An Unusual Etiology of Lemierre-Like Syndrome: Preseptal Cellulitis due to Methicillin-Resistant Staphylococcus aureus.

Lemierre's syndrome (LS) is a rare and potentially fatal condition that predominantly affects young adults with oropharyngeal infection. Fusobacterium necrophorum is the usual etiology and classically causes internal jugular vein septic thrombophlebitis, frequently complicated by septic emboli to several organs (most classically to the lungs). Lemierre-like syndrome (LLS) describes the same constellation of symptoms and pathophysiology as Lemierre's syndrome; however, Fusobacterium spp. are not the cause, and the source of infection may be nonoropharyngeal. We present a case with an unusual etiology of LLS: a patient with untreated preseptal cellulitis and associated methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in the setting of injection drug use. Physical exam revealed tachypnea and rhonchi with severe periorbital and bilateral eyelid edema. Imaging demonstrated bilateral preseptal and orbital cellulitis with thrombosis of both internal jugular veins and bilateral pulmonary cavitary lesions consistent with septic pulmonary emboli. She was managed with anticoagulation and parenteral antibiotics. To our knowledge, this is the first case of LLS originating from preseptal cellulitis without evidence of preceding pharyngitis. While facial and orbital infections are rare etiologies of LLS, the potentially devastating sequelae of LLS warrant its inclusion in differential diagnoses.

ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas.

ERBB3, a member of the EGFR family of receptor tyrosine kinases, has been implicated in activation of the PI3K pathway in human lung adenocarcinomas driven by EGFR mutations. We investigated the contribution of ERBB3 to the initiation, progression, and therapeutic response of EGFR-induced lung adenocarcinomas using tetracycline- and tamoxifen-inducible transgenic mouse models. Deletion of Erbb3 at the time of induction of mutant EGFR had no effect on tumorigenesis, demonstrating that ERBB3 is not required to initiate tumorigenesis. Tumors that developed in the absence of ERBB3 remained sensitive to EGFR tyrosine kinase inhibitors and retained activation of the PI3K-AKT pathway. Interestingly, acute loss of Erbb3 suppressed further growth of established EGFR(L858R)-mediated lung tumors. Four weeks after deletion of Erbb3, the tumors exhibited phosphorylation of EGFR, of the adaptor proteins GAB1 and GAB2, and of the downstream signaling molecules AKT and ERK, suggesting that alternative signaling pathways could compensate for loss of Erbb3. Similar to our observations with mouse tumors, we found that GAB adaptor proteins play a role in ERBB3-independent activation of the PI3K pathway by mutant EGFR in EGFR-mutant human cell lines. Finally, in such cell lines, increased levels of phosphorylation of ERBB2 or MET were associated with reduced sensitivity to acute loss of ERBB3, suggesting remarkable plasticity in the signaling pathways regulated by mutant EGFR with important therapeutic implications.

Isolation of epithelial, endothelial, and immune cells from lungs of transgenic mice with oncogene-induced lung adenocarcinomas.

Genetically engineered mouse models of lung adenocarcinoma have proven invaluable for understanding mechanisms of tumorigenesis, therapy response, and drug resistance. However, mechanistic studies focused on studying these processes in tumor-bearing mouse lungs are confounded by the fact that, in most cases, relevant signaling pathways are analyzed in whole-lung preparations, which are composed of a heterogeneous mixture of cells. Given our increasing knowledge about the roles played by different subpopulations of cells in the development of lung adenocarcinoma, separating the major cellular compartments of the tumor microenvironment is recommended to allow for a precise analysis of relevant pathways in each isolated cell type. In this study, we optimized magnetic- and fluorescence-based isolation protocols to segregate lung epithelial (CD326/epithelial cell adhesion molecule-positive), endothelial (CD31-positive), and immune (CD45-positive) cells, with high purity, from the lungs of transgenic mice with mutant epidermal growth factor receptor-induced lung adenocarcinomas. This approach, which can potentially be extended to additional lung adenocarcinoma models, enables delineation of the molecular features of individual cell types that can be used to gain insight into their roles in lung adenocarcinoma initiation, progression, and response to therapy.