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Background: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. Patients and methods: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged

Topical and systemic prophylactic measures, which are administered before the development of epidermal growth factor receptor (EGFR)-related acneiform rash, are appropriate interventions to mitigate the intensity of skin toxicity. We have performed a systematic review and meta-analysis to evaluate whether prophylactic antibiotics may reduce the occurrence and severity of anti-EGFR drug-related skin rashes. A systematic review was performed by searching Medline, Scopus, Embase, CINAHL, LILACS, Web of Science and the Cochrane Library from inception until March 2016 for publications regarding the pre-emptive role of antibiotics for EGFR-induced skin rashes. Fixed- or random-effects meta-analyses, according to heterogeneity, were used to summarize odds ratios of skin toxicity with antibiotic use. Of the 827 citations found in the search, 13 studies comprising 1073 patients were included in the analysis. In 12 studies, patients in the prophylactic antibiotic arms had a lower risk of developing a skin rash (odds ratio 0·53, 95% confidence interval 0·39-0·72, P < 0·01) than patients without antibiotic prophylaxis. In particular, moderate-to-severe toxicities (grades 2-4) were reduced by nearly two-thirds (odds ratio 0·36, 95% confidence interval 0·22-0·60, P < 0·01) in 13 studies. This translated to a 26% absolute difference of high-grade skin rash compared with the control arms (from 50% to 24%). The results of this meta-analysis show that the risk of skin rash after treatment with anti-EGFR agents for solid tumours was significantly lower in patients taking prophylaxis with antibiotics than in those who were not. Therefore, taking pre-emptive tetracyclines for several weeks at the start of anti-EGFR treatment can significantly reduce the incidence and severity of cutaneous acneiform rash.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

Objective: To explore the role of personality traits in at-risk drinking and current cannabis use among medical students. Methods: This cross-sectional study evaluated 707 medical students from two universities. Multiple logistic regression models for at-risk drinking and current cannabis use were constructed including sociodemographic, psychiatric, and personality variables. Results: At-risk drinking and current cannabis use were reported by 19.3% and 14.9% of participants, respectively. Models including Big Five measures showed associations of at-risk drinking with higher extraversion (p < 0.00001, adjusted odds ratio [AOR] = 1.9) and lower conscientiousness (p = 0.00001, AOR = 0.5); cannabis use was also associated with lower conscientiousness (p = 0.003, AOR = 0.6), besides higher openness to experience (p = 0.002, AOR = 1.9). Models including measures of the Behavioral Inhibition and Activation Systems scales (BIS/BAS) showed associations of at-risk drinking with lower BIS (p = 0.002, AOR = 0.9) and higher BAS fun-seeking (p = 0.0005, AOR = 1.2); cannabis use was also associated with higher BAS fun-seeking (p = 0.008, AOR = 1.2). Personality variables had modest effects on model fit. Conclusion: Specific personality traits were independently associated with at-risk drinking and current cannabis use, albeit with modest effect sizes.

Advanced hepatocellular carcinoma (HCC), for which locoregional treatment is not an option, is a candidate for palliative systemic therapy, but an accepted chemotherapy regimen does not exist. We have conducted a systematic literature review and meta-analyses to quantify the benefits of oxaliplatin (OXA)-based chemotherapy in advanced HCC in patients not exposed to sorafenib. Studies that enrolled advanced HCC patients treated with first-line OXA-based chemotherapy were identified using PubMed, Web of Science, SCOPUS, The Cochrane Register of Controlled Trials and EMBASE. A systematic review was conducted to calculate the pooled response rate and 95% confidence interval. The pooled median progression-free survival (PFS) and overall survival, weighted on the number of patients of each selected trials, were also calculated. We tested for significant heterogeneity by Cochran's chi-squared test and I-square index. Thirteen studies were included in this review, with a total of 800 patients analysed. The pooled response rate was 16.8%. The median PFS and overall survival were 4.2 and 9.3 months, respectively, with a 1 year overall survival of 37%. The weighted median PFS/overall survival and response rate were 4.5/11 months and 20% in Western patients. Conversely, in Asiatic studies, the median PFS/overall survival and response rate were 2.43/6.47 months and 13.2%, respectively. OXA-based chemotherapy is effective in advanced HCC and represents a viable option in these patients. A head to head comparison with sorafenib or a second-line agent should be verified in prospective trials.

High levels of human epidermal growth receptor 2 (HER2) expression are associated with recurrence and death in breast cancer (BC) patients. We have performed a systematic review and meta-analysis in order to evaluate the prognosis for HER2+ pT1a–bN0M0 BC patients. A search of PubMed and Embase was performed. Studies were included if they reported hazard ratios (HRs) with a 95% confidence interval (CI) for multivariate analyses of relapse or survival in pT1a–bN0M0, HER2+ BC patients treated with surgery and chemotherapy and/or endocrine therapy, but not with trastuzumab. A total of 764 patients from seven studies were included in the meta-analysis. In the pooled analysis, HER2 had a detrimental effect on relapse-free (HR 4.68, 95% CI 3.05–7.18; p

Introduction Les tests de provocations alimentaires (TPO) ne sont pas standardises. Le but de cette etude etait d’evaluer les modalites d’execution de ces TPO en France. Methodes Entre janvier et mai 2017, un questionnaire, realise par la Societe italienne d’allergologie pediatrique, a ete mis en ligne et dissemine chez les allergologues en France, grâce a l’aide du Prof Just (Paris), du Dr Deschildre (Lille) et du Prof Demoly (Montpellier). Resultats Vingt-cinq centres ont repondu au questionnaire. Ce sont surtout les infirmieres (36 %) qui preparent les doses des TPO. D’abord les medecins demandent les tests cutanes (surtout realistes), suivi par un dosage d’IgE specifiques et d’allergenes moleculaires, et dans 40 % des cas, des patch tests sont aussi realises. Dans la plupart des cas, on ne tient pas en consideration des seuils de positivite pour affirmer le diagnostic (surtout en ce qui concerne les resultats des tests cutanes), mais parfois (64 %), le regime d’eviction d’epreuve et considere comme suffisant. Dans 60 % des cas, une voie veineuse peripherique est toujours mise en place. Les TPO ont une duree moyenne de 4–6 heures (60 %), en cas d’histoire immediate. Si l’histoire est retardee, 34,8 % des centres preferent le realiser de facon differente, sur plusieurs jours. Seulement la moitie des centres se base sur les resultats des IgE specifiques pour decider le degre de cuisson des aliments a tester. En cas d’histoire immediate, la periode de surveillance a une duree de 3–4 heures apres la fin du test pour le 52 % des repondeurs. Parmi les centres, 45,8 % ne planifient pas de TPO pour avoir un diagnostic de SEIPA, et 83,3 % des medecins ne demandent pas de TPO en cas de SOA. Tous les centres ont a disposition tous les medicaments necessaires en cas d’urgences. La plupart des centres ont a disposition une dieteticienne (72 %), mais pas toujours une psychologue (28 %). Dans 88 % des cas, de protocoles d’induction de tolerance peuvent etre mis en place (surtout pour lait, œuf, arachide, ble). Conclusion Il y a de grandes differences parmi les centres, surtout en ce qui concerne les reactions de type retardees. Des recommandations nationales et internationales pourraient aider a standardiser les TPO alimentaires.

Macrolides are considered safe antibiotics with reduced allergenic activity. However, studies on the safety of macrolides are scarce, particularly in children.The aim of this study was to assess the frequency of hypersensitivity reactions to clarithromycin and azithromycin in a group of children referred to our allergy unit for suspected macrolide allergy.We retrospectively reviewed the charts of 90 children aged 1-17 years with symptoms suggestive of hypersensitivity reaction to clarithromycin or azithromycin between December 31, 2008 and December 31, 2013. The allergy workup included skin tests (ie, skin prick tests and/or intradermal tests), determination of serum specific IgE (sIgE) to clarithromycin and azithromycin, and, if necessary to reach a diagnosis, oral provocation tests.Seventy-seven children completed the allergy workup. A reaction to clarithromycin was recorded in 58 children (75.3%): 21 (36.2%) had a history of immediate reactions, and 37 (63.8%) had a history of nonimmediate reactions. A reaction to azithromycin was recorded in 19 children (24.6%): 6 (31.5%) had a history of immediate reaction, and 13 (68.42%) had a history of nonimmediate reaction. Positive results in skin tests and oral provocation tests with the suspect drug confirmed the diagnosis in 15.5% of reactions to clarithromycin (9 of 58) and in 47.3% of reactions to azithromycin (9 of 19) (P = .004).A complete allergy workup enabled us to confirm a diagnosis of clarithromycin and azithromycin allergy in 15.5% and 47.3% of cases, respectively. Azithromycin was more allergenic than clarithromycin in children.

Aims and Background Rarely are conclusions from clinical trials summarized in international consensus conferences and promptly transferred to patient care. The adjuvant therapy for colorectal cancer used in daily clinical practice in Italy is described and compared with the recommendations of the 1990 NIH Consensus Conference. Patients and Methods We audited prescriptions of adjuvant systemic therapies for Italian colorectal cancer patients in 82 centers during a fixed one-week period. Results Among 434 patients receiving adjuvant chemotherapy there were 139 (42.5%) colon cancer patients with N- and 169 (51.7%) with N+ regional nodal involvement. Treatment at academic centers, a young age, T4 and a low total number of lymph nodes removed at surgery were the factors potentially justifying the decision for adjuvant chemotherapy in stage II colon cancer patients. The most common chemotherapy used was a bolus of 5-fluorouracil/folinic acid for 6 months (75.8%). Adjuvant radiotherapy was not administered to 37 (38.5%) of 96 patients with stage II and III rectal cancer. Conclusions The study shows that a substantial proportion of patients on adjuvant treatment at a certain time point in a large enough sample of Italian centers are stage II (potential over-treatment) and that an under-treatment of stage II and III rectal cancer patients (lack of radiotherapy) occurs too often in daily clinical practice in this country.

Over the last 50 years, many species of amphibians have declined markedly, and even become extinct throughout the world. The cause of this is not clear, and several factors may be involved, including exposure to contaminants. The effects of some pollutants (i.e., chromium and heptachlor epoxide) on the green frog (.Rana kl. esculenta) were assessed experimentally, using morpho‐histological techniques. At the lowest doses used (0.5 ppm for Cr, 4 ppb ‐ 40 ppb for heptachlor epoxide), the hepatocytes showed no relevant structural or functional changes. The highest dose (5 ppm for chromium and 400 ppb for heptachlor epoxide) proved to affect the hepatocytes, as revealed mainly by intense ROS reactivity and by increased SDH activity. In addition, relevant variations in melanin content and distribution, as well as in hemo‐siderin deposits, were observed in melanomacrophages. These cells also showed an intense dose‐dependent reactivity for both acid phosphatase and catalase in the liver of treated anima...

Background: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m 2 day 1, LV 100 mg/m 2 as 2 h infusion and 5-FU 400 mg/m 2 as bolus, days 1 and 2 followed by 600 mg/m 2 /day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P= 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P= 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01640782.

Nonproductive cough is a frequent and distressing symptom in patients with lung cancer, and it is not even relieved by palliative chemotherapy. A double-blind, randomized clinical trial regarding the treatment of nonproductive cough was performed in 140 adults with primary lung cancer or metastatic cancer of the lungs. The therapeutic efficacy and the tolerability of a 7-day treatment with levodropropizine drops (75 mg t.i.d.) were evaluated in comparison with dihydrocodeine drops (10 mg t.i.d.; 7 days). Efficacy was assessed on the basis of cough severity scores, number of night awakenings due to cough, and overall estimate of antitussive efficacy. Tolerability was evaluated by laboratory results, vital signs and any adverse event occurring during the clinical trial, including presence or absence of somnolence. Subjective cough severity was significantly reduced during treatment with either levodropropizine and dihydrocodeine, the antitussive effect and its time-profile being similar for both drugs. Also, according to the investigator's evaluation, both levodropropizine and dihydrocodeine produced a significant decrease in cough severity. Concurrently with the relief of cough, the number of night awakenings was decreased significantly by both drugs, with no difference between the two treatments. No change in laboratory test values was considered clinically relevant, and vital signs were not clinically affected. The number of patients reporting adverse events was similar in the levodropropizine (n=6) and dihydrocodeine (n=4) group. However, the percentage of patients experiencing somnolence in the group receiving levodropropizine (8%) was significantly lower as compared with that of the dihydrocodeine group (22%). These results confirm the antitussive effectiveness of levodropropizine and suggest a more favourable benefit/risk profile when compared to dihydrocodeine.

Summary Background This study examined the impact of breast cancer therapy on women's sexuality. Patients and methods A questionnaire concerning various sexual problems experienced before and after treatment was anonymously completed by 50 women in the outpatient clinic of our hospital's Division of Radiation Oncology. To be eligible, subjects had to be disease-free and sexually active. They also had to have undergone surgery at least one year previously and have completed CT and/or RT. Fifty-eight percent of the women involved had undergone mastectomy and 42% had undergone quadrantectomy followed by RT. Results Ninety percent of the subjects continued sexual activity after treatment, but there was an increase in the incidence of sexual problems which resulted in a slight reduction in the quality of their sex lives. Sixty-four percent of the women experienced an absence of sexual desire and 48% low sexual desire, while 38% had dyspareunia, 44% frigidity and 42% lubrication problems. Vaginismus, brief intercourse and female orgasmic disorder were reported by 30% of the subjects. Thirty-six percent suffered from sexual dysfunction before treatment, which worsened in about 27%, while in 49% of women sexual problems arose mainly after chemotherapy (26%) or surgery (12%). About one-half experienced changes in the relationship with their partner. Conclusion Breast cancer patients experienced sexual dysfunction; ours found it easier to discuss the problems with their partner during their illness (62%) than with doctors and psychologists (15%).

Background Polychemotherapy and biological drugs have increased therapeutic options and outcomes of advanced colorectal cancer (CRC). We examined the relation between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in trials of modern (oxaliplatin- and irinotecan-based) chemotherapy alone or with targeted therapies for advanced CRC. We also evaluated surrogacy of PFS and OS. Patients and methods A PubMed search identified 34 randomized trials. We split the OS, PFS and PPS and evaluated the correlation between OS and either PFS or PPS. Results The median PPS and PFS were 10.75 and 8.4 months, respectively. For all trials, PPS was strongly associated with OS [regression coefficient (R2) = 0.8; Spearman's rank correlation coefficient (r) = 0.88], whereas PFS was moderately associated with OS (R2 = 0.43; r = 0.64). In trials with targeted therapies, the correlation of PPS with OS was 0.88. However, across all trials, correlation between differences in median PFS (ΔPFS) and median OS (ΔOS) is 0.59 (P = 0.0007), confirming PFS/OS surrogacy. Conclusion Our findings indicate that in recent first-line, phase III, trials, OS becomes more associated with PPS than PFS. However, improvements in PFS are strongly associated with improvements in OS. In this setting so, PFS may be an appropriate surrogate for OS.

Cetuximab (C) and panitumumab (P) increase response rate and survival in KRAS wild-type metastatic colorectal cancer (mCRC). We performed a meta-analysis of randomised controlled trials (RCTs) to assess their effect on overall response rate (ORR), the rate of radical resection (R0) and survival in patients with liver-limited initially unresectable mCRC.We searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for RCTs comparing first-line chemotherapy plus or minus C or P and reporting data in patients with KRAS wild-type, unresectable liver-limited mCRC. Relative risks (RRs) with 95% confidence interval were calculated. Meta-analysis of hazard ratios (HRs) for progression-free and overall survival (PFS and OS) was also performed.Four RCTs involving 484 KRAS wild-type patients were included. Compared to chemotherapy alone, the addition of C or P significantly increased the ORR (RR 1.67, p = 0.0001), the R0 resection rate from 11% to 18% (RR 1.59, p = 0.04) and PFS (HR 0.68, p = 0.002), but not OS (p = 0.42).The addition of C and P increased the R0 resection rate by 60% and reduced the risk of progression by 32% in patients with mCRC and unresectable liver-limited disease. This combination represents one of the preferred choices as conversion therapy in KRAS wild-type patients with unresectable liver metastases.

Cisplatin (cisPt) is a chemotherapeutic drug used for several human malignancies. CisPt cytotoxicity is primarily mediated by its ability to cause DNA damage and subsequent apoptotic cell death. DNA is the primary target of cisPt; however, recent data have shown that cisPt may have important direct interactions with mitochondria, which can induce apoptosis and may account for a significant part of the clinical activity associated with this drug. We have previously demonstrated that in the rat neuronal cell line B50, at 20 h-treatment with cisPt activates apoptosis through an intrinsic pathway involving an alteration of mitochondrial membrane permeability and the release of cytochrome c. The present study investigates different death pathways induced in the same cell line by a prolonged treatment with 40 µM cisPt for 48 h. To address this issue, we focused on caspases-8 and -12, and on the mitochondrial apoptosis inducing factor (AIF), which translocates to the nucleus and induces cell death via caspase-independent pathway. We found that cisPt activates different forms of cell death, i.e. the receptor-mediated apoptotic extrinsic pathway and a death process mediated by endoplasmic reticulum stress. Moreover, we demonstrated that AIF-mediated death occurs, being characterized by the translocation of AIF from mitochondria to the nucleus. On the whole, we provided evidence that prolonged cisPt treatment is able to activate both caspase-dependent and caspase-independent apoptotic pathways in B50 rat neuronal cells.

Polychemotherapy represents the only standard medical therapy of metastatic soft tissue sarcomas (STS), whereas the recent biotherapies with cytokines, such as interleukin-2 (IL-2), seem not to have a relevant therapeutic role. The pineal hormone melatonin (MLT), whose immunomodulating activity is well known, would seem to exert a direct cytostatic action on STS cell proliferation. Moreover, MLT has been proven to amplify IL-2 efficacy. On this basis, a pilot phase II study with low-dose IL-2 plus MLT has been performed in untreatable metastatic STS patients. The study included 13 evaluable metastatic STS patients with poor PS, who progressed on at least one previous polychemotherapeutic line. IL-2 was injected subcutaneously at 3 million IU/day for 6 days/week for 4 weeks and MLT was given orally at 40 mg/day in the evening. A partial response was achieved in one patient with leiomyosarcoma. Eight other patients had a stable disease (SD) whereas the remaining 4 patients progressed. A survival longer than 1 year was achieved in 6/13 patients and the percent of 1-year survival was significantly higher in patients with response or SD than in the progressed ones (6/9 vs 0/4). Mean increases in lymphocyte and eosinophil numbers were significantly higher in patients with response or SD than in the progressed ones. These preliminary results would suggest that immunotherapy with low-dose IL-2 plus MLT may have some impact at least on the survival time of untreatable metastatic STS patients with poor clinical conditions.

Increasing interest in safety evaluation of carbon nanotubes (CNTs) has risen in relation to their wide applications, together with the evidence of their cytotoxic effects. It has been shown that chemical functionalization extends the applications of CNTs, conferring them new functions that cannot otherwise be acquired by pristine CNTs, but also impacts on biological response to CNTs, modifying their toxicological profile. We assessed the onset of pulmonary toxic effects caused by pristine MW-CNTs and functionalized MW-NH₂ or MW-COOH, 16 days after intratracheal instillation (1 mg/kg b.w.); major endpoints tested included (i) histopathology of lung (Haematoxylin/Eosin Staining), (ii) apoptotic/proliferating features examined by TUNEL and PCNA immunostaining, and (iii) presence/distribution of (1) Transforming Growth Factor-beta1 (TGFß1), (2) Interleukin-6 (IL-6) and (3) Collagen (Type I) investigated by immunochemical methods, as markers of lung toxicity, inflammation, and fibrosis, respectively. Lung histopathology from exposed animals showed dark, particulate-laden macrophages, reflecting carbon nanomaterial engulfing, both at alveolar and bronchiolar levels, after treatment with all the tested CNTs. Alteration of lung architecture was also observed in several areas showing collapsed thick-walled alveoli and the presence of micro-haemorrhagic foci. TUNEL and PCNA, indicative of apoptosis and cell proliferation respectively, showed a significant increase of immunopositive cells at bronchiolar, alveolar and macrophagic levels, as expression of an improved cellular turnover. Increased immunoreactivity for pulmonary TGFß1 and IL-6 was observed in treated rats, particularly in bronchiolar areas, collapsed alveoli and at stromal level, while evident changes for collagen were not detected. Taken together these findings demonstrated the general pulmonary toxicity coupled with inflammatory response after in vivo exposure to CNTs, without overt signs of fibrosis and granuloma formation, irrespectively of nanotube functionalization.

As of today, advanced non-small cell lung cancer is still an incurable disease. However, recent researches on the biology of adenocarcinoma have led to considerable progress in the treatment of this subgroup of patients. The administration of bevacizumab and pemetrexed as first-line therapy, erlotinib in the maintenance phase and erlotinib again combined with vandetanib as second-line therapy, gives patients with lung adenocarcinoma new hope. In particular, in metastatic adenocarcinoma with an EML4-ALK fusion oncogene, crizotinib (a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases), led to a response rate of 64%, which is similar to the results achieved in chronic myeloid leukemia and GIST with imatinib. Overall, the application of all available active therapies during the natural history of adenocarcinoma may lead to a survival benefit that was unimaginable only a few years ago. This article reviews the main studies on molecular targeted therapies in various lines of treatment of advanced lung adenocarcinoma.

Nasal topical steroids (INCSs) are well established effective therapy in allergic rhinitis both in children and adults. There is clear benefit in using INCSs over antihistamines in allergic rhinitis while short courses of oral corticosteroids (CSs) may be indicated in severe cases. The addition of INCSs to oral antibiotics has been proven to be more effective than antibiotics alone for achieving symptomatic improvement in patients with acute rhino sinusitis. INCSs as monotherapy are also effective in the treatment of allergic rhinosinusitis (ARS). Several randomized controlled trials have evaluated the role of INCSs in chronic RS with the majority demonstrating a beneficial effect. In adults, the clinical efficacy of oral corticosteroids in the management of chronic RS with nasal polyposis is well established. There are no randomized controlled trials evaluating the efficacy of systemic CSs in chronic RS without nasal polyposis.

The effect of gravity on human lymphocytes in-vitro has been extensively studied by our team in true microgravity in space /1-3/, in simulated lowgravity in the clinostat /4,5/ and in hypergravity in the centrifuge /5-7/. Lymphocytes are easily purified from peripheral blood and can be ictivated either chemically or by exposure to mitogens in culture. Thereby, cells start to proliferate, T—lymphocytes secrete lymphokines (IL-2, IL-3, IL—4 as well as interferon). The mechanism of the in-vitro activation is analogous to that occurring in—vivo when the immune system is challenged by antigens.

Urticaria is a rash, that typically involves skin and mucosa, and is characterized by lesions known as hives or wheals. In some cases there is an involvement of deep dermis and subcutaneous tissue that causes a skin/mucosa manifestation called angioedema. Urticaria and angioedema are very often associated: urticaria-angioedema syndrome. The acute episodic form is the most prevalent in the pediatric population, and it is often a recurrent phenomenon (recurrent urticaria). Acute episodic urticaria it is usually triggered by viruses, allergic reactions to foods and drugs, contact with chemicals and irritants, or physical stimuli. In many instances it is not possible to identify a specific cause (idiopathic urticaria). Chronic urticaria is a condition that can be very disambling when severe. In children is caused by physical factors in 5-10% of cases. Other trigger factors are infections, foods, additives, aeroallergens and drugs. The causative factor for chronic urticaria is identified in about 20% of cases. About one-third of children with chronic urticaria have circulating functional autoantibodies against the high affinity IgE receptor or against IgE. (chronic urticaria with autoantibodies or "autoimmune" urticaria). It is not known why such antibodies are produced, or if the presence of these antibodies alter the course of the disease or influence the response to treatment. Urticaria and angioedema can be symptoms of systemic diseases (collagenopathies, endocrinopathies, tumors, hemolytic diseases, celiachia) or can be congenital (cold induced familiar urticaria, hereditary angioedema). The diagnosis is based on patient personal history and it is very important to spend time documenting this in detail. Different urticaria clinical features must guide the diagnostic work-up and there is no need to use the same blood tests for all cases of urticaria. The urticaria treatment includes identification of the triggering agent and its removal, reduction of aspecific factors that may contribute to the urticaria or can increase the itch, and use of anti-H1 antihistamines (and/or steroids for short periods if antihistamines are not effective). In some instances an anti-H2 antihistamine can be added to the anti-H1 antihistamines, even if the benefits of such practice are not clear. The antileucotriens can be beneficial in a small subgroup of patients with chronic urticaria. In case of chronic urticaria resistant to all the aforementioned treatments, cyclosporine and tacrolimus have been used with good success. When urticaria is associated to anaphylaxis, i.m epinephrine needs to be used, together with antihistamines and steroids (in addition to fluids and bronchodilatators if required).

Several studies demonstrated that the pineal gland plays a regulatory role in PRL secretion. At present, however, there are few clinical data only about the pineal function in PRL secretion disorders. To further clarify which is the pineal importance in the dysfunctions of PRL release, we have evaluated the effect of an acute injection of the pineal hormone melatonin in 19 patients with hyperprolactinemia, 8 of whom had idiopathic hyperprolactinemia, while the other 11 had a prolactinoma. Melatonin was given im at a dose of 20 mg at 09:00 h, and venous blood samples were collected at -20, 0, 20, 60, 120, 180 min. A normalization of PRL levels was achieved after melatonin injection in 3/8 patients with idiopathic hyperprolactinemia, while no effect was seen in patients with prolactinoma. Further studies, by evaluating the effect of a chronic treatment, will be required to define which is the action of melatonin on PRL release in PRL secretion disorders, and to evaluate its possible therapeutic role.

Within the Meliponini, a widely distributed group of stingless bees, Melipona rufiventris has been considered as a single, cohesive species. Recently, analysis of morphological characters led to the splitting of this species into two species, M. mondury and M. rufiventris. The former occurs in the Atlantic Rain Forest ranging from Santa Catarina to Bahia States, while the latter is found in other parts of Brazil. We used PCR + RFLP to identify genetic marker patterns of the mtDNA between these species. Nine mtDNA regions were amplified and digested with four restriction enzymes (EcoRI, EcoRV, HindIII, and HinfI). Six species-specific restriction sites were identified for M. mondury and M. rufiventris with all enzymes, except for HindIII. The molecular data agree with the morphological classification.

The biochemical modulation of 5-fluorouracil (5-FU) by means of methotrexate (MTX) and 6-S leucovorin (LV) seems mainly directed at two different intracellular targets, supporting the hypothesis of possible non-cross resistance between these two methods of 5-FU potentia-tion. Thirty-one patients, all previously treated with 5-FU and LV for advanced colorectal cancer (ACC), were treated with MTX=200 mg/m2 iv day 1 and 5-FU 600 mg/m2 day 2 with 6-S LV 10 mg/m2 po q 6 h X 6 starting 24 h after MTX, repeated every 2 weeks. Of 30 eva-luable patients, 2 Partial Remissions (PR) were achieved (Response Rate=6.6%; 95% Confidence Interval 0%-14%). Eight patients had disease stabilization (SD). The overall median survival was 5 months (range 1-11). No WHO grade III-IV toxicities were reported. Despite the good tolerability, this combination of MTX, 5-FU and LV rescue has minimal activity in ACC after the failure of 5FU+LV-based chemotherapy.

Summary Background: Among the cytotoxic agents commonly combined with cisplatin in the treatment of advanced NSCLC, vinorelbine has led to significant outcome improvements. Adding more than four cycles of the combination regimen increase toxicities. The availability of an oral form of vinorelbine appeared as a particularly convenient way to provide a consolidation treatment to patients who have achieved an objective response or stable disease. Patients and methods: This multi-centre phase II open-label, non-comparative study was designed to evaluate the treatment with four cycles of the combination chemotherapy with oral vinorelbine at the dose of 60mg/m 2 on day 1 and day 8 for the first cycle and then 80mg/m 2 plus cisplatin 80mg/m 2 on day 1 every 3 weeks followed for patients with objective response or stable disease by consolidation therapy with oral vinorelbine at 80mg/m 2 weekly on patients with unresectable localised or metastatic non-small-cell lung cancer (NSCLC). The primary endpoint was tumor response. The secondary objectives were progression free-survival, overall survival and toxicity assessment. Visual analogue scales (VAS) filled by the patients were also used to evaluate subjective changes under treatment, reflecting patients' clinical benefit. Results: Fifty-six patients enrolled into the study from April 2001 to April 2002 received the combination regimen. Twenty-five patients (43.9%) also received the subsequent consolidation treatment. Partial tumor responses were obtained in 13 patients (26.5%, 95% CI 15.0–41.1) of 49 evaluable patients. Stable disease was observed in 22 (44.9%) of patients. The median duration of response was 6 months (95% CI 4.3–8.2). The median progression free-survival was 4.2 months (95% CI 2.8–6). The median overall survival time was 10 months (95% CI 7.4–14) and the 1 year survival was 42.6%. The main toxicities recorded were haematological. Grade 3 and 4 neutropenia were observed in 16 patients (29.1%). Nausea, vomiting and fatigue were the major non-haematological toxicities reported. Among the symptoms recorded by the patients on VAS scales (appetite, fatigue, pain, cough, dyspnea, haemoptysis), except anorexia, all symptoms were improved during the combination therapy and in the consolidation phase. Conclusion: This study confirms that the efficacy of the cisplatin/oral vinorelbine combination in NSCLC is comparable to cisplatin/I.V. vinorelbine. This study also suggests that consolidation therapy with vinorelbine alone may probably prolong the efficacy of the combination regimen. The convenience offered to patients by an oral form of vinorelbine is a definite asset for consolidation therapy.

Twenty-one patients with advanced colorectal cancer, all previously pretreated with a fluoropyrimidine-based regimen, received oral etoposide: 100 mg/die for 21 consecutive days, every three weeks. No objective response was achieved; 6 pts had a short-lasting stabilization of their disease. Toxicity was substantial and mainly represented by myelosuppression and alopecia. Protracted administration of etoposide is inactive as second-line treatment of colorectal cancer.

Hyperinsulinism is an important cause of hypoglycemia in early infancy. Many forms of hyperinsulinemic hypoglycemia are described: transient, prolonged, persistent. Transient forms are well recognized in infants of diabetic mother; prolonged forms are responsible for the hypoglycemia in small-for-date (SGA) infants and asphyxiated newborns. Persistent hyperinsulinemic hypoglycemia occurs in a group of congenital disorders associated with an abnormality of beta-cell regulation throughout the pancreas. Accurate diagnosis and treatment are essential in all various forms of hyperinsulinism also because newborns are at high risk of permanent brain damage. We report a case of prolonged hyperinsulinemic hypoglycemia in a SGA preterm, immediately treated with a high dose of glucose and glucocorticoid and then with diazoxide. Hypoglycemia was continued until 2 months of age when it resolved spontaneously and completely.

The vascular endothelial growth factor (VEGF) plays a central role in promoting angiogenesis, and it is the target of innovative anti-cancer therapies. In colorectal carcinomas, differences in the VEGF expression have been found between the primary tumor and its metastases. We postulated that differences in the VEGF expression may also exist between liver and abdominal metastases from colon cancer. Consecutive colon cancer patients with liver or abdominal metastases were considered eligible for the study. Biopsies had to be performed before chemotherapy and the VEGF analysis were conducted through immunohistochemistry. The staining results were correlated to the metastatic pattern. The study population consisted of 41 patients with a metastatic site in the liver in 19 patients and the abdomen in 22 patients. A positive VEGF staining was found in 19 of the 41 metastatic samples (46%). Cases with positive VEGF expression were found more frequently in abdominal (15 out of 22 patients; 68%) than in liver metastases (4 out of 19 patients; 21%). Also, the degree of VEGF immunoreactivity was significantly higher in abdominal than in liver metastases. Evidence is supported that the VEGF expression may be different between colon cancer metastatic sites. The efficacy of anti-VEGF treatments may depend on the VEGF expression status, and this finding deserves further investigation.