Meta-analyses of the efficacy of pharmacotherapies and sublingual allergy immunotherapy tablets for allergic rhinitis in adults and children.

BACKGROUND: Treatment options for seasonal and perennial allergic rhinitis (SAR/PAR) include pharmacotherapies and allergy immunotherapy. These meta-analyses evaluated the efficacy of pharmacotherapies and sublingual immunotherapy tablets (SLIT-tablets) versus placebo on nasal symptoms associated with SAR and PAR. METHODS: Randomized, double-blind, placebo-controlled trials were identified from systematic PubMED/EMBASE searches through 7/18/2019 (PROSPERO protocol CRD42018105632). The primary outcome was mean numerical difference in total nasal symptom score (TNSS; 0-12) between active treatment and placebo at the end of the assessment period. Random-effects meta-analyses estimated the mean difference for each medication group weighted by the inverse of the trial variance. Publication bias assessments and sensitivity analyses were conducted. RESULTS: Rescue symptom-relieving pharmacotherapy was prohibited in most pharmacotherapy trials but was allowed in all SLIT-tablet trials. For adult/adolescent SAR, the mean numerical difference (95% CI) in TNSS versus placebo was: intranasal corticosteroids (INCS)=1.38 (1.18, 1.58; 39 trials); combination intranasal antihistamine/INCS=1.34 (1.15, 1.54; 4 trials); intranasal antihistamines=0.72 (0.56, 0.89; 13 trials); oral antihistamine=0.62 (0.35, 0.90; 18 trials); SLIT-tablets=0.57 (0.41, 0.73; 4 trials); and montelukast=0.48 (0.36, 0.60; 10 trials). For adult/adolescent PAR, mean difference in TNSS versus placebo (95% CI) was: INCS=0.82 (0.66, 0.97; 14 trials); SLIT-tablets=0.65 (0.42, 0.88; 3 trials); and oral antihistamine=0.27 (0.11, 0.42; 3 trials). The number of eligible trials limited meta-analyses for pediatric SAR/PAR. CONCLUSIONS: All treatments significantly improved nasal symptoms versus placebo. SLIT-tablets provided improvement in TNSS despite access to rescue symptom-relieving pharmacotherapy. Extensive trial heterogeneity and strong indications of publication bias preclude the comparison of treatment effects among treatment classes.

Exploring factors associated with health disparities in asthma and poorly controlled asthma among school-aged children in the U.S.

Objective: Certain populations suffer disproportionately from asthma and asthma morbidity. The objective was to provide a national descriptive profile of asthma control and treatment patterns among school-aged children (SAC: aged 6-17) in the U.S. Methods: This was a cross-sectional analysis using the nationally representative 2007-2014 Medical Expenditure Panel Survey. Among SAC with asthma, indicators of poor control included: exacerbation/asthma attack; >3 canisters short-acting beta agonist (SABA)/3 months; and asthma-specific Emergency Department or inpatient visits (ED/IP). Results: Non-Hispanic black, non-Hispanic multiple races, Puerto Rican, obese, Medicaid, poor, ≥2 non-asthma chronic comorbidities (CC), and family average CC ≥ 2 were associated with higher odds of having asthma. The following had significantly higher odds ratios (OR) of excessive SABA use compared to non-Hispanic whites [OR; CI; p < 0.05]: Puerto Rican (3.8; 2.1-6.9), Mexican (3.6; 2.0-6.4), Central/South American (3.0; 1.2-7.7), Hispanic-other (3.1; 1.1-9.0), non-Hispanic black (2.5; 1.6-3.9), and non-Hispanic Asian (4.0; 1.7-9.2). SABA OR were also significant for Spanish spoken at home (2.5; 1.6-3.8), obese (2.1; 1.3-3.3), Medicaid (2.9; 2.0-4.1), no medical insurance (2.1; 1.1-4.1), no prescription insurance (2.5; 1.8-3.5), poor (2.8; 1.7-4.7), CC ≥ 2 (2.1; 1.6-2.8), parent-without high-school degree (2.5; 1.8-3.6), parent-SF-12 Physical Component Scale <50 (1.6; 1.2-2.1) and Mental Component Scale <50 (1.5; 1.1-2.0). Significant differences also existed across subgroups for ED/IP visits. Conclusions: There are disparities in asthma control and prevalence among certain populations in the U.S. These results provide national data on disparities in several indicators of poor asthma control beyond the standard race/ethnicity groupings.

Non-communicable chronic diseases and timely breast cancer screening among women of the Eastern Caribbean Health Outcomes Research Network (ECHORN) Cohort Study.

PURPOSE: The Caribbean population faces a growing burden of multiple non-communicable chronic diseases (NCDs). Breast cancer is the leading cause of cancer death for women in the Caribbean. Given the substantial burden of NCDs across the region, cancer prevention and control strategies may need to be specifically tailored for people with multiple co-morbidities. Preventive screening, such as timely mammography, is essential but may be either facilitated or hampered by chronic disease control. The main objective of this study is to examine the relationship between a chronic disease and timely breast cancer screening. METHODS: We conducted a cross-sectional data analysis using baseline data from the Eastern Caribbean Health Outcomes Research Network (ECHORN) Cohort Study-ECS. Our independent variables were presence of chronic diseases (hypertension or diabetes), defined as having been told by a clinical provider. Our dependent variable was timely screening mammography, as defined by receipt of mammography within the past 2 years. We examined bivariate and multivariate associations of covariates and timely screening mammography. RESULTS: In our sample (n = 841), 52% reported timely screening mammography. Among those with timely screening, 50.8% reported having hypertension, and 22.3% reported having diabetes. In our bivariate analyses, both diabetes and hypertension were associated with timely screening mammography. In partially adjusted models, we found that women with diabetes were significantly more likely to report timely screening mammography than women without diabetes. In our fully adjusted models, the association was no longer significant. Having a usual source of healthcare and a woman's island of residence were significantly associated with timely screening mammography (p < 0.05). CONCLUSIONS: We found that half of eligible women received timely screening mammography. Diabetes and hypertension, though common, are not associated with timely screening mammography. Usual source of care remains an important factor to timely breast cancer screening.

The national burden of poorly controlled asthma, school absence and parental work loss among school-aged children in the United States.

OBJECTIVE: The degree of poorly controlled asthma and its association with missed school days and parental missed work days is not well understood. METHODS: This was a retrospective analysis of missed school days and missed work days for school-aged children (SAC; aged 6-17) and their caregivers in the nationally representative 2007-2013 Medical Expenditure Panel Survey (MEPS). Indicators of poor asthma control included: exacerbation in previous 12 months; use of >3 canisters of short-acting beta agonist (SABA) in 3 months; and annual asthma-specific (AS) Emergency Department (ED) or inpatient (IP) visits. Negative binomial regression was used for missed school days, and a Heckman two-step selection model was used for missed work days. All analyses controlled for sociodemographics and other covariates. RESULTS: There were 44,320 SAC in MEPS, of whom 5,890 had asthma. SAC with asthma and an indicator of poor control missed more school days than SAC without asthma: exacerbation (1.8 times more; p < 0.001); >3 canisters SABA (2.7 times more; p < 0.001) and ED/IP visit (3.8 times more; p < 0.001). The parents/caregivers of SAC with asthma and an exacerbation missed 1.2 times more work days (p < 0.05), while those with SAC with asthma and an ED/IP visit missed 1.8 times more work days (p < 0.01) than the parents of SAC without asthma. CONCLUSIONS: This study provides evidence of the significant national burden of poorly controlled asthma due to missed school and work days in the United States. More effective and creative asthma management strategies, with collaboration across clinical, community and school-based outreach, may help address this burden.

Assessment of treatment patterns associated with injectable disease-modifying therapy among relapsing-remitting multiple sclerosis patients.

BACKGROUND: Availability of oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (RRMS) may affect injectable DMT (iDMT) treatment patterns. OBJECTIVE: The objective of this paper is to evaluate iDMT persistency, reasons for persistency lapses, and outcomes among newly diagnosed RRMS patients. METHODS: Medical records of 300 RRMS patients initiated on iDMT between 2008 and 2013 were abstracted from 18 US-based neurology clinics. Eligible patients had ≥3 visits: pre-iDMT initiation, iDMT initiation (index), and ≥1 visit within 24 months post-index. MS-related symptoms, relapses, iDMT treatment patterns (i.e. persistency, discontinuation, switching, and restart), and reasons for non-persistency were tracked for 24 months. RESULTS: At 24 months, iDMT persistency was 61.0%; 28.0% of patients switched to another DMT, 8.0% discontinued, and 3.0% stopped and restarted the same iDMT. The most commonly identified reasons for non-persistency were perceived lack of efficacy (22.2%), adverse events (18.8%), and fear of needles/self-injecting (9.4%). At 24 months, 38.0% of patients had experienced a relapse and 11.0% had changes in MRI lesion counts. Patients without MS-related symptoms at index reported increases in the incidence of these symptoms at 24 months. CONCLUSIONS: Non-persistency with iDMT remains an issue in the oral DMT age. Many patients still experienced relapses and disease progression, and should consider switching to more effective therapies.

Quantum walks: The first detected passage time problem.

Even after decades of research, the problem of first passage time statistics for quantum dynamics remains a challenging topic of fundamental and practical importance. Using a projective measurement approach, with a sampling time τ, we obtain the statistics of first detection events for quantum dynamics on a lattice, with the detector located at the origin. A quantum renewal equation for a first detection wave function, in terms of which the first detection probability can be calculated, is derived. This formula gives the relation between first detection statistics and the solution of the corresponding Schrödinger equation in the absence of measurement. We illustrate our results with tight-binding quantum walk models. We examine a closed system, i.e., a ring, and reveal the intricate influence of the sampling time τ on the statistics of detection, discussing the quantum Zeno effect, half dark states, revivals, and optimal detection. The initial condition modifies the statistics of a quantum walk on a finite ring in surprising ways. In some cases, the average detection time is independent of the sampling time while in others the average exhibits multiple divergences as the sampling time is modified. For an unbounded one-dimensional quantum walk, the probability of first detection decays like (time)^{(-3)} with superimposed oscillations, with exceptional behavior when the sampling period τ times the tunneling rate γ is a multiple of π/2. The amplitude of the power-law decay is suppressed as τ→0 due to the Zeno effect. Our work, an extended version of our previously published paper, predicts rich physical behaviors compared with classical Brownian motion, for which the first passage probability density decays monotonically like (time)^{-3/2}, as elucidated by Schrödinger in 1915.

The first polluted river? Repeated copper contamination of fluvial sediments associated with Late Neolithic human activity in southern Jordan.

The roots of pyrometallurgy are obscure. This paper explores one possible precursor, in the Faynan Orefield in southern Jordan. There, at approximately 7000cal. BP, banks of a near-perennial meandering stream (today represented by complex overbank wetland and anthropogenic deposits) were contaminated repeatedly by copper emitted by human activities. Variations in the distribution of copper in this sequence are not readily explained in other ways, although the precise mechanism of contamination remains unclear. The degree of copper enhancement was up to an order of magnitude greater than that measured in Pleistocene fluvial and paludal sediments, in contemporary or slightly older Holocene stream and pond deposits, and in the adjacent modern wadi braidplain. Lead is less enhanced, more variable, and appears to have been less influenced by contemporaneous human activities at this location. Pyrometallurgy in this region may have appeared as a byproduct of the activity practised on the stream-bank in the Wadi Faynan ~7000years ago.

Motor stereotypies and cognitive perseveration in non-human primates exposed to early gestational irradiation.

A number of psychiatric illnesses have been associated with prenatal disturbance of brain development, including autism, attention deficit hyperactivity disorder, and schizophrenia. Individuals afflicted with these disorders exhibit both repetitive motor and cognitive behavior. The potential role that environmental insult to the developing brain may play in generating these aberrant behaviors is unclear. Here we examine the behavioral consequences of an early gestational insult in the non-human primate. Rhesus macaques were exposed to x-irradiation during the first trimester of development to disrupt neurogenesis. The behavior of five fetally irradiated monkeys (FIMs) and five control monkeys (CONs) was observed as they matured from juvenile (1.5 years) to adult ages (4-5 years). Home-cage behavior was indistinguishable in the two groups. In the testing cage, circling was prevalent in both groups at juvenile ages, persisting to adulthood in three of the five FIMs. One FIM executed a ritualized motor sequence marked by semi-circling and undulating head movements. Seven macaques (4 FIMs, 3 CONs) were tested on a spatial Delayed Alternation (DA) task as adults. Perseverative errors and non-perseverative errors were recorded in early stages of the testing, at the 0 delay interval. While performing DA, FIMs made more errors of perseveration than CONs yet the number of total errors committed did not differ between groups. The presence of motor stereotypies and cognitive perseveration in fetally irradiated non-human primates suggests that environmental insult to the embryonic brain may contribute to repetitive motor and cognitive behaviors in neuropsychiatric diseases.

Impact of the human immunodeficiency virus on early multidrug-resistant tuberculosis treatment outcomes in Botswana.

SETTING: The impact of the human immunodeficiency virus (HIV) on multidrug-resistant tuberculosis (MDR-TB) treatment outcomes in sub-Saharan Africa, where extensive rollout of highly active antiretroviral therapy (HAART) has occurred, remains unclear. OBJECTIVE: To compare the time to initial culture conversion among patients with and those without HIV infection in a setting of individualized MDR-TB care in Botswana. DESIGN: Prospective cohort study of MDR-TB patients receiving ambulatory, integrated TB-HIV care at two public clinics in Botswana. The time to culture conversion was compared by HIV status using Cox proportional hazard ratios (HRs). RESULTS: A total of 40 HIV-infected and 30 non-HIV-infected patients with MDR-TB and follow-up cultures were identified. The median time to initial culture conversion was 78 days (interquartile range [IQR] 42-186) for HIV-infected and 95 days (IQR 70-133) for non-HIV-infected individuals (log rank P > 0.5; unadjusted HR 0.9, 95%CI 0.5-1.5). Adjusting for age, sex, treatment history and number of active anti-tuberculosis drugs did not change this result (adjusted HR 0.8, 95%CI 0.4-1.4). CONCLUSION: We found no difference in the proportion of or time to initial sputum culture conversion between an HIV-infected and a non-infected cohort of MDR-TB patients in Botswana, suggesting that outcomes may be comparable in similar settings with access to individualized anti-tuberculosis treatment and HAART.

Micro- and nano-spheres of low melting point metals and alloys, formed by ultrasonic cavitation.

Metals and alloys of low melting points (<430 °C) can be melted in hot silicone oil to form two immiscible liquids. Irradiation of the system with ultrasonic energy induces acoustic cavitation in the oil, which disperses the molten metals into microspheres that solidify rapidly upon cooling. This method has been applied to seven pure metals (Ga, In, Sn, Bi, Pb, Zn, Hg) and two eutectic alloys of gold (Au-Ge and Au-Si). The morphology and composition of the resulting microspheres were examined by SEM and EDS. Eutectic Au-Si formed also crystalline Au nanoparticles, which were separated and studied by HRTEM.

Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours.

BACKGROUND: Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient. METHODS: The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1. RESULTS: Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC(50)=1.7 µM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O(6)-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WÜ cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry). CONCLUSION: A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient.

A change in the apparent diffusion coefficient after treatment with bevacizumab is associated with decreased survival in patients with recurrent glioblastoma multiforme.

OBJECTIVES: The aim of this study was to determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to treatment with bevacizumab and irinotecan in patients with recurrent glioblastoma multiforme. METHODS: 15 patients with recurrent glioblastoma multiforme underwent serial 1.5 T MRI. Axial single-shot echo planar DTI was obtained on scans performed 3 days and 1 day prior to and 6 weeks after initiation of therapy with bevacizumab and irinotecan. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were registered to whole brain contrast-enhanced three-dimensional (3D) spoiled gradient recalled and 3D fluid attenuation inversion recovery (FLAIR) image volumes. Anatomic image volumes were segmented to isolate regions of interest defined by tumour-related enhancement (TRE) and FLAIR signal abnormality (FSA). Mean ADC and mean FA were calculated for each region. A Bland-Altman repeatability coefficient was also calculated for each parameter based on the two pre-treatment studies. A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the repeatability coefficient for that parameter. Survival was compared using a Cox proportional hazard model. RESULTS: DTI detected a change in ADC within FSA after therapy in nine patients (five in whom ADC was increased; four in whom it was decreased). Patients with a change in ADC within FSA had significantly shorter overall survival (p=0.032) and progression free survival (p=0.046) than those with no change. CONCLUSION: In patients with recurrent glioblastoma multiforme treated with bevacizumab and irinotecan, a change in ADC after therapy in FSA is associated with decreased survival.

Prognostic significance of parameters derived from co-registered 18F-fluorodeoxyglucose PET and contrast-enhanced MRI in patients with high-grade glioma.

OBJECTIVE: The aim of this study was to determine the prognostic significance of the volume and intensity of abnormal (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) accumulation within areas of contrast enhancement on post-therapeutic volumetric MRI. METHODS: A total of 10 patients with Grade III or IV glioma were treated with resection followed by intracavitary radiation therapy with (131)I-labelled antitenascin monoclonal antibody. Patients underwent serial FDG-PET and 1.5 T MR imaging. For each patient, MR and FDG-PET image volumes at each time point were aligned using a rigid-body normalised mutual information algorithm. Contrast-enhancing regions of interest (ROIs) were defined using a semi-automated k-means clustering technique. Activity within the ROI on the co-registered PET scan was calculated as a ratio (mean activity ratio; MAR) to activity in contralateral normal-appearing white matter (NAWM). The PET lesion was defined as the portion of the ROI associated with activity greater than two standard deviations above the mean in NAWM. Survival was assessed using the logrank test. RESULTS: Larger contrast-enhancing ROIs were strongly associated with an increased MAR (r = 0.51; p<0.002). Enhancing lesions with an MAR >1.2 were associated with decreased survival (p<0.016). In nine patients who died, the MAR on PET correlated inversely with survival duration (r = -0.43; p<0.01), whereas PET lesion volume did not. CONCLUSION: Following intracavitary radiation therapy, the development of contrast-enhancing lesions that are associated with high mean FDG-PET accumulation suggests poor prognosis.

The impact of adherence and disease control on resource use and charges in patients with mild asthma managed on inhaled corticosteroid agents.

OBJECTIVE: Inadequate asthma control may affect asthma resource use and treatment charges, consequently contributing to the growing economic burden of asthma. The study objective was to determine the impact of medication adherence and asthma control on resource use and charges in mild asthmatic patients treated with inhaled corticosteroids (ICSs). RESEARCH DESIGN AND METHODS: A claims database was analyzed retrospectively from October 2001-December 2007 to identify mild asthmatic patients aged 12-65 years who began ICS treatment. Demographics, drug utilization, and resource use for each patient were identified for the 365-day period before and after the index date (pre-index and post-index periods, respectively). Patients were designated as having high control high adherence (HCHA) or low control low adherence (LCLA) based on post-index exacerbations and the percentage of days covered; not all patients who qualified for study inclusion met adherence designation requirements. Differences between the HCHA and LCLA cohorts in resource use (eg, asthma treatment days) and asthma-related treatment charges were assessed. RESULTS: Compared with the HCHA cohort (n = 483), the LCLA cohort (n = 258) had more asthma treatment days (2.9 vs 3.9, respectively; P < 0.0001) and higher overall asthma treatment charges ($2655 vs $3345, respectively; P < 0.0001) in the post-index period. An adjusted odds ratio suggested that patients receiving mometasone furoate (MF) were approximately 5 times more likely to belong to the HCHA cohort than patients receiving any other ICS (P < 0.0001). CONCLUSIONS: Better asthma control and adherence to prescribed ICSs are associated with lower asthma-related resource use and charges. Mild asthmatic patients receiving MF were more likely to be in the HCHA cohort than patients receiving other ICSs, perhaps due to the once-daily dosing of MF. Current NAEPP guidelines recommend low-dose ICS monotherapy for mild persistent asthma; thus, it is critical to optimize mild persistent asthma control and limit unnecessary resource use and charges.

BDNF regulation under GFAP promoter provides engineered astrocytes as a new approach for long-term protection in Huntington's disease.

Brain-derived neurotrophic factor (BDNF) is the main candidate for neuroprotective therapeutic strategies for Huntington's disease. However, the administration system and the control over the dosage are still important problems to be solved. Here we generated transgenic mice overexpressing BDNF under the promoter of the glial fibrillary acidic protein (GFAP) (pGFAP-BDNF mice). These mice are viable and have a normal phenotype. However, intrastriatal administration of quinolinate increased the number of reactive astrocytes and enhanced the release of BDNF in pGFAP-BDNF mice compared with wild-type mice. Coincidentally, pGFAP-BDNF mice are more resistant to quinolinate than wild-type mice, suggesting a protective effect of astrocyte-derived BDNF. To verify this, we next cultured astrocytes from pGFAP-BDNF and wild-type mice for grafting. Wild-type and pGFAP-BDNF-derived astrocytes behave similarly in nonlesioned mice. However, pGFAP-BDNF-derived astrocytes showed higher levels of BDNF and larger neuroprotective effects than the wild-type ones when quinolinate was injected 30 days after grafting. Interestingly, mice grafted with pGFAP-BDNF astrocytes showed important and sustained behavioral improvements over time after quinolinate administration as compared with mice grafted with wild-type astrocytes. These findings show that astrocytes engineered to release BDNF can constitute a therapeutic approach for Huntington's disease.

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway.

The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is cytotoxic primarily by inducing DNA monoadducts and ultimately, interstrand cross-links, which block DNA replication. In this study, we investigated the activation of the ATR-Chk1 pathway in response to BCNU treatment and the dependence of this response on the DNA mismatch repair (MMR) capacity. Medulloblastoma cells were exposed to low and moderate doses of BCNU, and the effects on this DNA damage signaling pathway were examined. In response to BCNU, Chk1 was found to be phosphorylated at serine 345 and exhibited increased kinase activity. Caffeine and wortmannin, which are broad-spectrum inhibitors of ATM and ATR, reduced this phosphorylation. Cell cycle analysis further revealed an accumulation of cells in the S phase in response to BCNU, an effect that was attenuated by caffeine. Small interfering RNA knockdown of ATR also reduced Chk1 phosphorylation after exposure to BCNU. However, knockdown of ATM had no effect on the observed Chk1 phosphorylation, suggesting that ATR was primarily responsible for Chk1 activation. Analysis of Chk1 activation in cells deficient in MMR proteins MutLalpha or MutSalpha indicated that the DNA damage response induced by BCNU was independent of the MMR apparatus. This MMR-independent activation seems to be the result of DNA interstrand cross-link formation.