Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification.

INTRODUCTION: Amyloid beta (Aß) oligomers are one of the most toxic structural forms of the Aß protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients' brain tissue. We previously demonstrated that antagonists of the sigma-2 receptor complex effectively block Aß oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma-2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aß oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567). METHODS: Experiments were performed to measure the impact of CT1812 versus vehicle on Aß oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe /PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aß oligomer-induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild-type littermates. A multicenter, double-blind, placebo-controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini-Mental State Examination 18-26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme-linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo-treated dosing groups. RESULTS: CT1812 significantly and dose-dependently displaced Aß oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aß oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD-related proteins dysregulated in CSF. DISCUSSION: These preclinical studies demonstrate the novel disease-modifying mechanism of action of CT1812 against AD and Aß oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease-related signaling pathways in AD patients, supporting further development of CT1812.

Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.

BACKGROUND: Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease. METHODS: We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11). FINDINGS: Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. INTERPRETATION: The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon. FUNDING: TauRx Therapeutics.

PRISM II: an open-label study to assess effectiveness of dextromethorphan/quinidine for pseudobulbar affect in patients with dementia, stroke or traumatic brain injury.

BACKGROUND: Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI). METHODS: Participants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C). RESULTS: The study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, -7.7 [6.1]; P < .001, 95 % CI: -8.4, -7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, -8.2 [-9.4, -7.0]) and numerically exceeds the improvement seen with placebo in that study (-5.7 [-6.8, -4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P < .001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were "much" or "very much" improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related. CONCLUSIONS: DM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01799941, registered on 25 February 2013.

An open-label study to assess safety, tolerability, and effectiveness of dextromethorphan/quinidine for pseudobulbar affect in dementia: PRISM II results.

BACKGROUND: Dextromethorphan (DM)/quinidine (Q) is an approved treatment for pseudobulbar affect (PBA) based on trials in amyotrophic lateral sclerosis or multiple sclerosis. PRISM II evaluated DM/Q effectiveness and tolerability for PBA secondary to dementia, stroke, or traumatic brain injury; dementia cohort results are reported. METHODS: This was an open-label, multicenter, 90 day trial; patients received DM/Q 20/10 mg twice daily. Primary outcome was change in Center for Neurologic Study-Lability Scale (CNS-LS) score. Secondary outcomes included PBA episode count and Clinical and Patient/Caregiver Global Impression of Change scores with respect to PBA (CGI-C/PGI-C). RESULTS: 134 patients were treated. CNS-LS improved by a mean (SD) of 7.2 (6.0) points at Day 90/Endpoint (P<.001) vs. baseline. PBA episodes were reduced 67.7% (P<.001) vs. baseline; global measures showed 77.5% CGI-C and 76.5% PGI-C "much"/"very much" improved. Adverse events included headache (7.5%), urinary tract infection (4.5%), and diarrhea (3.7%); few patients dropped out for adverse events (10.4%). CONCLUSIONS: DM/Q significantly reduced PBA symptoms in patients with dementia; reported adverse events were consistent with the known safety profile of DM/Q. Trial Registration clinicaltrials.gov identifier: NCT01799941.

Effect of Dextromethorphan-Quinidine on Agitation in Patients With Alzheimer Disease Dementia: A Randomized Clinical Trial.

IMPORTANCE: Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE: To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score ≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS: In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS: A total of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders) showed significantly reduced NPI Agitation/Aggression scores for dextromethorphan-quinidine vs placebo (ordinary least squares z statistic, -3.95; P < .001). In stage 1, mean NPI Agitation/Aggression scores were reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0 to 5.3 with placebo. Between-group treatment differences were significant in stage 1 (least squares mean, -1.5; 95% CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scores were reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatment differences were also significant in stage 2 (least squares mean, -1.6; 95% CI, -2.9 to -0.3; P=.02). Adverse events included falls (8.6% for dextromethorphan-quinidine vs 3.9% for placebo), diarrhea (5.9% vs 3.1% respectively), and urinary tract infection (5.3% vs 3.9% respectively). Serious adverse events occurred in 7.9% with dextromethorphan-quinidine vs 4.7% with placebo. Dextromethorphan-quinidine was not associated with cognitive impairment, sedation, or clinically significant QTc prolongation. CONCLUSIONS AND RELEVANCE: In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01584440.

Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study.

OBJECTIVE: A single-agent, extended-release formulation of hydrocodone (HC) has been developed for treatment of chronic moderate-to-severe pain. This study was designed to examine the safety and efficacy of HC extended release in opioid-experienced adults with moderate-to-severe chronic low back pain (CLBP). METHODS: This multicenter, enriched enrollment, randomized withdrawal study comprised an open-label conversion/titration phase (≤6 weeks) followed by placebo-controlled, double-blind treatment (12 weeks). During the conversion/titration phase, subjects (N = 510) converted from their current opioid and were titrated to a stabilized dose of HC extended release (20-100 mg every 12 hours). During treatment, subjects (N = 151 per group) received HC extended release or placebo; rescue medication was permitted. The primary efficacy end point was mean change in average pain intensity from baseline to day 85. Response rates (30% pain improvement) and satisfaction (Subject Global Assessment of Medication) were assessed. RESULTS: Demographic and baseline characteristics were similar between groups. Mean ± SD change in average pain intensity score from baseline to day 85 was significantly lower in the HC extended-release treatment group vs placebo (0.48 ± 1.56 vs 0.96 ± 1.55; P = 0.008). Significantly more responders were in the treatment group (68% vs 31%; P < 0.001). Mean Subject Global Assessment of Medication scores increased significantly (0.8 ± 1.3 vs 0.0 ± 1.4; P < 0.0001), indicating greater satisfaction with HC extended release. The adverse event profile was consistent with other opioids. CONCLUSIONS: Extended-release HC is well tolerated and effective, without acetaminophen-associated risks of liver toxicity, for treatment of CLBP.

Safety and effectiveness of diazepam nasal spray in male and female patients: Post hoc analysis of data from a phase 3 safety study.

Sex differences in drug pharmacokinetics include variations in the expression of the cytochrome P450 enzymes, which are involved in the metabolism of benzodiazepines. It is unclear whether sex influences outcomes associated with intranasally administered drugs. A post hoc analysis of sex differences was conducted to evaluate the effectiveness and safety of diazepam nasal spray, which included examining changes in the number of days between seizure clusters over time (SEIzure interVAL [SEIVAL]). Diazepam nasal spray is approved for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Data from a phase 3 safety study were used to determine the proportion of second doses used within 24 h (ie, a proxy for effectiveness) and SEIVAL. Adverse events were recorded. Of 163 treated patients, 89 were female, and 74 were male. Approximately 16% of both sexes self-administered the study drug. A slightly higher proportion of seizure clusters was treated with a second dose in female (14.7%) than male (9.4%) patients. SEIVAL increased significantly and substantially over a year for all patients. The safety profile was generally similar between the sexes. These results suggest that potential sex differences in benzodiazepine pharmacokinetics do not meaningfully influence outcomes associated with diazepam nasal spray. PLAIN LANGUAGE SUMMARY: Some drugs may have differences in absorption and metabolism between genders that could translate into differences in safety and effectiveness. This safety study looked at diazepam nasal spray for treating seizure clusters in patients at least 6 years old. It found that safety was about the same for females and males. For both groups, most clusters stopped after only 1 dose of the drug, and the time between treated clusters got longer over a year.

Analyses of patients who self-administered diazepam nasal spray for acute treatment of seizure clusters.

For acute treatment of seizure clusters in patients with epilepsy, intranasal administration of acute seizure therapies has been shown to provide accessibility and ease of use to care partners as well as the potential for self-administration by patients. Diazepam nasal spray (Valtoco®) was approved by the US Food and Drug Administration for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Self-administration consistent with the prescribing information is feasible and was reported by a subgroup of patients (n = 27 of 163) in a long-term phase 3 safety study. Data regarding self-administration among these patients with seizure clusters are examined here to explore the safety profiles and measures of effectiveness, as well as the quality of life of those who self-treated. In addition, this focused look at patients who self-administered diazepam nasal spray may offer some insights into the characteristics of patients who may be appropriate for self-administration.

A phase 1 open-label pilot study of low-dose interleukine-2 immunotherapy in patients with Alzheimer's disease.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05821153, Registered April 20 2023, Retrospectively registered, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05821153.

Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer's Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial.

BACKGROUND: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. OBJECTIVES: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. METHODS: Mild AD patients (n = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n = 79) versus 4 mg twice a day as randomized (n = 396), and 4 mg twice a day as monotherapy (n = 76) versus 4 mg twice a day as add-on therapy (n = 297), with strong control of family-wise type I error. RESULTS: The revised analyses were statistically significant at the required threshold of p < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. CONCLUSIONS: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis.

A Randomized, Double-Blind, Active- and Placebo-Controlled Efficacy and Safety Study of Arhalofenate for Reducing Flare in Patients With Gout.

OBJECTIVE: Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout. METHODS: This was a 12-week, randomized, double-blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5-12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure. RESULTS: A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo (P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine (P = 0.091). Mean changes in serum UA level were -12.5% with 600 mg arhalofenate and -16.5% with 800 mg arhalofenate (P = 0.001 and P = 0.0001, respectively, versus -0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5-fold the baseline value were observed in the arhalofenate-treated groups. CONCLUSION: Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate-lowering antiflare therapy.

Failure of BRCA1 dysfunction to alter ovarian cancer survival.

PURPOSE: Many factors modify ovarian cancer survival. There are conflicting reports regarding survival of individuals with hereditary BRCA1-related ovarian cancer. None have controlled for other mechanisms of BRCA1 silencing in the control cohort. EXPERIMENTAL DESIGN: Fifty-nine cancers with presumed BRCA1 dysfunction because of mutation (24 germ-line and 16 somatic) or absent BRCA1 mRNA because of promoter hypermethylation (n = 19) were identified among 250 consecutively screened ovarian cancers. Controls were matched from the same population based on p53 mutation type, age at diagnosis, Fédération Internationale des Gynaecologistes et Obstetristes surgical stage and histological grade, residual disease, preoperative CA125, disease site, and the presence of BRCA1 mRNA translatable in an in vitro protein expression assay. BRCA1 promoter hypermethylation was determined by the methylation-specific PCR technique. The significance of promoter hypermethylation was confirmed by the absence of detectable BRCA1 mRNA. RESULTS: The median survival for individuals with ovarian cancer BRCA1 dysfunction was 4.1 years versus 3.5 years in the case matched controls (P = 0.98). Grouped on the basis of the mechanism of BRCA1 dysfunction, median survival was 4.5, 2.8, and 2.3 years for germ-line, somatic, and BRCA1 promoter-silenced ovarian cancers. However, for the corresponding matched controls with wild-type BRCA1 sequence, the median survival was virtually identical: 4.6, 2.8, and 3.3 years, respectively. In a Cox proportional hazards analysis, only residual disease (P = 0.0001), age (P = 0.01), and Fédération Internationale des Gynaecologistes et Obstetristes stage (P = 0.011) entered the survival model. CONCLUSIONS: In contrast with other published reports, we are unable to detect large survival differences between matched case-control cohorts of ovarian cancers with BRCA1 inactivation by any of three independent mechanisms.

Inhibition of oral cancer cell growth by adenovirusMnSOD plus BCNU treatment.

We hypothesized that inhibitors of peroxide removal, such as BCNU, an indirect inhibitor of glutathione peroxidase (GPx), and 3-amino-1,2,4-triazole (AT), a direct inhibitor of catalase (CAT), should cause toxicity to cancer cells after manganese superoxide dismutase (MnSOD) overexpression due to elevated peroxide levels. In vitro, hamster cheek pouch carcinoma cells (HCPC-1) and human oral squamous carcinoma cells (SCC-25) were infected with various combinations of adenovirus containing MnSOD cDNA (AdMnSOD). Cells were then treated with or without BCNU and assayed for viability using Annexin/PI staining and flow cytometry. In AdMnSOD plus BCNU-treated SCC-25 and HCPC-1 cells, a 30-60% decrease in cell viability was observed compared to BCNU alone. In vivo, HCPC-1 and SCC-25 xenografts were allowed to grow to approximately 70 mm(3) and 10(9) plaque forming units (pfu) of AdMnSOD were injected directly into the tumors. Two days later, 15 or 30 mg/kg BCNU was injected intratumorally. Tumor growth was greatly inhibited (4- to 20-fold) by this combined treatment, as well as increasing animal survival. Tumor volume could be decreased further by giving multiple doses of AdMnSOD or inhibiting catalase activity with AT. These results suggest that, by using these combination therapies, a significant decrease in tumor mass can be achieved.

Preoperative CA 125 levels: an independent prognostic factor for epithelial ovarian cancer.

OBJECTIVE: To estimate the association of preoperative CA 125 levels with outcome in primary ovarian cancer patients. METHODS: One hundred forty-two patients with epithelial ovarian cancer, who had a serum CA 125 level drawn before surgery, were retrospectively evaluated. The relationship of preoperative CA 125 levels and various preoperative and postoperative variables was evaluated. CA 125 levels were determined using a solid-phase immunoassay. RESULTS: The median CA 125 value for all patients was 582 U/mL (range 7-52,930 U/mL). Preoperative CA 125 values did not correlate with increasing age (P =.40), but were found to be significantly associated with serous histology compared with other histology (median CA 125 of 870 versus 334 U/mL, P =.02), high-stage (III/IV) compared with low-stage (median CA 125 of 893 versus 174 U/mL, P <.001), high tumor grade (3) compared with grade 1 or 2 (median CA 125 of 928 versus 323 U/mL, P <.001), and the presence of ascites compared with absence of ascites (median CA 125 of 893 versus 220 U/mL, P <.001). Suboptimal cytoreduction (more than 1 cm residual) was associated with significantly higher CA 125 levels (1067 U/mL) compared with individuals with optimal cytoreduction (399 U/mL, P <.001). Preoperative CA 125 values less than 500 U/mL had a positive predictive value for optimal cytoreduction of 82%, but a poor negative predictive value of 48%. After adjusting for covariates, there was a significant association between CA 125 levels and disease-specific survival. As preoperative CA 125 levels increased, the risk of death increased except at the highest values of CA 125. CONCLUSION: Preoperative CA 125 is an independent risk factor for death due to disease in ovarian cancer, but not a reliable predictor of optimal cytoreduction.

Workplace accommodations for people with disabilities: National Health Interview Survey Disability Supplement, 1994-1995.

As American workers age, workers with impairments and functional limitations make up a larger percentage of our workforce. This investigation presents data from the National Health Interview Survey Disability Supplement 1994-1995 (NHIS-D) describing the nature of workplace accommodations in the American workforce and factors associated with the provision of such accommodations. Of a nationally representative sample of workers aged 18 to 69 years with a wide range of impairments, 12% reported receiving workplace accommodations. Males (odds ratio (OR) 0.64: 95% confidence interval (CI) 0.53-0.78) and Southerners (OR 0.57; 95% CI = 0.47-0.70) were less likely than others to receive workplace accommodations. Those with mental health conditions were less likely than others to receive accommodations (OR 0.56; 95% CI = 0.44-0.70). College graduates (OR 1.53; 95% CI = 1.22-1.91), older workers, full time workers (OR 3.99; 95% CI = 2.63-3.87), and the self-employed (OR 1.76; 95% CI = 1.28-2.41) were more likely than others to receive accommodations.

Workforce participation by persons with disabilities: the National Health Interview Survey Disability Supplement, 1994 to 1995.

Using the National Health Interview Survey Disability Supplement of 1994 to 1995, we examined the factors associated with employment among Americans with disabilities. Persons with disabilities who were more educated were more likely to be working. Married men were more likely to work than unmarried men (odds ratio [OR], 1.58). Blacks were less likely to work than whites (OR, 0.56). Persons with disabilities related to cardiovascular disease (OR, 0.23), musculoskeletal disease (OR, 0.37), and respiratory disease (OR, 0.23) were less likely to work than other Americans with disabilities. Among persons with psychiatric disorders, there was considerable variety in the propensity to work. Persons with schizophrenia (OR, 0.24) and paranoid delusional disorder (OR, 0.34) were markedly less likely to work; persons with bipolar disorder (OR, 0.60) and major depression (OR, 0.69) were also less likely to work. Lastly, persons with self-reported alcohol abuse (OR, 1.30) were more likely to work, and persons with self-reported drug abuse (OR, 0.93) were not less likely to work, than others in our study population of Americans with disabilities.

Radiation-induced kidney injury: a role for chronic oxidative stress?

Kidney irradiation clearly leads to a progressive reduction in function associated with concomitant glomerulosclerosis and/or tubulointerstitial fibrosis. However, the particular cell types, mediators and/or mechanisms involved in the development and progression of radiation nephropathy remain ill defined. Angiotensin II (Ang II) plays a major pathogenic role; administration of Ang II blockers markedly abrogates the severity of radiation nephropathy in experimental models. Both ionizing radiation and Ang II signal via generation of reactive oxygen species (ROS). Thus, we hypothesized that localized kidney irradiation might lead to a chronic oxidative stress. In view of the difficulty in measuring ROS in vivo we adopted an indirect immunohistochemical approach in which we used a monoclonal antibody specific for 8-hydroxy-2'-deoxyguanosine (8-OHdG), one of the most commonly used markers of DNA oxidation. The right kidney of 7-8 week-old male Sprague-Dawley rats was removed. Five to 6 weeks later the remaining hypertrophied kidney was irradiated with single doses of 0-20.0 Gy X-rays. Groups of rats, three per dose, were killed at 4, 8, 16 and 24 weeks post-irradiation, their kidneys fixed, and sections stained with the 8-OHdG-specific antibody N45.1. For quantitation of glomerular DNA oxidation with the N45.1 antibody stained sections, 50 glomeruli/animal were counted. The presence of any intensely stained nuclei within the glomerular tuft was scored as positive. Quantitation of tubular DNA oxidation employed a 10 x 10 point ocular grid. Sections were examined at 400 magnification; 250 tubular profiles were counted. All tubules with any nuclear staining were scored as positive.Sham-irradiated kidneys showed little evidence of DNA oxidation over the experimental period. In contrast, localized kidney irradiation led to a marked, dose-independent increase in glomerular and tubular cell nuclear DNA oxidation. This increase was evident at the first time point studied, i.e. 4 weeks after irradiation, and persisted for up to 24 weeks postirradiation. DNA oxidation in the irradiated kidney was only seen in apparently viable glomerular and tubular cells. Thus, while from 16 to 24 weeks post-irradiation structural alterations had progressed to glomerular sclerosis and tubular atrophy, positive staining for 8-OHdG was not observed in severely atrophic tubules. Similarly, fewer positive staining cells were noted in glomeruli undergoing sclerosis, while none were seen in totally sclerotic glomeruli. These data support the hypothesis that renal irradiation is associated with a chronic and persistent oxidative stress.

Issues in planning a placebo-controlled trial of manual methods: results of a pilot study.

OBJECTIVE: There are fundamental differences between the administration of medications and the application of manual procedures, such as those used by chiropractors. The objective of this study was to gather preliminary information on how to address these differences in the design of a multisite, randomized placebo-controlled trial of chiropractic care for women with chronic pelvic pain (CPP). DESIGN: Pilot study for a multisite, randomized, placebo-controlled clinical trial. SETTING: Three chiropractic research clinics in the midwest United States. SUBJECTS: Thirty-nine (39) women with CPP of at least 6 months' duration, diagnosed by board-certified gynecologists. INTERVENTIONS: The active intervention consisted of the chiropractic technique, lumbar spine flexion-distraction, combined with manual Trigger Point Therapy. The placebo intervention consisted of a sham chiropractic procedure performed with an instrument combined with effleurage (light massage). OUTCOME MEASURES: The primary outcome measure was the change in the Pain Disability Index (PDI) from baseline to the end of treatment (6 weeks), assessed by group and site. If the change score was in the same direction at all sites, the results were to be combined to estimate treatment effect size. RESULTS: Patient characteristics were similar to those of patients with CPP in other studies. Recruitment methods, particularly in respect to the eligibility criteria and screening protocols, would require modification in order to recruit an adequate sample for the planned randomized controlled trial. Clinicians followed standardized procedures with apparently minimal deviation, patients in both groups were satisfied with their care and blinding appeared to be successful. PDI change scores were not consistent across sites and so results were not combined and overall treatment effect sizes were not estimated. CONCLUSIONS: The technical and personnel resources required to achieve adequate standardization of procedures at multiple sites may make a placebo-controlled trial unfeasible, given our current lack of knowledge about the active agent in manual chiropractic procedures.