Noninvasive graft monitoring using donor-derived cell-free DNA in Japanese liver transplantation.

AIM: To evaluate the use of donor-derived cell-free DNA (dd-cfDNA) in diagnosing graft injuries in Japanese liver transplantation (LTx), including family-related living donors. METHODS: A total of 321 samples from 10 newly operated LTx recipients were collected to monitor the early dynamics of dd-cfDNA levels after LTx. Fifty-five samples from 55 recipients were collected during protocol biopsies (PB), whereas 36 samples from 27 recipients were collected during event biopsies, consisting of 11 biopsy-proven acute rejection (AR), 20 acute dysfunctions without rejection (ADWR), and 5 chronic rejections. The levels of dd-cfDNA were quantified using a next-generation sequencer based on single nucleotide polymorphisms. RESULTS: The dd-cfDNA levels were elevated significantly after LTx, followed by a rapid decline to the baseline in patients without graft injury within 30 days post-LTx. The dd-cfDNA levels were significantly higher in the 11 samples obtained during AR than those obtained during PB (p < 0.0001), which decreased promptly after treatment. The receiver operator characteristic curve analysis of diagnostic ability yielded areas under the curve of 0.975 and 0.897 for AR (rejection activity index [RAI] ≥3) versus PB and versus non-AR (ADWR + PB). The dd-cfDNA levels during AR were elevated earlier and correlated more strongly with the RAI (r = 0.740) than aspartate aminotransferase/alanine aminotransferase. The dd-cfDNA levels were neither associated with graft fibrosis based on histology nor the status of donor-specific antibodies in PB samples. CONCLUSIONS: Donor-derived cell-free DNA serves as a sensitive biomarker for detecting graft injuries in LTx. Further large-scale cohort studies are warranted to optimize its use in differentiating various post-LTx etiologies.

Historical Cohort Study of Congenital Isolated Hypoganglionosis of the Intestine: Determining the Best Surgical Interventions.

No standard diagnostic method or surgical treatment for congenital isolated hypoganglionosis (CIHG) has been established. This study aimed to analyze the clinical outcomes of patients with CIHG and identify the best surgical interventions provided thus far. Data on surgical interventions in 19 patients were collected between 1992 and 2020, including the type of enterostomy, type of revision, and length of the intestines. Ganglion cells in the myenteric plexus were enumerated using Hu C/D staining. The ratio of the length of the small intestine to its height was defined as the intestinal ratio (IR). The outcomes were assessed using the stoma output, growth parameters including the body mass index (BMI), and parenteral nutrition (PN) dependency. All patients required a diverting enterostomy. The IR ranged from 0.51 to 1.75 after multiple non-transplant surgeries. The stoma types were tube-stoma, end-stoma, Santulli-type, and Bishop-Koop (BK)-type. Patients with Santulli- or BK-type stomas had better BMIs and less PN dependency in terms of volume than those with end-stomas or tube-stomas. Two patients with BK-type stomas were off PN, and three who underwent an intestinal transplantation (Itx) achieved enteral autonomy. The management of CIHG involves a precise diagnosis using Hu C/D staining, neonatal enterostomy, and stoma revision using the adjusted IR and Itx if other treatments do not enable enteral autonomy.

Abnormal distribution of fat tissue and its association with intestinal failure-associated liver disease in children and adolescents with long-time parenteral nutrition support: A case-control study.

BACKGROUND: Patients with intestinal failure (IF) often present with abnormal body composition characterized by high fat mass. However, the distribution of fat and its association with the development of IF-associated liver disease (IFALD) remain unclear. This study aims to investigate the body composition and its relationship with IFALD in older children and adolescents with IF. METHODS: This retrospective case-control study enrolled patients with IF receiving parenteral nutrition (PN) at Keio University Hospital who initiated PN before the age of 20 years (cases). The control group included patients with abdominal pain, with available computed tomography (CT) scan and anthropometric data. CT scan images of the third lumbar vertebra (L3) were used for body composition analysis and compared between the groups. Liver histology was compared with CT scan findings in IF patients who underwent biopsy. RESULTS: Nineteen IF patients and 124 control patients were included. To account for age distribution, 51 control patients were selected. The median skeletal muscle index was 33.9 (29.1-37.3) in the IF group and 42.1 (39.1-45.7) in the control group (P < 0.01). The median visceral adipose tissue index (VATI) was 9.6 (4.9-21.0) in the IF group and 4.6 (3.0-8.3) in the control group (P = 0.018). Among the 13 patients with IF who underwent liver biopsies, 11 (84.6%) had steatosis, and there was a tendency for fibrosis to correlate with VATI. CONCLUSION: Patients with IF exhibit low skeletal muscle mass and high visceral fat, which may be related to liver fibrosis. Routine monitoring of body composition is recommended.

Prepregnancy Assessment of Liver Function to Predict Perinatal and Postpregnancy Outcomes in Biliary Atresia Patients with Native Liver.

Considering that some biliary atresia (BA) survivors with native liver have reached reproductive age and face long-lasting complications, specific attention needs to be paid to pregnant cases. This study aimed to investigate the relationship between liver function, perinatal outcomes, and prognosis. A database review was conducted to identify pregnant BA cases with native liver and perinatal data, and clinical information on BA-related complications was analyzed. Perinatal serum cholinesterase (ChE) levels, model for end-stage liver-disease (MELD) score, and platelet trends were analyzed, and the association between these indicators and perinatal outcomes was investigated. Patients were categorized into three groups according to the perinatal clinical outcomes: favorable (term babies with or without several episodes of cholangitis; n = 3), borderline (term baby and following liver dysfunction; n = 1), and unfavorable (premature delivery with subsequent liver failure; n = 1). Lower serum ChE levels, lower platelet counts, and higher MELD scores were observed in the unfavorable category. Borderline and unfavorable patients displayed a continuous increase in MELD score, with one eventually needing a liver transplantation. Pregnancy in patients with BA requires special attention. Serum ChE levels, platelet counts, and MELD scores are all important markers for predicting perinatal prognosis.

Maintenance treatment with infliximab for ulcerative ileitis after intestinal transplantation: A case report.

BACKGROUND: Evidence has been published on the successful applications of the anti-tumor necrosis factor alpha antibody infliximab, such as induction therapy, salvage treatment for acute cellular rejection, and treatment for chronic ulcerative inflammation, in intestinal transplant recipients. However, the optimal protocol for the effective use of infliximab remains largely undetermined due to scarcity of available clinical data. We report a continuative application of infliximab as maintenance therapy for recurrent chronic ulcerative ileitis in a recipient of isolated intestinal transplantation (ITx). CASE SUMMARY: The patient was a 11-year-old boy with intestinal motility disorder classified as a hypogenic type of intestinal dysganglionosis. The patient underwent living-donor related intestinal transplant. His immunosuppression regimen consisted of daclizumab, tacrolimus, and steroids. Although he did not show rejection while on tacrolimus monotherapy, routine screening endoscopy showed several ulcerative lesions in the distal end of the graft 2 years after the intestinal transplant. Endoscopic work up to evaluate the progression of anemia revealed stenosis with ulcerative inflammatory changes and multiple longitudinal ulcers in the graft. Since the endoscopic findings suggested ulcerative lesions in Crohn's disease, infliximab treatment was considered. Treatment with infliximab and a small dose of oral prednisolone afforded successful withdrawal of total parenteral nutrition and maintenance of a well-functioning graft without infectious complications for 5 years since the administration of the first dose of infliximab. CONCLUSION: Infliximab is effective as maintenance therapy for recurrent chronic ulcerative ileitis in an isolated ITx patient.

Prognosis of ultrasonographic low-grade pediatric appendicitis treated with supportive care.

BACKGROUND: A previous report proposed ultrasonography-based classification as a promising means of predicting pediatric spontaneously resolving appendicitis. The present study investigated the long-term prognosis of supportive care for low-grade appendicitis identified by ultrasonography, defined as an appendix with a smooth submucosal layer irrespective of blood flow or an appendix with an irregular layer and increased blood flow. METHODS: The present, retrospective cohort study enrolled patients under 16 years of age with acute appendicitis at a children's hospital between October 2010 and September 2016. The inclusion criteria were ultrasonography findings showing an appendix with (1) full visualization, (2) a diameter ≥6 mm, (3) a smooth submucosal layer or an irregular layer with increased blood flow, and (4) no appendiceal mass, abscess, or perforation. The exclusion criteria were: (1) a history of acute appendicitis, (2) antibiotic administration within 72 hours before diagnosis, and (3) antibiotic administration or surgery before supportive care. The primary outcome was the event-free duration, defined as a period of supportive care alone with no additional intervention or recurrence of appendicitis. RESULTS: One hundred and eighty-two patients were enrolled. The median Alvarado score was 7 (interquartile range, 6-8), and the median follow-up duration in event-free cases was 1,922 days (interquartile range, 1,347-2,614 days). The event-free rate was 75.0%, 67.0%, and 62.5%, at 1, 2, and 5 years, respectively. CONCLUSION: The long-term, event-free rate exceeded 60% in patients with low-grade appendicitis defined by ultrasonography who received neither surgery nor antibiotic treatment. Most recurrences occurred within 2 years of the initial diagnosis.

Oral sodium phenylbutyrate for hyperammonemia associated with congenital portosystemic shunt: a case report.

OBJECTIVES: The efficacy of sodium phenylbutyrate (SPB) for hyperammonemia associated with congenital portosystemic shunt (CPSS) remains unknown. We show the effectiveness of oral SPB. CASE PRESENTATION: Our patient had CPSS with severe hypoplasia of extrahepatic portal veins. At 9 months of age, to assess the efficacy of oral SPB, we evaluated the 24 h fluctuations of venous ammonia levels. In the first two days without SPB, ammonia levels were above 80 µmol/L for half a day. On the third and fourth days, administration of oral SPB three times a day decreased ammonia to acceptable levels, except at midnight. On the fifth day, another oral SPB administration at 8 pm decreased ammonia at midnight. Low levels of branched-chain amino acids, as well as coagulation disturbances, were observed without apparent symptoms. At 12 months of age, he showed normal psychomotor development. CONCLUSIONS: Oral SPB may be effective for hyperammonemia associated with CPSS.

The effectiveness of transoral marsupialization for lingual thyroglossal duct cysts - Twelve successfully treated cases at a single institution.

PURPOSE: Lingual thyroglossal duct cysts (L-TGDCs) are rare and sometimes lethal owing to their association with asphyxia. We aimed to analyze our single institutional experience with L-TGDCs. METHODS: Twelve L-TGDC cases treated at our institution between January 2010 and December 2017 were investigated. RESULTS: The male/female ratio was 6/6. The age at the diagnosis was 2 ±â€¯1.4 months (7 days to 6 months), and 3 patients were diagnosed in the neonatal period. The patients presented with stridor (n = 12; 100%), growth retardation (n = 5; 42%), apnea (n = 3; 25%), and vomiting (n = 1; 8.3%). Lateral X-rays were obtained in 8 cases (66.7%); a lingual mass was suspected in 7 (87.5%). Transoral marsupialization of the cyst was performed under direct vision in all cases. All cases were nasally and orally intubated using a laryngoscope, bronchoscope, or airway scope. The mean operative time was 18 ±â€¯2.9 min. The mean cyst size was 10.5 ±â€¯1.8 mm. No recurrence was observed during the follow-up period (37.5 ±â€¯18 months). CONCLUSION: L-TGDC requires a precise diagnosis and rapid intervention because of the risk of asphyxia resulting in sudden death. Transoral marsupialization under direct vision is an effective and secure approach. L-TGDC should be considered when patients younger than six months of age present with respiratory distress. TYPE OF STUDY: Retrospective Study. LEVEL OF EVIDENCE: Level IV.

Endoscopic chemocauterization for pyriform sinus fistula in children.

BACKGROUND: Although complete excision is the standard treatment for pyriform sinus fistula (PSF), it has recently been suggested that chemocauterization via the internal orifice of the fistula could be an effective non-invasive treatment for the condition. The present report describes the details of our experience with and the efficacy of endoscopic chemocauterization for pediatric PSF. METHOD: Between January 2010 and June 2015, four patients were diagnosed with PSF and scheduled to undergo endoscopic chemocauterization. Under general anesthesia, trichloroacetic acid (TCA) solution was endoscopically injected through the opening of the fistula using a fine plastic tube. Esophagogram was obtained at 3 weeks after the procedure to search for recurrence. Complete closure of the fistula was confirmed on endoscopy at 2-3 months after chemocauterization. RESULTS: Two of the four patients were treated once, and the remaining patients required further chemocauterization procedures. No recurrence developed in any patient after it had been confirmed that the fistula's internal orifice had been obliterated. Some transient complications, such as sore throat, nausea or temporary vocal fold paresis, occurred. CONCLUSION: Chemocauterization with TCA seems to be a useful first-choice treatment for PSF.

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.

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.

Reappraisal of adhesive strapping as treatment for infantile umbilical hernia.

BACKGROUND: Most umbilical hernias spontaneously close by 3-5 years of age; therefore, surgical repair is considered only in children whose hernias have not closed by this point. At present, adhesive strapping is not the preferred treatment for umbilical hernias because of the lack of supporting evidence regarding its efficacy, and its association with skin complications. This aim of this study was to examine umbilical hernia closure on ultrasonography, and reassess the merits of adhesive strapping. METHODS: Between January 2013 and December 2014, 89 infants underwent adhesive strapping for umbilical hernia. The strapping was changed once a week. The diameter of the hernia orifice was measured on ultrasonography every 2 weeks until closure. The closure speed (CS) of the hernia orifice was compared between the infants treated with adhesive strapping and those undergoing observation alone. The association between CS and birthweight, gestational age, diameter of the hernia orifice, and timing of treatment (before 12 weeks of age vs between 12 and 26 weeks of age) was also analyzed. RESULTS: Closure was achieved after 2-13 weeks of strapping in 81 infants (91%), and the likelihood of closure was not affected by the diameter of the hernia orifice, gestational age, or the timing of treatment. The mean CS of the infants treated with adhesive strapping was significantly faster than that of the infants undergoing observation alone (2.59 vs 0.37 mm/week, P < 0.05). Adhesive strapping was discontinued in five of the 89 infants (5.6%) due to severe skin complications. CONCLUSION: Adhesive strapping promoted early spontaneous umbilical hernia closure compared with observation alone, regardless of the diameter of the hernia orifice. Adhesive strapping is an effective alternative to surgery and observation.

Spleen stiffness measurements by acoustic radiation force impulse imaging after living donor liver transplantation in children: a potential quantitative index for venous complications.

BACKGROUND: Living donor liver transplantation in children often results in venous complications, leading to portal hypertension. Spleen stiffness measurements have been recently proposed as a new, noninvasive parameter for portal hypertension in cirrhotic patients. OBJECTIVE: To evaluate the diagnostic value of spleen stiffness measurements by acoustic radiation force impulse (ARFI) imaging in diagnosing venous complications after pediatric living donor liver transplantation. MATERIALS AND METHODS: We prospectively enrolled 69 patients after pediatric living donor liver transplantation using a left-side liver allograft. Around the time of the protocol liver biopsy examination, spleen stiffness measurements by ARFI imaging were performed via the left intercostal space at the center of the spleen parenchyma and repeated five times. Imaging examinations around the time of the spleen stiffness measurements were retrospectively reviewed. Regarding venous complications, significant portal and hepatic venous stenosis was defined as >50% stenosis on multiphasic computed tomography. RESULTS: After post hoc exclusion, 62 patients were studied. Portal and hepatic venous stenosis was identified in three and two patients, respectively. The median spleen stiffness values were 2.70 and 4.00 m/s in patients without and with venous complications, respectively (P < 0.001). Spleen stiffness measurements showed good diagnostic power for venous complications, and the cutoff value was determined as 2.93 m/s, with 100% sensitivity and 78.9% specificity. Spleen stiffness measurements decreased with the relief of venous stenosis resulting from an interventional radiology procedure. CONCLUSION: Spleen stiffness measurements by ARFI imaging might provide a useful quantitative index for venous complications after pediatric living donor liver transplantation.