Keisuke Imafuku

Autoantibodies of non-inflammatory bullous pemphigoid hardly deplete type XVII collagen of keratinocytes

Type XVII collagen (COL17) and the non‐collagenous 16A (NC16A) domain is regarded as the major pathogenic domains for bullous pemphigoid (BP). Some patients with BP have autoantibodies against parts of COL17 outside the NC16A domain (hereinafter the non‐NC16A domain) and show less inflammatory manifestations. There were no significant differences in titres and IgG subclasses between NC16A‐BP and non‐NC16A‐BP as determined by indirect immunofluorescent microscopy. The neutrophil activation capacities determined by ROS release did not differ between NC16A‐BP and non‐NC16A‐BP. However, NC16A‐BP IgG depleted COL17 in a dose‐dependent manner. Treatment with NC16A‐BP IgG, but not with non‐NC16A‐BP IgG, significantly decreased the adhesion strength. We speculate that the differences in clinical severity between NC16A‐BP and non‐NC16A‐BP relate to the degree of COL17 depletion.

Severe rash associated with vemurafenib administration following nivolumab therapy.

poly-chemotherapy, only one paper reported an occurrence of Steve-Johnson syndrome in a patient treated with rituximab. However, no case of TEN have been reported in humans, but only in two Rhesus Macaques (Macaca Mulatta). The pathogenesis of TEN is still unclear. It was observed that activated T cells secrete a large amount of TNF-a and interferon-c, resulting in a Fas-ligand (FasL) up-regulation and Fasmediated keratinocyte apoptosis. This pathway could explain the pathogenesis of TEN after rituximab administration, since rituximab induces a sensitization to Fas-mediated apoptosis through the activation of caspase-8. At the same time, etanercept blocks this inflammatory pathway via TNF-a inhibition. As reported in a previous paper 7, only a 50 mg sub-cutaneous administration of etanercept was needed to block TEN. TEN can be a serious, sudden, and unexpected side effect in patients treated with rituximab, as well as with other drugs. The current report highlights how etanercept is a useful and manageable drug to treat this dangerous skin condition.

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.

Pazopanib does not bring remarkable improvement in patients with angiosarcoma

Pazopanib is a potent and selective multi‐targeted tyrosine kinase inhibitor that has been reported to extend progression‐free survival in cases of metastatic soft‐tissue sarcoma. However, the efficacy of pazopanib for cutaneous angiosarcoma has not been confirmed. We report eight cases of angiosarcoma treated with pazopanib, and review the efficacy and safety of pazopanib therapy. We retrospectively investigated the clinical information, including age, sex, body surface area, location, performance status, lung or pleural metastasis, preceding treatment, oral dose of pazopanib, response rate, progression‐free survival and adverse effects. Five of the eight patients needed to stop the pazopanib treatment due to severe adverse effects, including thrombocytopenia, anemia, drug‐associated pancreatitis, acute fulminant hepatitis and general fatigue. Progression‐free survival ranged 0.5–3.5 months (mean ± standard deviation, 1.81 ± 1.03). Overall survival ranged 3–26 months (14.13 ± 9.47). Six of the eight cases showed progressive disease, and two of the eight cases showed stable disease. To assess overall survival in angiosarcoma treated with pazopanib, we compared the pazopanib‐treated group (n = 8) with the non‐pazopanib‐treated control group (n = 10). There was no significant difference between two groups (P = 0.19, log–rank test). In conclusion, our case series suggests that pazopanib does not bring remarkable improvement in patients with angiosarcoma.

Isolated adrenocorticotropic hormone deficiency associated with nivolumab therapy.

Dear Editor, Nivolumab (anti-PD-1 antibody) is known to induce immunerelated adverse events (irAE) such as interstitial pneumonitis, colitis and endocrinopathies. We herein report the first case of nivolumab-associated isolated adrenocorticotropic hormone (ACTH) deficiency. A 76-year-old woman with metastatic melanoma had been treated with nivolumab (2 mg/kg, every 3 weeks). After nine courses of nivolumab therapy, the patient reported bradykinesia and loss of appetite. Laboratory tests revealed hyponatremia (123 mEq/L), low ACTH level (7.18 pg/mL; normal range, 7.20– 63.30) and undetectable serum cortisol level (<1.0 lg/dL; normal range, 4.0–23.3). Other serum pituitary hormone levels, including those of thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin and growth hormone, were within normal limits. The anterior pituitary stimulation test revealed ACTH reactivity to corticotropin-releasing hormone to be selectively impaired (ACTH level, 9.15 pg/mL; normal reactive range, 14.40–126.60), whereas the other pituitary hormones (TSH, FSH, LH, prolactin and growth hormone) rose reactively to their stimulation tests. Therefore, the patient was diagnosed with isolated ACTH deficiency (IAD). She had been treated with systemic cortisol (15 mg/day) for 13 days, resulting in the blood sodium level returning to the normal range (141 mEq/L). The fatigue and poor appetite were also improved. Thirty-three days after systemic cortisol therapy, nivolumab therapy could be resumed. The patient has been treated with both cortisol (15 mg/day) and nivolumab (2 mg/kg, every 3 weeks) for 3 months. During this period, serum sodium levels have been within normal limits. This case is the first report of nivolumab-associated IAD. The common hematological finding of IAD are hypoglycemia, hyponatremia, anemia, neutropenia, and low values of serum ACTH and serum cortisol. Some patients with IAD are positive for anti-thyroglobulin antibodies or anti-pituitary antibodies, suggesting the involvement of an autoimmune mechanism. Pooled analysis of 148 patients treated with nivolumab found immune-related hypothyroidism, hyperthyroidism and hypophysitis as endocrine irAE. Most of the endocrine irAE occurred beyond 10 weeks after the initial treatment. The data from clinical trials of nivolumab show that the serum nivolumab level continues to rise until 18 weeks, suggesting that high serum nivolumab is associated with the nivolumab-related endocrinopathies. Also, nivolumab-related endocrinopathies may differ with ethnicity. In the ONO-4538-02 study (2 mg/kg, every 3 weeks) on Japanese patients, endocrinopathies occurred in 14.3% of cases. In the CA209-037 and -066 studies (3 mg/kg, every 2 weeks) on non-Asian patients, endocrinopathies occurred in 7.5% and 7.8% of cases, respectively. These results suggest that not only are high serum nivolumab levels associated with the incidence of nivolumabrelated endocrinopathies, but so are ethnic differences. Recent studies on the side-effects of immune-checkpoint blockade did not establish the extent to which high-dose corticosteroid therapy or hormone replacement therapy of the affected axes is sufficient. Also, longer term supplementation of affected hormones is necessary because of secondary hypoadrenalism. Thus, there seems to be a trend towards hormone replacement therapy instead of high-dose corticosteroid treatment. In conclusion, we have described the first report of nivolumab-associated isolated ACTH deficiency. We should keep in mind that isolated ACTH deficiency can occur during nivolumab therapy.

PCTAIRE1/CDK16/PCTK1 is overexpressed in cutaneous squamous cell carcinoma and regulates p27 stability and cell cycle ☆

BACKGROUND PCTAIRE1 (also known as cyclin-dependent kinase 16 (Cdk16) and PCTK1) is a Cdk family protein that has been implicated in spermatogenesis. We recently revealed the function of PCTAIRE1 in the tumorigenesis of malignancies, including breast and prostate cancers; however, the tumorigenic function of PCTAIRE1 in cutaneous squamous cell carcinoma (SCC) remains unclear. OBJECTIVE In this study, we investigated the role of PCTAIRE1 in the tumorigenesis of cutaneous SCCs. METHODS AND RESULTS In cutaneous/oral SCC A431, DJM-1, HSC-3 cells, PCTAIRE1 gene-knockdown was found to diminish cell proliferation as assessed by cell counting and clonogenic assays. FACS analyses of annexin V-PI staining and DNA content showed PCTAIRE1 knockdown to cause G2/M arrest followed by apoptosis. The depletion of PCTAIRE1 was found to lead to the accumulation of tumor suppressor p27 and down-regulation of c-Myc. In tumor xenografts of A431 cells, the conditional knockdown of PCTAIRE1 restores p27 protein expression and suppresses tumor growth. Clinically, in primary tumors from patients with SCC, PCTAIRE1 is more highly expressed in malignant lesions than in adjacent normal epidermis. Conversely, expression levels of p27 are significantly lower in SCC than in normal epidermis. CONCLUSIONS Our findings reveal a crucial function for PCTAIRE1 in regulating p27, c-Myc levels and tumor growth in cutaneous SCC cells, suggesting that PCTAIRE1 could be a novel target for skin tumor treatment.

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.

Pazopanib can preserve cosmetic quality of life even in end-stage angiosarcoma

patients with neurogenic rosacea, all of whom had partially successful treatment with pregabalin. Given the paucity of reports on its existence, neurogenic rosacea is probably under-recognized. It should be suspected in any patients with rosacea where the predominant symptom is pain and/or burning sensation out of proportion to the flushing. We hope our report raises awareness of this potentially treatable clinical variant of rosacea, which requires a different therapeutic approach to that of other variants.

Pazopanib-Induced Severe Acute Pancreatitis

Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and c-Kit approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Nonselective kinase inhibitors, such as sunitinib and sorafenib, are known to be associated with acute pancreatitis. There are few case reports of severe acute pancreatitis induced by pazopanib treatment. We present a case of severe acute pancreatitis caused by pazopanib treatment for cutaneous angiosarcoma. The patient was an 82-year-old female diagnosed with cutaneous angiosarcoma. She had been refractory to docetaxel treatment and began pazopanib therapy. Three months after pazopanib treatment, CT imaging of the abdomen showed the swelling of the pancreas and surrounding soft tissue inflammation without abdominal pain. After she continued pazopanib treatment for 2 months, she presented with nausea and appetite loss. Abdominal CT showed the worsening of the surrounding soft tissue inflammation of the pancreas. Serum amylase and lipase levels were 296 and 177 IU/l, respectively. She was diagnosed with acute pancreatitis induced by pazopanib treatment and was managed conservatively with discontinuation of pazopanib, but the symptoms did not improve. Subsequently, an abdominal CT scan demonstrated the appearance of a pancreatic pseudocyst. She underwent endoscopic ultrasound-guided pseudocyst drainage using a flared-end fully covered self-expandable metallic stent. Then, the symptoms resolved without recurrence. Due to the remarkable progress of molecular targeted therapy, the oncologist should know that acute pancreatitis was recognized as a potential adverse event of pazopanib treatment and could proceed to severe acute pancreatitis.

Enhanced IL-34 expression in Nivolumab-resistant metastatic melanoma

BackgroundImmunotherapies that target immune-checkpoint molecules such PD-1 have helped to achieve durable responses in melanoma treatment. However, 25% of melanoma patients who showed objective responses to PD-1 blockade develop resistance and suffer from disease progression and ultimately death, which necessitates the identification of related resistance mechanisms.IL-34 is a cytokine that controls the biology of myeloid cell lineage through binding to CSF-1R. IL-34 is importantly involved in the pathogenesis of various diseases. In cancer, the expression of IL-34 has been suggested to associate with tumor growth, metastasis, angiogenesis, and therapeutic resistance such as in lung cancers and malignant pleural mesotheliomas. In this study, we evaluate the possible involvement of IL-34 in immunotherapeutic resistance.Case presentationMelanoma resection species were obtained from a patient who developed a refractory melanoma against immunotherapy with Nivolumab, and stained with anti-IL-34, anti-melanoma antigens and anti-CD163 antibody. Staining of these markers was compared between primary or metastatic refractory melanoma tissues. Immunohistochemistry staining of melanoma tissues showed an enhanced expression of IL-34 in metastatic refractory melanoma compared to primary melanoma tissues, which correlates with increased frequencies of CD163+ macrophages.ConclusionWe introduce for the first time a clinical case of a patient with metastatic refractory melanoma that acquired resistance to anti-PD-1 immunotherapy, showing an enhanced expression of IL-34 in refractory melanoma tissues.