Immunogenicity and safety of porcine circovirus-free human rotavirus vaccine in healthy infants: a phase III, randomized trial.

BACKGROUND: Porcine circovirus type 1 (PCV-1) material was detected in the human rotavirus vaccine (HRV) in 2010. In this study (NCT02914184) we compared immunogenicity and safety of the PCV-free HRV vaccine (PCV-free HRV) with HRV. PCV-free HRV is an HRV with no detection of PCV-1 and PCV-2 according to the limit of detection of the tests used. METHODS: Healthy infants 6-12 weeks of age were randomized (1:1:1:1) to receive 2 doses of 1 of the 3 lots of PCV-free HRV or HRV. The study objectives were to demonstrate lot-to-lot consistency of the PCV-free HRV and non-inferiority of PCV-free HRV as compared to HRV in terms of immunogenicity, 1-2 months post-dose 2. Reactogenicity and safety were also assessed. RESULTS: Overall, 1612 infants were enrolled and 1545 completed the study. Study objectives were demonstrated since the pre-defined criteria were met. Among participants receiving PCV-free HRV and HRV, 79.27% and 81.76% seroconverted and geometric mean concentrations were 159.5 and 152.8 U/mL, respectively. The incidences of adverse events and serious adverse events were similar between the pooled PCV-free HRV and HRV groups. CONCLUSIONS: The 3 PCV-free HRV lots demonstrated consistency and PCV-free HRV was non-inferior compared to HRV in terms of immunogenicity.

Immunogenicity and safety of the diphtheria, pertussis, tetanus and inactivated poliovirus vaccine when co-administered with the human rotavirus vaccine (Rotarix) in healthy Japanese infants: a phase IV randomized study.

Rotavirus infections have been reported to account for 40-50% of all hospitalized acute gastroenteritis cases in young children (<5 years) in Japan. Since 2011, Rotarix containing the live attenuated human rotavirus RIX4414 strain (HRV) has been licensed in Japan for infants. Vaccination against rotavirus is optional in Japan whereas administration of diphtheria, pertussis, tetanus, and inactivated poliovirus (DPT-IPV) vaccine is part of the national routine immunization program. In this open-label, randomized, controlled, multicenter study, we evaluated the immunogenicity and safety of the DPT-IPV vaccine (Squarekids) administered concomitantly or staggered with the liquid HRV (Rotarix) vaccine in healthy Japanese infants. A total of 292 infants aged 6-12 weeks were randomly assigned to receive DPT-IPV vaccine and HRV vaccine co-administered (n = 147) or staggered (n = 145). Immune responses to DPT-IPV vaccine were evaluated by measuring the post-vaccination serum antibody titers/concentrations to each antigen at one month following the third dose of DPT-IPV vaccine. Seroprotection/seropositivity against each of the diphtheria, pertussis (pertussis toxin and filamentous hemagglutinin), tetanus, and poliovirus type 1, 2 and 3 antigens was 92.8% or higher in both groups. In terms of immunogenicity, DPT-IPV vaccine co-administered with HRV vaccine was shown to be non-inferior to DPT-IPV vaccine with a staggered administration. The safety profile was comparable in the two vaccine groups with no vaccine-related serious adverse events, no deaths and no cases of intussusception. These results support co-administration of HRV vaccine with DPT-IPV vaccine in Japan. ClinicalTrials.gov NCT02907216.

Liver transplantation for deterioration in native liver function after portoenterostomy for biliary atresia in Japan: Short- versus long-term survivors.

PURPOSE: We reviewed our post-Kasai portoenterostomy biliary atresia (BA) patients who required liver transplantation (LTx) for deterioration in native liver (NL) function to investigate mortality in relation to age at LTx. METHODS: BA patients indicated for LTx when less than 18years old (U18; n=17) and when 18 or older (18+; n=13) were compared. All achieved jaundice clearance postoperatively (TBil ≤1.2mg/dL (≈20µmol/L)). RESULTS: In U18, living-donor (LD) LTxs were performed at a median of 6.1years (range: 0.5-16.7; n=14) and cadaveric (CD) LTxs at a median of 1.3years (1.1-1.5; n=3). In 18+, LDLTxs were performed at a median of 28years (18-37; n=8), and 1 case died from graft versus host disease. CDLTxs were indicated in 5, but 4 died at a median of 30years (26-32), a mean of 1.4years (0.7-1.8) after NL deterioration commenced. One case is awaiting CDLTx. At the time of review, all U18 and 7 LDLTx cases in 18+ were clinically stable. Mortality rates were 0% in U18 and 38% in 18+ (P=.006). CONCLUSION: Our results highlight the extremely grave prognosis for long-term BA patients requiring LTx when 18 or older because of poor donor availability in Japan. LEVEL OF EVIDENCE: Level III.

Prognostic implications of bile lakes after surgery for biliary atresia.

PURPOSE: The aim of the study was to establish the natural history of bile lakes (BLs) in patients with postportoenterostomy biliary atresia (BA) and assess their prognostic implications, in particular, if they are a risk factor for cholangitis. METHODS: One hundred twenty-one postsurgical BA patients were divided into 2 groups as follows: period 1, or preliver transplantation era group (n = 56), and period 2, or liver transplantation era group (n = 65). Presence of BL and outcome were examined in relation to the incidence of cholangitis. RESULTS: In period 1, there were more multiple BLs (MBLs) in nonsurvivors than survivors. Non-BL survivors had significantly lower mean total number of episodes of cholangitis than MBL survivors (P < .01). In period 2, 58 survived (native liver in 35; transplanted liver in 23). Bile lakes were present in 9/58 (16%) survivors (single in five, multiple BLs in four), and 1/7 (14%) nonsurvivors had MBLs. Mean total number of episodes of cholangitis in the 4 MBL survivors and the 49 non-BL survivors were not significantly different. CONCLUSION: Our results suggest that presence of BL is a risk factor for cholangitis in the long-term but not in the short-term.

Long-term outcome of hepatic portoduodenostomy with interposition of the ileocecoappendix for biliary atresia.

Hepatic portoduodenostomy with interposition of the ileocecoappendix (HPI) can be used for the surgical treatment of biliary atresia (BA). The purpose of this study was to evaluate the long-term outcome of patients with HPI. The records of nine patients who had HPI performed for BA were reviewed. Mean age at portoenterostomy was 68.1 days (range 26-113 days). At the end of 2006, seven of the nine subjects were alive, although two required liver transplantation (LT). The two deaths occurred 94 days and 2 years after HPI due to varicella infection and variceal bleeding, respectively. Length of follow-up for the seven survivors ranged from 17 to 19 years (mean 18 years). Three subjects achieved normal liver function after HPI and have remained jaundice-free to date. Another three who were initially jaundice-free required Roux-en-Y jejunostomy (RYJ) to the ileocecum for severe obstructive cholestasis 6 months, 3 years, and 19 years after HPI secondary to stones in the cecum. RYJ was successful in these three cases, and liver function returned to normal within a few months. Two of these three have continued to have almost normal liver function, but one required LT 5 years after RYJ. The remaining case had LT because of liver dysfunction 14 months after HPI. There is a high risk for stone formation and obstruction with the HPI procedure because bile can stagnate in the ileocecum.

Maternal microchimerism in biliary atresia.

BACKGROUND: The aim of this study was to determine the existence and extent of maternal microchimerism in the livers of biliary atresia (BA) patients. METHODS: Two series of investigations were performed based on the sex of our subjects. Subjects for series I were men, of which 6 had BA. Livers were analyzed using X and Y chromosome probes and fluorescent in situ hybridization. Subjects for series II were woman. Nine BA cases and their mothers were HLA typed (class I). Daughter livers were also tested for antibodies to maternal and other HLA. Two cases of neonatal hepatitis, 2 cases of Alagille syndrome, and 1 case of Byler syndrome acted as controls. RESULTS: All male BA livers were found to contain a mixture of cells with 1 and 2 X chromosomes (ie, XY or XX). All livers from male controls had only 1 X chromosome (ie, XY). All female BA subjects had varying intensities of antimaternal HLA class I (HLA-A) antibodies in their bile duct epithelium and hepatocytes (strong, 5; mild, 3; weak, 1). The liver from the female control did not display any antimaternal HLA class I antibodies (HLA-Ab). CONCLUSION: Our preliminary data appear to show that maternal microchimerism is present within the livers of patients with progressive postnatal type BA. We suggest that BA could in fact be a graft-vs-host disease masquerading as an autoimmune reaction triggered by maternal microchimerism, and we intend to pursue this hypothesis further to clarify the etiology of BA.

Inchin-ko-to prevents medium-term liver fibrosis in postoperative biliary atresia patients.

The oriental herbal formulation inchin-ko-to (ICKT) inhibits liver cell apoptosis induced by transforming growth factor-beta 1 (TGF-beta1). This study evaluated the effect of ICKT on serum markers of liver function and liver fibrosis in postoperative biliary atresia (BA) patients. Twenty-one postoperative BA patients with elevated GOT, GPT and gamma-GTP, but normal serum total bilirubin levels, were divided into two groups arbitrarily; an ICKT group (n = 12), and a no-ICKT group (n = 9). Serum markers of liver function [GOT, GPT, gamma-GTP, total bile acids (TBA)], and serum markers of liver fibrosis [hyaluronic acid (HA), type IV collagen (C-IV)], were measured in both groups at the beginning of the study, and at 1, and 3 years after the beginning of the study and the results compared statistically. All patients tolerated ICKT well, and there were no side effects. In the ICKT group, mean serum HA levels were significantly decreased at 1 year (P < 0.012), and at 3 years, both mean serum HA and C-IV were significantly decreased (P < 0.001 and P < 0.003, respectively). However, mean serum levels of GOT, GPT, gamma-GTP, and TBA did not change significantly following ICKT use for any length of time (all P > 0.05). Administration of ICKT in postoperative BA patients appears to lower the serum levels of markers of fibrosis in the medium-term. Whether this in fact correlates with prevention cannot be determined from this paper, but ICKT would appear to protect against liver fibrosis. Long-term studies are required to determine the exact role ICKT plays in prognosis of BA patients.

The role of monocyte chemoattractant protein-1 in biliary atresia.

BACKGROUND: The aim of this study was to explain the role of monocyte chemoattractant protein-1 (MCP-1) in biliary atresia (BA). METHODS: Concentrations of serum MCP-1 and collagen type IV were measured in 38 patients with BA by using commercially available kits. MCP-1 was also assessed in liver biopsy specimens by using immunohistochemistry. Subjects were classified into groups. Group 1 comprised BA patients with normal liver function (n = 13), group II comprised BA patients with moderate liver dysfunction (n = 18), group III comprised BA patients older than 20 years awaiting liver transplantation (n = 7), and the control group comprised age-matched patients without evidence of liver disease (n = 23). RESULTS: Serum MCP-1 levels were significantly increased in group II compared with group I (P < .0001) and the control group (P < .0001). Serum MCP-1 levels in group III were lower than in the control group (P < .0001). There was a significant linear correlation between serum MCP-1 levels and type IV collagen levels in group II. Group II subjects with portal hypertension (PH) had higher MCP-1 levels than those without PH (P = .0009). Biopsy specimens showed MCP-1 was expressed mainly on biliary epithelial cells, vascular endothelial cells, and hepatocytes in group II. CONCLUSIONS: These findings suggest that MCP-1 probably plays a significant role in the development of progressive liver fibrosis in BA.

Management of a prenatally diagnosed huge teratoma arising from the soft palate.

Teratomas arising from the oral cavity are relatively rare and can cause life-threatening airway obstruction immediately after birth. We report a case of a huge teratoma arising from the soft palate detected prenatally. To save the patient, a caesarean section and ex utero intrapartum treatment (EXIT) were planned at 29 weeks of gestation. However, during EXIT, the patient's cardiopulmonary status deteriorated due to unstable cord blood flow secondary to uterine contractions. EXIT was abandoned, the patient was delivered and an emergency tracheotomy performed. The tumour was successfully excised 4 hours after tracheotomy. The tumour weighed 1,591 g and was 20 x 22 x 12 cm. The patient, a female, weighed 715 g. Histopathology showed Grade II teratoma. The postoperative course was uneventful and she is now 5 years old with no neurological sequelae. EXIT is indicated in patients who have a high risk for airway obstruction immediately after birth. However, if EXIT must be abandoned, as in this case, urgent tracheotomy is mandatory. Planned prevention of airway obstruction at delivery is indispensable for successful outcome and requires excellent coordination among obstetricians, neonatologists, anaesthesiologists and paediatric surgeons.

Optimum prednisolone usage in patients with biliary atresia postportoenterostomy.

PURPOSE: Prednisolone is used routinely after portoenterostomy (PE) in patients with biliary atresia (BA). The authors reviewed their patients with BA post-PE to assess prednisolone protocols. METHOD: Severity of fibrosis at PE (moderate or severe), age at PE (30-70 days), size of bile ductules in the fibrotic biliary remnant at the porta hepatis (>100 microm), and type of BA (uncorrectable type) were used as criteria for selecting 63 subjects from our patients with BA post-PE. Subjects were divided into 5 groups according to prednisolone dosage: group 1, no prednisolone; groups 2 to 4, single courses of intravenous prednisolone commencing on day 7 post-PE administered in decreasing dose for 3 days each as follows: group 2, 6, 4, and 2 mg; group 3, 10, 5, and 2.5 mg; group 4, 20, 15, 10, 5, and 2.5 mg; group 5, same as group 4, but stool color was used to monitor bile excretion and a course was restarted from 20 mg whenever stools began to turn pale. If necessary, single courses were repeated until serum total bilirubin was less than 2.0 mg/dL. Protocol efficacy was assessed by comparing the number of patients who became jaundice free, the period taken to become jaundice free, and the incidence of side effects related to prednisolone. RESULTS: The number of patients who became jaundice free in the no prednisolone group (group 1, 7/12 or 58.3%) was not significantly different from the number in the single-course groups (group 2, 8/12 or 66.6%; group 3, 10/13 or 76.9%; and group 4, 11/15 or 73.3%). The number in the stool-monitored group (group 5, 10/11 or 90.9%) was significantly greater (P < .05). The mean period taken to become jaundice free in group 1 (82.6 +/- 29.1 days) was not significantly different from the single-course groups (group 2, 74.5 +/- 29.3 days; group 3, 49.6 +/- 19.8 days; and group 4, 48.3 +/- 26.0 days). The mean period taken in the stool-monitored group (group 5, 33.3 +/- 6.4 days) was significantly shorter (P < .05). The number of subjects who developed cholangitis after becoming jaundice free was not significantly different (group 1, 2/7; group 2, 2/8; group 3, 2/10; group 4, 2/11; group 5, 2/10). There were no prednisolone-related complications identified in any subject. CONCLUSIONS: These results provide strong evidence that large-dose prednisolone therapy with stool color monitoring of bile flow has a positive impact on the time taken for patients with BA post-PE to become jaundice free and the number of patients who remain jaundice free.

Primary mucinous cystadenoma arising from behind the posterior peritoneum of the descending colon in a child: a case report.

This is the first report of a primary mucinous cystadenoma (MCA) arising from behind the posterior peritoneum of the descending colon in a paediatric patient. A large intra-abdominal cystic lesion was found incidentally during renal ultrasonography in a 14-year-old girl. Imaging studies showed a 13 x 9 x 15 cm homogeneous cystic lesion with mild contrast enhancement of the wall. The cyst appeared to originate from the retroperitoneum, but was separated from the left kidney, ovary, and pancreas. At laparotomy, there was a cyst behind the posterior peritoneum of the descending colon. The cyst was successfully excised, and histopathology showed MCA. Although primary MCA in the retroperitoneum is extremely rare in children, it should be considered in the differential diagnosis of an intra-abdominal cyst, since it needs to be excised to eliminate the risk of infection, recurrence, and malignancy.