Drug Development Clinical Trials Research Articles

Frequency and Predisposing Factors for Drug-Induced Hypoglycemia in Patients with Type-2 Diabetes Mellitus.

Objective:Hypoglycemia is the most common complication of the treatment for diabetes mellitus. Various factors predispose an individual for drug-induced hypoglycemia. The aim of this study was to explore the relative frequency and likely predisposing factors for drug-induced hypoglycemia among type-2 diabetic patients in the United Arab Emirates (UAE).Methods:In this cross-sectional survey-based study which was conducted from February to April 2018 in two local community pharmacies in the UAE, diabetic patients underwent a structured interview on their diabetes mellitus status and management and specific open-ended questions related to hypoglycemic symptoms that they might have experienced and the occurrence of symptoms. Collected data were used to estimate the relative frequency of drug-induced hypoglycemia and to identify the probable predisposing factors and their contribution in causing hypoglycemia using relative risk, Chi-square test, and Fisher's exact test.Findings:The relative frequency of drug-induced hypoglycemia in our study was 46.25%. Patients' age of ≥65 years, duration of diabetes mellitus for more than 1 year, patients with more than one comorbid condition, and patients using more than one antidiabetic medication were predisposing for developing drug-induced hypoglycemia.Conclusion:The relative frequency of drug-induced hypoglycemia in a nontrial environment which lacks the special cares routinely provided in drug development clinical trials is high. We suggest that more attention should be paid to identify, prevent, and manage drug-induced hypoglycemia in type-2 diabetic patients who have more than 1 year of diabetes, more than one comorbidity, using more than one antidiabetic medication, and elderly.

Accurate measurement of androgen after androgen esters: problems created by exvivo esterase effects and LC-MS/MS interference.

BackgroundEx vivo androgen prodrug conversion by blood esterases after oral androgen ester administration may result in an overestimation of the measured blood androgens.ObjectiveWe investigated whether blood collection tubes with esterase inhibitors decreased the conversion of testosterone undecanoate (TU) and dimethandrolone undecanoate (DMAU) to their active metabolites, testosterone (T), and dimethandrolone (DMA), providing a more accurate assessment of circulating T/DMA levels.MethodsBlood was collected in tubes with/without esterase inhibitors from: (i) four healthy and four hypogonadal men receiving no androgens and spiked ex vivo with TU/DMAU; (ii) four men taking oral TU (Andriol®); and (iii) eight hypogonadal men dosed with oral 316 mg TU and 15 healthy men with 200 mg DMAU. T/DMA levels were measured by LC‐MS/MS.ResultsSodium fluoride (NaF, an esterase inhibitor) decreased measured T levels by 14.2% in men not receiving TU. Increasing amounts of TU/DMAU added to blood collected into plain tubes resulted in a concentration‐dependent overestimation of T/DMA that was reduced by collecting blood into NaF tubes (by 30–85%), and keeping samples at 4 °C and minimizing time prior to centrifugation. After oral TU/DMAU administration to men, when TU/DMAU levels were >15/10 ng/mL, respectively, blood collected in NaF tubes yielded lower measured T concentrations by 15–30% and DMA by 22% due to an additional inhibitory effect of NaF on blood esterases.ConclusionNaF directly lowers plasma T/DMA levels measured by LC‐MS/MS and also inhibits blood esterase activity. Overestimation of T/DMA in blood collected in tubes without NaF after oral TU/DMAU administration is important for pharmacokinetics studies in drug development clinical trials but may have limited impact in clinical practice/utilization because the differences between measured and true androgen values are modest and the wide therapeutic androgen efficacy ranges obviate the need for highly accurate androgen measurements during therapy.

Utility of Integrated Analysis of Pharmacogenomics and Pharmacometabolomics in Early Phase Clinical Trial: A Case Study of a New Molecular Entity.

In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.

Optimal seamless phase 2/3 oncology trial designs based on Probability of Success (PoS).

In recent years, there has been an increasing trend in conducting seamless phase 2/3 clinical trials for drug development in the pharmaceutical industry due to the visible advantages compared with traditional approaches for separate phase 2 and 3 development. Innovative study designs have been proposed for seamless phase 2/3 trials, which mainly focus on the traditional aspects of study design, such as how to control the Type I error rate, sample size re-estimation after the phase 2 portion, and how to make treatment selection at the end of the phase 2 portion. However, there are still some questions unresolved such as how to determine the go/no-go boundary and how to plan the phase 2 portion sample size. In this paper, we discuss how to determine the phase 2 portion and phase 3 portion sample sizes as well as the corresponding go/no-go criteria for a seamless phase 2/3 oncology trial based on Probability of Success. In addition, we further expand the methodology to include designs with an interim look within the phase 2 portion to speed up the go/no-go decision-making process. In case of overwhelming efficacy, this design would further shorten the overall trial duration. In case of inefficacy, this design can stop the trial earlier without exposing more patients to inefficacious treatment.

Exploratory evaluation of a commercially available Japanese medical record database as an external control for comparative clinical trials in new drug development: Amyotrophic lateral sclerosis

AbstractClinical trials with internal control groups may not always be feasible, especially for rare diseases. We performed an exploratory evaluation of the Medical Data Vision Co., Ltd. (MDV) medical record database as an external control in clinical trials for drug development. Survival curves for amyotrophic lateral sclerosis (ALS) patients in the MDV database were compared with those for ALS patients in phase 3 trials of riluzole inside (1997) and outside (1996) Japan. Considering the time difference between MDV data collection (2008–2016) and riluzole trials (1996–1997), survival curves for ALS patients in the riluzole‐prescribed group in the MDV database and the placebo group in a celecoxib phase 3 trial (2006) in which 71% of patients received riluzole as first‐line treatment were also compared. The MDV database survival curves for the riluzole‐not prescribed and riluzole‐prescribed groups differed markedly from those for placebo groups and riluzole groups in two riluzole phase 3 trials. The survival curve for the placebo group in a celecoxib phase 3 trial was similar to that for the riluzole‐prescribed group in the MDV database until around 300 days after the start of observation. Our results were consistent with reports that patients diagnosed with ALS more recently survived longer and had slower disease progression than those diagnosed earlier. External comparative controls should consist of patient data collected in the same time period as when clinical trials were performed if the natural history of a disease is changing.

Alignment of parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple CEGIR sites

Patient-reported outcome metrics for eosinophilic esophagitis (EoE) have been developed and validated but not used in a multicenter pediatric population or systematically aligned with histology. We sought to understand (1) the potential of caregiver report to predict patient self-reported symptoms and (2) the correlation of patient-reported outcome domains with histology. Patients with EoE (n=310) and their parents participating in the Consortium of Gastrointestinal Eosinophilic Disease Researchers (CEGIR) observational clinical trial were queried for baseline patient symptoms and quality of life (QOL) by using the Pediatric Eosinophilic Esophagitis Symptom Score, version 2 (PEESSv2.0), and the Pediatric QOL EoE module (PedsQL-EoE), and biopsy specimens were analyzed by using the EoE Histology Scoring System. PEESSv2.0 parental and child reports aligned across all domains (r=0.68-0.73, P<.001). PedsQL-EoE reports correlated between parents and children across ages and multiple domains (r=0.48-0.79, P<.001). There was a tight correlation between symptoms on PEESSv2.0 and their effects on QOL both on self-report and parental report (P<.001). Self-reported symptoms on PEESSv2.0 (positively) and PedsQL-EoE (inversely) showed a weak correlation with proximal, but not distal, peak eosinophil counts and features and architectural tissue changes on the EoE Histology Scoring System (P<.05). Parents of children with EoE aged 3 to 18years accurately reflected their children's disease symptoms and QOL. Self- and parent-reported symptoms correlate with proximal esophageal histology. Our data suggest that parental report in young children can function as an adequate marker for self-reported symptoms and that self-reported symptoms can reflect changes in tissue histology in the proximal esophagus. These findings should be considered during clinical trials for drug development.

Integrating rare genetic variants into pharmacogenetic drug response predictions

BackgroundVariability in genes implicated in drug pharmacokinetics or drug response can modulate treatment efficacy or predispose to adverse drug reactions. Besides common genetic polymorphisms, recent sequencing projects revealed a plethora of rare genetic variants in genes encoding proteins involved in drug metabolism, transport, and response.ResultsTo understand the global importance of rare pharmacogenetic gene variants, we mapped the variability in 208 pharmacogenes by analyzing exome sequencing data from 60,706 unrelated individuals and estimated the importance of rare and common genetic variants using a computational prediction framework optimized for pharmacogenetic assessments. Our analyses reveal that rare pharmacogenetic variants were strongly enriched in mutations predicted to cause functional alterations. For more than half of the pharmacogenes, rare variants account for the entire genetic variability. Each individual harbored on average a total of 40.6 putatively functional variants, rare variants accounting for 10.8% of these. Overall, the contribution of rare variants was found to be highly gene- and drug-specific. Using warfarin, simvastatin, voriconazole, olanzapine, and irinotecan as examples, we conclude that rare genetic variants likely account for a substantial part of the unexplained inter-individual differences in drug metabolism phenotypes.ConclusionsCombined, our data reveal high gene and drug specificity in the contributions of rare variants. We provide a proof-of-concept on how this information can be utilized to pinpoint genes for which sequencing-based genotyping can add important information to predict drug response, which provides useful information for the design of clinical trials in drug development and the personalization of pharmacological treatment.

A review on bioactive secondary metabolites reported from actinomycetes isolated from marine soil samples of indian peninsula

The aim of this review is to give an update on actinobacteria derived bioactive secondary metabolites reported from Indian Peninsula. Several research groups in India are working on actinomycetes diversityand focusing more on antimicrobial, antiparasitic, anticancer activity and enzymes produced by these species. Several reports are available on multiple biological activitiesof culture filtrate/crude extracts obtained from actinomycetes isolates. Bioactivity guided extraction, purification andcompound identification has yielded several novel compounds. Scalable production of bioactive compounds from potential actinomycetes is under different phases of clinical trials for drug development as antibiotics worldwide. Currently actinomycetes research is more intense and more predominant not only in India but throughout the world due to its well-known ability to produce novel antibiotics and new chemical entities. The demand for new antibiotics from marine actinomycetes to overcome microbial drug resistance and to develop a new anticancer drug leads is ever persistent. Several novel antibiotics and anticancer metabolites are already been reported from actinomycetes in the recent past. In this review the bioactive compounds reported from marine actinomycetes species isolated from samples collected at various locations of Indian Peninsula has been reviewed.. The focus of the present review is to summarize the antimicrobial (antibacterial-ESBL, MRSA, VRE, antidermatophytic and anticandidal) and anticancer secondary metabolites reported from actinomycetes.

Psychometric validation of the SF-36 Health Survey in light chain amyloidosis: results from community-based and clinic-based samples.

BackgroundLight chain (AL) amyloidosis, a rare and life-threatening protein misfolding disorder, causes organ damage and severely impacts health-related quality of life (HRQoL). No patient-reported outcome (PRO) HRQoL measure has been validated for use in an AL amyloidosis patient population, leaving a gap for researchers conducting observational studies and clinical trials for drug development. The SF-36 Health Survey (SF-36) has been the most frequently used PRO in AL amyloidosis studies to date, and early qualitative validation studies support its use in this population. The aim of this study was to assess the psychometric properties of the SF-36 among patients with AL amyloidosis.MethodsData from community-based (n=341) and clinic-based (n=1,438) observational studies were used to document the psychometric properties of the SF-36 in this disease population. Reliability was estimated using internal consistency (Cronbach’s alpha) and test–retest reliability (intraclass correlation). Convergent validity, known-groups validity, and the ability to detect change were assessed with available criterion variables.ResultsScale reliability (Cronbach’s alpha ≥0.780 for all scores) and test–retest reliability (intraclass correlation coefficients ≥0.731 for all) were acceptable. Scale convergent validity was supported by strong correlations with conceptually related measures. Mean SF-36 scores varied by response to treatment (P<0.05 for all scores) and a self-reported measure of disease severity (P<0.001 for all scores). Data indicate that the SF-36 is sensitive to changes in other measures over time.ConclusionThis study provided clear and consistent evidence of the psychometric properties of the SF-36 in both community-based and clinic-based samples of patients with AL amyloidosis.

Predicting tuberculosis treatment outcome using metabolomics.

Predicting a poor treatment outcome would offer significant benefits for patient care and for new drug development. Materials, methods & results: Urine samples from tuberculosis-positive patients with a successful and unsuccessful treatment outcome were collected at baseline and analyzed. The identified metabolites were used in a forward logistic regression model, which achieved a receiver operating characteristic area under the curve of 0.94 (95%CI: 0.84-1) and cross-validated well in a leave-one-out context, with an area under the curve of 0.89 (95%CI: 0.7-1). Two possible predictors were identified, which are associated with a gut microbiota imbalance. Our findings show the capacity of metabolomics to predict treatment failure at the time of diagnosis, which potentially offers significant benefits for the use in new drug development clinical trials and individualized patient care.

The clinical utility of circulating tumour cells in patients with small cell lung cancer.

Small cell lung cancer (SCLC) accounts for 15% of lung cancer diagnosed worldwide. It is aggressive and characterised by early metastatic spread with rapid development of chemo resistance such that less than 5% of patients diagnosed survive 5 years. Surgery is rarely performed and failure to identify new effective treatments has been attributed in a large part to lack of good quality tumour biopsies available for translational research. Liquid biopsies provide a minimally invasive alternative to traditional tumour biopsy. Circulating tumour cells (CTCs) are abundant in SCLC and can be enriched and isolated from a venous blood sample. In recent years progress has been made into the molecular characterisation of CTCs and their use to form tumour xenografts in mice for preclinical studies. This review will discuss the current status of the clinical utility of CTCs in patients with SCLC, highlighting their potential application to treatment decision making, drug development in clinical trials and preclinical testing.

Analysis of anticoagulants for blood-based quantitation of amyloid β oligomers in the sFIDA assay.

Early diagnostics at the preclinical stage of Alzheimer's disease is of utmost importance for drug development in clinical trials and prognostic guidance. Since soluble Aβ oligomers are considered to play a crucial role in the disease pathogenesis, several methods aim to quantify Aβ oligomers in body fluids such as cerebrospinal fluid (CSF) and blood plasma. The highly specific and sensitive method surface-based fluorescence intensity distribution analysis (sFIDA) has successfully been established for oligomer quantitation in CSF samples. In our study, we explored the sFIDA method for quantitative measurements of synthetic Aβ particles in blood plasma. For this purpose, EDTA-, citrate- and heparin-treated blood plasma samples from five individual donors were spiked with Aβ coated silica nanoparticles (Aβ-SiNaPs) and were applied to the sFIDA assay. Based on the assay parameters linearity, coefficient of variation and limit of detection, we found that EDTA plasma yields the most suitable parameter values for quantitation of Aβ oligomers in sFIDA assay with a limit of detection of 16 fM.

Are We Ready to Abandon Placebo in Randomised Clinical Trials for Inflammatory Bowel Disease? Pros and Cons.

The role of placebo in clinical trials for drug development in inflammatory bowel disease [IBD] was the topic of a panel discussion held during the 10th Congress of the European Crohn's and Colitis Organisation [ECCO], in Barcelona, Spain, in 2015. Panellists discussed a number of issues around placebo-controlled trials in IBD, noting issues such as difficulties with recruitment, leading to less then representative patient populations in clinical studies. It was noted that, whereas the easiest answer may be to drop placebo, it is much more complicated than that. The relevance of placebo is affected by a number of factors, including the phase of the trial, as well as the nature of the drug. In most cases where placebo has been left out in drug development, it has been for trials involving a new formulation, a new dosing schedule, or a biosimilar, for example. The panel agreed that placebo-controlled trials are of particular importance early in the development programme, perhaps not so much in phase III, although placebo is important for monitoring safety. The current trial paradigm, in which patients remain on a plethora of, likely ineffective and toxic, background medication, was also questioned. The applicability of placebo in the paediatric population was also discussed. The overall consensus from this panel discussion was that placebo is still necessary in clinical trials in inflammatory bowel disease, but there remain questions as to how and when placebo should be used.

Adequacy of Using Consensus Guidelines for Diagnosis of Dementia with Lewy Bodies in Clinical Trials for Drug Development

Background/Aims: To evaluate the adequacy of using the consensus diagnostic criteria for dementia with Lewy bodies (DLB) to recruit patients with homogeneous characteristics in future clinical trials, where multiple departments of multinational centres are expected to participate with a long enrolment period, and additionally, to contribute to the possible future criteria revision. Methods: Using data from 2 trials of donepezil for DLB, conducted 3 years apart, characteristics in patients with probable DLB were analysed and compared between studies and between psychiatric and neurological centres. Results: In 273 patients (phase II: 135, phase III: 138; psychiatric: 73, neurological: 184), clinical characteristics overall were very similar between studies, and between specialty centres, excluding distinctive parkinsonism in the neurological versus psychiatric centres: incidence of parkinsonism (91.8 vs. 71.2%, p < 0.001), Hoehn and Yahr stage (III: 55.0 vs. 21.2%, p < 0.001), and concomitant anti-Parkinson medication (24.5 vs. 11.0%, p = 0.017). Rapid eye movement sleep behaviour disorder, depression, and delusion, suggestive or supportive features, were observed in 35-40%. Additionally, a high prevalence (55.3%) of anxiety was observed. Conclusion: Employing the consensus criteria is adequate to enrol homogeneous DLB patients into future clinical trials regardless of the specialty of centres and time. Further discussion could involve adding anxiety to future criteria.

Dose-Finding Trials: Optimizing Phase 2 Data in the Drug Development Process.

Clinical trials in drug development are commonly divided into 3 categories or phases. The first phase aims to find the range of doses of potential clinical use, usually by identifying the maximum tolerated dose. The second phase aims to find doses that demonstrate promising efficacy with acceptable safety. The third phase aims to confirm the benefit previously found in the second phase using clinically meaningful end points and to demonstrate safety more definitively. Dose-finding trials—studies conducted to identify the most promising doses or doses to use in later studies—are a key part of the second phase and are intended to answer the dual questions of whether future development is warranted and what dose or doses should be used. If too high a dose is chosen, adverse effects in later confirmatory phase 3 trials may threaten the development program. If too low a dose is chosen, the treatment effect may be too small to yield a positive confirmatory trial and gain approval from a regulatory agency. A well-designed dose-finding trial is able to establish the optimal dose of a medication and facilitate the decision to proceed with a phase 3 trial. Selection of a dose for further testing requires an understanding of the relationships between dose and both efficacy and safety. These relationships can be assessed by comparing the data from each dose group with placebo, or with the other doses, in a series of pairwise comparisons. This approach is prone to both false-negative and false-positive results because of the large number of statistical comparisons and the relatively small number of patients receiving each dose. These risks can be mitigated by combining data from patients receiving multiple active doses into a single treatment group for comparison with placebo (“pooling”), but only if it is possible to reliably predict which doses are likely to be effective. In general, dose-response relationships are best examined through dose-response models that make flexible, justifiable assumptions about the potential dose-response relationships and allow the integration of information from all doses used in the trial. This can reduce the risk of both false-negative and false-positive results; incorporating all data into the estimates of efficacy and safety for each dose produces more accurate estimates than evaluating the response to each dose separately. In this issue of JAMA, Gheorghiade et al 1 report the results of

The genetic landscape of Alzheimer disease: clinical implications and perspectives.

The search for the genetic factors contributing to Alzheimer disease (AD) has evolved tremendously throughout the years. It started from the discovery of fully penetrant mutations in Amyloid precursor protein, Presenilin 1, and Presenilin 2 as a cause of autosomal dominant AD, the identification of the ɛ4 allele of Apolipoprotein E as a strong genetic risk factor for both early-onset and late-onset AD, and evolved to the more recent detection of at least 21 additional genetic risk loci for the genetically complex form of AD emerging from genome-wide association studies and massive parallel resequencing efforts. These advances in AD genetics are positioned in light of the current endeavor directing toward translational research and personalized treatment of AD. We discuss the current state of the art of AD genetics and address the implications and relevance of AD genetics in clinical diagnosis and risk prediction, distinguishing between monogenic and multifactorial AD. Furthermore, the potential and current limitations of molecular reclassification of AD to streamline clinical trials in drug development and biomarker studies are addressed.Genet Med 18 5, 421–430.

Multiplicity in confirmatory clinical trials: a case study with discussion from a JSM panel.

An invited panel session was conducted in the 2012 Joint Statistical Meetings, San Diego, California, USA, to stimulate the discussion on multiplicity issues in confirmatory clinical trials for drug development. A total of 11 expert panel members were invited and 9 participated. Prior to the session, a case study was previously provided to the panel members to facilitate the discussion, focusing on the key components of the study design and multiplicity. The Phase 3 development program for this new experimental treatment was based on a single randomized controlled trial alone. Each panelist was asked to clarify if he or she responded as if he or she were a pharmaceutical drug sponsor, an academic panelist or a health regulatory scientist.

Clinical trials in drug development: the Brazilian experience

Clinical research in Brazil today can be seen in three distinct areas. In the first, still acting shy and with few resources, the research is funded through government agencies that seek the understanding of some diseases or peculiar conditions in the country. These include neglected diseases still endemic in Brazil that do not interest large international industries. In the second area, funded with abundant resources coming from international pharmaceutical industries, research studies are carried out to evaluate the efficacy and safety of drugs in multicenter trials. The third area, new in the country, is the clinical research of bioavailability and bioequivalence of drugs that emerged due to the need for assessing the quality of generic drugs, which was funded in part with public funds and in part with funds from national pharmaceutical industries. Although there are criticisms to all three, they have contributed to boosting clinical research in the country. At the moment, it is necessary to use a policy to guide their future directions and coordinate the actions of groups that have academic competence and are already working traditionally in the sector, avoiding the opportunism that often takes place. It is always important to keep in mind that clinical research is not done only by dilettantism or on behalf of scientific knowledge. This research involves humans and therefore it should be conducted in compliance with ethical principles of autonomy, beneficence, non-maleficence, justice and equity, concerning the participation of the research subject and the social relevance of their results. It should also be considered that the research carried out in Brazil by major international pharmaceutical conglomerates had the merit of introducing the country to the international circuit of multicenter clinical research, to emphasize the quality of our scientists in academia and to introduce new research protocols. However, neither the design of these experiment nor the elaboration of protocols and even the management of the experiments were in charge of our research groups. When they are not the responsibility of the industry itself, they are outsourced to international CROs (Contract Research Organizations), leaving the Brazilian researcher only in an operational role. In another scenario we find domestic industries that are still groping in drug research and development. However, some have begun to realize the impossibility of surviving in the market doing just similar and generic drugs. Therefore, it is necessary that our clinical research is prepared to support the national pharmaceutical industry that invests in the development of new drugs, and do so with the same competence displayed in the quality control of generic medications. Furthermore, it is of critical importance that clinical research is also prepared to assist public and private institutions in obtaining information regarding the diseases prevalent in the population.

Abstract 2058: Molecular imaging of glutaminolysis as a tool for evaluating therapeutic response in preclinical models of colorectal cancer

Abstract The metabolic repertoire of cancer cells diverge significantly from that of normal cells. Energy production in cancer cells tends to depend on aerobic glycolysis, a feature that is routinely monitored by positron emission tomography (PET) imaging using 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG). In addition to predilection for glycolysis, cancer cells may possess other unique metabolic characteristics, such as increased consumption of glutamine. As with glucose, glutamine also serves as a key carbon source for ATP production and biosynthesis. Given this, quantitative measures of glutaminolysis may reflect critical processes in oncology. Accordingly, PET agents targeting glutamine uptake, such as 4-[18F]fluoro-glutamine ([18F]4F-GLN), have been reported and used in preclinical models of cancer. The goal of this study was to elucidate the feasibility of using [18F]4F-GLN PET to predict response to targeted therapy within the context of colorectal cancer (CRC). Initially we validated expression of SLC1A5, the primary plasma membrane transporter of glutamine, in tumor and normal colon specimens for 58 patients with primary and advanced CRC. We found that SLC1A5 expression was elevated in over 80%of primary tumor specimens but did not correlate with grade or gender. Furthermore, elevated SLC1A5 expression correlated strongly with elevated Ki67, a molecular marker of proliferation. Given this, we evaluated [18F]4F-GLN PET in preclinical models of V600EBRAF-expressing CRC as a means of detecting anti-proliferation responses to targeted therapeutics. Simulating a clinical study within the context of the Vanderbilt GI SPORE, the regimen included an inhibitor of mutant BRAF, a PI3K/mTOR inhibitor, and a combination there of. Strikingly, [18F]4F-GLN PET was found to correlate more closely to markers of anti-proliferative responses in vivo than analogously performed [18F]FDG PET imaging studies. We believe that these findings not only provide a greater understanding of the role that glutaminolysis plays in CRC but also illuminate the potential impact that glutaminolysis derived PET could have towards guiding drug development clinical trials as an imaging metric of early therapeutic response detection. Citation Format: Matthew R. Hight, Michael L. Schulte, Samir Saleh, Gregory D. Ayers, Frank L. Revetta, M. Kay Washington, Robert J. Coffey, H. Charles Manning. Molecular imaging of glutaminolysis as a tool for evaluating therapeutic response in preclinical models of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2058. doi:10.1158/1538-7445.AM2014-2058

Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria

Background: Current research criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable.Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD.Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD.Eligibility criteria: (1a) Systematic reviews with meta-analysis; (1b) Primary studies published after the new revised diagnostic criteria; (2) Evaluation of the diagnostic performance of at least one CSF core biomarker.Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for mild cognitive impairment (MCI) prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia.Limitations: (1) Use of clinical diagnosis as standard instead of pathological postmortem confirmation; (2) variability of methodological aspects; (3) insufficiently long follow-up periods in MCI studies; and (4) lower diagnostic accuracy in primary care compared with memory clinics.Conclusion: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development.