Preet Paul Singh

Statins Are Associated With a Reduced Risk of Hepatocellular Cancer: A Systematic Review and Meta-analysis

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Several studies have shown that statins could have chemopreventive effects on HCC. We performed a systematic review and meta-analysis of studies that evaluated the effects of statins on the risk of HCC. METHODS We conducted a systematic search of MEDLINE, Embase, and Web of Science through May 2012 and manually reviewed the literature. Studies were included if they evaluated and clearly defined exposure to statins, reported the incidence of HCC, and reported relative risks or odds ratios (ORs) or provided data for their estimation. Ten studies reporting 4298 cases of HCC in 1,459,417 patients were analyzed. Summary OR estimates with 95% confidence intervals (CIs) were calculated using the random effects model. Statistical heterogeneity was assessed with the Cochrans Q statistic and I(2) statistic. RESULTS Statin users were less likely to develop HCC than statin nonusers (adjusted OR, 0.63; 95% CI, 0.52-0.76), although the results were heterogeneous (P = .01, I(2) = 59%). This heterogeneity could be accounted for by study location (Asian population [n = 4]: adjusted OR, 0.52; 95% CI, 0.42-0.64; Western population [n = 6]: adjusted OR, 0.67; 95% CI, 0.53-0.85) and design (observational studies [n = 7]: adjusted OR, 0.60; 95% CI, 0.49-0.73; clinical trials [n = 3]: adjusted OR, 0.95; 95% CI, 0.62-1.45). CONCLUSIONS Based on meta-analysis, statin use is associated with a reduced risk of HCC, most strongly in Asian but also in Western populations. Randomized clinical trials in populations at high risk for HCC (especially in Asian populations with hepatitis B) are warranted.

Chemopreventive strategies in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well-designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents.

Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis

Background and aims Acid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barretts oesophagus (BO). We performed a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BO-HGD) in patients with BO. Methods We performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated. Results We identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta-analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose–response relationship with PPI use for >2–3 years protective against OAC or BO-HGD (three studies; PPI use >2–3 years vs <2–3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect. Conclusions Based on meta-analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.

Statins Are Associated with Reduced Risk of Esophageal Cancer, Particularly in Patients with Barrett’s Esophagus: A Systematic Review and Meta-Analysis

BACKGROUND & AIMS The incidence of esophageal cancer is increasing in the United States, especially among patients with Barretts esophagus (BE). Statins might prevent this cancer. We performed a systematic review with a meta-analysis of studies that evaluated the effect of statins on the risk of esophageal cancer. METHODS We conducted a systematic search of Medline, Embase, and Web of Science through August 2012. Studies were included if they evaluated exposure to statins, reported the development of esophageal cancer, and reported relative risks or odds ratios (OR), or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were calculated using the random-effects model. The analysis included 13 studies (including a post hoc analysis of 22 randomized controlled trials) reporting 9285 cases of esophageal cancer among 1,132,969 patients. RESULTS A meta-analysis of the studies showed a significant (28%) reduction in the risk of esophageal cancer among patients who took statins (adjusted OR, 0.72; 95% CI, 0.60-0.86), although there was considerable heterogeneity among studies. In analyzing a subset of patients known to have BE (5 studies, 312 esophageal adenocarcinomas [EAC] developed in 2125 patients), statins were associated with a significant (41%) decrease in the risk of EAC, after adjusting for potential confounders (adjusted OR, 0.59; 95% CI, 0.45-0.78) with consistent results among all studies. The number needed to treat with statins to prevent 1 case of EAC in patients with BE was 389. CONCLUSIONS Based on meta-analysis of observational studies, statin use may be associated with lower risk of esophageal cancer, particularly risk of EAC in patients with BE.

Prevalence, risk factors, and outcomes of interval colorectal cancers: a systematic review and meta-analysis.

OBJECTIVES:We performed meta-analysis to estimate pooled prevalence, risk factors, and outcomes of interval colorectal cancers (CRCs).METHODS:Systematic literature search through October 2013, identified population-based studies, reporting prevalence of interval CRCs (CRCs diagnosed within 6–36 months of colonoscopy). We estimated the pooled prevalence, patient, endoscopist, and tumor-related risk factors, as well as outcomes of interval CRCs, as compared with detected CRCs (CRCs diagnosed at or within 6 months of colonoscopy).RESULTS:Twelve studies reporting on 7,912 interval CRCs were included. Pooled prevalence of interval CRCs was 3.7% (95% confidence interval (CI)=2.8–4.9%). These cancers were 2.4 times more likely to arise in the proximal colon (6.5%; 95% CI=4.9–8.6%) as compared with distal colon (2.9%; 95% CI=2.0–4.2%). Patients with interval CRCs were older (age >65–70 years vs. <65–70 years: odds ratio (OR)=1.15; 95% CI=1.02–1.30), have more comorbidities (high Charlson comorbidity index: OR=2.00; 95% CI=1.77–2.27), and have diverticular disease (OR=4.25; 95% CI=2.58–7.00). There was a nonsignificant time trend of declining prevalence of interval CRCs from 4.8% in 1990s to 4.2% between 2000 and 2005 and 3.7% beyond 2005. Patients with interval CRCs were less likely to present at an advanced stage (OR=0.79; 95% CI=0.67–0.94), although there was no survival benefit. Considerable heterogeneity was observed in most of the analyses.CONCLUSIONS:Based on meta-analysis, approximately 1 in 27 CRCs are interval CRCs, although the confidence in these estimates is low because of the heterogeneity among the studies. These are more likely to arise in the proximal colon and are diagnosed in older patients, patients with comorbidities or diverticular disease.

Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: A systematic review and meta-analysis

OBJECTIVES:Several preclinical and observational studies have shown that anti-diabetic medications (ADMs) may modify the risk of pancreatic cancer (PaC). We performed a systematic review and meta-analysis evaluating the effect of metformin, sulfonylureas (SUs), thiazolidinediones (TZDs), and insulin on the risk of PaC in patients with diabetes mellitus (DM).METHODS:We conducted a systematic search of Medline, EMBASE, and Web of Science, up to June 2012, and published abstracts from major gastroenterology and oncology meetings from 2003 to 2012. Studies were included if they (1) evaluated and clearly defined exposure to metformin, SU, TZDs, and/or insulin, (2) reported PaC outcomes in patients with DM and (3) reported relative risks or odds ratio (OR) or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CIs) were estimated using the random-effects model.RESULTS:Eleven studies (6 cohort, 3 case-control, and 2 randomized controlled trials (RCTs)) reported 1770 cases of PaC in 730,664 patients with DM. Meta-analysis of observational studies showed no significant association between metformin (n=9 studies; adjusted OR 0.76, 95% CI 0.57–1.03, P=0.073), insulin (n=7 studies; adjusted OR 1.59, 95% CI 0.85–2.96, P=0.144), or TZD (n=4 studies; adjusted OR 1.02, 95% CI 0.81–1.30, P=0.844) use and risk of developing PaC. Use of SU was associated with a 70% increase in the odds of PaC (n=8 studies; adjusted OR 1.70, 95% CI 1.27–2.28, P<0.001). There was considerable inherent heterogeneity between studies not explained by study design, setting, or comparator drug and is likely related to confounding by indication and reverse causality. The pooled analyses of the two RCTs were underpowered and provided non-significant results with wide, non-informative 95% CIs.CONCLUSIONS:Although SU seems to be associated with increased risk of PaC, meta-analysis of existing studies does not support a protective or harmful association between ADM use and risk of PaC in patients with DM. There was considerable heterogeneity across studies, and future, well-designed, prospective studies would be required to understand this association better.

YouTube for Information on Rheumatoid Arthritis — A Wakeup Call?

Objective. Rheumatoid arthritis (RA) is a common debilitating autoimmune disease, with unmet need for knowledge among patients and the general population. YouTube is a popular, consumer-generated, video-sharing website, which can be a source of information on RA. We investigated the quality of information on RA on YouTube and analyzed audience interaction. Methods. YouTube was searched using the term “Rheumatoid Arthritis,” for videos uploaded on RA. Two physicians independently classified videos as useful, misleading, or patient views, and rated them on a 5-point global quality scale (GQS; 1 = poor quality, 5 = excellent quality). Useful videos were rated for reliability and content, on a 5-point scale (higher scores represent more reliable and comprehensive videos). Source of videos was also noted. Audience interaction was assessed through video viewership. Results. A total of 102 relevant videos were identified; 54.9% were classified as useful (GQS 2.9 ± 1.0) and 30.4% deemed misleading (GQS 1.3 ± 1.6). Mean reliability and content score of useful videos was 3.2 (± 1.0) and 2.5 (± 1.2), respectively. All videos uploaded by university channels and professional organizations provided useful information but formed only 12.7% of total videos, whereas 73.9% of medical advertisements and videos by for-profit organizations were misleading. There was no difference in the viewership/day (10.0 vs 21.5; p = nonsignificant) of useful and misleading information. Conclusion. YouTube is a source of information on RA, of variable quality, with wide viewership and potential to influence patients’ knowledge and behavior. Physicians and professional organizations should be aware of and embrace this evolving technology to raise awareness about RA, and empower patients to discriminate useful from misleading information.

Quantification of clonal circulating plasma cells in newly diagnosed multiple myeloma: implications for redefining high-risk myeloma

The presence of clonal circulating plasma cells (cPCs) is a marker of high-risk disease in all stages of monoclonal gammopathies. However, the prognostic utility of quantitating cPCs using multiparametric flow cytometry in multiple myeloma (MM) patients with current treatments is unknown. There were 157 consecutive patients with newly diagnosed MM seen at the Mayo Clinic, Rochester from 2009 to 2011 that had their peripheral blood evaluated for cPCs by multiparameter flow cytometry. Survival analysis was performed by the Kaplan–Meier method and differences assessed using the log-rank test. Using a receiver operating characteristics (ROC) analysis, ⩾400 cPCs were considered as the optimal cutoff for defining high-risk disease. The presence of ⩾400 cPCs was associated with higher plasma cell (PC) proliferation and adverse cytogenetics. The median time-to-next-treatment and overall survival (OS) in patients with ⩾400 cPCs (N=37, 24%) was 14 months and 32 months compared with 26 months and not reached for the rest (P<0.001). In a multivariable model, the presence of ⩾400 cPCs and older age adversely affected OS. Flow cytometry to quantify cPCs is a valuable test for risk stratifying newly diagnosed MM patients in the era of novel agents. Future studies are needed to determine its role in developing a risk-adapted treatment approach.

Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study

BACKGROUND Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA. METHODS We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169. RESULTS We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported. INTERPRETATION To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease. FUNDING National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.

Antidiabetic Medications and the Risk of Colorectal Cancer in Patients with Diabetes Mellitus: A Systematic Review and Meta-analysis

Background: Antidiabetic medications (ADM) may modify colorectal cancer risk in patients with diabetes mellitus. We performed a systematic review and meta-analysis, evaluating the effect of metformin, thiazolidinediones (TZD), sulfonylureas, and insulin on colorectal cancer risk in diabetic patients. Methods: We conducted a systematic search of multiple bibliographic databases, up to September 2012, for articles that evaluated exposure to metformin, TZD, sulfonylureas, and insulin, reported colorectal cancer risk in patients with diabetes mellitus, and reported OR or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were estimated using the random-effects model. Results: Fifteen studies reporting 13,871 cases of colorectal cancer in 840,787 patients with diabetes mellitus were included. Meta-analysis of observational studies showed an 11% reduction in colorectal cancer risk associated with metformin use (n = 9 studies; OR, 0.89; 95% CI, 0.81–0.99), whereas TZD use was not associated with colorectal cancer risk (n = 5 studies; OR, 0.96; 95% CI, 0.87–1.05). Conversely, a trend toward higher colorectal cancer risk was observed with sulfonylurea (n = 7 studies; OR, 1.11; 95% CI, 0.97–1.26) and insulin (n = 9 studies; OR, 1.33; 95% CI, 0.91–1.94) use, although these associations were not statistically significant. There was considerable heterogeneity across studies, partly explained by study location and adjustment for concomitant use of other ADMs. Post-hoc analysis of randomized controlled trials did not reveal any significant association between ADM and colorectal cancer risk. Conclusions: Meta-analysis of published studies supports a protective association between metformin use and colorectal cancer risk in patients with diabetes mellitus. Impact: Clinical trials on the chemopreventive effect of metformin against colorectal cancer are warranted. Cancer Epidemiol Biomarkers Prev; 22(12); 2258–68. ©2013 AACR.