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While it is known that exhaled nitric oxide (ENO) is increased in adults and school children with asthma exacerbation probably as an expression of disease activity, no studies have investigated whether this phenomenon also occurs in infants and young children with recurrent wheeze exacerbation. We measured ENO in 13 young children (mean age 20.2 mo) with recurrent wheeze (Group 1) during an acute episode and after 5 d of oral prednisone therapy. ENO was measured also in nine healthy control subjects (Group 2) (mean age 16.9 mo) and in six children with a first-time viral wheezy episode (Group 3) (mean age 11 mo). To measure ENO, infants inhaled NO-free air via a face mask from a reservoir and, through a nonrebreathing valve, exhaled in a collecting bag that was analyzed by chemiluminescence. To address the question of whether the levels of ENO collected in the bag are a reflection of the pulmonary airway, ENO determinations were performed in two healthy infants before and after tracheal intubation for elective surgery. During the acute episode of wheezing the mean (+/- SEM) value of ENO in children with recurrent wheeze (Group 1) was 14.1 +/- 1.8 ppb, almost threefold higher than in healthy control subjects (5.6 +/- 0.5 ppb, p < 0.001). After steroid therapy we found a mean fall of 52% in ENO (5.9 +/- 0.7 ppb, p < 0.01) compared with baseline values. ENO values measured before and after intubation in two infants were 6 ppb and 5 ppb in one child and 7 ppb and 6 ppb in the other one. The mean value of ENO of children with first-time wheeze (Group 3) was 8.3 +/- 1.3 ppb, significantly lower (p < 0.05) than the value of children with recurrent wheeze (Group 1). In conclusion, we describe a method to measure ENO in young children and show that infants with recurrent wheeze have elevated levels of ENO during exacerbation that rapidly decrease after steroid therapy. This suggests that, in these children, airway inflammation could be present at a very early stage.

Lung cancer represents the major cause of cancer-related death in Europe and North America, accounting for 28% of all cancer deaths. Seventy to 80% of all lung cancers are non-small cell lung cancers (NSCLCs), and approximately 75 % of these patients present with locally advanced or disseminated disease. Even though chemotherapy is now recommended in the majority of cases of unresectable NSCLC, it still fails to substantially modify the fate of these patients. In recent years, several active cytotoxic drugs (paclitaxel, docetaxel, vinorelbine, gemcitabine, and irinotecan) have been developed, showing an overall response rate (ORR) <20% in NSCLC. Phase II/III trials testing these new agents in combination with cisplatin have been carried out in recent years with inconsistent results. Large randomized trials testing cisplatin-paclitaxel, carboplatin-paclitaxel, and cisplatin-gemcitabine regimens have been reported showing no substantial superiority of these combinations over standard treatments. The ORR remained well below 50%, and the median survival times were quite far from one year. These data could suggest that the addition of a single new agent to a platinum compound could be insufficient to substantially improve the prognosis of advanced NSCLC patients. In view of these disappointing data, the Southern Italy Cooperative Oncology Group has tried to improve the fate of patients with advanced NSCLC by testing new triplet combinations, which combined cisplatin with two rather than one of the newest chemotherapy agents. To avoid an unacceptable increase in toxicity and/or a marked decrease in dose intensity, the standard schedules of administration of the three agents used in these studies were changed, and the schedule changes were evaluated in phase I trials aimed at determining the maximum tolerated dosages of the drugs. Subsequently, phase II and III trials were conducted. The present paper summarizes the results of the clinical trials either completed or under way and aims to evaluate whether this strategy will result in a substantial prognostic improvement.

The aim of this prospective study was to evaluate the bone mineral density (BMD) at lumbar spine and femoral neck levels and biochemical parameters of bone turnover in 20 consecutive hyperprolactinemic males before and after an 18-month treatment with different dopamine agonists. Six patients received bromocriptine at a dose of 2.5-10 mg/day; 7 patients received quinagolide at a dose of 0.075-0.3 mg/day; 7 patients received cabergoline at a dose of 0.5-1.5 mg/week. BMD, serum PRL, testosterone, dihydrotestosterone, and osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were measured before and every 6 months during treatment. At study entry, BMD values were lower in patients than controls at both lumbar spine (0.82 +/- 0.03 vs. 1.18 +/- 0.01 g/cm2; P < 0.001) and femoral neck (0.85 +/- 0.02 vs. 0.92 +/- 0.02 g/cm2; P < 0.05) levels. Osteopenia or osteoporosis was diagnosed in 16 patients at the lumbar spine and in 6 of them at the femoral neck level. A significant inverse correlation was found between lumbar spine and femoral neck BMD values and both PRL levels and disease duration (P < 0.01). In the 20 patients, serum OC levels were significantly lower (2.1 +/- 0.1 vs. 9.3 +/- 2.4 microg/L; P < 0.01), whereas Ntx levels were significantly higher (157.8 +/- 1.1 vs. 96.4 +/- 7.4 nmol bone collagen equivalent/mmol creatinine; P < 0.001) than control values. A significant inverse correlation was found between serum PRL and OC (P < 0.01), but not Ntx, levels. After 18 months of treatment, serum PRL levels were suppressed, and gonadal function was restored in all 20 patients, as shown by the normalization of serum T (from 2.2 +/- 0.2 to 5.0 +/- 0.2 microg/L) and dihydrotestosterone (0.3 +/- 0.02 vs. 0.5 +/- 0.01 nmol/L) levels, without any significant difference among groups. A progressive significant increase in serum OC levels together with a significant decrease in Ntx levels were observed after 6, 12, and 18 months of treatment in the 3 groups of patients. A slight, although significant, increase in BMD values was recorded in all patients after 18 months of bromocriptine, quinagolide, and cabergoline treatment, serum OC levels were normalized after treatment, whereas neither urinary Ntx levels nor BMD values were normalized by 18 months of treatment with dopaminergic agents. In conclusion, treatment with bromocriptine, quinagolide, and cabergoline for 18 months, although successfull in suppressing serum PRL levels and restoring gonadal function, was unable to restore lumbar spine and femoral neck BMD and normalize Ntx levels. However, BMD was slightly increased during treatment, suggesting that additional bone loss was prevented after treatment of hyperprolactinemia.

Aim of our study was to evaluate the uptake of Indium-111 Octreotide (OCT) at the level of thyroid and orbits in autoimmune thyroid diseases. Nine patients with Graves' disease (GD) who were also affected with thyroid associated ophthalmopathy (TAO) and four patients with Hashimoto's thyroiditis (HT) were evaluated. A patient with lung cancer, presenting ophthalmopathy did not related to autoimmune dysthyroidism, was also studied. All patients with ophthalmopathy were evaluated by a Clinical Activity Score and an A-scan standardized echography. Multiple planar images were acquired over a 24-hour period after i.v. injection of 111 MBq of 111In-OCT. A SPECT study was also obtained in 7 patients five hours after the injection. A qualitative analysis was performed. Semiquantitative ratios comparing the counts on the thyroid with respect to background (T/BK) and on the orbits and brain with respect to the blood-pool were also obtained. Thyroid uptake of OCT was higher in GD with respect to HT, and was not related to the functional state of the gland. The highest T/BK ratio was observed at the 24 hour control. Intense orbital uptake was observed only in case where a clinically active ophthalmopathy was present.

Thyroid Associated Ophthalmopathy (TAO) is an autoimmune disorder generally associated with Graves' disease (GD). The aim of our study was to evaluate the uptake of indium-111 Octreotide (111In-OCT), a somatostatin (SS) analogue able to bind specific SS receptors, at the level of the thyroid and orbits in patients with TAO. Seven patients with exophthalmos were investigated: six had GD while one was affected with a non small cell lung cancer (NSCLC). One patient with GD had undergone total thyroidectomy (TT) for a thyroid cancer. At the time of the study two patients were hyperthyroid, four were euthyroid and one was hypothyroid. 111 MBq of 111In-OCT were i.v. injected and two 30-minute scans were performed at 4 and 24 hours; 5 minute planar images were also obtained at 25, 60 and 120 minutes. A 180 degrees SPECT was carried out 5 hours after the injection in one patient. A qualitative analysis was performed, comparing these images with those obtained in 7 control patients without thyroid illness or exophthalmos. Moreover, in the TAO patients thyroid, orbit and brain counts were evaluated in comparison with background (BK) and blood activity (BA), measured at the level of the venous longitudinal sinus. In GD intense thyroid uptake was demonstrated independently of the functional state, with highest ratio compared to BK seen at 24 hours. Low uptake in the patient with NSCLC, no activity in the patient with GD that underwent TT, and slight or absent thyroid uptake in the controls were observed. Intense uptake was seen in the orbits of the patient who clinically had the most severe ophthalmopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

A 55-year-old woman with total situs inversus viscerum was subjected to total thyroidectomy for a well-differentiated follicular thyroid carcinoma. After surgery the patient remained euthyroid for two months and serum TSH did not rise. A whole body scan with iodine-131 (131I) showed mediastinal uptake. A chest computed tomography visualized a sequestered substernal goiter. Upon the patient's refusal to undergo surgery, she was treated with 150 mCi of 131I. A further dose of 100 mCi of 131I was administered six months later. Ten years after treatment, the patient is still alive and disease-free.

The aim of this study was to evaluate through the auditory brainstem responses (ABRs) the electrical events generated along the auditory pathway in 56 adult patients affected with hyper- and hypothyroidism. Twenty-four normal-hearing hyperthyroid patients affected with Graves' disease and 32 normal-hearing hypothyroid patients (9 with subclinical and 23 with overt hypothyroidism) were subjected to standard (clicks at 21 pps) and sensitized ABR with masking wide-band (masking noise). In addition, thyroid scintiscan and ultrasonography, free T3 and T4, total T3 and T4, TSH, antimicrosomal and antithyroglobulin antibodies, audiogram and impedance tests were performed in all the patients. This study was repeated after 6-12 months of treatment in conditions of euthyroidism. The results showed changes of ABRs both in the standard procedure as well as in the sensitized test in 6 hyperthyroid (25%) and 8 hypothyroid patients (25%). All the patients with abnormal ABRs had overt hypothyroidism (8/23; 34.7%). The ABRs became normal in 5 out of 6 Graves' patients after 6-12 months of methimazole treatment. ABRs remained abnormal in all the hypothyroid patients despite their having been on L-thyroxine treatment for 6-12 months and were euthyroid for at least 5 months before the study was repeated. These findings suggest that ABR abnormalities are indicative only of a nonspecific injury in the bulbo-ponto-mesencephalic centers. Alterations of ABRs in thyroid diseases are not specific in relation to hyper- or hypothyroidism. Lastly, there is a relationship between ABR abnormalities and the degree of hypothyroidism, even if ABR alterations are not always reversible after long-term therapy.

A ten-year experience on 36 patients bearing macroprolactinomas (MP) and 86 others bearing microprolactinomas (mP) is reported in this study. Different therapeutical approaches were used: 1) trans-sphenoidal surgery in 24 patients with MP and in 25 with mP; 2) medical therapy with the oral form of bromocriptine (BRC) in all the 24 patients with MP previously subjected to surgery, in 48 patients with mP ab initio, and in 16 out of 25 patients with mP previously subjected to surgery; 3) medical therapy with the long-acting injectable forms of BRC in 12 MP- and 13 mP-bearing patients, and 4) conventional radiotherapy in 12 of the 24 patients with MP previously subjected to surgery. The follow-up, performed five years after surgery, showed that: a) all the 24 patients with MP but one had normal PRL levels during BRC administration, with a rebound of hyperprolactinemia in all cases after withdrawal; b) during the treatment BRC caused normalization of PRL in 15 of the 16 mP-bearing patients surgically treated and in all the 48 mP-bearing patients only treated with BRC; c) in 20 of the 25 patients the treatment with injectable retard BRC caused the normalization of plasma PRL and the shrinkage of the tumor mass in all the patients with MP but one, as revealed by seriate CT scans. In conclusion, the surgical treatment of prolactinomas was ineffective to normalize plasma PRL levels in most patients whereas BRC, in standard or in retard forms, was able to normalize plasma PRL levels, reduce the tumoral mass and preserve the pituitary residual tissue. BRC should be, therefore, used as first choice therapy both for MP and mP.

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 metaiodobenzylguanidine ((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 (131I)-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.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor Associated Glycoprotein 72 (TAG-72) is common to most epithelial tumors. In this study serum levels of TAG-72 were measured in 36 healthy female subjects, in 94 patients with breast cancer, and in 43 others with epithelial ovarian cancer. More particularly, 27 out of the 94 patients with breast cancer had early disease (Stage I-I; or T 0-2b; N 0-1b; M 0), while the remaining 67 had advanced disease (Stage III-IV; or T 0-4; N 0-3; M 0-1). All the 43 subjects with ovarian cancer were at stage III-IV (FIGO Classification), 12 of whom had minimal disease (lesions less than 2 cm) and the other 31 had bulky disease. 3.5 U/ml being the highest value found in the control group, we arbitrarily assumed 3.85 U/ml (mean +/- 3 SD) as the cut-off limit in this preliminary study. Among the patients with breast cancer, 17 out of the 67 subjects with advanced disease (25.3%) and 1 out of the 27 others with early disease (3.7%) exceeded the TAG-72 cut-off limit. Among the patients with ovarian cancer, 2 out of the 12 subjects with minimal disease (16.7%) and 22 out of the others 31 with bulky disease (70.9%) had TAG-72 levels above cut-off limit. High TAG-72 levels were found in all the histotypes of ovarian cancer including the mucinous type. Preliminary data seem to indicate that in ovarian cancer variations in serum levels of TAG-72 are in agreement with the trend of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The content of DNA and oestradiol receptors was measured in two different samples taken from the same tumoral mass of 33 primary infiltrating ductal carcinomas. The results were related to the total cytoplasmic protein and to the DNA of the tissue. The results showed that variations of both DNA and oestradiol receptors are frequent and often significant. The reliability of analyses carried out on a single biopsy is discussed.

Cyclophosphamide (CP) metabolites, rather than the parent compound, show mutagenic activity towards Salmonella typhimurium TA 1535 tester strain when S9 fraction from phenobarbital (PB)-induced rat liver is used as in vitro metabolizing system. On the other hand, inhibition of CP in vitro mutagenicity was observed by adding increasing amounts of beta-carotene (beta-C) to the system. A typical dose-dependent mutagenic response was observed by assaying 24 h urine samples of PB-induced rats injected i.p. with different amounts of CP. Addition of beta-C to urines of CP-treated rats failed to inhibit their mutagenicity. Conversely, a marked decrease in urine mutagenicity was observed when rats were simultaneously treated with the two drugs. These data show that beta-carotene partially inhibits, in vitro and in vivo, CP metabolism via hepatic mixed-function oxidase enzymes to mutagenic species.

Radioimmunoscintigraphy (RIS) using 131I-labelled B72.3, a monoclonal antibody (MoAb) reacting against a tumor associated antigen (TAA) called TAG-72, has been performed in 36 patients with epithelial ovarian cancer. The patients were divided in three groups as follows: 17 patients with primary cancer before any therapy (Group 1); 10 patients studied after a partial therapeutic approach, having either bulky or minimal disease (Group 2); 9 patients with microscopic disease or in clinical remission at the moment of the study (Group 3). All the most important epithelial histotypes, including mucinous, were present. Results were confirmed at surgery and/or by other diagnostic procedures. Immunocytochemical (ICC) and immunocytofluorimetric (ICF) studies on ascitic collections were performed in order to demonstrate specificity of B72.3 and TAG-72 distribution on neoplastic cells. Immunohistochemistry (IHC) on tissue sections was also obtained. No cross reactions between B72.3 and mesothelial cells in the presence of specific uptake by neoplastic cells was found. Moreover, a non-homogeneous distribution of TAG-72 in the neoplastic population was demonstrated by ICF. RIS proved the intraperitoneal presence of disease in 15 out of 17 and in 5 out of 10 patients in Groups 1 and 2, respectively. One out of four (Group 1) and two out of four (Group 2) extraperitoneal metastases were also seen. False negative results were explained by lack of expression of the antigen, size and location of the lesion, and patho-physiological conditions. One false positive due to an aspecific uptake by a post-surgical active scar was also observed in a disease-free patient.

The estrogen receptors presence or absence in the thymus gland represents the basic element to assert or to exclude any estrogenic action in the thymus. Now we have measured the presence of cytoplasmatic estrogen receptors in the female rabbits thymus, using some methods (sucrose gradient, protamine sulphate, dextran-coated charcoal). Finally, we have investigated, using the sucrose gradient assay, the nuclear ER presence in 1000g thymic pellet. The results exclude high levels of estrogen-binding proteins while don't suggest their total absence in the female rabbit thymus.

A group of 20 patients affected with thyroid carcinoma, all from Southern Italy, was typed for HLA-A, -B, -C and -DR antigens. Sixteen of them (80%) typed for DR1, while in the control group (120 unrelated healthy individuals from the same region) only 22 (18.3%) shared the same antigen (chi 2 = 32.96). The data indicate a highly significant association between the HLA-DR1 gene and the thyroid carcinoma.

Transglutaminase (TGase) activity was reduced in intact mitogen-stimulated human peripheral blood lymphocytes (PBL) when compared to intact resting PBL. Moreover, a treatment of the same quiescent immunocompetent cells with purified liver TGase and Ca2+ completely suppressed the mitogen-induced blast transformation. A decrease in TGase activity in neoplastically transformed seminal vesicle epithelial cells with respect to their normal parent counterpart was also observed. Our data support the notion of a possible implication of TGase in cell proliferation and transformation.

Mutagenic activity on Salmonella typhimurium strains of some cytostatic drugs in the absence and in the presence of beta-carotene was evaluated. Cyclophosphamide mutagenicity was reduced by the retinoid both in vitro and in vivo. Conversely, its metabolite 4'-hydroxy-cyclophosphamide, which does not require enzymatic transformation to exert genotoxic activity against bacteria, was not affected by the presence of beta-carotene. Moreover, the mutagenic activity of cis-Platinum, Adriamycin and 4'Epiadriamycin, which are typical direct-acting mutagens, was not affected by beta-carotene. Data obtained confirm that beta-carotene is able to prevent mutagenic activity of cyclophosphamide by interfering with its metabolic activation but failed to inhibit the interaction of genotoxic compounds with bacterial DNA.

The effects of the dopamine (DA) receptor antagonist metoclopramide on the plasma thyroid stimulating hormone (TSH) and prolactin (PRL) levels were studied in 8 patients with subclinical hypothyroidism (defined as absence of clinical signs of hypothyroidism with normal thyroid hormone levels, normal or slightly increased basal plasma TSH levels and increased and long-lasting TSH response to TRH) before and after l-thyroxine replacement therapy. Metoclopramide induced a significant (p less than 0.01) TSH release in the subclinical hypothyroid patients. Two weeks after l-thyroxine replacement therapy (50 micrograms/day), the TSH response to metoclopramide was completely blunted in subclinical hypothyroidism. In these patients a significant (p less than 0.01) inhibition of TSH response to intravenous thyrotropin-releasing hormone (TRH) was also observed after treatment with thyroid hormone. In analogy to the TSH behavior, plasma PRL secretion in response to metoclopramide and TRH administration was significantly (p less than 0.05) inhibited in the subclinical hypothyroid patients after l-thyroxine replacement therapy.