Immune checkpoint CD155 promoter methylation profiling reveals cancer-associated behaviors within breast neoplasia.

BACKGROUND: CD155 immune checkpoint has recently emerged as a compelling immunotherapeutic target. Epigenetic DNA methylation changes are recognized as key molecular mechanisms in cancer development. Hence, the identification of methylation markers that are sensitive and specific for breast cancer may improve early detection and predict prognosis. We speculate that CD155 promoter methylation can be a valuable epigenetic biomarker, based upon strong indications for its immunoregulatory functions. METHODS: Methylation analyses were conducted on 14 CpGs sites in the CD155 promoter region by bisulfite pyrosequencing. To elucidate the related gene expression changes, a transcriptional study using RT-qPCR was performed. Statistical analyses were performed to evaluate correlations of CD155 methylation profiles with mRNA expression together with clinical-pathological features, prognosis and immune infiltrate. RESULTS: CD155 promoter methylation profile was significantly associated with SBR grade, tumor size, molecular subgroups, HER2 and hormonal receptors expression status. Low CD155 methylation rates correlated with better prognosis in univariate cox proportional hazard analysis and appeared as an independent survival predictor in cox-regression multivariate analysis. Further, methylation changes at CD155 specific CpG sites were consistent with CD155 membranous mRNA isoform expression status. Statistical analyses also showed a significant association with immune Natural Killer cell infiltrate when looking at the CpG7, CpG8, CpG9 and CpG11 sites. CONCLUSION: Altogether, our results contribute to a better understanding of the impact of CD155 immune checkpoint modality expression in breast tumors, revealing for the first time that specific CpG sites from CD155 promoter may be a potential biomarker in breast cancer monitoring.

Hyperreactio luteinalis incidentally found in the second trimester of pregnancy with normal hCG levels: a case report.

Hyperreactio luteinalis (HL) is a rare entity in which both ovaries are multicystic and enlarged under the action of human chorionic gonadotropin (hCG), mostly seen in the third trimester of pregnancy. This benign condition is usually asymptomatic and doesn't need any specific treatment, as the ovaries spontaneously reduce in size after birth. This is a case report of a 33-year-old woman diagnosed with hyperreactio luteinalis during the second trimester of her induced pregnancy. An ultrasound scan at 22 weeks of gestation revealed bilateral multicystic enlarged ovaries along with multiple fetal malformations and hydropsfetalis. Usually, HL is most commonly seen in situations in which there are high levels of hCG, but our patient had normal levels of hCG during all her pregnancy, which makes our case even rarer. In conclusion, the most important challenge when faced with HL is to differentiate between it and other differential diagnosis especially malignant tumors, because unlike them, this benign condition doesn't need surgical treatment.

Immune checkpoint molecules B7-H6 and PD-L1 co-pattern the tumor inflammatory microenvironment in human breast cancer.

B7-H6 and PD-L1 belong to the B7 family co-stimulatory molecules fine-tuning the immune response. The present work investigates the clinical effect of B7-H6 protein expression with PD-L1 status and the infiltration of natural killer cells as potential biomarkers in breast tumor inflammatory microenvironment. The expression levels of B7-H6 protein by cancer cells and immune infiltrating cells in human breast cancer tissues and evaluate their associations with PD-L1 expression, NK cell status, clinical pathological features and prognosis were explored. The immunohistochemistry labeling method was used to assess B7-H6 and PD-L1 proteins expression by cancer and immune cells. The associations between immune checkpoint, major clinical pathological variables and survival rates were analyzed. B7-H6 protein was depicted in both breast and immune cells. Results showed that Tumor B7-H6 expression is highly associated with Her-2 over expression. B7-H6 + immune cells are highly related to the Scarff-Bloom-Richardson grade and associated with PD-L1 expression and NK cells status. Survival analysis revealed a better prognosis in patients with low expression of B7-H6 by cancer cells. Conversely, B7-H6 + immune cells were significantly associated with longer survival. Findings strongly suggest an interaction between B7 molecules that contributes to a particular design of the inflammatory microenvironment. This may influence the efficiency of therapies based on antibodies blocking the PD-L1/PD1 pathway and can explain the detection of clinical benefits only in a fraction of patients treated with immune checkpoint inhibitors.

CD155 expression in human breast cancer: Clinical significance and relevance to natural killer cell infiltration.

AIMS: CD155 is a ligand of the NK activating receptor DNAM-1, it has been described in a variety of human malignancies, but its expression in breast cancer remains unclear and poorly studied. MAIN METHODS: CD155 expression and NK cells infiltration were investigated in 158 patients with breast cancer by immunohistochemistry (IHC). Statistical analyses were performed to evaluate correlations of CD155 expression with clinical-pathological features, prognosis and tumor immunity. KEY FINDINGS: Tumor cytoplasmic CD155 (cyt-CD155) was associated with lymphovascular invasion (p = 0.011), and membranous CD155 (m-CD155) was strongly correlated with the presence of Tumor Infiltrating natural killer cells (NK-TILs) (p = 0.0003). Survival analysis demonstrated that patients with high cyt-CD155 had a significantly worse overall survival (p < 0.001) and death free survival (p = 0.014) than those with low expression, while high levels of m-CD155 correlated with a better prognosis (p = 0.037). Furthermore, we found that patients with m-CD155Low/NKLow tumors had a significantly reduced overall survival (p = 0.012). Multivariate analysis showed that positive tumor m-CD155 status was a significant independent marker of good prognosis. Meanwhile, high cyt-CD155 expression was identified as an independent poor prognostic predictor, suggesting a key role in this malignancy. SIGNIFICANCE: Altogether, our results revealed that cyt-CD155 was associated with invasiveness and poorer prognosis, but the concomitant presence of m-CD155 and NK-TILs had an opposite prognostic relevance in breast cancer. These results raised the importance of CD155 IHC analysis to elucidate biomarker localization, leading to better understand and design therapeutic molecule targeting CD155 in breast tumors.

The prognostic significance of pathological features in Her-2 overexpressing breast carcinomas: A single institution experience in southern Tunisia.

BACKGROUND: Breast cancer is the most frequent malignant neoplasm affecting Tunisian women. It represents 25 to 35% of all female cancers. There is no published study about the features of Her-2 overexpressing breast carcinomas in North African women. OBJECTIVE: The aim of this study is to assess the prognostic significance of pathological features in a cohort of a Her-2 overexpressing breast carcinoma originating from the region of south Tunisia. METHODS: This study investigated a series of 100 patients followed from January 2006 to December 2011 for a Her-2 positive invasive breast carcinoma. Pathological features included in this study were: histological type, histological grade, tumor size, vascular invasion, perineural invasion, mitotic index, lymph nodes stage, positive lymph node capsular effraction, inflammatory infiltrates, nipple involvement and hormone receptors status. RESULTS: Multivariate analysis showed that pT stage, pN stage, capsular effraction, vascular invasion, perineural invasion and Nipple involvement were independent prognostic factors for overall survival and disease free survival in patients free from distant metastasis at diagnosis. For patients with synchronous metastasis, there is no independent pathologic prognostic factor for survival. CONCLUSIONS: Our study demonstrates that pathological features are important prognostic factors for non metastatic Her-2 overexpressing breast carcinomas. This supports the idea that HER2-positive disease is a heterogeneous entity. We believe that these findings reinforce the need to identify molecular predictors of benefit and resistance to anti-Her-2 based therapies.

Bilateral atrophic squirrhus of breast in neglected breast cancer: case report.

The atrophic squirrhus carcinoma is an advanced form of breast cancer, which is most often neglected by patients. These days it has become very rare. The bilaterality of this form is even more exceptional. We present a case of atrophic squirrhus breast cancer of a 58 years old woman, rural origin, which is particular for its bilaterality and rapid evolution causing the death after 22 months from the first abnormal functional sign.

Mammary neuroendocrine carcinoma with mucinous differentiation: a clinicopathological study of 15 cases.

BACKGROUND: Mammary neuroendocrine carcinoma (NEC) displays morphological features including mucinous type. OBJECTIVE: To describe clinicopathological of NEC with mucinous differentiation. METHODS: A total of 15 cases of mammary NEC with mucinous differentiation were reviewed. RESULTS: All patients in this study were women aged from 37 to 78 year olds (median 68.1 years). The tumors ranged in size from 1.2 cm to 16 cm (mean 3.74 cm). The amount of extracellular mucin varied from 10% to 90%. Histological grade was I in 7 cases and II in 8 cases. Immunohistochemically, estrogen receptor (ER) and progesteron receptor (PR) were expressed in 12 and 14 cases, respectively. All tumors were negative for Her-2. Ki-67 proliferative index was lesser than 1% in all cases and no cases had demonstrated p53 overexpression. Three patients died of disease with a follow-up of 3 to 6 months. One patient was alive with metastasis at 96 months. Ten patients were disease free (follow-up range from 15 to 125 months). CONCLUSIONS: Mammary NEC with mucinous differentiation affects mostly older women. All tumors were low grade and immunoreactive for ER/PR and negative for Her-2. Mammary NEC with mucinous differentiation seems associated with well survival parameters.

[Exploration of post-menopausal uterine bleeding. Hysteroscopy-histology correlation in 94 cases]. / Exploration des métrorragies postménopausiques par hystéroscopie : à propos de 94 cas.

INTRODUCTION: Post-menopausal uterine bleeding is the reason for nearly 70% of gynaecological consultations. Because the cause may be a malignant disease, a thorough work-up is necessary to attempt to identify an organic cause. PATIENTS AND METHODS: This retrospective study examined 94 cases of post-menopausal bleeding in which both a hysteroscopic and a histological examination were performed in the gynaecology and obstetrics department of the Hedi Chaker University of Sfax from 1 January 2004 to 28 February 2005. We examined correlations between the hysteroscopy and histology findings as well as the causes determined. RESULTS: By hysteroscopy, we observed atrophic uterine linings in 53 patients (56%), endometrial polyps in 43 patients (45%), endometrial hyperplasia in 23 patients (24%) and myomas in 24 patients (25.5%). This examination suggested malignancy in 12 patients, among 6 of whom endometrial cancer was confirmed histologically. The sensitivity and specificity of hysteroscopy were relatively poor for the diagnosis of endometrial atrophy (about 48.7% and 68.5%), acceptable for endometrial polyps (75% and 86.6%), endometrial hyperplasia (64.7% and 85.5%), and endometrial cancer (60% and 92.7%). CONCLUSION: Hysteroscopy is the most reliable technique for exploration, offering a direct view of the uterine cavity and allowing direct biopsy. Its sensitivity varies according to the indication and diagnosis and is sometimes very good. However, histology remains the reference examination for diagnosis of the cause of post-menopausal uterine bleeding.

[Tubo-ovarian actinomycosis. A report of two cases and literature review]. / L'actinomycose tubo-ovarienne. A propos de deux cas et revue de la littérature.

Actinomycosis is an infection due to an anaerobic Gram-positive bacilus bacteria: Actinomyces. Tubo-ovarian locallisation is rare. It more often appears clinically as a pseudo-tumoral and feverish syndrom, evoking wrongly a malignant tumoral pathology, and often leads to a mutilating surgical treatment. Intra-uterine device appears as the principal favorable factor of this pathology. Basing on two cases reported by the authors, and after literature review, physiopathology, clinical and paraclinical expression, and treatment of this affection are discussed. A set up is made.