Paracrine Crosstalk between Fibroblasts and ER+ Breast Cancer Cells Creates an IL1ß-Enriched Niche that Promotes Tumor Growth.

Breast cancer-induced activated fibroblasts support tumor progression. However, the role of normal fibroblasts in tumor progression remains controversial. In this study, we used modified patient-derived organoid cultures and demonstrate that constitutively secreted cytokines from normal breast fibroblasts initiate a paracrine signaling mechanism with estrogen receptor-positive (ER+) breast cancer cells, which results in the creation of an interleukin (IL)-1ß-enriched microenvironment. We found that this paracrine signaling mechanism is shared between normal and activated fibroblasts. Interestingly, we observed that in reconstructed tumor microenvironment containing autologous ER+ breast cancer cells, activated fibroblasts, and immune cells, tamoxifen is more effective in reducing tumor cell proliferation when this paracrine signaling is blocked. Our findings then suggest that ER+ tumor cells could create a growth-promoting environment without activating stromal fibroblasts and that in breast-conserving surgeries, normal fibroblasts could be a significant modulator of tumor recurrence by enhancing the proliferation of residual breast cancer cells in the tumor-adjacent breast tissue.

Xanthogranulomatous endometritis mimicking endometrial carcinoma: A case report and review of literature.

Xanthogranulomatous endometritis (XGE) is an extremely rare chronic inflammatory condition, which may be associated with endometrial hyperplasia, endometrial carcinoma, or cervical stenosis. Imaging features can be easily misdiagnosed as an aggressive malignancy. We present a case of XGE, which is the first case of XGE with serial multimodality imaging examinations, in addition to clinical, surgical and pathologic correlations. As such, this unique case illustrates the evolution of this rare disease.

Blastomyces species and orbital apex syndrome: Unsuspected co-infection.

Blastomyces species are thermally dimorphic fungi existing as yeast in tissue. We report an initially immunocompetent patient with orbital apex syndrome (OAS) whose presentation suggested giant cell arteritis. Subsequently, metastatic carcinoma was entertained as a cause of OAS until bronchoscopy yielded Blastomyces species. The patient rapidly succumbed with multiorgan failure despite Amphotericin B administration. At post-mortem, Blastomyces co-infection with fungal hyphae in keeping with Aspergillus species was found in cavernous sinus and in infarcted optic nerve. To the best of our knowledge, co-infection with these two organisms in this clinical setting has not been reported.

Breast Cancers Activate Stromal Fibroblast-Induced Suppression of Progenitors in Adjacent Normal Tissue.

Human breast cancer cells are known to activate adjacent "normal-like" cells to enhance their own growth, but the cellular and molecular mechanisms involved are poorly understood. We now show by both phenotypic and functional measurements that normal human mammary progenitor cells are significantly under-represented in the mammary epithelium of patients' tumor-adjacent tissue (TAT). Interestingly, fibroblasts isolated from TAT samples showed a reduced ability to support normal EGF-stimulated mammary progenitor cell proliferation in vitro via their increased secretion of transforming growth factor ß. In contrast, TAT fibroblasts promoted the proliferation of human breast cancer cells when these were co-transplanted in immunodeficient mice. The discovery of a common stromal cell-mediated mechanism that has opposing growth-suppressive and promoting effects on normal and malignant human breast cells and also extends well beyond currently examined surgical margins has important implications for disease recurrence and its prevention.

Population-based analysis of breast cancer treatment by intrinsic sub-type in Manitoba, Canada.

BACKGROUND: Few descriptive epidemiological studies on the incidence, treatment and survival can accurately reflect a whole population. Manitoba, Canada has an accurate cancer registry, a drug information program network and a breast screening program since 1995. This combined with a stable population provides true population data that can accurately describe the region. METHODS: Using a retrospective cohort design all Breast Cancer cases were obtained from 2004-2010 (N=5399) and grouped by Intrinsic sub-type. Identifiable co-morbidities, prescribed endocrine therapy, staging, surgery, treatment and overall and disease-free survival by intrinsic sub-type were evaluated. RESULTS: Prevalence of Luminal A (41.7%), Luminal B HER2- (15.6%), Luminal B HER2+ (8.9%), Basal-like(10.8%), and HER2+ non-luminal (5.1%) were consistent with other descriptive studies in Canada and Spain. Over this time period the number of lumpectomies increased 1.7% per year (P=0.007). There was a steady increase of 3.4% per year in the use of aromatase inhibitors (P=0.005). Pre-menopausal patients had an increased proportion of HER2+ and Basal-like sub-types. The 7year overall/disease-free survival percentages for Luminal A, Luminal B HER2-, Luminal B HER2+, Basal-like, and HER2+ non-luminal were 88.7%/83.6, 78.2%/73.0, 81.5%/73.3%, 67.7%/63.2%, 70.4%/65.6% respectively. CONCLUSIONS: Reasons for variability in the prevalence of intrinsic sub-type by region is not fully understood. Manitoba is unique due the stability of the population, completeness of the registry and length of breast cancer screening program. Few true population-based studies grouped by intrinsic sub-type are available. IMPACT: Descriptive epidemiological studies guide future research by identifying factors that can affect treatment, recurrence, and survival.

Adipose-Derived Stromal Vascular Fraction Differentially Expands Breast Progenitors in Tissue Adjacent to Tumors Compared to Healthy Breast Tissue.

BACKGROUND: Autologous fat grafts supplemented with adipose-derived stromal vascular fraction are used in reconstructive and cosmetic breast procedures. Stromal vascular fraction contains adipose-derived stem cells that are thought to encourage wound healing, tissue regeneration, and graft retention. Although use of stromal vascular fraction has provided exciting perspectives for aesthetic procedures, no studies have yet been conducted to determine whether its cells contribute to breast tissue regeneration. The authors examined the effect of these cells on the expansion of human breast epithelial progenitors. METHODS: From patients undergoing reconstructive breast surgery following mastectomies, abdominal fat, matching tissue adjacent to breast tumors, and the contralateral non-tumor-containing breast tissue were obtained. Ex vivo co-cultures using breast epithelial cells and the stromal vascular fraction cells were used to study the expansion potential of breast progenitors. Breast reduction samples were collected as a source of healthy breast cells. RESULTS: The authors observed that progenitors present in healthy breast tissue or contralateral non-tumor-containing breast tissue showed significant and robust expansion in the presence of stromal vascular fraction (5.2- and 4.8-fold, respectively). Whereas the healthy progenitors expanded up to 3-fold without the stromal vascular fraction cells, the expansion of tissue adjacent to breast tumor progenitors required the presence of stromal vascular fraction cells, leading to a 7-fold expansion, which was significantly higher than the expansion of healthy progenitors with stromal vascular fraction. CONCLUSIONS: The use of stromal vascular fraction might be more beneficial to reconstructive operations following mastectomies compared with cosmetic corrections of the healthy breast. Future studies are required to examine the potential risk factors associated with its use. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Genetic profiling by single-nucleotide polymorphism-based array analysis defines three distinct subtypes of orbital meningioma.

Orbital meningiomas can be classified as primary optic nerve sheath (ON) meningiomas, primary intraorbital ectopic (Ob) meningiomas and spheno-orbital (Sph-Ob) meningiomas based on anatomic site. Single-nucleotide polymorphism (SNP)-based array analysis with the Illumina 300K platform was performed on formalin-fixed, paraffin-embedded tissue from 19 orbital meningiomas (5 ON, 4 Ob and 10 Sph-Ob meningiomas). Tumors were World Health Organization (WHO) grade I except for two grade II meningiomas, and one was NF2-associated. We found genomic alterations in 68% (13 of 19) of orbital meningiomas. Sph-Ob tumors frequently exhibited monosomy 22/22q loss (70%; 7/10) and deletion of chromosome 1p, 6q and 19p (50% each; 5/10). Among genetic alterations, loss of chromosome 1p and 6q were more frequent in clinically progressive tumors. Chromosome 22q loss also was detected in the majority of Ob meningiomas (75%; 3/4) but was infrequent in ON meningiomas (20%; 1/5). In general, Ob tumors had fewer chromosome alterations than Sph-Ob and ON tumors. Unlike Sph-Ob meningiomas, most of the Ob and ON meningiomas did not progress even after incomplete excision, although follow-up was limited in some cases. Our study suggests that ON, Ob and Sph-Ob meningiomas are three molecularly distinct entities. Our results also suggest that molecular subclassification may have prognostic implications.

Endophthalmitis: A review of recent trends.

Endophthalmitis is a feared complication of trauma, surgical procedures and septicemia. Although uncommon, its potential for significant visual loss is well recognized. Especially over the past decade, complicated surgeries and medical techniques have increased and seriously ill patients are being sustained in ever increasing numbers. New pathogens are being recognized and known ones reclassified thanks to advances in molecular analysis. Continuously evolving PCR methodologies also add a new dimension to the diagnosis of infectious endophthalmitis. As well, medical literature is now truly international, encompassing studies from around the world that expand our understanding of ocular infectious disease. This report reviews some of these changes as they relate to endophthalmitis and particularly to the spectrum of organisms involved.

Keeping an open mind about meningitis: a case report of carcinomatous meningitis.

Carcinomatous meningitis is defined as leptomeningeal infiltration by malignant cells. A case of carcinomatous meningitis, originally diagnosed as viral meningitis, is presented here to highlight the importance of maintaining a broad differential diagnosis in patients with evidence of meningeal irritation. Clinical and laboratory clues that suggest a diagnosis of carcinomatous meningitis in a patient with meningeal irritation include the presence and type of underlying malignancy (more common with breast cancer, lung cancer, and melanoma), absence of fever, presence of radicular pain, evidence of both cranial and spinal involvement, consistent cerebrospinal fluid (CSF) findings (increased opening pressure, elevated protein concentration, decreased glucose, increased white cell count), and supportive neuroimaging. Diagnosis is based on positive CSF cytology results, which may require multiple lumbar puncture procedures to obtain. For patients with a known primary malignancy who present to the emergency department with symptoms and/or signs of meningeal irritation, carcinomatous meningitis should be included in the differential diagnosis.