Personalized treatment in metastatic triple‐negative breast cancer: The outlook in 2020

Compared with other breast cancer subtypes, patients with triple‐negative breast cancer (TNBC), and irrespective to their disease stage, were always recognized to have the worst overall survival data. Although this does not seem different at the present time, yet the last few years have witnessed many breakthrough genomic and molecular findings, that could dramatically improve our understanding of the biological complexity of TNBC. Based on genomic analyses, it was consistently evident that TNBC comprises a heterogeneous group of cancers, which have numerous diverse molecular aberrations. This—in return—has provided a platform for a new generation of clinical trials using many innovative therapies, directed against such novel targets. At the present time, two PARP inhibitors and one anti‐PD‐L1 monoclonal antibody (in combination with chemotherapy) have been approved in certain subpopulations of metastatic TNBC (mTNBC) patients, which have finally brought this disease into the era of personalized medicine. In the current review, we will explore the genomic landscape of TNBC, through which many actionable targets were graduated. We will also discuss the results of the key—practice changing—clinical studies, and some upcoming personalized treatment options for patients with mTNBC, that may be clinically adopted in the near future.     

Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors

Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Stat5 has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a growth factor whose local production is also increased in high-grade prostate cancers. The first aim of this study was to use prostate-specific PRL transgenic mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1–positive cells identified as a stem/progenitor-like subpopulation. Because basal epithelial stem cells are proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a previously unexplored therapeutic target. Using a double-transgenic approach, we show that Δ1–9-G129R-hPRL, a competitive PRL-receptor antagonist, prevented early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal-cell pattern, and frequency or grade of intraepithelial neoplasia. This study identifies PRL receptor/Stat5 as a unique pathway, initiating prostate tumorogenesis by altering basal-/stem-like cell subpopulations, and strongly supports the importance of further developing strategies to target locally overexpressed PRL in human prostate cancer.     

Inflammatory pseudotumor of the spleen: two case reports

Inflammatory pseudotumor (IPT) of the spleen is an uncommon entity with debated etiology, characterized by a mixture of inflammatory cells and a component of myofibroblastic spindle cells. This lesion needs to be distinguished from the follicular dendritic cell tumor and the inflammatory myofibroblastic tumor. We report two cases of splenic PTI in a 69-year old and a 62-year old women. The tumors measured respectively 80 and 30 mn in greatest dimension. An inflammatory pseudotumor was histopathologically diagnosed following a splenectomy.     

Polarized expression of cystic fibrosis transmembrane conductance regulator and associated epithelial proteins during the regeneration of human airway surface epithelium in three-dimensional culture

We have previously shown that, in normal human airway tissue, localization of the cystic fibrosis transmembrane conductance regulator (CFTR) can be affected by epithelial maturation, polarity, and differentiation and that CFTR trafficking and apical localization depend on the integrity of the airway epithelium. In this study, we addressed the question of whether the three-dimensional (3-D) organization of adult human airway epithelial cells in suspension culture under rotation, leading to spheroid-like structures, could mimic the in vivo phenomenon of differentiation and polarization. The kinetics of the differentiation, polarity, and formation of the CFTR-ZO-1-ezrin complex was analyzed by transmission, scanning, and immunofluorescence microscopy. Functional activity of the airway surface epithelium was assessed by monitoring the degree of cAMP-stimulated chloride efflux from cultured cells. Our results show that after the initial step of dedifferentiation, characterized by a loss of ciliated cells and disappearance of epithelial subapical CFTR-ezrin-ZO-1 complex, the isolated cells formed 3-D spheroid structures within 24 hours. After 15 days, progressive ciliogenesis was observed and secretory cells could be identified. After 35 days of 3-D culture, ZO-1, CFTR, ezrin, and CD59 were apically or subapically located, and well-differentiated secretory and ciliated cells were identified. CFTR functionality was assessed by analyzing the Cl(-) secretion after amiloride and forskolin perfusion. After 35 days of culture of spheroids in suspension, a significant increase in Cl(-) efflux was observed in well-differentiated ciliated cells.     

Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North‐African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi‐allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North‐African patients. This mutation is estimated to date back at least 1,400–1,750 years ago. The identification of this major allele allowed us to suggest a cost‐effective genetic diagnostic strategy in North‐African patients with PCD.     

Endometrial atypical complex hyperplasia with extensive squamous metaplasia: two cases

We report two cases of endometrial atypical complex hyperplasia with an extensive squamous hyperplasia occurring in two women aged 48 and 31 years old. The histological study showed an increase in the gland to stroma ratio with a false crowding aspect due to an extensive area of squamous metaplasia; some metaplastic areas were centered by necrosis. There was glandular cytologic atypia. Histologic examination is necessary to confirm the diagnosis and to definitively rule out adenocarcinoma.     

A new automatic image analysis method for assessing estrogen receptors’ status in breast tissue specimens

Manual assessment of estrogen receptors′ (ER) status from breast tissue microscopy images is a subjective, time consuming and error prone process. Automatic image analysis methods offer the possibility to obtain consistent, objective and rapid diagnoses of histopathology specimens. In breast cancer biopsies immunohistochemically (IHC) stained for ER, cancer cell nuclei present a large variety in their characteristics that bring various difficulties for traditional image analysis methods. In this paper, we propose a new automatic method to perform both segmentation and classification of breast cell nuclei in order to give quantitative assessment and uniform indicators of IHC staining that will help pathologists in their diagnostic. Firstly, a color geometric active contour model incorporating a spatial fuzzy clustering algorithm is proposed to detect the contours of all cell nuclei in the image. Secondly, overlapping and touching nuclei are separated using an improved watershed algorithm based on a concave vertex graph. Finally, to identify positive and negative stained nuclei, all the segmented nuclei are classified into five categories according to their staining intensity and morphological features using a trained multilayer neural network combined with Fisher's linear discriminant preprocessing. The proposed method is tested on a large dataset containing several breast tissue images with different levels of malignancy. The experimental results show high agreement between the results of the method and ground-truth from the pathologist panel. Furthermore, a comparative study versus existing techniques is presented in order to demonstrate the efficiency and the superiority of the proposed method.