Statin use and breast cancer: do we need more evidence and what should this be?

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have been proved highly effective treatments for primary and secondary prevention of cardiovascular diseases. Despite widespread and long-term use of statins, there is still a debate concerning their association with cancer at various sites, including breast. As of today, the accumulated epidemiological evidence does not support the hypothesis that statin use affects the risk of developing breast cancer when taken at low doses for managing hypercholesterolemia. However, current evidence cannot exclude an increased risk of breast cancer with statin use in subsets of individuals, for example, the elderly. On the other hand, some studies show that statins might be useful to prevent recurrence and improve survival in patients already suffering from certain breast cancer types. They could also be combined with certain anticancer drugs and potentiate their effects, ameliorate their side effects or prevent the development of resistance. Further research is warranted to clarify these issues.

Topotecan and pegylated liposomal doxorubicin combination as palliative treatment in patients with pretreated advanced malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive disease with poor or modest responses to chemotherapy and dismal prognosis. In most of the cases the scope of the treatment is only palliative. In the current study, the combination of i.v. topotecan and pegylated liposomal doxorubicin (PLD) in advanced multi-treated MPM was tested. Primary objective was palliation of the symptoms, with the secondary ones being the establishment of the regimen's safety and efficacy. PATIENTS AND METHODS: Nine patients were enrolled (7 males/2 females, median age 57.5 years, ECOG performance status ≤ 2), having progressed after 2 or 3 lines of chemotherapy including pemetrexed and cisplatin. Main symptoms were dyspnea, cough, chest pain, fatigue, and anorexia. The treatment included topotecan 1.2 mg/m2 i.v. on Days 1 - 3 and PLD 40 mg/m2 on Day 4, every 28 days. The patients received 4 - 8 chemotherapy cycles (median 5.8). RESULTS: In all cases, symptoms were significantly improved after the 2nd treatment cycle. Respiratory function tests showed considerable enhancement, while cough and pain were drastically reduced. All patients had objective clinical benefit, 1 patient achieving partial response and 8 stable disease. Median time to progression and overall survival was 7 and 9 months, respectively. The chosen dose of the topotecan/ PLD combination was well-tolerated with no Grade 3/4 toxicities. Quality of life, as it was evaluated by the QLQ-C30 and QLQLC13 questionnaires, had improved scores especially the ones referring symptomatology. CONCLUSION: The current study shows a significant palliative effect of the topotecan/ PLD combination in pretreated patients with advanced MPM.

Indications for an alternative effective treatment of head and neck squamous cell carcinoma with temsirolimus plus bevacizumab: from bench to bedside?

Head and neck squamous cell carcinoma (HNSCC) is a group of tumors known to be sensitive to chemotherapy and radiotherapy in patients who are treatment naive. However, when recurrences do occur, these tumors generally become resistant and objective responses to therapy at that point tend to be less effective. There has been an increasing interest in developing novel molecular-targeted agents that specifically modulate growth factor and signaling pathways that are unregulated in HNSCC tumor cells. Combinations of vascular endothelial growth factor and mammalian target of rapamycin inhibitors have been used in some types of neoplasms, but no such efforts have been made in HNSCC. In this study, we investigated the in vitro, in vivo, and clinical effects of the temsirolimus (mammalian target of rapamycin inhibitor, Tem) and bevacizumab (antivascular endothelial growth factor antibody, Bev) combination. In-vitro studies were carried out on the A431 human squamous epidermoid carcinoma cell line and in-vivo studies were carried out on A431 tumor cells implanted on female Nu/Nu*nuBR (athymic nude) mice. Also, the effectiveness of the Tem and Bev combination was tested clinically in two separate clinical cases of chemoresistant HNSCC. The in-vitro, in-vivo, and clinical results showed that this combination can be significantly effective. In conclusion, we discuss the theoretical basis of the molecular pharmacological interactions between Bev and Tem that could explain these good results. If the therapeutic index is ultimately well determined, the antitumor effect of Bev and Tem is very likely to yield fruitful results.

The controversy over the association between statins use and progression of age-related macular degeneration: a mini review.

OBJECTIVE: Age-related macular degeneration (AMD) is the leading cause of blindness in western societies. Statins comprise a class of pharmacological agents that reduce plasma cholesterol levels, and have been shown to prevent progression of atherosclerosis and reduce cardiovascular mortality. The relationship between these medications and AMD has been evaluated in several recent studies. Herein, we examine the current evidence for an association between statin use and risk of AMD. METHODS: Literature database search (Medline, Scopus, and Science Citation Index Expanded) for articles published up to March 2010, using particular search terms. RESULTS: From the current evidence available, it is not safe to conclude upon the assumption of a protective effect of statins against age-related maculopathy and AMD. CONCLUSION: There is a need for large scale prospective studies with a long follow-up period and accurate assessment of AMD to further explore this matter.

Can statin therapy reduce the risk of melanoma? A meta-analysis of randomized controlled trials.

A growing body of literature suggests that statins may have a chemopreventive potential against melanoma through pleiotropic anti-inflammatory, immunomodulatory, and antiangiogenesis mechanisms. Our aim was to examine this association through a detailed meta-analysis of randomized controlled trials (RCTs). A comprehensive search for trials published up to June 2009 was performed, reviews of each study were conducted and data were abstracted. Prior to meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates (RR) and 95% confidence intervals (CIs) were calculated using the fixed- and the random-effects models. Subgroup and sensitivity analyses were also conducted. Sixteen RCTs of statins for cardiovascular outcomes, involving 62,568 individuals with a mean age of 60 years and an average follow-up of nearly 4.7 years, contributed to the analysis. We found no evidence of publication bias (P = 0.47) or heterogeneity among the studies (P = 0.25). Statin use did not significantly affect the risk of developing melanoma assuming either a fixed- (RR = 0.92, 95% CI: 0.67-1.26), or a random-effects model (RR = 0.92, 95% CI: 0.62-1.36). This neutral effect was further supported by the results of subgroup and sensitivity analyses. Our findings do not support a protective effect of statins against melanoma.

HIV/AIDS: recent advances in antiretroviral agents.

Despite the considerable progress in antiretroviral therapy, the eradication of HIV-1 remains unfeasible. Therefore, novel agents are under investigation. The aim of this review is to summarize the conventional compounds, to describe the recently approved agents, and to take a comprehensive look at the clinically relevant findings of current research.

The diagnostic role of glycosaminoglycans in pleural effusions: a pilot study.

BACKGROUND: Pleural effusions are classified into transudates and exudates. Various criteria have been used with Light's et al being the most accepted ones. Glycosaminoglycans (GAGs) have been detected during pleural fluids (PF) analysis in various causes. In this pilot study, we investigated: (a) the usefulness of GAGs in the assessment of pleural effusions, and (b) whether and in what way GAGs correlate with established criteria used to indicate an exudate. METHODS: LDH, total protein, cholesterol and GAG levels were measured in pleural fluid and serum from 50 patients with pleural effusion. GAG levels were defined by the photometric method of Hata. The discriminative properties of pleural GAGs (pGAG), pleural fluid/serum GAG ratio (GAGR), serum GAGs (sGAG) and serum LDH (sLDH) were explored with ROC analysis. RESULTS: According to ROC analysis, pGAG and GAGR exhibited satisfactory discriminative properties in the separation of pleural effusions. For GAGR, at a 1.1 cut off point, sensitivity and specificity reached 75.6%; 95%CI: 60.5-87.1 and 100%; 95%CI: 47.8-100, respectively. For pGAG at a cut off value of 8.4 microg/ml, these percentages changed to 86.7%; 95%CI: 73.2-94.9 and 100%; 95%CI: 47.8-100. The study also revealed the differential role of sGAG between malignancies and benign cases, scoring 68.8%; 95%CI: 50.0-83.9 for sensitivity, and 84.6%; 95%CI: 54.5-97.6 for specificity at a 7.8 microg/ml cut off. CONCLUSION: Our results suggest that glycosaminoglycan measurement of both serum and pleural effusions could be useful for simultaneous differentiation of exudates from transudates, and of malignant from benign exudates.

Statins are not associated with a reduced risk of pancreatic cancer at the population level, when taken at low doses for managing hypercholesterolemia: evidence from a meta-analysis of 12 studies.

OBJECTIVES: Recent experimental research on a class of pharmacological agents that reduce plasma cholesterol, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), has shown promise in pancreatic cancer chemoprevention. While the mechanism remains unclear, several epidemiological studies have also evaluated the relationship between statin use and pancreatic cancer. Our aim was to examine the strength of this association through a detailed meta-analysis of the studies published on the subject in peer-reviewed literature. METHODS: A comprehensive search for articles published up to December 2007 was performed, reviews of each study were conducted, and data were abstracted. Prior to meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. RESULTS: Twelve studies (3 randomized placebo-controlled trials [RCTs], 4 cohort, and 5 case-control studies) contributed to the analysis. The studies were grouped on the basis of study design, and separate meta-analyses were conducted. There was no evidence of an association between statin use and pancreatic cancer among either the RCTs (RR 0.99, 95% CI 0.44-2.21) or the observational studies (RR 0.86, 95% CI 0.60-1.24). Similarly, we found no evidence of publication bias. However, a high heterogeneity was detected among the observational studies. CONCLUSION: Despite the chemopreventive potential of statins demonstrated in experimental studies, our results do not support the hypothesis that these agents reduce the risk of pancreatic cancer at the population level, when taken at low doses for managing hypercholesterolemia.

Cancer chemoprevention: a summary of the current evidence.

Cancer chemoprevention is defined as the use of natural, synthetic, or biological chemical agents to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. At present, the circle of agents with an established chemopreventive effect is restricted to tamoxifen and raloxifene in breast cancer, finasteride in prostate cancer, and celecoxib in colon polyp prevention. However, in recent years, there has been an exponential increase in the study of agents that have a chemopreventive potential against cancer. In this review, the current evidence regarding cancer chemoprevention in major target organs is summarised, discussing the epidemiological as well as the experimental data.

Statin use and the risk of prostate cancer: A metaanalysis of 6 randomized clinical trials and 13 observational studies.

Statins have been suggested to prevent prostate cancer. Our aim was to examine statin use in relation to both total prostate cancer and the more clinically important advanced prostate cancer, through a detailed metaanalysis of the epidemiologic studies published on the subject in peer-reviewed literature. A comprehensive search for articles published up to November 2007 was performed, reviews of each study were conducted and data were abstracted. Prior to metaanalysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Subgroup and sensitivity analyses were also performed. Nineteen studies [6 randomized clinical trials (RCTs), 6 cohort and 7 case-control studies] contributed to the analysis. There was no evidence of an association between statin use and total prostate cancer among either RCTs (RR = 1.06, 95% CI: 0.93-1.20) or the observational studies (RR = 0.89, 95% CI: 0.65-1.24). However, high heterogeneity was detected among the observational studies. Moreover, long-term statin use did not significantly affect the risk of total prostate cancer (RR = 0.93, 95% CI: 0.77-1.13). In contrast, synthesis of the available reports that had specifically examined statin use in relation to advanced prostate cancer indicated a protective association (RR = 0.77, 95% CI: 0.64-0.93). Our results do not support the hypothesis that statins reduce the risk of total prostate cancer. However, further research is required to investigate whether the particular association of statin use with lower risk of advanced prostate cancer is indeed causal.

Monitoring aspirin treatment in patients with thrombocytosis: comparison of the platelet function analyzer (PFA)-100 with optical aggregometry.

Aspirin provides satisfactory protection against thrombotic episodes in essential thrombocythemia (ET), but at higher platelet counts has been less effective. Our aim was to compare the platelet function analyzer (PFA)-100 with optical aggregometry in order to determine a reliable method in monitoring aspirin's influence on platelet function in patients with thrombocytosis. We studied 36 patients with thrombocytosis. Sixteen of them, receiving aspirin, composed group A, while group B consisted of 20 patients not taking aspirin. In all patients, we compared the platelet function measured by classic optical aggregation tests with closure times (CT) obtained by the PFA-100. The definition of platelet responses as normal or pathological showed that PFA-100 collagen and/or epinephrine (CEPI) CTs and epinephrine-induced aggregometry is the pair of methods with the higher agreement in monitoring of platelet dysfunction due to ASA treatment (a=94%). Satisfactory results were also obtained for group B (a=81%). The comparison between PFA-100 CEPI CTs and arachidonic acid-induced aggregometry exhibited moderate agreement both in the total number of patients and in group A (a=79% and 94%, respectively). PFA-100 collagen and/or ADP (CADP) CTs and ADP-induced aggregometry were not concordant. The PFA-100 system appears to be a reliable and rapid method in the assessment of aspirin's antiplatelet effect in patients with thrombocytosis. Regarding aggregometry, the selection of the inducer, its concentration and cut-off points is crucial in defining the response to antiaggregating agents. It still remains to determine whether there is any relevance between the measurements obtained by these methods and clinical outcome in thrombocythemic patients.

Statins and the risk of colorectal cancer: a meta-analysis of 18 studies involving more than 1.5 million patients.

PURPOSE: Statins have been suggested to prevent colorectal cancer. Several epidemiologic studies have evaluated this association, whereas randomized controlled trials (RCTs) on cardiovascular outcomes provide relevant data as a secondary end point. Our aim was to examine the strength of this association through a detailed meta-analysis of the studies published on the subject in peer-reviewed literature. METHODS: A comprehensive search for studies published up to December 2006 was performed, reviews of each study were conducted, and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates with 95% CIs were calculated using the fixed- and random-effects models. RESULTS: Eighteen studies involving more than 1.5 million participants contributed to the analysis. They were grouped on the basis of study design, and separate meta-analyses were conducted. There was no evidence of an association between statin use and risk of colorectal cancer either among RCTs (RR = 0.95; 95% CI, 0.80 to 1.13; n = 6) or among cohort studies (RR = 0.96; 95% CI, 0.84 to 1.11; n = 3). However, statin use was associated with a modest reduction in the risk of colorectal cancer among case-control studies (RR = 0.91; 95% CI, 0.87 to 0.96; n = 9). Low evidence of publication bias or heterogeneity was found. CONCLUSION: Our meta-analysis results do not support the hypothesis that statins strongly reduce the risk of colorectal cancer, when taken for management of hypercholesterolemia. However, we cannot rule out a modest reduction in risk or an effect associated with higher doses of statins.