Pollinator population size and pollination ecosystem service responses to enhancing floral and nesting resources.

Modeling pollination ecosystem services requires a spatially explicit, process-based approach because they depend on both the behavioral responses of pollinators to the amount and spatial arrangement of habitat and on the within- and between-season dynamics of pollinator populations in response to land use. We describe a novel pollinator model predicting flower visitation rates by wild central-place foragers (e.g., nesting bees) in spatially explicit landscapes. The model goes beyond existing approaches by: (1) integrating preferential use of more rewarding floral and nesting resources; (2) considering population growth over time; (3) allowing different dispersal distances for workers and reproductives; (4) providing visitation rates for use in crop pollination models. We use the model to estimate the effect of establishing grassy field margins offering nesting resources and a low quantity of flower resources, and/or late-flowering flower strips offering no nesting resources but abundant flowers, on bumble bee populations and visitation rates to flowers in landscapes that differ in amounts of linear seminatural habitats and early mass-flowering crops. Flower strips were three times more effective in increasing pollinator populations and visitation rates than field margins, and this effect increased over time. Late-blooming flower strips increased early-season visitation rates, but decreased visitation rates in other late-season flowers. Increases in population size over time in response to flower strips and amounts of linear seminatural habitats reduced this apparent competition for pollinators. Our spatially explicit, process-based model generates emergent patterns reflecting empirical observations, such that adding flower resources may have contrasting short- and long-term effects due to apparent competition for pollinators and pollinator population size increase. It allows exploring these effects and comparing effect sizes in ways not possible with other existing models. Future applications include species comparisons, analysis of the sensitivity of predictions to life-history traits, as well as large-scale management intervention and policy assessment.

Radiation plus docetaxel and cisplatin in locally advanced pancreatic carcinoma: a non-comparative randomized phase II trial.

BACKGROUND: We performed a randomized, non-comparative phase II study evaluating docetaxel in combination with either daily continuous (protracted IV) 5-fluorouracil or cisplatin administered weekly, concurrent to radiotherapy in the treatment of locally advanced pancreatic carcinoma. Results of the docetaxel plus cisplatin regimen are reported. METHODS: Forty chemotherapy-naive patients with locally advanced pancreatic carcinoma were randomly assigned to receive 5-fluorouracil and docetaxel or docetaxel 20mg/m(2) and cisplatin 20mg/m(2)/week, plus concurrent radiotherapy for 6 weeks. The radiation dose to the primary tumour was 54Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate. RESULTS: 51 patients from 7 centres were included in the docetaxel-cisplatin treatment group. Six-month non-progression rate was 39% (95% confidence interval: 26-53). Median overall survival was 9.6 months (95% confidence interval: 2.4-60.7); 6 complete and 8 partial responses were obtained. Six patients survived more than 2 years after their inclusion in the trial. Grade ≥3 toxicity was reported in 63% of patients; no treatment-related death occurred. Severe toxicities were mainly anorexia (22%), vomiting (20%) and fatigue (24%). CONCLUSIONS: Despite inadequate efficacy according to the main end point, this regimen gave a satisfactory rate of objective response (27%) with tolerable toxicity.

Evaluation of heart murmurs in chinchillas (Chinchilla lanigera): 59 cases (1996-2009).

OBJECTIVE: To determine the prevalence of heart murmurs in chinchillas (Chinchilla lanigera) and determine whether heart murmurs were associated with cardiac disease. DESIGN: Retrospective multi-institutional case series. ANIMALS: 260 chinchillas. PROCEDURES: Medical records of all chinchilla patients evaluated at the Tufts University Foster Hospital for Small Animals between 2001 and 2009, the University of California-Davis William R. Pritchard Veterinary Medical Teaching Hospital between 1996 and 2009, and the University of Wisconsin Veterinary Medical Teaching Hospital between 1998 and 2009 were reviewed. RESULTS: Prevalence of heart murmurs was 23% (59/260). Of 15 chinchillas with heart murmurs that underwent echocardiography, 8 had echocardiographic abnormalities, including dynamic right ventricular outflow tract obstruction, mitral regurgitation, hypertrophy of the left ventricle, tricuspid regurgitation, and hypovolemia. Echocardiographic abnormalities were approximately 29 times as likely (OR, 28.7) to be present in chinchillas with a murmur of grade 3 or higher than in chinchillas without a murmur. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that heart murmurs are common in chinchillas and that chinchillas with heart murmurs often have echocardiographic abnormalities, with valvular disease being the most common. On the basis of these results, we believe that echocardiography should be recommended for chinchillas with heart murmurs, especially older chinchillas with murmurs of grade 3 or higher. Further prospective studies are needed to accurately evaluate the prevalence of cardiac disease in chinchillas with heart murmurs.

Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a highly vascularized tumor in which neoangiogenesis contributes to growth and metastasis. We assessed the safety, efficacy, and potential biomarkers of activity of bevacizumab in patients with advanced HCC. METHODS: In this phase II trial, eligible patients received bevacizumab, 5 mg/kg or 10 mg/kg every 2 weeks. The disease-control rate at 16 weeks (16W-DCR) was the primary endpoint. Circulating endothelial cells (CECs) and plasma cytokines and angiogenic factors (CAFs) were measured at baseline and throughout treatment. RESULTS: The 16W-DCR was 42% (95% confidence interval, 27%-57%). Six of the 43 patients who received bevacizumab achieved a partial response (objective response rate [ORR], 14%). Grade 3-4 asthenia, hemorrhage, and aminotransferase elevation occurred in five (12%), three (7%), and three (7%) patients, respectively. During treatment, placental growth factor markedly increased, whereas vascular endothelial growth factor (VEGF)-A dramatically decreased (p < .0001); soluble VEGF receptor-2 (p < .0001) and CECs (p = .03) transiently increased on day 3. High and increased CEC counts at day 15 were associated with the ORR (p = .04) and the 16W-DCR (p = .02), respectively. Lower interleukin (IL)-8 levels at baseline (p = .01) and throughout treatment (p ≤ .04) were associated with the 16W-DCR. High baseline IL-8 and IL-6 levels predicted shorter progression-free and overall survival times (p ≤ .04). CONCLUSION: Bevacizumab is active and well tolerated in patients with advanced HCC. The clinical value of CECs, IL-6, and IL-8 warrants further investigation.

Effect of chemotherapy in patients with resected small-cell or large-cell neuroendocrine carcinoma.

INTRODUCTION: Surgical resection of an undiagnosed lung lesion may lead to unintentional removal of small-cell lung cancer (SCLC). The benefit of perioperative chemotherapy in resected SCLC or large-cell neuroendocrine carcinomas (LCNEC) is not clear. METHODS: This retrospective analysis included limited disease SCLC and LCNEC that had been surgically removed between 1979 and 2007 at a single institution. Perioperative treatments were analyzed, and survival followed up. Log rank tests were used to compare overall survival. RESULTS: Among 74 patients who had a tumor resection, 45 received chemotherapy, four had preoperative radiotherapy, and 21 had postoperative radiotherapy. Eleven patients were women. The median age was 64 in the surgery group and 58 in the surgery plus chemotherapy group, and four and 11 patients in these groups, respectively, had LCNEC. There were 10 node positive tumors and only two incomplete resections in the surgery group versus 27 node positive tumors and three incomplete resections in the surgery plus chemotherapy group. The median follow-up was shorter in the group with surgery alone: 4.5 years (1.4-7) versus 5.8 years (0.6-19.6). Among the patients with a survival or a follow-up of at least 6 months, the median survival was 2.3 and 6.1 years in the surgery (n = 20) and surgery plus chemotherapy (n = 39) groups, respectively, such that the hazard ratio for death was 0.48 (95% confidence interval, 0.24-0.99, p = 0.04). CONCLUSION: These results suggest that perioperative chemotherapy may be beneficial in patients with resected SCLC or LCNEC.

Docetaxel- and 5-FU-concurrent radiotherapy in patients presenting unresectable locally advanced pancreatic cancer: a FNCLCC-ACCORD/0201 randomized phase II trial's pre-planned analysis and case report of a 5.5-year disease-free survival.

BACKGROUND: To explore possible improvement in the treatment of locally advanced pancreatic carcinoma (LAPC) we performed a randomized, non-comparative phase II study evaluating docetaxel - plus either daily continuous 5 FU or weekly cisplatin concurrent to radiotherapy. We report here the results of the docetaxel plus 5 FU regimen stopped according to the interim analysis. The docetaxel plus cisplatin arm was continued. METHODS: Forty (40) chemotherapy-naive patients with unresectable LAPC were randomly assigned (1:1) to either continuous fluorouracil (5-FU) 200 mg/m(2)/day (protracted IV) and docetaxel (DCT) 20 mg/m(2)/week or DCT 20 mg/m2 and cisplatin (CDDP) 20 mg/m(2), plus concurrent radiotherapy for a period of 6 weeks. The radiation dose to the primary tumor was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate (NPR). Secondary endpoints were tolerance, objective response rate, and overall survival. Accrual was to be stopped if at 6 months more than 13 disease progressions were observed in 20 patients. RESULTS: Eighteen (18) progressions occurred at 6 months in the 5-FU-DCT arm. Six-month NPR was 10% (95%CI: 0-23). Six and 12-month survivals were 85% (95%CI: 64-95) and 40% (95%CI: 22-61); median overall survival was 10.1 months. Median progression-free survival was 4.3 months. We report the case of one patient who was amenable to surgery and has been in complete response (CR) for 5.5 years. Toxicities grade ≥ 3 were reported in 75% of patients; no treatment-related death occurred. Severe toxicities were mainly vomiting (35%), abdominal pain (10%) and fatigue (10%). CONCLUSIONS: Combination of 5-FU, docetaxel and radiotherapy has inadequate efficacy in the treatment of LAPC despite good tolerance for the 5-FU-DCT regimen. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00112697.

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site.

INTRODUCTION: The recently updated meta-analysis of chemotherapy in head and neck cancer (MACH-NC) demonstrated the benefit of the addition of chemotherapy in terms of overall survival in head and neck squamous cell carcinoma (HNSCC). The magnitude of the benefit according to tumour site is unknown as well as their potential interactions with patient or trial characteristics. METHODS: Eighty seven randomized trials performed between 1965 and 2000 were included in the present analysis. Patients were divided into four categories according to tumour location: oral cavity, oropharynx, hypopharynx and larynx. Patients with other tumour location were excluded (999, 5.7%). For each tumour location and chemotherapy timing, the logrank-test, stratified by trial, was used to compare treatments. The hazard ratios of death or relapse were calculated. Interactions between patient or trial characteristics and chemotherapy effect were studied. RESULTS: Individual patient data of 16,192 patients were analysed, with a median follow-up of 5.6years. The benefit of the addition is consistent in all tumour locations, with hazard ratios between 0.87 and 0.88 (p-value of interaction=0.99). Chemotherapy benefit was higher for concomitant administration for all tumour locations, but the interaction test between chemotherapy timing and treatment effect was only significant for oropharyngeal (p<0.0001) and laryngeal tumours (p=0.05), and not for oral cavity (p=0.15) and hypopharyngeal tumours (p=0.30). The 5-year absolute benefits associated with the concomitant chemotherapy are 8.9%, 8.1%, 5.4% and 4% for oral cavity, oropharynx, larynx and hypopharynx tumours, respectively. CONCLUSION: The benefit of the addition of chemotherapy to locoregional treatment is consistent in all tumour locations of HNSCC. The higher benefit of concomitant schedule was demonstrated only for oropharyngeal and laryngeal tumours but this may be only a consequence of a lack of power.

Effect of a misspecification of response rates on type I and type II errors, in a phase II Simon design.

Phase-II trials are a key stage in the clinical development of a new treatment. Their main objective is to provide the required information for a go/no-go decision regarding a subsequent phase-III trial. In single arm phase-II trials, widely used in oncology, this decision relies on the comparison of efficacy outcomes observed in the trial to historical controls. The false positive rate generally accepted in phase-II trials, around 10%, contrasts with the very high attrition rate of new compounds tested in phase-III trials, estimated at about 60%. We assumed that this gap could partly be explained by the misspecification of the response rate expected with standard treatment, leading to erroneous hypotheses tested in the phase-II trial. We computed the false positive probability of a defined design under various hypotheses of expected efficacy probability. Similarly we calculated the power of the trial to detect the efficacy of a new compound for different expected efficacy rates. Calculations were done considering a binary outcome, such as the response rate, with a decision rule based on a Simon two-stage design. When analysing a single-arm phase-II trial, based on a design with a pre-specified null hypothesis, a 5% absolute error in the expected response rate leads to a false positive rate of about 30% when it is supposed to be 10%. This inflation of type-I error varies only slightly according to the hypotheses of the initial design. Single-arm phase-II trials poorly control for the false positive rate. Randomised phase-II trials should, therefore, be more often considered.

Mixed treatment comparison meta-analysis of altered fractionated radiotherapy and chemotherapy in head and neck cancer.

OBJECTIVE: Different treatments have been investigated in head and neck cancers (HNCs) but not all of them have been appraised using pairwise comparison. This has resulted in failure to directly identify the best treatment with standard methods. Mixed treatment comparison (MTC) meta-analysis allows one to perform simultaneous inference regarding all treatments and select the best among them. STUDY DESIGN AND SETTING: We applied MTC models to the Meta-Analyses of Chemotherapy and Radiotherapy in HNC, which pooled individual patient data concerning more than 24,000 patients involved in 102 trials. Fixed- and random-effects models, models with or without consistency factors, possibly adapted to multiarm trials are discussed. RESULTS: Altered fractionated concomitant chemoradiotherapy (AF-CRT) leads to the highest probability of survival in nonmetastatic HNC. The probability that AF-CRT is the best treatment is 94% with random-effects models. There was no relevant inconsistency. When only the most recent trials were selected, AF-CRT and concomitant chemoradiotherapy (CRT) were the two best treatments. AF-CRT remains better than CRT but with a lower posterior probability. CONCLUSION: MTC is a powerful method for investigating networks of randomized trials. Homogeneity, similarity of trial designs, populations, and the consistency of the network should be thoroughly checked.