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.

Psychiatric Features of Children with Chronic Functional Constipation: Focusing on Individuals with Autism Spectrum Disorder.

PURPOSE: The present study aimed to assess the psychiatric characteristics of children with chronic functional constipation using the Aberrant Behavior Checklist-Japanese version and the Pervasive Developmental Disorders/Autism Society Japan Rating Scale, and to examine the frequency of autism spectrum disorder in children with chronic functional constipation. We also investigated differences in treatment duration between children with and without autism spectrum disorder. METHODS: Treatment outcomes were examined retrospectively for 55 participants (chronic functional constipation group: n = 30, mean age 3.4 years; control group: n = 25, mean age, 4.5 years). The association between chronic functional constipation and autism spectrum disorder was evaluated using multivariable logistic regression analysis. RESULTS: The mean Aberrant Behavior Checklist score and frequency of individuals with autism spectrum disorder were significantly higher in the chronic functional constipation group. After adjusting for age and sex, chronic functional constipation was significantly associated with autism spectrum disorder. In the chronic functional constipation group, the frequency of onset was significantly higher in children with autism spectrum disorder under 1 year of age. When treated, the mean duration of constipation was significantly longer in children with autism spectrum disorder. CONCLUSION: Pediatricians, pediatric surgeons, and child psychiatrists should work closely to ensure appropriate treatment of chronic functional constipation in children with autism spectrum disorder.

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.

Atypical Presentation of Duodenal Atresia Concomitant with Type-A Esophageal Atresia in Fetal Life: A Case Report.

Duodenal atresia concomitant with type-A esophageal atresia (DA + TA-EA) is rare. A pronounced enlargement of a closed loop of the upper gastrointestinal tract serves as an early clue for its prenatal detection. We describe an atypical case of DA + TA-EA in which the dilatation of the upper gastrointestinal tract remained mild. Ultrasonographic examination at 28 weeks of gestation showed mild polyhydramnios. Subsequent detailed sonographic and magnetic resonance imaging studies revealed a mildly enlarged stomach and duodenum that resembled a "double bubble," mild ascites, and polydactyly of the right thumb. Fetal abdominal circumference measurements were within normal range. A female neonate born at 36 weeks gestation did not show abdominal distension. DA + TA-EA was diagnosed based on clinical characteristics and X-ray studies of the neonate; the diagnosis was confirmed by surgery. Duodenoduodenostomy and gastrostomy in the first week of life and esophagoesophagostomy at six months of age were performed with satisfactory results, and the infant developed well. Prominent and/or increasing C-shaped fluid collection in the upper abdomen is a highly useful diagnostic sign for DA + TA-EA, but it is not applicable for all fetuses with this disease. Physicians should bear this caveat in mind to avoid diagnostic delays and initiate prompt postnatal therapy.

Treatment guidelines for persistent cloaca, cloacal exstrophy, and Mayer-Rokitansky-Küster-Häuser syndrome for the appropriate transitional care of patients.

We developed treatment guidelines (TGs) for appropriate transitional care of the genitourinary system in patients with persistent cloaca (PC), cloacal exstrophy (CE), or Mayer-Rokitansky-Küster-Häuser syndrome (MRKH). These TGs are in accordance with the Medical Information Network Distribution Service (Minds), published in 2014 in Japan. Clinical questions (CQs) concerning treatment outcomes of the genitourinary system, pregnancy and delivery, and quality of life in adulthood were prepared as six themes for PC and CE and five themes for MRKH. We were able to publish statements on chronic renal dysfunction, hydrometrocolpos, and pregnancy, based on four CQs about PC, four about CE, and two about MRKH, respectively. However, due to the paucity of proper manuscripts, we were unable to make conclusions about the correct timing and method of vaginoplasty for patients with PC, CE, and MRKH or the usefulness of early bladder closure for patients with CE. These TGs may help clarify the current treatments for PC, CE, and MRKH in childhood, which have been carried out on an institutional basis. To improve clinical outcomes, systematic clinical trials revealing comprehensive clinical data of the urinary and reproductive systems, especially the length of the common channel in PC, are essential.

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.

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.

A curative treatment strategy using tumor debulking surgery combined with immune checkpoint inhibitors for advanced pediatric solid tumors: An in vivo study using a murine model of osteosarcoma.

BACKGROUND/PURPOSE: This study aimed to assess the significance of tumor debulking surgery by using immune checkpoint inhibitors for advanced pediatric solid tumors in a murine model of advanced osteosarcoma. METHODS: In C3H mice, 5 × 106 LM8 (osteosarcoma cell line with a high metastatic potential in the lungs originating from the C3H mouse) cells were transplanted subcutaneously. Thereafter, the mice were divided into 4 groups as follows: the control group received no intervention (CG, n = 5), the surgery group underwent subcutaneous tumor resection (tumor debulking surgery) 11 days after transplantation (SG, n = 10), the immunotherapy group received a cocktail consisting of 200 µg each of three antibodies (anti-Tim-3, anti-PD-L1, and anti-OX-86) intraperitoneally on posttransplantation days 11, 14, 18, and 21 (IG, n = 10), and the combination therapy group, tumor debulking surgery on day 11 and the cocktail intraperitoneally on days 11, 14, 18, and 21 (COMBG, n = 10). Survival curves were plotted by using the Kaplan-Meier method and compared with those plotted using the log-rank test. Next, the lungs of mice in the 4 groups were pathologically evaluated. RESULTS: The COMBG showed significantly longer survival than the other three groups (P ≤ 0.002), whereas the SG and IG revealed no difference in survival rate compared to CG. Pathological evaluations revealed no lung metastasis 16 weeks after tumor transplantation in the survivors of COMBG. CONCLUSIONS: The results of this study suggest that tumor debulking surgery combined with immune checkpoint inhibitors could be a curative treatment for advanced pediatric solid tumors.

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.

Surgical Treatment of Inguinal Hernia with Prolapsed Ovary in Young Girls: Emergency Surgery or Elective Surgery.

OBJECTIVE: Inguinal ovarian hernias are common in young girls. Many articles in medical literature recommend early surgery for inguinal ovarian hernia because of the risk of torsion of the prolapsed ovary. However, since many irreducible herniated ovaries in newborn infants and during early infancy undergo spontaneous reduction by the age of 9 months, the policy at our institute is to obtain informed consent from the patient's family and then wait to perform surgery until after 9 months of age. In the present study, we assessed the indications for surgery for inguinal ovarian hernia in newborn infants and during early infancy. METHODS: Between 2003 and 2011, a total of 673 girls with inguinal hernias (age at the time of onset of symptoms: mean, 42.5 months; median, 39 months) were brought to our outpatient clinic for consultation. We reviewed their age at the time of the onset of hernia symptoms and their age at the time of surgery, their history of surgery, and their history of inguinal ovarian hernia using information obtained from their medical records. RESULTS: Among the 673 outpatients, 71 patients (mean/median age at the time of onset of symptoms: 11.2/1.5 months) were diagnosed as having an inguinal ovarian hernia at the time of diagnosis. Among these patients, surgery was performed for 58 patients (mean/median age at the time of surgery: 21.3/11 months). Of these patients, the ovary had already spontaneously reduced into the abdomen in 35 cases (mean/median age at the time of surgery: 24.1/12months), whereas the ovaries were on the wall of the hernia sac in 22 cases (mean/median age at the time of surgery: 17.3/10 months). In one case, a testis instead of an ovary was observed in the hernia sac at the time of surgery. Surgeries were performed in 611 of the 673 patients (mean/median age at the time of surgery: 54/50 months). In 35 cases (mean/median age at the time of surgery: 21.6/10 months), the ovary was still on the hernia sac wall at the time of surgery, but an inguinal ovarian hernia had not been diagnosed before surgery in 13 of these cases. A severe complication occurred in only one case, in which a hernia sac that contained a fallopian tube and ovary was ligated. None of the cases exhibited torsion of the ovary within the inguinal canal. CONCLUSION: Since the ovary can be expected to undergo spontaneous reduction into the abdomen by late infancy in many young patients with inguinal ovarian hernias, patients with inguinal ovarian hernias can be treated by elective surgery at the most convenient age, after 9 months of age.

Internal anal sphincter achalasia: data from a nationwide survey of allied disorders of Hirschsprung's disease in Japan.

PURPOSE: To investigate the incidence and treatment of internal anal sphincter achalasia (IASA) in Japan based on an analysis of data from a nationwide retrospective cohort study of the allied disorders of Hirschsprung's disease. METHODS: Five cases of definitive IASA were collected from a nationwide retrospective cohort study conducted from 2001 to 2010 and a search of the Japanese literature. RESULTS: Symptoms developed during the neonatal period in two patients, during early childhood in two, and at school age in one. Symptoms included abdominal distension with severe constipation (n = 4) and enterocolitis (n = 1). Rectocolonography showed megarectum and no narrow segment in most of the patients. All patients were negative for rectosphincteric reflex. The presence of ganglion cells was demonstrated by H&E or AChE staining from rectal mucosal biopsies or resected full-thickness segments. Two patients were treated conservatively, and three were treated surgically by internal anal sphincter myotomy (n = 2) or Lynn procedure (n = 1), with satisfactory outcomes. CONCLUSION: IASA is a rare but distinct entity in Japan. Although the clinical features of IASA resemble those of short- and ultrashort-segment HD, characteristic pathological findings include the presence of ganglion cells. The outcomes of both conservative and surgical treatment are good.

Protein-losing Enteropathy Caused by Spontaneous Reduction of Intussusception with Meckel's Diverticulum.

Protein-losing enteropathy (PLE) is a relatively rare condition. In this article, we report the case of a 6-year-old boy diagnosed with PLE who developed intussusception, in whom at operation Meckel's diverticulum was identified in his intestine. Spontaneous reduction of intussusception is thought to relate to the mechanism of PLE.

Care of children in a natural disaster: lessons learned from the Great East Japan earthquake and tsunami.

The Great East Japan earthquake was one of the most devastating natural disasters ever to hit Japan. We present features of the disaster and the radioactive accident in Fukushima. About 19,000 are dead or remain missing mainly due to the tsunami, but children accounted for only 6.5% of the deaths. The Japanese Society of Pediatric Surgeons set up the Committee of Aid for Disaster, and collaborated with the Japanese Society of Emergency Pediatrics to share information and provide pediatric medical care in the disaster area. Based on the lessons learned from the experiences, the role of pediatric surgeons and physicians in natural disasters is discussed.

Rare variant of inguinal hernia, interparietal hernia and ipsilateral abdominal ectopic testis, mimicking a spiegelian hernia. Case report.

We report a case in which the combination of an interparietal inguinal hernia and ipsilateral ectopic testicle mimicked a spigelian hernia. The patient was a 22-day-old boy who presented with a reducible mass that extended from the right lumbar region to the iliac fossa region. The right testis was palpable in the right lumbar region. Ultrasonography and magnetic resonance imaging revealed that a small bowel had herniated through the inguinal region below the external oblique aponeurosis. Surgery was performed when the patient was 23 months old. Laparoscopic examination to identify the hernia orifice revealed that it was the deep inguinal ring, and the testicular vessels and the vas deferens passed beneath the hernia sac. An inguinal incision was made, and a hernia sac was observed passing through the deep inguinal ring and extending superiorly below the aponeurosis. The testis was found in the hernia sac. Traditional inguinal herniorrhaphy and traditional orchidopexy were performed, and the postoperative course was uneventful. It is difficult to understand the surgical anatomy of interparietal hernias, but once the surgical anatomy is understood, surgical repair is simple. We report the case with a review of the literature and also emphasize that laparoscopic exploration is helpful during surgery.

Japanese guidelines for the management of intussusception in children, 2011.

BACKGROUND: The Japanese Society of Emergency Pediatrics has formulated evidence-based guidelines for the management of intussusception in children in order to diagnose intussusceptions promptly, to initiate appropriate treatment as early as possible, and to protect intussuscepted children from death. METHODS: Literature was collected systematically via the Internet using the key words "intussusception" and "children." The evidence level of each paper was rated in accordance with the levels of evidence of the Oxford Center for Evidence-based Medicine. The guidelines consisted of 50 clinical questions and the answers. Grades of recommendation were added to the procedures recommended on the basis of the strength of evidence levels. RESULTS: Three criteria of "diagnostic criteria,""severity assessment criteria," and "criteria for patient transfer" were proposed aiming at an early diagnosis, selection of appropriate treatment, and patient transfer for referral to a tertiary hospital in severe cases. Barium is no longer recommended for enema reduction (recommendation D) because the patient becomes severely ill once perforation occurs. Use of other contrast media, such as water-soluble iodinated contrast, normal saline, or air, is recommended under either fluoroscopic or sonographic guidance. Delayed repeat enema improves reduction success rate, and is recommended if the initial enema partially reduced the intussusception and if the patient condition is stable. CONCLUSIONS: The guidelines offer standards of management, but it is not necessarily the purpose of the guidelines to regulate clinical practices. One should judge each individual clinical situation in accordance with experiences, available devices, and the patient's condition.

Turner syndrome with ulcerative colitis.

Turner syndrome is a chromosomal disease frequently associated with autoimmune disorders including diabetes mellitus, thyroid disease and inflammatory bowel disease (IBD). Although the etiology of IBD has not been fully elucidated, genetic analysis has recently revealed several susceptibility genes. Recently, cases with Turner syndrome associated with IBD have been reported. We report here a 13-yr-old girl with Turner syndrome associated with ulcerative colitis. The patient was undergoing growth hormone treatment and presented with abdominal discomfort and bloody diarrhea. Her karyotype pattern was 46,X,i(Xq). Barium enema revealed punctate collections of barium suggesting microulcerations in the descending and sigmoid colon with loss of haustra. Flexible sigmoidoscopy showed that the mucosa was erythematous and friable upon touch and that the wall had frank hemorrhage and inflammatory polyp formation from the anal verge through the splenic flexure. Histologically, mucosal and submucosal inflammation was prominent, suggesting cryptitis and crypt abscess formation. Based on these findings, she was diagnosed as having ulcerative colitis, and 5-aminosalicylic acid, prednisolone and dietary therapy were initiated. Our observations in this patient suggest that X chromosome abnormality may influence the development of IBD and that screening for gastrointestinal disease in patients with Turner syndrome may help lengthen life expectancy in these patients.

Telangiectatic focal nodular hyperplasia of the liver in an infant with spontaneous regression: a case report.

A distinctive mass in the liver in a two-month-old girl with elevated serum alpha-fetoprotein (AFP) level was diagnosed as telangiectatic focal nodular hyperplasia (FNH) after biopsy. The tumor spontaneously regressed and finally became no longer detectable by any imaging study within normal range of AFP. The nature of this novel entity and its management are discussed based on literature review.