Efficacy of salvage therapies for advanced acral melanoma after anti-PD-1 monotherapy failure: a multicenter retrospective study of 108 Japanese patients.

Background: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF. Patients and methods: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS (p = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups. Conclusion: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma.

Efficacy comparison between anti-PD-1 antibody monotherapy and anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy for advanced acral melanoma: A retrospective, multicenter study of 254 Japanese patients.

BACKGROUND: Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM. METHODS: This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups. RESULTS: In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P < 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002). CONCLUSIONS: The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM.

Real-world efficacy of anti-PD-1 antibody or combined anti-PD-1 plus anti-CTLA-4 antibodies, with or without radiotherapy, in advanced mucosal melanoma patients: A retrospective, multicenter study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have a lower efficacy in mucosal melanoma (MUM) than in cutaneous melanoma. The use of combination treatments with radiotherapy (RT) to improve the efficacy in MUM, however, requires further investigation. METHODS: We retrospectively evaluated 225 advanced MUM patients treated with anti-PD-1 monotherapy (PD1; 115) or anti-PD-1 + anti-CTLA-4 combination therapy (PD1+CTLA4; 42) with or without RT (56 and 12, respectively). Treatment efficacy was estimated by determining the objective response rate (ORR) and survival rate with the Kaplan-Meier analysis. RESULTS: The baseline characteristics between the two groups in each ICI cohort were similar, except for Eastern Cooperative Oncology Group performance status in the PD1 cohort. No significant differences in ORR, progression-free survival (PFS), and overall survival (OS) were observed between the PD1 alone and PD1+RT groups in the PD1 cohort (ORR 26% versus 27%, P > 0.99; median PFS 6.2 versus 6.8 months, P = 0.63; median OS 19.2 versus 23.1 months, P = 0.70) or between the PD1+CTLA alone and PD1+CTLA4+RT groups in the PD1+CTLA4 cohort (ORR 28% vs 25%, P = 0.62; median PFS 5.8 versus 3.5 months, P = 0.21; median OS 31.7 versus 19.8 months, P = 0.79). Cox multivariate analysis indicated that RT in addition to PD1 or PD1+CTLA4 did not have a positive impact on the PFS or OS. CONCLUSIONS: A prolonged survival benefit with RT in combination with ICIs was not identified for advanced MUM patients, although RT may improve local control of the tumour and relieve local symptoms.

Systemic treatment of patients with advanced cutaneous squamous cell carcinoma: response rates and outcomes of the regimes used.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer. Few patients with cSCC experience metastases, but the prognosis of advanced cSCC (acSCC) is dismal. Evidence regarding systemic therapy for acSCC is limited. Therefore, we aimed to determine the most effective systemic treatment for acSCC. PATIENTS AND METHODS: This retrospective study involved 16 Japanese institutions. We documented patient and tumour characteristics and disease course of patients with acSCC who received systemic therapy between 1st January 2006 and 31st December 2015. We compared the overall survival (OS) and progression-free survival (PFS) for (1) platinum versus non-platinum groups, (2) radiation plus chemotherapy first-line therapy (RCT) versus non-RCT groups and (3) platinum-based RCT versus non-platinum-based RCT groups. RESULTS: Although the use of platinum-based systemic therapy was not associated with statistically significant improvements in PFS and OS, there were significant differences between the RCT and non-RCT groups (PFS: p < 0.001, OS: p = 0.003). In the subgroup analysis, RCT significantly prolonged PFS and OS in the nodal SCC (nSCC) group. For the RCT and non-RCT groups, the median OS was 110 and 14 months, respectively, and the 5-year OS rate was 54% and 21%, respectively. CONCLUSION: RCT could improve OS in patients with nSCC. However, further multicenter prospective studies are needed to establish evidence for superiority of RCT.

Involvement of Periostin in Skin Function and the Pathogenesis of Skin Diseases.

Skin is a large organ that is susceptible to damage by external forces, chronic inflammation, and autoimmune reactions. In general, tissue damage causes alterations in both the configuration and type of cells in lesional skin. This phenomenon, called tissue remodeling, is a universal biological response elicited by programmed cell death, inflammation, immune disorders, and tumorigenic, tumor proliferative, and cytoreductive activity. During this process, changes in the components that comprise the extracellular matrix are required to provide an environment that facilitates tissue remodeling. Among these extracellular matrix components, periostin (a glycoprotein secreted predominantly by dermal fibroblasts) has attracted much attention. In normal skin, periostin localizes mainly in the papillary dermis and basement membrane of the epidermis. However, it is expressed at higher levels in the dermis of lesional skin of those with atopic dermatitis, scars, systemic/limited scleroderma, melanoma, and cutaneous T cell lymphoma; expression is also increased by damage caused by allergic/autoimmune responses. Furthermore, periostin induces processes that result in development of dermal fibrosis; it also activates or protracts the immune response. The aim of this review is to summarize recent knowledge about the role of periostin in the pathogenesis of dermatoses.

Clinical and histopathological significance of PD-1 expression in cutaneous lesions of adult T-cell leukemia-lymphoma.

BACKGROUND: Adult T-cell leukemia-lymphoma (ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection and is known to exhibit cutaneous involvement in 50% or more patients. Few studies have evaluated the clinicopathological significance of programmed death-1 (PD-1) expression in the cutaneous lesions of ATL. METHODS: Skin biopsy specimens from 29 ATL patients with cutaneous lesions were evaluated regarding the clinicopathological feature, survival outcome, and PD-1 expression level on infilitrated CD3+CD4 + CD25+ cells. The optimal cut-off point of PD-1 expression for clinicopathological feature and outcome was determined as the value of the maximum Youden index by receiver operating characteristic (ROC) analysis. RESULTS: PD-1 was expressed broadly from zero to 90% on the skin biopsy specimens of the 29 patints, with the median value of 50%. The PD-1-expression level was significantly higher in the poorer-prognosis eruption group (nodulotumoral, erythrodermic and purpuric types) (P = 0.003), in the poorer histopathological infiltration patterns (diffuse and nodular) (P = 0.007), and in the poorer infiltrating cell-size group (large-sized cells) (P = 0.017) than in the corresponding group. ROC curve analyses showed that the optimal cut-off value for PD-1-expression level to predict the poorer-prognosis eruption, the poorer- histopathological infiltration pattern, the poorer infiltration cell size, and the poorer outcome (death) was 60%, 50%, 50%, and 80%, respectively. Patients with high PD-1 expression had a shorter median survival time than those with low PD-1 expression (18.2 months vs. 26.0 months), but the difference was not statistically significant. CONCLUSIONS: ATL patients with cutaneous lesions in which PD-1 were highly expressed have more advanced dermatological and histopathological patterns and possibly worse survival than those with low PD-1 expression on cutaneous lesions. Further large-scale studies are warranted to verify these findings.

Diffuse alveolar hemorrhage with pseudoprogression during nivolumab therapy in a patient with malignant melanoma.

Nivolumab, an anti-PD-1 antibody, has been shown to be effective in many cancers, such as malignant melanoma and lung cancer; however, nivolumab therapy can result in pseudoprogression. Diffuse alveolar hemorrhage (DAH) is persistent or recurrent pulmonary hemorrhage as a result of drugs, autoimmune diseases, or infections. DAH with pseudoprogression during nivolumab administration has rarely been reported. Herein, we describe our experience with one such case. A 41-year-old woman exhibited bloody sputum and ground glass opacities in the lungs along with tumor growth during nivolumab therapy for multiple lung metastases of malignant melanoma. We diagnosed DAH with pseudoprogression as a result of nivolumab and administered steroid therapy. The DAH subsequently improved and the tumor shrank. This case illustrates that nivolumab can cause DAH with pseudoprogression, which can be controlled by steroid therapy. Thus, if bloody sputum and ground glass opacities in the lungs are observed with tumor growth during nivolumab administration, steroid therapy should be considered to control DAH with pseudoprogression.

Coexistence of keloids and pilomatricoma in a patient with Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS) is an autosomaldominant hereditary disease, which contains many skeletal and organ anomalies as well as mental retardation. Although high incidence of keloids in RTS is known, it is difficult to find a detailed report on the clinical features of keloids. In the following letter, we report an RTS patient fulfilling diagnostic criteria whosuffered from both keloids and pilomatricoma. We also performed a literature search, which identified the possible involvement of the Wnt/ß-catenin signaling pathway in the pathogenesis of these two skin lesions.

Calcification in dermal fibroblasts from a patient with GGCX syndrome accompanied by upregulation of osteogenic molecules.

Gamma-glutamyl carboxylase (GGCX) gene mutation causes GGCX syndrome (OMIM: 137167), which is characterized by pseudoxanthoma elasticum (PXE)-like symptoms and coagulation impairment. Here, we present a 55-year-old male with a novel homozygous deletion mutation, c.2,221delT, p.S741LfsX100, in the GGCX gene. Histopathological examination revealed calcium deposits in elastic fibers and vessel walls, and collagen accumulation in the mid-dermis. Studies of dermal fibroblasts from the patient (GGCX dermal fibroblasts) demonstrated that the mutated GGCX protein was larger, but its expression level and intracellular distribution were indistinguishable from those of the wild-type GGCX protein. Immunostaining and an enzyme-linked immunosorbent assay showed an increase in undercarboxylated matrix gamma-carboxyglutamic acid protein (ucMGP), a representative substrate of GGCX and a potent calcification inhibitor, indicating that mutated GGCX was enzymatically inactive. Under osteogenic conditions, calcium deposition was exclusively observed in GGCX dermal fibroblasts. Furthermore, GGCX dermal fibroblast cultures contained 23- and 7.7-fold more alkaline phosphatase (ALP)-positive cells than normal dermal fibroblast cultures (n = 3), without and with osteogenic induction, respectively. Expression and activity of ALP were higher in GGCX dermal fibroblasts than in normal dermal fibroblasts upon osteogenic induction. mRNA levels of other osteogenic markers were also higher in GGCX dermal fibroblasts than in normal dermal fibroblasts, which including bone morphogenetic protein 6, runt-related transcription factor 2, and periostin (POSTN) without osteogenic induction; and osterix, collagen type I alpha 2, and POSTN with osteogenic induction. Together, these data indicate that GGCX dermal fibroblasts trans-differentiate into the osteogenic lineage. This study proposes another mechanism underlying aberrant calcification in patients with GGCX syndrome.

Yusho patients show increased serum IL-17, IL-23, IL-1ß, and TNFα levels more than 40 years after accidental polychlorinated biphenyl poisoning.

The Yusho poisoning incident, caused by rice oil contaminated with polychlorinated biphenyls (PCBs), polychlorinated quarterphenyls (PCQs), and polychlorinated dibenzofurans (PCDFs) generated by heat-denatured PCBs, occurred in 1968 in western Japan. Although severe symptoms are rarely observed today, the levels of PCBs and PCDFs in the sera of Yusho patients remain high. The aryl hydrocarbon receptor (AhR), which also acts as a dioxin receptor, is a transcriptional regulator that mediates dioxin toxicity. Recent studies show that dioxin mediates its immune toxic effects via AhR and that AhR activation induces dysregulation of interleukin (IL)-17- producing T (TH17) cells. This study therefore hypothesized that Yusho patients would show dysregulated TH17 cell-mediated immune responses. To validate the hypothesis, levels of IL-17 and IL-22, each secreted by TH17 cells, along with IL-1ß and IL-23 were measured in serum samples from 40 Yusho patients and 40 age-matched controls. Levels of tumor necrosis factor (TNF)-α potentially secreted by TH17 cell-stimulated neutrophils and macrophages were also measured. The results indicated that serum IL-17 levels, as well as those of IL-1ß, IL-23, and TNFα, were significantly higher in Yusho patients than in controls. In contrast, serum IL-22 levels were significantly lower in the Yusho patients. These results suggest that Yusho patients have dysregulated TH17 cell-mediated immune responses that may be linked to inflammation.

Increased serum levels of soluble CD163 in patients with scleroderma.

CD163 is a 130-kDa, type I transmembrane protein belonging to group B of the cysteine-rich scavenger receptor family. Expression of CD163 is constitutive and/or induced by some stimuli on circulating monocytes and most tissue macrophages. An approximately 130-kDa soluble form of human CD163 is released from the cell surface by proteolysis after oxidative stress or inflammatory stimuli. Thus, an elevated level of circulating soluble CD163 (sCD163) has been reported in diabetes mellitus, which is one of the oxidative conditions. We have already acknowledged that scleroderma (SSc) is one of the oxidative conditions. Therefore, we conducted the measurement of serum sCD163 in SSc patients. After receiving the informed consents, 56 SSc patients were examined; 20 dermatomyositis patients were used as disease controls and 40 persons were used as healthy controls. Blood samples were collected, and the concentration of serum sCD163 was measured by ELISA (human CD163, R&D Systems). Other parameters in the blood of SSc patients were also examined. Statistical analyses were performed using Mann-Whitney U test, and the relationship between parameters was statistically examined by Spearman's rank test. Serum sCD163 levels were elevated in SSc patients compared with normal controls (p < 0.01), with similar levels between limited SSc and diffuse SSc patients. SSc patients with pulmonary fibrosis had increased serum levels of sCD163 than those without pulmonary fibrosis (p < 0.05). SSc patients with elevated sCD163 levels had increased serum levels of IgG than those with normal sCD163 levels (p < 0.05). Serum sCD163 levels correlated positively with pulsatility index in SSc patients (p = 0.0009, r = 0.534). These results suggest that oxidative stress may play an important role in immunological abnormalities, renal circulation, and pulmonary fibrosis of SSc.

Decreased levels of autoantibody against histone deacetylase 3 in patients with systemic sclerosis.

Systemic sclerosis (SSc) is characterized by immunological abnormalities, especially the production of autoantibodies against various cellular components. Treatment with histone deacetylase (HDAC) inhibitors prevents collagen accumulation in a mouse SSc model. Additionally, autoantibody against HDAC-3 is produced in colon cancer patients, while HDAC-1 and HDAC-2 do not elicit autoantibody response. To determine the presence and levels of antibodies (Abs) against HDAC-3 in SSc. Anti-HDAC-3 Ab was examined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting using human recombinant HDAC-3. The HDAC-3 activity was evaluated by ELISA using the fluorimetric HDAC lysyl substrate that comprises an acetylated lysine side chain. Contrary to our hypothesis that autoimmune background in SSc induced the production of autoantibody against HDACs, IgG and IgM anti-HDAC-3 Ab levels in SSc patients were significantly lower than in normal controls (p < 0.0005 and 0.001, respectively). Furthermore, decreased levels of IgG anti-HDAC-3 Ab were specific to SSc, since IgG anti-HDAC-3 Ab levels in patients with dermatomyositis (DM) and those with systemic lupus erythematosus (SLE) were similar and slightly increased relative to normal controls, respectively. Immunoblotting analysis showed that anti-HDAC-3 Ab was detected in normal controls and patients with DM or SLE, while it was absent in SSc patients. The HDAC-3 activity was significantly inhibited by IgG isolated from sera of normal controls, whereas such inhibitory effect was not observed by IgG isolated from sera of SSc patients. These results indicate the lack of anti-HDAC-3 autoantibody in SSc patients, which is produced in healthy individuals as well as DM and SLE patients, suggesting that this autoantibody might function as protective Ab.