Everolimus Rescue Treatment for Chronic Rejection After Pediatric Living Donor Liver Transplantation: 2 Case Reports.

Chronic rejection (CR) remains a challenging complication after liver transplantation. Everolimus, which is a mammalian target of rapamycin inhibitor, has an anti-fibrosis effect. We report here the effect of everolimus on CR. Case 1 was a 7-year-old girl who underwent living donor liver transplantation (LDLT) shortly after developing fulminant hepatitis at 10 months of age. Liver function tests (LFTs) did not improve after transplantation despite treatment with tacrolimus + mycophenolate mofetil (MMF). Antithymoglobulin (ATG) and steroid pulse therapy were also ineffective. The patient was diagnosed with CR, and everolimus was started with a target trough level of about 5 ng/mL. LFTs improved and pathological examination showed no progression of hepatic fibrosis. Case 2 was a 10-year-old girl with Alagille syndrome who underwent LDLT at 1 year of age. She had biopsy-proven acute cellular rejection with prolonged LFT abnormalities beginning 3 years after transplantation. She was treated with steroid pulse therapy, followed by MMF, tacrolimus, and prednisolone. Her condition did not improve, even after subsequent ATG administration. CR was suspected based on liver biopsy in the fourth postoperative year, and everolimus was introduced. The target trough level was around 5 ng/mL, but was reduced to 3 ng/mL due to stomatitis. Four years have passed since the initiation of everolimus, and LFTs are stable with no progression of liver biopsy fibrosis. We describe 2 cases in which everolimus was administered for CR. In both cases, LFTs improved and fibrosis did not progress, suggesting that everolimus is an effective treatment for CR after LDLT.

Pulmonary Arterial Pressure Management Based on Oral Medicine for Pediatric Living Donor Liver Transplant With Portopulmonary Hypertension.

Pediatric living donor liver transplantation (LDLT) in patients with advanced portopulmonary hypertension (PoPH) is associated with poor prognoses. Recently, novel oral medications, including endothelin receptor antagonists (ERAs), phosphodiesterase 5 (PDE5) inhibitors, and oral prostacyclin (PGI2) have been used to treat PoPH. Pediatric patients with PoPH who underwent LDLT from 2006 to 2016 were enrolled. Oral pulmonary hypertension (PH) medication was administered to control pulmonary arterial pressure (PAP). Four patients had PoPH. Their ages ranged from 6 to 16 years, and their original diseases were biliary atresia (n = 2), portal vein obstruction (n = 1), and intrahepatic portal systemic shunt (n = 1). For preoperative management, 2 patients received continuous intravenous PGI2 and 2 oral medications (an ERA alone or an ERA and a PDE5 inhibitor), and 2 received only oral drugs (an ERA and a PDE5 inhibitor). One patient managed only with intravenous PGI2 died. In the remaining 3 cases, intravenous PGI2 or NO was discontinued before the end of the first postoperative week. Postoperative medications were oral PGI2 alone (n = 1), an ERA alone (n = 1), or the combination of an ERA and a PDE5 inhibitor (n = 1). An ERA was the first-line therapy, and a PDE5 inhibitor was added if there was no effect. New oral PH medications were effective and safe for use in pediatric patients following LDLT. In particular, these new oral drugs prevent the need for central catheter access to infuse PGI2.

Fibroadenoma in adolescent females after living donor liver transplantation.

Breast FA is the most common breast tumor diagnosed in young women. Female renal transplant recipients on CsA have an increased risk of developing FA. However, reports of FA after LDLT have not been described. Our objectives were to determine the incidence of FA, analyze risk factors for FA, and evaluate treatment strategies in adolescent females after LDLT. A total of 18 female patients aged 10-19 years who underwent LDLT and survived at least one year after transplantation were enrolled in our study. The incidence of FA was 11.1%. To determine pre- or post-transplant conditions that are associated with FA after transplantation, the patients were divided into two groups according to the presence or absence of FA: FA group (n=2) and non-FA group (n=16). There were no differences in mean age at LDLT, mean age at breast evaluation, and mean duration between transplantation and breast evaluation between the two groups. However, there was a difference in the immunosuppressive regimen between the two groups. The FA group was maintained on CsA, whereas the non-FA group was maintained on tacrolimus. CsA might be implicated in FA development in adolescent females after LDLT.

Liver Failure From Ultra-Short Bowel Syndrome on the Intestinal Transplant Waiting List: A Retrospective Study.

BACKGROUND: Patients with intestinal failure (IF) are candidates for intestinal transplantation (ITx). In Japan, these patients have few opportunities to undergo cadaveric ITx because of low rates of organ donation. The donor criteria and recipient priority for ITx are still unknown. We reviewed our cases of IF to investigate which patients should be prioritized for ITx. METHODS: Patients with IF who were registered as candidates for cadaveric ITx between January 2010 and November 2015 in our institute were included in this retrospective study. Their data were gathered from their charts and analyzed. RESULTS: Five patients were included. Their primary diseases included total colon aganglionosis (n = 1), chronic idiopathic intestinal pseudo-obstruction syndrome (n = 2), superior mesenteric vein embolization (n = 1), and graft loss after ITx (n = 1). Two patients died of liver failure (LF) during the waiting period. The remaining three are now alive and waiting for transplantation. The lengths of the remaining intestine were more than 20 cm in living cases but less than 20 cm in fatal cases. In the fatal cases, they had several episodes of catheter-related blood stream infection, which caused LF and acute renal failure. CONCLUSIONS: We identified two patients with less than 20 cm residual small bowel who died after acute deterioration of liver function. Patients with ultra-short bowel could have a higher risk of LF. Therefore, they should be referred as soon as possible to a specialized hospital where ITx is a choice of treatment for IF.

Impact of Donor-Specific Antibodies on Graft Fibrosis After Pediatric Living Donor Liver Transplantation for Biliary Atresia.

BACKGROUND: Pediatric living donor liver transplant (LDLT) patients sometimes develop graft fibrosis after non-recurrent diseases such as biliary atresia (BA). Donor-specific antibodies (DSA) have recently been shown to play a possible role in graft damage after liver transplantation. We report the impact of DSA on pediatric LDLT for BA patients. METHODS: Patients under age 18 years who received LDLT for BA at our institution and who had at least 5 years' follow-up were identified, and 23 were eventually enrolled in this study. Pathological findings were assessed with the use of the last available biopsy. Patients were divided into 2 groups, DSA-positive and DSA-negative. Graft fibrosis after LDLT was assessed according to DSA groups. RESULTS: The mean patient age at transplant was 2.6 years. The mean time to the last available biopsy after LDLT was 8.2 years (4.8-15.6 years); 6 patients (26%) showed no fibrosis, whereas fibrosis was graded as F1, F2, or F3 in 8 patients (35%), 8 patients (35%), and 1 patient, respectively. DSA were observed in 12 patients (52%). Moderate graft fibrosis (F2 and F3) was found in 7 (58%) of the DSA-positive group, but only 2 (18%) of the DSA-negative group, showing a statistically significant difference (P < .05). Pre-transplant cross-matching was performed in 17 patients. The 2 patients with a positive cross-match were DSA-positive. Six cross-match-negative patients developed de novo DSA after LDLT. CONCLUSIONS: Graft fibrosis was observed after LDLT for BA during long-term follow-up, more commonly in DSA-positive patients. DSA may play a role in fibrosis formation.

Disseminated Metastatic Tissue Calcification After Orthotopic Liver Transplantation: A Case Report.

BACKGROUND: Hypercalcemia has been observed in patients after liver transplantation. However, it is rare that the hypercalcemia induced disseminated tissue calcification and heart failure. CASE REPORT: We report a rare case of heart failure caused by disseminated metastatic tissue calcification that involved extensive progressive myocardial calcification after liver transplantation. A 20-year-old man with end-stage liver disease due to biliary atresia underwent ABO-incompatible living donor liver transplantation. After successful transplantation, he suffered from antibody-mediated rejection. Subsequently, ABO-matched cadaveric liver retransplantation was successfully performed. Hypercalcemia developed gradually following the second transplantation. His serum calcium level increased to 18.3 mg/dL with sudden onset of ventricular tachycardia. Although he was resuscitated with a cardiopulmonary support device, he died of heart and liver failure. Histopathologic examination revealed systemic disseminated metastatic tissue calcification, including massive myocardial calcification. CONCLUSION: Progressive worsening of hypercalcemia resulted in disseminated metastatic tissue calcification and massive metastatic myocardial calcification, which led to heart failure after liver transplantation. Because hypercalcemia after liver transplantation can cause fatal tissue calcification, early intervention for hypercalcemia should be considered.

Clinical outcome of laparoscopically assisted endorectal pull-through in Hirschsprung's disease: comparison of abdominal and perineal approaches.

BACKGROUND/PURPOSE: Laparoscopically assisted endorectal pull-through (EPT) via a perineal approach using a prolapsing technique (PA) for Hirschsprung's disease (HD) has been reported. However, the clinical outcome after this approach has not been reported. The purpose of this study was to compare the clinical outcome of PA and the conventional transabdominal approach (TA). METHODS: In the period between 1990 and 2001, 20 cases of HD underwent EPT with TA (group O), and 21 underwent EPT with PA (group L). There was no difference in age and weight distribution between the 2 groups. Clinical outcome was assessed 3 years after surgery. RESULTS: The operation time was comparable in the 2 groups (4.9 +/- 0.8 v 5.2 +/- 0.8 hr), whereas blood loss (98 +/- 52 v 36 +/- 30 mL) and postoperative complications requiring surgical intervention (26% v 0%) were significantly lower in group L. The incidence of postoperative enteritis (27% v 28%) and voluntary defecation (more than once every/2 days) were compatible in the 2 groups (70% v 87%). Soiling (small amount of involuntary stooling; >1 per month) was significantly less frequent in group L (45% v 14%). CONCLUSIONS: Laparoscopically assisted ETP with PA is less invasive and can provide a better clinical outcome compared with TA in terms of postoperative soiling.

Endorectal pull-through with posterior sagittal approach to the repair of postoperative rectourethral and rectovaginal fistula.

BACKGROUND/PURPOSE: Rectourethral (RUF) or rectovaginal fistula (RVF) is a troublesome complication after anorectal surgery because of dense adhesions around the fistula. The authors applied a new technique for the redo surgery. METHODS: Case 1 is Hirschsprung's disease in a 1-year-old boy who underwent modified Duhamel's procedure and had RUF. Case 2 is rectovestibular fistula in an 11-year-old girl who had anterior sagittal anorectoplasty complicated by RVF. Case 3 is multiple urogenital anomalies including rectovesical fistula in a 4-year-old boy in whom transvesical repair was unsuccessful. The colon was mobilized as far as possible at laparotomy. The rectum was opened via a posterior sagittal approach leaving 1 cm of the anal canal. Extended endorectal mucosectomy was performed to the dentate line, and the fistula was closed from inside of the rectum. The remaining mucosal cuff was everted out of the anus and the intact colon was pulled through the rectum and anastomosed to the cuff extraanally. RESULTS: The postoperative contrast enema showed no recurrent fistula, and defecation was not impaired. CONCLUSIONS: Endorectal pull-through of the intact colon can spare troublesome mobilization of the fistula and can prevent the recurrence of fistula. Rectal incision via a posterior sagittal approach provides a direct view of the fistula.

The effect of hypoxia on permeability and bacterial translocation in Caco-2 adult and I-407 fetal enterocyte cell culture models.

Hypoxia has been implicated in the breakdown of the intestinal epithelial barrier in animals, leading to bacterial translocation (BT); however, the mechanism of this hypoxic insult is unknown. To determine the effects of hypoxic injury in vitro on epithelial membrane integrity, transepithelial electrical resistance (TEER), mannitol permeability (Ma-Pm), and BT were measured in both an adult (Caco-2) and fetal (I-407) intestinal epithelial cell culture model. Caco-2 adult and I-407 fetal epithelial cell monolayers were treated with or without bacteria (1 x 10(7) Escherichia coli. C-25), and then incubated under either normoxic (5% CO(2) in room air) or hypoxic (5% CO(2) and 95% N(2)) conditions at 37 degrees C for 6 h. Hypoxia caused a 10% increase in Ma-Pm in the I-407 fetal cell model independent of the bacterial challenge. In contrast, a bacterial challenge in the Caco-2 adult model caused a 485% increase in Ma-Pm independent of hypoxia. Neither hypoxia, nor C-25 bacteria, for 6 h caused BT in either cell culture model. In the adult cell culture model, bacteria appear to mediate changes in epithelial barrier function, with hypoxia having no effect. On the other hand, hypoxia is the major factor in the loss of epithelial barrier function in fetal epithelium, but has no effect on adult epithelium. The data suggest that the breakdown of barrier function caused by a hypoxic insult is the primary stimulus for subsequent BT in neonates.

Interleukin-6 changes tight junction permeability and intracellular phospholipid content in a human enterocyte cell culture model.

Proinflammatory cytokines and secretory phospholipase A(2) (sPLA(2)) are elevated in patients with inflammatory bowel disease (IBD). We previously reported that the proinflammatory cytokine IL-6 increased the expression of sPLA(2) (a hydrolyzer of phosphatidylcholine) and decreased membrane integrity in an intestinal epithelial cell culture model. To determine the physiological effects of the IL-6 mediated increase in sPLA(2) on decreased epithelial layer integrity, we investigated alterations of intracellular/secretory phospholipid (PL) composition in a cell culture model. In addition, since other PLs may also mediate epithelial membrane activity, we investigated the effect of IL-6 on PL activity in a Caco-2 enterocyte culture model. Caco-2 cells were incubated for 72 h with IL-6 or media alone (control). Both media and cell lysate were analyzed for PL composition using thin-layer chromatography. The PL composition in the media did not show any differences between the two groups ( p>0.1). Total intracellular PL contents were also unchanged; however, IL-6 led to significant changes in PL composition including an increase in phosphatidylethanolamine (PE) and sphingomyelin (SM) and a decrease in phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) ( p<0.05). Both PE and SM are known as inflammatory signaling factors involved in human IBD. Our study suggests that the decreased membrane integrity seen with IL-6 application may occur via intracellular PL alterations, rather than through the direct effects of sPLA(2).

Pectus excavatum repair using a costal cartilage graft for patients with tracheobronchomalacia.

BACKGROUND: Pectus excavatum is sometimes associated with tracheobronchomalacia, which usually manifests left mediastinal shift, atelectasis of the left lung, and recurrent pulmonary infection. Standard repair of pectus excavatum alone usually failed to improve symptoms. METHODS: Pexis of the great vessels and pericardium combined with the support of the lower sternum, using a contralateral costal cartilage graft following the standard Ravitch's repair of pectus excavatum, has been used in 6 children during the past 5 years. In addition to respiratory symptoms, diagnosis of tracheobronchomalacia was made by bronchoscopy using an ultrathin fiberscope. RESULTS: Using the described operative technique, an excellent cosmetic and functional result was obtained in 5 of 6 children. However, atelectasis of the left lower lobe and the narrowing of the left mainstem bronchus continued postoperatively in one patient, which required the insertion of the Palmaz stent in the left mainstem bronchus. CONCLUSION: This technique may help improve tracheobronchomalacia in patients with pectus excavatum and should be tried before the insertion of an internal stent.

Insulin-like growth factor-I stimulates amino acid transport in a glutamine-deprived human neuroblastoma cell line.

It is still unknown how insulin-like growth factor-I (IGF-I) regulates cancer cell growth in the condition of the limited availability of key nutrients, such as glutamine. We investigated the effects of IGF-I on cell growth and amino acid transport in a glutamine-deprived human neuroblastoma cell line, SK-N-SH. Cell growth was measured, and 3H-labeled amino acid transport was assayed after treatment with or without IGF-I (50 ng/ml) in 2 mM (control) and 100 microM glutamine concentrations. Cell growth rates were dependent on glutamine concentrations. IGF-I stimulated cell growth in both 2 mM and 100 microM glutamine. IGF-I stimulated glutamine transport in 100 microM glutamine with the mechanism of increasing carrier Vmax, but had no effect in 2 mM glutamine. IGF-I also stimulated leucine, glutamate and 2-(methylamino)isobutyric acid transport in 100 microM glutamine. There were significant increases in [3H]thymidine and [3H]leucine incorporation in IGF-I-treated cells in both 2 mM and 100 microM glutamine. These data suggest that IGF-I stimulates cell growth by increasing amino acid transport in the condition of low glutamine levels in a human neuroblastoma cell line. This mechanism may allow to maintain cell growth even in nutrient-deprived tumor tissues.

Congenital diaphragmatic hernia in identical twins.

The authors present a pair of identical twins with congenital diaphragmatic hernia (CDH) diagnosed prenatally, who underwent successful surgical repair. They were diagnosed as having CDH at 32 weeks' gestation and showed respiratory distress soon after cesarean section at 33 weeks' gestation. Both survived after scheduled perinatal management followed by surgery, for which the prenatal diagnosis of CDH was valuable.

Airway anomalies in patients with congenital diaphragmatic hernia.

PURPOSE: Congenital diaphragmatic hernias (CDH) sometimes are associated with airway anomalies such as congenital stenosis, abnormal branching of the bronchi, and pulmonary hypoplasia. The incidence of these associated airway anomalies has not been reported previously. METHODS: Bronchoscopy was performed in all neonates with CDH from 1987 to 1999. In addition to anatomic anomalies, bronchial hypoplasia was defined as narrowing and shortening of the bronchi at bronchoscopy. RESULTS: Anatomic anomalies were identified in 7 of 39 patients with CDH: 1 had congenital tracheal stenosis with pulmonary artery sling, 1 had a defect of the right upper lobe bronchus, 2 had a tracheal bronchus, and 3 had a trifurcated trachea. Bronchial hypoplasia on the affected side was identified in 15 patients and was seen in all patients with anatomic anomalies of the tracheobronchial tree except the 2 with tracheal bronchus. After excluding 5 patients with severe associated anomalies, 6 of 14 patients with an abnormal tracheobronchial tree died, whereas 1 of 20 patients without airway abnormalities died. CONCLUSIONS: Anatomic anomalies of the tracheobronchial tree and bronchial hypoplasia on the affected side were identified in 17.9% and 38.4% of patients with CDH, respectively. CDH patients who exhibited these abnormalities showed a poor outcome.

Use of a Palmaz stent for tracheomalacia: case report of an infant with esophageal atresia.

A male infant with congenital cardiac anomalies and esophageal atresia with tracheoesophageal fistula (EA-TEF) showed intractable respiratory symptoms after delayed primary repair of EA-TEF. Computed tomography demonstrated that the trachea was compressed by the enlarged aorta. Artificial ventilation was necessary even after aortopexy performed at 2 months of age. At 140 days of age, an expandable metallic stent (Palmaz stent) was inserted through a rigid bronchoscope into the trachea underfluoroscopic control. His respiratory status improved dramatically, and he was extubated in 18 hours. Although the follow-up period has been 9 months, the short-term result is satisfactory. The expandable metallic stent placement should be considered in patients with EA-TEF who show intractable respiratory symptoms caused by tracheomalacia.

Mechanisms underlying the antireflux effect of Nissen fundoplication in children.

BACKGROUND/PURPOSE: It is reported that the main mechanism responsible for gastroesophageal reflux (GER) is transient lower esophageal sphincter (LES) relaxation in children. However, the effect of Nissen fundoplication on transient LES relaxation has not been investigated in children. This study examined the effect of Nissen fundoplication on motor patterns of the LES in children with pathological GER. METHODS: Esophageal manometry and pH were recorded concurrently for 2 hours after administration of apple juice (10 mL/kg). In seven children documented to have pathological GER by prolonged esophageal pH monitoring (%time pH less than 4.0>5.0), studies were performed preoperatively and 1 to 3 months after surgery. RESULTS: Nissen fundoplication virtually eliminated reflux in all patients. Percentage of time pH was less than 4.0 reduced from 15+/-9 to 0+/-0. Basal LES pressure did not change significantly (pre, 21+/-10 mm Hg v post, 27+/-9 mm Hg). The number of transient LES relaxation reduced significantly from 13+/-4 to 7+/-7, and the mean nadir LES pressures during swallow-induced LES relaxation and transient LES relaxation increased significantly from 1+/-1 mm Hg to 13+/-5 mm Hg and from 0+/-0 mm Hg to 11+/-7 mm Hg, respectively. CONCLUSIONS: Our findings suggest the antireflux effects of Nissen fundoplication may be based on changes of LES motor patterns that result in incomplete LES relaxation and reduction of the number of transient LES relaxation.

Portal hypertensive enteropathy in biliary atresia.

This paper describes a rare case of biliary atresia (BA) in which massive postoperative bleeding developed due to portal hypertensive enteropathy. A 15-year-old boy had been doing well after Kasai's operation for BA. At around the age of 6 years he developed recurrent episodes of esophageal variceal bleeding and underwent esophageal transection, splenectomy, sclerotherapy, and embolization of the left gastric vein. At the age of 15 years he suddenly developed abdominal pain, hematemesis, and massive tarry stools. His hemoglobin level was 6.3 g/dl. Endoscopy showed several small, polypoid lesions in the jejunum beyond Treitz' ligament. The source of the bleeding was one of these lesions located in the proximal jejunojejunostomy of the Roux-en-Y loop. Because he had repeated episodes of melena, he underwent partial resection of the jejunum under endoscopic guidance. He has since been free of gastrointestinal (GI) bleeding. From this experience, we conclude that the polypoid lesions of an enteropathy may be a cause of massive GI bleeding in the postoperative portal hypertension of BA.

Purification and properties of a novel sulfatase from Pseudomonas testosteroni that hydrolyzed 3 beta-hydroxy-5-cholenoic acid 3-sulfate.

A novel sulfatase hydrolyzing the sulfate ester bond in 3 beta-hydroxy-5-cholenoic acid 3-sulfate (delta 5-3 beta-sulfate) was purified from Pseudomonas testosteroni ATCC 11996 as the second bile acid sulfatase. The molecular weight was 95,000 and the molecule was composed of a homodimer of a subunit of which the molecular weight was 46,000. This sulfatase hydrolyzed delta 5-3 beta-sulfate to 3 alpha-hydroxy-5-cholenoic acid and sulfuric acid with inversion of beta- to alpha-configuration of the hydroxyl group at the C-3 position of the substrate. The optimum pH and the stable pH of the enzyme were 8.5 and 6.5-9.7, respectively. 3 beta-Sulfate ester bonds of steroids such as isolithocholic acid, pregnenolone, and epiandrosterone, in which the side chain of the steroid ring was shorter than cholesterol, were also hydrolyzed to 3 alpha-hydroxyl compounds corresponding to each steroid compound and sulfuric acid. We tentatively named this novel enzyme bile acid 3 beta-sulfate sulfohydrolase (beta-BSS).

The doughnut sign: an ultrasound finding in pediatric intestinal Burkitt's lymphoma.

This paper describes a doughnut-like ultrasound (US) finding in pediatric intestinal Burkitt's lymphoma. A 9-year-old boy had a fist-sized, hard, non-movable mass in the lower abdomen. US showed a thickened, layered ring like a doughnut. The outer, low-level echoes seemed to be consistent with mucosa and muscle layers and the inner, high-level echoes seemed to be intraluminal air or mucus. The serum lactic dehydrogenase level was high. At surgery, a solid, hard tumor 15 x 10 cm in size was found in the jejunum. The intestinal wall was diffusely thickened with an intact mucosa. From this experience, the US doughnut sign may be a helpful diagnostic finding in pediatric intestinal Burkitt's lymphoma.

Transumbilical resection and umbilical plasty for patent omphalomesenteric duct.

This paper describes a transumbilical resection and umbilical plasty for treatment of a patent omphalomesenteric duct (POMD). In a newborn infant with a POMD, a skin incision was made circumscribing the mucocutaneous junction of the protruded duct. The duct was completely extirpated with a wedge resection of the connection to the intestine and an umbilical plasty was performed. The postoperative appearance was excellent. It appears that transumbilical resection and umbilical plasty may be a satisfactory operation for POMD.