Parental mood during pregnancy and post-natally is associated with offspring risk of Tourette syndrome or chronic tics: prospective data from the Avon Longitudinal Study of Parents and Children (ALSPAC).

Little is known about risk factors for Tourette syndrome (TS) and chronic tic disorders (CT) but maternal psychological morbidity in pregnancy may be associated with TS/CT. We examined whether pre- and post-natal parental anxiety and/or depression are associated with risk of TS/CT in the Avon Longitudinal Study of Parents and Children. We compared self-reported anxiety and depression measures collected prospectively at four time points (18 and 32 weeks prenatally, and 8 weeks and 8 months post-natally) among parents of children who subsequently met criteria for TS/CT at 13 years of age as compared to other children from the cohort. We adjusted for various socioeconomic measures and tested both for time period-specific exposure and chronic exposure using multivariable logistic regression models. 122 children had TS/CT (50 TS, 72 CT) and 5968 children had no tics. In crude analyses, both pre- and post-natal maternal anxiety and depression, but only post-natal paternal depression at 8 months, showed associations with TS/CT. In the final, adjusted multivariable models, chronic maternal anxiety (odds ratio 2.17, 95% CI 1.23, 3.84, p = 0.007) and pre-natal maternal depression (odds ratio 1.86, 95% CI 1.02, 3.39, p = 0.04) showed associations with TS/CT though the latter was consistent with chance (p = 0.07) after adjustment for past maternal depression. We find associations between maternal psychological morbidity pre- and post-natally and risk of future TS/CT in offspring. These associations may reflect either shared genetic susceptibility or a pre-natal exposure. Further work is required to see if these findings can be replicated in larger datasets.

Genome-wide association study of shared components of reading disability and language impairment.

Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language.

D-cycloserine or similar physiochemical compounds may be uniquely suited for use in Bacillus anthracis spore decontamination strategies.

AIMS: As observed in the aftermath of the anthrax attacks of 2001, decontamination and remediation of a site contaminated by the accidental or intentional release of Bacillus anthracis spores is difficult, costly and potentially damaging to the environment. The identification of novel strategies that neutralize the threat of spores while minimizing environmental damage remains a high priority. We investigated the efficacy of d-cycloserine (DCS), an antibiotic and inhibitor of the spore-associated enzyme (alanine racemase) responsible for converting l-alanine to d-alanine, as a spore germination enhancer and antimicrobial agent. METHODS AND RESULTS: We characterized the impact of DCS exposure on both germinating spores and vegetative cells of fully virulent B. anthracis by evaluating spore germination kinetics, determining the minimum inhibitory concentrations (MICs) required to affect growth of the bacteria and performing macrophage viability assays. DCS enhanced germination induced by l-alanine and also efficiently killed the newly germinated spores. Furthermore, DCS proved nontoxic to macrophages at concentrations that provided protection from the killing effects of spores. Similar tests were conducted with Bacillus thuringiensis (subspecies kurstaki and Al Hakam) to determine its potential as a possible surrogate for B. anthracis field trials. Bacillus thuringiensis spores responded in a similar manner to B. anthracis spores when exposed to DCS. CONCLUSIONS: These results further support that DCS augments the germination response of spores in the presence of l-alanine but also reveal that DCS is bactericidal towards germinating spores. SIGNIFICANCE AND IMPACT OF THE STUDY: DCS (or similar compounds) may be uniquely suited for use as part of decontamination strategies by augmenting the induction of spore germination and then rendering the germinated spores nonviable.

Selenium bioaccumulation in stocked fish as an indicator of fishery potential in pit lakes on reclaimed coal mines in Alberta, Canada.

Pit lakes are a common reclamation strategy for open pit mines; however, there is a concern about their water quality and suitability as fish habitat because they are often contaminated by metals or metalloids. This study assessed the exposure of fish and invertebrates to selenium (Se) and other metals and metalloids in pit lakes formed by open pit coal mining in Tertiary (thermal coal) and in Cretaceous (metallurgical coal) bedrock. Juvenile hatchery rainbow trout, Oncorhynchus mykiss, and brook trout, Salvelinus fontinalis, were stocked into two thermal coal pit lakes (water Se < 2 µg/L, low water Se) and two metallurgical coal pit lakes (water Se > 15 µg/L, high water Se). Se accumulation in stocked fish and concentrations in invertebrates were characterized over a period of 2 years. In the metallurgical pits, invertebrates had higher Se concentrations and fish accumulated Se to higher levels (exceeding USEPA tissue Se guidelines) than biota in the thermal pits. Rainbow and brook trout accumulated similar concentrations of Se in their muscle and exhibited a similar relationship between whole-body and muscle Se concentrations. These results may be used by resource managers to assess compliance with whole-body tissue Se guidelines and to determine if pit lakes in coal mining areas pose a significant Se risk to wildlife or human health. The high Se exposure in metallurgical coal pits indicates that under the current mining and reclamation strategy, these lakes are not suitable for management as recreational "put and take" fisheries.

Species-specific sensitivity to selenium-induced impairment of cortisol secretion in adrenocortical cells of rainbow trout (Oncorhynchus mykiss) and brook trout (Salvelinus fontinalis).

Species differences in physiological and biochemical attributes exist even among closely related species and may underlie species-specific sensitivity to toxicants. Rainbow trout (RT) are more sensitive than brook trout (BT) to the teratogenic effects of selenium (Se), but it is not known whether all tissues exhibit this pattern of vulnerability. In this study, primary cultures of RT and BT adrenocortical cells were exposed to selenite (Na(2)SO(3)) and selenomethionine (Se-Met) to compare cell viability and ACTH-stimulated cortisol secretion in the two fish species. Cortisol, the primary stress hormone in fish, facilitates maintenance of homeostasis when fish are exposed to stressors, including toxicants. Cell viability was not affected by Se, but selenite impaired cortisol secretion, while Se-Met did not (RT and BT EC(50)>2000mg/L). RT cells were more sensitive (EC(50)=8.7mg/L) to selenite than BT cells (EC(50)=90.4mg/L). To identify the targets where Se disrupts cortisol synthesis, selenite-impaired RT and BT cells were stimulated with ACTH, dbcAMP, OH-cholesterol, and pregnenolone. Selenite acted at different steps in the cortisol biosynthesis pathway in RT and BT cells, confirming a species-specific toxicity mechanism. To test the hypothesis that oxidative stress mediates Se-induced toxicity, selenite-impaired RT cells were exposed to NAC, BSO and antioxidants (DETCA, ATA, Vit A, and Vit E). Inhibition of SOD by DETCA enhanced selenite-induced cortisol impairment, indicating that oxidative stress plays a role in Se toxicity; however, modifying GSH content of the cells did not have an effect. The results of this study, with two closely related salmonids, provided additional evidence for species-specific differences in sensitivity to Se which should be considered when setting thresholds and water quality guidelines.

Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis.

In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA. We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg·kg(-1)) or higher dose (10, 10 and 20 mg·kg(-1)). The study enrolled 19 patients (10 males and nine females aged 19-57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p<0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p<0.001) and 56% (p = 0.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild. Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability.

The physiological stress response and oxidative stress biomarkers in rainbow trout and brook trout from selenium-impacted streams in a coal mining region.

Selenium (Se) is an essential element that can be toxic at concentrations slightly greater than those required for homeostasis. The main chronic toxic effects of Se in fish are teratogenic deformities, but Se can also activate the physiological stress response and redox cycle with reduced glutathione causing oxidative damage. Rainbow trout, Oncorhynchus mykiss, appear to be more sensitive to Se than brook trout, Salvelinus fontinalis. The objective of this study was to compare the physiological stress response (plasma cortisol, glucose, triiodothyronine, thyroxine, gill Na+/K+ ATPase, cortisol secretory capacity, K and liver somatic index) and oxidative stress biomarkers (liver GSH, GPx, lipid peroxidation, vitamin A and vitamin E) in rainbow trout (RNTR) and brook trout (BKTR) collected from reference and Se-exposed streams. The physiological stress response was not impaired (cortisol secretory capacity unchanged); although there were species differences in plasma cortisol and plasma glucose levels. Liver GSH, GPx and vitamin levels were higher in RNTR than BKTR, but lipid peroxidation levels were not different. The elevated GSH reserves may make RNTR more sensitive to Se-induced lipid peroxidation, but this may be offset by the RNTR's higher antioxidant (GPx and vitamin) levels. Species-specific biochemical differences may mediate differences in Se sensitivity and be used in aquatic Se risk assessments.

Physiological stress response in white suckers from agricultural drain waters containing pesticides and selenium.

To assess the effect of agriculture drain water, a complex mixture containing pesticides and selenium (Se), on the physiological stress response, white suckers were collected from irrigation return flows in the summer and the fall and subjected to a stress challenge. Water (0.40-26.71microg/L) and muscle Se (0.37-1.52microg/g ww) levels were elevated at two sites and plasma acetylcholinesterase (AChE) activity (a marker of pesticide exposure) was lower in the fall (5.97+/-0.45micromol/min/mL) than the summer (10.73+/-0.73micromol/min/mL). Fish raised plasma cortisol levels in response to the stress challenge 11.8 times above basal levels (12.8+/-4.9ng/mL). Multivariate statistics linked Se exposure to elevated plasma glucose levels, and pesticide exposure to elevated liver glycogen levels generating hypotheses for further testing. This study showed that white suckers accumulated Se from agricultural drain water and the complex mixtures present in the drain water influenced the physiological stress response.

A comparison of measures of reading and intelligence as risk factors for the development of myopia in a UK cohort of children.

AIM: Evidence suggests that reading may be an important risk factor for myopia, but recent reports find that performance in non-verbal intelligence tests may be more important or that near-work is not associated with myopia. METHODS: Non-cycloplegic autorefraction data were available at the ages of 7 and 10 years from a birth cohort study. Children whose right eye spherical equivalent autorefraction was

Effects of acute and subchronic exposures to waterborne selenite on the physiological stress response and oxidative stress indicators in juvenile rainbow trout.

Selenium (Se) is an essential element that may bioaccumulate to toxic levels. In fish, the major toxicity symptom is larval teratogenic deformities, but little is known about the effect of Se on other systems such as the physiological stress response and oxidative stress. To test the hypothesis that Se is a chemical stressor that causes toxicity through oxidative stress, juvenile rainbow trout were exposed to waterborne sodium selenite, and physiological stress response and stress-related parameters (plasma cortisol, glucose, T3 and T4, gill Na+/K+-ATPase, the ability of the head kidney to secrete cortisol, and condition factor) and hepatic oxidative stress indicators (reduced glutathione, glutathione peroxidase, and lipid peroxidation) were measured after 96 h (acute exposure to 0-2.67 mg/L Se) and 30 days (sub-chronic exposure to 0-0.16 mg/L). Acute exposure to waterborne sodium selenite significantly increased plasma cortisol levels (control=0.01+/-0.0 ng/mL, and 2.52 mg/L Se=73.5+/-22 ng/mL) and plasma glucose levels (control=0.75+/-0.1 mg/mL, and 3.60 mg/L Se=1.64+/-0.2 mg/mL), but gill Na+/K+-ATPase activities, plasma T3 and T4 levels, and condition factor were unchanged. The 96 h acute selenite exposure decreased hepatic reduced glutathione levels (control=18.4+/-1.5 micromol/mg protein, and 3.60 mg/L Se=12.4+/-1.1 micromol/mg protein). Lipid peroxidation levels (0.03-0.08 U/mg protein) and glutathione peroxidase (3.7-6.0 mU/mg protein) activities significantly varied with treatment. The 30 days sub-chronic exposure increased plasma cortisol, T3, and T4, but there was no effect on plasma glucose levels, gill Na+/K+-ATPase activity, the ability to secrete cortisol, and condition factor. The 30 days sub-chronic exposure to selenite did not alter antioxidant activities or lipid peroxidation levels. These experiments show, for the first time, that exposure to waterborne selenite up to 0.1mg/L, activates the physiological stress response in fish but does not impair cortisol secretion after 30 days. The decrease in reduced glutathione in juvenile rainbow trout subjected to the acute sodium selenite exposure suggests that oxidative stress may play an important role in the effects of Se in fish.

Missing quasiparticles and the chemical potential puzzle in the doping evolution of the cuprate superconductors.

The evolution of Ca2-xNaxCuO2Cl2 from Mott insulator to superconductor was studied using angle-resolved photoemission spectroscopy. By measuring both the excitations near the Fermi energy as well as nonbonding states, we tracked the doping dependence of the electronic structure and the chemical potential with unprecedented precision. Our work reveals failures in the standard weakly interacting quasiparticle scenario, including the broad line shapes of the insulator and the apparently paradoxical shift of the chemical potential within the Mott gap. To resolve this, we develop a model where the quasiparticle is vanishingly small at half filling and grows upon doping, allowing us to unify properties such as the dispersion and Fermi wave vector with the chemical potential.

A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin.

BACKGROUND: Irinotecan (CPT-11) and 5-fluorouracil (5-FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN-38 followed by 5-FU/leucovorin in vitro led us to conduct a phase I trial of CPT-11 followed by 5-FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors. PATIENTS AND METHODS: Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT-11 (90 min infusion) on day 1, followed by leucovorin 20 mg/m(2) (intravenous push) and 5-FU (90 min infusion) on days 2-5 of each 21-day cycle. RESULTS: A total of 347 treatment cycles (median 4, range 1-25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy. CONCLUSIONS: CPT-11 and 5-FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT-11 275 mg/m(2) over 90 min on day 1, and 5-FU 400 mg/m(2) plus leucovorin 20 mg/m(2) on days 2-5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT-11 and 5-FU.

Parity-forbidden excitations of Sr(2)CuO(2)Cl(2) revealed by optical third-harmonic spectroscopy.

We present the first study of nonlinear optical third-harmonic generation (THG) in the strongly correlated charge-transfer insulator Sr(2)CuO(2)Cl(2). For fundamental excitation in the near infrared, the THG spectrum reveals a strongly resonant response for photon energies near 0.7 eV. Polarization analysis reveals this novel resonance to be only partially accounted for by three-photon excitation to the optical charge-transfer exciton, and indicates that an even-parity state at 2 eV, with a(1g) symmetry, participates in the third-harmonic susceptibility.

Analysis of speech characteristics in children with velocardiofacial syndrome (VCFS) and children with phenotypic overlap without VCFS.

OBJECTIVE: To address two questions of theoretical importance regarding the profile and course of communication impairment associated with velocardiofacial syndrome (VCFS): (1) do speech characteristics of children with VCFS differ from a group of children with some of the phenotypic characteristics of VCFS who do not have the syndrome, and (2) do younger children with VCFS demonstrate speech patterns that differ from older children with VCFS? DESIGN: Prospective, cross-sectional study comparing two groups of children at two age levels. PATIENTS: Thirteen children with VCFS and eight children with some of the phenotypic features of VCFS who did not have the syndrome. Children ranged in age from 3 to 10 years. MAIN OUTCOME MEASURE: (1) Broad phonetic transcription of speech yielding measures of number of consonant types, Percent Consonant Correct, and percentage of glottal stops used; and (2) composite ratings of velopharyngeal function made from perceptual, aerodynamic, and endoscopic evaluations. RESULTS: Younger children with VCFS demonstrated greater speech impairment than older children with VCFS or the children without VCFS, such as smaller consonant inventories, greater number of developmental errors, greater severity of articulation disorder, and higher frequency of glottal stop use. The relationship between ratings of velopharyngeal function and the speech variables analyzed was not straightforward. CONCLUSIONS: Some young children with VCFS demonstrated speech impairment that is qualitatively and quantitatively different from older children with VCFS or children without VCFS. This finding supports the hypothesis that some children with VCFS demonstrate a profile of speech production that is different from normal but also may be specific to the syndrome.

Over-expression of the INO2 regulatory gene alters regulation of an INO1-lacZ reporter gene but does not affect regulation of INO1 expression.

The yeast INO2 gene encodes a transcriptional activator. Inositol and choline repress transcription of the INO2 gene, and its target genes. That is, INO2 transcription is auto-regulated. This observation prompted two separate investigations to determine if regulation of INO2 is required for regulation of its target genes. One study, using northern blot hybridization, showed that constitutive INO2 transcription did not affect regulation of the INO1 gene, while another study revealed that it severely dampened regulation of an INO1-lacZ gene. By repeating both assays from a single yeast strain we demonstrate that this disparity is due to the different reporter systems.

A prospective randomized phase II trial of GM-CSF priming to prevent topotecan-induced neutropenia in chemotherapy-naive patients with malignant melanoma or renal cell carcinoma.

We conducted a phase II randomized trial of recombinant granculocyte-macrophage colony-stimulating factor (GM-CSF) administered before topotecan chemotherapy to determine whether it could prevent myelosuppression and to determine the antitumor activity of this topoisomerase I inhibitor in 53 patients with metastatic malignant melanoma and renal cell cancer. All patients received GM-CSF after topotecan at a dose of 250 microg/m(2) daily for at least 8 days. Patients randomly assigned to receive GM-CSF priming were treated with GM-CSF at 250 microg/m(2) twice daily for 5 days before treatment. Twenty-five patients were randomly assigned to receive GM-CSF priming and 28 to receive topotecan without priming. The primary analysis was restricted to the protective effects seen during the first cycle of therapy. Grade 4 neutropenia occurred in 8 of 23 patients (35%) and grade 3 neutropenia in 5 of 23 patients (22%) randomized to GM-CSF priming, whereas 18 of 26 (69%) and 5 of 26 (19%) patients experienced grade 4 or 3 neutropenia, respectively, without GM-CSF priming (P =.0074). The mean duration of neutropenia was reduced by GM-CSF priming: grade 3 neutropenia from 5.2 +/- 0.7 to 2.8 +/- 0.7 days (P =.0232) and grade 4 neutropenia from 2.7 +/- 0.6 to 1.1 +/- 0.4 days (P = 0.0332). The protective effects of GM-CSF extended to the second cycle of treatment. The incidence of febrile neutropenia was also reduced. Chemotherapy-induced anemia and thrombocytopenia were similar in both groups. One partial response was seen in a patient with melanoma, and one patient with renal cell cancer had complete regression of pulmonary metastases and was rendered disease-free by nephrectomy. (Blood. 2001;97:1942-1946)

Irinotecan plus fluorouracil/leucovorin for metastatic colorectal cancer: a new survival standard.

BACKGROUND: Irinotecan is a topoisomerase I inhibitor that prolongs survival in patients with colorectal cancer refractory to fluorouracil (5-FU) and leucovorin (LV). This demonstrated activity of irinotecan as effective second-line therapy for colorectal cancer led to evaluation of combination irinotecan/5-FU/LV as first-line therapy for patients with metastatic disease. The results of two prospective phase III randomized, controlled, multicenter, multinational clinical trials in patients with previously untreated metastatic colorectal cancer served as the basis for U.S. and European approval of irinotecan/5-FU/LV for this indication. An overview of the findings of these two pivotal studies provides insights regarding the application of this new combination in clinical practice. METHODS: Patients were randomly assigned to receive 5-FU/LV, either alone, or with concurrent irinotecan. The study conducted primarily in North America (study 1), employed bolus 5-FU/LV schedules, while the study performed primarily in Europe (study 2), employed infusional 5-FU/LV regimens. Major endpoints included tumor response rate, time to tumor progression (TTP), overall survival, quality of life, and safety. RESULTS: In study 1, the respective confirmed response rates for irinotecan/5-FU/LV versus 5-FU/LV were 39% and 21% (p <.001); median TTPs were 7.0 months and 4.3 months, respectively (p =.004). In study 2, response rates for irinotecan/5-FU/LV versus 5-FU/LV alone were 35% and 22% (p =.005); median TTPs were 6.7 months and 4.4 months, respectively (p <.001). Survival time increased significantly with irinotecan/5-FU/LV versus 5-FU/LV alone in both studies (study 1: median 14.8 months versus 12.6 months, p =.042; study 2: median 17.4 months versus 14.1 months, p =.032). The combined analysis of the data from the two studies showed median survivals of 15.9 months versus 13.3 months, favoring the irinotecan-containing combinations (stratified-by-study p =.003). Patients in study 1 had a 36% lower risk of tumor progression and a 20% lower risk of death with the irinotecan combination than with 5-FU/LV alone; comparable risk reduction values in study 2 were 42% and 23%. While grade 3 diarrhea and vomiting were more common with irinotecan/5-FU/LV, grade 4 neutropenia, neutropenic fever, and mucositis were less common with irinotecan/5-FU/LV than with the Mayo Clinic 5-FU/LV regimen. CONCLUSION: The combination of irinotecan/5-FU/LV is superior to 5-FU/LV alone as first-line therapy for patients with metastatic colorectal cancer, offering consistently improved tumor control and prolonged survival. Irinotecan-based combination therapy sets a new survival standard for the treatment of this life-threatening disease.

Phase I trial of the combination of irinotecan, paclitaxel, and carboplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB/IV NSCLC were enrolled to this multicenter, phase I study. The initial regimen was paclitaxel 225 mg/m(2)/3 h, followed by carboplatin area under the curve (AUC) 6 over 30 minutes on day 1, and CPT-11 starting at 40 mg/m(2) over 90 minutes, days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of seven patients. The regimen was amended, with doses reduced to paclitaxel 175 mg/m(2)/3 h, carboplatin AUC 5 and CPT-11 at 40 mg/m(2), all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m(2) then 125 mg/m(2) before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m(2). RESULTS: Thirty-three patients were enrolled; 32 patients were assessable for safety, and 31 were assessable for tumor response. The primary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia (16 patients [50%], with six [19%] developing neutropenic fever). Objective tumor response was observed in 39% (12/31, 95% confidence interval, 22% to 58%). The median time to tumor progression was 6.8 months, median survival 11.0 months, and 1-year survival probability 0.46. CONCLUSION: CPT-11 100 mg/m(2), paclitaxel 175 mg/m(2), and carboplatin AUC 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable.

Irinotecan (CPT-11) in triplet combinations in patients with advanced non small-cell lung cancer: a review and report of a phase I/II trial.

The objectives of this phase I/II trial were to determine the maximum tolerated dose, toxicities, and the dose suitable for phase II/III trials of irinotecan (CPT-11) combined with paclitaxel and carboplatin in patients with advanced non small-cell lung cancer (NSCLC). Seventy-three patients with stage IIIB/IV NSCLC were enrolled in this multicenter, phase I/II study. The initial regimen was paclitaxel 225 mg/m2 over 3 hours, followed by carboplatin at an area under the curve (AUC) of 6 over 30 minutes on day 1 and CPT-11 starting at 40 mg/m2 over 90 minutes on days 1 and 8, every 3 weeks. Dose-limiting toxicity occurred in three of the original seven patients. The regimen was amended with doses reduced to paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 at 40 mg/m2, all on day 1 every 3 weeks. Dose escalation of CPT-11 proceeded to 80 mg/m2 and 125 mg/m2 before dose-limiting toxicities were experienced. Subsequent patients received an intermediate CPT-11 dose of 100 mg/m2. Doses suitable for phase II study were determined to be paclitaxel 175 mg/m2 over 3 hours, carboplatin AUC = 5, and CPT-11 100 mg/m2. The pri-mary first-cycle dose-limiting toxicities were neutropenia and diarrhea. The most common grade 3/4 toxicity observed during all cycles was neutropenia. On the phase I portion of the study, objective tumor response was observed in 39% (12 of 31, 95% confidence interval: 22%-58%). The median time to tumor progression was 6.8 months, median survival was 11.0 months, and 1-year survival probability was 0.46. These data were confirmed in the phase II portion with a 30% objective response rate, median time to progression of 5.6 months, median survival of 12.5 months, and a 1-year survival probability of 0.50. In conclusion, CPT-11 100 mg/m2, paclitaxel 175 mg/m2, and carboplatin AUC = 5 given every 3 weeks can be safely administered in patients with advanced NSCLC. Neutropenia and diarrhea are the dose-limiting toxicities. The combination shows appreciable activity, and survival data are favorable, warranting further study of this regimen. A review of other irinotecan-containing triplet combinations is presented.

A phase II study of irinotecan with 5-fluorouracil and leucovorin in patients with previously untreated gastric adenocarcinoma.

BACKGROUND: A phase II study testing the safety and efficacy of irinotecan (CPT-11). 5-fluorouracil (5-FU), and leucovorin (LCV) was conducted in patients with advanced gastric adenocarcinomas. PATIENTS AND METHODS: Patients with metastatic or recurrent adenocarcinoma of the gastroesophageal junction (GEJ) or stomach were entered onto this study. Previous chemotherapy for metastatic disease was not allowed. Treatment consisted of repeated 6-week cycles comprising CPT-11 125 mg/m2 intravenously (i.v.) followed immediately by LCV 20 mg/m2 i.v. and 5-FU 500 mg/m2 i.v., all given weekly for four weeks followed by a two-week rest. RESULTS: Thirty-eight patients were enrolled and 36 eligible patients received protocol therapy. Grade 3-5 toxicities consisted primarily of neutropenia (36%) and diarrhea (28%). Neutropenic infection was observed in 14% of patients, with 3 (8%) dying of neutropenic sepsis. The overall response rate was 22% (95% confidence interval [CI] 8.5% to 35.5%). Median survival was 7.6 months, and median time to progression was 4.4 months. CONCLUSION: This weekly regimen of CPT-11 with bolus 5-FU/LCV is active in patients with advanced adenocarcinomas of the stomach or gastroesophageal junction. While rates of grade 3-4 neutropenia and diarrhea were similar to those observed historically in patients receiving this regimen for colorectal cancer, neutropenic fever/sepsis appeared to be more frequent, and dose modifications were substantial. Future trials of this combination in patients with gastric cancer should decrease the absolute starting drug doses and/ or employ altered scheduling that better accommodates the pattern of toxicity.