A phase I study of the VEGFR kinase inhibitor vatalanib in combination with the mTOR inhibitor, everolimus, in patients with advanced solid tumors.

Purpose Combining small-molecule inhibitors of different targets was shown to be synergistic in preclinical studies. Testing this concept in clinical trials is, however, daunting due to challenges in toxicity management and efficacy assessment. This study attempted to evaluate the safety and efficacy of vatalanib plus everolimus in patients with advanced solid tumors and explore the utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies as a predictive biomarker. Patients and Methods This single-center, phase I trial containing 70 evaluable patients consisted of a dose escalation proportion based on the traditional "3 + 3" design (cohort IA and IB) and a dose expansion proportion (cohort IIA and IIB). Toxicity was evaluated using the Common Terminology Criteria of Adverse Events. Antitumor activity was assessed using the Modified Response Evaluation Criteria in Solid Tumors. Results The maximum tolerated doses were determined to be vatalanib 1250 mg once daily or 750 mg twice daily in combination with everolimus 10 mg once daily. No treatment-related death occurred. The most common toxicities were hypertriglyceridemia, hypercholesterolemia, fatigue, vomiting, nausea and diarrhea. There was no complete response. Nine patients (12.9%) had partial response (PR) and 41 (58.6%) had stable disease (SD). Significant antitumor activity was observed in neuroendocrine tumors with a disease-control rate (PR + SD) of 66.7% and other tumor types including renal cancer, melanoma, and non-small-cell lung cancer. Conclusions The combination of vatalanib and everolimus demonstrated reasonable toxicity and clinical activity. Future studies combining targeted therapies and incorporating biomarker analysis are warranted based on this phase I trial.

Up-regulation of pro-angiogenic factors and establishment of tolerance in malignant pleural effusions.

INTRODUCTION: Malignant pleural effusions (MPEs) are a significant source of cancer morbidity and mortality. Currently there is no cure for MPEs and treatments only palliate the symptoms. The purpose of this study was to determine if there are differences in markers of angiogenesis and immune phenotypes between adenocarcinoma-induced MPEs and benign pleural effusions (BPEs). METHODS: Pleural effusions were collected from patients with MPEs and BPEs. Cells were isolated from effusions and characterized using fluorescent cell sorting (FACS). Pleural effusions were evaluated by ELISA for VEGF-A. An angiogenesis protein array was completed to compare protein expression in malignant and non-malignant effusions. RESULTS: FACS analysis demonstrated lower accumulation of cytotoxic T-cells and significantly higher accumulation of monocytes, dendritic cells, mesothelial and tumor cells in MPEs compared to benign pleural effusions. MPEs were found to have 77-fold higher VEGF-A levels compared to BPEs. The angiogenesis protein array demonstrated elevated levels of pro-angiogenic factors VEGF-A, CXCL4 and MMP-8, and low levels of pro-inflammatory cytokines IL-8, MCP-1, and TGF-ß1 in MPEs. CONCLUSIONS: MPE is biased toward a Th2 dominant state. There is an increase in expression of VEGF-A and other pro-angiogenic factors in MPE. These data suggest there is a role for anti-angiogenesis therapy in patients with MPEs.

Is Age ≥ 70 Years an Important Predictor of Adverse Events Among Patients Enrolled in Metastatic Melanoma Trials? Findings from Pooled Analyses of Therapeutic Trials.

BACKGROUND: The current study was undertaken to explore whether older age predicts adverse event rates in metastatic melanoma patients participating in cancer clinical trials. METHODS: Six phase II studies conducted at our institution for patients with metastatic disease were used in these pooled analyses: 1) ABT-510; 2) bortezomib, paclitaxel, and carboplatin; 3) everolimus; 4) bevacizumab, paclitaxel, carboplatin; 5) carboplatin and abraxane; and 6) temozolomide and everolimus. In total, 233 patients, 64 elderly (≥ 70 years) and 169 younger, were analyzed for age-based differences in grade 2 or worse adverse events and other clinical outcomes. RESULTS: Despite the fact that older patients had slightly worse performance scores, based on age, no differences in rates of adverse events were observed. Only worse baseline performance score predicted a higher rate of adverse events: patients with performance scores of one or worse were almost 4 times more likely to experience adverse events. Median cancer progression free survival and overall survival were comparable between older and younger patients. CONCLUSION: These findings suggest that concern for adverse event rates should not preclude the enrollment of elderly melanoma patients to cancer clinical trials. Such patients should continue to be monitored carefully for tumor response and toxicity.

Fluctuation of systemic immunity in melanoma and implications for timing of therapy.

Evidence suggests that immunological response in chronic inflammation is dynamic, oscillating between active immunity and tolerance. We hypothesized that a similar dynamic exists in melanoma and administration of therapy during a unique phase of such oscillation could impact clinical outcome. Patients with metastatic melanoma eligible to undergo temozolomide underwent serial measurements of C-reactive protein (CRP) and immune biomarkers every 2-3 days for 2 weeks before starting therapy. Treatment was initiated prior to the estimated next CRP peak, or on day 14 post-registration if a peak was not identified. Time profiles of measured biomarkers were analyzed by fitting serially measured data points to 9 mathematical functions and were correlated to time of therapy and outcome. Data suggested that metastatic melanoma patients exhibit a dynamic immune response. The fluctuation of several biomarkers fitted cosine functions with periods which were multiples of 3-4 days. Chemotherapy delivery during a unique phase of this cycle seemed to correlate with improved response. Individualized conventional chemotherapy delivery by synchronizing treatment with pre-existing patient-specific biorhythms may improve clinical outcomes in metastatic melanoma.

Genetic variations in multiple drug action pathways and survival in advanced stage non-small cell lung cancer treated with chemotherapy.

PURPOSE: Variations in genes related to biological activity of anticancer drugs could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, that is, glutathione metabolism, DNA repair, cell cycle, and epidermal growth factor receptor (EGFR), were systematically investigated to examine their association with survival in advanced stage non-small cell lung cancer (NSCLC) treated with chemotherapy. EXPERIMENTAL DESIGN: A total of 894 tagging single-nucleotide polymorphisms (SNP) in 70 genes from the four pathways were genotyped and analyzed in a 1,076-patient cohort. Association with overall survival was analyzed at SNP and whole-gene levels within all patients and major chemotherapy agent combination groups. RESULTS: A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway; HR = 1.45; 95% CI = 1.20-1.77 and HR = 1.25; 95% CI = 1.05-1.50, respectively). In the stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by the MAP3K1 variant (HR = 1.38; 95% CI = 1.11-1.72) and a protective effect by RAF1 (HR = 0.64; 95% CI = 0.50-0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF1 and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR = 0.54; 95% CI = 0.38-0.77; HR = 0.67; 95% CI = 0.52-0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR = 1.91; 95% CI = 1.30-2.80; HR = 1.83; 95% CI = 1.27-2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis. CONCLUSION: Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations.

Racial differences in smoking abstinence rates in a multicenter, randomized, open-label trial in the United States.

BACKGROUND: This study evaluates differences in smoking abstinence between white and minority smokers using pharmaceutical aids. METHODS: This is an analysis of data from a multi-center, randomized, clinical trial conducted in the United States. Of the 1,684 subjects randomized to one of three medications (nicotine inhaler, bupropion, or a combination of both), 60% were women and 10% were minority races. RESULTS: Factors associated with a decreased likelihood of smoking at 12 weeks were older age (OR = 0.971, p < 0.0001), being married (OR = 0.678, p = 0.0029), using bupropion SR (OR = 0.480, p < 0.0001), and using combination therapy (OR = 0.328, p < 0.0001). Factors associated with an increased likelihood of smoking were higher tobacco dependence scores (OR = 1.244, p < 0.0001), prior quit attempts (OR = 1.812, p = 0.004), and being a minority (OR = 1.849, p = 0.0083). Compared to white smokers, minority smokers were significantly older at time of study entry (46 vs. 42 years, p < 0.0001), less likely to be married (35% vs. 59%, p < 0.0001), older at smoking initiation (21 vs. 19 years of age, p < 0.0001), and had a lower abstinence rate (16% vs. 26%, p = 0.0065). CONCLUSION: Regardless of the treatment used, minority smokers in the US have lower smoking abstinence after treatment for tobacco dependence. Future research should focus on the improvement in treatment strategies for minority smokers.

A study of paclitaxel, carboplatin, and bortezomib in the treatment of metastatic malignant melanoma: a phase 2 consortium study.

BACKGROUND: Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3-drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma). METHODS: A 2-stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3-agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m2 intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m2; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21-day cycle. The primary endpoint of this trial was tumor response rate (TRR). RESULTS: Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1-7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade>or=3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression-free survival was 3.2 months, and the median overall survival was 7.0 months. CONCLUSIONS: Due to insufficient clinical efficacy, this trial did not proceed to second-stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity.

Perivascular epithelioid cell neoplasm of the uterine cervix: an unusual tumor in an unusual location.

A 46-year-old woman presented for a second opinion regarding a 3-4 cm mass of the uterine cervix. A prior biopsy had been interpreted as a malignant melanoma of the cervix, resulting in a radical hysterectomy with bilateral salpingooophorectomy. This was to be followed by external beam irradiation and immunotherapy; however, given the rarity of this diagnosis, the patient sought a second opinion at our institution. Further review of the pathological material from the hysterectomy revealed a morphologically benign perivascular epithelioid cell neoplasm rather than a malignant melanoma. Close monitoring of the patient was recommended; she is currently diseasefree more than three years after her initial presentation.

Do patients with schizophrenia receive state-of-the-art lung cancer therapy? A brief report.

OBJECTIVE: Patients with schizophrenia sometimes receive substandard medical care. This study explored such disparities among lung cancer patients with underlying schizophrenia. METHODS: This retrospective study focused on patients with pre-existing schizophrenia (or in some instances schizoaffective disorder) and a lung cancer diagnosis made between 1980 and 2004. 'Disparity' was defined as a patient's having been prescribed less aggressive therapy for a potentially curable cancer based on state-of-the-art treatment standards for the time and for the cancer stage. Qualitative methods were used to assess healthcare providers' decision-making. RESULTS: 29 patients were included. The median age was 59 years; 38% were men. Twenty-three had non-small cell lung cancer and 6 small cell lung cancer; 17 had potentially curable cancers. Five of 17 had a 'disparity' in cancer care: (1) no cancer therapy was prescribed because of chronic obstructive pulmonary disease; (2) no cancer therapy was prescribed because of infection; (3) no chemotherapy was prescribed because the patient declined it; radiation was provided; (4) no chemotherapy was prescribed because of the patient's schizophrenia symptoms; radiation was administered; and (5) no surgery was performed because of disorientation from a lobotomy; radiation was prescribed. Comments from healthcare providers suggest reflection and ethical adjudication in decision-making. CONCLUSION: Schizophrenia was never the sole reason for no cancer treatment in patients with potentially curable lung cancer. This study provides the impetus for others to begin to assess the effect of schizophrenia on lung cancer management in other healthcare settings.

Second primary tumors following tobacco dependence treatments among head and neck cancer patients.

OBJECTIVES: To estimate the cumulative percentage of second primary tumors (SPTs) in head and neck (H&N) cancer patients and primary cancers in general Nicotine Dependence Center (NDC) population controls following tobacco dependence consultation seen between 1988 and 2001. METHODS: A 1:1 matched pair design and a stratified Cox proportional hazard model were used. General NDC population controls were matched on age, gender, and NDC consult (type and date) to the H&N cancer patients. The study population included 101 H&N cancer patients (66 male, 35 female) with mean (SD) age of 58.7 (10.1) years. RESULTS: Baseline demographics and length of follow-up were similar between groups. However, H&N cancer patients smoked more cigarettes per day than controls (P < 0.003). For H&N cancer patients, the median time from initial H&N cancer diagnosis to NDC consult was 7 months (range, 0-292 months). Following the NDC consult, 27 H&N cancer patients developed 32 SPTs; whereas among the controls, 12 patients developed 12 other cancers (P = 0.013). There was no difference in the development of non-tobacco-related cancers (P = 0.273). However, H&N cancer patients were more likely to develop tobacco-related cancers (P = 0.01). Furthermore, there was a trend where the H&N cancer patients who continued to use tobacco were more likely to develop tobacco-related cancers than those who remained abstinent (P = 0.10). CONCLUSIONS: These findings confirm that H&N cancer patients are more prone to the development of tobacco-related cancers. Further, these findings suggest that H&N cancer patients who stop using tobacco are able to decrease the development of tobacco-related SPTs.

A phase I multiple dose, dose escalation study of cG250 monoclonal antibody in patients with advanced renal cell carcinoma.

The chimeric monoclonal antibody cG250 recognises the G250/CAIX/MN antigen found on 95% of clear cell renal cell carcinomas (RCCs). We performed a phase I clinical trial to evaluate the safety, blood pharmacokinetics (PK), and biodistribution of repeated doses of cG250. The primary endpoint was toxicity. Secondary endpoints were cG250 biodistribution and PK; measurement of human anti-chimeric-antibodies (HACA); and tumour response rates. Eligible patients had unresectable or metastatic clear cell RCC. Doses of 5, 10, 25, or 50 mg/m(2) were given weekly by intravenous infusion for six weeks. Three patients were treated at each dose level. Trace (131)I-labelled cG250 was administered on weeks 1 and 5. Thirteen patients participated and were evaluable. One patient developed brain metastases and was replaced. No grade 3 or 4 toxicities and no dose-limiting toxicity occurred. One patient died due to progressive disease within 30 days of receiving the study drug. One patient developed HACA during the second six-week cycle. PK analysis showed mean whole body and blood alpha and beta half-lives of cG250 of 18.99 +/- 6.84 and 180.19 +/- 86.68 hours, respectively. All patients had cG250 tumour localization by gamma camera imaging in week 1 and 5. One patient had a complete response, nine patients had stable disease, and three had progressive disease. One patient received 11 six-week cycles of treatment with no toxicity or HACA. In conclusion, repeated intravenous doses of up to 50 mg/m(2) of cG250 are safe. Furthermore cG250 has a long half-life and targets clear cell RCC effectively.

A phase II study of ABT-510 (thrombospondin-1 analog) for the treatment of metastatic melanoma.

OBJECTIVES: Thrombospondins are natural inhibitors of angiogenesis, tumor metastases, and tumor growth (melanoma). ABT-510 is a synthetic analog of thrombospondin-1, well tolerated in phase I studies. We conducted a phase II trial evaluating the clinical efficacy of ABT-510 and its effects on biomarkers of angiogenesis and immunity in patients with metastatic melanoma (MM). PATIENTS AND METHODS: A 2-stage phase II clinical trial was conducted to assess the clinical efficacy, safety, and pharmacodynamic effects (angiogenesis and immunity) of ABT-510 in patients with stage IV melanoma. The primary endpoint was 18-week treatment failure rate. Patients self-administered 100 mg of ABT-510 subcutaneously twice daily. Blood samples were collected at baseline and every 3 weeks while on therapy. Eligible patients demonstrated measurable disease, good performance status and no evidence of intracranial metastases. Correlative laboratory studies evaluated biomarkers of angiogenesis and immunity. RESULTS: Twenty-one patients were enrolled. Most patients were stage M1c (71%) and all had prior therapy for MM. Only 3 of the first 20 patients enrolled were progression free and on treatment at 18 weeks resulting in early termination of the study. Decreases in peripheral blood VEGF-A levels and VEGF-C levels, and CD146 and CD34/133 counts relative to pretreatment were detected. Limited changes in antitumor T cell immunity were observed. CONCLUSIONS: ABT-510 therapy administered at 100 mg twice/day in patients with MM did not demonstrate definite clinical efficacy. Further dose escalation or combination with cytotoxic therapy may be more effective therapeutically.

Randomized comparison of a nicotine inhaler and bupropion for smoking cessation and relapse prevention.

OBJECTIVE: To compare the combination of a nicotine inhaler and bupropion to either treatment alone for initiating smoking abstinence and relapse prevention. METHODS: Smokers were randomized to receive a nicotine inhaler, bupropion, or both for 3 months. At 3 months, smoking-abstinent study participants were randomized to their initial medications or placebo. Participants who were smoking at 3 months were randomized to an alternative treatment regimen or placebo. This study was conducted from July 2001 to January 2003. RESULTS: A total of 1700 smokers were randomized to treatment (phase 1) for 3 months. Among the 941 study participants eligible for randomization to the phase 2 trial, 837 continued in the study. For the phase 2 trial, 405 smoking-abstinent participants were randomized to relapse prevention for 9 additional months, and 432 smokers were randomized to re-treatment for an additional 3 months. At the end of the initial 3 months of treatment (phase 1), 82 (14%) of 566, 145 (26%) of 567, and 194 (34%) of 567 study participants receiving a nicotine inhaler, bupropion, or both, respectively, were abstinent from smoking. Of the 405 smoking-abstinent participants at the end of 3 months, the bupropion group had more smokers than the placebo group (mean No. of smokers, 1.5 vs 1.1; P < .001), and the nicotine inhaler group had higher smoking abstinence rates at 12 months than the placebo group. Those receiving combination therapy had reduced rates of relapse to smoking for the first 3 months of relapse prevention, but this difference disappeared after the initial 3 months. Of the 432 study participants who were smoking at the end of 3 months and who received an alternative treatment regimen, the 223 smokers initially assigned to a nicotine inhaler were more likely to stop smoking at 6 months if they were re-treated with bupropion instead of placebo (8 [7%] of 111 vs 0 [0%] of 112; P = .003), and the 209 smokers initially treated with bupropion and re-treated with a nicotine inhaler did not have significantly higher smoking abstinence rates (6 [6%] of 104 vs 3 [3%] of 105; P = -.50). CONCLUSION: Combined therapy with a nicotine inhaler and bupropion increased smoking abstinence rates. Continuation of the initial combination therapy does not appear to prevent relapse to smoking. Timing of re-treatment and alternative approaches to relapse prevention should be further examined.

A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.

PURPOSE: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. METHODS: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle. RESULTS: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. CONCLUSION: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.

The prevalence of weight concerns in a smoking abstinence clinical trial.

Recent research has demonstrated there is a high prevalence of weight concerns in smokers and that smokers with weight concerns may respond poorly to treatment for tobacco dependence. Most studies have focused only on females or have consisted of small samples. In this study of a 12-week randomized trial of nicotine inhaler, bupropion or both for smoking cessation, 50% of the 1012 female smokers and 26% of the 680 male smokers, at study entry, were weight concerned. In examining the impact of weight concerns on the 12-week point-prevalence smoking abstinence, 26% of non-weight-concerned smokers quit smoking compared to 22% of weight-concerned smokers (p=0.06). This study, which includes a large sample of both genders, provides further evidence that approximately half of females who are seeking smoking cessation treatment are weight concerned and that one quarter of male smokers are weight concerned. Additionally, being weight concerned may impact the short-term success rates of stopping smoking using pharmacotherapy.

Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma.

BACKGROUND: Patients with metastatic melanoma (MM) have very few therapy options. Based on reports of responses to paclitaxel and carboplatin (PC), 31 patients with MM were treated with PC. METHODS: Data regarding patients treated with PC were abstracted from medical records. Clinical outcomes as determined by the treating oncologist were used for this analysis. Response determination was retrospectively confirmed using Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Thirty-one patients with MM were treated with PC. Patients had a median of 2 previous therapies, with the majority (29; 94%) having failed prior temozolomide (TMZ) or dacarbazine (DTIC) therapy. The most commonly used regimen was weekly paclitaxel (at a dose of 100 mg/m(2)) and carboplatin (area under the curve 2) administered on Days 1, 8, and 15 of a 28-day cycle. An objective partial response was noted in 8 patients (26%) with an additional 6 patients (19%) having stable disease; therefore, a clinical benefit was noted in 45% of those patients treated. The median time to disease progression for the entire group was 3 months (range, 0-7 mos), with a median overall survival of 7.8 months (range, 1-14 mos). The clinical benefit derived by the 14 patients, which lasted for a median of 5.7 months (range, 2.5-7.3 mos), was considered to be clinically significant. At the time of last follow-up, eight patients continued to receive PC therapy. CONCLUSIONS: The PC combination appears to have definite and clinically meaningful activity when used as second-line therapy after TMZ or DTIC. Further evaluation of this regimen, alone or as a 'backbone' for other agents, needs to be considered.

Effects of biochemically confirmed smoking cessation on white blood cell count.

OBJECTIVES: To determine the relationship between white blood cell (WBC) Indices and several baseline variables In a large cohort of healthy smokers and to assess whether these changed after biochemically confirmed smoking cessation. SUBJECTS AND METHODS: The study consisted of 784 healthy smokers enrolled in a trial of sustained-release bupropion, 300 mg/d, for relapse prevention after smoking cessation from 1995 to 1998. Both WBC counts and absolute neutrophil counts (ANCs) were measured at baseline, week 7, and week 52. Smoking status was assessed at weeks 7 and 52 by self-report and biochemically confirmed with expired air carbon monoxide levels. Multivariate analyses compared changes in WBC count and ANC between smokers who did and did not stop smoking, adjusting for treatment group, age, sex, and body mass index. RESULTS: Of 784 smokers enrolled, 461 had biochemically confirmed tobacco abstinence after 7 weeks of bupropion; 429 were randomly assigned to receive continued bupropion therapy or placebo until week 52. Between baseline and week 7, there was a significantly larger decrease in WBC count in continuously abstinent subjects compared with continuing smokers (adjusted P = .03). At 52 weeks, continuously abstinent subjects, compared with continuing smokers, had a greater decline from baseline in WBC count (1.2 +/- 1.9 x 10(9)/L vs 0.1 +/- 1.9 x 10(9)/L; P < .001) and ANC (1.0 +/- 1.6 x 10(9)/L vs 0.2 +/- 1.5 x 10(9)/L; P < .001). CONCLUSION: Biochemically confirmed tobacco abstinence leads to a rapid and sustained decrease in WBC and ANC, possibly reflecting a decrease In an underlying state of tobacco-induced inflammation.

A phase I trial of the novel farnesyl protein transferase inhibitor, BMS-214662, in combination with paclitaxel and carboplatin in patients with advanced cancer.

PURPOSE: This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662. RESULTS: Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m(2)), paclitaxel (225 mg/m(2)) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (> 4 cycles) occurred in eight other patients. CONCLUSIONS: The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.

A contest to create media messages aimed at recruiting adolescents for stop smoking programs.

This project engaged adolescents in a contest to create advertising messages aimed at recruiting teens for stop smoking programs. Middle school students were invited to design a media message for television, radio, Web, or print (newspaper or billboard). Of 4,289 students in eight middle schools of Rochester, Minn., 265 (6.2%) developed 172 stop smoking messages. The quality of their work confirmed that teens can design media messages to encourage their smoking adolescent peers to enroll in a program to stop smoking.