Segmental arterial mediolysis (SAM) is a rare but serious nonatherosclerotic, noninflammatory vasculopathy of unknown etiology that often results in dissection, aneurysm, occlusion, or stenosis of, primarily, the abdominal arteries. Current literature lacks consensus on diagnostic criteria and management options for SAM. This review summarizes 143 cases and aims to advance appropriate recognition and management of SAM. Literature review of all relevant SAM case studies from 2005 to 2018 yielded 126 individual SAM cases from 66 reports. We identified 17 additional SAM cases from our center, bringing our analysis to 143 patients. Patients with SAM were most commonly men (68%) in their 60s. Hypertension (43%), tobacco use (12%), and hyperlipidemia (12%) were common comorbidities. Abdominal pain (80%) and intraabdominal bleeding (50%) were the most common presenting symptoms. Computed tomography was the most frequently used imaging method (78%), and histology was available in 44% of cases. The most commonly affected vessels were the superior mesenteric (53%), hepatic (45%), celiac (36%), renal (26%), and splenic (25%) arteries with aneurysm (76%), dissection (61%), and arterial rupture (46%). Treatments included coil embolization (28%), abdominal organ surgery (24%), open arterial repair (21%), and medical management (20%). Case-specific treatment modalities yielded symptom relief in the vast majority (91%) of patients, with a mortality rate of 7%.

The investigators present their analysis of primary cells from patients with human T-cell leukemia virus 1–associated adult T-cell leukemia/lymphoma treated in a phase 2 clinical trial with nivolumab to elucidate mechanisms of hyperprogression that halted the trial after just 3 patients received a single treatment.

The human T-cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, probably as a result of specific immunoediting, Tax expression is down-regulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL., K59R is the most common single-nucleotide variation of IRF4 and is found exclusively in ATL. High-throughput whole-exome sequencing revealed recurrent activating genetic alterations in the T-cell receptor, CD28, and NF-κB pathways. We found that IRF4, which is transcriptionally activated downstream of these pathways, is frequently mutated in ATL. IRF4 RNA, protein, and IRF4 transcriptional targets are uniformly elevated in HTLV-1-transformed cells and ATL cell lines, and IRF4 was bound to genomic regulatory DNA of many of these transcriptional targets in HTLV-1-transformed cell lines. We further noted that the K59R IRF4 mutant is expressed at higher levels in the nucleus than WT IRF4 and is transcriptionally more active. Expression of both WT and the K59R mutant of IRF4 from a constitutive promoter in retrovirally transduced murine bone marrow cells increased the abundance of T lymphocytes but not myeloid cells or B lymphocytes in mice. IRF4 may represent a therapeutic target in ATL because ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and overexpression of IRF4 induces the expansion of T lymphocytes .

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Background Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo. Results ATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo . To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo , transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and β, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2. Conclusions These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.