Upregulated expression of glucose transporter isoform 1 in invasive and metastatic extramammary Paget's disease.

Glucose transporter isoform 1 (GLUT1), which is upregulated in a variety of malignant tumors, facilitates cellular glucose uptake to boost rapid tumor growth and progression. In several types of cancer, inhibition of GLUT1 suppresses tumor proliferation and metastasis, indicating that GLUT1 is a potential target of anticancer therapy. The present study performed immunohistochemistry to analyze GLUT1 expression levels in 51 patients with extramammary Paget's disease (EMPD), including 23 with only intraepidermal lesions and 28 with dermal-invasive lesions. Of the 28 patients with dermal invasion, nine had available samples of lymph node metastasis. GLUT1 staining scores were significantly higher in dermal-invasive (P<0.0001) and metastatic lesions (P=0.0008) compared with in intraepidermal lesions. GLUT1 is upregulated during the transition from preinvasive to invasive or metastatic tumor in EMPD. Moreover, GLUT1 staining scores were statistically higher in intraepidermal tumor cells of dermal-invasive EMPD compared with tumor cells of only in situ EMPD (P=0.0338). GLUT1 is upregulated even during the preinvasive phase in patients with invasive EMPD, suggesting that GLUT1 immunostaining can predict the risk of dermal invasion. The present study provides novel evidence to pursue in vitro and in vivo studies to confirm that upregulated expression of GLUT1 enhances tumor aggressiveness in EMPD.

Acquired cutis laxa secondary to acute generalized exanthematous pustulosis: A case report and mini-review of literature.

Cutis laxa presents as loose redundant skin folds and loss of dermal elastic tissue. Acquired cutis laxa (ACL) is characterized by later onset. It has been reported in association with various kinds of neutrophilic dermatoses, drugs, metabolic disorders, and autoimmune disorders. Acute generalized exanthematous pustulosis (AGEP) is usually classified as a severe cutaneous adverse reaction characterized by T cell-mediated neutrophilic inflammation. We previously reported a mild case of AGEP caused by gemcitabine in a 76-year-old man. Here, we report a case of ACL secondary to AGEP in this patient. He developed AGEP 8 days after gemcitabine administration. Four weeks after beginning chemotherapy, his skin had become atrophic, loose, and darkly pigmented in areas previously affected by AGEP. Histopathological examination revealed edema and perivascular lymphocytic infiltration but no neutrophilic infiltration in the upper dermis. Elastica van Gieson staining showed that the elastic fibers in all layers of the dermis were sparse and shortened. Electron microscopy showed elevated numbers of fibroblasts and altered elastic fibers with irregular surfaces. Finally, he was diagnosed with ACL secondary to AGEP. He was treated with topical corticosteroids and oral antihistamines. Skin atrophy decreased over 3 months. We summarize 36 cases (including our case) with ACL secondary to neutrophilic dermatosis. We discuss these clinical manifestations, causative neutrophilic disorders, treatments, and outcomes. The mean age of patients was 3.5 years. Five patients had an aortic lesion as systemic involvement. The most common causative neutrophilic disorders were Sweet syndrome (24 cases), followed by urticaria-like neutrophilic dermatosis (11 cases). There were no cases of AGEP except for our case. Although treatment for ACL secondary to neutrophilic dermatosis, such as dapsone, oral prednisolone, adalimumab, and plastic surgery were reported, ACL is generally refractory and irreversible. Our patient was considered reversibly cured due to the absence of continuous neutrophil-mediated elastolysis.

Cost-Effectiveness Analysis of Atezolizumab versus Platinum-Based Chemotherapy as First-Line Treatment for Patients with Unresectable Advanced Non-small Cell Lung Cancer with PD-L1 Expression Status in Japan.

BACKGROUND AND OBJECTIVES: Atezolizumab has demonstrated safety and efficacy in patients with metastatic non-small cell lung cancer (NSCLC) in the IMpower110 trial. The aim of this study was to evaluate the cost-effectiveness of atezolizumab as the first-line treatment for patients with unresectable advanced NSCLC, including programmed cell death ligand-1 (PD-L1)-positive probability testing, from the perspective of healthcare costs in Japan. METHODS: A cost-effectiveness analysis model for atezolizumab, including PD-L1-positive probability testing, was used to construct a partitioned survival model with three health states. To assess the robustness, a probabilistic sensitivity analysis (PSA) was conducted. The acceptable probability was defined as the probability of willingness-to-pay (WTP) over the incremental cost-effectiveness ratio (ICER). Multiple repetitions at WTP thresholds were calculated by continuously reducing the atezolizumab price. RESULTS: The ICER per quality-adjusted life year (QALY) for atezolizumab therapy only for patients with high PD-L1 expression compared to platinum-based chemotherapy for all patients was 31,975,792 yen per QALY. This is higher than the WTP threshold of 15,000,000 yen. If the cost of atezolizumab were reduced to 54% of the original cost (563,917 yen), the strategy of using atezolizumab for patients with high PD-L1 could become more cost-effective. CONCLUSIONS: The results indicated that atezolizumab was not cost-effective compared to platinum-based chemotherapy as a first-line treatment for patients with unresectable advanced NSCLC. However, we suggest that the price of atezolizumab should be reduced to 54% of the original cost to meet the WTP threshold of 15,000,000 yen per QALY.

Two cases of cutaneous-type pemphigus vulgaris and a case of pemphigus foliaceus without mucosal involvement despite high anti-desmoglein 3 autoantibody levels.

Pemphigus is an autoimmune blistering disease with two major subtypes, pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Although most patients with PV show oral lesions, cutaneous type PV (C-PV) is a rare subtype clinically characterized by predominant cutaneous involvement with no or subtle mucosal lesions. Patients with PF present with only skin involvement; they do not have mucosal lesions. Serologically, autoantibodies against desmoglein (Dsg) 3 and Dsg1 are observed in C-PV whereas PF is associated with anti-Dsg1 antibodies only. Herein, we describe three cases of pemphigus presenting with predominant skin lesions and no mucosal involvement despite high anti-Dsg 3 autoantibody levels in chemiluminescent enzyme immune assays (CLEIAs). In addition, anti-Dsg 1 autoantibodies were positive in patients 2 and 3, but negative in patient 1 based on CLEIAs. Histological examination of the skin showed suprabasal acantholysis in patients 1 and 2, and blister formation in the upper epidermis in patient 3. Histopathology of the oral membrane in patients 1 and 2 showed subtle acantholysis in the suprabasal layer. Thus, we diagnosed patients 1 and 2 as having cutaneous type PV and patient 3 as having PF. Ethylenediaminetetraacetic acid-treated enzyme-linked immunosorbent assay demonstrated a low proportion of anti-Dsg3 autoantibodies recognizing Ca2+ -dependent epitopes, antibodies against which are thought to be the main contributor to acantholysis. Thus, along with Dsg1 antibodies, weak anti-Dsg3 antibodies could induce acantholysis in the skin, but they are insufficient to induce mucosal lesions.

Involvement of the genus Corynebacterium in the pathogenesis of pigmented intratarsal keratinous cyst.

Intratarsal keratinous cyst (IKC) is a benign cystic lesion of the eyelid that retains keratin flakes. IKCs are usually yellow to white cystic lesions but rarely become brown or gray-blue, making clinical diagnosis difficult. The mechanisms by which dark brown pigments are generated in pigmented IKC are unclear. The authors report a case of pigmented IKC that had melanin pigments within the lining of the cyst wall and within the cyst. Focal infiltrates of lymphocytes were observed in the dermis, particularly beneath the cyst wall in areas with more melanocytes and intense melanin deposition. These pigmented parts faced bacterial colonies inside the cyst, which were identified to be Corynebacterium species in a bacterial flora analysis. The pathogenesis of pigmented IKC in relation to inflammation and bacterial flora is discussed.

Dystrophic calcinosis cutis in a patient with cutaneous sarcoidosis in remission.

A 65-year-old Japanese woman was referred to our department because of a 5-month history of asymptomatic papules on the face. She was diagnosed with cutaneous sarcoidosis on the face 20 years ago. All of the lesions had completely disappeared with oral corticosteroids. Twenty years after the diagnosis of sarcoidosis, small papules developed in areas where the cutaneous sarcoidosis had been located. Physical examination revealed four yellow-white papules on the face. Dermoscopy revealed a homogenous, round, and yellow-white lesion. Serum levels of calcium and phosphorus were normal. Histopathology demonstrated calcium deposits in the dermis surrounded by inflammatory infiltrates without sarcoid granulomas. We made a diagnosis of calcinosis cutis. Basal cell carcinoma with calcinosis cutis, milia-like calcinosis cutis, and subcutaneous calcified nodule should be differentiated. Calcinosis cutis can be classified into four subtypes based on pathogenesis: dystrophic, metastatic, idiopathic, and iatrogenic. Dystrophic calcinosis cutis is caused by local tissue damage or abnormalities. Whereas, metastatic calcinosis cutis is often associated with hypercalcaemia, hyperphosphatemia, or hyperparathyroidism. There are reported cases of metastatic calcinosis cutis associated with sarcoidosis because patients with sarcoidosis often present with hypercalcaemia. However, dystrophic calcinosis cutis associated with sarcoidosis has been rarely reported. In the present case, systemic treatment for sarcoidosis may have degraded sarcoid granulomas and yielded necrotic tissue and dermal fibrosis, which might have induced ectopic calcification. Thus, we thought the present case consisted of dystrophic calcinosis cutis that developed in areas with cutaneous sarcoidosis in remission.

A severe case of primary erythromelalgia presenting as small fiber neuropathy with a novel SCN9A mutation.

Primary erythromelalgia (PEM) is a rare condition characterized by severe burning pain, erythema, and increased temperature in the extremeties. Mutations in the Nav1.7 sodium channel encoded by the SCN9A are responsible for PEM. The pathophysiology of PEM is unclear, but the involvement of neurogenic and vasogenic mechanisms has been suggested. Here we report a case of severe PEM in a 9-year-old child with a novel SCN9A mutation and examine the distribution of nerve fibers and expression of neuropeptides in the affected skin. Gene mutation analysis revealed a novel mutation p.L951I (c.2851C>A) in the heterozygous form of the SCN9A. An immunofluorescence study showed that intraepidermal nerve fibers were decreased in the affected leg, suggesting small fiber neuropathy. There was no increase in the expression of substance P (SP) or calcitonin gene-related peptide (CGRP) in the lesional skin tissue. These findings suggest SP and CGRP do not play a major role in the pathophysiology of primary erythromelalgia.

Recovery From Severe Systemic Peripheral Neuropathy Secondary to Erythropoietic Protoporphyria by Liver Transplant: A Case Report.

Erythropoietic protoporphyria is a rare inherited metabolic disorder involving the heme biosynthesis pathway and leads to the accumulation of protoporphyrin in the erythrocytes or liver. Although peripheral neuropathy is known to develop occasionally in other types of porphyria, it rarely occurs in patients with erythropoietic protoporphyria. A 16-year-old boy was transferred to our hospital due to end-stage liver disease secondary to erythropoietic protoporphyria. Severe systemic peripheral neuropathy, similar to that presented in Guillain-Barré syndrome, developed; it was promptly managed with mechanical ventilation. Electrophysiological assessment of the presented neuropathy showed no responsiveness, indicating severe axonopathy. Six weeks after the transfer, liver transplant was performed.Postoperatively, hepatorenal syndromes improved immediately, and his erythrocyte protoporphyrin level decreased from 6291 to 174 µg/dL red blood cells.The patient started to move his limbs gradually and was weaned from mechanical ventilation 2 months after liver transplant. Eventually, he was discharged from hospital and was able to ambulate with assistance 10 months after liver transplant. To our knowledge, this is the first report detailing the clinical course in a patient with erythropoietic protoporphyria who recovered from severe systemic peripheral neuropathy after liver transplant.

Role of phlebotomy in the treatment of liver damage related to erythropoietic porphyria.

Liver damage affects the prognosis of patients with erythropoietic protoporphyria (EPP). However, there is no radical cure for EPP patients with severe liver damage. This study aims to investigate the effectiveness of phlebotomy in patients with severe liver damage. We examined seven patients diagnosed with EPP and liver damage between 2010 and 2020. Of the 7 cases, phlebotomy was performed in 3 cases with severe hepatic disorder, and the improvement effect of hepatic disorder was observed in all cases. In addition, as an additional study, we also investigated the mechanism by which liver damage becomes more severe. Liver biopsy samples were stained with hematoxylin and eosin and immunohistochemistry was used to examine the expression of adenosine triphosphate-binding transporter G2 (ABCG2). Liver biopsies were performed in 3 of 7 patients with EPP. Of these three patients, ABCG2 expression was low in two patients, especially in the protoporphyrin (PP) deposition area. Two patients with reduced ABCG2 expression subsequently developed severe liver damage. However, the causal relationship between the decreased expression of ABCG2 and the exacerbation of liver damage has not been directly proved, and further investigation is required in the future. This study demonstrated the effectiveness of phlebotomy in EPP patients with severe liver damage.