***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: PURPOSE We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma ( HCC ) that had progressed following first-line sorafenib . PATIENTS AND METHODS Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function ( Child-Pugh class A ) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression , unacceptable toxicity , death or patient/physician decision to discontinue . The primary end-point was safety ; secondary end-points included efficacy ( including time to progression and overall survival ) . RESULTS The median treatment duration was 19.5 weeks ( range 2 - 103 ) . At data cutoff , three patients remained on treatment . Reasons for discontinuation were adverse events ( n=20 ) , disease progression ( n=10 ) , consent withdrawal ( n=2 ) and death ( n=1 ) . Seventeen patients required dose reductions ( mostly for adverse events [ n=15 ] ) ; 35 patients had treatment interruption ( mostly for adverse events [ n=32 ] or patient error [ n=11 ] ) . The most frequent treatment-related adverse events were h and -foot skin reaction ( any grade n=19 ; grade ≥3 n=5 ) , diarrhoea ( n=19 ; n=2 ) , fatigue ( n=19 ; n=6 ) , hypothyroidism ( n=15 ; n=0 ) , anorexia ( n=13 ; n=0 ) , hypertension ( n=13 ; n=1 ) , nausea ( n=12 ; n=0 ) and voice changes ( n=10 ; n=0 ) . Disease control was achieved in 26 patients ( partial response n=1 ; stable disease n=25 ) . Median time to progression was 4.3 months . Median overall survival was 13.8 months . CONCLUSION Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib Background Lenvatinib is an oral inhibitor of vascular endothelial growth factor receptor 1–3 , fibroblast growth factor receptor 1–4 , platelet-derived growth factor receptor alpha , RET , and KIT . This phase 2 , single-arm , open-label multicenter study evaluated lenvatinib in advanced hepatocellular carcinoma ( HCC ) . Methods Patients with histologically/ clinical ly confirmed advanced HCC who did not qualify for surgical resection or local therapies received lenvatinib at a dosage of 12 mg once daily ( QD ) in 28-day cycles . The primary efficacy endpoint was time to progression ( TTP ) per modified Response Evaluation Criteria in Solid Tumors v1.1 ; secondary efficacy endpoints included objective response rate ( ORR ) , disease control rate ( DCR ) , and overall survival ( OS ) . Results Between July 2010 and June 2011 , 46 patients received lenvatinib at sites across Japan and Korea .  The median TTP , as determined by independent radiological review , was 7.4 months [ 95 % confidence interval ( CI ) : 5.5–9.4 ] . Seventeen patients ( 37 % ) had partial response and 19 patients ( 41 % ) had stable disease ( ORR : 37 % ; DCR : 78 % ) . Median OS was 18.7 months ( 95 % CI : 12.7–25.1 ) . The most common any- grade adverse events ( AEs ) were hypertension ( 76 % ) , palmar-plantar erythrodysesthesia syndrome ( 65 % ) , decreased appetite ( 61 % ) , and proteinuria ( 61 % ) . Dose reductions and discontinuations due to AEs occurred in 34 ( 74 % ) and 10 patients ( 22 % ) , respectively . Median body weight was lower in patients with an early ( < 30 days ) dose withdrawal or reduction than in those without . Conclusions Lenvatinib 12-mg QD showed clinical activity and acceptable toxicity profiles in patients with advanced HCC , but early dose modification was necessary in patients with lower body weight . Further development of lenvatinib in HCC should consider dose modification by body weight . Trial registration IDwww . Clinical Trials.gov NCT00946153 An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma ( HCC ) has not yet been developed . Circulating tumour DNA ( ctDNA ) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive ' liquid biopsy ' for diagnosis and monitoring of cancer . Here , we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated . Using cfDNA sample s from a large cohort of 1,098 HCC patients and 835 normal controls , we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity ( P < 0.001 ) and was highly correlated with tumour burden , treatment response , and stage . Additionally , we constructed a prognostic prediction model that effectively predicted prognosis and survival ( P < 0.001 ) . Together , these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis , surveillance , and prognosis of HCC Summary Background Patients with cirrhosis are at high risk of hepatocellular carcinoma ( HCC ) . The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis . The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA ( mSEPT9 ) for diagnosing HCC among cirrhotic patients . Methods We report two phase II biomarker studies that included cirrhotic patients with or without HCC from France ( initial study ) and Germany ( replication study ) . All patients received clinical and biological evaluations , and liver imaging according to current recommendations . The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases . The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematic ally discussed in a multidisciplinary consultation meeting . HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later . The adjudicating physicians were blinded to patient results associated with the mSEPT9 test . Findings We included 289 patients with cirrhosis ( initial : 186 ; replication : 103 ) , among whom 98 had HCC ( initial : 51 ; replication : 47 ) . The  mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis , with an area under the receiver operating characteristic curve ( AUROC ) of 0.944 ( 0.900–0.970 , p < 0.0001 ) in the initial study ( replication : 0.930 [ 0.862–0.971 , p < 0.0001 ] ; meta- analysis : AUROC = 0.940 [ 0.910–0.970 , p < 0.0001 ] , no heterogeneity : I2 = 0 % , p = 0.67 ; and no publication bias ) . In multivariate logistic regression analysis , the number of positive mSEPT9 triplicates was the only independent variable significantly associated with HCC diagnosis ( initial : OR = 6.30 , for each mSEPT9 positive triplicate [ 2.92–13.61 , p < 0.0001 ] ; replication : OR = 6.07 [ 3.25–11.35 , p < 0.0001 ] ; meta- analysis : OR = 6.15 [ 2.93–9.38 , p < 0.0001 ] , no heterogeneity : I2 = 0 % , p = 0.95 ; no publication bias ) . AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 ( 0.930–0.989 ) and 0.942 ( 0.878–0.978 ) , respectively , with a pooled AUROC of 0.962 ( [ 0.937–0.987 , p < 0.0001 ] , no heterogeneity : I2 = 0 % , p = 0.36 ; and no publication bias ) . Interpretation Among patients with cirrhosis , the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level . Future prospect i ve studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC BACKGROUND Nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , disrupts PD-1-mediated signaling and may restore antitumor immunity . METHODS In this r and omized , open-label , international phase 3 study , we assigned patients with nonsquamous non-small-cell lung cancer ( NSCLC ) that had progressed during or after platinum-based doublet chemotherapy  to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS Overall survival was longer with nivolumab than with docetaxel .  The median overall survival was 12.2 months ( 95 % confidence interval [ CI ] , 9.7 to 15.0 ) among 292 patients in the  nivolumab group and 9.4 months ( 95 % CI , 8.1 to 10.7 ) among 290 patients in the docetaxel group ( hazard ratio for death , 0.73 ; 96 % CI , 0.59 to 0.89 ; P=0.002 ) . At 1 year , the overall survival rate was 51 % ( 95 % CI , 45 to 56 ) with nivolumab versus 39 % ( 95 % CI , 33 to 45 ) with docetaxel . With additional follow-up , the overall survival rate at 18 months was 39 % ( 95 % CI , 34 to 45 ) with nivolumab versus 23 % ( 95 % CI , 19 to 28 ) with docetaxel . The response rate was 19 % with nivolumab versus 12 % with docetaxel ( P=0.02 ) . Although progression-free survival did not favor nivolumab over docetaxel ( median , 2.3 months and 4.2 months , respectively ) , the rate of progression-free survival at 1 year was higher with nivolumab than with docetaxel ( 19 % and 8 % , respectively ) . Nivolumab was associated with even greater efficacy  than docetaxel across all end points in subgroups defined according to prespecified levels of tumor-membrane expression ( ≥1 % , ≥5 % , and ≥10 % ) of the PD-1 lig and . Treatment-related adverse events of grade 3 or 4 were reported in 10 % of the patients in the nivolumab group , as compared with 54 % of those in the docetaxel group . CONCLUSIONS Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy  , overall survival was longer with nivolumab than with docetaxel . ( Funded by Bristol-Myers Squibb ; CheckMate 057 Clinical Trials.gov number , NCT01673867 . ) BACKGROUND Patients with advanced squamous-cell non-small-cell lung cancer ( NSCLC ) who have disease progression during or after first-line chemotherapy have limited treatment options . This r and omized , open-label , international , phase 3 study evaluated the efficacy and safety of nivolumab , a fully human IgG4 programmed death 1 ( PD-1 ) immune-checkpoint-inhibitor antibody , as compared with docetaxel in this patient population . METHODS We r and omly assigned 272 patients to receive nivolumab , at a dose of 3 mg per kilogram of body weight every 2 weeks , or docetaxel , at a dose of 75 mg per square meter of body-surface area every 3 weeks . The primary end point was overall survival . RESULTS The median overall survival was 9.2 months ( 95 % confidence interval [ CI ] , 7.3 to 13.3 ) with nivolumab versus 6.0 months ( 95 % CI , 5.1 to 7.3 ) with docetaxel . The risk of death was 41 % lower with nivolumab than with docetaxel ( hazard ratio , 0.59 ; 95 % CI , 0.44 to 0.79 ; P<0.001 ) . At 1 year , the overall survival rate was 42 % ( 95 % CI , 34 to 50 ) with nivolumab versus 24 % ( 95 % CI , 17 to 31 ) with doc 
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The efficacy of ICB treatment in HCC is not as good as what was observed in lung cancer and melanoma , which might be due to the heterogeneity of the microenvironment of the liver