ABSTRACT
The recent biological invasion of box tree moth Cydalima perspectalis on Buxus trees has a major impact on European boxwood stands through severe defoliation. This can hinder further regrowth and threaten survival of populations. In a mesocosm approach and controlled larval density over a 2-month period, responses of B. sempervirens essential and specialized metabolites were characterized using metabolomics, combining 1H-NMR and LC-MS/MS approaches. This is the first metabolome depiction of major Buxus responses to boxwood moth invasion. Under severe predation, remaining green leaves accumulate free amino acids (with the noticeable exception of proline). The leaf trans-4-hydroxystachydrine and stachydrine reached 10-13% and 2-3% (DW), while root content was lower but also modulated by predation level. Larval predation promoted triterpenoid and (steroidal) alkaloid synthesis and diversification, while flavonoids did not seem to have a relevant role in Buxus resistance. Our results reveal the concomitant responses of central and specialized metabolism, in relation to severity of predation. They also confirm the potential of metabolic profiling using 1H-NMR and LC-MS to detect re-orchestration of metabolism of native boxwood after severe herbivorous predation by the invasive box-tree moth, and thus their relevance for plant-insect relationships and ecometabolomics.
ABSTRACT
Background: Economic evaluations are an integral component of many clinical trials. Costs used in those analyses are based on the prices of branded drugs when they first enter the market. The effect of genericization on the cost-effectiveness (ce) or cost-utility (cu) of an intervention is unknown because economic analyses are rarely updated using the costs of generic drugs. Methods: We re-examined the ce or cu of regimens previously evaluated in Canadian Cancer Trials Group (cctg) studies that included prospective economic evaluations and where genericization has occurred or is anticipated in Canada. We incorporated the new costs of generic drugs to characterize changes in ce or cu. We also determined acceptable cost levels of generic drugs that would make regimens reimbursable in a publicly funded health care system. Results: The four randomized controlled trials included (representing 1979 patients) were cctg br.10 (early lung cancer, adjuvant vinorelbine-cisplatin vs. observation, n = 172), cctg br.21 (metastatic lung cancer, erlotinib vs. placebo, n = 731), cctg co.17 (metastatic colon cancer, cetuximab vs. best supportive care, n = 557), and cctg ly.12 (relapsed or refractory lymphoma, gemcitabine-dexamethasone-cisplatin vs. cytarabine-dexamethasone-cisplatin, n = 619). Since the initial publication of those trials, the genericization of vinorelbine, erlotinib, cetuximab, and cisplatin has taken place or is expected in Canada. Costs of generics improved the ces and cus of treatment significantly. For example, genericization of erlotinib ($1460.25 per 30 days) resulted in an incremental cost-effectiveness ratio (icer) of $45,746 per life-year gained compared with $94,638 for branded erlotinib. Likewise, genericization of cetuximab ($275.80 per 100 mg) produced an icer of $261,126 per quality-adjusted life-year (qaly) gained compared with $299,613 for branded cetuximab. Decreases in the cost of generic cetuximab to $129.39 and $63.51 would further improve the icer to $150,000 and $100,000 per QALY respectively. Conclusions: Genericization of a costly oncology drug can modify the ce and cu of a regimen significantly. Failure to revisit economic analyses with the costs of generics could be a missed opportunity for funding bodies to optimize value-based allocation of health care resources. At current levels, the costs of generics might not be sufficiently low to sustain publicly funded health care systems.
Subject(s)
Antineoplastic Agents/economics , Drugs, Generic/economics , Lung Neoplasms/economics , Lymphoma/economics , Antineoplastic Agents/therapeutic use , Cetuximab/economics , Cetuximab/therapeutic use , Cisplatin/economics , Cisplatin/therapeutic use , Cost-Benefit Analysis , Cytarabine/economics , Cytarabine/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine/economics , Deoxycytidine/therapeutic use , Dexamethasone/economics , Dexamethasone/therapeutic use , Drug Costs , Drugs, Generic/therapeutic use , Erlotinib Hydrochloride/economics , Erlotinib Hydrochloride/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lymphoma/drug therapy , Randomized Controlled Trials as Topic , Vinorelbine/economics , Vinorelbine/therapeutic use , GemcitabineABSTRACT
BACKGROUND: Personal health information, including diagnoses and hospital admissions, is routinely collected in administrative databases. Patients enrolling on clinical trials consent to separate collection and storage of their personal health information. We evaluated patient preferences for linking long-term data from administrative databases with clinical trials. METHODS: Adults with cancer attending outpatient clinics at 3 Ontario hospitals were surveyed about their willingness, when faced with the hypothetical scenario of participating in a clinical trial, to provide potentially identifying information such as initials and date of birth to facilitate long-term research access to normally deidentified publicly collected databases. RESULTS: Of 569 patients surveyed, 335 (59%) were women, 452 (79%) were white, 385 (68%) had a post-secondary education, and 386 (68%) had never participated in a clinical trial. Median age in the group was 59 years. Most participants (93%, cohort 1) would allow long-term access to their information and allow personal information to be used to match clinical trial with administrative data. At the time of clinical trial closure, two thirds of participants (68%, cohort 2) preferred to make additional clinical information available through linkage with administrative databases, and 8 (9%) preferred to have no further information made available to researchers. No significant differences were found in the subset of patients who were part of a clinical trial and those who had never participated (p = 0.65). INTERPRETATION: Almost all patients would allow a clinical trial research team to access their confidential information, providing a more comprehensive assessment of an intervention's long-term risks and benefits.
ABSTRACT
Background: High-dose therapy and autologous stem cell transplantation (ASCT) is often considered for older patients (age >60 years) with relapsed/refractory aggressive lymphomas. Although registry data support the safety and potential efficacy of this approach, there are no prospective trials evaluating outcomes of ASCT in older patients. We evaluated the result of second-line chemotherapy and ASCT in older versus younger patients in the CCTG randomized LY.12 trial. Patients and methods: From August 2003 to November 2011, 619 patients with relapsed/refractory aggressive lymphoma were randomized to gemcitabine, dexamethasone, cisplatin (GDP) or dexamethasone, cytarabine, cisplatin (DHAP); 177 patients (28.6%) enrolled were >60.0 years of age (range, 60-74) and 442 were ≤60.0 years of age. After two to three cycles, responding patients proceeded to ASCT. Intention-to-treat analysis was used to compare response rate, transplantation rate, event-free survival (EFS) and overall survival (OS) between patients aged ≤60.0 and >60.0 years. Results: Patient characteristics were comparable between the two cohorts, except a larger proportion of older patients had high International Prognostic Index risk scores. Response to salvage therapy was 48.6% for patients aged >60.0 versus 43.0% for those aged ≤60.0 (P = 0.21). Transplantation rates were also similar: 50.3% versus 49.8% (P = 0.87) for older versus younger patients. Rates of febrile neutropenia and adverse events requiring hospitalization were comparable for older and younger patients (30.5% versus 22.9% and 37.9% versus 32.1%, respectively). With a median follow-up of 53 months, there was no difference in 4-year OS (36% and 40% for patients aged >60.0 and ≤60.0 years, P = 0.42), or 4-year EFS (20% versus 28%, P = 0.43). Mortality from salvage therapy was 8/174 (4.60%) and 5/436 (1.15%), and 100-day mortality post-ASCT was 7/88 (8.06%) and 4/219 (1.85%). Conclusion: This subgroup analysis suggests that older patients derive similar benefit from salvage therapy and ASCT to younger patients, with acceptable toxicity. ClinicalTrials.gov Identifier: NCT00078949.
Subject(s)
Lymphoma/therapy , Neoplasm Recurrence, Local/therapy , Salvage Therapy/adverse effects , Stem Cell Transplantation/adverse effects , Adult , Age Factors , Aged , Cisplatin/administration & dosage , Cytarabine/administration & dosage , Dexamethasone/administration & dosage , Disease-Free Survival , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Lymphoma/mortality , Lymphoma/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Cost avoidance occurs when, because of provision of a drug therapy [drug cost avoidance (dca)] or a pathology test [pathology cost avoidance (pca)] during trial participation, health care payers need not pay for standard treatments or testing. The aim of our study was to estimate the total dca and pca for Canadian patients enrolled in relevant phase iii trials conducted by the ncic Clinical Trials Group. METHODS: Phase iii trials that had completed accrual and resulted in dca or pca were identified. The pca was calculated based on the number of patients screened and the test cost. The dca was estimated based on patients randomized, the protocol dosing regimen, drug cost, median dose intensity, and median duration of therapy. Costs are presented in Canadian dollars. No adjustment was made for inflation. RESULTS: From 1999 to 2011, 4 trials (1479 patients) resulted in pca and 17 trials (3195 patients) resulted in dca. The total pca was estimated at $4,194,849, which included testing for KRAS ($141,058), microsatellite instability ($18,600), and 21-gene recurrence score ($4,035,191). The total dca was estimated at $27,952,512, of which targeted therapy constituted 43% (five trials). The combined pca and dca was $32,147,361. CONCLUSIONS: Over the study period, trials conducted by the ncic Clinical Trials Group resulted in total cost avoidance (pca and dca) of approximately $7,518 per patient. Although not all trials lead to cost avoidance, such savings should be taken account when the financial impact of conducting clinical research is being considered.
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BACKGROUND: Treatment options for patients with nonbulky stage IA-IIA Hodgkin lymphoma include combined modality therapy (CMT) using doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) plus involved-field radiation therapy (IFRT), and chemotherapy with ABVD alone. There are no mature randomized data comparing ABVD with CMT using modern radiation techniques. PATIENTS AND METHODS: Using German Hodgkin Study Group HD10/HD11 and NCIC Clinical Trials Group HD.6 databases, we identified 588 patients who met mutually inclusive eligibility criteria from the preferred arms of HD10 or 11 (n = 406) and HD.6 (n = 182). We evaluated time to progression (TTP), progression-free (PFS) and overall survival, including in three predefined exploratory subset analyses. RESULTS: With median follow-up of 91 (HD10/11) and 134 (HD.6) months, respective 8-year outcomes were for TTP, 93% versus 87% [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.24-0.78]; for PFS, 89% versus 86% (HR 0.71, 95% CI 0.42-1.18) and for overall survival, 95% versus 95% (HR 1.09, 95% CI 0.49-2.40). In the exploratory subset analysis including HD10 eligible patients who achieved complete response (CR) or unconfirmed complete response (CRu) after two cycles of ABVD, 8-year PFS was 87% (HD10) versus 95% (HD.6) (HR 2.8; 95% CI 0.64-12.5) and overall survival 96% versus 100%. In contrast, among those without CR/CRu after two cycles of ABVD, 8-year PFS was 88% versus 74% (HR 0.35; 95% CI 0.16-0.79) and overall survival 95% versus 91%, respectively (HR 0.42; 95% CI 0.12-1.44). CONCLUSIONS: In patients with nonbulky stage IA-IIA Hodgkin lymphoma, CMT provides better disease control than ABVD alone, especially among those not achieving complete response after two cycles of ABVD. Within the follow-up duration evaluated, overall survivals were similar. Longer follow-up is required to understand the implications of radiation and chemotherapy-related late effects. CLINICAL TRIALS: The trials included in this analysis were registered at ClinicalTrials.gov: HD10 - NCT00265018, HD11 - NCT00264953, HD.6 - NCT00002561.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hodgkin Disease/drug therapy , Adult , Bleomycin/therapeutic use , Chemoradiotherapy , Dacarbazine/therapeutic use , Disease-Free Survival , Doxorubicin/therapeutic use , Hodgkin Disease/mortality , Humans , Proportional Hazards Models , Randomized Controlled Trials as Topic , Retrospective Studies , Treatment Outcome , Vinblastine/therapeutic useABSTRACT
The identification of novel scaffolds for the development of effective and safe treatments to fight malaria is urgently needed. One of the main opportunities is the discovery of new molecules from natural origin. A simple, robust and cost-effective colorimetric assay based on the inhibition of ß-hematin has been adapted to routinely screen plant extracts with the ultimate goal to identify novel antimalarial ingredients. The development of this assay has included a careful optimization of all critical experimental parameters. The ß-hematin assay can be completed in less than one working day, requiring a 96-well UV-vis plate reader and low-cost commercially available reagents using a standard operating protocol. It can be used on its own or in combination with the well-known Plasmodium growth inhibition assay and has the obvious merit to be informative at the early stage of drug discovery regarding the mechanism of action of the actives. A total of 40 diverse natural products and 219 plants extracts were tested. Good correlations in respect with specificity (pure compounds 85%, extracts 93%) and positive predictive value (pure compounds 72%, extracts 50%) were obtained in comparison with Plasmodium growth inhibition assay that was used as the reference assay.
Subject(s)
Antimalarials/pharmacology , Hemeproteins/antagonists & inhibitors , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Animals , Antimalarials/isolation & purification , Hemeproteins/biosynthesis , Plasmodium/drug effects , Plasmodium/growth & development , Solid Phase Extraction , Spectrophotometry, UltravioletABSTRACT
Two new xanthones, caledonixanthone M 1 and caloxanthone L 2, and one new acid, caledonic acid 6 were isolated from the hexane-soluble extract of the stem bark of Calophyllum caledonicum. In the course of this phytochemical study, seven other known compounds - calothwaitesixanthone, calozeyloxanthone, allanxanthone, isoapetalic acid 3, calolongic acid 4, apetalic acid 5 and isocalolongic acid 7 - were isolated. Their antifungal activity against the growth of the human pathogenic fungus Aspergillus fumigatus was then investigated. The results indicated that the crude extract, calolongic acid 4 and isocalolongic acid 7 exhibited strong inhibitory effects with MIC (80) values of 8, 4, 2 microg/mL, respectively. Besides, calolongic acid 4, its lactone derivative 4a and isocalolongic acid 7 markedly reduced the respiration of pea seed mitochondria.
Subject(s)
Antifungal Agents/pharmacology , Calophyllum , Chromans/pharmacology , Electron Transport/drug effects , Phytotherapy , Antifungal Agents/administration & dosage , Antifungal Agents/therapeutic use , Aspergillus fumigatus/drug effects , Chromans/administration & dosage , Chromans/therapeutic use , Humans , Microbial Sensitivity Tests , Mitochondria/drug effects , Pisum sativum/metabolism , Plant Bark , Plant Extracts/administration & dosage , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , SeedsABSTRACT
Acoustic backscatter observations at 200 kilohertz were made of the buoyant plume from a submarine spring at a depth of 47 meters in Cambridge Fiord, Baffin Island. Vertical velocities of up to 37 centimeters per second are inferred from the ascent rates of discrete scattering structures in the plume.
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A turbidity current surge has been detected in a leveed submarine channel in Rupert Inlet, British Columbia, with the use of acoustic sounders operating at 42.5, 107, and 200 kilohertz.
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Continuous recordings were made of the EEG and ECG of one pilot during a series of instrument flights in a feeder-type transport aircraft. The flights were arranged to contain epochs of distinctly differing levels of workload. In addition, some flights were made after a night of sleep deprivation and others were made as the second and third flights of the day. Subjectively, there appeared to be marked differences in performance between the two types of tired flight. The EEG analyses showed changes that correlated well with differences in workload. In the highest workload areas during fresh flights, EEG activity increased by approximately a factor of 4 over that of the preflight resting values. This large increase did not occur in the tired flights. Further experiments are planned using flights in aircraft and in simulators using several subjects.