Effect of single-dose, live, attenuated dengue vaccine in children with or without previous dengue on risk of subsequent, virologically confirmed dengue in Cebu, the Philippines: a longitudinal, prospective, population-based cohort study.

BACKGROUND: A three-dose dengue vaccine (CYD-TDV) was licensed for use in children aged 9 years and older starting in 2015 in several dengue-endemic countries. In 2016, the Philippine Department of Health implemented a dengue vaccination programme, which was discontinued because of safety concerns. We assessed the relative risk of developing virologically confirmed dengue among children who did or did not receive a single dose of CYD-TDV by previous dengue virus (DENV) infections at baseline classified as none, one, and two or more infections. METHODS: In this longitudinal, prospective, population-based cohort study, we enrolled healthy children (aged 9-14 years) residing in Bogo or Balamban, Cebu, Philippines, between May 2, and June 2, 2017, before a mass dengue vaccination campaign, via the Rural Health Unit in Bogo and three Rural Health Units in Balamban. We collected demographic information and sera for baseline DENV serostatus and conducted active surveillance for acute febrile illness. Children who developed acute febrile illness were identified, clinical data were collected, and blood was drawn for confirmation of dengue by RT-PCR. The primary outcome was the relative risk of developing virologically confirmed dengue among children who received or did not receive a single dose of CYD-TDV by DENV serostatus at baseline. FINDINGS: A single dose of CYD-TDV did not confer protection against virologically confirmed dengue in children who had none or one previous DENV infection at baseline. One dose conferred significant protection against hospital admission for virologically confirmed dengue among participants who had two or more previous DENV infections at baseline during the first 3 years (70%, 95% CI 20-88; p=0·017) and the entire follow-up period (67%, 19-87; p=0·016). INTERPRETATION: The risk of developing virologically confirmed dengue after a single dose of CYD-TDV varied by baseline DENV serostatus. Since the study assessed the effect of only a single dose, the findings cannot inform decisions on vaccination by public health officers. However, the findings have implications for children who receive an incomplete vaccination regimen and these results should prompt more detailed analyses in future trials on dengue vaccines. FUNDING: The Philippine Department of Health, Hanako Foundation, WHO, Swedish International Development Cooperation Agency, International Vaccine Institute, University of North Carolina, and US National Institute of Allergy and Infectious Diseases.

Statistical considerations on real time and extended controlled temperature conditions (ECTC) stability data analysis of vaccines.

BACKGROUND: Although maintaining vaccines in a strict cold chain has cost and logistical implications in low- and middle-income countries, only a few vaccines have obtained approval for extended controlled temperature conditions (ECTC) application, which permits the administration of vaccines after storage outside of the cold chain for a defined period. We developed a methodology to evaluate stability data and calculate minimum release potency (MRP) in support of ECTC application. METHODS: The methodology is focused on statistical considerations consisting of stability data collection, statistical analysis plan, statistical modelling, and statistical report. It uses mock stability data from a hypothetical product and may serve as a helpful guide for other products. The statistical data analysis is performed using the R program which is an open-source program and validated using the SAS software. RESULTS: We developed a stability data testing scheme that included 24 lots with six-time points for up to 24 months under real-time and real condition (RT) in the cold chain samples stored at 2-8 °C and 12 lots with six timepoints for 14 days under ECTC samples stored at 40 °C. The log-transformed stability data met the linear regression assumptions and were poolable from representative lots with no significant lot variation. The linear regression analysis model with a common slope and intercept confirmed the stable antigen content over time under RT and ECTC by the mean regression line and 95% confidence interval. Based on the fitted models and the estimated coefficients, the antigen content value of 966 was derived as the MRP under RT for 24 months followed by 14 days under ECTC. CONCLUSION: The presented framework of statistical considerations, with practical methods and R program codes to perform statistical analysis, may serve as a guide for developing the CTC data for a vaccine's stability evaluation prospectively.

Prevalence of HPV infection among Thai schoolgirls in the north-eastern provinces in 2018: implications for HPV immunization policy.

Objective: The aim of this study was to determine the prevalence of high-risk (HR) and vaccine-type human papillomavirus (HPV) infection among Thai schoolgirls who were not included in the national HPV immunization program. Methods: Cross-sectional surveys were conducted among grade 10 (15-16 years old) and grade 12 (17-18 years old) schoolgirls in two provinces of Thailand. Urine samples were collected using the Colli-PeeⓇ device from November 2018 to February 2019. The samples were initially tested using CobasⓇ 4800. Subsequently, all Cobas-positive samples and 1:1 matched Cobas-negative samples were tested by AnyplexⓇ assay. Prevalences of any HPV, any HR HPV, vaccine-type HPV, and individual HR HPV types were estimated by school grade. Results: Prevalences of any HPV and any HR HPV were 11.6% and 8.6% for grade 10, and 18.5% and 12.4% for grade 12 schoolgirls, respectively. Prevalences of bivalent vaccine-type HPV infection in grades 10 and 12 were 3.4% and 4.5%, respectively. Prevalences of quadrivalent and nonavalent vaccine-type HPV infections were 4.0%/6.6% and 6.4%/10.4% in grades 10 and 12, respectively. HPV16 was the most common type detected, followed by HPV58, 51, and 52. Circulating HR HPV types were similar between the school grades. Conclusion: A substantial burden of HR HPV infections was found among unvaccinated high school girls in Thailand.

A Phase 3, Multicenter, Randomized, Controlled Trial to Evaluate Immune Equivalence and Safety of Multidose and Single-dose Formulations of Vi-DT Typhoid Conjugate Vaccine in Healthy Filipino Individuals 6 Months to 45 Years of Age.

Trial Design: Phase 3, randomized, controlled, multicenter, equivalence trial. Methods: Recruitment of participants occurred between 04Februray2020 and 15July2020 at four centers in the Philippines: University of the East - Ramon Magsaysay Memorial Medical Center Inc., Quezon City; University of Philippines Manila - National Institute of Health, Ermita Manila; Asian Hospital and Medical Center, Metro Manila, Philippines Study; and Medical Research Unit, Tropical Disease Foundation, Makati City, Metro Manila, Philippines. Participants: 1800 adults and children 6-months to 45-years of age. Interventions: Participants received a single injection of multidose (MD) or single dose (SD) Vi-DT as test vaccines or meningococcal conjugate vaccine as a comparator. Objective: To evaluate immune equivalence of SD and MD formulations of Vi-DT, and to assess the safety of both formulations compared with comparator vaccine. Outcome Measurement: Blood draw for immunogenicity was performed at baseline prior to vaccine receipt and at four weeks after vaccination for a subset of participants to determine anti-Vi IgG geometric mean titers (GMT) and seroconversion rates. The primary outcome was comparison of anti Vi-IgG seroconversion and GMT between the two formulations of Vi-DT at 4 weeks following vaccine administration. Immune equivalence of MD and SD formulations was confirmed when the two-tailed 95% confidence interval (CI) of the GMT ratio is within [0.67, 1.5] at a two-sided significance level of 0.05. All participants were followed for safety events for six months after vaccine administration. Randomization: Participants were randomized to receive SD Vi-DT, MD Vi-DT, or meningococcal conjugate vaccines in 2.5:2.5:1 allocation ratio. Blinding: Study participants and observers were blinded to treatment assignment. Findings: Immune equivalence of SD (n=252) and MD (n=247) formulations was confirmed by anti-Vi IgG GMT ratio of 1.14 (95%CI: 0.91, 1.43) with respective GMTs in the MD and SD groups of 640.62 IU/mL (95%CI: 546.39, 751.11) and 562.57 IU/mL (95%CI: 478.80, 661.00) (p=0.259). Similarly, anti-Vi IgG seroconversion rate difference between the two formulations of ‒0.43% (95%CI: -4.42, 3.56) confirmed immune equivalence with corresponding seroconversion rates of 98.38% (95%CI: 95.91, 99.37) and 98.81% (95%CI: 96.56, 99.59) in MD and SD Vi-DT formulations, respectively (p=0.722). Both formulations of Vi-DT had a satisfactory safety profile - all five serious adverse events reported during the study were unrelated to the investigational product. Interpretation: The MD and SD formulations of Vi-DT elicited robust and equivalent immune responses following one dose vaccination, and both formulations demonstrated a favorable safety profile. Trial Registration: ClinicalTrials.gov: NCT04204096. Funding: This study was funded by the Bill & Melinda Gates Foundation (OPP 1115556).

A community intervention effectiveness study of single dose or two doses of bivalent HPV vaccine (CERVARIX®) in female school students in Thailand.

Human papillomavirus (HPV) is a common infection principally spread through sexual activity. Most HPV infections are asymptomatic and resolve spontaneously. However, persistent infection may progress to cervical cancer. Highly efficacious HPV vaccines have been available since 2006, yet uptake into national programs has been slow in part due to cost. WHO guidelines call for a two-dose (0,6 month) schedule for girls 9-14 years of age. Post-hoc analyses of randomized trials have found high vaccine effectiveness following a single dose of vaccine. In order to provide additional data on the potential impact of single dose HPV vaccination in a real-world setting, we are conducting an effectiveness study among Thai schoolgirls. This is an observational study of a single dose (SD) or two doses (2D) of the bivalent HPV vaccine CERVARIX® (GlaxoSmithKline plc.) administered in a school-based program to 8-9,000 Grade 8 female students in two provinces of Thailand beginning in 2018; one province is assigned the SD, and the other the standard 2D regimen. The reduction in HPV vaccine-type prevalence will be assessed in each province two and four years after vaccination by comparing HPV prevalence in urine samples obtained through cross-sectional surveys of the immunized grade cohort as they age and compared to a historical "baseline" HPV prevalence of same age students.

Creatinine- and cystatin C-based estimated glomerular filtration rate slopes for the prediction of kidney outcome: a comparative retrospective study.

BACKGROUND: Many studies have evaluated the usefulness of creatinine- (eGFRcr) and cystatin C-based estimated glomerular filtration rate (eGFRcys) at specific time points in predicting renal outcome. This study compared the performance of both eGFR changing slopes in identifying patients at high risk of end-stage renal disease (ESRD). METHODS: From 2012 to 2017, patients with more than three simultaneous measurements of serum creatinine and cystatin C for 1 year were identified. Rapid progression was defined as eGFR slope < - 5 mL/min/1.73 m2/year. The primary outcome was progression to ESRD. RESULTS: Overall, 1323 patients were included. The baseline eGFRcr and eGFRcys were 39 (27-48) and 38 (27-50) mL/min/1.73 m2, respectively. Over 2.9 years (range, 2.0-3.8 years) of follow-up, 134 subjects (10%) progressed to ESRD. Both the eGFRcr and eGFRcys slopes were associated with a higher risk of ESRD, independently of baseline eGFR (hazard ratio [HR] = 0.986 [0.982-0.991] and HR = 0.988 [0.983-0.993], respectively; all p <  0.001). The creatinine- and cystatin C-based rapid progressions were associated with increased risk of ESRD (HR = 2.22 [1.57-3.13], HR = 2.03 [1.44-2.86], respectively; all p <  0.001). In the subgroup analyses, the rapid progression group, defined on the basis of creatinine levels (n = 503), showed no association between the eGFRcys slope and ESRD risk (p = 0.31), whereas the eGFRcr slope contributed to further discriminating higher ESRD risk in the subjects with rapid progression based on eGFRcys slopes (n = 463; p = 0.003). CONCLUSIONS: Both eGFR slopes were associated with future ESRD risk. The eGFRcr slope was comparable with the eGFRcys slope in predicting kidney outcome.

Impact of Extranodal Extension on Risk Stratification in Papillary Thyroid Carcinoma.

Background: The current American Thyroid Association risk-stratification system for papillary thyroid carcinoma (PTC) incorporates the number and size of positive lymph nodes (LNs) but places less weight on extranodal extension (ENE). This study investigated how to incorporate ENE into the current system to predict recurrence better in PTC N1 patients. Methods: A total of 369 N1 PTC patients without distant metastasis were enrolled. The combination of number of positive LNs and LNs with ENE that had the highest C-index were identified with multivariable Cox proportional hazards models. ENE number was incorporated into the current system considering the recurrence rate and unadjusted and adjusted hazard ratios (HRs) of the subgroups. Kaplan-Meier curves for recurrence based on current and alternative systems were compared by log-rank test. Results: The recurrence rate for the subgroup with five or fewer positive LNs and one to three ENEs (7/61; 11.5%) was higher than that of the subgroup with five or fewer positive LNs without ENE (5/129; 3.9%; adjusted HR = 3.42 [confidence interval (CI) 0.99-11.75]; p = 0.050). In contrast, adjusted HRs of the subgroup with more than five positive LNs and one to three ENEs (2.33 [CI 0.52-10.35]) or with four or more ENEs (3.86 [CI 1.05-14.17]) were not higher than those of the subgroup with more than five LNs without ENE (4.47 [1.16-17.19]). Incorporating ENE into the current system as an intermediate-risk group yielded a lower log-rank p-value (0.05 vs. 0.01) than the current system. Conclusions: The presence of ENE in low volume LN metastasis confers an intermediate risk of recurrence. Incorporating ENE into the current system allows more accurate decisions regarding further management of PTC N1 patients.

Refining the tumor-node-metastasis staging system for individualized treatment of differentiated thyroid carcinoma.

BACKGROUND: Patients with differentiated thyroid carcinoma (DTC) are staged according to the single age cut point in addition to anatomic extent. A novel staging system is needed to properly show the character and prognosis of DTC by considering age as a continuous variable. We aimed to refine stage and prognostic groups of the eighth edition tumor-node-metastasis (TNM-8) staging system for DTC and to suggest a possible revision. METHODS: We conducted a retrospective data abstraction study of patients with newly diagnosed DTC who were treated at one of two tertiary referral centres in Seoul, Korea between 1994 and 2005. We used recursive partitioning analysis to derive a new staging classification (TNM-RPA) and compared its prediction of cancer-specific survival with that of TNM-8. RESULTS: The cohort comprised 6342 patients with DTC who were followed up for a median of 11.4 years. Higher TNM-RPA groups were associated with increased risk of death (10-year cancer-specific survival for stages IA, IB, IIA, IIB, III, and IV: 99.6%, 98.1%, 93.0%, 92.4%, 75.1%, and 56.6%, respectively; P < 0.001). The C-index values were 0.869 (95% CI, 0.833-0.905) for the TNM-RPA and 0.819 (0.789-0.850) for TNM-8. The proportions of variance explained for the ability of the TNM-RPA and TNM-8 stages to predict cancer-specific survival were 7.1% and 5.7%, respectively. CONCLUSION: This study presents a RPA-based TNM stage groupings that incorporate multiple age cutoffs and essential anatomic information, which can be conveniently used to facilitate the individual prediction of long-term cancer-specific survival in patients with DTC.

Impact of sarcopenia on the risk of advanced colorectal neoplasia.

BACKGROUND AND AIM: Sarcopenia is a pathological condition characterized by the progressive loss of muscle mass and increased amount of visceral fat. Recent evidence has revealed that sarcopenia is associated with certain diseases. However, the impact of sarcopenia on colorectal neoplasia has not been documented clearly. We studied the association between sarcopenia and advanced colorectal neoplasia in a large screening population. METHODS: This cross-sectional study included 14 024 asymptomatic adults who underwent first-time screening colonoscopy. Sarcopenia (class II) was defined as an appendicular skeletal muscle mass (ASM)/bodyweight (%) value more than two standard deviations below the mean for healthy young adults. ASM was estimated using bioelectrical impedance analysis. RESULTS: In a multivariable model adjusted for age, sex, obesity (body mass index ≥ 25), smoking status, alcohol intake, regular exercise, and family history of colorectal cancer, the odds ratio (OR) for advanced colorectal neoplasia on comparing participants with sarcopenia (class II) to those without sarcopenia (class I + II) was 1.52 (95% confidence interval [CI], 1.23-1.86). Further adjustment for metabolic parameters attenuated this association, but the association was still significant (OR, 1.34; 95% CI, 1.07-1.68). Furthermore, the multivariable (traditional risk factors)-adjusted OR associated with a 1% decrease on the introduction of ASM/weight% as a continuous variable in regression models was 1.04 (95% CI, 1.01-1.07) for advanced colorectal neoplasia. CONCLUSIONS: Our findings indicate that sarcopenia is significantly and progressively associated with the risk of advanced colorectal neoplasia. This association might be explained by metabolic factors that could be potential mediators of the effect of sarcopenia.

Non-contrast liver MRI as an alternative to gadoxetic acid-enhanced MRI for liver metastasis from colorectal cancer.

BACKGROUND: Liver magnetic resonance imaging (MRI) provides reliable diagnostic performance for detecting liver metastasis but is costly and time-consuming. PURPOSE: To compare the diagnostic performance of non-contrast liver MRI to whole MRI using gadoxetic acid for detecting liver metastasis in patients with colorectal cancer (CRC). MATERIAL AND METHODS: We included 175 patients with histologically confirmed 401 liver metastases and 73 benign liver lesions. A non-contrast MRI (T1-weighted, T2-weighted, and diffusion-weighted images) with or without multidetector computed tomography (MDCT) and a whole MRI (gadoxetic acid-enhanced and non-contrast MRI) were analyzed independently by two observers to detect liver metastasis using receiver operating characteristic analysis. RESULTS: We found no significant differences in Az value (range = 0.914-0.997), sensitivity (range = 95.2-99.6%), specificity (range = 77.3-100%), or positive (range = 92.9-100%) or negative predictive value (range = 87.5-95.7%) between the non-contrast MRI with or without MDCT and the whole MRI for both observers for all lesions as well as lesions ≤1.0 cm and lesions >1.0 cm in size ( P = 0.203-1.000). Combined MDCT and non-contrast MRI led to similar numbers of false-positive diagnosis to the whole MRI (eight for Observers 1 and 4 vs. 3 for Observer 2). CONCLUSION: Non-contrast liver MRI may serve as an alternative to gadoxetic acid-enhanced MRI for detecting and characterizing liver metastasis from CRC, at least in patients with relatively high risk of liver metastasis who underwent MDCT. Non-contrast liver MRI could be beneficial especially for patients with lesions that are already documented as benign but require additional follow-up MRIs.

Refining the eighth edition AJCC TNM classification and prognostic groups for papillary thyroid cancer with lateral nodal metastasis.

BACKGROUND: In the eighth edition, TNM staging system omits location of nodal metastasis as a criterion for staging patients with papillary thyroid cancer (PTC). Accordingly, all of non-metastatic N1b PTC patients are classified as stage I or II solely according to an age-cutoff of 55 years. We hypothesized that incorporating other lymph node (LN) factors into TNM staging system would better predict cancer-specific mortality (CSM) in N1b patients. METHODS: We enrolled 745 N1b PTC patients without distant metastasis. Alternative prognostic LN factors and cut-off points were assessed using Cox regression and time-dependent ROC analysis. Alternative prognostic groupings were derived based on minimal hazard differences for CSM among groups stratified by LN risk and age. We assessed accuracy of CSM prediction. RESULTS: Lateral LN ratio (LNR) >0.3 and largest LN size >3 cm were prognostic factors for CSM. Stage II patients (eighth edition) with LN risk (lateral LNR >0.3 or largest LN size >3 cm) had a much higher CSM rate (20.9%) than those in the same stage without LN risk (3.2%). Alternative prognostic grouping (Group 1, <55 years without LN risk; Group 2, <55 years with LN risk or ≥55 years without LN risk; and Group 3, ≥55 with LN risk) achieved higher proportions of variance explained (PVEs) for predicting CSM (10.7%) than those of the eighth edition TNM staging system (4.8%). CONCLUSIONS: The proposed grouping for N1b patients using LN risk can distinguish patients with poor prognosis from those with good prognosis better than the eighth edition TNM staging system.

Higher Risk of Posttransplant Liver Graft Failure in Male Recipients of Female Donor Grafts Might Not Be Due to Anastomotic Size Disparity.

BACKGROUND: Posttransplant liver graft failure occurs most often in male recipients of livers from female donors. The respective role of donor sex itself and the size disparity in graft vessels/bile ducts according to donor sex are unclear. Thus, we aimed to evaluate the importance of donor sex with adjustment for anastomotic size disparity between female and male donor grafts. METHODS: A total of 309 male patients without hepatic tumors who underwent living donor liver transplantation were analyzed (109 female donors and 200 male donors). The primary outcome was posttransplant graft failure (ie, retransplantation or death). Survival analysis was performed using the Cox model. Analyzed anastomosis-related factors comprised graft weight, number and size of hepatic vessels/bile ducts, and anastomosis techniques. RESULTS: Graft failure probabilities at 1, 6, 12, 24, and 60 months posttransplantation were 9.1%, 19.5%, 20.2%, 23.0%, and 27.0%, respectively, with female donors and 2.0%, 5.5%, 8.1%, 10.1%, and 13.5% with male donors (hazards ratio [HR], 2.29; 95% confidence interval [CI], 1.35-3.88; P = 0.002). Multivariable analysis confirmed the significance of donor sex (HR, 2.30; 95% CI, 1.14-4.67; P = 0.021) after adjustment for anastomosis-related factors. All analyzed anastomosis-related factors showed no significant association with graft failure, although size of the graft hepatic artery showed marginal significance (HR, 0.50; 95% CI, 0.25-1.01; P = 0.053). The significance of donor sex was lost when donor was older than 36 to 40 years (age of poor ovarian reserve and the end of female fertility). Our institutional pediatric recipient cohort validated the inferiority of female-to-male donation. CONCLUSIONS: Donor sex appears to be an independent factor modulating graft failure risk in male liver transplant recipients.

Elevated High-Sensitivity Troponin I During Living Donor Liver Transplantation Is Associated With Postoperative Adverse Outcomes.

BACKGROUND: This study aimed to evaluate risk factors and postoperative clinical outcome associated with myocardial injury detected by an elevated high-sensitivity cardiac troponin I (hs-cTnI) immediately after living donor liver transplantation (LDLT). METHODS: Between January 2011 and December 2016, 313 adult recipients undergoing LDLT, with normal preoperative hs-cTnI were selected. Hs-cTnI level above 0.04 ng/mL according to 99th percentile reference limit was defined as myocardial injury. The recipients were divided into 2 groups according to postoperative hs-cTnI measured immediately after LDLT and postoperative clinical outcome was compared. RESULTS: The primary outcome was composite of death or graft failure during hospital stay. Risk factors associated with myocardial injury during LDLT was also evaluated. Of the 313 recipients with normal preoperative hs-cTnI level, 159 (50.8%) had elevated hs-cTnI level and 154 (49.2%) had normal level after LDLT. The incidence of all-cause death or graft failure during hospital stay was significantly higher in recipients with myocardial injury (1.9% vs 7.6%; hazard ratio, 4.15; 95% confidence interval, 1.01-17.14; P = 0.049). The same result was shown in propensity-matched population (0.9% vs 9.0%; hazard ratio, 9.08; 95% confidence interval, 1.16-71.01; P = 0.04). The results during 1-year follow-up were not consistent. Female sex, ischemia time, and presence of postreperfusion syndrome were independent predictors of myocardial injury during LDLT. CONCLUSIONS: Myocardial injury detected by elevation of hs-cTnI level immediately after LDLT was independently associated with adverse outcome during hospital stay.

High Serum TSH Level Is Associated With Progression of Papillary Thyroid Microcarcinoma During Active Surveillance.

Objective: Thyroid-stimulating hormone (TSH) is a growth factor affecting initiation or progression of papillary thyroid cancer (PTC), which supports TSH suppressive therapy in patients with PTC. In patients with papillary thyroid microcarcinoma (PTMC) during active surveillance, however, the association between serum TSH level and growth of PTMC has not been demonstrated. Patients: We analyzed 127 PTMCs in 126 patients under active surveillance with serial serum TSH measurement and ultrasonography. Design: The patients were categorized into groups with the highest, middle, and lowest time-weighted average of TSH (TW-TSH). PTMC progression was defined as a volume increase of ≥50% compared with baseline. Kaplan-Meier survival analysis according to TW-TSH groups and Cox proportional hazard modeling was performed. We identified the cutoff point for TSH level by using maximally selected log-rank statistics. Results: During a median follow-up of 26 months, PTMC progression was detected in 28 (19.8%) patients. Compared with the lowest TW-TSH group, the adjusted hazard ratio (HR) for PTMC progression in the highest TW-TSH group was significantly higher [HR 3.55; 95% confidence interval (CI), 1.22 to 10.28; P = 0.020], but that in the middle TW-TSH group was not (HR 1.52; 95% CI, 0.46 to 5.08; P = 0.489). The cutoff point for the serum TSH level for PTMC progression was 2.50 mU/L. Conclusions: Sustained elevation of serum TSH levels during active surveillance is associated with PTMC progression. Maintaining a low-normal TSH range with levothyroxine treatment during active surveillance of PTMC might be considered in future studies.

Restratification of survival prognosis of N1b papillary thyroid cancer by lateral lymph node ratio and largest lymph node size.

The current 7th TNM staging stratifies N1b papillary thyroid cancer (PTC) patients without distant metastasis into either stage I or stage IV merely by an age threshold (45 years). To date, no studies have adequately quantified the mortality risk of PTC patients with N1b disease. We hypothesized that incorporating lymph node (LN) factors into the staging system would better predict cancer-specific mortality (CSM). A total of 745 nonmetastatic PTC patients with N1b disease were enrolled. We identified factors related to LNs and cut-points using Cox regression and time-dependent ROC analysis. New prognostic groupings were derived based on minimal hazard differences for CSM among the groups stratified by LN risk and age, and prediction of CSM was assessed. Lateral lymph node ratio (LNR) and largest LN size were significant prognostic LN factors at cut-points of 0.3 and 3 cm. Without LN risk (lateral LNR >0.3 or largest LN size >3 cm), stage IV patients had prognosis [adjusted HR 1.10 (98% CI 0.19-6.20); P = 0.906] similar to stage I patients with LN risk. Patients were restratified into three prognostic groups: Group 1, <45 years without LN risk; Group 2, <45 years with LN risk or ≥45 years without LN risk; and Group 3, ≥45 with LN risk. This system had a lower log-rank P-value (<0.001 vs. 0.002) and higher C-statistics (0.80 vs. 0.71) than the 7th TNM. New prognostic grouping using lateral LNR and largest LN size predicts CSM accurately and distinguishes N1b patients with different prognosis.

Differentiation between cholangiocarcinoma and hepatocellular carcinoma with target sign on diffusion-weighted imaging and hepatobiliary phase gadoxetic acid-enhanced MR imaging: Classification tree analysis applying capsule and septum.

OBJECTIVES: To assess the usefulness of classification tree analysis (CTA) for discrimination of hepatocellular carcinoma (HCC) with target sign on hepatobiliary phase (HBP) and/or diffusion-weighted image (DWI) from intrahepatic cholangiocarcinoma (ICC). METHODS: This retrospective study was approved by the institutional review board. From among the 811 patients with histopathologically proven 79 ICCs and 732 HCCs, 69 patients with 69 (87.3%) ICCs and 115 patients with 115 HCCs (15.7%) including 25 scirrhous HCCs and 10 HCCs with central scar that showed the target sign either on HBP or on DWI were included. Two radiologists evaluated the presence of capsule, septum, and arterial enhancement pattern on MR imaging. Capsule, septum, arterial enhancement pattern, and target sign on HBP or DWI were used to classify the tumors using CTA. RESULTS: On CTA, capsule was the initial predictor for assessing the probability of tumors being HCC. The CTA model demonstrated a sensitivity of 86.1%, specificity of 76.8%, and accuracy of 82.6% for discriminating between ICCs and HCCs. In 115 HCCs, only 16 (13.9%) tumors were misclassified as high probability of ICC, and 64.0% (16/25) scirrhous HCCs and 90.0% (9/10) HCCs with central scar were correctly classified as high probability of HCC. CONCLUSIONS: Target sign either on HBP or on DWI was shown in 87.3% (69/79) of ICCs and 15.7% (115/732) of HCCs. The CTA applying capsule and septum may be useful for guiding correct diagnosis of atypical HCCs with the target sign from ICCs.

Capsule, septum, and T2 hyperintense foci for differentiation between large hepatocellular carcinoma (≥5 cm) and intrahepatic cholangiocarcinoma on gadoxetic acid MRI.

OBJECTIVE: To determine the added value of capsule, septum, and T2 hyperintense foci for differentiating large hepatocellular carcinoma (HCC; ≥ 5 cm) from intrahepatic cholangiocarcinoma (ICC) using gadoxetic acid MRI. METHODS: The study included 116 patients (94 men, 22 women; mean age, 56.8 years) with surgically confirmed HCCs (n = 87, 5.0-18.0 cm) or ICCs (n = 29, 5.0-14.0 cm) who underwent gadoxetic acid MRI. Three observers independently reviewed MRIs in two sessions, examining enhancement patterns only and then adding capsule, septum, and T2 hyperintense foci. Reviewers used a five-point scale to score accuracy, sensitivity, and specificity. RESULTS: A significant increase was observed in accuracy when ancillary features (96.1-98.3%) were added compared to enhancement pattern only (83.6-88.4%; p ≤ 0.02). Sensitivity was significantly increased with combined reading (97.1-98.3%) compared to enhancement features only (81.6-88.5%; p ≤ 0.006) for two observers, with no difference in specificity (84.5-89.7% vs. 86.2-98.3%; p > 0.05). We found substantial to excellent interobserver agreement for ancillary features (0.598-0.976). CONCLUSION: Adding capsule, septum, and T2 hyperintense foci to enhancement patterns for gadoxetic acid MRI increased diagnostic performance for characterizing large HCC by differentiating it from ICC. KEY POINTS: • Capsule, septum, and T2 hyperintense foci were useful for characterizing large HCC. • Adding ancillary features to enhancement pattern increased accuracy for diagnosing large HCC. • Interobserver agreement was substantial to excellent for ancillary features.

Dynamic Contrast-enhanced MR Imaging Parameters in Bone Metastases from Non-Small Cell Lung Cancer: Comparison between Lesions with and Lesions without Epidermal Growth Factor Receptor Mutation in Primary Lung Cancer.

Purpose To compare dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging parameters between metastatic bone lesions with and without the epidermal growth factor receptor (EGFR) mutation in consecutive patients with primary non-small cell lung cancer (NSCLC). Materials and Methods This study was approved by the institutional review board. Forty-seven patients with NSCLC and a confirmed EGFR mutation status (27 patients were positive and 26 were negative for EGFR mutation), who underwent DCE MR imaging for bone metastases between November 2012 and March 2016, were included in this study. Two radiologists independently analyzed the volume transfer constant (Ktrans), reflux rate (kep), and volume fraction of the extravascular extracellular matrix (ve) using image processing software. Intergroup comparisons of the mean measured parameters were performed with the Mann-Whitney U test. Interobserver agreement was calculated with the intraclass correlation coefficient. Results There was a high level of agreement between the two reviewers for all three parameters (intraclass correlation coefficient = 0.95 for Ktrans, 0.97 for kep, and 0.91 for ve). Ktrans was significantly higher in the EGFR mutation-positive group (P = .039 for reviewer 1, P = .032 for reviewer 2). kep was also higher in the EGFR mutation-positive group but showed statistical significance only in the evaluation performed by one reviewer (P = .048 for reviewer 2, P = .058 for reviewer 1). No significant difference was observed in ve (P = .873 for reviewer 1, P = .889 for reviewer 2). Conclusion The differences in the DCE MR imaging parameters between metastatic bone lesions with and without EGFR mutations in primary NSCLC may be attributed to differences in the vascular structure related to angiogenesis stimulated by the activation of the EGFR signaling pathway. © RSNA, 2017 Online supplemental material is available for this article.

Metabolically healthy obesity and the risk for subclinical atherosclerosis.

BACKGROUND AND AIMS: Although obesity and metabolic abnormalities are known risk factors for cardiovascular disease, the risk of cardiovascular disease among obese individuals without obesity-related metabolic abnormalities, referred to as metabolically healthy obese (MHO), remains unclear. We examined the association between body mass index categories and the development of subclinical carotid atherosclerosis in a cohort of metabolically healthy individuals. METHODS: We conducted a cohort study of 6453 men without subclinical carotid atherosclerosis or metabolic abnormalities at baseline, who underwent repeated health check-up examinations that included carotid ultrasound. A metabolically healthy state was defined as having no metabolic syndrome components and a homeostasis model assessment of insulin resistance <2.5. Subclinical carotid atherosclerosis was assessed using ultrasound. RESULTS: During the follow-up period of 34,797.9 person-years, subclinical carotid atherosclerosis developed in 1916 participants. Comparing overweight and obese with normal weight participants, the multivariable adjusted hazard ratios (95% confidence intervals) for incident subclinical carotid atherosclerosis were 1.24 (1.12-1.38) and 1.54 (1.38-1.72), respectively. The association persisted after further adjustment for metabolic variables. This association was also evident in MHO men without abdominal obesity (waist circumference > 90 cm) and it did not differ across any clinically relevant subgroups evaluated. CONCLUSIONS: In a large cohort study of strictly defined metabolically healthy participants, the MHO phenotype was associated with an increased risk of incident subclinical carotid atherosclerosis, providing evidence that the MHO phenotype is not protective from cardiovascular risk.

Measurement of tumor volume is not superior to diameter for prediction of lymph node metastasis in early gastric cancer with minute submucosal invasion.

BACKGROUND/AIM: The current indication for endoscopic resection in early gastric cancer (EGC) with minute (< 500 µm) submucosal invasion is based on tumor diameter, which may be insufficient to predict lymph node metastasis (LNM). We investigated whether tumor volume might more accurately predict LNM in EGC with minute submucosal invasion. MATERIALS AND METHODS: Among patients who underwent gastrectomy for gastric cancer, 346 with well/moderately differentiated EGC with submucosal invasion <500 µm were evaluated. Three-dimensional tumor volume was calculated using an endoscopically resected specimen and compared with 1-dimensional tumor diameter. Predictive ability of tumor diameter or volume for LNM was evaluated using receiver operating characteristic curve analysis. RESULTS: Tumor diameter and volume predicted LNM with an area under the curve (AUC) of 0.567 and 0.589, respectively. AUC, sensitivity, specificity, positive and negative predictive values, and accuracy of the 2 models were not significantly different. Tumor diameter ≥ 3 cm showed a significant association with LNM (odds ratio [OR], 2.57; 95% confidence interval [CI], 1.01-6.57; P = 0.049), whereas a tumor volume cutoff value of 752.8 cm3 showed no significant association with LNM (OR, 1.52; 95% CI, 0.59-3.88; P = 0.385). CONCLUSIONS: Tumor volume had no advantage over diameter for predicting LNM in well/moderately differentiated EGC with minute submucosal invasion.