Sara Samimi

Increased Programmed Death-1 Expression on CD4+ T Cells in Cutaneous T-Cell Lymphoma: Implications for Immune Suppression

OBJECTIVES To investigate the expression profile of programmed death-1 (PD-1) on T cells derived from patients with cutaneous T-cell lymphoma (CTCL), analyze a potential mechanism responsible for upregulation of PD-1, and assess the correlation between blockade of its signaling pathway and improvement in immunological function. DESIGN Translation research study. SETTING University medical center. PARTICIPANTS Patients with Sézary syndrome, patients with mycosis fungoides, and healthy volunteers. MAIN OUTCOME MEASURES Programmed death-1 expression on T cells by flow cytometry and interferon γ (IFN-γ) production by enzyme-linked immunosorbent assay. RESULTS We report significantly increased PD-1 expression on CD4(+) T cells from patients with Sézary syndrome compared with CD4(+) T cells from patients with mycosis fungoides and healthy volunteers. Both CD26(-) and CD26(+) populations of CD4(+) T cells demonstrated increased expression of PD-1, which was upregulated by the engagement of the T-cell receptor with anti-CD3/CD28 antibodies. In addition, blockade of the signaling pathway with blocking antibodies to PD-1 or its ligand PD-L1 led to an increase in the capacity to produce IFN-γ among some patients. Finally, longitudinal studies of 1 patient revealed a progressive decrease in PD-1 expression on CD4(+) T cells with improvement of clinical disease. CONCLUSION Our data imply that increased PD-1 expression in Sézary syndrome may play a role in attenuating the immune response and provide further insight into the immunosuppressive nature of CD4(+) T cells in Sézary syndrome and suggest another potential means of targeted therapy for these patients.

High Clinical Response Rate of S ézary Syndrome to Immunomodulatory Therapies: Prognostic Markers of Response

OBJECTIVES To quantify response rates of Sézary syndrome (SS) to multimodality immunomodulatory therapy and to identify the important prognostic parameters that affect overall response to treatment. DESIGN Retrospective cohort study. SETTING Cutaneous T-cell lymphoma clinic at The Hospital at the University of Pennsylvania. PARTICIPANTS Ninety-eight patients who met the revised International Society for Cutaneous Lymphomas (ISCL) and the European Organization of Research and Treatment of Cancer (EORTC) criteria for the diagnosis of SS and were seen over a 25-year period at the University of Pennsylvania. Intervention Patients were treated with at least 3 months of extracorporeal photopheresis and 1 or more systemic immunostimulatory agents. MAIN OUTCOME MEASURES Overall response to treatment was the main measurement of outcome. RESULTS A total of 73 patients had significant improvement with multimodality therapy: 30% had complete response, with clearing of all disease (n = 29), and 45% had partial response (n = 44). At baseline, the complete response group had a lower CD4/CD8 ratio than the nonresponse group (13.2 vs 44.2) (P = .04) and a lower median percentage of CD4(+)/CD26(-) cells (27.4% vs 57.2%) (P = .01) and CD4(+)/CD7(-) cells (20.0% vs 41.3%) (P < .01). Median monocyte percentage at baseline was higher for patients who had a complete response than for nonresponders (9.5% vs 7.3%) (P = .02). The partial response group did not have any statistically significant variables compared with the nonresponse group. CONCLUSIONS In this large cohort study of patients with SS, a high clinical response rate was achieved using multiple immunomodulatory therapies. A lower CD4/CD8 ratio, a higher percentage of monocytes, and lower numbers of circulating abnormal T cells at baseline were the strongest predictive factors for complete response compared with nonresponse and warrant further examination in a larger cohort.

Neonatal outcome after exposure to indomethacin in utero: a retrospective case cohort study

OBJECTIVE This study was undertaken to determine the clinical outcome for neonates who were exposed to indomethacin during gestation. STUDY DESIGN We identified 124 infants with in utero exposure to indomethacin and matched them to 124 infants whose mothers did not receive indomethacin. The two groups were matched for gestational age at birth, sex, and exposure to antenatal betamethasone. Sixty-two of the indomethacin-exposed infants were born within 48 hours of last exposure. These infants were also compared with their matched controls. RESULTS There were no significant differences between the indomethacin-exposed infants and control infants in birth weight, Apgar scores, frequency of cesarean section deliveries, and multiple gestation. The incidence of respiratory distress syndrome, need for surfactant treatment, patent ductus arteriosus, necrotizing enterocolitis, and intraventricular hemorrhage was similar between the indomethacin-exposed group and the control group. Indomethacin-exposed infants who were born within 48 hours of last exposure had similar incidence of respiratory distress syndrome but greater need for surfactant treatment (P=.02) compared with controls. All other complication rates were similar. CONCLUSION Indomethacin exposure in our study was not associated with increased neonatal complications for infants delivered within or beyond 48 hours of last exposure.

Peripheral blood findings in erythrodermic patients: Importance for the differential diagnosis of Sézary syndrome

Although Sézary syndrome (SS) represents an advanced stage of cutaneous T-cell lymphoma, this diagnosis presents a challenge even for the most experienced dermatologic clinicians. SS is characterized clinically by erythroderma, but can also be identified in the presence of specific histologic and peripheral blood findings. Erythrodermic cutaneous T-cell lymphoma can mimic a number of nonmalignant disorders with erythroderma, including pityriasis rubra pilaris, psoriasis, atopic dermatitis, and graft-versus-host disease. The diagnosis is made even more challenging because the histology of SS is often nonspecific and rarely pathognomonic. As a result, peripheral blood studies in patients with erythroderma are frequently informative in the diagnosis of SS. Peripheral blood abnormalities including elevated CD4/CD8 ratio, aberrant CD26, CD27 and CD7 expression, and T-cell clonality can all be used to help arrive at a diagnosis. This review evaluates current data on the usefulness and limitations of specific peripheral blood markers detected by flow cytometry and T-cell receptor gene rearrangement polymerase chain reaction.

Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas

Primary cutaneous CD8-positive aggressive epidermotropic T-cell lymphoma is a rare and poorly characterized variant of cutaneous lymphoma still considered a provisional entity in the latest 2016 World Health Organization Classification of Cutaneous lymphomas. We sought to better characterize and provide diagnostic and therapeutic guidance of this rare cutaneous lymphoma. Thirty-four patients with a median age of 77 years (range 19–89 years) presented primarily with extensive annular necrotic plaques or tumor lesions with frequent mucous membrane involvement. The 5-year survival was 32% with a median survival of 12 months. A subset of 17 patients had a prodrome of chronic patches prior to the development of aggressive ulcerative lesions. We identified cases with lack of CD8 or αβ T-cell receptor expression yet with similar clinical and pathological presentation. Allogeneic stem cell transplantation provided partial or complete remissions in 5/6 patients. We recommend the term primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma as this more broad designation better describes this clinical-pathologic presentation, which allows the inclusion of cases with CD8 negative and/or αβ/γδ T-cell receptor chain double-positive or double-negative expression. We have identified early skin signs of chronic patch/plaque lesions that are often misdiagnosed as eczema, psoriasis, or mycosis fungoides. Our experience confirms the poor prognosis of this entity and highlights the inefficacy of our standard therapies with the exception of allogeneic stem cell transplantation in selected cases.

Improvement in peripheral blood disease burden in patients with Sézary syndrome and leukemic mycosis fungoides after total skin electron beam therapy

BACKGROUND There is a paucity of effective therapies for patients with Sézary syndrome and advanced mycosis fungoides with peripheral blood involvement. Total skin electron beam (TSEB) radiation therapy is an extremely effective skin-directed therapy for these patients, but, until recently, it was thought not to signifcantly affect the peripheral blood malignant T-cell population. OBJECTIVE We conducted this study to determine if TSEB has therapeutic effect on the peripheral blood in patients with advanced mycosis fungoides and Sézary syndrome. METHODS All patients on stable medication regimens seen in our photopheresis facility who received TSEB therapy between January 2008 and October 2011 at Temple University Hospital, Philadelphia, PA, were analyzed retrospectively for improvement in the peripheral blood, as documented by flow cytometry. RESULTS Six of 11 patients achieved 50% or greater decrease in their peripheral blood malignant T-cell population after TSEB therapy, for an overall response rate of 55%. Within the group of patients who had a response in the skin, 67% also had a response in the peripheral blood. LIMITATIONS This analysis is limited in 3 ways. First, the sample described is small. Second, the results may be confounded by the fact that each patient was on other systemic therapies in addition to TSEB, albeit stable pre-existing regimens. The time interval between completion of TSEB therapy and repetition of flow cytometry was not standardized among patients, which may result in an underestimation of the overall response to TSEB therapy. CONCLUSION In patients with advanced mycosis fungoides and Sézary syndrome, the peripheral blood tumor burden may improve after treatment with TSEB.

Ulcerations within striae distensae associated with bevacizumab therapy

cysticercosis seen on skin biopsy specimen from a new urticarial papule on the left posterior thigh. Extravasated erythrocytes (yellow arrow) and a perivascular infiltrate composed of neutrophils with neutrophilic debris (black arrows), with some mononuclear cells around the blood vessels, are consistent with an early leukocytoclastic vasculitis. (Hematoxylin-eosin stain; original magnification: 340.) Fig 1. Neurocysticercosis in a patient with urticarial vasculitis: brain magnetic resonance imaging shows a 2.5-cm rim enhancing degenerating cyst (arrow) in the left frontal lobe. J AM ACAD DERMATOL VOLUME 72, NUMBER 1 Letters e33

Pityriasis Lichenoides and Cutaneous T Cell Lymphoma: An Update on the Diagnosis and Management of the Most Common Benign and Malignant Cutaneous Lymphoproliferative Diseases in Children

Although more common with advanced age, the entire spectrum of benign and malignant cutaneous lymphoproliferative disorders can present in the pediatric population. Nevertheless, these conditions are often mistaken for other more common, benign dermatoses, resulting in delayed diagnosis. Standardized management of these conditions is also lacking. The purpose of this review is to provide an update on the most common benign and malignant cutaneous lymphoproliferative disorders in children: pityriasis lichenoides and mycosis fungoides. The presentation, evaluation and management of each of these conditions are discussed.

Immune modulators as therapeutic agents for cutaneous T-cell lymphoma.

In choosing the ideal immune modulator, a number of factors should be considered. First, the agent should have the capacity to induce a robust antitumor immune response. The treatment should also directly produce high levels of apoptosis of the tumor cells. Finally, the ability to produce sustained immunologic memory against the tumor cells is of critical importance in an effort to produce prolonged clinical responses. A number of cytokines that are products of cells of the innate immune system, including interferon (IFN)-α, IFN-γ, and IL-12, meet at least 2 of the above criteria with IFN-α meeting all 3. IFN-α has been shown to produce high clinical response rates in

Trends in US dermatology residency and fellowship programs and positions, 2006 to 2016

hyperkeratosis alternated with basketweave hyperkeratosis, whereas in VEN, agranulosis alternated with a normal granular layer. None of the biopsies of nevus sebaceus, lichen striatus, nevus comedonicus, linear lichen planus, or linear lichen planus pigmentosus showed focal changes. Alternating histologic changes were seen in only 3 nonmosaic cases (4.41%) (Darier disease in 1 and Dowling-Degos disease in 2). Overall, focal changes with skipping of epidermis was seen significantly more frequently in blaschkoid dermatoses (in 37.7% vs in 4.41% [P\ .001]). Roughly one-third of the blaschkoid dermatoses in our study showed an alternating histologic pattern, which is significantly greater than in nonmosaic dermatoses. Of these, linear EHK and ILVEN showed the pattern most consistently. In a large study of 167 epidermal nevi that included several variants such as EHK, psoriasiform ILVEN, porokeratosis-like, focal acantholytic dyskeratosis, and nevus comedonicus, alternating histologic changes were reported only for ILVEN. Recently, Ross et al described this finding in mosaic EHK. The basis of this histologic pattern is not clear. Actinic keratosis shows an alternating pattern of parakeratosis due to the sparing of follicular structures, whereas the cornoid lamellae in porokeratotic eccrine ostial and dermal duct nevus overlie acrosyringia; however, a relationship with adnexal structures was not seen in any of our cases. Mosaicism is characterized by mutant and nonmutant cell lines in an organism. Our findings raise the question whether this coexistence of 2 cell populations extends to the tissue level even within lesional skin in mosaic disorders. Gene and expression studies may help answer this question. Also, why only some blaschkoid dermatoses show this distinctive histologic pattern is not clear. Our study is limited by the retrospective study design and the relatively small number of individual entities.