Anh Tran

Phase II Study of Bevacizumab Plus Temozolomide During and After Radiation Therapy for Patients With Newly Diagnosed Glioblastoma Multiforme

PURPOSE This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity. PATIENTS AND METHODS Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison. RESULTS The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials. CONCLUSION Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.

Combined analysis of O6-methylguanine-DNA methyltransferase protein expression and promoter methylation provides optimized prognostication of glioblastoma outcome

BACKGROUND Promoter methylation of the DNA repair gene, O-6-methylguanine-DNA methyltransferase (MGMT), is associated with improved treatment outcome for newly diagnosed glioblastoma (GBM) treated with standard chemoradiation. To determine the prognostic significance of MGMT protein expression as assessed by immunohistochemistry (IHC) and its relationship with methylation, we analyzed MGMT expression and promoter methylation with survival in a retrospective patient cohort. METHODS We identified 418 patients with newly diagnosed GBM at University of California Los Angeles Kaiser Permanente Los Angeles, nearly all of whom received chemoradiation, and determined MGMT expression by IHC, and MGMT promoter methylation by methylation-specific PCR (MSP) and bisulfite sequencing (BiSEQ) of 24 neighboring CpG sites. RESULTS With use of the median percentage of cells staining by IHC as the threshold, patients with <30% staining had progression-free survival (PFS) of 10.9 months and overall survival (OS) of 20.5 months, compared with PFS of 7.8 months (P < .0001) and OS of 16.7 months (P < .0001) among patients with ≥30% staining. Inter- and intrareader correlation of IHC staining was high. Promoter methylation status by MSP was correlated with IHC staining. However, low IHC staining was frequently observed in the absence of promoter methylation. Increased methylation density determined by BiSEQ correlated with both decreased IHC staining and increased survival, providing a practical semiquantitative alternative to MSP. On the basis of multivariate analysis validated by bootstrap analysis, patients with tandem promoter methylation and low expression demonstrated improved OS and PFS, compared with the other combinations. CONCLUSIONS Optimal assessment of MGMT status as a prognostic biomarker for patients with newly diagnosed GBM treated with chemoradiation requires determination of both promoter methylation and IHC protein expression.

Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.

The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.

Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase (GlmU)

Peptidoglycan is an essential component of the cell wall of bacteria, including Mycobacterium tuberculosis, that provides structural strength and rigidity to enable internal osmotic pressure to be withstood. The first committed step in the biosynthesis of peptidoglycan involves the formation of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) from uridine triphosphate (UTP) and GlcNAc-1-phosphate. This reaction is catalysed by N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme with two independent active sites that possess acetyltransferase and uridyltransferase activities. Herein, we report the first inhibition study targeted against the uridyltransferase activity of M. tuberculosis GlmU. A number of potential inhibitors were initially prepared leading to the discovery of active aminoquinazoline-based compounds. The most potent inhibitor in this series exhibited an IC50 of 74 μM against GlmU uridyltransferase activity and serves as a promising starting point for the discovery of more potent inhibitors.

Rapid assembly of potent type II dehydroquinase inhibitors via “Click” chemistry

The rapid synthesis of a library of potent type II dehydroquinase inhibitors is described. Inhibitors were prepared via a key quinate-derived ene-yne intermediate using Cu(I)-catalysed azide-alkyne cycloaddition (CuAAC) chemistry with a variety of aryl- and heteroaryl-azides.

Elucidation of Mycobacterium tuberculosis type II dehydroquinase inhibitors using a fragment elaboration strategy.

A library of novel Mycobacterium tuberculosis type II dehydroquinase (DHQase) inhibitors were discovered through the use of a fragment elaboration approach. Putative active site binding fragments were initially assessed in silico which led to the selection of two small aromatic fragments for further investigation. Synthetic elaboration of the fragments provided a library of 34 inhibitors that exhibited low‐micromolar inhibition of type II DHQase. A number of these inhibitors also showed antibacterial activity in the low‐micromolar range in screens against M. tuberculosis in vitro; these now serve as lead compounds for further development of therapeutics for the treatment of tuberculosis.

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

Synthesis and evaluation of potent ene-yne inhibitors of type II dehydroquinases as tuberculosis drug leads.

E-9: You sunk my battleship! Potent ene-yne-based inhibitors of typeII dehydroquinase are described. The majority of the compounds exhibited nanomolar inhibition of the Streptomyces coelicolor, Helicobacter pylori and Mycobacterium tuberculosis typeII dehydroquinases. The inhibitors also possessed moderate activity against the growth of M.tuberculosis in vitro.

Systematic Review of the Costs and Benefits of Prescribed Cannabis-Based Medicines for the Management of Chronic Illness: Lessons from Multiple Sclerosis

IntroductionCannabis-based medicines (CBMs) may offer relief from symptoms of disease; however, their additional cost needs to be considered alongside their effectiveness. We sought to review the economic costs and benefits of prescribed CBMs in any chronic illness, and the frameworks used for their economic evaluation.MethodsA systematic review of eight medical and economic databases, from inception to mid-December 2016, was undertaken. MeSH headings and text words relating to economic costs and benefits, and CBMs were combined. Study quality was assessed using relevant checklists and results were synthesised in narrative form.ResultsOf 2514 identified records, ten studies met the eligibility criteria, all for the management of multiple sclerosis (MS). Six contained economic evaluations, four studies reported utility-based quality of life, and one was a willingness-to-pay study. Four of five industry-sponsored cost–utility analyses for MS spasticity reported nabiximols as being cost-effective from a European health system perspective. Incremental cost-effectiveness ratios per quality-adjusted life-year (QALY) gained for these five studies were £49,257 (UK); £10,891 (Wales); €11,214 (Germany); €4968 (Italy); and dominant (Spain). Nabiximols for the management of MS spasticity was not associated with statistically significant improvements in EQ-5D scores compared with standard care. Study quality was moderate overall, with limited inclusion of both relevant societal costs and discussions of potential bias.ConclusionsPrescribed CBMs are a potentially cost-effective add-on treatment for MS spasticity; however, this evidence is uncertain. Further investment in randomised trials with in-built economic evaluations is warranted for a wider range of clinical indications.Systematic review registrationPROSPERO Registration Number: CRD42014006370.

Interventions to Improve Vaccination Uptake and Cost Effectiveness of Vaccination Strategies in Newly Arrived Migrants in the EU/EEA: A Systematic Review

Newly arrived migrants to the EU/EEA (arrival within the past five years), as well as other migrant groups in the region, might be under-immunised and lack documentation of previous vaccinations, putting them at increased risk of vaccine-preventable diseases circulating in Europe. We therefore performed a systematic review conforming to PRISMA guidelines (PROSPERO CRD42016045798) to explore: (i) interventions that improve vaccine uptake among migrants; and (ii) cost-effectiveness of vaccination strategies among this population. We searched MEDLINE, Embase, CINAHL, and Cochrane Database of Systematic Reviews (CDSR) between 1 January 2006 to 18 June 2018. We included three primary intervention studies performed in the EU/EEA or high-income countries and one cost effectiveness study relevant to vaccinations in migrants. Intervention studies showed small but promising impact only on vaccine uptake with social mobilization/community outreach, planned vaccination programs and education campaigns. Targeting migrants for catch-up vaccination is cost effective for presumptive vaccination for diphtheria, tetanus, and polio, and there was no evidence of benefit of carrying out pre-vaccination serological testing. The cost-effectiveness is sensitive to the seroprevalence and adherence to vaccinations of the migrant. We conclude that scarce but direct EU/EEA data suggest social mobilization, vaccine programs, and education campaigns are promising strategies for migrants, but more research is needed. Research should also study cost effectiveness of strategies. Vaccination of migrants should continue to be a public heath priority in EU/EEA.