Finger sweating levels evaluated by video capillaroscopy system are increased in patients with systemic sclerosis compared to pre-clinical stage patients.

New strategies for early diagnosis and careful follow-up of systemic sclerosis are urgently needed. We unconventionally used a video capillaroscopy system to measure the amount of sweating on finger pads, and investigated its clinical significance. Thirty-three Japanese patients who were diagnosed with typical or pre-clinical stage patients of systemic sclerosis were included in this study. Five healthy subjects were also included. Among twenty-one patients with typical systemic sclerosis that fulfilled ACR/EULAR 2013 classification criteria, seven had increased sweating levels. On the other hand, among twelve pre-clinical stage patients that did not fulfill the classification criteria, no patient showed increase in finger sweating. We found that there was statistically significant difference. The ratio of diffuse cutaneous systemic sclerosis was also found to be significantly higher in subjects with increased amounts of sweating than in subjects with normal levels. Furthermore, the positivity of topoisomerase I antibody was statistically higher in patients with increased sweating levels than in those without. These results indicated that measurement of finger sweating levels may be a useful tool for early diagnosis and clarification of pathogenesis in this disease.

Up-regulation of IGF-1, RANTES and VEGF in patients with anti-centromere antibody-positive early/mild systemic sclerosis.

OBJECTIVE: Multiple cytokine network may control the pathogenesis of vasculopathy in patients with systemic sclerosis (SSc). We aimed at comparing angiogenic cytokine profile among SSc patients at various clinical stage. METHODS: We divided nine patients with anti-centromere antibody (ACA) who were suspected of SSc and diagnosed as having SSc into three groups (group1: pre-clinical stage of SSc, group2: mild/early SSc and group3: typical lcSSc) according to the ACR/EULAR2013 classification criteria or ACR1980 preliminary classification, and serum sample were obtained from them. We evaluated the expression levels of 20 cytokines by membrane array. RESULTS: Average values of EGF, ENA-78, bFGF, IGF-I, IL-8, MCP-1, TGF-ß1, thrombopoietin, VEGF and VEGF-D in group2 were increased compared as those of group1 more than twofold. Statistically significant difference was found in serum levels of IGF-1, RANTES and VEGF between group1 and group2. There was also significant difference in the value of VEGF between group1 and group3. There were mild and significant correlations between serum IGF-1 and RANTES levels (r = 0.721, p = .028). CONCLUSION: IGF-1, RANTES and VEGF are thought to be involved in the disease development from pre-clinical stage of SSc to early/mild SSc. Thus, these cytokines may be utilized as a biomarker for early diagnosis.

Difference in distribution of malignant melanoma and melanocytic nevus in the palm and finger.

We conducted a study to try to plot the lesions of melanocytic nevus and malignant melanoma on the palm and fingers, and compared them to identify the different distribution pattern of both lesions. Data on 8 patients with melanomas (4 male and 4 female) and 26 patients with melanocytic nevus (6 male and 20 female) of palm and finger pulp who visited Wakayama Medical University Hospital between 1986 and 2018 was retrospectively collected. We found that all of the 8 lesions of melanoma were located on the finger pulps and distal to the 'distal transverse crease' of the palm, and that melanomas were not present proximal to the transverse crease. On the other hand, melanocytic nevus was present in the proximal area to the distal transverse crease of the palm more frequently than melanomas (50.0% vs. 0%), and there was statistically significant difference (p = 0.011 by Fisher's exact probability test). From these observations, our findings may reveal the contribution of mechanical stress to the cause of palmar melanoma, and may facilitate clinical differentiation between malignant melanoma and melanocytic nevus by the localization. Further studies with increased number of patients are needed to validate the finding.

Association of Baseline Serum Levels of CXCL5 With the Efficacy of Nivolumab in Advanced Melanoma.

Anti-programmed cell death protein 1 (PD1) antibodies are in wide use for the treatment of various cancers. PD1 antibody-based immunotherapy, co-administration of nivolumab and ipilimumab, is one of the optimal immunotherapies, especially in advanced melanoma with high tumor mutation burden. Since this combined therapy leads to a high frequency of serious immune-related adverse events (irAEs) in patients with advanced melanoma, biomarkers are needed to evaluate nivolumab efficacy to avoid serious irAEs caused by ipilimumab. This study analyzed baseline serum levels of CXCL5, CXCL10, and CCL22 in 46 cases of advanced cutaneous melanoma treated with nivolumab. Baseline serum levels of CXCL5 were significantly higher in responders than in non-responders. In contrast, there were no significant differences in baseline serum levels of CXCL10 and CCL22 between responders and non-responders. These results suggest that baseline serum levels of CXCL5 may be useful as a biomarker for identifying patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

Clinical and histological evaluation of a single high energy microwave treatment for primary axillary hyperhidrosis in Asians: A prospective, randomized, controlled, split-area comparative trial.

BACKGROUND AND OBJECTIVES: Microwave treatment is an effective non-invasive treatment option for primary axillary hyperhidrosis (PAH), but the treatment parameters vary and no histopathological studies have been performed to validate clinical outcomes. This study investigated its efficacy and safety and histopathological changes after a single microwave treatment at the maximum energy level for PAH in Asians. MATERIALS AND METHODS: A prospective, clinical, and histological split-area randomized controlled trial (RCT) was performed in Japan. Twenty-six subjects underwent a single microwave treatment at the maximum energy level 5 (5.8 GHz/axilla) on the randomized side of axillae. The primary outcome was the mean difference between both sides in the improvement of modified single-underarm Hyperhidrosis Disease Severity Scale (msHDSS) scores over the course of the 12-month study period from baseline. The secondary outcomes were; the percentage of responders with at least a 2-point drop in the msHDSS score of 3 or 4 group or with a 1-point drop in the msHDSS score of 2 group; the percentage of responders with at least a 75% reduction in sweat weight over 12 months; recurrence rate; and adverse effects. We also performed a histological assessment for 13 selected subjects. RESULTS: Twenty-four subjects completed the study. There were statistically significant differences in improvement of msHDSS scores between the microwave-treated and control sides (P < 0.05) from baseline at 0.5, 1, 3, 6, and 12 months. In the msHDSS score of 3 or 4 group, the percentage of responders with at least a 2-point drop on the microwave-treated side versus control side was 72.2 versus 11.1% (P < 0.05) at 1 month, 83.3 versus 5.6% (P < 0.05) at 3 months, 61.1 versus 38.9% (P = 0.317) at 6 months and 38.9 versus 16.7% (P = 0.264) at 12 months. The percentage of responders with at least a 75% reduction in sweat weight on the microwave-treated side versus control side was 75.0 versus 37.5% at 1 month, 75.0 versus 29.2% at 3 months, 83.3 versus 50.0% at 6 months and 70.8 versus 33.3% at 12 months (all P < 0.05). Recurrence on the microwave-treated side was observed in 4.2% and 12.5% of 24 subjects at 3 and 12 months, respectively. No serious side-effects were noted. Histology showed the diameter and density of secretory eccrine glands and nerve fiber lengths around eccrine glands were significantly decreased after treatment compared to baseline (P = 0.002, 0.027, 0.003, respectively). CONCLUSIONS: A single-session microwave treatment at the maximum energy level significantly improved the PAH of Japanese patients and had minimal side effects. This technique demonstrates that diminished size of secretory eccrine glands and nerve fiber degeneration could be useful markers for predicting the efficacy of the treatment. Lasers Surg. Med. 9999:1-8, 2019. © 2019 Wiley Periodicals, Inc.

Serum Level of Soluble CD163 May Be a Predictive Marker of the Effectiveness of Nivolumab in Patients With Advanced Cutaneous Melanoma.

Antibodies against programmed cell death protein 1, such as nivolumab and pembrolizumab, are widely used for treating various cancers, including advanced melanoma. Nivolumab significantly prolongs survival in patients with metastatic melanoma, and sequential administration with lipilimumab may improve outcomes when switched at the appropriate time. Biomarkers are therefore needed to evaluate nivolumab efficacy soon after first administration. This study analyzed serum levels of soluble cluster of differentiation 163 (sCD163) in 59 cases of advanced cutaneous melanoma and 16 cases of advanced mucosal melanoma treated using nivolumab. Serum levels of sCD163 were significantly increased after 6 weeks in responders compared to non-responders after initial administration of nivolumab for cutaneous melanoma. In contrast, no significant difference between responders and non-responders was seen among patients with non-cutaneous melanoma. These results suggest that sCD163 may be useful as a biomarker for selecting patients with advanced cutaneous melanoma most likely to benefit from anti-melanoma immunotherapy.

Prognostic factors of daily blood examination for advanced melanoma patients treated with nivolumab.

Biomarkers to distinguish patients with advanced melanoma responsive to nivolumab are of great interest. Therefore, we examined the possibility that laboratory data of daily blood examination become novel biomarkers. Laboratory data of 16 melanoma patients who were treated with nivolumab were retrospectively analyzed. Patients were classified as responder group or non-responder group. Examined were: white blood cell count (WBC), absolute lymphocyte counts (ALC), absolute neutrophil count (ANC), absolute monocyte count (AMC), absolute eosinophil count (AEC), and absolute basophil count (ABC), as well as levels of lactate dehydrogenase (LDH), C-reactive protein (CRP), one hour value of erythrocyte sedimentation rate (ESR), and 5-S-cysteinydopa (5-S-CD). Responder group showed significantly higher baseline levels of ESR or CRP and significantly lower ALC level before nivolumab treatment. Additionally, nivolumab treatment decreased the levels of CRP, ESR, and ANC, while it increased ALC level in the responder group. CRP was the most effective in distinguishing responder group from non-responder group both before and during treatment, according to the receiver operating characteristic (ROC) curve. We firstly showed that ESR is also the baseline biomarker of the efficacy of nivolumab. Furthermore, we confirmed that CRP is useful to predict the efficacy both before and during the treatment, and suggested that CRP is the most effective biomarker among daily blood examination by using ROC curve analysis. There is a possibility that nivolumab treatment may be more effective for malignant melanoma with stronger inflammation.

Serum levels of soluble CD163 and CXCL5 may be predictive markers for immune-related adverse events in patients with advanced melanoma treated with nivolumab: a pilot study.

Antibodies against PD-1, such as nivolumab and pembrolizumab, are widely used in the treatment of various cancers including advanced melanoma. The anti-PD-1 Ab significantly prolongs survival in patients with metastatic melanoma, and its administration in combination with local or systemic therapy may also lead to improved outcomes. Although anti-PD-1 Ab-based combined therapy might be effective for the treatment of advanced melanoma, the associated risk of irAEs is an important consideration. Therefore, being able to predict irAEs is of great interest to oncologists. The purpose of this study was to evaluate the value of using serum levels of sCD163 and CXCL5 to predict irAEs in patients with advanced melanoma who were administered nivolumab. To this end, we analyzed these serum levels in 46 cases of advanced melanoma treated with nivolumab. In addition, the tumor stroma was evaluated by immunohistochemistry and immunofluorescence. We measured the serum levels of sCD163 and CXCL5 on day 0 (immediately before nivolumab administration) and day 42. The serum absolute levels of sCD163 were significantly increased in patients who developed AEs (p = 0.0018). Although there was no significant difference in serum levels of CXCL5, the absolute value of CXCL5 could at least be a supportive marker for the increased absolute levels of serum sCD163. This study suggests that sCD163 and CXCL5 may serve as possible prognostic biomarkers for irAEs in patients with advanced melanoma treated with nivolumab.

Retrospective study of advanced melanoma patients treated with ipilimumab after nivolumab: Analysis of 60 Japanese patients.

BACKGROUND: Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching. OBJECTIVE: Investigate the outcome of ipilimumab switching in Japanese patients. METHODS: We retrospectively collected 60 patients who were treated with ipilimumab after nivolumab from 9 institutes in Japan. Information of the primary tumor, treatment, response, irAE), and survival was collected. RESULTS: In our cohort, acral lentiginous and mucosal melanoma accounted for 53% of the cases. The most common reason for initiating ipilimumab was disease progression (93%). Median interval from the last nivolumab administration to first ipilimumab administration was 29days. Only 38% of patients completed 4 injections of ipilimumab. The best overall response was 3.6%. IrAE occurred in 78% of patients and 70% of those were of grade 3/4 (G3/4) and 31% of patients experienced 2 or more irAEs. An within interval of 28days or less between the last nivolumab administration and ipilimumab administration was correlated with the development of G3/4 pyrexia and 3 or more irAEs, but irAE occurrence did not affect survival. Multivariate analysis showed that endocrine irAE (relative risk=0.22, P=0.015) and skin irAE (relative risk=2.78, P=0.048) were significant factors associated with survival. CONCLUSION: In our study, the response ratio to ipilimumab after nivolumab was unsatisfactory and associated with a high frequency of severe irAEs. As there are few second-line treatment options for patients with BRAF wild-type advanced melanoma after nivolumab failure, patients should be closely monitored if ipilimumab is initiated.

Fluctuations in routine blood count might signal severe immune-related adverse events in melanoma patients treated with nivolumab.

BACKGROUND: Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest. OBJECTIVE: We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated with nivolumab. METHODS: We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell [WBC] count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver-operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC). RESULTS: Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff value=-23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79, OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were independent factors associated with lung/GI irAEs. CONCLUSIONS: Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab.

Phospho-STAT5B Expression Is a Prognostic Marker for Merkel Cell Carcinoma.

BACKGROUND/AIM: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Although recent reports suggest that tumor-infiltrating leukocytes (TILs), especially CD8+ T-cells, contribute to the pathogenesis of MCC, it is difficult for a single Institute with a small number of patients with MCC to determine the threshold number of CD8+ cells. Therefore, clearer and easier methods of evaluating prognostic factors of MCC are needed. PATIENTS AND METHODS: In order to identify the prognostic factors of 24 cases of MCC, we employed immuno histochemical staining of phospho-signal transducer and activator of transcription 5B (pSTAT5B), which has been reported to be a prognostic marker for several types of cancers. RESULTS: All MCC cases with a good outcome (n=16) expressed pSTAT5B, whereas all MCC cases with a poor outcome (n=8) did not express pSTAT5B. Moreover, we additionally employed immunohistochemical staining of periostin (POSTN) and interleukin-4, as well as sub-populations of TILs (granulysin-bearing cells, regulatory T-cells, CD163+ cells, and CD206+ cells), and the deposition of matrix metalloproteinase 12 in the lesional skin of patients with MCC. The results suggested that there is no significant difference in stromal factors between MCC cases with a good and those with a poor outcome. CONCLUSION: pSTAT5B expression may be an indicator of positive prognosis in patients with MCC.

A Case of Malignant Melanoma of the Uterine Cervix with Disseminated Metastases throughout the Vaginal Wall.

Malignant melanoma (MM) in the female genital tract accounts for less than 2% of all melanomas, and the vast majority associated occur in the vulva and vagina. Primary MM of the uterine cervix is extremely rare and its prognosis is very poor. We report a case of primary MM of the cervix with dissemination throughout the vaginal wall. A 66-year-old woman presented with postmenopausal bleeding. Gynecologic examination demonstrated a 2 cm polypoid blackish-pigmented tumor on the cervix with multiple small blackish-pigmented lesions throughout the vaginal wall. Cervical Pap smear cytology showed malignant melanoma. MRI and PET/CT did not detect any distant or lymph node metastases. She underwent radical hysterectomy, pelvic lymphadenectomy, and total vaginectomy. The pathological diagnosis was FIGO stage IIIA primary cervical MM. She received adjuvant chemotherapy with 6 courses of dacarbazine, but 6 months later, multiple lung metastases were detected. Despite 4 courses of anti-PD-1 antibody (nivolumab) treatment, she died of the disease 13 months after surgery.

A Patient with Refractory Psoriasis Who Developed Sebaceous Carcinoma on the Neck during Cyclosporine Therapy and Showed Rapid Progression.

We report a patient who developed sebaceous carcinoma on the neck during therapy with immunosuppressive agents (cyclosporine, corticosteroid, methotrexate) for refractory psoriasis vulgaris, which showed rapid enlargement, leading to a fatal outcome. Multiple-organ metastases were detected. Weekly carboplatin + paclitaxel therapy resulted in the disappearance of tumor cells, but the patient died of febrile neutropenia. The development of sebaceous carcinoma is rare among psoriasis patients receiving immunosuppressive agents including cyclosporine.