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.

Peripheral nerves consist of 3 layers with differing characteristics: the endoneurium, perineurium, and epineurium. The perineurium represents a continuum with the pia-arachnoid from the central nervous system and extends distally with the sheath of capsular cells of peripheral sensorial organs and propioceptive receptors. It is made of layers of flattened cells surrounded by a basement membrane and collagen fibers, forming concentrically laminated structures around single nerve fascicles. Functionally, the perineurium modulates external stretching forces (that could be potentially harmful for nerve fibers), and along with endoneurial vessels, forms the blood-nerve barrier. Multiple pathologic conditions associated with the perineurium have been described. Perineurial invasion is considered an important prognostic factor in several malignant neoplasms. Perineuriomas are true benign infrequent perineurial cell neoplasms that have been divided in 2 categories: those with intraneural localization and a more common extraneural (soft tissue) group, including sclerosing and reticular variants. Sporadic cases of malignant perineuromas have been reported. Interestingly, neurofibromas and malignant peripheral nerve sheath tumors may also display perineurial cell differentiation. The histologic appearance of perineuriomas may overlap with other soft tissue spindle cell neoplasms. Immunohistochemistry is imperative for the diagnosis, although in certain cases ultrastructural studies may be needed. Typical perineuriomas are positive for epithelial membrane antigen, glucose transporter-1-1, and claudin-1, and negative for S-100 protein and neurofilaments. Perineuriomas have mostly simple karyotypes, with one or few chromosomal rearrangements or numerical changes and it seems that specific cytogenetic aberrations may correlate with perineurioma subtype.

Rosai-Dorfman disease is a histiocytic disorder with a poorly-defined pathogenesis. Recent molecular studies have revealed recurrent mutations involving genes in the MAPK/ERK pathway in Langerhans cell histiocytosis and Erdheim-Chester disease. However, cases of Rosai-Dorfman disease have rarely been assessed. We performed next-generation sequencing to assess 134 genes on 21 cases of Rosai-Dorfman disease, including 13 women and 8 men with a median age of 43 years (range, 3–82). Thirteen had extranodal, 5 had nodal, and 3 had coexistent nodal and extranodal disease. The head and neck region was the most common area involved (n=7). Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3). No mutations were identified in ARAF, BRAF, PIK3CA, or any other genes assessed. Immunohistochemistry demonstrated p-ERK overexpression in 3 cases, all harboring MAP2K1 mutations. Patients carrying mutated genes were younger (median age, 10 versus 53 years, p=0.0347) with more pediatric patients (4/7 versus 1/14, p=0.0251). The presence of mutations correlated with location being more common in the head and neck region; 6/7 (86%) mutated versus 1/14 (7%) unmutated cases (p=0.0009). All 5 (100%) mutated cases with available staging information had a multifocal presentation, whereas only 3/11 (27%) unmutated patients had multifocal disease (p=0.0256). Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3). With a median follow-up of 84 months (range, 7–352), 7 remained in clinical remission and 3 had persistent disease. No correlation between mutation status and clinical outcome was noted. In summary, we detected mutually exclusive KRAS and MAP2K1 mutations in one third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway. Our data contributes to the understanding of the biology of Rosai-Dorfman disease and points to potential diagnostic and therapeutic targets.

Objective. Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A 3 adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model.Methods. OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 g/kg given twice daily) was initiated. The A 3 adenosine receptor antagonist MRS1220 (100 g/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses.Results. CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-B signaling pathway, resulting in down-regulation of tumor necrosis factor ␣. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes.Conclusion. CF101 deregulated the NF-B signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.Osteoarthritis (OA) is the most common chronic joint disease. Articular cartilage is a major component of the joint, and its mechanical properties depend on the integrity of the extracellular matrix, which is composed mainly of proteoglycans and collagens. Degeneration of joint cartilage is the central feature in OA, but the disease is associated with concomitant changes in synovium and subchondral bone metabolism, causing inflammation of the synovial membrane in the involved joints (1).The cause of OA is multifactorial and includes both systemic and local biomechanical factors (2). Systemic factors that have been associated with OA include age, sex, race-and gene-based susceptibility, bone density, estrogen levels, and nutritional factors. OA results from the failure of chondrocytes that lie within the joint to synthesize a good-quality matrix and to maintain a balance between synthesis and degradation of the extracellular matrix. Synovial inflammation and local concentration of proinflammatory mediators seem to Supported by Can-Fite BioPharma.

MicroRNA-mediated regulation of gene expression appears to be involved in a variety of cellular processes, including development, differentiation, proliferation, and apoptosis. Mir-146a is thought to be involved in the regulation of the innate immune response, and its expression is increased in tissues associated with chronic inflammation. Among the predicted gene targets for mir-146a, the chemokine CCL8/MCP-2 is a ligand for the CCR5 chemokine receptor and a potent inhibitor of CD4/CCR5-mediated HIV-1 entry and replication. In the present study, we have analyzed changes in the expression of mir-146a in primary human fetal microglial cells upon infection with HIV-1 and found increased expression of mir-146a. We further show that CCL8/MCP-2 is a target for mir-146a in HIV-1 infected microglia, as overexpression of mir-146a prevented HIV-induced secretion of MCP-2 chemokine. The clinical relevance of our findings was evaluated in HIV-encephalitis (HIVE) brain samples in which decreased levels of MCP-2 and increased levels of mir-146a were observed, suggesting a role for mir-146a in the maintenance of HIV-mediated chronic inflammation of the brain.