Japanese clinical practice guidelines for vascular anomalies 2017.

The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety, and systematizing treatment, employing evidence-based medicine (EBM) techniques and aimed at improvement of the outcomes. Clinical questions (CQs) were decided based on the important clinical issues. For document retrieval, key words for literature searches were set for each CQ and literature published from 1980 to the end of September 2014 was searched in Pubmed, Cochrane Library, and Japana Centra Revuo Medicina (JCRM). The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System (MINDS) technique. A total of 33 CQs were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy, and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

Japanese Clinical Practice Guidelines for Vascular Anomalies 2017.

The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety and systematizing treatment, employing evidence-based medicine techniques and aimed at improvement of the outcomes. Clinical questions (CQ) were decided based on the important clinical issues. For document retrieval, key words for published work searches were set for each CQ, and work published from 1980 to the end of September 2014 was searched in PubMed, Cochrane Library and Japana Centra Revuo Medicina databases. The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System technique. A total of 33 CQ were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

Japanese clinical practice guidelines for vascular anomalies 2017.

The objective was to prepare guidelines to perform the current optimum treatment by organizing effective and efficient treatments of hemangiomas and vascular malformations, confirming the safety, and systematizing treatment, employing evidence-based medicine (EBM) techniques and aimed at improvement of the outcomes. Clinical questions (CQs) were decided based on the important clinical issues. For document retrieval, key words for literature searches were set for each CQ and literature published from 1980 to the end of September 2014 was searched in Pubmed, Cochrane Library, and Japana Centra Revuo Medicina (JCRM). The strengths of evidence and recommendations acquired by systematic reviews were determined following the Medical Information Network Distribution System (MINDS) technique. A total of 33 CQs were used to compile recommendations and the subjects included efficacy of resection, sclerotherapy/embolization, drug therapy, laser therapy, radiotherapy, and other conservative treatment, differences in appropriate treatment due to the location of lesions and among symptoms, appropriate timing of treatment and tests, and pathological diagnosis deciding the diagnosis. Thus, the Japanese Clinical Practice Guidelines for Vascular Anomalies 2017 have been prepared as the evidence-based guidelines for the management of vascular anomalies.

Comparison of ultrasonographic findings of schwannomas and angioleiomyomas.

A subcutaneous tumor accompanied by tenderness has a myriad of differential diagnoses. Indeed, using physical findings alone to achieve a diagnosis is often challenging. In this study, we focused on schwannomas and angioleiomyomas, which usually develop as hard subcutaneous tumors and are often associated with tenderness. We aimed to determine significant differentiating features between the tumor types, using ultrasonography. We compared clinical findings and ultrasonographic imaging and calculated the statistical significance for each item. In total, we analyzed 11 schwannomas and 13 angioleiomyomas of the extremities, trunk and head. There was no significant difference in patient characteristics or clinical findings. Meanwhile, the mean maximum diameter (P = 0.002), localization (P = 0.04) and entering or exiting nerves (P = 0.01) were significantly different according to ultrasonography findings. Thus, ultrasonography provides excellent information for the initial assessment of a slow-growing, painful, subcutaneous soft tissue mass. According to our study, it is difficult to identify a single, differentiating feature between angioleiomyoma and schwannoma on ultrasonography, but including multiple findings during the work-up can facilitate differential diagnosis.

Real-time monitoring for reforming processes of liquid hydrocarbon fuel-air pre-mixtures by non-thermal plasmas using ion attachment mass spectrometry.

Plasma induced reforming processes of fuel-air mixtures were investigated to understand the mechanism of the plasma-assisted combustion technique, which can improve the thermal efficiency and stability of internal combustion engines. In this study, a mixture of air with isooctane or n-heptane fuels was reformed by non-thermal plasma in a flow reactor, generated by a dielectric barrier discharge, and then directly analyzed using ion attachment mass spectrometry. Plasma irradiation of an air/hydrocarbon mixture produced an oxygen atom which then reacted with a hydrocarbon, leading to hydroxyl and alkyl radicals. The alkyl radical was immediately converted to alkyl hydroperoxide, which is suggested to be a long-living intermediate for the fuel reforming process. Finally, ketone and aldehyde were formed through the alkyloxy radical intermediate. The details of each reaction process were investigated by ab initio calculations. The proposed plasma induced fuel reforming processes are strongly supported by the computational results.

[Benign Subcutaneous Nodules for the Diagnosis of Which Ultrasonography Is Useful].

OBJECTIVE: We analyzed sonographic appearance of dermatofibroma, schwannoma, small-sized venous mal- formation, glomus tumor, nodular fasciitis, and thrombus for effective use in the diagnosis. METHODS: We evaluated with sonography 44 subcutaneous nodules in histopathologically proven cases. RESULTS AND DISCUSSION: 1) Sonography was the most useful for diagnosing schwannoma. Six of 8 lesions were diagnosed correctly from sonographic appearance. They had increased posterior echo and Doppler flow signals. 2) Sonography was helpful in diagnosis of subungual glomus tumor, though malignant melano- ma should be excluded. One of 6 glomus tumors was not detected but all of the other had well-defined mar- gins and showed internal vascularity. Three subungual glomus tumors were diagnosed from sonographic appearance although 2 nonsubungual tumors were not. 3) It was difficult to diagnose nodular fasciitis with sonography. Two of 5 cases were not detected. The other 3 lesions were ill-defined, and 2 were hy- perechoic and 2 showed internal vascularity. Interval between emergence of the lesion and sonography ex- amination was important. This duration was more than 50 days in lesions not detected with sonography, about 20 days in 2 hyperechoic lesions, and 6 days in a hypoechoic lesion. 4) Dermatofibromas (n =14) were also difficult to be diagnosed. The region was very characteristic, that is, in the upper dermis. Other find- ings, such as hypoechoic appearance and well-defined margin, were nonspecific. CONCLUSION: Sonography was more useful for diagnosing schwannoma and glomus tumor. We have to know their characteristic appearance on sonography to use sonography effectively. [Original].

The use of next-generation sequencing in molecular diagnosis of neurofibromatosis type 1: a validation study.

AIMS: We assessed the validity of a next-generation sequencing protocol using in-solution hybridization-based enrichment to identify NF1 mutations for the diagnosis of 86 patients with a prototypic genetic syndrome, neurofibromatosis type 1. In addition, other causative genes for classic genetic syndromes were set as the target genes for coverage analysis. RESULTS: The protocol identified 30 nonsense, 19 frameshift, and 8 splice-site mutations, together with 10 nucleotide substitutions that were previously reported to be pathogenic. In the remaining 19 samples, 10 had single-exon or multiple-exon deletions detected by a multiplex ligation-dependent probe amplification method and 3 had missense mutations that were not observed in the normal Japanese SNP database and were predicted to be pathogenic. Coverage analysis of the genes other than the NF1 gene included on the same diagnostic panel indicated that the mean coverage was 115-fold, a sufficient depth for mutation detection. CONCLUSIONS: The overall mutation detection rate using the currently reported method in 86 patients who met the clinical diagnostic criteria was 92.1% (70/76) when 10 patients with large deletions were excluded. The results validate the clinical utility of this next-generation sequencing-based method for the diagnosis of neurofibromatosis type 1. Comparable detection rates can be expected for other genetic syndromes, based on the results of the coverage analysis.

Translationally controlled tumor protein is a novel biological target for neurofibromatosis type 1-associated tumors.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that predisposes individuals to develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). Due to the lack of information on the molecular mechanism of NF1-associated tumor pathogenesis or biomarkers/therapeutic targets, an effective treatment for NF1 tumors has not been established. In this study, the novel NF1-associated protein, translationally controlled tumor protein (TCTP), was identified by integrated proteomics and found to be up-regulated via activated MAPK/PI3K-AKT signaling in response to growth factors in NF1-deficient Schwann cells. Immunohistochemical analysis of NF1-associated tumors revealed that the TCTP expression level correlated with tumorigenicity. In NF1-deficient MPNST cells, TCTP protein but not mRNA was down-regulated by NF1 GTPase-activating protein-related domain or MAPK/PI3K inhibitors, and this correlated with suppression of mammalian target of rapamycin (mTOR) signaling. mTOR inhibition by rapamycin also down-regulated TCTP protein expression, whereas knockdown or overexpression of TCTP suppressed or activated mTOR signaling, respectively, and affected cell viability. These results suggest that a positive feedback loop between TCTP and mTOR contributes to NF1-associated tumor formation. Last, the anti-tumor effect of artesunate, which binds to and degrades TCTP, was evaluated. Artesunate significantly suppressed the viability of MPNST cells but not normal Schwann cells, and the TCTP level inversely correlated with artesunate sensitivity. Moreover, combinational use of artesunate and rapamycin enhanced the cytotoxic effect on MPNST cells. These findings suggest that TCTP is functionally implicated in the progression of NF1-associated tumors and could serve as a biological target for their therapy.

[Sonographic appearance of benign subcutaneous nodules--including color Doppler sonography].

OBJECTIVE: Color Doppler sonography is used to distinguish malignant from benign subcutaneous nodules because many malignant tumors show an increased number of vessels. But benign lesions, such as inflammatory epidermal cysts, pilomatricomas, palmoplantar fibromatoses show vascular flow signals. We analyze diagnostic factors for subcutaneous nodules on the basis of ultrasonographic appearance including color Doppler sonography. METHODS: We evaluated with sonography 79 subcutaneous nodules in histopathologically proven cases. RESULTS AND DISCUSSION: The diagnostic findings for 28 epidermal cysts were increased posterior echo(sensitivity 77%, specificity 90%). Vascular flow signals were seen in 7 cases(25%). The signals were seen from periphery to adjacent zone of the mass. They were accompanied by inflammatory granulation tissues histologically. The percentage of blood flow may be related to the percentage of "ruptured" epidermal cysts. Pilomatricomas (n = 9) had internal echogenic foci or Doppler flow signals, and no posterior enhancement (sensitivity 89%, specificity 78%). Seven pilomatricomas showed Doppler flow signals in the mass. The percentage of flow signals is explained by the degree of internal echogenic foci because remarkable calcium deposits producing posterior acoustic shadowing prevent us from flow signals. Palmoplantar fibromatoses (n = 5) were ill-defined margins and showed internal vascularity with no posterior enhancement (sensitivity 80%, specificity 94%). CONCLUSION: More benign lesions showed vascular flow signals than reported previously. We have to diagnose subcutaneous nodules referring to not only color Doppler but also gray scale sonography.

Diagnostic usefulness of findings in Doppler sonography for amelanotic melanoma.

To evaluate the diagnostic usefulness of Doppler sonography for amelanotic melanoma (AM), the correspondence between the findings of dermoscopy and Doppler sonography was investigated in AM in comparison with other hypopigmented tumors. Seven cases with AM and 11 cases with squamous cell carcinoma (SCC), 10 cases with non- or hypopigmented basal cell carcinoma (NP-BCC) and six cases with eccrine poroma (EP) as hypopigmented tumors were investigated. EP is readily recognized by differences from AM and SCC based on a single vertical and non-torvtuous vessels. NP-BCC is distinguished from AM based on tortuosity running in a vertical direction. Though findings of tortuosity in vessels and heterogeneity of vessel size are recognized both in AM and SCC: (i) abundant blood flow was recognized more clearly in AM; (ii) total blood flow was more than 40% in most cases of AM (average, 60.9%); and (iii) more vessels which flow into a tumor are found in AM (85.7%). There is no relationship between dermoscopic findings of vessel types and Doppler sonography findings of vessels. In this study, the diagnostic usefulness of the above-mentioned specific findings in examination may suggest using Doppler sonography for AM as one non-invasive method.

[A case of neurocutaneous melanosis associated with focal cortical dysplasia].

A newborn baby boy presented with giant melanocytic nevi on the face, trunk and extremities, and focal cortical dysplasia on MRI. At 3 months of age, he developed intractable epilepsy, and MRI at 2 years of age revealed a high-intensity area in the bilateral cerebellum on T1-weighted images, indicative of melanosis. Based on the findings of the skin and MRI, we diagnosed the boy with neurocutaneous melanosis. Cytodiagnosis of cerebrospinal fluid showed no malignancies. EEG, magnetoencephalogram and ECD-SPECT indicated that the clonic seizures originated from a focus in the right focal cortical dysplasia. Complications also included sebaceous nevus of the head and face, which was characteristic of sebaceous nevus syndrome, lipoma of the face and cauda equina, and limbal dermoid. Sebaceous nevus syndrome may have been due to certain allelic defects that were independent of those for neurocutaneous melanosis.

Superficial type of multiple Basal cell carcinomas: detailed comparative study of its dermoscopic and histopathological findings.

We investigated in detail the dermoscopic and histopathological findings in a case of a superficial type of multiple basal cell carcinomas (BCCs). These multiple lesions (occurring in the chest, neck, and back) showed three different findings, respectively. Dermoscopy of the erythematous and brown-colored patch on the anterior chest showed spoke wheel areas, and the histopathological cross-section revealed vertical spoke wheel structures. In the black- and brown-colored patch at the neck, the dermatoscopy showed a maple leaf-like structure, which was in accordance with the strengthening of the histological lateral connection of the lesion. The brown-colored patch of the lateral back histologically showed irregularly enlarged spoke wheel-like areas with peripheral increased melanin pigments, which correlated with the dark black color of dermoscopic maple leaf-like areas. The vertical spoke wheel areas by dermatoscopy revealed a horizontal spoke wheel structure by histopathology.

Decreased expression of neurofibromin contributes to epithelial-mesenchymal transition in neurofibromatosis type 1.

Plexiform and/or dermal neurofibromas are nerve sheath tumors of the peripheral nervous system that are usually present in individuals with neurofibromatosis type 1 (NF1). Neurofibromas arise from Schwann cells with biallelic inactivation of NF1, the gene that encodes neurofibromin. This protein is responsible for regulation of the Ras-mediated pathway, which has been shown to play a crucial role in epithelial-to-mesenchymal transition (EMT). EMT is a biological process that occurs during embryogenesis and wound healing and is involved in pathological processes such as organ fibrosis and cancer metastasis. However, the relationship between neurofibromin and EMT has not been elucidated. We investigated whether the EMT-related signaling pathway was upregulated in NF1-associated neurofibromas and Schwann cells by assessing the expression levels of the EMT-related transcription factors Snail, Slug, Twist, ZEB1 and ZEB2. Immunohistochemical studies and quantitative reverse transcription polymerase chain reaction revealed an increase in the expression levels of EMT-related transcription factors in neurofibroma specimens and NF1-derived Schwann cells (sNF96.2). In addition, the silencing of NF1 by siRNA induced the expression of EMT-related transcription factors in normal human Schwann cells and in epithelial-like breast cancer cells. Our findings suggest that the loss of neurofibromin activated the EMT-related signaling pathway and that the excessive mesenchymal reaction may play a key role in the development of NF1-associated neurofibromas.

Two cases of childhood bullous pemphigoid.

This report describes two cases of childhood bullous pemphigoid (BP). These cases showed vesiculobullous lesions on the face, trunk, extremities, hands and feet. Histopathological analysis of skin lesions showed infiltration of numerous lymphocytes and eosinophils in the superficial dermis. Immunofluorescent analysis showed a linear IgG deposit along the basement membrane zone. In both cases ELISA showed circulating IgG autoantibodies against the NC16A domain of 180-KDa BP antigen (BP180). Both IgG and IgA (faint deposit) autoantibodies against the NC16A domain of BP180 were detected by an immunoblot analysis in both cases. Both patients showed a similar clinical course with a rapid remission after treatment with topical corticosteroids. Both patients received vaccinations within two weeks before the appearance of the eruption. These cases were considered to be childhood BP presenting both IgG and IgA autoantibodies against the NC16A domains of BP180.

Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity.

Hedgehog (Hh)-Patched1 (Ptch1) signaling plays essential roles in various developmental processes, but little is known about its role in postnatal homeostasis. Here, we demonstrate regulation of postnatal bone homeostasis by Hh-Ptch1 signaling. Ptch1-deficient (Ptch1+/-) mice and patients with nevoid basal cell carcinoma syndrome showed high bone mass in adults. In culture, Ptch1+/- cells showed accelerated osteoblast differentiation, enhanced responsiveness to the runt-related transcription factor 2 (Runx2), and reduced generation of the repressor form of Gli3 (Gli3rep). Gli3rep inhibited DNA binding by Runx2 in vitro, suggesting a mechanism that could contribute to the bone phenotypes seen in the Ptch1 heterozygotes. Moreover, systemic administration of the Hh signaling inhibitor cyclopamine decreased bone mass in adult mice. These data provide evidence that Hh-Ptch1 signaling plays a crucial role in postnatal bone homeostasis and point to Hh-Ptch1 signaling as a potential molecular target for the treatment of osteoporosis.

Color Doppler endoscopic ultrasonography in identifying groups at a high-risk of recurrence of esophageal varices after endoscopic treatment.

BACKGROUND: Our preliminary study indicated that either a high hepatofugal flow velocity in the left gastric vein (LGV) or an anterior branch dominant pattern seen under color Doppler EUS (CD-EUS) were possible contributing risk factors for variceal recurrence after endoscopic treatment. However, the sample size was too small, and in this study we aimed to validate the results of the preliminary study. METHODS: Sixty-eight patients treated for moderate or large esophageal varices between 2001 and 2004 at a single university hospital were enrolled in this study. CD-EUS was followed by endoscopic variceal ligation and sclerotherapy. RESULTS: Patients were classified into either a high-risk group, which exhibited anterior branch dominance and flow velocity of 12 cm/s or more, or a low-risk group, which included all other patients. Half of the patients in the high-risk group exhibited a recurrence within half a year, whereas it took almost 2 years for half of the patients in the other group to exhibit a recurrence (P=0.0044). Using the Cox proportional hazard model with multivariate analysis, only the features of the high-risk group were significant in triggering recurrence of varices (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.35-6.65; P<0.001). CONCLUSIONS: These results suggest that patients showing anterior branch dominance and rapid hepatofugal flow velocity in the LGV on CD-EUS examination may have a high risk of an early recurrence of esophageal varices.

Usefulness of D2-40 immunohistochemistry for differentiation between kaposiform hemangioendothelioma and tufted angioma.

BACKGROUND: Recent investigations have demonstrated the utility of the monoclonal antibody D2-40 as a marker for lymphatic endothelium. D2-40 can be used on formalin-fixed and paraffin-embedded materials. Our objective was to elucidate, using D2-40 immunohistochemistry, the differences among capillary hemangiomas, and especially between kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). We studied four cases of KHE, nine cases of TA, and 31 cases of other vascular tumors. Antibodies against CD31, CD34, factor VIII-related antigen, and GLUT1 were also applied. RESULTS: In KHE, D2-40 was markedly reactive for three and partially for one of four cases in the peripheral area of Kaposi's sarcoma-like proliferative capillaries and negative in the surrounding dilated vessels. In TA, D2-40 was partially positive in the surrounding dilated vessels and negative in cannonball-like proliferative capillaries. CONCLUSIONS: Our results suggest that D2-40 is a useful antibody for immunohistochemical discrimination between KHE and TA. In addition, the difference of immunostaining pattern of D2-40 is limited to the peripheral area of capillary proliferation and surrounding dilated vessels; therefore, it is suggested that KHE and TA may reflect different stages in the evolution of a single entity. Namely, they may originate from stem cells possessing the characteristics of both lymphatic and blood vessel endothelial lineages.

New approach to diagnosing ampullary tumors by magnifying endoscopy combined with a narrow-band imaging system.

BACKGROUND: A newly developed narrow-band imaging (NBI) system, which uses modified optical filters, can yield clear images of microvessels and surface structure in gastric and colonic diseases. In the present study, we investigated the ability of magnifying endoscopy with NBI (MENBI) to diagnose and differentiate between benign and malignant ampullary tumors. METHODS: Fourteen patients, whose ampullas were noted to be significantly enlarged or protruding with conventional endoscopy, were enrolled in the study. Specimens, which were obtained by forceps biopsy, endoscopic papillectomy, and/or surgery, were retrieved for histopathological examination. The correlation between MENBI images and histopathological findings was investigated. MENBI findings were classified as I, oval-shaped villi; II, pinecone/leaf-shaped villi; or III, irregular/nonstructured. In addition, tortuous, dilated, and network-like vessels noted on the ampullary lesions with MENBI were defined as abnormal vessels. RESULTS: In 6 of 14 patients, the ampullary changes were proven to be inflammatory in forceps biopsy specimens, without any evidence of malignancy after more than 1 year of follow-up. In five patients, ampullary lesions were treated by endoscopic papillectomy, and in three, by pancreatoduodenectomy. All adenomas and adenocarcinomas had type II and/or type III surface structures, and patients whose ampulla had a type I surface structure had only inflammatory or hyperplastic changes. In addition, abnormal vessels were seen only in adenocarcinomas and never in adenomas. CONCLUSIONS: MENBI has the ability and potential to predict histological characteristics of ampullary lesions.