Effect of cigarette smoking on epithelial ovarian cancer survival.

OBJECTIVE: To determine associations between smoking and survival in patients with ovarian cancer. STUDY DESIGN: We performed a retrospective review of patients undergoing surgery for ovarian cancer. Abstracted patient data included age, smoking history, stage, grade, extent of cytoreduction, and survival. Data were examined with Fisher's exact test, Kaplan-Meier survival analysis, and Cox regression analysis. RESULTS: A total of 130 patients met criteria for review. Seventeen (13%) smoked cigarettes at the time of initial laparotomy. Twenty-one (16%) were left with > 1 cm residual disease. Smoking did not correlate with the incidence of suboptimal cytoreduction. There were no statistical differences in incidence of hypertension, obesity, or coronary artery disease in smokers compared to nonsmokers. Smoking was found to negatively influence length of progression-free survival. Similarly, smokers were found to have decreased disease-specific overall survival compared to nonsmokers. Cigarette smoking retained independent significance as poor prognostic factors, after controlling for age, stage, and grade. CONCLUSION: These findings identify a negative correlation with cigarette smoking and survival in women with ovarian cancer. Further studies are proposed to elucidate the molecular mechanisms underlying these clinical observations.

Serum low-density lipoprotein levels correlate with survival in advanced stage epithelial ovarian cancers.

OBJECTIVE: Recent data suggest patients with epithelial ovarian cancers on statin therapy have improved survival. We have hypothesized that statins influence ovarian cancer outcome through alteration of lipoprotein profiles, and sought to determine correlations between lipoprotein levels and survival in women with advanced stage disease. METHODS: After IRB approval, we identified patients with stage IIIC/IV epithelial ovarian cancer with banked prediagnostic fasting serum. Serum was assayed for levels of total cholesterol (TC), high-density lipoprotein (HDL), and triglycerides (TG). LDL was calculated by subtraction of TG/5 and HDL from TC. Data were examined using Fisher's exact, Kaplan-Meier, and Cox regression analyses. RESULTS: One hundred thirty-two patients were studied. Twenty-six percent of patients had elevated LDL; 18% had elevated TC; 32% had elevated TG; and 48% had elevated HDL. No univariate associations were identified between elevated TC, HDL, TG, LDL and age, stage IV disease, high grade, or optimal cytoreduction. Median progression-free survival for patients with normal LDL levels was 27 months, compared to 12 months for patients with elevated LDL (p=0.0004). Overall disease-specific survival was longer for patients with normal LDL levels (59 months) compared to those with elevated LDL (51 months, p=0.04). Multivariate analysis indicated that LDL retained significance as an independent predictor of survival, after controlling for age, stage, grade, and suboptimal cytoreduction (p=0.003). CONCLUSIONS: These data suggest LDL is a significant predictor of clinical outcome, and warrant the further study of lipoproteins and statins on epithelial ovarian cancer biology.

Impact of statin therapy on survival in epithelial ovarian cancer.

OBJECTIVE: 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, are common therapeutic agents in the management of dyslipidemias. Epidemiologic and pharmacologic data also suggest statins have an effect on cancer biology. We sought to determine the association between use of statins and epithelial ovarian cancer survival, disease progression, and clinico-pathologic factors. METHODS: After IRB approval, we performed a retrospective review of all patients with advanced stage (III/IV) epithelial ovarian or primary peritoneal cancer undergoing primary cytoreductive surgery by a gynecologist oncologist between 6/1996 and 6/2001. Abstracted data included statin use at time of initial cytoreductive surgery, as well as clinico-pathologic factors and survival. Statistical analysis included Fisher's exact test, Kaplan-Meier survival, and Cox regression analyses. RESULTS: 126 patients met criteria for review. Seventeen (14%) patients were undergoing concurrent statin therapy at time of initial cytoreductive surgery. Statin users were statistically older (median age 67 years, versus 60 years for non-users, p=0.002) and had a greater incidence of diabetes mellitus (18% versus 3% in non-users, p=0.03). Of the entire cohort, 21 patients (17%) were suboptimally cytoreduced after initial surgery, with residual disease N1 cm; statin use did not correlate with incidence of optimal resection (p=0.3). Median progression-free survival for statin users was 24 months, compared to 16 months for statin non-users (p=0.007). Similarly, overall survival was significantly longer for statin users (62 months) compared to statin non-users (46 months, p=0.04). Multivariable analysis identified statin use as an independent positive prognostic factor, after controlling for age, stage, grade, and suboptimal cytoreduction (p=0.02). CONCLUSIONS: These data indicate statin use in patients diagnosed with epithelial ovarian cancer is associated with improved survival, and suggest a potential suppressive impact of HMG-CoA reductase inhibitors on tumor biology. Studies are proposed to explore the molecular mechanisms underlying these clinical observations.

Hyperandrogenism, mediated by obesity and receptor polymorphisms, promotes aggressive epithelial ovarian cancer biology.

OBJECTIVE: Epidemiologic data suggest that aberrant androgen homeostasis may promote aggressive epithelial ovarian cancer biology. Hyperandrogenism results from both obesity and expression of polymorphic androgen receptor (AR) allelotypes harboring short cytosine-adenine-guanine (CAG) repeat sequences; both have been shown to independently correlate with poor overall survival in ovarian cancer. We have hypothesized that the combination of these factors further manifests an aggressive ovarian cancer phenotype. METHODS: Genotype analysis of the AR CAG polymorphism was performed on 81 patients with papillary serous epithelial ovarian cancer. Medical records were reviewed for body mass index (BMI), clinico-pathologic factors, and survival. Data were examined using the Fishers exact test, Kaplan-Meier survival, and Cox regression analyses. RESULTS: Overweight or obese women (BMI > or = 25) with a short AR allele (< or = 19 CAG repeats) demonstrated statistically shorter progression-free survival (9 months) when compared to underweight or ideal body weight women (BMI < 25) and a long AR allele (> 19 CAG repeats; 26 months, p=0.0002). Overweight/obese women with a short AR allele also demonstrated shorter overall survival (34 months) when compared to underweight/ideal body weight women with a long AR allele (59 months, p=0.036). On multivariate analyses, the combination of a short AR allele and BMI > 25 was an independent poor prognostic factor after controlling for age, stage, grade, optimal cytoreduction, and AR allele length and BMI independently (p=0.05). CONCLUSION: These data provide further evidence that suggest that hyperandrogenism promotes an aggressive epithelial ovarian cancer phenotype.

Lack of response to all-trans retinoic acid supplementation in adult dogs following left pneumonectomy.

We showed previously that removing 55-58% of the lung by right pneumonectomy (R-PNX) in adult dogs triggers compensatory growth of the remaining lung, but removing 42-45% of the lung by left PNX (L-PNX) does not. We also showed that, following R-PNX, supplemental all-trans retinoic acid (RA) selectively enhances alveolar capillary endothelial cell volume (Yan X, Bellotto DJ, Foster DJ, Johnson RL, Jr., Hagler HH, Estrera AS, and Hsia CC. J Appl Physiol 96: 1080-1089, 2004). We hypothesized that RA supplementation might enhance compensation following L-PNX and tested this hypothesis by administering RA (2 mg.kg(-1).day(-1), 4 days/wk) or placebo orally to litter-matched adult foxhounds for 4 mo following L-PNX. Resting lung function was measured under anesthesia. Air and tissue volumes of the remaining lung were assessed by high-resolution computed tomography scan and by detailed postmortem morphometric analysis of the fixed lung. There was no significant difference in resting lung function, lung volume, alveolar structure, or septal ultrastructure between RA and placebo treatment groups. We conclude that RA supplementation does not induce post-PNX compensatory lung growth in the absence of existing cellular growth activities initiated by other primary signals.