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In Japanese melanoma patients, the response rate of N/I was lower (35.1%) and the rate of adverse events was similar (60.4%) compared to those reported in previous clinical trials. No survival difference was observed with the use of N/I between clinical types. Patients who achieved a good response had better outcomes. Elevated LDH level and ≥3 metastatic sites were poor prognostic factors.

Supplemental Table S1. Patients attributes.

Supplemental figures Supplemental Fig. 1. TRIM29 is highly expressed in stratified epithelial tissues. Supplemental Fig. 2. The expression levels of TRIM29 protein are as high in benign skin tumors as they are in normal epidermis. Supplemental Fig. 3. The expression level of TRIM29 is low in keratoacanthoma-like SCC, but not in keratoacanthoma. Supplemental Fig. 4. Reduced TRIM29 RNA expression is associated with DNA methylation in cutaneous SCC. Supplemental Fig. 5. TRIM29 expression is silenced in cutaneous SCC cells. Supplemental Fig. 6. The cell proliferation of TRIM29-knockdown cancer cells does not differ significantly from that of the control cells. Supplemental Fig. 7. siRNA-mediated TRIM29-knockdown does not affect cell proliferation. Supplemental Fig. 8. TRIM29 regulates migration of SCC cells and immortalized epidermal keratinocytes. Supplemental Fig. 9. TRIM29 regulates migration of SCC cells and immortalized epidermal keratinocytes. Supplemental Fig. 10. TRIM29 knockdown increases cell invasion in SCC cells and immortalized epidermal keratinocytes. Supplemental Fig. 11. TRIM29 knockdown increases cell invasion in oral SCC cells. Supplemental Fig. 12. TRIM29 knockdown enhances the cancer cell metastasis. Supplemental Fig. 13. The top 20 list of proteins bound with FLAG-TRIM29 in mass spectrometry analysis. Supplemental Fig. 14. TRIM29 co-localizes with FAM83H. Supplemental Fig. 15. TRIM29 co-localizes with FAM83H. Supplemental Fig. 16. The zinc finger, B-box, coiled-coil, and C-terminal domains of TRIM29 are necessary for the formation of the TRIM29-keratin-FAM83H complex. Supplemental Fig. 17. Schema of the keratin distribution patterns. Supplemental Fig. 18. Knockdown of TRIM29 alters the distribution of keratins.

TRIM29 (tripartite motif-containing protein 29) is a TRIM family protein that has been implicated in breast, colorectal, and pancreatic cancers. However, its role in stratified squamous epithelial cells and tumors has not been elucidated. Here, we investigate the expression of TRIM29 in cutaneous head and neck squamous cell carcinomas (SCC) and its functions in the tumorigenesis of such cancers. TRIM29 expression was lower in malignant SCC lesions than in adjacent normal epithelial tissue or benign tumors. Lower expression of TRIM29 was associated with higher SCC invasiveness. Primary tumors of cutaneous SCC showed aberrant hypermethylation of TRIM29. Depletion of TRIM29 increased cancer cell migration and invasion; conversely, overexpression of TRIM29 suppressed these. Comprehensive proteomics and immunoprecipitation analyses identified keratins and keratin-interacting protein FAM83H as TRIM29 interactors. Knockdown of TRIM29 led to ectopic keratin localization of keratinocytes. In primary tumors, lower TRIM29 expression correlated with the altered expression of keratins. Our findings reveal an unexpected role for TRIM29 in regulating the distribution of keratins, as well as in the migration and invasion of SCC. They also suggest that the TRIM29–keratin axis could serve as a diagnostic and prognostic marker in stratified epithelial tumors and may provide a target for SCC therapeutics.Significance:These findings identify TRIM29 as a novel diagnostic and prognostic marker in stratified epithelial tissues.

Supplementary Figures and Tables. Supplementary Fig. S1. Knockdown of PCTAIRE1 in PPC1 cells. Supplementary Fig. S2. Knockdown of PCTAIRE1 inhibits growth of Du145, MDA-MB-468 and HeLa cells. Supplementary Fig. S3. PCTAIRE1 regulates centrosome dynamics. Supplementary Fig. S4. PCTAIRE1 phosphorylates p27 at Ser10. Supplementary Fig. S5. PCTAIRE1 knockdown leads to accumulation of p27. Supplementary Fig. S6. Apoptosis induced by PCTAIRE1 knockdown, and subcellular localization of Eg5 in PCTAIRE1 knockdown cancer cells. Supplementary Fig. S7. Characterization of rabbit anti-PCTAIRE1 antibody and correlation of PCTAIRE1 and p27 expression. Supplementary Fig. S8. PCTAIRE1 expression is upregulated in cancers, and high PCTAIRE1 levels correlate with poor patient prognosis. Supplementary Table S1. Specific interaction of PCTAIRE1 with p27.

Patients with acquired idiopathic generalized anhidrosis (AIGA) demonstrate a sudden loss of sweating function without neurological or endocrine abnormalities. The main treatment is steroid pulse therapy. However, the number of courses required for improvement has been unclear. This study aims to clarify the factors associated with AIGA disease severity and with AIGA patients’ responses to steroid pulse therapy. We retrospectively analyzed the clinical information of 28 patients with AIGA at our department from the last 10 years. The median age was 25 years, and the male-to-female ratio was 6:1. The median duration from disease onset to consultation at our department was 9.5 months. Using the Minor test, we found the anhidrosis to be mild in 10 patients, moderate in 2 patients, and severe in 16 patients. Univariate analysis revealed that a history of heat stroke correlated positively and significantly with anhidrotic area score. Steroid pulse therapy was conducted for 18 of the 28 patients (median: two courses) and was effective for every patient who received it. The number of courses also correlated with the anhidrotic area. This retrospective study suggests that patients with a large anhidrotic area need multiple courses of steroid pulse therapy.

Cutaneous angiosarcoma (CAS) is a rare malignant tumor with a poor prognosis for which neither basic research on molecular pathomechanisms nor clinical prospective studies have progressed. A retrospective study of 28 CAS cases reported that chemoradiotherapy with taxanes was superior to conventional surgery. Since that time, chemoradiotherapy with paclitaxel (PTX + RT) has become a standard treatment. In this paper, we retrospectively investigate 21 cases of CAS that had been treated in the Department of Dermatology at Hokkaido University Hospital. Patients initially treated with PTX + RT followed by maintenance taxane chemotherapy showed better prognosis in overall survival (OS) and progression-free survival (PFS) (median OS, 28 months; median PFS, 12 months) compared to others (median OS, 10 months; median PFS, 5 months) (OS and PFS: p 0.05, log-rank test). Our results are consistent with those of a previous study that suggested that PTX + RT followed by maintenance taxane chemotherapy is a better therapeutic option than other interventions, including surgery.

Eccrine porocarcinoma, also known as porocarcinoma (PC) and malignant eccrine poroma, is very rare and is known to arise from the cutaneous intraepidermal ducts of the sweat glands. Its etiology is not well understood; however, some studies suggest that PC tumors originate from benign eccrine poroma. Recently, several gene alterations have been reported in PC that can reveal mechanisms of the oncogenic process. Since the clinical and histopathological findings of PC are variable, PC is difficult to diagnose precisely, especially when the histology resembles that of cutaneous squamous cell carcinoma or poroma. Immunohistochemical staining with carcinoembryonic antigen and epithelial membrane antigen may help to distinguish PC from other tumors. The standard treatment for local PC is wide local excision. The prognosis of patients with metastatic PC is poor, with mortality rates of approximately 60–70%. The efficacy of radiation and chemotherapy for metastatic PC is limited; however, immunotherapy with pembrolizumab, a programmed cell death protein 1 inhibitor, could be a promising treatment. This review focuses on the history, pathogenesis, pathological features, diagnosis, and treatment of eccrine porocarcinoma.

Adjuvant nivolumab therapy has been reported to improve the survival of melanoma patients. Acral lentiginous melanoma (ALM) has been reported to be less likely to respond to immune checkpoint inhibitors (ICIs) than other subtypes. However, the efficacy of adjuvant nivolumab therapy for ALM patients remains uncertain due to the low number of cases. In this single-center retrospective case series, we analyzed the clinical data of patients with resected stage III/IV ALM who were referred to our department between April 1, 2004 and March 31, 2022. The analyzed clinical data included age, sex, TNM stage, treatments, adverse events and disease-free survival (DFS). Enrolled patients were divided into a nivolumab group and a non-ICI group according to the adjuvant therapy they received. In total, 27 patients were included. The nivolumab and non-ICI groups had 5 and 22 patients, respectively. There were no significant differences in patient characteristics between the two groups. There were no serious treatment-related adverse events in the non-ICI group, but one patient in the nivolumab group developed type 1 diabetes. In the survival analysis, the DFS for the nivolumab group did not exceed that of the non-ICI group in postoperative adjuvant therapy for ALM patients. Given that adjuvant nivolumab therapy sometimes results in serious adverse effects, the administration of the therapy may need to be carefully considered, especially for ALM patients.

Although the prognosis of advanced extramammary Paget's disease (EMPD) is poor, there have been no preclinical research models for the development of novel therapeutics. This study aims to establish a preclinical research model for EMPD. We transplanted EMPD tissue into immunodeficient NOD/Scid mice. Histopathological and genetic analyses using a comprehensive cancer panel were performed. For in vivo preclinical treatments, trastuzumab, lapatinib, docetaxel, or eribulin were administered to patient-derived xenograft (PDX) models. Tissue transplanted from the EMPD patient was enlarged in NOD/Scid mice and was transplanted into further generations. Both the transplantation of PDX into nu/nu mice and the reanimation of the cryopreserved xenografted tumors in NOD/Scid mice were successful. We also established an EMPD-PDX-derived primary cell culture. Histopathologically, the xenografted tumors were positive for CK7, which was consistent with the patient's tumors. Genetically, the pathogenic mutation ERBB2 S310F was detected in the patient's tumors (primary intraepidermal lesion, metastatic lymph node) and was observed in the xenografted tumors even after continued passages. The xenografted tumors responded well to trastuzumab and lapatinib therapy. Also, cytotoxic agents (docetaxel and eribulin) were effective against the xenografted tumors. This PDX model (EMPD-PDX-H1) could be a powerful tool for the research and development of EMPD treatments.

BACKGROUND Taxanes are the current first-line treatment for advanced cutaneous angiosarcoma (CAS) for patients who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. However, no effective second-line therapy for such patients has been established. METHODS We designed a single-arm prospective observational study of eribulin mesylate (ERB) administered at a dose of 1·4 mg m-2 on days 1 and 8 in a 21-day cycle. Patients with advanced CAS who were previously treated with a taxane and were scheduled to begin ERB treatment were enrolled. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate (RR), progression-free survival (PFS) and toxicity assessment. RESULTS We enrolled a total of 25 patients. The median OS and PFS were 8·6 months and 3·0 months, respectively. The best overall RR was 20% (five of 25). In total, 16 grade 3/4 severe adverse events (SAEs) occurred; however, all patients recovered. Patients who achieved partial response or stable disease as best response had longer OS than those with progressive disease (median OS not reached and 3·3 months, respectively; P < 0·001). Patients who did not experience SAEs showed longer OS than those who did (median OS 18·8 months and 7·5 months, respectively; P < 0·05). Patients with distant metastasis had shorter median OS than those with locoregional disease, but without statistically significant difference. CONCLUSIONS ERB showed a promising RR and is a potential candidate for second-line treatment for patients with CAS, after treatment with taxanes. However, owing to the occurrence of SAEs in over half of the participants, caution should be exercised regarding ERB use in elderly patients. What is already known about this topic? Taxanes are the current first-line treatment for patients with advanced cutaneous angiosarcoma (CAS) who are considered difficult to treat with doxorubicin owing to advanced age or comorbidity. No effective therapy for taxane-resistant CAS has been established thus far. Eribulin suppresses microtubule polymerization and elicits an antitumour effect similar to that of taxanes. What does this study add? In our single-arm prospective observational study to evaluate the efficacy of eribulin for treating patients with advanced CAS who previously received taxanes, the median overall survival and progression-free survival were 8·6 and 3·0 months, respectively. Response rates at weeks 7, 13 and 25 were 20%, 17% and 14%, respectively. Although 16 grade 3/4 severe adverse events occurred, all patients recovered. Eribulin showed a promising response rate and is a potential candidate for second-line treatment in CAS after taxane treatment. Linked Comment: Smrke and Benson. Br J Dermatol 2020; 183:797-798.

Generalized verrucosis (GV) is a group of immunodeficiency disorders accompanied by widespread human papillomavirus infection. We revisit two cases of GV due to congenital interleukin-7 deficiency successfully treated with systemic retinoids. We also present a review of the literature on the use of systemic retinoids to treat GV. Our review suggests that systemic retinoids are a safe and effective option for managing recalcitrant wart lesions in cases of GV.

Extramammary Paget's disease (EMPD) is a rare adnexal neoplasm commonly seen in the genital areas among the senior population. The prognosis of advanced EMPD is not favorable; thus, the development of potential treatments has long been sought. Cyclin-dependent kinase (CDK) 4/6 inhibitors such as abemaciclib and palbociclib have been proven effective against metastatic breast cancer; however, no studies have addressed CDK4/6 inhibitors as an EMPD treatment. We herein examine the efficacy of CDK4/6 inhibitors against an EMPD patient-derived xenograft (PDX) model. Abemaciclib (50 mg/kg/day) or palbociclib (120 mg/kg/day) was given orally to tumor-bearing NOD/Scid mice over a 3-week period. We also investigated the protein expression levels of CDK4/6 and cyclin D1 through immunohistochemical staining using EMPD clinical samples. Treatment with abemaciclib or palbociclib as a single agent was found to significantly suppress tumor growth in EMPD-PDX. The Ki-67-positive ratio of the treated EMPD-PDX tumors was significantly lower than that of the nontreated tumors. Clinically, the expression levels of CDK4 and cyclin D1 were significantly higher in the EMPD tumor cells than in the normal epidermis. Our results suggest that CDK4/6 inhibitors could be novel and potent therapeutics for the treatment of EMPD.

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The expression of immune checkpoint proteins such as programmed cell death protein 1 (PD-1) and its ligand (PD-L1) has been shown to correlate with patient prognosis in many malignant cancers. The expression of PD-L1 is controlled by c-Myc; however, further upstream regulation of PD-L1 expression is largely unknown. We have previously shown that atypical protein kinase C lambda/iota (aPKCλ) phosphorylates the Forkhead box protein O1 (FoxO1) transcription factor at Ser218 to suppress its DNA-binding ability, thereby regulating c-Myc expression and controlling physiologic and pathologic endothelial proliferation. The presence of phosphorylation of FoxO1 at Ser218 (pSer218 FoxO1) in cutaneous angiosarcoma (CAS) strongly correlates with poor patient prognosis. Here, we reported that patients with PD-L1+ cells in CAS lesions showed significantly worse prognosis compared to those that were PD-L1- . Expression of PD-L1 correlated with that of aPKCλ or the presence of pSer218FoxO1. Moreover, suppression of aPKCλ expression or inhibition of its activity in HUVECs or AS-M, an established human angiosarcoma cell line, resulted in decreased PD-L1 expression. Our results suggest that combined treatment with immune checkpoint inhibitors and aPKCλ inhibitors could be a novel treatment strategy for CAS patients.

Simple Summary The prognosis for advanced Extramammary Paget's disease (EMPD) is almost always poor. HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven to be effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in cases with the ERBB2-mutation or ERBB2-overexpression. Extramammary Paget's disease (EMPD) is an adenocarcinoma that develops mainly in the genital region of older adults. The prognosis for advanced EMPD is almost always poor; thus, novel therapeutic strategies need to be developed. HER2-targeted antibody-drug conjugates (ADCs) such as trastuzumab emtansine and trastuzumab deruxtecan have proven effective against HER2-positive breast cancers; however, no studies have addressed HER2-targeted ADCs as treatments for EMPD. We examine the efficacy of ADCs against an EMPD patient-derived xenograft (PDX) model harboring pathogenic ERBB2 mutations and investigate the expression levels of HER2 using EMPD clinical samples. Trastuzumab emtansine or trastuzumab deruxtecan was administered intravenously to tumor-bearing NOD/Scid mice. Treatment with trastuzumab emtansine or trastuzumab deruxtecan was found to significantly regress EMPD-PDX tumors in only seven days, with no recurrence observed for 10 weeks. EMPD tumors extracted 48 h after drug administration revealed the TUNEL-positive ratio to be significantly higher for the HER2-targeted ADC-treated tumors than for the control tumors. EMPD patients' clinical samples revealed a significant correlation between HER2 positivity and invasion, suggesting that HER2 status is associated with tumor progression. Our results suggest that HER2-targeted ADCs could be novel and promising treatment options for patients with EMPD, especially in ERBB2-mutant or ERBB2-overexpressed cases.