Emilio Bombardieri, MDphone number: +39 02 2390 2220

e-mail: [email protected]

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.


In 2008 RD1 carried out 10,956 MRI scans and 36,529 conventional radiologicexaminations (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 DIVISIONDaniele Vergnaghi, MD

STAFF MEMBERSAlberto Laffranchi, MD; PaoloPotepan, MD; Giovanna Trecate, MD;Antonella Messina, MD; DavideScaramuzza, MD

RADIOLOGY TECHNICIANSValeria Tosi, RT; Carmelina Pannone,RT; Cinzia Fossaceca, RT; TinaMastrostefano; Antonella Laturra,RT; Nicola Pulerà, RT; MaurizioZattoni, RT; Annunziata Gaetano, RT;Luca Musumeci, RT


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 1Total Body Imaginga) T1 W imageb) T2 W fat satc) Fusion image between T1morfological e diffusion images.Arrows point pathologic tissuedue a myeloma disease.


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


WITHIN THE DIVISION OF DIAGNOSTIC RADIOLOGY 2 (RD2), TWO SPECIAL UNITS FOR SPECIFIC ACTIVITIESHAVE BEEN ESTABLISHED: THE UNIT OF COMPUTED TOMOGRAPHY AND THE UNIT OF INTRALESIONALTREATMENT WITH RADIOFREQUENCY. THE DIRECTOR OF THE RD2 DIVISION ALSO LEADS THE UNIT OFCOMPUTED TOMOGRAPHY.

HEAD OF DIVISIONAlfonso Marchianò, MD

STAFF MEMBERSFrancesco Garbagnati, MD; EnricoCivelli, MD; GiuseppeDi Tolla, MD; Laura F. Frigerio, MD;Rodolfo Lanocita, MD; Carlo Morosi,MD; Carlo Spreafico, MD

CONSULTANTSBruno Damascelli, MDGianluigi Patelli, MD

RADIOLOGY TECHNICIANSPietro Basile; Marilena Barbiero;Maria Ferrarello; Roberto Gallo;Giuseppina Gentile; EsterMazzarella; Roberto Nioi; GeremiaPorcelli (Radiogy Technicians'Coordinator); Salvatore Romaniello;Luciana Tanzini


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 2Improving CT imaging in oncology.High flow contrast mediuminjection through implantableinfusional devices. Illustrativeexample. Right small-cell lungcancer. Superior vena cavainjection at 5 mL/sec throughPowerPort allows 3 dimensional(3D) volume rendering (VR)reconstruction.


FIGURE 38 cm HCC treated in one session RFTAduring arterial stop flow withembolization. The pictures demonstrate TCevaluation of the HCC pre treatment (firstimage), the stop flow angiographicprocedures, TC evaluation during 3 yearsfollow with the complete necrosis of theHCC reduced in volume.After colecistectomy (calcoloticcolecistitis) it has been resected also thehepatic residual nodule (last picture)with the anatomopathological evidenceof 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.


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.


WITHIN THE DIVISION OF DIAGNOSTIC RADIOLOGY 3 (RD3) TWO UNITS FOR SPECIFIC ACTIVITIES HAVE BEENCREATED, 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 DIVISIONSilvana Bergonzi, MD

STAFF MEMBERSGuido Cozzi, MD; Claudio Ferranti,MD; Monica Marchesini, MD; MarcoMilella, MD; Monica Salvetti, MD;Gianfranco Scaperrotta, MD; LauraSuman, MD

RESEARCH MEMBERClaudia Costa, MD

POSTDOCTORAL FELLOWSSvetlanaTelyatnikova, MDAristeidis Livanos, MD

RADIOLOGY TECHNICIANSLuisa Colombo; Luciana Dedei;Enrico Depedri; Cristina Folini(Radiology TechnologistsCoordinator); Maria Pia Mannella;Stefania Sala; Anna Tavola


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.


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 4Right: on conventional B-mode image,the lesion was suspicious (BI-RADS 4)Left: totally blue Sonoelastographicimage coherent with malignancy.Histology: ductal infiltratingcarcinoma.


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 DIVISIONEmilio Bombardieri, MD

STAFF MEMBERSFlavio Crippa, MD; Ettore Seregni, MD;Maria Rita Castellani, MD; MarcoMaccauro, MD; Gianluca Serafini, MD;Gianluca Aliberti, MD; Orunesu EvaMD; Alessandra Alessi, MD; ClaudioPascali, Chemist; Carlo Chiesa,Physigist; Vinicio De Sanctis,Engineer; Anna Bogni, Biol Sci

RESEARCH ASSOCIATESAngela Coliva, Chemist; FedericaPallotti, MD; Crispu Ornella, Chemist

RADIOLOGY TECHNICIANSMonica Testoni (RadiologyTechnologists Coordinator), GraziaAprigliano, Elena Fraigola, RossanaPavesi, Sergio Bavusi, Lidia Spano,Roberto Segreti, Stefano Vola, MatteoRagazzoni

LABORATORY TECHNICIANSGianenrico Cucchetti, Rita Filieri,Giovanni Nido, Biagio Perrone, Pietro DiNuzzi, Danilo Baratella

THE PHYSICIANS OF THIS DIVISION ARE NUCLEAR MEDICINE SPECIALISTS; SOME OF THEM ARE SPECIALIZEDALSO IN ENDOCRINOLOGY AND ONCOLOGY. OTHER PROFESSIONALS INCLUDE PHYSICISTS, RADIOLOGISTS,RADIOCHEMISTS, ENGINEERS, AND BIOLOGISTS, WORKING TOGETHER IN A MULTIDISCIPLINARY TEAM.


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;


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 5PET provides metabolic images,since the uptake and thedistribution of theradipharmaceutical depends ontumour metabolism and thebackround activity. The same braintumour is differently visualizedaccording to fluorodeoxyglucose(FDG) and methionine (MET)pathways.

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 6Planar total body scintigraphy of apatient affected by ilealneuroendocrine carcinoma withhepatic and lymph-nodal metastasis.Images were acquired 72 hours postinjection of a) 90Y-DOTA-TATE (imageswere acquired exploitingbremsstrahlung of 90-yttrium) and b)177Lu-DOTA-TATE.


HEAD OF DIVISIONPatrizia Olmi, MD

STAFF MEMBERSNice 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

RESIDENTSBarbara Avuzzi, MD; Serena Berretta,MD; Marzia Franceschini, MD; SaraMorlino, MD; Patrizia Pittoni, MD

POSTDOCTORAL FELLOWSSimona Fantini; Emilia Pecori, MD

RADIOLOGIC TECHNOLOGISTSPintaudi Ciro (Radiology TechniciansCoordinator), Cosimo Attolino, AriannaBianchini, Giuseppina Bonanno,Alberto Buzzetti, Carmelo Campolo,Pasquale Contessa, Paolo D'Agnese,Daniele D'Alessio, Carmelo Di Marco,Lucio Donatone, Rosa Fortunato, SaraFrasca, Piera Fusar Poli, FrancaGaetano, Manuela Gatti, ManuelaGuerra, Daniela Pierograndi, CarlaValenti

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.


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 ratebrachytherapy. 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 ANDRADIOTHERAPY.

HEAD OF DIVISIONCarlo Fallai, MD

STAFF MEMBERSAnnamaria Cerrotta, MD

POSTDOCTORAL FELLOWMonica Alicia Garcia, MD


RT2 has taken part in the general accreditation process, and has contributed to theupdating 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).


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 DIVISIONRenato Marchesini, Physics D

STAFF MEMBERSMarta Borroni, Physics D; UgoCerchiari, Physics D; Valeria Mongioj,Physics D; Emanuele Pignoli, PhysicsD; Stefano Tomatis, Physics D;Giancarlo Zonca, Physics D

RESEARCH MEMBERManuela Lualdi, Physics D

POSTDOCTORAL FELLOWMauro Carrara, Physics D

RADIOLOGY TECHNICIANSVito Cosentino, Salvatore Manciero(Coordinator), Luca Marrone, DarioPosté, Claudio Stucchi

THE MAIN AREAS OF SCIENTIFIC INTEREST OF THE MEDICAL PHYSICS DIVISION ARE:DOSIMETRY IN HIGH DOSE RATE BRACHYTHERAPY.


FIGURE 7Experimental set-up of the 192Ir brachytherapy source and thetissue-equivalent phantom with (a) thermoluminescent dosimetersand (b) Fricke gel-layer dosimeters; (c) superficial dose distributionproduced by the source (activity: 285GBq) at 1cm distance,obtained by means of a circular gel dosimeter and a suitablydeveloped 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.

DIAGNOSTIC IMAGING

Health & Medicine

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