Cross-sectional associations between adipose tissue depots and areal bone mineral density in the UK Biobank imaging study.

The relationship between obesity and osteoporosis is poorly understood. In this study, we assessed the association between adiposity and bone. The fat-bone relationship was dependent on sex, body mass index classification, and menopausal status. Results highlight the importance of accounting for direct measures of adiposity (beyond BMI) and menopause status. INTRODUCTION: Assess the relationship between direct measures of adiposity (total body fat mass, visceral adipose tissue, and abdominal subcutaneous adipose tissue) with the whole body and clinically relevant bone sites of the lumbar spine, and femoral neck areal bone mineral density (aBMD) in men and women. METHODS: This cross-sectional analysis was conducted utilizing de-identified data from the UK Biobank on participants (n = 3674) with available dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) data. Sex-stratified multiple linear regression was used to assess the relationship between adiposity measures and aBMD outcomes, controlling for age, race, total body lean mass (DXA), height, BMI class, physical activity, smoking, menopausal status (women), and hormone use (women). RESULTS: In men, significant interactions were observed between measures of adiposity and BMI on aBMD for the whole body and lumbar spine. Interactions indicated a positive relationship between adiposity and aBMD in men classified as normal weight, but an inverse relationship in men with elevated BMI. In women, significant interactions between adiposity measures and menopausal status were observed primarily for the whole body and femoral neck aBMD bone outcomes which indicated a negative relationship between adiposity and aBMD in premenopausal women, but a positive relationship in postmenopausal women. CONCLUSION: Total body adiposity, abdominal subcutaneous adipose tissue, and visceral adipose tissue were all significantly associated with aBMD in both men and women. The strength and direction of association were dependent on sex, BMI classification, and menopausal status (women).

Physical activity, sedentary time, and longitudinal bone strength in adolescent girls.

The association between baseline physical activity and sedentary time with 2-year longitudinal bone strength was evaluated. The effect of physical activity on bone depended on maturity status. Sedentary time did not negatively impact bone outcomes, regardless of maturity. Maturity should be considered when developing exercise interventions to improve bone outcomes. INTRODUCTION: Physical activity during adolescence is important to obtain peak bone mass; however, adolescents are increasingly sedentary, potentially increasing risk for osteoporosis later in life. The aim of this study was to assess the association of physical activity and sedentary time with 2-year longitudinal bone outcomes in adolescent females (69% Hispanic/31% non-Hispanic). METHODS: Bone strength was assessed at the 66% tibia, 20% femur, and 66% radius of 9- to 12-year-old girls (n = 131) using peripheral quantitative computed tomography at baseline and 2-year follow-up. Physical activity and sedentary time were assessed via accelerometry. Linear regression analyses were used to assess whether baseline vigorous physical activity (VPA), moderate physical activity (MPA), light physical activity (LPA), or sedentary time predict longitudinal bone outcomes, adjusting for relevant confounders. RESULTS: Significant interactions were found between maturity offset and physical activity. In weight-bearing bones, significant interactions were primarily identified between VPA and maturity offset. Interactions indicated that VPA was associated with favorable bone outcomes at the tibia and femur in girls further past the age of PHV. However, this favorable effect was not observed in girls closer to the age of PHV. At the radius, interactions were primarily observed between LPA and maturity offset. Again, LPA was more beneficial for girls further past the age of PHV. Sedentary time did not significantly influence bone outcomes. CONCLUSION: The effects of physical activity on bone may be dependent on maturity. Therefore, physical activity interventions, with attention to maturity status, may be required to optimize bone strength in girls.

Comparative value-based pricing of an Ebola vaccine in resource-constrained countries based on cost-effectiveness analysis.

OBJECTIVES: Pricing, affordability, and access are important deliberations around infectious disease interventions. Determining a fair price that not only incentivizes development but ensures value and access for patients is critical given the increasing global health crisis. Using Ebola virus disease (EVD) as an exemplar, we aim to elucidate the estimation of a jurisdiction-specific value-based price (VBP) for a vaccine package and to consider how prices compare across selected countries that have experienced EVD outbreaks. METHODS: Using a dynamic transmission model, we assessed the cost-effectiveness of a vaccine package - composed of the vaccine, storage, maintenance, and administration - for vaccination toward herd immunity in 4 countries affected with EVD (Democratic Republic of Congo, Liberia, Sierra Leone, Uganda). Based on the cost-effectiveness metrics and using willingness-to-pay thresholds equal to varying percentages of the Gross Domestic Product (GDP), we demonstrated how a VBP is calculated using a cost-effectiveness-based approach. RESULTS: The VBP for the vaccine is directly proportional to effectiveness (DALYs prevented), cost-effectiveness (ICER) and GDP per capita. Higher effectiveness, greater cost-effectiveness, and higher GDP per capita resulted in higher price ceilings compared to lower cost-effectiveness and lower GDP. CONCLUSION: Despite the concerns with the cost-effectiveness-based approach, we illustrated that it is an easily comprehensible method for determining the VBP of a vaccine using cost-effectiveness analysis. Choice of data, population characteristics, and disease dynamics are among the factors that need to be considered when comparisons are made across countries.

In infectious diseases, issues related to pricing, affordability and access to interventions are very important; particularly in low-income countries (LIC) because of the scarcity of resources coupled with several competing priorities. Pricing interventions fairly in LICs facilitates the prevention and management of infectious diseases, promotes innovation, and ensures patient access to valuable interventions. We were interested in determining a fair price of an intervention for an infectious disease (here, vaccination against Ebola virus disease) based on the cost-effectiveness (or value) of vaccination in four African countries.Using data from EVD outbreaks in Liberia, the Democratic Republic of Congo, Uganda, and Sierra Leone, we estimated the number of susceptible people who were exposed to the virus, became infected, recovered, or died. We did this for two scenarios: not vaccinating versus vaccinating to achieve herd immunity. We determined how many disability-adjusted life years (DALY; loss of the equivalent of a year of full health) would be prevented by vaccination; setting this as our value metric. Using this value metric and percentages of the gross domestic product (GDP) per capita as the willingness-to-pay (WTP) threshold (the price a payer might be prepared to pay for the intervention) we demonstrate how to calculate the maximum price for the vaccine package.The combination of greater effectiveness (DALYs averted), greater cost-effectiveness (value) and higher GDP per capita (WTP) resulted in different price ceilings in the four countries. The method proposed here is easy to understand and requires minimum data to determine a price for an intervention's price based on its value.

Immunosuppressant therapy adherence and graft failure among pediatric renal transplant recipients.

The study objective was to determine the association between immunosuppressant therapy (IST) adherence and graft failure among pediatric renal transplant recipients (RTRs) using data reported in the United States Renal Data System (USRDS), which contains Medicare prescription claims. RTRs (

Predictive model for plasma concentration-versus-time profiles of investigational anticancer drugs in patients.

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--ln (CXT) = -1.6504 + [0.8408 X ln (LD10)], r = .84, P less than .0001, and ln (CXT) = -0.0754 + [0.8954 X ln (LD10)], r = .90, P less than .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.

Lack of ranitidine effects on cyclophosphamide bone marrow toxicity or metabolism: a placebo-controlled clinical trial.

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]cyclophosphamide (1000 muCi). 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-hydroxycyclophosphamide 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.

Antitumor activity and clinical pharmacology of sulofenur in ovarian cancer.

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/m2 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.

Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial.

Since cyclophosphamide is used by both oral and i.v. routes in the treatment of hematological and solid malignancies, we designed a randomized, crossover clinical trial to evaluate the pharmacokinetics of this anticancer agent after either administration route. Plasma levels of cyclophosphamide and its two cytotoxic metabolites, 4-hydroxycyclophosphamide and phosphoramide mustard, were determined in seven cancer patients randomly assigned to treatment initially with either orally or i.v. administered cyclophosphamide with a 30-day interim between alternate therapy courses. Oral treatment was used initially in five patients and i.v. treatment in two patients, and the pharmacokinetic parameter, area under the plasma disappearance curve, was determined for each metabolite in each patient for both routes of drug administration. Statistical comparison of area under the plasma disappearance curve values for this set of patients indicated no significant differences for either metabolite for oral versus i.v. drug treatment, suggesting equal efficacy for these two routes of cyclophosphamide administration.

A bile acid-induced apoptosis assay for colon cancer risk and associated quality control studies.

Bile acids are important in the etiology of colorectal cancer. Bile acids induce apoptosis in colonic goblet cells at concentrations comparable to those found in fecal water after high-fat meals. Preliminary evidence indicated that cells of the normal-appearing (nontumorous) portion of the colon epithelium of colon cancer patients are more resistant to bile salt-induced apoptosis than are cells from normal individuals. In the present study, 68 patients were examined, and biopsies were taken at 20 cm from the anal verge, cecum, and descending colon. The patients included 17 individuals with a history of colorectal cancer, 37 individuals with adenomas, and 14 individuals who were neoplasia free. The mean bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47 (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/- 3.12 in individuals with a history of colon cancer. The correlation between independent observers was 0.89 (P < 0.001), indicating good interobserver reliability. Components of variance comparing interindividual versus intraindividual sources of variation suggested that site-to-site variability, both between regions of the colon and for adjacent biopsies, was larger than the interpatient variability for individuals with a history of neoplasia. Therefore, there was "patchiness" of the susceptibility of regions of the colon to bile acid-induced apoptosis in individuals with a history of neoplasia (a patchy field effect). There was no obvious correlation of low-apoptotic index regions with regions in which previous neoplasias had been found and removed. On the other hand, for normal, i.e., neoplasia-free, individuals, there was relatively less intraindividual variation compared to interindividual variation. Our assay shows an association between resistance to bile acid-induced apoptosis, measured at 20 cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful as a biomarker of colon cancer risk.

Clinical pharmacology of a novel diarylsulfonylurea anticancer agent.

LY186641 (diarylsulfonylurea, [DSU]) is a novel anticancer agent because of its unique diarylsulfonylurea chemical structure, broad-spectrum antisolid-tumor activity in preclinical models, presumed novel mechanism of action and preclinical toxicities of methemoglobinemia (Met Hgb) and decreased red blood cell (RBC) survival. In this study, the in vitro drug sensitivity of human tumors as well as clinical pharmacology and toxicology of DSU in patients with cancer were examined. DSU was administered orally, daily for 7 days with a 3-week treatment cycle. Dose-limiting toxicities were Met Hgb and RBC hemolysis. The maximum-tolerated dose was found to be 1,200 mg/m2/d for 7 days. In pharmacokinetic studies, DSU was found to have a prolonged serum half-life (approximately 30 hours) and a large area under the plasma disappearance curve (8,883.3 micrograms.hr/mL at 1,200 mg/m2/d). A partial remission was observed in one patient with refractory ovarian cancer. In conclusion, DSU can be safely administered to cancer patients and does display antitumor activity. Potential means of obviating the toxicities of this compound are discussed.

Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.

Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancer, precancer, and noncancerous diseases.

Paired blood (collected after an overnight fast) and cervical tissue (cancerous, precancerous, and noncancerous) samples were obtained from 87 patients (age, 21-86 years) who had a hysterectomy or biopsy due to cervical cancer, precancer (cervical intraepithelial neoplasia I, II, and III), or noncancerous diseases. The samples were analyzed using high-performance liquid chromatography for 10 micronutrients (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, cis-beta-carotene, alpha-tocopherol, gamma-tocopherol, and retinol). The results indicated that: (a) among the three patient groups, the mean plasma concentrations of all micronutrients except gamma-tocopherol were lowest in the cancer patients; however, the mean tissue concentrations of the two tocopherols and certain carotenoids were highest in the cancerous tissue; and (b) among the 10 micronutrients, only the concentrations of beta-carotene and cis-beta-carotene were lower in both the plasma and tissue of cancer and precancer patients than in those of noncancer controls. These results suggest that: (a) not all of the micronutrient concentrations in plasma reflect the micronutrient concentrations in cervical tissue; thus, in some cases, it may be necessary to measure the tissue micronutrient concentrations to define the role of the micronutrients in cervical carcinogenesis; and (b) maintaining an adequate plasma and tissue concentration of beta-carotene may be necessary for the prevention of cervical cancer and precancer.

Effect of subacute ibuprofen dosing on rectal mucosal prostaglandin E2 levels in healthy subjects with a history of resected polyps.

Nonsteroidal antiinflammatory drugs are among the most promising chemopreventive agents for colorectal cancer. Although the mechanism by which nonsteroidal antiinflammatory drugs exert such effects remains to be further characterized, their best known pharmacological effect is inhibition of prostaglandin synthetase, which leads to decreases in tissue prostaglandin levels. We conducted a randomized, double-blind, controlled study to examine the effect of daily ibuprofen treatment on the rectal mucosal prostaglandin E2 (PGE2) levels in healthy subjects with a history of resected polyps. Study participants (n = 27) completed a 2-week run-in period and were then randomized to take a single, daily dose of ibuprofen (300 or 600 mg) or of a placebo for 4 weeks. Rectal biopsy specimens were taken before and after the run-in period and at 2 and 4 weeks after the ibuprofen/placebo treatment. Notably large between- and within-subject variability in the rectal mucosal PGE2 content was seen. The changes in PGE2 levels after ibuprofen/placebo treatment correlated with the baseline PGE2 content. After adjustment of the baseline values, 2 weeks of 300 mg/day of ibuprofen treatment resulted in significantly more suppression of PGE2 levels than that observed after the placebo treatment (55% versus 22% suppression from baseline; P = 0.033). Although other ibuprofen treatment schedules and doses appeared to result in suppression in the PGE2 levels, the suppression was not statistically significant because of the large variability in this measurement. Because lower doses are associated with fewer adverse effects, a dose of 300 mg of ibuprofen/day should be considered for future Phase II chemoprevention studies. Stratifying study participants, based on their baseline PGE2 levels and inclusion of a larger number of study subjects, are recommended for future trials where the rectal mucosal PGE2 level is to be used as a surrogate end point biomarker.

Reproducibility of the measurement of colonic proliferation using bromodeoxyuridine across laboratories.

Although measures of colonic cell proliferation are being used as potential intermediate markers in chemoprevention studies, measurement standardization is still ongoing. This study was designed to assess the reproducibility of the labeling index quantification, as measured by bromodeoxyuridine, across four laboratories experienced in its use. Each institution submitted 10 slides, with one circled area of each slide to be scored. Each site followed its standard procedures for scoring colonic crypts; no attempts to standardize these procedures were made. There was high concordance among the laboratories on whether scorable crypts were present on a particular slide, but only two pairs of laboratories demonstrated agreement statistically greater than that predicted by chance. The overall difference among the sites on the number of scorable crypts was marginally significant (P = 0.083), and there was a highly significant overall difference in the magnitude of the labeling index (P < 0.0001). Sites 1 and 2 tended to have similar results, as did sites 3 and 4, most likely due to common training. Even with these discrepancies, high correlation (r > 0.75) was observed among the reported labeling index values for each pair of laboratories. Without standardized training, these laboratories may differ in the crypts considered appropriate for counting and in whether cells are counted as labeled or unlabeled. These results suggest that standardized training in scoring across all sites performing labeling index determinations is required to assure reproducibility across sites or studies. These results may also help explain discrepancies in the average values of the labeling index reported in the literature.

Chemoprevention of human actinic keratoses by topical 2-(difluoromethyl)-dl-ornithine.

Alpha-2-(Difluoromethyl)-dl-ornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, has been shown to suppress skin carcinogenesis in murine models after oral or topical administration. We designed a randomized, placebo-controlled study using a topical hydrophilic ointment formulation with or without 10% (w/w) DFMO. Forty-eight participants with moderate-severe actinic keratoses (AKs) on their forearms (i.e., at least 10 well-circumscribed lesions on the lateral surface) completed a 1-month run-in on placebo ointment. Before randomization, all lateral forearm AKs were circled, counted, photographed, and skin biopsies were obtained for DFMO and polyamine levels. Then participants were randomized to receive DFMO ointment on the right versus the left forearm and placebo hydrophilic ointment on the contralateral forearm twice daily for 6 months. DFMO was not detected in the blood of any subject, and there were no systemic toxicities. None of a subsample of 17 placebo forearms had measurable concentrations of DFMO, whereas 13 of the corresponding DFMO-treated forearms had high DFMO skin levels. As compared with placebo, the 6-month DFMO treatment caused a 23.5% reduction in the number of AKs (P = 0.001) as well as significant suppression of AK biopsy spermidine levels (26%; P = 0.04). Seven of the 48 (14.6%) participants experienced severe (2; 4.2%) or moderate (5; 10.4%) inflammatory reactions on their DFMO-treated arms which required dosing modification. Topical DFMO for 6 months can reduce the number of AK lesions and skin spermidine concentrations in high-risk participants and deserves additional study as a skin cancer chemopreventive agent.

Progress report: the Arizona phase III study of the effect of wheat bran fiber on recurrence of adenomatous colon polyps.

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.

Natural thermal resistance of human tumor cells and the role of prostaglandin.

We found that human malignant melanoma cells had varying thermal sensitivity and that some exhibited natural thermal resistance, a heretofore unrecognized phenomenon. Samples of 73 melanoma cell suspensions were heated at 42 degrees C for 1 hour before plating in the soft agar clonogenic assay or the thymidine assay for proliferating cells. We observed greater than 75% cell kill after hyperthermia in 39 (53%) tumors. Native thermal resistance was apparent in 17 (23%) tumors and growth enhancement in 17 (23%) at this temperature and exposure time. We postulated that prostaglandin, known to protect stomach mucosa against thermal injury, has a role in stabilizing the tumor cell membrane exposed to heat. Three melanoma cell lines known to be thermosensitive were heated to 42 degrees C without and with exogenous prostaglandin E2 (PGE2). The survival of colony-forming cells was increased in all three lines in the presence of 30 microM PGE2. A naturally thermoresistant cell line was exposed to 1 microgram/ml indomethacin for 24 hours before hyperthermic treatment. The survival of colony-forming cells was significantly decreased compared to cells not treated with indomethacin. The addition of 30 microM of exogenous PGE2 to indomethacin-treated cells reestablished thermal resistance. These preliminary data suggest that some tumor cells synthesize prostaglandins to render the cell thermoresistant. Treatment with indomethacin blocks prostaglandin synthesis and induces thermosensitivity. These discoveries may have important clinical applications for hyperthermia treatment of human cancers.

Humoral immune response to intralymphatic immunotherapy for disseminated melanoma: correlation with clinical response.

Since September 1979, 44 stage III melanoma patients treated with intralymphatic immunotherapy (ILI) with an oncofetal antigen (OFA-I)--enriched tumor cell vaccine (TCV) had evaluable humoral immune responses and clinical follow-up. Fourteen patients (32%) had stabilization or regression of tumors or remained free of resected disease. The median survival was 17 months, compared with 6 months for controls (P less than 0.001). Humoral immune responses were monitored by immune adherence using an OFA-positive human melanoma cell line, M14, as target. Alloantibodies were removed by absorption with L14 lymphoblasts autologous to M14. Twenty-two patients (50%) developed elevated antibody titers within 4 months, and 12 of the 22 (55%) had no disease progression. In contrast, 20 of 22 patients (91%) who failed to develop elevated titers had disease progression (P less than 0.01). The median titer was significantly higher during the first 4 months in the group whose disease did not progress (P less than 0.04). This study demonstrated that ILI with allogeneic OFA-I-enriched TCV can induce objective tumor regression and prolonged survival in patients with disseminated melanoma. Furthermore, because the specific humoral immune response correlates with clinical results, immunization efficacy can be monitored within a short period of time, which should aid future efforts to achieve optimal immunotherapy.

Score for neonatal acute physiology and phlebotomy blood loss predict erythrocyte transfusions in premature infants.

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 postnatal days predicts which infants with a birth weight of 1500 g or less received erythrocyte transfusion 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, < or = 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 +/- SD of 1.9 +/- 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 +/- SD birth weight (971 +/- 238 g vs 1272 +/- 144 g; P < .001) and a lower gestational age (27.7 +/- 1.6 weeks vs 30.7 +/- 2.8 weeks; P < .001), and they had a greater mean phlebotomy blood loss (3.3 +/- 1.6 mL/kg per day vs 1.4 +/- 0.5 mL/kg per day; P < .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 < .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.

Medical pattern recognition pitfalls in a clinical setting: renal cell carcinoma survival prediction.

Three studies to predict renal cell carcinoma patient survival from tumor textures found in digitized early venous phase arteriograms were successful individually. However, when the three methods were compared, they were not consistent and no single method was clinically useful. The first study predicted 5 yr survival of 37 patients with 87% accuracy. The second study added 29 patients to the data base; the poor survival of the 21 patients who died within 5 yr of diagnosis was predicted with 80.9% accuracy. When 27 of these cases were redigitized with a laser scanner, average survival prediction accuracy was 78%. In these studies, digitization hardware, radiographic technique, normalization methods, window selection, and contrast medium distribution all contributed to differences in the statistics separating poor from good patient survival.