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Background: Several randomized clinical trials (RCTs) have demonstrated the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancer (BC). However, RCT patients may not invariably be representative of patients routinely seen in clinical practice (CP). To address this issue, we compared the clinical and tumor features of RCT and CP patients with HER2-positive BC., Patients and Methods: From January to December 2012, 650 consecutive patients with HER2-positive early BC, treated in 36 different types of Italian healthcare facilities, were enrolled in this study. Age, treatment, tumor size (T), nodes (N), grade (G), estrogen receptor (ER) and progesterone receptor (PgR) status were prospectively collected in these CP patients. The same data were extracted from the main adjuvant trastuzumab RCTs and pooled using the random-effects model of DerSimonian and Laird. RCT and CP patients were compared by using the Cochran Q statistics., Results: Versus RCT patients, CP patients were more likely to be older than 50 years (65 vs. 49 %; p < 0.0001) and to have HR (ER and/or PgR)-positive (72 vs. 54 %; p < 0.0001) BC and less likely to have tumor >2 cm (T ≥ 2 cm 39 vs. 59 %; p < 0.0001), positive N (47 vs. 89 %; p < 0.0001) and a high G (61 vs. 67 %; p = 0.0241). CP patients more frequently received adjuvant endocrine therapy (70 vs. 57 %; p < 0.0003) and less frequently adjuvant chemotherapy (97 vs. 99.7 %; p < 0.0001)., Conclusions: Most tumor and clinical features differed significantly between CP and RCT patients. These data raise concerns about the applicability of RCT results to CP patients.

Purpose: The calcium-sensing receptor (CaSR) is overexpressed in many pathological states including breast cancer. Since choline kinase may be activated in breast cancer cells by CaSR resulting in increased phosphocholine production, we sought to correlate the total choline peak in breast lesions as measured by in vivo proton magnetic resonance spectroscopy ((1)H-MRS) with the CaSR expression levels in surgical specimens., Procedures: Thirty-six patients with breast lesions were MR scanned at 3T scanner. Tumour morphology and DCE-MR kinetics were evaluated. (1)H-MRS was applied for Cho detection and compared with the CaSR immunohistochemistry analysis (score 0-5) on surgical breast specimens., Results: Thirty-four lesions demonstrated a DCE malignant kinetics curve (types 2 and 3), while two lesions showed a benign (type 1). Twenty of the 23 breast cancer lesions (87%) with a consistent Cho peak expressed a CaSR score of 3-5, and ten of the 11 breast lesions negative for Cho (91%) had a CaSR score of 1-2. The two benign lesions showed a non-uniform/weak intense expression of the CaSR (score 3) with a consistent Cho peak., Conclusions: The presence or absence of choline peak evaluated by (1)H-MRS, well correlated with the expression of CaSR in patients with breast lesions (p < 0.01), supports the hypothesis that CaSR may play an important role in the production of choline in breast cancer.

Objectives: To demonstrate that manganese can visualise calcium sensing receptor (CaSR)-expressing cells in a human breast cancer murine model, as assessed by clinical 3T magnetic resonance (MR)., Methods: Human MDA-MB-231-Luc or MCF7-Luc breast cancer cells were orthotopically grown in NOD/SCID mice to a minimum mass of 5 mm. Mice were evaluated on T1-weighted sequences before and after intravenous injection of MnCl(2). To block the CaSR-activated Ca(2+) channels, verapamil was injected at the tumour site 5 min before Mn(2+) administration. CaSR expression in vivo was studied by immunohistochemistry., Results: Contrast enhancement was observed at the tumour periphery 10 min after Mn(2+) administration, and further increased up to 40 min. In verapamil-treated mice, no contrast enhancement was observed. CaSR was strongly expressed at the tumour periphery., Conclusion: Manganese enhanced magnetic resonance imaging can visualise CaSR-expressing breast cancer cells in vivo, opening up possibilities for a new MR contrast agent., Key Points: • Manganese contrast agents helped demonstrate breast cancer cells in an animal model. • Enhancement was most marked in cells with high calcium sensing receptor expression. • Manganese uptake was related to the distribution of CaSR within the tumour. • Manganese MRI may become useful to investigate human breast cancer.

Aim: To investigate whether omitting intra-operative staging of the sentinel lymph node (SLN) in T1-N0 breast-cancer patients is feasible and convenient because it could allow a more efficient management of human and logistic resources without leading to an unacceptable increase in the rate of delayed axillary lymph node dissection (ALND)., Methods: According to the experimental procedure, T1a-T1b-patients were to not receive any intra-operative SLN evaluation on frozen sections (FS). In all T1c-patients, the SLN was macroscopically examined; if the node appeared clearly free of disease, no further intra-operative assessment was performed; if the node was clearly metastatic or presented a dubious aspect, the pathologist proceeded with analysis on FS. T2-patients, enrolled in the study as reference group, were treated according to the institutional standard procedure; they all received SLN staging on FS., Results: The study included 395 T1-N0-patients. Among the 118 T1a-T1b-patients whose SLN was not analyzed at surgery, 12 (10.2%) were recalled for ALND. In the group of 258 T1c-patients, 112 received SLN analysis on FS and 146 did not. An SLN falsely negative either at macroscopic or FS examination was found in 33 (12.8%) cases. Overall, the rate of recall for ALND was 11.6% as compared to 8.4% in T2-patients. Using the experimental protocol, the institution reached a 9.6% cost saving, as compared to the standard procedure., Conclusions: Omission of SLN intra-operative staging in T1-N0-patients is rather safe. It provides the institution with both management and economical advantages., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Investigation is lacking regarding the clinical impact of human leukocyte antigen (HLA) class I downregulation in breast cancer and results are inconsistent. In this study, we investigated the expression of HLA class I, the heavy chain, and beta2-microglobulin (beta2-m) by immunohistochemistry in 67 breast carcinomas (BC) and correlated results with clinical-pathologic parameters and patient outcomes. Seventy-six percent of BC were downregulated for HLA class I, whereas downregulation of heavy chain and beta2-m was observed in 57 and 46% of BC, respectively. A significant association existed between the absence of tumor necrosis and downregulation of class I and beta2-m and between the absence of lymphovascular invasion and patient's age and downregulated class I and heavy chain, respectively. Among the lymph node-positive BC patients, a significantly improved overall survival was observed in those showing beta2-m downregulation compared with patients with normal beta2-m. This result may correlate with the role of beta2-m in regulating cancer cell growth.

An automated enzyme metallographic silver in situ hybridization method (SISH) has been reported to successfully determine human epidermal growth factor receptor 2 (HER2) gene amplification. We evaluated the staining and interpretative reproducibility of the HER2 SISH assay at five laboratories and compared SISH results with other in situ hybridization (ISH) methods. The HER2 gene status of 89 breast carcinomas was analyzed in parallel using manual dual-color fluorescence ISH, manual chromogenic ISH, and bright-field automated SISH. A total of 1098 SISH-stained slides were evaluated. For comparison, all specimens were stained by 4B5 immunohistochemistry for HER2 protein expression. Interpretation was performed by pathologists at five different laboratories using the algorithms provided by the manufacturers and the guidelines of American Society of Clinical Oncology/College of American Pathologists. Staining and interpretative reproducibility were measured through the computation of weighted kappa statistics. Following the optimization of SISH staining, 1077/1098 (98%) of slides were evaluable. Excellent reproducibility and efficacy of HER2 SISH staining, and interobserver interpretation (Kw = 0.91), were observed among five sites. For the 89 invasive breast cancer cases, the overall rate of concordance between consensus 4B5 and consensus SISH, fluorescence ISH, and chromogenic ISH was 96.6% (86/89), 97.8% (87/89), and 96.6% (86/89), respectively. Overall concordance between positive and negative SISH and fluorescence ISH results, as well as between individual and consensus positive and negative SISH results, was excellent (P < 0.001).

Background: Biotin-labeled trastuzumab (BiotHER) can be used to test for HER2 by immunohistochemistry. We previously showed that BiotHER immunoreactivity is highly correlated with HER2 amplification and indicated that it could be associated with better clinical outcome in advanced breast cancer patients receiving trastuzumab., Patients and Methods: Tumor specimens and clinical information from 234 patients who received trastuzumab-based treatments were collected from 10 institutions. HER2 amplification and BiotHER immunoreactivity were assessed centrally. The effect of BiotHER positivity on response rate (RR), time to progression and survival were studied by univariate and multivariate analysis in patients presenting HER2-amplified breast cancer. The pathologic reviews of the assays were blinded to patient outcomes., Results: BiotHER was positive in 109/194 (56%) HER2-amplified breast cancers and in one not amplified tumor. RRs were 74% [95% (confidence interval) CI 64%-81%] and 47% (95% CI 36%-58%) in BiotHER-positive and -negative tumors, respectively (P < 0.001). BiotHER immunoreactivity was independently associated with increased probability of tumor response (odds ratio 3.848; 95% CI 1.952-7.582), with reduced risk of disease progression [hazard ratio (HR) 0.438; 95% CI 0.303-0.633] and with reduced risk of death (HR 0.566; 95% CI 0.368-0.870) by multivariate analysis., Conclusion: The results support a role for BiotHER testing in better tailoring trastuzumab-based treatments in patients with advanced HER2-amplified breast cancers.

Background: Primary melanoma of the esophagus is a very rare and aggressive neoplasm; only a small number of patients survive more than 1 year after initial diagnosis., Case Report: We describe a case of primary melanoma of the esophagus in a woman with a history of invasive breast cancer. The patient suffered from dysphagic and dyspeptic disorders. The abdomen ultrasonography and the esophagogastroscopy showed a lesion located at the esophago-gastric junction extending to the gastric fundus. Histological and immunohistochemical studies revealed a primary esophageal infiltrating melanoma. A total gastrectomy and regional lymphadenectomy with a partial resection of the distal esophagus was performed., Results: During laparotomic exploration, numerous dark lymp hnodes were found. On frozen sections, surprisingly neither malignant cells nor melanin were detected in the lymph nodes. Resection margins were not involved with the tumor., Conclusion: Patient is still alive with no evidence of recurrence at 24 months after surgical treatment, alone.