Clinical Utility Studies Research Articles

Counterpoint: Risk factors, including genetic information, add value in stratifying patients for optimal preventive dental care

BackgroundThere is disagreement as to whether patient stratification by a combination of diabetes, smoking, and genetic test results is useful for informing the frequency of dental prophylaxes. MethodsThe authors appeal to basic tenets of clinical study design and statistical analysis of clinical investigations, and highlight how secondary ad hoc analyses, such as those of Diehl and colleagues, are frequently underpowered and inconclusive. They also provide evidence from numerous studies supporting the use of genetics to identify risk. ResultsThe authors believe the conclusions reached from their original analyses are valid and the analyses of Diehl and colleagues serve to simply reinforce the authors' specific intent of avoiding such underpowered analyses altogether with the Michigan Personalized Prevention Study. ConclusionsUntil full genome sequencing in many people with highly specified disease phenotypes is feasible, experimental approaches based on biological findings and hypothesis testing should not be summarily discounted. Practical ImplicationsStratification of patients to provide “personalized” treatment remains an important, yet elusive, goal. The current debate serves to highlight the need for large, clinical utility studies that can adequately determine how phenotypic and genotypic data can be best used to improve oral health in the US population.

A call for accurate pharmacogenetic labeling: telling it like it is.

A call for accurate pharmacogenetic labeling: telling it like it is.

The 12-gene colon cancer assay validation and utility: Summary of clinical evidence.

523 Background: The 12-gene colon cancer assay is the first commercially available molecular assay to predict the risk of recurrence in stage II/III colon and rectal cancer. Rigorous evidence for clinical validity and utility of an assay is imperative since the result is used for treatment decision-making. This summary outlines the studies that meet an established definition of clinical validation and additional studies that support the utility of the assay. Methods: Prospectively designed studies using archival tissue with pre-specified methods, clinical outcomes, and analysis plan were considered clinical validation studies (Simon et al. JNCI 2009). Additional studies that demonstrated the utility of the assay in a clinical setting were considered supportive. Results: The assay has been clinically validated in four independent studies with 3315 patients (2390 stage II/628 stage III colon and 130 stage II/167 stage III rectal). All four studies demonstrated a significant association (p<0.05) between the result and outcome (e.g. recurrence risk and cancer specific survival). The score was examined in the context of other variables, including T and N stage, MMR status, number of nodes examined, lymphovascular invasion, and tumor grade; across all studies, the result consistently contributed to risk stratification beyond these variables. Three clinical utility studies with 502 patients showed that 29-45% of initial treatment recommendations in stage IIA colon cancer were changed, with a net reduction in use of adjuvant chemotherapy. Conclusions: Clinical validation of the 12-gene assay followed a now-standard approach of using archived tissue from multiple large, prospectively-designed studies with documented long-term outcomes; the 12-gene colon assay meets level IB evidence criteria. Subsequent studies showed the assay has impact on clinical practice. The underlying tumor biology assessed by the score is relevant in both colon (stage II and III) and rectal cancer, providing information beyond conventional features, and can help guide treatment decisions regarding adjuvant chemotherapy.

Prevalence of the HOXB13 G84E Mutation Among Unaffected Men with a Family History of Prostate Cancer

HOXB13 (G84E) was reported to significantly increase risk for prostate cancer. The goal of the current analysis was to assess the prevalence of G84E in ethnically-diverse high-risk men undergoing prostate cancer screening and place the carrier frequency within the context of prevalence estimates from reported studies to gain insight into the future role of this mutation in genetic counseling. PRAP is a prostate cancer screening program for unaffected men ages 35-69 with a family history of prostate cancer or African descent. HOXB13 G84E was genotyped by pyrosequencing in 649 PRAP participants with available DNA. Prevalence of the mutation was calculated for PRAP and for reported studies and exact binomial confidence intervals were generated. Prevalence of the G84E mutation in non-African PRAP men was 0.73%. When placed in context of the literature, this was higher than reported controls. One G84E mutation carrier was notably of Hispanic background. While the HOXB13 G84E mutation may be rare, there may be a future role in genetic testing for this mutation after further studies of clinical utility in assessing prostate cancer risk.

Analytical and clinical evaluation of biomarkers assays: When are biomarkers ready for prime time?

Biomarker assays can be evaluated for analytical performance (ability of assay to measure the biomarker quantity) and clinical performance (ability of assay result to inform of the clinical condition of interest). Additionally, a biomarker assay is said to have clinical utility if it ultimately improves patient outcomes when used as intended. This article reviews analytical and clinical performance studies of biomarker assay tests and also some designs of clinical utility studies. Appropriate design and statistical analysis of analytical and clinical evaluation studies depend on the intended clinical use of the test. Some key aspects to valid performance studies include using subjects who are independent of those used to develop the test, masking users of the test to any other available test or reference results, and including in the primary statistical analysis subjects with unavailable results in an intention-to-diagnose analysis. Ingenuity in study design and analysis may be required for efficient and unbiased estimation of performance. Performance studies need to be carefully planned as they can be prone to many sources of bias. Analytical inaccuracy can hamper the clinical performance of biomarkers. As biomedical research and technology advance, challenges in study design and statistical analysis will continue to emerge for analytical and clinical performance studies of biomarker assays. Although not emphasized in some circles, the analytical performance of a biomarker assay is important to characterize. Analytical performance studies have many study design and statistical analysis challenges that deserve further attention.

Abstract 59: Identifying tumor driving signaling pathways for companion diagnostics using computational pathway models.

Abstract Introduction Targeted drug treatment requires reliable companion diagnostics for therapy selection. Genomic and transcriptomic data can provide input for this, provided tools exist to convert this complex data into meaningful clinical information. We develop computational models of oncogenic pathways, to assess which one drives tumor growth in an individual patient and what is the causing (epi)genetic defect. Computational pathway models Based on a selection of experimentally validated direct target genes, we built initial models of the Wnt, ER, AR and Hedgehog pathways, covering their transcriptional program. We have modeled each pathway by a Bayesian network, which interprets the target genes’ mRNA levels (Affymetrix U133Plus2.0), and infers a probability that the respective pathway is active in a certain sample. Model parameters are based on literature insights and experimental data. Results A first Wnt model, calibrated on cell line data, validated perfectly on 32 normal colon samples and 32 colon adenomas from patients (GSE8671). A second Wnt model, calibrated on these 64 patient samples, correctly predicted no Wnt activity in all 44 normal colon samples, and Wnt activity in 97 of 101 colon cancer samples from GSE20916. Next, we tested the second Wnt model on other cancer types. On 25 breast cancer cell lines from GSE12777 with known Wnt status, the model correctly identified the two samples with an active pathway. On two patient data sets (GSE12276, n=204; GSE21653, n=266) Wnt activity was predicted in a higher number of basal samples compared to other subtypes (p=0.021 and p=2.7e-5, respectively), in line with increasing evidence for Wnt activity in this subtype. Finally, tests on liver (GSE9843, GSE6764) and medulloblastoma sets (GSE10327) confirm the power of these models to predict Wnt pathway activity. A first ER model was calibrated on estrogen-deprived and -stimulated MCF7 cell lines (GSE8697). Applied on breast cancer cell line data from GSE21618, increased incidence of ER pathway activity was found in tamoxifen-sensitive cell lines compared to resistant ones. On breast cancer patient data (GSE12276, GSE9195, GSE6532) the model showed no pathway activity in ER- samples, and an active ER pathway in 26-38% of the ER+ samples. Within the latter group, model-predicted ER activity correlated with improved survival. Clinical utility studies to correlate ER activity to hormone therapy response are in progress. Finally, the AR model showed promising results on prostate cancer cell lines (GSE34211, GSE36133), as did the Hedgehog model on medulloblastoma samples (GSE10327). Conclusion Our computational pathway models predict functional activity of oncogenic pathways for an individual patient based on mRNA data, complementary to existing molecular and histopathology staining tests. Clinical utility for therapy response prediction is currently being validated with clinical partners. Citation Format: Wim Verhaegh, Henk van Ooijen, Marcia Alves de Inda, Kalyan Dulla, Ralf Hoffmann, Dianne van Strijp, Pantelis Hatzis, Hans Clevers, Anja van de Stolpe. Identifying tumor driving signaling pathways for companion diagnostics using computational pathway models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 59. doi:10.1158/1538-7445.AM2013-59

Amyloid PET in clinical practice: Its place in the multidimensional space of Alzheimer's disease

Amyloid imaging is currently introduced to the market for clinical use. We will review the evidence demonstrating that the different amyloid PET ligands that are currently available are valid biomarkers for Alzheimer-related β amyloidosis. Based on recent findings from cross-sectional and longitudinal imaging studies using different modalities, we will incorporate amyloid imaging into a multidimensional model of Alzheimer's disease. Aside from the critical role in improving clinical trial design for amyloid-lowering drugs, we will also propose a tentative algorithm for when it may be useful in a memory clinic environment. Gaps in our evidence-based knowledge of the added value of amyloid imaging in a clinical context will be identified and will need to be addressed by dedicated studies of clinical utility.

Abstract P2-10-02: Clinical validation of the PAM50 risk of recurrence (ROR) score for predicting residual risk of distant-recurrence (DR) after endocrine therapy in postmenopausal women with ER+ early breast cancer (EBC): An ABCSG study

Abstract Aim: To assess the performance of the ROR score in predicting DR for postmenopausal patients with ER+ EBC treated with tamoxifen or tamoxifen followed by anastrozole when the PAM50 test is performed in a routine hospital pathology laboratory. Background: The multi-analyte gene-expression tests (Oncotype DX, MammaPrint) that are currently used in clinical practice to assess prognosis after endocrine therapy in primary ER+ breast cancer are performed in a central referral laboratory. PAM50 is a 50-gene test in development that is designed to be performed in local routine hospital pathology laboratories and has been optimized to separate intrinsic disease subtypes which are used to generate a ROR score. This ROR score has been clinically validated and demonstrated to contain more prognostic information than Oncotype Dx RS in the TransATAC patient population (Dowsett, SABCS, 2011). Methods: 1,251 women from the prospective randomized ABCSG-8 trial were entered into this study: the entry criteria were the availability of their FPET block and informed consent. Three unstained 10 micron sections and 1 H&E slide for each patient were sent to an independent academic pathology laboratory at BCCA where tissue review, manual micro-dissection and RNA extraction were performed. PAM50 analysis was then conducted on 250 ng of the extracted RNA using the NanoString nCounter® technology: both intrinsic subtype and ROR score were calculated. The median follow up of the patients entered into this study is 10 years. 912 are node negative and 339 are node positive. The baseline characteristics of the patients entered showed them to be a representative sample of the overall ABCSG-8 trial population. The primary analysis is designed to test whether the continuous ROR score adds prognostic value over and above the standard clinical variables, using a likelihood ratio test. Results: Results are currently being derived and will be presented in full at SABCS. Discussion: This large clinical trial serves both as a clinical validation study of the PAM 50 test and as a demonstration that a complex multi-analyte gene-expression test can be performed in a routine hospital pathology laboratory while meeting the same quality metrics as a central referral laboratory. The results of the primary analysis, when combined with the results already reported from the Trans ATAC population, yield Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC and form the basis of the design of the clinical utility studies of the PAM 50 test. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-02.

Analytical performance validation of a coronary heart disease risk assessment multi-analyte proteomic test

Coronary heart disease (CHD) remains prevalent despite efforts to improve CHD risk assessment. The authors developed a multi-analyte immunoassay-based CHD risk assessment (CHDRA) algorithm, clinically validated in a multicenter study, to improve CHDRA in intermediate risk individuals. Clinical laboratory validation of the CHDRA biomarker assays' analytical performance. Multiplexed immunoassay panels developed for the seven CHDRA assays were evaluated with donor sera in a clinical laboratory. Specificity, sensitivity, interfering substances and reproducibility of the CHDRA assays, along with the effects of pre-analytical specimen processing, were evaluated. Analytical measurements of the CHDRA panel proteins (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3 and sFas) exhibited acceptable accuracy (80 - 120%), cross-reactivity (< 1%), interference (< 30% at high concentrations of bilirubin, lipids, hemoglobin and HAMA), sensitivity and reproducibility (< 20% CV across multiple runs, operators and instruments). Recoveries from donor sera subjected to typical clinical laboratory pre-analytical conditions were within 80 - 120%. The pre-analytical variables did not substantively impact the CHDRA scores. The CHDRA panel analytical validation in a clinical laboratory meets or exceeds the specifications established during the clinical utility studies. Risk score reproducibility across multiple test scenarios suggests the assays are not susceptible to clinical laboratory pre-analytical and analytical variation.

Conversion of a molecular classifier obtained by gene expression profiling into a classifier based on real-time PCR: a prognosis predictor for gliomas

BackgroundThe advent of gene expression profiling was expected to dramatically improve cancer diagnosis. However, despite intensive efforts and several successful examples, the development of profile-based diagnostic systems remains a difficult task. In the present work, we established a method to convert molecular classifiers based on adaptor-tagged competitive PCR (ATAC-PCR) (with a data format that is similar to that of microarrays) into classifiers based on real-time PCR.MethodsPreviously, we constructed a prognosis predictor for glioma using gene expression data obtained by ATAC-PCR, a high-throughput reverse-transcription PCR technique. The analysis of gene expression data obtained by ATAC-PCR is similar to the analysis of data from two-colour microarrays. The prognosis predictor was a linear classifier based on the first principal component (PC1) score, a weighted summation of the expression values of 58 genes. In the present study, we employed the delta-delta Ct method for measurement by real-time PCR. The predictor was converted to a Ct value-based predictor using linear regression.ResultsWe selected UBL5 as the reference gene from the group of genes with expression patterns that were most similar to the median expression level from the previous profiling study. The number of diagnostic genes was reduced to 27 without affecting the performance of the prognosis predictor. PC1 scores calculated from the data obtained by real-time PCR showed a high linear correlation (r = 0.94) with those obtained by ATAC-PCR. The correlation for individual gene expression patterns (r = 0.43 to 0.91) was smaller than for PC1 scores, suggesting that errors of measurement were likely cancelled out during the weighted summation of the expression values. The classification of a test set (n = 36) by the new predictor was more accurate than histopathological diagnosis (log rank p-values, 0.023 and 0.137, respectively) for predicting prognosis.ConclusionWe successfully converted a molecular classifier obtained by ATAC-PCR into a Ct value-based predictor. Our conversion procedure should also be applicable to linear classifiers obtained from microarray data. Because errors in measurement are likely to be cancelled out during the calculation, the conversion of individual gene expression is not an appropriate procedure. The predictor for gliomas is still in the preliminary stages of development and needs analytical clinical validation and clinical utility studies.

The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation

To determine whether testing for cytochrome P450 (CYP) polymorphisms in adults entering antipsychotic treatment for schizophrenia leads to improvement in outcomes, is useful in medical, personal or public health decision-making, and is a cost-effective use of health-care resources. The following electronic databases were searched for relevant published literature: Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Technology Assessment database, ISI Web of Knowledge, MEDLINE, PsycINFO, NHS Economic Evaluation Database, Health Economic Evaluation Database, Cost-effectiveness Analysis (CEA) Registry and the Centre for Health Economics website. In addition, publicly available information on various genotyping tests was sought from the internet and advisory panel members. A systematic review of analytical validity, clinical validity and clinical utility of CYP testing was undertaken. Data were extracted into structured tables and narratively discussed, and meta-analysis was undertaken when possible. A review of economic evaluations of CYP testing in psychiatry and a review of economic models related to schizophrenia were also carried out. For analytical validity, 46 studies of a range of different genotyping tests for 11 different CYP polymorphisms (most commonly CYP2D6) were included. Sensitivity and specificity were high (99-100%). For clinical validity, 51 studies were found. In patients tested for CYP2D6, an association between genotype and tardive dyskinesia (including Abnormal Involuntary Movement Scale scores) was found. The only other significant finding linked the CYP2D6 genotype to parkinsonism. One small unpublished study met the inclusion criteria for clinical utility. One economic evaluation assessing the costs and benefits of CYP testing for prescribing antidepressants and 28 economic models of schizophrenia were identified; none was suitable for developing a model to examine the cost-effectiveness of CYP testing. Tests for determining genotypes appear to be accurate although not all aspects of analytical validity were reported. Given the absence of convincing evidence from clinical validity studies, the lack of clinical utility and economic studies, and the unsuitability of published schizophrenia models, no model was developed; instead key features and data requirements for economic modelling are presented. Recommendations for future research cover both aspects of research quality and data that will be required to inform the development of future economic models.

Prediction of adjuvant chemotherapy benefit in endocrine responsive, early breast cancer using multigene assays

Multigene assays performed on the primary tumors from women with non-metastatic breast cancer provide useful prognostic information and discriminate excellent versus poor outcome potential in diverse clinical scenarios. Recently, analyses were conducted to determine if these assays predict who benefits from adjuvant chemotherapy added to endocrine therapy and conversely, who might avoid chemotherapy because of lack of substantial benefit. This literature-based review summarizes these data and provides a perspective on the limitations and clinical utility of these assays. The literature regarding multigene assays and signatures in early breast cancer was surveyed. Only two assays-- the 21-gene recurrence score (RS) assay (Oncotype DX) and the 70-gene signature (MammaPrint)--were analyzed in randomized or non-randomized clinical populations in order to determine the predictive utility of the test in the adjuvant chemotherapy setting in patients whose tumors were estrogen-receptor positive. These data are summarized by type of clinical analysis, with information on clinical utility and comparative studies with standard clinical-pathologic factors. From 2 independent analyses in phase III clinical trial settings with tamoxifen-alone control arms, the 21-gene RS assay defines a group of patients with low scores who do not appear to benefit from chemotherapy, and a second group with very high scores who derive major benefit from CMF or CAF chemotherapy. One study was conducted in node-negative disease, and the second in a node-positive population. Interaction terms were significant in both studies, and the effect of the assay remained upon adjustment for other standard factors. Utilizing a non-randomized clinical setting, the 70-gene signature could also predict chemotherapy benefit in the high risk group, versus no apparent benefit in the low risk group, an effect that remained after adjustment for standard factors. For both assays, the discordance rate between the assay prediction and clinical-pathologic risk category was approximately 30%. Clinical utility studies showed use of the assay results in a change in treatment decision in 25-30% of cases, most commonly from chemoendocrine therapy to endocrine therapy alone. The prediction of adjuvant chemotherapy benefit over and above endocrine therapy using multigene assay-determined risk category differs greatly across risk level and challenges the previous adjuvant therapy paradigm that degree of benefit is the same regardless of risk. These data justify current clinical use of these assays, while ongoing prospective studies will refine their role in practice settings.

5166 The prognostic significance of age at diagnosis in patients with breast cancer younger than 35 years

Multigene assays performed on the primary tumors from women with non-metastatic breast cancer provide useful prognostic information and discriminate excellent versus poor outcome potential in diverse clinical scenarios. Recently, analyses were conducted to determine if these assays predict who benefits from adjuvant chemotherapy added to endocrine therapy and conversely, who might avoid chemotherapy because of lack of substantial benefit. This literature-based review summarizes these data and provides a perspective on the limitations and clinical utility of these assays.The literature regarding multigene assays and signatures in early breast cancer was surveyed. Only two assays – the 21-gene recurrence score (RS) assay (Oncotype DX) and the 70-gene signature (MammaPrint) – were analyzed in randomized or non-randomized clinical populations in order to determine the predictive utility of the test in the adjuvant chemotherapy setting in patients whose tumors were estrogen-receptor positive. These data are summarized by type of clinical analysis, with information on clinical utility and comparative studies with standard clinical-pathologic factors.From 2 independent analyses in phase III clinical trial settings with tamoxifen-alone control arms, the 21-gene RS assay defines a group of patients with low scores who do not appear to benefit from chemotherapy, and a second group with very high scores who derive major benefit from CMF or CAF chemotherapy. One study was conducted in node-negative disease, and the second in a node-positive population. Interaction terms were significant in both studies, and the effect of the assay remained upon adjustment for other standard factors. Utilizing a non-randomized clinical setting, the 70-gene signature could also predict chemotherapy benefit in the high risk group, versus no apparent benefit in the low risk group, an effect that remained after adjustment for standard factors. For both assays, the discordance rate between the assay prediction and clinical-pathologic risk category was approximately 30%. Clinical utility studies showed use of the assay results in a change in treatment decision in 25–30% of cases, most commonly from chemoendocrine therapy to endocrine therapy alone.The prediction of adjuvant chemotherapy benefit over and above endocrine therapy using multigene assay-determined risk category differs greatly across risk level and challenges the previous adjuvant therapy paradigm that degree of benefit is the same regardless of risk. These data justify current clinical use of these assays, while ongoing prospective studies will refine their role in practice settings.

CONTRA: Hydroxyethyl starch solutions are unsafe in critically ill patients

To describe the risk-benefit profile of hydroxyethyl starch (HES). Narrative review. (1) EFFICACY: no single clinical study or systemic review has shown that administration of any HES solution confers a clinically relevant benefit compared to crystalloids in critically ill patients or surgical patients in need of volume replacement. Contrary to beliefs expecting a ratio of 4:1 or more for crystalloid to colloid volume need, recent studies of goal-directed resuscitation observed much lower ratios of between 1 and 1.6. (2) SAFETY: HES administration is associated with coagulopathy, nephrotoxicity, pruritus and increased long-term mortality. Clinical studies claiming that modern HES 130/0.4 is safe have serious methodological drawbacks and do not adequately address the safety concerns. Given the complete lack of superiority in clinical utility studies and the wide spectrum of severe side effects, the use of HES in the ICU should be stopped. The belief that four times as much crystalloid as colloid fluid volume is needed for successful resuscitation is being seriously questioned.

A Markov model of treatment of newly diagnosed epilepsy in the UK

Long-term comparative trials among newer antiepileptic drugs are lacking; therefore decision models are needed to guide treatment decisions. The goal of this study was to develop an economic model of newly diagnosed epilepsy in the UK and to provide the first assessment of topiramate. A Markov model was developed combining data from clinical trials, cost-of illness, mortality, and utility studies. Expected costs and utilities associated with treatment strategies (first- and second-line treatments) were compared to find the cost-effectiveness frontier. First- and second-line monotherapy with topiramate or carbamazepine in partial seizures was less costly and more effective than other scenarios. In generalised seizures first-line topiramate was cost-effective with valproate or lamotrigine as second-line treatments depending on the set of utilities used. Models provide a relevant framework within which costs and health gains of antiepileptic drugs treatment options can be studied. Our findings are further evidence of the promising role of topiramate for patients with newly diagnosed epilepsy.

Bispectral index monitoring

The Bispectral Index (BIS) is a newly processed electroencephalogram parameter that was specifically developed to measure the hypnotic effects of anesthesia. Results from volunteer studies demonstrate that BIS correlates well with clinical assessments of sedation induced by sedative-hypnotic drugs. Clinical utility studies have shown also that BIS monitoring allows for better titration of anesthesia, resulting in lower hypnotic drug use and improved recovery. The data suggest that improved anesthetic titration with BIS provides sufficient clinical and economic benefits to justify its routine use. This article summarizes the clinical development and validation of BIS and describes how BIS monitoring can be used to improve anesthetic outcomes.

Cannabinoids and pain.

Cannabinoids have been used to treat pain for many centuries. However, only during the past several decades have rigorous scientific methods been applied to understand the mechanisms of cannabinoid action. Cannabinoid receptors were discovered in the late 1980s and have been found to mediate the effects of cannabinoids on the nervous system. Several endocannabinoids were subsequently identified. Many studies of cannabinoid analgesia in animals during the past century showed that cannabinoids block all types of pain studied. These effects were found to be due to the suppression of spinal and thalamic nociceptive neurons, independent of any actions on the motor systems. Spinal, supraspinal and peripheral sites of cannabinoid analgesia have been identified. Endocannabinoids are released upon electrical stimulation of the periaqueductal gray, and in response to inflammation in the extremities. These observations and others thus suggest that a natural function of cannabinoid receptors and their endogenous ligands is to regulate pain sensitivity. The therapeutic potential of cannabinoids remains an important topic for future investigations, with previous work suggesting utility in clinical studies of cancer and surgical pain. New modes of delivery and/or new compounds lacking the psychotropic properties of the standard cannabinoid ligands offer promise for cannabinoid therapeutics for pain.

Content and quality of 2000 controlled trials in schizophrenia over 50 years

Objective To provide a comprehensive survey of the content and quality of intervention studies relevant to the treatment of schizophrenia.Design Data were extracted from 2000 trials on the Cochrane Schizophrenia...

Industry, ethics, and general medicine: workshop no. 5.

Charles MacKay, Ph.D. (Co-Chair) I Patricia D. Murphy, Ph.D. (Co-Chair) t has long been recognized that the new genetic knowledge has been accompanied by a number of challenges for which the public, Robert A. Smith, Ph.D. (Rapporteur) health care providers, and the health care industry are not well preLisa Bailey, M.D.* pared, and in which different parties may have different interests. It Jeff Boyd, Ph.D.* is important that issues related to quality assurance, patient rights Wylie Burke, M.D., Ph.D.* and confidentiality, and a balance between economic interests and Robert K. Gleeson, M.D.* safeguards for the public are resolved at the earliest opportunity. Randi Gould* Michael L. Moore, M.D.* Recommendations Karen Steinberg, Ph.D.* 1. The American Cancer Society should support clinical utility studies G. Fred Worsham, M.D.* and outcome benefit studies. 2. Providers of genetic testing should agree on a standardized decision tree for referral (a flowchart or algorithm). 3. High quality lab performance must be assured. Appropriate professional agencies should develop high standards of quality control to assure the accuracy of genetic information. These standards could be established as a voluntary accreditation program or as regulations. 4. There should not be direct marketing to the public for genetic testing. 5. The workgroup is concerned about privacy and the multiple potential routes to possible disclosure of genetic test results. Laboratories should only disclose information about genetic test results to the referring provider. Genetic information should be released to third parties only with the signed consent of the individual for each specific use. Patients should be fully informed about how genetic information results will and may be used. 6. Genetic information is important medical information that should be kept in the patient’s chart. The American Cancer Society should work with other organizations to protect the confidentiality of this information. * Workshop participant.

Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis.

We measured concentrations of defensins (human neutrophil peptides) in the plasma of healthy volunteers and patients with sepsis and meningitis. When a sensitive enzyme immunoassay was used, defensins were detected in plasma samples from 13 of 24 healthy blood donors, with a mean +/- SD of 42 +/- 53 ng/ml. Defensin levels in plasma samples from seven patients with sepsis at the onset of disease ranged from 900 ng/ml to 170,000 ng/ml. In 10 patients with meningitis in the initial phase of disease, plasma defensin concentrations ranged from 120 ng/ml to 910 ng/ml. Defensin concentrations in the plasma of both patient groups were significantly higher than those in healthy blood donors (p << 0.01), and patients with sepsis had higher defensin levels than patients with meningitis (p < 0.01). Defensin levels were significantly (p < 0.01) lower after the beginning of specific antibiotic therapy. Defensin concentrations in the plasma of patients with sepsis and meningitis correlated only weakly (r = 0.38) with blood neutrophil count. In vitro studies of defensin added to plasma indicated that all defensin was bound to plasma proteins. At high concentrations (1000 micrograms/ml), defensins caused precipitation of plasma proteins. Because plasma defensin levels may reflect neutrophil activation at sites of infection and inflammation, studies of the clinical utility of defensin ELISA are indicated.