A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy.

PURPOSE: Some breast cancer survivors report cognitive difficulties greater than 1 year after chemotherapy. Acetylcholinesterase inhibitors (AChEI) may improve cognitive impairment. We conducted a randomized, placebo-controlled, pilot study to assess the feasibility of using the AChEI, donepezil, to improve subjective and objective measures of cognitive function in breast cancer survivors. METHODS: Women who received adjuvant chemotherapy 1-5 years prior with current cognitive dysfunction symptoms were randomized to 5 mg of donepezil/day vs placebo for 6 weeks and if tolerated 10 mg/day for 18 weeks for a total of 24 weeks. A battery of validated measures of attention, memory, language, visuomotor skills, processing speed, executive function, and motor dexterity and speed was administered at baseline and at 24 and 36 weeks. Subjective cognitive function, fatigue, sleep, mood, and health-related quality of life were evaluated at baseline and at 12, 24, and 36 weeks. RESULTS: Sixty-two patients were enrolled, 76 % completed the study, self-reported compliance was 98 %, and toxicities were minimal. At the end of treatment, the donepezil group performed significantly better than the control group on two parameters of memory-the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall (p = 0.033) and HVLT-R Discrimination (p = 0.036). There were no significant differences on other cognitive variables or in subjective cognitive function or quality of life. CONCLUSION: Accrual to this feasibility trial was robust, retention was good, compliance was excellent, and toxicities were minimal. IMPLICATIONS FOR CANCER SURVIVORS: Randomized clinical trials in breast cancer survivors to improve cognitive dysfunction are feasible. A phase III trial testing the efficacy of donepezil is warranted given these pilot results.

Prestroke physical activity and early functional status after stroke.

BACKGROUND: The importance of physical activity as a modifiable risk factor for stroke in particular and cardiovascular disease in general is well documented. The effect of exercise on stroke severity and stroke outcomes is less clear. This study aimed to assess that effect. METHODS: Data collected for patients enrolled in the Ischemic Stroke Genetics Study were reviewed for prestroke self-reported levels of activity and four measures of stroke outcome assessed at enrollment and approximately 3 months after enrollment. Logistic regression was used to assess the association between physical activity and stroke outcomes, unadjusted and adjusted for patient characteristics. RESULTS: A total of 673 patients were enrolled; 50.5% reported aerobic physical activity less than once a week, 28.5% reported aerobic physical activity one to three times weekly, and 21% reported aerobic physical activity four times a week or more. Patients with moderate and high levels of physical activity were more likely to have higher Barthel Index (BI) scores at enrollment. A similar association was detected for exercise and good outcomes for the Oxford Handicap Scale (OHS). After 3 months of follow-up, moderate activity was still associated with a high BI score. No significant association was detected for activity and the OHS or Glasgow Outcome Scale at follow-up after adjustment for patient characteristics. CONCLUSIONS: Higher levels of self-reported prestroke physical activity may be associated with functional advantages after stroke. Our findings should be seen as exploratory, requiring confirmation, ideally in a longitudinal study of exercise in an older population.

Family history of stroke and severity of neurologic deficit after stroke.

BACKGROUND: A family history of stroke is an independent risk factor for stroke. OBJECTIVE: To assess whether severity of neurologic deficit after stroke is associated with a family history of stroke. METHODS: The Ischemic Stroke Genetics Study, a five-center study of first-ever symptomatic ischemic stroke, assessed case subjects prospectively for a family history of stroke-affected first-degree relatives. Certified adjudicators used the NIH Stroke Scale (NIHSS) to determine the severity of neurologic deficit. RESULTS: A total of 505 case subjects were enrolled (median age, 65 years; 55% male), with 81% enrolled within 1 week of onset of symptoms. A sibling history of stroke was associated with more severe stroke. The odds of an NIHSS score of 5 or higher were 2.0 times greater for cases with a sibling history of stroke compared with cases with no sibling history (95% CI, 1.0 to 3.9). An association of family history of stroke in parents or children with stroke severity was not detected. CONCLUSIONS: A sibling history of stroke increased the likelihood of a more severe stroke in the case subjects, independent of age, sex, and other potential confounding factors. Other family history characteristics were not associated with stroke severity.

Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study.

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m(-2)) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5(1/2) weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m(-2)) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35-79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control.

Intervention to increase screening mammography among women 65 and older.

This paper reports the results of a practice-based intervention program to increase mammography screening among women 65 and older who receive their health care in the private sector. Forty-three primary-care practices and 2147 women in central and western North Carolina were enrolled in the study, and 1911 women completed all phases of the study. The intervention was a three-stage educational and counseling program designed to become progressively more intensive at each stage. The interventions included provider education in the form of current information on issues in mammography for older women, simply written educational materials on breast cancer and screening mailed to women, and a brief telephone counseling session for the women. While the analysis revealed no overall effect across all three stages of the intervention program, tests for interaction indicated a significant program effect for women who were 80 or older, had less than 9 years of education, were black, or had no private insurance to supplement Medicare. The results suggested that providing primary-care physicians with information on screening older women and providing the women with useful educational materials can increase participation in screening mammography among subgroups of women currently least likely to receive mammography screening.

Phase I study of twice-weekly gemcitabine and concurrent thoracic radiation for patients with locally advanced non-small-cell lung cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity of twice-weekly gemcitabine and concurrent thoracic radiation in patients with Stage IIIa/IIIb non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Seventeen patients with histologically confirmed Stage IIIa and IIIb NSCLC were studied. Gemcitabine was administered via a 30-min i.v. infusion twice weekly for 6 weeks concurrent with 60 Gy of thoracic radiation. Gemcitabine, starting at a twice-weekly dose of 10 mg/m2 (20 mg/m2/week), was escalated in 10-15 mg/m2 increments in successive cohorts of 3 to 6 patients until dose-limiting toxicity was observed. RESULTS: Of the 17 patients entered, 16 were evaluable for toxicity. The dose-limiting toxicity at 50 mg/m2 given twice weekly (100 mg/m2/week) was Grade 3 pneumonitis observed in 1 patient, Grade 3 pulmonary fibrosis in a second patient, and Grade 4 esophagitis observed in two additional patients. Twice-weekly gemcitabine at a dose of 35 mg/m2 was determined to be the MTD. The overall response rate for the 16 evaluable patients was 88%. The median survival for the entire group is 16.0 months. CONCLUSIONS: The MTD of twice-weekly gemcitabine is 35 mg/m2 (70 mg/m2/week) given with thoracic radiation. A Phase II study within the Cancer and Leukemia Group B to ascertain the potential efficacy of this treatment regimen is in development.

Sleep histories are seldom documented on a general medical service.

BACKGROUND: Sleep disorders are common, but the frequency of sleep history documentation in hospitalized patients is unknown. METHODS: We reviewed 442 initial histories and physical examinations recorded by 122 house officers and 47 medical students in 208 consecutive general medicine ward patients. RESULTS: Any reference to sleep was recorded in only 18 patients (9%), including 12 of 141 (9%) with conditions associated with obstructive sleep apnea. Sleep histories were recorded more often in women (13% vs 4%) and less often than histories of cigarette smoking or alcohol use. Medical students recorded such histories more often than did house officers. Patients with sleep histories more often had pulse oximetry (78% vs 37%), pulmonary function testing (11% vs 1%), arterial blood gas analysis (67% vs 30%), or electrocardiograms (78% vs 49%). CONCLUSIONS: Sleep histories are documented infrequently in hospitalized patients. Patients with a recorded sleep history more often have tests that suggest increased concerns about cardiorespiratory risk and/or a different process of care.

A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy.

PURPOSE: To prospectively assess the health-related quality of life (HRQOL) and changes in HRQOL during the first year after 3 different treatments for clinically localized prostate cancer. METHODS AND MATERIALS: Ninety men with T1-T2 adenocarcinoma of the prostate were treated with curative intent between May 1998 and June 1999 and completed a quality-of-life Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire before treatment (T0) and 1 month (T1), 3 months (T3), and 12 months (T12) after treatment. Forty-four men were treated with permanent source interstitial brachytherapy (IB), 23 received external beam radiotherapy (EBRT), and 23 men were treated with radical prostatectomy (RP). The mean age of the entire study population was 65.9 years (median 67, range 42-79). The mean pretreatment prostate-specific antigen level of the entire study population was 6.81 ng/mL (median 6.25, range 1.33-19.6). The Gleason score was

Tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine (gemcitabine) after deoxycytidine kinase gene transfer: correlation with in vivo tumor response.

PURPOSE: We hypothesized that tumor uptake and elimination of 2',2'-difluoro-2'-deoxycytidine/2',2'-difluoro-2'-deoxycytidine 5'-triphosphate (dFdCyd/dFdCTP) would be altered after dCK gene transfer and that this change would result in an enhanced cytotoxic effect. To test this hypothesis, we examined dFdCyd/dFdCTP uptake and clearance in HT-29 human colon carcinoma xenografts in nude mice by high-performance liquid chromatography (HPLC) and fluorine-19 magnetic resonance spectroscopy (F-19 MRS). EXPERIMENTAL DESIGN: HT-29 tumors were grown from cells infected with either the retroviral vector alone (LNPO-LacZ) or vector containing the dCK gene (LNPO-dCK). HPLC and F-19 MRS analyses were performed after a single 160 mg/kg i.p. injection of dFdCyd. Tumor response was determined in animals receiving a similar dosing schedule of dFdCyd. RESULTS: HPLC experiments revealed an increased tumor accumulation of dFdCTP in xenografts overexpressing dCK compared with wild-type controls (P < or = 0.05). dFdCTP in the dCK-infected tumors was easily identified at 24 h postinjection. Conversely, no dFdCTP could be detected in the control xenografts 14 h postinjection. Subsequent F-19 MRS experiments confirmed an altered uptake, revealing a 2.5-fold greater accumulation of dFdCyd/dFdCTP in the dCK xenografts. Whereas a modest tumor growth delay was observed in the wild-type tumors receiving dFdCyd, dCK xenografts demonstrated a marked tumor growth delay following treatment (P < or = 0.05). CONCLUSIONS: These data support the hypothesis that increased expression of dCK cDNA in HT-29 xenografts results in an enhanced dFdCTP accumulation and prolonged elimination kinetics, and ultimately a potentiated in vivo tumor response to dFdCyd. Related to these effects, changes in the overall tumor metabolism of dFdCyd/dFdCTP was detectable by noninvasive F-19 MRS. These data are relevant to future preclinical and clinical studies evaluating dCK gene transfer and dFdCyd therapy.

Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity.

Although several variants of DNA repair genes have been identified, their functional significance has not been determined. Using samples collected from 135 cancer-free women, this study evaluated whether amino acid substitution variants of DNA repair genes contribute to ionizing radiation (IR) susceptibility as measured by prolonged cell cycle G2 delay. PCR-restriction fragment length polymorphism (RFLP) assays were used to determine four genotypes: X-ray repair cross complementing group 1 (XRCC1, exon 6, C/T, 194 Arg/Trp and exon 10, G/A, 399 Arg/Gln), XRCC group 3 (XRCC3, exon 7, C/T, 241 Thr/Met) and apurinic/apyrimidinic endonuclease 1 (APE1, exon 5, T/G, 148 Asp/Glu). Fluorescence-activated cell sorter (FACS) analysis was used to measure cell cycle delay. APE1 (exon 5) genotype was significantly associated with mitotic delay (P = 0.01), with the Glu/Glu genotype having prolonged delay compared with the other two genotypes. The mitotic delay index (mean +/- SD) in women with the APE1 codon 148 Asp/Asp, Asp/Glu and Glu/Glu genotypes was 30.95 +/- 10.15 (n = 49), 30.65 +/- 10.4 (n = 60) and 39.56 +/- 13.12 (n = 21), respectively. There was a significant interaction between family history (FH) and APE1 (exon 5) genotype (P = 0.007) as well as FH and XRCC1 (exon 10) genotype (P = 0.005) in mitotic delay. Lastly, prolonged cell cycle delay was significantly associated with number of variant alleles when APE1 Asp148Glu and XRCC1 Arg399Gln genotypes were evaluated in a four-level model (chi(2) for linear trend = 10.9; P = 0.001). These results suggest that amino acid substitution variants of XRCC1 and APE1 may contribute to IR hypersensitivity.

Duration of accrual and follow-up for two-stage clinical trials.

Group sequential trials with time to event end points can be complicated to design. Not only are there unlimited choices for the number of events required at each stage, but for each of these choices, there are unlimited combinations of accrual and follow-up at each stage that provide the required events. Methods are presented for determining optimal combinations of accrual and follow-up for two-stage clinical trials with time to event end points. Optimization is based on minimizing the expected total study length as a function of the expected accrual duration or sample size while providing an appropriate overall size and power. Optimal values of expected accrual duration and minimum expected total study length are given assuming an exponential proportional hazards model comparing two treatment groups. The expected total study length can be substantially decreased by including a follow-up period during which accrual is suspended. Conditions that warrant an interim follow-up period are considered, and the gain in efficiency achieved by including an interim follow-up period is quantified. The gain in efficiency should be weighed against the practical difficulties in implementing such designs. An example is given to illustrate the use of these techniques in designing a clinical trial to compare two chemotherapy regimens for lung cancer. Practical considerations of including an interim follow-up period are discussed.

Predictors of successful extubation in neurosurgical patients.

A respiratory therapist-driven weaning protocol incorporating daily screens, spontaneous breathing trials (SBT), and prompts to caregivers has been associated with superior outcomes in mechanically ventilated medical patients. To determine the effectiveness of this approach in neurosurgical (NSY) patients, we conducted a randomized controlled trial involving 100 patients over a 14-mo period. All had daily screens of weaning parameters. If these were passed, a 2-h SBT was performed in the Intervention group. Study physicians communicated positive SBT results, and the decision to extubate was made by the primary NSY team. Patients in the Intervention (n = 49) and Control (n = 51) groups had similar demographic characteristics, illness severity, and neurologic injuries. Among all patients, 87 (45 in the Control and 42 in the Intervention group) passed at least one daily screen. Forty (82%) patients in the Intervention group passed SBT, but a median of 2 d passed before attempted extubation, primarily because of concerns about the patient's sensorium (84%). Of 167 successful SBT, 126 (75%) did not lead to attempted extubation on the same day. The median time of mechanical ventilation was 6 d in both study groups, and there were no differences in outcomes. Overall complications included death (36%), reintubation (16%), and pneumonia (9%). Tracheostomies were created in 29% of patients. Multivariate analysis showed that Glasgow Coma Scale (GCS) score (p < 0.0001) and partial pressure of arterial oxygen/fraction of inspired oxygen ratio (p < 0.0001) were associated with extubation success. The odds of successful extubation increased by 39% with each GCS score increment. A GCS score > or = 8 at extubation was associated with success in 75% of cases, versus 33% for a GCS score < 8 (p < 0.0001). Implementation of a weaning protocol based on traditional respiratory physiologic parameters had practical limitations in NSY patients, owing to concerns about neurologic impairment. Whether protocols combining respiratory parameters with neurologic measures lead to superior outcomes in this population requires further investigation.

Vitamin and mineral supplement use by older rural adults.

BACKGROUND: Vitamin and mineral supplement products are widely consumed by older adults. This study describes supplement product use in a multiethnic rural population, relates supplement usage to dietary nutrient intake, and determines predictors of supplement usage. METHODS: Data are from a population-based sample of 130 community-dwelling adults aged 70 years and older in two rural North Carolina counties. The sample was 34% African American, 36% European American, and 30% Native American. Interviewer-administered semiquantitative food frequency questionnaires were used to obtain data on usual diet and supplement use. In-home interviews allowed verification of supplement composition. Intakes from diet and supplement products were examined for vitamins A, E, B6, C, folate, iron, zinc, and calcium. RESULTS: Of those who participated in the study, 47% reported using one or more supplement products. African Americans were significantly less likely to take supplements than Native Americans or European Americans. Based on dietary intakes, 65% of the participants were deficient (<2/3 recommended dietary allowance [RDA]) for at least one nutrient. The use of supplement products for the eight nutrients investigated was not related to dietary nutrient deficiency. For all nutrients investigated, except iron and calcium, a greater proportion of those without dietary deficiency took a supplement product than those with deficiency. Using logistic regression, ethnicity (European American and Native American), and gender (women) were significant predictors of supplement use. CONCLUSIONS: These findings suggest that although both dietary deficiencies of vitamins and minerals and supplement use are relatively high in this population, there is no association between supplement use and deficient dietary intakes for the eight nutrients examined. Health care providers should be aware that nutritional counseling and guidance on appropriate supplement usage is needed in this population.

Increasing use of bronchoscopic needle aspiration to diagnose small cell lung cancer.

OBJECTIVE: To review pathology reports to determine whether a temporal change in diagnostic procedures that included bronchoscopic needle aspiration (BNA) in evaluation of small cell lung cancer (SCLC) had occurred. METHODS: A retrospective review of the computerized pathology database of the Wake Forest University Baptist Medical Center from 1990 to 1998 was performed. All pathology reports of patients newly diagnosed with SCLC were reviewed and abstracted. RESULTS: The number of patients newly diagnosed with SCLC during the 9-year study period totaled 277. Of these, 173 underwent bronchoscopy. From January 1990 to December 1991, 32% (8/25) of bronchoscopies done in patients with SCLC included BNA compared with 81% (120/148) (P < .001) from January 1992 to December 1998. In addition to the increased use of BNA in patients with SCLC undergoing bronchoscopy, the overall diagnostic yield for BNA in SCLC significantly increased over the 9-year study period from 50% (4/8) in 1990 and 1991 to 88% (106/120) thereafter (P = .001). Overall sensitivity of BNA during bronchoscopy was 86% for SCLC with only a small increase in sensitivity with use of all procedures (including BNA) to 91%. The use of forceps biopsy and bronchial brushings decreased over this period. CONCLUSION: With progressive experience with BNA, the frequency of its performance and its diagnostic yield in patients with SCLC increased markedly. The SCLC yield may be a worthwhile marker of BNA program development.

Phase II trial of adjuvant radiation and intraperitoneal 5-fluorouracil for locally advanced colon cancer: results with 10-year follow-up.

PURPOSE: To determine the toxicity, disease-free survival, and overall survival for patients with Modified Astler-Coller (MAC) B2-3 or C1-3 colon cancer receiving adjuvant radiation and sequential intraperitoneal 5-fluorouracil (5-FU). METHODS AND MATERIALS: From August 1984 to June 1989, 45 patients were accrued to this Phase II trial and received a 21-week course of intraperitoneal 5-FU (20 mg/kg/d x 5) and external beam radiation. The radiation was delivered to the tumor bed and para-aortic lymph nodes in two split-courses of 22.5 Gy, alternating with the first two cycles of chemotherapy. All patients then received 4 additional cycles of intraperitoneal 5-FU. RESULTS: The therapy was well tolerated with 4 patients experiencing Grade 3 peritonitis. Four patients developed small bowel obstruction requiring surgery; in each instance, recurrent tumor was found at the time of laparotomy. The median and overall survivals at 10 years were 9.3 months and 53% respectively. Local failures were infrequent, occurring in only 11% of patients treated. CONCLUSIONS: Sequential intraperitoneal 5-FU and tumor-bed/para-aortic irradiation is tolerable in patients with resected colon cancer. Although the incidence of local and regional relapse appeared to be lower than anticipated, this did not appear to translate into improved survival.

A preliminary analysis of health-related quality of life in the first year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer.

PURPOSE: To prospectively assess the health-related quality of life (HRQOL) and changes in HRQOL during the first year after permanent source interstitial brachytherapy (PIB). METHODS AND MATERIALS: Thirty-one men treated with PIB between September 1997 and March 1998 completed a quality of life (functional assessment of cancer therapy-prostate: FACT-P) and a urinary symptom questionnaire (international prostate symptom score: IPSS) prior to treatment (T0), 1 month (T1), 3 months (T3), 6 months (T6), and 12 months (T12) following PIB. All participants were treated with 125I alone. Repeated measures analyses of variance (ANOVA) were conducted on all quality of life and urinary outcome measures for all 31 patients at all time points. RESULTS: The median age of the study population was 66 (range 51-80). All men had clinical T1c-T2b prostate cancer. The Gleason score was < or =6 in 27/31 (87%). Median pretreatment PSA was 7.8 ng/ml (range 1.1-20.6). The mean score (and standard deviation) at T0, T1, T3, T6, and T12 for the FACT-P questionnaire are as follows: 140.5 (13.5), 132.7 (15.3), 137.2 (17.4), 140.1 (16.0), and 142.4 (15.3). For the global test across time, statistically significant differences were observed for the cumulative scores of FACT-P (p<0.0012). The decrease in HRQOL was most marked 1 month following PIB. Examination of the subscales within the FACT-P instrument demonstrated statistically significant changes over time for the following: physical well-being (PWB), functional well-being (FWB), and prostate cancer (PCS). By 3 months, all HRQOL measures had returned to near baseline. The mean score (and standard deviation) at T0, T1, T3, T6, and T12 for the IPSS questionnaire are as follows: 8.3 (5.5), 18.4 (8.0), 15.7 (7.4), 13.7 (7.4), and 10.2 (5.7). For the global test across time, statistically significant differences were observed for the IPSS scores (p<0.0001). The maximum increase in IPSS occurred 1 month following PIB. CONCLUSION: The results of this preliminary analysis suggest that clinically meaningful decreases in HRQOL, as measured by the FACT-P instrument, are evident within weeks after PIB. By 3 months, however, FACT-P scores return to near baseline levels. A validated instrument designed to measure urinary symptoms (IPSS) demonstrates that moderate to severe urinary symptoms persist for at least 3-6 months following PIB. One year following PIB, the scores on the FACT-P and IPSS questionnaires had returned to baseline.

Phase II study of pyrazine diazohydroxide (NSC 361456) for advanced non small-cell lung cancer.

Pyrazine diazohydroxide (NSC 361456) (PZDH) was selected for further development after demonstrating more stability than its parent compound and significant antitumor activity in a number of in vivo tumor models. Its proposed mechanism of action is through the formation of DNA adducts via the reactive pyrazine diazonium ion. The aim of this phase II trial was to determine the toxicity and antitumor activity of PZDH in advanced non small-cell lung cancer (NSCLC). From May 1995 through April 1996, 17 chemo-therapy-naive patients were entered into this study. PZDH was administered via a 5-minute intravenous bolus injection at a dose of 100 mg/m2 for 5 days and repeated every 42 days. Per interim guidelines, the study was closed early due to lack of activity. Seventeen patients were evaluable for toxicity while 15 patients were evaluable for response. The median number of cycles administered was 2 (range, 1-7). Toxicity was moderate with grade 3-4 thrombocytopenia being the most common and occurring in six of 17 patients. Of the 15 patients evaluable for response, no partial or complete responses were observed (95% confidence interval [CI]: 0%-22%), while seven patients had stable disease and eight patients progressed during therapy. All but one patient have died. The median survival for the group is 6.6 months (95% CI: 3.4-10.8 months). PZDH possesses modest but acceptable hematologic toxicity when delivered at the above dose and dosing scheme. Our results demonstrate that PZDH has no clinical activity in advanced NSCLC with this dose and schedule.

Strain-dependent lung tumor formation in mice transplacentally exposed to 3-methylcholanthrene and post-natally exposed to butylated hydroxytoluene.

The carcinogenic effects of in utero exposure to 3-methylcholanthrene (MC) have been demonstrated in the tumor-resistant C57BL/6 (B6) and DBA (D2) strains of mice. In this study, we determined the effects of in utero exposure to MC in BALB/c mice, a strain which demonstrates greater susceptibility to lung tumor induction, and compared our findings with those previously found in [D2xB6D2F(1)]F(2) mice. In addition, we assessed the molecular pathogenesis of the chemically induced tumors and examined the effects of the putative lung tumor promoter butylated hydroxytoluene (BHT) in BALB/c mice. BALB/c mice were treated on day 17 of gestation with 5, 15 or 45 mg/kg MC and 6 weeks after birth with BHT for 6 consecutive weeks. Mice were killed at 6 months of age. Ki-ras, p16Ink4a and p19ARF gene loci were amplified from paraffin-embedded lung tumor tissue and screened for the presence of point mutations via allele-specific oligonucleotide hybridization and single strand conformation polymorphism (SSCP) analyses. Ki-ras point mutations were found in 56% (20/36) of BALB/c lung tumors, with 33% (2/6) of the hyperplasias, 58% (10/19) of the adenomas and 73% (8/11) of the carcinomas exhibiting point mutations at this gene locus. Similar incidences of Ki-ras mutations were previously found following transplacental exposure of [D2xB6D2F(1)]F(2) mice to MC and treatment of adult A/J mice with urethane. Interestingly, a strain-dependent difference was observed in the mutational spectrum. Sixty-two and 38% of the lung lesions in BALB/c mice exhibited G-->C and G-->T transversions, respectively, in contrast to the 13 and 84% incidences previously observed in [D2xB6D2F(1)]F(2) mice. SSCP analysis of the tumor suppressor gene p16Ink4a showed a 6% incidence of point mutations, consistent with that found in [D2xB6D2F(1)]F(2) mice. No mutations were found in exon 1beta of the p19ARF gene of either strain. BHT, a lung tumor promoter in adult mice, had no statistically significant effects on either tumor incidence, tumor multiplicity or the mutational spectrum produced in the Ki-ras gene by in utero MC treatment. However, though not significant, there was an observable trend in increased tumor multiplicity in mice co-treated with BHT. These data demonstrate the transplacental carcinogenic effect of MC in BALB/c mice and show that mutagenic damage to Ki-ras is a critical early event mediating murine lung tumorigenesis in both the tumor-sensitive and tumor-resistant strains. Unlike what occurs when adult BALB/c mice are treated with MC, BHT does not appear to significantly promote the formation of lung tumors following transplacental exposure to MC, possibly due to the rapid growth and cell proliferation in the developing organism. Strain-dependent differences in the Ki-ras mutational spectrum may be associated with their differential susceptibility to lung tumor initiation.

Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer.

PURPOSE: To determine the maximum-tolerated dose, dose-limiting toxicities, and potential antitumor activity of twice-weekly gemcitabine and concurrent radiation in patients with locally advanced pancreatic cancer. PATIENTS AND METHODS: Nineteen patients with histologically confirmed adenocarcinoma of the pancreas were studied at the Wake Forest University Baptist Medical Center and the University of North Carolina at Chapel Hill. The initial dose of gemcitabine was 20 mg/m(2) by 30-minute intravenous infusion each Monday and Thursday for 5 weeks concurrent with 50.4 Gy of radiation to the pancreas. Gemcitabine doses were escalated in 20-mg/m(2) increments in successive cohorts of three to six additional patients until dose-limiting toxicity was observed. RESULTS: The dose-limiting toxicities at 60 mg/m(2) given twice-weekly were nausea/vomiting, neutropenia, and thrombocytopenia. Twice-weekly gemcitabine at a 40-mg/m(2) dose was well tolerated. Of the eight patients eligible for a minimum follow-up of 12 months, three remain alive, one of whom has no evidence of disease progression. CONCLUSION: A dose of twice-weekly gemcitabine at 40 mg/m(2) produced mild thrombocytopenia, neutropenia, nausea, and vomiting when delivered with concurrent radiation to the upper abdomen in patients with advanced pancreatic cancer. These data suggest this regimen is well tolerated and may possess significant activity. These data and other observations have resulted in a phase II Cancer and Leukemia Group B study to ascertain the efficacy of this treatment regimen in patients with locally advanced pancreatic cancer.

Receptivity of a worksite breast cancer screening education program.

A breast cancer screening education program was offered to 97 major worksites in Forsyth County, North Carolina. Worksites could design a program by choosing components that consisted of (1) brochures, (2) breast cancer education classes taught by program staff or (3) sending company nurses to be trained by program staff to then teach employees at the worksite. A total of 63 out of the original 97 companies (65%) accepted and offered a program to their employees. Worksites that chose to sponsor a program were more likely to have already sponsored breast cancer education programs at their worksites (P = 0.027) or to have a medical department (P = 0.006). The type of component selected was significantly associated with a history of sponsoring other health education programs (P < 0.001). Fourteen worksites chose the more intensive component, the training of a company nurse. More than half of the worksites that had never sponsored and had no plans to sponsor worksite breast education programs were receptive to our program (43 of 73, 59%). The majority of these sites (67%) chose the brochure. These results indicate that worksites are receptive to offering breast cancer educational programs if varying types of components can be selected.