Gemcitabine, irinotecan and celecoxib in patients with biliary cancer.

The incidence of hepatobiliary cancers is increasing and no standard therapy currently exists. Gemcitabine is an active drug in this disease. Previous studies suggest that the combination of gemcitabine and irinotecan is active with reasonable toxicity profiles in pancreatic and hepatobiliary cancers. COX-2 induction and overexpression have been documented in biliary dysplasia and biliary malignancies. We report on a case series of the efficacy and toxicity of gemcitabine plus irinotecan plus celecoxib in patients with advanced biliary cancer. The treatment consisted of gemcitabine 1000 mg/m given intravenously on days 1 and 8, irinotecan 100 mg/m given intravenously on days 1 and 8, and celecoxib 400 mg orally twice daily every 21 days. Six patients were enrolled, one was ineligible, therefore data were examined on the five remaining patients. One patient had a complete response, one had a partial response, two had stable disease, and one received one cycle of treatment and decided on surgery hence could not be assessed. The treatment was well tolerated with one grade 4 adverse event of thrombocytopenia. In conclusion, the combination of gemcitabine, irinotecan, and celecoxib appears to be well tolerated with some activity against biliary cancer. Further studies using this combination are warranted.

Surveillance of coyotes to detect bovine tuberculosis, Michigan.

Bovine tuberculosis (TB) is endemic in white-tailed deer (Odocoileus virginianus) in the northeastern portion of Michigan's Lower Peninsula. Bovine TB in deer and cattle has created immense financial consequences for the livestock industry and hunting public. Surveillance identified coyotes (Canis latrans) as potential bio-accumulators of Mycobacterium bovis, a finding that generated interest in their potential to serve as sentinels for monitoring disease risk. We sampled 175 coyotes in the bovine TB-endemic area. Fifty-eight tested positive, and infection prevalence by county ranged from 19% to 52% (statistical mean 33%, SE 0.07). By contrast, prevalence in deer (n = 3,817) was lower (i.e., 1.49%; Mann-Whitney U4,4 = 14, p<0.001). By focusing on coyotes rather than deer, we sampled 97% fewer individuals and increased the likelihood of detecting M. bovis by 40%. As a result of reduced sampling intensity, sentinel coyote surveys have the potential to be practical indicators of M. bovis presence in wildlife and livestock.

Improved behavior and sleep after adenotonsillectomy in children with sleep-disordered breathing.

OBJECTIVE: To determine changes in behavior and sleep in children before and after adenotonsillectomy for sleep-disordered breathing (SDB) using the validated Pediatric Sleep Questionnaire (PSQ) and Conners' Parent Rating Scale-Revised Short Form (CPRS-RS). DESIGN: Prospective, nonrandomized study. SETTING: Ambulatory surgery center affiliated with an academic medical center. PATIENTS: A total of 117 consecutive children (61 boys and 56 girls) (mean [SD] age, 6.5 [3.1] years) who were clinically diagnosed as having SDB and who had undergone adenotonsillectomy. Complete follow-up data were available in 71 of 117 patients (61%). INTERVENTIONS: Parents completed the PSQ and CPRS-RS before surgery and 6 months after surgery. MAIN OUTCOME MEASURES: Changes in age- and sex-adjusted T scores for all 4 CPRS-RS behavior categories (oppositional behavior, cognitive problems or inattention, hyperactivity, and Conners' attention-deficit/hyperactivity disorder [ADHD] index) were determined for each subject before and after surgery. Changes in PSQ scores from a select 22-item sleep-related breathing disorder subscale were also determined. RESULTS: Preoperatively, the mean (SD) T scores on the CPRS-RS for oppositional behavior, cognitive problems or inattention, hyperactivity, and ADHD index were 59.4 (13.7), 59.5 (13.6), 62.0 (14.4), and 59.9 (13.4), respectively. A T score of 60.0 in any category placed a child in the at-risk group. Postoperatively, T scores for each category were 51.0 (9.6), 51.2 (8.8), 52.4 (10.52), and 50.6 (7.8), respectively. All changes were statistically significant (P<.001) and clinically significant by approximating a change of 1 SD from the baseline score. For the PSQ, the preoperative and postoperative mean (SD) scores were 0.6 (0.1) and 0.1 (0.1), respectively, on a scale of 0 to 1, with scores higher than 0.33 suggesting obstructive sleep apnea. Correlations between sleep and behavior scores were statistically significant before surgery (P=.004 for ADHD index and cognitive problems, P=.008 for oppositional behavior) and after surgery (P=.049 for cognitive problems, P=.03 for oppositional behavior). Higher baseline T scores for the CPRS-RS were associated with larger changes in T scores for the CPRS-RS in all 4 domains (oppositional behavior, cognitive problems or inattention, hyperactivity, and ADHD index). CONCLUSIONS: Children diagnosed as having SDB experience improvement in both sleep and behavior after adenotonsillectomy. The PSQ and CPRS-RS may be useful adjuncts for screening and following children who undergo adenotonsillectomy for SDB.

Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3'-diindolylmethane.

We have completed a phase I trial in women of the proposed chemopreventive natural product indole-3-carbinol (I3C). Women received oral doses of 400, 600, 800, 1,000, and 1,200 mg I3C. Serial plasma samples were analyzed by high-performance liquid chromatography-mass spectrometry for I3C and several of its condensation products. I3C itself was not detectable in plasma. The only detectable I3C-derived product was 3,3'-diindolylmethane (DIM). Mean Cmax for DIM increased from 61 ng/mL at the 400-mg I3C dose to 607 ng/mL following a 1,000-mg dose. No further increase was observed following a 1,200-mg dose. A similar result was obtained for the area under the curve, which increased from 329 h ng/mL at the 400-mg dose to 3,376 h ng/mL after a 1,000-mg dose of I3C. Significant interindividual quantitative variation was seen in plasma DIM values within each dosing group, but the overall profiles were qualitatively similar, with no quantifiable DIM before dosing, tmax at approximately 2 h, and DIM levels near or below 15 ng/mL (the limit of quantitation), by 24 h. Different results were obtained for 14 subjects who received a 400-mg dose of I3C after 8 weeks of twice-daily I3C dosing. Although the predose sampling occurred at least 12 h after the last known ingestion of I3C, 6 of 14 subjects exhibited Cmax for DIM in their predose plasma. Despite this high initial value, plasma DIM for all subjects decreased to near or below the limit of quantitation within the 12-h sampling period. Possible reasons for this disparity between apparent t1/2 of DIM and the high predose values are discussed.

Treatment of pediatric suppurative mastoiditis: is peripherally inserted central catheter (PICC) antibiotic therapy necessary?

OBJECTIVE: A review of the treatment of pediatric acute mastoiditis requiring surgical intervention managed with and without PICC therapy postoperatively. STUDY DESIGN AND SETTING: Retrospective study of 42 cases from 1989 to 2004 treated at a regional children's hospital. RESULTS: Sixteen patients received postoperative PICC therapy and 26 received a course of oral antibiotics. The PICC group received on average 12.12 days of intravenous antibiotics compared to only 3.53 days for the non-PICC group (P < 0.001). No differences were observed between the two groups in treatment outcomes. One patient from each group required rehospitalization. One minor complication was experienced in a patient in the PICC group. There were no surgical complications. The total cost for outpatient PICC therapy increased treatment costs by approximately $1500 to $2500. CONCLUSIONS: Oral antibiotic therapy is sufficient after surgical intervention for acute pediatric suppurative mastoiditis without intracranial complications and does not result in adverse treatment outcome. SIGNIFICANCE: Use of PICC therapy after surgical intervention for mastoiditis should be limited. EBM RATING: B-3b.

A phase I study of indole-3-carbinol in women: tolerability and effects.

We completed a phase I trial of indole-3-carbinol (I3C) in 17 women (1 postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort. After a 4-week placebo run-in period, subjects ingested 400 mg I3C daily for 4 weeks followed by a 4-week period of 800 mg I3C daily. These chronic doses were tolerated well by all subjects. Hormonal variables were measured near the end of the placebo and dosing periods, including determination of the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio. Measurements were made during the follicular phase for premenopausal women. Serum estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin showed no significant changes in response to I3C. Caffeine was used to probe for cytochrome P450 1A2 (CYP1A2), N-acetyltransferase-2 (NAT-2), and xanthine oxidase. Comparing the results from the placebo and the 800 mg daily dose period, CYP1A2 was elevated by I3C in 94% of the subjects, with a mean increase of 4.1-fold. In subjects with high NAT-2 activities, these were decreased to 11% by I3C administration but not altered if NAT-2 activity was initially low. Xanthine oxidase was not affected. Lymphocyte glutathione S-transferase activity was increased by 69% in response to I3C. The apparent induction of CYP1A2 was mirrored by a 66% increase in the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio in response to I3C. The maximal increase was observed with the 400 mg daily dose of I3C, with no further increase found at 800 mg daily. If the ratio of hydroxylated estrone metabolites is a biomarker for chemoprevention, as suggested, then 400 mg I3C daily will elicit a maximal protective effect.

A phase I study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies.

PURPOSE: This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. METHODS: Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50-275 mg/m(2)) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). RESULTS: Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration-time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450-2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. CONCLUSIONS: Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.

Improved behavior and sleep after adenotonsillectomy in children with sleep-disordered breathing: long-term follow-up.

OBJECTIVE: To determine whether previously published changes are maintained over time in children after adenotonsillectomy for sleep-disordered breathing using the validated Pediatric Sleep Questionnaire (PSQ) and the Conners Parent Rating Scale-Revised: Short Form (CPRS-R:S). DESIGN: Prospective, nonrandomized interventional study. SETTING: Ambulatory surgery center affiliated with an academic medical center. PATIENTS: Long-term follow-up data were available (ranging from 2.4 to 3.6 years after adenotonsillectomy) for 44 of the 71 patients who completed our initial study comparing PSQ and CPRS-R:S data before and 6 months after surgery. INTERVENTIONS: Parents completed the PSQ and CPRS-R:S at least 2 years after surgery. MAIN OUTCOME MEASURES: Follow-up PSQ data and long-term changes in age- and sex-adjusted T scores for all 4 CPRS-R:S behavior categories (oppositional behavior, cognitive problems or inattention, hyperactivity, and the attention-deficit/hyperactivity disorder [ADHD] index) were determined for each patient. Linear mixed models were used to analyze the data. RESULTS: Globally, across time, most variables remained below baseline levels (P < .05). There was a significant increase in PSQ scores during follow-up, but over this period they did not reach baseline levels. Comparing short-term with long-term follow-up, the Conners scores in all behavioral categories did not increase significantly (ADHD index, P = .61; cognitive problems or inattention, P = .02; hyperactivity, P < .001; and oppositional behavior, P < .001). The ADHD index at long-term follow-up was not different from that at baseline, a finding that might be attributable to the high degree of variability in this measure. CONCLUSIONS: Improvements in sleep experienced by children after adenotonsillectomy for sleep-disordered breathing were not as great 2.5 years after surgery as they were 6 months after surgery but were still significant compared with baseline levels. Improvements in behavior were maintained in all categories of the Conners scores except for the ADHD index.

Cardiorespiratory fitness in early-stage Alzheimer disease.

There is an increasing interest in exercise and fitness in Alzheimer disease (AD) given evidence suggesting a role in the maintenance of cognitive health. There is, however, little data on the objective measure of cardiorespiratory fitness in individuals with AD. Thus, we assessed cardiorespiratory fitness in early AD and its relationship with physical activity levels, health markers, and cognitive performance in nondemented (Clinical Dementia Rating 0, n=31) and early-stage AD (Clinical Dementia Rating 0.5 and 1, n=31) participants. Cardiorespiratory fitness was assessed with maximal exercise testing to determine peak oxygen consumption (VOpeak2). Additionally, dual emission x-ray absorptiometry scanning for body composition and glucose tolerance tests were conducted. Despite reductions in physical performance and habitual physical activity levels in early AD, cardiorespiratory fitness (VOpeak2) was comparable in the 2 groups (19.8 in early AD vs. 21.2 mL/kg/min in nondemented, P=0.26). AD participants performed well on treadmill tests with similar levels of perceived exertion, maximal heart rate, and respiratory exchange ratio compared with nondemented individuals. After controlling for age and sex, VOpeak2 was associated with a beneficial glucoregulatory profile and inversely associated with percent body fat, body mass index, and triglycerides. A relationship between cognitive performance measures and VOpeak2 was not apparent. These results suggest that individuals in the early stages of AD have the capacity for maximal exercise testing and have comparable levels of cardiorespiratory fitness as nondemented individuals. Reduced physical activity associated with early AD underscores the need for further defining the role of exercise as a potential therapeutic intervention in the early stages of AD.

The frequency of Barrett's esophagus in high-risk patients with chronic GERD.

BACKGROUND: The reported frequency of Barrett's esophagus (BE) in patients with reflux symptoms varies from 5% to 15%. The exact frequency of long-segment BE (LSBE) (>3 cm) and short-segment BE (SSBE) (<3 cm) in patients with chronic symptoms of GERD is uncertain. The aim of this study was to determine the frequency of LSBE and SSBE in consecutive patients presenting for a first endoscopic evaluation with GERD as the indication. METHODS: Consecutive patients presenting to the endoscopy unit of a Veterans Affairs Medical Center for a first upper endoscopy with the indication of GERD were prospectively evaluated. Demographic information (gender, race, age), data on tobacco use and family history of esophageal disease, and body mass index (BMI) were recorded for all patients. Before endoscopy, all patients completed a validated GERD questionnaire. The diagnosis of BE was based on the presence of columnar-appearing mucosa in the distal esophagus, with confirmation by demonstration of intestinal metaplasia in biopsy specimens. All patients with erosive esophagitis on the initial endoscopy underwent a second endoscopy to document healing and to rule-out underlying BE. Patients with a history of BE, alarm symptoms (dysphagia, weight loss, anemia, evidence of GI bleeding), or prior endoscopy were excluded. RESULTS: A total of 378 consecutive patients with GERD (94% men, 86% white; median age 56 years, range 27-93 years) were evaluated. A diagnosis of BE was made in 50 patients (13.2%). The median length of Barrett's esophagus (BE) was 1.0 cm (range 0.5-15.0 cm). Of the patients with BE, 64% had short-segment BE (SSBE) (overall SSBE frequency 8.5%). The overall frequency of long-segment BE (LSBE) was 4.8%. A hiatal hernia was detected in 62% of the patients with BE. Of the 50 patients with BE (median age 62 years, range 29-81 years), 47 (94%) were men and 98% were white. Eighteen patients (36%) were using tobacco at the time of endoscopy; 23 (46%) were former users. The median body mass index (BMI) of patients with BE was 27.3 (overweight). There were no significant differences between patients with LSBE and SSBE with respect to age, gender, ethnicity, BMI, and GERD symptom duration. CONCLUSIONS: The frequency of BE in a high-risk patient group (chronic GERD, majority white men, age > 50 years) who sought medical attention is 13.2%, with the majority (64%) having SSBE. These data suggest that the frequency of BE in patients with GERD has not changed. The true prevalence of BE in the general population, including those who do not seek care, is undoubtedly lower, currently and historically. The majority of patients with BE are overweight and have a hiatal hernia. Demographic data for patients with LSBE and SSBE are similar, indicating that these are a continuum of the same process.