Shinya Kitamura

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.

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.

Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma

BACKGROUND Dynamin-related protein 1 (Drp1) mediates mitochondrial fission. Recently, several studies have shown that Drp1 plays an important role in some cancers. However, little is known about Drp1 in cutaneous squamous cell carcinoma (SCC). OBJECTIVE To investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs. METHODS AND RESULTS We investigated cell proliferation, cell cycle, mitochondrial morphology, and MAPK signaling pathway using cutaneous SCC A431 and DJM1 cells that were transfected with shRNA vectors targeting Drp1. The Drp1 gene-knockdown SCC cells showed lower cell proliferation than scramble-control cells, as assessed by direct cell counting and clonogenic assays. DNA content analysis showed Drp1 knockdown to cause G2/M arrest. Morphologically, the depletion of Drp1 resulted in an elongated, hyper-fused mitochondrial network. The MEK inhibitor PD325901 suppressed cell proliferation, as well as inhibiting the phosphorylation of ERK1/2 and Drp1Ser616. Also, PD325901 caused the dysregulation of the mitochondrial network. In tumor xenografts of DJM1 cells, the knockdown of Drp1 suppressed tumor growth in vivo, and clinically, the expression levels of Drp1 were higher in cutaneous SCCs than in normal epidermis, and correlated positively with the advanced clinical stages. CONCLUSION Our results reveal a crucial function for Drp1 in regulating tumor growth, mitochondrial morphology, and cell cycle in cutaneous SCC, suggesting that Drp1 could be a novel target for skin tumor therapies.

A case of erythroplasia of Queyrat successfully treated with combination carbon dioxide laser vaporization and surgery.

matitis after cardiac catheterism and in 1997, Knautz described the first case of radiodermatitis after TIPS. In the literature are reported 12 cases of patients affected by radiodermatits after TIPS: it is a very rare complication, often making for difficult diagnoses. Generally, some weeks or months after the procedure, patients feel a worsening pain and may develop cutaneous manifestations up to 1 year later. The rarity of the complication, as well as the development time of radiodermatitis, makes it difficult to make a solid association with the fluorososcopy procedure. Therefore, incorrect diagnoses such as morfea, fixed drug eruption, lichen scleroatrophicus, panniculitis, are likely to occur. Patients are thus often subjected to unsuitable and ineffective therapies for controlling the throbbing and distressing pain. In the case we were able to observe, which because of the rarity of the onset led to diagnosis problems, there was the peculiarity of showing cutaneous lesions just a few days after the procedure. Lack of diagnosis led to it becoming chronic, thus causing not only diagnostic problems but therapeutic ones as well. As involved radiographic procedures such as TIPS became more prevalent, physicians need to be aware of possible risks such as radiodermatitis to prevent side-effects. It is important to initiate an exact and early diagnosis to ensure operative therapeutic strategies and ensure a long-term follow-up for malignancy screening.

Ultrasound B-mode and elastographic findings of mixed tumour of the skin on the scalp.

cal, histological and immunopathological features of both entities. Authenticity of this condition is still controversial. Our subjects presented characteristics distinctive of each disease and thus do not seem to be cases of LE/LP overlap syndrome. In conclusion, we report seven patients with coexisting forms of PCA: FFA and DLE. Evidence suggests that both diseases have a common pathogenic background. Future reports may strengthen this association helping to evaluate if such coexistence is merely coincidental; or a new piece of evidence in the study of this challenging group of disorders. Moreover, these cases are an additional reminder that presence of cutaneous lesions elsewhere might be a double-edged sword when diagnosing PCA.

Dermoscopic findings of irritated seborrheic keratosis.

association with development of de novo congenital MM. Recent studies have established common association with several chromosomal abnormalities and de novo CMM. According to other data, de novo CMM is established in only one among 23 cases of childhood melanoma, described by Trozak et al. in 1975. Twenty-three cases of cutaneous congenital and infantile melanoma have been reported in the English literature since 1925 to the present day, as the disease is recognized either at birth (congenital) or within the first year of life (infantile). The prognosis for congenital melanomas is poor, with a mortality of 40% within 18 months of diagnosis. No risk factors have been currently established to warrant foetal screening for melanoma. According to a study, amniocentesis may be useful in screening the presence of desquamated melanoma cells in certain instances in which there is no evidence of maternal disease. G. Tchernev,* A.A. Chokoeva Policlinic for Dermatology and Venereology, University Hospital Lozenetz, Sofia, Bulgaria, “Onkoderma” -Policlinic for Dermatology and Dermatologic Surgery, Sofia, Bulgaria *Correspondence: G. Tchernev. E-mail: georgi_tchernev@yahoo.de

The Unique Dermoscopic Structure 'Large black web' in basal cell carcinoma on the areola.

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