Holly J. Smith

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

BACKGROUND The reported frequency of Barretts 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 Barretts 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.

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 ∼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. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2477–81)

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/16α-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/16α-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.

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 (VO2peak). 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 (VO2peak) 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, VO2peak 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 VO2peak 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.

Grading invasive ductal carcinoma of the breast: advantages of using automated proliferation index instead of mitotic count

Breast carcinomas are graded according to the “Nottingham modification of the Bloom–Richardson system” (SBR). The system is hindered, however, by lack of precision in assessing all three parameters including nuclear grade, mitosis, and tubular formation, leading to an element of subjectivity. Our objective was to evaluate a new grading system [the nuclear grade plus proliferation (N+P) system] for subjectivity, ease, and better representation of tumor biology. Its components are nuclear grade and automated proliferation index. Invasive ductal carcinomas, consisting of 137 SBR grade I, 247 grade II, and 266 grade III, were re-evaluated by the N+P system. The two systems were compared with each other and correlated with patients’ overall survival, tumor size, angiolymphatic invasion, lymph node status, and biomarker status including estrogen receptor, progesterone receptor, p53, epidermal growth factor receptor, BCL-2, and Her-2. Although there was an agreement between the two systems with histologic and prognostic parameters studied, there was 37% disagreement when grading individual tumors. Fifty-three percent of SBR grade II tumors were “down-graded” to N+P grade I, and 7% were “up-graded” to N+P grade III. Distinction among the different histologic grades for overall survival curves was better indicated by the N+P than the SBR system.

Potential Role of Platelet-Derived Growth Factor Receptor Inhibition Using Imatinib in Combination with Docetaxel in the Treatment of Recurrent Non-small Cell Lung Cancer

Introduction: Platelet-derived growth factor receptor (PDGFR) is expressed in lung cancer and is involved in angiogenesis. Preclinical models demonstrated that imatinib (Im) regulates angiogenesis through PDGFR inhibition and enhances efficacy of chemotherapy. Hypothesis: We hypothesized that Im plus docetaxel (D) would have a synergistic effect detectable by an increase in response rate in patients with recurrent non-small cell lung cancer (NSCLC). Methods: A phase II trial to evaluate Im in combination with D in patients with recurrent NSCLC was conducted. The primary end point was response rate, using a Simon two-stage design. Eligible patients had measurable disease and no more than two chemotherapy regimens. D was given at 30 mg/m2/wk intravenously ×3 every 4 weeks and oral Im at 600 mg daily for four cycles. Patients required two cycles to be evaluable for response. Nonprogressors after four cycles continued with Im maintenance until progression or for a total of 12 months. Results: Twenty-three patients were enrolled in the first stage. Toxicity was mainly nonhematologic. We observed one partial response (5.5%), four stable disease (22.2%), and 13 progressed (72.2%). Median time to progression was 1.9 months, and median overall survival was 6.1 months. Two patients who went on Im maintenance had time to progression of 7.78 months and 15.8 months. Conclusion: Im in combination with D did not achieve its primary objective of improving response rate in patients with recurrent NSCLC. An increased understanding of the complex PDGFR pathway in lung cancer and alternative strategies to inhibit it are needed.

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 childrens 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

Impact Study: MK-0646 (Dalotuzumab), Insulin Growth Factor 1 Receptor Antibody Combined with Pemetrexed and Cisplatin in Stage IV Metastatic Non-squamous Lung Cancer

1500 to

Gemcitabine, irinotecan and celecoxib in patients with biliary cancer.

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

Improved Behavior and Sleep After Adenotonsillectomy in Children With Sleep-Disordered Breathing

Background Insulin-like growth factor 1 receptor (IGF-1R) regulates cell growth, proliferation, and apoptosis. Adenocarcinoma and never-smokers have a higher expression of IGF-1R, which is associated with worse overall survival. Dalotuzumab-MK0646 (D) is a humanized monoclonal antibody that targets IGF-1R. Pemetrexed (P) has higher activity in non-squamous lung cancer (NSQL). We initiated a randomized phase II trial to test the combination of P and Cisplatin (C) ± D in NSQL. Methods Eligibility criteria were untreated NSQL stage IV, ECOG 0 or 1, measurable disease, adequate renal, hepatic and hematologic function, and no other intercurrent illness. P at 500 mg/m2 and C at 75 mg/m2 IV were given every 3 weeks. D was given at 10 mg/kg IV weekly on days 1, 8, and 15 of every 3-week cycle in the experimental group. The patients had a radiographic assessment after every two cycles and were treated for a maximum of six cycles if there was a response or stable disease. The primary objective of the study was to compare the clinical response rates of PC vs. PC + D. Results From 1/2009 to 2/2011, the study accrued 26 subjects: 16 male and 10 female, with a median age of 59; 14 were treated with PC and 12 were treated with PC + D. We observed two partial responses (PR), seven stable disease (SD), three progressive disease (PD), and two not evaluable (NE) in the PC arm. In comparison, for the PC + D arm, there were three PR, four SD, four PD, and one NE. The hematologic toxicity was similar in both groups. There was higher incidence of hyperglycemia in the experimental group; four cases with grade 3 and one case with grade 4. Conclusion PC + D had a similar response rate compared to PC, with a higher rate of hyperglycemia. Identification of responders using predictive markers would be key to continuing the study of D in NSQL. Trial Registration NCT00799240, clinicaltrials.gov