TCR-L: an analysis tool for evaluating the association between the T-cell receptor repertoire and clinical phenotypes.

BACKGROUND: T cell receptors (TCRs) play critical roles in adaptive immune responses, and recent advances in genome technology have made it possible to examine the T cell receptor (TCR) repertoire at the individual sequence level. The analysis of the TCR repertoire with respect to clinical phenotypes can yield novel insights into the etiology and progression of immune-mediated diseases. However, methods for association analysis of the TCR repertoire have not been well developed. METHODS: We introduce an analysis tool, TCR-L, for evaluating the association between the TCR repertoire and disease outcomes. Our approach is developed under a mixed effect modeling, where the fixed effect represents features that can be explicitly extracted from TCR sequences while the random effect represents features that are hidden in TCR sequences and are difficult to be extracted. Statistical tests are developed to examine the two types of effects independently, and then the p values are combined. RESULTS: Simulation studies demonstrate that (1) the proposed approach can control the type I error well; and (2) the power of the proposed approach is greater than approaches that consider fixed effect only or random effect only. The analysis of real data from a skin cutaneous melanoma study identifies an association between the TCR repertoire and the short/long-term survival of patients. CONCLUSION: The TCR-L can accommodate features that can be extracted as well as features that are hidden in TCR sequences. TCR-L provides a powerful approach for identifying association between TCR repertoire and disease outcomes.

Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load.

UNLABELLED: Controversy exists about whether antiviral therapy (AVT) should be recommended for compensated cirrhosis patients with chronic hepatitis B virus (HBV) infection and detectable, but low, serum HBV-DNA levels. A retrospective cohort of 385 treatment-naïve, HBV-related compensated cirrhosis patients (mean age: 51.1 ± 9.7 years; 66% male) with low HBV-DNA levels (<2,000 IU/mL) was assessed for the development of hepatocellular carcinoma (HCC). During a median of 5.6 years of follow-up, HCC had developed in 37 (9.6%) patients. The 5-year cumulative HCC incidence rate was 2.2%, 8.0%, and 14.0% for patients with undetectable HBV DNA (<12 IU/mL), low HBV-DNA levels plus normal alanine aminotransferase (ALT) levels, and low HBV-DNA levels plus elevated ALT levels at baseline (P = 0.011). During follow-up, 71 patients maintained undetectable HBV-DNA levels, and 126 experienced HBV-DNA elevation over 2,000 IU/mL. AVT was initiated in 77 patients. In patients without AVT, the 5-year cumulative HCC incidence rates were 13.3%, 8.8%, and 1.4% for those who experienced HBV-DNA elevation, those who maintained detectable, but low, HBV-DNA levels, and those who maintained undetectable HBV-DNA levels, respectively. The 5-year cumulative HCC incidence rate was 5.9% for patients who started AVT; longer AVT duration and longer complete virological response (<12 IU/mL) duration was associated with lower HCC risk. CONCLUSION: Compensated cirrhosis patients with detectable, but low, viral load were not at low risk for HCC, and AVT was associated with lower HCC risk, suggesting that prompt AVT should be considered for these patients.

Identification of Imaging Predictors Discriminating Different Primary Liver Tumours in Patients with Chronic Liver Disease on Gadoxetic Acid-enhanced MRI: a Classification Tree Analysis.

OBJECTIVES: To identify predictors for the discrimination of intrahepatic cholangiocarcinoma (IMCC) and combined hepatocellular-cholangiocarcinoma (CHC) from hepatocellular carcinoma (HCC) for primary liver cancers on gadoxetic acid-enhanced MRI among high-risk chronic liver disease (CLD) patients using classification tree analysis (CTA). METHODS: A total of 152 patients with histopathologically proven IMCC (n = 40), CHC (n = 24) and HCC (n = 91) were enrolled. Tumour marker and MRI variables including morphologic features, signal intensity, and enhancement pattern were used to identify tumours suspicious for IMCC and CHC using CTA. RESULTS: On CTA, arterial rim enhancement (ARE) was the initial splitting predictor for assessing the probability of tumours being IMCC or CHC. Of 43 tumours that were classified in a subgroup on CTA based on the presence of ARE, non-intralesional fat, and non-globular shape, 41 (95.3 %) were IMCCs (n = 29) or CHCs (n = 12). All 24 tumours showing fat on MRI were HCCs. The CTA model demonstrated sensitivity of 84.4 %, specificity of 97.8 %, and accuracy of 92.3 % for discriminating IMCCs and CHCs from HCCs. CONCLUSIONS: We established a simple CTA model for classifying a high-risk group of CLD patients with IMCC and CHC. This model may be useful for guiding diagnosis for primary liver cancers in patients with CLD. KEY POINTS: • Arterial rim enhancement was the initial splitting predictor on CTA. • CTA model achieved high sensitivity, specificity, and accuracy for discrimination of tumours. • This model may be useful for guiding diagnosis of primary liver cancers.

Quantification of Aortic Valve Calcifications Detected During Lung Cancer-Screening CT Helps Stratify Subjects Necessitating Echocardiography for Aortic Stenosis Diagnosis.

No study has been published on aortic valve calcification (AVC) extent at lung cancer screening low-dose CT (LDCT) and its relationship with aortic stenosis (AS). The purpose of this study was to estimate the cutoff value of AVC on LDCT for detecting AS in asymptomatic Asian subjects. Six thousand three hundred thirty-eight subjects (mean age, 55.9 years ±â€Š8.6) self-referred to health-promotion center underwent LDCT, coronary calcium scoring CT (CSCT), and echocardiography. AVC was quantified using Agatston methods on CT. AVC extent on LDCT was compared with that on CSCT, and AVC threshold for diagnosing AS was calculated. Clinical factors associated with AS and AVC were sought.AVC was observed in 403 subjects (64.9 years ±â€Š8.7) on LDCT (6.4%), and AVC score measured from LDCT showed strong positive correlation with that from CSCT (r = 0.83, P < 0.0001). Of 403 subjects, 40 (10%) were identified to have AS on echocardiography. Cutoff value of AVC score for detecting AS was 138.37 with sensitivity of 90.0% and specificity 83.2%. On multivariate analysis, age (odds ratio [OR] = 1.10, 95% CI: 1.09-1.12) and hypertension (OR = 1.39, 95% CI: 1.10-1.76) were associated with the presence of AVC, whereas AVC extent at LDCT (OR = 104.32, 95% CI: 16.16-673.70) was the only significant clinical factor associated with AS; AVC extent on LDCT (OR = 104.32, 95% CI: 16.16-673.70) was the significant clinical factor associated with AS.The AVC extent on LDCT is significantly related to the presence of AS, and we recommend echocardiography for screening AS based on quantified AVC values on LDCT.

Comparison of weekly versus triweekly cisplatin delivered concurrently with radiation therapy in patients with locally advanced nasopharyngeal cancer: A multicenter randomized phase II trial (KCSG-HN10-02).

PURPOSE: Triweekly delivery of cisplatin concurrent with a course of radiation therapy (RT) has been the standard regimen for treatment of locally advanced nasopharyngeal carcinoma (NPC) despite a high level of concern regarding treatment-related complications. We conducted a randomized phase II study to compare weekly and triweekly cisplatin delivery during RT with respect to efficacy and toxicity profiles. MATERIAL AND METHODS: Patients with locally advanced NPC (stage II-IVb) were randomly assigned to a regimen of either seven doses of cisplatin (40 mg/m(2)) given once a week or three doses of cisplatin (100mg/m(2)) given every 3 weeks concurrently during RT. RESULTS: Of 109 eligible patients, 53 were assigned to the weekly regimen and 56 to the triweekly regimen. The two groups were comparable with respect to demographic and clinical characteristics. There were no significant differences in mean RT dose (68.3 Gy vs. 67.3 Gy, p=0.559) and mean cisplatin dose (248.9 mg/m(2)vs. 256.6 mg/m(2), p=0.433) between the two regimens. The primary endpoint was 3-year progression-free survival, which was not different between the regimens (64.9% vs. 63.8%, p=0.074). Overall, the occurrence of grade 3-4 toxicities was similar between the two arms (47.2% vs. 39.3%, p=0.443). Quality of life (QoL) related to functional outcomes 3 weeks after treatment completion was better for the weekly regimen. CONCLUSIONS: Although no definitive conclusions can be made, a once-weekly cisplatin regimen appears to be associated with improved QoL and is not inferior to the standard triweekly regimen with respect to efficacy and toxicity profiles.