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Biomedical subjects

Joan Guitart

Publications and source records attributed to Joan Guitart.

At least 19 recordsLinked to original sources
PubMed2006

The selective protein kinase C beta inhibitor enzastaurin induces apoptosis in cutaneous T-cell lymphoma cell lines through the AKT pathway.

Enzastaurin displays pro-apoptotic properties against a spectrum of malignancies and is currently being investigated in clinical trials. We have investigated the effects of enzastaurin on the viability of the cutaneous T-cell lymphoma cell lines HuT-78 and HH by using 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, cell cycle analysis, propidium iodide and annexin-V staining, and caspase-3-mediated proteolytic activation. Enzastaurin-treatment decreased cell viability, increased annexin V-FITC-positive cells, and increased the proportion of sub-G1 populations in both cell lines that was not reversed by the T-cell growth stimulating cytokines IL-2, IL-7, IL-15. Enzastaurin-induced cell death involved caspase-3-activated cleavage of poly(ADP-ribose) polymerase that was inhibited by the pan-caspase inhibitor ZVAD-fmk, whereas the increase in sub-G1 population was only partially inhibited by ZVAD-fmk. Furthermore, enzastaurin downregulated AKT activity and its downstream effectors GSK3beta and ribosomal protein S6. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in the growth and survival of hematologic malignancies and inhibition of this pathway is considered as a therapeutic target. Protein kinase C activation contributes to PI3K/AKT activation, but it is unknown how enzastaurin may interfere with signaling through this pathway. These results demonstrate that enzastaurin, at clinically achievable concentrations, induces apoptosis and affects AKT signaling, and provide a rationale for further in vivo studies addressing the therapeutic efficacy in cutaneous T-cell lymphoma patients.

Apoptosis↗
PubMed2006

Safety of radiofrequency treatment over human skin previously injected with medium-term injectable soft-tissue augmentation materials: a controlled pilot trial.

BACKGROUND AND OBJECTIVES: Several soft-tissue augmentation materials are now available for reduction of nasolabial fold creases and perioral rhytides. Nasolabial folds and perioral rhytides can also be improved by skin tightening delivered by non-ablative radiofrequency (RF) treatment. The purpose of this study was to assess the safety of RF treatment over skin areas recently injected with medium-term injectable soft-tissue augmentation materials. STUDY DESIGN/MATERIALS AND METHODS: Five subjects were assigned to the experimental arm (augmentation materials plus RF) and one to the control arm (augmentation materials alone). Each subject received injections of 0.3 mL of hyaluronic acid derivative (Restylane) and calcium hydroxylapatite (Radiesse) 3 cm apart on the upper inner arm. Two weeks later, two non-overlapping passes of RF (Thermage ThermaCool TC) were delivered at 63.5 setting with medium-fast 1.5 cm2 tip over injected sites in all of the experimental subjects. Punch skin biopsies were obtained 3 days later from each of the two injection sites on each subject. RESULTS: Light microscopy and digital photomicrographs obtained at low, medium, and high power showed no difference between filler materials in experimental and control subjects. In both cases filler was evident at the deep dermal-subcutaneous junction. Nodule formation, foreign body extravasation, or hemorrhage/clot was not observed grossly or histologically. Subjects and physicians did not report any difference in signs and symptoms between the experimental and control arms. Slightly increased transitory pain was noted when RF was delivered over filler versus over normal skin. CONCLUSION: Applying RF treatment over the same area 2 weeks after deep dermal injection with hyaluronic acid derivatives or calcium hydroxylapatite does not appear to cause gross morphological changes in the filler material or surrounding skin. Further studies with different parameters are necessary to confirm these findings.

Adult↗
PubMed2006

The acanthosis nigricans form of epidermal nevus.

We observed 4 individuals with the acanthosis nigricans (AN) form of epidermal nevus, with clinical and histopathologic features of AN oriented along Blaschko's lines. Three patients had stable lesions since childhood. One patient concurrently had typical bilateral AN lesions. This condition may represent a mosaic form of AN.

Acanthosis Nigricans↗
PubMed2006

Combination treatment modalities in cutaneous T-cell lymphoma (CTCL).

A wide variety of cutaneous T-cell lymphoma therapies are now used in clinical practice. Treatment options include phototherapy, radiation, topical therapy, systemic mono-chemotherapy, combination chemotherapy, and combined modalities. Many patients fail or develop resistance to monotherapy, resulting in a need for combined treatment modalities to improve therapeutic results in terms of quality of life and duration of response. Recently, bexarotene, a selective antagonist of the retinoid X receptor, has been approved in the treatment of patients with cutaneous T-cell lymphoma. Bexarotene offers new opportunities for combination treatment strategies because of its novel and unique mechanism of action. In this article we review the rationale and examine key published evidence on combining these new treatment modalities.

Anticarcinogenic Agents↗
PubMed2006

Bexarotene in the treatment of cutaneous T-cell lymphoma.

Primary cutaneous T-cell lymphomas encompass a spectrum of non-Hodgkin's lymphomas that are characterised by clonal proliferation of skin-homing malignant T lymphocytes. Mycosis fungoides and the leukaemic variant Sézary syndrome, collectively referred to as cutaneous T-cell lymphomas, are the most common entities. No curative therapy exists and patients ultimately develop advanced or relapsed disease that is refractory to standard treatment options. Therefore, there is a great need for the development of novel emerging therapies. Bexarotene is the first synthetic nuclear retinoid X receptor-selective retinoid approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma in all stages, as both an oral capsule and a topical gel formulation. Bexarotene was found to induce apoptosis in a variety of preclinical in vitro and in vivo models including cutaneous T-cell lymphoma cells, and has shown efficacy in two multi-centre, open-label Phase II - III clinical trials for early and advanced stages of cutaneous T-cell lymphoma in patients who have failed or were refractory to standard therapies. New insights into the immunomodulatory function of bexarotene have indicated opportunities for combined treatment with IFN-alpha, denileukin diftitox or phototherapy. This article reviews the biological properties, pharmacokinetics, clinical efficacy, safety and role of bexarotene in the treatment of cutaneous T-cell lymphoma.

Animals↗
PubMed2005

Long-term follow-up of patients with early-stage cutaneous T-cell lymphoma who achieved complete remission with psoralen plus UV-A monotherapy.

OBJECTIVES: To evaluate long-term outcomes, impact of maintenance therapy and potential curability of patients with mycosis fungoides (MF) treated with psoralen plus UV-A (PUVA) monotherapy. DESIGN: Single-center retrospective cohort analysis. SETTING: Academic referral center for cutaneous lymphoma. PATIENTS: A total of 66 of 104 patients with clinical stages IA to IIA MF who achieved complete remission (CR) after PUVA monotherapy between 1979 and 1995. MAIN OUTCOME MEASURES: Kaplan-Meier actuarial survival and disease-free survival curves were compared between stage IA and IB/IIA cases. Patients were stratified into relapse and nonrelapse groups based on whether their MF relapsed during study follow-up. Baseline characteristics and treatment were compared between these groups. RESULTS: Median follow-up time was 94 months (range, 5-242 months). Thirty-three patients maintained CR for 84 months (range, 5-238 months), and 33 patients experienced relapse with a median disease-free interval of 39 months (range, 2-127 months). There was no significant difference in baseline characteristics between patients in the nonrelapse and relapse groups. Those in the nonrelapse group received a higher cumulative dosage to CR (P = .03) and required longer treatment periods to achieve CR (P = .03). Disease-free survival rates at 5 and 10 years for all patients with stage IA were 56% and 30%, respectively, and for stage IB/IIA, 74% and 50%. Actuarial survival rates at 5, 10, and 15 years were 94%, 82%, and 82%, respectively, in patients with stage IA, and 80%, 69%, and 58% in patients with stage IB/IIA. The overall survival rate for the nonrelapse and relapse groups did not show any statistical difference. One third of the patients developed signs of chronic photodamage and secondary cutaneous malignancies. CONCLUSIONS: Psoralen UV-A is an effective treatment for MF, inducing long-term remissions and perhaps in some cases disease "cure." Thirty percent to 50% of patients remain disease free for 10 years, but late relapses occur. Long-term survival is not affected by relapse status, and the risk of photodamage needs to be measured against the possible benefit of greater disease elimination.

Adult↗
PubMed2005

Cyclin D1 expression in melanocytic lesions of the skin.

BACKGROUND: Progression through the cell cycle is controlled by cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitory proteins. The role of cyclin D1 in the development and progression of melanomas is controversial. The goal of this study is to evaluate the role of cyclin D1 in benign and malignant melanocytic lesions of the skin. METHODS: A total of 126 pigmented lesions of the skin including compound nevi (21), intradermal nevi (18), melanoma in situ (28), primary invasive melanomas (30), and metastatic melanoma (29) were evaluated for cyclin D1 expression. The following tiered system was used for scoring: 0% nuclear staining (score 0), 1% to 19% nuclear staining (score 1), 20% to 49% nuclear staining (score 2), and 50% or greater nuclear staining (score 3). RESULTS: Average scores were significantly higher for primary melanomas compared with nevi and for in situ melanomas compared with primary invasive melanomas. The average score for metastatic melanomas was not significantly different compared with primary invasive melanomas. Scores for primary invasive melanomas did not correlate with depth of invasion or presence of metastases. Compound nevi exhibited a slightly higher level of cyclin D1 expression compared with intradermal nevi. CONCLUSION: Although primary melanomas show a higher level of cyclin D1 expression compared with nevi, cyclin D1 appears to have little role in development of a metastatic phenotype. It is not clear why lesions localized near the dermal-epidermal junction express higher levels of cyclin D1. Further studies are indicated to ascertain the biologic role and practical utility of cyclin D1 in melanocytic lesions of the skin.

Biomarkers, Tumor↗
PubMed2005

Defining early mycosis fungoides.

This editorial review summarizes the results of 5 meetings sponsored by the International Society for Cutaneous Lymphoma at which the clinicopathologic and ancillary features of early mycosis fungoides were critically examined. Based on this analysis, an algorithm was developed for the diagnosis of early mycosis fungoides involving a holistic integration of clinical, histopathologic, immunopathologic, and molecular biological characteristics. A novel aspect of this algorithm is that it relies on multiple types of criteria rather than just one, for example, histopathology. Before its finalization, the proposed diagnostic algorithm will require validation and possibly further refinement at multiple centers during the next several years. It is anticipated that a more standardized approach to the diagnosis of early mycosis fungoides will have a beneficial impact on the epidemiology, prognostication, treatment, and analysis of clinical trials pertaining to this most common type of cutaneous lymphoma.

Algorithms↗
PubMed2005

The spectrum of cutaneous T-cell lymphomas: new insights into biology and therapy.

PURPOSE OF REVIEW: Cutaneous T-cell lymphomas represent clinically and biologically a heterogeneous group of non-Hodgkin lymphomas according to the new revised European Organization for Research and Treatment of Cancer and World Health Organization consensus classification for cutaneous lymphomas. Recent progress in immune and molecular biology and novel therapeutic targets have increased our understanding of these diseases and have led to novel treatment approaches. This review outlines the most recent advances. RECENT FINDINGS: New immunologic and molecular findings may influence tumor phenotype and growth and provide a biologic basis for novel treatment approaches. Several reports have focused on new prognostic markers. Among the novel therapies for cutaneous T-cell lymphoma, interleukin-2 fusion toxins, monoclonal antibodies, histone deacetylase inhibitors, and immunomodulatory cytosine-phosphorothiolated guanine oligomers have shown promising results and are under further investigation. SUMMARY: This review provides an update of recent findings of immunologic, molecular, and cytogenetic features and treatment approaches for patients with cutaneous T-cell lymphoma with special emphasis on mycosis fungoides and Sezary syndrome.

Anticarcinogenic Agents↗
PubMed2005

Lymphangioma-like Kaposi sarcoma.

BACKGROUND: Lymphangioma-like Kaposi's sarcoma (LLKS) is a rare morphologic expression of Kaposi's sarcoma (KS) that occurs in virtually all of the well-recognized clinical subtypes of the disease and has the potential to mimic other pathologic processes. In this study, we present the clinical and pathological features of four patients with LLKS. METHODS: Four cases of LLKS were retrieved from the dermatopathology files of our institution. All four tumours were tested immunohistochemically with anti-human herpesvirus-8 (HHV-8) latent nuclear antigen-1 (LNA-1) and anti-CD34 antibodies. RESULTS: Clinically, each patient presented with violaceous patches, papules or plaques; one patient presented with bullous lesions. All of the LLKS biopsy specimens revealed areas with characteristic light microscopic features of KS. Lymphangioma-like foci consisted of ectatic, irregularly shaped vascular spaces lined by mildly atypical endothelial cells. All tumour cells, including those associated with LLKS foci, showed a strong and diffuse reactivity for anti-HHV-8 LNA-1 and anti-CD34. KS progressed slowly in two patients with adequate follow-up. CONCLUSIONS: As LLKS can mimic other disease processes, the correct diagnosis relies heavily on the recognition of salient clinical and histological features of conventional KS, including a strong immunohistochemical expression of HHV-8-associated LNA-1 in lesional cells.

Adult↗
PubMed2004

Comparison of selective retinoic acid receptor- and retinoic X receptor-mediated efficacy, tolerance, and survival in cutaneous t-cell lymphoma.

Primary cutaneous T-cell lymphomas are non-Hodgkin's lymphomas with varied clinical presentation and prognosis. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Sézary syndrome. Treatment of mycosis fungoides has encompassed a variety of modalities including the use of retinoids with several studies evaluating their efficacy. The reported benefits and duration of response have varied in published data. The biological effect of retinoids is mediated by specific receptor families, retinoic acid receptor (RAR) and retinoic X receptor (RXR), with subsequently altered gene expression. There are no data available on cutaneous T-cell lymphomas that compare RAR and RXR retinoids. The objective of our retrospective, nonrandomized, single-center study was to compare the response, survival outcomes, and toxic effects in our phase II trial of the RAR-specific retinoid, all-trans retinoic acid, with clinical use of the RXR-specific retinoid, bexarotene, in patients with mycosis fungoides/Sézary syndrome who have relapsed. There was no statistical difference in response rates (12% vs 21%), response duration (20.5 vs 7.3 months), event-free survival time (4 vs 5 months), or median survival when corrected for length of follow-up. Both have favorable toxicity profiles that can be managed with medications. The toxicity profile caused by bexarotene seems to be more limited to laboratory values and better tolerated, although generally associated with more severe grades of toxicity. In conclusion, both retinoids have modest objective response rates and, therefore, most likely will have limited impact as monotherapeutic agents. However, the immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using retinoids in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy.

Adult↗
PubMed2004

Hydroxyurea-associated squamous dysplasia.

We report 2 cases of squamous dysplasia associated with long-term hydroxyurea therapy. The association between hydroxyurea and multiple aggressive squamous cell carcinomas, Bowen's disease, and multiple actinic keratoses in sun-exposed areas after a variable latency period has been increasingly reported. On reviewing the literature, 17 cases were identified and are reviewed, with emphasis on possible pathogenetic mechanisms of carcinogenicity. Squamous dysplasia, a precursor state to a more aggressive condition of multiple squamous cell carcinomas in photoexposed areas, should be added to the well-known cutaneous toxicities of hydroxyurea therapy.

Aged↗