Abe E. Sahmoun

Hormone replacement therapy is associated with decreased survival in women with lung cancer.

PURPOSE Lung cancer is the leading cause of cancer-related death in women. Hormone replacement therapy (HRT) is frequently prescribed to postmenopausal women, but there is little data on its effect on lung cancer. Hence, we conducted a retrospective study to examine the impact of HRT on the natural history of lung cancer. METHODS We conducted a retrospective chart review of women diagnosed with lung cancer between January 1994 and December 1999. Data collected included age, stage, past history of cancer, smoking history, family history of cancer, HRT use, treatment, and overall survival. The effects of various clinical features on survival were examined using Cox proportional hazards regression models. RESULTS Four hundred ninety-eight women (median age, 67 years; range, 31 to 93 years) with lung cancer were included. A history of smoking was present in 429 women (86%), whereas 86 women (17%) had taken HRT. Women with lung cancer who received HRT were younger than women with lung cancer who never received HRT (63 v 68 years old, respectively; P < .0001). Overall survival was significantly higher in patients with no HRT compared with patients who received HRT (79 v 39 months, respectively; hazard ratio = 1.97; 95% CI, 1.14 to 3.39). This effect seemed to be more pronounced in women with a smoking history. CONCLUSION HRT may affect outcomes from lung cancer adversely. Further studies examining the role of HRT use on outcomes from lung cancer, especially in women with a history of smoking, are urgently needed to clarify this important problem.

Cadmium and Prostate Cancer: A Critical Epidemiologic Analysis

Laboratory data implicate cadmium as a prostate carcinogen. However, epidemiological studies concerning the association between cadmium and prostate cancer are inconclusive. This article reviews the epidemiological literature on cadmium and prostate cancer with a special focus on highly exposed occupational cohorts. We searched the MEDLINE database from 1966 to 2002 for articles on cadmium and prostate cancer. All published analytical and descriptive studies that included relevant data were reviewed. In addition, we reviewed the experience of cohorts highly exposed to cadmium in nickel-cadmium battery plants. Of 4 descriptive studies, 3 reported a positive association between cadmium and prostate cancer. Of 10 case-control studies, 5 (50%) reported a positive association. Of 11 cohorts studies, 3 (33%) found a positive association. Finally, 4 studies on cohorts exposed in occupational nickel-cadmium batteries were identified and analyzed. The summary score of the standardized mortality ratios (SMRs) was weakly but not significantly positive 126 (95% confidence interval C.I.: 83–184). In contrast to laboratory studies, epidemiological studies do not convincingly implicate cadmium as a cause of prostate cancer. Future epidemiological studies that attempt to resolve the discrepancy between laboratory and epidemiological studies of cadmium carcinogenesis may benefit from incorporating biological measures of cadmium exposure.

Obesity increases the likelihood of total joint replacement surgery among younger adults

We conducted a retrospective review of medical charts of patients, aged 18 to 59 years old, who underwent either a total knee replacement (TKR) or total hip replacement (THR) from January 2002 to December 2004. Of the 204 study subjects, 52% had a TKR while 48% had a THR. Obesity was significantly associated with the need for a TKR or THR when comparing the study group to adults of similar age in the general population (P< 0.0001). Seventy-two percent (146) of the study group was obese and 21% (42) overweight (BMI 25.0 to 29.9 kg/m2) compared to only 26% (596) obese and 34% (732) overweight in the general population. Patients undergoing a TKR were significantly more likely to be obese (BMI>30 kg/m2) than those having a THR, 83% (89) compared to 59% (57) (P< .0006). Our findings support those previously observed in the elderly population. Primary and secondary prevention programs aimed at reducing obesity are strongly recommended.RésuméNous avons réalise une étude rétrospective chez les patients âgés de 18 à 59 ans et ayant nécessité la mise en place d’une prothèse totale de hanche ou du genou de janvier 2002 à décembre 2004. 204 patients ont été étudiés : 52% pour une prothèse du genou, 48% pour une prothèse de hanche. L’obésité est un facteur significativement associé à la nécessité de la mise en place d’une prothèse totale du genou ou d’une prothèse de hanche. Si l’on compare ce groupe, à un groupe similaire de personnes du même âge dans la population générale (p<0.001). 70% soit 146 patients du groupe étudié étaient obèses et 21%, soit 42 patients, en surpoids (BMI 25.0–29.9 Kg/m2) comparé à 26%, soit 596 patients obèses et 34% soit 732 patients en surpoids de la population générale. Les patients nécessitant un remplacement du genou étaient en surcharge pondérale plus importante que les patients nécessitant une prothèse de hanche (BMI> 30 kg/m2) 83% soit 89 patients contre 59% soit 57 patients. Il nous apparaît donc important à la lumière de ces constatations de préconiser une prévention de réduction de l’obésité dans la population.

Increase in Serum Ca2+/Mg2+ Ratio Promotes Proliferation of Prostate Cancer Cells by Activating TRPM7 Channels

Background: Mg2+ concentration regulates MagNuM channels; however, their role in prostate cancer is not known. Results: TRPM7 functions as an endogenous MagNuM channel, which facilitates Ca2+ entry at low Mg2+ levels and promotes cell proliferation. Conclusion: Alteration in Ca2+/Mg2+ ratio could lead to prostate cancer. Significance: Learning how extra/intracellular Ca2+/Mg2+ ratio is regulated is crucial for understanding and/or diagnosis of prostate cancer. TRPM7 is a novel magnesium-nucleotide-regulated metal current (MagNuM) channel that is regulated by serum Mg2+ concentrations. Changes in Mg2+ concentration have been shown to alter cell proliferation in various cells; however, the mechanism and the ion channel(s) involved have not yet been identified. Here we demonstrate that TRPM7 is expressed in control and prostate cancer cells. Supplementation of intracellular Mg-ATP or addition of external 2-aminoethoxydiphenyl borate inhibited MagNuM currents. Furthermore, silencing of TRPM7 inhibited whereas overexpression of TRPM7 increased endogenous MagNuM currents, suggesting that these currents are dependent on TRPM7. Importantly, although an increase in the serum Ca2+/Mg2+ ratio facilitated Ca2+ influx in both control and prostate cancer cells, a significantly higher Ca2+ influx was observed in prostate cancer cells. TRPM7 expression was also increased in cancer cells, but its expression was not dependent on the Ca2+/Mg2+ ratio per se. Additionally, an increase in the extracellular Ca2+/Mg2+ ratio led to a significant increase in cell proliferation of prostate cancer cells when compared with control cells. Consistent with these results, age-matched prostate cancer patients also showed a subsequent increase in the Ca2+/Mg2+ ratio and TRPM7 expression. Altogether, we provide evidence that the TRPM7 channel has an important role in prostate cancer and have identified that the Ca2+/Mg2+ ratio could be essential for the initiation/progression of prostate cancer.

Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells.

Cholesterol has been shown to promote cell proliferation/migration in many cells; however the mechanism(s) have not yet been fully identified. Here we demonstrate that cholesterol increases Ca(2+) entry via the TRPM7 channel, which promoted proliferation of prostate cells by inducing the activation of the AKT and/or the ERK pathway. Additionally, cholesterol mediated Ca(2+) entry induced calpain activity that showed a decrease in E-cadherin expression, which together could lead to migration of prostate cancer cells. An overexpression of TRPM7 significantly facilitated cholesterol dependent Ca(2+) entry, cell proliferation and tumor growth. Whereas, TRPM7 silencing or inhibition of cholesterol synthesis by statin showed a significant decrease in cholesterol-mediated activation of TRPM7, cell proliferation, and migration of prostate cancer cells. Consistent with these results, statin intake was inversely correlated with prostate cancer patients and increase in TRPM7 expression was observed in samples obtained from prostate cancer patients. Altogether, we provide evidence that cholesterol-mediated activation of TRPM7 is important for prostate cancer and have identified that TRPM7 could be essential for initiation and/or progression of prostate cancer.

Does a higher ratio of serum calcium to magnesium increase the risk for postmenopausal breast cancer

Breast cancer is the most commonly diagnosed cancer among United States (US) women. Established risk factors explain only about 13% of breast cancer incidence among women in the US. Thus, the cause of most cases of breast cancer remains unknown. In postmenopausal women, serum calcium (Ca) and serum magnesium (Mg) play an important role in skeletal health, cell proliferation and cancer. Mg is essential for DNA duplication and repair and Mg deficiency favors DNA mutations leading to carcinogenesis. Dietary intake of Mg in the US is less than the recommended amount, and the deficit is more pronounced in older individuals where gastrointestinal and renal mechanisms for Mg conservation are not as efficient. Furthermore, healthy postmenopausal women are frequently recommended to take supplemental Ca, but not Mg and vitamin D to maintain bone and overall health. Most women with hormone sensitive breast cancer are recommended to take aromatase inhibitors, which causes bone loss and thus are generally prescribed Ca and vitamin D, but not Mg. Although the association between serum Ca and breast cancer risk remains controversial, we hypothesize that this may be because Mg levels have not been accounted for. Mg level directly influences transient receptor potential melastatin 7 (TRPM7) related Ca influx, calcium-adenosine triphosphatase (Ca-ATP) levels, and cell proliferation, and thereby could lead to cancer. Thus a high serum Ca/Mg ratio is more appropriate and alterations in this ratio could lead to increased development of new and recurrent breast cancer.

Serum calcium, tumor size, and hormone receptor status in women with untreated breast cancer.

Elevated serum levels of calcium are frequently observed in advanced breast cancer, but data on serum calcium and breast cancer characteristics at the time of breast cancer diagnosis are limited. We conducted a cross-sectional study of 555 women with newly-diagnosed, untreated breast cancer in North Dakota. We examined the relationship between tumor size, serum calcium and other clinical characteristics of breast tumors, including age and hormone receptor status, using multiple linear regressions. Tumors that were estrogen receptor negative tended to be associated with higher serum calcium levels (p = 0.07). We observed a significant positive correlation between tumor volume and serum calcium levels (adjusted for patient age, body mass index, hormonal receptors, stage at diagnosis, and grade). The association between tumor volume and serum calcium was limited to post-menopausal women. Our finding that postmenopausal women with larger breast tumors had significantly higher serum calcium levels is consistent with a calciotropic effect of early breast cancer in postmenopausal women.

Serum calcium levels, TRPM7, TRPC1, microcalcifications, and breast cancer using breast imaging reporting and data system scores

BACKGROUND An association between higher serum calcium (Ca2+) levels and breast cancer has been previously reported. However, little is known regarding the relationship between serum Ca2+ levels and the expression of Ca2+ channels in the presence of breast microcalcifications. METHODS A retrospective analysis of women newly diagnosed with breast microcalcifications was performed based on the Breast Imaging Reporting and Data System (BI-RADS). The expression of TRPC1, TRPC3, and TRPM7 using normal biopsy without microcalcifications (controls) and infiltrating ductal carcinoma with microcalcifications was evaluated. RESULTS Data on 138 women were analyzed. Seventy percent of women had a BI-RADS score (1-3) corresponding to benign disease. Seventy-six percent of women with a BI-RADS score (4 or 5) were diagnosed with breast cancer, 56% were cancers in situ, and 93% were infiltrating ductal carcinomas. No difference in the distribution of corrected serum Ca2+ levels between BI-RADS scores (1-3) and BI-RADS scores (4-5) (P = 0.82) was observed. Serum Ca2+ levels were similar in women without cancer and women diagnosed with breast cancer (P = 0.94). However, the expression of TRPM7 and TRPC1, but not TRPC3, Ca2+ channels were increased in infiltrating ductal carcinoma samples with microcalcifications when compared with age-matched controls without calcification or cancer. CONCLUSION We observed an increase in the expression of TRPM7 and TRPC1 Ca2+ channels in infiltrating ductal carcinoma samples with microcalcifications, whereas no change in serum Ca2+ levels was observed. Together these data suggest that increased expression of these channels might lead to an increase in intracellular Ca2+ levels thereby restoring serum Ca2+ levels, but these can contribute to the breast microcalcifications. However, future studies exploring the intracellular Ca2+ levels as well as the role of TRPM7 and TRPC1 function according to BI-RADS scores are needed.

Ovarian cancer incidence in the United States in relation to manufacturing industry.

Objective Ovarian cancer is primarily a disease of the industrialized world. However, few factors associated with industrialization that contribute to the etiology of ovarian cancer have been identified. We sought to explore factors potentially associated with ovarian cancer by correlating ovarian cancer incidence rates in US states with the distribution of US manufacturing. Methods Data on age-adjusted incidence rates for ovarian cancer per state in the United States and manufacturing rates per state were analyzed using multiple linear regression controlling for access to ovarian cancer care, fertility rate, and other potential confounders. Results In univariate analyses, ovarian cancer incidence rates were positively correlated with the extent of manufacturing, with dairy production, and with the manufacturing of pulp and paper. Using multiple linear regression, only the correlation of ovarian cancer with pulp and paper manufacturing industry was significant. The correlation of ovarian cancer with pulp and paper manufacturing industry remained significant after adjusting for access to ovarian cancer care, fertility rates, and other potential confounders (P < 0.05). Conclusions Pulp and paper mills are associated with exposures to known ovarian carcinogens. Further epidemiological study of exposures involved in the manufacturing of pulp and paper in relation to risk of ovarian cancer is warranted.

Statins Use and Risk for Brain Metastasis From Lung Cancer

Laboratory data suggest an association between statins and risk of brain metastasis (BM) in patients diagnosed with lung cancer. Our retrospective cohort included 252 patients diagnosed with lung cancer and 55 (22%) patients subsequently developed BM. The risk of BM was significantly higher in younger patients (p < .0007). The multivariable Cox model did not show a significant association between statin use and BM from lung cancer (Hazard-Ratio (HR) = 1.20, 95% confidence interval (CI): 0.68–2.13). Future studies should focus on late stage NSCLC and examine the incidence of BM among statin users at the time of death.