Effect of surgical approach on risk of recurrence after vaginal brachytherapy in early-stage high-intermediate risk endometrial cancer.

OBJECTIVE: The objective was to determine if surgical approach affects time to recurrence in early-stage high-intermediate risk endometrial cancer (HIR-EC) treated with adjuvant vaginal brachytherapy (VBT). METHODS: In this retrospective cohort study, HIR-EC patients treated with VBT between 2005 and 2017 were identified and those who received open or minimally invasive hysterectomies (MIS) were included. Clinical and surgical variables were analyzed and time to recurrence was compared between surgical groups. RESULTS: We identified 494 patients, of which 363 had MIS hysterectomies, 92.5% had endometrioid histology, 45.7% were stage IA and 48.0% stage IB. Open hysterectomy patients had higher BMIs (p = 0.007), lower rates of lymph node sampling (p < 0.001) and lymphovascular space invasion (LVSI) (p = 0.036), however in patients who recurred, no differences were noted between groups. Overall, 65 patients (13.2%) recurred, 14 in the open group (10.7%) and 51 in the MIS group (14.0%) (p = 0.58), while vaginal recurrences were noted in 4.6% and 6.1% respectively. When compared to the open group, the MIS group had a significantly shorter time to any recurrence (p = 0.022), to pelvic (p = 0.05) and locoregional recurrence (p = 0.021) and to death from any cause (p = 0.039). After adjusting for age, BMI, grade, LVSI and surgery date, the MIS group had a higher risk of any recurrence (HR 2.29 (1.07-4.92), p = 0.034) and locoregional recurrence (HR 4.18 (1.44-12.1), p = 0.008). CONCLUSIONS: Patients with HIR-EC treated with VBT after MIS hysterectomy have a shorter time to recurrence and higher risk of recurrence when compared to open hysterectomy patients. Further studies into the safety of MIS in high-intermediate risk patients are required.

Physical activity and health-related quality of life among postmenopausal women with breast cancer treated with aromatase inhibitors.

PURPOSE: Breast cancer is the most common non-cutaneous cancer in women with an estimated 268,600 new cases diagnosed in 2019, joining the over 3 million women living with the disease. To reduce cancer recurrence, postmenopausal women (highest incidence and prevalence of breast cancer) who test positive for hormone receptors in their tumors are candidates for adjuvant endocrine therapy (i.e., aromatase inhibitors [AIs]). Despite the benefits of AIs in the treatment for breast cancer, many women remain at risk for complications, including osteoporosis and fractures, all of which can adversely affect health-related quality of life (HRQoL). Increased attention is being paid to the role physical activity (PA) may have in improving health outcomes in survivors of breast cancer, but few studies focus on postmenopausal women. We sought to examine (1) the percentage of women in our sample meeting (or not meeting) the American College of Sports Medicine (ACSM) PA recommendations, (2) the relationship between AI use and three types of PA (leisure time, strength training, and walking), and (3) the relationship between PA and HRQoL by AI use, controlling for covariates. METHODS: Postmenopausal women with breast cancer (n = 170), ages 50-95 years (M = 68.7), diagnosed with stage 1-3 disease, 45% on AIs, were recruited. Demographic, HRQoL, and PA data were collected via patient self-report, while clinical data (AI use) were abstracted from patient medical records. To address study aims, we utilized descriptive statistics, chi-square analyses, and multiple linear regressions, respectively. RESULTS: Half of the sample met the ACSM recommendations for total leisure-time PA (vigorous and moderate intensity combined), and 65.3% (n = 111) weekly walking. With regard to strength training, 36.5% of the women met these ACSM recommendations. Generally, there were positive relationships between AI use and most HRQoL domains. There were no statistically significant relationships between PA (meeting recommendations or not) and HRQoL by AI use. CONCLUSION: The proportion of women meeting guidelines for walking activity was encouraging. It is imperative that healthcare professionals providing care to breast cancer survivors follow up regarding symptoms, side effects, and physical activity in tandem to fully understand their relationship on an individual level.

Nitric oxide and TNF-alpha trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus-infected, Rag2-deficient mice.

Recombinase-activating gene-2-deficient (Rag2(-/-)) mice lacking functional lymphocytes provide a useful model of chronic inflammatory bowel disease-emulating events in human colon cancer. Infection of Rag2(-/-) mice with Helicobacter hepaticus led to accumulation of macrophages and neutrophils in the colon, a process temporally related to up-regulation of tissue inducible nitric oxide synthase (iNOS) expression at the site of infection and increased nitric oxide (NO) production, as evidenced by urinary excretion of nitrate. Progressive development of increasingly severe inflammation, hyperplasia, dysplasia, and cancer accompanied these changes. Concurrent administration of an iNOS inhibitor prevented NO production and abrogated epithelial pathology and inhibited the onset of cancer. The presence of Gr-1(+) neutrophils and elevated tumor necrosis factor-alpha (TNF-alpha) expression in colon were required for increased iNOS expression and cancer, whereas interleukin-10 (IL-10) down-regulated TNF-alpha and iNOS expression and suppressed cancer. Anti-inflammatory CD4(+) regulatory lymphocytes also down-regulated iNOS and reduced cancer formation. Collectively, these results confirm essential roles for inflammation, increased TNF-alpha expression, and elevated NO production in colon carcinogenesis.

Gut microbes define liver cancer risk in mice exposed to chemical and viral transgenic hepatocarcinogens.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) frequently results from synergism between chemical and infectious liver carcinogens. Worldwide, the highest incidence of HCC is in regions endemic for the foodborne contaminant aflatoxin B1 (AFB1) and hepatitis B virus (HBV) infection. Recently, gut microbes have been implicated in multisystemic diseases including obesity and diabetes. Here, the hypothesis that specific intestinal bacteria promote liver cancer was tested in chemical and viral transgenic mouse models. METHODS: Helicobacter-free C3H/HeN mice were inoculated with AFB1 and/or Helicobacter hepaticus. The incidence, multiplicity and surface area of liver tumours were quantitated at 40 weeks. Molecular pathways involved in tumourigenesis were analysed by microarray, quantitative real-time PCR, liquid chromatography/mass spectrometry, ELISA, western blot and immunohistochemistry. In a separate experiment, C57BL/6 FL-N/35 mice harbouring a full-length hepatitis C virus (HCV) transgene were crossed with C3H/HeN mice and cancer rates compared between offspring with and without H hepaticus. RESULTS: Intestinal colonisation by H hepaticus was sufficient to promote aflatoxin- and HCV transgene-induced HCC. Neither bacterial translocation to the liver nor induction of hepatitis was necessary. From its preferred niche in the intestinal mucus layer, H hepaticus activated nuclear factor-kappaB (NF-kappaB)-regulated networks associated with innate and T helper 1 (Th1)-type adaptive immunity both in the lower bowel and liver. Biomarkers indicative of tumour progression included hepatocyte turnover, Wnt/beta-catenin activation and oxidative injury with decreased phagocytic clearance of damaged cells. CONCLUSIONS: Enteric microbiota define HCC risk in mice exposed to carcinogenic chemicals or hepatitis virus transgenes. These results have implications for human liver cancer risk assessment and prevention.

Nitrate synthesis in the germfree and conventional rat.

Metabolic balance studies show that germfree and conventional Sprague-Dawley rats synthesize nitrate. Equivalent results for germfree and conventional rats eliminate the microflora as obligatory components of nitrate production. Nitrate synthesis appears to be a mammalian process.

Formation of cyanamides from secondary amines in human saliva.

1-Morpholinocarbonitrile (1-cyanomorpholine) was formed from morpholine when this amine was incubated in whole human saliva. Several other secondary amines appeared to form analogous products, and this transformation may therefore represent a general metabolic pathway for amines in saliva.

Growth of a thermophilic bacterium on hydrocarbons: a new source of single-cell protein.

A species of the genus Bacillus, capable of growth on normal alkanes at 70 degrees C, was isolated by the method known as enrichment culture. Preliminary analyses of its amino acid composition indicate that it would be a good source of protein for human nutrition. Possible advantages of the use of such organisms for the production of single-cell protein include simplification of fermentor cooling and asepsis.

Nitrite and nitrate are formed by endogenous synthesis in the human intestine.

Studies of nitrate balance in humans and analyses of fecal and ileostomy samples indicate that nitrite and nitrate are formed de novo in the intestine, possibly by heterotrophic nitrification. These findings significantly alter our previous conceptions of human exposure to nitrite and suggest an even wider role for nitrite in the etiology of human cancer.

Environmental nitroso compounds: reaction of nitrite with creatine and creatinine.

Creatine reacts with nitrite under acid conditions to produce first sarcosine and then N-nitrososarcosine, which is a weak carcinogen in the rat. Creatinine reacts with acidified nitrite to produce either creatinine-5-oxime or 1-methylhydantoin-5-oxime, depending on reaction conditions. The toxicity and environmental significance of these compounds is not yet known.

Interleukin-22 drives nitric oxide-dependent DNA damage and dysplasia in a murine model of colitis-associated cancer.

The risk of colon cancer is increased in patients with Crohn's disease and ulcerative colitis. Inflammation-induced DNA damage could be an important link between inflammation and cancer, although the pathways that link inflammation and DNA damage are incompletely defined. RAG2-deficient mice infected with Helicobacter hepaticus (Hh) develop colitis that progresses to lower bowel cancer. This process depends on nitric oxide (NO), a molecule with known mutagenic potential. We have previously hypothesized that production of NO by macrophages could be essential for Hh-driven carcinogenesis, however, whether Hh infection induces DNA damage in this model and whether this depends on NO has not been determined. Here we demonstrate that Hh infection of RAG2-deficient mice rapidly induces expression of iNOS and the development of DNA double-stranded breaks (DSBs) specifically in proliferating crypt epithelial cells. Generation of DSBs depended on iNOS activity, and further, induction of iNOS, the generation of DSBs, and the subsequent development of dysplasia were inhibited by depletion of the Hh-induced cytokine IL-22. These results demonstrate a strong association between Hh-induced DNA damage and the development of dysplasia, and further suggest that IL-22-dependent induction of iNOS within crypt epithelial cells rather than macrophages is a driving force in this process.

Gastric cancer in Colombia. IV. Nitrite and other ions in gastric contents of residents from a high-risk region.

Samples of gastric contents from 2 groups of patients from a region of high risk for gastric cancer were analyzed for pH, nitrite, nitrate, thiocyanate, and chloride. In each group, the patients could be divided into 2 subgroups: those with a gastric pH of less than 5 and those with a gastric pH of greater than 5. Above pH 5, nitrite was correlated with nitrate. The pH greater than 5 subgroups had significantly higher (P less than 0.01) nitrite content (20- to 100-fold). Some high- and low-nitrite samples were also analyzed for macro and trace metal ions, but differences were not significant. This is the first report in which patients with diagnosed gastric pathology related to a precancerous state were shown to have high levels of a putative carcinogen precursor. The results were compatible with our original hypothesis of intragastric nitrite formation by bacterial reduction of nitrate and concomitant synthesis of carcinogenic N-nitroso compounds.

Nitrosamine formation in human saliva.

Nitrosamines formed when secondary amines were added to normal human saliva. Fractionation of saliva into cells and supernatant showed that factors that accelerated and retarded the nitrosation reaction were both present. Acidification of saliva greatly increased the nitrosamine yield, but differences in nitrosamine yield among saliva fractions were still observable.

Reaction of nitrite with ascorbate and its relation to nitrosamine formation.

In this study of the nitrosation of morpholine in the presence of ascorbic acid, the amount of ascorbate required to inhibit completely the formation of nitrosomorpholine depended on whether oxygen was present in the system. The nitric oxide (produced during the oxidation of ascorbate by nitrous acid) might have reacted with oxygen to yield additional oxidizing equivalents, or oxygen might have directly oxidized the ascorbate semiquinone intermediate produced in the initial step of oxidation reaction. A pH- dependent induction period observed during the nitrosation of morpholine in the presence of ascorbate and excess nitrite was accounted for by the kinetics of the reactions.

Gastric cancer in Colombia. I. Cancer risk and suspect environmental agents.

A case control study of patients discharged from hospitals revealed fourfold differences in geographic variation in stomach cancer risk within the Department of Narino (Colombia). Data from gastroscopic surveys of population groups, samples of water supplies, and urine and saliva in Narino also indicated a generally positive correlation among the following parameters: 1) gastric cancer risk, 2) prevalence of chronic atrophic gastritis and intestinal metaplasia, 3) nitrate content of well waters, and 4) nitrate excretion by the population. Urinary excretion reflected the ingestion of nitrates, and this implied a higher average intake of nitrates in the populations at high risk for stomach cancer. The Narino data could be construed as presumptive epidemiologic evidence for the role of nitrate availability in the etiology of stomach cancer.

Diet and chronic atrophic gastritis: a case-control study.

A hospital-based case-control study of gastric cancer precursor lesions was conducted in a high-risk black population in southern Louisiana. Ninety-three subjects with biopsy-proved advanced chronic atrophic gastritis were compared to two control series: a gastroscopy clinic series and a general hospital-admission series. Dietary case-control differences indicated a protective effect associated with fruit and vegetable intake and with dietary vitamin C and a risk elevation associated with milk consumption. The protective effect associated with consumption of fruits, vegetables, and vitamin C is consistent with findings for gastric cancer and with the etiologic hypothesis of intragastric nitrosation. A twofold increased risk was associated with cigarette smoking. Gastric juice pH, NO3-, and NO2- were determined for subjects undergoing gastroscopy, and comparisons were made between this high-risk U.S. group and a Colombian population with a much greater magnitude of risk; the latter had higher NO3- and NO2- levels. An increase in pH was associated with increasing severity of gastric lesions. Levels of pH and NO2- concentration were significantly correlated (P less than .0005); however, in Louisiana the large difference in NO2- concentration associated with pH elevation is not associated with histopathologic severity. Divergent trends with severity of lesions for NO3- concentration were seen in the two populations.

Relationship between environmental tobacco smoke exposure and carcinogen-hemoglobin adduct levels in nonsmokers.

BACKGROUND: A potent bladder carcinogen for workers in the dye industry, 4-aminobiphenyl (4-ABP), is present in environmental tobacco smoke and has been shown to bond covalently with hemoglobin. PURPOSE: The goal of this study was to examine the relationship between exposure to environmental tobacco smoke and levels of 4-ABP-hemoglobin adducts in nonsmoking pregnant women and to compare adduct levels in those women with levels in smoking pregnant women. METHODS: A questionnaire on smoking and exposure to environmental tobacco smoke was administered to 15 pregnant women who smoked cigarettes and 40 who did not smoke. Exposure was quantified for 1 week with a personal diary and by air sampling with a monitor worn by each woman. The monitor collected nicotine by passive diffusion to a filter treated with sodium bisulfate, and the deposit on the filter was analyzed by gas chromatography. Aliquots of maternal blood and cord blood collected during delivery were analyzed for 4-ABP-hemoglobin adducts by gas chromatography with negative ion chemical ionization mass spectrometry. RESULTS: The mean adduct level in smokers (184 pg of 4-ABP per gram of hemoglobin) was substantially higher than that in nonsmokers (22 pg/g). This difference was statistically significant. Among nonsmokers, the levels of 4-ABP adducts increased significantly with increasing environmental tobacco smoke level (P = .009). Those in the lowest exposure category (< 0.5 micrograms/m3 weekly average nicotine) had median 4-ABP-hemoglobin adduct levels of 15 pg of 4-ABP per gram of hemoglobin, while those in the highest exposure category (> or = 2.0 micrograms/m3) had median levels of 26 pg/g. Nonsmokers in this study had a median adduct level of 20 pg/g, and smokers had a median level of 143 pg/g. CONCLUSIONS: 4-ABP-hemoglobin adduct levels in nonsmokers were 14% of the levels in smokers, which is consistent with findings of 20% in two other studies. Nonsmokers may receive a nontrivial dose of carcinogens from environmental tobacco smoke proportional to their exposure to environmental tobacco smoke. IMPLICATION: The relationship between environmental tobacco smoke exposure and 4-ABP-hemoglobin adduct levels supports epidemiologic evidence that environmental tobacco smoke is carcinogenic to passive smokers.

Administration of pentosan polysulfate to patients with human immunodeficiency virus-associated Kaposi's sarcoma.

BACKGROUND: Neovascularization induced by basic fibroblast growth factor (basic FGF) or FGF-like cytokines is thought to play a substantial role in the pathogenesis of human immunodeficiency virus (HIV)-associated Kaposi's sarcoma. Pentosan polysulfate has been shown to inhibit basic FGF and FGF-like dependent tumor growth both in vitro and in vivo. Moreover, it has been found to inhibit the growth of Kaposi's sarcoma-derived spindle cells in vitro. These observations suggested that pentosan polysulfate might be worth exploring as a potential agent for the treatment of Kaposi's sarcoma. PURPOSE: The purpose of this phase 1 clinical trial was to determine the maximum tolerated dose of pentosan polysulfate in patients with HIV-associated Kaposi's sarcoma and whether or not this compound had activity against this neoplasm. METHODS: Sixteen HIV-seropositive patients with Kaposi's sarcoma received pentosan polysulfate via continuous venous infusion for 3-6 weeks and then received a subcutaneous dose three times per week. Three different doses of pentosan polysulfate were administered: 2 mg/kg per day by infusion followed by 2 mg/kg per dose given subcutaneously (six patients), 3 mg/kg per day by infusion followed by 3 mg/kg per dose given subcutaneously (five patients), and 4 mg/kg per day by infusion followed by 4 mg/kg per dose given subcutaneously (five patients). Five of the 16 patients in the study also received injections of 1 mg of pentosan polysulfate into two different lesions two times a week for 3 weeks, followed by intralesional therapy once weekly. After receiving pentosan polysulfate for 6 weeks, patients were administered 100 mg zidovudine (AZT) orally every 4 hours in conjunction with pentosan polysulfate. RESULTS: The maximally tolerated dose of pentosan polysulfate given by continuous venous infusion was found to be 3 mg/kg per day. No patient had an objective clinical antitumor response to either systemic or intralesional pentosan polysulfate administration; however, three patients had stable Kaposi's sarcoma for 3-27 weeks. No statistically significant effect on CD4 cells or serum HIV p24 antigen was noted during pentosan polysulfate administration. Dose-limiting toxic effects were characterized by anticoagulation and thrombocytopenia and were reversible. CONCLUSION: Pentosan polysulfate was well tolerated in this patient population. However, no objective tumor response or evidence of anti-HIV activity was noted; therefore, no claim of activity can be made in this trial. IMPLICATION: Continued investigation into the use of angiogenesis inhibitors with improved activity and toxicity profiles or different mechanisms of action is warranted.

4-Aminobiphenyl hemoglobin adducts in fetuses exposed to the tobacco smoke carcinogen in utero.

Maternal-fetal exchange of a potent tobacco-related human carcinogen, 4-aminobiphenyl, was studied in smoking (n = 14) and nonsmoking (n = 38) pregnant women. N-Hydroxy-4-aminobiphenyl, the active metabolite of 4-aminobiphenyl, forms chemical addition products (adducts) with hemoglobin. Levels of 4-aminobiphenyl hemoglobin adducts were measured in maternal-fetal paired blood samples obtained from smoking and nonsmoking women during labor and delivery. Carcinogen-hemoglobin adducts were detected in all maternal and fetal blood samples. Levels of such adducts were significantly higher (P less than .001) in maternal and fetal blood samples from smokers: the mean 4-aminobiphenyl hemoglobin adduct level was 92 +/- 54 pg/g of hemoglobin in blood samples from fetuses of smokers, and 17 +/- 13 pg/g of hemoglobin in blood samples from fetuses of nonsmokers; the mean maternal 4-aminobiphenyl hemoglobin adduct level was 183 +/- 108 pg/g of hemoglobin in smokers, and 22 +/- 8 pg/g of hemoglobin in nonsmokers. Fetal carcinogen-adduct levels were consistently lower than maternal levels: the mean maternal to fetal ratio was 2.4 +/- 1.1 in smokers and 1.9 +/- .98 in nonsmokers. Fetal 4-aminobiphenyl hemoglobin adduct levels were strongly associated (correlation coefficient [r2] = .51, P = .002) with maternal 4-aminobiphenyl hemoglobin adduct levels when paired samples from smoking mothers were analyzed. A measure of third-trimester tobacco smoke exposure based on number of cigarettes smoked per day, amount of each cigarette smoked, and depth of inhalation was associated (r2 = .59, P = .029) with maternal 4-aminobiphenyl levels but not with fetal 4-aminobiphenyl levels. This study demonstrates that a potent tobacco-related carcinogen, 4-aminobiphenyl, or its active metabolite, N-hydroxy-4-aminobiphenyl, crosses the human placenta and binds to fetal hemoglobin in concentrations that are significantly higher in smokers than in nonsmokers.

Carcinogen hemoglobin adducts, urinary mutagenicity, and metabolic phenotype in active and passive cigarette smokers.

In 100 healthy volunteers, we have studied the relationship between the type (air- or flue-cured) and number of cigarettes smoked and different biomarkers relevant to the risk of bladder cancer, including the levels of 4-aminobiphenyl (ABP) hemoglobin adduct (a marker of internal dose), urinary mutagenicity in Salmonella typhimurium TA98, and the N-acetylation phenotype (a marker of susceptibility). ABP is a potent bladder carcinogen that is N-acetylated as an overall detoxification step. Levels of the ABP hemoglobin adduct were higher in smokers of black tobacco (air-cured) than in smokers of blond tobacco (flue-cured), confirming our earlier study. In addition, "slow" acetylators had higher levels of the ABP hemoglobin adduct for the same type and quantity of cigarettes smoked. Urinary mutagenicity was also associated with quantity of cigarettes but not with the acetylation phenotype. Convex dose-response relationships were found between the amount smoked and ABP hemoglobin adduct levels or urinary mutagenicity. In 15 nonsmokers who reported exposure to environmental tobacco smoke, ABP hemoglobin adduct levels, unlike urinary mutagenicity, were found to be an aspecific exposure indicator.

Gender- and smoking-related bladder cancer risk.

BACKGROUND: There is growing evidence that, when smoking habits are comparable, women incur a higher risk of lung cancer than men. Because smokers are also at risk for bladder cancer, we investigated possible sex differences in the susceptibility to bladder cancer among smokers. METHODS: A population-based, case--control study was conducted in Los Angeles, CA, involving 1514 case patients with bladder cancer and 1514 individually matched population control subjects. Information on tobacco use was collected through in-person interviews. Peripheral blood was collected from study participants to measure 3- and 4-aminobiphenyl (ABP)-hemoglobin adducts, a marker of arylamine exposure. Data were analyzed to determine whether the risk of bladder cancer differs between male and female smokers and whether female smokers exhibit higher levels of ABP-hemoglobin adducts than male smokers with comparable smoking habits. All statistical tests were two-sided. RESULTS: Cigarette smokers had a statistically significant 2.5-fold higher risk (95% confidence interval = 2.1 to 3.0) of bladder cancer than never smokers. Use of filtered versus nonfiltered cigarettes, low-tar versus higher tar cigarettes, or the pattern of inhalation did not modify the risk. The risk of bladder cancer in women who smoked was statistically significantly higher than that in men who smoked comparable numbers of cigarettes (P =.016 for sex-lifetime smoking interaction). Consistent with the sex difference in smoking-related bladder cancer risk, the slopes of the linear regression lines of the 3- and 4-ABP--hemoglobin adducts by cigarettes per day were statistically significantly steeper in women than in men (P values for sex differences <.001 and.006, respectively). CONCLUSION: The risk of bladder cancer may be higher in women than in men who smoked comparable amounts of cigarettes.