Citations

2 Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.

18 Background: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), a lesion found in ¼ of all BBD patients that is characterized by epithelial proliferation, disordered acinar architecture, and stromal fibrosis. Methods: A training set was developed from 86 patients diagnosed with sclerosing adenosis (SA), of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). A diagonal linear discriminate analysis (DLDA)-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of formalin fixed, paraffin-embedded (FFPE) biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. Results: The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Conclusions: Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, and that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.

AbstractPrimary CNS lymphoma (PCNSL) is a rare diffuse large B-cell lymphoma originating within the central nervous system. The overall incidence of PCNSL is rising, particularly in the elderly population. Immunosuppression is a strong risk factor, but most patients with this tumor are apparently immunocompetent. Diagnosis of PCNSL can be challenging. Non-invasive or minimally invasive tests such as ophthalmological evaluation and spinal fluid analysis may be useful, but the majority of patients require tumor biopsy for definitive diagnosis. Our knowledge concerning optimum treatment of PCNSL is fragmentary due to paucity of adequately sized trials. Most patients are now initially treated with high-dose-methotrexate-based chemotherapy alone, as the addition of whole-brain radiotherapy at standard doses has not been shown to increase survival and does increase the risk of neurological toxicity. Ongoing trials are addressing issues such as the roles of reduced-dose radiotherapy, the addition of the CD20 antibody rituximab to chemotherapy, high-dose chemotherapy followed by autologous stem cell transplantation, and maintenance therapy in the primary management of PCNSL.

Abstract Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD). Experimental Design: A breast tissue matched case–control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells). Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+ cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4–23.1) for subsequent breast cancer risk. Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945–52. ©2017 AACR.

Abstract We have investigated the distribution of PDGFR-a and -b in the stroma of normal breast tissue, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) by immunohistochemistry. Both receptors were expressed by fibroblasts of normal breast tissue. While the PDGFRb remained high during cancer progression, the PDGFRa was lost in most of the DCIS samples and not detectable in IDC. The patient group with PDGFRa(low)/PDGFRb(high) fibroblasts had the highest risk for local recurrences or metastasis. The characteristic loss of stromal PDGFRa expression was also observed in the PyMT mouse breast cancer model. In vitro co-culture experiments confirmed a tumor cell-induced differentiation of fibroblasts, resulting in a fibroblast population marked by PDGFRa(low)/PDGFRb(high) expression. We could identify the interaction of Jagged-1 expressed by the tumor cells with Notch-2 expressed on the fibroblasts, as an essential activator of TGFb signaling in fibroblasts. Gene expression analysis and reporter-gene assays of sorted cells from co-cultures revealed, that fibroblasts switch from a more anti-tumorigenic signaling (expression of BMPs and Wnt antagonists) towards a pro-tumorigenic signaling (expression of BMP inhibitors, TGFb and Wnt ligands). Co-cultured tumor cells show an increased migratory activity and the induction of a mesenchymal phenotype. Inhibition of Notch or TGF signaling in fibroblasts could block these phenotypes. To investigate the impact of fibroblasts on the progression of DCIS to IDC, a DCIS xenograft model was used. Co-injection of MCF10.DCIS cells with human breast fibroblasts, expressing both PDGFRs, into the mouse mammary fat pad resulted in an earlier tumor take with faster tumor growth. The corresponding co-injection experiments with fibroblast and tumor cells, that were depleted of Notch2 respectively Jagged-1 expression by CRISPR/CAS technology is currently ongoing. Collectively the study identifies a potentially druggable paracrine cross-talk between epithelial and stromal cells, which promotes DCIS progression and involves a Notch mediated up-regulation of TGFb signaling. The study also suggests that loss of PDGFRa marks a subset of fibroblasts with specific tumor-promoting activities. Citation Format: Carina Strell, Janna Paulsson, Artur Mezheyeuski, Shao-Bo Jin, Pernilla Roswall, Johanna Andrea, Oliver Frings, Fredrick Warnberg, Hemming Johansson, Karin Jirstrom, Kristian Pietras, Per Hall, Urban Lendahl, Christer Betsholtz, Derek C. Radisky, Arne Ostman. Cell-contact dependent epithelial-stromal cross talk, including a modulation of stromal PDGFR expression, drives the progression of early-stage breast cancer lesions. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B41.

Abstract Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277–87. ©2016 AACR.

AimsWe wished to quantify the extent of soft-tissue damage sustained during minimally invasive total hip arthroplasty through the direct anterior (DA) and direct superior (DS) approaches.Materials and MethodsIn eight cadavers, the DA approach was performed on one side, and the DS approach on the other, a single brand of uncemented hip prosthesis was implanted by two surgeons, considered expert in their surgical approaches. Subsequent reflection of the gluteus maximus allowed the extent of muscle and tendon damage to be measured and the percentage damage to each anatomical structure to be calculated.ResultsThe DA approach caused substantially greater damage to the gluteus minimus muscle and tendon when compared with the DS approach (t-test, p = 0.049 and 0.003, respectively). The tensor fascia lata and rectus femoris muscles were damaged only in the DA approach. There was no difference in the amount of damage to the gluteus medius muscle and tendon, piriformis tendon, obturator internus tendon, obturator externus tendon or quadratus femoris muscle between approaches. The posterior soft-tissue releases of the DA approach damaged the gluteus minimus muscle and tendon, piriformis tendon and obturator internus tendon.ConclusionThe DS approach caused less soft-tissue damage than the DA approach. However the clinical relevance is unknown. Further clinical outcome studies, radiographic evaluation of component position, gait analyses and serum biomarker levels are necessary to evaluate and corroborate the safety and efficacy of the DS approach. Cite this article: Bone Joint J 2016;98-B1036–42.