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Somatostatin receptor scintigraphy is useful in diagnosing tumors with increased expression of somatostatin receptors. The correct use of this technique reveals the localization of neuroendocrine primary tumors and unknown metastases in approximately 90% of patients. However, somatostatin receptor scintigraphy also can image many other human tumors expressing somatostatin receptors, including malignant lymphomas and thymomas. The sensitivity of somatostatin receptor scintigraphy to image somatostatin receptor-positive tumors is very high, but due to the variable expression of specific receptor subtypes, the specificity can be relatively low. This drawback is crucial in evaluating lymphoproliferative diseases, or, in general, when immune cells are involved. The sensitivity of somatostatin receptor scintigraphy for Hodgkin's lymphoma is 95%-100%, whereas for non-Hodgkin's lymphoma it is around 80%. It has been shown that the uptake of [(111)In-DTPA(0)]octreotide in lymphomas is lower compared to the uptake in neuroendocrine tumors. This is mainly attributed to the low number of receptors on immune cells compared to neuroendocrine cells; however, ligand-induced internalization and differential receptor regulation may also participate in determining this phenomenon. Therefore, caution should be taken when interpreting data from some studies. Several new ligands are currently under study to improve these limits and the expression of other neuropeptide receptors is being investigated to provide a molecular basis for in vivo multireceptor targeting of tumors. With the use of currently available somatostatin analogs, somatostatin receptor scintigraphy does not seem to have a significant impact in patients with lymphomas for diagnostic purposes. There are a few exceptions, however. Among these, the staging and restaging of extragastric lymphoma MALT-type may present some advantages. Conversely, somatostatin receptor scintigraphy in the imaging of thymic malignancies could enhance both our diagnostic and therapeutic capabilities. Somatostatin receptor scintigraphy is diagnostically relevant in differentiating malignant from benign lesions, especially in those patients with associated paraneoplastic syndromes, and is the main criterion to select patients suitable for therapy with somatostatin analogs. Recent findings emerging from in vitro studies on somatostatin receptor physiology in immune cells will certainly reopen and expand the potential applications of somatostatin analogs for in vivo diagnostic and therapeutic options.

Aims . The management of patients with cutaneous melanoma in the absence of lymph-node metastases is still controversial. The experience of the National Cancer Institute in Naples was analysed to evaluate the 3-year disease free survival and overall survival for all patients submitted to sentinel node biopsy (SNB). Methods . Data from 265 sentinel biopsies performed in the last five years were reviewed to determine the effect of the treatment on disease free survival and overall survival stratified the patients for node status and tumour ulceration. Results . Statistical analysis showed a 3-year survival advantage for sentinel node negative patients compared to sentinel node positive cases with a 88.4 and 72.9%, respectively ( p Conclusions . SNB provides an accurate staging of nodal status in patients with melanoma in the absence of clinical evidence of metastases. Longer follow-up and final results from multicenter selective lymphadenectomy (MSLT) are needed to clarify the role of this procedure.

9624 Background: Preoperative chemoradiation in LARC may produce downstaging and downsizing of the tumor, increases the change of better local control and, in selected cases, sphincter sparing proc...

Background In BRANCH study we assess the safety and efficacy of an experimental schedule of early (4 days before) bevacizumab (BEV) added to neoadjuvant chemotherapy (CT) and radiotherapy (RT) in poor-risk locally advanced rectal cancer (pLARC) patients (pts) and explore the potential of circulating endothelial cells (CECs) and tumor lesion glycolysis (TLG) as surrogate markers of pathological response(PR). Patients and methods 46 pts (cT4, cN + , cT3≤ 5 cm from the anal verge and/or positive circumferential margin, M1 resectable) received 3 biweekly courses of oxaliplatin (100 mg/m2)/raltitrexed (2.5 mg/m2) on day 1, and 5-FU (800 mg/m2)/folinic acid (250 mg/m2) on day 2 during pelvic RT (45 Gy). BEV (5 mg/kg) was given biweekly 4 days before beginning of CT/RT for 2 courses. Toxicity was graded with NCI-CTC v.3. PR was defined using Mandard tumor regression grade (TRG). According to the Simon's two-stage design, assuming an hypothesis of a 50% TRG1 (complete tumor regression) (α error = 0.05, β error = 0.20), at least 6/16 TRG1 should be obtained to continue accrual to 46 pts. CECs and TLG were evaluated at baseline (BL) on day 10 and before surgery, by flow cytometry and FDG-PET, respectively. Statistical analysis was by Mann-Whitney test. Results We obtained 23 TRG1 (50%), 14 TRG2 (30%) and 8 TRG3-4 (17%). Grade ¾ neutropenia was the most common adverse event (13/46 pts, 28%). TLG reduction on day 10 vs BL was significantly higher in responders TRG1-2 compared to non-responders TRG3-4 pts (median -72%, range -90% + 31% vs -38%, range -45% + 25%; p Conclusions Current scheme of BEV plus CT and RT appears safe and active, yielding high rate of TRG1 and TRG2 responses in pLARC. Early FDG-PET and CECs evaluation emerged as potential biomarkers for treatment selection to be incorporated in design of future studies with this regimen. CEP and citochine data will be provided at the meeting. Disclosure All authors have declared no conflicts of interest.

BACKGROUND Langerhans cell histiocytosis is a rare group of diseases of unknown pathogenesis, variable clinical presentation, and behavior. It encompasses highly aggressive, often fatal, and indolent diseases, with a variety of intermediate forms between the two extremes. Localization and monitoring of Langerhans cell histiocytosis deposits are based on the combined use of different imaging modalities, which include magnetic resonance, computed tomography, and nuclear medicine procedures. Somatostatin receptor scintigraphy recently has been used to image immune-mediated diseases with excellent results. METHODS In this study, the authors have evaluated the potential role of somatostatin receptor scintigraphy by using 111In-DTPA-D-Phe1-octreotide in a series of patients with Langerhans cell histiocytosis. Eight consecutive patients (2 males, 6 females; mean age, 43 years; age range, 29–60 years) with histologically proven Langerhans cell histiocytosis, in various phases of their disease, were imaged 24 hours after intravenous injection of 111–222 MBq of 111In-DTPA-D-Phe1-octreotide, by using total body and spot view images. The objective of the study was to preliminarly evaluate this technique in the evaluation of Langerhans cell histiocytosis. RESULTS Most Langerhans cell histiocytosis deposits were clearly documented by somatostatin receptor scintigraphy, independently from the anatomic location (i.e., skeleton, mucosae, soft tissue, etc.). The correlation between conventional imaging modalities and somatostatin receptor scintigraphy results was fairly good, though this was not considered a primary objective of the study. CONCLUSIONS Among the various imaging modalities for Langerhans cell histiocytosis, somatostatin receptor scintigraphy is unique, becuase it accurately depicts the active sites of disease and thus can help in monitoring the response to treatment, together with conventional imaging modalities. Further studies are necessary to confirm the diagnostic value of this technique and clarify the biologic significance of the expression of somatostatin receptors in Langerhans cell histiocytosis. Cancer 2002;94:633–40. © 2002 American Cancer Society. DOI 10.1002/cncr.10276

The eye complications associated most typically withhyperthyroidism caused by Graves’ disease range fromdiscomfort and lid retraction to disfiguring proptosis,diplopia and sight loss (1, 2). Usually called Graves’ophthalmopathy, this condition is better termedthyroid-associated ophthalmopathy (TAO), emphasis-ing the wide spectrum of thyroid disorders in thesepatients. TAO is one of the most difficult autoimmunedisorders to investigate; it is characterised by enlarge-ment of the extraocular muscles and an increase inthe retrobulbar fat, which cause eye proptosis, themain clinical manifestation of the disease (Table 1).Involvement of the cornea, the optic nerve and orbitalsoft tissues may occur during the natural course ofthe disease (3).An exact in vivo characterisation of the underlyingpatho-physiological mechanism of TAO has remaineddifficult because the affected retrobulbar space is noteasily accessible. The identification of patients withGraves’ ophthalmopathy is based primarily on clinicalsigns and symptoms affecting one or both eyes (4).Additional information can be obtained from conven-tional imaging methods such as magnetic resonanceimaging (MRI) or computed tomography (CT), whichallow gross changes in the retrobulbar space (e.g.muscle swelling, oedema or fibrosis) to be recognised(1, 2). By using histology, orbital infiltration withactivated T lymphocytes and evidence of local release ofcytokines and interactions of lymphocytes with retro-bulbar fibroblasts have been demonstrated, suggestingthat TAO is an organ-specific autoimmune disease (1,2, 5, 6). Although it is accepted that the pathogenesisof TAO is almost certainly multifactorial, the triggerevent seems to be the activation of T cells directedagainst a thyroid follicular cell antigen(s) that thenrecognise and bind to a similar antigen(s) in orbitaltissue (1, 2, 6). Thereafter, these activated orbital T cellsrelease a variety of substances and stimulate excessiveproduction of glycosaminoglycans and collagen byorbital fibroblasts. This causes the inflammatory andoedematous changes of thyroid ophthalmopathy (7). Infact, during the early stages of the disease, macro-phages, highly specialised T cells, mast cells and,occasionally, plasma cells infiltrate the orbital connec-tive, adipose and muscle tissue. Several cytokines, suchas interferon-g, tumour necrosis factor-a, interleukin-1 and transforming growth factor-b, as well as growthfactors, such as insulin-like growth factor-I (IGF-I) andplatelet-derived growth factor, have been detectedwithin the orbital tissues (5–8). All these substancesare probably produced both by infiltrating immuno-competent cells and by residential fibroblasts, adipo-cytes, myocytes and microvascular endothelial cells(9). Cytokines and growth factors stimulate cellproliferation, glycosaminoglycan synthesis and expres-sion of immunomodulatory molecules in orbitalfibroblasts and microvascular endothelial cells (Table2).No consensus exists regarding the common anti-gen in the orbit and thyroid, the thyrotrophin(thyroid-stimulating hormone, TSH) receptor or avariant, or on the role of circulating antibodiesagainst extraocular muscle and fibroblast compo-nents. The finding of expression of the TSH receptorin retro-orbital tissue may provide the link, pre-viously lacking, between orbital involvement andthyroid disease in Graves’ disease. Thyroid-stimulat-ing antibodies directed against the TSH receptorcould interact with the orbital components thatexpress the receptor, thus stimulating glycosamino-glycans, cellular matrix proteins and connectivetissue production and bringing about antibody-dependent cell-mediated cytotoxicity mediated bynatural killer cells. On the other hand, T cells thatreact with the TSH receptor will be targeted to theorbit where, in the presence of the antigen, they willsecrete various cytokines that stimulate fibroblasts toproliferate, to express the major complex of histo-compatibility class II antigens and to synthesizecollagen and connective tissue (10).

This case describes the first detection of solid lymphoma lesions by gallium-67 scintigraphy in a 12-year-old patient with Wiskott-Aldrich syndrome. Gallium 67 uptake was found in multiple sites in the patient who had developed an undifferentiated small, non-cleaved cell lymphoma. Response to chemotherapeutic treatment is correlated with findings on the gallium scintigraphy follow-up.

Corticosteroid treatment is successfully used in Graves' ophthalmopathy, and its effect varies according to the phase of the disease. The infiltration of the orbit by activated lymphocytes may explain the effectiveness of corticosteroid therapy. Scintigraphy with [111In-DTPA-D-Phe1]-octreotide was recently used to reveal the presence of activated lymphocytes in foci of autoimmune diseases, because elevated amounts of somatostatin receptors are expressed in the surface of these cells. The aim of the current study was to evaluate whether the degree of orbital [111In-DTPA-D-Phe1]-octreotide uptake is able to predict the response to corticosteroid therapy in patients with Graves' ophthalmopathy. Ten patients with Graves' ophthalmopathy entered the study. In all patients scintigraphy was performed, and subsequently, corticosteroid therapy (methylprednisolone, 1 g i.v. for 2 consecutive days a week for 6 weeks) was given. Clinical activity of Graves' ophthalmopathy was evaluated before and after treatment by calculating the ophthalmopathy index (OI). Planar and single photon emission computed tomography (SPECT) images of the head were obtained 24 h after the i.v. injection of 120-190 MBq of [111In-DTPA-D-Phe1]-octreotide. Radioligand uptake within each orbit (O) and brain (B) was measured using the region of interests (ROI) method and the O-to-B ratio was determined. According to the O-to-B ratio, the images were classified using the following three points score: 0 = O-to-B ratio < or =1; 1 = O-to-B ratio between 1 and 2.5; 2 = O-to-B ratio > or =2.5. The value of OI, measured before and after corticosteroid treatment, was correlated to the scintigraphic score. A significant change of OI was observed between posttreatment and pretreatment evaluation both in orbits with score 2 (OI: 15.4 +/- 1.5 vs. 9.6 +/- 0.5, P < 0.005) and in those with score 1 or 0 (OI: 12.9 +/- 1.5 vs. 11.5 +/- 1.4, P < 0.05) at the scintigraphy. However, when the OI was calculated excluding the changes in the soft tissue, which generally occur in all patients independently from the phase of the disease, a significant change of OI was observed only in the orbits with score 2 (OI: 12.9 +/- 1.3 vs. 8.3 +/- 0.5, P < 0.01) but not in those with score 0 or 1 (OI: 11.2 +/- 1.3 vs. 10.4 +/- 1.3). In particular, 6 weeks after corticosteroid treatment, the patients with orbital score 2 at the scintigraphy had a significant improvement of soft tissue changes, proptosis, lagophthalmos, extraocular muscle movements impairment, and diplopia, whereas patients with score 0 or 1 had only a significant improvement of the soft tissue inflammation. In conclusion, the current preliminary data suggested that [111In-DTPA-D-Phe1]-octreotide scintigraphy is able to predict the clinical response to corticosteroid treatment in patients with Graves' ophthalmopathy, and may be considered an useful approach to select the patients for the proper treatment.

The aim of the trial was to determine the diagnostic accuracy of scintimmammography with technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) in the detection of primary breast cancer and to verify its clinical usefulness. A total of 246 patients with a suspicious breast mass or positive mammogram were included in this prospective European multicentre trial. At 5 min and 60 min (optional) p.i. two lateral prone images were acquired for 10 min each; 30 min p.i. one anterior image was acquired for 10 min. There were 253 lesions (195 palpable and 58 non-palpable), in respect of which histology revealed 165 cancers and 88 benign lesions. Institutional and blinded read results were correlated to core laboratory histopathology results obtained during excisional biopsy. Diagnostic accuracy for the detection of breast cancer was calculated per lesion. The overall sensitivity and specificity of blinded read scintimammography were 71% and 69%, respectively. For palpable lesions, the sensitivity of blinded read and institutional read scintimammography was 83% and 91%, respectively. Sensitivity was not dependent on the density of the breast tissue. Invasive ductal and invasive lobular cancers showed similar sensitivity. The sensitivity and specificity of mammography were 91% and 42%, respectively, and did not depend on the tumour size. In 60% of false-negative mammograms, 99mTc-MIBI was able to diagnose malignancy (true-positive). High-quality imaging with 99mTc-MIBI has a high diagnostic accuracy for the detection of primary breast cancer. Used as a complementary method, scintimammography with 99mTc-MIBI can help to diagnose breast cancer at an earlier stage in patients with dense breasts.

The efficacy of dopaminergic agents in the medical treatment of pituitary adenomas is well known. Quinagolide is a nonergot derivative dopamine agonist, which binds dopamine D2 receptors with high affinity. The treatment with this drug is reported to suppress hormone levels and to cause tumor shrinkage in prolactinomas and in a few GH-secreting pituitary adenomas. In clinically nonfunctioning pituitary adenomas (NFPA), the efficacy of quinagolide treatment is controversial. The scintigraphy of the pituitary region using 123I-methoxybenzamide (123I-IBZM) allows us to visualize in vivo the expression of dopamine D2 receptors on pituitary tumors. In this study, the pituitary scintigraphy with 123I-IBZM was performed in 14 patients with macroadenoma before starting a long-term treatment with quinagolide: 6 NFPA with high circulating alpha-subunit levels, 4 PRL-secreting, and 4 GH-secreting adenomas. A 3-point score was used to grade the ligand accumulation within the pituitary adenomas: 0 = negative, 1 = moderate uptake (equal to that recorded in the cerebral cortex), and 2 = intense uptake (equal to that recorded in the basal nuclei). The treatment with quinagolide was carried out at the dose of 0.3-0.6 mg/day for 6-12 months. Clinical, biochemical and hormonal assessment was repeated monthly during the first 3 months, then quarterly. Sellar magnetic resonance imaging was performed before and after 6 and 12 months of quinagolide treatment, to evaluate tumor shrinkage (> 25% of baseline size). In all 14 patients, a significant positive correlation was found between the degree of 123I-IBZM uptake and the clinical response to quinagolide treatment (r = 0.90; P < 0.001). In particular, the normalization of serum alpha-subunit and PRL levels, respectively, was achieved in 3 patients with NFPA and in 2 patients with prolactinoma, who showed intense 123I-IBZM uptake in the pituitary region. In 4 of these 5 patients with positive scan, a significant tumor shrinkage occurred between 6 and 12 months after the beginning of quinagolide treatment. In all patients with GH-secreting adenoma, no significant uptake of 123I-IBZM was found and no significant decrease of circulating GH and/or insulin-like growth factor-I levels, and tumor shrinkage was obtained during long-term treatment with quinagolide. In conclusion, the pituitary scintigraphy with 123I-IBZM can be considered a useful tool to indicate adenomas with significant expression of functioning D2 receptors. This innovative technique may predict the response to long-term treatment with quinagolide in patients with NFPA, where the lack of pituitary hormone hypersecretion makes difficult the monitoring of medical treatment efficacy.

11008 Background: Early changes in tumor metabolism measured with positron-emission-tomography/computerized tomography (PET/CT) could predict the long-term efficacy of treatment better than dimensional RECIST response. Methods: We performed PET/CT before and after 1 cycle of treatment in patients with resectable liver metastases from colorectal cancer, within a phase II trial of preoperative FOLFIRI plus bevacizumab. For each lesion, the maximum SUV (SUVmax) and the total lesion glycolisis (TLG) were determined. For both, based on previous studies, a ≤-50% change from baseline was used as threshold for significant response. Metabolic response was categorized no/yes by using three different methods that enter into the calculation (i) the largest observed value (highest SUVmax/TLG), or (ii) the sum of all the observed values (Total SUVmax/TLG), or (iii) each observed values (SUVmax/TLG-by-lesion). Standard RECIST response was assessed after 3 months of treatment. The association between metabolic and RECIST response was tested with the Mc Nemar’s test and their agreement was expressed as Kappa statistics; the ability to predict progression-free (PFS) and overall (OS) survival was tested with Log-rank test and a multivariable Cox model. Results: 33 patients were analyzed. After treatment, there was a notable decrease of all PET/CT parameters, with a median change of -33.9% for the highest SUVmax, -61.5% for the highest TLG, -34.9% for the total SUVmax, and -65.5% for the total TLG. The association of SUV-based metabolic response (but not the TLG-based) with RECIST was statistically significant. However, the agreement between RECIST and PET/CT responses was consistently small. PFS and OS were significantly longer among PET/CT responding patients, whichever the measure used. On the contrary, no significant outcome difference was evident according to RECIST response. Conclusions: Early PET/CT response was significantly predictive of long-term outcomes during preoperative treatment of patients with liver metastases from colorectal cancer and its predictive ability was higher than that of RECIST response. Clinical trial information: 2006-006572-38.

Objectives : We have shown that pathological regression of LARC and relapse free survival can be predicted by early changes in FDG uptake during preoperative radiochemotherapy. We have attempted to improve efficacy of our neo-adjuvant treatment by adding an experimental bevacizumab (BEV) schedule. FDG PETCT was utilized to monitor response and correlate with pathological outcome. Methods : Forty six patients with poor prognosis LARC received 3 biweekly courses of oxaliplatin/ raltitrexed (day 1) and FU/ folinic acid (day 2) during pelvic RT (45 Gy). BEV (5 mg/kg) was administered on day -4 for the first 2 courses. PET-CT was performed at baseline, on day 12 and prior to surgery and lesion TLG (mean SUV x volume) values determined. Pathologic response was defined using a modified Mandard tumor regression grade (TRG) scale. Responders were defined as TRG1-2, non-responders as TRG3-4. Results : Thirty-seven patients (80%) showed pathologic response (65% with previous scheme). Eight patients (17%, previously 35%) were non-responders. Responders showed significantly higher TLG reduction on day 12 PET-CT (median -72% range -90%+31%) compared to non-responders (TRG3-4, median -38%, range -45% +25%, p < 0.05), confirming previous findings. Preoperative PET-CT studies, on the other hand, were not predictive of pathologic response (responders TLG change median -92%, range -100% +4%, non-responders median 86%, range -94%-76%, p = ns). Ongoing studies to define a correlation between FDG uptake and biomarkers of angiogenesis such as Circulating endothelial cells (CEC) will be presented. Conclusions : Our findings indicate that the current scheme significantly increases pathologic response. PET-CT confirms to be a powerful early surrogate marker of treatment efficacy. PET-CT may be used to tailor more aggressive treatment for non-responsive patient Citation Format: Antonio Avallone, Paolo Delrio, Biagio Pecori, Fabiana Tatangelo, Elena Di Gennaro, Antonella Petrillo, Vincenzo Rosario Iaffaioli, Alessandra Leone, Corradina caracò, Alfredo Budillon, Secondo Lastoria, Luigi Aloj. Predictive role of FDG PET-CT in monitoring locally advanced rectal cancer (LARC) during preoperative radiochemotherapy with an experimental bevacizumab schedule. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4695. doi:10.1158/1538-7445.AM2013-4695

In 10 patients with histologically proven neuroendocrine tumors (4 carcinoids, 4 pheochromocytomas, 1 medullary thyroid cancer and 1 Merkel tumor) the results of radiolabeled metaiodobenzylguanidine (MIBG) and somatostatin analogs were compared. A total of 24 tumor lesions was detected on standard imaging studies. MIBG scintigraphy correctly localized 12 (50%) of these lesions which were observed in 5 patients (4 with pheochromocytoma and 1 with carcinoid tumor). Scintigraphy using labeled somatostatin analogs correctly localized 21 (87%) lesions which occurred in 8 patients (4 with carcinoid, 2 with pheochromocytoma, 1 with medullary thyroid cancer and 1 with Merkel tumor). Concordant scintigraphic results were obtained in 1 patient with carcinoid and 2 with pheochromocytoma. In conclusion, although this series was limited, our results suggest that MIBG is more accurate than somatostatin analogs in imaging pheochromocytoma. Conversely, somatostatin analogs are more accurate than MIBG in detecting other neuroendocrine tumors such as carcinoids.

e19034 Background: Targeted therapy against the mutated form of BRAF V600 is a proven effective therapy for melanoma. Objective of this exploratory study was to describe the change over time of PET-scan results and verify the association of PET-scan examination with the objective response (OR) (defined by RECIST criteria) in melanoma pts treated with vemurafenib. These preliminary results reported here regards the description of changes over time of PET-scan. Methods: Patients treated with vemurafenib at our institution were considered eligible. Patients were evaluated with PET-scan at baseline and at day 7, 15 and 30 from the start of therapy. Maximal Standardized Uptake Value (SUVmax) and Total Lesion Glycolysis (mean SUV x lesion volume) were recorded and compared for single lesions in the 4 exams. Differences between each PET-scan performed during therapy and baseline were calculated and coded as yes/no response basing on predefined criteria. Association of PET responses and achievement of OR were estimated by means of logistic regression models. Odds ratio and C statistics were used to define strength of association and discriminant capability. C statistics obtained with PET/CT at different timepoints were compared. Results: As of January 2012, 7 out of 20 required pts have been enrolled. A total of 48 lesions were available for evaluation. A reduction in lesion SUVmax and TLG values compared to baseline was evident in all the post-therapy studies (reduction in SUV max at day 7 – 51 ± 28 %, day 14 – 67 ± 24 % and day 30 –69 ± 29 %, reduction in TLG at day 7 – 41 ± 83 %, day 14 – 69 ± 35 % and day 30 – 68 ± 37 %). A comparison of the day 15 and day 30 studies showed essentially stable uptake values (SUV max variation -3 ± 41 %, TLG 5 ± 56 %). However, 14/23 lesions in 3 patients showed increased SUV max and TLG values between the day 15 and day 30 studies likely indicating early signs of treatment resistance. Conclusions: Our preliminary results suggest that PET/CT may be an early surrogate marker of treatment response to vemurafenib. Sequential monitoring of targeted therapy with PET/CT may be useful in identification of treatment resistance, aid in tailoring alternative strategies and deserves further investigation.

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL BACKGROUND: The benefits of combining bevacizumab (BEV) plus chemotherapy have thus far been rather modest, stimulating interest in developing novel effective combination schedule as well as valid predictive biomarkers. Several evidences support the hypothesis that BEV can normalize the abnormal tumor vasculature, resulting in more efficient delivery of drugs and oxygen to cancer cells and that this effect seems to be transient and with a relatively narrow therapeutic window. In BRANCH study ([NCT01481545][1]) we assess the safety and efficacy of an experimental schedule of early (4 days before) BEV added to neoadjuvant chemotherapy (CT) and radiotherapy (RT) in poor-risk locally advanced rectal cancer (pLARC) patients (pts) and explore the potential of circulating endothelial cells (CECs) and tumor lesion glycolysis (TLG) as surrogate markers of pathological response. PATIENTS AND METHODS: 46 pts (cT4, cN+, cT3≤ 5 cm from the anal verge and/or positive circumferential margin, M1 resectable) received 3 biweekly courses of oxaliplatin (100 mg/m2)/raltitrexed (2.5 mg/m2) on day 1, and 5-FU (800 mg/m2)/folinic acid (250 mg/m2) on day 2 during pelvic RT (45 Gy). BEV (5 mg/kg) was given biweekly 4 days before beginning of CT/RT for 2 courses. Toxicity was graded with NCI-CTC v.3. Pathological response was defined using a modified Mandard tumor regression grade (TRG). According to the Simon's two-stage design, assuming an hypothesis of a 50% TRG1 (complete tumor regression) (α error=0.05, β error=0.20), at least 6/16 TRG1 should be obtained to continue accrual to 46 pts. CECs were quantified at baseline (BL) before BEV, at several time points thereafter during treatment and before surgery, by flow cytometry. TLG, was evaluated at BL, on day 10 and before surgery, by FDG-PET. Statistical analysis was by Mann-Whitney test. RESULTS: TRG1 required by statistical design was reached in the first 16 pts and in the final 46 pts: 23 TRG1 (50%), 14 TRG2 (30%) and 8 TRG3-4 (17%). One pt refused surgery. Grade ¾ neutropenia was the most common adverse event (13/46 pts, 28%). TLG reduction on day 10 vs BL was significantly higher in responders TRG1-2 compared to non-responders TRG3-4 pts (median -72%, range -90%+31% vs -38%, range -45%+25%; p < 0.05). Median CECs at BL were higher in TRG1-2 vs TRG3-4 pts (median 0.22/µl, range 0-3.98 vs 0/µl, range 0-0.174; p=0.009). Moreover, in TRG1-2 pts CECs were significantly reduced on day 10 vs BL (median 0.014/µl, range 0-2.29; p=0.002). This pattern was not seen in TRG3-4 pts with a tendency toward increased levels (median 0.316/µl, range 0-2.64; p=0.097). CONCLUSIONS: Early schedule of BEV plus CT and RT appears safe and active yielding high rate of TRG1 and TRG2 responses in pLARC. Early FDG-PET and CECs evaluation emerged as potential biomarkers for treatment selection to be incorporated in design of future studies with this regimen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-219. doi:1538-7445.AM2012-LB-219 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01481545&atom=%2Fcanres%2F72%2F8_Supplement%2FLB-219.atom

The rationale of this study was the evaluation of response to chemotherapy in children with advanced neuroblastoma using currently available diagnostic modalities.Iodine-131-metaiodobenzylguanidine (MIBG) imaging and 24-hr urinary vanillylmandelic acid (VMA) measurement were evaluated in 14 patients (7 males, 7 females, age range: 2-68 mo) with advanced neuroblastoma both pre- and postchemotherapy (5.6 +/- 2.8 mo) as well as serum ferritin (FER) and neuron-specific enolase (NSE) levels in 9 and 8 patients, respectively. MIBG images were qualitatively compared in each patient.Prechemotherapy, a total of 39 abnormal foci of MIBG uptake was detected. Postchemotherapy, 15 of these showed unchanged MIBG uptake, 7 had decreased uptake and 17 showed no uptake. In addition, four new abnormal foci of uptake were found. Postchemotherapy, a significant reduction of abnormal MIBG uptake (p0.01) was observed using a lesion-by-lesion analysis. When biochemical and MIBG postchemotherapy changes were compared, a significant relationship was found only between MIBG and VMA results (r = 0.84, p0.01).In postchemotherapy follow-up of children with advanced neuroblastoma, laboratory evaluation using VMA, FER and NSE measurements reflect only the global functional status of the disease, and are not helpful in defining the response of individual tumor lesions to treatment. Conversely, qualitative analysis using MIBG imaging may allow lesion-by-lesion evaluation of the heterogeneity of neuroblastoma response to chemotherapy. In this setting, changes in MIBG uptake are mirrored by the changes in catecholamine production, as measured by VMA levels.

Aims and Background In stage I oral squamous cell carcinoma, clinical examination and imaging techniques are unable to identify 60-90% of patients at risk of micrometastasis, while the sentinel node biopsy technique allows to avoid the morbidity of elective neck dissection in patients not actually affected by micrometastases. Materials and methods Forty-one T1-T2N0 patients underwent lymphoscintigraphy after peritumoral injection of human albumin labeled with 99Tc. Focal areas of radiotracer uptake were marked on the skin preoperatively. The sentinel lymph node (SLN) was identified by the combined use of blue dye and gamma probe and subsequently removed. Complete neck dissection was then performed in all patients and the histological findings were compared with those of SLN biopsy. Results The SLN was identified in 95% of the patients; in four cases (10%) two SLNs were isolated. In 18% of our patients the SLNs were located outside the expected drainage area. When the histology of the negative SLNs was compared with the pathological status of the neck dissection specimens no false negatives were found. Five SLNs in four patients contained micrometastases and were the only positive lymph nodes. Conclusion SLN biopsy can be a valuable staging technique in T1 and T2 oral cancer with uninvolved neck in patients whose lymphatic drainage of the neck has not been altered by previous surgery or radiotherapy. It provides reliable detection of micrometastasis, indicating which level(s) should be removed ipsilaterally or contralaterally, and allows the surgeon to accurately plan neck dissection, taking into consideration the pattern of lymphatic drainage of each individual patient. In this way unnecessary neck dissection and its morphofunctional sequelae can be avoided in a considerable number of patients.

e12502 Background: The extradomain B (ED-B) of fibronectin (FN) is a highly expressed marker of tumor angiogenesis and thus provides a molecular target for radioimmunotherapy (RIT). The RIT agent 1...

8063 Background: The extra-domain A1 (ED-A1) of tenascin-C is a highly expressed component of the tumor extracellular matrix and constitutes a valuable target for radionuclide therapy. Tenarad is a human antibody which is capable of recognizing ED-A1, has been labeled with I-131 and is expressed as small immunoprotein (SIP) for improving its biodistribution properties. Previous phase I/II studies with a similar compound (131I-L19SIP) have shown efficacy in a variety of cancer types. In this ongoing phase I/II trial, Tenarad is administered to patients with progressive Hodgkin lymphoma refractory to conventional treatment. Methods: Eight patients (4 M, 4 F, 19-41 yo) have been enrolled between April and December 2010. All patients had undergone at least three lines of chemotherapy; seven pts had prior external beam radiation therapy and six had prior autologous bone marrow or stem cell transplantation. All patients presented with nodal disease and some had involvement of the bone (n=3), lung (n=2) or liver...

Two hundred and thirty-four scintigraphic studies were performed in 34 patients (27 men, 7 women, age 17.3 +/- 7.7 years) with small, non-cleaved cell lymphoma who had follow-up for 3-96 months (mean 21.6 +/- 21.7 months). Whole-body scintigraphy was performed 48-72 h following i.v. injection of 370 MBq gallium-67 citrate. "Gold standards" for truth determinations were surgery, autopsy, histology, axial x-ray computed tomography, magnetic resonance imaging, ultrasonography and clinical follow-up. Overall, 181 of 234 studies were true negative. Eighty proven sites of disease had true positive 67Ga uptake (in 21 patients/37 studies). Nineteen sites (in 12 patients/15 studies) were false positive. In addition, 31 benign lesions were detected and interpreted correctly in terms of non-malignancy. Ten lymphoma sites (in 6 patients/10 studies) were missed by scintigraphy. Overall, sensitivity of gallium scintigraphy was 89% when calculated by sites and 79% when calculated by studies. Corresponding specificities were 91% and 92%, respectively. Positive predictive values were 81% (sites) and 71% (studies), and negative predictive values 95% (sites and studies). Thus, gallium scintigraphy proved to be a sensitive and specific method for staging and follow-up in patients with small, non-cleaved cell lymphoma.

Remarkable progress has been achieved in the field of tumor diagnosis with radiolabeled monoclonal antibodies. Here we summarize some of our previous clinical work concerning the use of radiolabeled monoclonal antibodies in the follow-up of patients with colon and ovarian cancer. We also discuss some of the limitations of the method derived from inadequate antibody delivery to the tumor and the importance of antigen density in determining tumor uptake. Finally we prospect the use of monoclonal antibodies for the in vivo characterization of tumors by external photoscanning.

Iodine-131 metaiodobenzylguanidine (MIBG) scintigraphy, computed tomography (CT) and ultrasonography (US) were used to localize tumour lesions in 28 children with histologically proven neuroblastoma. Overall, a total of 73 lesions were detected on imaging studies. MIBG scintigraphy, CT and US localized 63 (86%), 49 (67%) and 36 (49%) of these lesions, respectively. The findings of the three imaging techniques were concordant in respect of only 31 (42%) of the lesions. The best agreement among MIBG scintigraphy, CT and US was observed for abdominal lesions (the techniques were concordant for 22 of 23 lesions, i.e. 96%). MIBG scintigraphy detected nine out of ten (90%) liver metastases, but agreement with CT and US was observed in only six instances (60%). The imaging findings were concordant in respect of only two (33%) out of six lymph node metastases; the MIBG scan was normal in the other four cases. Imaging agreement was observed for a lesion located in the pelvis. MIBG and CT findings were concordant in four lesions located in the chest, but US was not performed. MIBG scintigraphy depicted the majority (96%) of the skeletal lesions (23/24); CT showed five of these, but, again, US was not performed. The imaging findings were not concordant as regards the remaining five lesions located in different anatomical sites. The results indicated that MIBG imaging is more sensitive that CT and US in localizing the majority of neuroblastoma lesions. Since the metastatic spread of neuroblastoma is unpredictable, we recommend MIBG scintigraphy as the initial imaging modality for staging of these patients. US and, particularly, CT should be performed thereafter to clarify the anatomical detail of the lesions detected on MIBG scans, or when MIBG findings are normal or equivocal.

Vascular endothelial growth factor (VEGF) has a crucial role in tumor angiogenesis, and its inhibition by bevacizumab (BEV) leads to normalization of tumor vessels increasing tumor oxygenation and drug delivery. However, the clinical benefits of current anti-VEGF treatments have thus far been rather modest, stimulating interest in developing novel effective ways to combine anti-VEGF drugs and chemotherapy (CT) and in the identification of valid predictive biomarkers of clinical benefit. We have previously shown that pre-operative oxaliplatin (OXA), raltitrexed (RTX), fluorouracil (5FU), and folinic acid (LFA) during pelvic radiotherapy (RT) have high rate of complete (TRG1) or subtotal (TRG2) tumor regression in locally advanced rectal cancer. In this study in order to demonstrate the relevance of the timing of BEV added to primary CT and RT we evaluate two different schedules of treatment. Changes of CECs and glucose metabolism, evaluated by flow cytometry and FDG-PET respectively, were used as early surrogate markers of tumor response. Thirty-two patients (inclusion criteria: cT4, cN+, cT3≤ 5 cm from the anal verge and/or +ve CRM, M1 resectable/initially unresectable) received 3 biweekly courses of OXA (100 mg/m2)/RTX (2.5 mg/m2) on day 1, and 5FU (800 mg/m2)/LFA (250 mg/m2) on day 2 during pelvic RT (45 Gy). In schedule A (16 pts) BEV (5 mg/kg) was given biweekly from day −14 for 4 courses, while in schedule B (16 pts) it was given from day −4 for 2 courses. Toxicity was graded with NCI-CTC version 3. According to the Simon's two-stage design, assuming an hypothesis of a 50% TRG1 (α error=0.05, β error=0.20), at least 6/16 TRG1 should be obtained (first stage) to continue pts accrual. Grade ¾ neutropenia was the most common adverse event with the schedule A (7 pts, 44%), but it was considerably lower with the schedule B (2 pts, 13%). Pre-treatment basal CEC amounts showed increased levels in the pts samples compared to the healthy controls. Notably, a significant difference of CEC levels, compared to basal levels, was observed 2 days after CT-RT between the two schedules of treatment (median +6% and −84% in schedule A and B, respectively, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3721.

Abstract 715 We previously reported interim results (Blood-ASH Annual Meeting Abstracts-2007 110: abstract 2324) of a prospective study evaluating dose-dense and dose-intense variants of ABVD regimen. Seventy pts with a newly diagnosis of cHL were enrolled from 06/04 to 03/08. Pts had intermediate-(INT) or advanced-stage (ADV) according to GHLSG criteria (Tab.1). INT (n=24) were treated with dd ABVD, and ADV (n=46) with dd-di ABVD. Briefly, the strategy concepts of treatment were: 6 cycles of chemotherapy; the inter-cycle period shortened from 28 to 21 days; drugs delivered at day 1 and 11 of each cycle; In the dd-di-ABVD, adriamycin was escalated from 50 to 70 mg/m2 in cycles 1-4; primary G-CSF was given; the therapy was driven by interim-FDG-PET; radiotherapy was planned with very stringent criteria. TOXICITY: On a total of 838 courses of chemo we had 18 events which needed red cell transfusion; 5 of severe thrombocytopenia completely reversed within one week; 25 of severe neutropenia ( DOSE INTENSITY STUDY: Median duration of chemotherapy (planned 18-wk) was 19.7-wk (range 17.6-21.7). Planned and delivered RDIs of drugs were significantly higher as compared with the most used regimens (Tab.2). RESPONSE: Early-CR (PETneg > 2 cycles) was obtained in 65/70 pts (95%). No statistical differences was noted between INT and ADV subsets. At the end of 6thcycle 69/70 pts (98,6%) were in CR. Three out of 69 complete responders (4.3%) had a biopsy-proven relapse: a 33-yr old man ( IVEA), a 27-yr old girl (IIB) and 29-yr old girl ( IVXEB). Relapsed occurred at 3, 10 and 14 months from the end of Tx, respectively. SURVIVAL: Data with a minimum follow up of 12-mo from the end of Tx were available in all 70 pts. Fig.1 shows the EFS rates of 24 INT-stage (95.8%), and 46 ADV-stage (91.3%) pts, respectively. A comparative analysis (Fig.2) between this series of 70 pts treated with dd ABVD or dd-di ABVD and the last 70 historical INT-stage (n=25) and ADV-stage (N=45) pts treated with baseline ABVD shows a statistically significant increment in EFS rate in pts receiving intensified ABVDs (93.0% vs 73.2% p=0.0041). CONCLUSIONS: The final results of this study shows that the activity of intensified ABVD is significantly higher than baseline ABVD in terms of response (CR) and survival (EFS) rates, still maintaining a low-toxicity profile. Based on these results a randomised comparison of intensified versus baseline ABVD seems justified. Disclosures: No relevant conflicts of interest to declare.

Fifteen patients with medullary carcinoma of the thyroid (MCT), who had persistently elevated levels of serum calcitonin (CT) and carcinoembryonic antigen (CEA) after total thyroidectomy, were studied in order to localize the sites of the recurrent disease. Routine diagnostic examinations, including ultrasonography (US) and computed axial tomography (CAT), were carried out in all the cases. Scintigraphy with radio-iodinated meta-iodobenzylguanidine ((131I)-MIBG) was performed in 13 cases; selective venous catheterization (SVC) to reveal a gradient of CT levels was performed in 12 cases. Ten patients underwent both (l31I)-MIBG scintigraphy and SVC. US and CAT revealed the sites of recurrent tumor in only 4 out of the total 15 patients. SVC in basal conditions showed the presence of small metastases in 2 cases, and after intravenous stimulus with pentagastrin in 4 others. The MIBG scan showed metastatic foci of sporadic MCT in 2 patients, residual medullary thyroid tissue in 4 others, and a pheochromocytoma in a previously undiagnosed patient with Sipple’s syndrome. More particularly, MIBG scan and SVC showed the localization of residual or metastatic tumor in 10 cases. In all 10 cases, results of the MIBG scan and SVC were confirmed as true positive by subsequent surgery and histopathologic examination. The conclusions of this study were twofold: (1) in the follow-up of MCT patients with persistently elevated CT and CEA levels, positive US and CAT findings make the MIBG scan useful, if positive, only to determine the nature of the lesion; (2) the association of the two approaches (MIBG scan and SVC) in patients with increased levels of CT and CEA but negative results of routine diagnostic examination can be useful to detect occult rnicrometastases, thus permitting an accurate clinicopathologic staging of the disease.

14500 Background: We have previously reported that 3 cycles of Oxaliplatin (OXA), Raltitrexed (TOM) and 5-Fluorouracile (FU) + levo-folinic acid (LFA) during pelvic RT had an acceptable toxicity and produced a complete (TRG1, 42%) or subtotal (TRG2, 29%) pathologic tumor regression in 71% of 31 pts with poor prognosis LARC (Avallone et al, Br J Cancer 2006). Here we report an expanded experience on such treatment. Methods: We enrolled 62 eligible pts (M, 33; F, 29), with median age of 58 (27–79) yrs, and adenocarcinoma of the extraperitoneal rectum, with at least one of the following characteristics: cT4 (N pts), cN+ (N), cT3N0 with tumor location = 5 cm from the anal verge and/or CRM +ve (assessed by MRI) (N). Pts received 3 biweekly courses of OXA 100 mg/sqm + TOM 2.5 mg/sqm on day 1, and LFA 250 mg/sqm + FU 900 mg/sqm (31 pts) or 800 mg/sqm (31 pts) on day 2, and concomitant pelvic RT (1.8 Gy/day, total dose 45 Gy). TME was planned 8 weeks after the end of treatment. Pathologic response was evaluated by tumor regression grading (TRG) according to Mandard’s modified classification. Pts with cT4, pN+ and pCRM +ve received also 4 months of weekly FU/FA. Results: All pts received full dose of RT, and 98% of the planned CT cycles. Neutropenia was the most common grade = 3 toxicity (40%), while grade 3 diarrhea was seen in 19% of pts with FU 900 mg/sqm, and in only 6% of pts with FU 800 mg/sqm. All but 2 pts had a TME with R0 resection, and no treatment-related or perioperative death occurred. Median number of sampled lymph nodes was 36 (range, 10–80). 28 (45%) pts obtained a TRG1, and 17 (27%) pts a TRG2. Activity of the treatment was similar in all risk groups, regardless of FU dosage. 1 pt suffered a local recurrence (after 9 months), and 3 pts had distant metastases (after 22, 33, and 47 months). After a median follow-up of 34 (range 6–54) months, all pts are alive, and the estimated 34-month RFS was 95%. All pts achieving a TRG1, and all but one with TRG2 (pCRM +ve), were recurrence-free. Conclusions: These data confirm the feasibility and activity of the whole treatment. A slight reduction of FU dosage appeared to improve the safety of this combination. Currently, we are now evaluating the addition of bevacizumab 5 mg/kg every 2 weeks before and during this concurrent treatment. No significant financial relationships to disclose.

Despite the mature results of the new intensive treatments, ABVD is still considered the standard therapy of the HL. Here we report the 2-year results of a phase 2 study which explore the possibility to ameliorate the performance of this (g)old schedule. Primary End-Points: CR and early cardio-toxicity. Secondary End-Points: survival (FFP,OS) and late cardio-toxicity. 23/25 CR (CI 90%) to validate the study (80% standard vs 90% DD-DI ABVD, CI +/− 10% one tail test, 5% sig stat level). Modifications of the standard (st) ABVD and strategy concepts are summarized as follow: Each patient received a total of 6 cycles without RT Adryamicin (ADM) was escalated from 50 to 70 mg/m2 in the cycles 1,2,3,4. The cumulative dose of ADM was 380 mg/m2. The intercycle period was shortened from 28 to 21 days for all 6 cycles; the 4 drugs were delivered at day 1 and 11 of each cycle G-CSF was given from d4 to d8, and from d14 to d18 of each cycle The therapy program was driven by dynamic indicators such as interim-PET and CT fusion images. Normalisation of PET images at the end of 2nd cycles was indicator of early CR, while the persistence of PET+ lesion(s) at the end of the 4th cycle was indicator of failure and consequently the treatment was shift to a high-dose CT/CD34+ rescue program. RT was eliminated. At the end of 6th cycle, PET- residual masses were monitored by PET/TC fusion images. An historical group of 94 HL pts treated with 6–8 cycles of st-ABVD +/− RT was used to compare response, survival and toxicity data. Compared to st-ABVD the theoretical relative dose-intensity (RDI) values of drugs were 1.86 for ADM, 1.33 for DTIC, Bleomycin and Vinblastine, and 1.46 for the entire schedule. Administered RDIs of the schedule (delivered cycles = 184) ranged between 1.10 to 1.55 (median value 1.39). Results: from June 2004 to August 2006 thirty-nine pts were enrolled (tab1). As the 8th August 2006 thirty-five out of 39 pts have performed the interim-PET-TC fusion images and thirty-two completed the treatment: 100% of valuable pts obtained the early CR (35/35) and CR (32/32). All pts are alive and free of disease (tab2 and fig.1). Cardiac functions were monitored by ECG, Ecography, MUGA scan, pro-BNP, and troponin T. Toxicity was mild and similar to standard ABVD. Dose-dense and dose-intense ABVD is feasible, well tolerated and highly active in newly diagnosed patients with advanced/intermediated Hodgkin’s lymphoma: six cycles without RT seem superior to 6–8 cycles of ABVD +/− RT (fig 1) and may be a promising program for optimal long-term results. tab1 presentation features Features total 39 100% Early unfavourable 9 23% Advanced 30 77% Age > 45 –yr 4 10% Bulky 19 44% Stage IV 13 33% B symptoms 25 64% Extranodal 9 23% VES > 50 mm 20 51% LDH Ratio > 1 15 38% IPS ≥ 3 10 26% N. Sites>3 28 72% Male 13 33% tab.2 Response and Survival N. of patients percent *n°. of valuable pts as 8 August 2006 Early CR 35/35* 100% CR 32/32* 100% FFP-2yr 32/32* 100% OS-2yr 32/32* 100% Freedom From Progression Freedom From Progression

Objective: Follicular lymphoma (FL) is the second most frequent type of non-Hodgkin’s lymphoma (NHL) representing 20–25% of all lymphomas worldwide. FDG-PET is currently adopted for staging and monitoring of patients (pts) with Hodgkin’s disease and aggressive NHL. Furthermore, the intensity of FDG uptake, as evaluated by standardized uptake value (SUV), has been recently shown to differentiate indolent from aggressive NHL and to correlate with tumor aggressiveness (Schöder H, et al. J Clin Oncol23: 1–9, 2005). In contrast, no data are yet available as to the prognostic significance of SUV in FL. Materials and methods: We investigated 62 consecutive patients (pts), median age 55 years (range 27–82 yrs), with newly diagnosed FL (WHO criteria) who underwent pre-treatment FDG-PET scanning at our institution. FDG-PET was performed before bone marrow biopsy and evaluators were blinded to the results of other diagnostic procedures. In all PET positive cases, areas of abnormal FDG uptakes were identified and the highest SUV per patient was calculated as previously described (Schöder H, et al. 2005). Study of SUV correlations with known prognostic factors in FL was performed by means of the SPSS (v11.01) statistical package using Chi-square, linear regression and receiver operating characteristic (ROC) curve analyses. Results: Overall, FDG-avid disease was demonstrated in 52 out of 62 pts (83.8%). The rate FDG-PET positivity did not correlate with histologic grading (G1, 76.9%; G2, 90.9 %; G3b, 85.7%; p=0.4), tumor cell proliferation rate (Ki-67 staining), extranodal involvement, bone marrow infiltration, B symptoms and bulky disease. Conversely, the rate of PET positivity appeared to progressively increase among pts with higher FL International Prognostic Index (FLIPI) score (low, 66.6%; intermediate, 93.7%, high, 95.4%; p=0.016), even though a direct correlation with single IPI components (age, stage, hemoglobin, LDH) was not statistically significant (p=0.49), except for the presence of > 4 involved nodal areas (p=0.04). The mean SUV of the entire pts population was 6.34 (r 1.2–24.5) and no significant differences were evidenced in relation to histologic grading (SUV: G1, 6.42; G2, 5.76; G3, 7.08). Even though a stepwise increase in mean SUV was evident among FLIPI risk subsets: low, 5.2(r 1.6–15), intermediate, 6.6 (r 1.3–24), high, 6.7 (r 1.2–16.2), statistical significance was not reached. In contrast, by stratifying pts according to 4 different groups with increasing SUV (i.e. 12) statistically significant associations were found with tumor cell proliferation rate (Ki-67; p=0.02), B symptoms (p=0.03) and bulky disease (p=0.0003). Finally, analysis of the ROC curve against prognostic factors confirmed that a SUV Conclusions: The intensity of FDG uptake in FL is independent from histologic grading but appears to correlate with some biologic features reflecting either tumor aggressiveness (i.e. proliferation rate) or host-tumor interplay (i.e. B symptoms) or high tumor load (i.e. bulky disease). While the rate of FDG-PET positivity is overall correlated with FLIPI risk, this appears mostly linked with nodal dissemination (> 4 sites) which may increase the probability of FDG uptake. These data suggest that serial FDG-PET evaluations are warrented in pts with FL.

To improve ABVD results we first developed a protocol which adds G-CSF to the standard ABVD treatment. From March 1997 to May 2004 69 patients with HL were treated with ABVD+G-CSF and 22 with a standard ABVD. Recently we designed a new dose-dense and dose-intensity ABVD scheme (escABVD-21) for advanced HL; in this new schedule the adriamycin was escalated from 25 to 35 mg/m2 (cycles 1,2,3,4) and the inter-cycle period was shortened from 28 to 21 days (for all 6 cycles); primary G-CSF was administered from d3 to d8 and drugs were delivered at d10 and d21 of every cycle. From June 2004, 19 patients were treated with this protocol. Relative dose-intensity (RDI) was calculated for any of these 110 newly diagnosed HL patients treated with ABVD. The results were also compared with a historical group of 70 patients who had undergone hybrid MOPP/ABVD. HL patients received from 4 to 8 cycles of CT +/− IF-RT. Patients were divided in 4 groups according to the RDI. The first group included 20 (11%) pts with RDI less than 0.80; the 2nd group, 64 (36%) pts with RDI values between 0.80 and 0.95, the 3rd group, 74 (42%) pts with RDI values between 0.96 and 1.10 and, finally, the 4th group included pts with RDI values of more than 1.10. In Tab 2 we report the CR, EFS and OS rates according to the 4 levels of RDI. Figures 1 shows EFS curve according to Kaplan-Meyer. Response and survival rates of groups 1,2,3 and 4 were: 50%vs91%vs97% vs 100%, for CR (p1.10. In particular, the new dose-dense and dose-intensity escABVD-21 protocol seems very promising in terms of complete response and toxicity profile: 19/19 pts (100%) obtained an early CR; (PET negative at the end of the 2nd cycle), and, as on 8th August 2005, all these19 patients were disease-free. The dose-escalation of adriamycin and the dose-density of the schedule were well-tolerated; toxicity was mild. These results show that subptimal RDI may compromise outcomes proportionally to the level of RDI reduction. On the contrary, Primary G-CSF permits to deliver dose-dense and dose intense schedules such as escABVD-21 maintaining the same profile of toxicity of standard ABVD, higher RDI levels, and consequently, a significant impact on complete response and survival rates. | n. of pts | male sex | age>45 yrs | advanced stage | E sites>1 | bulky | B symptoms | IPI score ≥ 3 | |:--------- | -------- | ---------- | -------------- | --------- | ----- | ---------- | ------------- | | 180 | 92 | 43 | 148 | 23 | 80 | 83 | 56 | | % | 51% | 24% | 82% | 13% | 44% | 46% | 31% | tab1 Presentation features | RDI level (range 0.5–1.5) | N. of pts. (%) | CR rate | Fisher’s Exact test (2-sided) | EFS rate | log-rank statistic | 0S rate | log-rank statistic | |:-------------------------:| -------------- | ------- | ----------------------------- | -------- | ------------------ | ------- | ------------------ | | overall | 180(100%) | 90% | | 80% | | 88% | | | 1.10 | 20 (11%) | 100% | | 100% | | 100% | | | significance | |

BackgroundParathyroid carcinoma is a rare malignancy, with an incidence of 0.5 to 4% of all cases of primary hyperparathyroidism. Surgery is the only curative treatment.Case presentationWe report the case of a 66-year-old man referred for a large suspicious substernal goitre associated with severe hypercalcemia due to hyperparathyroidism. After normalization of serum calcium levels, patient underwent surgery. The voluminous cervicomediastinal firm mass could not be removed through the cervical incision; therefore a cervicothoracic approach was employed. Histopathology revealed a giant parathyroid cancer of 450 grams. A review of the literature was also undertaken to summarize the current treatment approaches for this rare malignancy.ConclusionParathyroid cancer is usually not recognized either preoperatively or intra-operatively.En blocresection of the tumour with the adjacent tissue is the treatment of choice and it is very important to avoid the rupture of the capsule during operation. Neither tumour size, nor the lymph node status appears to play a role in prognosis. The management of parathyroid carcinoma is a challenge even for experienced surgeons.

A patient with an asymptomatic nonsecreting left adrenal pheochromocytoma concentrated I-123 MIBG. Iodine-123 MIBG scintigraphy showed abnormal uptake in the left adrenal bed. The authors conclude that I-123 MIBG imaging may allow the in vivo diagnosis of non-functioning pheochromocytomas when there is no clinical evidence of disease and other laboratory measurements are not helpful for tumor diagnosis.

Aimsand background The presence of lymph node metastases in patients with cutaneous melanoma represents the basis for correct therapy planning and is the most powerful prognostic factor to evaluate overall survival at diagnosis. Methods and Study Design Since 1992, when Dr Morton published his first experience, the sentinel lymph node (SLN) biopsy technique seems to have resolved this matter by correctly staging patients. We analyzed our data from 240 SLN biopsies performed in the last five years at the National Cancer Institute of Naples, evaluating the total identification rate and the nodal recurrence rate, and compared them with the preliminary data of the MSLT (melanoma sentinel lymph node trial). Results Of all SLNs evaluated 18.5% were micrometastatic and 14% were identified by immunohistochemical staining. Forty-one patients had metastatic SLNs and nodal dissection of the positive basins revealed no other tumor-positive lymph nodes in more than 80% of them. All patients with a Breslow thickness of less than 2 mm had micrometastases only in the SLN, while with increasing thickness two, three or more positive nodes were found. Among SLN-negative patients nine (4%) developed lymph node recurrence in the previously treated basin and were therefore considered as false negative SLN biopsies. Conclusions The prognostic value of SLN biopsy needs to be confirmed by the final results of the MSLT evaluating the therapeutic use of this procedure in patients with a Breslow thickness of less than 2 mm and its possible impact on the course of the disease.

Management of patients with cutaneous melanoma in the absence of lymph node metastases is still controversial. The experience at the National Cancer Institute in Naples was analyzed to evaluate 3-year disease-free survival and overall survival for all patients who underwent sentinel lymph node biopsy (SLB) with Breslow thickness greater than 4 mm. Data from 359 sentinel biopsies performed in the past 5 years were reviewed to determine the effect of the treatment on disease-free survival and overall survival after stratifying patients for node status, tumor ulceration, and Breslow thickness. Statistical analysis showed a better 3-year survival for sentinel node-negative patients than for sentinel node-positive cases (88.4% and 72.9%, respectively;P

To evaluate alterations induced by injected murine radiolabelled F(ab')2 fragments of the anti HMW-MAA MoAb 225.28S on the principal haemato-immunological parameters, 32 patients with advanced malignant melanoma were studied. No statistically significant change was found after MoAb administration, but monocytes (3 h after injection) and granular eosinophils (24 h after) were reduced and circulating immune complexes increased (3 h after). No toxic effect or adverse reaction was observed. Therefore, the controlled administration of purified MoAb fragments for diagnostic purposes seems to involve only a very low risk of immediate adverse reactions.

The most powerful prognostic factor in patients with oral cancer is the presence of lymph node metastases. The management of the neck at diagnosis in the absence of adenopathy is still controversial, but sentinel lymph node biopsy (SLB) may help resolve this issue. At the National Cancer Institute in Naples, we performed SLB in 41 patients with T1 to T2 oral cancer. All patients underwent lymphoscintigraphy. Intraoperative blue dye and gamma probe examination identified a sentinel node (SN) in 39 patients. Four patients (10%) had double drainage, and 7 (18%) had drainage beyond the expected anatomical site. Complete concordance between the pathology of the SN and nodes obtained from radical dissection confirmed SLB as a reliable staging procedure. Since January 2001, seven patients with T1 to T2 oral cancers have been staged with SLB only; modified radical neck dissection was carried out only in cases with a positive SN. The rate of SN identification was 100%, and all five cases with negative SNs were free of disease after a median follow-up of 10 months. Lymphoscintigraphy plus SLB seems to be a good staging system for guiding neck management in patients with oral cancer. A larger number of patients and a longer follow-up in a randomized trial will confirm the potential staging value of this procedure and determine which patients might benefit from a conservative approach that avoids radical neck dissection.