Systematic review and meta-analysis of temozolomide in animal models of glioma: was clinical efficacy predicted?

BACKGROUND: Malignant glioma is an aggressive tumour commonly associated with a dismal outcome despite optimal surgical and radio-chemotherapy. Since 2005 temozolomide has been established as first-line chemotherapy. We investigate the role of in vivo glioma models in predicting clinical efficacy. METHODS: We searched three online databases to systematically identify publications testing temozolomide in animal models of glioma. Median survival and number of animals treated were extracted and quality was assessed using a 12-point scale; random effects meta-analysis was used to estimate efficacy. We analysed the impact of study design and quality and looked for evidence of publication bias. RESULTS: We identified 60 publications using temozolomide in models of glioma, comprising 2443 animals. Temozolomide prolonged survival by a factor of 1.88 (95% CI 1.74-2.03) and reduced tumour volume by 50.4% (41.8-58.9) compared with untreated controls. Study design characteristics accounted for a significant proportion of between-study heterogeneity, and there was evidence of a significant publication bias. CONCLUSION: These data reflect those from clinical trials in that temozolomide improves survival and reduces tumour volume, even after accounting for publication bias. Experimental in vivo glioma studies of temozolomide differ from those of other glioma therapies in their consistent efficacy and successful translation into clinical medicine.

From a mouse: systematic analysis reveals limitations of experiments testing interventions in Alzheimer's disease mouse models.

The increasing prevalence of Alzheimer's disease (AD) poses a considerable socio-economic challenge. Decades of experimental research have not led to the development of effective disease modifying interventions. A deeper understanding of in vivo research might provide insights to inform future in vivo research and clinical trial design. We therefore performed a systematic review and meta-analysis of interventions tested in transgenic mouse models of AD. We searched electronically for publications testing interventions in transgenic models of AD. We extracted data for outcome, study characteristics and reported study quality and calculated summary estimates of efficacy using random effects meta-analysis. We identified 427 publications describing 357 interventions in 55 transgenic models, involving 11,118 animals in 838 experiments. Of concern, reported study quality was relatively low; fewer than one in four publications reported the blinded assessment of outcome or random allocation to group and no study reported a sample size calculation. Additionally, there were few data for any individual intervention-only 16 interventions had outcomes described in 5 or more publications. Finally, "trim and fill" analyses suggested one in seven pathological and neurobehavioural experiments remain unpublished. Given these historical weaknesses in the in vivo modelling of AD in transgenic animals and the identified risks of bias, clinical trials that are based on claims of efficacy in animals should only proceed after a detailed critical appraisal of those animal data.

Timing and quality of sleep in a rural Brazilian family-based cohort, the Baependi Heart Study.

Sleep is modulated by several factors, including sex, age, and chronotype. It has been hypothesised that contemporary urban populations are under pressure towards shorter sleep duration and poorer sleep quality. Baependi is a small town in Brazil that provides a window of opportunity to study the influence of sleep patterns in a highly admixed rural population with a conservative lifestyle. We evaluated sleep characteristics, excessive daytime sleepiness, and chronotype using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Morningness-Eveningness Questionnaire questionnaires, respectively. The sample consisted of 1,334 subjects from the Baependi Heart study (41.5% male; age: 46.5 ± 16.2 y, range: 18-89 years). Average self-reported sleep duration was 07:07 ± 01:31 (bedtime 22:32 ± 01:27, wake up time: 06:17 ± 01:25 hh:min), sleep quality score was 4.9 + 3.2, chronotype was 63.6 ± 10.8 and daytime sleepiness was 7.4 ± 4.8. Despite a shift towards morningness in the population, chronotype remained associated with reported actual sleep timing. Age and sex modulated the ontogeny of sleep and chronotype, increasing age was associated with earlier sleep time and shorter sleep duration. Women slept longer and later, and reported poorer sleep quality than men (p < 0.0001). This study provides indirect evidence in support of the hypothesis that sleep timing was earlier prior to full urbanisation.

The development of an online database for interventions tested in transgenic mouse models of Alzheimer's disease.

Despite many efforts by the research community, Alzheimer's disease (AD) is still an incurable neurodegenerative condition that affects an estimated 44 million individuals worldwide and this figure is expected to increase to 135 million by the year 2050. As the research community currently reflects on previous endeavours, it is essential that we maximize the use of existing knowledge to inform future trials in the field. This article describes the development of a systematically identified data set relating to over 300 interventions tested in over 10,000 animals. The data set includes cohort-level information for six structural outcomes and six behavioural assessments. We encourage others to use this dataset to inform the design of future animal experiments modelling AD and to promote effective translation to human health.

Self-administration of midazolam for postoperative anxiety: a double blinded study.

Anxiety is almost inevitably present in patients facing surgery. The optimal management of postoperative pain requires the acknowledgement of perioperative anxiety and the inclusion of pharmacological and/or non-pharmacological means of alleviating the fear and worry inherent in the surgical experience. In a double-blind randomized design, 39 patients undergoing total abdominal hysterectomies were given postoperative access to a standard patient-controlled analgesia (PCA) morphine pump for pain and a PCA pump dispensing either low-dose midazolam or saline for anxiety. Measures of anxiety and pain were completed pre-operatively and for 2 days postoperatively. Utilization of morphine and 'anxiolytic agent' were recorded. Analysis of covariance was applied to the data to control for the imbalance of cancer patients between the 2 groups. While both groups of patients chose to utilize their 'anxiety pump' throughout the study, those patients receiving midazolam had significantly lower postoperative Spielberger State Anxiety scores and visual analogue scale anxiety scores. Patient-controlled midazolam in doses used in this study were safe and effective in managing anxiety but did not influence pain scores or the amount of PCA morphine patients used. Pre-operative levels of depression were significantly associated with postoperative pain levels independent of treatment group or cancer diagnosis.

Comprehensive evaluation and treatment of 75 men referred to chronic prostatitis clinic.

We investigated the role of genitourinary tract infections, structural and psychologic abnormalities in 75 men referred to a "chronic prostatitis" clinic. Patients had had symptoms for an average of eighty-three months and had received an average of ten weeks of antimicrobial treatment during the three months prior to evaluation. Specific infectious diseases, structural or functional causes were identified in 34 (45%) of the 75 patients. Genitourinary tract pathogens were isolated from 26 patients and inflammation was documented in urethral or prostatic secretions of 24 patients. Structural or functional abnormalities that merited treatment were identified in 8 cases. In addition, major criteria for depression were documented in 9 of 17 patients who agreed to this evaluation. Overall, a comprehensive approach to diagnosis led to specific treatment for 37 (49%) of the 75 men with chronic prostatitis, despite longstanding symptoms and failure of multiple prior courses of therapy.

Chronic pelvic pains represent the most prominent urogenital symptoms of "chronic prostatitis".

OBJECTIVES: To refine and standardize evaluation of current symptoms in men with "chronic prostatitis." METHODS: We reviewed the literature, developed a symptom index, and evaluated the clinical utility of this tool in 50 patients with chronic prostatitis and 75 control patients (25 with benign prostatic hyperplasia [BPH] and 50 with sexual dysfunction). RESULTS: Patients with prostatitis reported more perineal, lower abdominal, testicular, penile, and ejaculatory pain than patients with BPH (P < 0.05 for each symptom) or sexual dysfunction (P < 0.01 for each symptom). Ejaculatory pain was also more common among men with prostatitis than among men with BPH (P = 0.07) or among men with sexual dysfunction (P < 0.01). Although described as characteristic of prostatitis in the literature, low back or rectal pain did not distinguish patients with prostatitis from those with BPH. Patients with prostatitis were intermediate between patients with BPH and sexual dysfunction on the voiding scale and similar to the BPH group on the sexual dysfunction scale. CONCLUSIONS: Pain symptoms were the predominant urologic manifestations of chronic prostatitis. The symptom index may prove valuable for evaluating patients and describing clinical results.

Psychological problems in chronic prostatitis patients with pain.

OBJECTIVE: Men with chronic prostatitis are frequently seen in urological practice and are difficult to treat with standard antimicrobial medications. This pilot study was designed to take a different perspective in assessing chronic prostatitis patients with pain by evaluating them using a standard chronic pain clinic psychological approach. DESIGN: Twenty men, 27% of the referred group of patients with chronic prostatitis and pain, completed the MMPI and a structured psychological interview. Their findings were compared to age- and education-matched men seeking treatment for chronic low back pain. SETTING: Data were collected at the Pain Clinic within the Department of Anesthesiology at the University of Washington Medical Center. PATIENTS: Patients were 20 men referred from a urology-based Prostatitis Clinic and 20 men referred to the Pain Clinic for chronic low back pain. RESULTS AND CONCLUSIONS: The two groups differed in the impact of their pain problem on their lives. Prostatitis patients were employed but reported that their symptoms greatly interfered with their sexual/romantic relationships. Back pain patients reported that their pain interfered primarily with work; most of these patients had long-term marital relationships, whereas few prostatitis patients did. Half of the prostatitis patients met criteria for major depression, but back pain patients were more somatically focused, depressed, and anxious. The constellation of relationship problems, disruptions in sexual functioning, levels of depression, along with failure of multiple previous medical treatments in men with chronic prostatitis indicates that continued antimicrobial therapy is unlikely to provide the "cure" these patients seek. Psychological evaluation, couples' counseling, individual counseling, and medications for depression all may play a role in a comprehensive approach to these patients. These results must be considered as preliminary and as representative of a possibly skewed sample of prostatitis patients since only those men who accepted the referral to a pain clinic psychologist for an evaluation were assessed. Clearly, they are likely to be among the patients who are most psychologically and sexually impaired by the chronic prostatitis and associated pain. A further study with less self-selection is indicated.

Acute pain management of the chronic pain patient on opiates: a survey of caregivers at University of Washington Medical Center.

OBJECTIVE: The provision of acute pain management for the chronic pain patient can pose a challenge. We sought to characterize management issues. SUBJECTS/SETTING: An anonymous survey was distributed to 270 physicians and 212 nurses at University of Washington Medical Center (UWMC) in an attempt to characterize management issues. DESIGN: Caregivers were queried regarding treatment modalities, efficacy of anxiolysis, patient attributes, concern of the quantity of medication, criteria for patient evaluation, and other management issues. RESULTS: Of the respondents, 61.8% were physicians, and 38.2% were nurses. The mean duration in practice was 7.7 years. The responses from the two groups were similar. Seventy-five percent reported using different pain-evaluation techniques for chronic pain patients than those utilized for the "average" patient. Pain scores were used frequently in the average patient, whereas ability to perform activities was used more commonly in the chronic pain patient (p < 0.0001). Half of the respondents expressed concern regarding the amount of medication used and level of sedation. The same proportion found anxiolysis to be a helpful adjunct. The use of a time-contingent "pain cocktail" as an oral medication was a useful strategy for 88% of respondents. The least labor-intensive modality reported was patient-controlled analgesia (PCA) for 84.5% of respondents; intravenous opiate fusion, 5.3%; and epidural analgesia, 11.2%. CONCLUSIONS: The survey describes caregiver concerns regarding this patient population, including medication use, sedation, length of hospital stay, and evaluation techniques.

Response to symptoms in healthy, low utilizers of the health care system.

From the literature, it is clear that a small proportion of people account for an inordinately high number of health care visits. Conversely, there exists a group of individuals who rarely seek professional medical intervention and, yet, who remain healthy. This study examines a sample of adults who have not received remedial treatment for any symptom in the previous year, who consider themselves as healthy and who pass a comprehensive physical examination. A gender and age balanced group of healthy low utilizers was administered the Symptom Response Questionnaire, an instrument designed to elicit response tendencies to thirteen standardized symptoms. There were significant differences between age groups in response to symptoms with the older individuals more likely to seek professional help. There were few gender differences within the healthy sample. This sample of healthy low-utilizers was not without symptoms, reporting an average of 20 symptoms occurring in the previous week as measured by the SCL-90. A clinical headache group was also administered the SRQ to provide information about their response tendencies to symptoms. This preliminary study suggests that response to illness may be significantly influenced by age and patient status and that reported gender differences in health care utilization may need to be examined more carefully. It is proposed that behavior patterns of healthy, low utilizers may have direct implications for intervention with high utilizers of the health care system.

Meta-analysis of data from animal studies: a practical guide.

Meta-analyses of data from human studies are invaluable resources in the life sciences and the methods to conduct these are well documented. Similarly there are a number of benefits in conducting meta-analyses on data from animal studies; they can be used to inform clinical trial design, or to try and explain discrepancies between preclinical and clinical trial results. However there are inherit differences between animal and human studies and so applying the same techniques for the meta-analysis of preclinical data is not straightforward. For example preclinical studies are frequently small and there is often substantial heterogeneity between studies. This may have an impact on both the method of calculating an effect size and the method of pooling data. Here we describe a practical guide for the meta-analysis of data from animal studies including methods used to explore sources of heterogeneity.

A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

BACKGROUND: The development of therapeutics is often characterized by promising animal research that fails to translate into clinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma. METHOD: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched for evidence of publication bias. RESULTS: We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53-1.67). Study quality was low and the type of gene therapy did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to the most common gene therapy. CONCLUSION: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.

Responses to illness and health in chronic pain patients and healthy adults.

Although it is clear that health care utilization rates differ among individuals, what is not so obvious is the explanation for the variation in illness responses, nor is it known whether responses to illness are consistent or predictable. This pilot study compared responses to common symptoms and health maintenance activities in 1) healthy subjects with no medical visits in the previous year, 2) patients with chronic headaches with high medical utilization who remained functional at work and home, and 3) patients with nonmalignant chronic pain who were seriously dysfunctional in work and home responsibilities. The chronic pain samples differed primarily in level of functioning with similar outpatient utilization levels; they reported greatly differing response tendencies to common symptoms, with the more functional group endorsing numerous self-help strategies along with medical care seeking. The dysfunctional pain patients responded consistently with only one illness behavior: they went to the doctor. Among all three groups, the severely impaired individuals were most likely to say that they made special efforts to maintain their health; however, there was no single pro-health activity they engaged in more than the other groups. There appear to be attitudinal as well as behavioral differences in response to health and illness issues between these groups of high and low utilizers and, within the high utilizer group, between those who are more or less impaired by their pain.

Patient satisfaction with intravenous PCA or epidural morphine.

In many institutions postoperative patients may receive morphine for analgesia administered into the epidural space, epidural opioid analgesia (EOA), or through intravenous self-administered patient-controlled analgesia pumps (PCA). Although a number of studies have compared the two approaches with regard to efficacy and side effects, there is less known with regard to patient satisfaction and its sources. In this study, 711 patients using PCA morphine and 205 patients receiving epidural morphine following a variety of gynaecological, urological, orthopaedic, and general surgical procedures rated their satisfaction with the method they used on a 0-10 verbal analogue satisfaction scale (0 = very dissatisfied; 10 = very satisfied). A consecutive subset of 100 patients (50 from EOA group and 50 from the PCA group) underwent further evaluation to identify advantages and disadvantages of the technique used which contributed to their satisfaction and/or dissatisfaction. Overall satisfaction (mean +/- SD) in the two large groups was 8.6 +/- 1.8 for PCA and 9.0 +/- 1.5 for EOA (P < 0.01). In the subset of 100 patients, there were differences between the EOA and PCA groups with regard to the advantages and disadvantages selected. Patients in the PCA group identified "personal control" and "method worked quickly" as advantages whereas patients receiving EOA selected "clear mind," "effective relief resting," and "effective relief while moving or coughing." The single disadvantage identified more frequently by PCA patients was "pain immediately after surgery before method became effective." Disadvantages identified more frequently by EOA patients were "side effects" and "poor pain relief." We conclude that overall patient satisfaction was high whether patients received PCA or EOA.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of alexithymia on morbidity in hypertensives.

Alexithymic and nonalexithymic hypertensives were assessed for severity of hypertension using a weighting system based on diastolic blood pressure, optic fundi, ECG, chest X ray, renal studies, and patient history. Outpatient hypertensives (diastolic blood pressure greater than 95 mm Hg) were selected as subjects because they are largely asymptomatic; thus, focusing on somatic ills to the exclusion of thoughts about emotions is not likely to be due to their hypertensive pathology but rather reflects psychological constitution. Controlling for age differences, it was found that alexithymics manifested more severe hypertensive sequelae than did nonalexithymics ; there was, however, no difference in severity of atherosclerosis. The results suggest that alexithymia is not only correlated with hypertension but may also play a role in its etiology.