Hisako Okuhira

Baseline neutrophil to lymphocyte ratio combined with serum lactate dehydrogenase level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population

Although immune checkpoint inhibitors (ICI) significantly improve the survival of advanced melanoma, more than half of the patients received no benefit. To predict outcomes, efforts to associate baseline peripheral blood biomarkers were started in patients given treatment with ipilimumab. Among the most critical markers is an increased neutrophil-to-lymphocyte ratio (NLR), which negatively correlates with outcome. Although several baseline factors have been reported to correlate with outcome in patients treated with nivolumab/pembrolizumab (eosinophil count, lymphocyte count, lactate dehydrogenase [LDH], and c-reactive protein [CRP]), a positive link between NLR and outcome has yet to be shown. This article is protected by copyright. All rights reserved.

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.

Case report of aquagenic wrinkling of the palms associated with impaired stratum corneum function.

Dear Editor, Aquagenic wrinkling of the palms (AWP) is an uncommon disease characterized by the rapid formation of transient edematous and whitish plaques on the palms after exposure to water. AWP usually occurs in young females with family history, and thus heredity may be related. Although the pathophysiology of AWP remains unknown, aberrant sweat glands and alterations of the stratum corneum are thought to be involved. Herein, we report a case of AWP in which histological and functional studies were carried out.

Successful treatment of tufted angioma with propranolol.

carcinoma. A 51-year-old Korean female presented with hyperpigmented, verrucous subungual mass and melanonychia with loss of lateral nail plate on her left middle finger for 2 years (Fig. 1a). She was misdiagnosed with verruca vulgaris referred for treatment from her private dermatologic clinic. A skin biopsy showed invasion of dermis and epidermis by atypical keratinocytes which are hyperchromatic, pleomorphic cells with atypical mitosis (Fig. 1b, c). The epidermis showed vacuolated superficial keratinocytes with pyknotic raisin-like nuclei (Fig. 1d). HPV immunohistochemistry showed positive stained infected cells (Fig. 1e). Based on both clinical and histopathological findings, the patient was diagnosed with subungual squamous cell carcinoma. The HPV subtypes, HPV66 and HPV11 were identified by AGBIO Diagnostics HPV DNA genotyping chip (AGBIO Diagnostics, Seoul, Korea). DNA extraction from the tissue specimen and the PCR amplifications of the target region were performed. PCR products were loaded onto HPV DNA Chip with type specific probe, and the scanner read the resulting signal. The HPV genome was localized by in-situ hybridization with the Ventana Inform HPVIII Family 16 probe (Ventana, Tuscon, AZ, USA). In the epidermis, HPV DNA showed typical dot-like positive signals in nuclei (data not shown). Wide excision and split thickness skin grafts were performed. Recurrence has not been observed after wide excision. Of the ungual and periungual HPV-associated SCCs, 27.4% have a history of HPV-associated genital pathology, such as genital warts, cervical or anogenital dysplasia and cancer, or a similar history in a sexual partner. According to the carcinogenic potential of the uterine cervix, HPV 66 is a possible carcinogenic subtype (group 2B) and HPV 11 is not classifiable as a carcionogenic subtype (group 3). Uncommon HPV subtype 66 as a possible carcinogen is associated with cervical dysplasia and cancer. Thus, we performed HPV DNA analyses of our patient’s cervix, but HPV was not detected. In conclusion, high-risk HPV types such as HPV 66 can induce ungual and periungual SCCs. High-risk HPV subtypes are associated with lesions on the cervix and have also been found in oral, ungual and periungual SCC, implying genital-digital and genital-oral viral spread. Dermatologists treating patients with ungual and periungual HPV associated SCC should be aware that these may harbor high-risk HPV subtypes with a risk of transmission by skin-to-skin contact or aerosolization of viral particles. Aggressive and extensive treatment and close follow-up of HPV-associated ungual and periungual squamous cell carcinoma is necessary due to the high recurrence rate, the possibility of metastasis and high proliferative activity.

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.

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.

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.