Background
Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations ...of these agents with temozolomide (TMZ).
Methods
Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose‐limiting toxicities (DLTs) were determined, using a 3 + 3 study design.
Results
Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2‐year survival rate was 43%.
Conclusions
Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.
Memantine, mefloquine, and metformin can be combined safely with temozolomide in patients with glioblastoma. The maximum tolerated doses determined by this study can be used in future phase 2 clinical trials.
Evidence is growing that low-dose aspirin used as an adjuvant treatment of cancer is associated with an increased survival and a reduction in metastatic spread. We therefore extended up to August ...2017 an earlier systematic search and meta-analyses of published studies of low-dose aspirin taken by patients with a diagnosis of cancer.
Searches were completed in Medline and Embase to August 2017 using a pre-defined search strategy to identify reports of relevant studies. References in all the selected papers were scanned. Two reviewers independently applied pre-determined eligibility criteria and extracted data on cause-specific cancer deaths, overall mortality and the occurrence of metastatic spread. Meta-analyses were then conducted for different cancers and heterogeneity and publication bias assessed. Sensitivity analyses and attempts to reduce heterogeneity were conducted.
Analyses of 29 studies reported since an earlier review up to April 2015 are presented in this report, and these are then pooled with the 42 studies in our earlier publication. Overall meta-analyses of the 71 studies are presented, based on a total of over 120 thousand patients taking aspirin. Ten of the studies also give evidence on the incidence of metastatic cancer spread. There are now twenty-nine observational studies describing colorectal cancer (CRC) and post-diagnostic aspirin. Pooling the estimates of reduction by aspirin which are reported as hazard ratios (HR), gives an overall HR for aspirin and CRC mortality 0.72 (95% CI 0.64-0.80). Fourteen observational studies have reported on aspirin and breast cancer mortality and pooling those that report the association with aspirin as a hazard ratio gives HR 0.69 (0.53-0.90). Sixteen studies report on aspirin and prostate cancer mortality and a pooled estimate yields an HR of 0.87 (95% CI 0.73-1.05). Data from 12 reports relating to other cancers are also listed. Ten studies give evidence of a reduction in metastatic spread; four give a pooled HR 0.31 (95% CI 0.18, 0.54) and five studies which reported odds ratio of metastatic spread give OR 0.79 (0.66 to 0.95).
Being almost entirely from observational studies, the evidence of benefit from aspirin is limited. There is heterogeneity between studies and the results are subject to important biases, only some of which can be identified. Nevertheless, the evidence would seem to merit wide discussion regarding whether or not it is adequate to justify the recommendation of low-dose therapeutic aspirin, and if it is, for which cancers?
Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations. Our ability to understand and predict changes in the forest ...carbon cycle--particularly net primary productivity and carbon storage--increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands. Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree, in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level and stand-level productivity can be explained, respectively, by increases in a tree's total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation and plant senescence.
Aspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. ...Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding. We therefore present a literature search and meta-analysis to ascertain fatal events attributable to low-dose aspirin.
In a systematic literature review we identified reports of randomised controlled trials of aspirin in which both total GI bleeding events and bleeds that led to death had been reported. Principal investigators of studies in which fatal events had not been adequately described were contacted via email and asked for further details. A meta-analyses was then performed to estimate the risk of fatal gastrointestinal bleeding attributable to low-dose aspirin.
Eleven randomised trials were identified in the literature search. In these the relative risk (RR) of 'major' incident GI bleeding in subjects who had been randomised to low-dose aspirin was 1.55 (95% CI 1.33, 1.83), and the risk of a bleed attributable to aspirin being fatal was 0.45 (95% CI 0.25, 0.80). In all the subjects randomised to aspirin, compared with those randomised not to receive aspirin, there was no significant increase in the risk of a fatal bleed (RR 0.77; 95% CI 0.41, 1.43).
The majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.
Abstract
Background
Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a ...histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.
Methods
This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary endpoints of overall survival (OS) and clinical outcomes assessment (MD Anderson Symptom Inventory Brain Tumor module MDASI-BT). Eligible patients were adults (≥18 y) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS ≥60, and no prior bevacizumab or HDAC inhibitors.
Results
Ninety patients (bevacizumab + vorinostat: 49, bevacizumab: 41) were enrolled, of whom 74 were evaluable for PFS (bevacizumab + vorinostat: 44, bevacizumab: 30). Median PFS (3.7 vs 3.9 mo, P = 0.94, hazard ratio HR 0.63 95% CI: 0.38, 1.06, P = 0.08), median OS (7.8 vs 9.3 mo, P = 0.64, HR 0.93 95% CI: 0.5, 1.6, P = 0.79) and clinical benefit were similar between the 2 arms. Toxicity (grade ≥3) in 85 evaluable patients included hypertension (n = 37), neurological changes (n = 2), anorexia (n = 2), infections (n = 9), wound dehiscence (n = 2), deep vein thrombosis/pulmonary embolism (n = 2), and colonic perforation (n = 1).
Conclusions
Bevacizumab combined with vorinostat did not yield improvement in PFS or OS or clinical benefit compared with bevacizumab alone or a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.
Governments and industries increasingly use offsets to compensate for the unavoidable impacts of development on biodiversity. However, high uncertainty about the biodiversity outcomes of offsetting ...strategies has led to significant criticism in the academic and policy literature, while the ad-hoc application of offset rules within a region may lead to offsets favouring some species and communities at the expense of others. Here we explored opportunities to improve offsetting outcomes through strategic regional offset approaches, underpinned by concepts of complementarity and irreplaceability from the conservation planning literature, in comparison to more commonly used like-for-like approach. We assessed different offsetting strategies in the Hunter Valley, NSW, a rapidly developing region in Australia with an active mining industry. We quantified regional-level biodiversity losses arising from minimal to extensive mining expansion, along with species-specific impacts for 569 flora and fauna species, and prioritized areas for protection, restoration or both to offset the anticipated losses. Accounting for how well the offsets would complement existing protected areas, we compared the area needed for offsetting and the expected biodiversity outcomes among the different strategies. Our results highlight the benefits of a more systematic approach to offsetting in terms of an enhanced understanding of regional-scale impacts, more efficient identification of offset sites and improved biodiversity outcomes. Our approach encourages forward thinking about impending threats to, and opportunities for, biodiversity conservation and could serve as a template for strategic regional offset planning based on plausible scenarios of future biodiversity loss.
•We explore strategic offsetting using complementarity and irreplaceability principles.•Strategic offsetting provided higher biodiversity returns than like-for-like approaches.•The like-for-like approaches tended to miss offsetting targets at medium to high levels of mining.•Mining impacts vary notably between species which is not captured by changes in vegetation types.•Species protection was more efficiently improved by strategic, species based offsetting.
Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.
We conducted a phase I/II ...study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.
Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.
Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.
BACKGROUND:Outcomes studies following successful closed reduction of late-detected developmental dysplasia of the hip (DDH) reveal high rates of secondary reconstructive surgery with limited ...comparative data demonstrating lower rates of residual dysplasia with open reduction. The purpose of this study was to compare long-term outcomes, with regard to radiographic evidence of residual dysplasia and secondary reconstructive procedures, between late closed and late open reduction for DDH in patients 6 to 24 months of age at reduction.
METHODS:We identified all patients between 6 and 24 months of age who underwent closed or open reduction for DDH between 1980 and 2008 and were followed until at least 10 years of age. Outcomes included radiographic measurement of acetabular dysplasia after triradiate cartilage closure, development of osteonecrosis, and the need for secondary procedures for residual dysplasia.
RESULTS:One hundred and four hips underwent index closed reduction and 54 hips underwent index open reduction. There was no significant difference in the age at reduction (p = 0.07). Among the 116 hips for which initial anteroposterior pelvic radiographs were available, most closed reductions (55%) were performed in International Hip Dysplasia Institute (IHDI) grade-III hips whereas most open reductions (71%) were performed in IHDI grade-IV hips. Analysis of the hips that did not undergo a secondary procedure showed that those with an index open reduction had a greater lateral center-edge angle (mean and standard deviation, 27.2° ± 10.0° versus 22.4° ± 6.8° in the closed reduction cohort; p = 0.02), lower femoral head extrusion index (22.2% ± 8.9% versus 26.0% ± 6.2%; p = 0.04), and lower Sharp angle (43.3° ± 6.0° versus 46.6° ± 3.1°; p = 0.002) at triradiate closure. There was no difference in the prevalence of osteonecrosis (Bucholz-Ogden grades II, III, and IV) between the closed and open reduction cohorts (22% versus 19%, respectively; p = 0.60). Secondary procedures were performed more frequently after closed reduction than after open reduction (47% versus 30%, respectively; p = 0.03).
CONCLUSIONS:In patients with late reduction of DDH, closed reduction was associated with increased residual dysplasia and it was associated with a higher rate of secondary surgery in those >12 months old despite a decreased severity of displacement based on the IHDI classification. Additional, prospective studies with assessment of functional outcomes are needed to validate these findings.
LEVEL OF EVIDENCE:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
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