Bexarotene-induced hypothyroidism and dyslipidemia; a nation-wide study.

Central hypothyroidism and dyslipidemia are well-known adverse events (AEs) of bexarotene therapy. Although hypothyroidism is known to cause dyslipidemia, no study has examined the association between hypothyroidism and dyslipidemia in patients undergoing bexarotene therapy. The aim of this study is to examine this association. A retrospective observational study was performed among 294 patients who initiated bexarotene therapy in Japan (nation-wide postmarketing complete surveillance). Jonckheere-Terpstra (one sided) test was performed to evaluate the effect of the bexarotene dose on lipid metabolisms, and regression analyses were performed to evaluate associations of bexarotene dose, free thyroxine (FT4), body mass index (BMI), and lipid metabolisms. Most patients developed hypothyroidism. Two-third of patients showed FT4 values below the lower limit at 1 week. Triglycerides (TG) increased in a bexarotene dose-dependent manner, and grade ≥3 AEs on hypertriglyceridemia was observed in 39% of the patients. Additionally, one-third of grade ≥3 AEs on hypertriglyceridemia occurred within 1 week. The delta_FT4 (difference in FT4 from baseline) negatively correlated with TG increase at 1 week (p = 0.012) but not with low density lipoprotein cholesterol (LDL-C) increase at any week. Bexarotene-induced hypothyroidism is almost inevitable and occurred quickly. Bexarotene-induced hypertriglyceridemia showed positive bexarotene dose dependency and negative delta_FT4 dependency. Prophylactic and appropriate thyroid hormone compensation therapy and starting bexarotene at low doses with subsequent titration while managing dyslipidemia may have a beneficial effect for the successful continuation of bexarotene therapy without severe endocrine and metabolic AEs.

Clinicopathological demographics of malignant melanomas of the vulva and vagina in Japan.

Malignant vulvar melanoma (VuM) and vaginal melanoma (VaM) represent a unique subgroup of rare malignant melanomas with critical biological properties that differ from other cancers. In Japan, adequate surveys have yet to be conducted. This study aimed to elucidate the clinicopathological demographics and outcomes of VuM and VaM in Japan. This retrospective observational study included women with invasive VuM or VaM identified from older medical records in Japan. We collected clinical data and used the Kaplan-Meier method to analyze progression-free survival (PFS) and overall survival (OS). Univariate and multivariate regression models were used to identify factors significantly related to survival. We identified 217 patients, 109 (50.2%) with VuM and 108 (49.8%) with VaM. The median PFS was 16.8 months in patients with VuM [95% confidence interval (CI), 23.1-87.7] and 15.6 months in those with VaM (95% CI, 8.4-12.6). The median OS was 43.9 months (95% CI, 60-138) and 31.1 months (95% CI, 24.8-45.3) in patients with VuM and VaM, respectively. Multivariate analysis showed that a disease stage higher than stage III, based on the American Joint Committee on Cancer (AJCC) guidelines, was associated with poorer PFS [hazard ratio (HR), 2.063; 95% CI, 0.995-4.278] and an unknown surgical margin was the only independent factor influencing OS (HR, 2.188; 95% CI, 1.203-3.977). The overall outcomes of invasive VuM and VaM in Japan remain poor. AJCC staging and surgical margins were significant predictors of survival.

Safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma: Real-world experience from post-marketing surveillance.

To establish real-world evidence about the safety and efficacy of bexarotene for Japanese patients with cutaneous T-cell lymphoma, we conducted a nationwide cohort study using data from post-marketing surveillance for bexarotene treatment. In total, 294 patients with cutaneous T-cell lymphoma were identified between June 2016 and June 2018. Of these, 267 patients were included as the safety analysis set. Of the 267 patients, 175 were included in the efficacy analysis set. Of these, 139 patients had mycosis fungoides, including 46 with early stage disease and 93 with advanced stage disease. Among the 139 patients with mycosis fungoides, the objective response rate was 46.8%. A significant difference in objective response rate was detected between patients who started with bexarotene at 300 mg/m2 (61.6%) and patients who started with bexarotene at less than 300 mg/m2 (22.6%, p < 0.001). Of the 139 patients with mycosis fungoides, 92 were treated with a combination of bexarotene plus photo(chemo)therapy. A significant difference in objective response rate was seen between bexarotene with a combination of photo(chemo)therapy (57.6%) and bexarotene without a combination of photo(chemo)therapy (25.5%, p < 0.001). Starting bexarotene at 300 mg/m2 and combination with photo(chemo)therapy were detected as independent factors influencing response. Common treatment-related adverse events included hypothyroidism (85.8%), hypertriglyceridemia (68.5%), hypercholesterolemia (43.8%), and neutropenia (21.3%). Hypertriglyceridemia, hypercholesterolemia, and neutropenia occurred more frequently in patients who started with bexarotene at 300 mg/m2 than patients who started with bexarotene at less than 300 mg/m2 (hypertriglyceridemia, 76.4% vs. 57.0%, p = 0.001; hypercholesterolemia, 49.0% vs. 36.4%, p = 0.045; neutropenia, 28.0% vs. 12.1%, p = 0.002; respectively). The present study indicates that starting bexarotene at 300 mg/m2 and combination of photo(chemo)therapy offer a promising efficacy for the treatment of patients with mycosis fungoides. Efficacy of low-dose bexarotene plus photo(chemo)therapy should be evaluated in future.

Pathogenesis of cutaneous T cell lymphoma: Involvement of Staphylococcus aureus.

Mycosis fungoides (MF) and Sézary syndrome (SS) are representative cutaneous lymphomas. In their early stage, a small number of tumor cells and a large number of non-malignant cells form a Th1-dominant tumor microenvironment. Increase in malignant T cells is accompanied by a decrease in CD8-positive T cells, with a shift toward a Th2-dominant milieu in advanced-stage lesions. The etiologies of MF/SS are diverse, and the underlying pathogenetic mechanisms are yet to be elucidated. Advanced MF/SS is known to be highly sensitive to Staphylococcus aureus, and the majority of deaths are caused by severe infections. The susceptibility to infection is associated with barrier dysfunction and immunosuppression, which are the main symptoms of MF. In recent years, skin-colonizing S. aureus has been identified to not only cause severe infections but also play an important role in the pathogenesis of MF/SS. Staphylococcal superantigens activate the proliferation of tumor cells and induce CD25 upregulation, FOXP3 expression, IL-17 expression, and miR-155 expression. Alpha-toxin eliminates non-neoplastic CD4-positive cells and CD8-positive cells and plays a major role in tumor cell selection. Lipoprotein may also be associated with the induction of Th2-dominant milieu. Antibiotic therapy for S. aureus eradication has been reported to cause considerable clinical improvement in the majority of individuals with advanced cutaneous T-cell lymphoma. Therefore, S. aureus may be a novel target for the treatment of advanced-stage MF/SS in the future.

Functional Depletion of HSP72 by siRNA and Quercetin Enhances Vorinostat-Induced Apoptosis in an HSP72-Overexpressing Cutaneous T-Cell Lymphoma Cell Line, Hut78.

Histone deacetylase inhibitors (HDACis) are one of the therapeutic options for cutaneous T-cell lymphoma (CTCL), but they have limited effects. We previously demonstrated that HSP72 overexpression is associated with chemoresistance to HDACis in lymphoma cells. The purpose of this study was to investigate whether the functional depletion of HSP72 enhances the effect of the HDACi vorinostat. First, we established a stable HSP72-knockdown CTCL cell line and confirmed the influence of HSP72 reduction on the antitumor effects of vorinostat. Next, we studied the effect of quercetin, an inhibitor of HSP72, on the antineoplastic effects of vorinostat. In five CTCL cell lines examined, HSP72 expression was highest in Hut78 cells, and HSP72 knockdown enhanced vorinostat-induced apoptosis in these cells. Low-dose quercetin reduced HSP72 expression, increased HDAC activity, and enhanced vorinostat-induced suppression of Hut78 cell proliferation. A single low dose of quercetin induced G2 arrest and only slightly increased the sub-G1 cell fraction. Quercetin also significantly enhanced vorinostat-induced apoptosis, caspase-3, caspase-8, and caspase-9 activity, and the loss of mitochondrial membrane potential. HSP72 knockdown enhanced vorinostat-induced apoptosis in an HSP72-overexpressing CTCL cell line, and thus, quercetin may be a suitable candidate for combination therapy with vorinostat in clinical settings.

Kinome profiling analysis identified Src pathway as a novel therapeutic target in combination with histone deacetylase inhibitors for cutaneous T-cell lymphoma.

BACKGROUND: Histone deacetylase inhibitors (HDACi) are used to treat patients with cutaneous T-cell lymphoma (CTCL), but they show limited efficacy. Hence, combination therapies should be explored to enhance the effectiveness of HDACis. OBJECTIVE: This study was conducted to identify novel therapeutic targets that can be combined with HDACis for treating CTCL. METHODS: We performed a global kinome profiling assay of three CTCL cell lines (HH, MJ, and Hut78) with three HDACis (romidepsin, vorinostat, and belinostat) using the PamChip® microarray. The three cell lines were co-treated with romidepsin and an inhibitor against the tyrosine kinase pathway. RESULTS: Principal component analysis revealed that kinome expression patterns were mainly related to the cell origin and were not affected by the drugs. Few kinases were commonly activated by the HDACis. Most identified kinases were Src-associated molecules, such as annexin A2, embryonal Fyn-associated substrate, and progesterone receptor. Phosphorylated Src was not observed in any untreated cell lines, whereas Src phosphorylation was detected in two of the three cell lines after HDACi treatment. Ponatinib, a Src inhibitor, significantly enhanced romidepsin-induced apoptosis not only in HH, MJ, and Hut78 cells, but also in Myla and SeAx CTCL cell lines. CONCLUSION: The Src pathway is a possible target for combination therapy involving HDACis for CTCL.