BackgroundAngiosarcomas are tumors of malignant endothelial origin that have a poor prognosis with a five-year survival of less than 40%. These tumors can be found in all age groups, but are more common in older patients; with the cutaneous form most common in older white men. Combined modality therapy including surgery and radiation appears to have a better outcome than each modality alone. When metastatic, agents such as liposomal doxorubicin, paclitaxel and ifosfamide have activity but it is short-lived and not curative. Immunotherapy targeting either the PD-1 receptor or PD-L1 ligand has recently been shown to have activity in multiple cancers including melanoma, renal, and non-small lung cancer. Although these agents have been used in sarcoma therapy, their ability to treat angiosarcoma has not been reported.Case presentationHere we describe the case of a 63-year-old man who presented initially with angiosarcoma of the nose and received surgery for the primary. Over 4 years he had recurrent disease in the face and liver and was treated with nab-paclitaxel, surgery, and radioembolization, but continued to have progressive disease. His tumor was found to express PD-L1 and he received off-label pembrolizumab 2 mg/kg every 21 days for 13 cycles with marked shrinkage of his liver disease and no new facial lesions. Secondary to this therapy he developed hepatitis and has been treated with decreasing doses of prednisone. During the 8 months off therapy he has developed no new or progressive lesions.ConclusionsAlthough occasional responses to immunotherapy have been reported for sarcomas, this case report demonstrates that angiosarcoma can express PD-L1 and have a sustained response to PD-1 directed therapy.
IntroductionKit is a member of the type III subclass of receptor tyrosine kinase (RTK), which also includes the platelet-derived growth factor receptors (PDGFRs) ␣ and , Flt3, and the CSF1R (c-fms, macrophage colony-stimulating factor receptor [M-CSFR]). The Kit protein is organized as an N-terminal extracellular domain containing 5 Ig-like domains, a transmembrane domain, and a cytoplasmic domain. The cytoplasmic domain contains a split catalytic domain, which is activated by ligand-mediated receptor dimerization. Loss-of-function mutations of Kit in mice result in the dominant W spotting defect, which is marked by defective pigmentation, hematopoiesis, and gametogenesis. 1,2 The severity of the phenotype of W mice is related to the degree of loss of Kit expression and function. Kit ligand (KL) is produced by stromal cells in either membrane-bound or soluble isoforms. 3 Loss-offunction mutations of the KL locus result in the Steel (Sl) phenotype closely resembling that of W mouse strains. 4 Oncogenic Kit can broadly be categorized as caused by mutations in the juxtamembrane region that cause ligandindependent dimerization (dimerizing mutants), or mutations in the carboxyl-terminal segment of the kinase domain that cause constitutive enzymatic activity (catalytic mutants). 5 Dimerizing mutants have been observed in gastro-intestinal stromal tumors (GISTs), a rare malignancy of mesenchymal cells in the gut. 6 A mouse model of a GIST demonstrated that constitutive Kit signaling through a dimerizing mutant is necessary and sufficient for hyperplasia of interstitial cells of Cajal and induction of a GIST. 7 Catalytic Kit mutants have been more commonly associated with mastocytosis. 8 Treatment of GISTs has been significantly improved by the introduction of imatinib-mesylate (referred to hereon as imatinib), 9 a small molecule inhibitor of Kit tyrosine kinase activity 10 that was originally developed as an inhibitor of the tyrosine kinase activity of the Bcr-Abl fusion oncogene in chronic myelogenous leukemia (CML). 11 However, only Kit-dimerizing mutants are broadly responsive to imatinib and, as observed in CML, the development of imatinib resistance in GIST patients is a serious problem and requires further therapeutic improvement, eg, combination with other tyrosine kinase inhibitors. 12 Among the various signaling pathways activated by wild-type Kit, the Src family kinase (SFK) and phosphatidylinositol 3-kinase (PI3-K) pathways have been studied in vivo by murine knock-in models. In vitro, SFKs have been shown to be necessary for Kit-mediated proliferation and chemotaxis. 13 Kit-mediated activation of SFKs regulates early lymphopoiesis. 14 On the other hand, gametogenesis was shown in vivo to depend on Kit-mediated activation of PI3-K. 15 Oncogenic Kit resembles signaling through wild-type Kit in that SFKs and PI3-K are both activated, the latter having been shown to be necessary for cellular transformation by catalytic Kit mutants. 16 For other pathways, there appear to be certain differences in substrate spec...
Systemic therapy plays an important role in both the definitive and palliative management of patients with HNSCC. The cornerstone for curative-intent management and organpreservation strategies remains cisplatin chemotherapy, irrespective of HPV status. Deintensification strategies are sought in good-risk HPV-positive patients, with the hypothesis that intensive multimodality regimens developed during the era of HPV-negative disease may represent overtreatment. In the setting of recurrent, metastatic HNSCC, 2 anti-PD1 monoclonal antibodies have been FDA approved in the platinum-refractory setting. New insights into the biology of immune escape by HNSCC have resulted in priority clinical trials adding immunotherapy to conventional CRT in high-risk patients. Advances in palliative and supportive care also aid the multidisciplinary team in assessing risk and benefit, communicating treatment options, managing the unique symptom burden, and comforting both patients and caregivers during the HNSCC journey.
In vivo analyses of thymopoiesis in mice defective in signaling through Kit and gammac or Kit and IL-7Ralpha demonstrate synergy and partial complementation of gammac or IL-7-mediated signaling by the Kit signaling pathway. Our molecular analysis in T-lymphoid cells as well as in nonhematopoietic cells shows that Kit and IL-7R signaling pathways directly interact. KL-mediated activation of Kit induced strong tyrosine phosphorylation of gammac and IL-7Ralpha in the absence of IL-7. Activated Kit formed a complex with either IL-7Ralpha or gammac, and tyrosine phosphorylation of both subunits occurred independently of Jak3, suggesting that gammac and IL-7Ralpha are each direct substrates of Kit. Kit activated Jak3 in an IL-7R-dependent manner. Moreover, deficient Stat5 activation of the Kit mutant YY567/569FF lacking intrinsic Src activation capacity was partially reconstituted in the presence of IL-7R and Jak3. Based on the molecular data, we propose a model of Kit-mediated functional activation of gammac-containing receptors such as IL-7R, similar to the interaction between Kit and Epo-R. Such indirect activation of the Jak-Stat pathway induced by the interaction between an RTK and type I cytokine receptor could be the underlying mechanism for a context-specific signaling repertoire of a pleiotropic RTK-like Kit.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.