David A. Amato

Cox-Type Regression Analysis for Large Numbers of Small Groups of Correlated Failure Time Observations

The Cox regression model has been used extensively to analyze survival data. For data that consist of large numbers of small groups of correlated failure time observations, we show that the standard maximum partial likelihood estimate of the regression coefficient in the Cox model is still consistent and asymptotically normal. However, the corresponding standard variance-covariance estimate may no longer be valid due to the dependence among members in the groups. In this article, a correct variance-covariance estimate that takes account of the intra-group correlation is proposed. Power comparisons are performed to show the advantage of the new proposal. Examples are provided for illustration.

Eszopiclone Co-Administered With Fluoxetine in Patients With Insomnia Coexisting With Major Depressive Disorder

BACKGROUND Insomnia and major depressive disorder (MDD) can coexist. This study evaluated the effect of adding eszopiclone to fluoxetine. METHODS Patients who met DSM-IV criteria for both MDD and insomnia (n = 545) received morning fluoxetine and were randomized to nightly eszopiclone 3 mg (ESZ+FLX) or placebo (PBO+FLX) for 8 weeks. Subjective sleep and daytime function were assessed weekly. Depression was assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Impression Improvement (CGI-I) and Severity items (CGI-S). RESULTS Patients in the ESZ+FLX group had significantly decreased sleep latency, wake time after sleep onset (WASO), increased total sleep time (TST), sleep quality, and depth of sleep at all double-blind time points (all p < .05). Eszopiclone co-therapy also resulted in: significantly greater changes in HAM-D-17 scores at Week 4 (p = .01) with progressive improvement at Week 8 (p = .002); significantly improved CGI-I and CGI-S scores at all time points beyond Week 1 (p < .05); and significantly more responders (59% vs. 48%; p = .009) and remitters (42% vs. 33%; p = .03) at Week 8. Treatment was well tolerated, with similar adverse event and dropout rates. CONCLUSIONS In this study, eszopiclone/fluoxetine co-therapy was relatively well tolerated and associated with rapid, substantial, and sustained sleep improvement, a faster onset of antidepressant response on the basis of CGI, and a greater magnitude of the antidepressant effect.

Superficial bladder cancer treated with bacillus Calmette-Guerin: A multivariate analysis of factors affecting tumor progression

A multivariate analysis was performed on data from 221 patients with superficial bladder tumors (papilloma in 30, grade II to III stage Ta in 51, grade II to III stage Tis in 111 and grade II to III stage T1 in 29) who were treated with intravesical bacillus Calmette-Guerin and followed for a minimum of 24 months or until progression. The purpose of this analysis was to identify prognostic variables predictive of tumor progression defined as muscle invasion, metastasis or endoscopically uncontrolled superficial bladder carcinoma involving the bladder and/or prostatic urethra. Variables examined before bacillus Calmette-Guerin, and at 3 and 6 months after bacillus Calmette-Guerin included age, sex, race, purified protein derivative reaction, duration of disease, tumor category, tumor grade, multifocality, results of cytology, flow cytometry, cystoscopy, biopsy, prior chemotherapy and bacillus Calmette-Guerin treatment regimen. Significant variables (Cox regression analysis, p less than 0.07) for tumor progression were before bacillus Calmette-Guerin--stage T1 tumors and duration of disease less than 1 year, at 3 months after bacillus Calmette-Guerin--stage T1 tumor, duration of disease less than 1 year, positive cytology studies and multifocality, and at 6 months after bacillus Calmette-Guerin--stage T1 tumor, positive cytology and positive biopsy other than stage T1 tumors. Prognostic risk groups were best defined at 6 months after bacillus Calmette-Guerin, the probability of tumor progression thereafter being at 1, 3 and 5 years, respectively, as follows: for risk group 1 (T1 tumor)--71, 100 and 100 per cent, for risk group 2 (positive biopsy other than T1 plus positive cytology)--25, 79 and 100 per cent, for risk group 3 (either positive biopsy other than stage T1 or positive cytology studies)--18, 40 and greater than 81 per cent, and for risk group 4 (negative biopsy and negative cytology studies)--2, 11 and 26 per cent, respectively. Evaluation of patients with superficial bladder carcinoma at 6 months after intravesical bacillus Calmette-Guerin therapy identifies the probability of tumor progression. Patients at high risk for tumor progression require alternative treatment strategies, whereas low risk patients can be observed for further therapy if necessary.

Verbal Fluency and Positron Emission Tomographic Mapping of Regional Cerebral Glucose Metabolism

Impairment in verbal fluency (VF) has been a consistently reported clinical feature of focal cerebral deficits in frontal and temporal regions. More recent behavioral activation studies with healthy control subjects using positron emission tomography (PET), however, have noted a negative correlation between performance on verbal fluency tasks and regional cortical activity. To see if this negative relationship extends to steady-state non-activation PET measures, thirty-three healthy adults were given a VF task within a day of their 18F-2-fluoro-2-deoxy-D-glucose PET scan. VF was found to correlate positively with left temporal cortical region metabolic activity but to correlate negatively with right and left frontal activity. VF was not correlated significantly with right temporal cortical metabolic activity. Some previous studies with normals using behavioral activation paradigms and PET have reported negative correlations between metabolic activity and cognitive performance similar to that reported here. An explanation for the disparate relationships that were observed between frontal and temporal brain areas and VF might be found in the mediation of different task demands by these separate locations, i.e., task planning and/or initiation by frontal regions and verbal memory by the left temporal area.

Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia

SUMMARY Objective: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia. The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia. Research design and methods: Patients (n = 308) were randomized to receive placebo or eszopiclone (2 mg or 3 mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo. Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44). Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST). Results: Eszopiclone 3 mg had significantly less time to sleep onset ( p ≤ 0.0001), more total sleep time and sleep efficiency ( p ≤ 0.0001), better sleep maintenance (p ≤ 0.01), and enhanced quality and depth of sleep ( p < 0.05) across the double-blind period compared with placebo. Eszopiclone 2 mg had significantly less time to sleep onset ( p ≤ 0.001), more total sleep time ( p ≤ 0.01) and sleep efficiency ( p ≤ 0.001), and enhanced quality and depth of sleep ( p < 0.05) compared with placebo, but did not significantly improve sleep maintenance. There was no evidence of tolerance or rebound insomnia after therapy discontinuation. Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group. Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste. Conclusions: Patients treated with nightly eszopiclone 3 mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial. There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.

Randomized comparison of doxorubicin and vindesine to doxorubicin for patients with metastatic soft‐tissue sarcomas

Two treatment regimens for metastatic soft‐tissue sarcomas were compared in a randomized trial in the cooperative group setting. Histopathologic diagnosis was affirmed by pathology reference panel review in 72% of the 347 patients. In 21% of patients, the reference panel affirmed the diagnosis of soft‐tissue sarcoma but disagreed as to type; 7% of patients were ineligible based upon cell type. Of 298 patients evaluable, measurable tumor regression (partial or complete response) occurred in 17% of patients to doxorubicin (70 mg/m2 intravenously) and 18% of patients to doxorubicin (70 mg/m2 intravenously) and vindesine (3 mg/m2 intravenously), each given every 3 weeks. No difference existed in complete response (4% for doxorubicin, 6% for doxorubicin and vindesine) or median survival (9.4 months for doxorubicin, 9.9 months for doxorubicin and vindesine). Overall, 60% of those patients on doxorubicin and vindesine and 46% on doxorubicin experienced a severe or worse toxicity of treatment (P = 0.01). With greater toxicity and lack of any gains in efficacy, the results do not support use of the combination of doxorubicin and vindesine for metastatic soft‐tissue sarcomas.

Fractionation and dose rate effects in mice: A model for bone marrow transplantation in man

This study was designed to compare several fractionation and dose rate schedules to optimize the therapeutic ratio for total body irradiation (TBI). C3H/HeJ mice were given TBI and the bone marrow survival fraction was calculated using the CFUS assay. Irradiation was given at two dose rates: low dose rate (LDR) at 5 cGy/min or high dose rate (HDR) at 80 cGy/min in single fraction and fractionated regimens. The fractionated regimens were given as either 120 cGy three times daily, 200 cGy twice daily, or 200 cGy daily. The Do was 80 cGy for the single fraction, HDR group and 85 for the LDR group. For the fractionated regimens, the apparent Dos ranged from 55-65 indicating no sparing effect of fractionation for the normal bone marrow stem cells. Indeed, the Dos were smaller suggesting an increased sensitivity to irradiation with fractionation. Low dose rate (LDR) and fractionation were also studied for their influence on normal tissue toxicity following upper half body irradiation (UHBI). All the fractionated regimens had higher LD50/30 and LD50/30-180 values than those achieved by single fraction LDR alone. There was no significant dose rate effect for LD50/30 when 120 or 200 cGy fractions were used. However, dose rate was important for LD50/30-180 with 200 cGy but not with 120 cGy fractions. These results demonstrate protection of non-hematopoietic tissues with fractionation and low dose rate without protecting hematopoietic stem cells and may have implications for human bone marrow transplantation.

The effect of eszopiclone in patients with insomnia and coexisting rheumatoid arthritis: a pilot study.

OBJECTIVE To evaluate the efficacy and safety of eszopiclone 3 mg, a nonbenzodiazepine medication/hypnotic indicated for the treatment of insomnia with comorbid rheumatoid arthritis (RA). METHOD This multicenter, double-blind, placebo-controlled pilot study was conducted in 153 patients aged 25-64 years with American College of Rheumatology-defined RA who met DSM-IV criteria for insomnia. The data were collected from February to November of 2004. Patients were randomly assigned to either eszopiclone or placebo nightly for 4 weeks, followed by a 2-week placebo run out. Efficacy was evaluated using patient reports of sleep (wake time after sleep onset [WASO], sleep latency [SL], and total sleep time [TST]), daytime function, pain, and RA assessments. Insomnia severity was evaluated using the Insomnia Severity Index. Safety was also evaluated. RESULTS Eszopiclone significantly improved all patient-reported sleep measures (WASO, SL, and TST), sleep quality, depth of sleep, and daytime function (P < .05 vs placebo). At week 4, 48% of eszopiclone-treated patients had no clinically meaningful insomnia as assessed by ISI score (versus 30% of placebo-treated patients, P = .03). Eszopiclone was significantly better than placebo on some RA-associated pain measures: (1) overall (P = .05), pain (P = .006), and pain and other symptoms (P = .02) scores of the Arthritis Self-Efficacy Scale, (2) tender joint counts (P = .03) and pain severity scores (P = .023), (3) the activities domain of the Health Assessment Questionnaire-Disability Index (P = .04), and (4) the role physical (P = .03) and bodily pain (P = .01) scales of the 36-item Medical Outcomes Study Short-Form General Health Survey. The most commonly reported adverse events with eszopiclone were unpleasant taste and transient increases in RA symptoms. CONCLUSIONS In this pilot study of patients with insomnia comorbid with RA, eszopiclone 3 mg improved all assessed sleep and daytime function measures over the treatment period, as well as some measures of RA-associated pain, disability, and quality of life. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00367965.

A generalized kaplan-meier estimator for heterogenous populations

Carrent methods for adjusting estimated survival curves for the effects of important prognostic factors are reviewed. These methods often are not useful because of the censoring pattern or because the underlying assumptions are not met. A new method, which is a generalization of the product-limit estimator, is proposed and its properties are considered. It also has limitations, but is useful in several cases where the existing methods are not suitable.

Split-course versus continuous pelvis irradiation in carcinoma of the uterine cervix: A prospective randomized clinical trial of the radiation therapy oncology group

In August 1980, the Radiation Therapy Oncology Group (RTOG) completed a prospective randomized clinical trial for the comparison of a split-course versus a standard continuous course of pelvic irradiation for carcinoma of the uterine cervix Stages II-B, III-A, III-B, and IV-A. The split-course consisted of 10 fractions of 250 rad each, 5 times a week, up to 2500 rad followed by a rest period of approximately 2 weeks and then another 2500 rad was given (250 X 10). The continuous course consisted of 30 fractions of 170 rad each, 5 times per week, for a total of 5100 rad. In both groups the external pelvis irradiation was followed by intracavitary brachytherapy in the uterus and vagina, with tandem-colpostat or tandem only, for a dose of 3000 rad at point A for the former, or at 2 cm from the center of the linear source for the latter. In cases where brachytherapy was not possible, a boost of external irradiation with reduced field, with a dose of 1600 rad (200 X 8) was advised. Three hundred and one patients were registered, of which 287 are currently evaluable. No differences between the treatments were detected for the following study end-points: treatment tolerance in terms of acute normal tissue reactions and completion of therapy, tumor control in the pelvis, severe late normal tissue reactions, and survival. In the entire study population the estimated tumor control in the pelvis at two years after initiation of therapy was: 81% for Stage II-B, 67% for III-A, 53% for Stage III-B, and 32% for Stage IV-A. The estimated two-year survival was: 70% for Stage II-B, 58% for III-A, 46% for III-B, and 23% for IV-A.