Multiple sclerosis in pediatric patients in Slovenia.

AIM: The purpose of this study is to review the Slovenian experience with the diagnostics, treatment and outcome in pediatric multiple sclerosis (MS) patients. METHODS: Children and adolescent diagnosed with MS and followed by Department of Child, Adolescent and Developmental Neurology, University Childrens' Hospital Ljubljana, between 1 January 2000 and 31 December 2012 were included. Data from patients' documentation were analyzed retrospectively to record demographic data, clinical presentation, paraclinical findings, disability progression, relapse rate and treatment strategies. RESULTS: The study includes 38 patients up to 18 years with MS diagnosis, with female: male ratio 2.8:1 and the incidence of 0.81 per 100.000 children of 0-18 years. The mean age at the time of diagnosis was 15 years 4 months. Most frequent presenting symptoms were sensory, motor, brain-stem, visual and ataxia and 65% of patients had a relapse in the first year. The value of paraclinical findings was asessed. 74% of patients with definite MS and 36% of those with clinically isolated syndrome received disease modifyng therapy and 68% of them was not affected at the follow-up. INTERPRETATION: The characteristics of pediatric MS patients in Slovenia disclose higher annual relapse rates than in adults but also favorable impact of disease modifying treatment on a clinical course. Our data suggest a good treatment tolerance but also the influence of the formulation on a decision to start or switch the treatment.

Pregabalin in neuropathic pain syndromes: A post-marketing surveillance study on efficacy,safety and tolerability

CONTEXT: Pregabalin has shown efficacy in the treatment of multiple chronic pain syndromes. OBJECTIVES: The objective was to evaluate the overall safety and tolerability of pregabalin in the treatment of a several neuropathic pain syndromes in a naturalistic setting using a flexible dosage regimen.METHODS: Patients aged >- 18 years with neuropathic pain of various etiologies participated in an open-label, non-comparative study at 95 sites in the Philippines. Treatment included pregabalin for 4 weeks, with upward dosage titration to 600 mg/day at investigator discretion. Efficacy was rated with an 11-point pain visual analog scale (VAS). Physicians and patients rated pregabalin on treatment satisfaction, efficacy and safety using a Clinical Global Impression (CGI) rating scale. Descriptive statistics were used for quantitative variables and categorical frequency counts for qualitative variables. RESULTS: The efficacy analysis (intent-to-treat) included 1603 patients. Mean VAS pain score improved from baseline (7.2 +- 1.6) to 3.8 +- 1.8 at second visit and 2.3 +- 1.4 at last visit. Physicians' and patients' impression of pregabalin regarding treatment satisfaction, efficacy and safety using a CGI rating scale showed> 75% who gave a rating of excellent at second visit gave the same rating at final visit. Adverse events (AEs) were generally mild to moderate, with dizziness and somnolence most frequently reported. DISCUSSION: Improvement in mean VAS pain scores as well as physicians' and patients' overall satisfaction with tolerability and efficacy support the usefulness of pregabalin in the treatment of various neuropathic pain syndromes in Asian patients. WHAT'S KNOWN? Pregabalin is effective for the treatment of chronic pain syndromes, including painful diabetic peripheral neuropathy, postherpetic neuralgia, spinal cord injury and fibromyalgia. WHAT'S NEW? This open-label, non-comparative study demonstrates safety, tolerability and efficacy for neuropathic pain syndromes in Asian patients.

Quality of life, mood, and sexual function: a path analytic model of treatment effects in men with erectile dysfunction and depressive symptoms.

Erectile dysfunction (ED) is commonly associated with depressed mood and diminished quality of life (QoL), but few studies have investigated the causal associations involved. Therefore, we evaluated the correlation between several measures of mood, QoL, and sexual function in a retrospective analysis of a sample of depressed men (n=152), with ED enrolled in a clinical trial of sildenafil citrate (VIAGRA). Strong correlations were observed at baseline among measures of erectile function (EF), mood, and overall QoL. Significant treatment effects were observed on all three domains, with significant interactions between changes in mood and QoL. Based on multiple regression and path analysis, a model was developed in which EF changes were associated with improved mood and quality of sexual life, which resulted in improved partner satisfaction, family life, and overall life satisfaction. These data suggest that QoL changes associated with ED therapy may be mediated by changes in sexual function, mood, and family relationships.

Clinical trials of sildenafil citrate (Viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo.

We pooled data regarding myocardial infarction (MI) and cardiovascular death from more than 120 clinical trials of sildenafil citrate (Viagra) conducted from 1993 to 2001. During placebo-controlled trials, the rate of MI or cardiovascular death was 0.91 (95% CI: 0.52-1.48) per 100 person-years (PY) of follow-up among sildenafil-treated patients compared with 0.84 (95% CI: 0.39-1.60) per 100 PY of follow-up among placebo-treated patients. The relative risk of MI or cardiovascular death was 1.08 (95% CI: 0.45-2.77) for sildenafil compared with placebo (p = 0.88). During open-label studies, the rate of MI or cardiovascular death was 0.56 (95% CI: 0.44-0.72) per 100 PY of follow-up. This analysis showed that the rates of MI and cardiovascular death were low and comparable between men treated with sildenafil and those treated with placebo. The use of sildenafil was not associated with an increase in the risk of MI or cardiovascular death.

Minimal time to successful intercourse after sildenafil citrate: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the minimal time to successful intercourse after taking sildenafil citrate for erectile dysfunction (ED). METHODS: Male patients with ED (mean age 60 years; mean ED duration 7.0 years) who were successfully treated with sildenafil (100 mg) for 2 months or longer were randomized to sildenafil (n = 115) or placebo (n = 113) for 4 weeks of double-blind treatment. Using a stopwatch, patients recorded the time needed to obtain an erection hard enough for sexual intercourse after taking the study drug at least 2 hours after eating. RESULTS: Within 14 and 20 minutes of sildenafil dosing, 35% and 51% of sildenafil-treated patients, respectively, versus 22% and 30% of placebo-treated patients, respectively, had an erection that led to successful intercourse (P <0.05 for both). The median time to erection leading to successful intercourse after sildenafil dosing was 36 minutes compared with 141 minutes for placebo. CONCLUSIONS: In this study, slightly more than one half of a population of prior sildenafil responders achieved an erection that led to successful sexual intercourse within 20 minutes of sildenafil administration, suggesting that the onset of action of sildenafil can be less than 30 minutes in men with ED.

Metrifonate treatment of the cognitive deficits of Alzheimer's disease. Metrifonate Study Group.

The efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, was evaluated clinically in patients diagnosed with mild to moderate Alzheimer's disease (AD). This was a prospective, 30-week, multicenter, double-blind, randomized, parallel group, dose-finding study, which included a 2-week screening period, a 12-week treatment period, and follow-up visits at 8 and 16 weeks post-treatment. Patients received placebo or metrifonate once daily. Metrifonate-treated patients received a loading dose of 0.5 mg/kg (25 to 45 mg), 0.9 mg/kg (45 to 80 mg), or 2.0 mg/kg (100 to 180 mg) for 2 weeks, followed by a maintenance dose of 0.2 mg/kg (10 to 20 mg), 0.3 mg/kg (15 to 25 mg), or 0.65 mg/kg (30 to 60 mg) for 10 weeks. Four hundred eighty patients were enrolled. Percentages of patients completing double-blind treatment were 96% in the placebo group and 89 to 94% in the metrifonate group. Metrifonate significantly improved cognitive ability, as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and enhanced global function, as assessed the Clinicians's Interview-Based Impression of Change with Caregiver Input (CIBIC-Plus). At 3 months, in the intent-to-treat patients, the treatment difference for the change in ADAS-Cog score in favor of metrifonate was 2.94 points (95% CI, 1.61 to 4.27; p = 0.0001). These patients also exhibited a 0.35-point improvement on the CIBIC-Plus relative to the placebo patients (95% CI, 0.15 to 0.54; p = 0.0007). Patients receiving lower drug doses had scores intermediate to those of the placebo and the 0.65 mg/kg metrifonate groups on both performance scales. The drug was well tolerated; side effects were predominantly gastrointestinal in nature, and no hepatic toxicity was observed. Therefore, in this study, metrifonate safely improved the cognitive deficits and benefited the global function of AD patients.

Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease.

OBJECTIVE: To evaluate the efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease (AD) of mild to moderate severity. METHODS: A prospective, 36-week, multicenter, double-blind, randomized, parallel group study of metrifonate in probable AD patients, including a 2-week screening period, a 26-week double-blind treatment period, and a follow-up visit at 8 weeks post-treatment. A total of 24 ambulatory clinics in the United States in a variety of settings, including contract research organizations, public health facilities, and universities. Patients met diagnostic criteria for probable AD as defined by the work group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association. Patients had Mini-Mental State Examination (MMSE) scores of 10 to 26 and Ischemic Scores (Rosen Modification) of <4. A total of 408 patients were enrolled. Percentages of patients completing double-blind treatment were 88% and 79% in the placebo and metrifonate groups, respectively. Rates of discontinuation due to adverse events were 4% in the placebo group and 12% in the metrifonate group. Placebo or metrifonate was administered once daily. Metrifonate-treated patients received a loading dose of 100 to 180 mg based on weight (2.0 mg/kg) for 2 weeks, followed by a maintenance dose of 30 to 60 mg based on weight (0.65 mg/kg) for 24 weeks. Primary efficacy variables were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus). Secondary efficacy variables included the Neuropsychiatric Inventory (NPI), the Disability Assessment in Dementia, the Global Deterioration Scale (GDS), the ADAS-Noncognitive subscale (ADAS-Noncog), the MMSE, and the Clinician's Interview-Based Impression of Severity with Caregiver Input (CIBIS-plus). Outcome measures reflected changes from baseline at week 26 for all variables. Safety was assessed with incidences of premature termination, treatment-emergent events and mortality, and routine safety evaluations. RESULTS: After 26 weeks of metrifonate therapy, a 2.86-point treatment difference (p = 0.0001) was observed in the ADAS-Cog scores of the intent-to-treat AD patients. The treatment difference in the mean CIBIC-plus score at this time was 0.28 points (p = 0.0071). At week 26, treatment differences also were observed in the mean NPI total score (p = 0.0161). Analysis of the remaining secondary efficacy variables showed treatment differences that favored metrifonate but did not reach statistical significance. Metrifonate adverse events were predominantly mild in intensity. No hepatotoxicity was observed. CONCLUSIONS: Metrifonate was safe and well-tolerated. It enhanced not only the cognitive and global function, but also the behavioral function of patients diagnosed with mild to moderate AD. Therefore, metrifonate appears to be useful in the symptomatic treatment of AD.

Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer's disease.

Metrifonate is converted nonenzymatically to 2.2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21-day, randomized, double-blind, placebo-controlled trial of metrifonate in patients with Alzheimer's disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75-135 mg), MD = 0.25 mg/kg (12.5-25 mg); panel 2, LD = 2.5 mg/kg (125-225 mg), MD = 0.40 mg/kg (20-35 mg); panel 3, LD = 4.0 mg/kg (200-335 mg), MD = 0.65 mg/kg (30-60 mg); and panel 4, LD = 4.0 mg/kg (200-335 mg), MD = 1.0 mg/kg (50-90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration-time curve (AUC) and maximum concentration (Cmax) for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose-independent mean values for time to Cmax (tmax) and half-life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long-term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimer's disease.

Clinical and pharmacology study of chloroquinoxaline sulfonamide given on a weekly schedule.

The in vitro human tumor colony-forming assay identified chloroquinoxaline sulfonamide (CQS) as an active agent at human plasma concentrations of > 100 micrograms/ml. In the initial phase I trial of CQS given every 28 days, peak plasma concentrations > 500 micrograms/ml were associated with reversible dose-limiting hypoglycemia and occasional cardiac arrhythmias. Therefore, we evaluated whether a weekly schedule of treatment might minimize the drug-associated toxicity while maintaining potential therapeutic concentrations. CQS was given intravenously over 1 h once per week for 4 weeks to 12 patients, beginning at a dose of 2,000 mg/m2. All patients underwent monitoring for cardiac arrhythmias and hypoglycemia. Plasma drug levels were measured following each dose. Mild hypoglycemia was the most common adverse effect. A median nadir plasma glucose concentration of 56 mg/dl was observed at a weekly dose of 2,500 mg/m2. Two patients experienced cardiac dysrhythmia while on study. Continuous electrocardiographic monitoring failed to identify any significant infusion-related arrhythmia. The median CQS plasma concentration measured 24 h following a 2,000-mg/m2 dose of CQS was > 100 micrograms/ml, and the cumulative area under the concentration x time curve (AUC) determined at concentrations of > or = 100 micrograms/ml was similar to that observed with the every-28-day schedule. The weekly schedule described herein appears to maximize the plasma AUC with an acceptable margin of safety. The recommended phase II dose and schedule for CQS is 2,000 mg/m2 given once per week. Although severe hypoglycemia is unlikely, glucose monitoring is appropriate for 6 h following CQS administration.

A nonparametric analysis of the transmission rate of human immunodeficiency virus from mother to infant.

Infants born to mothers who are infected with the human immunodeficiency virus (HIV) may or may not become infected by perinatal transmission. Unfortunately, passively transferred maternal antibodies make it hard to determine the infant's infection status from HIV antibody testing, because shortly after birth it is not possible to distinguish passively transferred maternal antibodies from antibodies produced by an infected infant. Usually, the infection status is unobservable for each infant, unless the infant reaches the age of 15 months or develops an HIV-related disease such as the acquired immunodeficiency syndrome (AIDS). Traditionally, statistical analyses of the perinatal transmission rate of HIV are based on infants who had been born at least 15 months before the date of analysis. Such analyses can be both inefficient and biased. In this note, we define a mixture model underlying the onset time of AIDS and then obtain the nonparametric maximum likelihood estimators of the HIV transmission rate and of the distribution function of AIDS onset time for infected infants. Nonparametric tests are also derived for detecting differences in HIV transmission rates among different groups of infants. Finally, the methods are applied to the Mothers and Infants Cohort Study in New York City. The transmission rate of HIV from infected mothers to their infants was estimated to be 30.0% with 95% confidence interval (22.3%, 39.1%).

Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer.

PURPOSE: This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Docetaxel was administered to 29 patients with unresectable stage III and IV NSCLC at a dose of 100 mg/m2 intravenously (IV) over 1 hour every 21 days. No premedication was given to the first 16 patients. Premedication with diphenhydramine was instituted for the remainder. No patient had previously received chemotherapy. Seven patients had undergone prior radiation therapy. RESULTS: All patients were assessable for response and toxicity. Eleven of 29 patients (38%) had a major objective response (95% confidence interval, 21% to 58%). The median duration of response was 5.3 months. Febrile neutropenia occurred in 41% of patients and in 11% of 134 courses of docetaxel. Nonhematologic toxicities included infusion-related hypersensitivity reactions, fluid retention, rash, alopecia, and sensory neuropathy. Premedication with diphenhydramine did not decrease the incidence of infusion-related hypersensitivity reactions. CONCLUSION: At this dose and schedule, docetaxel demonstrates significant antitumor activity in patients with advanced NSCLC. Further investigations of this agent in NSCLC are indicated.

Neoplastic transformation dose response of oncogene-transfected rat embryo cells by gamma rays or 6 MeV alpha particles.

We measured a dose-response relationship for induction of neoplastic transformation by 6 MeV alpha particles and 137Cs gamma rays in REC:myc and REC:ras cells, that is, rat embryo cells (REC) transfected with the c-myc or the Ha-ras oncogenes. The 6 MeV alpha particles simulated 222Rn emissions for risk assessment relative to low-LET radiations. The dose of gamma rays was approximately twice that of alpha particles for a neoplastic transformation frequency of 10(-3). The survival of the REC cells containing oncogenes was comparable to that of the commonly used C3H 10T1/2 cells for the same dose, but the former were more refractory to radiation-induced neoplastic transformation. Neoplastic transformation frequency measured in REC cells was 3 times lower than those typically measured in C3H 10T1/2 cells at a gamma-ray dose of 6 Gy, and 5-10 times lower at an alpha-particle dose of 3 Gy.

Three-dimensional conformal radiation therapy in locally advanced carcinoma of the prostate: preliminary results of a phase I dose-escalation study.

PURPOSE: The acute morbidity of doses of 64.8-75.6 Gy and preliminary observations of late complications and tumor response using 3-dimensional conformal radiation therapy in carcinoma of the prostate are assessed. METHODS AND MATERIALS: 123 patients (Stage A2-12, B1-17, B2-43, C-51) were irradiated to the prostate and seminal vesicles using a 3-dimensional conformal radiation therapy technique. The median follow-up time was 15.2 months. The minimum tumor dose was 64.8-66.6 Gy in 49 patients, 70.2 Gy in 46, and 75.6 Gy in 28. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading system. RESULTS: This technique of 3-dimensional conformal radiation therapy was well-tolerated with minimal acute morbidity. Only 32% of patients had grade 2 or 3 acute morbidity requiring short-term medication for relief of urinary symptoms or diarrhea. Only one patient (0.8%) has so far developed a severe (grade 4) late complication. Serum prostate specific antigen concentrations normalized in 67% of patients (64/96) within 1-14 months (median 4.5 months) after treatment and were progressively decreasing at last measurement in an additional 22% (21/96). Abnormal rising prostate specific antigen levels were observed in 15 patients, 11 of whom have already developed other evidence of relapsing disease. CONCLUSION: Acute toxicity for the doses tested with this 3-dimensional conformal radiation therapy technique is reduced compared to traditional treatment techniques, and the initial tumor response as assessed by prostate specific antigen measurement is highly encouraging with prostate specific antigen levels returning to normal in the majority of patients. Based on these results, a further increase of the dose to 81 Gy has been implemented in accordance with the schema of an ongoing Phase I dose-escalation study.

Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole.

BACKGROUND: All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA. PURPOSE: We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes. METHODS: Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer. RESULTS: The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01). CONCLUSION: Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.

Isoflurane versus fentanyl: hemodynamic effects in cancer patients treated with anthracyclines.

Cancer patients treated with anthracycline derivatives are at risk for perioperative cardiovascular decompensation. The authors studied hemodynamic performance before, during, and after laparotomy in 14 anthracycline-treated patients with ovarian carcinoma. General anesthesia was maintained with 70% N2O in O2, and patients were randomized to receive supplementation with either isoflurane, 0.59% end-tidal +/- 0.04 (mean +/- SE), or fentanyl, 2.67 micrograms/kg +/- 0.49 as a loading dose, and a total dose of 7.16 micrograms/kg +/- 0.71. The degree of hemodynamic stability relative to the baseline was assessed. There was no obvious superiority of either technique prior to the skin incision. However, during and immediately after surgery, a clearer tendency for isoflurane-N2O to result in better hemodynamic stability was found. Isoflurane-N2O demonstrated significantly smaller change scores in systemic vascular resistance (SVR) and cardiac index (CI). At the start of surgery, the isoflurane-N2O change in SVR was 228.08 dyne.sec.cm-5 compared to 479.58 for the fentanyl patients, (P = 0.002); at the end of surgery the corresponding means were -12.09 and 703.14 dyne.sec.cm-5, respectively, (P = 0.002). Isoflurane-N2O was associated with significantly greater CI stability in the early postoperative period: the isoflurane-N2O mean change was -0.081 L/min/m2, versus -0.993 for the fentanyl-N2O patients, (P = 0.005). The authors conclude that anthracycline-treated patients who do not have overt evidence of cardiomyopathy can be safely anesthetized with either anesthetic technique. However, during surgery and in the early postoperative period, an isoflurane-N2O technique appears to offer better hemodynamic stability.

Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung.

The epidermal growth factor receptor (EGFR) and one of its ligands, transforming growth factor alpha (TGF-alpha), are thought to function as a potential autocrine loop in non-small cell lung cancer (NSCLC). However, the expression pattern of EGFR and the TGF-alpha-related ligands have not been fully characterized in primary NSCLC and adjacent benign lung tissue. For this reason, we comprehensively examined the coexpression and differential expression of EGFR and its ligands, TGF-alpha, epidermal growth factor (EGF), and amphiregulin (AR), by Northern analysis, in paired samples of primary tumors and uninvolved lung. For those RNA species overexpressed in malignant lung, single cell expression patterns were studied by immunohistochemistry. Specimens were obtained from 57 consecutive patients who underwent resection of carefully staged resectable NSCLC and were followed prospectively. Most (112 of 114) tissue samples yielded high-quality RNA. EGFR was expressed in 82 of 88 (93%) tissue samples, while TGF-alpha was expressed in 62 of 72 (86%) samples, and AR was expressed in 64 of 70 (92%) samples. EGF was unexpressed in total cellular RNA in both tumor and uninvolved lung. In a comparison of RNA expression patterns in tumors and uninvolved lung, overexpression of EGFR was found in 45% (22 of 44) of tumors, while overexpression of TGF-alpha was seen in 61% (22 of 36) of tumors, and decreased expression of AR was seen in 63% (22 of 35) of tumors. Cell type and stage did not influence differential expression, indicating that this is a frequent event in primary NSCLC. Simultaneous overexpression of EGFR and TGF-alpha was seen in only 38% of tumors. Simultaneous overexpression of EGFR and decreased expression of AR were seen in only 21% of tumors. Thus far, the differential expression of EGFR, TGF-alpha, and AR does not correlate with either disease-free or overall survival. These findings indicate that histologically dissimilar tumors can express similar components of autocrine or paracrine growth factor loops. Differential expression of EGFR and its ligands in tumor specimens compared to uninvolved lung is a common event in NSCLC and may participate in tumor growth without necessarily influencing tumor progression or histology.

Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide.

Chloroquinoxaline sulfonamide (CQS) is a halogenated heterocyclic sulfanilamide identified by the in vitro human tumor colony-forming assay as an active agent in a variety of human solid tumors. In this phase I study, 182 courses of CQS were administered intravenously every 28 days to 88 patients at doses ranging from 18 to 4870 mg/m2. Hypoglycemia associated with hyperinsulinemia was the dose-limiting adverse effect at 4870 mg/m2. Supraventricular tachyarrhythmias were observed at doses > 4000 mg/m2. Less common reactions included infusion site phlebitis, nausea, anemia, alopecia, perioral numbness, and diarrhea. Cumulative toxicity was not observed. Minor objective antitumor responses were noted in 7 patients; 6 of the 7 responses occurred in patients with non-small cell lung cancer. Results of pharmacokinetic studies were consistent with the preclinical observations that CQS is highly bound to plasma protein. Plasma elimination followed a two-compartment model; the mean t 1/2 alpha was 2.7 +/- 0.3 h and the t 1/2 beta was 52 +/- 6 h (+/- SE). The total body clearance and the volume of distribution at steady state of CQS both increased with the dose (distribution at steady state, 3.7-10.5 liter/m2; total body clearance, 53-264 ml/h/m2 for doses of 18-4060 mg/m2) and may reflect saturation of the protein binding and "free" drug clearance. Although inactive against common animal tumors in preclinical screening systems both in vitro and in vivo, CQS has demonstrated definite activity in the human tumor stem cell colony-forming assays, as well as modest anticancer activity in this phase I study in patients with advanced solid tumors. The pharmacokinetic results and the limiting effect of transient hypoglycemia suggest that considerably higher cumulative doses of CQS could be administered using a more frequent dosing schedule.

Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: the case for studies in previously treated patients.

PURPOSE: This review was undertaken (1) to determine the antitumor activity of agents studied in phase II trials in small-cell lung cancer (SCLC) patients, (2) to evaluate the adequacy of published trials, (3) to determine if previously treated patients are suitable for phase II trials in SCLC, and (4) to develop an improved design for phase II trials. DESIGN: English-language, single-agent efficacy trials in SCLC, published from 1970 to 1990, were reviewed. Study design and reporting of results were assessed for clinical and statistical methodology. Response rates observed in previously treated patients were compared with those observed in previously untreated patients. RESULTS: One hundred forty-one articles evaluating 57 agents in 3,042 patients were reviewed. Eleven drugs were active (defined as a response rate greater than or equal to 20% in a trial with greater than or equal to 14 assessable patients), and 12 were inactive. Due to methodologic problems with the clinical trials, the usefulness of the remaining 34 drugs (60%) remains uncertain. Deficiencies identified in trials include inappropriate sample sizes, poorly defined response criteria, and failure to report important prognostic factors. When studied in adequate trials, all agents known to be active in SCLC had an observed response rate greater than or equal to 10% in previously treated patients. CONCLUSIONS: Over the past 2 decades, phase II trials in SCLC have failed in their primary task of effectively identifying agents that warrant further clinical study and rejecting inactive agents. If only previously treated patients had been entered into these trials, no useful agent would have been missed provided that a lower observed response rate had been used as evidence of antitumor activity. We propose a two-stage sequential study design, entering previously treated patients, for future phase II trials in SCLC.

Medicaid versus state funding of community residences: impact on daily life of people with mental retardation.

The unintended effects on quality of life that flow from decisions regarding funding sources used to support community-based residential programs were documented. Results show that community residence program structures play an important role in determining quality of life after deinstitutionalization. Clients living under program structures flowing from the Medicaid ICF/MR funding source were less active and involved in life than were clients living in programs funded by non-Medicaid state sources. We hypothesized that the reason for this differential outcome was the result of Medicaid funding regulations and their interpretation, which create an institutional-like set of program structures leading to restrictive care patterns.

Relationship among CT scans, neurological exam, and neuropsychological test performance in right-brain-damaged stroke patients.

Right-hemisphere stroke rehabilitation inpatients were assessed by: (1) CT scans; (2) neurological exam; and (3) cognitive and affective psychometric measures. Damage to temporal, parietal, and occipital regions was associated with visual-spatial impairments. Surprisingly, parietal damage was no more related than temporal and occipital damage to severity of visual inattention. While the neurologist's ratings of lability and depression were related to CT-scan measures, patients' self-report of depression was not so related. These findings support a less specific and probably greater interlobule organization of the right, as compared with left, hemisphere, and highlight the need for multifaceted affective assessment in such a brain-damaged group.