Ou-Chen Wang

The BRAF Mutation Is Predictive of Aggressive Clinicopathological Characteristics in Papillary Thyroid Microcarcinoma

BackgroundThis study analyzed the utility of BRAF mutation screening of ultrasonography-guided fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of papillary thyroid microcarcinoma (PTMC).MethodsWe assessed the T1799A BRAF mutation status in FNAB specimens obtained from 61 PTMC patients before undergoing operations for PTMC. We examined whether the BRAF mutation was associated with clinicopathologic characteristics in PTMC. Additionally, we reviewed the BRAF mutation status, and clinical, ultrasound (US), hematological, and pathology records of the patients and analyzed the associations between these characteristics and lateral lymph node metastasis (LNM).ResultsAnalysis of the preoperative FNABs accurately reflected the BRAF status of the resected tissues in 19 of the 20 paired samples (95% concordance). We observed that the BRAF mutation was statistically significantly associated with multifocality, extrathyroidal invasion, lateral LNM, and advanced tumor stages III and IV. The BRAF mutation, pathologic features (central LNM), and US features (upper pole location) were independent predictive factors for lateral LNM in a multivariate analysis with odds ratios of 18.144 (95% confidence interval [95% CI], 1.999–164.664; Pxa0=xa00.01), 8.582 (95% CI, 1.014–76.662; Pxa0=xa00.049) and 9.576 (95% CI, 1.374–66.728; Pxa0=xa00.023), respectively.ConclusionsBRAF mutation-positive PTMCs were more likely to manifest aggressive characteristics (extrathyroidal extension and LNM). The BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC. Lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating the following three characteristics: BRAF mutation, central LNM, and US features in the upper pole location.

Factors predictive of papillary thyroid micro-carcinoma with bilateral involvement and central lymph node metastasis: a retrospective study

BackgroundThe optimal resection extent for papillary thyroid microcarcinoma (PTMC) remains controversial. The objective of the study was to investigate risk factors of bilateral PTMC and central lymph node metastasis (CLNM) to guide surgical strategies for PTMC patients.MethodsWe retrospectively reviewed 211 PTMC patients who underwent total thyroidectomy (TT) and 122 clinical lymph node-negative (cN0) cases that underwent prophylactic central lymph node dissection (CLND) between 2010 and 2011. The frequency, pattern, and predictive factors for bilateral PTMC and CLNM in these patients were studied using univariate and multivariate analysis with respect to the following variables: age, gender, extrathyroidal extension (ETE), T stage, with Hashimoto thyroiditis (HT), tumor size and multifocality based on final pathology, and preoperative evaluation using ultrasonography (US).ResultsFifty-four of 211 (25.6%) patients had bilateral PTMC. In multivariate analysis, multifocality (Pu2009<u20090.001, ORu2009=u200923.900) and tumor size ≥7 mm (Pu2009=u20090.014, ORu2009=u20092.398) based on US were independent predictive factors for bilateral PTMC which was also independently associated with multifocality (Pu2009<u20090.001, ORu2009=u200929.657) and tumor size ≥7 mm (Pu2009=u20090.005, ORu2009=u20092.863) based on final pathology. Among 122 cN0 patients who underwent prophylactic CLND, we found 49.2% of patients had CLNM. CLNM was independently associated with men, age <50 years and tumor size ≥7 mm based on final pathology or preoperative US.ConclusionsTT should be considered for PTMC patients who are found multifocality and tumor size ≥7 mm based on preoperative US. CLND need be considered in cN0 patients who are men, aged <50 years or tumor size ≥7 mm based on preoperative US.

RSPO2–LGR5 signaling has tumour-suppressive activity in colorectal cancer

R-spondins are a family of secreted Wnt agonists. One of the family members, R-spondin 2 (RSPO2), has an important role in embryonic development, bone formation and myogenic differentiation; however, its role in human cancers remains largely unknown. Here we show that RSPO2 expression is downregulated in human colorectal cancers (CRCs) due to promoter hypermethylation, and that the RSPO2 reduction correlates with tumour differentiation, size and metastasis. Overexpression of RSPO2 suppresses CRC cell proliferation and tumorigenicity, whereas the depletion of RSPO2 enhances tumour cell growth. RSPO2 has an inhibitory effect on Wnt/β-catenin signaling in the CRC cells that show suppressed cell proliferation. In human CRC cells, the RSPO2-induced inhibition of Wnt signaling depends on leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5); RSPO2 interacts with LGR5 to stabilize the membrane-associated zinc and ring finger 3 (ZNRF3). Our data suggest that RSPO2 functions as a tumour suppressor in human CRCs, and these data reveal a RSPO2-induced, LGR5-dependent Wnt signaling-negative feedback loop that exerts a net growth-suppressive effect on CRC cells.

Overexpression of miR-221 is associated with aggressive clinicopathologic characteristics and the BRAF mutation in papillary thyroid carcinomas

Correlation between clinicopathogenetic features and the expression of specific miRNAs is unclear in papillary thyroid carcinoma (PTC). We therefore sought to assess whether miR-221 was associated with aggressive clinicopathologic characteristics and the BRAF mutation. We studied the expression levels of miR-221 using northern blot quantitated by scion image in 51 cases of PTCs. The status of BRAF of PTCs was analyzed through direct DNA sequencing. Mann–Whitney U test was used to analyze different expression of miR-221 in PTCs with distinct clinicopathogenetic characteristics including gender, age, tumor size, multifocality, extrathyroidal invasion, disease stages, node metastasis, and BRAF status. Compared with the normal thyroid tissues, the relative expression of miR-221 in tumor tissues was significantly upregulated (pxa0<xa00.001). Overexpression of miR-221 was significantly associated with extrathyroidal invasion (pxa0=xa00.001), lymph node metastasis (pxa0=xa00.046), advanced disease stages III–IV (pxa0=xa00.001), and the BRAF mutation (pxa0=xa00.014). While among BRAF wild tumors, miR-221 was only associated with extarthyroidal invasion, it showed strong association with all above aggressive features among BRAF mutation tumors. MiR-221 may be of potential importance in determining the aggressive properties of PTCs including the BRAF mutation, and it may further refine the risk stratification by BRAF mutation in PTCs.

Clinical significance of Neutrophil gelatinase-associated lipocalin(NGAL) expression in primary rectal cancer

BackgroundEmerging evidence has demonstrated that Neutrophil gelatinase-associated lipocalin (NGAL) is up-regulated in multiple malignancies, including oesophagus cancer, and plays a critical role in tumorigenesis and progression. However, till now, little is known about the role of NGAL in human rectal cancer. Its association with clinicopathologic characteristics and expression of MMP-9, one of its target genes, has not been reported systematically in rectal cancer. Therefore, to further determine the potential involvement of NGAL in rectal cancer, we have evaluated the expression level of NGAL mRNA by real time RT-PCR, and further elucidated the correlation of NGAL mRNA expression with clinicopathologic features and MMP-9 in rectal cancer.Methods100 paired samples of rectal cancer and adjacent normal tissues obtained from inpatients undergoing surgical operation were allocated into two groups (cancer group and control group). The mRNA expression of NGAL and MMP-9 was determined by real-time RT-PCR. The association between their expression and clinicopathological characteristics of rectal cancer were analysised.ResultsAmong the 100 rectal cancers, 69 cases of NGAL mRNA up-regulation were observed. NGAL mRNA up-regulation was positively correlated with MMP-9 (rs = 0.393, p < 0.001). In rectal cancer, NGAL mRNA overexpression was significantly associated with depth of invasion (p = 0.028), lymph node metastasis (p = 0.009), venous involvement (p = 0.023) and advanced pTNM stage (p = 0.011).ConclusionIn human rectal cancer, NGAL mRNA expression was elevated. NGAL mRNA up-regulation was correlated significantly with tumor progression and MMP-9 mRNA overexpression in rectal cancer, suggesting a more aggressive phenotype. NGAL could be used for rectal cancer characterization.

BRAF and TERT promoter mutations in the aggressiveness of papillary thyroid carcinoma: a study of 653 patients

The role of telomerase reverse transcriptase (TERT) gene promoter mutations in the aggressiveness of papillary thyroid cancer (PTC) remains to be further investigated. Here we examined the relationship of TERT promoter mutations and BRAF V600E with the clinicopathological features of PTC in 653 patients. Sanger sequencing of genomic DNA from primary PTC tumors was performed for mutation detection and genotype-clinicopathological correlation of the tumor was analyzed. BRAF V600E and TERT promoter mutations were found in 63.7% (416 of 653) and 4.1% (27 of 653) of patients, respectively; the latter became 9.8% when only tumors ≥ 1.5 cm were analyzed. TERT promoter mutations occurred more frequently in BRAF mutation-positive cases compared to wild-type cases, being 5.3% in the former versus 2.1% in the latter (P = 0.050). BRAF and TERT promoter mutations were each significantly associated with high-risk clinicopathological features of PTC, such as old patient age, large tumor size, extrathyroidal invasion, capsular invasion, and advanced disease stages. Coexistence of BRAF V600E and TERT promoter mutations was particularly associated with high-risk clinicopathological features, as exemplified by extrathyroidal invasion seen in 54.5% (12/22) of patients harboring both mutations versus 9.9% (23/232) of patients harboring neither mutation (P < 0.001). Thus, this study, the largest on TERT mutation so far, demonstrates a significant role of BRAF V600E and TERT promoter mutations in the aggressiveness of PTC, which is particularly robust and cooperative when the two mutations coexist. These results, together with previous studies, establish a significant role of these mutations in the aggressiveness of PTC.

Preoperative BRAF Mutation is Predictive of Occult Contralateral Carcinoma in Patients with Unilateral Papillary Thyroid Microcarcinoma

BACKGROUND AND OBJECTIVEnThe optimal resection extent for clinically unilateral papillary thyroid microcarcinoma (PTMC) remains controversial. The objective was to investigate risk factors associated with occult contralateral carcinoma, and put emphasis on the predictive value of preoperative BRAF mutation.nnnMATERIALS AND METHODSn100 clinically unilateral PTMC patients all newly diagnosed, previously untreated were analyzed in a prospective cohort study. We assessed the T1799A BRAF mutation status in FNAB specimens obtained from all PTMC patients before undergoing total thyroidectomy (TT) and central lymph node dissection (CLND) for PTMC. Univariate and multivariate analyses were used to reveal the incidence of contralateral occult cancer, difference of risk factors and predictive value, with respect to the following variables: preoperative BRAF mutation status, age, gender, tumor size, multifocality of primary tumor, capsular invasion, presence of Hashimoto thyroiditis and central lymph node metastasis.nnnRESULTSn20 of 100 patients (20%) had occult contralateral lobe carcinoma. On multi-variate analysis, preoperative BRAF mutation (p = 0.030, OR = 3.439) and multifocality of the primary tumor (p = 0.004, OR = 9.570) were independent predictive factors for occult contralateral PTMC presence. However, there were no significant differences between the presence of occult contralateral carcinomas and age, gender, tumor size, capsular invasion, Hashimoto thyroiditis and central lymph node metastasis.nnnCONCLUSIONSnTotal thyroidectomy, including the contralateral lobe, should be considered for the treatment of unilateral PTMC if preoperative BRAF mutation is positive and/or if the observed lesion presents as a multifocal tumor in the unilateral lobe.

Preoperative platelet to lymphocyte ratio is a valuable prognostic biomarker in patients with colorectal cancer.

Objectives Recent studies suggest that an elevated preoperative platelet to lymphocyte ratio (PLR) may be considered a poor prognostic biomarker in patients with colorectal cancer (CRC). The aim of this study was to evaluate the prognostic impact of PLR in patients with CRC. Methods We enrolled 1314 patients who underwent surgery for CRC between 2005 and 2011. Preoperative PLR level was stratified into quintiles for Kaplan-Meier analysis and multivariable Cox proportional hazard regression models. Results Higher PLR quintiles were significantly associated with poorer overall survival (P = 0.002). Multivariate analysis showed that PLR was an independent risk factor for overall survival (OS) (P = 0.034). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 1.701, 95% confidence interval (CI): 1.267–2.282, P < 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.522, 95% CI: 1.114–2.080, P = 0.008), this association was not significant after multivariable adjustment (P = 0.075). In the subgroup analysis, PLR remained an independent factor in terms of advanced tumor stage (III, IV), male sex, carcinoembryonic antigen (≤ 5 ng/ml), age (> 65 years) and body mass index (≤ 25) (P < 0.05 for all measurements). The results remained unchanged when the PLR was analyzed as a dichotomous variable by applying different cut-off values of 150, 185, 220. Conclusions Elevated preoperative PLR was independently associated with an increased risk of mortality in patients with CRC. The utility of PLR may help to improve prognostic predictors.

Sentinel lymph node biopsy is unsuitable for routine practice in younger female patients with unilateral low-risk papillary thyroid carcinoma

BackgroundSentinel lymph node (SLN) biopsy has been used to assess patients with papillary thyroid carcinoma (PTC). To achieve its full potential the rate of SLN identification must be as close to 100 percent as possible. In the present study we compared the combination of preoperative lymphoscintigraphy scanning by sulfur colloid labeled with 99 m Technetium, gamma-probe guided surgery, and methylene blue with methylene blue, alone, for sentinel node identification in younger women with unilateral low-risk PTC.MethodsFrom January 2004 to January 2007, 90 female patients, ages 23 to 44 (mean = 35), with unilateral low-risk PTC (T1-2N0M0) were prospectively studied. Mean tumor size was 1.3 cm (range, 0.8-3.7 cm). All patients underwent unilateral modified neck dissection. Prior to surgery, patients had, by random assignment, identification and biopsy of SLNs by methylene blue, alone (Group 1), or by sulfur colloid labeled with 99 m Technetium, gamma-probe guided surgery and methylene blue (Group 2).ResultsIn the methylene blue group, SLNs were identified in 39 of 45 patients (86.7%). Of the 39 patients, 28 (71.8%) had positive cervical lymph nodes (pN+), and 21 patients (53.8%) had pSLN+. In 7 of the 28 pN+ patients (25%), metastases were also detected in non-SLN, thus giving a false-negative rate (FNR of 38.9% (7/18), a negative predictive value (NPV) of 61.1% (11/18), and an accuracy of 82.1% (32/39). In the combined technique group, the identification rate (IR) of SLN was 100% (45/45). Of the 45 patients, 27 (60.0%) had pN+, 24 (53.3%) had pSLN+. There was a FNR of 14.3% (3/21), a NPV of 85.7% (18/21), and an accuracy of 93.3% (42/45). The combined techniques group was significantly superior to the methylene blue group in IR (p = 0.035). There were no significant differences between two groups in sensitivity, specificity, NPV, or accuracy. Location of pN+ (55 patients) in 84 patients was: level I and V, no patients; level II, 1 patient (1.2%); level III, 6 patients (7.2%); level III and IV, 8 patients (9.5%); level IV, alone, 8 patients (9.5%); level VI, 32 patients (38.1%). In all 90 patients, IR of SLN was 93.3%, FNR, 25.6%, NPV, 74.4%, and accuracy rate, 88.1 percent.ConclusionsCompared to a single technique, there was a significantly higher SLN identification rate for the combined technique in younger female with ipsilateral, low-risk PTC (T1-2N0M0). Thus, a combined SLN biopsy technique seems to more accurately stage lymph nodes, with better identification of SLN located out of the central compartment. Regardless of the procedure used, the high FNR renders the current SLN techniques unsuitable for routine practice. Based on these results, prophylactic node dissection of level VI might be considered because 38.1% of our patients had such node metastases.

Effectiveness of OK-432 (Sapylin) to reduce seroma formation after axillary lymphadenectomy for breast cancer.

BackgroundThe occurrence of seroma formation after axillary lymphadenectomy for breast cancer cannot be ignored. Various approaches have been used in an effort to reduce it, but these results are still controversial. We aimed to describe a new method of application of OK-432 (Sapylin, heat-treated Su strain of Streptococcus) to reduce seroma formation after axillary lymphadenectomy for breast cancer and to verify the safety and efficacy of it as a beneficial supplement for conventional surgery.MethodsA prospective, randomized analysis of consecutive quadrantectomy or mastectomy plus axillary lymphadenectomy using or not using OK-432 was designed. From July 2010 to November 2011, a total of 111 patients were enrolled in this prospective, randomized study and completed the follow-up. OK-432 applied to the axillary fossa plus placement of closed suction drainage was used in 54 patients (the experimental group); placement of closed suction drainage was used in 57 patients (the control group).ResultsThere were no statistical significance between the two groups in terms of age, body mass index, treatment received, tumor size, number of removed lymph nodes, and lymph node status. Postoperative drainage magnitude and duration were significantly reduced in the experimental group (Pxa0=xa00.008 and 0.003, respectively). One week after hospital discharge, fewer patients developed a palpable seroma in the experimental group: 10 in the experimental group versus 28 in the control group (Pxa0=xa00.001). Fewer seromas needed aspiration (mean 1 [range 0–3] in the experimental group vs. mean 4 [range 1–5] in the control group; Pxa0<xa00.001). There were no significant differences in terms of the incidence of complications associated with axillary lymphadenectomy (Pxa0=xa00.941).ConclusionsOK-432 is a feasible and safe option for axillary lymphadenectomy for breast cancer. The use of it does not always prevent seroma formation, but it can reduce drainage magnitude and duration, as well as decrease the incidence of seroma after the removal of drainage. It may be increasingly conducted in day surgery clinics.