Malignant Phyllodes of Breast.

Phyllodes tumors of breast (PTB) have been known to an uncommon and particular disease to handle owing to diagnostic ambiguity and unpredictable clinical outcome. Malignant phyllodes tumors (MPT) are diagnosed when there are marked stromal hypercellularity, atypia, increased mitoses of ≥10/10 HPFs, permeative tumor borders, and stromal overgrowth. The presence of a malignant heterologous element (MHE) places the tumor into the malignant category regardless of other histological features. Excision with negative margins should be achieved for recurrent and malignant phyllodes tumor. An ideal margin width remains to be determined, and may need to be considered in relation to factors such as tumor size and cosmesis. Without the convincing evidence of survival benefit, adjuvant RT has revealed more favorable local control rate compared with observation group. Stromal expression of Twist and Foxc2, epithelial-mesenchymal transition marker, was associated with high tumor grade and poor prognosis. Tumor-associated macrophage drives myoblast differentiation and malignant progression of PTB through a CCL18-driven signaling cascade amenable to antibody disruption. Recent targeted sequencing on PTBs provided insights into the molecular pathogenesis and genetic characterization with potential clinical implications.

Isoflavone intake on the risk of overall breast cancer and molecular subtypes in women at high risk for hereditary breast cancer.

PURPOSE: We investigated the association between isoflavone (ISF) intake and hereditary breast cancer (BC) risk, particularly by molecular subtype, in East-Asian BRCA1/2 mutation carriers and non-carriers at a high risk of hereditary breast cancer (i.e., family history of BC (FHBC) and early-onset BC [EOBC, age < 40 years]). METHODS: The association between ISF intake and BC risk by molecular subtypes was assessed in 1709 participants (407 BRCA1/2 carriers, 585 FHBC non-carriers, 586 EOBC non-carriers, and 131 unaffected non-carriers) from the Korean Hereditary Breast Cancer Study using hazard ratios (HRs) and 95% confidence intervals (CIs) in weighted Cox regression models. Daily ISF intake was assessed using a validated food frequency questionnaire. We evaluated gene-environment interactions between BRCA1/2 mutation and ISF intake in 1604 BC cases by calculating the case-only odds ratios (CORs) and 95% CIs in logistic regression models. RESULTS: ISF intake was inversely associated with luminal A BC risk in BRCA2 mutation carriers and FHBC non-carriers (HR = 0.14, 95% CI = 0.04-0.50 for high intake [ISF intake ≥ 15.50 mg/day]; HR = 0.27, 95% CI = 0.11-0.69 for high intake, respectively). We observed a reduced risk of triple negative BC (TNBC) in BRCA1 carriers and FHBC non-carriers (HR = 0.09, 95% CI = 0.02-0.40 for high intake; HR = 0.19, 95% CI = 0.05-0.69 for high intake, respectively). In the case-only design, an interaction between BRCA1 mutation carrier status and ISF intake emerged in TNBC patients (COR = 0.39, 95% CI = 0.16-0.95). CONCLUSIONS: This study suggests that ISF intake is inversely associated with BC risk in women at high risk of hereditary BC and that the effect could differ by molecular subtypes.

Reappraisal of conventional risk stratification for local recurrence based on clinical outcomes in 285 resected phyllodes tumors of the breast.

PURPOSE: To ensure a surgical margin of ≥1 cm for the effective treatment of phyllodes tumors of the breast (PTB) a second resection has been recommended, but the outcomes of an extensive series of cases employing the aforementioned criterion cast doubt on this clinical approach. The aim of this study was to identify the local recurrence (LR) risk factors of PTB and determine future optimal surgical treatment according to verified risks. METHODS: All cases given a diagnosis of PTB, and resected between 1989 and 2008, were retrospectively evaluated. Clinicopathologic data and clinical outcomes were analyzed and stratified according to the risks for LR. RESULTS: All 285 cases were categorized as benign (191, 67.0 %), borderline (61, 21.4 %), or malignant (33, 11.6 %). Median follow-up was 6.7 years and there were 20 LRs during follow-up. All benign PTB recurred as benign PTB lesions. Mitoses (p < 0.001) and tumor size (p = 0.021) were independent prognostic factors for LR in multivariate analysis. Neither margin status (p = 0.758) nor type of surgery (p = 0.922) had any significance for LR. In the risk stratification for LR, PTB ≤5 cm in size with ≥10 mitoses/10 high-power fields (HPFs) had the highest LR rate (55.6 %) compared with all other subgroups (p < 0.001). CONCLUSIONS: It is recommended a wide excision and clear margin of 1 cm be ascertained in only small PTB with frequent mitoses, if necessary by means of a second surgery, which could be considered in order to avoid the risk of LR in this distinct and limited group.

A prospective, randomized, controlled trial of the postoperative analgesic effects of spraying 0.25 % levobupivacaine after bilateral axillo-breast approach robotic thyroidectomy.

BACKGROUND: Robotic thyroidectomy (RoT) is frequently performed due to its excellent cosmesis and recovery features. However, postoperative pain in the operating field after RoT remains a concern due to extensive tissue dissection and tension during the operation. The aim of this study was to evaluate the anterior chest pain and the effect of levobupivacaine spraying on postoperative pain control after bilateral axillo-breast approach (BABA) RoT. METHODS: We randomized 55 adult patients scheduled for BABA RoT into the control group (group C, n = 27) or the levobupivacaine group (group L, n = 28). At the end of surgery, patients in groups C and L were sprayed with the same volume (30 ml) of normal saline and 0.25 % levobupivacaine, respectively, on the flap dissection area. Pain scores, the consumption of patient-controlled analgesia (PCA), and other adverse effects were assessed at 1, 6, 24, and 48 h postoperatively. RESULTS: Patients in group L showed lower pain scores than those of group C at 1 h (50 [0-100] vs. 80 [20-100]; p = 0.004), 6 h (30 [0-90] vs. 70 [30-90]; p < 0.001), 24 h (30 [0-80] vs. 50 [10-80]; p = 0.016) and 48 h (10 [0-80] vs. 30 [10-80]; p < 0.001) postoperatively. PCA consumption of group L was less than that of group C at 6, 24, and 48 h after surgery. There were no significant differences in postoperative nausea-vomiting, headache, or dizziness. Local anesthetic-related adverse effects were not reported. CONCLUSION: Levobupivacaine spray on the operative field at the end of BABA RoT reduced postoperative pain and PCA consumption without adverse events.

A multi-institutional study of the prevalence of BRCA1 and BRCA2 large genomic rearrangements in familial breast cancer patients.

BACKGROUND: Large genomic rearrangements (LGRs) in the BRCA1/2 genes are frequently observed in breast cancer patients who are negative for BRCA1/2 small mutations. Here, we examined 221 familial breast cancer patients from 37 hospitals to estimate the contribution of LGRs, in a nationwide context, to the development of breast cancer. METHODS: Direct sequencing or mutation scanning followed by direct sequencing was performed to screen small mutations. BRCA1/2 small mutation-negative patients were screened for the presence of LGRs using a multiple ligation-dependent probe amplification (MLPA) assay. RESULTS: Using a combined strategy to detect the presence of small mutations and LGRs, we identified BRCA1/2 small mutations in 78 (35.3%) out of 221 familial breast cancer patients and BRCA1 LGRs in 3 (2.1%) out of 143 BRCA1/2 small mutation-negative patients: the deletion of exons 11-13, the deletion of exons 13-15, and whole gene deletion of exons 1-24. The novel deletion of exons 11-13 is thought to result from a non-homologous recombination event mediated by a microhomology sequence comprised of 3 or 4 base pairs: c.3416_4357 + 1863delins187 (NG_005905.2: g.33369_44944delins187). CONCLUSIONS: In this study, we showed that LGRs were found in 3.7% (3/81) of the patients who had mutations in BRCA1 or BRCA2, and 7.5% (3/40) of patients with mutations in BRCA1. This suggests that the contribution of LGRs to familial breast cancer in this population might be comparable to that in other ethnic populations. Given these findings, an MLPA to screen for mutations in the BRCA1 gene is recommended as an initial screening test in highly selective settings.

Comparison of quality of life based on surgical technique in patients with breast cancer.

OBJECTIVE: More than 80% of women with breast cancer survive for more than 5 years; quality of life is an important issue in these patients. The aim of this study was to assess differences in quality of life among patients who have undergone breast-conserving surgery, total mastectomy and immediate reconstruction after total mastectomy. METHODS: A cross-sectional study was conducted during follow-up visits. Women who underwent surgical treatment at least 2 years prior were eligible if they were aged 20-70 years and had a diagnosis of breast cancer (Stages 0-III). Quality of life was evaluated based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer-specific module, Rosenberg Self-esteem Scale, Beck Depression Index, Body Image Scale and sexual scale of the Cancer Rehabilitation Evaluation System. RESULTS: A total of 407 patients completed the questionnaires; 254 were treated with breast-conserving surgery, 122 with total mastectomy and 31 with reconstruction after total mastectomy. The mean period between surgery and the survey was 49 months. Women in the breast-conserving surgery group showed better outcomes than women in the total mastectomy and reconstruction after total mastectomy groups with respect to emotional-social function, nausea/vomiting, financial difficulty, body image, arm symptoms and self-esteem. Patients in the reconstruction after total mastectomy group had significantly better outcomes on the sexual scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer-specific module and arm symptoms than the total mastectomy group. CONCLUSIONS: Quality of life was better in the breast-conserving surgery group than in the total mastectomy or reconstruction after total mastectomy groups, and the total mastectomy and reconstruction after total mastectomy groups had similar quality of life. Efforts to evaluate and improve the quality of life of patients with breast cancer should be continued.

Prospective randomized controlled trial on the use of flexible reinforced laryngeal mask airway (LMA) during total thyroidectomy: effects on postoperative laryngopharyngeal symptoms.

BACKGROUND: Sore throat, hoarseness, dysphagia, and cough are common laryngopharyngeal discomforts after thyroidectomy. The incidence and severity of laryngopharyngeal symptoms after the use of a flexible reinforced laryngeal mask airway (LMA) were compared with those that occur after the use of a plain endotracheal tube in patients after thyroidectomy. METHODS: Seventy-six patients scheduled for total thyroidectomy were randomized into a plain endotracheal tube group (group E) or a flexible reinforced LMA group (group L). Total intravenous anesthesia (propofol and remifentanil) was used for maintenance of anesthesia. Hemodynamic variables were recorded during induction of anesthesia. The incidence and severity (100-point numerical rating scales) of laryngopharyngeal symptoms, including sore throat, hoarseness, dysphagia, and cough, were assessed at 1, 24, and 48 h after surgery. RESULTS: All patients were placed successfully with an endotracheal tube or a flexible reinforced LMA. The postoperative incidence and severity of sore throat (25 vs. 33 at 24 h, p = 0.035, 17 vs. 28 at 48 h, p = 0.017; 50 [0-100] vs. 80 [20-100] at 1 h, p = 0.002; 30 [0-80] vs. 50 [0-100] at 24 h, p < 0.001; 0 [0-40] vs. 30 [0-90] at 48 h, p < 0.001) and hoarseness were lower in group L than in group E. At 48 h postoperatively, dysphagia (p = 0.005) and cough (p = 0.028) occurred less frequently in group L than in group E patients. CONCLUSION: A flexible reinforced LMA placed during surgery decreases the incidence and severity of laryngopharyngeal symptoms and is a feasible anesthetic tool compared with a conventional endotracheal tube for thyroidectomy.

Effect of a mixed solution of sodium hyaluronate and carboxymethyl cellulose on upper limb dysfunction after total mastectomy: a double-blind, randomized clinical trial.

Restricted shoulder mobility is a major upper limb dysfunction related to lower quality of life and disability after breast cancer surgery. We hypothesized that sodium hyaluronate-carboxymethyl cellulose (HA-CMC) applied to the surface of the pectoralis major muscle after mastectomy would significantly reduce pain and improve range of motion (ROM) of the shoulder in breast cancer patients. We conducted a double-blind, randomized controlled study to evaluate the clinical efficacy and safety of HA-CMC in the prevention of upper limb dysfunction after total mastectomy (TM). A total of 99 women with breast cancer were randomly assigned to one of two groups. In the HA-CMC group (n = 50), a mixed HA-CMC was applied to the surface of the pectoralis major and serratus anterior muscle after TM. In the control group (n = 49), TM was performed without the use of HA-CMC. The primary outcomes were ROM of the shoulder and motion-related pain assessed using a numeric rating scale measured before surgery (T0) and 3 (T1) and 6 months (T2) after surgery. Secondary outcomes included disabilities of the arm, shoulder, and hand (DASH) and the pectoralis minor length test. Compared with the control group, the HA-CMC group showed greater reductions in postoperative restriction of total shoulder ROM (sum of flexion and horizontal abduction) at 3 months (10.20°, P = 0.004). Mean pain levels related to flexion and horizontal abduction were significantly lower in the HA-CMC group (-1.32 and -0.93, respectively, P < 0.05). The DASH score was lower (-4.94; P = 0.057) in the HA-CMC group at T2. No adverse effect was observed in either group. These results provide evidence that HA-CMC may provide pain relief and improve ROM of the shoulder without causing adverse effects. The effect on pectoralis tightness should be investigated in further studies.

Prevalence of BRCA1 and BRCA2 mutations in non-familial breast cancer patients with high risks in Korea: the Korean Hereditary Breast Cancer (KOHBRA) Study.

Prevalence and phenotype of BRCA mutation can vary by race. The purpose of this study is to evaluate the prevalence of BRCA1/2 mutations in non-familial breast cancer patients with high risks in Korea. A subset of 758 patients was selected for this study from the KOHBRA nationwide multicenter prospective cohort study. Mutations in BRCA1/2 genes were tested using fluorescent-conformation sensitive gel electrophoresis, denaturing high performance liquid chromatography or direct sequencing. Mutation of BRCA1/2 genes were identified in 65 (8.6%) patients among total 758 patients [BRCA1 mutation: 25 (3.3%), BRCA2 mutation: 40 (5.3%)]. According to risk groups, mutation of BRCA1/2 genes were identified in 53 (8.5%) of 625 early onset patients (age ≤ 40), in 22 (17.7%) of 124 bilateral breast cancer patients, in 3 (50.0%) of 6 breast and ovarian cancer patients, in one (5.9%) of 17 male breast cancer patients, in 5 cases (7.6%) of 66 multiple organ cancer patients. The most common mutation was 509C>A for BRCA1 and 7708C>T for BRCA2. The prevalence of BRCA1/2 mutations by age in early onset patients was significantly different (age <35 vs age ≥35; 10.0 vs 2.9%, p = 0.0007). BRCA1/2 mutations for non-familial Korean breast cancer patients were detected at a high rate, particularly, in patients with early onset of less than 35 years of age, bilateral breast cancer, and breast and ovarian cancer. Individualized genetic counseling should be offered for non-familial breast cancer patients with these risk factors.

Limited value and utility of breast MRI in patients undergoing breast-conserving cancer surgery.

BACKGROUND: Our aim was to compare the accuracy of magnetic resonance imaging (MRI) and ultrasonography (US) in measuring the size of invasive breast cancer (IBC) and carcinoma in situ (CIS). We also examined the utility of routinely performing MRI in addition to US before breast-conserving surgery (BCS). PATIENTS AND METHODS: Data from 1558 consecutive patients diagnosed with IBC and/or CIS between 2003 and 2005 were reviewed. For comparing the accuracy of US and MRI, paired t test was done comparing pathologic and imaging (US and MRI) tumor size in 821 patients who received both breast US and MRI. In instance of attempted BCS (n = 794), operative approach, resection margins, and clinical outcomes of non-MRI and MRI groups were compared. RESULTS: For CIS, IBC without CIS, and IBC with CIS, MRI was more accurate in estimating tumor size than US. When BCS was attempted (n = 794), the rate of tumor involvement in initial resection margins did not differ between non-MRI and MRI groups (23.0% and 23.4%, P = .926). Similarly, rates of re-excision (13.1% vs 17.5%, P = .130) and conversion to mastectomy (2.3% vs 2.1%, P = .893) were comparable, as were ipsilateral breast tumor recurrence, locoregional recurrence, and disease-free survival (log rank P = .284, .950, and .955, respectively). CONCLUSIONS: Breast MRI provided more accurate estimates of tumor size, correlating better with pathologic tumor size than US for both IBC and CIS. However, no clear benefit in terms of lower re-excision rate, higher breast conservation success, or reduced recurrence emerged for routine use of breast MRI before BCS.

Clinical significance of high focal adhesion kinase gene copy number and overexpression in invasive breast cancer.

Increased expression and activation of focal adhesion kinase (FAK) was reported to be an unfavorable factor in various human cancers, including breast cancer. In order to study FAK gene status as a prognostic factor, we evaluated FAK gene copy number and FAK protein expression in invasive breast cancer. Tumors from 435 patients with invasive breast cancer were evaluated for FAK gene status using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) based on tissue array method. Survival analyses were performed using the Kaplan-Meier method in 267 patients. 42 out of 362 evaluable cases (11.6%) showed high polysomy and 22 cases (6.1%) had gene amplification by FISH. 108 out of 393 evaluable cases (27.5%) showed FAK overexpression by IHC. FAK FISH positivity was significantly associated with higher histologic grade, higher T stage, negative estrogen receptor expression, negative progesterone receptor expression and triple-negative phenotype; FAK overexpression with higher histologic grade and triple-negative phenotype. FAK overexpression was noted in 57.8% (37 of 64) of FAK FISH+ cases. The concordance of FISH and IHC results for FAK gene was observed in 74.9% (271 of 362). Survival analyses revealed the patients with FAK FISH+ breast cancer had significantly shorter overall survival and relapse-free survival compared to those with FISH- breast cancer. In node-positive breast cancer patients who received postoperative systemic treatment, the patients with FAK FISH+ showed significantly shorter 5-year survival rates. Despite of high significant concordance between the results of FISH and IHC for FAK gene in invasive breast cancer, only FAK FISH positivity was an unfavorable prognostic factor.

Overexpression of p53 is correlated with poor outcome in premenopausal women with breast cancer treated with tamoxifen after chemotherapy.

The aim of this study was to evaluate the difference in outcomes based on p53 overexpression of patients with breast cancer who received adjuvant therapy following local treatment for invasive ductal carcinoma, not otherwise specified. We analyzed data from 4,683 patients with cancer enrolled in two institutions between 1997 and 2006. We analyzed the correlation between p53 overexpression and relapse, response to adjuvant therapy, breast cancer-specific survival (BCSS), and relapse-free survival (RFS) in patients with primary breast cancer. Overexpression of p53 was noted in 1,091 patients (23.3%). A significant correlation existed between p53 overexpression and poor prognostic factors, an increased frequency of regional recurrence, visceral metastasis, and worse BCSS and RFS. Based upon subgroup analyses, combined age (<35, 35-50, and >50 years) and adjuvant therapy (hormone therapy only, chemotherapy only, and hormone therapy following chemotherapy), the greatest reduction of survival based on p53 overexpression was noted in patients 35-50 years of age who received hormone therapy following chemotherapy (P < 0.05). Multivariate analysis showed that p53 overexpression is an independent prognostic factor in patients treated with hormone therapy and chemotherapy (relative risk for BCSS, 2.003; 95% CI, 1.105-3.631; P = 0.022). The p53-overexpressing patients with breast cancer between 35 and 50 years of age who received tamoxifen following chemotherapy had the greatest adverse effect on outcome. Overexpression of p53 is significantly associated with tamoxifen resistance in premenopausal women with breast cancer.

Comparison of long-term outcomes of laparoscopy-assisted and open distal gastrectomy for early gastric cancer.

BACKGROUND: Application of laparoscopy-assisted distal gastrectomy (LADG) for early gastric cancer (EGC) is still controversial because of scant evidence of long-term safety and feasibility. We evaluated the long-term outcome of LADG compared with conventional open distal gastrectomy (ODG) for EGC. METHODS: Between March 1999 and July 2006, 106 patients underwent LADG and 105 patients underwent ODG for EGC. Clinicopathologic characteristics, postoperative outcomes, hospital course, postoperative morbidity, postoperative mortality, and long-term outcomes, including cancer recurrence and survival, were retrospectively compared between the two groups. Survival of all patients was confirmed with 55-month median follow-up. RESULTS: Postoperative recovery was significantly faster in the LADG group; passing flatus occurred earlier, starting a liquid diet began sooner, and postoperative hospital stay was shorter (p < 0.05). Mean operation time was significantly longer in the LADG group. Postoperative complications in the LADG group occurred less frequently compared with in the ODG group (4.7% versus 13.3%, p = 0.046). Tumor recurrence occurred in two cases (0.9%) and death related to recurrence occurred in only one patient (0.5%). Overall 5-year survival rate (5-YSR) of all patients was 95.5%, while disease-specific 5-YSR was 98.8%. There was no significant difference in survival rates between the two groups; overall 5-YSR of the ODG and LADG groups was 94.9% and 95.9%, respectively. CONCLUSIONS: Our data suggest that LADG for EGC is feasible and safe. We expect the results of the present study to be confirmed by prospective randomized analysis.

The use of an in vitro adenosine triphosphate-based chemotherapy response assay to predict chemotherapeutic response in breast cancer.

The adenosine triphosphate-based chemotherapy response assay (ATP-CRA) has the advantages of standardization, evaluability, reproducibility, and accuracy, and can be performed on relatively small numbers of tumor cells. A total of 43 patients were enrolled in the present study, and chemosensitivity tests were successfully performed in 40 (93.0%) of these patients. Twenty of the 40 received neoadjuvant chemotherapy or chemotherapy for metastatic breast cancer. The chemotherapy regimens used were doxorubicin plus docetaxel (n=9, 45.0%) or doxorubicin plus paclitaxel (n=11, 55.0%). Mean cell death rate, as determined by ATP-CRA, was lower in non-responders than in responders to therapy (P=0.012). Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for ATP-CRA were 78.6%, 100%, 100%, 66.7%, and 85.0%, respectively. Diagnostic accuracy achieved by immunohistochemistry using estrogen receptor or progesterone receptor was lower than that achieved using ATP-CRA. Expression of p53, erb-B2, Ki67, Bcl-2, Bcl-xL, and annexin I was not significantly associated with response to chemotherapy. Our results show that ATP-CRA has high specificity and positive predictive value for predicting response to chemotherapy.

Effect of short message service as a reminder on breast self-examination in breast cancer patients: a randomized controlled trial.

This study was a single-blind randomized controlled trial to assess the effectiveness of SMS as a reminder for breast self-examination (BSE). Participants who underwent surgery for breast cancer were recruited and randomized to the intervention group or the control group. Subjects in the intervention group received one text message on the first day of every month that reminded them to complete monthly BSE and the other text message on the fifteenth day of every month that contained information about breast cancer. Primary and secondary outcomes were self-reported BSE adherence and the frequency of BSE over 6 months. Between August 2010 and December 2011, 216 patients were randomly assigned to the SMS group (n = 110) or the control group (n = 106). A total of 202 patients were included in the final analysis. Self-reported BSE adherence and the frequency of BSE over the past six months were significantly higher in the intervention group than in the control group. Multivariate analysis showed that the SMS was the only significant factor for BSE adherence (p < 0.001). The short-term results of our study suggest that SMS is an effective and low-cost method to enhance adherence to BSE with existing information technology infrastructure.

Thyroid "atypia of undetermined significance" with nuclear atypia has high rates of malignancy and BRAF mutation.

BACKGROUND: "Atypia of undetermined significance" (AUS) in the Bethesda System for Reporting Thyroid Cytopathology is a heterogeneous category for cases that cannot be easily classified into benign, suspicious, or malignant. This study evaluated whether cytomorphology-based subcategorization could better predict the malignancy risk in cases designated as AUS, and how the subcategories correlated with BRAF mutation status in thyroid fine-needle aspirates (FNA). METHODS: Of 3589 cases of thyroid FNA diagnosed at the authors' institution in Seongnam, Korea, from January 2010 to December 2011, 331 cases of AUS were reviewed and subcategorized based on cytomorphological features, including nuclear atypia (NA), microfollicle formation (MF), Hürthle cell change (HC), and others (O). The malignancy rate of each subcategory was calculated using cases with histologic follow-up. Pyrosequencing was conducted to detect BRAF mutations. RESULTS: Malignancy was histologically proven in 23.3% (77 of 331) of cases diagnosed as AUS. In cytomorphology-based subcategories, the rate of malignancy was 30.8% (66 of 214) for AUS-NA, 14.5% (8 of 55) for AUS-O, 4.8% (2 of 42) for AUS-MF, and 5% (1 of 20) for AUS-HC. The BRAF V600E mutation was found in 40% (48 of 120) of AUS-NA, 30.8% (4 of 13) of AUS-HC, 6.7% (1 of 15) of AUS-O, and 2.8% (1 of 35) of AUS-MF. CONCLUSIONS: The AUS-NA subcategory was associated with the highest risk of malignancy and the greatest frequency of BRAF V600E (substitution of valine to glutamic acid at position 600) mutation. These findings suggest that subcategorization of AUS by cytomorphology and BRAF V600E mutation status is important for predicting the risk of malignancy.

Expression of indoleamine 2,3-dioxygenase and infiltration of FOXP3+ regulatory T cells are associated with aggressive features of papillary thyroid microcarcinoma.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is overexpressed in many different types of tumor and is associated with activation of FOXP3+ regulatory T cells (Treg cells) and downregulation of cytotoxic cellular immunity in the tumor microenvironment. It has been suggested that IDO inhibitors can be utilized as an effective therapeutic agent against human cancers. However, the expression of IDO and its association with tumor-infiltrating lymphocytes (TILs) remain unclear in papillary thyroid microcarcinoma (PTMC). METHODS: Immunohistochemical staining for IDO expression was performed on 124 PTMC samples. TIL subsets (CD3+, CD8+, and FOXP3+ T cells) were counted in serial sections. The relationships between the expression of IDO and infiltration of TIL subsets, as well as the relationships between these immunomodulating factors and clinicopathologic parameters of PTMCs, were analyzed. RESULTS: There was a significant correlation between IDO expression and reduced CD3+ TIL and increased FOXP3+ TIL. IDO expression was found in 31% of PTMC and was associated with aggressive clinicopathologic features of the tumor such as extrathyroidal extension (ETE) and multifocality. High infiltration of FOXP3+ Treg cells in the tumor was associated with lymph node metastasis, ETE, and multifocality. Furthermore, high FOXP3/CD8+ ratio was associated with multifocality and lymph node metastasis, and high FOXP3+/CD3+ ratio was related to ETE and multifocality. In multivariate analyses, IDO expression was found to be an independent predictive factor for ETE and tumor multifocality. CONCLUSIONS: IDO expression and infiltration of FOXP3+ Treg cells were closely related to each other and were associated with aggressive features of PTMC, suggesting that disruption of antitumor immunity by IDO expression, and thus, infiltration of FOXP3+ Treg cells may contribute to tumor progression in PTMC.

Factors affecting the decision to undergo risk-reducing salpingo-oophorectomy among women with BRCA gene mutation.

The objective of this study was to identify factors that affect the decision to undergo risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 or BRCA2 mutations carriers in South Korea. The medical records of 124 women who had been found to have BRCA1 or BRCA2 gene mutation at our institution between May 2003 and December 2011 were reviewed. The carriers were divided into RRSO and non-RRSO groups for comparison of their clinicopathologic, socio-economic, and psychosocial factors. Of the 71 carriers eligible for RRSO, 21 had undergone RRSO. In univariate analysis, classification of carriers into 3 groups by decade of life (4th, 5th, or 6th and later decade) and subsequent analysis revealed that 52.6% of carriers in the 5th decade had undergone RRSO, a rate significantly higher than that of the other age groups (p = 0.007). The RRSO rate was higher in carriers with a personal history of breast cancer than in those without (39.2% vs. 5.0%, p = 0.004), in carriers with a family history of breast cancer than in those without (35.5% vs. 11.8%, p = 0.065), and in carriers with a family history of ovarian cancer than in those carriers without a family history (66.7% vs. 24.2%, p = 0.016). Multivariate analysis identified age and personal history of breast cancer as independent factors affecting the decision to undergo RRSO. Age and personal history of breast cancer are important factors in the decision to undergo, and should thus be considered when counseling BRCA1/2 mutation carriers.

Leptin as a potential target for estrogen receptor-positive breast cancer.

PURPOSE: Leptin is a potent adipokine that plays a significant role in tumor development and the progression of breast cancer. The aim of this study was to evaluate whether leptin affects the response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancer cells. METHODS: Leptin, leptin receptor (Ob-R), and activation of signaling pathways were studied by Western immunoblotting. The effects of leptin on tamoxifen-dependent growth inhibition were studied in MCF-7 and T-47D cells. RESULTS: Leptin was expressed in MCF-7 and T-47D and had a proliferative effect on MCF-7 cells. Leptin significantly inhibited the antiestrogenic effect of tamoxifen in both cells only under ß-estradiol (E2) (20 nM) conditions. In MCF-7, the inhibitory effect against tamoxifen was a result from the activation of the ERK1/2 and STAT3 signal transduction pathway. CONCLUSION: Leptin interferes with the effects of tamoxifen under E2 stimulated conditions in ER-positive breast cancer cells. These results imply that inhibition of leptin is expected to enhance the response to tamoxifen in ER-positive breast cancer cells, and, therefore, could be a promising way to overcome endocrine resistance.

The prevalence of BRCA mutations among familial breast cancer patients in Korea: results of the Korean Hereditary Breast Cancer study.

The primary aim of this study was to estimate the prevalence of BRCA1/2 mutations among familial breast cancer (BC) patients in Korea. We analyzed 775 familial BC patients who were enrolled in the Korean Hereditary Breast Cancer (KOHBRA) study and treated at 36 institutions between May 2007 and May 2010. Patients with familial BC were defined as BC patients with family histories of BC or ovarian cancer (OC) in any relatives. All probands received genetic counseling and BRCA genetic testing was performed after obtaining informed consent. The mean age of BC diagnosis was 43.6 years. The numbers of probands with family histories of BC only and OC only were 682 and 93, respectively. The overall prevalence of the BRCA mutation among familial BC patients was 21.7 % (BRCA1 9.3 % and BRCA2 12.4 %). Subgroup analyses observed prevalences of the BRCA mutation as follows: 19.6 % among patients with BC family history only (BRCA1 7.6 % and BRCA2 12.0 %) and 36.6 % among patients with OC family history only (BRCA1 21.5 % and BRCA2 15.1 %). Most of the subgroups satisfied the 10 % probability criteria to undergo BRCA testing. However, the prevalence of the BRCA mutations among subgroups that had 2 BC patients in a family with both age at diagnosis of more than 50 years old did not reach the 10 % criteria (4.1 %). Korean familial BC patients are good candidates for BRCA testing even when they have family histories of single breast cancers. However, proband age at diagnosis should be carefully considered when selecting patients for testing.