Efficacy and safety of TM5614 in combination with paclitaxel in the treatment of paclitaxel-resistant cutaneous angiosarcoma: Phase II study protocol.

Cutaneous angiosarcoma (CAS) is an endothelial cell-derived, highly aggressive type of vascular tumour. Although chemoradiotherapy with paclitaxel (PTX) is recognized as a first-line therapy for CAS, second-line therapy for CAS remains controversial, and there is no standard therapy for taxane-resistant CAS. Plasminogen activator inhibitor-1 (PAI-1) is associated with poor clinical outcomes, and elevated levels of PAI-1 in both tissue and serum are correlated with poor response to therapy in various cancers, including skin cancers. Since PAI-1 protects endothelial cells from Fas ligand-mediated apoptosis, PAI-1 inhibition might induce apoptosis of endothelial cell-derived tumours such as CAS. This is a single-arm, open-label, multi-institutional, Phase 2 clinical trial to assess the efficacy and safety of PTX in combination with TM5614 (PAI-1 inhibitor) in patients with PTX-resistant CAS. PTX will be administered for 28 weeks, with oral administration of TM5614. The primary endpoint of this study will be the overall response rate (ORR) at 28 weeks after starting treatment (central image evaluation). The secondary endpoint will include the ORR at 28 weeks after starting treatment (investigator evaluation), ORR at 8 weeks and 16 weeks after initiation of treatment (central and investigator evaluation), progression-free survival, overall survival, disease control rate and safety profiles. Assuming the null hypothesis of a response rate of 13.6% and an alternative hypothesis of 45%, a minimum of 15 patients are required to achieve a two-sided, Type I error of 5% and power of 70% based on the exact binomial distribution. Data quality control will be conducted by a combination of centralized (remote) and on-site monitoring. This study will contribute to the development of novel combination therapy for PTX-resistant CAS patients, which remains an unmet clinical need.

The Evaluation of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in Different Therapy Lines for Metastatic Melanoma: A Retrospective Study.

Background: Nivolumab plus ipilimumab (nivo/ipi) combination therapy is highly effective in treating advanced melanoma, but serious immune-related adverse events (irAEs) are prevalent. The overall response rate (ORR) of the BRAF inhibitor plus MEK inhibitor (BRAFi/MEKi) combination therapy for BRAFV600-mutant advanced melanoma surpasses that of immune checkpoint inhibitors (ICIs). However, the OS and PFS of BRAFi/MEKi combination therapy are inferior to those of ICIs. Methods: We retrospectively evaluated 22 melanoma patients treated with nivo/ipi therapy and 13 patients treated with encorafenib plus binimetinib (enco/bini) between November 2018 and July 2023. Results: The ORR of nivo/ipi for metastatic melanoma patients was significantly higher in the first-line cohort [60.0% (95% CI: 31.2-83.3%)] than in the second-line or beyond cohort [8.3% (95% CI: 0-37.5%)], whereas the ORR of enco/bini was comparable between the first-line cohort [75.0% (95% CI: 28.9-96.6%)] and the second-line or beyond cohort [77.8% (95% CI: 44.3-94.7%)]. The median PFS of nivo/ipi significantly improved in the first-line cohort [7.7 months (95% CI: 2.0-11.9)] compared to the second-line or beyond cohort [2.3 months (95% CI: 0.5-6.0)] (p = 0.0109). In addition to efficacy, the incidence of grade 3 or greater AEs was comparable in the first-line and second-line or beyond cohorts. Conclusions: Although our present data are based on a small number of cases, they suggest that nivo/ipi should be administered as the first-line therapy for the treatment of BRAFV600-mutant metastatic melanoma, rather than enco/bini, aligning with findings from previous clinical trials.

Vogt-Koyanagi-Harada disease-like uveitis after drug therapy including BRAF/MEK inhibitors in melanoma patients with HLA-DRB1*04.

The combination of BRAF kinase inhibitors (BRAFis) and MEK kinase inhibitors (MEKis) is one of the most promising chemotherapy regimens in the treatment of BRAF-mutant melanoma. Although BRAFi plus MEKi combined therapy is widely used for the treatment of BRAFV600-mutated melanoma, the incidence of uveitis caused by BRAFi plus MEKi is limited. In this report, we described five cases (two men and three women) of Vogt-Koyanagi-Harada (VKH) disease-like uveitis in melanoma patients who received BRAFi plus MEKi combined therapy. Of note, all the patients had the HLA-DRB1*04 haplotype, which is frequently detected in VKH-like non-infectious uveitis. On the other hand, among BRAFi plus MEKi-treated patients who did not develop VKH disease-like uveitis, only one of five (20%) patients had the HLA-DRB1*04 haplotype. Collectively, BRAFi/MEKi might induce severe VKH disease-like uveitis in melanoma patients with the HLA-DRB1*04 haplotype.

Radiation-induced cutaneous squamous cell carcinoma showing a significant response to pembrolizumab: A case report.

Cutaneous squamous cell carcinoma (cSCC) arising from radiation dermatitis has a higher risk of metastasis than conventional cSCC. Immunosuppression is another risk factor for cSCC, suggesting that mycosis fungoides (MF) could be a risk factor for cSCC. Here we report a case of radiation-induced cSCC with a high level of tumor-mutation burden that developed in a patient with MF who was successfully treated with pembrolizumab. The present case suggests that pembrolizumab might be an optimal therapy for radiation-induced cSCC, even at advanced stages.

CD25 expression could be a prognostic marker of bexarotene monotherapy for cutaneous T-cell lymphomas.

Bexarotene is often administered to phototherapy-resistant early cutaneous T-cell lymphoma (CTCL) patients as one of the first-line therapies in real-world practice. Since bexarotene reduces the expression of CCR4 in CTCL cells and CCL22 to decrease serum CCL22 levels, bexarotene inhibits the migration of CTCL cells, as well as other CCR4+ cells, such as cytotoxic T cells and regulatory T cells, in the lesional skin of CTCL. In this report, the efficacy of bexarotene in 28 cases of CTCL, as well as its correlations with immunohistochemical profiles of tumour-infiltrating leucocytes (TILs), was retrospectively investigated. The overall response rate at 1 and 4 months for the total cohort was 70.8% (95% CI, 50.6%-86.3%) and 47.8% (95% CI, 29.2%-67.0%), respectively. The disease control rate for the total cohort at 4 months was 65.2% (95% CI, 44.8%-81.3%). The mean event-free survival for all patients was 4.1 months (0.3-68.5 months). In addition, the immunoreactive cells were calculated using digital microscopy, suggesting that the ratio of CD25+ cells among TILs was significantly increased in patients who responded to bexarotene (p = 0.0209), whereas there were no significant differences in the ratios of CD8+ cells, granulysin+ cells, and Foxp3+ cells among TILs between responder and non-responder patients. Collectively, the ratio of CD25 expression among TILs might be a predictive biomarker for the efficacy of bexarotene.

Quantitative Analysis of Immune-Reactive Cells among Leukocytes Is Useful for the Diagnosis of Drug Eruptions Caused by Bexarotene.

Bexarotene is a third-generation retinoid X receptor-selective retinoid that has been approved for use in the treatment of cutaneous T-cell lymphomas (CTCLs). Since the objective response rate of bexarotene is relatively high, with no racial differences, bexarotene can be administered to patients with phototherapy-resistant early CTCL as one of the first-line therapies in real-world clinical practice. Although various adverse events caused by bexarotene have been reported, there have been no reports of drug eruptions caused by bexarotene. One of the possible reasons is that it is difficult to distinguish a drug eruption from recurrence of CTCL, histologically. In this report, drug eruptions in 2 patients with CTCL treated with bexarotene diagnosed by quantitative analysis of immunohistochemical staining by digital microscopy are described.

Tubulointerstitial Nephritis in an Advanced Melanoma Patient Treated with Encorafenib plus Binimetinib Combination Therapy.

Encorafenib plus binimetinib combination therapy is one of the first-line therapies for advanced melanoma, and it is known to cause a different profile of adverse events (AEs) than dabrafenib plus trametinib combination therapy. Of such AEs, tubulointerstitial nephritis caused by BRAF plus MEK inhibitors combination therapy is limited. In this report, a case of tubulointerstitial nephritis that developed in a rheumatoid arthritis patient with advanced melanoma treated with encorafenib plus dabrafenib combination therapy is presented.

Matrix Metalloproteinase 28-Bearing Microcystic Adnexal Carcinoma on the Back.

Although microcystic adnexal carcinoma (MAC) recurs and expands locally without metastases to the lymph nodes and other organs, its biological behavior remains unknown. In this report, a case of a giant MAC on the back treated with radical excision and curative radiation therapy and its characteristic dermoscopic findings are presented. In addition, immunohistochemical staining showed the expression of matrix metalloproteinase (MMP) 28 on the tumor cells and MMP12 and periostin in the stroma. The present case suggests the possible biological behaviors of MAC and might provide a possible target for the treatment of MAC in the future.

Dermoscopy findings of hidroacanthoma simplex.

Hidroacanthoma simplex (HAS), also known as intraepidermal eccrine poroma, is a rare eccrine adnexal tumor that tends to be misdiagnosed as other types of benign skin tumor, including clonal seborrheic keratosis. Notably, HAS is sometimes misdiagnosed and treated by cryosurgery as seborrheic keratosis, which could trigger the later development of porocarcinoma. Therefore, accurate diagnosis of HAS is indispensable for dermatologists to avoid the development of malignant tumors by an unsuitable treatment. In this report, we present the characteristic dermoscopy findings of HAS. Indeed, the dermoscopy findings might be related to the melanin-rich necrotic cells in the epidermis, which are quite different from dermoscopy findings of clonal seborrheic keratosis. As a previous report suggested, it is difficult for a dermatologist to differentiate HAS from clonal seborrheic keratosis by the naked eye. Our findings might be supportive for the early diagnosis of HAS.