Current practice of diagnosis and treatment for rectourethral fistula in male patients with anorectal malformation: a multicenter questionnaire survey in Japan.

PURPOSE: Surgical procedures for anorectoplasty for anorectal malformations (ARMs), particularly rectourethral fistula (RUF), depend on the institution. We investigated the diagnosis and treatment of RUF in male patients with ARMs in Japan using a questionnaire survey. METHODS: An online survey inquiring about the diagnosis and treatment (diagnostic modalities, surgical approaches, fistula dissection devices, and fistula closure techniques) of each type of ARM in male patients was conducted among institutional members of the Japanese Study Group of Anorectal Anomalies. Fisher's exact test was used to compare surgical methods between posterior sagittal anorectoplasty (PSARP) and laparoscopy-assisted anorectoplasty (LAARP). RESULTS: Sixty-one institutions (100%) completed the survey. LAARP was the preferred approach for high-type ARM (75.4%). PSARP was preferred for intermediate-type ARM (59.0%). Monopolar devices were most commonly used (72.1%) for RUF dissection. Blunt dissection was more frequent in the PSARP group (PSARP vs. LAARP: 55.6 vs. 20.0%, p < 0.005). Cystoscopy/urethroscopy to confirm the extent of dissection was used more frequently in the LAARP group (70.0% vs. 25.0%, p < 0.005). Clips and staplers were used more frequently in the LAARP group (p < 0.05). CONCLUSION: Distinct fistula management strategies for PSARP and LAARP were revealed. Further studies are needed to investigate the postoperative outcomes associated with these practices.

Comprehensive targeted next-generation sequencing in patients with slow-flow vascular malformations.

Recent studies have shown that the PI3K signaling pathway plays an important role in the pathogenesis of slow-flow vascular malformations (SFVMs). Analysis of genetic mutations has advanced our understanding of the mechanisms involved in SFVM pathogenesis and may identify new therapeutic targets. We screened for somatic variants in a cohort of patients with SFVMs using targeted next-generation sequencing. Targeted next-generation sequencing of 29 candidate genes associated with vascular anomalies or with the PI3K signaling pathway was performed on affected tissues from patients with SFVMs. Fifty-nine patients with SFVMs (venous malformations n = 21, lymphatic malformations n = 27, lymphatic venous malformations n = 1, and Klippel-Trenaunay syndrome n = 10) were included in the study. TEK and PIK3CA were the most commonly mutated genes in the study. We detected eight TEK pathogenic variants in 10 samples (16.9%) and three PIK3CA pathogenic variants in 28 samples (47.5%). In total, 37 of 59 patients (62.7%) with SFVMs harbored pathogenic variants in these three genes involved in the PI3K signaling pathway. Inhibitors of this pathway may prove useful as molecular targeted therapies for SFVMs.

A fetus with large mediastinal cystic lymphatic malformation managed with prenatal serial thoracocentesis and postnatal sclerotherapy.

We report a very rare case of large fetal mediastinal cystic lymphatic malformation (cLM), formerly called lymphangioma, that was managed with prenatal serial thoracocentesis and postnatal sclerotherapy. A fetal pericardial effusion-like lesion gradually increased the size until it occupied more than half of the thoracic cavity. Thoracocentesis was performed three times, namely at 31 and 35 weeks of gestation, and also just before the delivery for decompression. The characteristic shape changes of the lesion were observed after thoracocentesis. A boy delivered by planned cesarian section at term required respiratory support after birth. Postnatal magnetic resonance imaging (MRI), which showed a large cystic lesion with septa and hemorrhage without solid components, led to the diagnosis of cLM. The fluid from the cyst continued to be drained. Neonatal sclerotherapy using OK-432 was effective and the infant recovered well. Fetal thoracocentesis may be useful for the diagnosis and management of a large mediastinal cLM.

Segmental Atrophy of Explanted Livers in Biliary Atresia: Pathological Data From 63 Cases of Failed Portoenterostomy.

OBJECTIVES: Atrophy of the left lateral segment (LLS) is often encountered in liver transplantation (LT) for biliary atresia (BA). To clarify the meaning of the heterogeneous atrophy, we compared the pathological characteristics of the LLS with the right posterior segment (RPS) of BA livers obtained during LT. METHODS: Among the 116 patients with BA who underwent LT at our hospital between 2014 and 2018, 63 patients with persistent cholestasis after the Kasai portoenterostomy (KP) were selected. Three pathologists evaluated tissues from the LLS and RPS for 5 pathological parameters. Positive areas in whole-slide image observed as portal inflammation, fibrosis, cholestasis, and ductular reaction, were analyzed with automated image quantitation. Moreover, we examined the relationship between the pathological score and the Pediatric End-stage Liver Disease (PELD) score. RESULTS: The median age at LT was 7 months (range 4-26 months). Inflammation and fibrosis were significantly greater in the LLS than in the RPS (P < 0.001, for both); however, there were no differences in cholestasis, ductular reaction, and hepatocellular damage (P = 0.3, 0.3, and 0.82). The same results were obtained in automated image quantitation. Moreover, the sums of the 5 pathological scores in the LLS showed a significant positive correlation with the PELD score (P = 0.016, rs = 0.3). CONCLUSIONS: More severe inflammation and fibrosis without cholestasis were observed in the LLS. The segmental atrophy may not be associated with poor bile drainage, but with etiopathogenesis of BA. Moreover, the proper site for biopsy during KP could be the LLS.

Efficacy and safety of sclerotherapy with polidocanol in children with internal hemorrhoids.

BACKGROUND: Hemorrhoids are an extremely rare condition in children, and data on its incidence and treatment in the pediatric population remains scarce. We retrospectively reviewed children who underwent sclerotherapy for internal hemorrhoids, and analyzed patients' characteristics and outcomes. METHODS: A total of 14 pediatric patients who underwent sclerotherapy were included. Patients' ages and the required amount of polidocanol, depending on the grade of hemorrhoids, and the correlation between age and volume of sclerosant, were statistically analyzed. RESULTS: Patients had a male predominance with a ratio of 2.5:1 (grade 2:6 patients, grade 3:8 patients). Four children had underlying conditions including portal hypertension and Klippel-Trenaunay syndrome. Of the 14 patients, 43% had constipation requiring medication or enema. Only one minor complication, a perianal ulceration, was found to be associated with sclerotherapy. Patients with grade 3 hemorrhoids required a significantly larger amount of polidocanol than those with grade 2 hemorrhoids. Two patients with grade 3 hemorrhoids required a second session of treatment for recurrence. The success rate of sclerotherapy with polidocanol was 86%. CONCLUSIONS: Sclerotherapy with polidocanol is a safe, effective, and less invasive treatment option for internal hemorrhoids in children. Further studies are needed to investigate this treatment approach.

[Dislodgement of a long-term inserted catheter from the connecting parts of an implantable central venous port in a child with hemophilia].

A central venous access device (CVAD) was implanted in a child with hemophilia for long-term replacement therapy with factor VIII. Four years and eight months after its insertion, malfunction was observed. Further study revealed migration of the transected catheter to both the pulmonary arteries. The retrieved catheter displayed a tear and dislodgement at the anastomosis between the port and catheter. To the best of our knowledge, no case of extensive CVAD damage in children with hemophilia has been reported. Patients with CVAD malfunction are often asymptomatic; however, this condition could lead to a fatal outcome. Therefore, clinicians need to be aware of this complication.

Immunologic Effects of Sirolimus in Patients With Vascular Anomalies.

Emerging data have suggested that sirolimus may be a treatment option for complicated vascular anomalies (VAs). The present study aimed to investigate the immunologic effects of sirolimus treatment for 6 months in patients with VAs. Blood samples obtained from the patients enrolled in 2 multicenter studies to investigate the efficacy of sirolimus for VAs before and after sirolimus treatment for 6 months were used. Data for total white blood cell count, absolute lymphocyte count, serum immunoglobulins (Igs) levels (IgG, IgA, IgM), lymphocyte proliferation assays with mitogens including phytohemagglutinin and concanavalin A, and flow cytometric analysis of lymphocyte subsets were evaluated. A total of 18 patients with VAs receiving sirolimus treatment were included in the study. Comparisons of white blood cell, absolute lymphocyte count, IgG, IgA, IgM, and reaction rates of phytohemagglutinin and concanavalin A revealed no significant differences before and after treatment. No significant differences were observed in the absolute counts of lymphocyte subtypes before and after treatment, except for regulatory T-cell counts, which were significantly decreased after treatment. Severe infections were not observed during sirolimus treatment. The immunologic parameters assessed in the present study were hardly affected by sirolimus treatment for 6 months in patients with VAs.

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.

Potential biomarkers of kaposiform lymphangiomatosis.

BACKGROUND: Kaposiform lymphangiomatosis (KLA) has recently been distinguished as a novel subtype of generalized lymphatic anomaly (GLA), and is characterized by foci of spindle endothelial cells amid a background of malformed lymphatic channels. The etiology of these diseases remains unknown and diagnosis is confounded by their similar clinical findings. This study aimed to clarify differences in the clinical findings and plasma cytokine profiles of GLA and KLA patients. PROCEDURE: Clinical features data of GLA and KLA patients were obtained from a national survey. Differences in clinical findings, plasma levels of cytokines, and survival were analyzed. Plasma was obtained from healthy controls and GLA and KLA patients. Thirty-six angiogenic and lymphangiogenic factors were evaluated for cytokine concentration. RESULTS: Twenty-one patients with GLA and 11 with KLA were recruited. Mediastinal masses, hemorrhagic pericardial and pleural effusion, coagulation disorders, and thrombocytopenia were more frequent in KLA than in GLA. KLA had a significantly poorer outcome than GLA (P = 0.044). Soluble VEGFR3, angiopoietin 2, HGF, soluble HER2, tenascin C, and soluble HGFR levels were higher in KLA. Notably, soluble VEGFR3 and angiopoietin 2 levels were approximately 10-fold higher than those of other molecules measured. However, soluble VEGFR1 and soluble TIE2 were lower in KLA than in GLA and the controls. CONCLUSIONS: Patients with KLA have an unfavorable prognosis and serious symptoms (hemorrhagic pleural effusion and coagulation disorders). Our data indicate that eight angiogenic cytokines might be potential biomarkers of KLA.

Indications for tracheostomy in children with head and neck lymphatic malformation: analysis of a nationwide survey in Japan.

PURPOSE: Airway obstruction caused by lymphatic malformation (LM) in the head and neck may require a tracheostomy. We present the results of our analysis of a nationwide survey on the indications for tracheostomy in children with head and neck LM. METHODS: We analyzed data in relation to tracheostomy based on a questionnaire about 518 children with head and neck LM without mediastinal involvement. RESULTS: Tracheostomy was performed for 43 of the 518 children. Most (32/43) of these children were younger than 1 year of age and the tracheostomy was almost always performed for airway obstruction (40/43). The lesion was in contact with the airway in 32 (72%) of these children, but in only 58 (12%) of the 473 children who were managed without tracheostomy. When the maximum circumferential area of contact was compared, only 20 (27%) of 74 patients with maximum contact of less than a half-circle required tracheostomy, whereas 11 of 13 with maximum contact of more than a half-circle required tracheostomy (P = 0.0001). Six patients without airway contact required tracheostomy because of acute swelling caused by hemorrhage, infection, or both. CONCLUSIONS: Children with head and neck LM required tracheostomy to relieve airway obstruction. Tracheostomy should be considered if the lesion is in contact with the airway and surrounds more than a half-circle, and when it causes acute swelling.

Treatment of mediastinal lymphatic malformation in children: an analysis of a nationwide survey in Japan.

PURPOSE: Clinical guidelines on lymphatic malformation (LM) influencing the airway have been crafted in the Research Project for Intractable Diseases. We herein report an analysis of a nationwide survey of mediastinal LM and the therapeutic recommendations. METHODS: Eighty-seven registered cases with mediastinal involvement were analyzed with a review of the literature. RESULTS: Mediastinal LM was located more often in the upper and anterior mediastinum and was found without any accompanying symptoms in 56/87 cases. Tracheostomy was required in 23/87 cases, mostly < 2 years of age (87%). All patients who needed tracheostomy had a lesion in contact with the airway, while only 55% of those without tracheostomy had contact. Tracheostomy tended to be placed more when the longer segment of the airway was in contact with the LM. Multimodal treatments were performed in 29 patients, but the lesions remained in most cases, and chylothorax, hemorrhaging, nerve palsy, and infections were noted as complications. CONCLUSIONS: In patients with mediastinal LM, tracheostomy may be necessary, especially when the lesion is extensive and contacts the airway. Extirpation of the mediastinal LM may be the only therapeutic option, but in cases with few or no symptoms, non-surgical treatment should be considered in light of potential postoperative complications.

Clinical Features and Prognosis of Generalized Lymphatic Anomaly, Kaposiform Lymphangiomatosis, and Gorham-Stout Disease.

BACKGROUND: Complex lymphatic anomalies are intractable lymphatic disorders, including generalized lymphatic anomaly (GLA), Gorham-Stout disease (GSD), and kaposiform lymphangiomatosis (KLA). The etiology of these diseases remains unknown and diagnosis is confused by their similar clinical findings. This study aimed to clarify the differences in clinical features and prognosis among GLA, KLA, and GSD, in Japanese patients. PROCEDURE: Clinical features, radiological and pathological findings, treatment, and prognosis of patients were obtained from a questionnaire sent to 39 Japanese hospitals. We divided the patients into three groups according to radiological findings of bone lesions and pathology. Differences in clinical findings and prognosis were analyzed. RESULTS: Eighty-five patients were registered: 35 GLA, 9 KLA, and 41 GSD. Disease onset was more common in the first two decades of life (69 cases). In GSD, osteolytic lesions were progressive and consecutive. In GLA and KLA, 18 patients had osteolytic lesions that were multifocal and nonprogressive osteolysis. Thoracic symptoms, splenic involvement, and ascites were more frequent in GLA and KLA than in GSD. Hemorrhagic pericardial and pleural effusions were more frequent in KLA than GLA. GSD had a significantly favorable outcome compared with combined GLA and KLA (P = 0.0005). KLA had a significantly poorer outcome than GLA (P = 0.0268). CONCLUSIONS: This survey revealed the clinical features and prognosis of patients with GLA, KLA, and GSD. Early diagnosis and treatment of KLA are crucial because KLA has high mortality. Further prospective studies to risk-stratify complex lymphatic anomalies and optimize management for KLA are urgently needed.

The optimal immunosuppressive protocol for the portal vein infusion of PGE1 and methylprednisolone in pediatric liver transplantation for fulminant hepatic failure of unknown etiology.

The outcome of LTx in pediatric patients with FHF of unknown etiology remains inferior to that of LTx in pediatric patients with cholestatic diseases. A higher incidence of steroid-resistant severe rejection has been increasingly recognized among the responsible factors. We assessed the efficacy of the administration of steroids and PGE1 via PVI in the management of LTx for FHF in pediatric patients. In our early cohort (1995-2007), seven patients who underwent LTx for FHF of unknown etiology were treated with conventional immunosuppressive therapy (calcineurin inhibitor and a steroid). Seven of eight grafts (one patient underwent re-LTx) sustained CV and/or CPV associated with ACR, and four patients died of a graft failure or infectious complications that were associated with the treatment for rejection. Of note, the pathological incidence of CV/CPV was significantly higher in recipients with FHF of unknown etiology than in recipients with biliary cholestatic disease during the same study period (87.5% vs. 13.7%, p < 0.00001). From 2008, three patients underwent LTx for cryptogenic FHF with PVI and conventional IS. PVI was well tolerated, and no relevant severe complications were observed. More strikingly, the patients who received PVI overcame biopsy-proven immunological events and are all currently doing well with excellent graft function after more than five yr. We conclude that PVI is technically safe and effective for preventing severe rejection in pediatric patients who undergo LTx for FHF of unknown etiology and that it does not increase the risk of fatal infectious complications.

Diagnosing native liver fibrosis and esophageal varices using liver and spleen stiffness measurements in biliary atresia: a pilot study.

BACKGROUND: Biliary atresia commonly leads to liver fibrosis and cirrhotic complications, including esophageal varices. OBJECTIVE: To evaluate liver and spleen stiffness measurements using acoustic radiation force impulse (ARFI) imaging for diagnosing grade of liver fibrosis and predicting the presence of esophageal varices in patients treated for biliary atresia. MATERIALS AND METHODS: ARFI imaging of the spleen and native liver was performed in 28 patients with biliary atresia. We studied the relation between ARFI imaging values and liver histology findings (n=22), upper gastrointestinal endoscopy findings (n=16) and several noninvasive test results. Diagnostic accuracy was assessed using receiver operating characteristic curve analyses. RESULTS: Liver stiffness measurements exhibited a significant difference among the different grades of liver fibrosis (P=0.009), and showed higher values in patients with high-risk esophageal varices than in the other patients (P=0.04). The areas under the receiver operating characteristic curves of liver stiffness measurements for liver fibrosis grades ≥ F2, ≥F3 and = F4 were 0.83, 0.93 and 0.94, respectively. Patients with high-risk esophageal varices were preferentially diagnosed by the combined liver and spleen stiffness measurements (area under the curve, 0.92). CONCLUSION: Liver and spleen stiffness measurements using ARFI imaging are potential noninvasive markers for liver fibrosis and esophageal varices in patients treated for biliary atresia.

Steroid minimization immunosuppression protocol using basiliximab in adult living donor liver transplantation for hepatitis C virus-related cirrhosis.

AIM: Recent randomized trials have failed to prove the benefit of steroid-free immunosuppression in liver transplantation for hepatitis C virus (HCV)-related cirrhosis. Furthermore, there is a lack of data on the use of basiliximab in living donor liver transplantation (LDLT). This pilot study evaluated the safety and efficacy of a steroid minimization protocol using basiliximab compared with standard immunosuppression. METHODS: A single center, prospective cohort analysis was conducted to compare two immunosuppression regimens in adult recipients who underwent LDLT for HCV since 2004: calcineurin inhibitor/mizoribine/basiliximab (the St- group) and calcineurin inhibitor/mizoribine/steroid (the St+ group). Study end-points were rejection rates, recurrent HCV, patient survival and other adverse events up to 2 years after transplantation. RESULTS: A total of 27 consecutive patients were enrolled. Transplantation characteristics were similar between the two groups (14 St- and 13 St+) except ABO incompatible cases being more common in the St+ group. Rejection rates, recurrent HCV, patient survival, fibrosis stage and new-onset diabetes mellitus at 2 years were comparable between the two groups. ABO incompatibility did not affect short- and long-term outcomes. Nine St- and seven St+ recipients underwent interferon and ribavirin therapy for recurrent HCV, with a sustained virological response rate of 33% and 29%, respectively. CONCLUSION: A steroid minimization protocol with basiliximab in adult LDLT for HCV is safe and affords equivalent rejection rates compared with standard immunosuppression. However, no significant differences are observed with respect to recurrent HCV, patient survival and metabolic complications.

Catheter-related blood stream infection caused by Dermacoccus barathri, representing the first case of Dermacoccus infection in humans.

A 7-year-old boy undergoing home parenteral nutrition with totally implantable central venous access device for chronic intestinal pseudo-obstruction experienced repeated episodes of fever with a temperature above 39.0 °C despite the antibiotic treatment. The fever was considered to be catheter-related blood stream infections, as no other etiology could be justified. Repeated blood culture tests revealed negative after 1-week incubation, whereas some samples of blood collected from the central venous catheter yielded positive and gram-positive rods were detected. These bacteria were detected repeatedly, then the central venous access device was removed with consideration for the possibility of this bacteria being a pathogen. Thereafter, the fever did not recur and the blood culture tests were negative. The causative agent was identified as Dermacoccus barathri based on the 16S rRNA gene sequence and phylogenetic analysis of 6118-bp concatenated sequences of 4 housekeeping genes. Genus Dermacoccus are one form of Actinomycetes isolated from human skin and water, but human infection with Dermacoccus spp. has not been previously reported and the pathogenicity of the bacteria remains unclear. To our knowledge, this is the first reported case of Dermacoccus infection in humans.