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Novel Protocol for Generating Physiologic Immunogenic Dendritic Cells

Extracorporeal photochemotherapy (ECP) is a widely used cancer immunotherapy for cutaneous T cell lymphoma (CTCL), operative in over 350 university ...

Yale University School of Medicine

Metopic synostosis is characterized by trigonocephaly, lateral supraorbital retrusion, and hypotelorism. Most phenotypic evaluations have focused on the forehead without much emphasis on the orbits. The study seeks to explore differences in orbital dysmorphology for metopic and control patients, along with different degrees of metopic synostosis.

Three-dimensional orbital dysmorphology in metopic synostosis.

Trigonocephalic treatment entails frontoorbital reshaping of the forehead, increasing bitemporal dimensions, and advancing lateral orbits. Various techniques can achieve this, but no consensus exists regarding effects on long-term skull growth. Overcorrecting forehead dimensions is one strategy though preserving a vascularized fronto-orbital bar can influence future growth. We therefore seek to craniomorphologically compare fronto-orbital advancement (FOA), using bandeau widening and advancement, to a pedicled "tilt" procedure to assess whether adequate 3D remodeling is achieved.

Comparing two fronto-orbital advancement strategies to treat trigonocephaly in metopic synostosis.

Secondary enophthalmos correction, especially in severe cases, represents a surgical challenge. The complex injury pattern involving the hard and soft tissue warrants individualized multimodality treatment strategies. Even with seemingly successfully surgical execution, relapse or incomplete correction of globe position can occur. In an attempt to improve ability for correction, we have implemented concurrent endo-orbital fat grafting and orbital framework reconstruction. The purpose of this study is to describe our treatment approach and objectively analyze the results.

Correction of severe enophthalmos by simultaneous fat grafting and anatomic orbital reconstruction.

To identify trends in patient presentation and outcomes data that may guide the development of clinical algorithms on Merkel Cell Carcinoma (MCC).

Understanding the influence of patient demographics on disease severity, treatment strategy, and survival outcomes in merkel cell carcinoma: a surveillance, epidemiology, and end-results study.

Extracorporeal photochemotherapy (ECP) is a cancer immunotherapy for cutaneous T-cell lymphoma (CTCL) operative in more than 350 centers worldwide. Although its efficacy and favorable safety profile have driven its widespread use, elucidation of its underlying mechanism has been difficult. In this study, we identify the principal contributors to the anticancer immunotherapeutic effects of ECP, with the goal of enhancing potency and broadening applicability to additional malignancies. First, we scaled down the clinical ECP leukocyte-processing device to mouse size. Second, we used that miniaturized device to produce a cellular vaccine that regularly initiated therapeutic antimelanoma immunity. Third, we individually subtracted key factors from either the immunizing inoculum or the treated animal to ascertain their contribution to the  antimelanoma response. Platelet-signaled monocyte-to-dendritic cell (DC) differentiation followed by sorting/processing/presentation of tumor antigens derived from internalized apoptotic tumor cells were absolute requirements. As in clinical ECP, immunogenic cell death of tumor cells was finely titrated by DNA cross-linkage mediated by photoactivated 8-methoxypsoralen (8-MOPA). ECP-induced tumor-loaded DC were effective immunotherapeutic agents only if they were spared exposure to 8-MOPA, indicating that healthy DC are required for ECP. Infusion of responder T cells into naïve tumor-challenged mice established the protective role of stimulated T-cell antitumor immunity. Collectively, these results reveal that selective antitumor effects of ECP are initiated by tumor antigen-loaded, ECP-induced DC, which promote potent collaboration between CD4 and CD8 tumor-specific T cells. These mechanistic insights suggest potential therapeutic applicability of ECP to solid tumors in addition to CTCL. These findings identify principal cellular contributors to the anticancer immunotherapeutic impact of ECP and suggest this treatment may be applicable to a broad spectrum of immunogenic malignancies. .

Harib Ezaldein

Department of Dermatology

Yale University School of Medicine

Novel Protocol for Generating Physiologic Immunogenic Dendritic Cells