Youn H Kim

All Publications

• Volumetric modulated arc therapy and 3-dimensional printed bolus in the treatment of refractory primary cutaneous gamma delta lymphoma of the bilateral legs. Practical radiation oncology Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019

  Abstract

  Patients with extensive dermal and subcutaneous disease present a technical challenge for treatment with radiation therapy (RT). Volumetric arc therapy (VMAT) can effectively treat disease on circumferential surfaces while minimizing dose to the core structures. However, treatment of extensive areas of the bilateral lower extremities with this technique has not been previously reported. Here we report the successful treatment of a patient with primary cutaneous gamma-delta T-cell lymphoma of the bilateral legs using VMAT and a custom 3-dimensional printed bolus. This approach is applicable for the treatment of cutaneous malignancies of the lower extremities.

  View details for DOI 10.1016/j.prro.2019.02.016

  View details for PubMedID 30836188

• Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. The Lancet. Oncology Kim, Y. H., Bagot, M., Pinter-Brown, L., Rook, A. H., Porcu, P., Horwitz, S. M., Whittaker, S., Tokura, Y., Vermeer, M., Zinzani, P. L., Sokol, L., Morris, S., Kim, E. J., Ortiz-Romero, P. L., Eradat, H., Scarisbrick, J., Tsianakas, A., Elmets, C., Dalle, S., Fisher, D. C., Halwani, A., Poligone, B., Greer, J., Fierro, M. T., Khot, A., Moskowitz, A. J., Musiek, A., Shustov, A., Pro, B., Geskin, L. J., Dwyer, K., Moriya, J., Leoni, M., Humphrey, J. S., Hudgens, S., Grebennik, D. O., Tobinai, K., Duvic, M., MAVORIC Investigators, Abhyankar, S., Akilov, O., Alpdogan, O., Beylot-Barry, M., Boh, E., Caballero, D., Cowan, R., Dreno, B., Dummer, R., Fenske, T., Foss, F., Fukuhara, N., Giri, P., Habe, K., Hamada, T., Hatake, K., Iida, S., Ishikawa, O., Iversen, L., Kiyohara, E., Koga, H., Korman, N., Kuss, B. J., Lamar, Z., Lansigan, F., Lechowicz, M. J., Lerner, A., Magnolo, N., Mark, L., Miyagaki, T., Munoz, J., Nicolay, J. P., Nishiwaki, K., Okamoto, H., Ohtsuka, M., Pacheco, T., Querfeld, C., Rapini, R. P., Sano, S., Tanaka, M., Tharp, M. D., Uehara, J., Wada, H., Wells, J., Wilcox, R. A., William, B., Yonekura, K. 2018

  Abstract

  BACKGROUND: Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.METHODS: In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sezary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sezary syndrome) and disease stage (IB-II vs III-IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.FINDINGS: Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7-10·3] in the mogamulizumab group vs 3·1 months [2·9-4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41-0·69; stratified log-rank p<0·0001). Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.INTERPRETATION: Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sezary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.FUNDING: Kyowa Kirin.

  View details for DOI 10.1016/S1470-2045(18)30379-6

  View details for PubMedID 30100375

• Variability in the Expression of Immunohistochemical Markers: Implications for Biomarker Interpretation in Cutaneous T-Cell Lymphoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Rahbar, Z., Li, S., Tavallaee, M., Novoa, R. A., Kim, J., Kim, Y. H. 2018; 138 (5): 1204–6

  View details for DOI 10.1016/j.jid.2017.11.035

  View details for Web of Science ID 000430533700040

  View details for PubMedID 29247659

• Transcript-indexed ATAC-seq for precision immune profiling. Nature medicine Satpathy, A. T., Saligrama, N., Buenrostro, J. D., Wei, Y., Wu, B., Rubin, A. J., Granja, J. M., Lareau, C. A., Li, R., Qi, Y., Parker, K. R., Mumbach, M. R., Serratelli, W. S., Gennert, D. G., Schep, A. N., Corces, M. R., Khodadoust, M. S., Kim, Y. H., Khavari, P. A., Greenleaf, W. J., Davis, M. M., Chang, H. Y. 2018

  Abstract

  T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy.

  View details for DOI 10.1038/s41591-018-0008-8

  View details for PubMedID 29686426

• Novel treatment of cutaneous T cell lymphoma: Targeting TNFR2, an oncogene and marker of potent Tregs, with anti-TNFR2 antibodies Torrey, H., Defusco, A., Baum, D., Rahbar, Z., Khodadoust, M., Kim, Y. H., Faustman, D. BMC. 2017

  View details for Web of Science ID 000460207200103

• Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial LANCET Prince, H., Kim, Y. H., Horwitz, S. M., Dummer, R., Scarisbrick, J., Quaglino, P., Zinzani, P., Wolter, P., Sanches, J. A., Ortiz-Romero, P. L., Akilov, O. E., Geskin, L., Trotman, J., Taylor, K., Dalle, S., Weichenthal, M., Walewski, J., Fisher, D., Dreno, B., Stadler, R., Feldman, T., Kuzel, T. M., Wang, Y., Palanca-Wessels, M., Zagadailov, E., Trepicchio, W. L., Zhang, W., Lin, H., Liu, Y., Huebner, D., Little, M., Whittaker, S., Duvic, M., ALCANZA Study Grp 2017; 390 (10094): 555–66

  Abstract

  Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499.Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

  View details for DOI 10.1016/S0140-6736(17)31266-7

  View details for Web of Science ID 000406855800020

  View details for PubMedID 28600132

• Primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphomas: reappraisal of a provisional entity in the 2016 WHO classification of cutaneous lymphomas MODERN PATHOLOGY Guitart, J., Martinez-Escala, M., Subtil, A., Duvic, M., Pulitzer, M. P., Olsen, E. A., Kim, E., Rook, A. H., Samimi, S. S., Wood, G. S., Girardi, M., Junkins-Hopkins, J., Ivan, D. S., Selim, M., Sable, K. A., Virmani, P., Pincus, L. B., Tetzlaff, M. T., Kim, J., Kim, Y. H. 2017; 30 (5): 761–72

  Abstract

  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.

  View details for DOI 10.1038/modpathol.2016.240

  View details for Web of Science ID 000400480100014

  View details for PubMedID 28128277

  View details for PubMedCentralID PMC5413429

• Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors. Cancer cell Qu, K., Zaba, L. C., Satpathy, A. T., Giresi, P. G., Li, R., Jin, Y., Armstrong, R., Jin, C., Schmitt, N., Rahbar, Z., Ueno, H., Greenleaf, W. J., Kim, Y. H., Chang, H. Y. 2017

  Abstract

  Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4(+) T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4(+) T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.

  View details for DOI 10.1016/j.ccell.2017.05.008

  View details for PubMedID 28625481

• First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results Bagot, M., Porcu, P., Ram-Wolff, C., Khodadoust, M., Battistella, M., Marie-Cardine, A., Mathieu, S., Vermeer, M. H., Whittaker, S., Duvic, M., Bensussan, A., Paturel, C., Bonnafous, C., Thonnart, N., Widemann, A., Bonin, C., Sicard, H., Paiva, C., Pilz, K., Kim, Y. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452308018

• A Single-Arm PHASE 2A Study of NM-IL-12 (rHu-IL12) in Patients with Mycosis Fungoides-Type CTCL (MF) Undergoing Low-Dose TOTAL Skin Electron BEAM Therapy (LD-TSEBT) Kim, Y. H., Hoppe, R. T., Rook, A. H., Maity, A., Geskin, L. J., Horowitz, D. P., Finnegan, G., Khodadoust, M., Weng, W., Lares, A., Hong, E., Buchanan, M., Ma, V., Kha, H., Lawrence, C. E., Vainstein, V., Basile, L. A. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452308077

• Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study Khodadoust, M., Rook, A. H., Porcu, P., Foss, F. M., Moskowitz, A. J., Shustov, A. R., Shanbhag, S., Sokol, L., Shine, R., Fling, S. P., Li, S., Rabhar, Z., Kim, J., Yang, Y., Yearley, J., Chartash, E., Townson, S. M., Subrahmanyam, P. B., Maecker, H., Alizadeh, A. A., Dai, J., Horwitz, S. M., Sharon, E., Kohrt, H., Cheever, M. A., Kim, Y. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803144

• Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study Kim, Y. H., Whittaker, S., Horwitz, S. M., Duvic, M., Dummer, R., Scarisbrick, J. J., Quaglino, P., Zinzani, P., Wolter, P., Wang, Y., Palanca-Wessels, M., Zagadailov, E., Trepicchio, W. L., Liu, Y., Little, M., Prince, H. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803146

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  Abstract

  In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

  View details for PubMedCentralID PMC5089160

• Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model. Journal of clinical oncology Scarisbrick, J. J., Prince, H. M., Vermeer, M. H., Quaglino, P., Horwitz, S., Porcu, P., Stadler, R., Wood, G. S., Beylot-Barry, M., Pham-Ledard, A., Foss, F., Girardi, M., Bagot, M., Michel, L., Battistella, M., Guitart, J., Kuzel, T. M., Martinez-Escala, M. E., Estrach, T., Papadavid, E., Antoniou, C., Rigopoulos, D., Nikolaou, V., Sugaya, M., Miyagaki, T., Gniadecki, R., Sanches, J. A., Cury-Martins, J., Miyashiro, D., Servitje, O., Muniesa, C., Berti, E., Onida, F., Corti, L., Hodak, E., Amitay-Laish, I., Ortiz-Romero, P. L., Rodríguez-Peralto, J. L., Knobler, R., Porkert, S., Bauer, W., Pimpinelli, N., Grandi, V., Cowan, R., Rook, A., Kim, E., Pileri, A., Patrizi, A., Pujol, R. M., Wong, H., Tyler, K., Stranzenbach, R., Querfeld, C., Fava, P., Maule, M., Willemze, R., Evison, F., Morris, S., Twigger, R., Talpur, R., Kim, J., Ognibene, G., Li, S., Tavallaee, M., Hoppe, R. T., Duvic, M., Whittaker, S. J., Kim, Y. H. 2015; 33 (32): 3766-3773

  Abstract

  Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers.Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS).Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%).To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

  View details for DOI 10.1200/JCO.2015.61.7142

  View details for PubMedID 26438120

  View details for PubMedCentralID PMC4979132

• Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2 NATURE GENETICS Ungewickell, A., Bhaduri, A., Rios, E., Reuter, J., Lee, C. S., Mah, A., Zehnder, A., Ohgami, R., Kulkarni, S., Armstrong, R., Weng, W., Gratzinger, D., Tavallaee, M., Rook, A., Snyder, M., Kim, Y., Khavari, P. A. 2015; 47 (9): 1056-?

  Abstract

  Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

  View details for DOI 10.1038/ng.3370

  View details for Web of Science ID 000360394100016

• Individuality and Variation of Personal Regulomes in Primary Human T Cells CELL SYSTEMS Qu, K., Zaba, L. C., Giresi, P. G., Li, R., Longmire, M., Kim, Y. H., Greenleaf, W. J., Chang, H. Y. 2015; 1 (1): 51-61

  Abstract

  Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

  View details for DOI 10.1016/j.cels.2015.06.003

  View details for Web of Science ID 000209925400012

  View details for PubMedCentralID PMC4522940

• Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: Results of a pooled analysis from 3 phase-II clinical trials. Journal of the American Academy of Dermatology Hoppe, R. T., Harrison, C., Tavallaee, M., Bashey, S., Sundram, U., Li, S., Million, L., Dabaja, B., Gangar, P., Duvic, M., Kim, Y. H. 2015; 72 (2): 286-292

  Abstract

  Standard-dose (36-Gy) total skin electron beam therapy (TSEBT) is a highly effective treatment in mycosis fungoides. However, the regimen is time-intensive and may be associated with significant toxicity.We sought to evaluate the efficacy and tolerability associated with low-dose (12-Gy) TSEBT.Data from 3 clinical trials using low-dose (12-Gy) TSEBT were pooled. In all trials, TSEBT-naïve patients with stage IB to IIIA mycosis fungoides were treated with TSEBT (12 Gy, 1 Gy per fraction over 3 weeks). The primary end point was clinical response rate. Secondary end points included time to response and duration of clinical benefit.In all, 33 patients enrolled. Eighteen were male; stages were 22 IB, 2 IIA, 7 IIB, and 2 IIIA. Overall response rate was 88% (29/33), including 9 patients with complete response. Median time to response was 7.6 weeks (3-12.4 weeks). Median duration of clinical benefit was 70.7 weeks (95% confidence interval 41.8-133.8 weeks). Toxicities from TSEBT were mild and reversible.Conclusions are limited because of the small number of patients.Low-dose TSEBT provides reliable and rapid reduction of disease burden in patients with mycosis fungoides, which could be administered safely multiple times during the course of a patient's disease with acceptable toxicity profile.

  View details for DOI 10.1016/j.jaad.2014.10.014

  View details for PubMedID 25476993

• Non-Myeloablative Allogeneic Transplantation Resulting in Clinical and Molecular Remission with Low Non-Relapse Mortality (NRM) in Patients with Advanced Stage Mycosis Fungoides (MF) and Sezary Syndrome (SS) Weng, W., Armstrong, R., Arai, S., Johnston, L., Laport, G. G., Lowsky, R., Miklos, D. B., Shizuru, J. A., Benjamin, J. E., Negrin, R. S., Reddy, S., Million, L., Hoppe, R. T., Kim, Y. H. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242701061

• Low Dose (12 Gy) Total Skin Electron Beam Therapy (TSEBT) for Mycosis Fungoides (mf): Results of Three Phase 2 Clinical Trials 56th Annual Meeting of the American-Society-for-Radiation-Oncology Hoppe, R. T., Harrison, C., Tavallaee, M., Bashey, S., Li, S., Million, L., Dabaja, B., Duvic, M., Kim, Y. H. ELSEVIER SCIENCE INC. 2014: S151–S151

  View details for Web of Science ID 000342331400346

• Minimal Residual Disease Monitoring with High-Throughput Sequencing of T Cell Receptors in Cutaneous T Cell Lymphoma SCIENCE TRANSLATIONAL MEDICINE Weng, W., Armstrong, R., Arai, S., Desmarais, C., Hoppe, R., Kim, Y. H. 2013; 5 (214)

  Abstract

  Mycosis fungoides (MF) and the leukemic presentation Sézary syndrome (SS) are clonal T cell lymphomas arising from the skin and are considered noncurable with standard therapies. To develop a specific and sensitive monitoring tool, we tested the ability of high-throughput sequencing (HTS) of T cell receptors (TCRB) to monitor minimal residual disease (MRD) after allogeneic hematopoietic cell transplantation. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) or skin samples. The rearranged TCRβ loci were amplified using Vβ- and Jβ-specific primers, followed by HTS, to generate up to 1,000,000 reads spanning the CDR3 region of individual cells. Malignant clones were identified in diagnostic samples in all cases by a dominant CDR3 sequence. Before transplant, four patients had circulating Sézary cells by the routine flow cytometry, which was confirmed by TCRB HTS. Although the flow cytometry found no detectable Sézary cells, malignant clones were detected by TCRB HTS in all other six cases. Five patients achieved "molecular remission" in blood between +30 and +540 days after transplant. Four of these patients also achieved molecular clearance in skin after transplant. Experiments using blood samples spiked with purified Sézary cells demonstrated that TCRB HTS can detect Sézary cells at the level of 1 in 50,000 PBMCs, which is more sensitive than standard diagnostics. We have thus demonstrated the utility of TCRB HTS to assess MRD with increased sensitivity and specificity compared to other current methodologies, and to monitor response to therapy in this MF/SS patient population.

  View details for Web of Science ID 000328057800011

  View details for PubMedID 24307695

• Topical Chemotherapy in Cutaneous T-cell Lymphoma Positive Results of a Randomized, Controlled, Multicenter Trial Testing the Efficacy and Safety of a Novel Mechlorethamine, 0.02%, Gel in Mycosis Fungoides JAMA DERMATOLOGY Lessin, S. R., Duvic, M., Guitart, J., Pandya, A. G., Strober, B. E., Olsen, E. A., Hull, C. M., Knobler, E. H., Rook, A. H., Kim, E. J., Naylor, M. F., Adelson, D. M., Kimball, A. B., Wood, G. S., Sundram, U., Wu, H., Kim, Y. H. 2013; 149 (1): 25-32

  Abstract

  To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. DESIGN Randomized, controlled, observer-blinded, multicenter trial comparing mechlorethamine, 0.02%, gel with mechlorethamine, 0.02%, compounded ointment. Mechlorethamine was applied once daily for up to 12 months. Tumor response and adverse events were assessed every month between months 1 and 6 and every 2 months between months 7 and 12. Serum drug levels were evaluated in a subset of patients.Academic medical or cancer centers.In total, 260 patients with stage IA to IIA mycosis fungoides who had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine therapy.Response rates of all the patients based on a primary clinical end point (Composite Assessment of Index Lesion Severity) and secondary clinical end points (Modified Severity-Weighted Assessment Tool and time-to-response analyses).Response rates for mechlorethamine gel vs ointment were 58.5% vs 47.7% by the Composite Assessment of Index Lesion Severity and 46.9% vs 46.2% by the Modified Severity-Weighted Assessment Tool. By the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI, 0.97-1.55), which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P< .01). No drug-related serious adverse events were seen. Approximately 20.3% of enrolled patients in the gel treatment arm and 17.3% of enrolled patients in the ointment treatment arm withdrew because of drug-related skin irritation. No systemic absorption of the study medication was detected.The use of a novel mechlorethamine, 0.02%, gel in the treatment of patients with mycosis fungoides is effective and safe.clinicaltrials.gov Identifier:NCT00168064.

  View details for Web of Science ID 000317668000003

  View details for PubMedID 23069814

  View details for PubMedCentralID PMC3662469

• Transcriptome sequencing in Sezary syndrome identifies Sezary cell and mycosis fungoides-associated lncRNAs and novel transcripts BLOOD Lee, C. S., Ungewickell, A., Bhaduri, A., Qu, K., Webster, D. E., Armstrong, R., Weng, W., Aros, C. J., Mah, A., Chen, R. O., Lin, M., Sundram, U., Chang, H. Y., Kretz, M., Kim, Y. H., Khavari, P. A. 2012; 120 (16): 3288-3297

  Abstract

  Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sézary cells (SCs) versus nonmalignant CD4(+) T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis-regulation of PI3K/Akt, TGFβ, and NF-κB pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sézary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3' end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies.

  View details for DOI 10.1182/blood-2012-04-423061

  View details for Web of Science ID 000311619200020

  View details for PubMedID 22936659

  View details for PubMedCentralID PMC3476540

• Romidepsin Is Effective in Subcutaneous Panniculitis-Like T-Cell Lymphoma JOURNAL OF CLINICAL ONCOLOGY Bashey, S., Krathen, M., Abdulla, F., Sundram, U., Kim, Y. H. 2012; 30 (24): E221-E225

  View details for DOI 10.1200/JCO.2012.41.5976

  View details for Web of Science ID 000308082300002

  View details for PubMedID 22753921

• Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma BLOOD Horwitz, S. M., Kim, Y. H., Foss, F., Zain, J. M., Myskowski, P. L., Lechowicz, M. J., Fisher, D. C., Shustov, A. R., Bartlett, N. L., Delioukina, M. L., Koutsoukos, T., Saunders, M. E., O'Connor, O. A., Duvic, M. 2012; 119 (18): 4115-4122

  Abstract

  Systemic treatment for cutaneous T-cell lymphoma (CTCL) involves the use of less aggressive, well-tolerated therapies. Pralatrexate is a novel antifolate with high affinity for reduced folate carrier-1. A dose de-escalation strategy identified recommended pralatrexate dosing for patients with CTCL that demonstrated high activity, good rates of disease control, and an acceptable toxicity profile for continuous long-term dosing. Eligibility included mycosis fungoides, Sézary syndrome, or primary cutaneous anaplastic large cell lymphoma, with disease progression after ≥ 1 prior systemic therapy. The starting dose and schedule was 30 mg/m(2)/wk intravenously for 3 of 4 (3/4) weeks. Subsequent starting doses were 20, 15, and 10 mg/m(2)/wk for 3/4 or 2 of 3 (2/3) weeks. Response was evaluated by the modified severity-weighted adjustment tool. Fifty-four patients were treated. The recommended regimen was identified as 15 mg/m(2)/wk for 3/4 weeks and was explored in the expansion cohort. In 29 patients treated overall with the recommended dosing regimen, the median number of prior systemic therapies was 4. Pralatrexate was administered for a median of 4 cycles; response rate was 45%. The most common grade 3 adverse event (AE) was mucositis (17%); the only grade 4 AE was leukopenia (3%). Pralatrexate 15 mg/m(2)/wk for 3/4 weeks shows high activity with acceptable toxicity in patients with relapsed/refractory CTCL.

  View details for DOI 10.1182/blood-2011-11-390211

  View details for Web of Science ID 000305284600007

  View details for PubMedID 22394596

• In situ vaccination against mycosis fungoides by intratumoral injection of a TLR9 agonist combined with radiation: a phase 1/2 study BLOOD Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J. D., Czerwinski, D. K., Ai, W. Z., Morales, A., Abdulla, F., Xing, L., Navi, D., Tibshirani, R. J., Advani, R. H., Lingala, B., Shah, S., Hoppe, R. T., Levy, R. 2012; 119 (2): 355-363

  Abstract

  We have developed and previously reported on a therapeutic vaccination strategy for indolent B-cell lymphoma that combines local radiation to enhance tumor immunogenicity with the injection into the tumor of a TLR9 agonist. As a result, antitumor CD8(+) T cells are induced, and systemic tumor regression was documented. Because the vaccination occurs in situ, there is no need to manufacture a vaccine product. We have now explored this strategy in a second disease: mycosis fungoides (MF). We treated 15 patients. Clinical responses were assessed at the distant, untreated sites as a measure of systemic antitumor activity. Five clinically meaningful responses were observed. The procedure was well tolerated and adverse effects consisted mostly of mild and transient injection site or flu-like symptoms. The immunized sites showed a significant reduction of CD25(+), Foxp3(+) T cells that could be either MF cells or tissue regulatory T cells and a similar reduction in S100(+), CD1a(+) dendritic cells. There was a trend toward greater reduction of CD25(+) T cells and skin dendritic cells in clinical responders versus nonresponders. Our in situ vaccination strategy is feasible also in MF and the clinical responses that occurred in a subset of patients warrant further study with modifications to augment these therapeutic effects. This study is registered at www.clinicaltrials.gov as NCT00226993.

  View details for DOI 10.1182/blood-2011-05-355222

  View details for Web of Science ID 000299268900012

  View details for PubMedID 22045986

  View details for PubMedCentralID PMC3257006

• REVISITING LOW-DOSE TOTAL SKIN ELECTRON BEAM THERAPY IN MYCOSIS FUNGOIDES INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Harrison, C., Young, J., Navi, D., Riaz, N., Lingala, B., Kim, Y., Hoppe, R. 2011; 81 (4): E651-E657

  Abstract

  Total skin electron beam therapy (TSEBT) is a highly effective treatment for mycosis fungoides (MF). The standard course consists of 30 to 36 Gy delivered over an 8- to 10-week period. This regimen is time intensive and associated with significant treatment-related toxicities including erythema, desquamation, anhydrosis, alopecia, and xerosis. The aim of this study was to identify a lower dose alternative while retaining a favorable efficacy profile.One hundred two MF patients were identified who had been treated with an initial course of low-dose TSEBT (5-<30 Gy) between 1958 and 1995. Patients had a T stage classification of T2 (generalized patch/plaque, n = 51), T3 (tumor, n = 29), and T4 (erythrodermic, n = 22). Those with extracutaneous disease were excluded.Overall response (OR) rates (>50% improvement) were 90% among patients with T2 to T4 disease receiving 5 to <10 Gy (n = 19). In comparison, OR rates between the 10 to <20 Gy and 20 to <30 Gy subgroups were 98% and 97%, respectively. There was no significant difference in median progression free survival (PFS) in T2 and T3 patients when stratified by dose group, and PFS in each was comparable to that of the standard dose.OR rates associated with low-dose TSEBT in the ranges of 10 to <20 Gy and 20 to <30 Gy are comparable to that of the standard dose (≥ 30 Gy). Efficacy measures including OS, PFS, and RFS are also favorable. Given that the efficacy profile is similar between 10 and <20 Gy and 20 and <30 Gy, the utility of TSEBT within the lower dose range of 10 to <20 Gy merits further investigation, especially in the context of combined modality treatment.

  View details for DOI 10.1016/j.ijrobp.2011.01.023

  View details for Web of Science ID 000309412300060

  View details for PubMedID 21489711

• In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Kim, Y. H., Gratzinger, D., Harrison, C., Brody, J., Czerwinski, D., Xing, L., Morales, A., Ai, W., Abdulla, F., Navi, D., Tibshirani, R. J., Advani, R., Natkunam, Y., Hoppe, R. T., Levy, R. AMER SOC HEMATOLOGY. 2010: 130–30

  View details for Web of Science ID 000289662200287

• Identification of An Active, Well-Tolerated Dose of Pralatrexate In Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma (CTCL): Final Results of a Multicenter Dose-Finding Study. 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Horwitz, S. M., Kim, Y. H., Foss, F. M., Zain, J. M., Myskowski, P., Lechowicz, M. J., Fisher, D. C., Shustov, A., Bartlett, N. L., Delioukina, M. L., Koutsoukos, T., Fruchtman, S. M., O'Connor, O. A., Duvic, M. AMER SOC HEMATOLOGY. 2010: 1154–55

  View details for Web of Science ID 000289662203132

• Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma JOURNAL OF CLINICAL ONCOLOGY Whittaker, S. J., Demierre, M., Kim, E. J., Rook, A. H., Lerner, A., Duvic, M., Scarisbrick, J., Reddy, S., Robak, T., Becker, J. C., Samtsov, A., McCulloch, W., Kim, Y. H. 2010; 28 (29): 4485-4491

  Abstract

  The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL).This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells).Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients.Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.

  View details for DOI 10.1200/JCO.2010.28.9066

  View details for Web of Science ID 000282643600038

  View details for PubMedID 20697094

• In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study JOURNAL OF CLINICAL ONCOLOGY Brody, J. D., Ai, W. Z., Czerwinski, D. K., Torchia, J. A., Levy, M., Advani, R. H., Kim, Y. H., Hoppe, R. T., Knox, S. J., Shin, L. K., Wapnir, I., Tibshirani, R. J., Levy, R. 2010; 28 (28): 4324-4332

  Abstract

  Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

  View details for DOI 10.1200/JCO.2010.28.9793

  View details for Web of Science ID 000282272700032

  View details for PubMedID 20697067

  View details for PubMedCentralID PMC2954133

• Prognostic Factors in Primary Cutaneous Anaplastic Large Cell Lymphoma Characterization of Clinical Subset With Worse Outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D. K., Jones, C. R., Vanoli-Storz, M. N., Kohler, S., Reddy, S., Advani, R., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2009: 667–74

  Abstract

  To identify prognostic factors in primary cutaneous anaplastic large cell lymphoma (pcALCL), focusing on extensive limb disease (ELD), defined as initial presentation or progression to multiple skin tumors in 1 limb or contiguous body regions, and to study gene expression profiles of patients with pcALCL.Retrospective cohort study.The Stanford Comprehensive Cancer Center and dermatology ambulatory clinics.A total of 48 patients with pcALCL evaluated from 1990 through 2005.Hazard ratios (HRs) for prognostic factors for overall survival (OS) and disease-specific survival (DSS) and risk factors for progression to extracutaneous disease were identified using Cox regression. Gene expression profiles of 9 typical pcALCL and 3 ELD samples were investigated using complementary DNA microarrays.Univariate analysis demonstrated age, ELD, and progression to extracutaneous disease as significant prognostic factors for OS, whereas ELD and progression to extracutaneous disease were significant for DSS. In multivariate analysis, age (HR, 1.83; 95% confidence interval [CI], 1.02-3.26) and progression to extracutaneous disease (HR, 6.42; 95% CI, 1.39-29.68) remained significant for OS, whereas ELD (HR, 29.31; 95% CI, 1.72-500.82) and progression to extracutaneous disease (HR, 13.12; 95% CI, 1.03-167.96) remained independent prognostic factors for DSS. Presentation with T3 disease was a risk factor for progression to extracutaneous disease (HR, 10.20; 95% CI, 1.84-56.72). Microarray data revealed that patients with ELD and typical pcALCL formed distinct clusters.Patients with ELD have a more aggressive course associated with a differential gene expression profile. More aggressive treatments may be indicated for patients with ELD and those whose disease progresses to extracutaneous disease because they have poorer outcomes.

  View details for Web of Science ID 000267010900006

  View details for PubMedID 19528422

• Low dose pralatrexate (PDX) is active in cutaneous T-cell lymphoma: Preliminary results of a multi-center dose finding trial 10th International Conference on Malignant Lymphoma Horwitz, S., Duvic, M., Kim, Y., Chance, L., Myskowski, P., Talpur, R., MORALES, A., Saunders, M., O'Connor, O. OXFORD UNIV PRESS. 2008: 162–162

  View details for Web of Science ID 000256693500278

• TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC) BLOOD Kim, Y. H., Willemze, R., Pimpinelli, N., Whittaker, S., Olsens, E. A., Ranki, A., Dummer, R., Hoppe, R. T. 2007; 110 (2): 479-484

  Abstract

  Currently availabel staging systems for non-Hodgkin lymphomas are not useful for clinical staging classification of most primary cutaneous lymphomas. The tumor, node, metastases (TNM) system used for mycosis fungoides (MF) and Sézary syndrome (SS) is not appropriate for other primary cutaneous lymphomas. A usable, unified staging system would improve the communication about the state of disease, selection of appropriate management, standardization of enrollment/response criteria in clinical trials, and collection/analysis of prospective survival data. Toward this goal, during the recent meetings of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC), the representatives have established a consensus proposal of a TNM classification system applicable for all primary cutaneous lymphomas other than MF and SS. Due to the clinical and pathologic heterogeneity of the cutaneous lymphomas, the currently proposed TNM system is meant to be primarily an anatomic documentation of disease extent and not to be used as a prognostic guide.

  View details for DOI 10.1182/blood-2006-10-054601

  View details for Web of Science ID 000248112400008

  View details for PubMedID 17339420

• Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma BLOOD Kim, Y. H., Duvic, M., Obitz, E., Gniadecki, R., Iversen, L., Osterborg, A., Whittaker, S., Illidge, T. M., Schwarz, T., Kaufmann, R., Cooper, K., Knudsen, K. M., Lisby, S., Baadsgaard, O., Knox, S. J. 2007; 109 (11): 4655-4662

  Abstract

  The efficacy and safety of zanolimumab in patients with refractory cutaneous T-cell lymphoma (CTCL) have been assessed in two phase 2, multicenter, prospective, open-label, uncontrolled clinical studies. Patients with treatment refractory CD4(+) CTCL (mycosis fungoides [MF], n = 38; Sézary syndrome [SS], n = 9) received 17 weekly infusions of zanolimumab (early-stage patients, 280 and 560 mg; advanced-stage patients, 280 and 980 mg). The primary end point was objective response (OR) as assessed by composite assessment of index lesion disease activity score. Secondary end points included physician's global assessment (PGA), time to response, response duration, and time to progression. ORs were recorded for patients in both CTCL types (MF, 13 ORs; SS, 2 ORs). In the high-dose groups (560 and 980 mg dose groups), a response rate of 56% was obtained with a median response of 81 weeks. Adverse events reported most frequently included low-grade infections and eczematous dermatitis. Zanolimumab showed marked clinical efficacy in the treatment of patients with refractory MF, with early onset of response, high response rate, and durable responses. The treatment was well tolerated with no dose-related toxicity other than the targeted depletion of peripheral T cells. A pivotal study has been initiated based on these findings.

  View details for DOI 10.1182/blood-2006-12-062877

  View details for Web of Science ID 000246946100017

  View details for PubMedID 17311990

• Novel in situ vaccination with intratumoral injection of CpG 7909, a TLR 9 agonist, combined with radiation in mycosis fungoides and primary cutaneous B-cell lymphoma 68th Annual Meeting of the Society-for-Investigative-Dermatology Morales, A. V., Hoppe, R., Shah, S., Levy, R., Kim, Y. NATURE PUBLISHING GROUP. 2007: S43–S43

  View details for Web of Science ID 000245387800257

• TLR9 agonist immunomodulator treatment of cutaneous T-cell lymphoma (CTCL) with CPG7909. 46th Annual Meeting of the American-Society-of-Hematology Kim, Y., Girardi, M., Duvic, M., Kuzel, T., Rook, A., Link, B., Pinter-Brown, L., Comerci, C., McAuley, S., Schmalbach, T. AMER SOC HEMATOLOGY. 2004: 212A–213A

  View details for Web of Science ID 000225127500745

• HuMax-CD4, fully human monoclonal antibody: Phase II trial in cutaneous T cell lymphoma 65th Annual Meeting of the Society-for-Investigative-Dermatology Kim, Y. H., Obitz, E., Iversen, L., Oesterborg, A., Whittaker, S., Illidge, T. M., Schwarz, T., Kaufmann, R., Gniadecki, R., Duvic, M., Cooper, K., Jensen, P., Baadsgaard, O., Knox, S. J. NATURE PUBLISHING GROUP. 2004: A57–A57

  View details for Web of Science ID 000220660500392

• Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides de Coninck, E., Kim, Y., Varghese, A., Hoppe, R. NATURE PUBLISHING GROUP. 2001: 534–34

  View details for Web of Science ID 000170668300900

• Measurement of Quality of Life in Patients with Mycosis Fungoides/Sezary Syndrome Cutaneous T-Cell Lymphoma: Development of an Electronic Instrument JOURNAL OF MEDICAL INTERNET RESEARCH McCaffrey, S., Black, R. A., Nagao, M., Sepassi, M., Sharma, G., Thornton, S., Kim, Y. H., Braverman, J. 2019; 21 (1): e11302

  Abstract

  Although the quality of life (QoL) plays an important role in treatment decision making and clinical management of mycosis fungoides (MF) or Sézary syndrome (SS) subtypes of cutaneous T-cell lymphomas (MF/SS-CTCLs), an MF- or SS-specific measure of QoL does not exist.The objective of this research was to develop and validate the first QoL instrument for MF/SS-CTCL using a patient-centered approach.A conceptual framework for the MF/SS-CTCL QoL was developed through a literature review and interviews with key opinion leaders. Concept elicitation with patients was utilized to refine the conceptual model and generate preliminary items. The items were then revised based on qualitative and quantitative feedback obtained through cognitive debriefing surveys and interviews with patients. Next, participants (N=126) completed the preliminary MF/SS-CTCL QoL and a comparator measure of health-related QoL (Skindex-29) through the PatientsLikeMe Open Research Exchange. The MF/SS-CTCL QoL was completed again 5 days later by 66 participants for the purposes of evaluating test-retest reliability. The MF/SS-CTCL QoL was finalized based on results from an empirical evaluation, which included both classical and modern test theory approaches. Specifically, this included evaluation of (1) the optimal item response theory measurement model; (2) item fit; (3) unidimensionality; (4) rating scale performance; (5) reliability; (6) test information (precision); (7) person-to-item map; (8) convergent and discriminant validity; and (9) presence of bias via differential item function.Results from the comprehensive psychometric evaluation utilizing a Rasch-Grouped Rating Scale model yielded a final 12-item instrument. The rating scale functioned as expected, and the instrument exhibited adequate person reliability (.87), good to excellent test-retest reliability (r=.89, P<.001), high levels of measurement precision, and good person-to-item targeting. The correlation between the MF/SS-CTCL QoL and the Skindex-29 (r=.852, P<.001) was significantly greater than the correlation between the MF/SS-CTCL QoL and syndrome stage (r=.260, P<.001), providing support for convergent and discriminant validity. Items did not show significant bias based on gender, age, or race. Rasch scores were converted to scaled scores with qualitative descriptive categories for ease of interpretation.Empirical evaluation demonstrated strong evidence of excellent psychometric properties. Utilizing a patient-centered measure development approach ensures that this QoL instrument captures the information that is most meaningful and clinically relevant to patients.

  View details for DOI 10.2196/11302

  View details for Web of Science ID 000454979600001

  View details for PubMedID 30617041

  View details for PubMedCentralID PMC6329422

• Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma NEOPLASIA Zhao, L., Okhovat, J., Hong, E. K., Kim, Y. H., Wood, G. S. 2019; 21 (1): 82–92

  Abstract

  Advanced-stage cutaneous T-cell lymphoma (CTCL) is usually a fatal malignancy despite optimal use of currently available treatments. In this preclinical study of novel CTCL therapy, we performed in vitro and ex vivo experiments to determine the efficacy of combination treatment with a panel of BET bromodomain inhibitors (BETi) (JQ1, OTX015, CPI-0610, I-BET762) and HDAC inhibitors (HDACi) (SAHA/Vorinostat, Romidepsin). BETi/HDACi combinations were synergistic (combination index <1) against cell viability and induced G0/G1 cell cycle arrest. Apoptosis was uniformly enhanced. From a mechanistic standpoint, proliferative drivers c-Myc, Cyclin D1, NFkB, and IL-15Rα were reduced. Inhibitory CDKN1A was increased. CDKN1B, IL-7R, IL-17Rα, STAT3, and STAT5 alterations varied. There were significant increases in extrinsic apoptotic pathway death receptors and ligands (FasL, DR4, DR5, TRAIL, and TNFR1). At clinically tolerable levels of single agents, Romidepsin (1 nM) + OTX015 (125 nM) induced the greatest apoptosis (60%_80%) at 96 hours. Ex vivo studies of leukemic CTCL cells obtained from patients with Sezary syndrome also showed higher levels of apoptosis (about 60%-90%) in response to combination treatments relative to single agents. In contrast, combination treatment of normal CD4+ T cells induced only minimal apoptosis (<10%). Our findings show that the mechanism of action of BETi/HDACi therapy in CTCL involves induction of both cell cycle arrest and apoptosis with reduced proliferative drivers and enhanced expression of apoptotic extrinsic pathway death receptors and ligands. Relative to single agents, the superior anti-CTCL effects of BETi/HDACi combinations in vitro and ex vivo provide a rationale for clinical trials exploring their efficacy as therapy for CTCL.

  View details for DOI 10.1016/j.neo.2018.11.006

  View details for Web of Science ID 000454509400008

  View details for PubMedID 30529073

  View details for PubMedCentralID PMC6280696

• Role of imaging in low grade cutaneous B-cell lymphoma presenting in the skin. Journal of the American Academy of Dermatology Kheterpal, M. K., Dai, J., Geller, S., Pulitzer, M., Ni, A., Myskowski, P. L., Moskowitz, A., Kim, J., Hong, E. K., Fong, S., Hoppe, R. T., Kim, Y. H., Horwitz, S. M. 2019

  Abstract

  Whole body imaging is current standard of care for staging all patients presenting with skin lesion(s) of B-cell lymphomas (BCL), regardless of skin disease extent, however supporting data are lacking.To determine the clinical utility of imaging in detection of systemic involvement in low grade cutaneous B-cell lymphoma presenting in the skin.Retrospective cohort analysis of patients presenting with cutaneous lesions of BCLs at Memorial Sloan Kettering Cancer Center (MSKCC) and Stanford University (SU) from 1997-2016.At initial staging, of the 522 patients (306 marginal zone and 216 follicle-center cell histology), extracutaneous disease was noted in 3.6% and 8.8% of patients with MZL and FCL histology respectively. In patients with systemic involvement, imaging alone identified 81.8% (9/11) of MZL and 89.4% of follicular lymphoma (FL) cases. In primary cutaneous MZL (pc-MZL) and primary cutaneous follicle center lymphoma (pc-FCL), 1.7% and 3.0% subsequently developed extracutaneous involvement (median follow-up of 45 and 47 months respectively).Retrospective nature of this study.Imaging is effective in identifying the patients with systemic involvement in indolent BCLs presenting in the skin, however incidence is low. After negative initial staging, pc-MZL patients may be followed clinically without routine imaging.

  View details for DOI 10.1016/j.jaad.2019.01.037

  View details for PubMedID 30703460

• Long-Term Clinical Benefit to Anti-CCR4 Mogamulizumab: Results from the Phase 3 Mavoric Study in Previously Treated Cutaneous T-Cell Lymphoma (CTCL) Bagot, M., Dalle, S., Sokol, L., Tsianakas, A., Musiek, A., Ortiz-Romero, P., Poligone, B., Duvic, M., Elmets, C., Leoni, M., Dwyer, K., Sun, W., Nikonova, E., Kim, Y. H. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-118473

  View details for Web of Science ID 000454842800098

• Utility of CD30, Ki-67, and p53 in assisting with the diagnosis of mycosis fungoides with large cell transformation. Journal of cutaneous pathology Raghavan, S. S., Hong, E. K., Kim, Y. H., Kim, J. 2018

  Abstract

  INTRODUCTION: Mycosis fungoides (MF) with large cell transformation (LCT) is an advanced stage of cutaneous lymphoma with a poor prognosis. Identification of LCT is critical and especially challenging when the number of large abnormal lymphocytes is near but below 25%. We propose that Ki-67 and p53 may be useful in making this diagnosis.METHODS: We identified 17 patients with advanced stage (T3 or T4) MF without LCT and 38 patients with a biopsy-confirmed new diagnosis of MF with LCT treated at our institution's cutaneous lymphoma clinic from 2012 to 2016. Seventeen patients underwent 22 biopsies with advanced stage MF (control), and 38 patients with 46 biopsies of MF with LCT were included in this study.RESULTS: The MF cohort had an average CD30 expression of 4%, while the MF-LCT cohort had an average CD30 expression of 22% (P<0.05). The MF cohort had an average Ki-67 staining of 13%, while the MF-LCT group had an average Ki-67 staining of 57% (P<0.05). Forty-seven percent of the MF-LCT group was positive for p53; on the other hand, none of the MF control group showed increased p53 expression (P<0.05).DISCUSSION: While CD30 shows some value in delineating large cell transformation, Ki-67 and p53 appear to be useful immunohistochemical markers in the diagnosis of LCT.

  View details for DOI 10.1111/cup.13375

  View details for PubMedID 30328119

• Epigenetically Enhanced PDT Induces Significantly Higher Levels of Multiple Extrinsic Pathway Apoptotic Factors than Standard PDT, Resulting in Greater Extrinsic and Overall Apoptosis of Cutaneous T-cell Lymphoma PHOTOCHEMISTRY AND PHOTOBIOLOGY Salva, K. A., Kim, Y. H., Rahbar, Z., Wood, G. S. 2018; 94 (5): 1058–65

  Abstract

  Aminolevulinate-based photodynamic therapy (ALA-PDT) selectively eliminates diseased tissues primarily through the induction of intrinsic apoptotic pathway. ALA-PDT is a first-line therapy for actinic keratosis, however, it is less effective for cutaneous T-cell lymphoma (CTCL). We have previously demonstrated that the resistance of CTCL to apoptosis correlates with decreased expression of death receptors such as FAS, and that methotrexate functions as an epigenetic regulator that reestablishes the susceptibility of CTCL to extrinsic pathway apoptosis. We showed previously that MTX augments the effectiveness of PDT by sensitizing cells to apoptosis by induction of apoptotic factors, a process we call "epigenetically enhanced" PDT (ePDT). Here, in CTCL cell lines, leukemic CTCL cells, and normal blood T cells, we analyzed multiple components of the FAS, TRAIL, and TNF families using multispectral imaging of immunostained cytopreparations, a quantitative technique with five-fold greater sensitivity than standard immunocytology. ePDT induced significantly greater FAS, FASL, TRAIL-R1 & -R2, and TNFα levels than standard PDT. This correlated with significantly greater induction of extrinsic pathway apoptosis and/or overall apoptosis in all CTCL samples. There was no appreciable effect on normal T cells. These data set the stage for clinical trials of ePDT as a novel localized treatment of CTCL.

  View details for DOI 10.1111/php.12925

  View details for Web of Science ID 000444423500026

  View details for PubMedID 29675945

  View details for PubMedCentralID PMC6135680

• Responses to romidepsin in patients with cutaneous T-cell lymphoma and prior treatment with systemic chemotherapy LEUKEMIA & LYMPHOMA Duvic, M., Bates, S. E., Piekarz, R., Eisch, R., Kim, Y. H., Lerner, A., Robak, T., Samtsov, A., Becker, J. C., McCulloch, W., Waksman, J., Whittaker, S. 2018; 59 (4): 880–87

  Abstract

  Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had ≥1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to romidepsin, and response rates were similar to those in patients who were chemotherapy naïve. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy.

  View details for DOI 10.1080/10428194.2017.1361022

  View details for Web of Science ID 000426932300013

  View details for PubMedID 28853310

• The optimal regimen of brentuximab vedotin for CD30+ cutaneous lymphoma: are we there yet? The British journal of dermatology Geller, S., Myskowski, P. L., Kim, Y. H., Moskowitz, A., Horwitz, S. 2018; 178 (2): 571

  View details for DOI 10.1111/bjd.16052

  View details for PubMedID 29023638

• Results from a Phase I/II Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-cell Lymphoma CLINICAL CANCER RESEARCH Duvic, M., Kim, Y. H., Zinzani, P., Horwitz, S. M. 2017; 23 (14): 3552–56

  Abstract

  Purpose: Pralatrexate is a folic acid analogue metabolic inhibitor similar to methotrexate, which has shown tolerability and efficacy with an overall response rate of 45% in a phase I dose deescalation study of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).Experimental Design: The object of this phase I/II open-label, multicenter clinical trial was to determine the MTD and recommended dose of pralatrexate plus oral bexarotene in 34 patients with relapsed/refractory CTCL who had failed prior systemic therapies. Pralatrexate was administered by intravenous push at 15 mg/m2 given weekly 3 weeks out of 4 weeks with daily oral bexarotene (150 or 300 mg/m2), levothyroxine, atorvastatin, folate, and with B12 every 2 months.Results: At the MTD of 15 mg/m2 bexarotene and 15 mg/m2 pralatrexate, the response rate was 60% [4 complete responses (CR), 14 partial responses (PR)], the maximum observed response duration was 28.9+ months, and duration of response for 4 CRs ranged from 9.0 to 28.3 months. The median progression-free survival was 12.8 months (0.5-29.9). Mucositis was the most common adverse event.Conclusions: The combination of pralatrexate (15 mg/m2) and oral bexarotene (150 mg/m2) is active with high response rates and minimal toxicity for cutaneous T-cell lymphomas. Clin Cancer Res; 23(14); 3552-6. ©2017 AACR.

  View details for DOI 10.1158/1078-0432.CCR-16-2064

  View details for Web of Science ID 000405678400010

  View details for PubMedID 28167509

  View details for PubMedCentralID PMC5511551

• An adolescent with granulomatous mycosis fungoides infiltrating skeletal muscle successfully treated with oral prednisone. JAAD case reports Lewis, D. J., Turkeltaub, A. E., Dai, J., Nagarajan, P., Rieger, K. E., Nunez, C. A., Kim, Y. H., Duvic, M. 2017; 3 (4): 276–79

  View details for DOI 10.1016/j.jdcr.2017.03.001

  View details for PubMedID 28653029

• Phase 1 trial evaluating MRG-106, a synthetic inhibitor of microRNA-155, in patients with cutaneous t-cell lymphoma (CTCL). Foss, F. M., Querfeld, C., Porcu, P., Kim, Y. H., Pacheco, T., Halwani, A., DeSimone, J., William, B. M., Seto, A. G., Ruckman, J., Landry, M. L., Jackson, A. L., Pestano, L. A., Dickinson, B. A., Sanseverino, M., Rodman, D. M., Rubin, P., Gordon, G., Marshall, W. S. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.7564

  View details for Web of Science ID 000411932200019

• Characterization of the peripheral neuropathy associated with brentuximab vedotin treatment of Mycosis Fungoides and Sézary Syndrome. Journal of neuro-oncology Corbin, Z. A., Nguyen-Lin, A., Li, S., Rahbar, Z., Tavallaee, M., Vogel, H., Salva, K. A., Wood, G. S., Kim, Y. H., Nagpal, S. 2017

  Abstract

  Chemotherapy-induced peripheral neuropathy (CIPN) is common, frequently limits chemotherapy dosing, and negatively impacts quality of life. The National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0, and the Total Neuropathy Score clinical version (TNSc) are both validated scores to quantify peripheral neuropathy (PN), with the TNSc being more sensitive to clinical changes. Mycosis fungoides and Sézary syndrome (MF/SS) are characterized by a chronic course, where current therapies are generally non-curative and treatment toxicities have the potential for significant lasting effects. Brentuximab vedotin (BV) is an antibody-drug-conjugate composed of an anti-CD30 monoclonal antibody linked to the microtubule-disrupting agent, monomethyl auristatin E, with a known associated CIPN. In our phase II clinical trial of BV in MF/SS, 25 (69%) of 36 patients developed PN, with 18 (50%) developing Clinically Significant PN, CTCAE v4.0 grade 2 or higher. The median time to grade 2 PN was 15 weeks (range 0.4-48) after the initial dose. By Kaplan-Meier calculation, the median time to improvement from Clinically Significant PN was 30 weeks from the last BV dose. Seventy-four percent had improvement by 24 months. We found that TNSc scores significantly correlated with CTCAE grade, with Spearman correlation coefficient 0.68 (p < 0.001). By logistic regression, for each 100 mg increase in BV total dose, the likelihood of developing Clinically Significant PN increased by 23% (95% CI 4-46%). Improved monitoring of CIPN associated with BV is of paramount importance in the MF/SS population.

  View details for DOI 10.1007/s11060-017-2389-9

  View details for PubMedID 28271282

• Zosteriform Mycosis Fungoides: A New Clinical Presentation With a Dermatomal Distribution. The American Journal of dermatopathology Rieger, K. E., Kim, J., Kim, Y. H. 2017; 39 (2): e17-e18

  Abstract

  Classic mycosis fungoides (MF) presents with patches and plaques on the trunk and proximal extremities. However, numerous clinicopathologic variants have been described, making diagnosis challenging. Here, the authors report a 21-year-old woman with immunophenotypically and molecularly confirmed MF occurring in a dermatomal distribution. Awareness of this and other rare variants of MF is critical to avoid misdiagnosis.

  View details for DOI 10.1097/DAD.0000000000000652

  View details for PubMedID 28134736

• Localized skin-limited blastic plasmacytoid dendritic cell neoplasm: A subset with possible durable remission without transplantation. JAAD case reports Amitay-Laish, I., Sundram, U., Hoppe, R. T., Hodak, E., Medeiros, B. C., Kim, Y. H. 2017; 3 (4): 310–15

  View details for DOI 10.1016/j.jdcr.2017.03.015

  View details for PubMedID 28752118

  View details for PubMedCentralID PMC5517837

• Neurotropic Gamma-Delta T-Cell Lymphoma With CD30-Positive Lymphoid Infiltrates AMERICAN JOURNAL OF DERMATOPATHOLOGY Gammon, B., Gammon, B. R., Kim, Y. H., Kim, J. 2016; 38 (9): E133-E136

  Abstract

  Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a clonal proliferation of gamma-delta T cells with a cytotoxic phenotype that is typically characterized by an aggressive clinical course with ulcerative plaques or subcutaneous nodules. In this report, the authors describe a patient who developed an ulcerated tumor on the left upper extremity and painful papules and nodules on the right lower extremity. Interestingly, several of the papulonodules on the right lower extremity underwent spontaneous involution. A skin biopsy of the papulonodular lesion demonstrated a superficial and deep perivascular interstitial infiltrate with a population of pleomorphic enlarged CD30-positive T cells. These enlarged lymphocytes lacked expression of TCR beta, CD4, CD8, and the pan T-cell antigen CD7, but were positive for TCR gamma, supporting the diagnosis of PCGD-TCL. The patient rapidly developed pain and severe weakness in the left upper limb and MRI revealed extensive neurolymphomatosis of the left brachial plexus. The patient was treated with chemotherapy with complete remission achieved. Unfortunately, her response was transient and the patient relapsed and ultimately died due to her disease. In this article, the authors describe an extraordinary case of a CD30-positive PCGD-TCL to expand the histopathological spectrum of CD30-positive and gamma-delta-positive lymphoproliferative disorders.

  View details for DOI 10.1097/DAD.0000000000000560

  View details for Web of Science ID 000382251800002

  View details for PubMedID 27391454

• Non-Hodgkin's Lymphomas, Version 3.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Horwitz, S. M., Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H., Porcu, P. 2016; 14 (9): 1067-1079

  Abstract

  Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

  View details for Web of Science ID 000382903900004

• Useful Parameters for Distinguishing Subcutaneous Panniculitis-like T-Cell Lymphoma From Lupus Erythematosus Panniculitis AMERICAN JOURNAL OF SURGICAL PATHOLOGY LeBlanc, R. E., Tavallaee, M., Kim, Y. H., Kim, J. 2016; 40 (6): 745-754

  Abstract

  Some cases of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and lupus erythematosus panniculitis (LEP) demonstrate clinical and histopathologic overlap, raising the possibility that they represent opposite ends of a disease spectrum. SPTCL, however, is typically associated with greater morbidity and risk for hemophagocytic lymphohistiocytosis (HLH); therefore, diagnostic distinction is clinically important. We present the histopathologic, immunophenotypic, and molecular findings with long-term clinical follow-up of 13 patients with SPTCL (median, 64 mo follow-up) and 7 with LEP (median, 50 mo follow-up) in our multidisciplinary cutaneous oncology clinic. Six SPTCL patients developed HLH, including 2 under the age of 21 years. In the SPTCL group, 2 of 13 patients died of disease. In contrast, we had no mortality or development of HLH in our LEP cohort. We demonstrate that a limited panel (Ki-67, CD3, CD4, and CD8 immunostains) reveals foci of "Ki-67 hotspots" enriched in cytotoxic atypical CD8+ T cells in SPTCL. Ki-67 hotspots were not identified in LEP, thus aiding the distinction of SPTCL from LEP. Lymphocyte atypia combined with adipocyte rimming of CD8+ T cells within Ki-67 hotspots was also highly specific for the diagnosis of SPTCL. Hyaline lipomembranous change, B-cell aggregates, plasmacytoid dendritic cell clusters, and plasma cell aggregates favored the diagnosis of LEP but were identified in some cases of SPTCL including patients with HLH. We confirm that SPTCL and LEP can show significant histologic overlap, suggest a role for high-throughput sequencing in confirming neoplastic clones, and introduce the concept of SPTCL "Ki-67 hotspots" in evolving disease.

  View details for Web of Science ID 000376458700004

  View details for PubMedID 26796503

• Experimental treatment strategies in primary cutaneous T-cell lymphomas CURRENT OPINION IN ONCOLOGY Rozati, S., Kim, Y. H. 2016; 28 (2): 166-171

  Abstract

  Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of malignancies derived from skin-homing or resident T cells. Effective treatments are limited, thus new therapies are in development to address the unmet medical need.Recent studies uncovering the genetic alteration in cutaneous T-cell lymphoma have enhanced our understanding of the importance of the T-cell activation/survival pathways, dysregulated immune system, and the relevance of chromatin modification in the pathogenesis of CTCL. New advances in cancer immunomodulation such as with PD1/PD-L1 inhibitors and novel targeted antitumor therapies such as brentuximab vedotin and mogamulizumab as well as potential combination strategies are promising for improving clinical efficacy with manageable toxicity profile.All these new therapeutic approaches have resulted in broadening the treatment landscape and a potential paradigm shift in the management of CTCL.

  View details for DOI 10.1097/CCO.0000000000000272

  View details for Web of Science ID 000369538700011

  View details for PubMedID 26844985

• Diffuse Large B-Cell Lymphoma Version 1.2016 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Zelenetz, A. D., Gordon, L. I., Wierda, W. G., Abramson, J. S., Advani, R. H., Andreadis, C. B., Bartlett, N., Byrd, J. C., Fayad, L. E., Fisher, R. I., Glenn, M. J., Habermann, T. M., Harris, N. L., Hernandez-Ilizaliturri, F., Hoppe, R. T., Horwitz, S. M., Kaminski, M. S., Kelsey, C. R., Kim, Y. H., Krivacic, S., LaCasce, A. S., Lunning, M., Nademanee, A., Porcu, P., Press, O., Rabinovitch, R., Reddy, N., Reid, E., Roberts, K., Saad, A. A., Sokol, L., Swinnen, L. J., Vose, J. M., Yahalom, J., Zafar, N., Dwyer, M., Sundar, H. 2016; 14 (2): 196-231

  Abstract

  Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

  View details for Web of Science ID 000369634300011

• Results from a Phase 1/2, Open-Label, Dose-Finding Study of Pralatrexate and Oral Bexarotene in Patients with Relapsed/Refractory Cutaneous T-Cell Lymphoma Duvic, M., Horwitz, S. M., Kim, Y. H., Zinzani, P., Bhat, G., Sharma, P., Yancik, S. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368020102189

• Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. Journal of clinical oncology Kim, Y. H., Tavallaee, M., Sundram, U., Salva, K. A., Wood, G. S., Li, S., Rozati, S., Nagpal, S., Krathen, M., Reddy, S., Hoppe, R. T., Nguyen-Lin, A., Weng, W., Armstrong, R., Pulitzer, M., Advani, R. H., Horwitz, S. M. 2015; 33 (32): 3750-3758

  View details for DOI 10.1200/JCO.2014.60.3969

  View details for PubMedID 26195720

• Subcutaneous Panniculitis-Like T-Cell Lymphoma: Pediatric Case Series Demonstrating Heterogeneous Presentation and Option for Watchful Waiting PEDIATRIC BLOOD & CANCER Johnston, E. E., LeBlanc, R. E., Kim, J., Chung, J., Balagtas, J., Kim, Y. H., Link, M. P. 2015; 62 (11): 2025-2028

  Abstract

  Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and primary cutaneous gamma delta T-cell lymphoma (PCGD-TCL) were initially both classified as subcutaneous panniculitis-like T-cell lymphoma. In 2008, SPTCL with alpha-beta T-cell receptor subtype was separated from primary cutaneous gamma delta T-cell lymphomas (PCGD-TCL). We report four pediatric cases that demonstrate the heterogeneity of each disease and show that PCGD-TCL in children can have an indolent course, whereas SPTCL can behave aggressively. Three patients had spontaneous, durable remissions without treatment, whereas the one patient with disease progression was treated successfully. Watchful waiting may thus be appropriate for initial management of children.

  View details for DOI 10.1002/pbc.25626

  View details for Web of Science ID 000364581100029

  View details for PubMedID 26146844

• Clinically significant responses achieved with romidepsin across disease compartments in patients with cutaneous T-cell lymphoma LEUKEMIA & LYMPHOMA Kim, E. J., Kim, Y. H., Rook, A. H., Lerner, A., Duvic, M., Reddy, S., Robak, T., Becker, J. C., Samtsov, A., McCulloch, W., Waksman, J., Whittaker, S. 2015; 56 (10): 2847-2854

  Abstract

  Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in clinical trials of CTCL there has been little consistency in how responses were defined in each disease "compartment"; some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy and/or blood involvement.

  View details for DOI 10.3109/10428194.2015.1014360

  View details for Web of Science ID 000365241700015

  View details for PubMedID 25791237

  View details for PubMedCentralID PMC4732431

• Occult Dermal Lymphatic Involvement Is Frequent in Primary Cutaneous Anaplastic Large Cell Lymphoma. American Journal of dermatopathology Gratzinger, D., Million, L., Kim, Y. H. 2015; 37 (10): 767-770

  Abstract

  Primary cutaneous anaplastic large cell lymphoma (pcALCL) is an indolent T-cell lymphoproliferative disorder managed with low-dose radiation therapy, surgery, and/or mild chemotherapy; patients with extensive limb disease (ELD) have a more aggressive clinical course. We have previously demonstrated that histologically apparent vascular involvement in pcALCL is lymphatic. We hypothesized that histologically occult lymphatic involvement may be associated with particular patterns of disease spread that could involve lymphangitic spread including locoregional spread of disease in the form of ELD and extracutaneous spread of disease. We have therefore set out to quantitate the incidence of occult lymphovascular involvement in pcALCL and to assess for an association between lymphovascular involvement and these patterns of disease. We performed immunohistochemistry for the lymphovascular marker D2-40 on skin biopsies from 29 patients with pcALCL followed in the Stanford Cutaneous Lymphoma Clinic. Immunohistochemically evident dermal lymphovascular involvement was found in nearly half of cases examined (48%; 95% confidence interval, 29%-67%). There was a nonsignificant trend toward a higher prevalence of ELD among patients with pcALCL involving dermal lymphatics (7% vs. 29%; p = 0.12). In this small cohort, there was no indication of a significantly more aggressive disease course in patients with lymphatic involvement either in the form of disease-related mortality (one each in the lymphatic and nonlymphatic groups) or in time to extracutaneous involvement.

  View details for DOI 10.1097/DAD.0000000000000377

  View details for PubMedID 26381026

• Lymph node involvement by mycosis fungoides and Sezary syndrome mimicking angioimmunoblastic T-cell Lymphoma HUMAN PATHOLOGY LeBlanc, R. E., Lefterova, M. I., Suarez, C. J., Tavallaee, M., Kim, Y. H., Schrijver, I., Kim, J., Gratzinger, D. 2015; 46 (9): 1382-1389

  Abstract

  Clinical management of cutaneous T-cell lymphoma (CTCL) and angioimmunoblastic T-cell lymphoma (AITL) differs markedly. Diagnostic distinction is critical. Herein, we describe a series of 4 patients with clinically, molecularly, and histopathologically annotated mycosis fungoides or Sézary syndrome whose nodal disease mimicked AITL. The patients otherwise exhibited classic clinical manifestations of mycosis fungoides/Sézary syndrome preceding the onset of lymphadenopathy by 1 to 5 years. Skin biopsies revealed epidermotropic infiltrates characteristic of CTCL. Lymph node biopsies revealed dense CD4+ T-cell infiltrates that coexpressed follicular helper T-cell markers and were accompanied by proliferations of high endothelial venules and arborizing CD21+ follicular dendritic cell networks. Two patients had T-cell receptor gene rearrangement studies performed on their skin, lymph node, and peripheral blood demonstrating identical polymerase chain reaction clones in all 3 tissues. A small secondary clonal B-cell population was present in 1 patient that mimicked the B-cell proliferations known to accompany AITL and persisted on successive nodal biopsies over several years. This latter phenomenon has not previously been described in CTCL. The potential for patients to be misdiagnosed with AITL for lack of consideration of advanced-stage CTCL with nodal involvement underscores the necessity of information sharing among the various pathologists and clinicians involved in the care of each patient.

  View details for DOI 10.1016/j.humpath.2015.05.024

  View details for Web of Science ID 000360779200017

• KIR3DL2 is a novel target for antibody-therapy of T cell lymphomas Chester, C., Lim, S., Marie-Cardine, A., Rajasekaran, N., Sicard, H., Kim, Y., Kohrt, H. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.AM2015-2473

  View details for Web of Science ID 000371578505073

• Primary Cutaneous Gamma-Delta T-Cell Lymphoproliferative Disorder in a 3-Year-Old Boy. American Journal of dermatopathology Soon, C. W., Link, M., Kim, Y. H., Kim, J. 2015; 37 (7): 567-569

  Abstract

  Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare disorder, constituting less than 1% of primary cutaneous lymphomas. Most cases occur in adults and may present as plaques or nodules with ulceration. Here we describe an unusual case of PCGD-TCL in a 3-year-old boy who presented with asymptomatic subcutaneous nodules. To our knowledge, this report represents one of the youngest reported patients with gamma-delta lymphoma/lymphoproliferative disorder. In addition, our patient has an indolent clinical presentation with greater than 1 year clinical follow-up. Because gamma-delta T-cell lymphomas are exceedingly rare in children, we acknowledge that the clinical course/outcome in young patients is still unclear. We hope to add to the recognition that PCGD-TCLs demonstrate a wide clinical spectrum of disease with relatively indolent presentations in some cases.

  View details for DOI 10.1097/DAD.0000000000000185

  View details for PubMedID 25072685

• Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma. Blood Duvic, M., Pinter-Brown, L. C., Foss, F. M., Sokol, L., Jorgensen, J. L., Challagundla, P., Dwyer, K. M., Zhang, X., Kurman, M. R., Ballerini, R., Liu, L., Kim, Y. H. 2015; 125 (12): 1883-1889

  Abstract

  This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927.

  View details for DOI 10.1182/blood-2014-09-600924

  View details for PubMedID 25605368

  View details for PubMedCentralID PMC4375715

• Reduction of Regulatory T Cells by Mogamulizumab, a Defucosylated Anti-CC Chemokine Receptor 4 Antibody, in Patients with Aggressive/Refractory Mycosis Fungoides and Sezary Syndrome CLINICAL CANCER RESEARCH Ni, X., Jorgensen, J. L., Goswami, M., Challagundla, P., Decker, W. K., Kim, Y. H., Duvic, M. A. 2015; 21 (2): 274–85

  Abstract

  The CC chemokine receptor 4 (CCR4) is expressed on malignant T cells in cutaneous T-cell lymphoma (CTCL) as well as on regulatory T cells (Treg). When mogamulizumab, a defucosylated monoclonal antibody, binds to CCR4, it induces antibody-dependent cellular cytotoxicity against CCR4(+) malignant T cells. The goal of this study was to determine the effect of mogamulizumab on CCR4(+) Tregs in patients with CTCL.Peripheral blood of 24 patients with CTCL participating in a phase I/II trial was analyzed for CCR4 expression on different T-cell subsets by flow cytometry, before and after one course of mogamulizumab. The number and function of natural killer (NK) cells were also analyzed. Lesional biopsies were examined for CCR4, Foxp3, and CD16 expression by immunohistochemistry.Malignant T cells in peripheral blood were 20.8%-100% positive for CCR4 at baseline. Fourteen patients who achieved a response in blood had high baseline CCR4 expression on malignant T cells. Tregs in blood were 58.6% to 100% positive for CCR4 at baseline and showed decreased numbers and CCR4 expression after treatment. CD8(+) T cells in blood were 3.2% to 23.2% positive for CCR4 at baseline and showed limited reduction of CCR4 expression with increased percentages of CD8(+) T cells after treatment. Of 14 patients tested for NK cells in blood, 10 showed increased percentages after treatment. Four of 6 patients tested showed increased NK cell cytotoxicity. Sixteen of 18 patients who had CCR4(+) lymphocytes in baseline lesions showed decreased numbers after treatment.Mogamulizumab reduces levels of CCR4(+) malignant T cells and also CCR4(+) Tregs in patients with CTCL, which may in turn improve immune profiles. Clin Cancer Res; 21(2); 274-85. ©2014 AACR.

  View details for DOI 10.1158/1078-0432.CCR-14-0830

  View details for Web of Science ID 000347938200008

  View details for PubMedID 25376389

• Responses to Romidepsin in Patients with Cutaneous T-Cell Lymphoma (CTCL) and Prior Treatment with Systemic Chemotherapy: Subanalysis from the Pivotal Phase 2 Study Duvic, M., Kim, Y. H., Rook, A. H., Lerner, A., Robak, T., Samtsov, A., McCulloch, W., Waksman, J., Whittaker, S. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243506159

• Dose-Escalated, Intratumoral TLR9 Agonist and Low-Dose Radiation Induce Abscopal Effects in Follicular Lymphoma Kohrt, H. E., Chu, J., Brody, J., Czerwinski, D. K., Chester, C., Sadaram, M., Advani, R., Kim, Y. H., Hoppe, R. T., Knox, S. J., Wapnir, I., Tibshirani, R. J., Levy, R. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233804172

• A Dose Finding Lead-in Study of E7777 (Diphtheria toxin fragment-Interleukin-2 Fusion Protein) in Persistent or Recurrent Cutaneous T-Cell Lymphoma (CTCL) Duvic, M., Kuzel, T. M., Dang, N. H., Prince, M., Feldman, T., Foss, F. M., Guo, M., Ottesen, L., Ooi, C., Kim, Y. H. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233801178

• Intralymphatic Cutaneous Anaplastic Large Cell Lymphoma/Lymphomatoid Papulosis: Expanding the Spectrum of CD30-positive Lymphoproliferative Disorders. American journal of surgical pathology Samols, M. A., Su, A., Ra, S., Cappel, M. A., Louissant, A., Knudson, R. A., Ketterling, R. P., Said, J., Binder, S., Harris, N. L., Feldman, A. L., Kim, J., Kim, Y. H., Gratzinger, D. 2014; 38 (9): 1203-1211

  Abstract

  Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.

  View details for DOI 10.1097/PAS.0000000000000217

  View details for PubMedID 24805854

• Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous t-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome). Annals of oncology Dummer, R., Duvic, M., Scarisbrick, J., Olsen, E. A., Rozati, S., Eggmann, N., Goldinger, S. M., Hutchinson, K., Geskin, L., Illidge, T. M., Giuliano, E., Elder, J., Kim, Y. H. 2014; 25 (9): 1807-1812

  Abstract

  Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL).In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients.All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure.Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

  View details for DOI 10.1093/annonc/mdu231

  View details for PubMedID 24948692

• Outcomes After Diagnosis of Mycosis Fungoides and Sezary Syndrome Before 30 Years of Age A Population-Based Study JAMA DERMATOLOGY Ai, W. Z., Keegan, T. H., Press, D. J., Yang, J., Pincus, L. B., Kim, Y. H., Chang, E. T. 2014; 150 (7): 709-715

  Abstract

  Mycosis fungoides and Sézary syndrome (MF/SS) are rare in children and young adults, and thus the incidence and outcomes in this patient population are not well studied.To assess the incidence and outcomes of MF/SS in patients diagnosed before 30 years of age.Retrospective study of 2 population-based cancer registries-the California Cancer Registry (n = 204) and 9 US cancer registries of the Surveillance, Epidemiology, and End Results program (SEER 9; n = 195)-for patients diagnosed with MF/SS before 30 years of age.Overall survival was calculated by the Kaplan-Meier method. The risk of a second cancer was assessed by calculating the standard incidence ratio (SIR) comparing observed cancer incidence in patients with MF/SS with the expected incidence in the age-, sex-, and race-standardized general population.The incidence of MF/SS is rare before 30 years of age, with an incidence rate of 0.05 per 100,000 persons per year before age 20 years and 0.12 per 100,000 persons per year between ages 20 and 29 years in the California Cancer Registry. At 10 years, patients with MF/SS had an overall survival of 94.3% (95% CI, 89.6%-97.2%) in the California Cancer Registry and 88.9% (95% CI, 82.4%-93.2%) in SEER 9. In SEER 9, there was a significant excess risk of all types of second cancers combined (SIR, 3.40; 95% CI, 1.55-6.45), particularly lymphoma (SIR, 12.86; 95% CI, 2.65-37.59) and melanoma (SIR, 9.31; 95% CI, 8.75-33.62). In the California Cancer Registry, the SIR for risk of all types of second cancers was similar to that in SEER 9 (SIR, 3.45; 95% CI, 0.94-8.83), although not statistically significant.Young patients with MF/SS have a favorable outcome, despite a strong suggestion of an increased risk of second primary cancers. Prolonged follow-up is warranted to definitively assess their risk of developing second cancers in a lifetime.

  View details for DOI 10.1001/jamadermatol.2013.7747

  View details for Web of Science ID 000339652400004

  View details for PubMedID 24718769

• Prognostic factors, prognostic indices and staging in mycosis fungoides and Sezary syndrome: where are we now? BRITISH JOURNAL OF DERMATOLOGY Scarisbrick, J. J., Kim, Y. H., Whittaker, S. J., Wood, G. S., Vermeer, M. H., Prince, H. M., Quaglino, P. 2014; 170 (6): 1226-1236

  Abstract

  Mycosis fungoides is the most prevalent form of primary cutaneous T-cell lymphoma. Patients frequently present with early-stage disease typically associated with a favourable prognosis and survival of 10-35 years, but over 25% may progress to advanced disease with a median survival < 4 years, and just 13 months in those with nodal involvement. Sézary syndrome presents in advanced disease with erythroderma, blood involvement and lymphadenopathy. The Bunn and Lamberg staging system (1979) includes stages IA-IIA (early-stage disease) and IIB-IVB (advanced-stage disease) and provides prognostic information, but some patients with tumour-stage disease (IIB) have a worse prognosis than those with erythrodermic-stage (III). Conversely, patients with plaque-stage (IB) folliculotropic mycosis fungoides may have a worse outcome than those with tumour-stage (IIB). The more recent staging system of the European Organisation for the Research and Treatment of Cancer/International Society for Cutaneous Lymphoma has been designed to reflect tumour burden at different sites. However, this staging system has not been validated prospectively for prognosis. Furthermore, this staging system does not include a detailed measurement of skin tumour burden, as indicated by the modified skin weighted severity assessment tool. This assessment measures body surface area of disease and is weighted to record patch, plaque and tumour to produce a numerical value from 0·5 to 400 and is an established endpoint for clinical studies. Nor does this staging include clinicopathological features associated with a poor prognosis such as folliculotropism. Here we review the clinical, haematological, pathological and genotypic parameters outside the staging system, which may affect survival in mycosis fungoides and Sézary syndrome. Most studies are retrospective and single centre. The identification of poor prognostic factors may be used to develop a prognostic index to use alongside staging, which may be of benefit in mycosis fungoides/Sézary syndrome to identify patients with a potentially poor prognosis.

  View details for DOI 10.1111/bjd.12909

  View details for Web of Science ID 000337952200131

  View details for PubMedID 24641480

• Responses to romidepsin in patients with cutaneous T-cell lymphoma (CTCL) with tumors and/or folliculotropic involvement. Foss, F. M., Duvic, M., Lerner, A., Rook, A., Whittaker, S., Kim, E. J., Kim, Y. H. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.8575

  View details for Web of Science ID 000358613204254

• Phase 3 study of anti-CCR4 monoclonal antibody mogamualizumab versus vorinostat in relapsed or refractory cutaneous T-cell lymphoma (CTCL) Kim, Y. H., Bagot, M., Eradat, H., Carson, K., Greer, J. P., Kim, E. J., Kuzel, T., Hughey, L. C., Pollgone, B., Lansigan, F., Zinrani, P., Grandinetti, L. M., Porcu, P., Shustov, A. R., Korman, N., Halwani, A., Sokol, L., Duvic, M., Kyowa Hakko Kirin Pharma Author's AMER SOC CLINICAL ONCOLOGY. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.tps8623

  View details for Web of Science ID 000358613202225

• Efficacy and safety of mechlorethamine (MCH) 0.04% gel in mycosis fungoides (MF) after treatment with topical MCH 0.02%. Kim, Y. H., Duvic, M., Guitart, J., Lessin, S. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for DOI 10.1200/jco.2014.32.15_suppl.9093

  View details for Web of Science ID 000358613204378

• Multicenter Case Series of Indolent Small/Medium-Sized CD8+ Lymphoid Proliferations With Predilection for the Ear and Face. American Journal of dermatopathology Li, J. Y., Guitart, J., Pulitzer, M. P., Subtil, A., Sundram, U., Kim, Y., Deonizio, J., Myskowski, P. L., Moskowitz, A., Horwitz, S., Querfeld, C. 2014; 36 (5): 402-408

  Abstract

  We report 7 cases of a CD8 lymphoid proliferation of the ear and face with a cytotoxic T-cell phenotype, but an indolent clinical course. All patients presented with stable or slowly growing asymptomatic lesions on the ear, nose, or lower eyelid. Histopathology showed a dense diffuse dermal infiltrate of small- to medium-sized atypical lymphocytes without destructive features. The lymphocytes were positive for CD3, CD8, β-F1, and TIA-1 and negative for CD4, CD30, CD56, granzyme B, and PD-1. Of note, the proliferation index was low in available cases. All patients remained in complete remission at median follow-up of 14 months regardless of treatment modality. Staging was negative for extracutaneous disease in all patients. The clinically indolent behavior and histopathologic phenotype together with a low proliferation index (10%-15%) emphasize the importance of accurate diagnosis and appropriate clinical management to avoid overtreatment and complications of therapy.

  View details for DOI 10.1097/DAD.0b013e3182a74c7a

  View details for PubMedID 24394306

• Utility of high-throughput sequencing of T cell receptor gene rearrangement to improve diagnosis in cutaneous T cell lymphoma Annual Meeting of the Society-for-Investigative-Dermatology (SID) Rozati, S., Weng, W., Tavallaee, M., Kim, J., Rieger, K., Armstrong, R., Kirsch, I., Kim, Y. H. NATURE PUBLISHING GROUP. 2014: S96–S96

  View details for Web of Science ID 000334560400549

• A multicenter, open-label, randomized, phase I/II study evaluating the safety and efficacy of low-dose (12 Gy) total skin electron beam therapy (TSEBT) combined with vorinostat versus low-dose TSEBT monotherapy in patients with mycosis fungoides Annual Meeting of the Society-for-Investigative-Dermatology (SID) Bashey, S., Tavallaee, M., Duvic, M., Dabaja, B., Talpur, R., Wilson, L., Grardi, M., Foss, F., Li, S., Rozati, S., Million, L., Hoppe, R., Kim, Y. H. NATURE PUBLISHING GROUP. 2014: S104–S104

  View details for Web of Science ID 000334560400596

• Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sezary syndrome. Blood Querfeld, C., Rosen, S. T., Guitart, J., Duvic, M., Kim, Y. H., Dusza, S. W., Kuzel, T. M. 2014; 123 (8): 1159-1166

  Abstract

  A phase 2 multicenter trial was performed to evaluate single-agent lenalidomide in advanced, refractory mycosis fungoides/Sézary syndrome. Thirty-two patients were enrolled with a median of 6 prior treatment regimens, including a median of 4 systemic therapies. Patients achieved an overall response rate of 28% (9 patients), and all were partial responses. Median overall survival was 43 months, median progression-free survival was 8 months, and median duration of response was 10 months. No grade 4 toxicities occurred. Grade 3 adverse events included fatigue (22%), infection (9%), and leukopenia (3%). Patients were frequently unable to tolerate the 25-mg starting dose of lenalidomide used in other hematologic malignancies due to fatigue, pain, and transient flare reaction (TFR) as a contributory factor. TFR appeared to correlate with clinical response, but the small sample size limited definitive conclusions, and the underlying mechanisms of this reaction are not known. Data from correlative studies on peripheral blood samples suggest that the effects of lenalidomide could be associated with decreased circulating CD25(+) T cells and CD4(+) T-cell numbers. Skin lesions showed a trend for increased CD8, CD25, and FoxP3 expression with decreased CD4:CD8 ratio. In conclusion, lenalidomide monotherapy demonstrated activity in refractory cutaneous T-cell lymphomas, along with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT00466921.

  View details for DOI 10.1182/blood-2013-09-525915

  View details for PubMedID 24335103

• Intravascular ALK-negative Anaplastic Large Cell Lymphoma With Localized Cutaneous Involvement and an Indolent Clinical Course Toward Recognition of a Distinct Clinicopathologic Entity AMERICAN JOURNAL OF SURGICAL PATHOLOGY Metcalf, R. A., Bashey, S., Wysong, A., Kim, J., Kim, Y. H., Gratzinger, D. 2013; 37 (4): 617-623

  Abstract

  Intravascular large T-cell or NK-cell lymphomas rarely present with cutaneous involvement. Intravascular cytotoxic T or NK lymphomas presenting in the skin (cIT/NKL) are often EBV, and reported cases follow a highly aggressive clinical course. Intravascular anaplastic large cell lymphoma (ALCL) by contrast is extraordinarily rare and, when it presents in the skin, raises the question of aggressive clinical behavior in the manner of cIT/NKL versus indolent clinical behavior in the manner of primary cutaneous ALCL. Here we describe a case of localized cutaneous intravascular anaplastic lymphoma kinase-negative ALCL (cIALCL) with a very indolent clinical course. The patient experienced a single cutaneous relapse and remains alive without disease 4 years after diagnosis. Review of the literature reveals multiple clinicopathologic differences between cIALCL and cIT/NKL: distribution (cIALCL, single skin region, P=0.021, Fisher exact test); histology (cIALCL, cohesive with necrosis, P=0.005); immunophenotype (cIALCL, strongly CD30, P=0.021; cIT/NKL, CD56 and/or EBV, P=0.003); and indolent clinical behavior with a trend toward better overall survival (P=0.067, Kaplan-Meier survival analysis). Our index case of cIALCL and 1 other tested case were immunohistochemically confirmed to be intralymphatic (contained within D2-40+vessels) as compared with the blood vessel localization of cIT/NKL. Recognition of cIALCLs as a distinct clinicopathologic entity, and in particular their distinction from aggressive, usually EBV cIT/NKLs, may be possible on the basis of a combination of clinicopathologic criteria, allowing for localized therapy in a subset of patients.

  View details for DOI 10.1097/PAS.0b013e318280aa9c

  View details for Web of Science ID 000316184000019

  View details for PubMedID 23480896

• Clonal Identity and Differences in Primary Cutaneous B-Cell Lymphoma Occurring at Different Sites or Time Points in the Same Patient AMERICAN JOURNAL OF DERMATOPATHOLOGY Fujiwara, M., Morales, A. V., Seo, K., Kim, Y. H., Arber, D. A., Sundram, U. N. 2013; 35 (1): 11-18

  Abstract

  Primary cutaneous B-cell lymphomas (PCBCL) are rare. Marginal zone lymphomas and follicle center lymphomas (FCL) represent a majority of these cases, and a significant number of cases present with multiple lesions. It is unclear whether multiple lesions in PCBCL represent dissemination of a single clone or multiple new primary lymphomas. In the current study, we analyzed paired samples from 20 PCBCL patients at more than 1 site (16) or at the same site at different time points (4) and 12 patients with benign lymphoid infiltrates to investigate for the presence or absence of a clone, and if present, whether the clones were identical. Both IGH@ and IGK@ rearrangements were tested using the BIOMED-2 protocol. We identified a clone (IGH@ and/or IGK@) in 19 of 20 (95%) PCBCL patients and 2 of 12 (17%) benign lymphoid infiltrate patients. The B-cell clones were proven to be identical in 11 of 20 (55%) PCBCL patients, including 7 of 16(44%) biopsies from patients with 2 different sites and 4 of 4 biopsies (100%) from patients at the same site but different time points. In 4 cases (3 FCL and 1 marginal zone lymphoma), different clones were detected at different sites, suggesting the possibility of a second simultaneous primary lymphoma. Our results indicate that the presence of identical clones is highly suggestive of lymphoma. To our knowledge, this is the first report to investigate the detection of identical clones in 2 distinct biopsies in PCBCL patients. Although the study is small and the results need to be confirmed in a larger study, these findings suggest that a subset of PCBCL at different sites may represent different primary tumors rather than occurrence of a single disease.

  View details for DOI 10.1097/DAD.0b013e318255dbae

  View details for Web of Science ID 000314103600006

  View details for PubMedID 22588547

• Clinically meaningful reduction in pruritus in patients with cutaneous T-cell lymphoma treated with romidepsin LEUKEMIA & LYMPHOMA Kim, Y. H., Demierre, M., Kim, E. J., Lerner, A., Rook, A. H., Duvic, M., Robak, T., Samtsov, A., McCulloch, W., Chen, S. C., Waksman, J., Nichols, J., Whittaker, S. 2013; 54 (2): 284-289

  Abstract

  Patients with cutaneous T-cell lymphoma (CTCL) frequently experience severe pruritus that can significantly impact their quality of life. Romidepsin is approved by the US Food and Drug Administration (FDA) for the treatment of patients with CTCL who have received at least one prior systemic therapy, with a reported objective response rate of 34%. In a phase 2 study of romidepsin in patients with CTCL (GPI-04-0001), clinically meaningful reduction in pruritus (CMRP) was evaluated as an indicator of clinical benefit by using a patient-assessed visual analog scale. To determine the effect of romidepsin alone, confounding pruritus treatments including steroids and antihistamines were prohibited. At baseline, 76% of patients reported moderate-to-severe pruritus; 43% of these patients experienced CMRP, including 11 who did not achieve an objective response. Median time to CMRP was 1.8 months, and median duration of CMRP was 5.6 months. Study results suggest that the clinical benefit of romidepsin may extend beyond objective responses.

  View details for DOI 10.3109/10428194.2012.711829

  View details for Web of Science ID 000313285400015

  View details for PubMedID 22839723

• Correlation of Target Molecule Expression and Overall Response in Refractory Cutaneous T-Cell Lymphoma Patients Dosed with Mogamulizumab (KW-0761), a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4) Duvic, M., Pinter-Brown, L., Foss, F., Sokol, L., Jorgensen, J., Ni, X., Challagundla, P., Goswami, M., Dwyer, K., Mohamed, N., Kim, Y. H. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049600221

• Brentuximab Vedotin Demonstrates Significant Clinical Activity in Relapsed or Refractory Mycosis Fungoides with Variable CD30 Expression 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Krathen, M., Sundram, U., Bashey, S., Sutherland, K., Salva, K., Wood, G. S., Advani, R. H., Hoppe, R. T., Reddy, S., Armstrong, R., Nagpal, S., Pulitzer, M., Horwitz, S. M., Kim, Y. H. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838900162

• Cutaneous gamma delta T-cell Lymphomas A Spectrum of Presentations With Overlap With Other Cytotoxic Lymphomas AMERICAN JOURNAL OF SURGICAL PATHOLOGY Guitart, J., Weisenburger, D. D., Subtil, A., Kim, E., Wood, G., Duvic, M., Olsen, E., Junkins-Hopkins, J., Rosen, S., Sundram, U., Ivan, D., Selim, M. A., Pincus, L., Deonizio, J. M., Kwasny, M., Kim, Y. H. 2012; 36 (11): 1656-1665

  Abstract

  We reviewed our multicenter experience with gamma-delta (γδ) T-cell lymphomas first presenting in the skin. Fifty-three subjects with a median age of 61 years (range, 25 to 91 y) were diagnosed with this disorder. The median duration of the skin lesions at presentation was 1.25 years (range, 1 mo to 20 y). The most common presentation was deep plaques (38 cases) often resembling a panniculitis, followed by patches resembling psoriasis or mycosis fungoides (10 cases). These lesions tended to ulcerate overtime (27 cases). Single lesions or localized areas of involvement resembling cellulitis or pyoderma were reported in 8 cases. The most common anatomic site of involvement was the legs (40 cases), followed by the torso (30 cases) and arms (28 cases). Constitutional symptoms were reported in 54% (25/46) of the patients, including some with limited skin involvement. Significant comorbidities included autoimmunity (12 cases), other lymphoproliferative disorders (5 cases), internal carcinomas (4 cases), and viral hepatitis (2 cases). Lymphadenopathy (3/42 cases) and bone marrow involvement (5/28 cases) were uncommon, but serum lactose dehydrogenase (LDH) was elevated in 55% (22/39) of the patients. Abnormal positron emission tomography and/or computed tomography scans in 20/37 subjects mostly highlighted soft tissue or lymph nodes. Disease progression was associated with extensive ulcerated lesions resulting in 27 deaths including complications of hemophagocytic syndrome (4) and cerebral nervous system involvement (3). Median survival time from diagnosis was 31 months. Skin biopsies varied from a pagetoid pattern to purely dermal or panniculitic infiltrates composed of intermediate-sized lymphocytes with tissue evidence of cytotoxicity. The most common immunophenotype was CD3+/CD4+/CD5+/CD8+/BF1+/γ-M1+/TIA-1+/granzyme-B+/CD45RA-/CD7-, and 4 cases were Epstein-Barr virus positive. This is the largest study to date of cutaneous γδ T-cell lymphomas and demonstrates a variety of clinical and pathologic presentations with a predictable poor outcome.

  View details for DOI 10.1097/PAS.0b013e31826a5038

  View details for Web of Science ID 000310059600008

  View details for PubMedID 23073324

• Exploratory study of brentuximab vedotin (SGN-35), a novel monoclonal antibody-drug-conjugate against CD30, in mycosis fungoides (MF) and Sezary syndrome (SS) demonstrates clinical responses regardless of CD30 expression levels 75th Annual Meeting of the Society-for-Investigative-Dermatology Bashey, S., Krathen, M., Sutherland, K., Sundram, U., Lingala, B., Horwitz, S., Hoppe, R., Pulitzer, M., Advani, R., Kim, Y. NATURE PUBLISHING GROUP. 2012: S95–S95

  View details for Web of Science ID 000302866900562

• Transcriptome sequencing in Sezary Syndrome identifies novel Sezary cell-associated transcripts 75th Annual Meeting of the Society-for-Investigative-Dermatology Lee, C., Ungewickell, A., Bhaduri, A., Qu, K., Webster, D., Armstrong, R., Weng, W., Aros, C., MAH, A., Kretz, M., Kim, Y. H., Khavari, P. A. NATURE PUBLISHING GROUP. 2012: S29–S29

  View details for Web of Science ID 000302866900174

• The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T-cell lymphoma patients AMERICAN JOURNAL OF HEMATOLOGY Kelly-Sell, M. J., Kim, Y. H., Straus, S., Benoit, B., Harrison, C., Sutherland, K., Armstrong, R., Weng, W., Showe, L. C., Wysocka, M., Rook, A. H. 2012; 87 (4): 354-360

  Abstract

  Romidepsin is the second histone deacetylase inhibitor (HDACi) approved for the treatment of advanced stages of cutaneous T-cell lymphoma (CTCL). Recent in vitro data suggest that HDACis suppress immune function although these findings have not been confirmed in patients. Thus, we serially examined the cellular immune function of eight CTCL patients undergoing treatment with three cycles of romidepsin. We measured the patients' natural killer (NK) and dendritic cell (DC) function and performed an in vitro terminal deoxynucleotidyl transferase dUTP nick end labeling assay to measure cellular apoptosis. Patients' NK cell cytolytic activity decreased from baseline to the third cycle of treatment (P = 0.018) but stimulation with a toll-like receptor (TLR) agonist increased this activity (P = 0.018). At baseline, a TLR agonist could both activate patients' DC (P = 0.043) and stimulate interleukin-12 protein production (P = 0.043) but both were suppressed after the first cycle of romidepsin. Finally, we observed increased specificity for romidepsin-induced CD4+ tumor cell apoptosis and dose-dependent increases in cellular apoptosis of healthy cells in multiple lineages (P < 0.05). These findings raise concern that HDACis suppress immune function in CTCL patients and they support the concurrent use of multiple immune stimulatory agents to preserve the host immune response.

  View details for DOI 10.1002/ajh.23112

  View details for Web of Science ID 000301429300003

  View details for PubMedID 22367792

  View details for PubMedCentralID PMC3638752

• A Comparative Analysis of Cutaneous Marginal Zone Lymphoma and Cutaneous Chronic Lymphocytic Leukemia AMERICAN JOURNAL OF DERMATOPATHOLOGY Levin, C., Mirzamani, N., Zwerner, J., Kim, Y., Schwartz, E. J., Sundram, U. 2012; 34 (1): 18-23

  Abstract

  The morphologic distinction between cutaneous marginal zone lymphoma (CMZL) and secondary cutaneous involvement by B-cell chronic lymphocytic leukemia (B-CLL) can be difficult. Both entities can show very similar architectural patterns of involvement in the skin and not uncommonly, the skin can be the first site of presentation of B-CLL in the elderly. We reviewed biopsies of 13 patients with cutaneous B-CLL and 14 patients with CMZL to compare their histologic and immunohistochemical features. CMZL and cutaneous B-CLL both predominantly exhibited a nodular pattern of skin involvement (9 of 13 B-CLL, 9 of 14 CMZL) with a minority of cases demonstrating a diffuse pattern (4 of 13 B-CLL, 4 of 14 CMZL). Although reactive germinal centers (12 of 14 cases) and plasma cells (10 of 14 cases) were seen more often in CMZL, plasma cells were also observed in cases of B-CLL (4 of 13). The lesional cells of B-CLL expressed CD79, CD5, CD23, and CD43, although CMZL did not express CD5 or CD43. Although we noted light chain restriction in 13 of 14 cases of CMZL cases, we also observed light chain restriction in 4 of 13 cases of B-CLL. Our results indicate that CMZL and B-CLL can be morphologically similar and both may show light chain restriction. Complete immunophenotyping is necessary to ensure that all cases are correctly classified.

  View details for DOI 10.1097/DAD.0b013e31821528bc

  View details for Web of Science ID 000299325900005

  View details for PubMedID 22257836

• Bexarotene Is Active Against Subcutaneous Panniculitis-Like T-Cell Lymphoma in Adult and Pediatric Populations CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Mehta, N., Wayne, A. S., Kim, Y. H., Hale, G. A., Alvarado, C. S., Myskowski, P., Jaffe, E. S., Busam, K. J., Pulitzer, M., Zwerner, J., Horwitz, S. 2012; 12 (1): 20-25

  Abstract

  Subcutaneous panniculitis-like T-cell lymphoma (SPTL-AB) and cutaneous gamma/delta T-cell lymphoma (CGD-TCL) are rare T-cell lymphomas with varying clinical courses. There is no standard treatment, although chemotherapy and hematopoietic stem cell transplantation are commonly used. We describe results using bexarotene for children and adults with these disorders.We identified 15 patients (12 adults, 3 children) who were treated with bexarotene between 2000 and 2010 from the Memorial Sloan-Kettering Cancer Center lymphoma database, the Stanford Cancer Center Registry, and the National Cancer Institute (NCI) pediatric lymphoma database. There were 8 females and 7 males, with a median age of 45 years (range, 3 years to 85 years). All patients had stage IV disease. Two of 15 and 4 of 15 patients had documented CGD-TCL and SPTL-AB, respectively; others were presumed to have SPTL-AB. Bexarotene was administered at flat doses corresponding to 91 to 339 mg/m(2)/d. Two of 15 patients received concurrent denileukin diftitox. Two children received bexarotene as maintenance therapy and were not evaluable for response.Among those treated with bexarotene alone, the overall response rate (ORR) was 82% (6/11 complete response [CR], 3/11 partial response [PR]). One of the 2 patients treated with concomitant denileukin diftitox responded for an ORR of 10/13 (77%), including 54% CR and 23% PR. Median progression-free survival was 38.4 months; median duration of response was 26.3 months. Six patients developed hypothyroidism and 9 developed hyperlipidemia; one patient developed dose-limiting hypertriglyceridemia. One pediatric patient developed insulin-dependent diabetes mellitus.In this retrospective series, bexarotene showed a high response rate in SPTL-AB and CGD-TCL. It was generally well-tolerated with durable responses; therefore, bexarotene represents a promising therapy for children and adults with these disorders.

  View details for DOI 10.1016/j.clml.2011.06.016

  View details for Web of Science ID 000300481800005

  View details for PubMedID 22001256

  View details for PubMedCentralID PMC3938280

• Phase II Multicenter Trial of Lenalidomide: Clinical and Immunomodulatory Effects in Patients with CTCL Querfeld, C., Rosen, S. T., Guitart, J., Duvic, M., Kim, Y. H., Goolsby, C., Kuzel, T. AMER SOC HEMATOLOGY. 2011: 712

  View details for Web of Science ID 000299597102233

• Effects of Anti-CCR4 Antibody (KW-0761) on Regulatory T Cells and Natural Killer Cells in Patients with Cutaneous T-Cell Lymphoma Ni, X., Jorgensen, J. L., Goswami, M., Challagundla, P., Decker, W. K., Kim, Y. H., Duvic, M. AMER SOC HEMATOLOGY. 2011: 204–5

  View details for Web of Science ID 000299597100445

• EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma BLOOD Kempf, W., Pfaltz, K., Vermeer, M. H., Cozzio, A., Ortiz-Romero, P. L., Bagot, M., Olsen, E., Kim, Y. H., Dummer, R., Pimpinelli, N., Whittaker, S., Hodak, E., Cerroni, L., Berti, E., Horwitz, S., Prince, H. M., Guitart, J., Estrach, T., Sanches, J. A., Duvic, M., Ranki, A., Dreno, B., Ostheeren-Michaelis, S., Knobler, R., Wood, G., Willemze, R. 2011; 118 (15): 4024-4035

  Abstract

  Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

  View details for DOI 10.1182/blood-2011-05-351346

  View details for Web of Science ID 000296282200008

  View details for PubMedID 21841159

  View details for PubMedCentralID PMC3204726

• A prospective trial of low-dose total skin electron beam therapy in mycosis fungoides and proposal of a new clinically meaningful endpoint Bashey, S., Harrison, C., Navi, D., Lingala, B., Armstrong, R., Weng, W., Sundram, U., Kim, Y., Hoppe, R. WILEY-BLACKWELL. 2011: 3–3

  View details for Web of Science ID 000296967300006

• The frequency of dual TCR-PCR clonality in granulomatous disorders JOURNAL OF CUTANEOUS PATHOLOGY Dabiri, S., Morales, A., Ma, L., Sundram, U., Kim, Y. H., Arber, D. A., Kim, J. 2011; 38 (9): 704-709

  Abstract

  A granulomatous infiltrate in association with cutaneous T-cell lymphoma is uncommon. The diagnosis of mycosis fungoides can be difficult in the setting of an exuberant granulomatous infiltrate that obscures the neoplastic lymphoid infiltrate, thereby mimicking a granulomatous dermatitis. Therefore, the clinical context and supplemental molecular analysis, such as the demonstration of a monoclonal T-cell population, may assist in diagnosis. Monoclonal T-cell populations have been reported in association with inflammatory conditions and serve as a diagnostic pitfall. The frequency of T-cell clonality in association with granulomatous dermatitides has not yet been established.We identified 29 patients with granulomatous dermatitis who had biopsies at two distinct body sites. Results were correlated with clinical follow up and with clonal T-cell receptor-gamma chain rearrangement as detected by polymerase chain reaction-based analysis (dual TCR-PCR).Clinical follow up was obtained in 17 of 29 cases (58.6%). Twenty-five of 29 cases of granulomatous dermatitis lacked T-cell monoclonality. Three cases of granuloma annulare contained a T-cell clone in one of the two biopsies. One case of necrobiotic xanthogranuloma showed an identical T-cell clone in multiple biopsies.The use of dual TCR-PCR analysis, that is, T-cell clonality analysis in biopsy specimens from two different sites, serves as an adjunct to assist in distinguishing granulomatous inflammatory reactions from granulomatous T-cell lymphoma, including granulomatous mycosis fungoides. The occasional finding of a T-cell clone in a granulomatous dermatitis underscores the importance of clinicopathological correlation in daily diagnosis.

  View details for DOI 10.1111/j.1600-0560.2011.01727.x

  View details for Web of Science ID 000293177000005

  View details for PubMedID 21645036

• Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma LEUKEMIA & LYMPHOMA Querfeld, C., Kuzel, T. M., Kim, Y. H., Porcu, P., Duvic, M., Musiek, A., Rook, A. H., Mark, L. A., Pinter-Brown, L., Hamid, O., Lin, B., Bian, Y., Boye, M., Day, J. M., Rosen, S. T. 2011; 52 (8): 1474-1480

  Abstract

  This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB-IVB, or Sézary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with ≥7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1-2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related.

  View details for DOI 10.3109/10428194.2011.572265

  View details for Web of Science ID 000292747300011

  View details for PubMedID 21649541

• Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer JOURNAL OF CLINICAL ONCOLOGY Olsen, E. A., Whittaker, S., Kim, Y. H., Duvic, M., Prince, H. M., Lessin, S. R., Wood, G. S., Willemze, R., Demierre, M., Pimpinelli, N., Bernengo, M. G., Ortiz-Romero, P. L., Bagot, M., Estrach, T., Guitart, J., Knobler, R., Sanches, J. A., Iwatsuki, K., Sugaya, M., Dummer, R., Pittelkow, M., Hoppe, R., Parker, S., Geskin, L., Pinter-Brown, L., Girardi, M., Burg, G., Ranki, A., Vermeer, M., Horwitz, S., Heald, P., Rosen, S., Cerroni, L., Dreno, B., Vonderheid, E. C. 2011; 29 (18): 2598-2607

  Abstract

  Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.

  View details for DOI 10.1200/JCO.2010.32.0630

  View details for Web of Science ID 000291684600038

  View details for PubMedID 21576639

  View details for PubMedCentralID PMC3422534

• The Stanford University Experience With Conventional-Dose, Total Skin Electron-Beam Therapy in the Treatment of Generalized Patch or Plaque (T2) and Tumor (T3) Mycosis Fungoides ARCHIVES OF DERMATOLOGY Navi, D., Riaz, N., Levin, Y. S., Sullivan, N. C., Kim, Y. H., Hoppe, R. T. 2011; 147 (5): 561-567

  Abstract

  To review the Stanford University experience with total skin electron-beam therapy (TSEBT) of 30 Gy or greater as monotherapy in patients with mycosis fungoides (MF) and compare with subgroups receiving adjuvant nitrogen mustard (HN2), and further update our experience with repeated courses of TSEBT.Retrospective study.Academic referral center, multidisciplinary clinic.A total of 180 patients with MF treated from 1970 through 2007 with T2 MF (103 with generalized patch or plaque disease) or T3 MF (77 with tumor disease). Patients with extracutaneous disease were excluded.Total skin electron-beam therapy with or without adjuvant topical HN2.Clinical response rate, freedom from relapse (FFR), overall survival (OS), and progression-free survival (PFS) after TSEBT.The overall response rate (ORR) was 100%; 60% of patients achieved a complete clinical response (patients with T2 MF = 75%, those with T3 MF = 47%). The 5- and 10-year OS rates of the entire cohort were 59% and 40%, respectively. There were no significant differences in FFR (P = .30 for T2 disease; P = .50 for T3 disease), PFS (P = .10 for T2 disease; P = .40 for T3 disease), or OS (P = .30 for T2 disease; P = .50 for T3 disease) between adjuvant HN2 and TSEBT monotherapy cohorts. The ORR was 100% in patients receiving a second course of TSEBT with median FFR of 6 months.A TSEBT of 30 Gy or greater is highly effective in treating T2-T3 MF, with better outcomes in T2 disease. There was no clinical advantage to adjuvant HN2 as used in our cohort. Second courses of TSEBT are safe and efficacious and provide clinically meaningful palliation for select patients.

  View details for Web of Science ID 000290632100008

  View details for PubMedID 21576575

• Sezary syndrome: Immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC) JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Olsen, E. A., Rook, A. H., Zic, J., Kim, Y., Porcu, P., Querfeld, C., Wood, G., Demierre, M., Pittelkow, M., Wilson, L. D., Pinter-Brown, L., Advani, R., Parker, S., Kim, E. J., Junkins-Hopkins, J. M., Foss, F., Cacchio, P., Duvic, M. 2011; 64 (2): 352-404

  Abstract

  Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

  View details for DOI 10.1016/j.jaad.2010.08.037

  View details for Web of Science ID 000286780400016

  View details for PubMedID 21145619

• Phase I trial of a Toll-like receptor 9 agonist, PF-3512676 (CPG 7909), in patients with treatment-refractory, cutaneous T-cell lymphoma JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Kim, Y. H., Girardi, M., Duvic, M., Kuzel, T., Link, B. K., Brown, L. P., Rook, A. H. 2010; 63 (6): 975-983

  Abstract

  Mycosis fungoides and Sézary syndrome are a class of lymphomas of skin-trafficking T cells, and they are the most common forms of cutaneous T-cell lymphoma (CTCL). Mycosis fungoides and Sézary syndrome are chronic, frequently incurable diseases with limited therapeutic options. PF-3512676 (formerly CPG 7909) is a Toll-like receptor 9 agonist that is being investigated for treatment of patients with advanced cancer.This study was conducted to determine the safety and tolerability of single-agent PF-3512676 in patients with CTCL.In this phase I dose-escalation study, patients (N = 28) with treatment-refractory, stage IB to IVA CTCL were enrolled in 6 sequential cohorts and treated with PF-3512676 (0.08, 0.16, 0.24, 0.28, 0.32, or 0.36 mg/kg) administered as 24 weekly subcutaneous injections. Primary end points were safety and tolerability.Common adverse events (fatigue, rigors, injection-site reactions, myalgia, lymphopenia, leukopenia, neutropenia, and pyrexia) were mostly grade 1 or 2, and no patient developed specific symptoms associated with autoimmune disease. Clinical response rate to PF-3512676, as determined by both Composite Assessment of Index Lesion Severity and Physician Global Assessment, was 32% (3 complete clinical responses, 6 partial responses); the majority of responses (7/9; 78%) were ongoing at the end of study.This trial was not designed to rigorously assess efficacy.Single-agent PF-3512676 was well tolerated and demonstrated antitumor activity in patients with refractory CTCL.

  View details for DOI 10.1016/j.jaad.2009.12.052

  View details for Web of Science ID 000284968100003

  View details for PubMedID 20888065

• Increased Risk of Second Malignancies In Young Patients with Mycosis Fungoides Diagnosed Before 30 Years of Age: A Population-Based Study Ai, W., Keegan, T., Fish, K., Laura, P., Soon, C., Kim, Y. H., Chang, E. AMER SOC HEMATOLOGY. 2010: 832

  View details for Web of Science ID 000289662202217

• Results of a Phase 1/2 Study for KW-0761, a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4), In CTCL Patients Duvic, M., Pinter-Brown, L., Foss, F. M., Sokol, L., Jorgensen, J., Spitalny, G. L., Kim, Y. H. AMER SOC HEMATOLOGY. 2010: 424

  View details for Web of Science ID 000289662201065

• Multidisciplinary Care in the Management of Patients With Cutaneous Lymphoma: A Perspective CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Kim, Y. H. 2010; 10: S106-S108

  View details for DOI 10.3816/CLML.2010.s.021

  View details for Web of Science ID 000281519500015

  View details for PubMedID 20826393

• Combined Use of PCR-Based TCRG and TCRB Clonality Tests on Paraffin-Embedded Skin Tissue in the Differential Diagnosis of Mycosis Fungoides and Inflammatory Dermatoses JOURNAL OF MOLECULAR DIAGNOSTICS Zhang, B., Beck, A. H., Taube, J. M., Kohler, S., Seo, K., Zwerner, J., Viakhereva, N., Sundram, U., Kim, Y. H., Schrijver, I., Arber, D. A., Zehnder, J. L. 2010; 12 (3): 320-327

  Abstract

  The distinction between mycosis fungoides (MF) and inflammatory dermatoses (ID) by clinicopathologic criteria can be challenging. There is limited information regarding the performance characteristics and utility of TCRG and TCRB clonality assays in diagnosis of MF and ID from paraffin-embedded tissue sections. In this study, PCR tests were performed with both TCRG and TCRB BIOMED-2 clonality methods followed by capillary electrophoresis and Genescan analysis using DNA samples from 35 MF and 96 ID patients with 69 and 133 paraffin-embedded specimens, respectively. Performance characteristics were determined for each test individually and in combination. TCRG and TCRB tests demonstrated identical sensitivity (64%) and specificity (84%) when analyzed as individual assays. The positive predictive value, negative predictive value, and change of posttest MF probability over a range of MF pretest probabilities were obtained. These data were used to construct an algorithm for sequential use of TCRG and TCRB. As single tests, commercially available BIOMED-2 PCR-based TCRG and TCRB clonality tests on paraffin-embedded tissue have no significant difference in terms of sensitivity and specificity. Combined use of the two tests in patients with intermediate pretest probabilities as proposed in the algorithm could improve test utility.

  View details for DOI 10.2353/jmoldx.2010.090123

  View details for Web of Science ID 000277531700009

  View details for PubMedID 20203005

  View details for PubMedCentralID PMC2860468

• T-Cell Receptor PCR from Separate Biopsies Distinguishes Granulomatous Dermatitis from Granulomatous Mycosis Fungoides 99th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Dabiri, S., Arber, D. A., Kim, Y. H., Sundram, U. N., Kim, J. NATURE PUBLISHING GROUP. 2010: 112A–112A

  View details for Web of Science ID 000274337300493

• Clinically Significant Responses Achieved with Romidepsin in 37 Patient with Cutaneous T-Cell Lymphoma (CTCL) with Blood Involvement 51st Annual Meeting and Exposition of the American-Society-of-Hematology Kim, Y. H., Demierre, M., Kim, E. J., Rook, A. H., Lerner, A., Duvic, M., Reddy, S., Robak, T., Becker, J. C., Samtsov, A., McCulloch, W., Whittaker, S. AMER SOC HEMATOLOGY. 2009: 1050–50

  View details for Web of Science ID 000272725803238

• Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial Horwitz, S. M., Duvic, M., Kim, Y., Zairi, J. M., Lechowicz, M., Myskowski, P., Fruchtman, S., O'Connor, O. A. AMER SOC HEMATOLOGY. 2009: 379

  View details for Web of Science ID 000272725801099

• Characterization of Cyclic Hematologic Changes Observed in Patients with Cutaneous T-Cell Lymphoma (CTCL) Receiving Romidepsin, a Novel Histone Deacetylase (HDAC) Inhibitor 51st Annual Meeting and Exposition of the American-Society-of-Hematology Whittaker, S., Kim, E. J., Prince, M., Demierre, M. F., Giver, C., Lonial, S., Pickarz, R., Kim, Y. H., Nichols, J., Nix, D., Bates, S. AMER SOC HEMATOLOGY. 2009: 1425–25

  View details for Web of Science ID 000272725804365

• A Phase II Study of SGN-30 in Cutaneous Anaplastic Large Cell Lymphoma and Related Lymphoproliferative Disorders CLINICAL CANCER RESEARCH Duvic, M., Reddy, S. A., Pinter-Brown, L., Korman, N. J., Zic, J., Kennedy, D. A., Lorenz, J., Sievers, E. L., Kim, Y. H. 2009; 15 (19): 6217-6224

  Abstract

  An open-label, multicenter, phase II study was conducted to define the safety and antitumor activity of the monoclonal antibody SGN-30 in patients with CD30(+) primary cutaneous anaplastic large cell lymphoma (pc-ALCL), lymphomatoid papulosis (LyP), or transformed mycosis fungoides (T-MF).In the initial course (six doses), patients received i.v. SGN-30 every 3 weeks; eligible patients could receive two additional courses. The initial dose level of 4 mg/kg was increased to 12 mg/kg by protocol amendment.The overall objective response rate [complete response (CR) + partial response (PR)] was 70% (16 of 23 patients): 10 patients achieved a CR and another 6 patients achieved a PR. Overall, clinical benefit of SGN-30, as assessed by achieving a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of patients during the study, including all patients with pc-ALCL or LyP and two thirds of patients with T-MF or with multiple clinical diagnoses. Nine of the 10 patients who achieved a CR and 5 of the 6 patients who achieved a PR were in remission at their follow-up evaluation (median duration, 84 days). Fifteen of 23 patients (65%) experienced at least one adverse event during the study, most of which were mild or moderate.SGN-30 was clinically active in 16 of 23 patients with heavily pretreated pc-ALCL, LyP, and T-MF and was well tolerated in this study.

  View details for DOI 10.1158/1078-0432.CCR-09-0162

  View details for Web of Science ID 000270498700034

  View details for PubMedID 19789316

• Cutaneous Peripheral T-Cell Lymphoma Associated With a Proliferation of B Cells AMERICAN JOURNAL OF CLINICAL PATHOLOGY Mattoch, I. W., Fulton, R., Kim, Y., Hoppe, R., Warnke, R. A., Sundram, U. N. 2009; 131 (6): 810-819

  Abstract

  Although the new World Health Organization-European Organization for Research and Treatment of Cancer classification focuses on providing uniformity in the diagnosis of cutaneous lymphomas, cutaneous peripheral T-cell lymphoma (PTL) remains a poorly defined subgroup. As follow-up to a study of systemic PTL complicated by a proliferation of B cells, we studied 16 cases of cutaneous PTL that contained morphologically atypical T cells associated with a significant infiltrate of B cells (about 20%-50%). A clonal T-cell receptor gamma chain gene rearrangement was present in all cases. In contrast, a clonal immunoglobulin heavy chain gene rearrangement was present in only 1 case. Clinical staging in 14 cases identified systemic involvement in 2. At last follow-up, both patients with systemic involvement had died of disease, and the majority of patients with primary cutaneous disease were alive (11/12). The presence of numerous atypical B cells and T cells caused diagnostic confusion in these cases. Comprehensive pathologic studies, coupled with clinical staging, are necessary for the accurate diagnosis of this unusual manifestation of cutaneous PTL.

  View details for DOI 10.1309/AJCP5W0VOCSVOBRA

  View details for Web of Science ID 000266238600010

  View details for PubMedID 19461087

• Pooled analyses of two international, multicenter clinical studies of romidepsin in 167 patients with cutaneous T-cell lymphoma (CTCL) 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Demierre, M., Whittaker, S., Kim, Y., Kim, E., Piekarz, R., Prince, M., Nichols, J., Balser, J., Prentice, A., BATES, S. AMER SOC CLINICAL ONCOLOGY. 2009

  View details for Web of Science ID 000276606605455

• Low Stage Follicular Lymphoma: Biologic and Clinical Characterization According to Nodal or Extranodal Primary Origin AMERICAN JOURNAL OF SURGICAL PATHOLOGY Weinberg, O. K., Ma, L., Seo, K., Beck, A. H., Pai, R. K., Morales, A., Kim, Y., Sundram, U., Tan, D., Horning, S. J., Hoppe, R. T., Natkunam, Y., Arber, D. A. 2009; 33 (4): 591-598

  Abstract

  Studies suggest that primary extranodal follicular lymphoma (FL) is not infrequent but it remains poorly characterized with variable histologic, molecular, and clinical outcome findings. We compared 27 extranodal FL to 44 nodal FL using morphologic, immunohistochemical, and molecular genetic techniques and evaluated the clinical outcome of these 2 similarly staged groups. Eight cases of primary cutaneous follicle center lymphoma were also studied. In comparison to nodal FL, a greater number of extranodal FL contained a diffuse growth pattern (P=0.004) and lacked CD10 expression (P=0.014). Fifty-four percent of extranodal and 42% of nodal FL cases showed evidence of t(14;18), with minor breakpoints (icr, 3'BCL2, 5'mcr) more commonly found in extranodal cases (P=0.003). Outcome data showed no significant differences in overall survival (P=0.565) and progression-free survival (P=0.627) among extranodal, nodal, and primary cutaneous follicle center lymphoma cases. Analysis of all cases by t(14;18) status indicate that the translocation-negative group is characterized by a diffuse growth pattern (P=0.043) and lower BCL2 expression (P=0.018). The t(14;18)-positive group showed significantly better overall survival (P=0.019) and disease-specific survival (P=0.006) in comparison with the t(14;18)-negative group. In low stage FL, the status of t(14;18) seems to be more predictive of outcome than origin from an extranodal versus nodal site.

  View details for Web of Science ID 000264818800014

  View details for PubMedID 19065102

  View details for PubMedCentralID PMC4847152

• Recombinant Human Relaxin in the Treatment of Systemic Sclerosis With Diffuse Cutaneous Involvement A Randomized, Double-Blind, Placebo-Controlled Trial ARTHRITIS AND RHEUMATISM Khanna, D., Clements, P. J., Furst, D. E., Korn, J. H., Ellman, M., Rothfield, N., Wigley, F. M., Moreland, L. W., Silver, R., Kim, Y. H., Steen, V. D., Firestein, G. S., Kavanaugh, A. F., Weisman, M., Mayes, M. D., Collier, D., Csuka, M. E., Simms, R., Merkel, P. A., Medsger, T. A., Sanders, M. E., Maranian, P., Seibold, J. R., Relaxin Investigators & Scleroderm 2009; 60 (4): 1102–11

  Abstract

  A phase II randomized controlled trial of recombinant human relaxin suggested that a dosage of 25 microg/kg/day was safe and clinically effective in improving skin disease and reducing functional disability in scleroderma (systemic sclerosis; SSc). We undertook a large randomized, double-blind, placebo-controlled clinical trial to compare placebo with 10 microg/kg/day and 25 microg/kg/day recombinant human relaxin, given for 24 weeks in patients with stable, diffuse, moderate-to-severe SSc.Men and women ages 18-70 years with diffuse cutaneous SSc (dcSSc) were administered recombinant human relaxin (10 microg/kg/day or 25 microg/kg/day) or placebo for 24 weeks as a continuous subcutaneous infusion. There was a followup safety visit at week 28.The primary outcome measure, the modified Rodnan skin thickness score, was similar among the 3 groups at baseline and at weeks 4, 12, and 24. Secondary outcomes such as functional disability were similar in all 3 groups, while the forced vital capacity decreased significantly in the relaxin groups. The discontinuation of both doses of relaxin at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as doubling of serum creatinine, renal crisis, or grade 3 or 4 essential hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo.Recombinant relaxin was not significantly better than placebo in improving the total skin score or pulmonary function or in reducing functional disability in patients with dcSSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.

  View details for DOI 10.1002/art.24380

  View details for Web of Science ID 000265152800024

  View details for PubMedID 19333948

  View details for PubMedCentralID PMC3711466

• The morphologic and immunohistochemical overlap between cutaneous marginal zone lymphoma and cutaneous chronic lymphocytic leukemia 69th Annual Meeting of the Society-of-Investigative-Dermatology Levin, C., Mizramani, N., Zwerner, J., Kim, Y., Sundram, U. NATURE PUBLISHING GROUP. 2009: S53–S53

  View details for Web of Science ID 000264994000314

• Indolent primary cutaneous B-cell lymphoma: Experience using systemic rituximab JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Morales, A. V., Advani, R., Horwitz, S. M., Riaz, N., Reddy, S., Hoppe, R. T., Kim, Y. H. 2008; 59 (6): 953-957

  Abstract

  Optimal treatment of indolent primary cutaneous B-cell lymphoma (CBCL), marginal zone lymphoma, and follicle center lymphoma, presenting as multiple lesions, has yet to be established. Rituximab is a chimeric monoclonal IgG1 antibody directed against the CD20 antigen of B cells. Clinical efficacy of systemic rituximab in CBCL has yet to be established.We sought to assess the efficacy of systemic rituximab in the treatment of CBCL.This was a retrospective study of 15 patients with indolent CBCL treated with intravenous rituximab (375 mg/m(2)) as a single agent. Variable maintenance regimen was used in a subset of patients. Responses were categorized as complete response, partial response, stable disease, or progressive disease. The efficacy end points included were objective response rate, time to response, time to progression, and duration of response.Ten patients with follicle center lymphoma and 5 with marginal zone lymphoma were included. The objective response rate was 87% (60% complete response, 27% partial response). All patients with follicle center lymphoma had a response with 80% achieving complete response. Of the patients with marginal zone lymphoma, 3 had a response, one stable disease, and one progressive disease. Median follow-up was 36 months. Median time to response, duration of response, and time to progression was 30 days, 24 months, and 24 months, respectively.The study was limited by the small sample size and retrospective design.This study, although small, suggests that rituximab is a reasonable first-line treatment option for indolent CBCL with multiple lesions where local treatment is not effective or desirable.

  View details for DOI 10.1016/j.jaad.2008.08.005

  View details for Web of Science ID 000261141600006

  View details for PubMedID 18817999

• Clinically Significant Responses Achieved with Romidepsin in Treatment-Refractory Cutaneous T-Cell Lymphoma: Final Results from a Phase 2B, International, Multicenter, Registration Study 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Kim, Y., Whittaker, S., Demierre, M. F., Rook, A. H., Lerner, A., Duvic, M., Reddy, S., Kim, E. J., Robak, T., Becker, J. C., Samtsov, A., McCulloch, W., Prentice, A. G. AMER SOC HEMATOLOGY. 2008: 103–4

  View details for Web of Science ID 000262104700264

• Cytologic Evaluation of Lymphadenopathy Associated With Mycosis Fungoides and Sezary Syndrome Role of Immunophenotypic and Molecular Ancillary Studies CANCER CYTOPATHOLOGY Pai, R. K., Mullins, F. M., Kim, Y. H., Kong, C. S. 2008; 114 (5): 323-332

  Abstract

  The most common presenting site of extracutaneous disease in mycosis fungoides and Sezary syndrome is the peripheral lymph node. Although fine-needle aspiration biopsy has been shown to be a valuable diagnostic technique in evaluating lymphadenopathy, its utility in patients with cutaneous T-cell lymphoma has not been extensively studied. With fine-needle aspiration biopsy, material can be collected for ancillary diagnostic studies and for morphologic evaluation.The authors report a series of 11 fine-needle aspiration biopsy specimens from 10 mycosis fungoides and Sezary syndrome patients. Flow cytometric immunophenotyping and T-cell receptor gamma chain polymerase chain reaction were performed on fine-needle aspiration biopsy material and correlated with cytologic findings.Seven of 10 patients had lymph node involvement by cutaneous T-cell lymphoma, with 3 cases exhibiting large-cell transformation and 4 cases exhibiting a small-cell pattern. Flow cytometric immunophenotyping identified an abnormal T-cell population in 6 cases. A clonal T-cell rearrangement by T-cell receptor gamma chain polymerase chain reaction (TCR-gamma PCR) was identified in 1 case in which insufficient events were present for evaluation by flow cytometry and in 1 case in which flow cytometry was not diagnostic of T-cell lymphoma. Two cases showed involvement by classic Hodgkin lymphoma diagnosed by immunohistochemistry on cell block material.Fine-needle aspiration biopsy in conjunction with immunophenotyping and T-cell receptor gamma chain polymerase chain reaction is significantly useful in evaluation of lymphadenopathy in patients with mycosis fungoides and Sezary syndrome, especially for triaging lymph nodes that would otherwise not be sampled or for evaluating multiple lymph nodes.

  View details for DOI 10.1002/cncr.23793

  View details for Web of Science ID 000260140500007

  View details for PubMedID 18798522

• Clinicopathologic features and treatment outcomes in Woringer-Kolopp disease JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Lee, J., Viakhireva, N., Cesca, C., Lee, P., Kohler, S., Hoppe, R. I., Kim, Y. H. 2008; 59 (4): 706-712

  Abstract

  Woringer-Kolopp disease, also known as pagetoid reticulosis, is an exceedingly rare variant of mycosis fungoides. Accurate diagnosis and effective treatment is essential to prevent progression to debilitating disease. We identified 7 patients with Woringer-Kolopp disease treated at our institution. We review the major clinical and pathologic characteristics of this disease, focusing on treatment strategies and patient outcomes. All of our patients were successfully treated with skin-directed therapies including topical steroids, topical nitrogen mustard, psoralen plus ultraviolet A, narrow-band ultraviolet B, and radiation therapy. Our observations confirm that Woringer-Kolopp disease carries an excellent prognosis, and support that the most effective and appropriate treatment for recalcitrant or severe Woringer-Kolopp disease is localized radiation therapy.

  View details for DOI 10.1016/j.jaad.2008.04.018

  View details for Web of Science ID 000259550100018

  View details for PubMedID 18550209

• Evaluation of B-cell clonality using the BIOMED-2 PCR method effectively distinguishes cutaneous B-cell lymphoma from benign lymphoid infiltrates AMERICAN JOURNAL OF DERMATOPATHOLOGY Morales, A. V., Arber, D. A., Seo, K., Kohler, S., Kim, Y. H., Sundram, U. N. 2008; 30 (5): 425-430

  Abstract

  Primary cutaneous B-cell lymphomas (CBCL) are a diverse group of lymphomas that are limited to the skin at the time of diagnosis. Recently, standardized polymerase chain reaction protocols for immunoglobulin (Ig) rearrangement in nodal malignancies using the BIOMED-2 method have been studied extensively. However, reports of investigations of Ig clonality in CBCL using the BIOMED-2 method have been scant. We hypothesized that clonality detection in CBCL with the BIOMED-2 method could effectively distinguish malignant from benign B-cell-rich infiltrates in the skin. Formalin-fixed tissue samples from 26 patients with CBCL and 23 with benign lymphoid infiltrates were analyzed for Ig clonality using standardized BIOMED-2 polymerase chain reaction protocols. The (14;18) translocation was also assessed. A clone was detected in 22 (85%) of the 26 patients with CBCL [12/15 (80%) marginal zone B-cell lymphoma; 10/11 (91%) follicle center lymphoma] and in 1 (4%) of the 23 patients with benign infiltrates. The (14;18) translocation was present in 3 (12%) of the 26 patients with CBCL [1/15 (7%) marginal zone B-cell lymphoma; 2/11 (18%) follicle center lymphoma]. Our preliminary data indicate that Ig clonality can be detected in formalin-fixed samples of CBCL with meaningful sensitivity (85%) and high specificity (96%) using the BIOMED-2 method. This study forms the basis for further investigating the role of Ig clonality in distinguishing CBCL from benign lymphoid infiltrates that may pose a challenge in morphologic diagnosis.

  View details for Web of Science ID 000259325000002

  View details for PubMedID 18806482

• European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas BLOOD Senff, N. J., Noordijk, E. M., Kim, Y. H., Bagot, M., Berti, E., Cerroni, L., Dummer, R., Duvic, M., Hoppe, R. T., Pimpinelli, N., Rosen, S. T., Vermeer, M. H., Whittaker, S., Willemze, R. 2008; 112 (5): 1600-1609

  Abstract

  Primary cutaneous B-cell lymphomas (CBCL) represent approximately 20% to 25% of all primary cutaneous lymphomas. With the advent of the World Health Organization-European Organization for Research and Treatment of Cancer (EORTC) Consensus Classification for Cutaneous Lymphomas in 2005, uniform terminology and classification for this rare group of neoplasms were introduced. However, staging procedures and treatment strategies still vary between different cutaneous lymphoma centers, which may be because consensus recommendations for the management of CBCL have never been published. Based on an extensive literature search and discussions within the EORTC Cutaneous Lymphoma Group and the International Society for Cutaneous Lymphomas, the present report aims to provide uniform recommendations for the management of the 3 main groups of CBCL. Because no systematic reviews or (randomized) controlled trials were available, these recommendations are mainly based on retrospective studies and small cohort studies. Despite these limitations, there was consensus among the members of the multidisciplinary expert panel that these recommendations reflect the state-of-the-art management as currently practiced in major cutaneous lymphoma centers. They may therefore contribute to uniform staging and treatment and form the basis for future clinical trials in patients with a CBCL.

  View details for DOI 10.1182/blood-2008-04-152850

  View details for Web of Science ID 000258956200013

  View details for PubMedID 18567836

• Expression of HGAL in primary cutaneous large B-cell lymphomas: evidence for germinal center derivation of primary cutaneous follicular lymphoma MODERN PATHOLOGY Xie, X., Sundram, U., Natkunam, Y., Kohler, S., Hoppe, R. T., Kim, Y. H., Cook, J. R., Hammel, J., Swerdlow, S. H., Guitart, J., Smith, M. D., Bosler, D., Listinsky, C., Lossos, I. S., Hsi, E. D. 2008; 21 (6): 653-659

  Abstract

  The classification of primary cutaneous large B-cell lymphoma (PCLBCL) is based on standard morphology, immunohistochemistry, and clinical presentation. There are two major subtypes in the current WHO-EORTC classification: follicle center lymphoma and diffuse large B-cell lymphoma, leg-type (DLBCL-LT). The goals of this study were to examine a series of DLBCLs to determine (1) whether the immunohistochemical paradigm of germinal center B-cell and non-germinal center B-cell types of systemic DLBCL could be applied to PCLBCL; (2) whether application of the newly described germinal center B-cell marker, human germinal center-associated lymphoma (HGAL) also discriminates between these types as a further support for germinal center B-cell origin for primary cutaneous center lymphoma; and (3) whether any of these biologic markers were of prognostic significance. To this end, 32 cases of diffuse PCLBCL (22 primary cutaneous follicular center lymphomas and 10 DLBCL-LT) were classified based on the WHO-EORTC criteria and studied for expression of CD20, BCL2, BCL6, CD10, MUM-1, and HGAL by immunohistochemistry. Results were correlated with clinical features. HGAL and BCL6 expression and germinal center B-cell phenotype were associated with primary cutaneous follicular center lymphoma. The combination of HGAL and BCL6 positivity had the highest sensitivity (88%) and specificity (100%) for predicting subtype compared to either marker alone. Both HGAL and BCL6 were associated with the germinal center B-cell phenotype. The correlation of HGAL expression with the germinal center B-cell phenotype demonstrates the role of this marker in the classification of cutaneous large B-cell lymphomas. BCL6 expression was the only immunohistochemical marker associated with overall survival. Characterizing PCLBCLs with markers of B-cell maturation stage is a useful framework for studying, classifying, and clinically stratifying these lymphomas.

  View details for DOI 10.1038/modpathol.2008.30

  View details for Web of Science ID 000256112900002

  View details for PubMedID 18264083

• International trial confirms romidpesin efficacy in refractory CTCL patients 10th International Conference on Malignant Lymphoma Prentice, A., Whittaker, S., Kim, Y., Kim, E., LERNER, A., Duvic, M., Robak, T., Baran, E., Becker, J., McCulloch, W. OXFORD UNIV PRESS. 2008: 116–116

  View details for Web of Science ID 000256693500120

• An FLT3 gene-expression signature predicts clinical outcome in normal karyotype AML BLOOD Bullinger, L., Doehner, K., Kranz, R., Stirner, C., Froeling, S., Scholl, C., Kim, Y. H., Schlenk, R. F., Tibshirani, R., Doehner, H., Pollack, J. R. 2008; 111 (9): 4490-4495

  Abstract

  Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation and to evaluate the utility of a FLT3 signature for prognostication. DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases, and supervised analysis, using the Prediction Analysis of Microarrays method, was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The optimal predictor, composed of 20 genes, was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases. The predictor exhibited modest performance (73% sensitivity; 85% specificity) in classifying FLT3-ITD status. Remarkably, however, the signature outperformed FLT3-ITD mutation status in predicting clinical outcome. The signature may better define clinically relevant FLT3 signaling and/or alternative changes that phenocopy FLT3-ITD, whereas the signature genes provide a starting point to dissect these pathways. Our findings support the potential clinical utility of a gene expression-based measure of FLT3 pathway activation in AML.

  View details for DOI 10.1182/blood-2007-09-115055

  View details for Web of Science ID 000255387400016

  View details for PubMedID 18309032

• Review of the treatment of mycosis fungoides and sézary syndrome: a stage-based approach. Journal of the National Comprehensive Cancer Network Horwitz, S. M., Olsen, E. A., Duvic, M., Porcu, P., Kim, Y. H. 2008; 6 (4): 436-442

  Abstract

  The NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Disease were recently revised to include recommendations for treating mycosis fungoides and Sézary syndrome. These uncommon lymphomas require a specialized evaluation and use a unique TNMB staging system. Unlike the other forms of non-Hodgkin's lymphomas, stage overwhelmingly determines prognosis and defines radically different treatment approaches. For patients with early-stage disease, initial treatment with skin-directed therapies is preferred, and many patients never require systemic therapy. For patients with refractory or advanced-stage disease, biologic therapies are often the first choices, whereas chemotherapies are reserved for later in the disease course. Many milder therapies may be repeated several times in the disease course, and maintenance and tapering strategies are common. This article also discusses the emerging role of allogeneic stem cell transplantation.

  View details for PubMedID 18433609

• Radiation therapy is an effective treatment for refractory Woringer-Kolopp disease International Investigative Dermatology Meeting Lee, I. L., Viakhireva, N., Cesca, C., Lee, P., Kohler, S., Hoppe, R., Kim, Y. NATURE PUBLISHING GROUP. 2008: S70–S70

  View details for Web of Science ID 000254353800412

• Romidepsin has activity in refractory ctcl: an international multicenter study International Investigative Dermatology Meeting Whittaker, S., Scarisbrick, J., Kim, Y., Reddy, S., Kim, E., Rook, A., LERNER, A., Demierre, M., Duvic, M., Robak, T., Baran, E., Becker, J., Samtsov, A., McCulloch, W., Prentice, A. NATURE PUBLISHING GROUP. 2008: S74–S74

  View details for Web of Science ID 000254353800441

• Prognostic factors in primary cutaneous anaplastic large cell lymphoma: Clinical and molecular characterization of a subset with worse outcome 49th Annual Meeting of the American-Society-of-Hematology Woo, D., Jones, C., Vanoli-Storz, M., Kohler, S., Reddy, S., Advani, R., Hoppe, R., Kim, Y. AMER SOC HEMATOLOGY. 2007: 1045A–1045A

  View details for Web of Science ID 000251100804610

• Belinostat (PXD101) in patients with recurrent or refractory peripheral or cutaneous T-Cell lymphoma: Results of a phase II study 49th Annual Meeting of the American-Society-of-Hematology Advani, R., Hymes, K., Pohlman, B., Jacobsen, E., McDonnell, J., Belt, R., LERNER, A., Kim, Y., MUNDIS, R., MANSFIELD, T., Buhl-Jensen, P., Ooi, C. E., Duvic, M., Foss, F. AMER SOC HEMATOLOGY. 2007: 1012A–1012A

  View details for Web of Science ID 000251100804490

• Response to oral forodesine in refractory cutaneous T-Cell lymphoma: Interim results of a phase I/II study Duvic, M., Forero-Torres, A., Foss, F., Olsen, E., Kim, Y. AMER SOC HEMATOLOGY. 2007: 44A

  View details for Web of Science ID 000251100800123

• Combined BIOMED-2 clonality assays for IGH and IGK and assessment of t(14;18) on formalin-fixed, paraffin embedded tissues effectively separates primary cutaneous B cell lymphomas from reactive cutaneous lymphoid hyperplasia. Morales, A. V., Seo, K., Arber, D. A., Kohler, S., Kim, Y. H., Sundram, U. AMER SOC HEMATOLOGY. 2007: 772A–773A

  View details for Web of Science ID 000251100803405

• Romidepsin (depsipeptide) induces clinically significant responses in treatment-refractory CTCL: An International, Multicenter study 49th Annual Meeting of the American-Society-of-Hematology Kim, Y. H., Reddy, S., Kim, E. J., Rook, A. H., Lerner, A., Demierre, M., Duvic, M., Whittaker, S., Robak, T., Becker, J. C., McCulloch, W., Prentice, A. G. AMER SOC HEMATOLOGY. 2007: 44A–44A

  View details for Web of Science ID 000251100800124

• T-cell clonality analysis in biopsy specimens from two different skin sites shows high specificity in the diagnosis of patients with suggested mycosis fungoides 43rd Annual Meeting of the American-Society-of-Dermatopathology Thurber, S. E., Zhang, B., Kim, Y. H., Schrijver, I., Zehnder, J., Kohler, S. MOSBY-ELSEVIER. 2007: 782–90

  Abstract

  The diagnosis of mycosis fungoides (MF) is often difficult because of significant clinical and histopathologic overlap with inflammatory dermatoses. T-cell receptor (TCR)gamma chain rearrangement by polymerase chain reaction (PCR) (TCR-PCR) is a helpful adjuvant tool in this setting, but several of the inflammatory dermatoses in the differential diagnosis of MF may contain a clonal T-cell proliferation.We examined whether analysis for T-cell clonality and comparison of the clones with the standardized BIOMED-2 PCR multiplex primers for the TCRgamma chain from two anatomically distinct skin sites improves diagnostic accuracy.We examined two biopsy specimens each from 10 patients with unequivocal MF, from 18 patients with inflammatory dermatoses, and from 18 patients who could initially not be definitively given a diagnosis based on clinical and histopathologic criteria.Eight of 10 patients with unequivocal MF had an identical clone in both biopsy specimens. Two of 18 patients with inflammatory dermatoses were found to have a clone in one of the biopsy specimens. On further follow-up of the 18 patients with morphologically nondiagnostic biopsy specimens, 13 of 18 were later confirmed to have MF and 5 of 18 had inflammatory dermatoses. Eleven of 13 patients with MF had an identical clone in both biopsy specimens; two of 13 had a polyclonal amplification pattern in both biopsy specimens. Four of 5 patients with inflammatory dermatoses had no clone in either biopsy specimen. One patient with an inflammatory dermatosis had an identical clone in both specimens. The sensitivity of TCR-PCR analysis to evaluate for an identical clone at different anatomic skin sites (dual TCR-PCR) is 82.6% and the specificity is 95.7%.The number of patients in the study group was limited.These data suggest that dual TCR-PCR is a very promising technique with high specificity in distinguishing MF from inflammatory dermatoses.

  View details for DOI 10.1016/j.jaad.2007.06.004

  View details for Web of Science ID 000250387100004

  View details for PubMedID 17646032

• Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC) BLOOD Olsen, E., Vonderheid, E., Pimpinelli, N., Willemze, R., Kim, Y., Knobler, R., Zackheim, H., Duvic, M., Estrach, T., Lamberg, S., Wood, G., Dummer, R., Ranki, A., Burg, G., Heald, P., Pittelkow, M., Bernengo, M., Sterry, W., Laroche, L., Trautinger, F., Whittaker, S. 2007; 110 (6): 1713-1722

  Abstract

  The ISCL/EORTC recommends revisions to the Mycosis Fungoides Cooperative Group classification and staging system for cutaneous T-cell lymphoma (CTCL). These revisions are made to incorporate advances related to tumor cell biology and diagnostic techniques as pertains to mycosis fungoides (MF) and Sézary syndrome (SS) since the 1979 publication of the original guidelines, to clarify certain variables that currently impede effective interinstitution and interinvestigator communication and/or the development of standardized clinical trials in MF and SS, and to provide a platform for tracking other variables of potential prognostic significance. Moreover, given the difference in prognosis and clinical characteristics of the non-MF/non-SS subtypes of cutaneous lymphoma, this revision pertains specifically to MF and SS. The evidence supporting the revisions is discussed as well as recommendations for evaluation and staging procedures based on these revisions.

  View details for DOI 10.1182/blood-2007-03-055749

  View details for Web of Science ID 000249671700010

  View details for PubMedID 17540844

• Nephrogenic systemic fibrosis - Relationship to gadolinium and response to photopheresis ARCHIVES OF DERMATOLOGY Richmond, H., Zwerner, J., Kim, Y., Fiorentino, D. 2007; 143 (8): 1025-1030

  Abstract

  Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an idiopathic condition seen in patients with renal disease that is characterized by cutaneous sclerosis that can often result in contractures, pain, and functional disability as well as systemic complications. Recent reports have suggested a possible link with exposure to gadolinium, a commonly used radiocontrast agent. No current therapy has clearly demonstrated efficacy for NSF, although case reports suggest that extracorporeal photopheresis (ECP) may be of benefit. The purpose of this study was to explore the plausibility of a gadolinium linkage with NSF as well as to assess the efficacy of ECP in the treatment of a cohort of patients with NSF.We report our experience with 8 consecutive patients with NSF seen at the Stanford Medical Center, Palo Alta, California, from 2004 to 2006. Of the 8 patients, 6 had a history of arterial or venous thrombotic disease and 7 had a documented exposure to gadolinium within 1 week to several months prior to the onset of NSF. Specifically, all patients were exposed to gadodiamide. We treated 5 of the patients with ECP. After a mean number of 34 treatment sessions over a mean of 8.5 months, 3 patients experienced a mild improvement in skin tightening, range of motion, and/or functional capacity.Our data support the hypothesis that exposure to gadolinium, perhaps specifically gadodiamide, plays a role in the pathogenesis of NSF. Larger epidemiologic studies will be needed to confirm this association. In addition, our experience suggests that, if used for extended periods, ECP might have some mild benefit for patients with NSF. Larger, randomized, placebo-controlled trials of ECP should be performed to more specifically assess the benefit of ECP in the treatment of NSF.

  View details for Web of Science ID 000248723900008

  View details for PubMedID 17709661

• Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma 48th Annual Meeting of the American-Society-of-Hematology Olsen, E. A., Kim, Y. H., Kuzel, T. M., Pacheco, T. R., Foss, F. M., Parker, S., Frankel, S. R., Chen, C., Ricker, J. L., Arduino, J. M., Duvic, M. AMER SOC CLINICAL ONCOLOGY. 2007: 3109–15

  Abstract

  To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in persistent, progressive, or recurrent mycosis fungoides or Sézary syndrome (MF/SS) cutaneous t-cell lymphoma (CTCL) subtypes.Patients with stage IB-IVA MF/SS were treated with 400 mg of oral vorinostat daily until disease progression or intolerable toxicity in this open-label phase IIb trial (NCT00091559). Patients must have received at least two prior systemic therapies at least one of which included bexarotene unless intolerable. The primary end point was the objective response rate (ORR) measured by the modified severity weighted assessment tool and secondary end points were time to response (TTR), time to progression (TTP), duration of response (DOR), and pruritus relief ( > or = 3-point improvement on a 10-point visual analog scale). Safety and tolerability were also evaluated.Seventy-four patients were enrolled, including 61 with at least stage IIB disease. The ORR was 29.7% overall; 29.5% in stage IIB or higher patients. Median TTR in stage IIB or higher patients was 56 days. Median DOR was not reached but estimated to be >or = 185 days (34+ to 441+). Median TTP was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32% of patients had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%); most were grade 2 or lower but those grade 3 or higher included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%). Eleven patients required dose modification and nine discontinued due to AE.Oral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.

  View details for DOI 10.1200/JCO.2006.10.2434

  View details for Web of Science ID 000248743800020

  View details for PubMedID 17577020

• Out on a limb: prognostic factors in primary cutaneous anaplastic large cell lymphoma 68th Annual Meeting of the Society-for-Investigative-Dermatology Jones, C. R., Kohler, S., Cobb, K., Friedman, G. D., Reddy, S., Adrani, R., Hoppe, R., Kim, Y. NATURE PUBLISHING GROUP. 2007: S62–S62

  View details for Web of Science ID 000245387800364

• Second lymphomas and other malignant neoplasms in patients with mycosis fungoides and Sezary syndrome - Evidence from population-based and clinical cohorts ARCHIVES OF DERMATOLOGY Huang, K. P., Weinstock, M. A., Clarke, C. A., McMillan, A., Hoppe, R. T., Kim, Y. H. 2007; 143 (1): 45-50

  Abstract

  To assess risks for developing second malignancies in patients with mycosis fungoides or Sézary syndrome.Retrospective study of 2 cohorts.Nine population-based US cancer registries that constitute the Surveillance, Epidemiology, and End Results Program (SEER-9), and Stanford University referral center cohort of patients with cutaneous lymphoma. Patients with mycosis fungoides or Sézary syndrome from the SEER-9 registry diagnosed and followed up from 1984 through 2001 and from the Stanford University cohort diagnosed and followed up from 1973 through 2001.Relative risk was estimated using the standardized incidence ratio (SIR). The expected cancer incidence for both cohorts was calculated using age-, sex-, race-, and calendar year-specific SEER-9 incidence rates for the general population. Nonmelanoma skin cancers were excluded because these cancers are not routinely reported by the SEER database.In the SEER-9 cohort (n = 1798), there were 197 second instances of cancer (SIR = 1.32; 95% confidence interval [CI], 1.15-1.52) at all sites. Significantly elevated risk (P<.01) was observed for Hodgkin disease (6 cases; SIR = 17.14; 95% CI, 6.25-37.26) and non-Hodgkin lymphoma (27 cases; SIR = 5.08; 95% CI, 3.34-7.38). Elevated risk (P<.05) was also observed for melanoma (10 cases; SIR = 2.60; 95% CI, 1.25-4.79), and urinary cancer (21 cases; SIR = 1.74; 95% CI, 1.08-2.66). In the Stanford University cohort (n = 429), there were 37 second instances of cancer (SIR = 1.04; 95% CI, 0.76-1.44). Elevated risk (P<.01) was observed for Hodgkin disease (3 cases; SIR = 27.27; 95% CI, 5.35-77.54). Elevated risk (P<.05) was also observed for biliary cancer (2 cases; SIR = 11.76; 95% CI, 1.51-42.02).Updated SEER (population based) and Stanford (clinic based) data confirm the generalizability of earlier findings of increased risk of lymphoma in patients with mycosis fungoides or Sézary syndrome.

  View details for Web of Science ID 000243509100006

  View details for PubMedID 17224541

• Phase II preliminary results of SGN-30 (anti-CD30 mAb) in patients with CD30+lymphoproliferative disorders. 48th Annual Meeting of the American-Society-of-Hematology Duvic, M., Kim, Y., Reddy, S., Forero-Torres, A., Pinter-Brown, L. C., Rarick, M. U., Zic, J., Worobec, S., Korman, N., Kuzel, T., Bohjanen, K., Flessland, K., Barton, J., Sievers, E. AMER SOC HEMATOLOGY. 2006: 773A–773A

  View details for Web of Science ID 000242440003522

• Preliminary report on a phase I/II study of intraturnoral injection of PF-3512676 (CpG 7909), a TLR9 agonist, combined with radiation in recurrent low-grade lymphomas. 48th Annual Meeting of the American-Society-of-Hematology Ai, W. Y., Kim, Y., Hoppe, R. T., Shah, S., Horning, S. J., Tibshirani, R., Levy, R. AMER SOC HEMATOLOGY. 2006: 767A–768A

  View details for Web of Science ID 000242440003505

• Oral forodesine (Bcx-1777) is clinically active in refractory cutaneous T-cell lymphoma: Results of a phase I/II study. Duvic, M., Forero-Torres, A., Foss, F., Olsen, E. A., Kim, Y. AMER SOC HEMATOLOGY. 2006: 698A

  View details for Web of Science ID 000242440003257

• Zanolimumab, a fully human monoclonal antibody: early results of an ongoing clinical trial in patients with CD4(+) mycosis fungoides (MF) type CTCL(stage IB-IVB) who are refractory or intolerant to targretin and one other standard therapy. Duvic, M., Kim, Y., Korman, N. J., Boh, E., Lerner, A., Heffernan, M. P., Hymes, K. B., Pacheco, T., Elmets, C. A., Lisby, S., Baadsgaard, O. AMER SOC HEMATOLOGY. 2006: 772A

  View details for Web of Science ID 000242440003520

• Cutaneous involvement by angioimmunoblastic T-cell lymphoma: a unique histologic presentation, mimicking an infectious etiology JOURNAL OF CUTANEOUS PATHOLOGY Jayaraman, A. G., Cassarino, D., Advani, R., Kim, Y. H., Tsai, E., Kohler, S. 2006; 33: 6-11

  Abstract

  Angioimmunoblastic T-cell lymphoma (AILT) is an aggressive peripheral T-cell lymphoma that is frequently accompanied by a cutaneous eruption. The cutaneous findings most commonly consist of a maculopapular eruption on the trunk. However, purpura, infiltrated or urticarial plaques, papulovesicular lesions, nodules, and erythroderma have also been reported. Histologic findings in the lymph node are characteristic, while those in the skin may show one of four patterns. Here, we review the previously reported histologic patterns and present a case of AILT involving the skin with a unique histologic appearance of necrotizing granulomas with abundant histiocytes and eosinophils, mimicking an infectious etiology.

  View details for Web of Science ID 000240405000002

  View details for PubMedID 16972945

• A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Knobler, R. M., French, L. E., Kim, Y., Bisaccia, E., Graninger, W., Nahavandi, H., Strobl, F. J., Keystone, E., Mehlmauer, M., Rook, A. H., Braverman, Systemic Sclerosis Study Grp 2006; 54 (5): 793–99

  Abstract

  Systemic sclerosis is a multisystemic connective tissue disease with marked involvement of the skin and joints for which few effective evidence based therapies are available. To further investigate the efficacy of extracorporeal photochemotherapy on early aggressive cutaneous disease, a randomized, double-blind, placebo-controlled trial was performed.Our aim was to evaluate the efficacy of photopheresis in the treatment of patients with systemic sclerosis (scleroderma).This randomized, double-blind, placebo-controlled clinical trial was conducted at 16 investigational sites in the United States, Canada, and Europe. Sixty-four patients with typical clinical and histologic findings of scleroderma, of less than 2 years' duration, were studied. Patients did not receive any other concomitant treatment for scleroderma. Patients were randomized to receive either active or sham photopheresis treatment on two consecutive days monthly for 12 months. Severity of skin (skin scores assessed in 22 body regions) and joint involvement (60 joints examined for contractures) were assessed on a monthly basis.A statistically significant improvement in skin scores as compared with baseline was observed at 6 months (P = .0024) and 12 months (P = .008) among those who received active photopheresis, but not among those who received sham photopheresis. Comparison of skin scores between the two study arms did not achieve statistical significance because of the small sample size of the study arms. Joint involvement was also significantly improved after 6 months (P = .002) and 12 months (P = .001) of active photopheresis when compared with baseline.The study lacks sufficient statistical power to reveal a significant difference in skin and joint manifestations between the active and sham photopheresis arms.Photopheresis induced significant improvement of skin and joint involvement in patients with scleroderma of recent onset; however, any effect when compared with sham treatment and a possible placebo effect may be modest.

  View details for DOI 10.1016/j.jaad.2005.11.1091

  View details for Web of Science ID 000237119600005

  View details for PubMedID 16635659

• Staging accuracy in mycosis fungoides and Sezary syndrome using integrated positron emission tomography and computed tomography 65th Annual Meeting of the Society-for-Investigative-Dermatology Tsai, E. Y., Taur, A., Espinosa, L., Quon, A., Johnson, D., Dick, S., Chow, S., Advani, R., Warnke, R., Kohler, S., Hoppe, R. T., Kim, Y. H. AMER MEDICAL ASSOC. 2006: 577–84

  Abstract

  To evaluate the usefulness of integrated positron emission tomography and computed tomography (PET/CT) in staging mycosis fungoides (MF) and Sézary syndrome and to correlate PET/CT data with histopathologic diagnosis of lymph nodes (LNs).A single-center, prospective cohort analysis.Academic referral center for cutaneous lymphoma.Thirteen patients with MF and SS at risk for secondary LN involvement. Interventions Patients were clinically evaluated based on general physical examination, total body skin examination, and laboratory screening. They underwent integrated PET/CT followed by excisional biopsy of LNs.We used PET/CT to assess LN size and metabolic activity. Enlarged LNs were defined as axillary or inguinal LNs with a short axis 1.5 cm or larger; or cervical LN, with a short axis 1.0 cm or larger. We classified LN pathologic results according to National Cancer Institute (LN1-4) and World Health Organization (WHO 1-3) criteria. We quantified PET activity using standardized uptake value (SUV) and correlated with LN grade.Based on CT size criteria alone, only 5 patients had enlarged LNs, whereas PET revealed hypermetabolic LNs in all 13 patients. Six patients had LN1-3, and 7 had effacement of LN architecture by lymphoma cells (LN4). Of the 7 patients with LN4 nodes, 4 had SS, and 3 had tumorous MF. Two patients with LN4 nodes had inguinal LNs smaller than 1.5 cm and would have been assigned an N0 classification without the use of integrated PET/CT. Correlation of SUV with LN grade revealed that LN1-3 nodes were associated with a mean SUV of 2.7 (median SUV, 2.2; range, 2.0-4.7) and LN4 nodes were associated with a mean SUV of 5.4 (median SUV, 3.9; range, 2.1-11.8). Patients with large cell transformation had the highest SUVs.For staging MF and SS, PET/CT was more sensitive in detecting LN involved by lymphoma compared with CT data alone and thus may provide more accurate staging and prognostic information. The intensity of PET activity correlated with histologic LN grade.

  View details for Web of Science ID 000237543100006

  View details for PubMedID 16702495

• Phase II preliminary results suggest SGN-30 (Anti-CD30 monoclonal antibody) is active and well-tolerated in patients with cutaneous anaplastic large cell lymphoma 67th Annual Meeting of the Society-for-Investigative-Dermatology Duvic, M., Kunishige, J., Kim, Y., Reddy, S., Forero-Torres, A., Pinter-Brown, L., Rarick, M., Zic, J., Worobec, S., Flessland, K., Barton, J. NATURE PUBLISHING GROUP. 2006: 45–45

  View details for Web of Science ID 000242891500269

• Superior clinical outcome for patients receiving allogeneic over autologous stem cell transplant in mycosis fungoides and Sezary syndrome 67th Annual Meeting of the Society-for-Investigative-Dermatology Wu, P. A., Stockerl-Goldstein, K., Reddy, S. A., Hoppe, R. T., Kim, Y. H. NATURE PUBLISHING GROUP. 2006: 40–40

  View details for Web of Science ID 000242891500240

• The Stanford experience with utilizing the new WHO classification of cutaneous lymphomas for cutaneous B cell lymphoma 67th Annual Meeting of the Society-for-Investigative-Dermatology Reddy, S., Kohler, S., Horwitz, S., Sutherland, K., Hoppe, R. T., Kim, Y. H. NATURE PUBLISHING GROUP. 2006: 44–44

  View details for Web of Science ID 000242891500264

• Bexarotene is highly active in the treatment of subcutaneous Panniculitis-like T-cell lymphoma. 47th Annual Meeting of the American-Society-of-Hematology Molina, A. M., Advani, R., Reddy, S., Hoppe, R., Friedberg, J. W., Sadan, S., Myskowski, P., Kim, Y. H., Horwitz, S. M. AMER SOC HEMATOLOGY. 2005: 934A–934A

  View details for Web of Science ID 000233426006128

• Expression of the bcl-6 and MUM1/IRF4 proteins correlate with overall and disease-specific survival in patients with primary cutaneous large B-cell lymphoma: a tissue microarray study JOURNAL OF CUTANEOUS PATHOLOGY Sundram, U., Kim, Y., Mraz-Gernhard, S., Hoppe, R., Natkunam, Y., Kohler, S. 2005; 32 (3): 227-234

  Abstract

  Systemic B-cell lymphomas have been studied using microarrays, which has led to a better understanding of their molecular characteristics. Initial microarray studies of these lymphomas have implicated several genes as important predictors of outcome. In this study, we used a tissue microarray (TMA) to characterize primary cutaneous large B-cell lymphomas (PCLBCL).We studied 14 patients for whom clinical follow up was available, including four patients whose lesions were limited to the leg on presentation. Immunohistochemical staining with CD20, CD44, CD21, CD5, CD10, bcl-2, bcl-6, Ki67, p53, and multiple myeloma 1 (MUM1) was examined.Our results identify two subgroups of lymphomas. The first group showed staining with bcl-6 and had an overall survival of 176 months (p = 0.003). The majority of this group was negative for MUM1. The second group lacked staining with bcl-6 and had an overall survival of 26 months, with a majority of these cases staining with MUM1. Three of four patients with PCLBCL of the leg showed no staining with bcl-6.Our study demonstrates the utility of TMAs in the analysis of PCLBCL and that expression of bcl-6 and MUM1 correlates with survival.

  View details for Web of Science ID 000226857100005

  View details for PubMedID 15701085

• Primary cutaneous CD30+ anaplastic large cell lymphoma: Analysis of the Stanford series reveals two clinical subsets of patients. 46th Annual Meeting of the American-Society-of-Hematology Reddy, S. A., Liu, H., Kohler, S., Hoppe, R. T., Kim, Y. H. AMER SOC HEMATOLOGY. 2004: 226B–226B

  View details for Web of Science ID 000225127700898

• Marked improvement in staging accuracy in mycosis fungoides/Sezary syndrome using integrated positron emission tomography and computed tomography (PET/CT) Tsai, E. Y., Taur, A., Espinosa, L., Quon, A., Dick, S. E., Chow, S., Advani, R., Warnke, R. A., Kohler, S., Hoppe, R. T., Kim, Y. H. AMER SOC HEMATOLOGY. 2004: 854A–855A

  View details for Web of Science ID 000225127503129

• Clinical and pathological features of posttransplantation lymphoproliferative disorders presenting with skin involvement in 4 patients ARCHIVES OF DERMATOLOGY Beynet, D. P., Wee, S. A., Horwitz, S. S., Kohler, S., Horning, S., Hoppe, R., Kim, Y. H. 2004; 140 (9): 1140-1146

  Abstract

  Posttransplantation lymphoproliferative disorders (PTLDs) are lymphoid proliferations that can develop in recipients of solid organ or allogeneic bone marrow transplants. They are clinically and pathologically heterogeneous and range from polyclonal hyperplastic lesions to malignant lymphomas. Although extranodal involvement in PTLD is common, cutaneous presentation is rare, with only 19 cases reported previously.We describe 4 patients with cutaneous presentations of PTLD. All patients had relatively late-onset PTLD (>1 year after transplantation) with a median of 8 years from organ allograft to tumor diagnosis. The extent, number, and anatomic location of skin lesions varied from a localized patch to widespread nodules. None of the patients exhibited systemic symptoms at the time of PTLD diagnosis. Pathological findings ranged from plasmacytic hyperplasia to monomorphic PTLD. In situ hybridization detected Epstein-Barr virus messenger RNA in all 3 cases with evaluable tissue. All patients underwent reduction in immunosuppressive therapy and received other individualized treatments. Median follow-up was 2.5 years. At the most recent follow-up, 3 patients were in complete remission and 1 had residual disease.In this study, PTLD lesions presenting in the skin responded to therapy. Despite their relatively late occurrence after transplantation, most of these cases were positive for Epstein-Barr virus. As observed with other cutaneous lymphomas, the PTLDs with predominant skin involvement had a relatively favorable outcome.

  View details for Web of Science ID 000223835000014

  View details for PubMedID 15381556

• CD30(+) cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Liu, H. L., Hoppe, R. T., Kohler, S., Harvell, J. D., Reddy, S., Kim, Y. H. 2003; 49 (6): 1049-1058

  Abstract

  CD30+ cutaneous lymphoproliferative disorders (CLPDs) include lymphomatoid papulosis, borderline cases of CD30+CLPDs, and primary cutaneous anaplastic large cell lymphoma (PCALCL). Prior studies have shown CD30+CLPDs have an excellent prognosis.We sought to present the single-center experience of Stanford University, Stanford, Calif, in the management of CD30+CLPDs.A retrospective cohort analysis of 56 patients with CD30+CLPDs treated at our institution was performed.No patients with lymphomatoid papulosis died of disease, and overall survival was 92% at 5 and 10 years. Disease-specific survivals at 5 and 10 years for PCALCL were 85%. Disease-specific survival at 5 years for localized versus generalized PCALCL was 91% versus 50% (P =.31). PCALCL was highly responsive to treatment, but the relapse rate was 42%. In all, 3 patients progressed to extracutaneous stage of disease. No clinical or histologic factors analyzed were predictive of worse outcome in lymphomatoid papulosis and PCALCL.Similar to prior reports from multicenter European groups, the single-center experience at our institution demonstrates CD30+CLPDs have an overall excellent prognosis; however, cases of PCALCL with poor outcome do exist.

  View details for DOI 10.1016/S0190-9622(03)02484-8

  View details for Web of Science ID 000186784800009

  View details for PubMedID 14639383

• HuMax-CD4, a fully human monoclonal antibody: Early results of an ngoing phase II trial in cutaneous T cell lymphoma Obitz, E., Kim, Y. H., Iversen, L., Osterborg, A., Jensen, P., Baadsgaard, O., Knox, S. J. AMER SOC HEMATOLOGY. 2003: 645A

  View details for Web of Science ID 000186536702381

• Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome - Clinical prognostic factors and risk for disease progression 63rd Annual Meeting of the Society-for-Investigative-Dermatology Kim, Y. H., Liu, H. L., Mraz-Gernhard, S., Varghese, A., Hoppe, R. T. AMER MEDICAL ASSOC. 2003: 857–66

  Abstract

  To study and update the clinical characteristics and long-term outcome of our patients with mycosis fungoides (MF) and Sézary syndrome (SS), and to identify important clinical factors predictive of survival and disease progression.A single-center, retrospective cohort analysis.Academic referral center for cutaneous lymphoma.Five hundred twenty-five patients with MF and SS evaluated and managed at Stanford University Cutaneous Lymphoma Clinic, Stanford, Calif, from 1958 through 1999.We calculated long-term actuarial overall and disease-specific survivals and disease progression by the Kaplan-Meier method, and relative risk (RR) for survival calculated from expected survivals in control populations.The majority of our patients presented with T1 (30%) or T2 (37%) disease; 18% presented with T3 and 15% with T4 skin involvement. Forty-three percent of deaths were attributable to MF, primarily in patients with T3 or T4 disease. The patients with a more advanced T classification and clinical stage had a worse survival outcome. Except for patients with T1 or stage IA disease, the RR for death is greater in patients with MF than in a control population (RR, 2.2 in stage IB/IIA disease, 3.9 in stage IIB/III disease, and 12.8 in stage IV disease). Despite similar overall survival in patients with stage IB or IIA disease, their disease-specific survivals were significantly different (P =.006). The most significant clinical prognostic factors in the univariate analysis were patient age, TNM and B classifications, overall clinical stage groupings, and the presence or absence of extracutaneous disease. In the multivariate analysis, patient age, T classification, and the presence of extracutaneous disease were the most important independent factors. The risk for disease progression to a more advanced TNM or B classification, worse clinical stage, or death due to MF correlated with the severity of the initial T classification. The risk for development of extracutaneous disease also correlated with T classification; none of these patients had T1 disease when their extracutaneous disease was detected.Patients with MF and SS have varying risks for disease progression or death. The most important clinical predictive factors for survival include patient age, T classification, and the presence of extracutaneous disease. The significant disease-specific survival differences between different clinical stages validate the usefulness of the present MF clinical staging system of the National Cancer Institute.

  View details for Web of Science ID 000184104500003

  View details for PubMedID 12873880

• Gene expression profiles of cutaneous B cell lymphoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Storz, M. N., van de Rijn, M., Kim, Y. H., Mraz-Gernhard, S., Hoppe, R. T., Kohler, S. 2003; 120 (5): 865-870

  Abstract

  We studied gene expression profiles of 17 cutaneous B cell lymphomas that were collected with 4-6 mm skin punch biopsies. We also included tissue from two cases of mycosis fungoides, three normal skin biopsies, and three tonsils to create a framework for further interpretation. A hierarchical cluster algorithm was applied for data analysis. Our results indicate that small amounts of skin tissue can be used successfully to perform microarray analysis and result in distinct gene expression patterns. Duplicate specimens clustered together demonstrating a reproducible technique. Within the cutaneous B cell lymphoma specimens two specific B cell differentiation stage signatures of germinal center B cells and plasma cells could be identified. Primary cutaneous follicular and primary cutaneous diffuse large B cell lymphomas had a germinal center B cell signature, whereas a subset of marginal zone lymphomas demonstrated a plasma cell signature. Primary and secondary follicular B cell lymphoma of the skin were closely related, despite previously reported genetic and phenotypic differences. In contrast primary and secondary cutaneous diffuse large B cell lymphoma were less related to each other. This pilot study allows a first glance into the complex and unique microenvironment of B cell lymphomas of the skin and provides a basis for future studies, which may lead to the identification of potential histologic and prognostic markers as well as therapeutic targets.

  View details for Web of Science ID 000182456200027

  View details for PubMedID 12713594

• Topical nitrogen mustard in the management of mycosis fungoides - Update of the Stanford experience ARCHIVES OF DERMATOLOGY Kim, Y. H., Martinez, G., Varghese, A., Hoppe, R. T. 2003; 139 (2): 165-173

  Abstract

  To evaluate and update the response and survival outcomes and toxic effects in patients treated with topical nitrogen mustard (mechlorethamine hydrochloride) as primary therapy.A single-center, retrospective cohort analysis.Academic referral center for cutaneous lymphoma.A total of 203 patients with mycosis fungoides (clinical stages I-III) treated with topical nitrogen mustard as initial therapy.Long-term actuarial survival, freedom-from-relapse, and freedom-from-progression results as calculated by the Kaplan-Meier method.The overall response rate for the 203 patients was 83%, with a complete response rate of 50%. The median time to achieve complete response was 12 months (T1, 10 months; T2, 19 months), and the median time to relapse was 12 months. The duration of complete response increased with longer maintenance therapy; however, after completion of therapy, the response duration or relapse rate was similar regardless of maintenance regimen. Patients with T1 disease had better response and survival outcomes than those with T2 disease, with overall and complete response rates in T1 of 93% and 65%, respectively, and in T2, 72% and 34%, respectively. A similar clinical response was seen for patients with stage IIA vs IB. Sixty-eight percent of 203 patients received only topical nitrogen mustard therapy throughout their follow-up course, including most of the patients who achieved an initial complete response. The clinical response to topical nitrogen mustard as salvage therapy was similar to initial response rates. The efficacy results were similar in patients treated with aqueous vs ointment preparations. Freedom-from-progression rates in T1 disease (no progression to higher T classification or worse clinical stage) at 5 and 10 years were 92% and 85%, respectively, and in T2, 83% at 5 and 10 years. Fewer than 10% of patients experienced contact hypersensitivity reactions when topical nitrogen mustard was used as an ointment preparation. Only 8 patients (4%) developed secondary cutaneous malignancy, none attributable to topical nitrogen mustard monotherapy. Pediatric patients experienced no significant toxic effects with topical nitrogen mustard therapy.Topical nitrogen mustard remains an effective primary initial or salvage therapy in mycosis fungoides for patients with T1 and T2 disease. Long-term follow-up results confirm its safety.

  View details for Web of Science ID 000180971400006

  View details for PubMedID 12588222

• Management with topical nitrogen mustard in mycosis fungoides. Dermatologic therapy Kim, Y. H. 2003; 16 (4): 288-298

  Abstract

  Topical nitrogen mustard (mechlorethamine, NM) has been used as primary therapy for management of patients with mycosis fungoides (MF) since the 1950s. Many investigators have demonstrated the efficacy of topical NM in patch and/or plaque disease of MF. Updated results from Stanford also confirm the clinical efficacy. The complete response (CR) rates reported are 76-80% for patients with limited patch/plaque (stage IA), and 35-68% for those with generalized patch/plaque (stage IB) disease. Topical NM can be used as an aqueous (water) or ointment-based preparation. The efficacy results are similar in patients who were treated with aqueous versus ointment preparations. Maintenance regimens used are variable, but there is no data to suggest that a longer maintenance duration results in greater potential for long-term remission. Most patients who achieve initial CR with topical NM tend to require NM-only for disease management. Topical NM is equally effective when used as salvage therapy with disease relapse. The most common toxicity of topical NM therapy is contact irritant or allergic reaction. The potential for allergic reaction is significantly reduced (< 10%) when NM is used as an ointment preparation. The potential for secondary skin cancer development is increased in patients who have used multiple sequential topical skin-damaging therapies or NM in the genital skin, but not in patients who have used NM as monotherapy (avoiding genital skin application). Topical NM is used safely in pediatric patients and there is no evidence of any clinically significant systemic absorption of topically applied NM.

  View details for PubMedID 14686971

• Management with topical nitrogen mustard in mycosis fungoides: Update of the Stanford experience Kim, Y. H., Hoppe, R. T. NATURE PUBLISHING GROUP. 2002: 234–34

  View details for Web of Science ID 000177428100161

• The largest single-center US study of cutaneous CD30+lymphoproliferative disorders Liu, H., Kohler, S., Harvell, J., Hoppe, R., Kim, Y. NATURE PUBLISHING GROUP. 2002: 237–37

  View details for Web of Science ID 000177428100180

• Clinical and pathological spectrum of post-transplant lymphoproliferative disorders with skin involvement Wee, S., Horowitz, S., Kohler, S., Kim, Y. H. NATURE PUBLISHING GROUP. 2002: 243–43

  View details for Web of Science ID 000177428100212

• Interstitial mycosis fungoides, a variant of mycosis fungoides resembling granuloma annulare and inflammatory morphea JOURNAL OF CUTANEOUS PATHOLOGY Su, L. D., Kim, Y. H., LeBoit, P. E., Swetter, S. M., Kohler, S. 2002; 29 (3): 135-141

  Abstract

  Interstitial mycosis fungoides (IMF) is a rare variant of mycosis fungoides that resembles the interstitial form of granuloma annulare and inflammatory morphea. IMF has received little attention in the literature.Clinical, histological, immunophenotypical, and genotypical findings of five cases of IMF were reviewed. The histological and immunophenotypical findings were compared with those of eight cases of interstitial granuloma annulare and six cases of inflammatory morphea.Five patients with IMF presented with non-indurated, erythematous macules; ill-defined erythematous plaques with slight scale; and nodules on the trunk and proximal limbs. Two of five patients had a prior diagnosis of mycosis fungoides. Skin biopsies revealed a striking dermal interstitial infiltrate of lymphocytes with rare histiocytes that resembled the interstitial form of granuloma annulare or inflammatory morphea. Epidermotropic lymphocytes were present at least focally in all cases. A band-like lymphocytic infiltrate was observed in two of five cases. In contrast, many plasma cells and histiocytes were observed in cases of inflammatory morphea and interstitial granuloma annulare, respectively. With Movat-pentachrome stains, increased dermal mucin deposition was observed in two of five IMF cases, in all cases of interstitial granuloma annulare, and in one of six cases of inflammatory morphea. There was focal loss of elastic fibers in all cases of inflammatory morphea. Immunohistochemical studies of IMF highlighted a dominant population of T cells (CD3+) in the dermis and epidermis. In contrast, moderate numbers of B cells (CD20+) were admixed with T cells and plasma cells in inflammatory morphea. Almost equal numbers of histiocytes (CD68+) and T cells comprised the infiltrate of interstitial granuloma annulare. In two of five IMF cases, a clonal T-cell population was detected by PCR T-cell gamma gene rearrangement analysis.Mycosis fungoides occasionally presents as an interstitial lymphocytic infiltrate that mimics granuloma annulare and inflammatory morphea. Hematoxylin & eosin (H&E) findings alone can sometimes distinguish the three disorders. Immunophenotyping and genotyping may be helpful in difficult cases.

  View details for Web of Science ID 000175587800002

  View details for PubMedID 11972709

• Bexarotene gel - A food and drug administration-approved skin-directed therapy for early-stage cutaneous T-cell lymphoma ARCHIVES OF DERMATOLOGY Liu, H. L., Kim, Y. H. 2002; 138 (3): 398–99

  View details for DOI 10.1001/archderm.138.3.398

  View details for Web of Science ID 000174367300015

  View details for PubMedID 11902993

• Quality-of-life improvements in cutaneous T-cell lymphoma patients treated with denileukin diftitox (ONTAK (R)) CLINICAL LYMPHOMA Duvic, M., Kuzel, T., Olsen, E. A., Martin, A. G., Foss, F. M., Kim, Y. H., Heald, P. W., Bacha, P., Nichols, J., Liepa, A. 2002; 2 (4): 222-228

  Abstract

  Cutaneous T-cell lymphoma (CTCL) can be associated with painful, pruritic, disfiguring lesions. As part of a multicenter, randomized phase III trial in patients with heavily pretreated advanced and/or recurrent CTCL, the effects of an interleukin-2 receptor-targeted fusion protein, denileukin diftitox (DAB389IL-2, ONTAK), on patient-rated overall quality of life (QOL), skin appearance, and pruritus severity were evaluated. A total of 71 patients with stage IB-IVA CTCL received intravenous denileukin diftitox 9 microg/kg/day or 18 microg/kg/day over 15-60 minutes for 5 consecutive days on an outpatient basis; cycles were planned for every 21 days for a total of 8 cycles over 6 months. Prior to each treatment cycle, patients were evaluated for disease response and were asked to self-rate their overall QOL via the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, skin appearance (7-point scale), and pruritus severity (10-cm visual analogue scale). Composite FACT-G and most individual subscale scores (physical, social/family, emotional, and functional well being) in documented responders (n = 21) gradually increased during the study period, generally reaching statistical significance (P < 0.05) by cycle 3, and were significantly (P < or = 0.041) higher than the scores of nonresponders at endpoint. Additionally for responders, assessments of skin severity and pruritus severity showed significant (P < or = 0.05) improvements at study endpoint compared with baseline. Adverse transfusion-related events (eg, hypersensitivity reactions, flu-like syndrome) were common during cycles 1 and 2, and vascular-leak syndrome occurred in 25% of patients. Denileukin diftitox was not associated with any clinically significant myelosuppression. Heavily pretreated patients with advanced and/or recurrent CTCL who responded to denileukin diftitox therapy showed significant improvements in self-rated overall QOL, skin appearance, and pruritus severity.

  View details for Web of Science ID 000174903400007

  View details for PubMedID 11970761

• Large atypical cells of lymphomatoid papulosis are CD56-negative: a study of 18 cases JOURNAL OF CUTANEOUS PATHOLOGY Harvell, J. D., Vaseghi, M., Natkunam, Y., Kohler, S., Kim, Y. 2002; 29 (2): 88-92

  Abstract

  Histologically, diffuse dermal infiltrates of large atypical lymphocytes can be seen in lesions as indolent as type C lymphomatoid papulosis (LyP) to ones as aggressive as NK/T-cell lymphoma. While lesions of lymphomatoid papulosis are definitionally positive for CD30, their ability to express CD56 has not been formally studied. The objective of the current study was to determine whether or not the large atypical cells of LyP express the natural killer cell marker, CD56.Biopsies from 18 patients with LyP were studied with monoclonal antibodies to CD30, CD56, CD8, and TIA-1. These included four type C LyP lesions. Clinical information was obtained by chart review and included extent of LyP lesions, presence/absence of disease at follow-up, and any associated hematologic malignancies,.None of the biopsies exhibited CD56 positivity within the large atypical cells of LyP. While some biopsies demonstrated CD56-positive, small, presumably reactive, lymphocytes within the infiltrate, their presence did not correlate with extent of disease, persistence of disease, or propensity for an associated non-LyP hematologic malignancy.The large atypical cells of types A and C LyP do not exhibit positivity for CD56, and thus a panel of antibodies that includes CD30 and CD56 can readily distinguish between the benign end of the spectrum of CD30-positive lymphoproliferations and aggressive NK/T-cell lymphoma.

  View details for Web of Science ID 000174804900004

  View details for PubMedID 12150138

• Natural killer/natural killer-like T-Cell lymphoma, CD56+, presenting in the skin: An increasingly recognized entity with an aggressive course JOURNAL OF CLINICAL ONCOLOGY Mraz-Gernhard, S., Natkunam, Y., Hoppe, R. T., Leboit, P., Kohler, S., Kim, Y. H. 2001; 19 (8): 2179-2188

  Abstract

  To describe and identify the clinical and pathologic features of prognostic significance for natural killer (NK) and NK-like T-cell (NK/T-cell) lymphoma presenting in the skin.This study was a retrospective review of 30 patients with CD56+ lymphomas initially presenting with cutaneous lesions, with analysis of clinical and histopathologic parameters.The median survival for all patients was 15 months. Those with extracutaneous manifestations at presentation (11 patients) had a shorter median survival of 7.6 months as compared with those without extracutaneous involvement (17 patients), who had a more favorable median survival of 44.9 months (P =.0001). Age, gender, extent of cutaneous involvement, and initial response to therapy had no statistically significant effect on survival. Seven patients (24%) had detectable Epstein-Barr virus (EBV) within neoplastic cells. The patients with tumor cells that coexpress CD30 (seven patients) have not yet reached a median survival after 35 months of follow-up as compared with those with CD30- tumor cells (20 patients), who had a median survival of 9.6 months (P <.02). Routine histopathologic characteristics had no prognostic significance nor did the presence of CD3epsilon, EBV, or multidrug resistance.NK/T-cell lymphoma is an aggressive neoplasm; however, a subset with a more favorable outcome is identified in this study. The presence of extracutaneous disease at presentation is the most important clinical variable and portends a poor prognosis. The extent of initial skin involvement does not reliably predict outcome. Patients from the United States with NK/T-cell lymphoma presenting in the skin have a low incidence of demonstrable EBV in their tumor cells. Patients with coexpression of CD30 in CD56 lymphomas tend to have a more favorable outcome.

  View details for Web of Science ID 000168178300009

  View details for PubMedID 11304770

• Clinical characteristics and outcome of patients with extracutaneous mycosis fungoides JOURNAL OF CLINICAL ONCOLOGY de Coninck, E. C., Kim, Y. H., Varghese, A., Hoppe, R. T. 2001; 19 (3): 779-784

  Abstract

  To identify prognostic factors predictive of outcome in patients with extracutaneous (stage IV) mycosis fungoides (MF) and to evaluate the risk of progression to extracutaneous disease by initial extent of skin involvement.One hundred twelve patients with extracutaneous disease at presentation or with progression and 434 patients with initial cutaneous-only disease were identified. Actuarial survival curves were plotted according to the Kaplan-Meier technique.The median survival of all stage IV patients was 13 months from the date of first treatment for stage IV disease. Sex, race, age, extent of skin involvement, and peripheral blood Sezary cell involvement were not significant to survival outcome. Eleven patients (10%) had a complete response to therapy resulting in a significantly improved median survival compared with patients with a partial or no response (1.70 v 0.91 years, P =.047 and 1.70 v 0.57 years, P =.011, respectively). At 20 years from diagnosis, the risk for progression to extracutaneous disease by initial extent of skin involvement was 0% for limited patch/plaque, 10% for generalized patch/plaque, 35.5% for tumorous disease, and 41% for erythrodermic involvement.This was a larger scale study over a longer time period than had been completed previously on extracutaneous MF. Prognostic factors important in the cutaneous stages of disease are no longer significant once extracutaneous disease develops. Patients who had a more favorable response to therapy may have had a biologically less aggressive disease than their less fortunate counterparts. The risk of developing stage IV MF is highest in patients presenting with tumorous or erythrodermic skin disease and is lowest in patients with limited skin involvement.

  View details for Web of Science ID 000166803100024

  View details for PubMedID 11157031

• Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma JOURNAL OF CLINICAL ONCOLOGY Olsen, E., Duvic, M., Frankel, A., Kim, Y., Martin, A., Vonderheid, E., Jegasothy, B., Wood, G., Gordon, M., Heald, P., Oseroff, A., Pinter-Brown, L., Bowen, G., Kuzel, T., Fivenson, D., Foss, F., Glode, M., Molina, A., Knobler, E., Stewart, S., Cooper, K., Stevens, S., Craig, F., Reuben, J., Bacha, P., Nichols, J. 2001; 19 (2): 376-388

  Abstract

  The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Pharmaceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured.Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity.Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

  View details for Web of Science ID 000166534000014

  View details for PubMedID 11208829

• Natural killer/natural killer-like T-cell lymphoma (CD56+) presenting in the skin: A study of clinical and pathologic characteristics affecting survival. Mraz-Gernhard, S. M., Hoppe, R. T., Natkunam, Y., Leboit, P., Kohler, S., Kim, Y. H. AMER SOC HEMATOLOGY. 2000: 124A–125A

  View details for Web of Science ID 000165256100537

• The clinical spectrum of cutaneous B-cell lymphomas (CBCL): Excellent prognosis for patients with disease limited to the skin. Mraz-Gernhard, S. M., Horwitz, S., Kim, Y. H., Kohler, S., Hoppe, R. AMER SOC HEMATOLOGY. 2000: 329A

  View details for Web of Science ID 000165256101420

• Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemical and molecular analyses of seven cases JOURNAL OF CUTANEOUS PATHOLOGY Natkunam, Y., Warnke, R. A., Haghighi, B., Su, L. D., Le Boit, P. E., Kim, Y. H., Kohler, S. 2000; 27 (8): 392-399

  Abstract

  Natural killer and natural killer-like T-cell lymphomas presenting in the skin usually demonstrate aggressive behavior, an angiocentric distribution and a characteristic immunophenotype. In contrast, primary cutaneous CD30+ lymphoproliferative disorders form a heterogeneous spectrum including anaplastic large cell lymphomas, the majority of which display a good prognosis. Lymphomas with co-expression of CD56 and CD30 are extremely rare and the significance of this co-expression is unknown.Seven retrospectively identified cases of lymphomas with co-expression of CD56 and CD30 presenting in the skin comprise this study. Immunohistochemistry, in situ hybridization for Epstein-Barr virus and T-cell receptor gene rearrangement studies were performed on paraffin sections.This subset of cutaneous lymphomas showed a variable clinical course that ranged from resolution without treatment, treatment-failure and recurrence, to death from disease. Histologic, immunophenotypic and molecular studies were of limited utility in predicting prognosis.Cutaneous lymphomas co-expressing CD56 and CD30 share many clinicopathologic features with natural killer and natural killer-like T-cell lymphomas or anaplastic large cell lymphomas, two entities with widely disparate clinical behavior. It is important to recognize that these lymphomas may behave more aggressively than primary cutaneous anaplastic large cell lymphomas do. Longer follow-up and further investigations on larger numbers of cases are necessary to fully characterize this rare subset of cutaneous lymphomas.

  View details for Web of Science ID 000088444100003

  View details for PubMedID 10955685

• Oral bexarotene is safe and effective in a phase II-III clinical trial in refractory or persistent early stage CTCL. Duvic, M., Martin, A., Kim, Y., Olsen, E., Wood, G., Yocum, R. AMER SOC HEMATOLOGY. 1999: 659A

  View details for Web of Science ID 000083790302976

• Epidermotropic cutaneous B-cell lymphoma mimicking mycosis fungoides JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chui, C. T., Hoppe, R. T., Kohler, S., Kim, Y. H. 1999; 41 (2): 271-274

  Abstract

  Cutaneous involvement by B-cell lymphoma is often secondary to systemic disease. Primary cutaneous B-cell lymphomas are less common, and patients generally have an excellent prognosis. We present a patient with cutaneous B-cell lymphoma with clinical and histologic features mimicking mycosis fungoides. Although the patient was initially misdiagnosed as having a T-cell lymphoma, immunophenotypic studies demonstrated that this was a B-cell lymphoma.

  View details for Web of Science ID 000081921900023

  View details for PubMedID 10426903

• Mycosis fungoides and the Sezary syndrome SEMINARS IN ONCOLOGY Kim, Y. H., Hoppe, R. T. 1999; 26 (3): 276-289

  Abstract

  Mycosis fungoides (MF) and the Sézary syndrome are a group of extranodal non-Hodgkin's lymphomas of T-cell origin with primary cutaneous involvement. The group distinguishes itself from other primary cutaneous T-cell lymphomas (CTCLs) by its unique clinical features and histopathology. In its early stages, it often resembles common benign dermatoses, and therefore, a definitive diagnosis can be delayed. The affected T cells are characterized by a predominant CD4+ phenotype with frequent loss of CD7 (pan-T-cell antigen) and often demonstrate T-cell receptor (TCR) rearrangement. The prognosis of patients with MF is highly dependent on the extent and type of skin involvement. The initial cutaneous presentation of MF can be patches, plaques, tumors, or erythroderma. Patients who present with limited patch/plaque disease have an outstanding prognosis with an overall long-term survival that is similar to the expected survival of a matched control population. It is exceedingly rare for patients who present with limited or generalized patch/plaque disease without peripheral lymphadenopathy to have extracutaneous involvement. Therefore, the staging evaluation differs for patients with MF versus patients with other non-Hodgkin's lymphomas and should be tailored to the clinical presentation. Patients who have tumorous or erythrodermic skin involvement have a less favorable prognosis, and patients who present with extracutaneous disease have a poor prognosis. There are multiple therapeutic options for patients with MF and the Sézary syndrome. Selection of a specific treatment plan is based primarily on the clinical stage of the disease. The primary therapy for patients with patch/plaque disease without extracutaneous involvement is a topical regimen, whereas chemotherapy or other aggressive systemic regimens are reserved for those with recalcitrant disease or extracutaneous involvement. There is no evidence that early aggressive systemic therapy is preferable to conservative therapy in the management of limited disease. There are newer combination topical and/or systemic regimens that result in an improved clinical response and possibly a prolonged response duration. For advanced disease, standard therapies are often palliative and successful clinical response is often very short-lived. Therefore, all patients with recalcitrant or extracutaneous disease should be considered for newer investigative therapies.

  View details for Web of Science ID 000080809400005

  View details for PubMedID 10375085

• Total skin electron beam therapy with or without adjuvant topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis fungoides 40th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Chinn, D. M., Chow, S., Kim, Y. H., Hoppe, R. T. ELSEVIER SCIENCE INC. 1999: 951–58

  Abstract

  To compare the efficacy of total skin electron beam therapy (TSEBT) with or without adjuvant topical nitrogen mustard (+/- HN2) with topical nitrogen mustard (HN2) alone as initial management of T2 and T3 mycosis fungoides (MF).A retrospective analysis of 148 patients presenting to Stanford from January, 1970 through January, 1995 within 4 months of pathologic diagnosis of MF. Fifty-five patients with T2 and 27 with T3 disease received TSEBT +/- HN2. Fifty-four patients with T2 and 12 with T3 disease received HN2 alone. Boosts with radiotherapy were usually administered to cutaneous tumors of patients with T3 disease.TSEBT +/- HN2 yielded significantly higher complete response (CR) rates than did HN2 alone in patients with T2 and T3 disease (76% vs 39%, p = 0.03 for T2, and 44% vs 8%, p < 0.05 for T3, respectively). In T2 disease, treatment with adjuvant HN2 was associated with a longer freedom from relapse following TSEBT when compared to observation following a CR to TSEBT (p = 0.068). However, no significant differences in survival were observed for different management programs for T2 or T3 disease. In T2 disease, both TSEBT and HN2 were as effective as salvage therapy as when utilized as initial therapy. However, salvage therapy in T3 disease was rarely effective. Limited tumor involvement in T3 disease did not correlate with improved survival compared to more generalized tumorous disease. MF contributed to 27% and 68% of deaths in patients with T2 and T3 disease, respectively.Because of high response rates, management of significantly symptomatic or extensive T2 MF should include TSEBT, and adjuvant HN2 should be administered after a CR to TSEBT. Patients with T2 disease who fail TSEBT or HN2 can be salvaged with the other modality. TSEBT is also an effective treatment for T3 disease. The small subset of patients with limited T3 disease may also be treated with HN2 and local radiotherapy to the tumors. Further investigations are necessary to improve the overall outcome for T3 mycosis fungoides.

  View details for Web of Science ID 000079279100002

  View details for PubMedID 10192339

• Clinical characteristics and long-term outcome of patients with generalized patch and/or plaque (T2) mycosis fungoides ARCHIVES OF DERMATOLOGY Kim, Y. H., Chow, S., Varghese, A., Hoppe, R. T. 1999; 135 (1): 26-32

  Abstract

  To study the long-term results of treatment of patients with generalized patch and/or plaque mycosis fungoides and to identify clinical characteristics predictive of survival and response to treatment.A single-center, 35.5-year retrospective cohort analysis.Private referral medical center.One hundred seventy-six patients with generalized patch and/or plaque (T2) mycosis fungoides.Long-term actuarial survival and freedom-from-relapse results as calculated by the Kaplan-Meier method.The long-term (35.5-year) survival of patients with T2 mycosis fungoides is worse than the expected survival of a race-, age-, and sex-matched control population (P<.001). The median survival of the T2 group is 11.7 years. Patients younger than 58 years (median age) at presentation have a more favorable overall and disease-specific survival than the patients who are 58 years or older (P<.001 vs P<.025). Patient sex or race had no significant effect on overall survival. Patients who presented with palpable clinically significant lymph nodes (stage IIA) had long-term survival results similar to those without lymphadenopathy (stage IB), despite improved freedom-from-relapse outcome for patients with stage IB. Twenty-four percent of patients who progressed to more advanced disease had a lower complete response rate to initial therapy than did other patients (21% vs 65%) (P<.001). Patients who received total skin electron beam therapy had a better complete response rate than patients treated with topical mechlorethamine hydrochloride alone; the relapse-free results were superior in patients with a total dose of 30 Gy or higher and in patients who received topical mechlorethamine as adjuvant therapy following total skin electron beam therapy. Despite differences in freedom-from-relapse results among different treatment groups, long-term overall or disease-specific survivals were not significantly different.A significant proportion (24%) of patients with generalized patch and/or plaque (T2) mycosis fungoides experience disease progression to a more advanced clinical stage, and nearly 20% eventually die of the disease. Younger patients have a more favorable disease-specific long-term outcome than patients who are older. Presence of lymphadenopathy (stage IIA) at diagnosis does not predict worse long-term survival outcome. Clinical features predictive of disease progression include initial lymphadenopathy (stage IIA) and lack of complete response to initial treatment. Despite superior complete response rate to a 30-Gy or higher dose of total skin electron beam therapy, topical mechlorethamine proves to be a cost-effective initial treatment for patients with T2 disease. The concept of an adjuvant therapy after irradiation is appealing, although it may not lead to improved long-term survival.

  View details for Web of Science ID 000078112200004

  View details for PubMedID 9923777

• Role of histology in providing prognostic information in mycosis fungoides JOURNAL OF CUTANEOUS PATHOLOGY SMOLLER, B. R., Detwiler, S. P., Kohler, S., Hoppe, R. T., Kim, Y. H. 1998; 25 (6): 311-315

  Abstract

  Many patients who present with patch and early plaque stage mycosis fungoides follow an indolent course and survive for many years following diagnosis. A certain subset of patients, however, have rapidly progressive disease leading to accelerated demise. We examined 21 histologic sections from initial biopsies taken from patients with stable disease and 26 from patients with rapidly progressive disease in order to evaluate the role of histology in predicting the disease course. Two or three authors examined each case and scored each of 24 histologic parameters using a previously described four-point scale with no knowledge of the patients' clinical courses. Interobserver agreement was quite high. The only histologic parameter that demonstrated statistical differences between the two groups of patients was degree of acanthosis. The degree of spongiosis, number of eosinophils, amount of hyperconvolution of dermal lymphocytes and density of the dermal infiltrate approached statistical significance but did not attain this level. All of these differences were quite small. No differences were seen for the other 19 parameters. Patients with rapidly progressive disease tended to have more acanthosis, a few more hyperconvoluted dermal lymphocytes, a slightly greater number of eosinophils and perhaps a slightly more dense dermal infiltrate than patients who had stable disease. However, as all of these changes were very slight, it appears unlikely that evaluation of any single biopsy specimen for the histologic parameters we studied is helpful in predicting the prognosis for a specific patient.

  View details for Web of Science ID 000074683500005

  View details for PubMedID 9694620

• Mycosis fungoides in young patients: Clinical characteristics and outcome JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Crowley, J. J., Nikko, A., Varghese, A., Hoppe, R. T., Kim, Y. H. 1998; 38 (5): 696-701

  Abstract

  Mycosis fungoides (MF) can begin as early as the first decade of life. Few studies have reviewed MF in younger patients and none has been large enough to assess prognosis and outcome.We reviewed the clinical characteristics, prognosis, factors related to disease progression, and therapy in patients with MF younger than 35 years of age.Fifty-eight patients were entered into this retrospective cohort analysis.Significantly fewer patients with MF who are younger than 35 years presented with erythroderma (T4) and more with limited patch/plaque (T1) disease than older patients. Duration of skin disease before diagnosis of MF did not vary between the two groups. The long-term survival of younger patients with MF is significantly decreased when compared with a race-, age-, and sex-matched control population (p < 0.001). Disease-specific survivals (DSS) of younger and older patients are similar, but young patients show a slight but significantly better overall DSS (p < 0.02). However, DSS comparison of generalized patch/plaque (T2) and tumor stage (T3) patients with MF showed no significant difference between young and old patients (p=0.47, p=0.59). Patient age was not a significant predictor of survival when controlled for T-stage. Sixteen of 58 young patients with MF have died, 13 because of MF (22%), compared with 138 of 500 older patients (28%) who died as a result of MF. All younger patients with MF who progressed had at least T2 disease at presentation. Fifty of 56 young patients with MF and T1-T3 disease were treated initially with total skin electron beam or topical nitrogen mustard. The response to therapy was similar in younger and older patients with MF.T1 disease is more common and T4 disease is unusual in young patients with MF compared with an older population of patients with MF. Young patients with T1 disease, all of whom were treated with either topical nitrogen mustard or total skin electron beam therapy, or both therapies, showed no disease progression. Overall, young patients with MF showed slightly better DSS, but this was because of differences in stage distribution.

  View details for Web of Science ID 000073485800006

  View details for PubMedID 9591813

• Changes in quality of life (QOL) for patients (pts) enrolled in a phase III trial of treatment with a diphtheria toxin fusion protein (DAB(389)IL-2) for mycosis fungoides (MF). Liepa, A., Bennett, C. L., Yarnold, P. R., Enas, N., Lozano, J., Kuzel, T., Olson, E., Martin, A., Kim, Y., Duvic, M., Frankel, A., Vonderheid, E., Bowen, G., Jegasothy, B., Wood, G., Gordon, M., PINTERBROWN, L., Fivenson, D., Heald, P., Oscroff, A., Foss, F., Glode, M., Stewart, S., Molina, A., Knobler, E., Nichols, J. AMER SOC HEMATOLOGY. 1997: 3924–24

  View details for Web of Science ID A1997YG42501234

• Histologic criteria for the diagnosis of erythrodermic mycosis fungoides and Sezary syndrome: A critical reappraisal 33rd Annual Meeting of the American-Society-of-Dermatopathology Kohler, S., Kim, Y. H., SMOLLER, B. R. MUNKSGAARD INT PUBL LTD. 1997: 292–97

  Abstract

  It is often difficult to make a clinical or histologic diagnosis of erythrodermic mycosis fungoides (MF) and Sezary syndrome (SS). Whereas the histologic parameters for making a diagnosis of MF with well-developed patch and plaque stage lesions are clearly defined, the same criteria appear to be less relevant for diagnosing MF in patients with erythroderma secondary to the disease. In order to better define the histologic features of erythrodermic MF and SS, we studied 28 routine histologic sections of 17 patients with known erythrodermic MF or SS. Sections were reviewed independently by 2 dermatopathologists. Each of 24 parameters was scored semi-quantitatively and the data were compared to data previously reported from a group of 64 patients with limited patch and plaque stage lesions of MF. When compared to biopsies from patients with limited patch/plaque lesions, biopsies taken from erythrodermic patients displayed more parakeratosis (p=0.0492) and acanthosis (p=0.0046), less disproportionate epidermotropism, fewer lymphocytes aligned within the basal layer (p=0.0045), fewer hyperconvoluted cells in the epidermis, more dermal hyperconvoluted cells (p=0.0191), more papillary dermal fibrosis (p=0.0002), more prominent teleangiectasias (p=0.0028) and more mitotic figures. The histologic features of erythrodermic MF and Sezary syndrome are even more subtle than the features of patch and plaque stage MF, thus rendering the histologic diagnosis more difficult.

  View details for Web of Science ID A1997XB68100005

  View details for PubMedID 9194582

• Blastomycosis-like pyoderma in a man with AIDS JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Crowley, J. J., Kim, Y. H. 1997; 36 (4): 633-634

  View details for Web of Science ID A1997WR63000022

  View details for PubMedID 9092755

• Clinical stage IA (limited patch and plaque) mycosis fungoides - A long-term outcome analysis ARCHIVES OF DERMATOLOGY Kim, Y. H., Jensen, R. A., WATANABE, G. L., Varghese, A., Hoppe, R. T. 1996; 132 (11): 1309-1313

  Abstract

  To study the long-term results of treatment of patients with stage IA mycosis fungoides and analyze the factors related to disease progression and the effect of initial therapy on survival and freedom from relapse.A single-center, 32(1/2)-year, retrospective cohort analysis.Private referral medical center.One hundred twenty-two patients with clinical stage IA (T1, N0, M0) mycosis fungoides.Long-term actuarial survival and freedom-from-relapse results as calculated by the technique of Kaplan-Meier.The long-term (30-year) survival of patients with stage IA mycosis fungoides is similar to the expected survival of a race-, age-, and sex-matched control population. The median survival of this group has not been reached at 32(1/2)-years. Eleven patients (9%) who progressed to more advanced disease had a lower complete response rate to initial therapy than did other patients (36% vs 82%) and an older mean age than did other patients with T1 disease (61 vs 48 years, P < .05). Only 3 (2%) of 122 patients died of disease. Among stage IA patients who achieved a complete response, 25% are relapse free at 10 years. Patients who received total skin electron beam therapy (n = 34) had a more favorable freedom-from-relapse outcome than those treated with topical mechlorethamine hydrochloride (nitrogen mustard) (n = 73, P < .05). No significant difference was seen in the long-term survival between the 2 treatment groups.Patients with clinical stage IA mycosis fungoides treated at Stanford University do not have an altered life expectancy. Fewer than 10% progressed to more advanced stages and few died of disease. Although the response rate to total skin electron beam therapy was superior to that of topical mechlorethamine, the longterm survival results were similar. Topical mechlorethamine is a cost-effective and convenient therapy for patients with limited patch and plaque mycosis fungoides.

  View details for Web of Science ID A1996VT34900008

  View details for PubMedID 8915308

• Evidence against a role for human T-cell lymphotrophic virus type I (HTLV-I) in the pathogenesis of American cutaneous T-cell lymphoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Wood, G. S., Salvekar, A., Schaffer, J., CROOKS, C. F., HENGHOLD, W., Fivenson, D. P., Kim, Y. H., SMOLLER, B. R. 1996; 107 (3): 301-307

  Abstract

  We used a standard polymerase chain reaction (PCR)/Southern blot assay (sensitivity > 10(-5)) to detect human T-cell lymphotrophic virus type I (HTLV-I) proviral pX, pol, and env genes in the lesional skin of 42 American patients with cutaneous T-cell lymphoma (CTCL). As in some prior reports using similar methods, a variable proportion of PCR tests were positive (seven of 42 for pX, three of 42 for pol, and two of 37 for env), resulting in an overall positive test rate of 12 of 121 (10%). To determine the significance of these positive test results, we performed several additional studies. D1S80 polymorphism analysis of CTCL cases and HTLV-I PCR analysis of non-CTCL dermatosis controls showed no evidence that positive PCR tests resulted from sample mislabeling, gross HTLV-I contamination, or human endogenous retroviruses. We then modified the standard PCR assay to incorporate ultraviolet (UV) light to destroy low-level PCR contamination. With this modified assay (sensitivity > 10(-5)), only three of 12 previously positive cases were still positive, suggesting that the earlier positives were due to trace contamination of PCR reagents or trace contamination of sample DNA. This interpretation was also supported by: (i) a match between pX and pol sequences cloned from one PCR-positive specimen and the MT4-positive control, (ii) our inability to confirm HTLV-I in any PCR-positive case using genomic dot blotting (sensitivity > 10(-2)), and (iii) negative PCR results when new samples from two of the remaining positive cases were analyzed. Finally, we used our modified UV/ PCR/Southern blot assay to test an additional 28 cases of American CTCL for pX. All of them were negative. Although these studies of 70 cases of American CTCL do not exclude the possibility that another virus is involved in the pathogenesis of this disease, they provide strong evidence against a role for HTLV-I. Furthermore, they emphasize the need for special strategies to control for false-positive PCR tests that can result from even trace levels of contamination with viral DNA. As a consequence, associations between diseases and viruses should be viewed skeptically if they are based primarily on conventional PCR data.

  View details for Web of Science ID A1996VD79000003

  View details for PubMedID 8751960

• Lack of the t(2;5) or other mutations resulting in expression of anaplastic lymphoma kinase catalytic domain in CD30(+) primary cutaneous lymphoproliferative disorders and Hodgkin's disease BLOOD Wood, G. S., Hardman, D. L., Boni, R., Dummer, R., Kim, Y. H., SMOLLER, B. R., Takeshita, M., Kikuchi, M., Burg, G. 1996; 88 (5): 1765-1770

  Abstract

  The t(2;5) (p23;q35) chromosomal translocation has been found in a high proportion of lymph node-based CD30+ large cell lymphomas of T-cell lineage. This translocation is believed to result in the expression of a fusion protein containing the catalytic domain of anaplastic lymphoma kinase (ALK) under the control of the promoter for nucleophosmin, a nucleolar phosphoprotein. Expression of ALK activity, which does not normally occur in lymphocytes, is postulated to be involved in the pathogenesis of lymphomas bearing the t(2;5) translocation. Several primary cutaneous lymphoproliferative disorders and Hodgkin's disease are also known to contain CD30+ large lymphoid cells. To determine the role of the t(2;5) translocation in these diseases, we developed a DNA-based polymerase chain reaction (PCR)/Southern blot assay to detect this translocation at the genomic level in lymphomatoid papulosis (14 cases), primary cutaneous CD30+ large cell lymphoma of T-lineage (10 cases) and Hodgkin's disease (13 cases). Two cases of pityriasis lichenoides were also studied. The t(2;5) translocation was not present in any of these specimens. To determine if some other somatic mutation might have resulted in inappropriate expression of ALK catalytic domain, we devised an RNA-based reverse transcriptase-PCR assay to detect transcripts encoded by this ALK region. None were found in the six additional cases of lymphomatoid papulosis that were studied. In aggregate, these results strongly suggest that inappropriate expression of ALK is not involved in the pathogenesis of these CD30+ lymphoproliferative disorders, and that lymph node-based CD30+ large cell lymphoma is a disease that is biologically distinct from skin-based CD30+ lymphoproliferative disorders and Hodgkin's disease. Using methods developed for this report, we also cloned and sequenced the t(2;5) genomic junctional sequences present in the SUP-M2 and SU-DHL-1 cell lines. These intron sequences will be useful for mapping t(2;5) breakpoint clusters.

  View details for Web of Science ID A1996VE23400028

  View details for PubMedID 8781433

• REASSESSMENT OF HISTOLOGIC PARAMETERS IN THE DIAGNOSIS OF MYCOSIS-FUNGOIDES AMERICAN JOURNAL OF SURGICAL PATHOLOGY SMOLLER, B. R., Bishop, K., Glusac, E., Kim, Y. H., Hendrickson, M. 1995; 19 (12): 1423-1430

  Abstract

  The histologic diagnosis of mycosis fungoides (MF) can be difficult to establish and is based on interpretation of numerous subtle changes, most of which may be present to some degree in many inflammatory and neoplastic cutaneous conditions. To reassess the diagnostic criteria for making a histologic diagnosis of MF, we retrospectively reviewed histologic sections from 64 patients with mycosis fungoides (MF+) and compared the findings with sections from 47 patients who were biopsied to exclude MF and were shown not to have the disease (MF-). Patients were selected as MF+ or MF- independent of histologic findings based on the clinical course with at least 3 years of follow-up and immunophenotyping results. Following patient selection, at least two observers reviewed each slide without knowledge of final diagnosis and graded the intensity of approximately 25 histologic parameters. On univariate analysis, the following parameters were significant at beyond the p = 0.01 level: Pautrier's abscesses, haloed lymphocytes, exocytosis, disproportionate epidermotropism, epidermal lymphocytes larger than dermal lymphocytes, hyperconvoluted intraepidermal lymphocytes, and lymphocytes aligned within the basal layer. Haloed lymphocytes proved to be the most robust discriminator of MF from non-MF on multivariate analysis. These findings show that whereas many previously described features do discriminate between MF and inflammatory mimics, others are much less specific. Furthermore, few cases demonstrate all histologic features; for example, Pautrier's microabscesses were seen in only 37.5% of our cases. We conclude that a combination of specific histologic parameters can be used to establish a microscopic diagnosis of MF without the necessity of confirmatory immunophenotyping in the vast majority of cases.

  View details for Web of Science ID A1995TG92600009

  View details for PubMedID 7503364

• CUTANEOUS GNATHOSTOMIASIS JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Crowley, J. J., Kim, Y. H. 1995; 33 (5): 825-828

  View details for Web of Science ID A1995TD25300021

  View details for PubMedID 7593786

• PROGNOSTIC FACTORS IN ERYTHRODERMIC MYCOSIS-FUNGOIDES AND THE SEZARY-SYNDROME ARCHIVES OF DERMATOLOGY Kim, Y. H., Bishop, K., Varghese, A., Hoppe, R. T. 1995; 131 (9): 1003-1008

  Abstract

  There are no large studies evaluating patients with erythrodermic mycosis fungoides and Sézary syndrome to determine the important prognostic factors that may influence survival. This is important since new treatment modalities have been proposed as superior to existing primary therapies. We performed a retrospective cohort study of 106 patients with erythrodermic mycosis fungoides and Sézary syndrome, followed up in the Stanford (Calif) Mycosis Fungoides Clinic, to define the important prognostic factors in this group.Patients younger than 65 years have a more favorable survival profile than those 65 years or older (P < .005). Longer duration of symptoms before diagnosis ( > or = 10 years) tends to be associated with more favorable prognosis (p = .055). Lymph node stage is significantly correlated with survival; patients with overall stage III disease have more favorable prognosis than those with stage IV disease (P < .001). Patients with circulating Sézary cells in their blood have a significantly worse prognosis than those without (P < .005). Patient sex or race had no significant effect on overall survival outcome. Three distinct prognostic groups were identified, "favorable," "intermediate," and "unfavorable," according to the number of unfavorable prognostic factors (P < .005). The median survival in each group is 10.2, 3.7, and 1.5 years, respectively.In patients with erythrodermic mycosis fungoides and Sézary syndrome, the important prognostic factors are patient age at presentation, the overall stage, and peripheral blood involvement. Survival varies widely, depending on these variables. These prognostic factors should be evaluated when analyzing survival and/or treatment efficacy data of these patients.

  View details for Web of Science ID A1995RU13500004

  View details for PubMedID 7661601

• LYMPHOCYTE ANTIGEN ABNORMALITIES IN INFLAMMATORY DERMATOSES APPLIED IMMUNOHISTOCHEMISTRY SMOLLER, B. R., Bishop, K., Glusac, E. J., Bhargava, V., Kim, Y. H., Warnke, R. A. 1995; 3 (2): 127-131

  View details for Web of Science ID A1995RB47200009

• PHENOTYPIC REVERSION OF JUNCTIONAL EPIDERMOLYSIS-BULLOSA KERATINOCYTES BY THE INTRODUCTION OF A THERAPEUTIC LAMININ-5 CHAIN GENE HOEFFLER, W. K., WANG, C. K., MATSUI, C., CANTRELL, C. F., GERECKE, D., KIM, Y., HERRON, G. S., BAUER, E. A. BLACKWELL SCIENCE PUBL INC CAMBRIDGE. 1995: 597

  View details for Web of Science ID A1995QR53200278

• REASSESSMENT OF LYMPHOCYTE IMMUNOPHENOTYPING IN THE DIAGNOSIS OF PATCH AND PLAQUE STAGE LESIONS OF MYCOSIS-FUNGOIDES APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY SMOLLER, B. R., Bishop, K., Glusac, E. J., Kim, Y. H., Bhargava, V., Warnke, R. A. 1995; 3 (1): 32-36

  View details for Web of Science ID A1995QH64600003

• CONSTITUTIVE ACTIVATION OF THE COLLAGENASE PROMOTER IN RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA FIBROBLASTS - ROLE OF ENDOGENOUSLY ACTIVATED AP-1 EXPERIMENTAL CELL RESEARCH Unemori, E. N., Mauch, C., Hoeffler, W., Kim, Y., Amento, E. P., BAUER, E. A. 1994; 211 (2): 212-218

  Abstract

  Recessive dystrophic epidermolysis bullosa (RDEB) is a mutilating disease of the skin characterized by recurrent blistering and erosions that result from compromised integrity of the basement membrane zone. In this study, fibroblasts derived from the skin of RDEB patients were characterized for expression of the major metalloproteinases, particularly interstitial collagenase. Consistent with previous reports on increased collagenase protein levels in fibroblasts from some RDEB patients, we found that steady-state levels of collagenase mRNA were significantly increased in fibroblast strains derived from three of five RDEB patients compared to fibroblasts obtained from normal donors. Stromelysin mRNA was elevated in the same three fibroblast strains, whereas expression of neither the 72- nor the 92-kDa type IV collagenases was different from that of controls. Tissue inhibitor of metalloproteinases was expressed in RDEB fibroblasts at levels similar to those observed in normal fibroblasts. To investigate the mechanism behind the steady-state elevation in collagenase and stromelysin expression, AP-1 expression and activation were studied. Although levels of Jun expression were not different from those seen in normal fibroblasts, AP-1 activity, as assessed by ability to bind to a TPA response element-containing oligonucleotide, was endogenously elevated in RDEB fibroblasts compared to normal fibroblasts. Transfection studies using a plasmid construct containing the collagenase promoter linked to a CAT reporter gene demonstrated that RDEB fibroblasts were able to support active transcription of the promoter compared to normal fibroblasts. These studies support the hypothesis that RDEB fibroblasts contain chronically activated AP-1, and perhaps other transactivating factors, that contribute to the cellular phenotype of collagenase and stromelysin overexpression.

  View details for Web of Science ID A1994NE89700006

  View details for PubMedID 8143767

• DETERMINATION OF HUMAN PAPILLOMA-VIRUS IN NON-ANOGENITAL SQUAMOUS-CELL CARCINOMAS BY POLYMERASE CHAIN-REACTION KIM, Y. H., SERKLAND, L. F., BAUER, E. A., PALEFSKY, J. M. BLACKWELL SCIENCE INC. 1994: 652

  View details for Web of Science ID A1994NF40600796

• Autoimmunity to anchoring fibrils. Advances in dermatology Kim, Y. H., Woodley, D. T. 1994; 9: 61-77

  View details for PubMedID 8060743

• RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA KERATINOCYTES SYNTHESIZE TYPE-VII COLLAGEN ALPHA-CHAINS OF NORMAL MOLECULAR-SIZE BUT THE ANCHORING FIBRIL ASSEMBLY IS IMPAIRED BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS IWASAKI, T., LAPIERE, J. C., UITTO, J., KIM, Y. H., WOODLEY, D. T. 1993; 193 (2): 604–10

  Abstract

  Recessive dystrophic epidermolysis bullosa is a blistering skin disease characterized by diminished anchoring fibrils within the cutaneous basement membrane zone. Because anchoring fibrils are composed of type VII collagen, we compared the synthesis of type VII collagen by keratinocytes from patients and normal subjects. By Western blot analysis and immunoprecipitation of cell extracts, we found that both cell types express type VII collagen alpha chains of equivalent size (Mr = 290,000). Transforming growth factor-beta enhanced type VII collagen in both cell types. In contrast, the expression of type VII collagen within the culture medium was markedly diminished or absent in cultures of keratinocytes from patients. The patients' keratinocytes are capable of synthesizing type VII collagen of a normal molecular size, but they cannot assemble or secrete type VII collagen properly into the extracellular space, or they secrete a product that is abnormally sensitive to proteolytic digestion.

  View details for DOI 10.1006/bbrc.1993.1667

  View details for Web of Science ID A1993LG15300021

  View details for PubMedID 7685597

• JUNCTIONAL EPIDERMOLYSIS-BULLOSA (JEB) KERATINOCYTES FAIL TO SECRETE HEMIDESMOSOME (HD)-ASSOCIATED MATRIX-ELEMENTS AND DEMONSTRATE ENHANCED LOCOMOTION Chen, J. D., LANGHOFER, M., Iwasaki, T., Kim, Y. H., Jones, J. C., Krueger, J. G., Carter, D. M., Woodley, D. T. SLACK INC. 1993: A408–A408

  View details for Web of Science ID A1993KW76101654

• BIOLOGIC CHARACTERISTICS OF RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA (RDEB) KERATINOCYTES Kim, Y. H., Kim, J. P., Chen, J. D., Iwasaki, T., Hernandez, G., SARAF, P., BAUER, E. A., Woodley, D. T. SLACK INC. 1993: A479–A479

  View details for Web of Science ID A1993KW76102082

• BIOLOGIC CHARACTERISTICS OF RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA (RDEB) KERATINOCYTES Kim, Y. H., Kim, J. P., Chen, J. D., Iwasaki, T., Hernandez, G., SARAF, P., BAUER, E. A., Woodley, D. T. NATURE PUBLISHING GROUP. 1993: 580–80

  View details for Web of Science ID A1993KW39500852

• RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA (RDEB) KERATINOCYTES SYNTHESIZE TYPE-VII (ANCHORING FIBRIL) COLLAGEN ALPHA-CHAINS OF NORMAL MOLECULAR-SIZE IWASAKI, T., LAPIERE, J. C., UITTO, J., KIM, Y. H., WOODLEY, D. T. BLACKWELL SCIENCE INC. 1993: 515

  View details for Web of Science ID A1993KW39500462

• JUNCTIONAL EPIDERMOLYSIS-BULLOSA (JEB) KERATINOCYTES FAIL TO SECRETE HEMIDESMOSOME (HD)-ASSOCIATED MATRIX-ELEMENTS AND DEMONSTRATE ENHANCED LOCOMOTION Chen, J. D., LANGHOFER, M., Iwasaki, T., Kim, Y. H., Jones, J. C., Krueger, J. G., Carter, D. M., Woodley, D. T. NATURE PUBLISHING GROUP. 1993: 517–17

  View details for Web of Science ID A1993KW39500470

• A DOUBLE-BLIND COMPARISON OF ADHESIVE BANDAGES WITH THE USE OF UNIFORM SUCTION BLISTER WOUNDS ARCHIVES OF DERMATOLOGY Woodley, D. T., Kim, Y. H. 1992; 128 (10): 1354-1357

  Abstract

  The assessment of cutaneous wound healing in humans has been hampered by the inability to evaluate multiple wounds with identical origins, treatment histories, and sizes. There have been no double-blind wound healing studies in humans that compared one wound dressing with another. The purpose of this study was to determine if identical suction blister wounds could serve as a model to evaluate and compare wound healing and overall cosmetic appearance of wounds treated with commercially available adhesive bandages. In a double-blind study, we compared superficial skin wounds of identical depth and diameter, created on the forearms of five human subjects by means of a suction blister device. The wounds were covered by two common, commercially available adhesive bandages or a copolymer of polyurethane membrane type of wound dressing. We compared the degree of reepithelialization, erythema, skin depression, and overall cosmetic appearance of wounds with respect to the specific adhesive bandages used.The wounds covered with the copolymer of polyurethane membrane were judged to have better overall appearance and advanced reepithelialization compared with identical wounds covered by the other wound dressings. With the use of x5 magnification for viewing the wounds on the final day of evaluation (between days 18 and 22), the wounds treated with the copolymer of polyurethane membrane were judged to be the least depressed wounds in fields of identical wounds in the three subjects studied. Concordance between the evaluators' "blinded" assessments was uniform, and no discrepancy between the evaluators' assessments occurred at any of the time points.Identical wounds created with a suction blistering device can be used reliably to detect differences between the performances of wound dressings in healing superficial wounds. Superficial cutaneous wounds covered with a copolymer of polyurethane dressing demonstrated a superior rate of reepithelialization, less depression, and a better overall cosmetic appearance than wounds covered with two commercially available adhesive bandages.

  View details for Web of Science ID A1992JT34300007

  View details for PubMedID 1417023

• RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA PHENOTYPE IS PRESERVED IN XENOGRAFTS USING SCID MICE - DEVELOPMENT OF AN EXPERIMENTAL INVIVO MODEL JOURNAL OF INVESTIGATIVE DERMATOLOGY Kim, Y. H., Woodley, D. T., WYNN, K. C., GIOMI, W., BAUER, E. A. 1992; 98 (2): 191-197

  Abstract

  Recessive dystrophic epidermolysis bullosa (RDEB) is a subgroup of hereditary blistering diseases characterized by repetitive wounding and healing with subsequent extensive scarring. The purpose of this study was to establish a xenograft model that retains the RDEB phenotype and thus might be used as an experimental in vivo model to explore the molecular and biochemical mechanisms of the chronically wounded phenotype of RDEB. Full-thickness, tumor-free RDEB skin tissues were grafted onto the dorsum of severe combined immunodeficiency (SCID) mice. At 4, 8, 12, and 24 weeks after grafting, the xenografts were removed for examination. Immunofluorescence studies were performed using species-specific antibodies to human class I antigen, mouse class I antigen, human type IV and VII collagens and with cross-reacting antibody against bullous pemphigoid antigen (BPA). Staining with the antibody to human class I antigen, W6/32, and with the antibody to mouse class I antigen, 20.8.4s, confirmed the species-specific results obtained with the type IV and type VII collagen and laminin antibodies. The RDEB grafts showed essentially no staining with the type VII collagen antibody. Antibodies against laminin and BPA showed normal staining patterns in RDEB grafts. There was an overall paucity of anchoring fibrils in the grafts when examined with electron microscopy. Blisters could be induced in these grafts with minor trauma and showed a sublamina densa separation by immunomapping and electron microscopy. As late as 24 weeks post-transplantation, the RDEB grafts remain human, are not significantly replaced by mouse cells, and retain the RDEB disease phenotype.

  View details for Web of Science ID A1992HB07100012

  View details for PubMedID 1370678

• H-1-NMR SPECTROSCOPY - AN APPROACH TO EVALUATION OF DISEASED SKIN INVIVO JOURNAL OF INVESTIGATIVE DERMATOLOGY Kim, Y. H., Orenberg, E. K., Faull, K. F., WADEJARDETZKY, N. G., Jardetzky, O. 1989; 92 (2): 210-216

  Abstract

  1H nuclear magnetic resonance (NMR) spectroscopy was tested for its applicability in evaluating diseased skin. In order to explore potential spectral markers characteristic of diseased tissue, perchloric acid (PCA) extracts of psoriasis and malignant melanoma tissues were compared with normal skin, and changes in melanoma after heat treatment were monitored. In psoriatic plaque extract, the spectral peak intensity ratios of Glu: Ser, creatine: Gly, and taurine: Ala were approximately three-fold compared with symptom-free or normal skin, whereas Val: Leu/Ile was one-half the normal skin ratio. In melanoma extracts, the phosphorylcholine (PC)/glycerophosphorylcholine (GPC): Ala, Glu: Ser, and lactate: Ala ratios were five-, three-, and two-fold higher, respectively, than normal skin and the Val: Leu/Ile ratio was two-thirds of normal skin. With heat treatment, PC/GPC: Ala and Glu: Ser ratios decreased, whereas lactate: Ala and Val: Leu/Ile ratios increased three-fold and one-third, respectively. Results indicate that 1H NMR spectroscopy is a sufficiently sensitive technique to distinguish normal from diseased skin. The main attraction of this technique lies in the possibility of non-invasive study of various skin diseases, malignant transformation of benign tumors, and responses to treatment. Several methodologic problems remain to be resolved before a meaningful interpretation of in vivo observations becomes feasible. Correlation of in vivo and in vitro findings is an essential step toward this goal.

  View details for Web of Science ID A1989T322300012

  View details for PubMedID 2537364