Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study.

OBJECTIVE: To perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products. DESIGN: Nationwide cohort study. SETTING: Danish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses. PARTICIPANTS: 5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant's exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag. MAIN OUTCOME MEASURES: Association between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analyses, the risk of individual cancers was determined. RESULTS: The final cohort comprised 5150 people followed for a median of 4.6 years. In total, 3625 cohort participants contributed 7344 person years classified as unexposed to NDMA, and 3450 participants contributed 11 920 person years classified as ever exposed to NDMA. With 104 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P=0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null. CONCLUSIONS: The results do not imply a markedly increased short term overall risk of cancer in users of valsartan contaminated with NDMA. However, uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk.

Monitoring for Extra-Intestinal Cancers in IBD.

Multiple studies have demonstrated an increased risk for extra-intestinal cancers in inflammatory bowel disease (IBD) patients, mainly from treatment modalities. Prominent cancers that are related to IBD treatment include the following: lymphoproliferative disorders associated with thiopurine use, hepatosplenic T cell lymphoma primarily in younger male patients on thiopurines and anti-tumor necrosis factor (TNF) agents, non-melanoma skin cancers in patients treated with thiopurines and anti-TNF agents, and melanomas in patients who are on monotherapy with anti-TNF agents. In addition, women with IBD may have higher rates of cervical dysplasia and cervical cancer. The focus of this review is to provide a comprehensive overview on extra-intestinal cancers in IBD patients and how to monitor for these malignancies.

Oral contraceptive use and cancer: final report from the Oxford-Family Planning Association contraceptive study.

BACKGROUND: This analysis provides the final results on cancer incidence in relation to oral contraceptive (OC) use from the Oxford-Family Planning Association (Oxford-FPA) contraceptive study, which closed at the end of 2010. An additional 6 years of observation have been added since our last report and there has been an increase in the numbers of cancers of over 50% at seven of the sites considered. STUDY DESIGN: The Oxford-FPA study includes 17032 women aged 25-39 years recruited from 1968 to 1974 at contraceptive clinics in England and Scotland. These women were using OCs, a diaphragm or an intrauterine device. Information about cancer incidence among them has been collected from recruitment until closure of the study. RESULTS: OC use was not related to nonreproductive cancer. Breast cancer findings (1087 cases) were entirely negative; the rate ratio (RR) comparing ever users of OCs with never users was 1.0 [95% confidence interval (CI): 0.9-1.1]. Only two cases of cervical cancer have been added since our last report (total: 61 cases); the RR comparing ever use with never use is now 3.4 (95% CI: 1.6-8.9). The risk of this disease increases sharply with duration of OC use and declines steadily with interval since last OC use. OC use protects against both uterine body cancer (124 cases) and ovarian cancer (143 cases). The RRs comparing ever use with never use were 0.5 (95% CI: 0.3-0.7) and 0.5 (95% CI: 0.4-0.7), respectively. Protection against both these cancers increased with duration of OC use and waned with interval since last use, but an effect was still present 28 or more years after discontinuation. CONCLUSIONS: In our study, OC use had no effect on nonreproductive cancers or on breast cancer. The risk of cervical cancer was increased and that of uterine body cancer and ovarian cancer was decreased by OC use. All these effects increased with duration of use and declined with interval since last use. The beneficial effects of OC use on cancer outweighed the adverse effects. These findings should reassure older women who used OCs in the past.

Risk of cancer among workers exposed to trichloroethylene: analysis of three Nordic cohort studies.

BACKGROUND: Trichloroethylene (TCE) is a widely used chlorinated solvent with demonstrated carcinogenicity in animal assays. Some epidemiologic studies have reported increased risk of cancer of the kidney, cervix, liver and biliary passages, non-Hodgkin lymphoma, and esophageal adenocarcinoma. METHODS: We established a pooled cohort, including 5553 workers with individual documented exposure to TCE in Finland, Sweden, and Denmark. Study participants were monitored for the urinary TCE metabolite trichloroacetic acid from 1947 to 1989 and followed for cancer. Standardized incidence ratios (SIRs) were calculated based on cancer incidence rates in the three national populations. Cox proportionate hazard analyses were used for internal comparisons. Tests of statistical significance are two-sided. RESULTS: Overall, 997 cases of cancer (n = 683 in men; n = 314 in women) were identified during 154 778 person-years of follow-up. We observed statistically significant elevated standardized incidence ratios for primary liver cancer (1.93; 95% confidence interval [CI] = 1.19 to 2.95) and cervical cancer (2.31; 95% CI = 1.32 to 3.75). The standardized incidence ratio for kidney cancer was 1.01 (95% CI = 0.70 to 1.42) based on 32 cases; we did not observe a statistically significant increased risk of non-Hodgkin's lymphoma (SIR = 1.26; 95% CI = 0.89 to 1.73) or esophageal adenocarcinoma (SIR = 1.84; 95% CI = 0.65 to 4.65). Tobacco- and alcohol-associated cancers were not statistically significantly increased. CONCLUSIONS: Our results suggest TCE exposure is possibly associated with an increased risk for liver cancer. The relationship between TCE exposure and risks of cancers of low incidence and those with confounding by lifestyle and other factors not known in our cohort require further study.

Tumors and proliferative lesions in adult offspring after maternal exposure to methylarsonous acid during gestation in CD1 mice.

Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the biological methylation of inorganic arsenic, could be a key carcinogenic species. Thus, pregnant CD1 mice were provided drinking water containing MMA3+ at 0 (control), 12.5, or 25 parts per million (ppm) from gestational days 8 to 18. Tumors were assessed in groups of male or female (initial n = 25) offspring up to 2 years of age. In utero treatment had no effect on survival or body weights. Female offspring exhibited increases in total epithelial uterine tumors (control 0%; 12.5 ppm 26%; 25 ppm 30%), oviduct hyperplasia (control 4%; 12.5 ppm 35%; 25 ppm 43%), adrenal cortical adenoma at 25 ppm (control 0%; 12.5 ppm 9%; 25 ppm 26%), and total epithelial ovarian tumors (control 0%; 12.5 ppm 39%; 25 ppm 26%). Male offspring showed dose-related increases in hepatocellular carcinoma (control 0%; 12.5 ppm 12%; 25 ppm 22%), adrenal adenoma (control 0%; 12.5 ppm 28%; 25 ppm 17%), and lung adenocarcinoma (control 17%; 12.5 ppm 44%). Male offspring had unusual testicular lesions, including two rete testis carcinomas, two adenomas, and three interstitial cell tumors. Overall, maternal consumption of MMA3+ during pregnancy in CD1 mice produced some similar proliferative lesions as gestationally applied inorganic arsenic in the offspring during adulthood.

Long-lasting immunoprotective and therapeutic effects of a hyperstable E7 oligomer based vaccine in a murine human papillomavirus tumor model.

Cervical cancer and many other anogenital and oropharyngeal carcinomas are strongly associated with high-risk human papillomavirus (HPV) persistent infections. HPV E7 oncoprotein is the major viral transforming factor, emerging as a natural candidate for immunotherapy, since it is constitutively expressed in HPV-induced cancer cells. We have previously shown that E7 can self-assemble into soluble and homogeneous spherical oligomers, named E7 soluble oligomers (E7SOs). These are highly resistant to thermal denaturation, providing an additional advantage given the demand for highly stable vaccine formulations. Here, we present a new chemically stabilized form of the E7SOs (E7SOx) and analyzed its effect in a murine HPV-tumor model. Vaccination of female mice with low doses of E7SOx combined with a CpG-rich oligonucleotide (ODN) as adjuvant elicits a strong long-lasting protection against E7-expressing tumor cells, preventing tumor outgrowth after rechallenge 90-days later. Therapeutic experiments showed that E7SOx/ODN vaccination significantly delays tumor growth and extends the time of survival of the treated mice in a dose-dependent manner. These proof-of-principle preclinical experiments denote the potential applicability of our E7SOx-based vaccine to the treatment of cervical cancer and other mucosal HPV-related neoplastic lesions. In addition to thermal, chemical and proteolysis stability, the combined recombinant and chemical modification nature of the E7SOx vaccine candidate, results in low-cost, of particular interest in developing countries, where most of the cervical cancer cases occur and the most affected population is at reproductive age.

Toxicology and carcinogenesis studies of trimethylolpropane triacrylate (technical grade) (CASRN 15625-89-5) in F344/N rats and B6C3F1/N mice (dermal studies).

BACKGROUND: Trimethylolpropane triacrylate (TMPTA) is used as an ingredient in a wide variety of coatings, resins, photosensitive materials, and superabsorbent baby diapers. We studied the effects of TMPTA on male and female rats and mice to identify potential toxic or cancer-related hazards. METHODS: We applied solutions containing TMPTA in acetone on the backs of male and female rats and mice. Groups of 50 male and female rats and mice received 0.3, 1, or 3 milligrams of TMPTA per kilogram of body weight five days per week for two years. Groups of animals receiving acetone alone served as the control groups. At the end of the study, tissues from more than 40 sites were examined for every animal. RESULTS: Survival and body weights of all groups of exposed animals were similar to the control groups. Epidermal hyperplasia was observed in the skin at the site where the chemical was applied in all groups of animals receiving 1 mg/kg or more. Hyperkeratosis at the site of application was also increased in rats receiving TMPTA, and chronic inflammation was also seen in the skin of male and female mice receiving TMPTA. Malignant mesotheliomas were seen in a few male rats exposed to TMPTA. Two different rare forms of liver cancer (hepatoblastoma and hepatocholangiocarcinoma) were observed in some of the female mice exposed to TMPTA, and tumors of the uterus (stromal polyp or stromal sarcoma) also occurred in some exposed female mice. CONCLUSIONS: We conclude that exposure to TMPTA caused rare cancers of the liver and tumors of the uterus in female mice and may have been related to the occurrence of malignant mesothelioma in male rats. No occurrences of cancer were associated with exposure to TMPTA in female rats or male mice. Skin lesions at the site of application, including hyperplasia in rats and mice, hyperkeratosis in rats, and inflammation in mice occurred in all animal groups exposed to higher concentrations of TMPTA.

High micronucleus frequency in peripheral blood lymphocytes of untreated cancer patients irrespective of gender, smoking and cancer sites.

Chromosomal instability could be one of primary causes for malignant cell transformation. The objective of the present study was to evaluate the spontaneous genetic damages in circulated lymphocytes of newly diagnosed cancer patients by using cytokinesis-block micronucleus (CBMN) assay, with respect to the factors that might affect micronucleus frequency (i.e. age, gender, smoking habits and cancer sites). Micronuclei (MN) are small nuclei that are originated from chromosome fragments or whole chromosomes. The analyzed samples included 44 untreated cancer patients (19 females and 25 males with mean age of 60.89 years) with different cancer sites (12 patients with breast cancer, 5 with uterine cancer and 27 with cancer of pharynx). Control group included 40 healthy donors (28 females and 12 males with mean age of 43.95 years). The mean baseline MN frequency was significantly higher (p < 0.001) in cancer patients (15.18 +/- 5.05 MN/1000 BN cells ranging from 4 to 27) than the baseline frequency in healthy controls (6.45 +/- 2.75 MN/1000 BN cells, ranging from 1 to 11). There was no gender difference in baseline MN frequency in cancer patients and healthy controls. Moreover, the MN frequency did not significantly differ among cancer sites, and between smokers and non-smokers in both patient and control samples. In conclusion, untreated cancer patients may be associated with an increase of chromosomal instability in peripheral blood lymphocytes, irrespective of gender, cigarette smoking and cancer sites.

Pharmacology and clinical applications of selective estrogen receptor modulators.

Compounds that can be described as selective estrogen receptor modulators (SERMs) have expanded dramatically over the past two decades. The ability of SERMs to act as estrogens in certain tissues while remaining inert or acting as an anti-estrogen in other tissues has opened up opportunities for treating specific estrogen-modulated diseases without accepting the risk of systemic estrogen activity. SERM development has resulted in significant therapeutic advances for breast cancer, osteoporosis and potentially other diseases associated with the menopause. After the publication of the Women's Health Initiative, interest in compound selectivity that reduces menopausal symptoms while protecting bone, breast, uterus and the heart has increased. Future SERMs may also have a therapeutic profile that can be tailored to specific patient populations, including men. This review paper summarizes the characteristics of different SERMs from various pharmacological categories and the feasibility and scope of their use for a large range of disease/health conditions.

[Relevant publications in ambulatory general internal medicine in 2007]. / Médecine interne générate ambulatoire: quelques enseignements de la littérature.

Screening procedures for genital Chlamydia infection, cancer risks linked to oral contraceptives, indications and efficacy of HPV vaccination, and diagnostic tools for celiac disease in adults; these are just a few of the general practice themes that were reviewed and analysed in 2007 by residents and chief residents at the Community medicine and primary care Service of the Geneva University Hospitals. These commented summaries, intended for all our colleagues, constitute Geneva's contribution to the literature data base initiated in 2005 by chief residents in Lausanne.

Analysis of chloroethane toxicity and carcinogenicity including a comparison with bromoethane.

Chloroethane (CE) gas carcinogenicity is analyzed and determined from a National Toxicology Program (NTP) bioassay where an inhalation concentration of 15,000 ppm CE gas in air produced the highest incidence of an uncommon-to-rare tumor ever observed by the NTP. Persistently inhaled CE produces endometrial cancers in female mice. The first-tumor-corrected uterine endometrial incidence (I) in B6C3F1 mice is 90%, but no significant tumors occurred in F344 rats. The endometrial cancers dispersed by 1) migrating locally to the adjacent myometrium, 2) then migrating to the bloodstream by intravasation, 3) entering 17 distal organs by extravasation and adapting to the new tissue environment. Distal cancers retained sufficient endometrial cell features to be recognized at each metastatic site. CE produced one of the highest metastasis rates ever observed by NTP of 79%. Comparing CE with bromoethane (BE), a structural analogue, it was found that BE too produced rare murine endometrial cancers yielding the second highest NTP incidence rate of I = 58% with a similar high malignancy rate of 56%. Because of the historical rarity of endometrial tumors in the B6C3F1 mouse, both of these SAR haloethanes seem to be evoking a strong, related carcinogenic potential in B6C3F1 mice, but not in F344 rats. The question of whether humans are similar to mice or to rats is addressed here and in Gargas, et al., 2008. The powerful carcinogenesis caused by these halohydrocarbons may have been caused by excessive and metabolically unresolved acetaldehyde (AC) which is directly generated by Cyp2E1 in the oxidative elimination of CE. With >95% AC metabolic production, as predicted from pharmacokinetic (PK) studies depending on CE exposure, AC is the main elimination intermediate. AC is a known animal carcinogen and a strongly suspected human carcinogen. Also, CE causes incipient decreases of tissue essential glutathione pools [GSH] by Phase II conjugation metabolic elimination of CE (and BE), by glutantione transferase (GST), in most organs (except brain) exposed to high circulating CE and it metabolites. In three laboratories, an excessive stress reaction of hyperkinesis was observed only during 15,000 ppm gas exposure but not when the exposure ceased or when exposure was presented at 150 ppm. Test rodents other than the female mice did not exhibit a pattern of visible stress nor did they have a carcinogenic response to CE gas. Unremitting stress has been documented to contribute a feedback to the hypothalamus which stimulates the hypothalamic-pituitary-axis (HPA), which in turn, induces the adrenal glands. Because estrus and estrogen and progesterone levels were unaltered by CE gas, the adrenal over stimulation, causing high steroid output, may be the penultimate step in this extraordinary carcinogenic response. High adrenal production of corticosteroids could adversely promote endometrial cells to cancers in mice - a mechanism that has already been observed in humans.

A phase I trial of BMS-247550 (NSC# 710428) and gemcitabine in patients with advanced solid tumors.

The purpose of this study is to establish the maximum tolerated dose and define the dose-limiting toxicity of the investigational epothilone BMS-247550 in combination with fixed dose-rate gemcitabine. Patients with advanced, recurrent solid tumors who had received or=7 days occurred in one of six patients. Two of three patients in cohort 2 (gemcitabine 900 mg/m2 plus BMS-247550 30 mg/m2) had dose-limiting toxicities of grade 4 neutropenia. An additional three patients were treated at dose level 1 with no additional dose-limiting toxicities observed. At an intermediate dose level (gemcitabine 750 mg/m2 plus BMS-247550 30 mg/m2), two of six patients experienced a dose-limiting toxicity (febrile neutropenia and grade 3 hypophosphatemia in 1, grade 3 hypophosphatemia and grade 3 hyponatremia in (1), and five of six patients experienced dose delays. In the final cohort (gemcitabine 750 mg/m2 plus BMS-247550 25 mg/m2), two of two patients experienced a dose-limiting toxicity. Treatment-related toxicities included neutropenia, thrombocytopenia, neutropenic fever, hypophosphatemia, and hyponatremia. Nine of 14 patients evaluable for response had stable disease. The maximum tolerated dose for this schedule is gemcitabine 900 mg/m2 over 90 min days 1 and 8 plus BMS-247550 20 mg/m2 on day 8. Attempts to increase the dose of BMS-247550 by decreasing the gemcitabine dose did not sufficiently ameliorate myelosuppression. Stable disease was observed in some patients with prior taxane exposure.

Adverse neoplastic and cardiovascular outcomes of HRT: the validity of the evidence.

The possibility that HRT may increase the risk of cancer, female cancers in particular, has been a general concern ever since HRT was first advocated in the mid-1950s. For cancer of the uterus that concern was vindicated when it was shown that unopposed estrogens greatly increase the risk. However, because HRT is undoubtedly effective in relieving menopausal symptoms, and because it was thought that HRT may reduce the risk of coronary heart disease, the use of estrogens in combination with progestins soon supplanted unopposed estrogen use (if less so among women who had undergone hysterectomies), in the belief, soon confirmed by epidemiological evidence, that combined therapy probably eliminates any increase in the risk of uterine cancer, or perhaps even reduces it.

Association between fertility drugs and gynecologic cancers, breast cancer, and childhood cancers.

Ovulation-inducing drugs have been widely used for various types of infertility since the beginning of 1960s and their use increases day by day parallel to the success achieved in fertility treatment. However, the researches performed in the last two decades have begun to discuss about the safety of these drugs and the risks associated with their use. Especially, the potential neoplastic effects of these drugs are increasingly questioned. The studies have discussed whether there is an association between the exposure to ovulation-inducing drugs and the incidence of various cancers. Moreover, several studies have been performed to reveal whether there is an increased risk of childhood cancers in children conceived after fertility treatment. The point we reached through the available data is that the risk of breast, uterine and invasive ovarian cancers is not increased, but the risk of borderline ovarian tumors might increase after such a therapy. The risk of cancer has been found similar for children conceived after fertility treatment and those conceived naturally. It should also be kept in mind that cancers are overdiagnosed in infertile women population because of the close medical surveillance, which may also contribute to the early detection of cancers. Although it is still early to state the last words on this topic, the possible association should be addressed when obtaining an informed consent before starting treatment.

Steroids as procarcinogenic agents.

Although hormones produced in the body are normally considered to be beneficial in such matters as life, male and female development, fertility, and blood pressure regulation, these same compounds can act in some circumstances as carcinogens or carcinogen facilitators, In some such cases increased amounts of the hormone or changes in the formation of its metabolites might be responsible. In other cases the timing of hormone release plays a critical role. In some cases the hormone acts independently, while in others two or more compounds act in concert to promote cancer. The various compounds will be discussed separately, since they usually cause different kinds of cancer. Of the various hormones produced in the body, only aldosterone does not cause any cancers, although excess aldosterone can cause Conn's syndrome, which may be detected by the resultant hypertension.