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Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Background: In the Phase III ‘GRETA’ trial 474 women aged ≥70 years with early breast cancer were randomly assigned to surgery plus tamoxifen for 5 years or tamoxifen alone for 5 years. This is a long-term update. Patients & methods: Focusing on patients still alive in 2003, outcome end points has been recalculated. Results: Median distant metastases disease-free survival is longer with tamoxifen alone for 5 years; (48.8 vs 37.9 months; p = 0.009). No difference was found in distant metastases rate, disease-free survival, breast cancer and overall survival. Conclusion: Primary endocrine treatment until the the best response, followed by minimal surgery and prosecution endocrine treatment for 5–10 years is a suitable option for elderly breast cancer patients. Delayed surgery does not prejudice overall survival.

Background and Aims Interactions between different yeast species used as starters may lead to inconsistent results in mixed fermentations. The aim of this study was to assess the influence of different nutrients on the association between a wine strain of Candida zemplinina (CDZ1) and a commercial wine strain of Saccharomyces cerevisiae (EC1118) in mixed culture fermentations. Methods and Results Laboratory-scale fermentations were carried out by inoculating CDZ1 and, after 3 days, EC1118 with the simultaneous addition of diammonium phosphate, yeast hulls, ergosterol and oleic acid, each provided separately. The addition of yeast hulls resulted in a higher cell population of CDZ1 and in a higher glycerol concentration of wine as compared with that of the other fermentations. Pilot-scale fermentations, carried out in a commercial winery, confirmed that the winemaking protocol based on the use of the mixed starters CDZ1/EC1118 with added yeast hulls results in wine with a higher glycerol content, more structured and persistent. Conclusions Addition of yeast hulls improved the fermentative performance of the mixed starters CDZ1/EC1118. Significance of the Study The high glycerol content of wines made with the combined use of yeast hulls and CDZ1/EC1118 mixed starters increases wine softness and body.

Changes of pasture communities consequent to management practices resulting from land abandonment considerably affect the structure and function of the ecosystem. This study analyses the consequences of grazing abandonment in terms of plant and soil microbial diversity and fertility, on a Mediterranean upland sheep pasture, over a short period (five years). Grazing was experimentally excluded by fencing ten 10×10 m permanent plots within an area that had supported grazing until 2000, by 0.23 sheep ha−1. Plant and soil microbial communities and physicochemical parameters were monitored within the fenced and unfenced control plots, during three sampling times from 2000 (before the fencing) to 2005. Grazing cessation notably altered the floral composition, with an average dissimilarity of 96.7% between the vegetation communities, over five years. No significant change occurred in the control plots that were grazed throughout the sampling period. This work highlighted that, over a short term, the structural change in the specific plant composition affected only the grass species, confirming that grazing favours the small-sized species over the annual species. Further, it was evident that species groups of conservational and phytogeographic interest, like the endemic and Mediterranean-Atlantic species, tended to disappear with pasture abandonment and were substituted by more widespread species throughout the Mediterranean or even the world. Pasture abandonment was accompanied by an increase of soil pH and a decrease in soil organic matter and soil nitrogen. The microbial parameters recorded at three different sampling times revealed a substantial effect of the plant community, or the time of grazing abandonment, on soil microbial abundance and diversity. Considerable importance is given to the consequences of pasture abandonment on the conservation of plant and microbial diversity and on soil fertility.

Purpose Unresponsiveness to erythropoiesis-stimulating agents, occurring in 30% to 50% of patients, is a major limitation to the treatment of chemotherapy-related anemia. We have prospectively evaluated whether intravenous iron can increase the proportion of patients with chemotherapy-related anemia who respond to darbepoetin. Patients and Methods Between December 2004 and February 2006, 149 patients with lung, gynecologic, breast, and colorectal cancers and ≥ 12 weeks of planned chemotherapy were enrolled from 33 institutions. Patients were required to have hemoglobin ≤ 11 g/L and no absolute or functional iron deficiency. All patients received darbepoetin 150 μg subcutaneously once weekly for 12 weeks and were randomly assigned to sodium ferric gluconate 125 mg intravenously (IV) weekly for the first 6 weeks (n = 73) or no iron (n = 76). Primary end point of the study was the percentage of patients achieving hematopoietic response (hemoglobin ≥ 12 g/dL or ≥ 2 g/dL increase). Results Hematopoietic response by intention-to-treat analysis was 76.7% (95%CI, 65.4% to 85.8%) in the darbepoetin/iron group and 61.8% (95%CI, 50.0% to 72.7%) in the darbepoetin group (P = .0495). Among patients fulfilling eligibility criteria and having received at least four darbepoetin administrations, hematopoietic responses in the darbepoetin/iron group (n = 53) and in the darbepoetin-only group (n = 50) were 92.5% (95% CI, 81.8% to 97.9%) and 70% (95% CI, 55.4% to 82.1%), respectively (P = .0033). Increase of hemoglobin during treatment period showed a time profile favoring darbepoetin/iron with statistically significant effect from week 5 on. The safety profile was comparable in the two arms. Conclusion In patients with chemotherapy-related anemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity.

Aim: To verify a possible correlation between cell lipid composition, expression of key genes in lipid metabolism and fermentative behaviour of Saccharomyces cerevisiae wine strains. Methods and Results: The fermentative abilities of two commercial wine strains of S. cerevisiae were tested under stressful conditions. Cell number, glucose and fructose concentrations, expression of ACS1, ACS2, ACC1, OLE1, ERG9, ERG10, ARE1 and ARE2 and lipid content were evaluated. The strain that failed to complete the fermentation had lower amounts of C16:1 and C16:0 fatty acids at the beginning of fermentation (0 h) and late logarithmic phase (72 h). While the amount of C18:1 in this strain was lower than that in the strain that completed the fermentation at 0 h, same levels were observed for both strains at 72 h. The sterol levels were generally higher in the strain that failed to complete the fermentation. Gene expression generally increased from the beginning of the fermentation to the late logarithmic phase in both strains. Conclusion: A positive correlation between good fermentative ability, elevated fatty acid content and ACC1 gene expression has been identified. Significance and Impact of the Study: The cell lipid content at the time of inoculum and expression of ACC1 gene of starter strains should be carefully considered in order to identify the possible stuck/sluggish fermentations.

This study was aimed at showing the capacity of probiotic VSL#3 to hydrolyze wheat flour allergens. Hydrolysis was investigated either by the use of baker's yeast bread treated with digestive enzymes and VSL#3, an experimental design that mimicked the activity of probiotics during gut colonization, or by the use of VSL#3 as a starter for dough fermentation, an experimental design that mimicked the predigestion of wheat flour proteins during food processing. Albumins, globulins, and gliadins extracted from wheat flour and chemically acidified and started dough and total proteins extracted from breads were analyzed by immunoblotting with pooled sera from patients with an allergy to wheat. Hydrolysis of wheat flour proteins was determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and two-dimensional electrophoresis (2DE). Mass spectrometry matrix-assisted laser desorption and ionization-time of flight was used to identify some immunoglobulin E (IgE)-binding proteins. As shown by immunoblotting with sera from allergic patients, several IgE-binding proteins persisted after treatment of baker's yeast bread by pepsin and pancreatin. The signal of all these IgE-binding proteins disappeared after further treatment by VSL#3. As shown by SDS-PAGE and related immunoblotting and 2DE analyses, when VSL#3 was used as a starter for bread making, it caused a marked degradation of wheat proteins, including some IgE-binding proteins such as the putative transcription factor APFI and wheat alpha-amylase inhibitors. Indeed, the IgE-binding profile of the bread manufactured by VSL#3 was largely different from that of baker's yeast bread. The IgE-binding proteins that persisted in the bread made with VSL#3 were completely degraded by pepsin and pancreatin.

Background: Myrtle (Myrtus communis L.) is a medicinal and aromatic plant belonging to Myrtaceae family, which is largely diffused in the Mediterranean areas and mainly cultivated in Tunisia and Italy. To the best of our knowledge, no studies have already considered the use of the lactic acid fermentation to enhance the functional features of M. communis. This study aimed at using a selected lactic acid bacterium for increasing the antioxidant features of myrtle berries, with the perspective of producing a functional ingredient, dietary supplement or pharmaceutical preparation. The antioxidant activity was preliminarily evaluated through in vitro assays, further confirmed through ex vivo analysis on murine fibroblasts, and the profile of phenol compounds was characterized. Results: Myrtle berries homogenate, containing yeast extract (0.4%, wt/vol), was fermented with Lactobacillus plantarum C2, previously selected from plant matrix. Chemically acidified homogenate, without bacterial inoculum and incubated under the same conditions, was used as the control. Compared to the control, fermented myrtle homogenate exhibited a marked antioxidant activity in vitro. The radical scavenging activity towards DPPH increased by 30%, and the inhibition of linoleic acid peroxidation was twice. The increased antioxidant activity was confirmed using Balb 3 T3 mouse fibroblasts, after inducing oxidative stress, and determining cell viability and radical scavenging activity through MTT and DCFH-DA assays, respectively. The lactic acid fermentation allowed increased concentrations of total phenols, flavonoids and anthocyanins, which were 5–10 times higher than those found for the non-fermented and chemically acidified control. As shown by HPLC analysis, the main increases were found for gallic and ellagic acids, and flavonols (myricetin and quercetin). The release of these antioxidant compounds would be strictly related to the esterase activities of L. plantarum. Conclusions: The lactic acid fermentation of myrtle berries is a suitable tool for novel applications as functional food dietary supplements or pharmaceutical preparations.

Background Osteopetrosis or Albers-Schonberg's disease is a heterogeneous group of rare hereditary troubles of the bone characterized by bone sclerosis due to an alteration of the bone reabsorption mediated by osteoclasts. The defect in the osteoclastic activity is responsible for complete or partial medullary cavities occlusion, with consequent reduced hemopoiesis, and for the excessive fragility of the affected bone segments. Case report We reported the case of a young man of 31 years affected by osteopetrosis in which a small cell lung cancer developed. Results Small cell lung cancer is a particularly rare neoplasm in the young, and even though it is highly sensitive to chemotherapeutic treatment its prognosis remains poor. The greatest clinical problem connected with chemotherapeutic treatment of patients affected by osteopetrosis is the variability of the reduction of their bone marrow reserve, which could expose them to an excessive hematological toxicity caused by the therapy. Conclusions The adoption of suitable prophylactic measures, such as the use of growth factors and drugs selected in relation to their toxicity or given in reduced doses, should be appropriately considered in these subjects.

The objective of this work was to investigate the structure and diversity of lactic acid bacteria (LAB) communities in sourdough used for the production of traditional breads (Carasau, Moddizzosu, Spianata, Zichi) in Sardinia. 16S rDNA sequencing and Randomly Amplified Polymorphic DNA (RAPD-PCR) was applied for the identification and typing of the LAB isolated from 25 samples of sourdoughs. Multivariate statistical techniques were applied to RAPD-PCR pattern to study the biological diversity of sourdough samples. Twelve different species of LAB were identified, and most isolates were classified as facultative heterofermentative lactobacilli. Lactobacillus pentosus dominated the lactic microflora of many samples while Lactobacillus sanfranciscensis was isolated only from a limited number of samples. Although heterofermentative species represented between between 30% and 60% of the isolates in Carasau, Spianata and Zichi sourdoughs, only 2% of the isolates from Moddizzosu sourdoughs were identified as heterofermentative LAB. RAPD-PCR with a single primer followed by cluster analysis did not allow the identification of the isolates at the species level. However, a multidimensional scaling/bootstrapping approach on the RAPD-PCR patterns uncovered the diversity of the LAB communities of LAB showing differences both within and between bread types.

The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2x2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95\% confidence intervals (CI): 0.73-1.09) for patients receiving FA and 0.99 (95\% CI 0.80-1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95\% CI: 0.80-1.30) and 0.94 (95\% CI 0.73-1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients..

BACKGROUND Factors that are predictive of carrying BRCA1 and BRCA2 germline mutations in patients with breast carcinoma are awaited widely. The genetically homogeneous Sardinian population may be useful for defining the role of such genetic alterations further through a clinical evaluation program. METHODS One hundred two of 659 patients with breast carcinoma (15.5%) who were collected consecutively had a family history of breast carcinoma and were screened for BRCA1/2 mutations by denaturing high-performance liquid chromatography and DNA sequencing. RESULTS Three deleterious germline BRCA1/2 mutations were detected in 15 of 102 families (14.7%), including 13 families (86.7%) with BRCA2 mutations and 2 families (13.3%) with BRCA1 mutations. A single variant, BRCA2-8765delAG, was the most recurrent mutation in the series and was found in 12 of 102 families (11.8%) and in 18 of 657 patients (2.7%). The average age at diagnosis was significantly younger in families with BRCA1/2 mutations (48.6 yrs) compared with the age of patients who had no detectable mutation (52.9 yrs; P = 0.039). Moreover, BRCA1/2 mutations were found at a significantly higher rate in families who had at least 1 member with ovarian carcinoma or male breast carcinoma (5 of 12 families; 41.7%) than in families without such an association (10 of 90 families; 11.1%; P = 0.003). CONCLUSIONS BRCA2 mutations were approximately 6 times more prevalent than BRCA1 mutations. A diagnosis of breast carcinoma before age 50 years, ovarian carcinoma, male breast carcinoma, and 3 affected generations all were associated significantly with BRCA1/2 mutations. Although the current findings provided further support for the hypothesis that additional breast carcinoma susceptibility genes remain to be identified, such indicators of the presence of BRCA1/2 mutations may be useful in counseling patients about undergoing genetic testing. Cancer 2005. © 2005 American Cancer Society.

Oxaliplatin 100 mg/m(2) iv on day 1, and capecitabine 1,000 mg/m(2) orally bid from day 1 (evening) to day 11 (morning) were administered every 2 weeks (OXXEL regimen) to 38 patients as first-line treatment for metastatic colorectal carcinoma. A total of 318 cycles were administered, with a median of 8 (range, 4-12) cycles per patient. Response rate (RR) was 45% (95% confidence interval (CI), 29%-62%), with 7 complete responses and 10 partial responses; furthermore, 12 patients showed a stable disease, so that a disease control was achieved in 29 (76%) patients. RR was greater among patients with performance status 0 (52%), without weight loss (52%), younger than 65 years (50%), and previously unexposed to adjuvant chemotherapy (48%), while no correlation was found with the actually delivered oxaliplatin dose intensity. Overall, haematological side effects were negligible, with no case of grade 4 toxicity, and only one patient suffering from an episode of grade 3 neutropenic fever. Severe anaemia occurred in 4 (11%) patients, and grade 3 neuropathy affected 9 (24%) patients. Median progression-free survival was 7.9 (95% CI, 6.2-9.6) months, and median overall survival has not been reached yet. In conclusion, the OXXEL regimen resulted safe and active, and it deserves further evaluation in metastatic colorectal cancer patients.

From September 2001 to November 2002, 35 patients aged 70–81 (median, 75) years, with measurable metastatic lesions from colorectal carcinoma, were treated with a combination of oxaliplatin (OXA) infused i.v. over 2 h on day 1, and capecitabine, assumed orally twice a day (12-h apart) from day 2 to day 15. An alternated dose escalation for both drugs was planned over the first three cycles for each patient, in the absence of WHO grade ≥2 toxicity on previous cycle: starting doses were 85 mg/m2 for OXA, and 2000 mg/m2 (day) for capecitabine on first cycle; on second cycle, OXA was planned at 100 mg/m2, while capecitabine was planned at 2500 mg/(m2 day) on third cycle. Treatment was repeated every 3 weeks until progression, or for a maximum of 12 cycles. A total of 212 cycles were administered, with a median of 6 (range, 1–12) cycles/patient. Dose escalation was performed in 18 (51%) patients for OXA, and in 4 (11%) patients for capecitabine. No grade 4, and 10 (29%) cases of grade 3 toxicity of any type were reported. Abdominal symptoms (pain, nausea, or vomiting) affected 66% of patients, but they were of grade 3 in only 2 (6%) patients. Grade 3 diarrhoea occurred in 3 (9%) patients. Two complete and 12 partial responses (PR) were reported, for an overall response rate of 40% (95% CI, 24–58%). Progression of disease occurred in 23 (66%) patients, and 18 (51%) died. The actuarial median progression-free and survival time were 6.9 and 14.1 months, respectively.

The sequential doxorubicin → CMF (CMF = cyclophosphamide, methotrexate, fluorouracil) regimen has never been compared to CMF in a randomised trial. The role of adding goserelin and tamoxifen after chemotherapy is unclear. In all, 466 premenopausal node-positive patients were randomised to: (a) CMF × 6 cycles (CMF); (b) doxorubicin × 4 cycles followed by CMF × 6 cycles (A → CMF); (c) CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (CMF → GT); and (d) doxorubicin × 4 cycles followed by CMF × 6 cycles followed by goserelin plus tamoxifen × 2 years (A → CMF → GT). The study used a 2 × 2 factorial experimental design to assess: (1) the effect of the chemotherapy regimens (CMF vs A × CMF or arms a + c vs b + d) and (2) the effect of adding GT after chemotherapy (arms a + b vs c + d). At a median follow-up of 72 months, A → CMF as compared to CMF significantly improved disease-free survival (DFS) with a multivariate hazard ratio (HR) = 0.740 (95% confidence interval (CI): 0.556-0.986; P = 0.040) and produced a nonsignificant improvement of overall survival (OS) (HR = 0.764; 95% CI: 0.489-1.193). The addition of GT after chemotherapy significantly improved DFS (HR = 0.74; 95% CI: 0.555-0.987; P = 0.040), with a nonsignificant improvement of OS (HR = 0.84; 95% CI: 0.54-1.32). A → CMF is superior to CMF. Adding GT after chemotherapy is beneficial for premenopausal node-positive patients. © 2005 Cancer Research UK.

This study compares two cytotoxic regimens comprising the same dose and schedule of cisplatin (CP) plus vinorelbine (VNR) or gemcitabine (GEM) administered under the same schedule to patients with advanced non-small cell lung cancers (NSCLC). From April 1998 to February 2003, 285 patients were randomised to receive either VNR 25 mg/m 2 on days 1 and 8 as an intravenous (i.v.) bolus plus CP 75 mg/m 2 on day 1 (regimen A) or GEM 1200 mg/m 2 on days 1 and 8 as an i.v. 30-min infusion plus CP 75 mg/m 2 on day 1 (regimen B). Both treatments were recycled every 21 days. If no progression had occurred after six cycles, the patients continued to receive VNR or GEM monochemotherapy weekly. Cross-over of the two single agents was considered if disease progression occurred. Objective response (OR), time to progression (TTP) and overall survival (OS) were analysed according to the intention-to-treat principle. 272 patients were ultimately eligible (137 on A and 135 on B). Their main characteristics were: male/female ratio 214/58; median age 63 (range 32-77) years; median Karnofsky Performance Status (PS) 80 (range 70-100); stage IIIB 34%, stage IV 61%, recurrent disease 5%; histology - epidermoid 29%, adenocarcinoma 53%, other NSCLC 18%. The characteristics of the patients in the two arms were well matched. The following response rates were observed in regimens A and B, respectively: complete response (CR) 0.7% and 3.7%, partial response (PR) 31.9% and 22.2% (P = 0.321). Median CR + PR duration was 8 months in both arms. Clinical benefit represented by an improvement in symptoms was evident in 25.7% and 28.1%, respectively. Median TTP was 5 months in both arms and median OS 11 months in both arms. Grade III-IV neutropenia occurred in 30.7% and 17.7% of the patients in arms A and B, respectively (P = 0.017); thrombocytopenia occurred in 0% and 9.3% (P = 0.004), respectively. No difference in the incidence of anaemia was observed. Non-haematological toxicity was generally mild: a higher incidence of grade 1-2 peripheral neurotoxicity and grade 1-2 local toxicity with regimen A and grade 1-2 liver toxicity with regimen B was reported. A pharmaco-economic comparison showed a difference between the two doublets, principally due to the different costs of VNR and GEM. Under the study conditions the combination of VNR or GEM with the same dose and schedule of CP produced similar OR, clinical benefits, TTP and OS in advanced NSCLC, and only mild toxicological differences were observed. Pharmaco-economic evaluation favoured the CP + VNR doublet. © 2004 Elsevier Ltd. All rights reserved.

The aim of this study was to assess the safety and efficacy of biweekly irinotecan plus leucovorin-modulated 5-fluorouracil i.v. bolus in metastatic colorectal carcinoma according to the age of patients. For this purpose, we have analysed 108 patients randomly allocated to receive irinotecan 200 mg m(-2) i.v. (1-h infusion) on day 1, and L-leucovorin 250 mg m(-2) i.v. (1-h infusion) plus 5-fluorouracil 850 mg m(-2) i.v. bolus on day 2 every 2 weeks (IRIFAFU) in our previous SICOG 9801 trial. According to age, patients were retrospectively divided into three groups: younger (/=54 years, n=37), middle-aged (55-69 years, n=64), and elderly (/=70 years, n=17). Apart from gender, pretreatment characteristics were well balanced across the three groups. WHO grade/=3 neutropenia and diarrhoea affected on the whole 46 and 16 patients, respectively, without any significant difference according to age-grouping. Patients aged/=54 years stayed on therapy for a longer time (median 24 vs 14-15 weeks), and received more cycles (median 9 vs 7), than the older ones. Only one patient in the young group withdrew consent to therapy as opposed to four patients each in the aged and elderly one. Response rate was 38% for younger patients, 34% for aged, and 35% for the elderly ones. Median time to progression was 7.4, 8.0, and 5.3 months, and median survival time was 13.4, 15.3, and 13.9 months, respectively. We conclude that IRIFAFU given every other week may represent a suitable therapeutic option also for elderly patients with metastatic colorectal carcinoma.

The behavior of the fungicide fenhexamid, N-(2,3-dichloro-4-hydroxyphenyl)-1-methyl-cyclohexanecarboxamide, has been studied at concentrations corresponding to the limits fixed for grapes (3 mg kg(-1)), or higher, during the alcoholic fermentation. The presence of the fungicide did not affect the amount of alcohol produced. The amount of fenhexamid in the liquid phase decreased by ca. 15%, but the missing fenhexamid was recovered unchanged from yeasts. This suggests that the fungicide is not degraded during the fermentation process, but adsorbed by yeasts. Two constituents of Saccharomyces cerevisiae cell wall, chitin and glucan, tested as potential adsorbents, exhibited affinity for fenhexamid.

Fig fruits dehydration is quite totally carried out by sun drying. This technology poses concern about safety of the end product, mainly for aflatoxin development. Most of the problems involved in sun drying may be solved by oven dehydration. Fig fruits of some local cultivars underwent hot air dehydration in a tangential air-flow cabinet dryer. At start, regular intervals and end of process sampling have been performed to calculate dehydration curves and quality loss. Microbiological counts, non enzymatic browning and quality parameters were also monitored during storage. Results obtained will be discussed.

Background To evaluate the efficacy of tamoxifen as primary treatment in women aged over 70 years with operable breast cancer versus surgery followed by adjuvant tamoxifen. Patients and methods Patients randomly received tamoxifen alone (160 mg day 1, then 20 mg/day) for 5 years or surgery followed by tamoxifen (20 mg/day) for 5 years. Overall survival was the main study end point; secondary objectives included breast cancer survival and local control of the disease. Results Between 1987 and 1992, 239 patients were assigned to surgery plus tamoxifen and 235 to tamoxifen alone. Treatment arms were comparable for tumor size, clinical nodal status and performance status. At a median follow-up of 80 months 274 patients had died. No difference between groups had emerged in overall and breast cancer survival. There were 27 local progressions in the surgery plus tamoxifen group and 106 in the tamoxifen-alone group (P = 0.0001). In the surgery plus tamoxifen group, no difference in overall survival had emerged according to the extension of operation. Conclusions The long-term results of the study confirm the 3-year interim analysis already reported. Surgery (radical or minimal) followed by adjuvant tamoxifen does not modify overall and breast cancer survival as compared with tamoxifen alone in early breast cancer of older women. Because of the high rate of local progressions with tamoxifen alone, minimal surgery followed by tamoxifen appears to be the appropriate treatment in such patients. More extensive surgery is not useful. Tamoxifen alone is an adequate alternative treatment in very old or frail patients.

PURPOSE: To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer. PATIENTS AND METHODS: Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m2 on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m2 on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 × 2 factorial design of this study. RESULTS: The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P = .10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P = .47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P = .08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue. CONCLUSION: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug’s tolerability.

Sardinian sherry strains of S. cerevisiae form a biofilm on the surface of wine at the end of the ethanolic fermentation, when grape sugar is depleted and when further growth becomes dependent on access to oxygen. A point mutation in HSP12 or deletion of the entire gene results in inability to form this film. HSP12 encodes a heat-shock protein previously foundby others to be active during stationary phase, in cells depleted for glucose, and in cells metabolizing ethanol and fatty acids, all conditions associated with sherry biofilms. The DNA sequence of HSP12 allele of strain Ar5-H12 has GenBank Accession No. AY046957. Copyright © 2002 John Wiley & Sons, Ltd.

Data currently available are insufficient to demonstrate a real utility for CA 15-3 in the diagnosis, staging or surveillance of breast cancer patients following primary treatment. The aim of this study was to determine if there was a correlation between supranormal CA 15-3 serum levels and clinical and biological variables in breast cancer patients at first disease relapse. From October 1988 to March 1998, 430 consecutive patients entered the study. Overall CA 15-3 sensitivity was 60.7%. Elevated CA 15-3 levels were found more frequently in patients with liver metastases (74.6%) and in those with pleural effusion (75.7%). CA 15-3 sensitivity was 70.4% in patients with estrogen-receptor-positive (ER+) primary tumors and 45.9% in those with estrogen-receptor-negative (ER-) tumors (p0.0001). In patients with a limited extent of disease, marker sensitivity was 57.7% in ER+ tumors and 25.7% in ER- tumors (p0.0001). Logistic regression analysis showed ER status, disease extent and pleural effusion as independent variables associated with CA 15-3 positivity. The multivariate Cox analysis showed ER and disease extent as independent variables predicting overall survival, whereas CA 15-3 failed to be statistically significant. CA 15-3 was an independent variable only when the disease extent variable was removed. This study suggests that CA 15-3 in advanced breast cancer patients is a marker of both disease extent and ER status. The direct relationship with ER status indicates that CA 15-3 diagnostic sensitivity in the early detection of disease recurrence could be greater in ER+ patients than in ER- ones. Furthermore, this suggests that patients with elevated CA 15-3 levels could have disease that is more sensitive to hormone manipulation than those with normal CA 15-3 values.

In this study, three flor strains of Saccharomyces cerevisiae were genetically characterized. They were isolated from biofilms on Sardinian sherry-like wines produced at family-run wineries where pure cultures of yeasts were not used. The study aimed to investigate the life cycle of these naturally-occurring flor strains, using a genetic procedure supplemented by analysis of subsequent meiotic generations. A semi-homothallic life cycle was found in three strains that could be helpful in a genetic improvement programme.

Our aim was to study the activity and toxicity of the gemcitabine plus vinorelbine (Gem Vin) combination and to identify the optimal dose. Previously untreated patients aged < 70 years, with stage IV or IIIb (not candidates for radiotherapy) non-small cell lung cancer were eligible. Studied dose-levels of Gem Vin, administered on days 1 and 8 every 3 weeks, were (mg m–2): level I = 1000/25; level II = 1200/25; level III = 1000/30; level IV = 1200/30. A feasibility study was performed at each dose-level, followed by a single-stage phase II study. Dose-level IV was unfeasible because of grade 4 neutropenia. Overall, out of 126 patients enrolled in phase II studies, there were one complete and 32 partial responses (response rate 26%: 95% CI 18–34%). Response rates were 27.9%, 21.4% and 29.3% at levels I, II and III, respectively. The treatment was well tolerated. Toxicity was less frequent and severe at level I. Overall median survival was 33 weeks (95% CI 28–40). Descriptive quality of life analysis showed that patients with a worse baseline global health status score tended to drop out of the study earlier than those with a better score. Gem Vin is feasible at different doses. It is sufficiently active and well tolerated. A phase III study to compare the effect on quality of life of Gem Vin (level I) vs cisplatin-based chemotherapy is ongoing. © 2000 Cancer Research Campaign

Cactus pear fruits ( Opuntia ficus indica Mill, cultivar Gialla) were manually peeled, placed in polystyrene trays and packaged with a heat-shrinkable film, then kept at 4 °C and 15 °C for 11 d. After 4, 8 and 11 d chemical-physical, microbiological and sensorial parameters were determined, while in-package gas concentrations were measured daily. Chemical-physical and sensorial parameters did not show significant changes in 4 °C-stored fruits until d 8, while those kept at 15 °C experienced a dramatic increase in acidity, ethanol accumulation, strong off-flavour development and loss of overall fruit freshness and firmness. Microbiological growth rate was much higher at 15 °C than at 4 °C. Visible manifestation of moulds was detected on 4 °C-stored fruits on d 11, while in the 15 °C-stored fruit, fungi colonization had already started on the fourth day. Based on these results, we conclude that quality of peeled cactus pear fruits can be maintained at 4 °C for 8 d, while abuse of temperature (15 °C) limits shelf-life to 4 d.

The influence of six fungicides (azoxystrobin, cyprodinil, fludioxonil, mepanipyrim, pyrimethanil, and tetraconazole) on the fermentative activity of two yeasts (Saccharomyces cerevisiae and Kloeckeraapiculata) and two lactic bacteria (Leuconostoc oenos and Lactobacillus plantarum) was studied. The possibility of their being degraded by these yeasts and bacteria was also investigated. The presence of the pesticides did not affect alcoholic fermentation, not even with levels higher than those normally found in grapes in field experiments. On the contrary, their presence stimulated the yeast, especially K. apiculata, to produce more alcohol. The fermentative process did not affect the amount of pesticides either by degradation or by adsorption. During malolactic fermentation by Le. oenos, malic acid decreased slightly less (by approximately 15%) in the presence of all pesticides, except mepanipyrim. A lower effect ( approximately 5%) was found during the fermentative process with La. plantarum. The bacteria studied did not show a degradative effect on pesticides during malolactic fermentation.

The effectiveness of a dehydration process on the quality of "Niedda longa" fig fruits was studied. Drying was carried out either with an industrial two-stage dehydration system, requiring no blanching treatment, or with a simulated sun-drying procedure. During the industrial process fruits were: (a) initially moved for 3 hours in a tunnel with a gradient air temperature from 95°C to 85°C; (b) then moved into a second tunnel at 85°C for 14 h. Sun-drying was simulated keeping fruits for 120 h at 32°C and 35% of relative humidity (RH). Finally dehydrated figs were rehydrated, or equilibrated with environmental RH (sun-dried figs), and both treated with potassium-sorbate solution, then film-packaged into hermetically sealed air tight bags. Moreover, half of the bags were packed in-modified atmosphere (MAP). Fruits were, then, stored at 20°C for 6 months. A 11 h dehydration time was sufficient to obtain microbially stable fruits without chemical treatments, reaching a dry matter content (DM) of 88 % and water activity (aw) of 0.60, whereas after 17 h DM and aw were 91% and 0.57, respectively. DM of industrial rehydrated figs and environmental equilibrated sun-dried figs were 71% and 74%, respectively, requiring a potassium-sorbate treatment. After packaging and 6 months of shelf life, no microbial growth was revealed on fruits. MAP resulted in no additional improvement on the microbial quality of the product. Based on these results we can state that industrial dehydration performed well, even if fruit calibration is needed before drying.

Vernaccia di Oristano, a sherry-like wine produced in Sardinia, Italy, was subjected to biological aging after inoculation with Saccharomyces cerevisiae var. bayanus (strain 1043) and S. cerevisiae var. prostoserdovii (strain 1739) and to aging under sterile conditions. Samples were withdrawn at three different stages of maturation of the sherry-like wine, and the volatiles were analyzed by gas chromatography and gas chromatography/mass spectrometry. Forty compounds were identified comprising alcohols, acids, esters, and dioxolanes. Analysis of variance showed significant effects of both aging conditions and duration on most of the volatiles, with differences maximized at the final sampling time, i.e., 20 days after film formation. Keywords: Vernaccia di Oristano; sherry; flavor; gas chromatography/mass spectrometry; Saccharomyces cerevisiae var. bayanus; Saccharomyces cerevisiae var. prostoserdovii; yeasts

BACKGROUND The combination of vinorelbine (VNR), cisplatin (CDDP), and 5-fluorouracil (5-FU) has previously been shown to be active in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCHNC). This multicenter Phase II study was carried out with the aim of evaluating the effectiveness of this combination in patients with previously untreated, unresectable locally advanced SCHNC. METHODS Sixty patients with previously untreated, unresectable SCHNC were treated with CDDP 80 mg/m2 on Days 1, 5-FU 600 mg/m2 as a 4-hour infusion on Days 2-5, and VNR 25 mg/m2 iv bolus on Days 2 and 8. There were 15 patients with laryngeal carcinoma, 19 patients with oropharyngeal carcinoma, 15 with carcinoma in the oral cavity, 5 with carcinoma in the hypopharynx, and 4 with carcinoma in the maxillary sinus. Most patients (78%) had Stage IV disease. After achievement of the best possible objective response, patients were subjected to definitive locoregional treatment, i.e., radiotherapy and/or surgery, as appropriate. RESULTS All patients completed the induction chemotherapy. After a mean of 3.86 cycles per patient, the overall response rate was 88% (95% confidence interval [CI], 82-94%), with a complete response rate of 23% (95% CI, 14-26%). Complete responses were more frequently seen in patients with N0-1 disease than in those with N2-3 disease (P = 0.037). No other statistically significant correlation between type of response and extent of disease was noted. Toxicity consisted mainly of myelosuppression and gastrointestinal side effects. After definitive locoregional treatment, 58% of patients were clinically free of disease. These patients included those who had complete response after induction chemotherapy, 19 of 39 patients who had partial response, and 2 with stable disease. Median disease free survival was 16 months, and median overall survival was 23 months. CONCLUSIONS The combination regimen of CDDP, 5-FU, and VNR was very active in previously untreated SCHNC. It was well tolerated in most cases, and neurotoxicity was not a major side effect. This regimen, which does not require hospitalization, should be compared with standard chemotherapy, such as the combination of CDDP and continuous-infusion 5-FU. Cancer 1997; 79:1394-400. © 1997 American Cancer Society.

The fate of folpet from the treatment on vine to the production of wine was studied. Sunlight degraded folpet to unknown products. Phthalimide was a minor metabolite formed on grapes from folpet. Folpet degraded in must, giving 80% phthalimide; the results obtained with model solutions showed that in must folpet can also give small amounts of phthalic acid. During wine-making folpet degraded completely, and at the end of fermentation phthalimide was only present in wine. This compound was stable in wine after several months. The presence of folpet in grapes inhibited the alcoholic fermentation of Saccharomyces cerevisiae and Kloeckera apiculata completely. Phthalimide, on the contrary, had no negative effect on the fermentative action of the two yeasts. GC and HPLC methods were developed to determine folpet and its metabolites. Keywords: Folpet; metabolites; residues; grapes; wine

Ninety strains of film-forming yeasts of the Saccharomyces genus were screened for their ability to use phenolic acids. None were able to use phenolic acids as a sole carbon source. When ethanol at 2% was added to the medium, however, the yeasts were able to grow, exhibiting florization accompanied by decolouration.

A multicentric randomized trial was performed in premenopausal women with node-positive, estrogen-receptor-negative breast tumors to assess the potential superiority of alternating adjuvant chemotherapy over ‘standard’ CMF chemotherapy. Between January 1989 and June 1992, 107 patients were entered into the study and randomly allocated to receive either cyclophosphamide 100 mg/m2 per os on days 1-14, methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 intravenously (IV) on days 1, 8 (CMF), every 4 weeks for a total of 6 cycles, or the following regimens: CMF as previously; epidoxorubicin 75 mg/m2 IV on day I and vincristine 0.75 mg/m2 IV on days 1, 8 (EV); mitomycin-C 10 mg/m2 IV on day 1 and vindesine 2 mg/m2 IV on days 1, 8 (MVs). The three regimens were given every 4 weeks for a total of 6 cycles according to the following schedule: CMF, EV, MVs, CMF, EV, MVs. At a median follow up of 48 months (range 30-72), 40 patients have relapsed and 17 have died overall. More patients in the triple-combination arm ...

Wine yeasts have been shown to be characterised by marked chromosome‐length polymorphism. Study of this polymorphism could explain some of the genetic characteristics of these strains and, furthermore, lead to their precise identification, which is still an unresolved problem in the farm‐produce industry. With this aim in mind, we characterised the electrophoretic karyotype of 52 flor strains, isolated from the films of the following Sardinian wines: Cannonau, Malvasia di Bosa and Vernaccia di Oristano.

Forty compounds were identified by gas chromatography and gas chromatography/mass spectrometry in the volatile fraction of Vernaccia di Oristano, an Italian sherry-like wine produced in Sardinia since the 11th century. The individual aromatic compounds were identified and quantified in the original wine, both after biological ageing by inoculation of the original wine with Saccharomyces cerevisiaevarbayanusandS cerevisiaevarprostoserdovii, and after ageing under sterile conditions. The effects of flor yeasts in terms of production or subtraction of flavour components are discussed.

The degradative action of two strains of Saccharomyces cerevisiae, producers of large quantities of H2S and SO2, on eight sulphur-containing insecticides (chlorpyrifos-methyl, dimethoate, fenitrothion, fenthion, malation, methidation, parathion, and quinalphos) was studied. Moreover, the influence of these compounds on the fermentative activity of the yeasts was investigated. The yeasts adsorbed and degraded the studied insecticides to various extents, but their fermentative activity was not affected. A moderate adsorbtion (approximately 10% of the residue) was observed for chlorpyrifos-methyl, fenitrothion, parathion, and quinalphos. When absorbed, the insecticides were also degraded by about 50%. The degraded pesticides belong to the thiophosphates, while the dithiophosphates showed higher stability. The two yeast strains showed analogous degradative actions.

Among primary liver cancers occurring worldwide, hepatocellular carcinoma (HCC) is the major histological type accounting for 70–85% of all cases. Phase III trials in patients with advanced HCC treated with sorafenib (SO), a multitargeted tyrosine kinase inhibitor, showed significant improvements in both overall and progression-free survival. We report the cases of two elderly patients with advanced HCC who had prolonged stable disease following treatment with SO (400 mg bid). Patient 1 was treated with SO for a period of 16 months until evidence of right sacral metastases was noted. Patient 2 received SO 400 mg bid from January 2009 to October 2009 until radiological evidence of disease progression was noted. Both patients experienced minimal toxicity, suggesting that SO can be safely administered to elderly patients.

The influence of six fungicides (benalaxyl, carbendazim, dichlofluanid, folpet, triadimefon and vinclozolin) on the fermentative activity of two lactic bacteria (Lactobacillus plantarum and Leuconostoc oenos) was studied. The possibility of their degradation by these bacteria was also investigated. Benalaxyl, carbendazim, triadimefon and vinclozolin did not show any interaction with the bacteria studied. Dichlofluanid reduced the fermentatwe activity of L. oenos, in proportion to its concentration, while it showed no influence on the fermentative activity of L. plantarum. Dichlofluanid was rapidly degraded by L. plantarum, while its degradation by L. oenos was lower.

Single photon emission computed tomography (SPECT)/CT is emerging as a useful diagnostic tool in several oncological fields. In this prospective study, we assessed the usefulness of Tc-99m-tetrofosmin SPECT/CT in the detection of both residual breast tumors and axillary lymph node metastases following neoadjuvant therapy. Thirty-seven consecutive breast cancer patients scheduled to surgery following neoadjuvant therapy preoperatively underwent a Tc-99m-tetrofosmin SPECT/CT study, using a dual head gamma camera integrated with a x-ray tube for low-dose CT, including both breasts and axillary regions in the field of view. Within 1 week of SPECT/CT, all 37 patients had breast surgery with associated axillary lymph node dissection in 33/37 cases. At surgery, 31/37 patients had breast residues (microscopic in 4/31 cases and macroscopic in 27/31 cases). Axillary lymph node metastases were ascertained in 19/33 cases (N1mi: 2 cases, N1a: 8 cases, N2a: 6 cases, N2b: 3 cases). SPECT/CT sensitivity, specificity, and accuracy in detecting residual tumors were 87%, 100%, and 89.2%, respectively; the corresponding values in detecting axillary lymph node metastases were 36.8%, 92.8%, and 60.6%. SPECT/CT missed breast cancer residues in 4/31 patients, including 2 cases with microscopic residual disease. Moreover, lymph node metastases were missed in 12/19 patients (10/12 with pN1mi or pN1a metastases), all with lymph nodes with post-therapy fibrotic changes and small deposits of metastases. Tc-99m-tetrofosmin SPECT/CT proved a useful diagnostic tool in the detection and in the localization of residual breast tumors following neoadjuvant therapy. The procedure lacked in sensitivity in identifying axillary lymph node metastases, especially in patients with a limited lymph node involvement. According to our data, SPECT/CT may guide the surgeon to the most appropriate breast surgical treatment and to eventually select the most suitable axillary lymph node sampling (axillary lymph node dissection or sentinel node biopsy).

The influence of fenamidone ((S)-1-anilino-4-methyl-2-methylthio-4-phenylimidazolin-5-one), pyraclostrobin (methyl 2-[1-(4-chlorophenyl)pyrazol-3-yloxymethyl]-N-methoxycarbanilate), indoxacarb (methyl 7-Chloro-2,5-dihydro-2-[[(methoxycarbonyl) [4- (trifluoromethoxy) phenyl] amino] carbonyl] indeno[1,2-e][1,3,4] oxadiazine-4a(3H)-carboxylate), and deltamethrin ([cyano-[3-(phenoxy)phenyl]methyl] 3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropane-1-carboxylate) on spontaneous fermentation carried out by natural yeast grapes microflora, was studied during the wine-making process. Aliquots of pesticide standard solutions were added to the grapes before crushing, to reach a concentration equal or half the maximum residue limit (MRL). Vinifications were performed, with maceration (R), or without maceration (W). During the wine-making process, samples were taken at the beginning (one hour after grapes crushing), at the middle and at the end of the spontaneous fermentation process. At half the MRL concentration, deltamethrin affected Pichia sp. population with a decrease of almost 50 %, while fenamidone decreased Candida sp., Candida stellata at 83, and 36%, respectively. Metschnikowia pulcherrima population decreased in all samples when compared to the control. Experiments at MRL levels showed a strong reduction for all non-Saccharomyces yeast species, when grapes had been treated with pyraclostrobin, fenamidone, and deltamethrine, except for Candida sp. which was found to have been affected only by fenamidone residues. Growth zone inhibition test showed only an in vitro activity of pyraclostrobin over Kloeckera spp., C. stellata, and M. pulcherrima. Microvinification experiments produced wines with no differences concerning S. cerevisiae population as well as production of ethanol and residual sugars. Experiments showed that at the end of the fermentation process pesticides were adsorbed by the lees and grape skins, and no pesticides residue was detectable in wine.

Eleven strains belonging to two physiological races of Saccharomyces cerevisiae endowed with different abilities of forming films at air-liquid interfaces were analysed in relation to cell fatty acid composition and cell hydrophobicity. Extensive individual differences in fatty acid profiles were observed both in the film and in the non-film phase. The ability of the cells to form a floating film seems to be an implicit strain character associated with an elevated unsaturation level and a mean chain length of fatty acid residues, as well as cellular hydrophobicities higher than those shown by non-film-forming strains belonging to the same species.

In the hope of increasing the incidence of objective remissions and the survival time of patients with small cell lung cancer, we conducted a randomized study designed to compare a treatment scheme of alternating chemotherapy featuring cisplatin+etoposide followed by cyclophosphamide+epirubicin versus conventional chemotherapy with cyclophosphamide+epirubicin+vincristine, in a total of 113 patients (56 treated with the alternating regime and 57 treated conventionally). Patients receiving the alternating drug regimen showed some increase in objective remission rates, and above all increased mean survival time (297 days versus 232). The higher incidence of side effects encountered was effectively controlled by the usual medical therapy.

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

Objective: Breast cancer patients with >3 involved nodes (N+) have a poor outcome. Chemotherapy (CT), alone or combined with endocrine therapy (ET) in hormone receptor (HOR)-positive patients, is the standard for these women. However, there are still questions surrounding the optimal adjuvant CT regimen. Methods: 244 patients with >3 N+ were randomized to receive either four 3-weekly courses of epirubicin (E: 100 mg/m2, day 1) followed by four 4-weekly cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF: 600, 40, 600 mg/m2, days 1, 8: n = 122) or four 3-weekly courses of paclitaxel (T: 175 mg/m2, day 1) followed by four 3-weekly cycles of epirubicin and vinorelbine (E: 75 mg/m2, day 1; V: 25 mg/m2, days 1, 8: n = 122). After CT, tamoxifen (plus an LH-RH analog in menstruating women) was given to all HOR-positive patients over a period of 5 years. Overall survival (OS) was the primary end point. Relapse-free survival (RFS) and toxicity were secondary end points. Results: At a median follow-up time of 102 months (range 3–146), OS and RFS did not differ significantly between groups (E-CMF vs. T-EV: OS, HR 0.94, 95% CI 0.59–1.48, p = 0.8; RFS, HR 0.86, 95% CI 0.57–1.29, p = 0.45). The lack of any difference between assigned treatments was confirmed by multivariate analysis (E-CMF vs. T-EV: RFS, HR 0.98, 95% CI 0.64–1.48, p = 0.9). The 2 regimens showed different toxicity profiles. In fact, significantly more women assigned to E-CMF were affected by stomatitis (p = 0.001) while significantly more women in the T-EV group developed peripheral neuropathy (p < 0.0001) and musculoskeletal disorders (p < 0.0001). However, side effects were moderate and manageable and no toxic death occurred in either arm of the study. Conclusions: T-EV was safe and moderately toxic but was not superior to E-CMF.

Most of 31 hybrids, obtained by fusion between the petite mutant of a nonsporous strain ofSaccharomyces cerevisiae SS-1090 and a Kar mutant K1 killer ofS. cerevisiae adenine and uracil auxotrophic, proved to be enologically as useful as the parent strain, and in some cases more so. In addition, all of them possessed killer factor, rendering them potentially more competitive against wild yeasts. Most of them also proved to be highly sporous.

Background In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Methods Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Results and Conclusion Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764_8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations.

Background: The steroidal aromatase inhibitor exemestane has demonstrated efficacy for the treatment of breast cancer in the metastatic and adjuvant settings. Smaller trials have also reported efficacy in the neo-adjuvant setting. Patients and methods: This phase II, open-label, multicentre study examined the efficacy and safety of neo- adjuvant exemestane in women aged >70 years with operable, receptor-rich breast cancer. Consecutive eligible patients received exemestane 25 mg/day for 6 months before planned surgery. The primary end point was clinical response. Results: Overall, 117 patients were recruited (median age 80 years). The objective response rate in 112 assessable patients (85 with clinical and mammographic evaluation; 27 with clinical evaluation only) was 69.6% (two complete responses; 76 partial responses). In patients who responded, median tumour size reduced from 4.81 to 2.12 cm. Seventy-seven patients (68.7%) continued to surgery. Of the 40 patients eligible for breast-conserving surgery, 34 (85%) deemed unfit for this procedure at baseline. Exemestane-related adverse events were unremarkable except for grade 3 allergic skin reactions in two patients (1.8%). Conclusion: Neo-adjuvant exemestane given for 6 months appears to be effective for receptor-rich breast cancer in older patients. There may now be sufficient evidence to support the use of neo-adjuvant in this patient population. Key words: aromatase inhibitor, breast cancer, endocrine therapy, exemestane, neo-adjuvant

The adsorption of fenhexamid (FEN) [N-(2,3-dichloro-4-hydroxyphenyl)-1-methylcyclohexanecarboxamide] on vineyard soil amended with wine lees (WL) produced by vinery was studied. The adsorption extent depends on WL fraction. The addition of the centrifuged solid lees (SWL) increases the FEN adsorption on soil. Most likely, the organic insoluble fraction formed mainly by dead fermentation yeasts is responsible for the observed increase. The adsorption measured on some deactivated yeasts of wine fermentation shows that Saccharomyces cerevisiae are the most active in FEN retention. On the other hand, the soil amendment with whole WL decreases considerably the fungicide adsorption. This opposite effect may be the result of FEN hydrophobic bonds with the dissolved organic matter of lees that keeps fungicide in solution. This hypothesis is substantiated by the increased FEN solubility in the supernatant of centrifuged wine lees (LWL). The results of soil column mobility confirm that the elution with LWL increases the mobility of FEN in soil.