Kikuchi-Fujimoto disease (KFD) is a rare entity characterized by subacute necrotizing lymphadenopathy and frequently associated with fever. Young adults of Asian ancestry are most commonly affected, but it has been reported worldwide. Despite many studies in the literature, the cause of KFD remains uncertain. Histologically, KFD is characterized by paracortical lymph node expansion with patchy, well-circumscribed areas of necrosis showing abundant karyorrhectic nuclear debris and absence of neutrophils and eosinophils. Three evolving histologic patterns—proliferative, necrotizing, and xanthomatous—have been recognized. By immunohistochemistry, histiocytes in KFD are positive for myeloperoxidase. There is a marked predominance of T cells in the lesions (with mostly CD8-positive cells) with very few B cells. The differential diagnosis of KFD includes infectious lymphadenitis, autoimmune lymphadenopathy (primarily systemic lupus erythematosus), and lymphoma. Clinicians and pathologists are poorly familiar with this entity, which frequently causes significant diagnostic challenges.

They have also served as consultants for Kura Oncology, have equity ownership in the company, and are coinventors (along with SK, TW, LS, and PR) on patent applications covering MI-3454 (PCT/US2017/022535). PR is an employee of Kura Oncology, Inc. and has a significant ownership interest in the parent of Wellspring Biosciences, Inc. FB is an employee of Kura Oncology, Inc. Kura Oncology, Inc. and the University of Michigan have filed patent applications covering MI-3454 and they hold intellectual property rights on this compound. OAW has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, and has received prior research funding from H3B Biomedicine unrelated to the current manuscript. MG receives research support from Cellectis and serves as a consultant in SeqRx.

We examined the associations of Epstein-Barr virus (EBV) status with characteristics and outcomes of post-transplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ transplant recipients diagnosed with PTLD between 1990 and 2013 [58 (33%) EBV-negative; 118 (67%) EBV-positive]. The proportion of EBV-negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (P<.001). EBV-negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high-risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV-positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; P=.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV-negative versus EBV-positive PTLD including when therapy was reduction of immunosuppression alone (35% vs 43% respectively, P= .60) or rituximab (43% vs 47%, P=1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; P=.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV-negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV-negative PTLD.

After a meal, insulin suppresses lipolysis through the activation of its downstream kinase, Akt, resulting in the inhibition of protein kinase A (PKA), the main positive effector of lipolysis. During insulin resistance, this process is ineffective, leading to a characteristic dyslipidemia and the worsening of impaired insulin action and obesity. Here, we describe a noncanonical Akt-independent, phosphoinositide-3 kinase (PI3K)-dependent pathway that regulates adipocyte lipolysis using restricted subcellular signaling. This pathway selectively alters the PKA phosphorylation of its major lipid droplet-associated substrate, perilipin. In contrast, the phosphorylation of another PKA substrate, hormone-sensitive lipase (HSL), remains Akt dependent. Furthermore, insulin regulates total PKA activity in an Akt-dependent manner. These findings indicate that localized changes in insulin action are responsible for the differential phosphorylation of PKA substrates. Thus, we identify a pathway by which insulin regulates lipolysis through the spatially compartmentalized modulation of PKA.

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