The Role of Statins in the Prevention of Ovarian and Endometrial Cancers.

Ovarian and endometrial cancers are the most common gynecologic malignancies and emerging evidence suggests that lipid metabolism and subsequent inflammation are important etiologic factors for both tumors. Statins (HMG-CoA reductase inhibitors) are the most widely prescribed lipid-lowering drugs in the United States and are used by 25% of adults aged 40+ years. In addition to their cardio-protective actions, statins have anti-inflammatory effects and have demonstrated antiproliferative and apoptotic properties in cancer cell lines, supporting a potential role in cancer prevention. To appropriately quantify potential public health impact of statin use for cancer prevention, there is a great need to understand the potential risk reduction among individuals at a higher risk of gynecologic cancers, the group that will likely need to be targeted to effectively balance risk/benefit of medications repurposed for cancer prevention. In this commentary, we focus on summarizing emerging evidence suggesting that the anti-inflammatory and lipid-lowering mechanisms of statins may provide important cancer-preventive benefits for gynecologic cancers as well as outline important unanswered questions and future research directions.

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. RESULTS: LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. CONCLUSIONS: LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Infiltrating T-cell markers in cervical carcinogenesis: a systematic review and meta-analysis.

BACKGROUND: The host adaptive immune response helps determine which cervical HPV infections persist and progress to precancer and cancer, and systematic characterisation of T-cell infiltration would help inform key steps in cervical carcinogenesis. METHODS: A systematic review and meta-analysis were conducted of infiltrating T-cells in normal cervix, low-grade lesions, high-grade lesions, and invasive cancers including epithelial, stromal, and total tissue and the following markers: CD3, CD4, CD8, FoxP3, CD25, and the CD4:CD8 ratio. An additional qualitative review summarised longitudinal data on associations between infiltrating T-cells and cervical disease persistence, regression, progression, or prognosis. RESULTS: There were fewer CD3+, CD4+, and CD8+ cells in cervical lesions and more cells in cancers compared to normal epithelium. FoxP3 and CD25+ regulatory T-cell infiltration is high in persistent and precancerous lesions, and longitudinal data show improved outcomes with lower regulatory T-cell levels. CONCLUSIONS: Successful immune evasion may reduce T-cell infiltration in HPV infected and precancerous epithelium, while invasive cancers are highly immunogenic, and regulatory T-cell infiltration increases with cervical disease progression. Understanding these factors may have prognostic value and could aid in novel treatment development and clinical guidelines, but published data are highly heterogeneous and leave important gaps to be filled by future studies.

Systematic review and meta-analysis of studies assessing the relationship between statin use and risk of ovarian cancer.

PURPOSE: The link between lipid-stabilizing medications and epithelial ovarian carcinogenesis is incompletely understood. Statins may reduce ovarian cancer risk, but results are inconclusive. METHODS: We conducted a systematic review and meta-analysis of studies reporting associations between statin use and ovarian cancer risk in PubMed. Summary risk ratios (RRs) and confidence intervals (CIs) were calculated. Subgroup analyses by cancer histotype, statin class (lipo- or hydrophilic) and duration of statin use were conducted. Use of individual statins in populations was assessed to determine population-specific differences in statin types. RESULTS: Nine studies with 435,237 total women were included (1 randomized controlled trial (RCT); 4 prospective; 4 case-control). Statin use was associated with a reduced risk of ovarian cancer (RR 0.87, 95% CI 0.74-1.03) and risk was significantly reduced in populations with low pravastatin use (RR 0.83, 95% CI 0.70-0.99). Risk estimates varied by statin class (3 studies; lipophilic: RR 0.88, 95% CI 0.69-1.12; hydrophilic: RR 1.06, 95% CI 0.72-1.57) and cancer histotype (3 studies; serous: RR 0.95, 95% CI 0.69-1.30; clear cell: RR 1.17, 95% CI 0.74-1.86). Long-term use was associated with a reduced risk of ovarian cancer (RR 0.77, 95% CI 0.54-1.10) that further reduced when pravastatin use was low (RR 0.68, 95% CI 0.46-1.01). Between-study heterogeneity was high overall and in subgroups (I2 > 60%). CONCLUSION: Statins may be associated with a reduced risk of ovarian cancer, but the effect likely differs by individual statin, duration of use and cancer histotype. Additional well-powered studies are needed to elucidate important subgroup effects.

Association of Anti-Mullerian Hormone, Follicle-Stimulating Hormone, and Inhibin B with Risk of Ovarian Cancer in the Janus Serum Bank.

BACKGROUND: Reproductive factors, including parity, breastfeeding, and contraceptive use, affect lifetime ovulatory cycles and cumulative exposure to gonadotropins and are associated with ovarian cancer. To understand the role of ovulation-regulating hormones in the etiology of ovarian cancer, we prospectively analyzed the association of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B with ovarian cancer risk. METHODS: Our study included 370 women from the Janus Serum Bank, including 54 type I and 82 type II invasive epithelial ovarian cancers, 49 borderline tumors, and 185 age-matched controls. We used conditional logistic regression to assess the relationship between hormones and risk of ovarian cancer overall and by subtype (types I and II). RESULTS: Inhibin B was associated with increased risk of ovarian cancer overall [OR, 1.97; 95% confidence interval (CI), 1.14-3.39; P trend = 0.05] and with type I ovarian (OR, 3.10; 95% CI, 1.04-9.23; P trend = 0.06). FSH was not associated with ovarian cancer risk overall, but higher FSH was associated with type II ovarian cancers (OR, 2.78; 95% CI, 1.05-7.38). AMH was not associated with ovarian cancer risk. CONCLUSIONS: FSH and inhibin B may be associated with increased risk in different ovarian cancer subtypes, suggesting that gonadotropin exposure may influence risk of ovarian cancer differently across subtypes. IMPACT: Associations between prospectively collected AMH, FSH, and inhibin B levels with risk of ovarian cancer provide novel insight on the influence of premenopausal markers of ovarian reserve and gonadotropin signaling. Heterogeneity of inhibin B and FSH effects in different tumor types may be informative of tumor etiology.

Achieving Protein Targets in the ICU Using a Specialized High-Protein Enteral Formula: A Quality Improvement Project.

BACKGROUND: To meet protein needs in critical illness (CI), guidelines suggest ≥1.2-2.5 g protein/kg/d; however, most intensive care unit (ICU) patients receive ≤0.7 g/kg/d. Higher protein enteral nutrition (EN) formulas may be part of the solution to provide prescribed protein. Our objective was to demonstrate that an EN formula with 37% protein can deliver ≥80% of prescribed protein, without overfeeding calories within the first 5 days of feeding and to describe ICU clinicians' experience. METHODS: This quality improvement (QI) project included patients requiring exclusive EN for up to 5 days from 6 Canadian ICUs. Rationale for choosing formula, patient's BMI (kg/m2 ), nutrition targets, daily protein and energy delivered, feeding interruptions, and general tolerance were recorded. RESULTS: Forty-four of 49 patients received the formula ≥2 days. Average protein prescribed was 137.5 g/d (82.5-200) or 1.9 g/kg/d (1.5-2.5). Average protein delivered was 116.9 g/d (33.5-180) or 1.6 g/kg/d (0.4-2.4). Seventy-five percent to 83% of patients received ≥80% prescribed protein on days 2-5. Average energy prescribed was 1638.6 kcal/d (990-2500) or 17.8 kcal/kg (11-26). Average energy delivered was 1523.9 kcal/d (693.0-2557.5) or 17.3 kcal/kg/d (1.35-64.7). The formula was well tolerated with no gastrointestinal symptoms reported in 38 (86%) patients. The most common reasons to prescribe the formula were obesity and use of fat-based medications. CONCLUSIONS: We demonstrated in a QI study that a high-protein EN formula was tolerated in a small, heterogeneous group of ICU patients and effective in meeting protein targets without overfeeding.

Acute Psychosis Following 1,1-Difluoroethane Inhalation.

Inhalants are often abused due to their ability to acutely induce feelings of euphoria. Difluoroethane is a toxic lipophilic hydrocarbon that crosses the blood-brain barrier and inhibits the central nervous system. Studies have shown the cardiac, renal, and respiratory effects it has when abused; however, our literature review yielded no previous report of acute psychosis after difluoroethane inhalation. In order to prevent poor outcomes by missed diagnosis, we present a case of difluoroethane-induced acute psychosis.

Plasma glucose and insulin response to two oral nutrition supplements in adults with type 2 diabetes mellitus.

OBJECTIVE: The purpose of this clinical trial was to compare the glucose usage of two oral nutritional supplement (ONS) products and to assess whether a diabetes-specific formulation provides improved glucose stabilization and management compared with a standard formula. RESEARCH DESIGN AND METHODS: A total of 12 subjects with type 2 diabetes (7 males and 5 females) completed a randomized, cross-over design trial. Each subject consumed isocaloric amounts of either the standard ONS or the diabetes-specific formula ONS on different dates, 1 week apart. Glucose and insulin measures were recorded at baseline, and 10, 20, 30, 60, 90, 120, 150, 180, 210 and 240 min after the beverage was consumed and then used to calculate area under the curve (AUC) for each subject. RESULTS: The mean glucose AUC was lower in the diabetes-specific ONS group than in the standard group (p<0.0001), but there was not a significant difference observed for mean insulin AUC (p=0.068). A sensitivity analysis of the mean insulin AUC measures was performed by removing a potential outlier from the analysis, and this resulted in a significant difference between the groups (p=0.012). First-phase insulin measures and an insulinogenic index calculated for the beverages showed no significant differences. CONCLUSIONS: On the basis of the results of this trial of 12 subjects, the diabetes-specific ONS appears to provide better glucose maintenance in persons with type 2 diabetes when compared to the standard formula ONS. TRIAL REGISTRATION NUMBER: NCT02612675.

Pathology and Quality of Life Outcomes Following Office-based Transperineal Prostate Biopsy.

OBJECTIVE: To report the incidence of prostate cancer diagnosis and quality of life outcomes following transperineal prostate biopsy. METHODS: Forty-six consecutive patients underwent office-based transperineal prostate biopsy for an elevated prostate-specific antigen and a normal digital rectal examination without prior prostate biopsy. Prior to biopsy, a repeat prostate-specific antigen was obtained to ensure persistent elevation. Silodosin (8 mg daily) was initiated the day prior to biopsy and continued for 1 week. A total of 18-20 biopsy cores were obtained per patient. All patients responded to a visual analog scale ranging from 0 to 10 immediately following the completion of both the local anesthesia and the biopsy procedure. In addition, an International Prostate Symptom Score (IPSS), Rectal Function Assessment Score, International Index of Erectile Function, Center for Epidemiologic Studies Depression Scale, and postvoid residual were obtained at baseline and 30 days following biopsy, except IPSS which was also obtained at day 7. RESULTS: The mean patient age was 63.3 years with a mean prostate volume of 41.8 cm(3). The mean visual analog scale was 4.2 for the local anesthesia and 3.0 for the biopsy. Thirty-one patients (67.4%) were diagnosed with prostate cancer, with 18 having a Gleason score ≥ 7. Compared to baseline, no adverse changes in IPSS, Rectal Function Assessment Score, International Index of Erectile Function, Center for Epidemiologic Studies Depression Scale, or postvoid residual were detected at day 30. No patient required catheterization, developed sepsis, or required hospitalization. CONCLUSION: Office-based transperineal prostate biopsy was well tolerated with reasonable treatment-related discomfort, a high rate of prostate cancer diagnosis, and the absence of significant morbidity including sepsis.

Dairy consumption and CVD: a systematic review and meta-analysis.

Inverse associations between dairy consumption and CVD have been reported in several epidemiological studies. Our objective was to conduct a meta-analysis of prospective cohort studies of dairy intake and CVD. A comprehensive literature search was conducted to identify studies that reported risk estimates for total dairy intake, individual dairy products, low/full-fat dairy intake, Ca from dairy sources and CVD, CHD and stroke. Random-effects meta-analyses were used to generate summary relative risk estimates (SRRE) for high v. low intake and stratified intake dose-response analyses. Additional dose-response analyses were performed. Heterogeneity was examined in sub-group and sensitivity analyses. In total, thirty-one unique cohort studies were identified and included in the meta-analysis. Several statistically significant SRRE below 1.0 were observed, namely for total dairy intake and stroke (SRRE=0·91; 95% CI 0·83, 0·99), cheese intake and CHD (SRRE=0·82; 95% CI 0·72, 0·93) and stroke (SRRE=0·87; 95% CI 0·77, 0·99), and Ca from dairy sources and stroke (SRRE=0·69; 95% CI 0·60, 0·81). However, there was little evidence for inverse dose-response relationships between the dairy variables and CHD and stroke after adjusting for within-study covariance. The results of this meta-analysis of prospective cohort studies have shown that dairy consumption may be associated with reduced risks of CVD, although additional data are needed to more comprehensively examine potential dose-response patterns.

Historical cancer incidence and mortality assessment in an Illinois community proximal to a former manufactured gas plant.

OBJECTIVES: Concern has been raised that the occurrence of cancer may be increased in neighbourhoods around a former manufactured gas plant in Champaign, Illinois, USA. Thus, we compared historical rates of cancer in this area to comparison communities as well as with nationally standardised rates. DESIGN: Retrospective population-based community cancer assessment during 1990-2010. SETTING: Champaign County, Illinois, USA, and zip codes encompassing the location of the former manufactured gas plant to counties that were similar demographically. PARTICIPANTS: Residents of the counties and zip codes studied between 1990 and 2010. MAIN OUTCOME MEASURES: The relative risk (RR) and 95% CI were used to compare cancer incidence and mortality in the areas near the gas compression site to the comparison counties. Standardised incidence ratios (SIRs) were calculated to compare rates in the areas near the gas compression site to expected rates based on overall US cancer rates. RESULTS: Total cancer mortality (RR=0.91, 95% CI 0.88 to 0.94) and incidence (RR=0.95, 95% CI 0.94 to 0.97) were reduced significantly in Champaign County versus the comparison counties. Similarly, a reduced rate of total cancer was observed in analyses by zip code (proximal to the former gas plant) when compared with either similar counties (RR=0.89, 95% CI 0.86 to 0.93) or national standardised rates of cancer (SIR=0.88, 95% CI 0.85 to 0.91). CONCLUSIONS: This historical cancer assessment did not find an increased risk of total cancer or specific cancer types in communities near a former manufactured gas plant site.