Pi3k/Akt/Mtor Pathway Activity Is Increased in Lymph Node Tissue from Idiopathic Multicentric Castleman Disease Patients with Tafro Syndrome

Autor: Dale Kobrin, Dustin Shilling, David C. Fajgenbaum
Rok vydání: 2018
Předmět:
Zdroj: Blood. 132:1121-1121
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2018-99-118434
Popis: Castleman disease (CD) describes a group of heterogeneous diseases defined by shared lymph node histopathology, including atrophic or hyperplastic germinal centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, and/or polytypic plasmacytosis. Unicentric CD (UCD) involves a solitary enlarged lymph node that displays CD histopathology, and patients rarely experience systemic symptoms. In contrast, multicentric CD (MCD) involves multiple regions of enlarged lymph nodes, systemic inflammation, cytopenias, and vital organ dysfunction due to a cytokine storm often including interleukin-6. MCD is caused by uncontrolled infection with Kaposi sarcoma-associated/human herpesvirus-8 (HHV-8) in ~50% of cases. The etiology of the remaining HHV-8-negative MCD cases is idiopathic (iMCD). In iMCD patients, blockade of IL-6 signaling with siltuximab, the only FDA-approved iMCD treatment, induced responses in 34% of cases in the phase II registrational trial. The large proportion of non-responders suggest that alternative pathways are responsible for driving disease pathogenesis in some patients. For these individuals, identification of molecular and cellular abnormalities for therapeutic targeting is urgently needed, particularly for those with the most severe clinical presentations. In fact, a clinical subgroup of iMCD was recently described with a very severe presentation: thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO). We previously reported increased phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling--a central pathway downstream of multiple cell surface receptors, implicated in both autoimmune and oncologic disorders--in a treatment refractory iMCD-TAFRO case that experienced an extended remission on treatment with an mTOR inhibitor. To extend these findings, herein we report immunohistochemistry for phosphorylated ribosomal protein S6 (phospho-S6), a marker of mTOR activation, in lymph node tissue from additional iMCD-TAFRO cases (n=10) and sentinel lymph nodes from breast cancer patients without evidence of metastasis (n=5). Anti-phospho-S6 (Ser235/236, Clone D57.2.2E) was used following standard protocols, and Aperio ImageScope and Image Analysis Toolkit software (color deconvolution v9 algorithm) were used to quantify pixel staining intensity in the germinal center, mantle zone, follicular and interfollicular regions. This analysis identified an increased number of pixels staining weak, medium, and strong for phospho-S6 in the interfollicular region of iMCD-TAFRO cases (p Disclosures Fajgenbaum: Janssen Pharmaceuticals, Inc.: Research Funding.
Databáze: OpenAIRE
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