Improvement in peripheral blood disease burden in patients with Sézary syndrome and leukemic mycosis fungoides after total skin electron beam therapy.

BACKGROUND: There is a paucity of effective therapies for patients with Sézary syndrome and advanced mycosis fungoides with peripheral blood involvement. Total skin electron beam (TSEB) radiation therapy is an extremely effective skin-directed therapy for these patients, but, until recently, it was thought not to signifcantly affect the peripheral blood malignant T-cell population. OBJECTIVE: We conducted this study to determine if TSEB has therapeutic effect on the peripheral blood in patients with advanced mycosis fungoides and Sézary syndrome. METHODS: All patients on stable medication regimens seen in our photopheresis facility who received TSEB therapy between January 2008 and October 2011 at Temple University Hospital, Philadelphia, PA, were analyzed retrospectively for improvement in the peripheral blood, as documented by flow cytometry. RESULTS: Six of 11 patients achieved 50% or greater decrease in their peripheral blood malignant T-cell population after TSEB therapy, for an overall response rate of 55%. Within the group of patients who had a response in the skin, 67% also had a response in the peripheral blood. LIMITATIONS: This analysis is limited in 3 ways. First, the sample described is small. Second, the results may be confounded by the fact that each patient was on other systemic therapies in addition to TSEB, albeit stable pre-existing regimens. The time interval between completion of TSEB therapy and repetition of flow cytometry was not standardized among patients, which may result in an underestimation of the overall response to TSEB therapy. CONCLUSION: In patients with advanced mycosis fungoides and Sézary syndrome, the peripheral blood tumor burden may improve after treatment with TSEB.

Paraneoplastic subacute cutaneous lupus erythematosus: an underrecognized entity.

Subacute cutaneous lupus erythematosus (SCLE) is a form of cutaneous lupus erythematosus that most often presents as scaly, erythematous, papulosquamous, or annular papules and plaques in a photodistributed pattern. Subacute cutaneous lupus erythematosus is classically considered to be either idiopathic or drug induced. There have been few reports of SCLE arising in the setting of malignancy, raising the possibility that paraneoplastic SCLE may be a rare distinct subset of lupus. We report a case of SCLE arising as a paraneoplastic phenomenon in the setting of small cell lung cancer. Given the close temporal proximity of the detection of malignancy and the development of the rash in our patient, we believe this report presents a case of paraneoplastic SCLE. The presentation of new-onset idiopathic SCLE should prompt a careful review of systems and age-appropriate cancer screening, as SCLE may be a sign of an occult malignancy.

Survival-Larval Density Relationships in the Field and Their Implications for Control of Container-Dwelling Aedes Mosquitoes.

Population density can affect survival, growth, development time, and adult size and fecundity, which are collectively known as density-dependent effects. Container Aedes larvae often attain high densities in nature, and those densities may be reduced when larval control is applied. We tested the hypothesis that density-dependent effects on survival are common and strong in nature and could result in maximal adult production at intermediate densities for Aedes aegypti, Aedes albopictus, and Aedes triseriatus. We surveyed naturally occurring densities in field containers, then introduced larvae at a similar range of densities, and censused the containers for survivors. We analyzed the survival-density relationships by nonlinear regressions, which showed that survival-density relationships vary among seasons, sites, and species. For each Aedes species, some sites and times yielded predictions that larval density reduction would yield the same (compensation), or more (overcompensation), adults than no larval density reduction. Thus, larval control targeting these Aedes species cannot always be assumed to yield a reduction in the number of adult mosquitoes. We suggest that mosquito control targeting larvae may be made more effective by: Imposing maximum mortality; targeting populations when larval abundances are low; and knowing the shape of the survival-density response of the target population.

Validity assessment of the cutaneous T-cell lymphoma severity index to predict prognosis in advanced mycosis fungoides/Sézary syndrome.

BACKGROUND: There is a need for standardized quantitative disease assessment measures in mycosis fungoides/Sézary syndrome. In 2005, a cutaneous T-cell lymphoma (CTCL)-severity index (SI) that not only measures disease extent (on a scale of 0-75) independent of the classic TNM(B) staging system but can also be used to estimate individual 5-year survival (SR5) was reported. OBJECTIVE: We sought to assess the generalizability of the CTCL-SI/SR5 equation (SR5 equation) to predict prognosis in our cohort of patients with advanced mycosis fungoides/Sézary syndrome (n = 50, photopheresis service, 1984-2001). METHODS: TNM(B) staging, CTCL-SI score (based on skin involvement, presence of tumors, lymph node/visceral/blood involvement), and SR5 (SR5 equation = 124 - 2 × [CTCL-SI]%) at initial diagnosis were calculated retrospectively and compared with overall survival by the Kaplan-Meier method. The prognostic significance of TNM(B) staging versus the CTCL-SI was determined by Cox proportional hazards models and Brier scores. RESULTS: Patients had stage IIA to IVA disease with a median actuarial overall survival of 58 months. By disease stage, the overall 5-year survival was 70% (stage IIA), 48% (stage IIB-IIIB), and 36% (stage IVA). In our cohort, the CTCL-SI itself was predictive of overall survival (P = .028) but the SR5 equation was not predictive of survival (Brier score of 0.29). LIMITATIONS: Small sample size, single academic center population, and retrospective design are limitations. CONCLUSIONS: The CTCL-SI is a relatively simple-to-use quantitative tool that measures disease activity in all compartments (skin, nodes, blood, viscera) and has prognostic significance in multivariate analysis. The CTCL-SI may be a useful adjunct to the TNM(B) staging for tracking disease activity quantitatively in all disease compartments (skin, nodes, blood, viscera) in clinical practice and trials, but the predictive ability of the SR5 equation needs further validation at other centers in larger groups of patients.

Update on treatment of cutaneous T-cell lymphoma.

PURPOSE OF REVIEW: Cutaneous T-cell lymphomas (CTCLs) are a heterogenous group of non-Hodgkin's lymphomas characterized by atypical, skin-homing T lymphocytes and have varying prognoses depending on subtype and disease stage. Numerous therapeutic options exist; however, many patients experience refractory disease and novel treatments are needed. RECENT FINDINGS: This review will highlight selected advances in CTCL treatment over the past year (2007-2008). Discoveries regarding the pathophysiology of mycosis fungoides and Sézary syndrome, the two most common CTCL types, have led to an expansion of new treatments and an increase in experience with multimodality therapy continues to increase. A number of reports have examined both combination regimens of currently available CTCL therapies as well as treatments approved for other dermatologic or oncologic conditions. Also, several novel skin-directed treatments and systemic compounds have been studied in all CTCL stages as well as in treatment-refractory disease. SUMMARY: There remains a continued impetus to develop and amass experience with new therapeutic options for CTCL, particularly for patients with advanced stage and treatment-refractory disease.

Thyroid Hormone Receptor-ß (TRß) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer.

Dysregulation of the thyroid hormone receptor (TR)ß is common in human cancers. Restoration of functional TRß delays tumor progression in models of thyroid and breast cancers implicating TRß as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRß as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRß is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TRß by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TRß levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TRß specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TRß suppressed Runx2 transcriptional activities, thus confirming TRß regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TRß and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRß-Runx2 signaling supports the emerging role of TRß as a tumor suppressor and reveals a novel pathway for intervention.

High clinical response rate of Sezary syndrome to immunomodulatory therapies: prognostic markers of response.

OBJECTIVES: To quantify response rates of Sézary syndrome (SS) to multimodality immunomodulatory therapy and to identify the important prognostic parameters that affect overall response to treatment. DESIGN: Retrospective cohort study. SETTING: Cutaneous T-cell lymphoma clinic at The Hospital at the University of Pennsylvania. PARTICIPANTS: Ninety-eight patients who met the revised International Society for Cutaneous Lymphomas (ISCL) and the European Organization of Research and Treatment of Cancer (EORTC) criteria for the diagnosis of SS and were seen over a 25-year period at the University of Pennsylvania. Intervention Patients were treated with at least 3 months of extracorporeal photopheresis and 1 or more systemic immunostimulatory agents. MAIN OUTCOME MEASURES: Overall response to treatment was the main measurement of outcome. RESULTS: A total of 73 patients had significant improvement with multimodality therapy: 30% had complete response, with clearing of all disease (n = 29), and 45% had partial response (n = 44). At baseline, the complete response group had a lower CD4/CD8 ratio than the nonresponse group (13.2 vs 44.2) (P = .04) and a lower median percentage of CD4(+)/CD26(-) cells (27.4% vs 57.2%) (P = .01) and CD4(+)/CD7(-) cells (20.0% vs 41.3%) (P < .01). Median monocyte percentage at baseline was higher for patients who had a complete response than for nonresponders (9.5% vs 7.3%) (P = .02). The partial response group did not have any statistically significant variables compared with the nonresponse group. CONCLUSIONS: In this large cohort study of patients with SS, a high clinical response rate was achieved using multiple immunomodulatory therapies. A lower CD4/CD8 ratio, a higher percentage of monocytes, and lower numbers of circulating abnormal T cells at baseline were the strongest predictive factors for complete response compared with nonresponse and warrant further examination in a larger cohort.