Immunotherapy with 4-1BBL-Expressing iPS Cell-Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma.

We have established an immune cell therapy with immortalized induced pluripotent stem-cell-derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8+ T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological "cold tumor" to "hot tumor".

Drug eruption caused by enzalutamide: A case and literature review of androgen receptor inhibitor-related drug eruptions.

Enzalutamide is an androgen receptor inhibitor. We report a new cutaneous eruption to this drug and review cases of drug eruptions caused by androgen receptor inhibitors.

Role of endothelin-1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis (NSF) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)-containing contrast agents used for magnetic resonance imaging trigger the development of NSF. However, the causative role of Gd and the mechanism of Gd-induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin-1 (ET-1)/ET receptor (ETR) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET-1/ETR signalling in Gd-induced fibrosis and calcification in NSF. First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue-derived mesenchymal stem cells (hMSC) in vitro. Next, we examined the expression of ET-1 and ETR-A in hMSC using proliferation or calcification assay. ET-1 and ETR-A expression in hMSC treated with Gd were elevated. ET-1/ETR signalling inhibitor, bosentan, inhibited Gd-induced proliferation and calcification of hMSC. In addition, bosentan inhibited Gd-induced phosphorylation of ERK and Akt in hMSC. Plasma ET-1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR-A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET-1/ETR signalling. Our results contribute to understand the pathogenesis of NSF.

Pyoderma gangrenosum-like lesions in the setting of IgA cutaneous vasculitis: Favourable response to adalimumab.

Pyoderma gangrenosum is a rare inflammatory skin disease classified within the group of neutrophilic dermatoses, and clinically characterised by painful, rapidly evolving cutaneous ulcers with undermined, irregular, erythematous-violaceous edges. Underlying diseases include rheumatoid arthritis, inflammatory bowel disease, haematopoietic malignancy, and aortitis syndrome. However, there was a limited number of cases of concomitant pyoderma gangrenosum and IgA vasculitis. Herein, we report a case presenting persistent large skin wounds as a diagnosis of pyoderma gangrenosum in the setting of IgA cutaneous vasculitis, which was successfully treated by a TNF-α inhibitor. A 67-year-old obese female presented palpable purpura on her lower extremities. A skin biopsy taken from the purpuric eruption showed leukocytoclastic vasculitis with IgA and C3 depositions in the vessel walls of the upper dermis, leading to the diagnosis of IgA vasculitis. Small skin ulcers rapidly expanded in several days, eventually developing perforating skin ulcers with irregular erythematous and violaceous edges on both lower extremities following the tapered oral prednisolone at a dose of 25 mg per day. Based on the clinical manifestation and histological analysis, we diagnosed her skin wound as pyoderma gangrenosum. After the adalimumab administration, the spreading ulceration was dampened, leading to the acceleration of wound epithelialisation.

A Case of Pan-TRK Positive Dermatofibrosarcoma Protuberans Located on the Nose.

Dermatofibrosarcoma protuberans (DFSP) is a rare and infiltrative soft tissue tumor. Our report details a distinctive case of DFSP with pan-TRK positivity in the right nasal dorsum of a 46-year-old female. Histological analysis identified NTRK fusion gene involvement in this patient, detectable through pan-TRK immunostaining. The case underscores the significance of comprehensive management for pan-TRK-positive DFSP in challenging facial locations, indicating the potential efficacy of TRK inhibitors.

Mycosis Fungoides Presenting With Multiple Tumors on the Face.

An 84-year-old female experienced progressive erythema on her limbs and chest over the past year. Initially managed with topical steroids, the erythema eventually spread throughout her body, forming erosions. A biopsy confirmed the diagnosis of mycosis fungoides (MF) (Stage IIB, T2bN0M0B0). Treatment with oral bexarotene (300 mg/day) and narrow-band UVB therapy showed limited improvement. Electron beam therapy (30 Gy in 10 fractions) applied to facial and plantar tumors resulted in a reduction of the tumors. This case highlights the treatment of tumors of MF on the face showing the effectiveness of combining electron beam therapy with bexarotene.

Ixekizumab-induced urticarial drug eruption.

Biological agents targeting inflammatory skin diseases have dramatically overcome many of the limitations of older oral therapeutic options. Among the various biological agents, ixekizumab is a humanised monoclonal antibody that blocks the biological activity of IL-17A, which exhibited high efficacy against psoriasis. Although there are a limited number of cutaneous adverse reactions, biologic-induced type I allergic reactions are rare. Herein, we report a case of ixekizumab-induced urticaria.

The Efficacy of Platinum Chemotherapy in a Japanese Malignant Melanoma Patient With a BRCA2 Mutation Identified by Gene Panel Testing.

A BRCA2 mutation increases the chance of developing cancer and has been linked to several diseases, including hereditary breast, ovarian, pancreatic, and prostate cancers. We present a case of advanced malignant melanoma treated with platinum-containing chemotherapy and demonstrate a momentarily favorable clinical outcome as determined by a Next Generation Sequencer (NGS) gene panel testing. A 54-year-old female with BRAF wild-type of anal primary melanoma received adjuvant immunotherapy with nivolumab following surgical resection. Novel distant lung metastasis was identified four months after the adjuvant therapy. Multi-gene panel testing figured out another potential treatment strategy using a sample from a distant metastatic tumor and identified a BRCA2 mutation in the tumor. Based on the sensitivity to platinum agents in BRCA2 mutation-positive tumors, DAC-Tam therapy (Dacarbazine, Nimustine, Cisplatin, and Tamoxifen) was administrated and showed tumor size reduction. After five rounds of DAC-Tam treatment, the metastatic lesion decreased from 17 mm to 5 mm. The parent was treated with platinum and Dacarbazine alone because of deteriorated renal function and grade 3 myelosuppression. In addition, the tumor showed resistance to the platinum plus Dacarbazine chemotherapy. Her chemotherapy-induced renal failure and bone marrow suppression did not improve well. Additionally, she felt significant weakness due to poor dietary intake and did not want to receive additional chemotherapy. To relieve her symptoms, she and her family desired the best supporting care and moved her to another hospital. The patient died 12 months after submitting the gene panel.

Identification of Multiple Bowen's Disease Skin Lesions by Careful Physical Examination in a Patient With Fanconi Anemia.

Because Fanconi anemia is a hereditary bone marrow failure disease caused by DNA repair dysfunction, malignant skin tumors have been recognized in patients with Fanconi anemia. Herein, we report a 32-year-old male with Fanconi anemia presenting multiple Bowen's disease skin lesions. He first recognized skin eruption in his scrotum, which was diagnosed with Bowen's disease by dermoscopy examination and histological analysis. Due to the elevated risk of skin cancers in Fanconi anemia, we conducted additional meticulous examinations using dermoscopy on the entire body's skin, revealing another skin tumor on his back. A skin biopsy confirmed the diagnosis of another site of Bowen's disease. Therefore, additional thorough examinations using dermoscopy might aid in identifying multiple skin tumors in high-risk cases of skin malignancies, such as Fanconi anemia.

Congenital Langerhans Cell Histiocytosis With the Skin and Lung Involvement: A Case and Literature Review.

Langerhans cell histiocytosis (LCH) is a clonal proliferative disease of immature Langerhans cells that expand in various organs, leading to organ and tissue dysfunction. Although LCH is most commonly seen in children under the age of three, a small number of cases of congenital LCH have been described. With a review of the literature on congenital LCH with lung and skin lesions, we present a case of congenital LCH with involvement of skin and lung, which was effectively treated with chemotherapy without recurrence for 3 years during the observational period. In addition, we summarized previously published case studies of congenital LCH with skin and lung involvement.

Cardiac Arrest Due to Kounis Syndrome Following Cephazolin Administration During Surgery Under Local Anesthesia.

The Kounis syndrome is described as the co-occurrence of allergic responses brought on by mast cell activation and acute coronary syndromes. We present a case of Kounis syndrome leading to cardiac arrest following the cephazolin sodium administration during the surgical resection of basal cell carcinoma. An 87-year-old woman was diagnosed with basal cell cancer. She received surgical excision of the tumor while anesthetized with lidocaine hydrochloride and 1% epinephrine. This patient began to itch around five minutes after cefazolin (CEZ) administration and eventually experienced cardiac arrest following diffuse rashes that spread throughout her body and edema in her eyelids. In line with the response, the electrocardiogram (ECG) also showed an elevated ST segment in V1-6, leading to possibly the diagnosis of Kounis syndrome. We also review the literature on Kounis syndrome following CEZ administration.

Survival rates of systemic interventions for psoriasis in the Western Japan Psoriasis Registry: A multicenter retrospective study.

Psoriasis affects approximately 0.3% of the Japanese population. Recently, various effective systemic drugs have become available, and the continuation of a given treatment has become critical because of the chronic nature of psoriasis. Factors affecting drug survival (the time until treatment discontinuation) in psoriasis treatment include efficacy, safety, ease of use, and patient preference. In the present study, the authors retrospectively surveyed a multifacility patient registry to determine the real-world evidence of the survival rate of systemic interventions for psoriasis treatment. Patients with psoriasis who visited 20 facilities in the Western Japan area between January 2019 and May 2020 and gave written consent were registered as study participants, and their medical history of systemic interventions for psoriasis (starting from 2010) was retrospectively collected and analyzed. The drugs investigated were adalimumab, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, cyclosporine, and apremilast. When drugs were discontinued, the reasons were also recorded. A total of 1003 patients with psoriasis including 268 with psoriatic arthritis (PsA) were enrolled. In biologics, more recently released drugs such as interleukin 17 inhibitors showed a numerically higher survival rate in the overall (post-2010) analysis. However, in the subset of patients who began treatment after 2017, the difference in the survival rate among the drugs was smaller. The reasons for discontinuing drugs varied, but a loss of efficacy against dermatological or joint symptoms were relatively frequently seen with some biologics and cyclosporine. The stratification of drug survival rates based on patient characteristics such as bio-naive or experienced, normal weight or obese, and with or without PsA, revealed that bio-experienced, obese, and PsA groups had poorer survival rates for most drugs. No notable safety issues were identified in this study. Overall, the present study revealed that the biologics show differences in their tendency to develop a loss of efficacy, and the factors that negatively impact the survival rate of biologics include the previous use of biologics, obesity, and PsA.

A rapid and efficient newly established method to detect COL1A1-PDGFB gene fusion in dermatofibrosarcoma protuberans.

The detection of fusion transcripts of the collagen type 1α1 (COL1A1) and platelet-derived growth factor-BB (PDGFB) genes by genetic analysis has recognized as a reliable and valuable molecular tool for the diagnosis of dermatofibrosarcoma protuberans (DFSP). To detect the COL1A1-PDGFB fusion, almost previous reports performed reverse transcription polymerase chain reaction (RT-PCR) using multiplex forward primers from COL1A1. However, it has possible technical difficulties with respect to the handling of multiple primers and reagents in the procedure. The objective of this study is to establish a rapid, easy, and efficient one-step method of PCR using only a single primer pair to detect the fusion transcripts of the COL1A1 and PDGFB in DFSP. To validate new method, we compared the results of RT-PCR in five patients of DFSP between the previous method using multiplex primers and our established one-step RT-PCR using a single primer pair. In all cases of DFSP, the COL1A1-PDGFB fusion was detected by both previous method and newly established one-step PCR. Importantly, we detected a novel COL1A1 breakpoint in exon 5. The newly developed method is valuable to rapidly identify COL1A1-PDGFB fusion transcripts in DFSP.

Vedolizumab Attenuates Immune-Checkpoint-Therapy-Induced Infliximab-Refractory Colitis.

Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, have drastically changed treatments of advanced melanoma. However, ICI-related enterocolitis is often the most common adverse event, and represents the main reason for ICI discontinuation and mortalities. Here, we report the case of a metastatic melanoma treated with vedolizumab for ICI-induced colitis. A 67-year-old man treated with ipilimumab and nivolumab developed ICI-induced colitis and grade 3 diarrhea refractory to methylprednisolone and infliximab. After his third dose of vedolizumab, oral prednisolone ceased, and the colitis had completely resolved with no recurrence. This case report supports vedolizumab use in treating severe colitis which failed to resolve with first- and second-line immunosuppressive therapy.

STING expression is an independent prognostic factor in patients with mycosis fungoides.

Mycosis fungoides is recognized as an indolent cutaneous malignant T-cell lymphoma. In contrast, there are few therapeutic options for advanced forms of mycosis fungoides. Since immunotherapy is desirable as an alternative therapeutic option, identifying candidate molecules is an important goal for clinicians. Although tumor-derived negative immunomodulatory molecules, such as PD-1/PD-L1, have been identified in various malignancies, the useful positive immunological drivers of mycosis fungoides are largely unknown. We found that the stimulator of interferon (IFN) genes (STING) was highly upregulated in early-stage mycosis fungoides. Immunohistochemical examination revealed different STING staining patterns in patients with mycosis fungoides. Although there were no significant differences in clinical factors' characteristics, STING expression was associated with the survival of patients with mycosis fungoides. The survival rate was significantly poor in patients with low STING-expressing mycosis fungoides. Univariate and multivariate analyses revealed that low STING expression was associated with an increased hazard ratio. Our results indicate that STING expression independently influences the prognosis of mycosis fungoides.