An observational, prospective, open label, multicenter study to evaluate the safety and effectiveness of pegfilgrastim as secondary prophylaxis to decrease the incidence of febrile neutropenia in Korean female patients with breast cancer.

PURPOSE: Pegfilgrastim is a widely used long-acting granulocyte colony-stimulating factor (G-CSF) that prevents febrile neutropenia (FN) in patients with breast cancer receiving chemotherapy. This study aimed to evaluate the incidence of chemotherapy-related FN events and other adverse events (AEs) during chemotherapy in Korean patients with breast cancer treated with pegfilgrastim as secondary prophylactic support. MATERIALS AND METHODS: This was a multicenter, open-label, prospective, observational study. A total of 1255 patients were enrolled from 43 institutions. The incidence of FN was evaluated as the primary endpoint. The secondary endpoints included (1) incidence of bone pain, (2) proportion of patients with a relative dose intensity (RDI) of ≥85%, and (3) proportion of patients with AE. RESULTS: Pegfilgrastim administration reduced FN by 11.8-1.6%. The highest incidence of bone pain was observed at the time point of the 1st day after the administration and mild bone pain was the most common of all bone pain severity. The mean RDI was 98.5 ± 7.3%, and the proportion of the patients with and RDI≥85% was 96.9% (1169/1233). AEs were reported in 52.6% of the patients, and serious drug reactions occurred in only 0.7%. CONCLUSION: The use of pegfilgrastim as secondary prophylaxis was effective and safe for preventing FN in patients with breast cancer who were treated with chemotherapy.

Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society.

BACKGROUND: There is an increasing interest in HER2-low breast cancer with promising data from clinical trials using novel anti-HER2 antibody-drug conjugates. We explored the differences in clinicopathological characteristics and survival outcomes between HER2-low and HER2-IHC 0 breast cancer. METHODS: Using nationwide data from the Korean Breast Cancer Registry between 2006 and 2011, 30,491 patients with stages I to III breast cancer were included in the analysis: 9,506 (31.2%) in the HER2-low group and 20,985 (68.8%) in the HER2-IHC 0 group. Kaplan-Meier and Cox proportional hazards regression survival analysis were used to compare breast cancer-specific survival between the two groups. RESULTS: HER2-low breast cancer was more frequent in patients with hormone receptor-positive breast cancer than in those with triple-negative breast cancer. In patients with hormone receptor-positive breast cancer, HER2-low breast cancer was associated with fewer T4 tumors, higher histological grade, and a negative lymphatic invasion. In patients with triple-negative breast cancer, HER2-low breast cancer was associated with a high lymph node ratio and positive lymphatic invasion. HER2-low breast cancer was significantly associated with a lower Ki-67 labeling index. No significant difference was observed in overall survival between the two groups. HER2-low breast cancer showed significantly better breast cancer-specific survival than HER2-IHC 0 breast cancer, regardless of the hormone receptor status. In multivariate analysis, the impact of low HER2 expression on breast cancer-specific survival was significant only in triple-negative breast cancer (HRs, 0.68; 95% CI, 0.49-0.93; P = 0.019). CONCLUSIONS: These findings suggest that the biology and clinical impact of low HER2 expression can differ according to the hormone receptor status and support the need for further investigation on the understanding of the biology of HER2-low breast cancer.

Label-free breast cancer detection using fiber probe-based Raman spectrochemical biomarker-dominated profiles extracted from a mixture analysis algorithm.

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.

Response to neoadjuvant chemotherapy based on pathologic complete response in very young patients with ER-positive breast cancer: a large, multicenter, observational study.

BACKGROUND: In estrogen receptor (ER)-positive breast cancer (BC), young age is associated with poor prognosis. While very young patients respond better to chemotherapy, chemotherapy is less effective in ER-positive tumors than in ER-negative tumors. The authors tried to evaluate chemotherapy response of very young patients with ER-positive BC 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 1048 ER-positive and 797 ER-negative patients aged < 50 years who had been treated with neoadjuvant chemotherapy were included for analysis. We compared pCR rate between patients aged < 35 years with ER-positive tumors and the other groups. RESULTS: The proportion of patients aged < 35 years was 14.0% of patients with ER-positive BC in this cohort of under 50 years old, and 16.8% of patients with ER-negative BC in this cohort of under 50 years old. Although most characteristics of tumors according to age were comparable, tumors with high Ki-67 expression were more common in patients aged < 35 years than in patients aged 35-49 years in both ER-positive and -negative group (P = 0.001). Breast conservation rates were not significantly different according to age (44.2% vs. 46.8% in ER-positive group, 55.2% vs. 48.0% in ER-negative group). pCR rate was not different according to age in ER-positive group (P = 0.71) but significantly better in patients aged < 35 years in ER-negative group (P = 0.009). After adjusting for confounding variables, young patients maintained the higher probability of pCR than older patients in ER-negative tumors. However, pCR rate did not differ according to age in ER-positive tumors. In multivariate analysis, young age (< 35 years) was correlated with poor overall survival (P = 0.003, HR = 1.98) and there was only one event in a few patients achieved pCR in ER-positive group. CONCLUSIONS: Chemotherapy response based on pCR was not better in young patients (< 35 years) with ER-positive BC than in older premenopausal patients with non-metastatic ER-positive BC. Young age cannot be a predictive factor of response to neoadjuvant chemotherapy in ER-positive BC. Different biological characteristics such as high proliferative index should be considered. TRIAL REGISTRATION: Retrospectively registered.

Clinical Outcomes Following Letrozole Treatment according to Estrogen Receptor Expression in Postmenopausal Women: LETTER Study (KBCSG-006).

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.

Clinical Significance of Receptor-Interacting Protein 3 and Parkin, Essential Molecules for Necroptosis, in Breast Cancer.

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.

A Randomized Controlled Trial for Doing vs. Omitting Intraoperative Frozen Section Biopsy for Resection Margin Status in Selected Patients Undergoing Breast-Conserving Surgery (OFF-MAP Trial).

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.

Clinical Characteristics and Prognosis Associated with Multiple Primary Cancers in Breast Cancer Patients.

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.

ALDH1 and tumor infiltrating lymphocytes as predictors for neoadjuvant chemotherapy response in breast cancer.

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.

Pectoral nerve block (Pecs block) with sedation for breast conserving surgery without general anesthesia.

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.

Prognostic value of putative cancer stem cell markers (CD24, CD44, CD133, and ALDH1) in human papillary thyroid carcinoma.

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.

Characteristics of quantitative perfusion parameters on dynamic contrast-enhanced MRI in mammographically occult breast cancer.

The purpose of this study was to compare the characteristics of quantitative per-fusion 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 prog-nostic 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 relation-ships 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 differ-ent 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 < 0.05). However, in the MV group, only kep showed significant correlation with age. The kep value was only the perfusion parameter of statistical significance between MO and MV breast cancers.

Surgical outcomes of robotic thyroidectomy vs. conventional open thyroidectomy for papillary thyroid carcinoma.

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 < 0.001). However, the mean hospital stay after surgery (3.6 ± 0.8 vs. 3.4 ± 1.2 days, P = 0.293), postoperative complication rates (major and minor, P = 0.754 and P = 0.852), and pain score (postoperative day, P = 0.669; postoperative day 1, P = 0.952) were comparable between the two groups. There was no difference in the number of metastatic lymph nodes, but the mean number of retrieved lymph nodes in the RT group was lesser than that in the OT group (3.5 ± 3.5 vs. 5.3 ± 5.2, P = 0.002). CONCLUSIONS: Robotic thyroidectomy via the BABA may be a safe and acceptable surgical technique. But, further development that resolves the limitation of central node dissection is needed.

Multiple Symmetric Lipomatosis (Madelung's Disease) Presenting as Bilateral Huge Gynecomastia.

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.

BRAF mutation may predict higher necessity of postoperative radioactive iodine ablation in papillary thyroid cancer.

PURPOSE: The primary aim of the present study was to analyze the association between high-risk clinicopathologic characteristics and the BRAFV600E mutation. METHODS: From March 2010 to September 2012, we performed analysis of the BRAF mutation (assessing V600E point mutation of BRAF gene, exon 15, on chromosome 7q34 by real-time polymerase chain reaction kit) from 499 papillary thyroid carcinoma (PTC) patients who underwent thyroidectomy. We analyzed the relation between the mutation and known clinicopathologic risk factors of PTC. RESULTS: BRAF mutations were found in 353 of 499 patients (70.7%). On univariate analysis, BRAF mutations were more frequently detected in patients with central lymph node metastasis (78.5% vs. 66.7%, P = 0.007) and classic PTC type (71.3% vs. 16.7%, P = 0.011). Patients with one or more aggressive pathologic feature such as lymph node metastasis, multifocality, and extrathyroidal extension showed higher BRAF mutation rate (73.5% vs. 62.3%, P = 0.022). BRAF mutation group showed more aggressive pathologic features, which is considered as higher necessity of radioactive iodine ablation (relative risk, 1.617; P = 0.035). CONCLUSION: This study found that BRAF mutation is associated with classic PTC and central lymph node metastasis and higher necessity of radioactive iodine ablation.

Double inversion recovery MR imaging of the breast: efficacy in detection of breast cancer.

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.

A genetic association analysis of polymorphisms, rs2282695 and rs12373539, in the FOSB gene and papillary thyroid cancer.

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.

Associations between promoter polymorphism -106A/G of interleukin-11 receptor alpha and papillary thyroid cancer in Korean population.

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.

Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer.

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.

A missense polymorphism (rs11895564, Ala380Thr) of integrin alpha 6 is associated with the development and progression of papillary thyroid carcinoma in Korean population.

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.