Search

The synergistic activity of pemetrexed with platinum agents in non-small cell lung cancer (NSCLC) and the renal safety of carboplatin suggest a balanced benefit/risk profile for this combination in elderly patients. This multicenter, single-arm, phase II study included 62 patients (≥70 years) with chemonaïve advanced NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and assigned to receive 6 cycles of 3-weekly pemetrexed 500 mg/m(2) and carboplatin AUC 5. The primary endpoint was objective tumor response rate (ORR). Sixty-two patients received at least one dose of chemotherapy. Median age was 76.4 years [70.2-86] and all patients had PS 0 (16.1%) or PS 1 (83.9%). Stage IIIb disease in 21% patients and stage IV in 79% patients. Non-squamous cell carcinoma in 66.1% patients (adenocarcinoma 51.6%, large cell carcinoma 8.1%, other 6.5%) and squamous cell carcinoma in 33.9% patients. ORR was 28.6% (95% confidence interval [CI], 16.58-43.26), all were partial responses. Stable disease rate was 42.9%. Grade 3/4 toxicities related to study drugs were: asthenia 16.1%, anorexia 4.8%, diarrhea 3.2%, neutropenia 51.6%, leucopenia 30.7%, thrombocytopenia 29%, anemia 19.4%. One related fatal septic shock occurred. In advanced NSCLC, pemetrexed use is restricted to non-squamous histology. The combination pemetrexed-carboplatin could be a valuable treatment option in elderly patients. Neutropenia was the most common toxicity. The ORR is within the range of data reported for pemetrexed-carboplatin in the general NSCLC population (24-31%)., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The objective of this study was to examine the effects of including corn dried distillers grains with solubles (DDGS) in the diet at the expense of corn and soybean meal on enteric CH4 emissions, ruminal fermentation characteristics, digestion (in sacco and apparent total-tract digestibility), N balance, and milk production of dairy cows. Twelve lactating Holstein cows were used in a triplicated 4×4 Latin square design (35-d periods) and fed (ad libitum intake) a total mixed ration containing (dry matter basis) 0, 10, 20, or 30% DDGS. Dry matter intake increased linearly, whereas apparent-total tract digestibility of dry matter and gross energy declined linearly as DDGS level in the diet increased. Increasing the proportion of DDGS in the diet decreased the acetate:propionate ratio, but this decrease was the result of reduced acetate concentration rather than increased propionate concentration. Milk yield increased linearly (up to +4kg/d) with increasing levels of DDGS in the diet and a tendency was observed for a quadratic increase in energy-corrected milk as the proportion of DDGS in the diet increased. Methane production decreased linearly with increasing levels of DDGS in the diet (495, 490, 477, and 475 g/d for 0, 10, 20, and 30% DDGS diets, respectively). When adjusted for gross energy intake, CH4 losses also decreased linearly as DDGS proportion increased in the diet by 5, 8, and 14% for 10, 20, and 30% DDGS diets, respectively. Similar decreases (up to 12% at 30% DDGS) were also observed when CH4 production was corrected for digestible energy intake. When expressed relative to energy-corrected milk, CH4 production declined linearly as the amount of DDGS increased in the diet. Total N excretion (urinary and fecal; g/d) increased as the amount of DDGS in the diet increased. Efficiency of N utilization (milk N secretion as a proportion of N intake) declined linearly with increasing inclusion of DDGS in the diet. However, productive N increased linearly with increasing proportions of DDGS in the diet, suggesting better efficiency of N use by the animal. Results from this study show that feeding DDGS to dairy cows can help to mitigate enteric CH4 emissions without negatively affecting intake and milk production., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Corn silage (CS) is associated with a reduction in milk fat content. The fact that CS is constituted of a grain and a forage fraction could explain this effect. This experiment evaluated the effect of grain fraction of CS on rumen fermentation, production performance and milk composition. Earless CS (ECS) was harvested after manually removing corn ears from the plant. Whole CS (WCS) was harvested from the same field on the same day. Eight (four ruminally fistulated) multiparous Holstein cows (84 days in milk) were utilized in a double 4 × 4 Latin square with 21-day periods. Treatments were (dry matter (DM) basis) (1) 23.0% WCS; (2) 12.4% ECS plus 10.6% high moisture corn (HMC) to obtain reconstituted CS (RCS); (3) 23.0% ECS; and (4) 23.0% timothy silage (TS). Diets were formulated to be isonitrogenous and were fed as total mixed ration once a day. DM intake (DMI), milk yield, 4.0% fat-corrected milk (FCM), as well as protein concentration and yield were higher for WCS than ECS. Compared with WCS, cows tended to eat less with RCS, and produced less milk and milk protein. However, yield of FCM was similar between WCS and RCS. Milk fat concentration and yield, as well as the specific ratio of t11 18:1 to t10 18:1 in milk fat did not differ among diets. Milk urea-N tended to be higher for ECS than WCS and TS, whereas ruminal NH3-N was higher with ECS than TS. Rumen pH decreased linearly with time after feeding but was not different between treatments. Higher acetate and lower propionate concentration resulted in greater acetate to propionate ratio with ECS compared with WCS. In conclusion, removing grain fraction from CS decreased milk production and modified rumen fermentation without affecting milk fat concentration and yield. Moreover, despite some differences in DMI and total ruminal volatile fatty acid concentration between WCS and RCS, the restoration of FCM yield, using HMC in RCS diets, to a level of production similar to WCS highlights the importance of energy and nutrients supplied by the grain fraction of CS to support milk yield.

Nutrient composition and organoleptic properties of milk can be influenced by cow diets. The objective of this study was to evaluate the forage type effects on volatile organic compounds, fatty acid (FA) profile, and organoleptic properties of milk. Timothy grass was fed as hay, pasture, or silage during a period of 27 d to a group of 21 cows in a complete block design based on days in milk. Each cow also received 7.2 kg/d of a concentrate mix to meet their nutrient requirements. Forage dry matter intake averaged 13.9 kg/d and was not different among treatments. Milk yield was higher for cows fed pasture, intermediate for cows fed silage, and lowest for cows fed hay. However, milk fat content was higher for cows fed hay and silage, compared with cows fed pasture. As a result, fat-corrected milk and fat yield were not different among treatments. Increasing the supply of dietary cis-9,cis-12 18:2 (linoleic acid) and cis-9,cis-12,cis-15 18:3 (α-linolenic acid) when feeding pasture enhanced the concentration of these 2 essential FA in milk fat compared with feeding hay or silage. Moreover, the ratio of 16:0 (palmitic acid) to cis-9 18:1 (oleic acid), which is closely related to the melting properties of milk fat, was lower in milk from cows on pasture than in milk from cows fed hay or silage. Cows fed hay produced milk with higher levels of several free FA and γ-lactones, but less pentanal and 1-pentanol. More dimethyl sulfone and toluene were found in milk of cows on pasture. Cows fed silage produced milk with higher levels of acetone, 2-butanone, and α-pinene. Results from a sensory evaluation showed that panelists could not detect a difference in flavor between milk from cows fed hay compared with silage. However, a significant number of assessors perceived a difference between milk from cows fed hay compared with milk from cows fed pasture. In a sensory ranking test, the percentage of assessors ranking for the intensity of total (raw milk, fresh milk, and farm milk), sweet (empyreumatic, vanilla, caramel, and sugar), and grassy (grass, leafy vegetable, and plant) flavors was higher for milk from cows fed pasture compared with hay and silage. Using timothy hay, pasture, or silage harvested at a similar stage of development, the current study shows that the taste of milk is affected by the forage type fed to cows. More research is, however, needed to establish a link between the sensory attributes of milk and the observed changes in volatile organic compounds and FA profile., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

This study examines validity findings in a particular behavioral pain disorder. We examined two types of validity scores in 73 participants with a primary diagnosis of the controversial Complex Regional Pain Syndrome Type I (CRPS-1). All participants were incentivized by a disability-seeking context. Failure rates on performance validity tests ranged from 23% (Test of Memory Malingering) to 50% (Reliable Digit Span). Positive findings on symptom validity tests (MMPI-2 or MMPI-2-RF) ranged from 15% to 50% of subsamples. At least 75% of the sample failed one performance validity indicator and over half showed at least one positive symptom validity score. This initial study suggests that CRPS-1 could serve as a good patient model for studying the role of simulation in pain-related disability.

Objectives: The objective of this study is to ascertain the effects of the left (LV) and right (RV) ventricular lead tip position in response to cardiac resynchronization therapy (CRT)., Background: The REVERSE randomized trial examined the effects of CRT in patients with asymptomatic or mildly symptomatic heart failure (HF)., Methods: We analysed data collected from the active group (CRT-ON) of REVERSE in whom the precise locations of the LV and RV ventricular lead tips were determined from postoperative chest roentgenograms as part of a prespecified sub-study. LV position was classified as lateral or non-lateral, and apical or non-apical. RV position was classified as apical or non-apical. Echocardiographic LV end-systolic volume index (LVESVi), QRS duration, and clinical outcomes at 12-24 months of follow-up were evaluated with respect to the lead tip position. The primary trial endpoint was the proportion of patients with a worsened HF clinical composite response, scored as improved, unchanged, or worsened., Results: Totally 346 patients included in this analysis were followed for a median of 12.6 months (interquartile range: 11.9-23.9 months). The proportion of worsened HF clinical composite response did not correlate with lead position, whereas a significantly greater decrease in the powered secondary endpoint of LVESVi was observed with the non-apical vs. the apical LV lead positions. CRT-paced QRS duration was significantly shorter than at baseline in patients with lateral vs. non-lateral LV position, as well non-apical vs. apical LV position. The incidence of composite endpoint of death and first hospitalization for HF was lower in the LV lateral than in the non-lateral (HR 0.44; 95% CI 0.19-0.99; P= 0.04), and in the LV non-apical than in the apical group (HR 0.27; 95% CI 0.11-0.63; P= 0.001). No significant differences were observed between RV apical and non-apical positions of the lead tip., Conclusions: A more favourable outcome of CRT with regard to LV reverse remodelling and the composite of time to death or first HF hospitalization was observed when the LV lead tip was implanted in the lateral wall, away from the apex, while the position of the RV lead tip was indifferent. The long-term change in QRS duration was significantly associated with the position of the LV lead tip. ClinicalTrials.gov Identifier: NCT00271154.

Purpose: This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced non-small-cell lung cancer (NSCLC) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy., Patients and Methods: Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine were randomly assigned to observation or to gemcitabine (1,250 mg/m(2) days 1 and 8 of a 3-week cycle) or daily erlotinib (150 mg/day) study arms. On disease progression, patients in all three arms received pemetrexed (500 mg/m(2) once every 21 days) as predefined second-line therapy. The primary end point was progression-free survival (PFS)., Results: PFS was significantly prolonged by gemcitabine (median, 3.8 v 1.9 months; hazard ratio [HR], 0.56; 95% CI, 0.44 to 0.72; log-rank P < .001) and erlotinib (median, 2.9 v 1.9 months; HR, 0.69; 95% CI, 0.54 to 0.88; log-rank P = .003) versus observation; this benefit was consistent across all clinical subgroups. Both maintenance strategies resulted in a nonsignificant improvement in overall survival (OS); patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit. Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events., Conclusion: Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.

Aim: The aim of the present study was to evaluate the impact of point spread function (PSF) reconstruction on quantitative values and diagnostic accuracy of FDG PET/CT for nodal staging in non-small cell lung cancer., Patients and Methods: Fifty-eight consecutive PET/CT examinations were reconstructed with both ordered subset expectation maximization (OSEM) and PSF algorithms. Two readers independently performed a randomized blinded review of PET/CT examinations and gave a nodal status (N0, N1, N2, or N3) to each PET data set. When discordant, a consensus was reached with a third reader. Sensitivity, specificity, positive and negative predictive values (NPV), and positive and negative likelihood ratios (LRs) were assessed and compared using a McNemar test. All PET data sets were then independently analyzed to extract quantitative PET values in 208 nodes and compare them using Bland-Altman analysis., Results: Bland-Altman analysis showed that, on average, PSF reconstruction increased SUVmax, SUVmean, and node/background ratios by 48%, 28%, and 27%, respectively. This increase was more marked for nodes less than 1 cm than for nodes 1 cm or greater (P < 0.0001 for SUVmax, SUVmean, and node/background ratios). Point spread function PET had higher sensitivity (97%) and NPV (92%) than OSEM PET (78% and 57%, respectively; P = 0.01 and P = 0.04, respectively). Negative LR was 0.04 for PSF PET and 0.31 for OSEM PET., Conclusions: By improving activity recovery, especially for nonenlarged nodes, PSF significantly improves the sensitivity, NPV, and negative LR of FDG-PET for nodal staging in non-small cell lung cancer. These data suggest that preoperative invasive nodal staging may be omitted in the case of a negative PSF FDG-PET/CT.

Background: Data are limited on the impact of the 2009 H1N1 influenza A pandemic on health care worker (HCW) vaccination, illness, absenteeism, and personal protective equipment (PPE) use., Methods: A survey was completed by HCWs from 14 hospitals participating in the Canadian Nosocomial Infection Surveillance Program who provided direct care to patients with pH1N1 influenza in high-risk units between September and December 2009., Results: Surveys were returned from 986 HCWs (80% nurses, 14% respiratory therapists, and 6% physicians). HCWs working in an intensive care unit (78%) or a designated influenza ward (67%) were more compliant with wearing an N95 respirator for aerosol-generating medical procedures than those working in an emergency department (47%; P < .001). HCWs who worked in health care for >11 years were more compliant with wearing protective eyewear than those who worked for ≤11 years (69% vs 54%; P < .001). A total of 815 HCWs (83%) reported having received the pH1N1 influenza vaccine, and 372 (38%) reported having received the 2009-2010 seasonal influenza vaccine. Influenza-like illness was reported by 236 (24%) HCWs, 170 of whom (72%) reported missing work., Conclusions: Experience working in health care improves PPE use and HCWs in emergency departments should be targeted for interventions to improve PPE compliance. pH1N1 influenza vaccine coverage was high, but seasonal influenza vaccine coverage was low, and significant HCW illness and absenteeism were reported., (Crown Copyright © 2012. Published by Mosby, Inc. All rights reserved.)

Background: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC., Methods: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225., Findings: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes., Interpretation: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors., Funding: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: In small cell lung cancer (SCLC), despite the high response rates induced by platinum-based first line chemotherapies, relapse happens in 85% of the first-line responding tumors. Since 1992 we used a combination of epirubicin and ifosfamide (EI) as a non-cross-resistant regimen in relapsed or refractory SCLC. With the topotecan approval in second line treatment, this combination has been moved from the second line to the third line setting., Methods: Patients presenting with a relapsed or refractory, histologically proven, SCLC were considered for this combination associating ifosfamide 3 g/m(2) day 1-2 with uroprotection using mesna, and epirubicin 90 mg/m(2) day 1 given every four weeks until progression or unacceptable toxicity., Results: Seventy patients were accrued between September 1992 and August 2010 (seven women). Median age was 56 years. Performance Status was 0, 1, 2 and 3 for 16 (23%), 25 (35%), 20 (29%) and 9 (13%) patients respectively. Proportion of refractory, resistant and sensitive tumors was 20, 21 and 59% respectively. Median time from first line chemotherapy until progression was 90 days (range 5-1720 days). Forty-four patients were treated in second line setting whereas the 26 others have had received two lines at time of accrual. A total of 203 cycles were delivered (median 2 cycles, range: 1-6). Fifteen patients (21.4%) achieved an objective response (including one complete), and 10% had a stable disease. Median overall survival was 3.9 months (95% confidence interval: 3.3-5.1). Overall NCI-CTC grade 3 and 4 toxicity was mainly hematological: neutropenia (71% of the patients, febrile neutropenia 9.4% of the cycles), thrombocytopenia (23%), and anemia (22%). In univariate analysis, previous anthracyclines treatment was associated with a trend towards shorter survival (median overall survival 3.9 versus 4.6 months, p=0.12). In multivariate analysis, only a high serum NSE level and presence of brain metastases were independent prognostic variables., Conclusion: The EI combination is an active regimen in relapsed or refractory SCLC. The trend towards a greater activity of this regimen in patients not pretreated using anthracyclines suggests that class of agents should be tested in SCLC relapsing after the etoposide-platinum standard regimen., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

During the past few years, medical treatments of cancer have improved thanks to the discovery of targeted therapies. These therapies are today widely used in cancer treatment. The mechanism of action of targeted therapies and the adverse effects they induce are different from the classic chemotherapies, and require a specific management. Most of these drugs are taken at home and orally, and as a consequence, general practitioners should be able to manage these side effects. The most current toxicities in general medicine are fatigue, high blood pressure, dermatologic, gastrointestinal and metabolic side effects. These effects, often moderate are frequent and diverse, and can impact the patient's quality of life and reduce treatment compliance. Management of these toxicities should then be well known by general practitioners in order to optimize care and improve patient wellness.

This open-label, phase II study evaluated the antitumor activity and safety of sunitinib monotherapy as maintenance treatment following first-line chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Following treatment with standard doublet chemotherapy (paclitaxel and carboplatin), patients received oral sunitinib (starting dose 50mg/day) in 6-week cycles (Schedule 4/2: 4 weeks on treatment, 2 weeks off treatment) until disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint was probability of survival at 1 year ≥55%. Of 84 patients who received first-line chemotherapy, 66 (79%) received sunitinib maintenance therapy (median sunitinib cycles started: 2 [range 1-20]). Probability of survival at 1 year was 40.5% (95% confidence interval [CI]: 29.8, 51.0). Median overall survival was 10.4 months (95% CI: 8.0, 12.2). The objective response rate was 27.4% (95% CI: 18.2, 38.2). The most frequently reported all-causality adverse events of any grade during sunitinib maintenance therapy were fatigue/asthenia (55%), diarrhea (36%), and nausea (32%). These data suggest that maintenance therapy may have value in NSCLC, although the primary endpoint of the study was not met., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Background: Brain metastases (BM) occur in up to 40% of non-small-cell lung cancer (NSCLC) patients. This trial assessed the safety and efficacy of pemetrexed-cisplatin in this population., Patients and Methods: Chemonaive NSCLC patients with BM ineligible for (radio)surgery, performance status (PS) of 0 to 2, were eligible for up to six cycles of cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) every 3 weeks. Whole -brain radiotherapy was given in case of disease progression or at chemotherapy completion. Primary end point was objective response rate (RR) on BM. Secondary end points included extracerebral and overall RR, safety profile and survival., Results: Forty-three patients were enrolled. Initial characteristics were mean age 60.4 years; males 29; PS: 0 in 37.2%, 1 in 60.5% and 2 in 22.3% of patients; adenocarcinoma in 36 patients, large cell in 4 patients (nonsquamous, 93%) and squamous carcinoma in 3 patients. Functional classification of neurological status was stage I/II 86.0%, III 2.3% and IV 11.6%. Grade 3-4 hematological toxic effects were neutropenia, 11 patients (febrile neutropenia, 1 patient), and anemia, 6 patients. Non-hematological toxic effects were grade 2 urinary infection, one patient; grade 3 pneumonia, two patients; and grade 3 hypoacousia, one patient. Cerebral, extracerebral and overall RR by intent to treat analysis were 41.9%, 34.9% and 34.9%, respectively. Median survival time and time to progression were 7.4 and 4.0 months, respectively., Conclusion: Pemetrexed-cisplatin is an effective and well-tolerated regimen as first-line therapy for NSCLC patients with BM who always suffer a poor prognosis.

Cetuximab, a chimeric mouse-human IgG1 monoclonal antibody against the epidermal growth factor receptor, has proven effective in the treatment of metastatic colorectal cancer and squamous cell carcinoma of the head and neck. However, a high incidence of immediate hypersensitivity reactions (HSR) to cetuximab after the first infusion has been observed. We have developed a test for identification of patients likely to show treatment-related HSR to cetuximab. An enzyme-linked immunosorbent assay (ELISA) for detecting anti-cetuximab IgEs was developed and tested on serum samples collected from cancer patients before start of cetuximab treatment, and from healthy blood donors. Similar levels of anti-cetuximab IgE were detected in pre-treatment patient sera (24/92, 26.1%) and sera from healthy blood donors (33/117, 28.2%). HSR were observed in 14 out of the 92 patients (15.2%), and 8 of these (57.1%) were grade 3-4. Anti-cetuximab IgEs were detected in 7/8 of the patients (87.5%) with severe HSRs as compared with 14/78 patients (17.9%) with no HSR (p=0.0002). Predictive value of the anti-cetuximab IgE test for HSR events of grades 3-4 was calculated using Receiver Operating Characteristics analysis. With a cut-off value of 29 arbitrary units for the anti-cetuximab IgE, the ELISA test showed a sensitivity of 87.5%, specificity of 82.1%, positive predictive value of 33.3% and negative predictive value of 98.5%. Anti-cetuximab IgE ELISA detection could be a valuable tool to help the physician anticipate an anaphylaxis episode following cetuximab infusion and opt for a suitable alternative treatment.

Background: Bevacizumab (BVZ) combined with platinum-based therapy is registered for first-line treatment of nonsquamous non-small-cell lung cancer (NSCLC). Patients with centrally located tumors are stated ineligible for BVZ treatment. The goal of this study was to assess the consistency in evaluating eligibility of patients with central tumors for BVZ treatment., Materials and Methods: The study group was composed of 150 NSCLC patients with centrally located tumors. Eligibility for BVZ was assessed by chest computed tomography (CT) scan. Eligibility was assessed independently using CT images reviewed on workstations. Inter- and intraobserver variations on 50 randomly extracted patients were estimated through a statistical modeling (multiple correspondence analysis)., Results: Discordance in eligibility was found for 82 patients (55%). The interobserver strength of agreement was fair to moderate (average kappa = 0.40). Contrarily, the intraobserver strength of agreement was good to very good (average kappa = 0.74). At multivariate analysis, the risk of discrepancy was essentially related to the assessment of the contact between the tumor and the vessels (odds ratio = 13.3, 95% confidence interval 2.8-62.6, P = 0.001)., Conclusions: The consistency in evaluating eligibility of patients with central tumors for BVZ treatment is weak. The study group indicated more stringent criteria to help physicians in taking the best treatment choice that need however to be prospectively validated.

Background: This is a phase II randomized study to evaluate the efficacy and safety of bortezomib and pemetrexed alone or in combination, in patients with previously treated advanced non-small-cell lung cancer (NSCLC). The primary end point was assessment of response rate., Methods: A total of 155 patients were randomized (1:1:1) to pemetrexed (500mg/m(2)) on day 1 plus bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm A) or pemetrexed (500mg/m(2)) on day 1 (Arm B) or bortezomib (1.6mg/m(2)) on days 1 and 8 (Arm C) of a 21 day cycle. Response rate was assessed by investigators using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and toxicity assessed by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grading system., Results: Response rate was 7% in Arm A, 4% in Arm B, and 0% in Arm C; disease control rates were 73%, 62%, and 43%, respectively. Median overall survival was 8.6 months in Arm A, 12.7 months in Arm B, and 7.8 months in Arm C; time to progression was 4.0 months, 2.9 months, and 1.4 months, respectively. Most common reported adverse events >/=grade 3 were neutropenia (19%), thrombocytopenia (15%), and dyspnea (13%) in Arm A, neutropenia (10%) in Arm B, and dyspnea (13%) and fatigue (10%) in Arm C., Conclusion: In previously treated NSCLC the addition of bortezomib to pemetrexed was well tolerated but offered no statistically significant response or survival advantage versus pemetrexed alone, while bortezomib alone showed no clinically significant activity., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: In February 2007, a general surgeon in Charlottetown, Prince Edward Island, tested positive for hepatitis C virus (HCV). The surgeon's infection onset date could not be determined; however, episodic hepatic enzyme elevations were first detected in November 2004 and again in February 2007. HCV transmission during surgery, alhough rare, has been documented. A phased look-back HCV screening program was conducted to detect HCV transmission from this surgeon to patients who underwent the highest-risk procedures in the three years before his positive test., Methods: Highest-risk procedures were defined as exposure-prone procedures (EPP) in which exposure to the surgeon's blood was most likely. EPP patients from January 2004 to February 2007 were identified using hospital and administrative records. Linkages with the provincial notifiable disease for HCV was performed, and death records for deceased EPP patients were reviewed. Eligible patients were invited for screening., Results: Of 6248 patients seen in phase 1, 272 (4.4%) were identified to be EPP. Of the 272 patients, 248 (91.1%) were invited for HCV testing and 24 (8.8%) were deceased. To date, 231 of 248 (93.1%) patients have presented for screening. Two patients (one alive, one deceased) were HCV positive before their EPP. Viral sequence of the surgeon's isolate is unrelated to the first patient; the second individual has a resolved infection (polymerase chain reaction negative). No new transmission events were identified in the screened patients. The 95% CI of the transmission probability was estimated to be 0 to 0.016., Interpretation: HCV transmission from the surgeon during a 38-month look back was unlikely. In the absence of protocols for investigating HCV transmission from infected health care workers, screening was initially prioritized to the highest-risk patients. The investigation has been satisfactorily terminated based on these results.

PURPOSE In the phase III INTEREST trial, 1,466 pretreated patients with advanced non-small cell lung cancer (NSCLC) were randomly assigned to receive gefitinib or docetaxel. As a preplanned analysis, we prospectively analyzed available tumor biopsies to investigate the relationship between biomarkers and clinical outcomes. METHODS Biomarkers included epidermal growth factor receptor (EGFR) copy number by fluorescent in situ hybridization (374 assessable samples), EGFR protein expression by immunohistochemistry (n = 380), and EGFR (n = 297) and KRAS (n = 275) mutations. Results For all biomarker subgroups analyzed, survival was similar for gefitinib and docetaxel, with no statistically significant differences between treatments and no significant treatment by biomarker status interaction tests. EGFR mutation-positive patients had longer progression-free survival (PFS; hazard ratio [HR], 0.16; 95% CI, 0.05 to 0.49; P = .001) and higher objective response rate (ORR; 42.1% v 21.1%; P = .04), and patients with high EGFR copy number had higher ORR (13.0% v 7.4%; P = .04) with gefitinib versus docetaxel. CONCLUSION These biomarkers do not appear to be predictive factors for differential survival between gefitinib and docetaxel in this setting of previously treated patients; however, subsequent treatments may have influenced the survival results. For secondary end points of PFS and ORR, some advantages for gefitinib over docetaxel were seen in EGFR mutation-positive and high EGFR copy number patients. There was no statistically significant difference between gefitinib and docetaxel in biomarker-negative patients. This suggests gefitinib can provide similar overall survival to docetaxel in patients across a broad range of clinical subgroups and that EGFR biomarkers such as mutation status may additionally identify which patients are likely to gain greatest PFS and ORR benefit from gefitinib.

Background: Minimizing delays to coronary reperfusion is critical in the management of acute myocardial infarction (AMI)., Aims: To determine delays in in-hospital management and factors associated with delays of over 45min., Methods: We analysed data from the Observatoire Régional Breton sur l'Infarctus, a registry of AMI patients admitted within 24h of symptom onset (July 2007 to December 2008) to an interventional cardiology centre in Brittany. Prehospital delay was defined as time between first responder arrival at the patient and patient arrival at an interventional cardiovascular centre. In-hospital delay was defined as time between admission to the interventional cardiovascular centre and first balloon inflation. Patients were grouped according to duration of in-hospital delay (>45 vs

Although the amygdala seems to be essential to the formation and storage of fear memories, it might store only some aspects of the aversive event and facilitate the storage of more specific sensory aspects in cortical areas. We addressed the time course of amygdala and cortical activation in the context of odor fear conditioning in rats. Using high temporal resolution (1-min sampling) intracerebral microdialysis, we investigated the dynamics of glutamate and GABA fluctuations simultaneously in basolateral amygdala (BLA) and posterior piriform cortex (pPCx) during the course of the acquisition session, which consisted of six odor (conditioned stimulus)-footshock (unconditioned stimulus) pairings. In BLA, we observed a transient increase in amino acid concentrations following the first odor-shock pairing, after which concentrations returned to baseline levels or slightly below. In pPCx, transient increases were seen after each pairing and were also observed after the last odor-shock pairing, corresponding to the predicted times of anticipated trials. Furthermore, we observed that for the first pairing, the increase in BLA occurred earlier than the increase in pPCx. These data suggest that the amygdala is engaged early during acquisition and precedes the activation of the olfactory cortex, which is maintained until the end of the session. In addition, our data raise the challenging idea that the olfactory cortex might store certain aspects of fear conditioning related to the timing of the associations.

It has previously been established that supplementation of trans-10, cis-12 18:2 reduces milk fat content and fat deposition in several species. The objectives of the study were 1) to examine whether potential mechanisms by which trans-10, cis-12 18:2 is reported to affect lipid metabolism in adipose tissue of different species could be partly responsible for the inhibition in milk fat synthesis in lactating dairy cows; and 2) to investigate the effects of trans-10, cis-12 18:2 on the expression of a newly identified isoform of stearoyl-coenzyme A desaturase (SCD) in bovine mammary tissue. Four primiparous Holstein cows in established lactation, fitted with indwelling jugular catheters, were used in a balanced 2 x 2 crossover design. For the first 5 d of each period, cows were infused intravenously with a 15% lipid emulsion providing 10 g/d of either cis-9, cis-12 18:2 (control) or trans-10, cis-12 18:2 (conjugated linoleic acid; CLA). On d 5 of infusion, mammary gland biopsies were performed and tissues were analyzed for mRNA expression of acetyl-coenzyme A carboxylase, fatty acid synthetase, lipoprotein lipase, SCD1, SCD5, sterol regulatory element-binding protein-1, IL6, IL8, and tumor necrosis factor-alpha by real-time PCR. Compared with the control treatment, CLA reduced milk fat concentration and yield by 46 and 38%, respectively, and increased the trans-10, cis-12 18:2 content in milk fat from 0.05 to 3.54 mg/g. Milk yield, milk protein, and dry matter intake were unaffected by treatment. Infusion of the CLA treatment reduced the mRNA expression of acetyl-coenzyme A carboxylase and fatty acid synthetase by 46 and 57%, respectively, and tended to reduce the expression of SCD1 and lipoprotein lipase. Abundance of mRNA for sterol regulatory element-binding protein-1 was reduced by 59% in the CLA treatment group. However, infusing trans-10, cis-12 18:2 did not affect the expression of transcripts for SCD5, tumor necrosis factor-alpha, IL6, and IL8. Results from the current study corroborate the idea that effects of trans-10, cis-12 18:2 reported on adipose tissue in animal models and humans are not part of the response in the inhibition of milk fat synthesis in lactating dairy cows. They also support the hypothesis that SCD1 and SCD5 present important differences in their regulation and physiological roles.

We report the case of a 61-year-old man who presented with coughing fits followed by sinus pauses and syncope. Cardiac and neurological diagnostic work-up was negative and the patient was considered to have cough syncope. As this occurred within the context of febrile pneumonia, an infectious disease was suspected but diagnostic work-up only revealed an increase of antibodies against Chlamydia pneumoniae. The responsibility of this agent is discussed. Clinical recovery was obtained with the prescription of antitussive medication.

Recent findings have revealed the importance of orthonasal and retronasal olfaction in food memory, especially in conditioned odor aversion (COA); however, little is known about the dynamics of the cerebral circuit involved in the recognition of an odor as a toxic food signal and whether the activated network depends on the way (orthonasal vs retronasal) the odor was first experienced. In this study, we mapped the modulations of odor-induced oscillatory activities through COA learning using multisite recordings of local field potentials in behaving rats. During conditioning, orthonasal odor alone or associated with ingested odor was paired with immediate illness. For all animals, COA retrieval was assessed by orthonasal smelling only. Both types of conditioning induced similarly strong COA. Results pointed out (1) a predictive correlation between the emergence of powerful beta (15-40 Hz) activity and the behavioral expression of COA and (2) a differential network distribution of this beta activity according to the way the animals were exposed to the odor during conditioning. Indeed, for both types of conditioning, the aversive behavior was predicted by the emergence of a strong beta oscillatory activity in response to the odor in the olfactory bulb, piriform cortex, orbitofrontal cortex, and basolateral amygdala. This network was selectively extended to the infralimbic and insular cortices when the odor was ingested during acquisition. These differential networks could participate in different food odor memory; these results are discussed in line with recent behavioral results that indicate that COA can be formed over long odor-illness delays only if the odor is ingested.

Aims: In CARE-HF, cardiac resynchronization therapy (CRT) lowered morbidity and mortality in patients with moderate to severe heart failure. We examined whether baseline and follow-up electrocardiographic characteristics might predict long-term outcome., Methods and Results: CARE-HF randomly assigned 409 patients to medical therapy (MT) plus CRT, and 404 patients to MT alone. Electrocardiographic measurements were made at baseline during sinus rhythm, and at 3 months during paced or spontaneous rhythm depending on treatment assignment. Favourable outcome was defined as freedom from death, urgent transplantation, or cardiovascular hospitalization. Among patients assigned to CRT, 39% had unfavourable outcomes including 55 deaths. By single variable analysis, (i) prolonged PR interval, left QRS axis (but not QRS duration), and left bundle branch block (BBB) at baseline, and (ii) heart rate, PR, and QRS duration at 3 months predicted unfavourable outcome. By multiple variable analysis, treatment assignment (P = 0.0001), PR (P = 0.0004), and right BBB (P < 0.00013) at baseline predicted outcome, whereas baseline JTc and QRS duration at 3 months predicted all-cause mortality and heart failure hospitalization (P = 0.0071)., Conclusion: In CARE-HF, QRS duration at baseline did not predict outcome, but QRS at 3 months was a predictor by single variable analysis. Patients with prolonged PR interval and the 5% of patients with right BBB had a particularly high event rate.

Purpose: To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer., Methods and Materials: In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received., Results: Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed., Conclusion: In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

Aims: Mitral regurgitation (MR) is common and independently predicts mortality in patients with left ventricular (LV) systolic dysfunction. Its management remains challenging because of the complexity and variety of potential mechanisms implicated. We sought to determine which LV functional characteristics are the most important determinants of the severity of the MR associated with dilated cardiomyopathies., Methods and Results: We performed echocardiographic studies in 87 consecutive patients with dilated cardiomyopathy. The degree of MR was quantified according to guidelines. LV, left atrial and mitral annulus dimensions, mitral valve tenting, estimated filling pressures, regional myocardial contractility, and dyssynchrony (using regional strain (epsilon) analysis) were recorded too. Determinants of significant MR was thus assessed using multivariate models. Mitral regurgitant volume correlated with mitral annulus diameter (P<0.001), mitral valve tenting height (P<0.001), LV volumes (P=0.004), LV ejection fraction, mid-lateral wall peak of epsilon (P=0.01), and its delay (P<0.001). That inter-relation between the mitral annulus, the ventricle shape, contractility, and dyssynchrony was founded in the multivariate analysis. As a matter of fact, the model predicting the best the MR volume (R=0.78) included: mitral annulus diameter, dyssynchrony, tenting heigh and contractility of the LV mid-lateral wall (measured by epsilon)., Conclusion: The MR of the dilated cardiomyopathy is multifactorial. Our data suggest that analysing only LV geometry and mitral orifice is insufficient to correctly describe functional MR determinant. LV contractility and dyssynchrony are essential too.

Aims: Exercise stress testing (EST) is recommended by guidelines to risk-stratify patients with asymptomatic valvular aortic stenosis (AS), though the role of quantitative exercise-Doppler echocardiography has rarely been studied. This prospective study sought to correlate standard EST results with the haemodynamic measurements made during exercise by Doppler echocardiography., Methods and Results: We performed rest and semi-supine exercise Doppler echocardiography in 44 consecutive patients (mean age=68+/-12 years) with aortic valve areas

Background: Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy., Methods: We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (>/=one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m(2) intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00076388., Findings: 1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio [HR] 1.020, 96% CI 0.905-1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1.09, 95% CI 0.78-1.51; p=0.62; median survival 8.4 vs 7.5 months). In the gefitinib group, the most common adverse events were rash or acne (360 [49%] vs 73 [10%]) and diarrhoea (255 [35%] vs 177 [25%]); whereas in the docetaxel group, neutropenia (35 [5%] vs 514 [74%]), asthenic disorders (182 [25%] vs 334 [47%]), and alopecia (23 [3%] vs 254 [36%]) were most common., Interpretation: INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer.

It has been previously established that trans-10, cis-12 conjugated linoleic acid plays an important role in milk fat depression (MFD). However, in many situations of dietary induced MFD, the reduction in milk fat synthesis is much greater than what would be predicted based on the milk fat concentration of trans-10, cis-12 18:2. These observations suggest that other biohydrogenation intermediates could be implicated in MFD. The objective of this study was to evaluate the effects on milk fat synthesis of an intravenous administration of 2 conjugated diene 18:3 isomers (cis-9, trans-11, cis-15 and cis-9, trans-13, cis-15 18:3), which are intermediates in ruminal biohydrogenation of alpha-linolenic acid. Three multiparous Holstein dairy cows (days in milk = 189 +/- 37 d; body weight = 640 +/- 69 kg; mean +/- standard deviation), fitted with indwelling jugular catheters, were randomly assigned to a 3 x 3 Latin square design. For the first 5 d of each period, cows were infused intravenously with a 15% lipid emulsion providing 1) cis-9, trans-11, cis-15 18:3 + cis-9, trans-13, cis-15 18:3 + trans-10, cis-12 18:2 (CD18:3 + CLA); 2) cis-9, cis-12, cis-15 18:3 + cis-9, cis-12 18:2 as a control (ALA + LA); or 3) cis-9, cis-12, cis-15 18:3 + trans-10, cis-12 18:2, as a positive control (ALA + CLA). Milk production was recorded, and milk was sampled daily at each milking for analyses of fat, protein, lactose, milk urea nitrogen, and somatic cell count. Dry matter intake, milk yield, and milk protein were not affected by treatment. Over the experimental period, milk fat content was decreased by 7% for cows that received either ALA + CLA or CD18:3 + CLA compared with ALA + LA. The temporal pattern of milk fat content showed a linear decrease during the infusion period for ALA + CLA and CD18:3 + CLA treatment groups. The transfer efficiencies of conjugated diene 18:3 isomers into milk fat averaged 39 and 32% for cis-9, trans-11, cis-15 18:3 and cis-9, trans-13, cis-15 18:3, respectively. The CD18:3 + CLA treatment had no effect on milk fat concentration beyond that attributable to its trans-10, cis-12 18:2 content. In conclusion, results from the current study offered no support for a role of either cis-9, trans-11, cis-15 18:3 or cis-9, trans-13, cis-15 in MFD.

Introduction: This randomized phase II study investigated the efficacy and safety of a new taxane, larotaxel (XRP9881), in combination with either cisplatin or gemcitabine in the first-line treatment of patients with nonirradiable stage IIIB or stage IV non-small cell lung cancer to select the combination having the most promising antitumor activity., Methods: Patients received either larotaxel (50 mg/m) as a 1-hour infusion, followed by a 1-hour infusion of cisplatin (75 mg/m), every 3 weeks (arm A), or gemcitabine (800 mg/m) as a 30 minute infusion, on days 1 and 8, and larotaxel (60 mg/m) as a 1-hour infusion, on day 8 (following gemcitabine), every 3 weeks (arm B). The primary end point was the objective response rate (per-protocol population)., Results: Thirty-two patients were randomized to arm A and 30 to arm B. The response rate was higher in arm A compared with arm B in both the per-protocol (26.7% versus 18.2%) and intention-to-treat (28.1% versus 13.3%) populations. In the intention-to-treat population, median progression-free survival for arm A versus arm B was 4.7 versus 3.3 months and median overall survival was 8.6 versus 7.3 months, respectively. Fifty percent of patients in arm A and 66.7% in arm B experienced at least one National Cancer Institute common toxicity criteria grade 3/4 adverse event and grade 3/4 neutropenia was observed in 46.9% and 41.4% of patients, respectively., Conclusions: Both larotaxel combinations were effective and manageable, however all measured efficacy parameters (response rate, progression free survival, and survival) seemed to favor the combination with cisplatin.

The concentration of CLA in adipose tissue can be increased in ruminants by feeding pasture and extruded soybeans. The objective of this study was to evaluate maternal supplementation of raw (RS) or extruded (ES) soybeans on the concentrations of CLA in milk fat of cows and s.c. adipose tissue of suckling calves. Thirty-two spring-calving cows (BW 624 +/- 76 kg; BCS 3.5 +/- 0.4; mean +/- SD) and calves (BW 127 +/- 15 kg) were separated into 2 groups. Cows were distributed to have 8 calves of each sex in both groups. When animals were turned out to pasture, dams received 2 kg/d of either RS or ES. Dietary treatments had no effect on average milk intake (P = 0.22) and pasture forage intake (P = 0.13) for calves over the course of the grazing season. As a result, no effect of treatments was observed on ADG (P = 0.26). At weaning, milk fat content of CLA reached 15.4 and 24.2 mg/g of total fatty acids for cows fed RS and ES, respectively (P = 0.02). The CLA concentrations in adipose tissue were 16.9 and 25.0 mg/g of total fatty acids for calves suckling dams fed RS and ES, respectively (P < 0.001). Overall, results demonstrated supplementing grazing cows with ES increased CLA content in milk and adipose tissue of suckling calves.

Objective: Doppler echocardiography is well recognized as the primary noninvasive imaging technique to assess global and regional cardiac function. Cardiopulmonary exercise testing has become a powerful tool to predict outcome in chronic heart failure (CHF). We looked for cardiac determinants, using resting echocardiographic parameters, of exercise tolerance in patients with CHF., Methods: Transthoracic echocardiography and standardized cardiopulmonary exercise testing were performed in 75 patients (59 +/- 11 years) with CHF, New York Heart Association functional class II to III. Systolic and diastolic function, filling pressures, and left ventricular, right ventricular, and left atrial (LA) regional function were assessed using Doppler tissue velocities and strain values., Results: Maximal workload (86 +/- 41 W) and peak oxygen (14.6 +/- 3.1 mL/min/kg) correlated with left ventricular filling pressure estimates (E/Ea and E/Vp) but also with end-diastolic pulsed Doppler tissue velocity at the mitral annulus (Aa), LA volume, and regional LA function assessed by strain analysis. In multivariate analysis, maximum workload and peak oxygen were shown to correlate with right ventricular peak strain, although Aa and E/Ea were the best predictors of exercise capacity., Conclusion: Capacity to exercise in patients with CHF is understandable by resting echocardiography. Filling pressures, and LA and right ventricular functions, are its cardiac best determinants. Adding Aa peak velocity in resting echocardiographic evaluation of patients with CHF is found useful.

Background: As chemotherapy gains wider acceptance for the treatment of earlier stages of NSCLC, particularly in the adjuvant and neoadjuvant setting, physicians face a growing population of high performance status patients who have relapsed after their first-line chemotherapy. The type of second-line chemotherapy after initial adjuvant or neoadjuvant treatment with a platinum-based regimen remains largely undefined. The current study has been designed to compare the classical mono chemotherapy docetaxel with a docetaxel cisplatin doublet., Methods: Patients will be randomized in 2 arms. Arm: docetaxel cisplatin (cycles repeated every 21 days), 4 cycles followed by 2 cycles of docetaxel alone in case of objective response or stabilisation. Arm B: docetaxel alone (cycles repeated every 21 days), 4 cycles followed by 2 cycles of docetaxel alone in case of objective response or stabilisation., Expected Results: 300 patients will be randomized with a statistical hypothesis of a progression free survival of 3 months in the control arm and of 4.5 months in the experimental arm.

Background: Early life adverse experience alters adult emotional and cognitive development. Here we assess early life learning about adverse experience and its consequences on adult fear conditioning and amygdala activity., Methods: Neonatal rats were conditioned daily from 8-12 days-old with paired odor (conditioned stimulus, CS) .5mA shock, unpaired, odor-only, or naive (no infant conditioning). In adulthood, each infant training group was divided into three adult training groups: paired, unpaired or odor-only, using either the same infant CS odor, or a novel adult CS odor without or with the infant CS present as context. Adults were cue tested for freezing (odor in novel environment), with amygdala (14)C 2-DG autoradiography and electrophysiology assessment., Results: Infant paired odor-shock conditioning attenuated adult fear conditioning, but only if the same infant CS odor was used. The (14)C 2-DG activity correlated with infant paired odor-shock conditioning produced attenuated amygdala but heightened olfactory bulb activity. Electrophysiological amygdala assessment further suggests early experience causes changes in amygdala processing as revealed by increased paired-pulse facilitation in adulthood., Conclusions: This suggests some enduring effects of early life adversity (shock) are under CS control and dependent upon learning for their impact on later adult fear learning.

Purpose: This randomized, double-blind, placebo-controlled phase III study aimed to determine whether thalidomide prolongs survival of patients with extensive-disease small-cell lung cancer (SCLC)., Patients and Methods: One hundred nineteen patients received two courses of etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin (PCDE). Responder patients who had recovered from chemotherapy toxicity were randomly assigned to receive four additional PCDE cycles plus thalidomide (400 mg daily) or placebo., Results: After the first two PCDE cycles, objective response rate was 81.5%, and 92 patients were randomly assigned to placebo (n = 43) or thalidomide (n = 49). Median exposure duration to placebo was 4.5 months, and median exposure to thalidomide was 4.9 months. Patients treated with thalidomide had a longer survival compared with patients who received placebo, although the difference was not statistically significant (minimal follow-up, 3 years; median survival time, 11.7 v 8.7 months, respectively; log-rank test: hazard ratio [HR] = 0.74; 95% CI, 0.49 to 1.12; P = .16). Patients with a performance status (PS) of 1 or 2 who received thalidomide had a significantly longer survival (HR = 0.59; 95% CI, 0.37 to 0.92; P = .02). The disease also progressed slower in patients with PS of 1 or 2 receiving thalidomide (HR = 0.54; 95% CI, 0.36 to 0.87; P = .02), whereas the difference did not reach statistical significance for the whole population (HR = 0.74; 95% CI, 0.49 to 1.12; P = .15). Neuropathy occurred more frequently in the thalidomide group compared with the placebo group (33% v 12%, respectively)., Conclusion: Treatment with thalidomide was not associated with a significant improvement in survival of SCLC patients. There was pronounced heterogeneity in survival outcomes between groups of patients. Some benefit was observed among patients with a PS of 1 or 2 (exploratory analyses), deserving further studies targeting angiogenesis in this disease.

Aims: To assess procedural characteristics and adjudicated procedure-related (300 cm(3); and, influence of the participating study-centres. Implantation was attempted in 404/409 patients assigned to CRT, and in 65/404 patients assigned to medical therapy. Among these 469 patients, 450 (95.9%) received a successfully implanted and activated device. Complications occurred within 24 h in 47 patients (10.0%), mainly lead dislodgments (n = 10, 2.1%) and coronary sinus dissection/perforation (n = 10, 2.1%), and between 24 h and 30 days in 26 patients (5.5%), mainly lead dislodgment (n = 13, 2.8%). Mean LV lead stimulation threshold was significantly higher than at the right atrium or right ventricle, though remained stable, delivering effective, and reliable CRT. Implanting experience was the only predictor of procedural outcome., Conclusion: Transvenous CRT system implantation, using a CS lead designed for long-term LV pacing, was safe and reliable. As implanting centres become more experienced, this success rate is expected to increase further.

Background: There is no standard second-line treatment for small cell lung cancer (SCLC). The prognosis of these patients is poor and special attention should be paid to both quality of life and economic factors., Methods: The aim of this phase II randomised trial (GFPC0501) is to compare, in patients with progressive SCLC after first-line platinum based chemotherapy, oral multi drug chemotherapy (CCNU, cyclophosphamide, etoposide) and classical intravenous chemotherapy with cyclophosphamide, doxorubicin and vincristine (CAV) in terms of tolerability, efficacy (response rate, median one year survival and overall survival), quality of life and consumption of health care resources. Based on a two-stage Bryant and Day approach, this study will require a total of 138 patients with an interim analysis of the first 38., Expected Results: This trial will provide information on several aspects of second-line chemotherapy for patients with SCLC. Thirty six patients have been enrolled in 16 centres by December 2006 and the results of the interim analysis will be available in June 2007.

The statistical analysis of experimentally recorded brain activity patterns may require comparisons between large sets of complex signals in order to find meaningful similarities and differences between signals with large variability. High-level representations such as time-frequency maps convey a wealth of useful information, but they involve a large number of parameters that make statistical investigations of many signals difficult at present. In this paper, we describe a method that performs drastic reduction in the complexity of time-frequency representations through a modelling of the maps by elementary functions. The method is validated on artificial signals and subsequently applied to electrophysiological brain signals (local field potential) recorded from the olfactory bulb of rats while they are trained to recognize odours. From hundreds of experimental recordings, reproducible time-frequency events are detected, and relevant features are extracted, which allow further information processing, such as automatic classification.

Electrophysiological recordings performed in the mammalian olfactory bulb (OB) aimed at deciphering neural rules supporting neural representation of odors. In spite of a fairly large number of available data, no clear picture emerges yet in the mammalian OB. This paper summarizes some important findings and underlines the fact that difference in experimental conditions still represents a major limitation to the emergence of a synthetic view. More specifically, we examine to what extent the absence or the presence of anaesthetic influence OB neuronal responsiveness. In addition, we will see that recordings of either single cell activity or populational activity provide quite different pictures. As a result some experimental approaches provide data underlying sensory properties of OB neurons while others emphasize their capabilities of integrating incoming sensory information with attention, motivation and previous experience.

Purpose: This open-label, randomized, multicenter, phase III study compared oral topotecan versus intravenous (IV) docetaxel in patients with previously treated non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with stage III or IV NSCLC, performance status < or = 2, who had received only one prior chemotherapy regimen, were randomly assigned to treatment with oral topotecan 2.3 mg/m2/d on days 1 to 5 or IV docetaxel 75 mg/m2 day 1 every 21 days., Results: A total of 829 patients were randomly assigned. In intent-to-treat analysis, 1-year survival rates were 25.1% with topotecan and 28.7% with docetaxel. The difference of -3.6% (95% CI, -9.59% to 2.48%) met the predefined criteria for noninferiority of topotecan relative to docetaxel because the lower limit of the 95% CI was above -10%. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Although not statistically significant (log-rank P = .057), the higher survival rate with docetaxel was maintained across the entire treatment period. The median time to progression was 11.3 weeks with topotecan versus 13.1 weeks with docetaxel (log-rank P = .02). The overall response rate was 5% in each group. Grade 3/4 neutropenia occurred more frequently with docetaxel (60% v 50%). Grade 3/4 anemia and thrombocytopenia occurred more frequently with topotecan (26% v 10% and 26% v 7%, respectively)., Conclusion: Oral topotecan provides activity in the treatment of relapsed, locally advanced, unresectable NSCLC. Both regimens were well tolerated with differing safety profiles. Topotecan may provide an option for patients who desire an orally available treatment after relapse.

Introduction: We designed this phase II trial to evaluate the efficacy and safety of weekly paclitaxel in combination with monthly carboplatin as first-line treatment in elderly patients with advanced non-small cell lung cancer (NSCLC)., Methods: Main eligibility criteria were histologically or cytologically proven stage IIIB or IV NSCLC, age > or =70 years, Eastern Cooperative Oncology Group performance status 0-2, and measurable disease. The 4-week-based chemotherapy regimen consisted of carboplatin infusion (area under the concentration-time curve 6 mg/ml/min) on day 1 and paclitaxel 90 mg/m as a 1-hour infusion on days 1, 8, and 15. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors criteria, and symptoms were evaluated using the Lung Cancer Symptoms Scale. Analyses were performed on an intention-to-treat basis., Results: From February 2002 to August 2003, 51 patients (median age, 74 years) participated in the study. One complete and 21 partial responses were reported by the independent review committee, leading to an intention-to-treat objective response rate of 43% (95% confidence interval, 30-57%). The median progression-free and overall survivals were 7.5 (95% confidence interval, 6.2-9.4) and 13.6 (95% confidence interval, 7.5-17) months, respectively. Longitudinal evaluation of the Lung Cancer Symptoms Scale demonstrated lack of quality of life modification during the treatment period. Neurotoxicity was mild to moderate, with 6% of patients suffering from a grade 3 or 4 neuropathy. Myelosuppression was the main toxicity; 39% of patients experienced grade 3 or 4 neutropenia, 18% experienced grade 3 anemia, and 8% experienced grade 3 or 4 thrombocytopenia. There was no treatment-related death., Conclusions: The combination of weekly paclitaxel 90 mg/m administered on days 1, 8, and 15 plus monthly carboplatin area under the curve 6 on day 1 of a 4-week cycle was feasible and active as a first-line treatment for elderly patients with NSCLC with a good safety profile. These results deserve further analysis to compare the standard care for these patients (monotherapies) with this doublet.

In trained behaving rats, the expression of a prominent beta oscillatory activity in the olfactory system was previously identified as a correlate of odour recognition. The aim of the present study was to assess the putative role of a functional coupling between the olfactory bulb (OB) and higher structures in this activity. We performed a unilateral inactivation of the medial part of the olfactory peduncle by lidocaine infusion. Inactivation deprived the OB from most of its centrifugal afferences, including feedback connections from the piriform cortex (PC) while sparing the ascending fibres from the OB to higher cortical structures. This treatment reduced the amplitude of odour-induced oscillatory beta responses both in OB and PC. In parallel, gamma activity classically observed in these two structures during spontaneous activity displayed a strong enhancement. Results suggest that odour-induced oscillatory response could be the emergent feature of an olfactory functional network set up through learning.

Aim: Positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) can be performed using a dedicated PET scanner (PET-I) or a dual-head coincidence gamma camera (CGC-I). The aim of this study was to comparatively assess the impact of PET-I and CGC-I on clinical management in cancer patients., Methods: From November 2000 to November 2002, PET-I and CGC-I were performed at an interval of 2 days in 151 patients with colorectal cancer (n=40), breast cancer (n=28), thyroid cancer (n=23), lung tumors (n=22), germ cell tumors (n=14), unknown primary cancer (n=7) and other cancers (n=17). PET-I and CGC-I were interpreted independently with knowledge of conventional imaging (CI). In June 2003, theoretical management, e.g. treatment modality/ies and treatment intent (curative or palliative), after CI, PET-I and CGC-I were stated during multidisciplinary sessions and were a posteriori considered as appropriate or inappropriate using pathological and follow-up data., Results: The theoretical management proposed after PET-I and after CGC-I was similar in 112/151 (74%; 95% CI: 66-81%) patients. In 125 assessable patients, theoretical management after PET-I was appropriate in 86% (95% CI: 79-92%), significantly higher (P=0.0033) than after CGC-I (70%; 95% CI: 62-78%). Both proportions were also higher than after CI (46%; 95% CI: 37-56%), (P<0.0001). A similar trend for higher proportions of appropriate management after PET-I than after CGC-I was observed for each tumor localization., Conclusions: The clinical impact of PET-I is superior to that of CGC-I in a large series of cancer patients. Although CGC-I could be considered as an acceptable alternative, PET-I remains the standard and should preferably equip nuclear medicine departments.

Objective: This study used the Medical Symptom Validity Test (MSVT) to examine exaggeration of memory impairment in disability claimants., Methods: The MSVT was administered to patients with soft tissue injuries undergoing an independent medical examination (IME). Their results were compared with those from groups of volunteers who were either trying their best on the test or simulating memory impairment., Results: Non-French-speaking volunteers, who were tested in French, showed near perfect performance on the effort subtests, but 42% of IME patients failed the effort tests in English. Their overall results were very similar to those of simulators., Conclusion: This study suggests that exaggeration of cognitive symptoms is widespread in disability-related evaluations. It would be unwise to accept self-reported memory complaints at face value. Criteria-normed symptom validity testing should be done to rule out symptom exaggeration.