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Biomedical subjects

Christiane Querfeld

Publications and source records attributed to Christiane Querfeld.

10 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

Primary cutaneous T-cell lymphomas.

Primary cutaneous T-cell lymphomas (CTCLs) encompass a clinically and biologically heterogeneous group of non-Hodgkin lymphomas (NHLs) defined by clonal proliferation of skin-homing malignant T lymphocytes and natural killer cells. They account for up to 75% to 80% of all cutaneous lymphomas. The current WHO-EORTC classification of cutaneous lymphomas with primary cutaneous manifestations lists 13 entities. The most common subtypes-mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, and lymphomatoid papulosis-which represent approximately 95% of CTCLs, will be discussed in the following review. Each entity has unique biological characteristics and clinical course. Topical and/or systemic therapies are employed based on the stage of the disease and the tempo of progression.

Clone Cells↗
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

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↗
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↗
PubMed2003

Primary cutaneous lymphomas: a review with current treatment options.

Primary cutaneous T- and B-cell lymphomas are a heterogenous group of diseases with varied clinical presentations and prognosis. The use of new molecular, histological, and clinical criteria have enhanced the recognition of primary cutaneous T- and B-cell lymphomas. Compared to their nodal counterpart they have a different clinical behavior and therefore require a different treatment approach. Independent predictive factors identified clinically, histologically, and by immunopheno- and immunogenotyping are essential to assess the appropriate treatment for each subtype. The European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Study Group provide a classification of cutaneous lymphomas taking into account of the histological and molecular features. Based on this classification we will provide a summary of the current medical literature in diagnosis, treatment, and prognosis for primary cutaneous lymphomas with emphasis on new treatment strategies.

Antibodies, Monoclonal↗
PubMed2003

Cutaneous T-cell lymphomas: a review with emphasis on new treatment approaches.

Primary cutaneous T-cell lymphomas represent a wide variety of non-Hodgkin lymphomas that are characterized by a distinct clinical presentation. Advanced molecular and biological techniques have enhanced the recognition of cutaneous T-cell lymphomas. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Sézary syndrome. At present, a stage-adjusted therapy is the best concept available, since early aggressive treatment options did not improve the prognosis of patients with cutaneous T-cell lymphomas. Accurate diagnostic and clinical assessment as well as identification of prognostic factors provides a helpful basis for treatment strategies. Current medical literature on diagnosis, prognosis, and treatment is reviewed with emphasis on new biologic response-modifying treatment options.

Biological Therapy↗