***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Numerous r and omized , double-blind , placebo-controlled studies and observational studies have shown that statins reduce mortality and major cardiovascular events in older high-risk persons with hypercholesterolemia . The Heart Protection Study showed that statins reduced mortality and major cardiovascular events in high-risk persons regardless of the initial level of serum lipids , age , or gender . The up date d National Cholesterol Education Program III guidelines state that in very high-risk persons , a serum low-density lipoprotein ( LDL ) cholesterol level of < 70 mg/dl ( 1.8 mmol/l ) is a reasonable clinical strategy for moderately high-risk persons ( 2 or more risk factors and a 10-year risk for coronary artery disease of 10 % to 20 % ) , and the serum LDL cholesterol should be reduced to < 100 mg/dl ( 2.6 mmol/l ) . When LDL cholesterol-lowering drug therapy is used to treat high-risk persons or moderately high-risk persons , the serum LDL cholesterol should be reduced by at least 30 % to 40 % . The serum LDL cholesterol should be decreased to less than 160 mg/dl in persons at low risk for cardiovascular disease . Addition of other lipid-lowering drugs to statin therapy has not been demonstrated to further reduce cardiovascular events and mortality Summary Purpose Pre clinical data has demonstrated the potential of simvastatin to overcome cetuximab resistance in KRAS mutant CRC patients . Therefore , we design ed a study using simvastatin/cetuximab/irinotecan for KRAS mutant CRC patients who are refractory to irinotecan and oxaliplatin-based chemotherapy . Patients and methods In this phase II study , patients received 500 mg/m2 cetuximab , 150–180 mg/m2 ( day 1 ) , and 80 mg simvastatin ( once daily , days 1–14 , every 2 weeks ) . The primary endpoint was the objective response rate ( ORR ) . Secondary endpoints were progression-free survival ( PFS ) , overall survival ( OS ) , the disease control rate ( DCR ) , and safety . We also analyzed the relationship between the RAS gene expression signature score and treatment response to simvastatin/cetuximab/irinotecan . Results Fifty-two KRAS mutant CRC patients were enrolled .  The ORR ( complete response [ CR ] , 0 ; partial response [ PR ] , 1 ) was 1.9 % ( 95 % confidence interval [ CI ] , −1.8–5.6 ) . The DCR ( CR , 0 ; PR , 1 ; stable disease , 33 ) was 65.4 % ( 95 % CI , 52.5–78.3 ) . The median PFS and OS from the time of study drug administration were 7·6 months ( 95 % CI , 4.4–10.8 ) and 12.8 months ( 95 % CI , 9.5–16.2 ) , respectively . The most common grade 3/4 adverse events were anemia ( 28.8 % ) , neutropenia ( 13.5 % ) , and diarrhea ( 7.7 % ) . The RAS signature score was significantly correlated with the maximal change in target lesions from baseline ( r = 0.57 , P = 0.014 ) . Conclusion The simvastatin/cetuximab/irinotecan regimen showed promising efficacy and safety in KRAS mutant CRC patients who failed irinotecan and oxaliplatin-based chemotherapy . The RAS signature may be a novel predictor of treatment response to cetuximab-combined chemotherapy in CRC patients Importance Patients with cancer who use statins  appear to have a substantially better survival than nonusers in observational studies . However , this inverse association between statin use and mortality may be due to selection bias and immortal-time bias . Objective To emulate a r and omized trial of statin therapy initiation that is free of selection bias and immortal-time bias . Design , Setting , and Participants We used observational data on 17 372 patients with cancer from the Surveillance , Epidemiology , and End Results (SEER)-Medicare data base ( 2007 - 2009 ) with complete follow-up until 2011 . The SEER-Medicare data base links 17 US cancer registries and cl aims files from Medicare and Medicaid in 12 US states . We included individuals with a new diagnosis of colorectal , breast , prostate , or bladder cancer who had not been prescribed statins for at least 6 months before the cancer diagnosis . Individuals were duplicated , and each replicate was assigned to either the strategy “ statin therapy initiation within 6 months after diagnosis ” or “ no statin therapy initiation . ” Replicates were censored when they stopped following their assigned strategy , and the potential selection bias was adjusted for via inverse-probability weighting . Hazard ratios ( HRs ) , cumulative incidences , and risk differences were calculated for all-cause mortality and cancer-specific mortality . We then compared our estimates with those obtained using the same analytic approaches used in previous observational studies . Exposures Statin therapy initiation within 6 months after cancer diagnosis . Main Outcomes and Measures Cancer-specific and all-cause mortality using SEER-Medicare data and data from previous studies . Results Of the 17 372 patients whose data were analyzed , 8440 ( 49 % ) were men , and 8932 ( 51 % ) were women ( mean [ SD ] age , 76.4 [ 7.4 ] years ; range , 66 - 115 years ) . The adjusted HR ( 95 % CI ) comparing statin therapy initiation vs no initiation was 1.00 ( 0.88 - 1.15 ) for cancer-specific mortality and 1.07 ( 0.93 - 1.21 ) for overall mortality . Cumulative incidence curves for both groups were almost overlapping ( the risk difference never exceeded 0.8 % ) . In contrast , the methods used by prior studies result ed in an inverse association between statin use and mortality ( pooled hazard ratio 0.69 ) . Conclusion and Relevance After using methods that are not susceptible to selection bias from prevalent users and to immortal time bias , we found that initiation of therapy with statins within 6 months after cancer diagnosis did not appear to improve 3-year cancer-specific or overall survival BACKGROUND & AIMS Statin use has been associated with a reduced incidence of colorectal cancer and might also affect survival of patients diagnosed with colon cancer .  Statins are believed to inhibit Ras signaling and may also activate the bone morphogenetic protein ( BMP ) signaling pathway in colorectal cancer cells . We investigated the effects of statins on overall survival of patients with a diagnosis of colon cancer , and whether their effects were associated with changes in KRAS or the BMP signaling pathways . METHODS Data were derived from the PHARMO data base network ( Netherl and s ) and linked to patients diagnosed with colon cancer from 2002 through 2007 , listed in the Eindhoven Cancer Registry . We obtained information on causes of death from statistics Netherl and s. We constructed a tissue microarray  of 999 colon cancer specimens from patients who underwent surgical resection from 2002 through 2008 . Survival was analyzed with statin user status after diagnosis as a time-dependent covariate . Multivariable Poisson regression survival models and Cox analyses were used to study the effect of statins on survival . Tumor tissues were analyzed by immunohistochemistry for levels of SMAD4 , BMPR1A , BMPR1B , and BMPR2 proteins . Tumor tissues were considered to have intact BMP signaling if they contained SMAD4 plus BMPR1A , BMPR1B , or BMPR2 . DNA was isolated from tumor tissues and analyzed by quantitative polymerase chain reaction to detect mutations in KRAS . The primary outcome measures were overall mortality and cancer-specific mortality . RESULTS In this cohort , 21.0 % of the patients ( 210/999 ) were defined as statin users after diagnosis of colon cancer . Statin use after diagnosis was significantly associated with reduced risk of death from any cause ( adjusted relative risk [ RR ] , 0.67 ; 95 % confidence interval [ CI ] , 0.51 - 0.87 ; P = .003 ) and death from cancer ( adjusted RR , 0.66 ; 95 % CI , 0.49 - 0.89 ; P = .007 ) . Statin use after diagnosis was associated with reduced risk of death from any cause or from cancer for patients whose tumors had intact BMP signaling ( adjusted RR , 0.39 ; 95 % CI , 0.22 - 0.68 ; P = .001 ) , but not for patients whose tumors did not have BMP signaling ( adjusted RR , 0.81 ; 95 % CI , 0.55 - 1.21 ; P = .106 ; P < .0001 for the interaction ) . Statin use after diagnosis was not associated with reduced risk of death from any cause or from cancer for patients whose tumors did not contain KRAS mutations ( adjusted RR , 0.81 ; 95 % CI , 0.56 - 1.18 ; P = .273 ) or whose tumors did have KRAS mutations ( adjusted RR , 0.59 ; 95 % CI 0.35 - 1.03 ; P = .062 ; P = .90 for the interaction ) . CONCLUSIONS In an analysis of 999 patients with a diagnosis of colon cancer , we associated statin with reduced risk of death from any cause or from cancer . The benefit of statin use is greater for patients whose tumors have intact BMP signaling , independent of KRAS mutation status . R and omized controlled trials are required to confirm these results BACKGROUND Atorvastatin , rosuvastatin and pitavastatin are available for intensive , aggressive low-density lipoprotein cholesterol (LDL-C)-lowering therapy in clinical practice . The objective of the R and omized Head-to-Head Comparison of Pitavastatin , Atorvastatin , and Rosuvastatin for Safety and Efficacy ( Quantity and Quality of LDL ) ( PATROL ) Trial was to compare the safety and efficacy of atorvastatin , rosuvastatin and pitavastatin head to head in patients with hypercholesterolemia . This is the first prospect i ve r and omized multi-center trial to compare these strong statins ( UMIN Registration No : 000000586 ) . METHODS AND RESULTS Patients with risk factors for coronary artery disease and elevated LDL-C levels were r and omized to receive atorvastatin ( 10mg/day ) , rosuvastatin ( 2.5mg/day ) , or pitavastatin ( 2mg/day ) for 16 weeks . Safety was assessed in terms of adverse event rates , including abnormal clinical laboratory variables related to liver and kidney function and skeletal muscle . Efficacy was assessed by the changes in the levels and patterns of lipoproteins .  Three hundred and two patients ( from 51 centers ) were enrolled , and these 3 strong statins equally reduced LDL-C and LDL particles , as well as fast-migrating LDL ( modified LDL ) by 40 - 45 % . Newly developed pitavastatin was non-inferior to the other 2 statins in lowering LDL-C. There were no differences in the rate of adverse drug reactions among the 3 groups , but HbA(1c ) was increased while uric acid was decreased in the atorvastatin and rosuvastatin groups . CONCLUSIONS The safety and efficacy of these 3 strong statins are equal . It is suggested that the use of these 3 statins be completely dependent on physician discretion based on patient background BACKGROUND Several studies have indicated that statins may have anticarcinogenic effects . The aim of the present study was to investigate if statin treatment was associated with a reduced risk of hepatocellular carcinoma ( HCC ) or colon cancer . METHODS A nationwide case-control study was carried out in which all cases of HCC and colon cancer in the Swedish population above 40 years of age between 1 July 2006 and 31 December 2010 were identified in the Swedish Cancer Register . For every case , five controls were selected and matched on age and sex . Data on statin use was extracted from the Swedish Prescribed Drug Register . We estimated risks using conditional logistic regression and adjusted for educational level , concomitant medications and comorbidity . RESULTS Identified were 3994 cases of HCC and matched with 19.970 controls , and 21.143 cases of colon cancer were identified and matched with 105.715 controls . In the adjusted analysis , the odds ratio ( OR ) for HCC among statin users was 0.88 ( 95 % confidence interval ( CI ) 0.81 - 0.96 ) , and the OR for colon cancer was 1.04 ( 95%CI 1.00 - 1.08 ) compared with non-users . CONCLUSION Statin use was associated with a modest decreased risk of HCC but did not influence the risk of colon cancer . Future r and omized placebo-controlled trials in HCC high-risk patients are warranted to further investigate the possible prophylactic effect of statins in HCC Pre clinical data showed anticancer effects of statins in melanoma , but meta‐analyses could not demonstrate a reduced melanoma incidence in statin users . 
    Output:
    
In vitro and animal studies have shown a potential chemopreventive effect of statins and their efficacy in adjuvant therapy of colorectal cancer .
Statins also show a potential role in chemoprevention of colorectal cancer in patients with inflammatory bowel disease .
CONCLUSIONS Accumulating evidence suggests that statins may have a role in colorectal cancer prevention and treatment .