Efficacy and safety of topically applied therapeutic ammonia oxidising bacteria in adults with mild-to-moderate atopic dermatitis and moderate-to-severe pruritus: a randomised, double-blind, placebo-controlled, dose-ranging, phase 2b trial.

Background: Topical anti-inflammatory therapy is a cornerstone of treatment for atopic dermatitis (AD). However, many unmet needs remain with existing therapies. B244 is a live topical biotherapeutic being tested for the reduction of pruritus and improvement of eczema signs in patients with AD. We aimed to assess the safety and efficacy of B244, compared to vehicle, for patients with mild-to-moderate AD and moderate-to-severe pruritus. Methods: In this randomised, placebo-controlled, double-blind phase 2b trial, adults aged 18-65 years with mild-to-moderate AD and moderate-to-severe pruritus were enrolled across 56 sites in the USA. Patients were randomised 1:1:1 into a low-dose (optical density at 600 nm [OD] 5.0), high-dose (OD 20.0), or vehicle group for the 4-week treatment period and a 4 week follow-up period. Patients were instructed to apply the topical spray twice daily throughout the treatment period. Randomisation was centrally based (random alternating blocks of 6 and 3) and stratified by site. All participants, investigators, and those assessing outcomes were blinded to the treatment group assignments. The primary endpoint was the mean change in pruritus as measured by the Worst Itch Numeric Rating Scale (WI-NRS) at 4 weeks. Safety was tracked throughout the study. Primary efficacy analyses included the modified intent-to-treat (mITT) population, encompassing those who received at least one dose of study drug and attended at least one post-baseline visit. The safety population included all participants who received at least one does of study drug. This study is registered with ClinicalTrials.gov, NCT04490109. Findings: Between June 4, 2020 and October 22, 2021, 547 eligible patients were enrolled. All study endpoints were meaningfully improved with B244 compared to vehicle. The WI-NRS score was reduced by 34% (-2.8 B244 vs -2.1 placebo, p = 0.014 and p = 0.015 for OD 20.0 and OD 5.0), from a baseline score of >8. B244 was well tolerated with no serious adverse events (SAEs); treatment-emergent adverse events (TEAEs) and treatment related TEAEs were low in incidence, mild in severity, and transient. 33 (18%) of 180 patients given B244 OD 5.0, 29 (16%) of 180 patients given B244 OD 20.0, and 17 (9%) of 186 patients given placebo reported treatment-emergent adverse events; headache was the most frequent (3%, 2%, and 1%, respectively). Interpretation: B244 was well tolerated and demonstrated improved efficacy compared to vehicle in all primary, secondary, and exploratory endpoints and should be further developed as a novel, natural, fast-acting topical spray treatment option for AD and associated pruritus. Funding: AOBiome Therapeutics.

Nutritional status and body composition in patients with peripheral arterial disease: A cross-sectional examination of disease severity and quality of life.

Nutritional and body weight recommendations for cardiovascular diseases are well established, yet there are no equivalent guidelines for peripheral arterial disease (PAD). This cross-sectional study measured the prevalence of cardiovascular-related nutritional and body composition risk factors in sixty PAD patients and their association with PAD severity. A diet that exceeds daily recommended intake of fat and that falls short of recommended intakes of fiber, folate, and vitamin D was associated with increased leg pain and walking difficulty. Increased body fat and waist circumference were associated with diminished walking ability and poorer psychosocial quality of life. Future prospective investigations are merited to inform both PAD clinical care and disease management guidelines.

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.

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.

Analyzing variability in pain management using electronic health record data.

Variability in pain management processes may affect outcomes. Researchers collected pain management documentation from electronic health record systems of 3 hospitals and constructed process and outcome variables. Simple linear regressions revealed that relationships exist between increased pain variability and less frequent assessment and more frequent intervention, identifying targeted areas for improvement. Researchers demonstrated the use of the electronic record output for improvement purposes.

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.

Estimating proximity to care: are straight line and zipcode centroid distances acceptable proxy measures?

BACKGROUND: Spatial accessibility of healthcare may be measured by proximity of patient residence to health services, typically in driving distance or driving time. Precise driving distances and times are rarely available. Although straight line distances between zipcode centroids and between precise address locations are used as proxy measures for distance to care, the accuracy of these measures has received little study. METHODS: Among a cohort of Medicare beneficiaries, actual driving distances and times between patient residence and clinic were obtained from commercial software (MapQuest). We used a split-sample design to build and validate linear regression models that predict actual driving distances and times from estimated distances between zipcode centroids and between precise residential and hospital locations, adjusting for urban/suburban/rural residential status. RESULTS: On average, predicted driving distances and times were larger than actual values. Zipcode centroid distances alone predicted longer driving distances than observed values: rural +19% (3.2 miles), suburban +23% (3.7 miles), and urban +27% (2.0 miles). Predicted time was 36% (9.4 min) longer in rural, 32% (6.8 min) longer in suburban, and 38% (4.7 min) longer in urban areas than observed values. Including urban/suburban/rural categorization of residence improved the accuracy of predicted driving distance and time for suburban and urban areas but diminished accuracy for rural areas. Similar trends were observed for distance estimates from precise locations. CONCLUSIONS: Distances between zipcode centroids and precise residential/hospital locations provide reasonable estimates of driving distance and time for epidemiologic research. Estimates are improved for suburban and urban residences when data are augmented by urban categorization.

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.

Adjusted significance cutoffs for hypothesis tests applied with generalized additive models with bivariate smoothers.

In spatial epidemiology, generalized additive models (GAMs) can be applied with bivariate locally weighted regression smoothing terms (LOESS), smoothing over longitude and latitude, to evaluate whether there is spatial variation in disease risk across a study region. Two hypothesis testing methods applicable with GAMs with bivariate LOESS smoothes, an approximate chi-square test (ACST) and the conditional permutation test (CPT), have inflated type I error rates. Using simulated data we determined empirical adjustments to significance cutoffs for nominal type I error rates of 0.01, 0.05, and 0.10. When applied with adjusted significance cutoffs, both ACST and CPT were appropriately sized across region shapes, population densities, sample sizes, and probabilities of disease.

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 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.

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.

Urinary biomarkers to assess exposure of cats to environmental tobacco smoke.

OBJECTIVE: To evaluate the use of urinary biomarkers to assess exposure of cats to environmental tobacco smoke (ETS). ANIMALS: 61 healthy client-owned cats (19 from households in which smoking was reported and 42 from households in which there was no smoking). PROCEDURES: Urine samples were obtained from each cat and assayed for total nicotine (nicotine plus nicotine glucuronide) and total cotinine (cotinine plus cotinine glucuronide) content by use of gas chromatography-mass spectrometry. In addition, total urinary content of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a major metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, was measured by use of gas chromatography with nitrosamine-selective detection. RESULTS: Cats from households in which smoking was reported had significantly higher concentrations of total nicotine (70.4 ng/mL), total cotinine (8.53 ng/mL), and total NNAL (0.0562 pmol/mL) in urine, compared with concentrations for cats that lived in households in which there was no smoking (4.89 ng/mL, 0.74 ng/mL, and 0.0182 pmol/mL, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of these data provided biochemical evidence of exposure to ETS and uptake of tobacco-specific carcinogens by cats that live in households with smokers. Biomarkers could facilitate investigation of the health effects of ETS in cats and other species.