Morphological parameters of lobular in situ neoplasia in stereotactic 11-gauge vacuum-assisted needle core biopsy do not predict the presence of malignancy on subsequent surgical excision.

Aims: The management of lobular in situ neoplasia (LN) when diagnosed on core biopsy remains a controversial issue. The present study aimed to investigate the association between morphological parameters of LN on vacuum-assisted needle core biopsy (VANCB) and the presence of malignancy (ductal carcinoma in situ, pleomorphic lobular carcinoma in situ, or invasive carcinoma) at surgical excision (SE).

Methods And Results: The study included 14 pathology departments in Italy.

Morphological parameters of flat epithelial atypia (FEA) in stereotactic vacuum-assisted needle core biopsies do not predict the presence of malignancy on subsequent surgical excision.

Flat epithelial atypia (FEA) may represent the earliest precursor of low-grade breast cancer and often coexists with more advanced atypical proliferative breast lesions such as atypical ductal hyperplasia (ADH) and lobular intraepithelial neoplasia (LIN). The present study aims to investigate the association between morphological parameters of FEA and presence of malignancy at surgical excision (SE) and the clinical significance of the association of FEA with ADH and/or LIN. This study included 589 cases of stereotactic 11-gauge vacuum-assisted needle core biopsy (VANCB), reporting a diagnosis of FEA, ADH or LIN with subsequent SE from 14 pathology departments in Italy.

Molecular oncology and the neoadjuvant setting: the perfect blend for treatment personalization and clinical trial design.

Breast cancer is a heterogeneous disease. Predictive molecular markers are crucial in patient management, but the only recommended predictive biomarkers are estrogen and progesterone receptors and HER2. There are many new targeted therapies, and although the target pathway expression is readily analyzed on conventional pathology, the dynamic response cannot be assessed and pathway expression is no guarantee it has a major driver role, even if mutated.

The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen.

Introduction: The purpose of the present study was to investigate the relationship of expression of hypoxia inducible factor (HIF)-1α-modifying enzymes prolyl hydroxylase (PHD)1, PHD2 and PHD3 to response of tumours and survival in breast cancer patients enrolled in a phase II trial of neoadjuvant anthracycline and tamoxifen therapy.

Methods: The expression of PHD1, PHD2 and PHD3 together with HIF-1α and the HIF-inducible genes vascular endothelial cell growth factor (VEGF) and carbonic anhydrase IX were assessed by immunohistochemistry using a tissue microarray approach in 211 patients with T2-4 N0-1 breast cancer enrolled in a randomised trial comparing single-agent epirubicin versus epirubicin and tamoxifen as the primary systemic treatment.

Results: PHD1, PHD2 and PHD3 were detected in 47/179 (26.

Clinicopathologic implications of the epidermal growth factor receptor, cyclooxygenase 2 expression, and human papillomavirus status in squamous cell carcinoma of the uterine cervix in the elderly.

Objectives: To find information on invasive squamous cervical carcinoma in the elderly, 110 invasive squamous cervical carcinomas obtained from 2 groups of patients (aged <60 and >60 years) were analyzed for human papillomavirus (HPV) status by polymerase chain reaction study, for immunohistochemical epidermal growth factor receptor (EGFR), cyclooxygenase 2 (Cox-2) expression, and clinicopathologic features.

Methods: The HPV status and the expression of Cox-2 and EGFR in the younger and older women were compared and correlated with the grading, staging neoplasm, and lymph nodal status, using Fisher test and Spearman nonparametric correlation test. Overall survival curves were drawn using Kaplan-Meier estimates and were compared using log-rank tests in the whole series of 110 patients.

Anti-angiogenic effect of tamoxifen combined with epirubicin in breast cancer patients.

Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are the key factors mediating neo-vascularization. They are often coexpressed in breast cancer. Sex steroids may stimulate angiogenesis via the estrogen receptor (ER) pathway.

Primary adenocarcinoma of the rectovaginal septum arising in pregnancy in the absence of endometriosis.

A case of primary adenocarcinoma of the rectovaginal septum (PARVS) is reported with clinical and pathological findings. A 37-year-old Caucasian woman with a history of sterility and small posterior leiomyoma, a few months after a cesarean section, was admitted because of vaginal spotting, abdominal pain and constipation. Her previous history did not reveal exposure to diethylstil bestrol (DES).

Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients.

Purpose: We have shown previously that tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-alpha signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival.

Experimental Design: FOXP3+ Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T2-4 N0-1) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.

Phosphorylated ERalpha, HIF-1alpha, and MAPK signaling as predictors of primary endocrine treatment response and resistance in patients with breast cancer.

Purpose: We aimed to identify signaling pathways involved in the response and resistance to aromatase inhibitor therapy in patients with breast cancer.

Patients And Methods: One hundred fourteen women with T2-4 N0-1, estrogen receptor (ER) alpha-positive tumors were randomly assigned to neoadjuvant letrozole or letrozole plus metronomic cyclophosphamide. Twenty-four tumor proteins involved in apoptosis, cell survival, hypoxia, angiogenesis, growth factor, and hormone signaling were assessed by immunohistochemistry in pretreatment samples (eg, caspase 3, phospho- mammalian target of rapamycin, hypoxia-inducible factor 1alpha [HIF-1alpha], vascular endothelial growth factor, mitogen-activated protein kinase [MAPK], phosphorylated epidermal growth factor receptor, phosphorylated ERalpha [pERalpha]).

Down-regulation of phosphatidylinositol 3'-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer.

Purpose: The phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown.

Experimental Design: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide.

Fluorescent in situ hybridization as a screening test for HER2 amplification in G2 and G3 breast cancers of lobular and ductal histotype and metastases.

The aim of the present study was to evaluate the effectiveness of fluorescence in situ hybridisation (FISH), as a screening test, in moderately- (G2) or poorly- (G3) differentiated breast cancers of the ductal (IDC) and lobular (ILC) histotypes and distant metastases. HER2 FISH was performed on 486 G2 and 477 G3 both of IDC and ILC histotypes and in 241 metastases. A significant difference in the HER2 amplification was observed between G2 (14.

Histological heterogeneity and somatic mtDNA mutations in gastric intraepithelial neoplasia.

Somatic mutations of mitochondrial DNA (mtDNA) are associated with various types of human cancer. To elucidate their role in gastric carcinogenesis, we analyzed mutations in the displacement loop region of mtDNA in 24 paraffin-embedded gastric intraepithelial neoplasias (formerly dysplasia) from a high gastric cancer risk area in northern Italy. Helicobacter pylori infection was assessed by histological examination (Giemsa staining).

Patients with advanced stage breast carcinoma immunoreactive to biotinylated Herceptin are most likely to benefit from trastuzumab-based therapy: an hypothesis-generating study.

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.

Regulation of hepatocyte growth factor activator inhibitor 2 by hypoxia in breast cancer.

Purpose: To examine the in vitro regulation of hepatocyte growth factor activator inhibitor type 2 (HAI-2) in breast cancer cells and the in vivo predictive role for the efficacy of chemoendocrine primary therapy in patients with breast cancer.

Materials And Methods: HAI-2 regulation was studied in a panel of breast cancer cell lines comparing normoxia to hypoxia. The effect of HIF-1alpha RNAi on HAI-2 expression was evaluated in these cells.

Role of carbonic anhydrase IX expression in prediction of the efficacy and outcome of primary epirubicin/tamoxifen therapy for breast cancer.

The purpose of this study is to investigate the role of carbonic anhydrase IX (CAIX) expression in predicting the response to epirubicin and disease-free survival (DFS) in breast cancer patients enrolled in a single institution trial of primary anthracycline and tamoxifen therapy. CAIX expression was assessed in 183 patients with T2-4 N0-1 breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin+tamoxifen as primary systemic treatment. All patients received postoperatively four cycles of the four weekly i.

Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer.

Purpose: To investigate the relationship of hypoxia-inducible factor-1alpha (HIF-1alpha) tumor expression in predicting the response to epirubicin and disease-free survival (DFS) in patients with breast cancer enrolled in a single institution trial of primary anthracycline and tamoxifen therapy.

Experimental Design: The expression of HIF-1alpha was assessed by immunohistochemistry in 187 patients with T(2-4) N(0-1) breast cancer enrolled in a randomized trial comparing four cycles of single agent epirubicin versus epirubicin + tamoxifen as primary systemic treatment. All patients postoperatively received four cycles of the four weekly i.

Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients.

Purpose: To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients.

Methods: One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial.

Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial.

This study was designed to address whether simultaneous primary chemo-hormonal therapy provides additional activity compared with chemotherapy alone in breast cancer patients with operable or locally advanced disease. Between January 1997 and January 2002, 211 consecutive patients with T2-4, N0-1, M0 breast cancer were randomized to receive either epirubicin alone (EPI) or epirubicin plus tamoxifen (EPI-TAM). Ki67 expression was evaluated immunohistochemically in tumor specimens obtained before chemotherapy by incision biopsy and at definitive surgery.

Magnetic resonance imaging in comparison to clinical palpation in assessing the response of breast cancer to epirubicin primary chemotherapy.

Purpose: To investigate whether magnetic resonance imaging (MRI) is superior to clinical palpation in the assessment of response of breast cancer to primary chemotherapy (PC).

Patients And Methods: Seventy-three patients with T2-4, N0, M0 breast cancer were treated with 3-4 cycles of single agent epirubicin before definitive surgery. MRI was performed at baseline condition and at the end of chemotherapy.

Pretreatment haemoglobin levels significantly predict the tumour response to primary chemotherapy in human breast cancer.

The purpose of this study was to evaluate whether tumour response to primary chemotherapy in human breast cancer is influenced by baseline haemoglobin (Hb) status. A total of 157 patients with T2-4, N0-1 M0 breast cancer were treated with chemotherapy consisting of either the CMF regimen + tamoxifen (the first 76 cases) or the single-agent epirubicin (the subsequent 81) before definitive surgery. In total, 144 patients were fully assessable.

Eosinophil-tumor cell interaction in advanced gastric carcinoma: an electron microscopic approach.

Background: Tumor-associated tissue eosinophils have been observed in human tumors and experimental tumor models, but their function is poorly understood.

Materials And Methods: One case of intestinal-type adenocarcinoma of the stomach, mainly infiltrated by eosinophils, is studied by light and electron microscopy, focusing on the relationships between eosinophils and tumor cells and on the nature of tumor cell death.

Results: Using light microscopy, eosinophils, single or in clusters, were present both in the stroma and within neoplastic glands.

Morphological evidence of neutrophil-tumor cell phagocytosis (cannibalism) in human gastric adenocarcinomas.

The phenomenon of neutrophil-tumor cell emperipolesis or phagocytosis has been documented by light microscopy in various human carcinomas, but little is known about the cellular pathological processes and the morphological changes involved. In an attempt to clarify the nature of this phenomenon, the authors' ultrastructural studies on the relationships among neutrophils and tumor cells in human gastric carcinomas are reviewed and analyzed. At the electron microscopy level, apoptotic neutrophils were found within vacuoles of adenocarcinoma cells in 2 cases.

Changes in microvessel density as assessed by CD34 antibodies after primary chemotherapy in human breast cancer.

Background: Several papers have shown that quantitationof tumor angiogenesis in primary breast cancer by counting blood vessels gives an independent assessment of prognosis. The impact of chemotherapy +/- endocrine therapy on the extent of angiogenesis is unknown.

Methods: Matched pair histological tumor samples were obtained before and after primary chemotherapy from 120 breast cancer patients recruited in the same institution.

Relationship between tumour shrinkage and reduction in Ki67 expression after primary chemotherapy in human breast cancer.

The association between tumour shrinkage and reduction in kinetic cell activity after primary chemotherapy in human breast cancer is still a matter of investigation. 157 patients with T2-4, N0-1, M0 breast cancer received primary chemotherapy consisting of either the CMF regimen + tamoxifen (the first consecutive 76 cases) or the single agent epirubicin (the subsequent 81). Ki67, p53, bcl2, c-erbB2 and steroid hormone receptors were evaluated immunohistochemically in tumour specimens obtained before chemotherapy and at surgery.