Breast Cancer Index and prediction of benefit from extended endocrine therapy in breast cancer patients treated in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial.

BACKGROUND: Extending the duration of adjuvant endocrine therapy reduces the risk of recurrence in a subset of women with early-stage hormone receptor-positive (HR+) breast cancer. Validated predictive biomarkers of endocrine response could significantly improve patient selection for extended therapy. Breast cancer index (BCI) [HOXB13/IL17BR ratio (H/I)] was evaluated for its ability to predict benefit from extended endocrine therapy in patients previously randomized in the Adjuvant Tamoxifen-To Offer More? (aTTom) trial. PATIENTS AND METHODS: Trans-aTTom is a multi-institutional, prospective-retrospective study in patients with available formalin-fixed paraffin-embedded primary tumor blocks. BCI testing and central determination of estrogen receptor (ER) and progesterone receptor (PR) status by immunohistochemistry were carried out blinded to clinical outcome. Survival endpoints were evaluated using Kaplan-Meier analysis and Cox regression with recurrence-free interval (RFI) as the primary endpoint. Interaction between extended endocrine therapy and BCI (H/I) was assessed using the likelihood ratio test. RESULTS: Of 583 HR+, N+ patients analyzed, 49% classified as BCI (H/I)-High derived a significant benefit from 10 versus 5 years of tamoxifen treatment [hazard ratio (HR): 0.35; 95% confidence interval (CI) 0.15-0.86; 10.2% absolute risk reduction based on RFI, P = 0.027]. BCI (H/I)-low patients showed no significant benefit from extended endocrine therapy (HR: 1.07; 95% CI 0.69-1.65; -0.2% absolute risk reduction; P = 0.768). Continuous BCI (H/I) levels predicted the magnitude of benefit from extended tamoxifen, whereas centralized ER and PR did not. Interaction between extended tamoxifen treatment and BCI (H/I) was statistically significant (P = 0.012), adjusting for clinicopathological factors. CONCLUSION: BCI by high H/I expression was predictive of endocrine response and identified a subset of HR+, N+ patients with significant benefit from 10 versus 5 years of tamoxifen therapy. These data provide further validation, consistent with previous MA.17 data, establishing level 1B evidence for BCI as a predictive biomarker of benefit from extended endocrine therapy. TRIAL REGISTRATION: ISRCTN17222211; NCT00003678.

Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer.

Prior studies have suggested a higher prevalence of high grade, ER-negative, HER2-positive, and basal-like carcinomas in young women with breast cancer. However, the precise distribution of poor prognostic features in this population remains unclear. We examined the pathologic features and distribution of molecular phenotype in relation to patient age in a large group of young women (≤40 years) with invasive breast cancer. Medical records were reviewed for clinical characteristics, tumor stage, and receptor status. Pathologic features, including those features associated with basal-like carcinomas, were examined by central review. Using tumor grade and biomarker expression, cancers were categorized as luminal A (ER+ and/or PR+ and HER2-, histologic grade 1 or 2); luminal B (ER+ and/or PR+ and HER2+, or ER and/or PR+, HER2- and grade 3); HER2 (ER and PR- and HER2+); and triple negative (ER-, PR-, and HER2-). Among 399 women of ≤40 years, 33% had luminal A tumors, 35% luminal B, 11% HER2 (ER-negative), and 21% triple negative. Compared to published results for all breast cancers, a greater proportion of young women had luminal B tumors, and a lesser proportion had luminal A. There were no significant differences in molecular phenotype, tumor stage or grade among the different age groups of young women. However, this population of young women presented with a different distribution of molecular phenotypes compared to the general population of women with breast cancer. These findings may have implications with regard to the etiology and prognosis of breast cancer in young women.

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib.

The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

Development and validation of a model predictive of occult nipple involvement in women undergoing mastectomy.

BACKGROUND: This prospective study aimed to build a predictive model using preoperative information to aid selection for nipple-sparing mastectomy. METHODS: Two hundred consecutive skin-sparing mastectomy specimens without overt nipple involvement were evaluated. Demographic, preoperative pathology and imaging information was collected. Nipple specimens (2 x 2 x 2 cm) were sectioned at 3-mm intervals. Haematoxylin and eosin-stained slides were examined by a breast pathologist for involvement by tumour. Logistic regression analyses of 65 therapeutic procedures identified factors associated with occult involvement and created a predictive model. This was tested on specimens from a further 65 therapeutic procedures. RESULTS: Occult nipple involvement was noted in 32 (24.6 per cent) of 130 mastectomy specimens. In the training set, imaging diameter of the lesion and its distance from the nipple predicted nipple involvement on univariable analysis (P = 0.011 and P = 0.014 respectively). The multivariable logistic regression model was validated in the test set. The areas under the receiver-operating characteristic curve were 0.824 and 0.709 for the training and test sets respectively. CONCLUSION: Three-quarters of women undergoing mastectomy did not have occult nipple involvement. A clinical tool including tumour size and distance from the nipple has been developed to improve patient selection for nipple-sparing mastectomy.

High frequency of beta-catenin mutations in borderline endometrioid tumours of the ovary.

Some low-grade endometrioid carcinomas arise from a background of endometrioid tumours of borderline malignancy. To determine the molecular mechanisms involved in the initiation of endometrioid carcinoma, the present study investigated whether the genetic alterations reported in these tumours (mutations in PTEN, KRAS, and beta-catenin genes, and microsatellite instability) are already present in endometrioid tumours of borderline malignancy. Eight endometrioid tumours of borderline malignancy were studied. By immunohistochemistry, beta-catenin was expressed in the nuclei of all tumours, suggesting the presence of stabilizing beta-catenin mutations. By mutational analysis, five different beta-catenin mutations were found in seven of eight cases (90%), affecting codons 32, 33, and 37. In contrast, only one tumour harboured a PTEN mutation, which affected codon 130. Neither KRAS mutations nor microsatellite instability was detected. A review of the literature indicated that beta-catenin mutations are characteristic of well-differentiated endometrioid carcinomas, since they were present in nearly 60% of grade I but in less of 3% of grade III tumours. In conclusion, the present study identifies beta-catenin mutation as a nearly constant molecular alteration in borderline endometrioid tumours, whereas PTEN and KRAS mutations and microsatellite instability are very infrequent. The findings in the present study, and previously reported data, strongly suggest that beta-catenin mutation is an early event in endometrioid ovarian carcinogenesis, and that it is involved in the development of low-grade endometrioid tumours.

Human skin Langerhans cells are targets of dengue virus infection.

Dengue virus (DV), an arthropod-borne flavivirus, causes a febrile illness for which there is no antiviral treatment and no vaccine. Macrophages are important in dengue pathogenesis; however, the initial target cell for DV infection remains unknown. As DV is introduced into human skin by mosquitoes of the genus Aedes, we undertook experiments to determine whether human dendritic cells (DCs) were permissive for the growth of DV. Initial experiments demonstrated that blood-derived DCs were 10-fold more permissive for DV infection than were monocytes or macrophages. We confirmed this with human skin DCs (Langerhans cells and dermal/interstitial DCs). Using cadaveric human skin explants, we exposed skin DCs to DV ex vivo. Of the human leukocyte antigen DR-positive DCs that migrated from the skin, emigrants from both dermis and epidermis, 60-80% expressed DV antigens. These observations were supported by histologic findings from the skin rash of a human subject who received an attenuated tetravalent dengue vaccine. Immunohistochemistry of the skin showed CD1a-positive DCs double-labeled with an antibody against DV envelope glycoprotein. These data demonstrate that human skin DCs are permissive for DV infection, and provide a potential mechanism for the transmission of DV into human skin.

[Fistula between the trachea and innominate artery--a rare complication following tracheostenosis treatment with silastic tubes]. / Tracheo-arterielle Anonymafistel--Eine seltene Komplikation nach trachealer Stent-Behandlung.

BACKGROUND: Fistulas between the trachea and innominate artery are rare but devastating complications that usually occur following tracheotomies. METHODS: One case a fistula after long-term treatment of a tracheal stenosis with an Montgomery silastic tube was analyzed. A literature review of the different strategies in diagnosis and treatment of this complication was undertaken. RESULTS: In the present case, the fistula occurred after long-term treatment of tracheal stenosis with silastic tubes (Montgomery). Summarizing our experience with this case and a review of the literature, it can be concluded that: Fistulas most frequently occur following tracheostomy or tracheal reconstructive surgery. Frequent bronchoscopic examination during long-term treatment of tracheal stenosis with silastic tubes is essential. Even minor tracheal hemorrhage in such cases must be thoroughly examined. In case of fistula hemorrhage, the most effective treatment consists of direct local compression, best obtained with a well placed respiration tube. CONCLUSION: Fistulas between the trachea and innominate artery constitute a rare but possible complication after tracheal stenosis treatment.

Differences in the germinal centres of palatine tonsils and lymph nodes.

The germinal centres of human palatine tonsils typically have four clearly recognizable compartments. The dark zone is identified by the presence of centroblasts and a thin follicular dendritic cell (FDC) network. The dense FDC network is divided into a CD23(low/-) portion adjacent to the dark zone (the basal light zone) and a CD23(high) portion, the apical light zone). The outer zone, which lies between the apical light zone and the follicular mantle, has only fine CD23- FDC processes. While these compartments were seen in 48 follicles from eight tonsils, the compartmental structure of 54 germinal centres in lymph nodes from 11 individuals was markedly different. The CD23+ FDC network in lymph node follicles extended into part of the dark zone and the inner part of the follicular mantle, and consequently no outer zone or basal light zone was identified. In both the lymph nodes and tonsils most T cells were CD4+ and located outside the dark zone; the concentration of these cells at the edge of germinal centres was typical of tonsil centres but was noted only occasionally in lymph nodes. The substantial minority of T cells that were CD4,CD57+ were located mainly in the dense FDC network.

[Histologic classification of HIV-1 induced lymphadenopathy. Current results on the pathogenesis of germinal center changes]. / Histologische Klassifikation des HIV-1-verursachten Lymphadenopathie. Beiträge zur Pathogenese der Keimzentrumsveränderungen.

At the IV International Conference on AIDS in Stockholm, a Symposium on the pathology of HIV-related diseases was organized. During this Symposium the "European Study Group on HIV-Pathology" presented a histological classification of lymph node alterations seen in HIV-associated lymphadenopathy. The goal of the Study group was to offer a common terminology for histologic changes previously described with different terms by different authors. In the present review the most important histological criteria used in the proposed classification are summarized. Since the classification is based on the conspicuous changes of the follicles, a brief review of the possible pathogenic mechanisms leading to disintegration of the germinal centers will also be given.