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Purpose Intraoperative frozen section biopsy is used to reduce the margin positive rate and re-excision rate and has been reported to have high diagnostic accuracy. A majority of breast surgeons in the Republic of Korea routinely perform frozen section biopsy to assess margins intraoperatively, despite its long turnaround time and high resource requirements. This study aims to determine whether omitting frozen section biopsy for intraoperative margin evaluation in selected patients is non-inferior to performing frozen section biopsy in terms of resection margin positivity rate. Methods This study is a phase III, randomized controlled, parallel-group, multicenter non-inferiority clinical trial. Patients meeting the inclusion criteria and providing written informed consent will be randomized to the “frozen section biopsy” or “frozen section biopsy omission” group after lumpectomy. Patients with clinical stage T1–T3 disease who are diagnosed with invasive breast cancer by core-needle biopsy and plan to undergo breast-conserving surgery will be included in this study. If a daughter nodule, non-mass enhancement, or microcalcification is identified on preoperative imaging, these features must be within 1 cm of the main mass for inclusion in the trial. The target sample size is 646 patients per arm. The primary endpoint will be the resection margin positive rate, and the secondary endpoints include the reoperation rate, operating time, residual cancer after reoperation, residual cancer after re-excision according to the frozen section biopsy result, resection volume, patient quality of life, and cost-effectiveness. Discussion This is the first randomized clinical trial utilizing frozen section biopsy for intraoperative margin evaluation and aims to determine the non-inferiority of omitting frozen section biopsy in selected patients compared to performing frozen section biopsy. We expect that this trial will help surgeons perform the procedure more efficiently while ensuring patient safety. Trial Registration ClinicalTrials.gov Identifier: NCT03975179; Clinical Research Information Service Identifier: KCT0004606

We report the development of a label-free, simple, and high efficiency breast cancer detection platform with multimodal biomarker analytic algorithms on a portable 785 nm Raman setup with an endoscopic Raman-lensed fiber optic probe. We propose a multimodal biomarker extraction algorithm (PCMA) implemented by combining a multivariate statistics principal component analysis (PCA) algorithm and a multivariate curve resolution-alternating least squares (MCR-ALS) computational model for extraction of the biomarker information hidden in Raman spectrochemical data. We show that the six Raman spectrochemical peaks at 1009, 1270, 1305/1443, 1658, and 1750 cm-1 assigned to phenylalanine, amide III in proteins, CH2 deformation in lipids, amide I in proteins, and carbonyl, respectively, can be used as a biomarker for breast cancer diagnosis using the biomarker-dominated PCMA spectrochemical spectra of breast tissues. From 20 human breast tissues, the PCMA-linear discriminant analysis (PCMA-LDA) identification method achieved high classification performance with a sensitivity and specificity >99% along with an improvement of approximately 4.5% compared to the performance without the PCMA mixture analysis algorithm. Our label-free breast cancer detection method has the potential for clinical application to diagnose breast cancer in real-time during surgery.

Background In estrogen receptor (ER)-positive breast cancer, young age is associated with poor prognosis. Several reports have suggested hormonal mechanism as the possible reason. Conversely, very young patients respond better to chemotherapy, and chemotherapy is less effective in ER-positive tumors than in ER-negative tumors. The authors tried to evaluate the chemoinsensitivity of very young patients with ER-positive breast cancer by pathologic complete response (pCR) after neoadjuvant chemotherapy excluding the effect of endocrine treatment to the extent possible.Methods We collected individual patient data from 1992 to 2013 from the Korean Breast Cancer Society (KBCS). Total 1,048 ER-positive and 797 ER-negative patients aged Results The proportion of very young patient aged Conclusions Chemotherapy response based on pCR rates was not better in young patients (Trial registration: retrospectively registered

Background In estrogen receptor (ER)-positive breast cancer, young age is associated with poor prognosis. Several reports have suggested hormonal mechanism as the possible reason. Conversely, very young patients respond better to chemotherapy, and adjuvant chemotherapy is less effective in ER-positive tumors than in ER-negative tumors. The authors tried to evaluate the chemoinsensitivity of very young patients with ER-positive breast cancer excluding the effect of endocrine treatment to the extent possible. Methods We collected individual patient data from 1992 to 2013 from the Korean Breast Cancer Society (KBCS), and 1,049 ER-positive patients aged

Surface-enhanced Raman scattering (SERS) is an ultrasensitive molecular screening technique with greatly enhanced Raman scattering signals from trace amounts of analytes near plasmonic nanostructures. However, research on the development of a sensor that balances signal enhancement, reproducibility, and uniformity has not yet been proposed for practical applications. In this study, we demonstrate the potential of the practical application for detecting or predicting asymptomatic breast cancer from human tears using a portable Raman spectrometer with an identification algorithm based on multivariate statistics. This potentiality was realized through the fabrication of a plasmonic SERS substrate equipped with a well-aligned, gold-decorated, hexagonal-close-packed polystyrene (Au/HCP-PS) nanosphere monolayer that provided femtomole-scale detection, giga-scale enhancement, and

Many studies have reported that Aldehyde dehydrogenase 1 (ALDH1) and tumor-infiltrating lymphocytes (TIL) are related to breast cancer prognosis. However, the clinical significance of ALDH1 and tumor-infiltrating immune cells in breast cancer has not been fully investigated in patients who received neoadjuvant chemotherapy (NAC). We studied the significance of the expression of ALDH1 and the population of TIL for predicting the prognosis and chemotherapeutic response of patients with breast cancer who had received NAC. Forty patients who underwent NAC were enrolled in this study. ALDH1 and TIL (T cells and tumor associated macrophages) were evaluated before and after NAC. The influences of ALDH1 expression status and TIL populations on both prognosis and chemotherapeutic response were evaluated. ALDH1 positivity was related to estrogen receptor (p = 0.026) and progesterone receptor negativity (p = 0.025). Positive change of ALDH1 after NAC tended to be associated with a poor NAC response (p = 0.078). Patients with more CD8+ T cells before NAC and fewer CD68 (+) macrophages after NAC tended to have better OS, respectively (p = 0.086, p = 0.096). The chemotherapeutic response and prognosis of patients with breast cancer who received NAC are thought to be determined by the tumor microenvironment. Further research with more patients and a longer study period is needed.

Purpose Breast cancer is one of the most common malignancies worldwide and the second most common cancer among Korean women. The prognosis of breast cancer is poor in patients with other primary cancers. However, there have been few clinical studies regarding this issue. Therefore, we analyzed the characteristics and prognosis of patients with breast cancer with multiple primary cancers (MPCs). Methods Data from the Korean Breast Cancer Society Registry were analyzed. Data from enrolled patients who underwent surgery for breast cancer were analyzed for differences in prognosis dependent on the presence of MPCs, and which MPC characteristics affected their prognosis. Results Among the 41,841 patients analyzed, 913 patients were found to have MPCs, accounting for 950 total MPCs. There was a significant difference in survival rates between the breast cancer only group and the MPC group. The 5-year survival rates were 93.6% and 86.7% and the 10-year survival rates were 87.5% and 70.4%, respectively. Among the 913 patients with MPCs, patients with two or more MPCs had significantly worse prognoses than patients with a single MPC. With respect to the time interval between breast cancer and MPC occurrence, patients with a 5-year or greater interval had significantly better prognoses than patients with less than 1 year between occurrences. Among MPCs, thyroid cancer was the most common primary cancer. However, this type was not related to the prognosis of breast cancer. Gynecologic cancer, colorectal cancer, upper gastrointestinal cancer, and lung cancer were related to breast cancer prognosis. Conclusion MPCs were a poor prognostic factor for patients with breast cancer. Two or more MPCs and a shorter time interval between occurrences were worse prognostic factors. Although MPCs were a poor prognostic factor, thyroid cancer did not affect the prognosis of patients with breast cancer.

We hypothesized that cancer stem cells (CSCs) are responsible for the poor outcome and aggressive clinicopathological factors. We surveyed the expression of selected CSC markers that are specifically expressed in thyroid papillary carcinoma (PTC). A total of 80 patients with PTC from 2011 to 2012 were enrolled. We selected CD24, CD44, CD133, and dehydrogenase 1 (ALDH1), as they have been suggested to be candidate CSC markers. Expression of these markers was investigated by immunohistochemical (IHC) staining. IHC staining for CD24, CD44, CD133 and ALDH1 was evaluated according to staining intensity and proportion. The intensity and proportion scores were multiplied together for a total score, which was either 0-2 (negative) or 3-7 (positive). IHC for CD133 in PTC was positive in 49 (61.3%) patients, and CD24 was positive in 28 (35.0%). Seventy-eight (97.5%) patients were CD44 positive and 79 (98.8%) were ALDH1 positive. When we assessed the relationship between CSC markers and clinicopathological factors in PTC, CD24 expression was inversely correlated with multifocality (p=0.045; odds ratio [OR], 0.370; 95% confidence interval [CI], 0.138-0.991) and CD44 expression was significantly correlated with a BRAF mutation (p=0.001; OR, 7.091; 95% CI, 4.101-12.262). However, CD133 and ALDH1 were not associated with any of the clinicopathological parameters. CD24 expression was inversely correlated with multifocality, and CD44 expression was significantly correlated with a BRAF mutation. Therefore, CD24 and CD44 are related to clinicopathological aggressive features and important for determining surgical extent in patients with PTC.

We aimed to investigate the prognostic influence of primary tumor site on the survival of patients with breast cancer.Data of 63,388 patients with primary breast cancer from the Korean Breast Cancer Registry were analyzed. Primary tumor sites were classified into 5 groups: upper outer quadrant, lower outer quadrant, upper inner quadrant, lower inner quadrant (LIQ), and central portion. We analyzed overall survival (OS) and breast cancer-specific survival (BCSS) according to primary tumor site.Central portion and LIQ showed lower survival rates regarding both OS and BCSS compared with the other 3 quadrants (all P .05) and hazard ratios were 1.267 (95% CI, 1.180-1.360, P .001) and 1.215 (95% CI, 1.097-1.345, P .001), respectively. Although central portion showed more unfavorable clinicopathologic features, LIQ showed more favorable features than the other 3 quadrants. Primary tumor site was a significant factor in univariate and multivariate analyses for OS and BCSS (all P .001). For lymph node-negative patients, LIQ showed a worse OS than the other primary tumor sites in the subgroup with no chemotherapy (P .001), but that effect disappeared in the subgroup with chemotherapy (P = .058).LIQ showed a worse prognosis despite having more favorable clinicopathologic features than other tumor locations and it was more prominent for lymph node-negative patients who received no chemotherapy. The hypothesis of possible hidden internal mammary node metastasis could be suggested to play a key role in LIQ lesions.

Purpose Receptor-interacting protein 3 (RIP3) is the main initiator of necroptosis. Parkin prevents the formation of the RIP1-RIP3 complex by promoting polyubiquitination of RIP3. However, the mechanism by which necroptosis affects the clinical features of breast cancer and prognosis is not known. Here, we aimed to study the effect of necroptosis on the clinical features and prognosis of breast cancer by assessing the expression of RIP3 and Parkin. Methods Tissue microarrays (TMAs) were constructed from 257 cases of breast cancer. Immunohistochemistry was performed on 4-μm tissue sections from each TMA block. The χ² test, Kaplan-Meier survival analysis with log-rank test, and Cox regression proportional hazard model were used for statistical analysis. Results Low RIP3 expression resulted in a large tumor size and high nuclear grade. Low RIP3 expression was correlated with human epidermal growth factor receptor 2 positivity, short overall survival (OS), and short disease-free survival (DFS). The triple negative breast cancer group with low RIP3 expression and lymph node (LN) positive group with low RIP3 expression had the shortest OS. High Parkin expression was associated with high histological grade, estrogen and/or progesterone receptor negativity, and lymphatic emboli, but was not correlated with OS and DFS. OS was correlated with LN metastasis and RIP3 loss and DFS with large tumor size, LN metastasis, and RIP3 loss. Conclusion Low RIP3 and high Parkin expression are associated with aggressive clinical features in breast cancer. RIP3, a molecular marker of necroptosis, is an independent factor associated with survival in breast cancer. Further in-depth studies are needed to investigate the role of necroptosis in breast cancer development, metastasis, and treatment in the future.

Purpose In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels. Methods In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3-4, 5-6, and 7-8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate. Results Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8-96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively (p = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively (p = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity. Conclusion Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression. Trial registration ClinicalTrials.gov Identifier: NCT01069211.

Background Invasive ductal carcinoma with predominant intraductal component (DCIS-IDC) has a favorable survival outcome. However, whether subtypes of DCIS-IDC have prognostic significance remains unknown. We assessed the prognostic value of immunohistochemical subtypes in DCIS-IDC compared with DCIS or IDC without predominant intraductal component. Methods We retrospectively studied 37,049 early breast cancer patients enrolled in the Korean Breast Cancer Registry between January 1993 and February 2011. We categorized DCIS, DCIS-IDC and IDC by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expressions, such as luminal A, B, HER2 and Triple negative breast cancer(TNBC). Multivariate Cox regression analysis was used to estimate associations between subtypes and survival. Results In total, 8346 patients (26.3%) had DCIS, 20,427 (64.4%) had IDC and 2938 (9.3%) had DCIS-IDC. Luminal A type was the most predominant type in all three groups (DCIS=66.5%, IDC=64.7%, DCIS-IDC=46.9%). HER2 subtype was more frequent in DCIS-IDC (27.0%) than in IDC (8.3%) and DCIS (13.3%) ( p p Conclusions Different distribution of subtypes and indistinct prognostic effects in DCIS-IDC indicates that DCIS-IDC is a distinct clinical and biological entity from pure IDC or pure DCIS. MicroAbstract Through a large-sized, registery-based study, we reported differences of IHC-breast cancer subtypes or outcomes in pure IDC, pure DCIS and mixed DCIS-IDC cases with a predominant DCIS component (more than 80% of tumor was DCIS). IHC-breast cancer subtypes of invasive ductal carcinoma with predominant intraductal component were not significant prognostic factor unlike either pure IDC or DCIS. Clinical Practice points We subdivide breast cancer into pure IDC (64%), pure DCIS (26%) and mixed DCIS-IDC cases (9%) with a predominant DCIS component (more than 80% of tumor was DCIS). Within IDC, they observed differences in outcome that correlated with phenotype, among approximately 37,000 cases entered into the Korean cancer registry. They did not observe statistical differences in outcome with phenotypes for the DCIS-IDC group. This study supports that there is a biologic difference between DCIS-IDC cases compared to pure DCIS or pure IDC.

Purpose There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. Methods Self-reported quality of life (QoL) scores were serially assessed for 3 years during adjuvant letrozole treatment using the Korean version of the Functional Assessment of Cancer Therapy-Breast questionnaires (version 3). Changes in bone mineral density (BMD) and serum cholesterol levels were also examined. Results All 897 patients received the documented informed consent form and completed a baseline questionnaire before treatment. Adjuvant chemotherapy was administered to 684 (76.3%) subjects, and 410 (45.7%) and 396 (44.1%) patients had stage I and II breast cancer, respectively. Each patient completed questionnaires at 3, 6, 12, 18, 24, 30, and 36 months after enrollment. Of 897 patients, 749 (83.5%) completed the study. The dropout rate was 16.5%. The serial trial outcome index, the sum of the physical and functional well-being subscales, increased gradually and significantly from baseline during letrozole treatment (p

Multiple symmetric lipomatosis (MSL), or Madelung's disease, is a rare disease of unknown etiology. It is characterized by the presence of loose adipose tissue deposits localized in the cervical region and upper body. MSL presenting as bilateral huge gynecomastia is an extremely rare phenomenon. The present report describes a case of MSL in a 66-year-old man. The patients presented with bilateral breast bulging. He had a history of cigarette and alcohol use. His condition was treated with a bilateral nipple-sparing mastectomy. MSL can present as a form of gynecomastia, for its accurate diagnosis and proper treatment of MSL, increasing awareness of the clinical characteristics of the disease is required, especially amongst breast surgeons. Herein, we review the literature and discuss the clinical characteristics, pathology, and surgical treatment of MSL.

Purpose To investigate the efficacy of the double inversion recovery sequence (DIR) in breast cancer detection. Materials and methods Fifty-six patients with biopsy-proven breast cancers underwent preoperative breast MRI, including sagittal DIR and contrast-enhanced T1-weighted images (CE-T1WI). Twenty-four of the 56 patients additionally underwent sagittal T1WI and T2WI. The signal intensities of the lesion (L) and ipsilateral normal breast tissue (N) were measured. The lesion-to-normal ratio (LNR) was defined as LNR = 100(L-N)/N. We compared LNRs among the four sequences, and then assessed the differences of LNRs between CE-T1WI and DIR in each pathologic subgroup (IDC and non-IDC group). Multiple regression analysis was performed to identify predictors of the signal-to-noise ratios (SNR) of the normal tissue or lesion and LNRs. Results The mean LNR did not differ significantly between DIR (58.65 ± 71.55) and CE-T1WI (59.78 ±31.04), nor did the LNRs between DIR and CE-T1WI in the two subgroups. The LNRs of DIR did not differ significantly between the two subgroups (P = 0.247). The SNR of lesions in DIR was correlated with the intraductal component percentage (r(2) = 0.485, P = 0.037). Conclusion DIR and CE-T1WI showed similar tumor detection efficacy, and DIR could complement dynamic MRI for detecting breast cancer without a contrast agent.

Background The purpose of this study was to compare the surgical outcomes of robotic thyroidectomy (RT) using bilateral axillo-breast approach (BABA) with conventional open thyroidectomy (OT) in papillary thyroid carcinoma patients. Methods Between January 2009 and December 2013, 815 patients who had received thyroidectomy for papillary thyroid carcinoma were enrolled. Of these, 126 patients received RT and 689 patients underwent OT. Age, gender, body mass index, extent of surgery, tumor size, multiplicity, bilaterality, extrathyroidal extension, and tumor stage were used for the propensity score matching analysis. One hundred and nine patients were selected in each group, and surgical outcomes were compared between the two groups. Results The RT group showed a significantly longer operating time (290.6 ± 74.4 vs. 107.9 ± 30.8 min, P

The purpose of this study was to compare the characteristics of quantitative perfusion parameters obtained from dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) in patients with mammographically occult (MO) breast cancers and those with mammographically visible (MV) breast cancers. Quantitative parameters (AUC, Ktrans,kep,ve,vp, and wi) from 13 MO breast cancers and 16 MV breast cancers were mapped after the DCE‐MRI data were acquired. Various prognostic factors, including axillary nodal status, estrogen receptor (ER), progesterone receptor (PR), Ki‐67, p53, E‐cadherin, and human epidermal growth factor receptor 2 (HER2) were obtained in each group. Fisher's exact test was used to compare any differences of the various prognostic factors between the two groups. The Mann‐Whitney U test was applied to compare the quantitative parameters between these two groups. Finally, Spearman's correlation was used to investigate the relationships between perfusion indices and four factors — age, tumor size, Ki‐67, and p53 — for each group. Although age, tumor size, and the prognostic factors were not statistically different between the two groups, the mean values of the quantitative parameters, except wi in the MV group, were higher than those in the MO group without statistical significance (p=0.219). The kep value was significantly different between the two groups (p=0.048), but the other parameters were not. In the MO group, vp with size, ve with p53, and Ktrans and vp with Ki‐67 had significant correlations (p

The FOSB gene is involved in cell proliferation, differentiation and transformation in several tumor types. We investigated whether coding single-nucleotide polymorphisms (cSNPs) and promoter SNPs of FOSB contribute to the development of papillary thyroid cancer (PTC). We also assessed the associations between FOSB SNPs and the clinicopathological characteristics of PTC. One coding SNP (rs2282695, Ala39Ala) and one promoter SNP (rs12373539, -158) in the FOSB gene were genotyped using direct sequencing in 94 PTC patients and 213 healthy controls. Genetic data were analyzed using SNPStats, HelixTree and SNPAnalyzer. PTC patients were dichotomized and compared with respect to clinicopathological characteristics of PTC. We detected an association between PTC and cSNP (rs2282695) in FOSB [codominant model 1 (C/C vs. G/C); OR=1.75; 95% CI, 1.04-2.94; P=0.024; codominant model 2 (C/C vs. G/G): OR=2.55; 95% CI, 1.15-5.64; P=0.045; dominant model: OR=1.89; 95% CI, 1.16-3.08; P=0.010; Log-additive model: OR=1.64; 95% CI, 1.15-2.35; P=0.007]. The G allele was a risk allele in the geno-type and allele analyses of cSNP (rs2282695) in the FOSB gene (OR=1.57; 95% CI, 1.10-2.24; P=0.012). A promoter SNP (rs12373539) in FOSB was associated with cervical lymph node metastasis of PTC [codominant model 1 (G/G vs. A/G): OR=0.23; 95% CI, 0.07-0.72; P=0.016; codominant model 2 (G/G vs. A/A): OR=0.21; 95% CI, 0.02-1.96; P=0.0.05; dominant model: OR=0.22; 95% CI, 0.08-0.66; P=0.004; overdominant model: OR=0.27; 95% CI, 0.09-0.84; P=0.02; log-additive model: OR=0.31; 95% CI, 0.12-0.78; P=0.006]. The A allele was a protective allele in the genotype and allele analyses of SNP (rs12373539) in the FOSB gene promoter (OR=0.34; 95% CI, 0.14-0.83; P=0.017). Variation in a FOSB cSNP (rs2282695) may be associated with risk of PTC. The FOSB promoter SNP (rs12373539) may be associated with lymph node metastasis of PTC.

Cancer cells show a higher rate of anaerobic respiration than normal cells. The exact mechanisms for this higher glycolysis rate in cancer cells remain to be elucidated. The results of recent studies have indicated that p53, the most commonly mutated tumor suppressor gene, may have important functions in the regulation of energy-generating metabolic pathways that switch from oxidative phosphorylation to glycolysis via the synthesis of cytochrome c oxidase 2 (SCO2), p53-transactivated TP53-induced glycolysis (TIGAR), and apoptosis regulator. We evaluated the expression of p53, SCO2, TIGAR, and COX in 113 cases of invasive breast cancer using immunohistochemistry. A high expression of p53, SCO2, TIGAR, and COX was noted in 27.5% (31 cases), 84.1% (95 cases), 74.3% (84 cases), and 73.4% (83 cases) of the breast tumors, respectively. A high p53 expression was significantly associated with low expression levels of SCO2 (P = .008), COX (P < .0001), and TIGAR (P = .007). On the survival analysis, the low SCO2-expressing breast cancer patients showed a significantly poorer prognosis than that of the high SCO2-expressing breast cancer patients (P = .0078). These results suggest that p53 can modulate the metabolic pathways via the proteins SCO2 and TIGAR in human breast cancer.

Background The interleukin11 (IL11) and IL11 receptor alpha (IL11RA) are involved in cellular growth, differentiation, invasiveness, and tumor progression in several tumors. We investigated whether coding single nucleotide polymorphisms (cSNPs) of IL11 and promoter SNP IL11RA would contribute to the development of papillary thyroid cancer (PTC). We also assessed the relationships between IL11 and IL11RA SNPs and the clinicopathologic characteristics of PTC. Methods One coding SNP, designated as rs1126757, Ala82Ala, in IL11 and one promoter SNP, designated as rs1061758, −106A/G, in IL11RA were genotyped using direct sequencing in 94 patents with PTC and 213 patients without PTC (controls). Genetic data were analyzed using commercially available software. The patients with PTC were dichotomized and compared with respect to clinicopathologic characteristics of PTC. Results We found an association between PTC and the coding SNP(rs1061758) in IL11RA (codominant model 1 [G/G vs A/G], odds ratio [OR] = 2.91, 95% confidence interval [CI], 1.44–5.89; P = .003; codominant model 2 [G/G vs A/A], OR = 2.95, 95% CI, 1.30–6.72; P = .01; and dominant model, OR = 2.92, 95% CI, 1.47–5.80; P = .002). Moreover, SNP rs1061758 in IL11RA was associated with the multifocality of PTC (codominant model 2 [A/A vs G/G], OR = 9.56, 95% CI, 1.77–51.69; P = .009; and recessive model, OR = 7.22, 95% CI, 1.72–30.3; P = .007). Genotype and allele analyses of SNP variant rs1126757 in IL11 revealed no statistically significant differences between patients with PTC and controls. Conclusion Our results suggest that an IL11RA promoter polymorphism — rs1061758 — may be associated with the risk of PTC in the Korean population. In addition, rs1061758 might be related to the multifocality of PTC.

Purpose: Integrins play crucial roles in the pathogenesis of papillary thyroid carcinoma (PTC). The aim of this study was to investigate whether two single nucleotide polymorphisms (SNPs) (rs2141698, -1687A/G; rs11895564, Ala380Thr) of the integrin alpha 6 (ITGA6) gene are associated with the development and clinicopathologic characteristics of PTC such as the size (＜1 cm and ≥1 cm), number (unifocality and multifocality), location (one lobe and both lobes), extrathyroid invasion, and cervical lymph node metastasis. Methods: We enrolled 104 PTC patients and 318 control subjects. Genotypes of each SNP were determined by direct sequencing. SNPStats, SNPAnalyzer, and Helixtree programs were used to evaluate odds ratios (ORs), 95% confidence intervals (CIs), and P-values. Multiple logistic regression models were performed to analyze genetic data. Results: A missense SNP rs11895564 was associated with the development of PTC. The A allele frequency of rs11895564 was higher in PTC patients than in controls (13.5% vs. 7.1%; P = 0.005; OR, 2.04; 95% CI, 1.24 to 3.37). In the clinicopathologic characteristics, the A allele frequency of rs11895564 showed difference in the size (19.6% in ＜1 cm vs. 6.9% in ≥1 cm; P = 0.010; OR, 0.30; 95% CI, 0.12 to 0.75) and number (8.5% in unifocality vs. 20.8% in multifocality; P = 0.015; OR, 2.85; 95% CI, 1.23 to 6.59) of PTC. Conclusion: These results suggest that the A allele of rs11895564 (Ala380Thr) in ITGA6 may be a risk factor of PTC, and also contribute to the progression of PTC in the Korean population.

Kim H-S, Kim G Y, Kim Y W, Park Y-K, Song J-Y & Lim S-J (2010) Histopathology 56, 708–719 Stromal CD10 expression and relationship to the E-cadherin/β-catenin complex in breast carcinoma Aims: Previous investigations have indicated that stromal CD10 expression, and altered levels of both E-cadherin and β-catenin, are associated with the biological aggressiveness of human carcinoma. The aim was to evaluate stromal CD10 expression and the association of stromal CD10 with E-cadherin and β-catenin in breast carcinoma. Methods and results: The expression of CD10, E-cadherin and β-catenin was immunohistochemically analysed in tissue microarrays containing 104 cases of invasive ductal carcinoma (IDC) and 10 cases of ductal carcinoma in situ (DCIS). Stromal CD10 was detected in 49.5% (50/101) of the IDC. No immunoreactivity was identified in the stromal cells of normal breast, DCIS or intraductal components of IDC. Accumulation of the cytoplasmic β-catenin was found in 87.0% (87/100) of the IDC. Stromal CD10 expression in IDC was significantly correlated with tumour size (P = 0.027), stage (P

To evaluate the potential of Tc-99m diphosphonate as a tracer for sentinel lymph node biopsy in breast cancer.Lymphoscintigraphs of 35 patients (50.9 ± 10.2 years) with breast cancer were acquired after administering a subareolar intradermal injection of Tc-99m diphosphonate 18 h before surgery. Static images were taken within 15 min (early phase) and 15 h after injection (delayed phase). The lymphoscintigraphic identification rate was defined as the percentage of subjects studied with visible foci at axillae. Sentinel lymph node biopsies were performed using a gamma probe and by blue dye injection. Any node that was radioactive or stained with blue dye was labeled as a sentinel lymph node. Lymph nodes without radioactivity or blue dye staining were defined as non-sentinel lymph nodes. The intraoperative identification rate was defined as the percentage of patients with a radioactive sentinel lymph node. Percentages of lymphoid cells expressing S-100, CD83, and CD1a were compared.The lymphoscintigraphic identification rate was 94.3% (33/35) during the early phase and 96.9% (31/32) during the delayed phase, whereas the intraoperative identification rate was 94.3% (33/35). The mean percentages of lymphoid cells that stained positively for S-100 or CD83 were lower in sentinel lymph nodes than in non-sentinel lymph nodes (1.5% vs. 9.0% for S-100, and 4.5% vs. 9.3% for CD83, respectively, p = 0.0286). The mean percentages of lymphoid cells in sentinel lymph nodes and non- sentinel lymph nodes expressing CD1a were 3.3% and 7.0%, respectively (p = ns).Tc-99m diphosphonate can reliably detect regional lymph nodes in breast cancer.

To find new biomarkers by stimulating acupuncture point GB34 (Yangneungcheon) which has neuroprotective effect on the mouse model of Parkinson's disease, analysis of cDNA microarray on mRNAs of the substantia nigra was performed.Male C57BL/6 mice were divided into two groups: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice (MPTP group, n=3); 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and acupuncture (GB34)-treated mice (MPTP + ACU group, n=3). The mice received an intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg) once daily for 3 consecutive days. Manual acupuncture was performed 2 hours after every injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The total RNA in the substantia nigra of each mouse was isolated on 3 days after the last 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Agilent mouse whole genome 44K chip was used for microarray analysis and the hybridization image was analysed by GenePix Pro 6.0. Data normalization and analysis were performed using GeneSpring GX 7.3.1 program.The acupuncture stimulation revealed 799 genes (424 up- and 375 down-regulated) of which expression levels were changed more than two-folds in the MPTP + ACU group, compared to the MPTP group. The genes selected were classified into several categories based on their functions using DAVID Bioinformatics Resources 2008 (http://david.abcc.ncifcrf.gov/) and KEGG PATHWAY Database (http://www.genome.jp/kegg/pathway.html).Biomarkers in response to acupuncture stimulation to GB34 were identified in a mouse model for Parkinson's disease. These biomarkers might provide a promising clue for understanding the neuroprotective effect of acupuncture in Parkinson's disease.

Most regional anesthesia in breast surgeries is performed as postoperative pain management under general anesthesia, and not as the primary anesthesia. Regional anesthesia has very few cardiovascular or pulmonary side-effects, as compared with general anesthesia. Pectoral nerve block is a relatively new technique, with fewer complications than other regional anesthesia. We performed Pecs I and Pec II block simultaneously as primary anesthesia under moderate sedation with dexmedetomidine for breast conserving surgery in a 49-year-old female patient with invasive ductal carcinoma. Block was uneventful and showed no complications. Thus, Pecs block with sedation could be an alternative to general anesthesia for breast surgeries.

Previous investigations have indicated that stromal CD10 expression, and altered levels of both E-cadherin and beta-catenin, are associated with the biological aggressiveness of human carcinoma. The aim was to evaluate stromal CD10 expression and the association of stromal CD10 with E-cadherin and beta-catenin in breast carcinoma.The expression of CD10, E-cadherin and beta-catenin was immunohistochemically analysed in tissue microarrays containing 104 cases of invasive ductal carcinoma (IDC) and 10 cases of ductal carcinoma in situ (DCIS). Stromal CD10 was detected in 49.5% (50/101) of the IDC. No immunoreactivity was identified in the stromal cells of normal breast, DCIS or intraductal components of IDC. Accumulation of the cytoplasmic beta-catenin was found in 87.0% (87/100) of the IDC. Stromal CD10 expression in IDC was significantly correlated with tumour size (P = 0.027), stage (P0.001) and histological grade (P = 0.006), the presence of nodal (P = 0.048) and distant (P = 0.015) metastases, oestrogen receptor-negative status (P = 0.016), cytoplasmic beta-catenin accumulation (P = 0.031) and lower overall survival rate (P = 0.041).Stromal CD10 expression in IDC may constitute an important prognostic marker. Stromal CD10 expression with associated aggressive features might be related to aberrant beta-catenin expression.

Early stressors can influence the development of biological and neurological systems. Maternal separation (social isolation) in early life may increase vulnerability to neurodegenerative diseases and neuropsychiatric disorders over the lifespan. To identify new proteins on acupuncture effects in maternally separated rats, an animal model for study of early environmental insults, proteomic approach on the expression of the hypothalamic proteins was performed.On post-natal day 14, rat pups were randomly divided into four groups: pups kept with their mothers for 7 days; pups kept with their mothers with acupuncture daily to HT8 (Sobu); maternally separated pups; maternally separated pups with acupuncture. The hypothalamic proteins were analysed by two-dimensional electrophoresis coupled with matrix assisted laser desorption/ionization time-of-flight mass spectrometer.The results showed that 27 spots were differentially and commonly expressed. Of 27 spots, 21 spots were identified while six spots were not, and 15 proteins were known proteins. In maternally separated group, the expressions of 14 proteins were down-regulated, compared to control group. In group of maternally separation with acupuncture, five proteins were down-regulated and nine were up-regulated, compared to the maternally separated group. Among nine proteins up-regulated by acupuncture treatment, we found four proteins (dihydropyrimidinase-like 2, dystrophin-related protein 2, tubulin, alpha 1a and syntaxin 1b) related to neurodevelopment.The result suggests that acupuncture to HT8 may affect neurodevelopment, and acupuncture may be a possible therapy for neurodevelopmental disorders.

The regulation of gene expression in eukaryotes is controlled atboth the transcriptional and posttranscriptional level (1). Post-transcriptional gene regulatory events, especially regulation ofmRNA turnover, have emerged as fundamental and effective meansto alter the expression of functionally related genes (2). Theinvestigation of post-transcriptional regulatory mechanisms centerson the association of a given RNA-binding protein with its targetmRNA (3). The proteins make mRNA stable by binding to AU-richelements (AREs) in the 3’-untranslated region of some mRNAs.Thus, the binding effectively lengthens the presence of a givenmRNA and consequently, the amount of protein expressed isincreased. Among the ARE-binding proteins identified, the humanfamily embryonic lethal abnormal vision (ELAV)-like proteins thatconsist of four members (Hel-N1/HuB, HuC, HuD and HuR) havebeen well characterized (4). HuR is expressed in many cell types,mainly in the cellular nucleus, while the other three proteins areusually expressed in terminally differentiated tissue (4). Severalstudies have shown that HuR can shuttle between the nucleus andcytoplasm and localization of HuR in the cytoplasm is required forits mRNA stabilizing function (5). HuR binds to labile transcriptscontaining AREs, such as mRNAs for proto-oncogenes, cytokinesand cytokine-response genes in the nucleus. The HuR-mRNAcomplex is then transported to the cytoplasm (6), where thestabilized mRNA can be translated into protein more efficiently.Increased expression of cyclooxygense-2 (Cox-2) has beenCancer Res Treat. 2009;41(2):87-92

Signal transducer and activator of transcription 4 (STAT4), a STAT family member, mediates interleukin 12 (IL12) signal transduction. IL12 is known to be related to calorie-restricted status. In the central nervous system, IL12 also enhances the production of nitric oxide (NO), which regulates food intake. In this study, the expression of neuronal NO synthase (Nos1), which is also related to food intake, was investigated in the hypothalamic areas of Stat4 knockout (KO) mice using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry, a marker for neurons expressing Nos1 enzyme. Western blots were also performed to evaluate Nos1 and Fos expression. Wild-type Balb/c (WT group, n=10 male) and Stat4 KO mice (Stat4 KO group, n=8 male) were used. The body weight and daily food intake in the WT group were 22.4+/-0.3 and 4.4 g per day, while those in the Stat4 KO group were 18.7+/-0.4 and 1.8 g per day, respectively. Stat4 mice had lower body weight and food intake than Balb/c mice. Optical intensities of NADPH-d-positive neurons in the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) of the Stat4 KO group were significantly higher than those of the WT group. Western blotting analysis revealed that the hypothalamic Nos1 and Fos expression of the Stat4 KO group was up-regulated, compared to that in the WT group. These results suggest that Stat4 may be related to the regulation of food intake and expression of Nos1 in the hypothalamus.

The human beclin-1 gene, located on chromosome 17q21, has been identified as the mammalian orthologue of Atg6 (autophagy-related gene) and may be a haploinsufficient tumor suppressor gene. The function and expression of beclin-1 in human breast cancer are largely unknown. We investigated the expression of beclin-1 and bcl-2 in human breast cancer. Tissue samples from 125 cases of invasive breast cancer were used for the present study. Immunohistochemical staining for beclin-1 and bcl-2 was evaluated using tissue microarray, then the 2 proteins were correlated with clinicopathologic parameters. Positive beclin-1 expression and bcl-2 expression in breast cancer tissue were observed in 53 cases (42.4%) and 48 cases (38.4%), respectively. Beclin-1 expression was inversely correlated with bcl-2 expression in breast cancer tissue (P = .035). Beclin-1 expression significantly correlated with nuclear pleomorphism and mitotic count. Bcl-2 expression in breast cancer tissue significantly correlated with histologic grade, tubule formation, nuclear pleomorphism, mitotic count, estrogen receptor, and distant metastasis. Our results suggest that beclin-1 might play a role in the inhibition of the development of breast cancer and that inhibition might be due to an interaction with bcl-2 protein.

Purpose A chemotherapy response assay test is performed to evaluate the degree of tumor growth inhibition by a chemotherapeutic agent. Several studies have been done on its usefulness; however, to the best of our knowledge, only a few studies concerning the relationship between chemotherapy response assay test results and breast cancer patients' prognoses have been conducted. Thus, we performed this study to analyze this relationship. Methods Among breast cancer patients who underwent curative surgery and neoadjuvant or adjuvant chemotherapy between August 2004 and December 2009, 102 were enrolled in this study. Chemotherapeutic regimens for patients were doxorubicin plus taxane or doxorubicin plus cyclophosphamide followed by taxane. We divided these patients into two groups (sensitive group [n=19] and resistant group [n=83]) and analyzed the relationship between chemosensitivity results and patient prognosis. Results The sensitive group was associated with poor disease-free survival (DFS) (p=0.003) and overall survival (OS) (p

Purpose: Hypoxia, which is a loss of oxygen in tissues, is a common condition in solid tumors due to the tumor outgrowing existing vasculature. Under hypoxic conditions, hypoxia-inducible factor (HIF)-1α rapidly accumulates and transactivates hundreds of genes, such as matrix metalloproteinases (MMPs). MMPs contribute to invasion and metastasis of tumor cells by degrading the surrounding basement membrane and extracellular matrix barriers, which enables the easy migration and spread of cancer cells. We examined whether hypoxia increases tumor cell invasion, and whether increased invasiveness was due to HIF-1α and MMP-9 expression. Methods: Transwell invasion assays were performed to demonstrate whether hypoxia enhance tumor invasion by use of MDA-MB-231 breast cancer cells. An immunofluorescence assay was used to demonstrate expression of HIF1α and MMP-9 under hypoxic conditions. Luciferase and ChiP assays were performed to demonstrate that MMP-9 promoter activity was regulated by HIF-1α. Results: HIF-1α was stabilized under hypoxic conditions and stimulated MMP-9 expression, which affected the tumor invasiveness of breast cancer cells. HIF-1α transactivated the MMP-9 promoter by forming a transcriptional unit with p300, thus increasing expression of MMP-9 transcripts. Zymography indicated that MMP-9 had more gelatinase activity under hypoxic conditions than normoxic conditions. Furthermore, the small GTPase Ras was also activated in response to hypoxia, which then aids stabilization of HIF-1α, and in turn upregulates MMP-9 expression. We also demonstrate that MMP-9 is upregulated concurrently with HIF-1α in tumor tissues from patients with breast cancer. Conclusion: These results suggest that HIF-1α promotes cell invasion through a MMP-9-dependent mechanism and that future antitumor agents could be used to target HIF-1α and MMP-9.

Purpose: Recent studies have shown that cyclooxygenase (COX)-2 may be involved in colorectal carcinogenesis. In this study, we evaluate the differences of COX-2 expression in patients with synchronous and metachronous hepatic metastasis of colorectal cancer. In addition, the expression of COX-1 and E-cadherin were also evaluated. Methods: Paraffin embedded blocks were obtained from 41 patients who underwent surgery for colorectal cancer with hepatic metastasis. Samples from primary colorectal cancer, synchronous and metachronous hepatic lesions were stained by immunohistochemistry for monoclonal antibody against COX-1, COX-2, and E-cadherin. Results: In colonic COX-1 expression, there was no significant difference in the degree of COX-1 expression between primary colorectal cancer with synchronous hepatic metastasis and that of metachronous hepatic metastasis (P=0.507). In colonic COX-2 and E-cadherin expression, the degree of COX-2 expression was not different between the two groups. But, the patient survival rate in the positive group of COX-1 and COX-2 expression was lower than in the negative group, respectively (P=0.023, P=0.006). Conclusion: The degree of colonic COX-1 and COX-2 expression has an impact on prognosis in synchronous and metachronous hepatic metastasis. Further large-scale study is necessary to determine the meaning of COX-2 expression in colorectal cancer.

Gastrointestinal stromal tumors (GISTs) constitute the most common primary mesenchymal tumors of the digestive tract and characteristically express c-kit (CD117). GISTs are the most common non-epithelial tumor of the GI tract and frequently originate from the stomach and small bowel. Specifically, the synchronous occurrence of a GIST with other epithelial tumors is rarely reported. Recently, we discovered one case of a concurrent gastric cancer and a small bowel GIST that was initially suspected to be peritoneal seeding from gastric cancer. The patient was initially admitted with epigastric pain. Gastric cancer with peritoneal seeding was suspected after an evaluation. Following a laparoscopic examination, a distal gastrectomy with D2 lymph node dissection and small-intestine segmental resection was performed. The final pathologic diagnosis was early gastric cancer and high-risk small bowel GIST. The patient refused adjuvant therapy for the GIST, and currently shows no other marked indisposition. He has been disease-free for 14 months.

Background : Uncoupling protein 2 (UCP2) is a recently identified mitochondrial inner membrane anion carrier and a negative regulator of reactive oxygen species production. In this study, we evaluated the characteristics and relationships of UCP2 and p53 expression in breast cancer tissues. Methods : Tissue microarray slides from 107 cases of invasive ductal carcinoma of the breast were constructed, UCP2 and p53 immunohistochemical staining was conducted, and clinicopathological correlations were investigated. Results : UCP2 expression in invasive ductal carcinoma was high in 53 cases (49.5%), while p53 expression in invasive ductal carcinoma was high in 37 cases (34.6%). UCP2 expression was correlated significantly with histological grade (p = 0.038) and mitotic count (p = 0.050). UCP2 expression was correlated significantly with p53 expression in invasive ductal carcinoma of the breast (p = 0.045). UCP2 expression (p = 0.8308) and p53 expression (p = 0.3292) showed no significant difference for the overall survival rate in patients with invasive ductal carcinoma. Conclusions : UCP2 expression in invasive ductal carcinoma increased proportionally with histological grade and mitotic count. High UCP2 expression in invasive ductal carcinoma was observed in conjunction with high p53 expression.

A goblet cell appendiceal carcinoid (GCAC) is an uncommon tumor. It shares the histologic features of both adenocarcinoma and conventional carcinoids. The metastatic potential of GCAC is higher than that of classic appendiceal carcinoids. Their management, whether an appendectomy alone is an adequate treatment or whether a right hemicolectomy is indicated, is still under debate. The metastatic potential of GCAC is similar to that of classic appendiceal carcinoids and depends on the tumor size and the mitosis rate. Therefore, some authors advocate a simple appendectomy, not expanding beyond the appendix adventitia, for selected patients with tumors less than 1 cm in diameter with a low mitosis rate (

Ingestion of foreign bodies is a common clinical problem encountered in early childhood. But ingestion of multiple magnets can cause serious lethal complications. Magnets located within another bowel loop may attract each other across the intestinal walls, resulting pressure necrosis, bowel perforation, fistula formation, intestinal obstruction, and death. Clinicians who care for children should be aware of this unexpected risk of magnetic ingestion. We report a case of ileal perforation caused by ingestion of multiple magnets in a child.

Rotenone, a mitochondrial complex I inhibitor, can induce the pathological features of Parkinson's disease (PD). In the present study, naringin, a grapefruit flavonoid, inhibited rotenone-induced cell death in human neuroblastoma SH-SY5Y cells. We assessed cell death and apoptosis by measuring mitogen-activated protein kinase (MAPKs) and caspase (CASPs) activities and by performing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 4,6-diamidino-2-phenylindole (DAPI) staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. Naringin also blocked rotenone-induced phosphorylation of Jun NH2-terminal protein kinase (JNK) and P38, and prevented changes in B-cell CLL/lymphoma 2 (BCL2) and BCL2-associated X protein (BAX) expression levels. In addition, naringin reduced the enzyme activity of caspase 3 and cleavages of caspase 9, poly (ADP-ribose) polymerase (PARP), and caspase 3. These results suggest that naringin has a neuroprotective effect on rotenone-induced cell death in human neuroblastoma SH-SY5Y cells.