Lifetime risks of hip fracture in patients with type 2 diabetic: Taiwan Diabetes Study.

This study is to estimate the lifetime risks of hip fracture in Chinese patients with type 2 diabetes. INTRODUCTION: The lifetime risks of hip fracture have not been reported across the age spectrum in male adults and female adults with type 2 diabetes. METHODS: A retrospective cohort study was conducted on 25275 men and 27953 women with type 2 diabetes aged 30-100 years old and participated in the National Diabetes Case Management Program in 2002-2004 in Taiwan. Sociodemographic factors, biomarkers, and comorbidity at the baseline and hip fracture events were analyzed with Cox proportional hazards regression models with age as the time scale. RESULTS: Significant differences in the lifetime risks of hip fracture were observed between men and women with type 2 diabetes. The cumulative lifetime incidences (%) of hip fracture at 50, 60, 65, 70, 75, 80, and 85 years old for men were 0.11, 0.40, 0.84, 1.84, 3.82, 8.53, and 16.72, respectively. The corresponding lifetime incidences (%) for women at 50, 60, 65, 70, 75, 80, and 85 years old were 0.05, 0.50, 1.36, 3.89, 9.56, 21.19, and 35.45, respectively. With competing risks, the significant multivariate-adjusted hazard ratio of developing hip fracture included smoking, alcohol drinking, duration of diabetes, type of oral hypoglycemic drugs use (no medication, sulfonylurea only, thiazolidinediones (TZD) only or TZD plus others, other single or multiple oral agents, insulin use, insulin plus oral hypoglycemic drug use), loop diuretics use, use of corticosteroids, normal weight or underweight, hyperlipidemia, and chronic obstructive pulmonary disease. CONCLUSIONS: The gender differences in lifetime hip fracture risk were significant. Thiazolidinediones and insulin use are factors with the greater magnitude of strength of association among those significantly associated with hip fracture.

Independent and joint effect of type 2 diabetes and gastric and hepatobiliary diseases on risk of pancreatic cancer risk: 10-year follow-up of population-based cohort.

BACKGROUND: Type 2 diabetes mellitus, gastric and hepatobiliary comorbidities, and cancer share common risk factors: for example, tobacco, obesity, physical inactivity, high calorie intake, and metabolic disorders. Prior studies find type 2 diabetes and gastric and hepatobiliary comorbidities heightening risk of pancreatic cancer. Yet joint association of type 2 diabetes mellitus and gastric and hepatobiliary comorbidities on pancreatic cancer risk has not been assessed. METHODS: This study rates independent/joint effects of type 2 diabetes as well as gastric and hepatobiliary comorbidity on pancreatic cancer risk for a retrospective population-based cohort of 166,850 type 2 diabetics identified in 1997-1998 and followed for 10-11 years, comparing their cancer incidence with that of 166,850 non-diabetics matched for age, gender, and locale. Time-dependent Cox's proportional hazards model evaluted joint association of type 2 diabetes and chronic conditions on pancreatic cancer risk. RESULTS: A total of 1178 subjects were newly diagnosed with pancreatic cancer during follow-up, with incidence rates of 0.49 per 1000 person-years in type 2 diabetes and 0.26 per 1000 person-years in the non-diabetics. We observed greater magnitude of hazard ratios (HRs) of pancreatic cancer for patients with type 2 diabetes along with acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer compared with patients without type 2 diabetes or counterpart comorbidity (HR: 1.36, 95% confidence interval (CI): 1.19-1.56; 1.74, 1.23-2.45; 9.18, 7.44-11.33; and 2.31, 1.98-2.70, respectively). Main effects of type 2 diabetes were all statistically with narrow 95% CI and remained similar across risk stratification with various comorbidities: range 1.59-1.80. CONCLUSIONS: Our study demonstrates that pre-existing type 2 diabetes, acute alcoholic hepatitis, acute pancreatitis, cholecystitis, and gastric ulcer independently or jointly predict subsequent pancreatic cancer risk. Clinicians must recognise burden of these gastric and hepatobiliary comorbidities and keep clinically vigilant for their diagnosis.

LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling.

EGFR overexpression and chromosome 3p deletion are two frequent events in head and neck cancers. We previously mapped the smallest region of recurrent copy-number loss at 3p12.2-p14.1. LRIG1, a negative regulator of EGFR, was found at 3p14, and its copy-number loss correlated with poor clinical outcome. Inducible expression of LRIG1 in head and neck cancer TW01 cells, a line with low LRIG1 levels, suppressed cell proliferation in vitro and tumor growth in vivo. Gene expression profiling, quantitative RT-PCR, chromatin immunoprecipitation, and western blot analysis demonstrated that LRIG1 modulated extracellular matrix (ECM) remodeling and EGFR-MAPK-SPHK1 transduction pathway by suppressing expression of EGFR ligands/activators, MMPs and SPHK1. In addition, LRIG1 induction triggered cell morphology changes and integrin inactivation, which coupled with reduced SNAI2 expression. By contrast, knockdown of endogenous LRIG1 in TW06 cells, a line with normal LRIG1 levels, significantly enhanced cell proliferation, migration and invasiveness. Such tumor-promoting effects could be abolished by specific MAPK or SPHK1 inhibitors. Our data suggest LRIG1 as a tumor suppressor for head and neck cancers; LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers.

Selenium is inversely associated with interleukin-6 in the elderly.

BACKGROUND: Selenium is an essential trace element with antioxidant property. Decreased serum selenium concentration with aging had been found in previous report. In this study, we aim to investigate the association between serum selenium and the inflammatory cytokine interleukin-6 in the elderly living in long-term care facilities in Taiwan. MATERIALS AND METHODS: A total of 336 subjects aged 65 years and older (range of age: 65 - 101 years) were recruited from eight long-term care facilities in 2002-2003. Baseline characteristics, anthropometric indices, and biochemical data were obtained. Selenium deficiency was defined as serum selenium concentration < 80 µg/L. Multiple logistic and linear regression analyses were used to examine the relationships between selenium deficiency and interleukin-6 (divided into quartiles). RESULTS: The prevalence of selenium deficiency was 35.6% in men and 43.2% in women, respectively. After adjusting for potential confounders using multiple logistic regression analysis, interleukin-6 quartiles were significantly associated with selenium deficiency. Compared to the interleukin-6 quartile I, the adjusted odds ratios of having selenium deficiency for interleukin-6 quartile II, III, IV were 1.00(0.50~2.01), 1.24 (0.62~2.50), and 2.35(1.15~4.83), respectively. The increasing odds ratios for selenium deficiency in higher interleukin-6 quartiles revealed dose-response effects (p < 0.05). Moreover, multiple linear regression analysis showed that serum selenium was significantly inversely associated with interleukin-6 after adjusting for potential confounders. CONCLUSIONS: Serum selenium was inversely associated with inflammatory cytokine interleukin-6 among elderly living in long-term care facilities in Taiwan. Monitoring serum selenium should be considered in these institutionalized elderly.

Gene expression array testing of FFPE archival breast tumor samples: an optimized protocol for WG-DASL sample preparation.

Archived formalin-fixed, paraffin embedded (FFPE) tissues constitute a vast, well-annotated, but underexploited resource for the molecular study of cancer progression, largely because degradation, chemical modification, and cross-linking, render FFPE RNA a suboptimal substrate for conventional analytical methods. We report here a modified protocol for RNA extraction from FFPE tissues which maximized the success rate (with 100% of samples) in the expression profiling of a set of 60 breast cancer samples on the WG-DASL platform; yielding data of sufficient quality such that in hierarchical clustering (a) 12/12 (100%) replicates correctly identified their respective counterparts, with a high self-correlation (r = 0.979), and (b) the overall sample set grouped with high specificity into ER+ (38/40; 95%) and ER- (18/20; 90%) subtypes. These results indicate that a large fraction of decade-old FFPE samples, of diverse institutional origins and processing histories, can yield RNA suitable for gene expression profiling experiments.

Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer.

The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal (IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival estrogen receptor (ER)-positive tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip(R) Mapping 10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by, the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%) common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly higher frequency of LOH events across the genome than ILC (fractional allelic loss = 0.186 and 0.156). By comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly (P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We identified additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size, mitotic rate, or DNA content. Of 5,754 informative SNPs (>25% informativity), we identified 78 and 466 individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respectively. Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their patterns of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q.

Microalbuminuria and the metabolic syndrome and its components in the Chinese population.

BACKGROUND: Microalbuminuria and the metabolic syndrome (MetS) have both been linked to chronic kidney disease and cardiovascular disease. This study investigated the association between urinary albumin-to-creatinine ratio (ACR) and MetS and its components. MATERIALS AND METHODS: A total of 2311 subjects aged 40 years and over were recruited in 2004 in a metropolitan city in Taiwan. The biochemical indices, such as fasting glucose levels, urinary albumin, urinary creatinine and anthropometric indices, were measured. We defined microalbuminuria as a urinary ACR ranging from 30 to 300 mg g(-1) creatinine. MetS was defined using the American Heart Association and the National Heart, Lung and Blood Institute (AHA/NHLBI) and the International Diabetes Federation (IDF) definitions. The relationship between MetS and microalbuminuria was examined using multiple logistical regression analysis. RESULTS: Subjects with microalbuminuria had higher age, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, triglycerides, total cholesterol (TCHOL)/high-density lipoprotein cholesterol (HDL-C) ratio, prevalence of diabetes mellitus and hypertension and lower HDL-C than subjects with normoalbuminuria. After adjusting for age and BMI, microalbuminuria was associated with the individual components of MetS, except in central obesity in women and elevated fasting glucose in men. After adjusting for age, BMI, smoking and alcohol consumption status, multiple logistical regressions revealed that microalbuminuria is strongly associated with MetS in both genders and according to both definitions. The odds ratio of having MetS using the AHA/NHLBI and IDF definition was 1.76 (1.16-2.67) and 1.73 (1.06-2.83) in men and 2.19 (1.38-3.50) and 2.09 (1.24-3.51) in women, respectively. CONCLUSIONS: Microalbuminuria was strongly associated with MetS and its components. There is an increased likelihood of having MetS if subjects have microalbuminuria.

Clinical characteristics of different histologic types of breast cancer.

Breast cancer is a heterogeneous disease, though little is known about some of its rarer forms, including certain histologic types. Using Surveillance, Epidemiology, and End Results Program data on 135 157 invasive breast cancer cases diagnosed from 1992 to 2001, relationships between nine histologic types of breast cancer and various tumour characteristics were assessed. Among women aged 50-89 years at diagnosis, lobular and ductal/lobular carcinoma cases were more likely to be diagnosed with stage III/IV, > or =5.0 cm, and node-positive tumours compared to ductal carcinoma cases. Mucinous, comedo, tubular, and medullary carcinomas were less likely to present at an advanced stage. Lobular, ductal/lobular, mucinous, tubular, and papillary carcinomas were less likely, and comedo, medullary, and inflammatory carcinomas were more likely to be oestrogen receptor (ER) negative/progesterone receptor (PR) negative and high grade (notably, 68.2% of medullary carcinomas were ER-/PR- vs 19.3% of ductal carcinomas). In general, similar differences were observed among women diagnosed at age 30-49 years. Inflammatory carcinomas are associated with more aggressive tumour phenotypes, and mucinous, tubular, and papillary tumours are associated with less aggressive phenotypes. The histologic types of breast cancer studied here differ greatly in their clinical presentations, and the differences in their hormone receptor profiles and grades point to their likely different aetiologies.

Epidemiologic and molecular risk factors for contralateral breast cancer among young women.

Women diagnosed with a first breast cancer before the age of 45 years have a greater than 5.0-fold risk of developing a second primary contralateral breast cancer (CBC) than women in the general population have of developing a first breast cancer. Identifying epidemiologic or molecular factors that influence CBC risk could aid in the development of new strategies for the management of these patients. A total of 1285 participants in two case-control studies conducted in Seattle, Washington, who were 21-44 years of age when diagnosed with a first invasive breast carcinoma from 1983 to 1992, were followed through December 2001. Of them, 77 were diagnosed with CBC and 907 tumour tissues from first cancers were analysed. Women with body mass indices (BMIs) >/=30 kg m(-2) had a 2.6-fold greater risk (95% CI: 1.1-5.9) of CBC compared to women with BMIs

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.

Multiple primary breast and thyroid cancers: role of age at diagnosis and cancer treatments (United States).

BACKGROUND: Breast and thyroid cancer have been observed to occur more frequently than expected as multiple primary tumors in women. The study presented herein focuses on the effects of age at diagnosis and treatment for the first cancer on the development of the second cancer. METHODS: This retrospective cohort study used a study population consisting of 38,632 women diagnosed with primary invasive breast cancer and 2189 women diagnosed with primary invasive thyroid cancer between 1974 and 1994. Cases were identified from records of the Cancer Surveillance System of western Washington and followed for subsequent cancer development through 1995. RESULTS: Seventy-one women were diagnosed during their lives with both breast and thyroid cancers. Including cancers diagnosed during the same month as or after the initial cancer, the relative risk (RR) of breast cancer among women with thyroid cancer was 1.5 (95% confidence interval [CI] 1.1-2.0), and the RR of thyroid cancer among women with breast cancer was 1.5 (95% CI 1.1-2.2). Among women with thyroid cancer, risk of breast cancer was greatest when the latter cancer was diagnosed under 45 years of age (RR = 2.3, 95% CI 1.1-4.4). First course of treatment, including radiation or hormonal therapy to treat thyroid cancer, and radiation, chemotherapy, or hormonal therapy to treat breast cancer, did not alter a woman's risk of developing the second cancer. CONCLUSIONS: The data suggest that the incidence of breast and thyroid cancer may be related, and that in particular women with thyroid cancer may be at a moderately increased risk of developing breast cancer before age 45.

Changing incidence rate of invasive lobular breast carcinoma among older women.

BACKGROUND: In 1998, an unusually large number of invasive lobular breast carcinoma cases were seen at the University of Washington. The purpose of this study was to assess whether the incidence rate of invasive lobular carcinoma has been increasing disproportionately compared with the incidence rate of invasive ductal carcinoma. METHODS: Age specific and age-adjusted breast carcinoma incidence rates from 1977-1995 were obtained from the nine population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) program. Three histologic groupings were used: lobular, ductal, and all invasive breast carcinomas. Overall incidence rates for each grouping, as well as for each stage (local, regional, and distant), were obtained. RESULTS: The rate of incidence of lobular carcinoma increased steadily from 1977-1995 in women age >/= 50 years whereas it remained stable in women age < 50 years. Alternatively, the rate of incidence of ductal carcinoma increased steadily from 1977-1987, but from 1987-1995 it remained relatively constant across all age groups. CONCLUSIONS: The incidence rates of invasive lobular breast carcinomas increased steadily since 1977 whereas the incidence rates of invasive ductal carcinoma have plateaued since 1987. This rise occurred specifically among women age >/= 50 years and may be related to postmenopausal status. Further epidemiologic, clinical, and laboratory research is required to assess what factors are contributing to this trend.

Hormone replacement therapy in relation to risk of lobular and ductal breast carcinoma in middle-aged women.

BACKGROUND: In the majority of studies, long term, recent use of hormone replacement therapy has been associated with an increased risk of breast carcinoma. However, little attention has been paid to the possibility that the magnitude of this association may vary according to the histologic type of breast carcinoma. METHODS: In this population-based case-control study, interviews were conducted with 537 female residents of King County, Washington who were ages 50-64 years and who had been diagnosed with primary breast carcinoma between January 1, 1988 and June 30, 1990. Interviews with 492 randomly selected King County women without a history of breast carcinoma served as a basis for comparison. Analyses were performed separately for women with lobular and for those with ductal tumors. RESULTS: Compared with nonusers of menopausal hormones, those who currently were using combined estrogen and progestin hormone replacement therapy (CHRT) and had done so for at least 6 months had an elevated risk of lobular breast carcinoma (odds ratio [OR] = 2.6; 95% confidence interval [95% CI], 1.1-5.8), but no change in their risk of ductal breast carcinoma was noted (OR = 0.7; 95% CI, 0.5-1. 1). The OR associated with current use of unopposed estrogen for at least 6 months was 1.5 (95% CI, 0.5-3.9) for lobular tumors and 0.7 (95% CI, 0.4-1.1) for ductal tumors. Similar results were found when cases of invasive tumor were analyzed separately. CONCLUSIONS: The results of this study suggest that CHRT use increases the risk of lobular, but not ductal, breast carcinoma in middle-aged women.

Anthropometric variables in relation to risk of breast cancer in middle-aged women.

BACKGROUND: Many epidemiological studies have assessed the relationships between anthropometric variables and breast cancer risk. However, methodological approaches for analysing these factors differ appreciably. Also, age when maximum height is achieved has been identified as a potential risk factor for breast cancer in premenopausal women, but this issue has not been studied in postmenopausal women. METHODS: The participants in this population-based case-control study were postmenopausal women 50-64 years of age from the general female population of western Washington State. It included 479 women with incident primary breast cancer and 435 controls. RESULTS: This study found that: (i) women who gained over 70 pounds since age 18 had an increased risk of breast cancer relative to those who stayed within 10 pounds of their weight at age 18 (odds ratio [OR] = 2.7; 95% CI: 1.5-4.9), (ii) women with body mass indices (BMI) below what is considered healthy had a decreased risk (OR = 0.4; 95% CI: 0.2-1.1) while women with a BMI in the obese range had an increased risk of breast cancer (OR = 1.4; 95% CI: 1.0-2.1), and (iii) women who reached their maximum height at or after the age of 18 had a decreased risk of breast cancer compared to women who reached their maximum height at age 13 or younger (OR = 0.7; 95% CI: 0.5-1.0). CONCLUSIONS: By examining various anthropometric variables using clinically relevant strata, a clearer picture of how these variables relate to postmenopausal breast cancer risk was developed. Similar to younger women, postmenopausal women who reached their maximum height at later ages had a decreased risk of breast cancer.

Age when maximum height is reached as a risk factor for breast cancer among young U.S. women.

We evaluated height as a potential risk factor for breast cancer in a case-control study of 747 young women diagnosed with invasive breast cancer before age 46 years and 961 control subjects recruited by random digit dialing. We found that total height attained did not affect a woman's risk of the disease. The age when a women reached her maximum height, however, was a risk factor for breast cancer. There was a trend of decreasing risk of breast cancer in relation to increasing age of height attainment, culminating in a 30% reduction in the risk of breast cancer for women who reached their maximum height when they were 18 years or older compared with women who reached their maximum height when they were 13 years old or less (odds ratio = 0.7; 95% confidence interval = 0.5-1.0). Although the age at menarche was correlated with the age at maximum height, the effect of age at maximum height persisted after adjustment for age at menarche. Previous studies have reported that age at menarche is an important determinant of risk, but this study indicates that age when maximum height is reached may be another, and possibly more important, landmark of puberty that is related to breast cancer risk. The physiologic basis for this claim may lie in the influence on breast development of exposure to growth hormone and insulin-like growth factor during puberty, and on a decreased time between the end of puberty and a woman's first livebirth, both of which are believed to affect a woman's risk of breast cancer.

Serum and tissue levels of estradiol during estrogen-induced renal tumorigenesis in the Syrian hamster.

The estrogen-induced renal tumor in the hamster has emerged as a major animal model in hormonal carcinogenesis. However, a fundamental aspect of this experimental model has as yet not been investigated. In the present study, comparisons between the serum and tissue 17 beta-estradiol (E2) levels in cyclic female hamsters and corresponding hormone levels in E2-treated castrated male hamsters have been made. Data is provided concerning the concentration of estrogenic hormones in the serum and target tissue typically required to elicit renal tumorigenesis in this species. Serum E2 levels in the cyclic female hamster average 79 pg/ml on days 1-2 and 311 pg/ml on days 3-4, attaining a maximum of 358 pg/ml on day 4 of the cycle. Elevation in uterine, renal and hepatic E2 tissue levels during days 3-4 of the cycle reflect increases in serum E2 levels which were 3.0-, 2.0-, and 2.6-fold higher when compared to day 1 of the cycle in these tissues. As expected, serum E2 levels of untreated castrated male hamsters did not appreciably vary over a 6 month period of aging and averaged about 32 pg/ml. Under conditions which produced essentially 100% renal tumor incidence, a rapid rise in serum E2 levels, averaging 71.0-fold higher than untreated castrated levels, was seen. A steady state serum E2 level of 2400 to 2700 pg/ml was maintained from 45-180 days of continuous estrogen treatment. Compared to kidneys of untreated hamsters, renal E2 levels in E2-treated hamsters rose only on average 5.4-fold between 15-180 days of hormone exposure. Serum levels of E2-treated hamsters were 5.7- to 8.0-fold higher than those observed in cyclic female hamsters on days 3 and 4. However, at these higher E2-treated serum levels there was no apparent effect either on weight loss or mortality of the animals.