Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study.

BACKGROUND: CI-994, an oral histone deacetylase inhibitor, has antineoplastic activity and synergism with gemcitabine preclinically. This randomized phase II trial explored whether CI-994 plus gemcitabine improves overall survival, objective response, duration of response, time to treatment failure and change in quality of life (QoL) or pain compared with gemcitabine alone. PATIENTS AND METHODS: A total of 174 patients received CG (CI-994 6 mg/m(2)/day days 1-21 plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 each 28-day cycle) or PG (placebo plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 of each 28-day cycle days 1-21). RESULTS: Median survival was 194 days (CG) versus 214 days (PG) (P = 0.908). The objective response rate with CG was 12% versus 14% with PG when investigator-assessed and 1% versus 6%, respectively, when assessed centrally. Time to treatment failure did not differ between the two arms (P = 0.304). QoL scores at 2 months were worse with CG than with PG. Pain response rates were similar between the two groups. There was an increased incidence of neutropenia and thrombocytopenia with CG. CONCLUSIONS: Adding CI-994 to gemcitabine in advanced pancreatic carcinoma does not improve overall survival, response rate or time to progression; CG produced decreased QoL and increased hematological toxicity and appears inferior to single-agent gemcitabine.

Bias and error rates for premorbid IQ estimators: comment on Veiel and Koopman (2001).

H. O. F. Veiel and R. F. Koopman (2001) advance statistical and legal theses. They correctly point out that the usual regression formula for estimating a pre-event IQ underestimates high IQs and overestimates low IQs (due to regression to the mean). They call this a conditional bias and show it can be sizeable. The author takes issue with their claim that a new estimator they propose should be used in place of the usual formulas, because it negates this statistical bias. Their argument against the usual estimator conflates statistical bias and legal bias. Their discussion in favor of their new estimator mentions, but does not derive a general formula for, a gross loss of precision entailed by use of the new estimator. The author quantifies this loss of precision and, using Veiel and Koopman's numerical example, shows that their estimator quadruples error.

Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives.

OBJECTIVE: Performance on measures of saccadic inhibition and control was investigated in a large family study of schizophrenia to evaluate the utility of using antisaccade task performance as an endophenotypic marker of genetic liability for schizophrenia. METHOD: Ninety-five patients with acute schizophrenia and 116 of their first-degree biological relatives, 13 schizophrenia patients whose illness was in full remission, 35 patients with acute psychotic affective disorder, and 109 nonpsychiatric comparison subjects were administered antisaccade and prosaccade tasks. RESULTS: Both schizophrenia patient groups had a greater number of errors on the antisaccade task than did the first-degree relatives and the affective disorder group, which both had more errors than the comparison subjects. Among the first-degree relatives of the probands with acute schizophrenia, relatives of poor-performing patients performed worse on the antisaccade task than relatives of patients with good performance. Reflexive errors were not likely the result of interfering psychotic symptoms, medication, or medication side effects. Although the schizophrenia patients demonstrated other signs of saccadic abnormalities, these problems, which were not observed in their relatives even though they had high antisaccade error rates, seem unlikely to account for the higher antisaccade error rate of the schizophrenia patients. CONCLUSIONS: These findings suggest that saccadic disinhibition is strongly associated with the genetic liability for schizophrenia.

Toward a resolution of the Rorschach controversy.

Comments are made about the articles comprising the first round of the Special Series on the Rorschach. G. Stricker and J. R. Gold (1999) and D. J. Viglione (1999) praised the Rorschach, but they consistently failed to cite negative findings. R. M. Dawes (1999) obtained results that provide modest support for the Rorschach, but one of his data sets is flawed. J. B. Hiller, R. Rosenthal, R. F. Bornstein, D. T. R. Berry, and S. Brunell-Neuleib (1999) reported the results of a meta-analysis, but, among other problems, their coders were not blind to the results of all the studies. J. Hunsley and J. M. Bailey (1999) made a strong case for concluding that there is no scientific basis for using the Rorschach. Recommendations are made for resolving the Rorschach controversy.

A phase I and pharmacologic evaluation of the DNA intercalator CI-958 in patients with advanced solid tumors.

5-[(2-Aminoethyl)amino]-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyra no[4,3,2-cd]-indazol-8-ol trihydrochloride (CI-958) is the most active member of a new class of DNA intercalating compounds, the benzothiopyranoindazoles. Because of its broad spectrum and high degree of activity as well as a favorable toxicity profile in preclinical models, CI-958 was chosen for further development. The Phase I study described here was undertaken to determine the toxicity profile, maximum tolerated dose, and pharmacokinetics of CI-958 given as an i.v. infusion every 21 days. Adult patients with advanced refractory solid tumors who had adequate renal, hepatic, and hematological function, life expectancy, and performance status were eligible for this study. Written informed consent was obtained from all patients. Patients received a 1- or 2-h infusion of CI-958 at 21-day intervals. The starting dose was 5.2 mg/m2, and at least three patients were evaluated at each dose level before proceeding to a new dose level. A pharmacokinetically guided dose escalation design was used until reaching a predetermined target area under the plasma concentration versus time curve (AUC), after which a modified Fibonacci scheme was used. Forty-four patients (21 men and 23 women; median age, 59 years) received 162 courses of CI-958. Neutropenia and hepatorenal toxicity were the dose-limiting toxicities, which defined the maximum tolerated dose of CI-958 to be 875 mg/m2 when given as a 2-h infusion every 21 days. There were no tumor responses. Two patients had stable disease for >250 days. The recommended Phase II dose is 560 mg/m2 for patients with significant prior chemotherapy and 700 mg/m2 for patients with minimal prior chemotherapy. Pharmacokinetic analysis of plasma and urine concentration-time data from each patient was performed. At the recommended Phase II dose of 700 mg/m2, mean CI-958 clearance was 370 ml/min/m2, mean AUC was 33800 ng-h/ml, and mean terminal half-life (t1/2) was 15.5 days. The clearance was similar at all doses, and plasma CI-958 AUC increased proportionally with dose, consistent with linear pharmacokinetics. The percentage reduction in absolute neutrophil count from baseline was well predicted by AUC using a simple Emax model. The pharmacokinetically guided dose escalation saved five to six dose levels in reaching the maximum tolerated dose compared with a standard dose escalation scheme. This may represent the most successful application to date of this dose escalation technique.

Fluorescence in situ hybridization identifies inversion 16 masked by t(10;16)(q24;q22), t(7;16)(q21;q22), and t(2;16)(q37;q22) in three cases of AML-M4Eo.

Bone marrow or peripheral blood from three patients had a t(10;16)(q24;q22), t(7;16) (q21;p13.1), and t(2;16)q37;q22), respectively. In all cases, fluorescence in situ hybridization confirmed an inv(16) masked by the translocation. The three patients were diagnosed with acute myelomonocytic leukemia and increased eosinophils. Because inv(16) has a favorable prognosis, identification of masked inv(16) will promote improved management of these cases. Therefore, all cases that have atypical rearrangement of chromosome 16 should be investigated for a possible inversion.

Clinical versus mechanical prediction: a meta-analysis.

The process of making judgments and decisions requires a method for combining data. To compare the accuracy of clinical and mechanical (formal, statistical) data-combination techniques, we performed a meta-analysis on studies of human health and behavior. On average, mechanical-prediction techniques were about 10% more accurate than clinical predictions. Depending on the specific analysis, mechanical prediction substantially outperformed clinical prediction in 33%-47% of studies examined. Although clinical predictions were often as accurate as mechanical predictions, in only a few studies (6%-16%) were they substantially more accurate. Superiority for mechanical-prediction techniques was consistent, regardless of the judgment task, type of judges, judges' amounts of experience, or the types of data being combined. Clinical predictions performed relatively less well when predictors included clinical interview data. These data indicate that mechanical predictions of human behaviors are equal or superior to clinical prediction methods for a wide range of circumstances.

A phase II trial of CI-958 in patients with hormone-refractory prostate cancer.

PURPOSE: To assess the antitumor activity of the benzothiopyranoindazole CI-958 ¿5-[(2-aminomethyl)amino]-2-[2-(diethylamino)ethyl]-2H- [l]benzothiopyrano[4,3,2-cd]-indazol-8-ol trihydrochloride¿ in hormone-resistant prostate carcinoma, using an intravenous dose of 700 mg/m(2) every 3 weeks. PATIENTS AND METHODS: Patients eligible for this study had advanced prostate carcinoma that had failed hormonal treatment. Changes in an initially elevated prostate-specific antigen (PSA) level and regression of objectively measurable disease were used as response criteria. RESULTS: All 33 patients enrolled were evaluated. Of 30 with elevated PSA levels, 6 had a >50% decline maintained for >30 days; response durations ranged from 105 to 623 days. Eleven patients had objectively measurable disease; two had partial responses (lasting 316 and 461 days) consisting of shrinkage of retroperitoneal nodes and of masses surrounding the rectum and bladder. The survival of all responding patients ranged from 366 days to 709 days and the median survival of all patients was 12 months (range 1-23 + months). Neutropenia was common, but thrombocytopenia was not. Nonhematologic side effects included nausea, vomiting, anorexia, asthenia, and chills, but were usually mild. The drug caused phlebitis when given into peripheral veins and central venous administration is recommended. No consistent reductions in cardiac function were documented by sequential assessment of left ventricular ejection fractions. CONCLUSIONS: CI-958 has modest but definite antitumor activity in hormone-resistant prostate carcinoma. Its toxicities include neutropenia, nausea, vomiting, anorexia, asthenia, chills and phlebitis.

The Iowa Personality Disorder Screen: development and preliminary validation of a brief screening interview.

The length and expense of comprehensive personality disorder interviews makes them unwieldy for routine use. A brief but sensitive screen could eliminate administration of longer instruments in many instances. We describe the development of the Iowa Personality Disorder Screen (IPDS)--a mini-structured interview which can be completed in less than 5 minutes. Retrospective analyses using 1,203 SIDP-R interviews suggested that the IPDS items should provide good sensitivity and specificity. We present results from a prospective validation study, using a mixed group of 52 nonpsychotic inpatients and outpatients who were diagnosed using the SIDP-IV. Blind administration of the IPDS yielded excellent sensitivity (92%) and good specificity (79%), using a subset of five screening items. Addition of two more items leads to an estimated sensitivity of 79% and specificity of 86%. The IPDS shows promise as a quick personality disorder screen for use in research settings or standard clinical interviews.

Phase II study of i.v. CI-980 in patients with advanced platinum refractory epithelial ovarian carcinoma.

CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine site, inhibiting the polymerization of microtubules and arresting cellular division in metaphase. Myelosuppression and neurotoxicity were dose-limiting in phase I studies. Sixteen patients with stage III and IV platinum-refractory ovarian cancer received 4.5 mg/m2/day of CI-980 as a continuous i.v. infusion for 72 h, repeated every 3 weeks. Eleven patients had progression and four patients had stable disease. One patient (6%; 95% CI 0-25%) achieved a partial response after 9 months of treatment which lasted for 27 months. The overall median survival was 7 months. Grade 4 granulocytopenia occurred in five patients, with two episodes of neutropenic fever. Neurological toxicity was mild with 12 episodes of transient subclinical recent memory loss documented in four patients by specialized neuropsychological evaluations. One patient each had hallucinations and mild truncal ataxia, and four patients had mild, reversible neurosensory toxicity. One episode of severe hypoxemia and dyspnea occurred in a patient with chronic obstructive pulmonary disease. CI-980 has minimal activity and is tolerable in a population of heavily pretreated patients with platinum refractory ovarian cancer.

The cooccurrence of DSM-III-R personality disorders.

The distinction between personality disorder diagnoses is often unclear because of the frequent cooccurrence of one or more of the diagnoses. To date, studies using sample sizes large enough to evaluate the rates of cooccurrence in the less prevalent personality disorders have not been conducted. The Structured Interview for Diagnosis of Personality-Revised, a semistructured instrument designed to yield reliable personality disorder diagnoses, was used to evaluate 1116 subjects for the presence of DSM-III-R personality disorder diagnoses. Cooccurrence rates and odds ratios were calculated for each pair of diagnoses. There was a high degree of cooccurrence between the cluster A personality disorders, between the cluster C personality disorders, and between narcissistic, borderline, and histrionic disorders. In addition, there was also a high frequency of avoidant personality disorders within the cluster A personality disorder diagnoses. Possible explanations for the high degree of cooccurrence and the potential implications for the DSM-IV personality disorder diagnoses are discussed.

Phase II trial of intravenous CI-980 (NSC 370147) in patients with metastatic colorectal carcinoma. Model for prospective evaluation of neurotoxicity.

CI-980 (NSC 370147)--a synthetic mitotic inhibitor that binds to tubulin at the colchicine binding site--has significant activity against a broad spectrum of tumor models and greater in vitro cytotoxicity when given over > 24 hours than 4 hours or less. Phase I studies demonstrated central nervous system (CNS) toxicity to be dose-limiting when CI-980 was administered as a 24-hour infusion. When a 72-hour infusion was given, CNS toxicity was reduced and granulocytopenia became the dose-limiting toxicity. In this phase II study, CI-980, 4.5 mg/m2, was administered as a 24-hour continuous intravenous infusion for 3 consecutive days and repeated every 21 days. Fourteen patients who had measurable metastatic colorectal cancer were entered in the trial. Eight patients had received one prior chemotherapy regimen for metastatic disease. Patients were prospectively monitored by neurologic examinations and neuropsychologic assessment of cognitive functioning. No complete or partial responses were observed. Grade 4 granulocytopenia was the dose-limiting toxicity. Reversible declines in recent memory function were noted in all patients. After each course of CI-980, there were also transient non-significant declines in motor coordination, compared with the preinfusion assessment. At the stated dose and schedule, CI-980 lacks activity in metastatic colorectal carcinoma. The agent's toxicity profile (granulocytopenia and CNS effects) was comparable with previously described effects of this agent.

Antisaccade performance in patients with schizophrenia and affective disorder.

The authors examined psychotic patients with schizophrenia, major depression, and bipolar disorder; "normal" participants; and 1st-degree relatives of patients with schizophrenia on an antisaccade task in which participants were instructed to move their eyes in the opposite direction of a target that moved unpredictably and abruptly either to the left or right of central fixation. Patients with schizophrenia were found to make significantly more errors than their relatives, and the latter made more errors than the controls. The poor performance of the relatives could not be attributed to their having a psychiatric disorder. Comparison of the 3 patient groups indicated that antisaccade deficits were more pronounced in schizophrenia and bipolar disorder.

Neurotoxicity of CI-980, a novel mitotic inhibitor.

CI-980 is a chemotherapeutic agent currently in Phase II trials that arrests cellular division by binding to tubulin. It is structurally and functionally similar to colchicine, a potent nonreversible neurotoxin, and is able to cross the blood-brain barrier. In Phase I studies, neurotoxicity was noted. The neurotoxicity of CI-980 was prospectively evaluated in two Phase II studies by neurological evaluation, quantitative sensory testing, and neuropsychological assessment of cognitive functioning. The results revealed a significant but reversible decline in recent memory functioning after each course of CI-980, with no effect on overall mental status or neurological function. Sixty-seven percent of patients performed in the impaired range on the memory test after their first infusion, whereas only one exhibited a decline on a brief cognitive screen. The results are consistent with the known effects of colchicine on the brain. Colchicine selectively blocks choline acetyltransferase in the hippocampus and basal forebrain, the area of the brain responsible for memory consolidation. Although the effect of CI-980 was reversible at the dose and schedule used, this study suggests that careful monitoring of cognitive function in patients receiving this agent should be performed if dose or schedule parameters are changed. In addition, this study demonstrates the feasibility of incorporating neuropsychological assessment in clinical trials of new anticancer agents having potential neurotoxic side effects.

A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors.

CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and murine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m2. The maximum tolerated dose was 14.4 mg/m2. Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level 8 (intended dose was 19.2 mg/m2; actual dose was 15.6 mg/m2) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T1/2 = 5.52 hours, plasma clearance 1163 mL/min/m2, and Vdss 376 L/m2.

Collapse of child from undiagnosed diaphragmatic hernia after normal barium investigation.

A 16-month-old child who died suddenly from an undiagnosed congenital diaphragmatic hernia is described. She had previously been investigated for persistent vomiting and had undergone a barium study.

The D5 dopamine receptor gene in schizophrenia: identification of a nonsense change and multiple missense changes but lack of association with disease.

To determine whether mutations in the D5 dopamine receptor gene (DRD5) are associated with schizophrenia, the gene was examined in 78 unrelated schizophrenic individuals (156 DRD5 alleles). After amplification by the polymerase chain reaction, products were examined by dideoxy fingerprinting (ddF), a screening method related to single strand conformational polymorphism analysis that detects essentially 100% of mutations. All samples with abnormal ddF patterns were sequenced. Nine different sequence changes were identified. Five of these were sequence changes that would result in protein alterations; of these, one was a nonsense change (C335X), one was a missense change in an amino acid conserved in all dopamine receptors (N351D), two were missense changes in amino acids that are identical in only some dopamine receptors and in only some species (A269V; S453C), and one was a missense change in a non-conserved amino acid (P330Q). To investigate whether the nonsense change (C335X), predicted to prematurely truncate the receptor protein and result in a 50% diminution of functional protein, was associated with schizophrenia, other neuropsychiatric diseases, or specific neuropsychological, psychophysiological, or personality traits, both case-control and family analyses were performed. No statistically-significant associations were detected with schizophrenia or other neuropsychiatric disease. There also were no significant associations between any one measure of neuropsychological function. However, a post-hoc analysis of combined measures of frontal lobe function hinted that heterozygotes for C335X may have a vulnerability to mild impairment, but these findings must be interpreted with caution.(ABSTRACT TRUNCATED AT 250 WORDS)