Type of cigarettes and cancers of the upper digestive and respiratory tract

The relationship between type of cigarettes smoked and the risk of cancer of upper digestive and respiratory sites was investigated in a case-control study conducted in Northern Italy on 291 males with cancer of the oral cavity or pharynx, 288 with cancer of the esophagus, 162 with cancer of the larynx, and 1,272 control subjects in hospital for acute conditions unrelated to tobacco or alcohol consumption. Using a distinction based on tar-yield or the brand smoked for the longest time (<22 mg, low to medium tar; 22 mg, high tar), the multivariate relative risks among ever-smokers were 8.5 for low/medium and 16.4 for high tar cigarettes for oral and pharyngeal neoplasms, 3.3 and 7.8 for esophageal, and 4.8 and 7.1 for laryngeal cancers. The differences according to type of cigarettes were similar in proportional terms, and hence larger in absolute terms, when analysis was restricted to current smokers only. Thus, these data provide further quantitative evidence on the importance of type of cigarette smoked on the risk of upper-digestive and respiratory tract cancers and have important public health implications.Drs La Vecchia, D'Avanzo and Negri are at the Istituto di Richerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy. Dr La Vecchia is also at the Institute of Social and Preventive Medicine, University of Lausanne, 1005 Lausanne, Switzerland. Drs Bidoli, Barra, Talamini and Franceschi are in the Aviano Cancer Center, 33081 Aviano, Prodenone, Italy. Reprint requests should be addressed to Dr La Vecchia at the Istituto di Ricerche Farnacologiche. This work was conducted within the framework of the National Research Council (CNR), Applied Projects Oncology (Contract No. 87.01544.44) and Risk Factors for Disease, with contributions from the Italian Association for Cancer Research and the Italian League against Tumours, Milan.     

A case-control study of risk factor for renal cell cancer in northern Italy

A hospital-based case-control study of renal cell cancer was conducted in northern Italy betwen 1986 and 1989, with 240 cases of renal cell cancer (150 males and 90 females), and 665 controls (445 males and 220 females) chosen on the basis of age, sex, and area of residence. No associations were found between renal cell cancer and: body mass index (BMI); number of cigarettes smoked; age at starting to smoke; years of smoking; consumption of wine, beer, spirits, coffee, decaffeinated coffee; tea; intake of animal protein, fruits, and vegetables; various resproductive factors; hormonal use; sexual habits; sexually transmitted diseases; or selected occupational exposures. The odds ratio (OR) was above unity in smokers (OR=1.34 for 15 cigarettes/day), but the trends in risk with dose or duration were not statistically significant. Significant positive associations were found between renal cell cancer and sources of fat intake, especially margarine (OR for highest vs lowest intake = 1.71), and oils (OR=1.89) whereas carrot intake showed a negative association (OR=0.62). Also, a history of nephrolithiasis and multiple episodes of cystitis showed weak positive associations (OR=2.00, 95 percent confidence interval (CI) 1.07–3.73; and OR=1.60, 95 percent CI 0.95–2.70, respectively).Address reprint requests to Dr Talamini. The work was conducted with the contribution of the Italian Association for Cancer Research, Milan, Italy and the CNR (Italian National Research Council) Applied Projects Oncology (Contract n. 85.02209.44).Drs Talamini, Barón, Barra, Bidoli, Serraino, and Franceschi are in the Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ. 33081 Aviano (PN) Italy. At the time of this work, Dr Barón was a visiting biostatistician from the Department of Preventive Medicine and Biometrics, University of Colorado, Health Science Center, CO, funded by the National Cancer Institute (US) and the Italian National Research Council. Dr Franceschi is also chief of the Hormones and Sexual Factors and Cancer Working Group of the European Organization for Cooperation in Cancer Prevention Studies, Bruxelles, Belgium. Drs La Vecchia and Negri are in the Mario Negri Institute for Pharmacological Research, Milan, Italy. Dr La Vecchia is also in the Institute of Social and preventive Medicine, University of Lausanne, Switzerland.     

Tissue inhibitor of metalloprotease (TIMP)‐1 and proliferative behaviour of clonal breast cancer cells

In the present paper, we have examined whether human tissue inhibitor of metalloprotease1 (hTIMP1) is able to exert a growth factorlike effect on two clonal cell lines (BC3A and BC61), isolated from a parental line of human breast carcinoma cells (8701BC), and endowed with different growth and invasive behaviour in vitro and in nude mouse. The data obtained indicate that only the more tumorigenic clonal cell line (BC61) is responsive to hTIMP1 treatment by increasing its proliferative rate in a dosedependent manner. It was also found that BC61 cells selectively express a transmembrane protein of about 80kDa able to bind hTIMP1 in vitro and in vivo with high affinity (K_d of 0.07 ± 0.004 nM), and that treatment of BC61 cells with a proliferationpromoting concentration of hTIMP1 is able to stimulate tyrosinetargeted phosphorylation. The cumulative results obtained strongly support the hypothesis that hTIMP1, classically regarded as a collagenase inhibitor, may be a crucial element of the extracellular signalling network during breast cancer development by controlling cell growth phenotype in autocrine and paracrine manner, and that intratumoural heterogeneity for the biological response to TIMP1 may exist within the composite cell population of the primary tumour site.     

Involvement of nuclear steroid/thyroid/retinoid receptors and of protein kinases in the regulation of growth and of c‐erbB and retinoic acid receptor expression in MCF‐7 breast cancer cells

Nuclear steroid/thyroid/retinoid receptors and cerbB membrane receptor tyrosine kinases control epithelial growth and differentiation. Retinoid receptors can dimerize with the vitamin D receptor, the glucocorticoid receptor or the thyroid receptor. Furthermore, multiple cerbB receptor dimers have been identified. It has been shown that some of these receptor pathways communicate with each other via crossconnected regulatory networks. Molecular interactions between retinoid receptors or estrogen receptors (ER) and cerbB2, and between ER and retinoic acid receptor(RAR) have been reported. Here, we demonstrate the effects of steroids/thyroids/retinoids and of activators of protein kinase A (forskolin, Forsk) and C (12Otetradecanoylphorbol13acetate, TPA), on growth and expression of cerbB and RARs in MCF7 breast cancer cells, which contain high levels of RAR and , and which express significant amounts of cerbB2 and 3. All transretinoic acid (tRA), the antiestrogen ICI 182 780 (ICI), Forsk and TPA reduced, whereas triiodothyronine and 17estradiol (E₂) stimulated cell growth. Flow cytometry revealed that tRA and E₂ reduced cerbB2 and 3, whereas tamoxifen, Forsk and TPA upregulatedcerbB2. cerbB3 was coregulated with cerbB2. Northern analysis demonstrated that RAR was downregulated by dexamethasone, ICI, and TPA, whereas vitamin D₃ and E₂ upregulated RAR. RAR expression was less responsive to such treatment, being reduced only by ICI and Forsk. These data indicate that nuclear receptor and protein kinase signaling communicate with each other and control the expression of RARs and cerbB receptors. Efficient growth control requires the coordinated interplay of both receptor systems.     

Blood vessel invasion as a predictor of long-term survival for Japanese patients with breast cancer

A wide range of frequencies has been reported for blood vessel invasion (BVI) among patients with breast cancer, however, the prognostic significance of BVI remains controversial. Three hundred ninety-eight Japanese patients with breast cancer, operated on during the period between 1971 and 1987, were studied. We investigated five factors, including BVI, lymph-node status (n), clinical tumor size (T), histological grade (HG), and tumor necrosis (TN), followed for a median of 10years. BVI was detected by hematoxylin and eosin (HE) staining and both factor VIII-related antigen and elastica van Gieson staining. BVI detected by HE staining alone was defined as BVIh. The subtypes of BVI were classified as follows: BVI e, BVI detected only by elastica van Gieson staining; BVI f, BVI detected only by factor VIII-related antigen staining; and BVI e/f, BVI detected by both factor VIII-related antigen and elastica van Gieson staining. BVI-positive tumors were defined as lesions showing BVI e, BVI f, or BVI e/f. BVI and BVIh were presented in 27.4%, 6.5% of all cases, respectively. The mean diameters of the calibers of BVI e, BVI f, and BVI e/f were 141.9±80.5m, 61.0±37.4m, 136.0±102.0m, respectively (P < 0.0001). Seventy-three patients (18.3%) had recurrence and 60 patients (15.1%) died of breast cancer. Univariate analysis showed that BVIh (P<0.0001), BVI (P<0.0001), n, T, and HG were significantly predictive of 20-year RFS and OS. Multivariate analysis showed that BVI (P<0.0001, P=0.0088, respectively), n, T, and HG were all significant and independent prognostic factors for RFS and OS. On the other hand, BVIh was an independent factor for RFS (P= 0.0475), but of borderline significance for OS (P= 0.0506). When stratified by BVI, BVI e, and BVI e/f were significantly predictive of 20-year RFS or OS (P>0.0001). We can confirm BVI, especially BVI e and BVI e/f, are significant independent prognostic factors associated with long-term survival in Japanese breast cancer patients.     

Tumor necrosis factor-alpha induces interleukin-6 production via extracellular-regulated kinase 1 activation in breast cancer cells

Interleukin-6 (IL-6) and interleukin-11 (IL-11) are frequently produced by breast cancer cells. These interleukins promote osteoclast formation and may mediate osteolysis at the site of breast cancer bone metastases. Transforming growth factor- (TGF-), tumor necrosis factor- (TNF-) and interleukin-1 (IL-1) up-regulate IL-6 and IL-11 production in a cytokine-dependent fashion in breast cancer cells, but very little is known about their intracellular signaling pathways in breast cancer cells. To study TGF-, TNF- and IL-1 regulation of IL-6 and IL-11 production in human MDA-MB-231 breast cancer cells, we established single cell clones stably expressing dominant negative (DN) forms of the mitogen-activated protein kinases p38 (p38/AF) or ERK1 (ERK1K71R). We show here, that while basal, TGF- and IL-1 induced IL-6 production was similar in parental cells and in pcDNA3 control, ERK1K71R and p38/AF clones, TNF- induced IL-6 production was blunted in the ERK1K71R clones. TGF- and IL-1, but not TNF-, induced IL-11 production in parental MDA-MB-231 cells. Similar findings were detected in clones stably expressing p38/AF and ERK1K71R, which did not change basal IL-11 production either. In conclusion, TNF- induced IL-6 production is mediated via ERK1 activation in MDA-MB-231 cells. These observations may be helpful in designing new anti-osteolytic therapies.     

Occupation and soft-tissue sarcoma in northeastern Italy

The influence of occupation and exposure to different agents on the risk of developing soft-tissue sarcoma (STS) was assessed in a case-control study based on 93 cases of STS (53 men and 40 women) and 721 controls (371 men and 350 women), conducted in northeastern Italy. No risk elevation was found in subjects employed in agriculture (odds ratio [OR] for > 10 years = 0.8,95 percent confidence interval [CI]=0.4–1.5), nor in those who reported exposure to pesticides or herbicides (OR=0.4, CI=0.1–1.2). Similarly, neither occupation in the furniture, upholstery, and mechanics industries, nor exposure to livestock or meat processing, wood dust, metal dust, and dyes or paints were associated with STS risk. Workers who reported exposure to chemical agents or to benzene or other solvents for more than 10 years had, respectively, a 1.8-fold (CI=0.7–4.4) and a 2.2-fold (CI=0.9-5.5) higher risk of developing STS. Although the small number of STS cases limits the interpretation of the study results, these findings weigh against the hyphothesis that pesticides, herbicides, or other exposures related to agriculture, play an important role in the etiology of STS. The direct associations with exposure to chemical agents and benzene or other solvents, albeit not statistically significant, may provide a useful hint for future investigations.Drs Serraino and Franceschi are with the Epidemiology Unit, and Dr Carbone is with the Department of Pathology at the Aviano Cancer Center, Aviano, Italy. Dr La Vecchia is with the Mario Negri Institute for Pharmacological Research, Milan, Italy and the Institute of Social and Preventive Medicine, Lausanne, Switzerland. Address correspondence to Dr Serraino at the Epidemiology Unit, Aviano Cancer Center, Via Pedemontana Occ. 33081 Aviano (PN), Italy. The work was supported by the contribution of the Italian Association for Cancer Research, Milan, and the Italian National Research Council (CNR Applied Project Clinical Application of Oncological Research, Contract 87.01544.44).     

Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer

Fresh organically grown pomegranates (Punica granatum L.) of the Wonderful cultivar were processed into three components: fermented juice, aqueous pericarp extract and cold-pressed or supercritical CO₂-extracted seed oil. Exposure to additional solvents yielded polyphenol-rich fractions (polyphenols) from each of the three components. Their actions, and of the crude whole oil and crude fermented and unfermented juice concentrate, were assessed in vitro for possible chemopreventive or adjuvant therapeutic potential in human breast cancer. The ability to effect a blockade of endogenous active estrogen biosynthesis was shown by polyphenols from fermented juice, pericarp, and oil, which inhibited aromatase activity by 60–80%. Fermented juice and pericarp polyphenols, and whole seed oil, inhibited 17--hydroxysteroid dehydrogenase Type 1 from 34 to 79%, at concentrations ranging from 100 to 1,000g/ml according to seed oilfermented juice polyphenols>pericarp polyphenols. In a yeast estrogen screen (YES) lyophilized fresh pomegranate juice effected a 55% inhibition of the estrogenic activity of 17--estradiol; whereas the lyophilized juice by itself displayed only minimal estrogenic action. Inhibition of cell lines by fermented juice and pericarp polyphenols was according to estrogen-dependent (MCF-7)estrogen- independent (MB-MDA-231)>normal human breast epithelial cells (MCF-10A). In both MCF-7 and MB-MDA-231 cells, fermented pomegranate juice polyphenols consistently showed about twice the anti-proliferative effect as fresh pomegranate juice polyphenols. Pomegranate seed oil effected 90% inhibition of proliferation of MCF-7 at 100g/ml medium, 75% inhibition of invasion of MCF-7 across a Matrigel membrane at 10g/ml, and 54% apoptosis in MDA-MB-435 estrogen receptor negative metastatic human breast cancer cells at 50g/ml. In a %% murine mammary gland organ culture, fermented juice polyphenols effected 47% inhibition of cancerous lesion formation induced by the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). The findings suggest that clinical trials to further assess chemopreventive and adjuvant therapeutic applications of pomegranate in human breast cancer may be warranted.     

Correlation of Fcγ receptors on peripheral blood mononuclear cells and survival in patients with metastatic breast cancer

Summary Patients with carcinomas have elevated levels of Fc receptors for IgG (FcR) on their peripheral blood mononuclear cells (PBMC). The purpose of the present study was to determine whether there is a correlation between FcR levels on PBMC and survival in patients with metastatic breast cancer. Binding assays were performed on PBMC using¹²⁵I-labeled fibrinogen complexed with rabbit IgG (or as a control F(ab)₂) anti-human fibrinogen. Twenty-two metastatic breast cancer patients had significantly (p<0.001) elevated FcR levels as compared to either 22 breast cancer patients receiving adjuvant chemotherapy following mastectomy without clinical evidence of tumor, or to 34 non-malignant controls. Significantly more metastatic patients with elevated FcR levels died at 6 months (p<0.001) as compared to those with low levels. A direct correlation between FcR levels and hazard probability was found (correlation coefficient = 0.3321, p<0.005). These results raise the possibility that FcR levels on PMBC from metastatic breast cancer patients may be clinically useful as a prognostic marker of disease activity.     

Alcohol consumption and risk of breast cancer: a cohort study

Objectives: To study the association between alcohol consumption and breast cancer risk. Methods: A case–cohort analysis was undertaken within the cohort of 56,837 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40–59 at recruitment.) The cohort was recruited between 1980 and 1985, and during follow-up to the end of 1993 a total of 1469 women in the dietary cohort were diagnosed with biopsy-confirmed incident breast cancer. For comparative purposes a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons the analyses were based on 1336 cases and 5238 noncases. Results: When compared to nondrinkers the adjusted incidence rate ratios (95% confidence intervals) for those consuming>0 and 10g of alcohol/day, >10 and 20g/day, >20 and thinsp;30g/day, >30 and 40g/day, >40 and 50g/day, and >50g/day were 1.01 (0.84–1.22), 1.16 (0.91–1.47), 1.27 (0.91–1.78), 0.77 (0.51–1.16), 1.00 (0.57–1.75), and 1.70 (0.97–2.98), respectively; the associated p value for the test for trend was 0.351. Similar findings were obtained when analyses were conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, for screen-detected and interval-detected breast cancer, and by levels of other breast cancer risk factors. Conclusions: The results of this study suggest that alcohol consumption might be associated with increased risk of breast cancer at relatively high levels of intake.     

Immunologic response to cryoablation of breast cancer

Summary Purpose.With improvements in breast imaging and image-guided interventions, there is interest in ablative techniques for breast cancer. Cryosurgery initiates inflammation and leaves tumor-specific antigens intact, which may induce an anti-tumor immune response. To help define the mechanisms involved in the cryoimmunologic response, we compared cryosurgery to surgery in a murine model of breast cancer. Experimental designBALB/c mice with MT-901 tumors underwent cryoablation or resection. Mice successfully treated were re-challenged with MT-901 or RENCA. Serum cytokine levels were analyzed by ELISA. Tumor draining lymph nodes (TDLN) and spleens were harvested, lymphocytes were activated and assessed for a specific anti-tumor response by both an interferon- (IFN) release assay and ELISPOT. NK cell activity was assessed by cytotoxicity against YAC-1, an NK-susceptible cell line. Results.After re-challenge, tumors developed in 86% of mice treated by surgical excision compared to 16% of mice treated by cryosurgery (p=0.025). Cryoablation of MT-901 had no effect on re-challenge with RENCA. Cryoablation led to significantly higher levels of interleukin (IL)-12 (383.6pg/ml±32.8 versus 251.6±16.5, p=0.025) and IFN- (1564pg/ml±49 versus 1244pg/ml±101, p=0.009), but no changes in IL-4 or IL-10. Tumor-specific T-cell responses were evident after cryosurgery in lymphocytes from TDLN but not from spleen. Cryoablation also increased NK activity compared to surgery (24.5%±17.3 versus 16.5%±5.9, p<0.001). Conclusion.Cryoablation results in the induction of both a tumor-specific T-cell response in the TDLN and increased systemic NK cell activity, which correlates with rejection of tumors upon re-challenge.     

Alcohol and Breast Cancer Mortality in a Cohort Study

Available epidemiological evidence indicates that alcohol intake is associated with a higher risk of developing breast cancer. Plausible biological pathways include its effect on levels of estrogens, cell membrane integrity and cell-to-cell communication, inhibition of DNA repair, and congener effect. The present study evaluated the impact of alcohol on mortality from breast cancer, an area with relatively few studies in the literature. The subjects were participants in a Canadian prospective cohort study, the National Breast Screening Study (NBSS). Women were enrolled in the cohort from 1980 to 1985 to evaluate the efficacy of mammographic screening. Information on usual diet and alcohol intake at enrolment and other epidemiological variables was collected by means of a mailed, self-administered questionnaire. Mortality from breast cancer during follow- up to 31 December, 1993 was ascertained by record linkage to the Canadian Mortality Data Base maintained by Statistics Canada. During the follow-up period of 1980–1993 (average 10.3 years), 223 deaths from breast cancer were identified for this analysis. The hazard ratios for the risk of death from breast cancer increased with intakes of total alcohol of 10–20g/day (1.039, 1.009–1.071) and >20g/day (1.063, 1.029–1.098). This increase was contributed largely by the intake of wine, a 15% increase in risk at intakes higher than 10g/day of alcohol from wine. Alcohol from spirits was associated with a small decrease in risk of death (hazard ratio at 10g/day, 0.945, 0.915–0.976). The effect of alcohol from beer was not significant in the two categories studied. Although our results were statistically significant, the magnitude of the change in risk was small.     

Alcoholic beverage consumption and risk of breast cancer in Spain

The relation between alcoholic beverage consumption and risk of breast cancer was examined. We used data from a population-based, case-control study that included almost all incident cases occurring in five Spanish regions from February 1990 to July 1991. A total of 762 women between 18 and 75 years of age, with a histologically confirmed, first diagnosis of breast cancer, were compared with 988 control women. Alcoholic beverage intake was measured by an interviewer-administered, semiquantitative food-frequency questionnaire. We used nondrinkers as the reference category and divided the remainder into four categories according to alcohol intake. The multiple logistic analyses included not only alcohol intake but also possible confounding factors such as total caloric intake, age, socioeconomic status, and reproductive and medical histories. Even at moderate levels of alcohol intake (less than 8 g/day), a 50 percent increase in risk of breast cancer was found. The trend across categories of intake was statistically significant for wine and distilled drinks, as well as total alcohol intake. Consumption of 20 g or more of alcohol per day was associated with a 70 percent elevation in breast cancer risk compared with that of nondrinkers (adjusted relative risk (RR)=1.7,95 percent confidence interval = 1.3–2.3). Although the magnitude of the RR observed in our study was modest, our findings provide further support for a positive association between alcohol consumption and risk of breast cancer.This work was supported by Grant No. 89/0059 from the Spanish Fondo de Investigacion Sanitaria. Dr Martin-Moreno is indebted to the Italian Fondazione per la Formazione Oncologica for awarding him a Paolo Baffi Fellowship in 1991–1992, and to the Spanish Fundacion Mapfre Medicina for a research fellowship award in 1991. Dr Gorgojo is a postdoctoral fellow of the Programa de Formación de Personal del Instituto de Salud Carlos III.     

Prevention of rat mammary carcinoma utilizing leuprolide as an equivalent to oophorectomy

A clinical trial is currently under way to examine the effectiveness of leuprolide as a breast cancer chemopreventive agent and contraceptive. This trial, as well as similar proposed studies, is based on the assumption that leuprolide is as effective as surgical castration in preventing the onset of mammary tumors; however, this has not been well documented in the DMBA animal model. We directly compared leuprolide and oophorectomy in this model and examined a combined therapy of leuprolide/bromocriptine. Twenty-seven day old female Sprague-Dawley rats were randomly allocated into one of eight groups. All rats received a 20-mg dose of DMBA at the age of 55 days. Group 1 (n=10), no treatment; Group 2 (n=9), leuprolide (100g/kg/day) for eight weeks beginning four weeks prior to DMBA; Group 3 (n=10), oophorectomy four weeks prior to DMBA with replacement estrogen beginning four weeks following DMBA. Estrogen replacement was achieved with a 0.05-mg estradiol tablet releasing 0.833g/day over a 60-day period. Group 4 (n=10), leuprolide (100g/kg/day) initiated two weeks prior to DMBA and continuing for two weeks following DMBA; Group 5 (n=9), oophorectomy two weeks prior to DMBA with 0.05mg of estradiol in depot form, releasing 0.833g/day, beginning four weeks following DMBA and continuing until week 16 of the study; Group 6 (n=10), leuprolide (100g/kg/day) beginning two weeks prior to DMBA and continuing for the duration of the experiment; Group 7 (n=10), leuprolide (100g/kg/day) for eight weeks beginning two weeks prior to DMBA; Group 8 (n=9), leuprolide (100g/kg/day) and bromocriptine (83g/day) for eight weeks beginning two weeks prior to DMBA. At nineteen weeks (15 weeks post DMBA), animals were sacrificed and autopsies performed. One hundred percent of untreated animals developed tumors. No animals undergoing oophorectomy four weeks prior to DMBA or receiving leuprolide four weeks prior to and simultaneously with DMBA developed tumors. In animals pretreated two weeks prior to DMBA with leuprolide or oophorectomy, each group had one animal with tumor development. No tumors developed in the animals receiving ongoing injections of leuprolide. However, one tumor developed in those receiving leuprolide for the first eight weeks beginning two weeks prior to DMBA administration. One animal receiving both leuprolide and bromocriptine developed one tumor. We conclude that chemical oophorectomy (with leuprolide) is as effective as surgical oophorectomy in inhibiting DMBA induced carcinogenesis.     

Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer

Purpose The study objectives were to define subcutaneous (s.c.) interferon gamma (IFN-) disposition in patients with gastrointestinal malignancies receiving 5-fluorouracil (5-FU) and leucovorin (LV) and to examine the relationship between IFN- exposures and Fas upregulation in vivo and in vitro.Methods Patients received IFN- (10, 25, 50, 75, and 100 g/m²) with LV and 5-FU, and serial samples were collected after the first dose. IFN- concentrations were measured by ELISA. A linear one-compartment model with a lag was fitted to the IFN- plasma concentration-time data. To examine the relationship between IFN- systemic exposure and biological activity in vivo, cell surface Fas upregulation was assessed in peripheral blood mononuclear cell (PBMC) subcompartments.Results The median (range) apparent IFN- clearance was 46 l/m² per hour (2.6–92 l/m² per hour). With increasing IFN- dosages, the area under the concentration-time curve (AUC₀) and C_max increased; however, significant interpatient variability was observed. IFN- AUC₀ and time above 33.3 pg/ml significantly correlated with Fas upregulation in several PBMC compartments, but dosage was significantly correlated with this pharmacodynamic marker only in CD4⁺ and CD56⁺ cells. In vitro studies in HT29 cells demonstrated that clinically relevant IFN- concentrations (1 to 10 U/ml for 6.5 h) with 5-FU/LV upregulated Fas expression 3.5-fold, similar to that in PBMC in vivo.Conclusions We characterized IFN- disposition and developed a limited sampling model for use in future pharmacokinetic studies. Our results showed that IFN- upregulates Fas in PBMC in vivo and in HT29 cells in vitro at tolerable, clinically relevant exposures and that monitoring IFN- pharmacokinetics/pharmacodynamics may be warranted in IFN- clinical use.This work was supported in part by US Public Health Service awards CA23099, CA32613 and CA23944, the Wings Cancer Foundation, and American Lebanese Syrian Associated Charities (ALSAC).     

Association between endometrial cancer and tamoxifen treatment of breast cancer

A retrospective cohortstudy in 4109 breast cancer patients was undertaken to determine how tamoxifen affected the risk of endometrial cancer. Data on 1701 tamoxifentreated women were analysed. Two thousand four hundred and eight nontamoxifen users served as control group. The occurrence of new primary uterine cancers was assessed by computerized linkage to the Austrian Cancer Registry. Twentyfive women who subsequently developed endometrial cancer were identified. Eight uterine cancers occurred in the tamoxifen group, whereas 17 uterine cancers were found in the control group. The estimate of the relative risk (RR) showed an increased risk to develop endometrial cancer for the tamoxifen group RR 1.136 (95% CI 0.71; 1.80). Analysis of relevant confounding variables did not show any differences in the two groups.In conclusion, this retrospective study demonstrated a nonsignificant increased risk of endometrial cancer in women receiving tamoxifen as treatment for breast cancer. However, the magnitude of RR and the absolute number of endometrial cancer cases in this long term observation demonstrate clearly that the clinical benefit of tamoxifen therapy greatly outweighs the risk.     

Inflammatory Breast Cancer Survival: The Role of Obesity and Menopausal Status at Diagnosis

No previous studies have evaluated the effect of body size and menopausal status at diagnosis on survival from inflammatory breast cancer (IBC). We evaluated whether obesity and menopausal status had an impact on IBC survival in a cohort of 177 female IBC patients seen from 1974 to 1993 at The University of Texas MD Anderson Cancer Center. Survival time was defined as time from diagnosis until death or censorship at last date of contact. We categorized women by body size by using the National Institutes of Health/National Heart, Lung, and Blood Institute's definitions of obesity as body mass index ((BMI)=weight in kg/(height in m)²)30, overweight as 25BMI <30kg/m², and normal/lean as BMI <25kg/m². Cox proportional hazards analysis, adjusting for axillary lymph node involvement and chemotherapy protocol, revealed a modifying effect of menopausal status at diagnosis on the association between obesity and IBC survival (P=0.02). Relative to postmenopausal women, premenopausal women had significantly worse survival (hazard ratio (HR)=1.51, 95% confidence interval (CI)=1.03–2.22). After stratifying by menopausal status, premenopausal obese women had non-significantly better survival than their leaner premenopausal counterparts (HR=0.63, 95% CI=0.34–1.15) while postmenopausal obese women had significantly worse survival than their leaner counterparts (HR=1.86, 95% CI=1.02–3.40). These findings suggest that factors associated with larger body size at diagnosis may contribute to shorter IBC survival among postmenopausal women but not premenopausal women, who were found to have poorer survival regardless of body size.     

Prognostic significance of acute presentation with emergency complications of gastric cancer

Background Although acute complications necessitating emergency hospital admission are well documented in patients with carcinoma of the colon, comparable data for patients with gastric carcinoma is thin. The aim of this study, therefore, was to examine the outcomes of patients presenting to hospital as acute admissions with emergency complications of previously undiagnosed gastric cancer.Methods Three hundred consecutive patients with gastric adenocarcinoma were studied prospectively, and subdivided into two groups according to whether the patients were referred as acute emergencies (n = 116) or as outpatients (n = 184).Resuslts The commonest emergency complications were: abdominal pain (57%), vomiting (41%), gastrointestinal bleeding (37%), dysphagia (26%), and a palpable mass (18%). Stages of disease were significantly more advanced in patients presenting acutely (I:II:III:IV = 7:11:27:71) compared with patients referred via outpatients (20:23:50:91, ² = 3.955; DF, 1; P = 0.047). R0 gastrectomy was significantly less likely after acute presentation (23 patients; 20%) compared with patients referred via outpatients (70 patients; 38%; ² = 11.037; DF, 1; P = 0.001). Cumulative 5-year survival for patients referred acutely was 9%, compared with 22% after outpatient referral (² = 9.11; DF, 1; P = 0.0025). Multivariate analysis revealed two factors to be significantly and independently associated with durations of survival: stage of disease (hazard ratio [HR], 1.742; 95% confidence interval [CI], 1.493–2.034; P = 0.0001) and presentation with acute complications (HR, 1.561; 95% CI, 1.151–2.117; P = 0.004).Conclusion Emergency complications of gastric cancer are a significant and independent prognostic marker of poor outcome.Presented at: British Society of Gastroenterology, Birmingham 2003, and 5th International Gastric Cancer Congress, Rome 2003.     

Adjuvant anthracycline therapy as a prognostic factor in metastatic breast cancer

Background. Prognostic factors in metastatic breast cancer continue to be identified. Previous adjuvant chemotherapy appeared to have poor prognosis in some studies but, despite this, the prior use of anthracyclines in the adjuvant setting has not been clearly established as an adverse prognostic factor once metastatic disease develops. Patients and methods. Patients (n=1,436) with stages I–IIIa breast cancer were surgically treated with/without radiotherapy and/or systemic adjuvant treatment. Of these, 297 patients who relapsed with metastatic disease constitute the sample population of this retrospective study. Survival, as a function of time since diagnosis of metastatic disease, was assessed in relation to the following factors: age, size of the primary tumor, grade, number of positive axillary nodes, type of surgery, type of adjuvant treatment administered, time to relapse, number of metastatic sites, presence of visceral metastases and type of treatment employed at the time of relapse. Results. In multivariable analysis three factors remained significant predictors of short survival time: more than 1 site of metastases (p=0.00003), shorter time to relapse (p=0.003) and the previous administration of anthracyclines as adjuvant therapy (p=0.005). Conclusions. The prior use of adjuvant anthracyclines, with other known clinical prognostic factors, confers a poorer outcome in metastatic disease, perhaps as a result of resistant clones selection or by induction of de novo resistance.     

Infertility and risk of fatal ovarian cancer in a prospective cohort of US women

Objectives: It is difficult to separate the possible role of fertility drugs from underlying infertility as risk factors for ovarian cancer. The present study examined the relationship between self-reported infertility and death from ovarian cancer among married women unlikely to have been exposured to fertility drugs.Methods: Women were selected for study from the 676,526 female participants in Cancer Prevention Study II (CPS-II). After twelve years of follow-up, 797 deaths from ovarian cancer were observed among women with no prior history of cancer or hysterectomy and 40 years of age or older in 1967 when ovulatory stimulants were approved in the United States. Cox proportional hazards modeling was used to compute rate ratios (RRs) and to adjust for other potential risk factors.Results: Overall, self-reported infertility was not significantly associated with ovarian cancer mortality (adjusted rate ratio (RR)=1.1, 95 percent confidence interval (CI)=0.9-1.3). Ovarian cancer death rates among nulligravid women with self-reported infertility, however, were 40 percent higher than for nulligravid women who never tried to become pregnant (RR=1.4, 95 percent CI=0.9-2.4). Multigravid women who reported infertility problems were not at increased risk.Conclusions: These results suggest that infertility itself, without concomitant exposure to fertility drugs, may increase risk of fatal ovarian cancer among nulligravid women.