Hiroaki Iwata

TM5614, a plasminogen activator inhibitor‐1 (PAI‐1) inhibitor, has demonstrated potential in overcoming nivolumab resistance in patients with unresectable, anti‐PD‐1 antibody‐refractory malignant melanoma. Previous Phase II trials have shown promising response rates, warranting further investigation through a randomised, placebo‐controlled Phase III trial. This Phase III, randomised, double‐blind, placebo‐controlled, investigator‐initiated clinical trial aims to evaluate the efficacy and safety of TM5614 in combination with nivolumab for treating patients with unresectable, anti‐PD‐1 antibody‐refractory malignant melanoma. The study will enrol 124 participants across 18 medical institutions in Japan. Patients will receive either TM5614 plus nivolumab or placebo plus nivolumab for 48 weeks. The primary endpoint is overall survival (OS), while secondary endpoints include objective response rate (ORR), progression‐free survival (PFS), disease control rate (DCR), and the incidence of treatment‐related adverse events. This study is designed to compare OS between the TM5614 plus nivolumab group and the placebo plus nivolumab group. Statistical analyses will be conducted using the Kaplan–Meier method and Cox proportional hazards models. This Phase III trial will provide critical insights into the efficacy of TM5614 in combination with nivolumab as a novel treatment strategy for unresectable, anti‐PD‐1 antibody‐refractory malignant melanoma. The results may offer new therapeutic options to improve patient outcomes and overcome resistance to immune checkpoint inhibitors. Trial Registration: jRCT2021240049 ( https://jrct.niph.go.jp/en‐latest‐detail/jRCT2021240049 ). Protocol version: Ver.1.2 (3rd February, 2025)

A 49‐year‐old man with pemphigus vegetans (PVeg) relapsed several times due to cessation of therapy. At the age of 66, vegetative plaques developed at the left oral commissure following mechanical plucking of approximately 500 beard hairs. Treatment with prednisolone (20 mg/day) was continued but yielded no clinical improvement. Subsequently, rituximab (1000 mg twice, 2 weeks apart) led to a rapid decline of anti‐desmoglein 3 (Dsg3) autoantibody and clinical improvement. The lesion resolved after 18 months, and prednisolone was tapered without recurrence. Based on the site‐specific recurrence and chronicity, we hypothesized that tissue‐resident memory T (T _RM ) cells and high endothelial venules (HEV)‐like vessels contributed to disease persistence. Immunohistochemical analysis revealed a substantial presence of IL‐17A‐producing CD69 + ⁺ CD103 + ⁺ T _RM cells in the dermis. In addition, PNAd+ ⁺ HEV‐like vessels were increased, accompanied by infiltrates of B cells and plasma cells. Notably, Dsg3‐specific B cells were also detected, indicating that rituximab‐mediated B cell depletion likely contributed to lesion resolution in this case.

A 50‐year‐old man presented with a subcutaneous mass on the posterior neck. A skin biopsy suggested lipoma, leading to observation. Over the next 5 years, the tumor gradually enlarged. Clinical evaluation found the tumor to be a soft, mobile mass of 10 × 7 cm. Magnetic resonance imaging showed the lesion to be cystic, with hyperintense mural nodules on T2‐weighted sequences, and with scattered, hyperintense foci indicative of fatty components on T1‐weighted imaging. Fat‐suppressed contrast‐enhanced T1‐weighted imaging revealed moderately enhanced mural nodules. Surgical resection revealed a well‐circumscribed cystic mass containing fluid, surrounded by a fibrous capsule. We suspected spindle cell lipoma associated with fluid and performed a marginal resection. Gross examination showed a heterogeneous mixture of reddish‐brown and yellowish zones interspersed with fissures. Histological analysis revealed a leaf‐like or reticular pattern, with slender, spindle‐shaped cells and ropey collagens within a mucinous matrix, along with mature adipocytes. There were many irregular, branching, cleft‐like vascular spaces lined by flattened cells. Immunohistochemical staining revealed tumor cells positive for CD34 and negative for retinoblastoma protein. Luminal endothelial‐like cells showed positivity for D2‐40, CD31, and erythroblastosis transformation‐specific regulated gene 1. Based on these findings, the diagnosis of pseudoangiomatous spindle‐cell lipoma was confirmed, with the luminal endothelial‐like cells exhibiting characteristics of lymphatic endothelium.