Breast implant-associated anaplastic large cell lymphoma: a review

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado.Breast implant-associated anaplastic large cell lymphoma is a newly recognized provisional entity in the 2017 revision of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. It is an uncommon, slow growing T-cell lymphoma with morphology and immunophenotype similar to anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. However, the presentation and treatment are unique. Breast implant-associated anaplastic large cell lymphoma often presents as a unilateral effusion confined to the capsule of a textured-surface breast implant, a median time of 9 years after the initial implants have been placed. Although it follows an indolent clinical course, breast implant-associated anaplastic large cell lymphoma has the potential to form a mass, to invade locally through the capsule into breast parenchyma or soft tissue and/or to spread to regional lymph nodes. In most cases, an explantation with a complete capsulectomy removing all disease, without chemotherapy is considered to be curative and confers an excellent event free and overall survival. Here we provide a comprehensive review of breast implant-associated anaplastic large cell lymphoma, including history, epidemiology, clinical features, imaging and pathology findings, pathologic handling, pathogenic mechanisms, model for progression, therapy and outcomes as well as an analysis of causality between breast implants and anaplastic large cell lymphoma.Revisión por pare

ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas

Anaplastic large cell lymphoma (ALCL) is a subtype of CD30+ large T-cell lymphoma (TCL) that comprises ~2% of all adult non-Hodgkin lymphomas. Based on the presence/absence of the rearrangement and expression of anaplastic lymphoma kinase (ALK), ALCL is divided into ALK+ and ALK-, and both differ clinically and prognostically. This review focuses on the historical points, clinical features, histopathology, differential diagnosis, and relevant cytogenetic and molecular alterations of ALK- ALCL and its subtypes: systemic, primary cutaneous (pc-ALCL), and breast implant-associated (BIA-ALCL). Recent studies have identified recurrent genetic alterations in this TCL. In systemic ALK- ALCL, rearrangements in DUSP22 and TP63 are detected in 30% and 8% of cases, respectively, while the remaining cases are negative for these rearrangements. A similar distribution of these rearrangements is seen in pc-ALCL, whereas none have been detected in BIA-ALCL. Additionally, systemic ALK- ALCL—apart from DUSP22-rearranged cases—harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway. The JAK1/3 and STAT3 mutations have also been identified in BIA-ALCL but not in pc-ALCL. Although the pathogenesis of these alterations is not fully understood, most of them have prognostic value and open the door to the use of potential targeted therapies for this subtype of TCL

Enhanced fungal specificity and in vivo therapeutic efficacy of a C-22-modified FK520 analog against C. neoformans

ABSTRACT Fungal infections are of mounting global concern, and the current limited treatment arsenal poses challenges when treating such infections. In particular, infections by Cryptococcus neoformans are associated with high mortality, emphasizing the need for novel therapeutic options. Calcineurin is a protein phosphatase that mediates fungal stress responses, and calcineurin inhibition by the natural product FK506 blocks C. neoformans growth at 37°C. Calcineurin is also required for pathogenesis. However, because calcineurin is conserved in humans and inhibition with FK506 results in immunosuppression, the use of FK506 as an anti-infective agent is precluded. We previously elucidated the structures of multiple fungal calcineurin-FK506-FKBP12 complexes and implicated the C-22 position on FK506 as a key point for differential modification of ligand inhibition of mammalian versus fungal target proteins. Through in vitro antifungal and immunosuppressive testing of FK520 (a natural analog of FK506) derivatives, we identified JH-FK-08 as a lead candidate for further antifungal development. JH-FK-08 exhibited significantly reduced immunosuppressive activity and both reduced fungal burden and prolonged survival of infected animals. JH-FK-08 exhibited additive activity in combination with fluconazole in vivo. These findings further advance calcineurin inhibition as an antifungal therapeutic approach. IMPORTANCE Fungal infections cause significant morbidity and mortality globally. The therapeutic armamentarium against these infections is limited, and the development of antifungal drugs has been hindered by the evolutionary conservation between fungi and the human host. With rising resistance to the current antifungal arsenal and an increasing at-risk population, there is an urgent need for the development of new antifungal compounds. The FK520 analogs described in this study display potent antifungal activity as a novel class of antifungals centered on modifying an existing orally active FDA-approved therapy. This research advances the development of much-needed newer antifungal treatment options with novel mechanisms of action

LAB-METABOLIC PATHWAYS

Glioblastoma continues to rank among the most lethal primary human tumors. Despite treatment with the most rigorous surgical, chemotherapeutic, and radiation regimens, the median survival is just 12-15 months after diagnosis for patients with glioblastoma. One feature of glioblastoma associated with poor prognosis is the degree of hypoxia and expression levels of hypoxia-inducible factor-1 α (HIF-1α). HIF-1α expression allows metabolic adaptation to low oxygen availability, partly through upregulation of vascular endothelial growth factor (VEGF) and increased tumor angiogenesis. In this study, we demonstrate an induced level of astrocyte-elevated gene-1 (AEG-1) in high-grade as compared to low-grade astrocytomas and association of AEG-1 with necrotic areas in glioblastoma. AEG-1 was recently demonstrated to be an oncogene that can induce angiogenesis in glioblastoma. Results from in vitro studies show that AEG-1 is induced by hypoxia in a HIF-1α-dependent manner and that PI3K inhibition abrogates AEG-1 induction during hypoxia. Furthermore, we show that AEG-1 is induced by glucose deprivation and that prevention of intracellular reactive oxygen species (ROS) accumulation prevents this induction. Additionally, AEG-1 knockdown results in increased, whereas AEG-1 overexpression results in decreased, ROS production and glucose deprivation-induced cytotoxicity, indicating that AEG-1 induction is necessary for cells to survive this type of stress. Moreover, AEG-1 modulates the expression of glycolytic enzymes in glioblastoma cells in vitro and in vivo and regulates the expression of these enzymes as well as glycolytic flux during metabolic stress, such as glucose deprivation. The AEG-1-induced glycolytic profile in glioblastoma cells is also modulated by glycolytic inhibition. Studies in nude mice demonstrate that AEG-1 knockdown reduces the growth of glioblastoma xenografts and also promotes chemosensitivity to glycolytic inhibition in vitro. These findings identify a novel role for AEG-1 in the regulation of glycolysis in glioblastoma and indicate that anti-glycolytic therapies may be useful in treating malignancies that demonstrate AEG-1-overexpression