A phase II study of bevacizumab, oxaliplatin, and docetaxel in locally advanced and metastatic gastric and gastroesophageal junction cancers.

BACKGROUND: Bevacizumab has demonstrated antitumor activity in multiple diseases. This phase II study was undertaken to determine the effects of adding bevacizumab to a regimen of docetaxel and oxaliplatin in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. PATIENTS AND METHODS: Previously untreated patients with locally advanced or metastatic disease and a performance status (PS) of 0-1 were eligible for this study. Patients received bevacizumab at 7.5 mg/kg, docetaxel at 70 mg/m(2), and oxaliplatin at 75 mg/m(2) administered on day 1 of a 21-day cycle. The primary end point of the study was progression-free survival (PFS). RESULTS: A total of 38 eligible patients (median age 57 years, 45% gastric, 55% PS 0) were enrolled on to the study. Median PFS was 6.6 months [95% confidence interval (CI) 4.4-10.5] and median survival 11.1 months (95% CI 8.2-15.3). Complete responses were documented in 2 (5%) patients, partial responses in 14 (37%), and stable disease in 14 (37%). No treatment-related deaths were observed. The most commonly reported grade 3-4 toxicity was neutropenia (34%), and gastrointestinal perforation occurred in three patients (8%). CONCLUSION: The combination of bevacizumab, docetaxel, and oxaliplatin has promising activity for further evaluation in randomized trials.

Non-bacterial infections in allogeneic non-myeloablative stem cell transplant recipients.

Data on non-bacterial infections during allogeneic non-myeloablative hematopoietic stem cell transplantation (HSCT) are widely different. We evaluated data on 48 consecutive patients who received a conditioning regimen with fludarabine and cyclophosphamide (73%) or fludarabine and total body irradiation (27%) and then underwent allogeneic non-myeloablative HSCT. Cytomegalovirus (CMV) infection was common and occurred in 48% of patients; 3 patients developed CMV disease, and all survived. CMV reactivation was found to be common with both conditioning regimens in our patient population. Invasive aspergillosis occurred in 4 patients (8%) and 3 died. Other serious non-bacterial infections were uncommon. Review of the available literature on non-myeloablative HSCT suggests that the frequency and type of opportunistic infections vary considerably.

Intra- and inter-individual variability in measurements of biomarkers for oxidative damage in vivo: Nutrition and Breast Health Study.

Oxidative stress has been implicated in the pathogenesis of various chronic diseases, such as cancer, cardiovascular disease and inflammatory conditions, as well as in ageing. Although a number of markers are now available, little is known about the reliability of single measurements of such markers in healthy individuals. The study examined the distribution of variance for three oxidative stress markers, 8-oxo-2'-deoxyguanosine (8-oxodG), 5-hydroxymethyl-2'-deoxyuridine (5-OHmdU) and total 8-isoprostane-F2alpha, which were measured every 3-6 months over 1 year in blood and breast nipple aspirate fluid (NAF) for 103 premenopausal women. For both plasma and NAF, the between-subject variances of 8-isoprostane-F2alpha were consistently greater than the within-subject variances. Consequently, their reliability coefficients were close to the level of those for cholesterol. On the other hand, the within-subject variances were much greater than the between-subjects variances for blood 5-OHmdU, resulting in low reliability coefficients, i.e. <0.3. Overall, the reliability coefficients for blood 8-oxodG were between those of 8-isoprostane-F2alpha and 5-OHmdU, but closer to those of 8-isoprostane-F2alpha. The results suggest that the reliability of oxidative stress markers may vary considerably depending on the type of marker. Caution should be exercised in selecting markers as well as in determining the number of study subjects or the number of samples per subject in a study. There also may be ample room to optimize laboratory techniques to quantify markers of oxidative DNA damage.

Safety of low-dose low-molecular-weight-heparins in thrombocytopenic stem cell transplantation patients: a case series and review of the literature.

Few attempts have been made to examine the feasibility of safely administering low-molecular-weight-heparins (LMWHs) in the presence of concurrent thrombocytopenia. We retrospectively investigated the safety of low-dose LMWH in BMT patients, a population at risk of bleeding. In total, 26 patients received at least one dose of low-dose enoxaparin (ie <1 mg/kg/day) during thrombocytopenia. s.c. enoxaparin 40 mg once daily was given in 85% of the cohort. The mean number of platelet days <55 x 10(9) and <20 x 10(9)/l were 16.5 days (95% CI=8.04-24.96) and 4.14 days (95% CI=2.35-5.93), respectively. The mean number of low-dose enoxaparin administration days when platelet <55 x 10(9) and 20 x 10(9)/l were 9.89 days (95% CI=3.26-16.53) and 2.25 days (95% CI=0.57-3.93), respectively. Minor bleeding occurred in four patients (15%) whereas major episodes developed in two patients (8%). The latter two events occurred during the transition between full therapeutic (ie 1.5-2 mg/kg/day) and low-dose enoxaparin close to the onset of thrombocytopenia. The present case series, along with the discussed literature, descriptively suggests that low-dose enoxaparin may be safely administered at a platelet count in the range of 20 and 55 x 10(9)/l in BMT patients who weigh >55 kg.

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.

Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer.

PURPOSE: This phase II study was undertaken to determine the efficacy of adding infusional fluorouracil (FU) to the chemotherapy doublet of gemcitabine and cisplatin in patients with advanced pancreatic cancer. PATIENTS AND METHODS: The eligibility criteria included histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m2 intravenously (IV) on days 1, 8, and 15; cisplatin 50 mg/m2 IV on days 1 and 15; and FU 175 mg/m2/d from days 1 to 15 by continuous IV infusion. Cycles were repeated every 28 days. Objective tumor response and toxicity were evaluated according to the World Health Organization criteria. RESULTS: A total of 47 patients (median age, 57 years; males, 59%) were enrolled. Sixteen patients had locally advanced (LA) disease, and 31 patients had metastatic disease. A total of 183 cycles of chemotherapy were administered. In patients with metastatic disease (n = 31), the probability of survival at 6 and 12 months was 66% and 34%, respectively. Objective partial response or stable disease was observed in 26% (90% confidence interval [CI], 0.14 to 0.41) and 61% (90% CI, 0.45 to 0.74) of patients, respectively. In patients with LA disease (n = 16), there were three partial responses (19%; 90 CI, 0.07 to 0.39). One patient in this group was successfully resected after FU-based radiotherapy. The most common grade 3 to 4 toxicities were neutropenia (60%), thrombocytopenia (42%), and anemia (26%). Thirteen patients were hospitalized for treatment-related complications. CONCLUSION: The combination of gemcitabine, cisplatin, and infusional FU has significant activity in patients with advanced pancreatic cancer.

A phase I clinical trial of spicamycin derivative KRN5500 (NSC 650426) using a phase I accelerated titration "2B" design.

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m2/d x 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m2/d x 5. The recommended Phase II dose i s 4.3mg/m2/d x 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8-8.4 mg/m2/d x 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.

Effect of participant motivation on rapid dietary changes in an intervention trial.

BACKGROUND: Dietary intervention research with free-living subjects relies on the ability of study participants to meet their dietary goals within the study timeframe. Little is known about underlying factors affecting compliance. METHOD: Here, we examined whether motivation to enroll in a trial of low-fat and/or energy-reduced diets influenced the ability of healthy women to reach their dietary goals quickly. RESULTS: Of the women who had energy-reduction goals (n=43), the 18 with an altruistic reason for participation had a much higher energy reduction success rate at 4 weeks (83%) than the 25 who gave self-rewarding reasons (48%). CONCLUSIONS: Education, body weight, family history of cancer and previous diet experience did not appreciably affect dietary outcomes. This observation suggests that the societal importance of the research should be stressed in strategies that seek to affect rapid reduction of energy intake in clinical trials.

Effect of soy isoflavone supplementation on markers of oxidative stress in men and women.

Dietary intake of soy has been linked with decreased cancer risk, and the active compounds in soy that have been identified include the isoflavones genistein and daidzein. Since these compounds have antioxidant properties, we examined levels of oxidative damage in blood of six women and six men before and during soy supplementation using Novasoy tablets. Blood samples were obtained at weekly intervals for 3 weeks from the women taking 50-mg isoflavones once daily and the men taking 50-mg isoflavones twice daily. Plasma levels of genistein and daidzein increased after supplementation with maximal levels occurring at 2 weeks for the women while levels in men kept increasing over the 3 weeks of study. There was wide variation between individuals in the levels of isoflavones achieved. Mean levels of 5-hydroxymethyl-2'-deoxyuridine (5-OHmdU) in DNA from nucleated blood cells decreased after 1 week of supplementation in the women, with a decrease of 47% in mean 5-OHmdU levels after 3 weeks. In men, mean 5-OHmdU levels did not decrease until after 3 weeks of supplementation, at which there was 61% decrease. Mean plasma levels of 8-isoprostanes were not changed appreciably in either men or women. These pilot results suggest that soy isoflavone supplementation decreases levels of oxidative DNA damage in humans, and this may be a mechanism behind the cancer-preventive effects of soy isoflavones.

Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma.

BACKGROUND: Pancreatic carcinoma is considered among the most chemoresistant of human malignancies. The most commonly used cytotoxic single agents, 5-fluorouracil and 2'-deoxy-2',2'-difluorocytidine (gemcitabine), have objective response rates of less than 10% in large studies. Hypothesizing noncross resistance and a synergistic interaction between gemcitabine and cisplatin, early clinical studies have demonstrated significant activity with this combination in patients with several types of malignant disease. A Phase II study was undertaken to determine the efficacy of gemcitabine in combination with cisplatin in patients with locally advanced and metastatic pancreatic carcinoma based on these considerations. METHODS: The eligibility criteria included histologically confirmed, locally advanced, unresectable or metastatic exocrine carcinoma of the pancreas with no prior gemcitabine therapy; prior adjuvant therapy was allowed provided the last day of therapy was at least 6 months prior to starting treatment; clinically measurable or evaluable disease; a Southwest Oncology Group scale performance status of 0-2; a life expectancy of > 12 weeks; and adequate bone marrow, hepatic, and renal function. A total of 42 patients, 4 patients with locally advanced, unresectable disease and 38 patients with metastatic disease, were treated and received a total of 211 cycles of therapy between May 1997 to March 1999. The median age of patients was 61.5 years. The patients were treated in the outpatient setting with a combination of gemcitabine 1,000 mg/M(2) intravenously over 30 minutes administered on Days 1, 8, and 15 of each cycle and cisplatin 50 mg/M(2) intravenously administered after gemcitabine infusion on Days 1 and 15 with adequate prehydration accompanied by adequate urinary output. Cycles were repeated every 28 days. Response and toxicity were assessed according to World Health Organization and standard criteria. RESULTS: The complete and partial response rate among all 42 registered patients was 11 of 42 patients (26%; 95% confidence interval, 0.14-0.42). Stabilization of disease was seen in 15 patients (38%). Two additional patients with metastatic disease who achieved major responses to chemotherapy were rendered free of disease surgically, achieving a complete response status. The median overall survival was 7.1 months (95% confidence interval [CI], 6.3-9.1 months), with 64% of patients alive at 6 months and 19% of patients alive at 12 months. The median time to disease progression was 5.4 months (range, 0.9-20.8 months). Major toxicities were neutropenia and thrombocytopenia, with one episode of neutropenic fever. CONCLUSIONS: The combination of gemcitabine and cisplatin appeared to have significantly greater activity than single-agent gemcitabine in this Phase II study, with tolerable toxicity. The antitumor activity of this combination needs to be confirmed in multi-institutional or comparative trials.

Chronic oral administration of CI-994: a phase 1 study.

OBJECTIVES: CI-994 (N-acetyl dinaline, PD 123654) is a novel oral agent active in a broad variety of murine and human tumor xenografts. While cytotoxic in the Brown Norway (BN) rat leukemia model, growth inhibition in other murine and human tumor xenografts is predominantly cytostatic. Its specific mechanism of action remains unknown. Following CI-994 administration, inhibition of both histone deacetylation and cellular proliferation at the G1 to S transition phase of the cell cycle are observed. This Phase 1 study in patients with solid tumors was carried out to determine a maximum tolerated daily oral dose (MTD) for CI-994 administered on a chronic basis. METHODS: Fifty-three patients received CI-994 daily for treatment durations ranging from 2 to 10 weeks. Dosage escalation proceeded in 2 phases; an Acute Dosing Phase (n = 11) to define the MTD for CI-994 administered over 2 weeks and a Chronic Dosing Phase (n = 29) to define the MTD for daily administration for 8 weeks. Upon completion of the Chronic Dosing Phase, a third cohort of patients (n = 13) received CI-994 at the recommended Phase 2 dose and schedule with 2 additional single doses of drug administered separated by a 1-week washout to assess the effect of food on CI-994 pharmacokinetics. RESULTS: Thrombocytopenia was dose limiting at the MTD of 8 mg/m2/day for 8 weeks. Other toxicities included fatigue and gastrointestinal effects such as nausea, vomiting, diarrhea, constipation and mucositis. Pharmacokinetic studies revealed that peak plasma levels and AUC's generally increased with dose and that food intake did not affect the rate or extent of drug absorption. One patient with heavily pre-treated adenocarcinoma of the lung achieved a Partial Response (PR) lasting over 2 years and 3 additional patients achieved Stable Disease (SD), 1 each with non-small cell lung, colorectal, and renal cancer. CONCLUSIONS: The recommended Phase 2 starting dose is 8 mg/m2/day for 8 weeks repeated after a 2-week drug-free interval.

Levels of 5-hydroxymethyl-2'-deoxyuridine in DNA from blood of women scheduled for breast biopsy.

Systemic oxidative stress is thought to contribute to risk of various cancers, including breast cancer. DNA repair ability also has been associated with breast cancer risk. In this work, we examined levels of oxidative DNA damage as an indication of breast cancer risk in women because oxidative DNA damage levels should reflect the net balance of oxidative stress and DNA repair ability. Levels of 5-hydroxymethyl-2'-deoxyuridine, one form of oxidative DNA damage, were measured in DNA from blood of women scheduled for breast biopsy. The blood samples analyzed included women whose biopsy results indicated invasive breast cancer, high-risk lesions (atypical hyperplasia or carcinoma in situ), or benign lesions. Mean levels of 5-hydroxymethyl-2'-deoxyuridine were significantly higher in blood of women who had high risk or invasive breast lesions versus women with benign lesions. If atypical hyperplasia or carcinoma in situ are precursor lesions for breast cancer, then these results suggest that oxidative DNA damage may be involved in the cancer process before invasive cancer develops.

A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer.

Current chemotherapy for patients with advanced colorectal cancer is relatively ineffective and may be associated with significant toxicity. Bryostatin 1 (bryo 1) influences cell proliferation, intracellular metabolism and signaling, differentiation, and apoptosis in human cancer cell lines via modulation of protein kinase C (PKC) activity. This trial investigates the efficacy and toxicity of bryo 1 as a novel therapeutic agent for patients with advanced colorectal cancer who have had previous 5-fluorouracil therapy. The primary end point was tumor response to bryo 1. Toxicity was also assessed. Twenty-eight patients with advanced colorectal cancer were enrolled. The mean age was 59 years (range, 38-76), with 16 men and 12 women, and good minority representation (11 African-Americans). The first 10 patients initially received 25 microg/m2 of bryo 1 weekly as a 24-h infusion for 3 weeks of every 4-week cycle, with dose escalation to 35 microg/m2 starting with the second cycle. The remaining patients were started at 35 microg/m2 and escalated to 40 microg/m2, if toxicity was minimal. Twenty-five patients were evaluable for objective tumor response, and complete data on toxicity were collected on 26 patients. No partial or complete tumor responses were observed. All 25 patients had disease progression within four cycles. Myalgia was the most common toxicity. Myelosuppression was not seen. bryo 1 as a weekly 24-h continuous infusion lacks single-agent antitumor activity in advanced colorectal cancer. Toxicity differs from that of traditional chemotherapeutic drugs.

Comparison of dietary assessment methods in a low-fat dietary intervention program.

The food frequency questionnaire (FFQ) is commonly utilized for assessment of dietary fat intake, but its validity among individuals following a low-fat diet is unclear. We evaluated the agreement of nutrient estimates derived from FFQ, 24-h recall, and 3-day food records obtained from 104 participants in a randomized trial of a low-fat dietary intervention for women at elevated breast cancer risk. Comparisons were made for total calories, percent calories from fat, and total fat after 1 yr. Correlation was assessed using standard methods based on a null hypothesis of no agreement between instruments as well as by a methodology based on a null hypothesis that the instruments should be in agreement. With the use of standard methods, FFQ estimates for women on the low-fat diet were significantly correlated to records only for percent calories from fat (r = 0.39), whereas recall and record estimates were significantly correlated for all three dietary variables. Using the new method, we found no significant correlation between FFQ and either recalls or records for women following a low-fat diet but significant correlation between recall and record estimates for total calories (r = 0.67). Traditional correlation testing may overestimate the extent of agreement in dietary instruments among women on a low-fat diet. We found empirical support for the nontraditional method.

Phase I pharmacokinetic study of the novel antitumor agent SR233377.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

Weekly 1-hour infusion of paclitaxel. Clinical feasibility and efficacy in patients with hormone-refractory prostate carcinoma.

BACKGROUND: Preclinically, paclitaxel given according to an intense bolus schedule has significant antitumor activity against human prostate carcinoma cell lines in SCID mice. The authors evaluated the feasibility and efficacy of weekly 1-hour infusion of paclitaxel in patients with metastatic hormone-refractory prostate carcinoma (HRPC). METHODS: A total of 18 patients with progressive metastatic HRPC were enrolled. Patients had to have no prior chemotherapy. Paclitaxel was infused weekly at a dose of 150 mg/m(2) over 1 hour for 6 weeks every 8 weeks. RESULTS: Eighteen patients with a median age of 68.5 years and a median prostate specific antigen (PSA) level of 82 ng/mL (range, 2.17-3196 ng/mL) were enrolled. The median number of prior hormone treatments was 2, and 12 patients on antiandrogens completed antiandrogen withdrawal. Ten of eighteen patients had bone-only metastasis and eight had metastasis to bone with lymph node and/or visceral metastasis. Seventeen patients received a total of 31 cycles (157 courses) and 1 patient refused chemotherapy. All patients were included in response evaluation. Of the 8 [corrected] patients with measurable disease, 4 achieved a major response, with 1 complete response (in the lung) and 3 partial responses (1 in the liver and 2 in the lymph nodes). Seven of eighteen patients (39%) had a PSA decline of >/=50%. The major high grade toxicity was peripheral neuropathy, with 6 patients (35%) developing Grade 3 toxicity. CONCLUSIONS: Weekly 1-hour paclitaxel has activity in patients with HRPC. The major toxicity is peripheral neuropathy. The minimal myelosuppressive effects make a modified schedule (lower doses on the same schedule or a shorter schedule of the same dose) attractive for future combination chemotherapy trials.

Recruitment for a pilot case control study of oxidative DNA damage and breast cancer risk.

Oxidative DNA damage (ODD) can result from numerous endogenous metabolic processes as well as from exposure to environmental and dietary oxidants. One important type of ODD that may have a role in carcinogenesis is the formation of hydroxylated DNA bases. Our major purpose was to determine the potential for subject accrual for a multisite case-control study of ODD and breast cancer risk within a large urban university medical center. We examined the levels of a hydroxylated thymine residue, 5-hydroxymethyl-2'-deoxyuridine in DNA obtained from the peripheral blood of 26 women with breast cancer and an age-matched group of 29 control women without breast cancer. The isolated DNA was analyzed for levels of 5-hydroxymethyl-2'-deoxyuridine by gas chromatography with mass spectral detection. Our recruitment methods resulted in a relatively high yield of eligible cases (72%) and a lower yield of controls (46%). We evaluated the dose-response relationship of ODD level to breast cancer risk, using quartiles of ODD. The covariate-adjusted odds ratio of breast cancer exceeded 2.0 for women in the highest quartile of ODD (compared with the lowest quartile), although this result was not statistically significant. ODD levels were significantly more variable among African-American controls (SD = 224.1) than among white controls (SD = 57.5), p < 0.001. Overall, these results suggest a possible slight increase in breast cancer risk among women in the highest ODD quartile, after adjusting for race, menopausal status, and family history of breast cancer.

A clinical trial to selectively change dietary fat and/or energy intake in women: the Women's Diet Study.

Dietary fat and energy intake have been implicated in breast cancer etiology. To examine the relative importance of these dietary factors on markers of cancer risk in women, we designed an intervention trial to selectively decrease fat and/or energy intake in free-living, premenopausal women who were somewhat overweight. The study used a 2 x 2 factorial design to evaluate the independent and interactive effects of dietary fat and energy. The diets were nonintervention, low fat (15% of energy from fat, maintenance of energy intake), low energy (25% energy reduction), and combination low fat and low energy. We utilized an individualized counseling approach with self-selection of foods. Women on the low-fat and combination diets were asked to meet given daily goals for fat grams and food group exchanges, while women on the low-energy diet used only food group exchanges. Of the 113 premenopausal women randomized who were eligible for analysis, 43% were African-American. A total of 88 women completed the 12-week program, and adherence to the dietary goals was similar in both racial groups. Women on the low-fat diet were able to reduce dietary fat intake to 19% of energy by 4 weeks and to 17% by 12 weeks with a slight decrease in energy intake. Women on the low-energy diet met their energy reduction goals by four weeks while maintaining percentage of energy from fat. Women on the combination diet largely met their goals by four weeks as well. These data indicate that it is possible to selectively manipulate dietary fat and energy intake in women over a short period of time, which makes clinical studies on the relative effects of these two dietary variables on cancer risk biomarkers readily feasible.

Evaluation of pyrazoloacridine in patients with advanced pancreatic carcinoma.

PURPOSE: Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad pre-clinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced pancreatic cancer was conducted. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 21 days. Seventeen patients were treated receiving a total of 46 courses of PZA. RESULTS: Of the 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0-22%). Major toxicities directly attributable to PZA included moderate neutropenia and mild neurotoxicity. CONCLUSION: PZA at this dose and schedule of administration was inactive in patients with pancreatic carcinoma.

Oxidative DNA damage levels in blood from women at high risk for breast cancer are associated with dietary intakes of meats, vegetables, and fruits.

OBJECTIVE: We examined the relationship between intakes of specific foods--namely, meats, vegetables, and fruits--with levels of oxidative DNA damage in women consuming their own usual diet or a diet low in fat. DESIGN: Blood was obtained from women who had been assigned randomly to a low-fat or nonintervention diet for 3 to 24 months. Levels of 5-hydroxymethyluracil, a type of oxidative DNA damage, were determined. Diet data were obtained from 3-day food records. SUBJECTS/SETTING: The 21 women were participating in an outpatient clinic. All the women were healthy but had a first-degree relative with breast cancer. INTERVENTION: The intervention was a self-selected diet with a goal of 15% of energy from fat. MAIN OUTCOME MEASURES: Existing data on oxidative DNA damage levels were evaluated for possible relationships to foods eaten. Intakes of raw and cooked vegetables were examined separately. Meat intake was examined by type of meat (pork, beef, fish, chicken) and by cooking temperature. STATISTICAL ANALYSES: Initial univariate analyses relied on Spearman rank correlations of each food item with DNA damage. Further analyses of the data were performed with univariate and multivariate weighted least squares regression models. RESULTS: The model that best explained DNA damage levels was a bivariate regression model that included the intake of cooked vegetables and the sum of beef and pork intake. This model accounted for 85% of the variation in DNA damage levels among women. Preliminary results are suggestive of a positive association of DNA damage with beef and pork intake and a negative association with cooked vegetable intake. APPLICATION: These observations, if confirmed in larger studies, suggest specific dietary changes to reduce oxidative DNA damage levels and possibly cancer risk.