Phase I Study of Pazopanib and Ixabepilone in Patients With Solid Tumors.

OBJECTIVES: Pazopanib is a tyrosine kinase inhibitor predominantly acting on tumor endothelium, and ixabepilone is a semisynthetic analog of epothilone B that promotes microtubule stabilization inducing tumor and tumor endothelial cell apoptosis. The purpose of this study was to determine the optimal tolerated dose (OTD) of the combination of pazopanib and ixabepilone for the treatment of metastatic previously treated solid tumors. METHODS: Dose escalation started at 32 mg/m of ixabepilone and increased to 40 mg/m. Pazopanib was administered initially at 400 mg and escalated at 200 mg increments up to 800 mg. Pharmacokinetic analysis assessed effect of ixabepilone on pazopanib metabolism. Correlative studies evaluated changes in angiogenic cytokines. RESULTS: Thirty-one patients (20 male and 11 female; median age, 58 y) with ECOG PS of 0 or 1 were enrolled. Three patients had dose-limiting toxicities (fatigue and neutropenia) at dose level 2 (ixabepilone 40 mg/m and pazopanib 400 mg), and therefore the ixabepilone dose was decreased (32 mg/m) before escalating pazopanib to levels 3 and 4. One patient had a dose-limiting toxicity (thrombocytopenia) at dose level 4 (ixabepilone 32 mg/m and pazopanib 800 mg). Dose level 3 was determined to be the OTD (pazopanib 600 mg and ixabepilone 32 mg/m). The most common toxicities were cytopenias. A significant decrease in the level of sE-selectin was associated with improvement in progression free survival. CONCLUSIONS: The OTD for combination of pazopanib and ixabepilone was established. There was no impact of ixabepilone on pazopanib pharmacokinetics. The relationship between sE-selectin and progression free survival warrants further investigation.

Motivating underserved Vietnamese Americans to obtain colorectal cancer screening: evaluation of a culturally tailored DVD intervention.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death among Vietnamese Americans, yet screening remains underutilized. We investigated the effectiveness of a culturally tailored DVD intervention in promoting CRC screening among unscreened Vietnamese Americans age 50 and over. MATERIALS AND METHODS: Using a community-based participatory research approach, we conducted a trial comparing twenty-eight subjects who received a mailed DVD in Vietnamese, with twenty-eight subjects who received a mailed brochure in Vietnamese. Subjects completed telephone surveys at baseline, One-month, and one-year. The primary outcome was receipt of screening. Secondary measures were participants' knowledge, attitudes, and beliefs about CRC screening. Two focus groups explored the intervention's acceptability and effectiveness. RESULTS: At one year, CRC screening rates of 57.1% and 42.9% were observed in experimental and control group respectively (p=0.42), Subjects in both groups showed increased knowledge about CRC after one month. Focus group findings revealed that the DVD was an effective method of communicating information and would help promote screening. CONCLUSIONS: The findings suggest that culturally tailored, linguistically appropriate content is more important than the type of media used. This relatively low intensity, low cost intervention utilizing a DVD can be another useful method for outreach to the often hard-to-reach unscreened population.

Monitoring tobacco-specific N-nitrosamines and nicotine in novel smokeless tobacco products: findings from round II of the new product watch.

INTRODUCTION: Analysis of novel smokeless tobacco products purchased in Round I of the New Product Watch (NPW)-a national tobacco monitoring network-demonstrated that some tobacco constituents vary not only across various brands but also regionally and over time within the same product. In this study, we analyzed snus and dissolvable tobacco products that were purchased in Round II of the NPW. METHODS: We analyzed tobacco-specific N-nitrosamines (TSNA) and nicotine in snus and dissolvable tobacco products that were purchased in various regions of the country during the spring and summer of 2011. The results were compared against the Round I data, across different U.S. regions, and among products. RESULTS: A total of 216 samples were received from different states representing 6 regions of the country. Compared with the previous analyses, TSNA levels increased significantly in Marlboro and Camel Snus and some dissolvable Camel products. The levels of unprotonated nicotine in Marlboro Snus and Camel Snus in this study were not different from Round I but varied significantly by regions; the differences between the highest and the lowest average regional levels were ~3.2-fold in Marlboro Snus ~1.7-fold in Camel Snus. CONCLUSIONS: Our results indicate that some novel smokeless tobacco products contain TSNA at the levels found in the conventional moist snuff. Observation of regional variations in unprotonated nicotine content in both Round I and Round II of NPW suggest that manufacturers may tailor the levels of this constituent consistently to different regions.

Multiple-type human papillomavirus (HPV) infections: a cross-sectional analysis of the prevalence of specific types in 309,000 women referred for HPV testing at the time of cervical cytology.

OBJECTIVES: To determine the frequency of multiple-type cervical human papillomavirus (HPV) infections, and whether any types are involved in multiple-type infections more or less frequently than might be expected if these infections occur randomly. METHODS: In this retrospective analysis of type-specific HPV testing, results from women 18 to 65 years old with samples collected between July 2007 and May 2011 were considered.Multivariate logistic regression analysis was used to model the presence of each of the 24 most prevalent HPV types, adjusting for one other HPV type, age, laboratory region, and age-by-region interactions. RESULTS: Human papillomavirus infection was present in 74,543 (24.1%) of 309,471 women and 65,492 (21.1%) were positive for one of the top 24 most prevalent HPV types. The most common HPV type was type 16, occurring in 4.1% of the entire sample. A total of 14,181 women were positive for 2 or more HPV types (4.6% of entire sample and 19.0% of HPV-positive sample). Two-way HPV type comparisons were analyzed. Types 52, 53, 81, and 83 were more likely to occur in multiple infections with other types; and types 16, 58, and 66 were less likely to occur in multiple infections with other types. Human papillomavirus types 72 and 81 have the strongest positive relationship (odds ratio, 5.2; 95% confidence interval, 3.6-7.4). Human papillomavirus types 33 and 66 have the strongest negative relationship (odds ratio, 0.4; 95% confidence interval, 0.2-0.6). CONCLUSIONS: In this population, multiple-type HPV infections were present in 4.6% of all women. Our findings suggest that there may be both competitive and cooperative interactions between HPV types.

Phase II study of topotecan and bevacizumab in advanced, refractory non--small-cell lung cancer.

BACKGROUND: This clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non--small-cell lung cancer in a second-line setting. PATIENT AND METHODS: Patients aged 18 years old and older received topotecan (4.0 mg/m(2)) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan. RESULTS: Forty-two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7-7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression. CONCLUSION: Bevacizumab in combination with topotecan as a salvage therapy for metastatic non--small-cell lung cancer is well tolerated and is worthy of further investigation.

Risk factors for revision of primary total hip arthroplasty: a systematic review.

BACKGROUND: Numerous papers have been published examining risk factors for revision of primary total hip arthroplasty (THA), but there have been no comprehensive systematic literature reviews that summarize the most recent findings across a broad range of potential predictors. METHODS: We performed a PubMed search for papers published between January, 2000 and November, 2010 that provided data on risk factors for revision of primary THA. We collected data on revision for any reason, as well as on revision for aseptic loosening, infection, or dislocation. For each risk factor that was examined in at least three papers, we summarize the number and direction of statistically significant associations reported. RESULTS: Eighty-six papers were included in our review. Factors found to be associated with revision included younger age, greater comorbidity, a diagnosis of avascular necrosis (AVN) as compared to osteoarthritis (OA), low surgeon volume, and larger femoral head size. Male sex was associated with revision due to aseptic loosening and infection. Longer operating time was associated with revision due to infection. Smaller femoral head size was associated with revision due to dislocation. CONCLUSIONS: This systematic review of literature published between 2000 and 2010 identified a range of demographic, clinical, surgical, implant, and provider variables associated with the risk of revision following primary THA. These findings can inform discussions between surgeons and patients relating to the risks and benefits of undergoing total hip arthroplasty.

Risk factors for posttraumatic heterotopic ossification of the elbow: case-control study.

PURPOSE: Heterotopic ossification (HO) is well-known after surgical repair of elbow fractures, but little is known about risk factors for its development in these patients. The purpose of this study was to define factors associated with development of HO. METHODS: We used a prospective fracture registry collected in 2 Level I trauma centers and medical chart review to examine all elbow fractures treated surgically between 2002 and 2009. We determined which of these patients developed HO with an impact on range of motion (Hastings class II and III). We conducted a matched case-control study to examine factors associated with risk of HO. We used conditional logistic regression to compare occurrences of risk factors between cases and controls, matched by fracture type, age, and sex. RESULTS: Our database contained 786 elbow fractures treated surgically. Of these, 55 developed clinically relevant HO. The risk of HO varied among types of elbow fractures, with combined olecranon and radial head fractures having no HO and floating elbows (fractures on both sides of the elbow joint) having the highest incidence of HO at 36%. In multiple conditional logistic regression, risk factors for the development of HO were days to surgery, with subjects waiting 8 or more days having 12 times the odds of HO than subjects having surgery within a day of injury, and time to postoperative mobilization, with subjects who had at least 15 days to mobilization having greater odds of HO than those who had less than 7 days to mobilization. CONCLUSIONS: Heterotopic ossification of the elbow occurs frequently after surgical repair of elbow fractures, with an incidence of 7% in this registry. In the case-control sample, conditions associated with development of HO included longer time to surgery and longer time to mobilization after surgery.

Time course of DNA adduct formation in peripheral blood granulocytes and lymphocytes after drinking alcohol.

Alcohol consumption is an established risk factor for cancers of the head and neck, colorectum, liver and female breast. Acetaldehyde, the primary metabolite of ethanol, is suspected to play a major role in alcohol-related carcinogenesis. Acetaldehyde binds to DNA resulting in formation of adducts. DNA adducts are involved in mutagenesis and carcinogenesis. N (2)-Ethylidenedeoxyguanosine (N (2)-ethylidene-dGuo) is the major adduct formed in this reaction. Studies have shown an association between alcohol drinking and levels of this DNA adduct, suggesting its potential use as a biomarker for studying alcohol-related carcinogenesis. However, there are no reports on the kinetics of formation and repair of N (2)-ethylidene-dGuo after alcohol consumption. Therefore, we investigated levels of N (2)-ethylidene-dGuo in DNA from human peripheral blood cells at several time points after consumption of increasing doses of alcohol. Ten healthy non-smokers were recruited and asked to abstain from alcohol consumption except for the study doses. The subjects were given measured doses of alcohol once a week for 3 weeks, targeting increasing blood alcohol levels. Blood was collected at several time points before and after each dose, DNA was isolated from granulocytes and lymphocytes and N (2)-ethylidene-dGuo was quantified as its NaBH(3)CN reduction product N ( 2 )-ethyldeoxyguanosine by liquid chromatography-electrospray ionisation-tandem mass spectrometry. Significant increases in N (2)-ethylidene-dGuo were observed after all doses and in both cell types. However, there was substantial intraindividual variability, indicating that there are other important sources of this adduct in peripheral blood DNA. Further studies are needed to better understand the origins of N (2)-ethylidene-dGuo in blood cells, the exposures it reflects, and thus its potential use as a marker of alcohol's genotoxic effects.

Kinetics of DNA adduct formation in the oral cavity after drinking alcohol.

BACKGROUND: Alcohol consumption is one of the top 10 risks for the worldwide burden of disease and an established cause of head and neck cancer, as well as cancer at other sites. Acetaldehyde, the major metabolite of ethanol, reacts with DNA to produce adducts, which are critical in the carcinogenic process and can serve as biomarkers of exposure and, possibly, of disease risk. Acetaldehyde associated with alcohol consumption is considered "carcinogenic to humans." We have previously developed the technology to quantify acetaldehyde-DNA adducts in human tissues, but there are no studies in the literature defining the formation and removal of acetaldehyde-DNA adducts in people who consumed alcohol. METHODS: We investigated levels of N(2)-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at several time points after consumption of increasing alcohol doses. Ten healthy nonsmokers were dosed once a week for three weeks. Mouthwash samples were collected before and at several time points after the dose. N(2)-Ethylidene-dGuo was measured as its NaBH(3)CN reduction product N(2)-ethyl-dGuo by liquid chromatography-electrospray-tandem mass spectrometry. RESULTS: N(2)-ethylidene-dGuo levels increased as much as 100-fold from baseline within 4 hours after each dose for all subjects and in a dose-responsive manner (P = 0.001). CONCLUSION: These results show an effect of alcohol on oral cell DNA adduct formation, strongly supporting the key role of acetaldehyde in head and neck cancer caused by alcohol drinking. IMPACT: Our results provide some of the first conclusive evidence linking exposure to a lifestyle carcinogen and kinetics of DNA adduct formation in humans.

Increased pouch sizes and resulting changes in the amounts of nicotine and tobacco-specific N-nitrosamines in single pouches of Camel Snus and Marlboro Snus.

INTRODUCTION: Initial analyses of the novel smokeless tobacco products Camel Snus and Marlboro Snus demonstrated that these products contain relatively low amounts of nicotine and the carcinogenic tobacco-specific nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), as compared with traditional smokeless products. It is unknown whether the modifications in packaging, flavors, and pouch sizes that occurred for both Camel Snus and Marlboro Snus since their first introduction to the market were accompanied by any changes in nicotine or nitrosamine levels. METHODS: We examined the available data on nicotine and NNN and NNK levels in 60 samples of Camel Snus and 87 samples of Marlboro Snus that were analyzed in our laboratory between 2006 and 2010. RESULTS: Due to the increase in pouch size, the amounts of total nicotine, unprotonated nicotine, and the sum of NNN and NNK present in the large Camel Snus pouches released in 2010 are 1.9-fold, 2.4-fold, and 3.3-fold higher, respectively, than in the original smaller pouches that entered the market in 2006. Total and unprotonated nicotine content in the current version of Marlboro Snus pouches are 2.1-fold and 1.9-fold higher, respectively, and the sum of NNN and NNK is 1.5-fold lower than in the original version. CONCLUSIONS: We observed an increase in nicotine content in single portions of Camel Snus and Marlboro Snus, and an increase in tobacco-specific N-nitrosamine content in single portions of Camel Snus, due to the increases in pouch size that occurred between 2006 and 2010. This finding stresses the importance of tobacco product regulation and ingredient disclosures.

Monitoring tobacco-specific N-nitrosamines and nicotine in novel Marlboro and Camel smokeless tobacco products: findings from Round 1 of the New Product Watch.

INTRODUCTION: Information on chemical composition of the new oral "spitless" smokeless tobacco products is scarce, and it is not clear whether there is some variability as a function of purchase place or time due to either unintended or intended manufacturing variations or other conditions. METHODS: We analyzed tobacco-specific N-nitrosamines (TSNA) and nicotine in Marlboro Snus, Camel Snus, and dissolvable Camel products Orbs, Sticks, and Strips that were purchased in various regions of the country during the summer of 2010. RESULTS: A total of 117 samples were received from different states representing six regions of the country. Levels of unprotonated nicotine in Marlboro Snus and Camel Snus varied significantly by regions, with the differences between the highest and the lowest average regional levels being relatively small in Marlboro Snus (∼1.3-fold) and large in Camel Snus (∼3-fold). Some regional variations in TSNA levels were also observed. Overall, Camel Snus had significantly higher TSNA levels than Marlboro Snus, and Camel Strips had the lowest TSNA levels among all novel products analyzed here. The amount of unprotonated nicotine in the dissolvable Camel products was comparable to the levels found in Marlboro Snus. CONCLUSIONS: Our study demonstrates some regional variations in the levels of nicotine and TSNA in Marlboro and Camel novel smokeless tobacco products. Continued monitoring of this category of products is needed as the existing products are being test marketed and modified, and new products are being introduced. This information is particularly important given its relevance to Food and Drug Administration regulation of tobacco products.

Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK.

INTRODUCTION: Protein tyrosine kinases (PTKs) are frequently overexpressed and/or activated in human malignancies, and regulate cancer cell proliferation, cellular survival, and migration. As such, they have become promising molecular targets for new therapies. The non-receptor PTK termed breast tumor kinase (Brk/PTK6) is overexpressed in approximately 86% of human breast tumors. The role of Brk in breast pathology is unclear. METHODS: We expressed a WAP-driven Brk/PTK6 transgene in FVB/n mice, and analyzed mammary glands from wild-type (wt) and transgenic mice after forced weaning. Western blotting and immunohistochemistry (IHC) studies were conducted to visualize markers of mammary gland involution, cell proliferation and apoptosis, as well as Brk, STAT3, and activated p38 mitogen-activated protein kinase (MAPK) in mammary tissues and tumors from WAP-Brk mice. Human (HMEC) or mouse (HC11) mammary epithelial cells were stably or transiently transfected with Brk cDNA to assay p38 MAPK signaling and cell survival in suspension or in response to chemotherapeutic agents. RESULTS: Brk-transgenic dams exhibited delayed mammary gland involution and aged mice developed infrequent tumors with reduced latency relative to wt mice. Consistent with delayed involution, mammary glands of transgenic animals displayed decreased STAT3 phosphorylation, a marker of early-stage involution. Notably, p38 MAPK, a pro-survival signaling mediator downstream of Brk, was activated in mammary glands of Brk transgenic relative to wt mice. Brk-dependent signaling to p38 MAPK was recapitulated by Brk overexpression in the HC11 murine mammary epithelial cell (MEC) line and human MEC, while Brk knock-down in breast cancer cells blocked EGF-stimulated p38 signaling. Additionally, human or mouse MECs expressing Brk exhibited increased anchorage-independent survival and resistance to doxorubicin. Finally, breast tumor biopsies were subjected to IHC analysis for co-expression of Brk and phospho-p38 MAPK; ductal and lobular carcinomas expressing Brk were significantly more likely to express elevated phospho-p38 MAPK. CONCLUSIONS: These studies illustrate that forced expression of Brk/PTK6 in non-transformed mammary epithelial cells mediates p38 MAPK phosphorylation and promotes increased cellular survival, delayed involution, and latent tumor formation. Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways.

A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer.

BACKGROUND: Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. METHODS: Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) × 5 doses, cyclophosphamide 60 mg/kg × 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week × 6 doses after NK cell infusion to promote expansion, defined as detection of ≥100 donor-derived NK cells/µL blood 14 days after infusion, based on molecular chimerism and flow cytometry. RESULTS: Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was 2.16 × 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. CONCLUSIONS: Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed.

Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker.

Early detection of ovarian cancer is difficult owing to the lack of specific and sensitive tests available. Previously, we found expression of nectin 4 to be increased in ovarian cancer compared with normal ovaries. Reverse transcriptase-polymerase chain reaction (RT-PCR) and quantitative RT-PCR validated the overexpression of nectin 4 messenger RNA in ovarian cancer compared with normal ovarian cell lines and tissues. Protein levels of nectin 4 were elevated in ovarian cancer cell lines and tissue compared with normal ovarian cell lines as demonstrated by Western immunoblotting, flow cytometry, and immunohistochemical staining of tissue microarray slides. Cleaved nectin 4 was detectable in a number of patient serum samples by enzyme-linked immunosorbent assay. In patients with benign gynecologic diseases with high serum CA125 levels, nectin 4 was not detected in the majority of cases, suggesting that nectin 4 may serve as a potential biomarker that helps discriminate benign gynecologic diseases from ovarian cancer in a panel with CA125.

The use of sodium hyaluronate-carboxymethylcellulose (HA-CMC) barrier in gynecologic malignancies: a retrospective review of outcomes.

Concerns exist regarding the safety of sodium hyaluronate-carboxymethylcellulose (HA-CMC, Seprafilm) adhesion barrier in regard to cancer survival as a result of in vitro data demonstrating that hyaluronan, a component of HA-CMC, may promote tumor growth. We sought to determine whether use of HA-CMC is associated with duration of disease-free or overall survival and rates of immediate complication in patients with gynecologic malignancies. We identified 202 consecutive patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer who underwent initial surgical staging or interval debulking at the University of Minnesota between January 2001 and December 2004. Information on patients' demographics, medical history, surgical procedures, postoperative complications, disease stage, histology, adjuvant therapy, and disease-free and overall survival was collected from medical records. Survival curves were compared between patients receiving or not receiving HA-CMC by stratified Cox regression models, log rank, and Wilcoxon tests. The level of significance was set to alpha = .05 for each test. Eighty patients received intraoperative placement of HA-CMC and 122 did not. Immediate postoperative complication rates were equivalent in both groups. Median follow-up was 2.1 years. There was no difference in disease-free survival (5-year estimate 23.6% vs. 33.3%, P = .80) or overall survival (5-year estimate 29.7% vs. 40.3%, P = .75) between those who received HA-CMC and those who did not. Our retrospective analysis suggests that HA-CMC adhesion barrier does not affect disease-free survival or overall survival; nor does it increase the immediate postoperative complication rates in patients undergoing abdominal surgery for ovarian, fallopian tube, and primary peritoneal carcinomas.

The RealU online cessation intervention for college smokers: a randomized controlled trial.

OBJECTIVES: To determine the efficacy of providing online cessation intervention for college smokers. METHODS: This is a two-group randomized controlled trial. The intervention group received $10 weekly incentives to visit an online college life magazine that provided personalized smoking cessation messages and peer email support. Evaluation assessments occurred at baseline and 8, 20, and 30 weeks after enrollment. The primary outcome is self-reported 30-day abstinence at week 30. Carbon monoxide (CO) breath testing was performed for participants reporting 30-day abstinence at week 30. RESULTS: Five-hundred and seventeen college smokers at the University of Minnesota were enrolled via internet health screening (control=260, intervention=257) in the fall of 2004. Intervention participants completed an average of 18.9 (SD 2.5) of 20 weekly website visits over the course of the study. The rate of 30-day abstinence at week 30 was higher for the intervention compared to the control group (41% vs. 23%, p<0.001). CO testing showed low rates of under-reporting. There was no difference in self-reported 6-month prolonged abstinence measured at week 30. CONCLUSION: Providing personalized smoking cessation messages as part of a general interest online college life magazine increased 30-day abstinence by the end of this two semester intervention.

Inhibitory effects of a dietary phytochemical 3,3'-diindolylmethane on the phenobarbital-induced hepatic CYP mRNA expression and CYP-catalyzed reactions in female rats.

3,3'-diindolylmethane (DIM), derived from indole-3-carbinol (I3C), is used as a dietary supplement for its putative anticancer effects that include suppression of mammary tumor growth in female rats. The mechanism of action DIM may involve its interaction(s) with hepatic cytochromes P450 (CYPs) catalyzing oxidations of 17beta-estradiol (E2). Our study showed that DIM added to hepatic microsomes of female Sprague-Dawley rats was primarily a competitive inhibitor of beta-naphthoflavone (beta-NF)- or I3C-induced CYP1A1 probe activity, and a potent mixed or uncompetitive inhibitor of phenobarbital (PB)-induced CYP2B1 or CYP2B2 probe activity, respectively. Microsomal metabolites of DIM were tentatively identified as two mono-hydroxy isomers of DIM, each formed preferentially by CYP1A1- or CYP2B1/2-catalyzed reaction. Evaluation of the effects of co-treatment of rats with PB and DIM by a full factorial ANOVA showed that DIM decreased the PB-induced CYP2B1 and CYP2B2 mRNA expression levels, and the rates of 2- and 4-hydroxylation of E2, and total E2 metabolite formation. The results suggest that interactions of DIM, and/or its mono-hydroxy metabolites, with CYP2B1 and CYP2B2 found to occur in hepatic microsomes upon addition of DIM or co-treatment of rats with DIM affect the rates of relevant oxidations of E2, and potentially protect against estrogen-dependent tumorigenesis.

Smoking reduction fails to improve clinical and biological markers of cardiac disease: a randomized controlled trial.

Cigarette reduction has been proposed as a treatment goal for smokers who are not interested in stopping completely. This randomized controlled trial was designed to determine the effect of a smoking reduction intervention on smoking behavior, symptoms of heart disease, and biomarkers of tobacco exposure. It included 152 patients with heart disease who did not intend to stop smoking in the next 30 days. Participants were randomly assigned to smoking reduction (SR) or usual care (UC). SR subjects received counseling and nicotine replacement therapy to encourage > or =50% reduction in cigarettes per day (CPD). They were followed at 1, 3, 6, 12 and 18 months to assess smoking, heart disease symptoms, quality of life and nicotine, cotinine, carbon monoxide (CO), white blood cell (WBC) count, fibrinogen, hs-C-reactive protein (hs-CRP), F2-isoprostane, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and 1-hydroxypyrene (1-HOP). At 6 months SR participants reduced by 10.9 CPD, compared with 7.4 CPD in UC (difference NS). At 18 months, 9/78 SR vs. 9/74 UC participants quit smoking. There were no significant differences between treatment groups in angina, quality of life or adverse events, nicotine, cotinine, CO, WBC count, fibrinogen, hs-CRP, F2-isoprostane, total NNAL or 1-HOP levels at any time point. To determine if smoking reduction, regardless of treatment condition, was associated with improved outcomes, we compared all subjects at 6 months to baseline (mean reduction in CPD from 27.4 to 18.1, p<.01). There were no significant changes in outcome variables except CO, which decreased by 5.5 ppm (p<.01). There were also no significant improvements considering only subjects who reduced by > or =50%, or those who had no history of reduction prior to enrollment in the study. The SR intervention did not significantly reduce CPD or toxin exposure, or improve smoking cessation or clinical outcomes compared to UC. These results emphasize the importance of abstinence for smokers with heart disease to minimize health risks from tobacco.

Tumorigenicity and genotoxicity of an environmental pollutant 2,7-dinitrofluorene after systemic administration at a low dose level to female rats.

Environmental pollution with nitroaromatic compounds may pose health hazards. We have examined the tumorigenicity in female Sprague-Dawley rats of 2,7-dinitrofluorene (2,7-diNF) and 9-oxo-2,7-diNF administered by intraperitoneal (i.p.) and oral routes at 10 micromol/kg body weight, 3 times per week for 4 weeks. After i.p. treatment, the estimated median latency for the combined malignant and benign mammary tumors was decreased in 2,7-diNF- (p = 0.003) or 9-oxo-2,7-diNF-treated (p = 0.007), relative to vehicle-treated rats (42 or 64 vs. 80 weeks, respectively), whereas after oral dosing, there were no significant differences. At 90 weeks, the malignant mammary tumor incidence in 2,7-diNF-, 9-oxo-2,7-diNF- and vehicle-i.p. treated rats was 44 (p = 0.02 vs. vehicle-treated), 25 and 6%, respectively. Liver and mammary gland DNA was analyzed by HPLC combined with electrospray tandem mass spectrometry for the presence of a deoxyguanosine (dG-2,7-diNF) adduct and a deoxyadenosine (dA-2,7-diNF) adduct derived from 2,7-diNF, and a deoxyguanosine (dG-9-oxo-2,7-diNF) adduct derived from 9-oxo-2,7-diNF. Both dG-2,7-diNF and dA-2,7-diNF were detected in DNA of 2,7-diNF-treated rats, whereas only very low levels of dG-9-oxo-2,7-diNF were detected in DNA of 9-oxo-2,7-diNF-treated rats. After i.p. treatment, the dA-2,7-diNF level was higher (p < 0.01) in the mammary gland than liver (13.6 vs. 7.8 adducts/10(8) nucleotides). In the mammary gland, the dG-2,7-diNF level was higher (p < 0.05) after i.p. than oral dosing and also higher (p < 0.05) than in the liver (36 vs. 8.6 and vs. 9.1 adducts/10(8) nucleotides, respectively). The preferential display of carcinogenicity and genotoxicity in the mammary gland by low doses of 2,7-diNF signifies its potential relevance for environmental breast cancer.

A prospective randomized trial of thalidomide with topotecan compared with topotecan alone in women with recurrent epithelial ovarian carcinoma.

BACKGROUND: Thalidomide is an antiangiogenic agent with immune modulating potential. The objective of this study was to determine response rates among women who were treated for recurrent ovarian cancer using topotecan with or without thalidomide. METHODS: Women were enrolled in this multicenter, prospective, randomized phase 2 trial between April 2001 and July 2005. Eligible patients had recurrent epithelial ovarian carcinoma with measurable disease or elevated CA 125 values. Patients had received prior platinum-based chemotherapy. Treatment arms received topotecan at a dose of 1.25 mg/m(2) on Days 1 through 5 of a 21-day cycle with or without thalidomide starting at a dose of 200 mg per day and then increasing the dose as tolerated. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria. The chi-square test was used to assess differences in response and toxicity, and the log-rank test was used to compare Kaplan-Meier survival curves. RESULTS: The analysis included 69 women (39 women in the control arm and 30 women in the thalidomide arm). Known prognostic factors, including platinum sensitivity, were represented equally in each arm. The median thalidomide dose was 200 mg per day. The overall response rate in the control arm was 21% (complete response [CR] rate, 18%; partial response [PR] rate, 3%) compared with 47% in the thalidomide arm (CR rate, 30%; PR rate, 17%) (P= .03). The median progression-free survival for the control arm was 4 months compared with 6 months in the thalidomide arm (P= .02). The median overall survival was 15 months in the control arm and 19 months in the thalidomide arm (P= .67). Toxicities were similar between groups. CONCLUSIONS: The addition of thalidomide to topotecan for the treatment of recurrent ovarian cancer appears to improve response rates, and the authors believe that it warrants study through larger phase 3 trials.