A Case of Superficial Siderosis with Elevated Anti-Ro/SSA Antibody.

Superficial siderosis (SS) of the central nervous system is a rare disorder that is caused by chronic or recurrent hemorrhage in the subarachnoid space via a dural defect at the spinal level. The most common clinical features of SS include slow-progressive sensorineural deafness, cerebellar symptoms, and pyramidal tract signs. Considering that SS can present with broad clinical manifestations, for precise diagnosis, this disease must be understood. Anti-Ro/SSA antibodies are commonly detected in patients with Sjögren's syndrome and are utilized as markers for autoimmune diseases. In this report, we present a unique pathological condition in which SS coincided with a positive anti-Ro/SSA antibody test result. During the diagnosis of gait disturbance, an elevation in anti-Ro/SSA antibody was detected, and steroid pulse therapy was initiated as the initial treatment for autoimmune diseases. Head magnetic resonance imaging (MRI) revealed extensive hypointensity as a dark band that surrounded the intracranial basal structures and cerebellar hemispheres. Spinal MRI indicated ventral longitudinal intraspinal fluid collection extending from C7 to T5 as well as a defect in the ventral T2-3 dura mater. Intraoperative visualization revealed that the intradural venous plexus was the source of bleeding that caused the SS. To our knowledge, this report is the first to discuss the presence of anti-Ro/SSA antibodies in patients with SS. The role of anti-Ro/SSA antibodies in the pathophysiology of SS remains unclear; therefore, to confirm a possible association, further research and accumulation of cases are required.

Skill Proficiency, Efficacy, and Safety of the Transradial Approach in Transarterial Treatments for Hepatocellular Carcinoma.

Introduction Abdominal angiography procedures such as transarterial chemoembolization (TACE) are essential for hepatocellular carcinoma treatment. One method commonly used is transfemoral access (TFA). However, issues associated with this method, which include postoperative compression of the puncture site and long periods of bed rest, can affect patient satisfaction. Thus, transradial access (TRA), a minimally invasive treatment method that improves treatment quality, was developed for TACE. This retrospective, multicenter study aimed to investigate the efficacy and safety of abdominal angiography using the radial artery approach. Methods In total, 1,601 patients underwent abdominal angiography using TRA and received treatment (radial access for visceral intervention (RAVI)) at 14 institutions in Japan. The treatment time, procedure completion rate, patient satisfaction, and complications were investigated. Results The success rate of RAVI was 99.4%, and the complication rate was 1.2%. Approximately 98.2% of the patients requested the radial artery approach again. There were no significant differences in the success rate of RAVI and the incidence of complications based on the operator's years of experience or the patient's age. Some patients developed minor complications such as puncture site bleeding, hematoma, vascular pain, and vasospasm. Further, serious complications (cerebral infarction (n = 1), cerebellar infarction (n = 1), and aortic dissection (n = 1)) were observed. Conclusion Similar to the conventional TFA, RAVI helped in facilitating peritoneal angiography safely. In abdominal angiography, this method can reduce patient burden and can be widely used in the future from the perspective of clinical benefit.

Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial.

Introduction: Intractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs. Methods: This was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5-15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration. Results: Eleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham-Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4-83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable. Conclusion: Sirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.

Interposition of great saphenous vein on lymphatic venous anastomosis for infantile intractable chylothorax.

Central lymphatic diseases such as intractable chylothorax can be fatal. Lymphatic venous anastomosis at the venous angle level is expected to give a direct therapeutic effect because it opens the obstructed outlet of the main lymphatic vessels. However, the original methods resulted in some important issues, such as the potential for venous reflux. In the present case, we modified the original anastomosis method by interposing a vein graft with venous valves to increase the distance and prevent venous reflux. Collecting the lymphatic flow resulted in termination of the chylothorax with preserved postoperative patency for years, without any complications, including at the graft-harvested extremity.

Distribution and favorable prognostic implication of genomic EGFR alterations in IDH-wildtype glioblastoma.

BACKGROUND: We aimed to evaluate the mutation profile, transcriptional variants, and prognostic impact of the epidermal growth factor receptor (EGFR) gene in isocitrate dehydrogenase (IDH)-wildtype glioblastomas (GBMs). METHODS: We sequenced EGFR, evaluated the EGFR splicing profile using a next-generation sequencing oncopanel, and analyzed the outcomes in 138 grade IV IDH-wildtype GBM cases. RESULTS: EGFR mutations were observed in 10% of GBMs. A total of 23.9% of the GBMs showed EGFR amplification. Moreover, 25% of the EGFR mutations occurred in the kinase domain. Notably, EGFR alterations were a predictor of good prognosis (p = 0.035). GBM with EGFR alterations was associated with higher Karnofsky Performance Scale scores (p = 0.014) and lower Ki-67 scores (p = 0.005) than GBM without EGFR alterations. EGFRvIII positivity was detected in 21% of EGFR-amplified GBMs. We identified two other EGFR variants in GBM cases with deletions of exons 6-7 (Δe 6-7) and exons 2-14 (Δe 2-14). In one case, the initial EGFRvIII mutation transformed into an EGFR Δe 2-14 mutation during recurrence. CONCLUSIONS: We found that the EGFR gene profiles of GBM differ among cohorts and that EGFR alterations are good prognostic markers of overall survival in patients with IDH-wildtype GBM. Additionally, we identified rare EGFR variants with longitudinal and temporal transformations of EGFRvIII.

Investigating developmental and disease mechanisms of the cerebellum with pluripotent stem cells.

The cerebellum is a brain region located in the dorsal part of the anterior hindbrain, composed of a highly stereotyped neural circuit structure with small sets of neurons. The cerebellum is involved in a wide variety of functions such as motor control, learning, cognition and others. Damage to the cerebellum often leads to impairments in motor skills (cerebellar ataxia). Cerebellar ataxia can occur as a result of neurodegenerative diseases such as spinocerebellar ataxia. Recent advances in technologies related to pluripotent stem cells and their neural differentiation has enabled researchers to investigate the mechanisms of development and of disease in the human brain. Here, we review recent applications of leading-edge stem cell technologies to the mechanistic investigation of human cerebellar development and neurological diseases affecting the cerebellum.

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 (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.

Bilateral Stress Fractures of the Femoral Neck after Total Knee Arthroplasty: Importance of Early Diagnosis.

Unilateral stress fracture of the femoral neck following total knee arthroplasty (TKA) is a rare complication; only 21 cases are described in English literature so far. Bilateral stress fractures of the femoral neck occurring simultaneously following a bilateral TKA have been seen in only 2 cases till now. We report a patient suffering from rheumatoid arthritis of both knees, who was treated with bilateral TKA. She developed spontaneous fractures of the femoral neck on both sides 12 months following the TKA. She was treated with bilateral total hip arthroplasty (THA). Stress fracture of the femoral neck should be suspected in patients complaining of hip pain who have undergone TKA.

Inhibition of microtubule assembly competent tubulin synthesis leads to accumulation of phosphorylated tau in neuronal cell bodies.

Neurofibrillary tangles, a pathological hallmark of Alzheimer's disease (AD), are somatodendritic filamentous inclusions composed of hyperphosphorylated tau. Microtubule loss is also a common feature of affected neurons in AD. However, whether and how the disruptions of microtubules and the microtubule-associated proteins occur in the pathogenesis of AD remain unclear. Recent evidence indicates that reduced expression of tubulin by knocking down a tubulin chaperon can cause tau neurotoxicity. Thus, the disruption of tubulin homeostasis may result in the acquisition of tau pathogenesis and ultimately cause tauopathy. To investigate whether the disruption of tubulin maintenance induces tau abnormalities in mammalian neurons, we developed a miRNA-mediated knockdown system of tubulin-specific chaperon E (Tbce), which is a factor required for the de novo synthesis of tubulin. Tbce knockdown in mouse primary cultured neurons induced an increase in tubulin in the cell body at 14 days in vitro. Accumulated tubulin was not acetylated or incorporated in microtubules, indicating that they were functionally inert. Concomitantly, tau also accumulated in neuronal cell bodies. The mis-localized tau was phosphorylated at Ser202/Thr205 and Ser396/Ser404. These results indicate that Tbce knockdown in mammalian neurons induces not only a reduction in properly folded tubulins, which are microtubule assembly competent, but also an accumulation of phosphorylated tau in the cell body of mammalian neurons. These findings suggest that disruption of the homeostatic mechanism for maintaining tubulin biosynthesis and/or microtubules can cause tau accumulation in the cell body, which is commonly observed in tauopathies.

Regulatory mechanisms for the axonal localization of tau protein in neurons.

Tau is a microtubule (MT)-associated protein that is thought to be localized to the axon. However, its precise localization in developing neurons and mechanisms for the axonal localization have not been fully addressed. In this study, we found that the axonal localization of tau in cultured rat hippocampal neurons mainly occur during early neuronal development. Interestingly, transient expression of human tau in very immature neurons, but not in mature neurons, mimicked the developmental localization of endogenous tau to the axon. We therefore were able to establish an experimental model, in which exogenously expressed tau can be properly localized to the axon. Using this model, we obtained a surprising finding that the axonal localization of tau did not require stable MT binding. Tau lacking the MT-binding domain (MTBD) exhibited high diffusivity but localized properly to the axon. In contrast, a dephosphorylation-mimetic mutant of the proline-rich region 2 showed reinforced MT binding and mislocalization. Our results suggest that tight binding to MTs prevents tau from entering the axon and results in mislocalization in the soma and dendrites when expressed in mature neurons. This study therefore provides a novel mechanism independent of MTBD for the axonal localization of tau.

Colorectal neuroendocrine carcinoma: A case report and review of the literature.

BACKGROUND: Colorectal neuroendocrine carcinoma (NEC) is a rare tumor that demonstrates aggressive growth pattern with ingrowth into the tract, metastasis to the other organs, and invasion to the surrounding organs; these clinical characteristics result in poor prognosis. Surgical resection appears as an effective approach; however, because it is difficult to accurately diagnose NEC during the early stage and owing to its aggressive growth pattern, development of a reliable standard chemotherapy regimen and management strategies are essential. CASE SUMMARY: Here, we report the case of patient with NEC showing an aggressive growth pattern that resulted in the rupture of the tumor to the outside the colon after stenting of the internal colonic stenosis. In addition, the tumor invaded into the duodenum, thereby causing duodenal stenosis that required an additional stent in the duodenum. This aggressive growth pattern is one of the main features of the NEC that is different from adenocarcinoma. To clarify the clinical characteristics, we reviewed 60 recently reported cases, including data on tumor location, size, treatment, and prognosis. CONCLUSION: We consider that the information presented here is of great significance for the diagnosis, treatment, and management of symptoms of the patients with NEC.

A Simple Skin Incision Design for Pediatric Superficial Branch of Superficial Circumflex Iliac Artery.

BACKGROUND: Superficial circumflex iliac artery (SCIA) perforator flap is one of the demanding flaps. However, little is known about SCIA anatomy, which is crucial for successful SCIA perforator flap elevation, in children. We assessed the efficacy of our incision design to detect the superficial branch of the SCIA in vivo. METHODS: Eleven consecutive pediatric patients who required harvesting (eg, skin grafts or vascularized lymph node transfer) were assessed. All possible congenital vascular malformation cases were excluded. To reduce potential bias, all groin procedures were performed on the contralateral side of malformations. After inguinal area mapping, 1.5-cm skin incision was made. From the window opened by the skin incision, tiny perforation to the skin surface was detected for further dissection. Following the tiny branch, the main trunk of the superficial circumflex vascular bundle was dissected. The whole vascular bundle, artery, and major vein from the bundle were dissected and their sizes were measured. RESULTS: Of the 11 patients, 4 were boys; the age range was 5 months to 14 years (mean age: 3.2 years). Vessel bundle size was 0.7-1.5 (mean: 1.1 mm). In all cases, the bundle was detected within 5 min (1-5, mean: 2.5 min). No vascular damage was observed, and all arteries pulsated well, without requiring additional skin incision. The superficial branch of the SCIA was mainly detected right below the initial skin incision. CONCLUSIONS: Our skin incision design can effectively detect the SCIA in pediatric patients and may be used in adult patients.

Flow Pattern Classification in Lymphatic Malformations by Indocyanine Green Lymphography.

BACKGROUND: Lymphatic malformation is a congenital lymphatic disorder. Although a few lymphangiographic and lymphoscintigraphic studies of lymphatic malformation exist, its lymphatic flow has not been fully assessed, and a classification system has not yet been established. However, indocyanine green lymphography has been developed to safely provide a fine assessment of lymph flow in the treatment of lymphedema. In addition, indocyanine green lymphography has been shown to be helpful in detecting the lymphatic malformation inflow for the treatment of refractory microcystic type lymphatic malformation using the venous anastomosis technique. Therefore, the authors aimed to reveal the in vivo lymph flow around the lymphatic malformation using indocyanine green lymphography, and to design a classification system according to the observed patterns. METHODS: Indocyanine green lymphography was performed in 20 sequential pediatric patients with lymphatic malformation (aged 11 months to 10 years). Most of the cases were intractable, with microcystic or mixed-type lymphatic malformation. RESULTS: All patients successfully completed lymphography with clear observations. The flow patterns were classified into four types: type 1 had a strong detectable inflow; type 2 had multiple small observable inflows; type 3 had a superficial lymph flow over the lesion; and type 4 had a flow around the lymphatic malformation, without any connections to the lesion. CONCLUSION: The proposed classification system may aid in the further development of surgical treatments for lymphatic malformation.

Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies: A study protocol for an open-label, single-arm, multicenter, prospective study (SILA).

INTRODUCTION: Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials. METHODS: This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5-15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data. RESULTS: This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature. CONCLUSIONS: We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs.

Flow-oriented Venous Anastomosis to Control Lymph Flow of Lymphatic Malformation.

Less-invasive surgeries, such as lymphaticovenular anastomosis (LVA), are the widely accepted intervention for lymphedema. This study aimed to assess the outcomes of flow-oriented LVA modification on lymphatic malformation (LM). METHODS: We included 19 patients diagnosed with LM mixed type or microcystic type, who came to our clinic from June 2015 to December 2017. Under general anesthesia, all patients were administered an indocyanine green lymphography injection subcutaneously. In the case of a strong inflow, the patient underwent afferent lymph vessel of LM to venous anastomosis (LMVA). Otherwise, the side wall of LMVA was performed to the cysts. Outcomes were classified into the following groups based on the size changes: treatment effect (TE) 4 = >80% reduction rate; TE 3 = 50%-80% reduction rate; TE 2 = 20%-50% reduction rate; and TE 1 = 0%-20% reduction rate. RESULTS: All cases underwent surgery, with no case having an increased size. The results were as follows: TE 4 = 4 (21%) patients; TE 3 = 6 (32%) patients; TE 2 = 5 (26%) patients; and TE 1 = 4 (21%) patients. No case required study termination due to disease progression. Minor complication occurred in 3 cases. One vesicle increased at the labial mucosa and one wound dehiscence that epithelized within 1 month. CONCLUSION: LMVA could be a novel, minimally invasive lymph flow-oriented surgical method for intractable LM.

Costochondral Grafting for Nasal Airway Reconstruction in an Infant With Frontonasal Dysplasia.

Frontonasal dysplasia (FND) is a congenital malformation of the central portion of the face, including the eyes, nose, and forehead. Owing to its rarity and wide spectrum of phenotypes, the optimal timing and technique of surgery remain controversial. Here, we report a case of a patient with FND, who presented with respiratory distress. The deformed nostrils were so small that the patient could not normally breathe through the nose immediately after birth. Rhinoplasty using a costochondral graft was performed at 16 months of age. After surgery, the nostrils enlarged and the appearance of the nose improved. Although congenital nasal deformity is frequently corrected during adolescence, surgery at an early stage can be considered when important issues are noted, such as inability to breathe through the nose.

Video Super-microsurgery Amplified using Close-up Lens Filter on the Operative Field Camera: Preliminary Report.

BACKGROUND: Super-microsurgery has widely spread due to the improvement of high magnification microscopes. The cost of multiple microscopes is high. Furthermore, the microscope heads are too large to fit in multiple surgical fields for pediatric patients. We adapted a 2-dimensional magnification system for performing lymphatic venous anastomosis on pediatric lymphedema cases. METHODS: We attached a close-up lens filter to the suspended camera (CHZ-1,360-PTR camera, Carina system, Tokyo, Japan) in the operative field. This was done to achieve 26× magnification using a small camera head, making it possible to perform super-micro anastomoses. Anastomoses time, scar length, and lymph vessel diameters were measured, and the outcomes were statistically analyzed and compared with the contralateral side. RESULTS: Four pediatric lymphedema patients underwent the aforementioned technique, using the multisite microscopic approach. All anastomoses were completed within 20 minutes. The results were not significantly different from the conventional microscopic lymphatic venous anastomosis. CONCLUSION: This system is advantageous because (1) it has less costly initial investments; (2) it requires a small camera head, which provides available space for the multisite microscopic approach even for pediatric patients; and (3) it allows for a wider surgical working space.

Identification of a novel zinc-binding protein, C1orf123, as an interactor with a heavy metal-associated domain.

Heavy metal-associated (HMA) domains bind metal ions at its Cys-x-x-Cys (CxxC) motif and constitute an intracellular network for trafficking of metal ions for utilization and detoxification. We thus expect that novel metalloproteins can be identified by screening proteins interacting with a HMA domain. In this study, we performed yeast two-hybrid screening of the human proteome and found an uncharacterized protein encoded as open reading frame 123 in chromosome 1 (C1orf123) that can interact specifically with the HMA domain of a copper chaperone for superoxide dismutase (CCSdI). Our X-ray structural analysis of C1orf123 further revealed that it binds a Zn2+ ion in a tetrahedral coordination with four thiolate groups from two conserved CxxC motifs. For the interaction between C1orf123 and CCSdI, the CxxC motifs in both C1orf123 and CCSdI were required, implying metal-mediated interaction through the CxxC motifs. Notably, C1orf123 did not interact with several other HMA domains containing CxxC motifs, supporting high specificity in the interaction between C1orf123 and CCSdI. Based upon these results, we further discuss functional and structural significance of the interaction between C1orf123 and CCS.