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Synchronous cancers are not such rare clinical conditions. Nevertheless, even after the 8th edition of the TNM classification of the lung cancer, the surgical approach for patients presenting with synchronous bilateral lung cancer is still under debate. The resection of both lesions in the case of synchronous bilateral lung cancer is reasonable, but, on the other hand, is the lobectomy the correct choice in the event of the single primary with a contralateral metastatic lesion? In this case report, we describe how the molecular analysis and the detection of the EGFR, KRAS and TP53 mutations in both tumours have determined in a patient the two tumours as primary and both the right surgical approach. We also discuss how molecular analysis found differences in all the three genes examined in the two lesions and allowed to exclude the clonal nature of the two tumours. In conclusion, genetic studies help to offer a more radical surgical treatment to this patient., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Aim: This study aimed at assessing the impact of attenuation correction performed by means of a new hardware device (Beacon(tm)) in the assessment of coronary artery disease with myocardial SPECT and, afterwards, at identifying what specific risk class of patients would mostly benefit from the technique., Methods: The first 500 consecutive patients, referred to our facility for coronary artery disease (CAD) assessment, were included in this study. Myocardial SPECT was performed after i.v. of 740 MBq of (99m)Tc Tetrofosmin (Myoview, Amersham Health) both after stress and at rest. Studies were acquired by means of a 3 head system (IRIX, Philips Medical System) equipped with the Beacontm option to correct for non-uniform attenuation. Out of the whole population studied, 130 patients underwent coronary angiography (CAG), 108 of which were proven to be affected by significant CAD, defined as a >50% coronary vessel lumen reduction. Attenuation corrected (AC) as well as non-attenuation corrected studies (NAC) were reconstructed, blindly read and qualified as: normal; borderline normal; borderline abnormal and definitely abnormal., Results: In the group of 130 patients who underwent CAG, sensitivity for CAD detection did not vary significantly (96% and 93%, for NAC and AC studies, respectively, p=ns) whereas specificity increased from 73% (NAC studies) to 91% (AC studies), p<0.01. Normalcy rate, assessed in a small subgroup (n=21) with a <5% likelihood for CAD, was found to be 80% for NAC studies vs 93% for AC studies (p<0.05). As regards synthetic clinical judgements, when we grouped normal and probably normal readings into a single ''normal'' category and, conversely, probably abnormal and definitely abnormal into a single ''pathological'' category, we see that after attenuation correction studies reported as ''pathological'' are reclassified as ''normal'' in 17.8% of the cases (25.2% in males and 6.9% in females, p<0.05). The opposite is seen in only 1.6% of the cases (1.3% in males and 4.4% in females). According to established criteria, 155 patients were classified at low risk for CAD (<15%), 115 at intermediate risk (from >15% to <50%) and 230 at high risk (>50%). The intermediate risk class showed the greatest impact: ''normal'' findings increased from 52% to 72%, thus reducing the rate of ''pathological'' reports from 48% to 28%., Conclusions: This study shows that, while sensitivity for CAD is not affected by attenuation correction, specificity increases significantly, as well as normalcy rate. Out of the whole population studied, the main finding was that attenuation correction increases the rate of normal reports, more frequently in males than in females, and that studies carried out in patients at intermediate risk for CAD are more likely to be affected.

To investigate somatostatin receptors (SSTRs) in primary or metastatic high-grade osteosarcoma, 18 patients (12 without metastases, 4 with synchronous lung, and 2 with metachronous bone metastases) underwent SSTR scintigraphy. After intravenous (i.v.) injection of 200-250 MPq of 111In-pentreotide, images were recorded at 4 and 24 hours. All patients underwent 99mTc-methylene diphosphonate (MDP) bone scan (BS). Scans were interpreted both with qualitative evaluation and with semiquantitative image processing, by means of tumor-to-background ratio modification over time. Primary tumor: SSTR scintigraphy was positive in 12 (75%) patients: 10 (83%) of the 12 nonmetastatic patients, and 2 (50%) of those with synchronous metastases. Metastases: SSTR scintigraphy was positive only in one (17%) of the six patients with metastatic disease. No relation was found between SSTR scintigraphy results and gender, histologic subtype, site, and size of the tumor. After primary chemotherapy, 15 patients underwent surgery of primary tumor; a good histologic response was found in 7 (64%) of the 11 patients with positive SSTR scintigraphy versus 1 (25%) of the 4 patients with negative SSTR scintigraphy. High-grade osteosarcoma exhibits somatostatin receptors, usually detectable in the primary tumor, but not in the metastatic lesions. The different expression of somatostatin receptors observed in primary and metastatic lesions, and in patients with tumors having different chemosensitivity, could indicate a possible relation between somatostatin receptors and biological behavior of the tumor.

The aim of this study was to determine the maximum tolerated dose of (90)Y-DOTATOC per cycle administered in association with amino acid solution as kidney protection in patients with somatostatin receptor-positive tumours. Forty patients in eight groups received two cycles of (90)Y-DOTATOC, with activity increased by 0.37 GBq per group, starting at 2.96 and terminating at 5.55 GBq. All patients received lysine +/- arginine infusion immediately before and after therapy. Forty-eight percent developed acute grade I-II gastrointestinal toxicity (nausea and vomiting) after amino acid infusion whereas no acute adverse reactions occurred after (90)Y-DOTATOC injection up to 5.55 GBq/cycle. Grade III haematological toxicity occurred in three of seven (43%) patients receiving 5.18 GBq, which was defined as the maximum tolerable activity per cycle. Objective therapeutic responses occurred. Five GBq per cycle is the recommended dosage of (90)Y-DOTATOC when amino acids are given to protect the kidneys. Although no patients developed acute kidney toxicity, delayed kidney toxicity remains a major concern, limiting the cumulative dose to ~25 Gy. The way forward with this treatment would seem to be to identify more effective renal protective agents, in order to be able to increase the cumulative injectable activity and hence tumour dose.

Gaucher disease (GD), the most prevalent lysosomal storage disease characterized by a remarkable degree of clinical variability, results from deleterious mutations in the glucocerebrosidase gene (GBA). In this paper we report the molecular characterization of 144 unrelated Italian GD patients with the three types of the disease. The allelic frequencies of Italians are reported and the mutation profile is analyzed. Besides the common N370S, L444P, RecNciI, G202R, IVS2+1G>A, D409H, F213I mutations, the different molecular strategies, used for the mutation detection, identified the rare N107L, R131C, R170C, R170P, N188S, S196P, R285C, R285H, W312C, D399N, A446P, IVS10-1G>A, RecDelta55, total gene deletion, as well as 12 mutant alleles that were exclusively present in the Italian population until now: the previously reported R353G, N370S+S488P mosaicism, IVS8(-11delC)-14T>A), Rec I, Y418C, and the seven novel alleles D127X, P159T, V214X, T231R, L354X, H451R, and G202R+M361I. The wide phenotypic differences observed within the genotypic groups as well as between siblings implicate a significant contribution of other modifying genetic and/or non-genetic factors and claim a comprehensive valuation of the patient including clinical., biochemical and molecular investigations for prognosis, appropriate interventive therapy and reliable genetic counseling., (Copyright 2002 Wiley-Liss, Inc.)

A newly developed somatostatin radioligand, DOTA-[D-Phe1-Tyr3]-octreotide (DOTATOC), has been synthesised for therapeutic purposes, because of its stable and easy labelling with yttrium-90. The aim of this study was to determine the dosage, safety profile and therapeutic efficacy of 90Y-DOTATOC in patients with cancers expressing somatostatin receptors. We recruited 30 patients with histologically confirmed cancer. The main inclusion criterion was the presence of somatostatin receptors as documented by 111In-DOTATOC scintigraphy. 90Y-DOTATOC was injected intravenously using a horizontal protocol: patients received equivalent-activity doses in each of three cycles over 6 months. The first six patients received 1.11 GBq per cycle and the four successive groups of six patients received doses increasing in 0.37-GBq steps. Toxicity was evaluated according to WHO criteria. No patient had acute or delayed adverse reactions up to 2.59 GBq 90Y-DOTATOC per cycle (total 7.77 GBq). After a total dose of 3.33 GBq, one patient developed grade II renal toxicity 6 months later. The maximum tolerated dose per cycle has not yet been reached, although transient lymphocytopenia has been observed. Total injectable activity is limited by the fact that the maximum dose tolerated by the kidneys has been estimated at 20-25 Gy. Complete or partial tumour mass reduction occurred in 23% of patients; 64% had stable and 13% progressive disease. It is concluded that high activities of 90Y-DOTATOC can be administered with a low risk of myelotoxicity, although the cumulative radiation dose to the kidneys is a limiting factor and requires careful evaluation. Objective therapeutic responses have been observed.

Recent advances in receptor mediated tumor imaging led to the development of a new somatostatin analogue DOTA-D-Phe1-Tyr3-Octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, stable labeling with yttrium-90 (90Y) and favourable biodistribution in patients. The aim of this work was to evaluate acute and late toxicity and the response rate in cancer patients administered 90Y-DOTATOC. Twenty patients received three equal i.v. injections of 90Y-DOTATOC. Cohorts of 5 patients were treated starting with 1.1 GBq per cycle in escalating dosage (0.4 GBq increments) in subsequent groups. No patients showed acute or delayed major adverse reactions up to the dose of 2.2 GBq of 90Y-DOTATOC per cycle (6.6 GBq total). Maximum tolerated dose has not been determined yet. One patient, after 4.4 GBq total dose, developed delayed kidney grade II toxicity. Complete and partial tumor mass reduction (CR and PR) was measured in 25% of patients along with 55% showing stable disease (SD) and 20% progressive disease (PD). These results indicate that high activities of 90Y-DOTATOC can be administered with low risk of myelotoxicity, although the radiation doses to the kidneys require careful consideration. Tumor doses were high enough in most cases to obtain objective therapeutic responses.

Recent advances in receptor-mediated tumour imaging have resulted in the development of a new somatostatin analogue, DOTA-dPhe(1)-Tyr(3)-octreotide. This new compound, named DOTATOC, has shown high affinity for somatostatin receptors, ease of labelling and stability with yttrium-90 and favourable biodistribution in animal models. The aim of this work was to evaluate the biodistribution and dosimetry of DOTATOC radiolabelled with indium-111, in anticipation of therapy trials with (90)Y-DOTATOC in patients. Eighteen patients were injected with DOTATOC (10 microg), labelled with 150-185 MBq of (111)In. Blood and urine samples were collected throughout the duration of the study (0-2 days). Planar and single-photon emission tomography images were acquired at 0.5, 3-4, 24 and 48 h and time-activity curves were obtained for organs and tumours. A compartmental model was used to determine the kinetic parameters for each organ. Dose calculations were performed according to the MIRD formalism. Specific activities of >37 GBq/ micromol were routinely achieved. Patients showed no acute or delayed adverse reactions. The residence time for (111)In-DOTATOC in blood was 0.9+/-0.4 h. The injected activity excreted in the urine in the first 24 h was 73%+/-11%. The agent localized primarily in spleen, kidneys and liver. The residence times in source organs were: 2.2+/-1.8 h in spleen, 1.7+/-1.2 h in kidneys, 2.4+/-1.9 h in liver, 1.5+/-0.3 h in urinary bladder and 9. 4+/-5.5 h in the remainder of the body; the mean residence time in tumour was 0.47 h (range: 0.03-6.50 h). Based on our findings, the predicted absorbed doses for (90)Y-DOTATOC would be 7.6+/-6.3 (spleen), 3.3+/-2.2 (kidneys), 0.7+/-0.6 (liver), 2.2+/-0.3 (bladder), 0.03+/-0.01 (red marrow) and 10.1 (range: 1.4-31.0) (tumour) mGy/MBq. These results indicate that high activities of (90)Y-DOTATOC can be administered with low risk of myelotoxicity, although with potentially high radiation doses to the spleen and kidneys. Tumour doses were high enough in most cases to make it likely that the desired therapeutic response desired would be obtained.

While the incidence of brain tumours seems to be increasing, median survival in patients with glioblastoma remains less than 1 year, despite improved diagnostic imaging and neurosurgical techniques, and innovations in treatment. We have developed an avidin-biotin pre-targeting approach for delivering therapeutic radionuclides to gliomas, using anti-tenascin monoclonal antibodies, which seems potentially effective for treating these tumours. We treated 48 eligible patients with histologically confirmed grade III or IV glioma and documented residual disease or recurrence after conventional treatment. Three-step radionuclide therapy was performed by intravenous administration of 35 mg/m2 of biotinylated anti-tenascin monoclonal antibody (1st step), followed 36 h later by 30 mg of avidin and 50 mg of streptavidin (2nd step), and 18-24 h later by 1-2 mg of yttrium-90-labelled biotin (3rd step). 90Y doses of 2.22-2.96 GBq/m2 were administered; maximum tolerated dose (MTD) was determined at 2.96 GBq/m2. Tumour mass reduction (>25%-100%), documented by computed tomography or magnetic resonance imaging, occurred in 12/48 patients (25%), with 8/48 having a duration of response of at least 12 months. At present, 12 patients are still in remission, comprising four with a complete response, two with a parital response, two with a minor response and four with stable disease. Median survival from 90Y treatment is 11 months for grade IV glioblastoma and 19 months for grade III anaplastic gliomas. Avidin-biotin based three-step radionuclide therapy is well tolerated at the dose of 2.2 GBq/m2, allowing the injection of 90Y-biotin without bone marrow transplantation. This new approach interferes with the progression of high-grade glioma and may produce tumour regression in patients no longer responsive to other therapies.

In stage I cutaneous melanoma, biopsy of the first tumour-draining lymph node (sentinel node, SN) may replace routine elective lymph node dissection (ELND). The patent blue dye (PBD) technique has been shown to be an original method for the localization of the SN, but its sensitivity is sometimes unsatisfactory, depending on the basin where the SN is located. We compared three methods to locate the SN: intraoperative PBD mapping, lymphoscintigraphy (LS) with an aspecific tracer (colloid) and LS with a specific tracer (monoclonal antibody, MoAb). Fifty patients with cutaneous melanoma were enrolled in this study. The day before surgery LS was performed following an intradermal injection of 55 MBq technetium-99m-labelled HSA colloidal particles (25 patients: group A) or 220 MBq of 99mTc-F(ab')2 MoAb 225.28 S (25 patients: group B) around the site of the primary lesion. In group B an equal amount of tracer was injected, as a control, in the contralateral site. Early and delayed images were acquired with a gamma camera and SN(s) marked on the skin. In all 50 patients the PBD technique was also performed immediately before surgery. When a blue node was identified intraoperatively, its radioactivity level was measured with a gamma probe. In the absence of blue coloration, the probe alone was used to detect the SN. Lymphoscintigraphic visualization of SNs was possible in 50/50 patients (100%), a total of 73 SNs (38 in group A and 35 in group B) were found, distributed in 55 basins. Gamma probe detection (GPD) allowed the identification of SNs in 49/50 patients (98%), and 72 SNs in 54 basins were localized. By contrast, using PBD, SNs were stained only in 40/50 patients (50 SNs in 40 basins). A tumour-positive SN was histologically proven in 13 patients (26%). In group B, no increase uptake was observed in the seven positive SNs (6/25 patients) compared with the contralateral uninvolved nodes. In conclusion this study demonstrates that LS combined with GPD is a safe method for detecting SNs and is more sensitive than the PBD technique. The use of MoAb fragments did not show any advantage over the non-specific tracer.

Unlabelled: Eight children affected by idiopathic chronic thrombocytopenia were studied for history of food allergy, anti-platelet antibodies, total IgE, prick test for food antigens, AGA and EMA. They were free of treatment for thrombocytopenia since at least six months before. Three children had in the first year of life intolerance to cow's milk proteins with atopic dermatitis and/or poor growth. None had AGA or EMA positivity. 6/8 had positivity for anti-platelet antibodies. A 15-days oligoantigenic diet was instituted in all of them. Platelet count was unaffected in all but one, in which a sharp increase was noted (from 19x 10(9)/l. to 150x 10(9)/l.). He was a 12-year-old boy with a previous history of cow's milk intolerance and actual skin prick test positivity for casein and lactoglobulin. A one-year follow up for this case was instituted and he was put on two further 15-days periods of oligoantigenic diet, but no change in platelet count was noted any more., Conclusion: we were not able to correlate chronic thrombocytopenia to food allergy.

The present multicentre study, conducted in patients with angina pectoris on chronic therapy with continuous 24-hour transdermal nitroglycerin was aimed at investigating: (1) the actual incidence of nitrate tolerance; (2) the clinical features that characterize those who do not develop tolerance; (3) whether the evidence of clinical and ergometer benefits at 1-month assessment predicts their long-term maintenance. Eligible patients (n = 110; average age 56 +/- 5 yrs) had stable angina pectoris (78 effort angina, 32 mixed angina) with symptom-limited, reproducible cycloergometer tests and were responsive to s.l. nitroglycerin. After a 7-day washout period and a placebo run-in week, all patients were assigned to continuous 10 mg/24-hour nitroglycerin patches (T0). Exercise tests were performed again after 1 month (T1) and 6 months (T6) of treatment. At T1, ergometric data in each patient were compared with those at T0 and showed an increase (> or = 15%) in exercise tolerance in only 61/110 patients: 38 (49%; Group A) of the 78 patients with effort angina and 23 (72%; Group B) of the 32 patients with mixed angina (p < 0.05). Those patients with no significant change in exercise tolerance were assigned to conventional antianginal therapy and were excluded from the study. At T6, both group A and B patients maintained the favourable effects on total exercise duration, time and maximum workload at ischemic threshold and maximal ST depression recorded at T1 vs T0. The weekly attacks of angina and nitroglycerin s.I. consumption decreased significantly in both Group A and Group B patients from the beginning of therapy and throughout the study. These results show that: 1) tolerance to continuous 24-hour transdermal nitroglycerin therapy is not constant phenomenon, but occurs only in a subgroup of patients; 2) patients with mixed angina are more resistant to develop tolerance than those patients with effort angina; 3) the 1-month evidence of clinical and ergometric benefits predicts their maintenance during long-term treatment, as well. These results allow one to hypothesize that the loss of nitrate efficacy on venous pooling capability, but not on arterial tone, might constitute the more frequent cause of tolerance.