ERβ-specific agonists and genistein inhibit proliferation and induce apoptosis in the large and small intestine

Epidemiological data indicate that intake of estrogens and isoflavones may be beneficial for the prevention of colorectal cancer (CRC). Based on this data, the aim of the study was to investigate estrogen receptor (ER) subtype-specific effects on intestinal homeostasis. Ovariectomized (OVX) female Wistar rats were either treated with 17β-estradiol (4 μg/kg body wt/day) (E2), an ERα-specific agonist (ALPHA) (10 μg/kg body wt/day), an ERβ-specific agonist (BETA) (100 μg/kg body wt/day) or genistein (GEN) (10 mg/kg body wt/day) for three weeks. Vehicle-treated OVX and SHAM animals and those cotreated with BETA and the pure antiestrogen Fulvestrant (ICI 182780) (100 μg/kg body wt/day and 3 mg/kg body wt/day) served as controls. GEN and BETA treatment but not E2 and ALPHA administration reduced proliferation in ileal and colonic mucosa cells. The rate of apoptosis in the small intestine and colon was increased by treatment with BETA and GEN, but not by E2. BETA induced antiproliferative and proapoptotic activity also in SHAM animals. The effects were antagonized by the pure antiestrogen Fulvestrant. Polymerase chain reaction gene array analysis revealed that BETA resulted in the downregulation of the oncogene transformation-related protein 63 (p63). Our data indicate that activation of the ERβ by specific ERβ agonists and GEN induces antiproliferative and proapoptotic effects in the intestinal tract. This observation can be taken as an indication that intake of GEN and specific ERβ agonists may protect the ileal and colonic epithelium from tumor development via modulation of tissue homeostasis.     

CCR7 and CXCR4 Expression in Primary Head and Neck Squamous Cell Carcinomas and Nodal Metastases – a Clinical and Immunohistochemical Study

Background: Squamous cell carcinomas (SCCs) are common head and neck malignancies demonstrating lymph node LN involvement. Recently chemokine receptor overxpression has been reported in many cancers. Of particular interest, CCR7 appears to be a strong mediator of LN metastases, while CXCR4 may mediate distant metastases. Any relations between their expression in primary HNSCCs and metastatic lymph nodes need to be clarified. Aims: To investigate CCR7 andCXCR4 expression in primary HNSCCs of all tumor sizes, clinical stages and histological grades, as well as involved lymph nodes, then make comparisons, also with control normal oral epithelium. Materials and Methods: The sample consisted of 60 formalin-fixed, paraffin-embedded specimens of primary HNSCCs, 77 others of metastasi-positive lymph nodes, and 10 of control normal oral epithelial tissues. Sections were conventionally stained with H&E and immunohistochemically with monoclonal anti-CCR7 and monoclonal anti-CXCR4 antibodies. Positive cells were counted under microscopic assessment in four fields (X40) per case. Results: There was no variation among primary HNSCC tumors staining positive for CCR7 and CXCR4 with tumor size of for CCR7 with lymph node involvement. However, a difference was noted between primary HNSCC tumors stained by CXCR4 with a single as compared to more numerous node involvement. CXCR4 appear to vary with the clinical stagebut no links were noted with histological grades. Staining for primary HNSCC tumors and metastatic lymph nodes correlated.     

Physical and emotional well-being and support in newly diagnosed head and neck cancer patient–caregiver dyads

The purpose of this study was to examine the physical and emotional well-being and social support in newly diagnosed head and neck cancer (HNC) patients and caregivers and identify sociodemographic, clinical, and behavioral risk factors associated with compromised well-being in patients and caregivers. Newly diagnosed HNC patients and their primary caregivers (N = 72 dyads) completed questionnaires before treatment assessing physical and mental well-being, depression, cancer worry, and open-ended support questions. Patients reported worse physical well-being than caregivers (p < 0.05) but similar levels of mental well-being. Caregivers reported providing emotional and instrumental support most frequently with an emphasis on nutrition and assistance with speech, appearance, and addictions. Both patients and their caregivers reported suboptimal mental well-being and depression. Smoking was associated with compromised well-being in patients, caregivers, and dyads. Compromised well-being in patients and their caregivers was more likely when patients were younger, had worse symptoms, and smoked/consumed alcohol (p < 0.05). While patients face more physical strain than caregivers, both equally confront emotional challenges. Results highlight risk factors for compromised well-being in both patients and their caregivers that should be assessed at diagnosis to guide identification of needed dyadic-focused supportive care resources.     

Iron intake and markers of iron status and risk of Barrett’s esophagus and esophageal adenocarcinoma

Objective  

To investigate the association between iron intake and iron status with Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC).     

Supraglottic and glottic carcinomas. clinically and biologically distinct entities?

This study aimed to examine the clinical and biological differences in 198 patients with either T1-T2 local glottic or supraglottic squamous cell carcinomas. The patients with supraglottic cancer had a poorer prognosis, as well as more advanced and histologically aggressive tumours than the patients with glottic tumours. They also had lower levels of haemoglobin and a poorer nutritional and performance status. Expression of alpha-catenin, hyaluronan, CD44, p53, p21/WAF1 and bcl-2 in the primary tumour were not associated with the site of the laryngeal carcinoma. In supraglottic tumours, the rate of spontaneous apoptosis and mitotic indices were significantly higher than in glottic tumours. The results suggest that clinical parameters including the haemoglobin level of the patient together with the tumour cell kinetics (mitotic and apoptotic rates) may contribute to the aggressive nature of supraglottic carcinoma.     

Cancer incidence patterns among adolescents and young adults in the United States

Objective The purpose of this study was to examine age-specific cancer incidence patterns among adolescents and young adults (ages 15–49).Method Cancer incidence data for 1995–1999 from 22 population-based central cancer registries, covering about 47% of the US population, were used. Relative frequencies and average annual age-specific incidence rates per 100,000 person-year were computed for the five-year age groups from age 15–19 years through 45–49 years. Tests of significance for comparison were at a level of p<0.05.Results The age at crossover from a predominance of non-epithelial cancers to a predominance of epithelial cancers during adolescence and young adulthood varied by gender and race. Epithelial cancer became the predominant type of tumor after age 40 years among males while it was the predominant type after age 25 years among females. There was also a shift in the top five cancer types with increasing age, which varied by race and gender. Epithelial cancers of the thyroid, breast, ovary, and cervix uteri started to increase sharply among young women in their 20s while among males epithelial cancers rarely occurred untill the early 30s (ages 30–34). Cancers of the female breast, colon and rectum, and lung began to occur at an earlier age and increased more sharply among blacks than among whites. However, the incidence rates of epithelial thyroid and ovarian cancers rose more quickly among whites than blacks. Non-Hodgkin lymphoma and soft tissue sarcoma (excluded Kaposis sarcoma) increased with age among both whites and blacks but the rates were significantly higher among blacks than among whites. Both Kaposis sarcoma and testicular cancer incidence increased with age and peaked in the early 30s (ages 30–34). The former was significantly higher among blacks than whites while the latter was significantly higher among whites than blacks. Cervical cancer incidence leveled offf when white women reached their 30s, but for black women the rate continued to rise with advancing age. Cutaneous melanoma rates were significantly higher among females than among males between the ages of 15 and 39.Conclusion Cancer incidence patterns among adolescents and young adults are distinctive. Specific cancer prevention and control strategies should be targeted accordingly and tailored to their specific needs.     

Distinct incidence patterns among <Emphasis Type="Italic">in situ</Emphasis> and invasive breast carcinomas,with possible etiologic implications

Background. Incidence patterns are well-established for invasive breast carcinoma (InvBC) overall and for InvBC defined by estrogen receptor (ER) expression, but are not as well-defined for breast carcinoma in situ (CIS). Methods. We, therefore, examined and compared the incidence patterns for CIS and InvBC in the SEER program to define these patterns and to generate etiologic hypotheses. Data were stratified by age <50 and 50years to approximate menopause. Results. During the years 1973–2000, annual age-adjusted incidence rates rose 660% for CIS and 36% for InvBC, with the most rapid increases occurring in women age 50years. Age-specific incidence rate curves for CIS increased until age 50years, and then flattened, irrespective of ER expression. On the other hand, rates for InvBC overall and for InvBC defined by ER-positive expression increased continuously with aging, whereas rates for InvBC defined by ER-negative expression flattened after 50years. Age frequency distribution for CIS and for ER-negative InvBC demonstrated bimodal populations, with a predominant early onset peak incidence at age 50years. Age frequency distribution for ER-positive InvBC showed bimodal populations with a predominant late-onset mode at age 71years. Conclusion. Over the last three decades, age-adjusted incidence trends differed for CIS and InvBC in the United States, possibly due to screening mammography and/or etiologic diversity. Indeed, age-specific incidence patterns suggested that carcinogenic events operating early in reproductive life had greater impact upon CIS and InvBC defined by ER-negative expression than upon InvBC overall and InvBC defined by ER-positive expression.     

Qualitative age interactions in breast cancer studies: a mini-review

A qualitative age interaction is defined as the reversal of relative risks or rates according to age at onset, and is often evident in studies that examine the etiology, prognosis and treatment of breast cancer. For example, incidence rates (or risks) are higher for aggressive when compared with indolent breast cancers prior to age 40-50 years, after which rates are higher for indolent tumors. Nulliparity and obesity decrease breast cancer risk in younger women, but increase risk in older women. Curves depicting the annual hazard of breast cancer death are shaped differently for the early- and late-onset tumors. Clinical trials for mammography screening, fenretinide chemoprevention and neo-adjuvant chemotherapy show opposite effects in younger and older women. Finally, high-risk/early onset breast cancers are more common among African-American women than Caucasian women, and this may partly account for the racial survival disparities. Taken together, these examples imply that aging may modify breast cancer risk, prognosis and treatment. These qualitative age interactions (or effect modifications) are important because they suggest that high-risk/early-onset and low-risk/late-onset breast cancers are different diseases, derived from different carcinogenic pathways. When age interactions are suspected, breast cancer studies should be stratified by early versus late age of onset or analyzed age specifically.     

Sequencing of Endocrine Therapies in Breast Cancer – Integration of Recent Data

Background. Researchers question whether estrogen receptor-negative (ERN) and -positive (ERP) represent different stages of one disease or different breast cancer types. Objective. To further examine ER phenotypes, we stratified incident tumor characteristics in the Surveillance, Epidemiology, and End Results (SEER) Database (n = 82,488) by ERN and ERP. Methods. Study variables included black–white race, age-at-diagnosis, and standard incident tumor characteristics. These characteristics were arbitrarily dichotomized into good versus poor prognostic factor groups, for example, good (tumor size 2.0 cm, negative axillary lymph nodes, and good histologic grade) versus poor (tumor size > 2.0 cm, positive nodes, and poor grade). Age frequency density plots were generated from the corresponding age-at-diagnosis frequency histograms. Average annual age-specific incidence rates (or risks) were adjusted to the 1970 United States standard female population. Results. Age frequency density plots demonstrated bimodal premenopausal and postmenopausal breast cancer populations. ERN was correlated with premenopausal disease, black race, and poor prognostic factor groups, whereas ERP was associated with postmenopausal disease, white race, and favorable tumor characteristics. ERN rates increased premenopausally and then flattened to a nearly constant level after 50 years of age. ERP risk rose for most of a woman's lifetime with the greatest risk occurring between 75 and 79 years. Conclusions. ER exhibited bimodal age frequency distribution with a dichotomous pattern for age-specific rates, racial, and prognostic factor profiles. Menopause had a greater effect on ERN than ERP. Possible implications for breast carcinogenesis and cancer prevention are discussed in the text.     

Cancer incidence in migrants to New South Wales (Australia) from the Middle East, 1972–91

The incidence of cancer in migrants to New South Wales (NSW) from Cyprus, Egypt, Iran, Iraq, Israel, Lebanon, Syria, and Turkey has been compared with that in the Australian-born population using data from the NSW Central Cancer Registry for 1972–91. Age-standardized incidence rates showed overall cancer incidence to be less common in migrants from each Middle Eastern country than in the Australian-born. There was a clear pattern of generally low rates for cancers of the mouth and pharynx, esophagus, colon and rectum, lung (men only), ovary, prostate and testis, and melanoma. Cancers which tended to be more common in migrants were nasopharynx, stomach (women only), liver (men only), gallbladder (chiefly in women), bladder (men only), and thyroid. Breast cancer did not show a uniform pattern among migrant groups, rates being high in the Egyptian-born but low in Lebanese-born women. The overall low incidence of cancers related to tobacco and alcohol, and to a high fat, low fiber diet, emphasizes the potential role of preventable lifestyle factors in the burden of cancer in Australia.     

Age- and time-dependent changes in cancer incidence among immigrants to Sweden: colorectal, lung, breast and prostate cancers

To examine the role of gender, age at immigration and length of stay on incidence trends of common cancers, we studied risk of colorectal, lung, breast and prostate cancers in immigrants to Sweden from 1958 to 2008. The nationwide Swedish Family-Cancer Database was used to calculate standardized incidence ratios for common cancers among immigrants compared to Swedes. Immigrants were classified into "high-risk" countries when their risk was increased, into "low-risk" when their risk was decreased and into "other" when their risk was nonsignificant. Among those who immigrated at younger age (<30 years), we found an increasing trend for colorectal cancer risk in low-risk men and high-risk women. Among those who immigrated at older age (≥ 30 years), a decreasing lung cancer risk in high-risk men and an increasing breast cancer risk in low-risk women were observed. The increasing trend of prostate cancer risk was independent of age at immigration. The risk trends for "other" immigrants were between the risks of low- and high-risk countries. The gender-specific shifts in cancer risks in immigrants toward the risk in natives indicate a major role of sex, age at immigration and environmental exposures in colorectal and lung cancers risks. In contrast, the unchanged trend of breast cancer among those who immigrated at younger ages and an increasing trend for those who migrated at older ages may suggest a limited effect for environmental exposures, especially at younger age. Our study points out a role of age at immigration on the risk trend of cancer.     

Familial and histological analyses of 138 breast cancer patients

Summary A histological analysis was conducted in 138 female breast cancer patients, and the results were classified in accordance with Histological Typing of Breast Tumours (WHO, Geneva 1981). Since about half of these tumors showed more than one histological type of carcinoma, a simplified classification system with four groups was adopted. When patients were categorized according to the number and degree of kinship of their relatives with breast cancer, no specific association with the histological types was found. Familial tumors also encompassed a wide spectrum of histopathologic diagnoses. This suggests the absence of a histological marker in familial breast cancer.Pedigrees of all the patients were then analyzed, special emphasis being placed on relatives suffering from the same and other malignancies. It was found that 13.8% of the probands had at least one first-degree relative with breast cancer and that, compared with the tumor spectra in the male and female population, there was a significantly higher number of esophageal carcinomas in the fathers, of stomach cancers in the uncles and grandfathers, of brain tumors in the mothers, and of sarcomas in the brothers. An accumulation of the same tumors, especially stomach cancer and tumors related to the SBLA syndrome, was observed in families of index patients with tubular or medullary breast cancer. The SBLA syndrome is a complex familial cancer syndrome characterized by a proclivity toSarcomas,Breast cancers, brain tumors,Lung and laryngeal cancers, leukemia, andAdrenocortical carcinomas.     

Heritability of breast cancer and its role in pre-menopausal cases

The causes for the pre-menopausal incidence peak in breast cancer are still controversial. Other cancers also show an early incidence peak. Since the mammary tissue only starts to develop in puberty, the premenopausal incidence peak for breast cancer is comparable to the juvenile peak in other cancers (retina, kidney).The four-mutation model for oncogenesis can explain pre-menopausal breast cancer. The model suggests that malignant transformation of a cell is due to four specific oncogenic mutations. These specific mutations accumulate during the proliferation of somatic cells. According to the model, one inherited oncogenic mutation can cause hereditary cancer. In this case only three additional specific mutations have to be accumulated during somatic cell proliferation. Epidemiological data and mathematical calculations indicate that in this case tumors occur early in life. Thus, the four-mutation model for oncogenesis predicts that the impact of heritability in pre-menopausal breast cancer is more significant than is generally believed. At this point, molecular biological studies are needed, to identify the involved specific mutations. Other implications of the model are an increased incidence of second primary tumors and an increased sensitivity for mutagenic factors in these patients.     

Cancer incidence in multiple sclerosis and effects of immunomodulatory treatments

Multiple sclerosis (MS) has been linked to reduced rates of cancer prior to the era of immunomodulating treatments. We assessed the incidence of cancer in a cohort of 1338 MS patients and evaluated the effect of exposure to immunomodulatory treatment. Cancer incidence in the MS population was compared with the expected age- and gender-matched incidence rates in the Israeli population for the period 1960–2003. Time-dependant Cox model analysis was used to estimate hazard ratios for glatiramer acetate, -interferons (1a and 1-b) and intravenous immunoglobulins (IVIg). Among 892 female MS patients, 15 (1.7%) developed breast cancer, and 31 (3.5%) developed cancers of any type. Seventeen of 446 (3.8%) male MS patients developed cancer. The standardized incidence ratios (SIRs) computed until the time of first immunomodulatory treatment were 0.60 (95% CI, 0.38–0.92, p = 0.02) for all female cancer, and 1.11 (95% CI, 0.64–1.91) for all male cancer. Time-dependent covariate analyses for female breast cancer yielded a relative risk for glatiramer acetate of 3.10 (95% CI, 0.86–11.1) and 0.52 (95% CI, 0.07–4.05) for -interferons. For IVIg, the analyses were uninformative. Our findings indicate that cancer incidence is significantly lower in female MS patients than in the general population. Female MS patients treated with glatiramer acetate showed an elevated rate of breast cancer and all MS patients treated with -interferons showed an elevated risk of non-breast cancers though not statistically significant (p = 0.122 and 0.072, respectively). Further study is needed to assess possible associations between long-term exposure to the novel immunomodulatory treatments in MS and rate of caner.     

C-erbB-2 overexpression and survival in early onset breast cancer

Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer.A population consisting of 110 young breast cancer patients, 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein.Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P=0.002) and for patients with axillary nodal metastases (P=0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy.The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.