Biomedical subjects

Madeleine Duvic

Publications and source records attributed to Madeleine Duvic.

At least 37 records · Page 2Linked to original sources

PubMed2006

Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell lymphoma.

PURPOSE: The purpose of this study was to investigate safety and efficacy of gemcitabine monotherapy for cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Twenty-five patients with CTCL on a phase II open-label trial and 8 patients off study received intravenous gemcitabine (1000 mg/m2) on day 1, 8, and 15 for > or = 6 cycles. Physicians' global assessment was based on body surface area involvement in skin, measurement of lymph nodes, and blood by flow cytometry. RESULTS: Two patients with CD30+ anaplastic large T-cell lymphoma and 31 with mycosis fungoides (stage IB [T2, n = 2], stage IIA [T2, n = 1], stage IIB [T3, n = 13], stage IVA [T3 N3, n = 3; T4b2, n = 2; T4b2 N3, n = 2], and stage IVB [T4b2 N1, n = 6; T4 N3b2 M1, n = 1; T3 N3 M1, n = 1]) had received a median of 5 previous therapies (range, 1-13 therapies). Responses were seen in 17 of 25 (68%) study patients (2 complete responses [8%]) and 4 of 8 patients (1 complete response) off protocol. Seven of 13 patients with mycosis fungoides (T3) responded, 10 had tumor burden reductions, and 8 of 11 patients with Sezary syndrome responded. Gemcitabine was well tolerated. Myelosuppression (n = 14; grade 3, n = 8), hemolytic uremic syndrome (in 2 elderly patients with Sezary syndrome), pulmonary embolism (n = 2), and 1 episode each of congestive heart failure, acute myocardial infarction, and stable angina were observed. Increased hepatic transaminases (n = 4), mucositis (n = 3), lethargy (n = 7), fever (n = 8), cutaneous hyperpigmentation (n = 6), infusion-related maculopapular rash (n = 1), and radiation recall (n = 1) were also seen. CONCLUSION: Gemcitabine is an effective monotherapy with a 68% overall response rate in patients with advanced, heavily pretreated CTCL.

Adult↗

PubMed2006

Mycosis fungoides with coccidioidomycosis.

Mycosis fungoides is an indolent, epidermotropic, cutaneous T-cell lymphoma of helper/memory T cells that presents as heterogeneous, papulosquamous patches, plaques, and tumors. We present a patient with mycosis fungoides and infection with Coccidioides immitis of the skin, which has not been previously reported.

Adenocarcinoma↗

PubMed2005

In vitro sensitivity to ultraviolet B light and skin cancer risk: a case-control analysis.

BACKGROUND: Mutagen sensitivity, measured as mutagen-induced chromatid breaks per cell in primary lymphocytes in vitro, has been used to study susceptibility to various epithelial cancers. Patients with xeroderma pigmentosum are highly sensitive to ultraviolet (UV) light due to inherited defects in DNA repair and have a 1000-fold higher risk of UV-induced skin cancer than the general population. However, an association between UV-induced chromosomal aberrations and risk of skin cancer in the general population has not been established. METHODS: We assessed in vitro UVB-induced chromatid breaks in a hospital-based case-control study. The study included 469 patients with skin cancer (231 with nonmelanoma skin cancer [NMSC] and 238 with cutaneous malignant melanoma [CMM]) and 329 cancer-free control subjects. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: Compared with the frequency of UVB-induced chromatid breaks per cell in control subjects (mean = 0.28 breaks per cell, 95% CI = 0.27 to 0.30), that in NMSC patients (basal cell carcinoma [BCC], n = 143, mean = 0.36 breaks per cell, 95% CI = 0.33 to 0.39 and squamous cell carcinoma [SCC], n = 88, mean = 0.35 breaks per cell, 95% CI = 0.32 to 0.38) was higher (P = .001 and P < .001, respectively), but that in CMM case patients (mean = 0.30 breaks per cell, 95% CI = 0.28 to 0.33) was not (P = .22). A frequency of chromatid breaks per cell above the median of control subjects was associated with nearly threefold increased risks for BCC (OR = 2.78, 95% CI = 1.79 to 4.30) and SCC (OR = 2.62, 95% CI = 1.50 to 4.60), but not with an increased risk of CMM. A dose-response relationship was evident between mutagen sensitivity and risk for both BCC (Ptrend < .001) and SCC (Ptrend < .001). Multiplicative interactions between mutagen sensitivity and sun exposure variables on risk, particularly for sunburn in BCC and hair color, tanning ability, and family history of skin cancer in SCC, were seen for NMSC but not CMM. CONCLUSIONS: UVB-induced mutagen sensitivity may play a role in susceptibility to NMSC but not to CMM.

Adult↗

PubMed2005

Scleromyxedema: role of high-dose melphalan with autologous stem cell transplantation.

Scleromyxedema, the most severe manifestation of the spectrum of lichen myxedematosus, is characterized by cutaneous mucinosis, extracutaneous manifestations, and a monoclonal gammopathy. Seven of 8 patients evaluated at our center were treated with high-dose melphalan (180 mg/m(2) intravenously) and autologous peripheral blood stem cell transplantation, with marked improvement of gastrointestinal, central nervous system, pulmonary manifestations, and Karnofsky performance status. Five patients obtained a cutaneous complete remission and 2 patients had partial remissions. Three patients with slight progression in the skin at 12, 8, and 4 months after treatment received a second cycle of high-dose melphalan and had further symptomatic improvement. The lichen myxedematosus-scleromyxedema spectrum appears to be a continuum that requires the presence of a serum paraprotein and differs in severity of skin lesions, extracutaneous manifestations, and performance status. High-dose melphalan followed by autologous transplantation appears effective for improving the symptoms and systemic manifestations of scleromyxedema.

Adult↗

PubMed2005

Triterpenoid electrophiles (avicins) suppress heat shock protein-70 and x-linked inhibitor of apoptosis proteins in malignant cells by activation of ubiquitin machinery: implications for proapoptotic activity.

Avicins are plant-derived triterpenoid stress metabolites that have both proapoptotic and cytoprotective properties. Avicins induce apoptosis in Jurkat T leukemia cells by targeting mitochondria and release of cytochrome c that occurs in a p53-independent manner. However, postmitochondrial antiapoptotic barriers, such as increased expression of heat shock proteins (Hsp) and X-linked inhibitor of apoptosis proteins (XIAP), frequently exist in cancer cells and often account for resistance to chemotherapy and a poor prognosis. In this article, we show the role of avicins in the activation of stress-regulated ubiquitination and degradation of Hsp70 and XIAP. This is the first report showing the regulation of Hsp70 via the ubiquitin/proteasome pathway. We also show the induction of E3alpha ubiquitin ligase in avicin-treated Jurkat T leukemia cells, and its involvement in the degradation of XIAP. Avicin-mediated suppression of Hsp70 and XIAP was further confirmed in other leukemic/lymphoma cell lines and freshly isolated peripheral blood lymphocytes from Sezary syndrome patients. No change in the Hsp70 and XIAP proteins was observed in peripheral blood lymphocytes from normal donors. We propose that the ability of avicins to induce ubiquitination and regulate the degradation of Hsp70 and XIAP in leukemia cells could have important implications in the treatment of drug-resistant neoplasia and inflammatory disorders.

Apoptosis↗

PubMed2005

Mortality risk from squamous cell skin cancer.

PURPOSE: To identify nonmelanoma skin cancer patients with squamous cell carcinoma (SCC) who are at greatest risk of disease-specific mortality. PATIENTS AND METHODS: Prospectively enrolled patients with a minimum of one pathologically confirmed skin SCC lesion, definitive treatment of the SCC lesion(s) resulting in no evidence of disease, and at least 2 months of follow-up after definitive treatment were eligible for the present longitudinal analysis. They received comprehensive clinical, pathologic evaluations and follow-up for patterns of failure and mortality. RESULTS: We enrolled 210 patients (187 men and 23 women) with a total of 277 skin SCC lesions and a median enrollment age of 68 years (range, 34 to 95 years). Median follow-up of surviving patients was 22 months. Three-year overall and disease-specific survival (DSS) rates were 70% and 85%, respectively. In univariate analyses, the clinical-pathologic factors associated with adverse DSS were local recurrence at presentation (P = .05), invasion beyond subcutaneous tissues (P = .009), perineural invasion (P = .002), lesion size (P = .0003), and depth of invasion (P = .05). Statistical models identified a homogeneous high-risk group of patients with lesions > or = 4 cm, perineural invasion, and deep invasion beyond subcutaneous structures. Three-year DSS was 100% for patients with no risk factors versus 70% for patients with at least one risk factor. CONCLUSION: Lesion size > or = 4 cm and histologic evidence of perineural invasion and deep invasion beyond subcutaneous structures were the clinical-pathologic factors most significantly associated with disease-specific mortality in skin SCC.

Adult↗

PubMed2005

Primary cutaneous B-cell lymphoma.

Primary cutaneous B-cell lymphomas include extranodal marginal zone B-cell lymphoma, follicular lymphoma, large B-cell lymphoma, and, rarely, mantle cell lymphoma. Our purpose in conducting this review was to determine the clinical and behavioral characteristics of primary cutaneous B-cell lymphomas, their relationship to infectious triggers, and therapeutic response. We conducted a retrospective chart review of 23 adult patients presenting to the dermatology clinic at M. D. Anderson Cancer Center with primary cutaneous B-cell lymphoma between January 1999 and May 2003. Primary cutaneous B-cell lymphomas generally present on the head and neck, with the trunk and extremities afflicted to a lesser extent. Patients were found to have serologic evidence of prior infection with Borrelia burgdorferi (n = 10), Helicobacter pylori (n = 5), and Epstein-Barr virus (n = 6). Overall, treatment of primary cutaneous B-cell lymphoma should involve multiple modalities; however, specific treatment aimed at concurrent or suspected infection, particularly B burgdorferi, is a helpful adjunct and may achieve complete remission in a small subset of patients.

Adult↗

PubMed2005

Toxic epidermal necrolysis associated with denileukin diftitox (DAB389IL-2) administration in a patient with follicular large cell lymphoma.

Denileukin diftitox (DAB(389)IL-2 or Ontak) is a synthetic fusion protein with demonstrated efficacy in a number of lymphoproliferative disorders, including non-Hodgkin's lymphoma. We report the case of a 45-year-old man with progressive follicular large cell lymphoma following an autologous stem cell transplant treated with denileukin diftitox who developed a fatal skin rash associated with extensive erythema, edema and large bullae involving his entire body. The clinical features and pathology were compatible with toxic epidermal necrolysis. This is the first reported case of toxic epidermal necrolysis in the literature associated with denileukin diftitox.

Antineoplastic Agents↗

PubMed2005

Resistance to activation-induced cell death and bystander cytotoxicity via the Fas/Fas ligand pathway are implicated in the pathogenesis of cutaneous T cell lymphomas.

By engaging Fas, Fas ligand (FasL) on activated T lymphocytes induces activation-induced cell death (AICD), and also triggers apoptosis of target cells during immune downregulation. We previously showed that within cutaneous T cell lymphoma (CTCL) lesions, malignant CD4(+) T cells expressing FasL accumulated, and were inversely distributed with CD8(+) T cells. We thus determined the responses of human CTCL cells to AICD and their cytotoxic to Fas(+) target T cells in vitro. CTCL cells expressing Fas were resistant to AICD following activation by CD3 monoclonal antibody (mAb) whereas still undergoing apoptosis if Fas was ligated to Fas mAb. CTCL cell lines, as well as Sezary Syndrome patients' peripheral blood lymphocytes, exhibited ratio-dependent cytotoxicity to Fas(+) Jurkat cells. The kinetic study showed that FasL surface expression was absent before activation, and its expression was low and/or delayed after activation. We therefore hypothesize that CTCL cells express functional FasL possibly contributing to bystander cytotoxicity within tumor infiltrates. In addition, decreased and/or delayed FasL surface expression following activation may in part contribute to their resistance to AICD. Both bystander cytotoxicity and resistance to AICD are likely to contribute to the loss of cytotoxic anti-tumor CD8(+) T cells as well as the accumulation of malignant T cells in CTCL.

Antibodies, Monoclonal↗

PubMed2005

Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: relevance to mechanism of therapeutic action.

Suberoylanilide hydroxamic acid (SAHA), an orally administered inhibitor of histone deacetylases, is currently in phase II clinical trials for cutaneous T cell lymphomas (CTCL), but the mechanism of SAHA action is unknown. In this study, we investigated the anti-tumor effects of SAHA in CTCL cell lines and freshly isolated peripheral blood lymphocytes (PBL) from CTCL patients with high percentage of circulating malignant T cells. Three cell lines (MJ, Hut78, and HH) and PBL from 11 patients and three healthy donors were treated with SAHA (1, 2.5, and 5 microM) for 24 and/or 48 h. Apoptosis was determined by flow cytometry analysis of sub-G1 hypodiploid nuclei and/or annexin V binding populations. Acetylated histones and apoptosis-associated proteins were detected by Western blotting. SAHA at 1-5 microM for 24 and 48 h induced apoptosis in a concentration- and time-dependent manner in three cell lines: MJ (0%-7% and 1%-32%), Hut78 (4%-36% and 5%-54%), and HH (4%-67% and 8%-81%). SAHA at 1-5 muM for 48 h also induced more apoptosis of patients' PBL than healthy donors' (15%-32%versus 6%-13%, p < 0.05). SAHA treatment caused an accumulation of acetylated histones (H2B, H3, and H4), an increase of p21(WAF1) and bax proteins, a decrease of Stat6 and phospho-Stat6 proteins, and activation of caspase-3 in CTCL cells. Our data suggest that selective induction of malignant T cell apoptosis and modulation of acetylated histones, p21(WAF1), bax, Stat6, and caspase-3 may underlie the therapeutic action of SAHA in CTCL patients.

Acetylation↗

PubMed2005

Primary Sézary syndrome commonly shows low-grade cytologic atypia and an absence of epidermotropism.

The dermatopathologic findings in cases of Sézary syndrome (SS) that arise in patients without a previous diagnosis of mycosis fungoides have not been well characterized. We evaluated the histologic findings in skin biopsy specimens from 31 patients with such primary SS and correlated them with clinical and hematologic parameters at the time of biopsy. The most characteristic histologic finding was the presence of a dermal perivascular lymphoid infiltrate, usually with mild to moderate cytologic atypia and variable numbers of eosinophils; epidermotropism was absent or minimal in 19 cases (61%). Reactive epidermal changes such as spongiosis, parakeratosis, and acanthosis also were present frequently (27 [87%], 17 [55%], 19 [61%] cases, respectively). The number of eosinophils present in skin biopsy specimens correlated with the level of peripheral blood lymphocytosis. In erythrodermic patients or patients with persistent xerosis and pruritus, it is important to carefully evaluate the degree of lymphocyte atypia in the dermal perivascular infiltrate and correlate with blood flow cytometric findings to diagnose primary SS. Many cases will lack the epidermotropism usually seen in mycosis fungoides.

Antigens, CD↗

PubMed2005

Acral necrotizing mycosis fungoides.

A 65-year-old male with long-standing acral "eczema" and patches of mycosis fungoides suddenly developed a transformed, necrotizing ulcerative cutaneous T-cell lymphoma manifesting as necrotic lesions of the toe and lip. The tumor had brown and/or black eschars on the surface and grew multiple opportunistic organisms. Markers CD3, Epstein-Barr virus-encoded small RNA, and T-cell receptor g gene rearrangement were positive, with CD4, 8, 30, 56, and TIA-1 negative. In spite of initial response to radiation, the patient succumbed to infection within 3 months.

Aged↗

PubMed2004

Up-regulation of Flotillin-2 is associated with melanoma progression and modulates expression of the thrombin receptor protease activated receptor 1.

Flotillin 2 (flot-2) is a highly conserved protein isolated from caveolae/lipid raft domains that tether growth factor receptors linked to signal transduction pathways. Flot-2 protein and mRNA were increased in tumorigenic and metastatic melanoma cell lines in vitro, and the immunostaining intensity increased substantially across a tissue array of melanocytic lesions. Flot-2 transfection transformed SB2 melanoma cells from nontumorigenic, nonmetastatic to highly tumorigenic and metastatic in a nude mouse xenograft model. SB2 cells stably transfected with the flot-2 cDNA (SB2-flot)-2 cells proliferated faster in the absence of serum, and their migration through Matrigel was additionally enhanced by thrombin. When SB2-flot-2 cells were compared with SB2-vector-control cells on a cancer gene pathway array, SB2-flot-2 cells had increased expression of protease activated receptor 1 (PAR-1) mRNA, a transmembrane, G-protein-coupled receptor involved in melanoma progression. PAR-1 and flot-2 were coimmunoprecipitated from SB2-flot-2 cells. Up-regulation of PAR-1 was additionally confirmed in SB2-flot-2 cells and melanoma cell lines. SB2-flot-2 cells transfected with flot-2-specific small-interfering RNAs made substantially less flot-2 and PAR-1 mRNA. In conclusion, flot-2 overexpression is associated with melanoma progression, with increased PAR-1 expression, and with transformation of SB2 melanoma cells to a highly metastatic line. Flot-2 binds to PAR-1, a known upstream mediator of major signal transduction pathways implicated in cell growth and metastasis, and may thereby influence tumor progression.

Animals↗

PubMed2004

Degree of CD25 expression in T-cell lymphoma is dependent on tissue site: implications for targeted therapy.

PURPOSE: Using concurrent tumor samples from different anatomical sites, we compared expression of the therapeutic targets CD25 and CD30 in T-cell lymphoma (TCL). EXPERIMENTAL DESIGN: We examined levels of CD25 and CD30 by flow cytometry in tumor cells from peripheral blood and lymph node in 13 cutaneous TCL patients and by immunohistochemistry in concurrent lymph node and skin biopsy specimens in 17 additional TCL cases, mostly mycosis fungoides. Tumor cell expression was correlated with patterns of expression in nonneoplastic lymphocytes in 14 reactive lymph node and 10 skin samples showing chronic dermatitis. Expression of CD25 and CD30 in all biopsy samples was compared with that of cutaneous lymphocyte antigen (CLA), a mediator of skin homing. RESULTS: By flow cytometry, we noted significantly decreased expression of CD25 in lymph node compared with peripheral blood in 8 of 13 TCLs, with no changes in CD30 levels in 4 cases studied. Using immunohistochemistry, CD25 was strongly expressed in epidermotropic tumor cells in 13 of 17 (76%) TCL skin specimens but was decreased in the corresponding lymph node in 12 of these cases. CD30 was expressed at roughly equal intensity in tumor cells from both sites, except in 1 case. CLA showed a similar pattern to CD25, being expressed by tumor cells in 16 of 17 (94%) skin specimens, but was largely absent in tumor cells in the corresponding lymph node in 12 of these patients. In T cells from reactive lymph node biopsy specimens, CD25 was highly expressed only in dermatopathic lymphadenitis associated with transient skin rashes. CONCLUSIONS: We demonstrate in vivo that decreased levels of CD25 expression occur in TCL when it involves lymph node, similar to what is seen with CLA. This demonstrable variation related to anatomical localization has implications for the measurement of surface expression of CD25 and for understanding the response of patients with cutaneous TCL to interleukin 2 receptor-targeted immunotherapy.

Antigens, CD↗

PubMed2004

Skin cancer detection by spectroscopic oblique-incidence reflectometry: classification and physiological origins.

Data obtained from 102 skin lesions in vivo by spectroscopic oblique-incidence reflectometry were analyzed. The participating physicians initially divided the skin lesions into two visually distinguishable groups based on the lesions' melanocytic conditions. Group 1 consisted of the following two cancerous and benign subgroups: (1) basal cell carcinomas and squamous cell carcinomas and (2) benign actinic keratoses, seborrheic keratoses, and warts. Group 2 consisted of (1) dysplastic nevi and (2) benign common nevi. For each group, a bootstrap-based Bayes classifier was designed to separate the benign from the dysplastic or cancerous tissues. A genetic algorithm was then used to obtain the most effective combination of spatiospectral features for each classifier. The classifiers, tested with prospective blind studies, reached statistical accuracies of 100% and 95% for groups 1 and 2, respectively. Properties that related to cell-nuclear size, to the concentration of oxyhemoglobin, and to the concentration of deoxyhemoglobin as well as the derived concentration of total hemoglobin and oxygen saturation were defined to explain the origins of the classification outcomes.

Algorithms↗

PubMed2004

Cardiac toxicity of alemtuzumab in patients with mycosis fungoides/Sézary syndrome.

Alemtuzumab is a monoclonal antibody to CD52 that has activity in T-cell leukemia and lymphoma. This study aims to describe the complications and outcomes of a subset of patients with mycosis fungoides/Sézary syndrome who were treated with alemtuzumab. Four of 8 patients, with no prior history of cardiac problems, developed significant cardiac toxicity (congestive heart failure or arrhythmia) that mostly improved after alemtuzumab discontinuation. The role of this agent in potentially inducing important cardiac side effects is suggested and argues for further investigation.

Adult↗

PubMed2004

A systematic approach to diagnosis of mature T-cell leukemias reveals heterogeneity among WHO categories.

The current World Health Organization (WHO) classification of hematopoietic malignancies defines several types of mature T-cell leukemia including T-cell prolymphocytic leukemia (T-PLL), Sezary syndrome (SS), and T-cell large granular lymphocytic (T-LGL) leukemia. These neoplasms can show overlapping features with each other and with T-cell lymphomas involving peripheral blood (PB). We analyzed the spectrum of clinicopatho-logic features in 102 mature T-cell leukemias and compared them to 10 hepatosplenic T-cell lymphomas that involved PB. T-PLL, defined as a T-cell leukemia showing rapidly rising PB lymphocyte counts, was the only tumor type expressing the oncoprotein TCL1 (71% of cases) and could present with relatively low lymphocyte levels or small tumor cell morphology. SS, defined by accompanying erythrodermic skin disease, was frequently associated with peripheral eosinophilia but could also develop high numbers of prolymphocytes, especially late in the disease course. T-LGL leukemia, defined by accompanying cytopenias or autoimmune phenomena (or both), had the best clinical outcome and generally showed the lowest circulating lymphocyte levels with only a few cases developing marked lymphocytosis. Using the dominant clinical or phenotypic feature, we describe here the degree of overlap among currently recognized WHO categories and identify areas where further clarification is needed. Our results indicate that incorporation of additional criteria, such as TCL1 expression status and hematologic parameters, can assist in a more accurate classification.

Adult↗

PubMed2004

Activity of interferon-alpha and isotretinoin in patients with advanced, refractory lymphoid malignancies.

BACKGROUND: Interferon-alpha (IFN-alpha) and retinoids have shown nonoverlapping toxicity and each has shown antitumor activity in patients with lymphoma. The aim of the current study was to assess the toxicity, safety, and efficacy of IFN-alpha combined with isotretinoin in patients with advanced, refractory lymphoid malignancies. METHODS: Adults with biopsy-proven advanced lymphoid malignancy were treated. Patients with compromised bone marrow function (platelet counts as low as 30 x 10(9)/L) were eligible. Treatment was comprised of IFN-alpha at a starting daily dose of 3 mega units subcutaneously and isotretinoin orally starting at a dose of 1 mg/kg daily in 2 divided doses. RESULTS: Forty-four patients were evaluable. Their median age was 57 years (range, 18-82 years). Eighteen patients had advanced cutaneous T-cell lymphoma, 6 patients had peripheral T-cell lymphoma, 14 patients had Hodgkin disease, and 6 patients had a variety of other lymphoid malignancies. Patients with Hodgkin disease had received a median of 6 previous therapies (range, 3-12 therapies) and patients with other lymphoid malignancies had received a median of 4 previous therapies (range, 1-9 therapies). The median duration of treatment was 4 months (range, 0.25-38 months). The overall response rate was 38.6% (complete response in 5 patients [11.3%] and partial response in 12 patients [27.3%]). The median response duration was 3 months (range, 1-95+ months). The most common toxicities were low-grade fever, flu-like symptoms, and fatigue (IFN-alpha effects); dry mouth and skin and hypertriglyceridemia (cis-retinoic acid effects); and thrombocytopenia (which generally occurred in patients with low baseline platelet counts). CONCLUSIONS: IFN-alpha and isotretinoin combination therapy had antitumor activity and was well tolerated in heavily pretreated patients with lymphoid malignancies.

Adolescent↗