Polymorphisms in the estrogen receptor alpha gene (ESR1), daily cycling estrogen and mammographic density phenotypes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown. METHODS: We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol. RESULTS: We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002-0.026), these associations were strongest in lean women (BMI, ≤23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3-6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025-0.079) that the level of 17ß-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype. CONCLUSION: Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.

Pre-diagnostic high-sensitive C-reactive protein and breast cancer risk, recurrence, and survival.

Inflammation may initiate and promote breast cancer development, and be associated with elevated circulating levels of inflammation markers. A total of eight 130 initially healthy women, participated in the population-based Tromsø study (1994-2008). Pre-diagnostic high-sensitivity C-reactive protein (hs-CRP) was assessed. During 14.6 years of follow-up, a total of 192 women developed invasive breast cancer. These cases were followed for additional 7.2 years. Detailed medical records were obtained. We observed an overall positive dose-response relationship between pre-diagnostic hs-CRP and breast cancer risk (hazard ratio (HR) = 1.06, 95 % CI 1.01-1.11). Postmenopausal women with above median levels of hs-CRP (>1.2 mg/l) had a 1.42 (95 % CI 1.01-2.00) higher breast cancer risk compared to postmenopausal women with hs-CRP below median. Postmenopausal women, who were hormone replacement therapy non-users, and were in the middle tertile (0.8-1.9 mg/l), or highest tertile of hs-CRP (>1.9 mg/l), had a 2.31 (95 % CI 1.31-4.03) and 2.08 (95 % CI 1.16-3.76) higher breast cancer risk, respectively, compared with women in the lowest tertile. For each unit increase in pre-diagnostic hs-CRP levels (mg/l), we observed an 18 % increase in disease-free interval (95 % CI 0.70-0.97), and a 22 % reduction in overall mortality (95 % CI 0.62-0.98). Our study supports a positive association between pre-diagnostic hs-CRP and breast cancer risk. In contrast, increased pre-diagnostic hs-CRP was associated with improved overall mortality, but our findings are based on a small sample size, and should be interpreted with caution.

Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies.

BACKGROUND: Positive association between obesity and survival after breast cancer was demonstrated in previous meta-analyses of published data, but only the results for the comparison of obese versus non-obese was summarised. METHODS: We systematically searched in MEDLINE and EMBASE for follow-up studies of breast cancer survivors with body mass index (BMI) before and after diagnosis, and total and cause-specific mortality until June 2013, as part of the World Cancer Research Fund Continuous Update Project. Random-effects meta-analyses were conducted to explore the magnitude and the shape of the associations. RESULTS: Eighty-two studies, including 213 075 breast cancer survivors with 41 477 deaths (23 182 from breast cancer) were identified. For BMI before diagnosis, compared with normal weight women, the summary relative risks (RRs) of total mortality were 1.41 [95% confidence interval (CI) 1.29-1.53] for obese (BMI >30.0), 1.07 (95 CI 1.02-1.12) for overweight (BMI 25.0-<30.0) and 1.10 (95% CI 0.92-1.31) for underweight (BMI <18.5) women. For obese women, the summary RRs were 1.75 (95% CI 1.26-2.41) for pre-menopausal and 1.34 (95% CI 1.18-1.53) for post-menopausal breast cancer. For each 5 kg/m(2) increment of BMI before, <12 months after, and ≥12 months after diagnosis, increased risks of 17%, 11%, and 8% for total mortality, and 18%, 14%, and 29% for breast cancer mortality were observed, respectively. CONCLUSIONS: Obesity is associated with poorer overall and breast cancer survival in pre- and post-menopausal breast cancer, regardless of when BMI is ascertained. Being overweight is also related to a higher risk of mortality. Randomised clinical trials are needed to test interventions for weight loss and maintenance on survival in women with breast cancer.

Effects of individual and combined dietary weight loss and exercise interventions in postmenopausal women on adiponectin and leptin levels.

BACKGROUND: Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. METHODS: Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay. RESULTS: Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, -40.1%, P < 0.0001; diet, -27.1%, P < 0.0001; exercise, -12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001). CONCLUSION: Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.

Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials.

BACKGROUND: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. PATIENTS AND METHODS: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m(2) and cisplatin 100 mg/m(2). Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. RESULTS: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. CONCLUSIONS: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments.

Ovarian hormones and reproductive risk factors for breast cancer in premenopausal women: the Norwegian EBBA-I study.

BACKGROUND: Ovarian hormones, parity and length of 'menarche-to-first birth' time interval are known risk factors for breast cancer, yet the associations between 17ß-estradiol, progesterone and these reproductive factors remain unclear. METHODS: A total of 204 women (25-35 years) who participated in the Norwegian EBBA-I study collected daily saliva samples for one complete menstrual cycle, and filled in a reproductive history questionnaire. Anthropometry was measured and saliva samples were analyzed for ovarian hormones. Associations between parity, the interval and ovarian hormones, and effects of hormone-related lifestyle factors were studied in linear regression models. RESULTS: Mean age was 30.7 years, and age of menarche 13.1 years. Parous women had on average 1.9 births, and age at first birth was 24.5 years. No association was observed between parity and ovarian steroids. In nulliparous women, higher waist circumference (≥ 77.75 cm) and longer oral contraceptive (OC) use (≥ 3 years) were associated with higher levels of 17ß-estradiol. Short (<10 years) versus long (>13.5 years) 'menarche-to-first birth' interval was associated with higher overall mean (P(trend) = 0.029), 47% higher maximum peak and 30% higher mid-cycle levels of 17ß-estradiol. We observed a 2.6% decrease in overall mean salivary 17ß-estradiol with each 1-year increase in the interval. CONCLUSIONS: Nulliparous women may be more susceptible to lifestyle factors, abdominal overweight and past OC use, influencing metabolic and hormonal profiles and thus breast cancer risk. Short time between 'menarche-to-first birth' is linked to higher ovarian hormone levels among regularly cycling women, suggesting that timing of first birth is related to fecundity.

Adiposity changes after a 1-year aerobic exercise intervention among postmenopausal women: a randomized controlled trial.

OBJECTIVE: We examined the effects of an aerobic exercise intervention on adiposity outcomes that may be involved in the association between physical activity and breast cancer risk. DESIGN: This study was a two-centre, two-armed, randomized controlled trial. The 1-year-long exercise intervention included 45 min of moderate-to-vigorous aerobic exercise five times per week, with at least three of the sessions being facility based. The control group was asked not to change their activity and both groups were asked not to change their diet. SUBJECTS: A total of 320 postmenopausal, sedentary, normal weight-to-obese women aged 50-74 years who were cancer-free, nondiabetic and nonhormone replacement therapy users were included in this study. MEASUREMENTS: Anthropometric measurements of height, weight and waist and hip circumferences; dual energy X-ray absorptiometry measurements of total body fat; and computerized tomography measurements of abdominal adiposity were carried out. RESULTS: Women in the exercise group exercised a mean of 3.6 days (s.d.=1.3) per week and 178.5 min (s.d.=76.1) per week. Changes in all measures of adiposity favored exercisers relative to controls (P<0.001). The mean difference between groups was: -1.8 kg for body weight; -2.0 kg for total body fat; -14.9 cm(2) for intra-abdominal fat area; and -24.1 cm(2) for subcutaneous abdominal fat area. A linear trend of greater body fat loss with increasing volume of exercise was also observed. CONCLUSION: A 1-year aerobic exercise program consistent with current public health guidelines resulted in reduced adiposity levels in previously sedentary postmenopausal women at higher risk of breast cancer.

Experience of the use of trabectedin (ET-743, Yondelis) in 21 patients with pre-treated advanced sarcoma from a single centre.

AIMS: Trabectedin (ET-743, Yondelis) is a marine-derived alkaloid that has two actions. It binds in the minor groove of DNA resulting in a conformational change; thus potentially altering interactions with transcription factors and other DNA binding proteins and it also interacts with the transcription-coupled nucleotide excision repair machinery to induce lethal double-stranded DNA breaks. In recent phase II trials it has shown considerable activity in the treatment of sarcomas. Here the use of trabectedin in patients with advanced refractory sarcoma from a single institution is presented. MATERIALS AND METHODS: Twenty-one patients with advanced refractory sarcoma from a single UK centre were treated with trabectedin on a named patient compassionate basis programme. All patients had received prior treatment with an anthracycline, and 95% had received ifosfamide. RESULTS: The patients received a median of four cycles of treatment. Objective partial responses were seen in three patients (14%) and a further eight patients (38%) achieved durable stable disease for a median duration of 4.5 months. The estimated 3- and 6-month progression-free survival was 58.8 and 17.6%, respectively. Six patients experienced early disease progression, and four patients died while on treatment. One death was due to treatment-related toxicity. Overall the drug was relatively well tolerated, with hepatic and haematological toxicities most commonly encountered. Both necessitated delays and/or dose reductions in a proportion of patients. Other significant toxicities were nausea, vomiting and asthenia. CONCLUSION: The disease responses and durable nature of disease stabilisation seen in a proportion of our patients support the continued investigational use of this drug in the treatment of advanced soft tissue sarcomas.

The ADRB3 Trp64Arg variant and obesity in African-American breast cancer cases.

OBJECTIVE: To determine if a missense change at codon 64 of ADRB3 (Trp64Arg), a candidate obesity gene, is associated with obesity and levels of subcutaneous or visceral fat in African-American breast cancer cases. Several observational studies have found that women, who are overweight or obese at the time of diagnosis, as well as those who gain weight after diagnosis, are at greater risk for breast cancer recurrence and death than non-overweight women. DESIGN: Prospective cohort of breast cancer cases. SUBJECTS: 219 African-American breast cancer patients participating in the Los Angeles component of the Health, Eating, Activity and Lifestyle Study. MEASURES: ADRB3 Trp64Arg genotype, measures of weight including body mass index (BMI), weight gain (weight 5 years before diagnosis compared with weight at 30 months after diagnosis), obesity (BMI> or =30 kg/m(2)), waist/hip circumference and visceral or subcutaneous fat were determined by magnetic resonance imaging. RESULTS: African-American women who were homozygous for the ADRB3 wild-type allele had significantly higher mean visceral fat levels than women who carried the variant (P=0.04), and were significantly more likely to be obese (odd ratios (OR)=2.1, 95% confidence interval (CI)=1.1-4.2). The association with obesity was most pronounced among women who were premenopausal (OR=4.8, 95% CI=1.3-18), who received chemotherapy for their breast cancer (OR=6.1, 95% CI=1.8-20), or who were not physically active (OR=3.9, 95% CI=1.5-9.7). CONCLUSION: The wild-type allele of the ADRB3 missense change was associated with measures of obesity in our sample of African-American women. The association was modified by menopausal status, history of chemotherapy and modest levels of physical activity. These results will need to be confirmed in an independent sample.

Sleep, ghrelin, leptin and changes in body weight during a 1-year moderate-intensity physical activity intervention.

OBJECTIVE: To investigate cross-sectional and longitudinal relationships among exercise, sleep, ghrelin and leptin. METHODS: We randomly assigned 173 post-menopausal sedentary overweight (body mass index >or=24.0 kg/m(2) and >33% body fat) women aged 50-75 years living in western Washington State to either a facility- and home-based moderate-intensity physical activity intervention or a stretching control group. Fasting plasma ghrelin, leptin, measured height, weight and self-reported sleep were assessed at baseline and 12 months. RESULTS: There were no consistent cross-sectional patterns between self-reported sleep measures and ghrelin or leptin at baseline. The weight loss differences between exercisers and stretchers were greater for those who slept less at follow-up than at baseline compared to those whose sleep duration did not change (-3.2 kg, 95% confidence interval (CI) -5.8, -0.5). Improvements in sleep quality were associated with significantly greater differences between exercisers and stretchers for ghrelin increases (improved vs same sleep quality: +115 pg/ml, 95% CI +25, +206) and leptin decreases (improved vs worsened sleep quality: -5.7 ng/ml, 95% CI -9.5, -1.5). CONCLUSION: There was only limited evidence that changes in sleep duration or quality modified exercise-induced changes in weight, ghrelin or leptin. Moreover, the observed differences were not in the directions hypothesized. Future longitudinal studies including population-based samples using objective measures of sleep and long follow-up may help to clarify these relationships.

High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours.

BACKGROUND: The outcome for patients with recurrent or progressive Ewing's sarcoma family of tumours (ESFT) is poor. High dose therapy (HDT) has been used for a number of years in an attempt to improve survival; however, evidence for the efficacy of this treatment remains limited. PATIENTS AND METHODS: Between 1992 and 2004, 33 patients with recurrent or progressive ESFT were treated with HDT with bone marrow (n=2), peripheral blood stem cell (n=30), or bone marrow and peripheral blood stem cell support (n=1), at a single institution. HDT was with busulphan and melphalan in 22 patients; melphalan and etoposide in seven patients, three with total body irradiation (TBI); melphalan in three patients (2 with TBI), and busulphan and cyclophosphamide in one patient. RESULTS: The 2 and 5 year event free survival was 42.5% (95% CI, 26-59%) and 38.2% (95% CI, 21-55%) respectively. There was one treatment related death from colitis, and grade 4 infection was observed in two patients. CONCLUSIONS: Long-term survival can be attained in patients with recurrent or refractory ESFT treated with HDT. However, this treatment is associated with severe toxicity. A need remains for prospective randomised clinical trials of HDT in this group of patients.

Association of body composition and weight history with breast cancer prognostic markers: divergent pattern for Hispanic and non-Hispanic White women.

Body composition and weight gain are breast cancer risk factors that may influence prognosis. The Health, Eating, Activity, and Lifestyle Study was designed to evaluate the relations of body composition, weight history, hormones, and lifestyle factors to prognosis for women with breast cancer. In the cross-sectional analysis of this cohort study specific to 150 Hispanic and 466 non-Hispanic White women in New Mexico diagnosed between 1996 and 1999, the authors hypothesized that obesity measures are associated with baseline prognostic markers and that these associations are modified by ethnicity. Ethnic-stratified multiple logistic regression analyses showed divergent results for a tumor size of 1.0 cm or more and, to a lesser extent, positive lymph node status. Among Hispanics, the highest quartile for body mass index (29.5 vs. <22.5 kg/m2: odds ratio (OR) = 0.16, 95% confidence interval (CI): 0.03, 0.84) and for waist circumference (> or =95.0 vs. <78.5 cm: OR = 0.09, 95% CI: 0.01, 0.78) was significantly associated with a reduced tumor size. In contrast, for overweight and obese non-Hispanic White women, there was an increased association with obesity-related measures, particularly striking for the highest quartile of waist circumference (OR = 2.76, 95% CI: 1.45, 5.26). These findings suggest that Hispanics may have a different breast cancer phenotype than non-Hispanic Whites, which associates differently with body composition and weight history.

Issues surrounding the participation of adolescents with cancer in clinical trials in the UK.

Cancer in adolescents is rare with approximately 600 adolescents being diagnosed with cancer in the UK each year. With such small numbers, clinical trials are imperative if improvements in treatment and prognosis are to be achieved. However, the availability of such trials and the issues surrounding clinical trials in adolescents with cancer has rarely been reviewed. There are a number of issues regarding clinical trials that are particularly pertinent to this group. Primarily, despite evidence that adolescents with cancer fare better when treated on clinical trials, it would appear that adolescents do not have equal access to trials because of the fragmentation of adolescent cancer care between adult and paediatric oncology. For those who are treated within clinical trials, issues of informed consent need to be addressed, such as who should give consent and the provision of age-appropriate information. Finally, it has been suggested that adolescents are less compliant with treatment than both their adult and paediatric counterparts. As many adolescents with cancer can now be cured, this should be an area of great concern and more research is needed to ascertain the full extent of the problem and ways of overcoming it. The availability of clinical trials, along with the issues surrounding clinical trials in adolescents, need to be addressed if continued improvements in the outcome of this group of patients are to be seen.

Single center experience of a new intensive induction therapy for ewing's family of tumors: feasibility, toxicity, and stem cell mobilization properties.

PURPOSE: To examine the feasibility, tolerability, and toxicity of an intensified induction regimen (vincristine, ifosfamide, doxorubicin, and etoposide [VIDE]) in patients with newly diagnosed Ewing's family of tumors (EFT); to assess ability to maintain dose-intensity, and predictability of peripheral-blood stem cell mobilization. PATIENTS AND METHODS: Thirty patients were treated with vincristine 1.4 mg/m2 (maximum 2 mg) on day 1, doxorubicin 20 mg/m2, ifosfamide 3 g/m2 plus mesna and etoposide 150 mg/m2 on days 1 to 3. Cycles were given every 21 days for up to six cycles. RESULTS: One-hundred and seventy cycles of VIDE were given. The median treatment interval was 21 days (21 to 42) and nadir count: hemoglobin 8.3 (6.3 to 11.9), neutrophils 0.045 (0.0 to 2.1), and platelets 45 (3 to 343). There were 96 episodes of infection requiring hospitalization (56%). Growth factor support reduced infectious complications by 34%. Etoposide dose was reduced, or omitted, in 24% of cycles. Four patients did not complete six cycles due to unacceptable toxicity and one patient progressed on treatment. Twenty patients underwent peripheral-blood stem cell harvesting, 15 after cycle 3, and five after cycle 4. Median CD34+ yield was 4.6 x 106/kg per patient (1.8 to 14.5). Overall response to treatment, measured in 24 patients, was 88%. Seven of 11 patients undergoing surgery achieved greater than 90% necrosis of tumor (64%). CONCLUSION: VIDE is an effective induction regimen with substantial but acceptable toxicity that allows predictable mobilization of stem cells. Maintenance of dose-intensity is feasible in the majority of patients. Growth factors play a role in maintaining dose-intensity and reduce infectious complications.

A Phase II Study of Docetaxel in Patients with Relapsed and Refractory Ewing's Tumours.

Purpose. The prognosis for patients with Ewing's tumours who have metastases at presentation or who are refractory to standard chemotherapy regimens remains poor. There is therefore a need to evaluate the role of new agents. This report describes the initial results of a prospective phase II trial of docetaxel in patients with progressive or refractory Ewing's tumours.Patients and methods. Fourteen patients with Ewing's tumours who had all relapsed or progressed after treatment with multi-drug cytotoxic therapy were treated with docetaxel 100 mg/m(2) infused over 1 h, three weekly for a maximum of six cycles. Nine patients received granulocyte colony-stimulating factor with all cycles.Results. A partial response was observed in one patient and stable disease in two. The remaining patients progressed on treatment. The major toxicity was myelosuppression and infection with 36% patients experiencing grade 3 or 4 neutropenia and/or infection.Conclusion. Docetaxel appears to have some activity in Ewing's tumours even in heavily pre-treated patients. Further evaluation of its efficacy at an earlier stage of the disease is warranted.

A pilot study of short-course intensive multiagent chemotherapy in metastatic and axial skeletal osteosarcoma.

BACKGROUND: This pilot study was undertaken to assess the feasibility, toxicity and response to short-course multiagent chemotherapy followed by high-dose chemotherapy (HDC) in patients with poor prognosis osteosarcoma. PATIENTS AND METHODS: A total of 30 patients entered the study. Chemotherapy consisted of four blocks of multiagent chemotherapy administered sequentially over a short period in a dose-intensive manner. This therapy was followed by HDC which consisted of carboplatin at an AUC8 x 3 days, etoposide 400 mg/m(2) x 3 days and cyclophosphamide 60 mg/kg x 2 days. RESULTS: A total of 227 cycles of chemotherapy were administered. The main toxicity (for blocks 1-4) was haematological. There were two treatment-related deaths: one post HDC due to sepsis and one during surgery. High-dose chemotherapy was administered to 11 patients (10 with extremity tumours and only one with a pelvic tumour). Twenty-seven patients underwent surgery to the primary. Histological response was assessed in 23 patients. Seven patients (30%) had >90% necrosis. Eight patients underwent pulmonary metastatectomy. The median survival time for the whole group was 16 months. The 2- and 3-year survival rates were 50% and 21% for those with extremity tumours and 19% and 13% for those with axial skeletal tumours. CONCLUSIONS: Dose-intensive multiagent chemotherapy though feasible in the group of patients with extremity tumours did not significantly improve the treatment outcome compared with conventional relapse therapy. Inferior survival rates in the axial skeletal group are attributed to less intensive treatment and poor local tumour control.

Melanoma risk in relation to height, weight, and exercise (United States).

Height and weight and derivations thereof are positively associated with a number of cancers. While several authors have reported an increased risk of melanoma among people at the higher extremes of these measures, the association has not been fully explored. New cases of primary cutaneous melanoma in 1997 in western Washington State (n = 386) were compared to controls selected by random-digit dialing (n = 727). Each study participant completed a telephone survey, and data were collected on height, weight, sun-related melanoma risk factors, demographic characteristics, as well as habits such as diet and exercise. Risk of melanoma was analyzed by logistic regression with adjustment for age, hair color, lifetime sun exposure, and fruit and vegetable intake. An excess risk of melanoma was identified in men in the upper quartiles of height (OR = 2.4, 95% confidence interval (CI) = 1.3-4.5), weight (OR = 2.8, CI = 1.5-5.2), and body surface area (OR = 2.8, CI = 1.5-5.1) vs. the lowest quartiles. In women, no association was present for any anthropometric measure. In addition, we found that men and women exercising five to seven days per week were at a decreased risk of melanoma (OR = 0.7, CI = 0.5-1.0). The anthropometric findings are largely consistent with previous studies, while this is the first report of an association of exercise with melanoma risk. The mechanisms for the effect of exercise and for the difference between men and women in the effect of anthropometric factors are unknown. Future research in basic and epidemiologic science should focus on biochemical or behavioral explanations for these observations.

Menopause, hormone replacement therapy and cancer.

OBJECTIVE: To comparatively review available evidence on hormone replacement therapy (HRT) and cancer. METHODS: Qualitative literature review. RESULTS: Most potential favorable and adverse effects on cancer risk of HRT are restricted to current users. On the basis of observational epidemiological data, the RR of breast cancer is moderately elevated in current and recent HRT users, and increases by about 2.3% per year with longer duration of use, but the effect drops after cessation and largely, if not totally, disappears after about 5 years. Unopposed estrogen use is strongly related to endometrial cancer risk, but cyclic combined oestrogen-progestin treatment appears to largely or totally reduce this side effect, if progestin are used for at least 14 days per cycle. However, combined HRT may be associated with higher risk of breast cancer as compared to unopposed estrogens. HRT has been inversely related to colorectal cancer, although the issue of causal relation remains open to discussion. No consistent association was reported for ovarian, liver, other digestive or lung cancer. CONCLUSIONS: Recommendations for prolonged HRT use must be considered on an individual basis, taking into account the presence of other risk factors mainly for breast cancer, such as family history of breast cancer or a personal history of benign breast disease, as well as individual risk for other chronic diseases.

Echocardiographic examination of women previously treated with fenfluramine: long-term follow-up of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Fenfluramine hydrochloride was withdrawn from the market in September 1997 after reports of heart valve abnormalities in patients who used it. The prevalence of echocardiographic abnormalities and the clinical cardiovascular status of patients who received fenfluramine monotherapy remains uncertain. METHODS: A long-term, follow-up evaluation was undertaken in subjects who were randomly assigned to receive either fenfluramine hydrochloride (60 mg daily) or placebo as part of a double-blind smoking cessation therapy study. Cardiovascular status was evaluated by echocardiography, medical history, and physical examination. RESULTS: From the group of 720 smokers who had originally participated in the smoking cessation therapy trial, 619 women were enrolled; data from 530 (276 in the fenfluramine group and 254 in the placebo group) were evaluable. No statistically significant differences were identified in the prevalence of aortic or mitral regurgitation by Food and Drug Administration criteria or by grade, aortic or mitral valve leaflet mobility restriction or thickening, elevated pulmonary artery systolic pressure, or abnormal left ventricular ejection fraction. No significant differences were demonstrated in cardiovascular status by physical examination, and no serious cardiac events were noted among fenfluramine-treated subjects. CONCLUSION: There was no evidence of drug-related heart disease up to 4.9 years after anorexigen therapy in subjects who were randomly assigned to receive fenfluramine at the recommended dose for up to 3 months.

Body mass index and asthma in the military population of the northwestern United States.

BACKGROUND: Patients with asthma commonly have other medical problems such as obesity, but it is unclear if obesity independently relates to asthma occurrence. OBJECTIVE: To examine the association between asthma and obesity. METHODS: We studied enrollees aged 17 to 96 years in region 11 of TRICARE, a military managed health care program encompassing Washington, Oregon, and northern Idaho, using an enrollment questionnaire from January 1997 to December 1998. We performed case-control analyses on 2788 asthma cases and 39 637 controls. From these cases and controls, we selected a random sample of 1000 asthma cases and 1000 controls, linking them to a computerized military health record system to verify if medications indicated for asthma therapy were prescribed. After excluding cases not prescribed bronchodilator medications and excluding controls prescribed bronchodilator medications or steroids, we used logistic regression to estimate associations among asthma, body mass index, and demographic, lifestyle, and comorbid risk factors in 386 verified cases and 744 verified controls. RESULTS: Increasing body mass index, younger age, female sex, non-active duty beneficiary status, and arthritis were significant independent predictors of asthma prevalence in both our larger analysis and our verified substudy, whereas stomach ulcer, depression, hypertension, and white race are also independent predictors of asthma prevalence in our larger analysis. CONCLUSIONS: Increasing body mass index is a key factor predicting prevalence of asthma and, if determined to be etiologically related to asthma incidence, is a potentially modifiable risk factor for asthma.