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Dive into the research topics where Gulsun Erdag is active.

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Featured researches published by Gulsun Erdag.


Cancer Research | 2012

Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic Melanoma

Gulsun Erdag; Jochen T. Schaefer; Mark E. Smolkin; Donna H. Deacon; Sofia M. Shea; Lynn T. Dengel; James W. Patterson; Craig L. Slingluff

Immune cells infiltrating the microenvironment of melanoma metastases may either limit or promote tumor progression, but the characteristics that distinguish these effects are obscure. In this study, we systematically evaluated the composition and organization of immune cells that infiltrated melanoma metastases in human patients. Three histologic patterns of immune cell infiltration were identified, designated immunotypes A, B, and C. Immunotype A was characterized by no immune cell infiltrate. Immunotype B was characterized by infiltration of immune cells limited only to regions proximal to intratumoral blood vessels. Immunotype C was characterized by a diffuse immune cell infiltrate throughout a metastatic tumor. These immunotypes represented 29%, 63%, and 8% of metastases with estimated median survival periods of 15, 23, and 130 months, respectively. Notably, from immunotypes A to C, there were increasing proportions of B cells and decreasing proportions of macrophages. Overall, the predominant immune cells were T cells (53%), B cell lineage cells (33%), and macrophages (13%), with natural killer and mature dendritic cells only rarely present. Whereas higher densities of CD8(+) T cells correlated best with survival, a higher density of CD45(+) leukocytes, T cells, and B cells also correlated with increased survival. Together, our findings reveal striking differences in the immune infiltrate in melanoma metastases in patients, suggesting microenvironmental differences in immune homing receptors and ligands that affect immune cell recruitment. These findings are important, not only by revealing how the immune microenvironment can affect outcomes but also because they reveal characteristics that may help improve individualized therapy for patients with metastatic melanoma.


OncoImmunology | 2016

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

Joseph M. Obeid; Gulsun Erdag; Mark E. Smolkin; Donna H. Deacon; James W. Patterson; Leiping Chen; Timothy Bullock; Craig L. Slingluff

ABSTRACT Therapeutic blockade of PD-1/PD-L1 can have dramatic therapeutic benefit in some patients; however, the prognostic associations of PD-1 and its ligands, in the absence of therapeutic blockade have not been definitively addressed. In particular, associations of PD-L2 with immune infiltrates and with outcome have yet to be explored. We hypothesized that surface expression of both PD-L1 and PD-L2 by melanoma cells would be associated with immune cell infiltration and with overall patient survival, independent of checkpoint blockade therapy. We also characterized the heterogeneity of their distribution within a tumor and within tumors of the same patient. Tissue microarrays of metastatic melanoma samples from 147 patients were quantified for CD8+, CD45, CD4+, CD3, CD163, CD20, CD138, FoxP3, PD-1, PD-L1 and PD-L2 markers by immunohistochemistry. Relationships between the proportions of PD-L1 and PD-L2 expressing tumor cells with the immune cell count, distribution (immunotype) and patient survival were studied. Expressions of both PD-L1 and PD-L2 correlated significantly with increasing densities of immune cells in the tumor specimens and with immunotype. Positive PD-L2 expression was associated with improved overall survival and the simultaneous positive expression of both PD-1 ligands showed a higher association with survival. Significant heterogeneity of PD-L1 and PD-L2 expressions within tumors were observed, however, they were less pronounced with PD-L2. In conclusion, both are markers of immune infiltration and PD-L2, alone or in combination with PD-L1, is a marker for prognosis in metastatic melanoma patients. Larger tumor samples yield more reliable assessments of PD-L1/L2 expression.


Clinical Cancer Research | 2013

Clinical activity and safety of combination therapy with temsirolimus and bevacizumab for advanced melanoma: a phase II trial (CTEP 7190/Mel47).

Craig L. Slingluff; Gina R. Petroni; Kerrington R. Molhoek; David L. Brautigan; Kimberly A. Chianese-Bullock; Amber L. Shada; Mark E. Smolkin; Walter C. Olson; Alison Gaucher; Cheryl Murphy Chase; William W. Grosh; Geoffrey R. Weiss; Aubrey G Wagenseller; Anthony J. Olszanski; Lainie P. Martin; Sofia M. Shea; Gulsun Erdag; Prahlad T. Ram; Jeffrey E. Gershenwald; Michael J. Weber

Purpose: A CTEP-sponsored phase II trial was conducted to evaluate safety and clinical activity of combination therapy with CCI-779 (temsirolimus) and bevacizumab in patients with advanced melanoma. Experimental Design: Patients with unresectable stage III to IV melanoma were treated intravenously with temsirolimus 25 mg weekly and bevacizumab 10 mg every 2 weeks. Adverse events were recorded using CTCAE v3.0. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors and overall survival was recorded. Correlative studies measured protein kinases and histology of tumor biopsies and immune function in peripheral blood. Results: Seventeen patients were treated. Most patients tolerated treatment well, but 2 had grade 4 lymphopenia and 1 developed reversible grade 2 leukoencephalopathy. Best clinical response was partial response (PR) in 3 patients [17.7%, 90% confidence interval (CI) 5, 0–39.6], stable disease at 8 weeks (SD) in 9 patients, progressive disease (PD) in 4 patients, and not evaluable in 1 patient. Maximal response duration for PR was 35 months. Ten evaluable patients had BRAFWT tumors, among whom 3 had PRs, 5 had SD, and 2 had PD. Correlative studies of tumor biopsies revealed decreased phospho-S6K (d2 and d23 vs. d1, P < 0.001), and decreased mitotic rate (Ki67+) among melanoma cells by d23 (P = 0.007). Effects on immune functions were mixed, with decreased alloreactive T-cell responses and decreased circulating CD4+FoxP3+ cells. Conclusion: These data provide preliminary evidence for clinical activity of combination therapy with temsirolimus and bevacizumab, which may be greater in patients with BRAFwt melanoma. Mixed effects on immunologic function also support combination with immune therapies. Clin Cancer Res; 19(13); 3611–20. ©2013 AACR.


Melanoma Research | 2010

Evaluation of molecular markers of mesenchymal phenotype in melanoma.

Leann M. Mikesh; Manish Kumar; Gulsun Erdag; Kevin T. Hogan; Kerrington R. Molhoek; Marty W. Mayo; Craig L. Slingluff

The epithelial to mesenchymal transition is a developmental process allowing epithelial cells to dedifferentiate into cells displaying mesenchymal phenotypes. The pathological role of epithelial to mesenchymal transition has been implicated in invasion and metastasis for numerous carcinomas, yet limited data exist addressing whether mesenchymal transition (MT) occurs in malignant melanoma cells. Our group developed an in-vitro three-dimensional culture system to address MT in melanoma cells upon transforming growth factor-β/ tumor necrosis factor-α treatment. Loss of E-cadherin is one of the best indicators of MT in epithelial cells. Not surprisingly, E-cadherin was expressed in only three of 12 (25%) melanoma cell lines and all three mesenchymal proteins, N-cadherin, vimentin, and fibronectin, were expressed by seven (58%) melanoma cell lines. However, after cytokine treatment, two or more mesenchymal proteins were elevated in nine (75%) melanoma cell lines. Data support the transforming growth factor-β production by melanoma cells which may induce/support MT. Evaluation of E-cadherin, N-cadherin, and Snail expression in melanoma tissue samples are consistent with an inverse coupling of E-cadherin and N-cadherin expression, however, there are also examples suggesting a more complex control of their expression. These results indicate that malignant melanoma cell lines are susceptible to MT after cytokine treatment and highlight the importance of understanding the effects of cytokines on melanoma to undergo MT.


International Journal of Dermatology | 2014

The great imitator revisited: the spectrum of atypical cutaneous manifestations of secondary syphilis

Yevgeniy Balagula; Peter L. Mattei; Oliver J. Wisco; Gulsun Erdag; Anna L. Chien

Syphilis is a well‐known sexually transmitted infection infamous for its protean cutaneous manifestations. Over the last decade, the rate of infection in the USA has risen, particularly among human immunodeficiency virus (HIV)‐infected individuals and certain ethnic groups. Although the primary chancre developing at the site of inoculation usually has typical and well‐characterized features, cutaneous manifestations of secondary syphilis span a wide spectrum and mimic those of other dermatoses. This may be particularly evident in patients with HIV. Such deviations from the expected typical papulosquamous eruption may present a diagnostic challenge and delay diagnosis and therapy. Given the increasing incidence of syphilis among the immunosuppressed patient population, recognition of atypical cutaneous manifestations is critical for adequate management. We review a range of cutaneous manifestations of secondary syphilis and the skin diseases it may mimic.


International Journal of Cancer | 2011

VEGFR-2 expression in human melanoma: revised assessment.

Kerrington R. Molhoek; Gulsun Erdag; Jk J. Rasamny; Cheryl F. Murphy; Donna H. Deacon; James W. Patterson; Craig L. Slingluff; David L. Brautigan

Vascular endothelial growth factor (VEGF) is an angiogenic factor that also functions as an autocrine growth factor for VEGF receptor (VEGFR)‐2+ melanomas. In multiple studies, VEGFR‐2 was detected by immunostaining in 78–89% of human melanoma cells, suggesting that most patients with melanoma would benefit from anti‐VEGF therapy. Here, we evaluated 167 human melanoma specimens in a tissue microarray to verify the presence of VEGFR‐2, but found disparities in staining with commercial antibodies A‐3 and 55B11. Antibody A‐3 stained melanoma cells in 79% of specimens, consistent with published results; however, we noted extensive nonspecific staining of other cells such as smooth muscle and histiocytes. In contrast, antibody 55B11 stained melanoma cells in only 7% (95% confidence interval: 3.3–11.5) of specimens. As an internal positive control for VEGFR‐2 detection, vascular endothelial cells were stained with antibody 55B11 in all specimens. We compared VEGFR‐2+ and VEGFR‐2− melanoma cell lines by immunoblotting and immunohistochemistry after small interfering RNA (siRNA) knockdown and transient overexpression of VEGFR‐2 to validate antibody specificity. Immunoblotting revealed that A‐3 primarily cross‐reacted with several proteins in both cell lines and these were unaffected by siRNA knockdown of VEGFR‐2. In contrast, 55B11 staining of VEGFR‐2+ cells was mostly eliminated by siRNA knockdown of VEGFR‐2 and increased in VEGFR‐2− melanoma cell lines following transfection to express ectopic VEGFR‐2. Our results show that relatively few melanoma cells (<10%) express detectable levels of VEGFR‐2, and therefore, the majority of patients with melanoma are unlikely to benefit from antiproliferative effects of anti‐VEGF therapy.


Archives of Dermatology | 2011

Two patients with hailey-hailey disease, multiple primary melanomas, and other cancers

Melinda R. Mohr; Gulsun Erdag; Amber L. Shada; Michael E. Williams; Craig L. Slingluff; James W. Patterson

BACKGROUND Hailey-Hailey Disease (HHD) is an autosomal dominant skin disorder that is characterized by erythematous and sometimes vesicular, weeping plaques of intertriginous regions. Squamous cell carcinoma and basal cell carcinoma arising in lesions of HHD have been described in the literature. To our knowledge, there are no reports of melanoma or noncutaneous malignant neoplasms associated with HHD. OBSERVATIONS We discuss the mechanisms of oncogenicity, including genetic, environmental, and iatrogenic factors, in 2 patients with HHD, multiple primary melanomas, and other cancers. Patient 1 had a mucoepidermoid carcinoma of the parotid gland. Patient 2 had a history of acute monoblastic leukemia and malignant peripheral nerve sheath tumor as well as radiologic evidence of an acoustic neurilemmoma. CONCLUSIONS The cause of the cancers in these 2 patients is likely multifactorial. We describe the patients to draw attention to the possible association between HHD and cancer. Additional research should be performed to determine whether patients with HHD have an increased incidence of cancer.


Journal of Cutaneous Pathology | 2011

A case of pityriasis rubra pilaris with associated focal acantholytic dyskeratosis complicated by Kaposi's varicelliform eruption

Gulsun Erdag; Deborah Lockman; Jennifer Tromberg; Thomas G. Cropley; James W. Patterson

The clinical and histopathological diagnosis of pityriasis rubra pilaris (PRP) can be difficult because clinical findings are often subtle in early stages, and microscopic findings can overlap with those of other skin diseases. Focal acantholytic dyskeratosis (FAD) can rarely be seen in PRP and can mimic Dariers disease, Grovers disease or other disorders characterized by these histopathologic features. Kaposis varicelliform eruption is a widespread infection due to herpes simplex virus (HSV) types 1 and 2, coxsackievirus A16 or vaccinia virus, occurring in a preexisting dermatosis; only one case has been reported in PRP. We report a patient with PRP whose biopsies showed both herpes simplex infection and FAD. A complete understanding of the mechanism behind this eruption evolved gradually, aided in great measure by the histopathologic findings.


OncoImmunology | 2016

Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate

Sylvain Ladoire; Laura Senovilla; David Enot; François Ghiringhelli; Vichnou Poirier-Colame; Kariman Chaba; Gulsun Erdag; Jochen T. Schaefer; Donna H. Deacon; Laurence Zitvogel; Craig L. Slingluff; Guido Kroemer

ABSTRACT Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2α; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4+, CD8+, CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3. LC3B puncta positively correlated with the infiltration of metastases by CD163+ macrophages, while expression of HMGB1 correlated with infiltration by FOXP3+ regulatory T cells and CD56+ lymphocytes. eIF2α phosphorylation was associated with an augmentation of nuclear diameters, reflecting an increase in ploidy. Interestingly, therapeutic vaccination led to a reduction of eIF2α phosphorylation suggestive of immunoselection against cells bearing this sign of endoplasmic reticulum (ER) stress. None of the stress/death-related biomarkers had a significant prognostic impact, contrasting with the major prognostic effect of the ratio of cytotoxic T lymphocytes (CTL) over immunosuppressive FOXP3+ and CD163+ cells. Altogether, these results support the idea of a mutual dialog between, on one hand, melanoma cells with their cell-intrinsic stress pathways and, on the other hand, immune effectors. Future work is required to understand the detailed mechanisms of this interaction.


American Journal of Dermatopathology | 2013

Locally invasive dermal squamomelanocytic tumor with matrical differentiation: a peculiar case with review of the literature.

Nemanja Rodić; Janis M. Taube; Paul Manson; Manisha J. Patel; James W. Patterson; Gulsun Erdag

Abstract:Dermal-based combined squamous and melanocytic neoplasms are emerging clinicopathologic entities that tend to appear on sun-exposed areas of elderly patients. The biologic behavior of such cutaneous neoplasms remains uncertain because of their rarity. Histopathologic differential includes the following diagnostic entities: (1) dermal squamomelanocytic tumor, (2) melanocytic matricoma, and (3) rare histologic variant of pilomatrical carcinoma, the so-called pilomatrical carcinoma with intralesional melanocytes. Herein, we present a novel case of locally invasive dermal squamomelanocytic tumor. A 72-year-old man presented with a pigmented papule on nasal ala that was clinically concerning for basal cell carcinoma. Histopathologic evaluation demonstrated atypical melanocytic cells architecturally and intimately intermixed with single units and clusters of atypical squamous cells. Most notable feature of this case is focal matrical differentiation and locally invasive tumor growth, characterized by multifocal perineural invasion.

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James W. Patterson

University of Virginia Health System

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