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Biomedical subjects

Madeleine Duvic

Publications and source records attributed to Madeleine Duvic.

At least 55 records · Page 3Linked to original sources
PubMed2004

Phase II study of pentostatin in advanced T-cell lymphoid malignancies: update of an M.D. Anderson Cancer Center series.

BACKGROUND: The goal of the current study was to assess the toxicity, safety, and efficacy of pentostatin in patients with T-cell lymphoid malignancies. METHODS: Patients were eligible if they had biopsy-proven T-cell lymphoma or leukemia and failure to respond to previous therapy or an expected complete response rate to conventional therapy of < 20%. Pentostatin was administered at an initial dose of 3.75 or 5.0 mg/m(2) by intravenous bolus daily over a consecutive 3-day period every 3 weeks. RESULTS: Forty-two of 44 patients enrolled in the study were evaluable. The median age of the patients was 62 years (range, 38-86 years). Patients received a median of 3 previous therapies (range, 0-10 previous therapies). Of these patients, 32 (76%) had mycosis fungoides/Sézary syndrome and 10 patients (24%) had other T-cell leukemias or lymphomas. The overall response rate was 54.8% (complete remission, 6 patients [14.3%]; partial remission, 17 patients [40.5%]). Durable responses were observed mainly in patients with Sézary syndrome or peripheral T-cell lymphoma. The median follow-up period for surviving patients was 20 months (range, 1-83+ months). The median duration of response was 4.3 months (range, 1-61 months). The most common toxicities were neutropenia, nausea, and CD4 suppression. A transient early "flare" of disease was observed in some responders. CONCLUSIONS: At these doses, pentostatin was reasonably well tolerated and is an effective drug for the treatment of T-cell lymphomas.

Adult↗
PubMed2004

Pilot study of etanercept in patients with relapsed cutaneous T-cell lymphomas.

BACKGROUND: Tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of cutaneous T-cell lymphoma (CTCL). OBJECTIVE: To assess the toxicity, safety, and efficacy of etanercept (soluble TNF receptor) in patients with relapsed CTCL. METHODS: Etanercept was administered twice weekly at a dose of 25 mg subcutaneously. Patients with improvement after two months could be continued on treatment. RESULTS: Twelve out of the 13 patients enrolled on study were evaluable (Stage I-IIA, 3 patients; Stage IIB-IV disease, 9 patients). The median number of previous therapies was 7 (range, 3-12). Etanercept induced partial remission in one patient (8%) and minor response in one patient (8%), both of whom had Stage IB disease. Most patients experienced no side effects. CONCLUSION: This pilot study suggests that etanercept is safe and generally well tolerated in patients with CTCL. The effect of etanercept in a larger cohort of patients with early disease merits investigation.

Adult↗
PubMed2004

Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an open-label pilot study.

BACKGROUND: Topical skin-directed therapies are used to induce remissions in early-stage mycosis fungoides (MF). They are rarely curative, and responding patients are subject to frequent relapses, emphasizing the need for alternative therapies. OBJECTIVE: We sought to evaluate the efficacy and tolerability of topical tazarotene 0.1% gel as adjuvant therapy in the treatment of refractory MF lesions. METHODS: A total of 20 adult patients with early patch or plaque MF limited to less than 20% body surface area (BSA) involvement whose lesions were either stable or refractory to therapy for at least 8 weeks enrolled in an open-label pilot study. Tazarotene 0.1% gel was applied to MF lesions once daily for 24 weeks. Continued concomitant use of other medications such as low- to mid-potency topical corticosteroids was permitted for the alleviation of skin irritation. Global improvement, overall disease severity, percent BSA involvement, and pruritus were evaluated every 4 weeks. Up to 6 index lesions were followed up for area, plaque elevation, scaling, and erythema scores. Skin biopsy specimens were to be taken at baseline, week 8, and week 24. Evaluable specimens were stained with hematoxylin and eosin, CD8 antibody, and CD45RO antibody. RESULTS: In all, 20 patients enrolled, 19 received treatment, and 16 completed at least 4 weeks of topical treatment. By intent-to-treat analysis, 11 of 19 patients (58%) achieved at least a moderate (>50%) global improvement in BSA, and 35% of 99 index lesions cleared completely. Significant reductions (mean differences) were also found in the median lesional area score (-37, P =.0013), mean plaque elevation score (-.67, P =.016), mean scaling (-0.70, P =.033), and mean erythema score (-1.03, P =.002). Analysis of overall disease also disclosed statistical differences in percent of change for BSA involvement of 22% (P =.013) and of mean overall disease severity score of 34% (P =.011). Of 19 patients, 16 (84%) experienced mild or moderate local skin irritation manifested by peeling, erythema, burning, and tenderness that was managed successfully with topical steroids or reducing the frequency of treatment. Histopathology and immunohistochemistry results showed reductions in lymphocytic infiltrates and percentage of CD45RO(+) lymphocytes, and increases in the percentage of CD8(+) lymphocytes during the course of therapy. CONCLUSION: In this small pilot study, tazarotene 0.1% gel was a well-tolerated and effective adjuvant topical for the treatment of refractory MF lesions by clinical and histologic assessments.

Administration, Topical↗
PubMed2004

Severe radiation dermatitis is related to Staphylococcus aureus.

Acute radiation dermatitis commonly occurs following local radiation therapy for various cancers and, when severe, may necessitate disruption of treatment. Intense inflammatory reaction may result in a breakdown of the skin's barrier function and accompanying bacterial colonization. Bacterial superantigens may exacerbate inflammation through activation of T-cells and subsequent cytokine release. We report six cases of severe radiation dermatitis in cancer patients. Four of the six grew pathogenic bacteria, and three had psoriasiform or eczematous reactions at distant sites. Both the radiation dermatitis and the distant cutaneous reactions resolved rapidly on a combination of topical steroids and oral plus topical antibiotic therapy. We suggest that staphylococcal superinfection of acute radiodermatitis intensifies the inflammatory process and hinders repair of the epidermal barrier. Patients with acute radiation dermatitis should be investigated for secondary infection. We emphasize the importance of including topical and oral antibiotic therapy in conjunction with topical corticosteroids to eradicate infection as well as hasten repair of the skin's barrier function. These cases are presented to call attention to the role of Staphylococcus aureus in the pathogenesis of severe radiation dermatitis and the need to include appropriate antibiotic therapy based on culture in the management of acute radiation dermatitis.

Aged↗
PubMed2004

The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) induces apoptosis in Mycosis fungoides/Sézary syndrome cells.

The novel synthetic oleanane triterpenoid CDDO (2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid) can serve as a ligand for the peroxisome proliferator activator receptor-gamma (PPAR-gamma) and has been shown to inhibit cell proliferation, and to induce differentiation and apoptosis in tumor cell lines. Bexarotene is an RXR-selective retinoid that can induce apoptosis of mycosis fungoides (MF) and Sézary syndrome (SS) cells. Since the PPAR-gamma and RXR receptors can form heterodimers, we studied the effects of CDDO and its synergism with bexarotene on apoptosis in MF/SS cell lines (MJ, Hut78, and HH) and freshly isolated peripheral blood lymphocytes (PBL) from SS patients with circulating atypical T cells (CD4+CD26-). CDDO treatment at 1-5 microM for 48 h caused a concentration-dependent apoptosis in three MF/SS cell lines and patients' PBL compared to vehicle controls. Bexarotene augmented CDDO-induced apoptosis in these cells. PPAR-gamma was expressed but decreased by 47% in MJ, 42% in Hut78, and 77% in HH cells following CDDO treatment. The anti-apoptotic protein bcl-xL, but not bcl-2, was decreased by 69% in MJ, 31% in Hut78, and 59% in HH cells and caspase-3 was activated following CDDO treatment. Interestingly, the PPAR-gamma antagonist T007 did not block CDDO-induced apoptosis, and the more potent PPAR-gamma agonist rosiglitazone required much higher concentrations (>50 microM) than CDDO to induce apoptosis in MF/SS cells. In summary, CDDO induces apoptosis that is further enhanced by bexarotene and decreases the PPAR-gamma and bcl-xL proteins in MF/SS cells. CDDO's effects on MF/SS cells may be at least partly mediated through a PPAR-gamma-independent mechanism. Our findings suggest the rationale for further investigation of the clinical potential of CDDO, either alone or in combination with bexarotene for MF/SS patients.

Anticarcinogenic Agents↗
PubMed2004

Lymphomatoid papulosis from childhood with anaplastic large-cell lymphoma of the small bowel.

Lymphomatoid papulosis (LyP) is a lymphoproliferative disorder that exists on a spectrum of diseases with cutaneous CD30+ anaplastic large-cell lymphoma (ALCL). Multiple treatment options are available, although none are curative. The typical age of onset for LyP is in the third and fourth decades, but it has been seen occasionally in children. Lymphomatoid papulosis is associated with primary cutaneous ALCL and other lymphoproliferative malignancies, but is rarely associated with extranodal systemic ALCL. A 43-year-old man developed lymphomatoid papulosis lesions at 3 years of age, which persisted into adulthood, and he later developed ALCL of the duodenum. Treatment with standard CHOP (cyclophosphamide/doxorubicin/vincristine/prednisolone) chemotherapy resulted in complete remission of his gastrointestinal lymphoma and temporary improvement of his skin lesions. However, the LyP relapsed and proved refractory to psoralen plus ultraviolet-A phototherapy, and was only temporarily and partially responsive to bexarotene and denileukin diftitox.

Adult↗
PubMed2003

Repair of UV light-induced DNA damage and risk of cutaneous malignant melanoma.

BACKGROUND: The mechanism underlying the role of UV light exposure from sunlight in the etiology of cutaneous malignant melanoma (CMM) is unclear. Patients with xeroderma pigmentosum, a disease characterized by severe sensitivity to UV radiation and a defect in nucleotide excision repair, have a high incidence of CMM, which suggests that DNA repair capacity (DRC) plays a role in sunlight-induced CMM in the general population as well. METHODS: We conducted a hospital-based case-control study of DRC and CMM among 312 non-Hispanic white CMM patients who had no prior chemotherapy or radiation therapy, and 324 cancer-free control subjects who were frequency-matched to case patients on age, sex, and ethnicity. Information on demographic variables, risk factors, and tumor characteristics was obtained from questionnaires and medical records. We used the host-cell reactivation assay to measure the DRC in study subjects' lymphocytes. All statistical tests were two sided. RESULTS: Case patients had a 19% lower mean (+/- standard deviation [SD]) DRC (8.5 +/- 3.4%) than control subjects (10.5 +/- 5.1%), a statistically significant difference (P<.001). DRC that was at or below the median value (i.e., 9.4%) in control subjects was associated with increased risk for CMM after adjustment for age, sex, and other covariates (odds ratio [OR] = 2.02, 95% confidence interval [CI] = 1.45 to 2.82). We observed a dose-response relationship between decreased DRC and increased risk of CMM (P(trend)<.001). Patients with tumors on sun-exposed skin had statistically significantly lower DRC than patients with tumors on unexposed skin (8.2 +/- 3.3% versus 9.5 +/- 3.5%; P =.004). CONCLUSIONS: Reduced DRC is an independent risk factor for CMM and may contribute to susceptibility to sunlight-induced CMM among the general population.

Adult↗
PubMed2003

Topical and systemic retinoid therapy for cutaneous T-cell lymphoma.

Because curative therapies for CTCL are not yet available, short of TSEB in patients who have early-stage disease and allogeneic bone marrow transplantation in patients who have more advanced disease, the goal of current therapies is to prevent progression of MF and to preserve quality of life. The overall conclusion drawn from the studies reported in the literature, is that retinoids as monotherapy, or in combination with other nonaggressive treatment modalities, represent a low-risk treatment alternative that is especially suitable for controlling early stages of MF and other CTCL. A combination of therapies may be more effective in controlling CTCL as shown with IFN-alpha plus retinoids, and, recently, IFN-alpha with bexarotene and other modalities. For example, isotretinoin, followed by TSEB (for stage I to II disease) or preceded by chemotherapy (for stage II and IV disease) and bexarotene plus PUVA or photopheresis plus IFN, gave overall response rates of 82% and 69% in patients who had MF and SS, respectively. Retinoids as monotherapy may induce complete remissions, but usually these responses are of short duration and relapses are common. Clinical response is not identical to histologic clearance. Even in cases with clinically complete clearance of skin lesions, lymphoid infiltrates persisted, which are most likely the source of recurrences. The new generation of retinoids, the RXR selective agonists like bexarotene, represent a promising approach for refractory or persistent MF that is unresponsive to first-line therapies. Individual differences in response to retinoids may be due to different expression of retinoid receptors, functional polymorphisms in metabolizing retinoids, or resistance to some retinoids. In the future, pharmacogenomic studies are needed to clarify the mechanisms that underlie the differing response rates of patients who have CTCL to retinoids. In addition, new agonists of RAR and RXR, either selective or pan agonists, will become available and will enlarge the spectrum of vitamin A analogs that have antitumoral properties.

Adjuvants, Immunologic↗
PubMed2003

Mycosis fungoides-like reaction in a patient treated with Gleevec.

BACKGROUND: Gleevec trade mark is a protein tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumor. Currently, Gleevec is also being used in protocols for treatment of other malignancies such as melanoma. A few, non-descript cutaneous eruptions have been reported in patients receiving Gleevec. CASE REPORT: A patient with a gastrointestinal stromal tumor developed a centripetal, slightly pruritic, predominantly macular eruption. Histologically, there was a superficial and mid-perivascular cellular infiltrate of hyperchromatic, large lymphocytes with focal epidermotropism, thus resembling mycosis fungoides. The infiltrate was composed predominantly of T cells (CD3), with a 1:1 CD4:CD8 ratio, therefore consistent with a reactive process, i.e. a drug reaction induced by Gleevec. CONCLUSION: Gleevec should be considered in the differential diagnosis of pseudolymphoma drug eruptions.

Antineoplastic Agents↗
PubMed2003

Alopecia areata registry: an overview.

The National Alopecia Areata Registry was awarded as a five-year contract by NIAMS to promote research on the genetic basis of alopecia areata. The registry is Web based and can be accessed online at http://www. AlopeciaAreata Registry.org. Samples of DNA, lymphoblast lines, and sera, as well as epidemiology and quality-of-life data, are being collected from well-characterized individuals, multiplex families, and sib pairs for future research studies and investigators.

Alopecia Areata↗
PubMed2003

Long-term control of mycosis fungoides of the hands with topical bexarotene.

BACKGROUND: Limited Stage IA mycosis fungoides (MF) is often treated with topical steroids, which can cause atrophy, or with nitrogen mustard, which imposes several limitations on the patient's lifestyle. Topical bexarotene is a novel synthetic rexinoid with few side-effects that has shown efficacy for treatment of mycosis fungoides skin lesions in recent Phase II-III clinical trials. The Phase I-II trial involving 67 stage IA-IIA MF patients demonstrated complete response (CR) in 21% and partial response (PR) in 42% of the patients. The median time to response was approximately 20 weeks. In the phase III trial of refractory stage IA, IB and IIA MF, the patients demonstrated a 44% response rate (8% CR). Patients with no prior therapy for mycosis fungoides responded at a higher rate (75%) than those with prior topical therapies. METHODS: Case report of a patient with MF limited to the hands treated with topical bexarotene 0.1% gel in a open label phase II clinical trial. RESULTS: Partial response occurred after 2 weeks of topical bexarotene therapy and the lesions were well controlled for 5 years using bexarotene monotherapy, with only occasional mild local irritation. CONCLUSIONS: Topical bexarotene is effective as long-term treatment monotherapy for limited MF lesions. To our knowledge this is the longest use of the drug by any individual.

Administration, Topical↗
PubMed2003

Tazarotene-induced gene 3 is suppressed in basal cell carcinomas and reversed in vivo by tazarotene application.

Basal cell carcinomas are the most common form of skin cancer. Tazarotene is a retinoic acid receptor selective retinoid that upregulates a tumor suppressor, tazarotene-induced gene 3 (TIG-3), in keratinocytes and psoriasis. Expression of TIG-3 in basal cell carcinomas was studied in an opened-label pilot biomarker study of 22 patients with basal cell carcinomas who applied tazarotene 0.1% gel for up to 12 wk prior to excision. Nineteen paired baseline and treated specimens were compared using immunohistochemistry and in situ hybridization. Compared to overlying normal epidermis, TIG-3 protein and mRNA were decreased in 14 and 18 of 19 basal cell carcinomas (74% and 95%), respectively (p < 0.001). Tazarotene treatment was associated with increased TIG-3 protein and mRNA expression in basal cell carcinomas compared to baseline levels (p < or = 0.001 and p = 0.028, respectively). Sixty percent of basal cell carcinomas treated with tazarotene decreased in size by at least 25%. Ten of 19 lesions improved histologically, including three complete responses. There was a correlation between the increased expression of TIG-3 protein and histologic improvement (p = 0.020), suggesting that suppression of TIG-3 may underlie the development of basal cell carcinomas. This association suggests that reversal of TIG-3 expression may help to explain the mechanism of retinoid action in epidermal differentiation and chemoprevention.

Administration, Topical↗
PubMed2003

p53 codon 72 Arg homozygotes are associated with an increased risk of cutaneous melanoma.

The p53 gene plays an important role in cell cycle control, facilitating DNA repair activities in response to DNA damage. Aberrant cell cycle control impairs DNA repair and increases the probability of mutations that can lead to carcinogenesis. The p53 gene is polymorphic at codon 72 (Arg/Pro) of its protein, which is functionally distinct, leading to inquiry into its role in carcinogenesis. In this hospital-based case-control study of 289 newly diagnosed patients with melanoma and 308 cancer-free control subjects, we evaluated whether the p53 codon 72 variant is associated with risk of cutaneous melanoma (CM). The controls were frequency-matched to the cases by age, sex, and ethnicity. The frequency of the p53 Arg allele was 78.2% in cases and 73.2% in controls (p=0.045), and the genotype frequencies of p53 Arg/Arg, Arg/Pro, and Pro/Pro were 62.6%, 31.1%, and 6.3%, respectively, in the cases, and 53.9%, 38.6%, and 7.5%, respectively, in the controls (p=0.096). Logistic regression analysis revealed that the p53 Arg/Arg genotype was associated with a significantly increased risk of melanoma (adjusted odds ratio (OR)=1.43; 95% confidence interval (CI)=1.02-2.02) compared with other genotypes, and this association was more evident in subgroups of older subjects (OR=2.32; 95% CI=1.39-388), and subjects with Fitzpatrick's skin type III or IV (OR=1.69; 95% CI=1.11-2.59). In conclusion, this study found some evidence that in subjects over 50, p53 Arg/Arg genotype is associated with increased risk of CM as compared to genotypes Arg/Pro or Pro/Pro. Further larger studies are needed to substantiate our findings.

Adolescent↗