A Propensity Score-matched Analysis of Long-term Oncologic Outcomes After Nipple-sparing Versus Conventional Mastectomy for Locally Advanced Breast Cancer.

OBJECTIVES: To compare the long-term oncologic outcomes of nipple-sparing mastectomy (NSM) with those of conventional mastectomy (CM) in patients with locally advanced breast cancer (LABC) receiving neoadjuvant chemotherapy (NACT). SUMMARY OF BACKGROUND DATA: NSM has been increasingly implemented in patients with breast cancer. However, oncologic efficacy of NSM in patients with LABC has not been sufficiently demonstrated. METHODS: The study group comprised 850 patients with clinical stage IIB to IIIC breast cancer who underwent NACT followed by either NSM and immediate breast reconstruction or CM alone. After propensity score-matching, 418 patients were included in the analysis. Local recurrence-free survival, disease-free survival (DFS), distant metastasis-free survival, and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared using log-rank tests between the NSM and CM groups. RESULTS: After matching, the mean follow-up period was 70 ± 25 months for the NSM group and 74 ± 27 months for the CM group ( P = 0.181). There were no significant differences between the groups in terms of 6-year local recurrence-free survival (91.6% vs. 95.8%; P = 0.239), DFS (70.5% vs. 73.4%; P = 0.583), distant metastasis-free survival (79.8% vs. 77.4%; P = 0.320), or OS (87.6% vs. 84.8%; P = 0.465) rates. Additionally, we identified 30 patients in the NSM group who initially presented with tumor extension in the subareolar area; the nipple-areola complex was successfully preserved after NACT, and no recurrence at the nipple was observed in these patients. CONCLUSIONS: In this matched control study, we demonstrated comparable long-term oncologic outcomes between NSM with immediate reconstruction and CM alone after NACT for LABC. In patients who had tumors extending to the subareolar area before NACT, NSM can be tried if tumor involvement of the nipple-areola complex appears resolved on imaging studies after chemotherapy.

Oncologic Outcomes of Nipple-sparing Mastectomy and Immediate Reconstruction After Neoadjuvant Chemotherapy for Breast Cancer.

OBJECTIVES: To evaluate the oncologic outcomes and risk factors for locoregional recurrence (LRR) and nipple-areola complex recurrence (NR) in a large series of breast cancer patients who underwent nipple-sparing mastectomy (NSM) and immediate reconstruction after neoadjuvant chemotherapy (NACT). SUMMARY OF BACKGROUND DATA: The use of NSM and immediate reconstruction in breast cancer patients receiving NACT is increasing. However, the oncologic safety of this approach is unclear. PATIENTS AND METHODS: A total of 310 breast cancer patients (319 breasts) who underwent NACT and NSM between February 2010 and November 2016 were retrospectively analyzed. Clinical and pathologic factors associated with increased risks of LRR and NR were analyzed using univariate (Chi-square or Fisher exact test) and multivariate (Cox proportional hazard regression model) analyses. RESULTS: During a mean follow-up of 63 ± 22 months, 38 cases had LRR as the first event, including 6 cases of NR as the first event. The 5-year cumulative LRR and NR rates were 11.0% and 1.9%, respectively. In univariate analysis, clinical T stage, pathologic nodal status, histologic grade, lymphovascular invasion, and post-NACT Ki67 status were associated with increased LRR risk, and post-NACT Ki67 status was the only significant risk factor for NR. In multivariate analysis, post-NACT Ki67 ≥10% (hazard ratio, 4.245; 95% confidence interval, 1.865-9.663; P = 0.001) was an independent risk factor for LRR. CONCLUSIONS: NSM and immediate reconstruction seem to be oncologically safe with acceptable LRR and NR rates for appropriately selected breast cancer patients treated with NACT. Post-NACT Ki67 ≥10% was associated with increased risk of LRR or NR, and therefore, necessitates cautious follow-up.

Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer.

INTRODUCTION: Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer. PATIENTS AND METHODS: In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints. RESULTS: A total of 187 patients were assigned to receive NCT (n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6-44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4-24.9, p = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p = 0.531) and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group. CONCLUSIONS: Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01622361. Registration June 19, 2012.

Recurrence Outcomes After Nipple-Sparing Mastectomy and Immediate Breast Reconstruction in Patients with Pure Ductal Carcinoma In Situ.

BACKGROUND: Nipple-sparing mastectomy (NSM) has become increasingly prevalent for patients with ductal carcinoma in situ (DCIS) requiring mastectomy. However, few data regarding recurrence outcomes after NSM are available for this patient population. This study evaluated the locoregional recurrence (LRR) rate for patients with pure DCIS who underwent NSM followed by immediate breast reconstruction without adjuvant radiotherapy and investigated potential risk factors for LRR and/or nipple-areola complex recurrence (NR). METHODS: A retrospective chart review was performed for 199 consecutive patients with pure DCIS who underwent NSM and immediate breast reconstruction between March 2003 and December 2015. Risk factors for LRR and NR were analyzed using univariate (Chi square test) and multivariate (Cox model) methods. RESULTS: The median follow-up duration after surgery was 97 months (range, 39-186 months). At 10 years, the LRR rate was 4.5%, and the NR rate was 3%. The univariate analysis showed that high nuclear grade, negative receptor status, positive human epidermal growth factor receptor 2 (HER2) status, and negative hormone receptor/positive HER2 subtype were associated with increased risk for NR. The multivariate analysis demonstrated that negative progesterone receptor status was an independent risk factor for LRR. However, margin status and tumor-to-nipple distance (TND) were not associated with increased risk for either LRR or NR. CONCLUSIONS: The study findings suggest that NSM can be a feasible surgical option even for DCIS with a TND of 1 cm or less if the retroareolar resection margin is negative for malignancy. Determining the molecular subtype of DCIS might be helpful in identifying patients at high risk for recurrence.

Clinical Implication of HER2 Status in Hormone Receptor-Positive Mucinous Breast Cancer.

PURPOSE: Mucinous carcinoma (MC) is a rare breast cancer with favorable outcome. Unlike typical breast cancer, the current guidelines do not recommend chemotherapy or anti-human epidermal growth factor receptor 2 (HER2) therapy for hormone receptor (HR)-positive MC, regardless of HER2 status. We evaluated the prognostic implication of HER2 status in HR-positive MC. METHODS: We retrospectively reviewed the data of 471 patients with pure MC (stages I-III) who underwent curative surgery. We analyzed 5-year disease-free survival (DFS) and distant metastasis-free survival (DMFS), according to clinicopathological characteristics. RESULTS: The median follow-up duration was 79.0 months. Overall, the 5-year DFS rate was 95.7% and the 5-year DMFS rate was 96.2%. Nodal status was the only significant factor for DFS (relative risk [RR], 3.40; 95% confidence interval [CI] 3.40-9.67, p = 0.021). Among HR-positive/node-negative patients with tumor size ≥ 3 cm, HER2-positive patients showed significantly worse DFS (RR, 8.76; 95% CI 1.45-52.76, p = 0.018) and DMFS (RR, 11.37; 95% CI 1.37-74.70, p = 0.011). This finding was consistently significant, when combining both "HR-positive/node-negative/tumor size ≥ 3 cm" and "HR-positive/node-positive" MC (n = 125) for DFS (RR, 4.30; 95% CI 1.43-12.97, p = 0.009) and DMFS (RR, 4.93; 95% CI 1.63-14.90, p = 0.005). Intriguingly, within this subgroup, among HER2-positive tumors, whereas 5-year DFS was 60.2% in patients who did not receive trastuzumab, 100% of those who received trastuzumab were disease free (p = 0.053). CONCLUSIONS: In HR-positive, node-negative MC with tumor size ≥ 3 cm, patients with HER2-positive MC showed worse survival, suggesting a potential role of an anti-HER2 strategy in this subgroup.

Significance of EZH2 expression in canine mammary tumors.

BACKGROUND: Current studies report that aberrations in epigenetic regulators or chromatin modifications are related to tumor development and maintenance. EZH2 (Enhancer of zeste homolog 2) is one of the catalytic subunits of Polycomb repressive complex 2, a crucial epigenetic regulator. EZH2 has a master regulatory function in such processes as cell proliferation, stem cell differentiation, and early embryogenesis. In humans, EZH2 is linked to oncogenic function in several carcinomas, including breast cancer, and dysregulation of EZH2 has been particularly associated with loss of differentiation and the development of poorly differentiated breast cancer. In our present study, we were interested in determining whether EZH2 is increased in canine mammary tumors, which show similarities to human breast cancer. RESULTS: Investigation of the expression of EZH2 in canine mammary tumors revealed that EZH2 protein was overexpressed in canine mammary carcinomas, as in human breast cancer. In addition, the immunohistochemical expression level of EZH2 was associated with the degree of malignancy in canine mammary carcinoma. This is the first report to describe EZH2 expression in canine mammary tumors. CONCLUSIONS: Because the expression of EZH2 was similar in canine mammary carcinoma and human breast cancer, spontaneous canine mammary tumors may be a suitable model for studying EZH2 and treatment development.

Detection of internal mammary lymph node metastasis with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with stage III breast cancer.

PURPOSE: The present study assessed the positive predictive value (PPV) of (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for the detection of internal mammary node (IMN) metastasis in patients with clinical stage III breast cancer. METHODS: Patients who were diagnosed with clinical stage III breast cancer and underwent pretreatment (18)F-FDG PET/CT were retrospectively analyzed. The (18)F-FDG PET/CT scans were prospectively reviewed by two board-certified nuclear medicine physicians in a blinded manner. The intensities of IMNs were graded into four categories (no activity and lower, similar, and higher activities than that of the mediastinal blood pool). IMNs were measured from the combined CT (largest diameter of the short axis). Histologic data of the IMNs were obtained by ultrasonography-guided fine-needle aspiration biopsy or surgical excision. The PPV was calculated for pathologically confirmed IMNs. Visual grade, maximum standardized uptake values (SUVmax), and sizes were analyzed according to the pathology results. RESULTS: There were 249 clinical stage III breast cancer patients (age 48.0 ± 10.1 years, range 26-79 years) who had undergone initial (18)F-FDG PET/CT prior to treatment. Excluding 33 cases of stage IV breast cancer, 62 of 216 patients had visible IMNs on (18)F-FDG PET/CT, and histologic confirmation was obtained in 31 patients. There were 27 metastatic and four nonmetastatic nodes (PPV 87.1%). Metastatic nodes mostly presented with visual grade 3 (83.9%), and SUVmax and size were 3.5 ± 4.3 and 5.6 ± 2.0 mm, respectively. CONCLUSION: (18)F-FDG PET/CT has a high PPV for IMN metastasis in clinical stage III breast cancer, indicating the possibility of metastasis in IMNs with FDG uptake similar to/lower than that of the blood pool or small-sized nodes.

Lymph node ratio and pN staging in patients with node-positive breast cancer: a report from the Korean breast cancer society.

Patients with node-positive breast cancer are currently classified according to pN stage. Lymph node ratio (LNR), the ratio of positive to total removed lymph nodes, maybe a more useful prognostic factor in these patients. We therefore compared LNR and pN staging as prognostic factors in patients with node-positive breast cancer. Using two large prospective databases of the Korean Breast Cancer Registry (KBCR) and the Asan Medical Center (AMC) Breast Cancer Center of patients with LN-positive breast cancer from 1988 to 2005, we compared the ability of LNR and pN stage to predict patient survival by Cox regression analysis in the overall patient cohort and in subgroups categorized by age and intrinsic subtype. Patients were categorized into low- (≤ 0.20), intermediate- (>0.20 and ≤ 0.65), and high-risk (>0.65) LNR groups. The difference in mortality risk was greater among LNR groups than among patients staged pN1, pN2, and pN3, as assessed by disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. In contrast to LNR risk categories, the survival curves for pN1 and pN2 stage patients overlapped in those aged <35 years and those with her2/neu-enriched or triple-negative tumors. These findings were validated by analyzing a nationwide registry of 15,488 node-positive patients, which showed that patients with pN1 and intermediate LNR risk had poorer DFS (HR 1.7, 95% CI 1.4-2.2) and CSS (HR 1.6, 95% CI 1.1-2.2) than patients with pN2 and low LNR risk. LNR is a better predictor of prognosis than pN stage in women with breast cancer, especially in high-risk patients, including younger women and women with her2/neu-enriched or triple-negative tumors. Treatment decisions should be based on LNR rather than on pN stage.

Vitamin D deficiency is correlated with poor outcomes in patients with luminal-type breast cancer.

PURPOSE: Vitamin D deficiency may be an indicator of poor prognosis in patients with breast cancer before surgery. We investigated the association between serum vitamin D concentration and breast cancer prognosis according to intrinsic cancer subtypes. METHODS: From June to December 2006, serum 25-OHD was measured in 310 Korean women with breast cancer who were treated at the Asan Medical Center, Korea. Clinicopathologic data were examined to determine the prognostic effects of serum 25-OHD. Expression of estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (Her2) were measured using tissue microarrays. Patients were classified with luminal A, luminal B, Her2-enriched, or basal-like subtypes of breast cancer. RESULTS: Mean patient age was 48.7 years, and mean serum 25-OHD concentration was 31.4 ± 16.1 ng/ml. The 25-OHD levels were deficient (< 20 ng/ml) in 75 patients (24.2%), insufficient (20-29 ng/ml) in 95 (30.6%), and sufficient (30-150 ng/ml) in 140 (45.2%). Women with deficient 25-OHD levels were at increased risk of recurrence compared with those with sufficient vitamin D levels (P = 0.002). The 25-OHD concentration was inversely associated with prognosis of patients with cancer of the luminal A (P = 0.012) and luminal B subtypes (P =0.023), but not with the prognosis of patients with Her2/neu-enriched (P = 0.245) or triple-negative (P = 0.879) cancer subtypes. This association remained valid after adjustment for age, tumor size, nodal status, and estrogen receptor status (hazards ratio = 3.97; 95% confidence interval = 1.77-9.61). CONCLUSIONS: Vitamin D deficiency may be associated with poor outcomes in patients with luminal-type breast cancer.

Comparison of metabolic changes after neoadjuvant endocrine and chemotherapy in ER-positive, HER2-negative breast cancer.

Survival of breast cancer patients has improved, and treatment-related changes regarding metabolic profile deterioration after neoadjuvant systemic treatment (NST) become important issues in cancer survivors. We sought to compare metabolic profile changes and the neutrophil-to-lymphocyte ratio (NLR) between patients undergoing neoadjuvant chemotherapy (NCT) and neoadjuvant endocrine therapy (NET) 3 years after the treatment. In a prospective, randomized, phase III trial which compared 24 weeks of NCT with adriamycin and cyclophosphamide followed by docetaxel and NET with goserelin and tamoxifen (NEST), 123 patients in the Asan Medical Center were retrospectively reviewed to evaluate metabolic changes, such as body mass index (BMI), blood pressure (BP), total cholesterol (TC), fasting glucose, and the NLR. The mean age of patients was 42 years. The changes in BMI, serum glucose, and TC during NST and after 3 years were significantly different between NCT and NET. The proportion of overweight + obese group and the mean BMI were significantly increased during NCT (26.6% to 37.5%, 22.84 kg/m2 to 23.87 kg/m2, p < 0.05), and these attributes found to have normalized at the 3-year follow-up. In the NET group, BMI changes were not observed (p > 0.05, all). There were no differences in changes over time among in the Hypertension group during NCT and NET (p = 0.96). The mean value of serum TC and fasting glucose significantly increased (< 0.05, both) during NCT and decreased 3 years after NCT (p < 0.05); however, no significant changes were observed in the NET group. The NLR was increased from 1.83 to 3.18 after NCT (p < 0.05) and decreased from 1.98 to 1.43 (p < 0.05) after NET. Compared with minimal metabolic effect of NET, NCT worsens metabolic profiles, which were recovered over 3 years. The NLR was increased after NCT but decreased after NET.

Normal and abnormal sonographic findings at the thyroidectomy sites in postoperative patients with thyroid malignancy.

OBJECTIVE: We describe typical sonography characteristics of locally recurrent tumors after thyroidectomy for thyroid cancer and the benign conditions mimicking tumor recurrence, with an emphasis on the differential diagnosis. CONCLUSION: Ultrasound is an effective imaging technique not only for the detection of locally recurrent tumors but also for the differential diagnosis of locally recurrent tumors and other abnormalities mimicking tumor recurrence.

Analysis of the serial circulating tumor cell count during neoadjuvant chemotherapy in breast cancer patients.

We evaluated the prognostic implications of the circulating tumor cell (CTC) count in non-metastatic, HER2-negative breast cancer patients who failed to achieve pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT). A total of 173, non-metastatic breast cancer patients treated with NCT were prospectively enrolled. CTCs were obtained from blood drawn pre-NCT and post-NCT using a SMART BIOPSY SYSTEM isolation kit (Cytogen Inc., Seoul, Korea) with immunofluorescence staining. Excluding 26 HER2-positive patients, Relapse-free survival (RFS) and overall survival (OS) related to the CTC count and the association of the CTC count with the treatment response to given therapy were analyzed in 147 HER2-negative patients. Among 147 HER2-negative patients, 28 relapses (19.0%) and 13 deaths (8.8%, all breast cancer-specific) were observed during a median follow-up of 37.3 months. One hundred and seven patients (72.8%) were hormone receptor-positive, and 40 patients (27.2%) had triple-negative breast cancer (TNBC). One or more CTCs were identified in 88 of the 147 patients (59.9%) before NCT and 77 of the 134 patients (52.4%) after NCT. In the entire HER2-negative patient cohort, the initial nodal status was the most significant factor influencing RFS and OS. In TNBC, 11 patients (27.5%) achieved pCR and patients that failed to achieve pCR with ≥ 5 CTCs after NCT, showed worse RFS (HR, 10.66; 95% CI, 1.80-63.07; p = 0.009) and OS (HR, 14.00; 95% CI, 1.26-155.53; p = 0.032). The patients with residual tumor and a high number of the CTCs after NCT displayed the worse outcome. These findings could provide justification to launch a future, well designed trial with longer follow-up data to obtain regulatory approval for clinical use of the assay, especially for the ER-positive, HER2-negative breast cancer subset.

Breast Cancer Recurrence in the Nipple-Areola Complex After Nipple-Sparing Mastectomy With Immediate Breast Reconstruction for Invasive Breast Cancer.

Importance: The main concern associated with nipple-sparing mastectomy (NSM) is the risk of local breast cancer recurrence at the retained nipple-areola complex (NAC) consequent to occult nipple involvement. Long-term follow-up data regarding the oncologic safety of modern therapeutic NSM in terms of cancer recurrence at the NAC and survival are limited. Objective: To assess the incidence, risk factors, treatment, and long-term outcomes associated with cancer recurrence at the NAC in a large series of patients with invasive breast cancer who underwent NSM and immediate breast reconstruction. Design, Setting, and Participants: In this retrospective cohort study at a single institution (Asan Medical Center) in Seoul, Republic of Korea, 962 breasts from 944 patients who underwent NSM and immediate breast reconstruction for invasive breast cancer were analyzed between March 3, 2003, and December 31, 2015. Patients who underwent neoadjuvant systemic therapy or palliative surgery were excluded. Data analysis was performed from June 4, 2018, to August 31, 2018. Main Outcomes and Measures: Univariate and multivariate Cox proportional hazards regression models were used to analyze the association between clinicopathologic variables and cancer recurrence at the NAC. To evaluate the association between cancer recurrence at the NAC and prognosis, distant metastasis-free survival, and overall survival were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Among the 944 study patients (median age at diagnosis, 43 years [range, 23-67 years]) during a median follow-up of 85 months (range, 14-185 months), 39 cases (4.1%) of cancer recurrence at the NAC were identified as the first event after NSM. The 5-year cumulative incidence of cancer recurrence at the NAC was 3.5% (n = 34). In multivariate analyses, multifocality or multicentricity (hazard ratio [HR], 3.309; 95% CI, 1.501-7.294; P = .003), negative hormone receptor or ERBB2 (formerly HER2 or HER2/neu)-positive subtype (HR, 3.051; 95% CI, 1.194-7.796; P = .02), high histologic grade (HR, 2.641; 95% CI, 1.132-6.160; P = .03), and extensive intraductal component (HR, 3.338; 95% CI, 1.262-8.824; P = .02) were independently associated with cancer recurrence at the NAC after NSM. All 39 recurrent cases involved wide local excision. Patients with and without cancer recurrence at the NAC as the first event did not differ significantly with regard to distant metastasis-free survival (P = .95) or overall survival (P = .21). The 10-year distant metastasis-free survival rates were 89.3% among patients with cancer recurrence at the NAC and 94.3% among patients without recurrence. The 10-year overall survival rates were 100% among patients with cancer recurrence at the NAC and 94.5% among those without recurrence. Conclusions and Relevance: Patients had a low incidence of cancer recurrence at the NAC after NSM and immediate breast reconstruction in this study. The findings suggest that multifocal or multicentric disease, hormone receptor-negative/ERBB2-positive subtype, high histologic grade, and positive extensive intraductal component should be considered before determining the NSM procedure.

MRI-based 3D-printed surgical guides for breast cancer patients who received neoadjuvant chemotherapy.

Magnetic resonance imaging (MRI) is the most accurate technique for evaluating residual tumor after neoadjuvant chemotherapy. However, precise determination of the extent of dispersed residual tumor in the breast following treatment remains a difficult task. We hereby introduce three-dimensional (3D)-printed surgical guides for use in breast cancer patients undergoing breast-conserving surgery after receiving neoadjuvant chemotherapy. We prospectively applied the 3D-printed surgical guides on breast cancer patients who underwent partial breast resection after receiving neoadjuvant chemotherapy. Breasts and tumors were modeled in 3D by using pretreatment magnetic resonance images, and surgical guides were created by using a 3D printer to mark the primary tumor. Out of the five patients who participated in the study, all patients had clear resection margins, and two patients experienced complete pathological remission. There were no recurrences during the median follow-up period of 21.9 months. Thus, our newly-developed 3D-printed surgical guides were useful for accurately marking the extent of breast tumor based on pretreatment magnetic resonance images, which is important for designating the extent of surgery needed in patients who have received neoadjuvant chemotherapy.

Interleukin-2 gene-encoded stromal cells inhibit the growth of metastatic cholangiocarcinomas.

AIM: To demonstrate bone marrow stromal cells (BMSCs) can be used as an attractive target for genetic modification in the treatment of malignant diseases. METHODS: Using a hamster model of biliary cancer, we investigated the therapeutic effects of interleukin-2 (IL-2) gene-modified BMSCs. Syrian golden hamsters were injected via the femoral vein with 5 x 10(5) cells of the KIGB-5 biliary cancer cell line (n=20). One week later, the hamsters were injected intraperitoneally with BMSCs containing Ad/hIL-2 and Ad/ Delta E1, unmodified BMSCs, or RPMI only (control) and observed for 12 wk (n=5 /each group). RESULTS: All hamsters treated with BMSCs containing Ad/hIL-2 survived with no evidence of the disease during this period. In contrast, hamsters in the other three groups showed disseminated metastases involving the lungs as early as 4 wk. CONCLUSION: Ad/IL-2 therapy is effective in the treatment of biliary cancer.

Clinical and cytologic features of papillary neoplasms of the breast.

OBJECTIVE: To compare the cytologic features benign and malignant papillary breast lesions. STUDY DESIGN: We reviewed the clinical and cytologic features in 29 cases of intraductal papilloma and 26 cases of atypical papilloma or papillary carcinoma that had been diagnosed by histologic examination. The diameter of the mass was examined as a clinical feature. The cytologic features evaluated were as follows: bloody background, row of tall columnar cells, naked bipolar nuclei, hemosiderin-laden macrophages, myoepithelial cells, single scattered atypical cells, cellularity, nuclear atypia, nuclear grade, apocrine metaplasia, eosinophilic cytoplasmic granules, papillary clusters, small papillae, cell balls and large sheets. RESULTS: Of the features evaluated, the diameter of the mass, naked bipolar nuclei and cell balls differed significantly between benign and atypical or malignant papillary neoplasms. The average diameter of a benign papillary neoplasm was 1.8 cm, and that of an atypical or malignant papillary neoplasm was 2.2 cm (p = 0.042). Naked bipolar nuclei were found in 27 cases of benign papillary neoplasm (93.1%) versus 19 cases of atypical or malignant papillary neoplasm (73.1%) (p = 0.050). Cell balls were found in 14 (48.3%) and 21 (80.8%) cases, respectively (p = 0.012). All 6 cases in which cell balls were present and naked bipolar nuclei were absent proved to be atypical or malignant papillary neoplasms. Of 17 cases in which cell balls were absent and naked bipolar nuclei present, 13 (76.5%) were benign papillary neoplasms. CONCLUSION: Most cytologic features overlapped in benign and atypical or malignant papillary neoplasms. Although they were not pathognomonic, naked bipolar nuclei and cell balls were cytologic features that differed significantly between benign and atypical or malignant papillary neoplasms. When papillary neoplasms of the breast are suspected in a cytologic smear, the combination of clinical examination, mammography and cytologic features should be considered to make the correct diagnosis.

Enhanced biglycan gene expression in the adipose tissues of obese women and its association with obesity-related genes and metabolic parameters.

Extracellular matrix (ECM) remodeling dynamically occurs to accommodate adipose tissue expansion during obesity. One non-fibrillar component of ECM, biglycan, is released from the matrix in response to tissue stress; the soluble form of biglycan binds to toll-like receptor 2/4 on macrophages, causing proinflammatory cytokine secretion. To investigate the pattern and regulatory properties of biglycan expression in human adipose tissues in the context of obesity and its related diseases, we recruited 21 non-diabetic obese women, 11 type 2 diabetic obese women, and 59 normal-weight women. Regardless of the presence of diabetes, obese patients had significantly higher biglycan mRNA in both visceral and subcutaneous adipose tissue. Biglycan mRNA was noticeably higher in non-adipocytes than adipocytes and significantly decreased during adipogenesis. Adipose tissue biglycan mRNA positively correlated with adiposity indices and insulin resistance parameters; however, this relationship disappeared after adjusting for BMI. In both fat depots, biglycan mRNA strongly correlated with the expression of genes related to inflammation and endoplasmic reticulum stress. In addition, culture of human preadipocytes and differentiated adipocytes under conditions mimicking the local microenvironments of obese adipose tissues significantly increased biglycan mRNA expression. Our data indicate that biglycan gene expression is increased in obese adipose tissues by altered local conditions.

Manganese dipyridoxyl diphosphate (MnDPDP)-enhanced magnetic resonance imaging of acute reperfused myocardial injury in a cat model: part I: comparison with pathologic examination.

RATIONALE AND OBJECTIVES: To investigate the capacity of manganese dipyridoxyl diphosphate (MnDPDP)-enhanced magnetic resonance imaging (MRI) to discriminate the injured myocardium from the normal myocardium in a cat model. MATERIALS AND METHODS: Fourteen cats were prepared for acute myocardial infarction with 90-minute occlusion followed by 120-minute reperfusion. Inversion recovery gradient-recalled echo (IR-GRE) MR images were obtained at 60-minute intervals for 4 hours after the injection of MnDPDP, and ex vivo after the cats were killed. We evaluated the differences between the unenhanced area on the in vivo and ex vivo MR images and the unstained area on triphenyl tetrazolium chloride (TTC) staining. RESULTS: The unenhanced area on the in vivo MR images was well correlated with that on the ex vivo MR images. The unenhanced area on the ex vivo MR images was significantly larger than the unstained area on TTC staining. CONCLUSIONS: This study suggests that the MnDPDP-unenhanced area on the MR images includes not only the infarcted myocardium but also the stunned myocardium.