Shihua Zhao

Differential Clinicopathological Risk and Prognosis of Major Papillary Thyroid Cancer Variants

CONTEXT Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. OBJECTIVE This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). METHODS This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo). RESULTS The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. CONCLUSION This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.

Obesity is an independent risk factor for non‐alcoholic fatty liver disease: evidence from a meta‐analysis of 21 cohort studies

The association between obesity and nonalcoholic fatty liver disease (NAFLD) has not been fully quantified, and the magnitude of NAFLD risk associated with obesity is still unclear. A meta‐analysis of cohort studies was performed to elucidate the NAFLD risk associated with obesity.

Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis

BACKGROUND Results of several studies have shown a possible beneficial effect of renin-angiotensin system (RAS) inhibitors on diabetic retinopathy, but the findings were contradictory. We did a systematic review and meta-analysis to assess the effect of RAS inhibitors on diabetic retinopathy. METHODS We identified relevant publications in PubMed, Embase, Cochrane Library Central Register of Controlled Trials, and abstracts from main annual meetings. Only randomised controlled trials comparing angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) monotherapy with other antihypertensive drugs or placebo in type 1 or type 2 diabetes were eligible for inclusion in the analysis. The primary outcomes were progression and regression of diabetic retinopathy in all patients and several subgroups. Risk ratios (RRs) with corresponding 95% CIs were pooled. We also did a network meta-analysis to assess the effect of different antihypertensive drugs on diabetic retinopathy by ranking order. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42013004548. FINDINGS 21 randomised clinical trials with 13,823 participants were included in the meta-analysis. RAS inhibitors were associated with reduced risk of progression (absolute risk difference -3%, 95% CI -5 to -1; pooled RR 0.87, 95% CI 0.80-0.95; p=0.002) and increased possibility of regression of diabetic retinopathy (8%, 1-16; RR 1.39, 95% CI 1.19-1.61; p=0.00002). In normotensive patients, RAS inhibitors decreased risk of diabetic retinopathy progression (0.81, 0.69-0.94; p=0.007) and increased possibility of regression (1.43, 1.14-1.79; p=0.002). In hypertensive patients, RAS inhibitors were not associated with difference in risk of progression of diabetic retinopathy (0.93, 0.79-1.10; p=0.42) or possibility of diabetic retinopathy regression (2.21, 0.92-5.31; p=0.08). ACE inhibitors were associated with reduced risk of diabetic retinopathy progression (0.84, 0.75-0.94; p=0.002) and higher possibility of disease regression (1.50, 1.20-1.86; p=0.0003). ARBs were associated with a higher possibility of diabetic retinopathy regression (1.32, 1.07-1.61; p=0.008), but had no effect on disease progression (0.92, 0.80-1.06; p=0.25). Network meta-analysis showed the association of antihypertensive drugs with risk of diabetic retinopathy progression was lowest for ACE inhibitors, followed by ARBs, β blockers, calcium channel blockers, and placebo in rank order. The association of antihypertensive drugs with possibility of diabetic retinopathy regression was highest for ACE inhibitors, followed by ARBs, placebo, and calcium channel blockers in rank order. INTERPRETATION In patients with diabetes, RAS inhibitors reduce the risk of diabetic retinopathy, and increase the possibility of diabetic retinopathy regression. ACE inhibitors might be better than ARBs for treating diabetic retinopathy, and might exert the most beneficial effect on diabetic retinopathy of all widely used antihypertensive drug classes.

Association between height and thyroid cancer risk: a meta-analysis of prospective cohort studies.

While several epidemiological studies have investigated the relationship between height and risk for thyroid cancer, the results were inconsistent. In the present study, a systematic review and meta‐analysis of prospective cohort studies was conducted to assess the impact of height on thyroid cancer risk. Online databases were searched up to December 30, 2014, for prospective cohort studies on the association between height and thyroid cancer risk. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random‐effects model of meta‐analysis. In all, 11 articles were included in this meta‐analysis, including 15 prospective cohort studies, containing 6,695,593 participants and 7,062 cases of thyroid cancer. By comparing the highest versus the lowest categories of height, we reported that risk of thyroid cancer was increased with height in both men (summary RR = 1.40, 95%CI 1.09–1.78, p = 0.008) and women (summary RR = 1.54, 95%CI 1.30–1.83, p < 0.001). The summary RR of thyroid cancer per 5‐cm increase in height was 1.16 (95%CI 1.09–1.23, p < 0.001). The results were similar among men (per 5‐cm increase RR = 1.13, 95%CI 1.03–1.23, p = 0.011) and women (per 5‐cm increase RR = 1.18, 95%CI 1.10–1.27, p < 0.001). No obvious risk of publication bias was observed. Our meta‐analysis provides strong evidence for a dose–response relationship between height and risk of thyroid cancer in both men and women.

Independent Risk Factors Predicting Central Lymph Node Metastasis in Papillary Thyroid Microcarcinoma

The incidence of papillary thyroid microcarcinoma (PTMC) has risen rapidly in recent years, and PTMC patients with central lymph node metastasis (CLNM) usually have poor prognosis. Independent risk factors predicting CLNM in PTMC have not been well understood. The aim of our study was to identify useful clinicopathological risk factors predicting CLNM in PTMC patients. This was a retrospective study of 917 patients with PTMC treated with surgery from January 2014 to December 2015 in our hospital. The relationship between clinicopathological factors and CLNM was analyzed to identify those factors predicting CLNM in PTMC. Univariate and multivariate logistic regression analyses were further performed. Of 917 PTMC patients, 344 (37.5%) were found to have CLNM confirmed by intraoperative frozen-section examination. Multivariate logistic regression analyses further found several independent factors predicting CLNM in PTMC patients, including male gender (OR=1.75, 95% CI 1.17-2.61; p=0.006), younger age (<45 years) (OR=1.69, 95%CI 1.20-2.38; p=0.002), positive CLNM on ultrasonography (OR=10.20, 95% CI 5.51-18.88; p<0.001), multifocality (OR=1.69, 95% CI 1.00-2.85; p=0.04), and larger tumor size (>5 mm) (OR=2.80, 95% CI 2.01-3.91; p<0.001). The findings of our study identified several useful and independent risk factors predicting CLNM in PTMC patients, such as male gender, younger age, multifocality, positive CLNM on ultrasonography, and larger tumor size. The CLNM is very common in PTMC patients, and routine prophylactic central neck dissection may be recommended in PTMC patients with those independent risk factors of CLNM.

The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer

Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished. Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC. Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow‐up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation. Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular‐variant PTC, tall‐cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database. Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.

BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.