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Background: Ursodeoxycholic acid (UDCA) treatment is associated with a reduced incidence of colonic neoplasia in preclinical models and in patients with conditions associated with an increased risk for colon cancer. We conducted a phase III, double-blind placebo-controlled trial of UDCA to evaluate its ability to prevent colorectal adenoma recurrence. Methods: We randomly assigned 1285 individuals who had undergone removal of a colorectal adenoma within the past 6 months to daily treatment with UDCA (8-10 mg/kg of body weight; 661 participants) or with placebo (624 participants) for 3 years or until follow-up colonoscopy. Recurrence rates (number of recurrent adenomas per unit time) were compared by use of a Huber-White variance estimator. Proportions of participants with one or more recurrent adenomas were compared with a Pearson chi-square statistic; adjusted odds ratios (ORs) were obtained by logistic regression. All statistical tests were two-sided. Results: We observed a non-statistically significant 12% reduction in the adenoma recurrence rate associated with UDCA treatment, compared with placebo treatment. However, UDCA treatment was associated with a statistically significant reduction (P = .03) in the recurrence of adenomas with high-grade dysplasia (adjusted OR = 0.61, 95% confidence interval = 0.39 to 0.96). We observed no statistically significant differences between UDCA and placebo groups in recurrence with regard to adenoma size, villous histology, or location. Conclusions: UDCA treatment was associated with a non-statistically significant reduction in total colorectal adenoma recurrence but with a statistically significant 39% reduction in recurrence of adenomas with high-grade dysplasia. Because severely dysplastic lesions have a high risk of progression to invasive colorectal carcinoma, this finding indicates that future chemoprevention trials of UDCA in individuals with such lesions should be considered.

Background: The Wheat Bran Fiber (WBF) trial was a double-blind, high-fiber versus low-fiber phase III intervention trial in which participants were randomly assigned to receive a cereal fiber supplement of either 2.0 g/day or 13.5 g/day to assess whether a high-fiber supplement could decrease risk of recurrent colorectal adenomas. Although no effect of the supplement on polyp recurrence was observed, participants consumed a baseline average of 17.5 grams of fiber per day, which may have been sufficient to protect against adenoma recurrence. Therefore, we examined whether baseline fiber intake affected colorectal adenoma recurrence or modified the effect of treatment group in the WBF trial participants. Methods: Quartiles of baseline fiber intake were calculated on the basis of the distribution in the study population. Odds ratios (ORs) for adenoma recurrence were calculated using the lowest quartile of fiber intake as the reference. The effect of fiber from specific food sources on adenoma recurrence was also assessed. All statistical tests were two-sided. Results: Adjusted ORs (95% confidence intervals) for adenoma recurrence were 0.79 (0.56 to 1.12), 0.76 (0.54 to 1.08), and 0.83 (0.57 to 1.19) for the second, third, and fourth quartiles, respectively. Fiber from the three primary food sources (fruits; breads, cereals and crackers; and vegetables) had no appreciable effect on adenoma recurrence. Baseline fiber intake also had little effect on adenoma recurrence when the population was stratified by treatment group. In addition, there was no interaction between treatment group and quartile of baseline fiber intake. Conclusions: No association was found between amount of fiber consumed at baseline and adenoma recurrence in the WBF trial participants. The baseline fiber intake, whether considered as a whole or from specific sources, did not modify the effect of treatment group. [J Natl Cancer Inst 2002;94:1620-5]

Byline: Frank G Walter, Raquel L Gibly, Robert K Knopp, Denise J Roe Abstract: Study objective: To determine whether squamous cells in urine indicate bacterial contamination. Methods: We prospectively studied 105 consecutive women who presented to the emergency department with symptoms suggestive of a urinary tract infection. Two urine samples were collected from each woman, a midstream clean-catch (MSCC) sample and a catheterized (CATH) sample. Microscopic urinalyses to assess for squamous cells and urine cultures to assess for bacterial contamination were performed on all samples. Bacterial contamination was defined as growth of fewer than 10,000 colonies of a single species per milliliter or growth of three or more species of commensal bacteria (mixed flora) in a urine sample. Results: Squamous cells were found in 99 of 105 CATH samples (94%); however, no CATH samples had bacterial contamination. Squamous cells were found in 101 of 105 MSCC samples (96%); however, only 22 MSCC samples (21%) had bacterial contamination. Conclusion: The presence of squamous cells in CATH urine samples obtained from women is not indicative of bacterial contamination. The presence of squamous cells in MSCC urine samples obtained from women also is not a good indicator, with an overall predictive value for bacterial contamination of 21%. [Walter FG, Gibly RL, Knopp RK, Roe DJ: Squamous cells as predictors of bacterial contamination in urine samples. Ann Emerg Med April 1998;31:455-458.] Article History: Received 10 October 1996; Revised 25 June 1997; Revised 4 November 1997; Accepted 16 November 1997 Article Note: (footnote) [star] From the Department of Emergency Medicine, Valley Medical Center, Fresno, * and the Department of Medicine, University of California San Francisco School of Medicine, San Francisco,a CA; and the Division of Emergency Medicine, Department of Surgery,As. and Department of Family and Community Medicine, II The University of Arizona College of Medicine, Tucson, AZ., [star][star] Supported by a grant from the Medical Research Committee of Valley Medical Center, Fresno, CA., a Address for reprints: Raquel L Gibly, MD, Division of Emergency Medicine, 1501 North Campbell Avenue, Tucson, AZ 85724-5057, 520-626-6312, Fax 520-626-2480, E-mail raquel@aemrc.arizona.edu, aa 47/1/88631

Objective: To test the hypothesis that utilization of a previously described measure of acuity (ie, the score for neonatal acute physiology [SNAP]) during the first 7 post-natal days predicts which infants with a birth weight of 1500 g or less received erythrocyte transfusions during the initial hospitalization. Design: Retrospective chart review. Setting: A regional tertiary care newborn intensive care unit at the Arizona Health Sciences Center, University Medical Center, Tucson. Materials: Medical records of premature infants (birth weight, [is less than or equal to] 1500 g) who were admitted from October 1993 to January 1995. Main Outcome Measures: Occurrence or nonoccurrence of erythrocyte transfusion was determined in 47 infants who were compared for demographic information, phlebotomy blood loss, diagnoses, medications, and the SNAP at 0, 1, 2, and 7, days of life. Results: Infants with a birth weight of 1500 g or less received a mean [+ or -] SD of 1.9 [+ or -] 2.9 transfusions, with 22 (47%) of the infants given transfusions. infants who were given transfusions vs those who were not given transfusions were of a lower mean [+ or -] SD birth weight (971 [+ or -] 238 g vs 1272 [+ or -] 144 g; P [less than] .001) and a lower gestational age (27.7 [+ or -] 1.6 weeks vs 30.7 [+ or -] 2.8 weeks; P [less than] .001), and they had a greater mean phlebotomy blood loss (3.3 [+ or -] 1.6 mL/kg per day vs 1.4 [+ or -] 0.5 mL/kg per day; P [less than] .001) during the first postnatal week. The SNAP indexes in those who received transfusions were higher at 1, 2, and 7 days of life (P=.03, P=.001, and P [less than] .001, respectively). Using stepwise logistic regression, phlebotomy blood loss and the SNAP at 7 days of life were significant predictors of the number of transfusions. The logistic model predicted which infants had been administered transfusions with 86% sensitivity and 88% specificity. Conclusions: The efficacy and cost-effectiveness of recombinant human erythropoietin therapy in premature infants remain under study. As earlier treatment with recombinant human erythropoietin may be more efficacious, early identification of which infants currently undergo transfusion may identify those who will receive the greatest benefit from recombinant human erythropoietin therapy. The SNAP distinguished those infants who were given transfusions from those who did not receive transfusions, even after adjusting for phlebotomy blood loss., Premature newborns who are sicker and who have more blood draws appear more likely to require transfusions. Identifying these infants would prove helpful in determining who might benefit from treatment to stimulate red blood-cell production. Researchers reviewed the medical records of 47 infants weighing 1,500 grams or less at birth. Twenty-two required transfusions. High scores at seven days on an evaluation test of physical status and greater average blood loss from blood sampling accurately identified 86% of the infants requiring transfusions and 88% of the infants who did not require transfusions.

AbstractBackgroundWith the increasing occurrence of infectious diseases in lower-and-middle-income countries (LMICs), emergency preparedness is essential for rapid response and mitigation. Economic evaluations of mitigation technologies and strategies have been recommended for inclusion in emergency preparedness plans. We aimed to perform an economic evaluation using dynamic transition modeling of ebola virus disease (EVD) vaccination in a hypothetical community of 1,000 persons in the Democratic Republic of Congo (DRC).MethodUsing a modified SEIR (Susceptible, Exposed, Infectious, Recovered, with Death added [SEIR-D]) model that accounted for death and epidemiological data from an EVD outbreak in the DRC, we modeled the transmission of EVD in a hypothetical population of 1,000. With our model, we estimated the cost-effectiveness of an EVD vaccine and an EVD vaccination intervention.ResultsThe results showed vaccinating 50% of the population at risk prevented 670 cases, 538 deaths, and 22,022 disability-adjusted life years (DALYs). The vaccine was found to be cost-effective with an incremental cost-effectiveness ratio (ICER) of $95.63 per DALY averted. We also determined the minimum required vaccination coverage for cost-effectiveness to be 40%. Sensitivity analysis showed our model to be fairly robust, assuring relatively consistent results even with variations in such input parameters as cost of screening, as well as transmission, infection, incubation, and case fatality rates.ConclusionEVD vaccination in our hypothetical population was found to be cost-effective from the payer perspective. Our model presents an efficient and reliable approach for conducting economic evaluations of infectious disease interventions as part of an emergency preparedness plan.

Background: Sulofenur is a diarylsulfonylurea with demonstrated antitumor activity in patients with advanced epithelial ovarian cancer refractory to standard chemotherapy. The dose-limiting toxic effects observed in phase I clinical trials have been anemia and methemoglobinemia, resulting in cyanosis. Purpose: The purposes of this study were to further define the response rate, toxic effects, and pharmacokinetics and pharmacodynamics of sulofenur in patients with advanced ovarian cancer. Methods: We conducted a phase II trial of sulofenur at a dose of 800 mg/ [m.sup.2] per day in 35 patients with stage III or IV ovarian cancer refractory to standard chemotherapy. Pharmacokinetics and pharmacodynamics were analyzed by comparing sulofenur parent and metabolite plasma levels with methemoglobin levels. Results: Partial responses lasting 6.5-18 weeks occurred in four (15%; 95% confidence interval = 4%-35%) of the 26 patients assessable for response. In addition, 42% (11) of the assessable patients had prolonged stable disease (median, 20 weeks). The first nine patients received sulofenur as a daily oral dose for 14 days, with a 21-day treatment cycle. However, they developed substantial anemia and methemoglobinemia. As a result, the next 26 patients received sulofenur daily for 5 days followed by 2 days of rest for 3 consecutive weeks, with a 28-day treatment cycle (5/2-day schedule). Preclinical models predicted that 2 days of rest would decrease toxicity while maintaining antitumor activity. Patients treated with the 5/2-day schedule had relatively less severe anemia and methemoglobinemia and needed fewer red blood cell transfusions (31% versus 78% of patients), but 31% still required dose reductions because of these toxic effects. The hydroxy and keto metabolites of sulofenur had prolonged plasma half-lives relative to the parent compound, and the difference was statistically significant. In addition, the correlations of metabolite concentrations with methemoglobin levels were higher than the correlation of sulofenur concentrations with methemoglobin levels, and those differences were statistically significant. Conclusion: We conclude that sulofenur has modest clinical activity in heavily pretreated patients with ovarian cancer. Implications: The toxic effects of anemia and methemoglobinemia may limit the ultimate clinical utility of diarylsulfonylureas until less toxic derivatives with alternate metabolic pathways can be identified. [J Natl Cancer Inst 84:1798-1802, 1992]

The immune checkpoint ligand PD-L1 has emerged as a molecular target for skin cancer therapy and might also hold promise for preventive intervention targeting solar UV light–induced skin damage. In this study, we have explored the role of PD-L1 in acute keratinocytic photodamage testing the effects of small-molecule pharmacological inhibition. Epidermal PD-L1 upregulation in response to chronic photodamage was established using immunohistochemical and proteomic analyses of a human skin cohort, consistent with earlier observations that PD-L1 is upregulated in cutaneous squamous cell carcinoma. Topical application of the small-molecule PD-L1 inhibitor BMS-202 significantly attenuated UV-induced activator protein-1 transcriptional activity in SKH-1 bioluminescent reporter mouse skin, also confirmed in human HaCaT reporter keratinocytes. RT-qPCR analysis revealed that BMS-202 antagonized UV induction of inflammatory gene expression. Likewise, UV-induced cleavage of procaspase-3, a hallmark of acute skin photodamage, was attenuated by topical BMS-202. NanoString nCounter transcriptomic analysis confirmed downregulation of cutaneous innate immunity- and inflammation-related responses, together with upregulation of immune response pathway gene expression. Further mechanistic analysis confirmed that BMS-202 antagonizes UV-induced PD-L1 expression both at the mRNA and protein levels in SKH-1 epidermis. These data suggest that topical pharmacological PD-L1 antagonism using BMS-202 shows promise for skin protection against photodamage.

Aim:To determine whether differences in joint and tendon stiffness as measured by ultrasound shear wave elastography are present in breast cancer patients with aromatase inhibitor-associated arthralgias compared to age-comparable healthy control women. Methods:Postmenopausal women with stage I–III breast cancer who were taking adjuvant aromatase inhibitors and complained of joint pain were enrolled (n= 6). Postmenopausal women with no history of breast cancer, hormone treatment, or joint pain served as controls (n= 7). All subjects had bilateral hands and wrists evaluated by gray-scale and power Doppler ultrasound, and shear wave elastography ultrasound. Results:Patients with AI-associated arthralgias had significantly stiffer tendons than controls in the 1stextensor compartment (long axis; p= 0.001), 4thextensor compartment (long axis; p= 0.014), 3rdmetacarpophalangeal joint (p= 0.002), the pooled values of the extensor compartments, both long (p= 0.044) and short axes (p= 0.035), and the pooled values for the metacarpophalangeal joints (p= 0.002). On ultrasound, the patients (but not controls) presented with hyperemia and increased tenosynovial fluid in the flexor and extensor tendon sheaths, and the median nerves were symptomatic and bifid; however, these differences were not statistically significant. Conclusions:This is the first study to identify increased tendon stiffness as a putative physiological characteristic of aromatase inhibitor–associated arthralgias. Future studies should determine whether increased tendon stiffness is a risk factor for the development of aromatase inhibitor–associated arthralgias, or a result of aromatase inhibitor treatment.

Background: Evidence suggests a relationship between prostaglandin levels in colonic mucosa and risk of colon cancer. Physical inactivity and a higher body mass index (BMI; weight in kilograms divided by [[height in meters].sup.2]) have been consistently shown to increase risk of this cancer. We investigated whether higher levels of leisure-time physical activity or a lower BMI was associated with lower concentrations of prostaglandin [E.sub.2] ([PGE.sub.2]) in rectal mucosa. Methods: This study was conducted in 41 men and 22 women, 42-78 years of age, with a history of polyps, who participated in a randomized clinical trial testing the effects of piroxicam on rectal mucosal [PGE.sub.2] levels. An [[sup.12]I][PGE.sub.2] radioimmunoassay kit was used to determine [PGE.sub.2] levels in samples of extracted rectal mucosa collected before randomization. Leisure-time physical activity was assessed through a self-administered questionnaire collected at baseline. The reported time spent at each activity per week was multiplied by its typical energy expenditure, expressed in metabolic equivalents (METs), to yield a MET-hours per week score. A repeated measures model was used to assess the effect of BMI and physical activity as predictors of [PGE.sub.2] concentration. All statistical tests were two-sided. Results: After adjustment for age, a higher BMI was associated with higher [PGE.sub.2] levels (P = .001). A higher level of leisure-time physical activity was inversely associated with [PGE.sub.2] concentration (P [is less than] .03). An increase in BMI from 24.2 to 28.8 kg/[m.sup.2] was associated with a 27% increase in [PGE.sub.2]. An increase in activity level from 5.2 to 27.7 MET-hours per week was associated with a 28% decrease in [PGE.sub.2]. Conclusions: Physical activity and obesity may alter the risk of colon cancer through their effects on [PGE.sub.2] synthesis. [J Natl Cancer Inst 1999;91:950-3]

Women face particular challenges when quitting smoking, especially those with weight concerns. A multi-behavioral smoking cessation intervention addressing these concerns and incorporating guided imagery may assist women to engage in healthy lifestyle behaviors. An mHealth app can easily disseminate such an intervention. The goals of this pilot study were to develop and test the feasibility and potential of the See Me Smoke-Free™mHealth app to address smoking, diet, and physical activity among women smokers. We used pragmatic, direct-to-consumer methods to develop and test program content, functionality, and the user interface and conduct a pre-/post-test, 90-day pilot study. We enrolled 151 participants. Attrition was 52%, leaving 73 participants. At 90 days, 47% of participants reported 7-day abstinence and significant increases in physical activity and fruit consumption. Recruitment methods worked well, but similar to other mHealth studies, we experienced high attrition. This study suggests that a guided imagery mHealth app has the potential to address multiple behaviors. Future research should consider different methods to improve retention and assess efficacy.

Purpose. Screening rates for colorectal cancer (CRC) lag for low-income, minority populations, contributing to poorer survival rates. A model of storytelling as culture-centric health promotion was tested for promoting CRC screening.Design. A two-group parallel randomized controlled trial.Setting. Primary care, safety-net clinics.Subjects. Low-income patients due for CRC screening, ages 50 to 75 years, speaking English or Spanish.Intervention. Patients were exposed to either a video created from personal stories composited into a drama about “Papa” receiving CRC screening, or an instrument estimating level of personal cancer risk. Patients received a health care provider referral for CRC screening and were followed up for 3 months to document adherence.Measures. Behavioral factors related to the narrative model (identification and engagement) and theory of planned behavior.Analysis. Main effects of the interventions on screening were tested, controlling for attrition factors, and demographic factor associations were assessed. Path analysis with model variables was used to test the direct effects and multiple mediator models.Results. Main effects on CRC screening (roughly half stool-based tests, half colonoscopy) did not indicate significant differences (37% and 42% screened for storytelling and risk-based messages, respectively; n = 539; 33.6% male; 62 % Hispanic). Factors positively associated with CRC screening included being female, Hispanic, married or living with a partner, speaking Spanish, having a primary care provider, lower income, and no health insurance. Engagement, working through positive attitudes toward the behavior, predicted CRC screening.Conclusion. A storytelling and a personalized risk-tool intervention achieved similar levels of screening among unscreened/underscreened, low-income patients. Factors usually associated with lower rates of screening (e.g., no insurance, being Hispanic) were related to more adherence. Both interventions' engagement factor facilitated positive attitudes about CRC screening associated with behavior change.

Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC-714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m2 IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014.

A double-blind, placebo-controlled Phase III cancer prevention trial in subjects with previous resection of adenomatous colon polyps is nearing completion. The study's primary objective is to evaluate the effects of daily dietary supplementation with large (13.5 g/day) versus small (2.0 g/day) doses of wheat bran fiber for 3 years. A summary of the study design and a progress report are presented. Am J Med. 1999;106(1A):43S-45S. [C] 1999 by Excerpta Medica, Inc.

•Partial replacement of PT-CY with PT-BEN on day +4 (PT-CY/BEN) is well tolerated•PT-CY/BEN is associated with earlier trilineage engraftment compared to PT-CY•A trend toward less cGVHD is seen with PT-Cy/BEN in multivariate analysis (P=0.06)•Multivariate analysis shows improved GFRS with PT-CY/BEN versus PT-CY (P=0.039)

No relevant conflicts of interest to declare.

Objective: The purpose of this investigation was to assess the association between smoking and clearance of oncogenic human papillomavirus (HPV) infection. Methods: A prospective cohort study of 346 women aged 18–35 years was conducted. HPV testing was conducted with the Hybrid Capture II (HC II) system and polymerase chain reaction (PCR) with genotyping using the reverse line blot method. At each visit tobacco exposure, reproductive, and sexual histories were assessed. Probability of clearing an oncogenic HPV infection and duration of oncogenic HPV infections by smoking status was assessed. Results: Regardless of method used, HC II or PCR, ever smokers maintained an HPV infection significantly longer (median duration of 8.5 months vs10.7 months, never vsever smokers), and had a lower probability of clearing an oncogenic infection compared with women who never smoked. Smoking duration was significantly associated with HPV clearance, and a dose response was observed. Older age (> 13 years) at smoking initiation was significantly associated with a reduced probability of clearing an oncogenic HPV infection. Conclusion: This is the first study to demonstrate that smoking promotes early cervical carcinogenic events by increasing duration of oncogenic HPV infections and decreasing probability of clearing oncogenic infections.

Risk factors for non-melanoma skin cancer among populations with evidence of precursor damage are not well described. We examined and compared risk factors associated with the development of cutaneous basal-cell (BCC) or squamous-cell (SCC) carcinoma among a group of 918 adults with significant sun damage (≥10 clinically assessable actinic keratoses) but no prior history of skin cancer. These adults were participants in a 5-year skin chemoprevention trial between 1985 and 1992, who had been randomized to the placebo group and followed for occurrence of skin cancer. During the study, a total of 129 first SCC and 164 first BCC lesions were diagnosed. The overall BCC and SCC incidence rates for this group of men and women, mean age 61 years, were 4,106 and 3,198 per 100,000 person-years, respectively. Different constitutional and exposure factors were independently associated with BCC compared to SCC. Only increased age independently predicted BCC occurrence among this population. In contrast, older age along with male gender, natural red hair color and adult residence in Arizona for 10 or more years independently predicted SCC occurrence. The substantial incidence of skin cancer found among this population confirms the need for active dermatological monitoring among individuals with multiple visible actinic lesions. © 2001 Wiley-Liss, Inc.

Background

Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1), doxorubicin (Adriamy-cin) and vincristine sensitivity, and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro, but did not enhance sensitivity of cells that were drug sensitive (P≪ .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials, 22 patients with myeloma refractory to vincristine-Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve, five achieved a partial remission (23%). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive, four responded clinically (40%), whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil, whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development, in vitro tests of MDR1 expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosen-sitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies, including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.

Micronutrients, such as β-carotene and vitamins A and ?, are potential chemopreventive agents; however, their concentrations in human target tissues are largely unknown. Because these micro-nutrients may exert their action at the site of target tissues, the tissue concentrations of the micronutrients need to be determined. In this cross-sectional study, we have measured the concentrations of seven carotenoids, two retinoids, and two tocopherols in paired plasma, buccal mucosal cells (BMC), and skin samples from 96 healthy subjects (ages 26-82 yrs). The plasma-tissue, as well as the diet-plasma and diet-tissue relationships of the micronutrients, and the impact of various potential confounders on the micronutrient concentrations were evaluated. The micro-nutrient concentrations of plasma and BMC used in the evaluation were the average of three measurements over a one-month period. Our data indicated that 1) the correlations between the plasma and BMC (Spearman r = 0.40-0.91, p < 0.05) and the plasma and skin (r = 0.24-0.75, p < 0.05) concentrations of most micronutrients were significant in all subjects, suggesting that the status of these micronutrients in the BMC and skin may be estimated from their plasma concentrations; 2) the correlations between the diet and plasma/tissue concentrations of the micronutrients were generally not as strong as the plasma-tissue relationships; the diet-plasma and diet-tissue relationships of the carotenoids were particularly poor in the smokers; 3) the plasma and tissue concentrations of most micronutrients were lower in smokers than in nonsmokers and higher in vitamin supplement users than in nonsupplement users; the differences remained significant after adjustment for age, gender, and diet intake estimates; 4) among the seven carotenoids examined, lycopene was unique, because its concentration was not lower in smokers or higher in supplement users but was inversely associated with age.

The frequency of micronuclei assayed in lymphocytes obtained from 73 young adults increases significantly with the age, but not the sex, of the donor. The dose of medical X-rays absorbed by the lymphocytes in the 2 years before the examination has no significant effect on micronucleus frequency, provided the data are adjusted for age. However, a small significant increase in frequency is associated with X-ray examinations that involve the injection of contrast media into the blood.

This research examined the applicability of using a neural network approach to analyze population pharmacokinetic data. Such data were collected retrospectively from pediatric patients who had received tobramycin for the treatment of bacterial infection. The information collected included patient-related demographic variables (age, weight, gender, and other underlying illness), the individual's dosing regimens (dose and dosing interval), time of blood drawn, and the resulting tobramycin concentration. Neural networks were trained with this information to capture the relationships between the plasma tobramycin levels and the following factors: patient-related demographic factors, dosing regimens, and time of blood drawn. The data were also analyzed using a standard population pharmacokinetic modeling program, NON-MEM. The observed vs predicted concentration relationships obtained from the neural network approach were similar to those from NONMEM. The residuals of the predictions from neural network analyses showed a positive correlation with that from NONMEM. Average absolute errors were 33.9 and 37.3% for neural networks and 39.9% for NONMEM. Average prediction errors were found to be 2.59 and −5.01% for neural networks and 17.7% for NONMEM. We concluded that neural networks were capable of capturing the relationships between plasma drug levels and patient-related prognostic factors from routinely collected sparse within-patient pharmacokinetic data. Neural networks can therefore be considered to have potential to become a useful analytical tool for population pharmacokinetic data analysis.

In most experimental pharmacokinetic studies, parameter estimates are computed separately for each subject, then averaged across subjects. Average estimators for ratios and functions of parameters are often of interest; examples include half-life and clearance. For these parameters, recommendations regarding averaging using the arithmetic versus the harmonic mean have been based on computer simulations.^1–3 The goal in this paper was to demonstrate that these empirically generated results can be derived using approximations for the expected values of reciprocals and ratios. We first consider estimating the reciprocal of a parameter, and predict the earlier simulation results for half-life. We additionally predict results for clearance when computed as dose divided by area under the curve. Next we consider estimating the ratio of two parameters, and predict the earlier simulation results for clearance in a first-order exponential model. As a further example, we predict results for the mean residence time in noncompartmental analysis. These approximations provide a unifying approach that can be used to determine optimal summary estimators, without the need for extensive computer simulations.

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein-negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+patients as compared with 68% of LRP-patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P =.0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P = .0304). Significant associations were observed between LRP and age greater than 55 years (P= .017), Pgp (P= .040), and prior treatment with mitoxantrone (P= .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.

Statistical modeling methods have had increasing use in drug disposition studies, both to estimate pharmacokinetic parameters and to develop regression models that relate these parameter estimates to patient characteristics. These methods are particularly flexible as they allow non-linearity and sparse within-patient information. In the past few years, multiple analysis methods have become available, but there is a lack of systematic comparisons of their estimates on the same data sets. Two simulated data sets were therefore developed by the Population Modeling Workgroup of the Biopharmaceutical Section of the American Statistical Association. We analysed these data sets using seven population modeling programs, some of which contain multiple analysis methods. Although each data set represents a single replicate from a given model and data collection design, the results suggest that the behaviour of some methods differs from that of the others. © 1997 by John Wiley & Sons, Ltd.

• In 82 white patients with myasthenia gravis, a high serum human acetylcholine receptor (AChR) antibody titer was related to the presence of the HLA-B8 antigen and increasing severity of the disease and not to age at onset, sex, presence of thymoma, or mode of treatment. Among patients without thymomas a high antibody titer was also associated with HLA-B8, particularly in those patients whose age at onset was less than 35 years. Thymectomy was associated with a lower median antibody titer when compared in two groups of HLA-B8-positive patients without thymoma who were similar for all other factors. Patients with thymomas who had received corticosteroids had a lower median titer than those who had not received steroids. This study supports the possibility that immune-response genes near the HLA-B8 segment of the major histocompatibility complex participate in the regulation of the humoral response to autoantigens, such as AChR protein.

In an effort to develop a clinically useful approach to overcoming P-glycoprotein-mediated multidrug resistance (MDRl), we evaluated combined chemosensitiration with verapamil and quinine in a multidrug-resistant (MDR) human myeloma cell line model. In clonogenic assay, verapamil was used at concentrations from 0.1 to 1.0 μg/mL, bracketing the plasma levels achieved by oral administration and high-dose intravenous (IV) infusion, respectively. The dose of quinine was held constant at 1.0 μg/mL, a plasma concentration readily achieved by oral administration. At each dose level of verapamil tested, the combination with quinine proved more effective than either drug individually in reversing resistance to doxorubicin and vinblastine and synergistic chemosensitizing interaction was observed. Verapamil at 0.1 μg/mL combined with quinine was capable of restoring sensitivity to doxorubicin fully and reduced resistance to vinblastine as effectively as verapamil alone at 1.0 μg/mL. Furthermore, the combination of 1.0 pmol verapamil with 10 pmol quinine increased accumulation and retention of anthracycline in the resistant cells to a greater extent than did either drug individually (P < -001) and inhibited drug efflux as effectively as verapamil alone at 10 pmol. Our findings suggest that combined chemosensitiration with verapamil and quinine may prove useful for overcoming MDRl in patients with drug-refractory B-cell neoplasms such as multiple myeloma or nomHodgkin's lymphomas.

Background: Maternal obesity and gestational diabetes mellitus (GDM) contribute to increased risk for type 2 diabetes mellitus (T2DM) among both mothers and their offspring. Randomized trials demonstrated T2DM risk reduction in adults following lifestyle behavior change and modest weight loss; the evidence base for at-risk children remains limited.Purpose: Evaluate the feasibility, acceptability, and preliminary efficacy of a T2DM prevention intervention for mother-child dyads delivered by Federally Qualified Health Center staff.Methods: A group randomized design tested the effects of a behavioral lifestyle intervention on T2DM risk factors in women with a history of GDM and their 8- to 12-year-old children. Mother-child dyads were recruited and randomized to intervention or wait-listed control conditions. Intervention participants completed the 13-week intervention; control participants received standard of care. Baseline and 13-week measures assessed program acceptability and feasibility, and explored effects on body weight, waist circumference, hemoglobin A1c, and lifestyle behaviors.Results: Forty-two dyads were randomized and 35 (83%) completed pre-/post-measurements. Participants and program leaders positively rated content and engagement. Nearly all strongly agreed that activities were enjoyable (97%), applicable (96%), useful (97%), and motivational (96%). Attendance averaged 65% across 2 cohorts; delivery costs were approximately $225/dyad. There were no significant differences in body weight, BMI (or BMI z-score), waist circumference, hemoglobin A1c, diet quality, physical activity, sleep, or home environment changes between intervention and control groups.Conclusions: A family T2DM prevention program was feasibly delivered by FQHC staff, and acceptable to mothers and children. Program efficacy will be evaluated in an adequately powered clinical trial.

Lentz: Novo Nordisk Inc.: Consultancy, Honoraria, Research Funding.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

GASTROENTEROLOGY 2000;119:591

We previously reported that cimetidine but not ranitidine significantly enhances cyclophosphamide-induced bone marrow toxic effects and the appearance of cyclophosphamide alkylating species in a murine leukemia mouse model, and we advised caution in the use of cimetidine with microsomally metabolized anticancer drugs. Both drugs have been used for the treatment of gastric complications of chemotherapy. Using a randomized, double-blind, crossover study design, we have now evaluated the potential interaction of ranitidine with cyclophosphamide in seven cancer patients, who received two courses of cyclophosphamide, one with ranitidine and one with placebo. Four patients received ranitidine in the first course, and three received placebo. Ranitidine or placebo was started 3 days before a single dose of cyclophosphamide and given for 17 consecutive days. Ranitidine or placebo was given orally (300 mg/d), and cyclophosphamide (600 mg/m2) was given intravenously with [3H]cyclophospha-mide (1000 μCi). Cyclophosphamide treatment was repeated at 4 weeks plus or minus 4 days. Blood samples were collected at intervals from 5 minutes to 24 hours after cyclophosphamide treatment and analyzed by thin-layer chromatography and radioassay for the drug and its metabolites. On days 0, 7, 14, and 21 after cyclophosphamide administration, complete blood cell counts, white blood cell differential counts, platelet counts, and SMA-17 were determined. The differences in mean nadir white blood cell counts, granulocyte counts, hemoglobin levels, and hematocrit values during ranitidine versus placebo treatment were not statistically significant In a statistical but not a clinical sense, mean nadir platelet counts were significantly lower with ranitidine. There was a statistically significant increase in area under the curve for drug concentration in plasma x time (AUC) with ranitidine as well as a statistically significant decrease in the total-body clearance rate of the cyclophosphamide molecule. However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophospha-mide and phosphoramide mustard was not statistically significant. The lack of toxicologic or metabolic interaction between ranitidine and cyclophosphamide suggests that ranitidine can be used safely with cyclophosphamide. [J Natl Cancer Inst 83:1739–1743, 1991]

We report a model that provides a strong correlation between mouse toxicity data [mouse lethal dose 10% (LD10)] and human plasma concentration-versus-time (CXT) data for 22 commonly used anticancer agents. Mouse toxicity data (LD10) from two dosing schedules, daily times one and daily times seven, were evaluated for the two mouse strains BDF/1 and Swiss. Data from BDF/1 mice were selected for analysis because they were more abundant. Strong correlations were found between LD10 and human plasma CXT data for both daily times one and daily times seven dosing schedules—In (CXT) = −1.6504 + [0.8408 × In (LD10)], r = .84, P < .0001, and In (CXT) = −0.0754 + [0.8954 × In (LD10)], r = .90, P < .0001, respectively. These correlations may serve as useful models to predict the maximally tolerated dose of an investigational anticancer agent prior to entry into clinical trials and to assist in the selection of clinically relevant in vitro CXTs for new-agent screening against human tumors.