Successful treatment of young childhood standard-risk hepatoblastoma with cisplatin monotherapy using a central review system.

BACKGROUND: The JPLT3-S (Japanese Study Group for Pediatric Liver Tumors-3) study, conducted cisplatin (CDDP) monotherapy for young children (<3 years old) with standard-risk hepatoblastoma (HB) using a central review system in Japan. In the previous JPLT2 study, cases with resectable tumors without any annotation factors in the PRETEXT (PRETreatment EXTent of disease) classification (standard-risk HB) showed favorable outcomes with treatment consisting of CDDP and pirarubicin, but showed toxicities and late complications. In the JPLT3-S trial, a less intense regimen consisting of CDDP alone was evaluated. METHODS: Patients who were less than 3 years of age and with PRETEXT I, II, or III HB without any annotation factors (e.g., E1, E1a, E2, E2a, H1, N1, P2, P2a, V3, and V3a) were eligible for inclusion in this study. In this trial, the central radiological and pathological features of all patients were reviewed. The primary outcome was the 3-year progression-free survival (PFS). RESULTS: A total of 38 patients (23 female) were included. The median patient age was 12 months (range: 2-34). Two patients discontinued treatment because of progressive disease, and five patients discontinued treatment for other reasons. The 3-year PFS rate was 93.9% (95% confidence interval [CI]: 86.4%-100%). All 38 patients survived (follow-up period 38-98 months), and the OS rate was 100% (CI: 100). Eighteen of the 38 patients (47.4%) experienced ototoxicity as a late complication. CONCLUSION: CDDP monotherapy regimen is feasible in young patients with localized HB, as classified by a central review.

Selective enlargement of left lateral segment liver volume as a potential diagnostic predictor for biliary atresia.

PURPOSE: To determine an early diagnostic indicator of biliary atresia (BA), we focused on morphological left-right differences of BA livers. METHODS: Of 74 infants with suspected BA at our hospital in the last 12 years, 25 met the conditions for investigation: 15 infants with BA (BA group) and 10 with other pathologies (non-BA group). CT volumetry of the liver in each patient was performed using a 3D image analysis system. Patient characteristics, blood data, and proportion of the left lateral segment to the total liver volume (LLS ratio) were compared between the two groups. RESULTS: Among the patient characteristics and liver function tests, only γ-glutamyl transpeptidase (GGT) were significantly higher in the BA group (p < 0.001). The LLS ratio was 0.321 (0.227-0.382) in the BA group and 0.243 (0.193-0.289) in the non-BA group (p = 0.01). The summary cut-off, area under the curve, sensitivity, and specificity were 0.322, 0.813, 53.3, and 100% for the LLS ratio and 94.26, 0.95, 86.7, and 100% for the GGT × LLS ratio, respectively. CONCLUSIONS: The LLS ratio is highly specific and may be an early diagnostic predictor of BA. Moreover, this segmental LLS enlargement may be associated with the etiology of BA.

Results of mass screening for neuroblastoma in 18-month-old infants in Osaka area, Japan.

PURPOSE: In 2004, the Japanese government halted nationwide mass screening for neuroblastoma in 6-month-old infants as it led to overdiagnosis of localized tumors with favorable prognoses and failed to reduce neuroblastoma-related mortality. However, a new mass screening program for neuroblastoma in 18-month-old infants (18MS) was conducted in the Osaka prefecture. We assessed the efficacy of the 18MS in screening unfavorable cases. METHODS: Public health centers in Osaka prefecture, excluding the Osaka city area, provided test kits to the guardians of infants who received a check-up at 18 months of age between 2004 and 2017. For patients whose standardized urinary levels of vanillylmandelic acid or homovanillic acid exceeded the threshold, they were further examined and treated in two specific hospitals Osaka University Hospital and Osaka Women's and Children's Hospital. Screening-positive patients with and without neuroblastoma were retrospectively reviewed. RESULTS: Among 142,423 children screened during the 18MS, 85 tested positive, and 14 were diagnosed with neuroblastoma. Twelve patients were classified as very low risk, while 2 were classified as high risk, based on the International Neuroblastoma Risk Group risk classification. CONCLUSION: The 18MS did not screen unfavorable cases with neuroblastoma efficiently, although few participants benefited from it.

Effect of microscopy-assisted portoenterostomy (MAPE) for biliary atresia.

PURPOSE: Portoenterostomy (PE) is the standard treatment for biliary atresia (BA). However, micro-bile ducts are difficult to identify with surgical loupes and dissect systematically. We report the effects of our attempts to dissect hilar tissue using a surgical microscope. METHODS: Microscopy-assisted portoenterostomy (MAPE) was initiated in 2014. Patients born between 2000 and 2013 who underwent PE until day 70 without a surgical microscope for BA were gathered as historical control. MAPE in re-do PE cases (Re-MAPE) was evaluated in the same manner. RESULTS: Ten patients underwent MAPE for BA during the study period. 17 patients in the conventional PE group were gathered. In the MAPE group, the jaundice clearance rate was 80%, compared with 53% in the conventional PE group. Re-MAPE was performed in four patients, who had a jaundice clearance rate of 75%, essentially identical to the rate with initial MAPE. At age 4 years, the native liver survival rate was 58% in the MAPE group and 38% in the conventional PE group. The native liver survival rate in the Re-MAPE group was 75%. CONCLUSION: MAPE is useful for sharing the surgical field during open PE in patients with BA. It may improve the rate of jaundice clearance.

Thoracoscopic repair of esophageal atresia.

Thoracoscopic repair (TR) of esophageal atresia (EA) has been performed with increasing frequency over the last two decades, with the expectation of improved outcomes by avoiding thoracotomy. To understand the current practice and outcomes of TR of EA, we reviewed the relevant literature, including 15 case series, 7 comparative studies, and 3 meta-analysis comparing TR with conventional open repair (COR). Most of the studies had a retrospective design and small numbers of patients. Although the evidence level is low because of the lack of prospective studies, this review found that TR is as safe as COR, with comparative outcomes. Moreover, there were several advantages of TR over COR, such as less blood loss and a shorter hospital stay. The long-term outcomes of TR remain unclear because of limited data. Moreover, there is a significant learning curve over the first 10-20 TRs performed. We conclude that TR of EA, when conducted by experienced surgeons, is a safe and minimally invasive alternative to COR and may yield better results than COR in appropriately selected patients.

Can plain chest X-ray replace computed tomography for the follow-up of children who have undergone the Nuss procedure?

PURPOSE: To establish whether new indices on plain chest X-ray (CXR) can replace those on computed tomography (CT) for the follow-up of children who have undergone the Nuss procedure. METHODS: The subjects of this retrospective study were 45 children who underwent the Nuss procedure between 2000 and 2016. The Haller index (HI) was measured by preoperative CT. Preoperative and postoperative chest deformities were evaluated by two CXR measurements: the concave rate on the lateral view (CR; the depth of the concavity divided by the anterior-posterior diameter of the rib cage) and the tracheal bifurcation angle (TBA) on the anterior view. Data are expressed as the median with range. RESULTS: The median age and HI of the children, when they underwent the Nuss procedure, was 9.3 (3.8-17.3) years and 4.5 (3.2-10.1), respectively. The preoperative CR was correlated significantly with the HI. The postoperative CR was significantly lower than the preoperative CR [pre: 0.17 (0.08-0.37), post: 0.09 (0.01-0.18), p < 0.05], and the low value was sustained after bar removal. The TBA decreased significantly after the Nuss procedure from 74.2° (55-104) preoperatively to 65.0° (45-92) postoperatively (p < 0.05). CONCLUSIONS: These results suggest that CXR can replace CT for the follow-up of patients after the Nuss procedure, with lower radiation exposure.

Recombinant human soluble thrombomodulin reduces the severity and incidence of necrotizing enterocolitis in a newborn rat model.

PURPOSE: Necrotizing enterocolitis (NEC) remains the leading cause of death in preterm infants. Recombinant human soluble thrombomodulin (rTM) has been reported to have anti-inflammatory effects as well as antithrombogenic effects. The aim of this study was to evaluate the effect of rTM in a rat NEC model. METHODS: NEC was induced by enteral feeding with hyperosmolar formula, gavage administration of lipopolysaccharide and asphyxia stress. Controls were fed by their mother ad libitum. In the treatment group, rTM was administered subcutaneously twice (once each on the first and second day). All animals surviving beyond 96 h or that developed signs of distress were euthanized. The ileum was harvested for a histological evaluation and the measurement of the mRNA and protein expression. RESULTS: The rate of NEC-like intestinal injury in the treatment group (9/25, 36%) was significantly lower than in the NEC group (25/34, 73.5%). Tissue levels of TNF-α, IL-6 and HMGB1 were significantly elevated in the NEC group, whereas those in the treatment group were decreased to similar values as in the control group. CONCLUSIONS: Our experimental study showed that rTM is able to reduce the severity and incidence of NEC. It may be an alternative option for the treatment of NEC.

Laparoscopic ligation of a congenital extrahepatic portosystemic shunt for children with hyperammonemia: a single-institution experience.

PURPOSE: A congenital extrahepatic portosystemic shunt (CEPS) associated with hyperammonemia requires occlusion of the shunt vessels. We evaluated the effectiveness and safety of laparoscopic ligation of a CEPS in children with hyperammonemia. METHODS: The subjects of this retrospective study were seven children with hyperammonemia who underwent laparoscopic ligation of a CEPS. Their median age was 5.2 years (range 1-16 years). Before the laparoscopic procedure, a catheter was inserted through the femoral vein and placed in the portal vein via the shunt vessel. The shunt vessel was dissected and taped laparoscopically. After measuring the portal vein pressure under temporal occlusion, the shunt vessels were ligated. RESULTS: The types of shunts according to location were patent ductus venosus (n = 2), splenorenal shunt (n = 2), gastrorenal shunt (n = 2), and superior mesenteric vein-inferior vena cava shunt (n = 1). Laparoscopic ligation of the shunt vessel was completed uneventfully in all patients. The median portal vein pressure was 19 mmHg after ligation. The median preoperative blood ammonia level was 94 µg/dL (range 71-259 µg/dL), which decreased after ligation in all patients. There was no incidence of postoperative liver failure. CONCLUSION: Laparoscopic ligation of a CEPS is safe and effective for children with hyperammonemia.

Long-term outcomes of patch tracheoplasty using collagenous tissue membranes (biosheets) produced by in-body tissue architecture in a beagle model.

PURPOSE: Although various artificial tracheas have been developed, none have proven satisfactory for clinical use. In-body tissue architecture (IBTA) has enabled us to produce collagenous tissues with a wide range of shapes and sizes to meet the needs of individual recipients. In the present study, we investigated the long-term outcomes of patch tracheoplasty using an IBTA-induced collagenous tissue membrane ("biosheet") in a beagle model. METHODS: Nine adult female beagles were used. Biosheets were prepared by embedding cylindrical molds assembled with a silicone rod and a slitting pipe into dorsal subcutaneous pouches for 2 months. The sheets were then implanted by patch tracheoplasty. An endoscopic evaluation was performed after 1, 3, or 12 months. The implanted biosheets were harvested for a histological evaluation at the same time points. RESULTS: All animals survived the study. At 1 month after tracheoplasty, the anastomotic parts and internal surface of the biosheets were smooth with ciliated columnar epithelium, which regenerated into the internal surface of the biosheet. The chronological spread of chondrocytes into the biosheet was observed at 3 and 12 months. CONCLUSIONS: Biosheets showed excellent performance as a scaffold for trachea regeneration with complete luminal epithelium and partial chondrocytes in a 1-year beagle implantation model of patch tracheoplasty.

Postoperative decrease in plasma acyl ghrelin levels after pediatric living donor liver transplantation in association with hepatic damage due to ischemia and reperfusion injury.

PURPOSE: Ghrelin was recently reported to promote recovery from hepatic injury. We hypothesized that it could also be associated with clinical recovery of the transplanted liver from ischemia and reperfusion injury. Our aims were to investigate perioperative ghrelin changes following pediatric living donor liver transplantation (LDLT) and to analyze the association of these changes with postoperative hepatic function. METHODS: We measured plasma acyl ghrelin (AG) concentrations before surgery, at the end of surgery and on postoperative days (PODs) 1, 3 and 7 in 12 children who underwent LDLTs, and, as controls, pre- and post-operatively and on POD1 in 7 children who underwent benign abdominal mass resection. The correlations between the participants' ghrelin profiles and hepatic function-related data were evaluated. RESULTS: AG levels significantly declined to 15.6% of preoperative levels after LDLT and almost returned to baseline on POD3. Post-operative AG levels were significantly reduced to a greater extent following LDLT than benign abdominal mass resection. AG levels on POD1 inversely correlated with aspartate aminotransferase levels and cold/total ischemia time (P < 0.05). CONCLUSION: These results suggest that reduced AG levels on POD1 may reflect the degree of damage to the transplanted liver due to ischemia and reperfusion injury.

Serum Mac-2-binding protein (M2BPGi) as a marker of chronological liver fibrosis in biliary atresia patients with cirrhosis.

PURPOSE: Biliary atresia (BA) is characterized by progressive liver fibrosis, but it is difficult to assess the progression after the patient develops cirrhosis. Mac-2-binding protein glycosylation isomer (M2BPGi) is a new marker for hepatic fibrosis. We examined the chronological changes in M2BPGi levels in BA patients with cirrhosis. METHODS: Patients with cirrhosis were selected from among pediatric BA patients who had their native livers. Serum M2BPGi levels and Child-Pugh classification were evaluated. A total of 11 pediatric BA patients with cirrhosis were recruited. RESULTS: Initial M2BPGi level after diagnosis of liver cirrhosis based on liver biopsy was on average 3.4, and the most recent M2BPGi level under observation was on average 4.3. The follow-up period from the initial M2BPGi measurement averaged 22.6 months. The ratio of the initial and most recent values (M2BPGi ratio) was on average 1.3 (0.5-2.4). Three cases with improved fibrosis (M2BPGi ratio < 1.0) remained in Child A, as did six cases (1.0 ≤ M2BPGi ratio < 2.0), but two cases with marked fibrosis progression (2.0 ≤ M2BPGi ratio) advanced to decompensated cirrhosis Child B. CONCLUSION: M2BPGi is useful as a prognostic factor for BA patients with liver cirrhosis. In addition, fibrosis improved even after the development of cirrhosis.

The effect of maternal grafts in early acute cellular rejection after pediatric living-donor liver transplantation.

PURPOSE: Living-donor liver transplantations (LDLTs) with maternal grafts can be more successful than those with paternal grafts because of their tolerance to non-inherited maternal antigens. We reviewed LDLT patients to investigate the relationship between acute rejection and donor sex. METHODS: LDLT patients between January 2010 and November 2015 were enrolled. ACR was defined by a rejection activity index of > 3. RESULTS: Forty-six patients (22 males and 24 females), of whom 28 had biliary atresia, were enrolled. The median age of the patients was 2.8 years and the donor types were maternal (n = 25) and paternal (n = 21). Acute cellular rejection (ACR) was observed in 22 patients. Twelve (48%) of the 25 patients in the maternal group had at least one episode of rejection compared with 10 (48%) of the 21 in the paternal group. Among the patients with ACR, the first rejection in the maternal group occurred significantly earlier than that in the paternal group (p < 0.01). In the multivariable analysis, the only variable significantly related to the first rejection day after LDLT was donor sex (male) (p < 0.005). CONCLUSION: Our results showed that maternal grafts had an effect on causing earlier ACR in LDLT.

Clinical implications of serum Mac-2-binding protein (M2BPGi) during regular follow-up of patients with biliary atresia.

PURPOSE: The Mac-2-binding protein glycosylation-modified isomer (M2BPGi) is a new marker for progression of hepatic fibrosis. We examined the relationship between serum M2BPGi levels and liver histological findings in patients with biliary atresia (BA) who were not transplant candidates. METHODS: Patients with BA who were not transplant candidates with good liver function were included. We examined M2BPGi levels and histological findings in relation to other laboratory markers of liver fibrosis, including aspartate aminotransferase (AST) to platelet ratio index, fibrosis-4 index, and type IV collagen 7s domain. Liver fibrosis was evaluated based on the METVIR score. RESULTS: 37 patients were included. The median age was 18 years (range 3-38 years). M2BPGi values ranged from 0.3 to 6.9 cutoff index (COI) (median 1.6). The degree of liver fibrosis varied with M2BPGi level. For predicting cirrhosis (F4) and advanced liver fibrosis (≥ F3), M2BPGi had higher areas under the curve (AUCs; 0.93, respectively) with cutoff COIs of 1.84 and 1.67, respectively, than for the four conventional markers for fibrosis. CONCLUSION: M2BPGi is a novel marker for liver fibrosis in patients with BA. It is especially useful for following patients with BA with a native liver and supporting liver biopsy interpretation findings.

Image-based surgical risk factors for Wilms tumor.

PURPOSE: The standard treatment for Wilms tumor (WT) is primary resection. However, in cases with unresectable tumor or tumor spillage, which are considered to have high surgical risks, more intensive chemotherapy and radiotherapy are required. In the present study, we retrospectively analyzed preoperative image parameters to identify factors associated with surgical risks. METHODS: Twenty-nine patients with WT were enrolled in this study. Data on various preoperative image parameters, such as tumor size, tumor volume, displacement of great vessels, and contralateral extension of the tumor were collected, and their relationship with surgical factors, including operative time, hemorrhage, tumor spillage, and unresectability were analyzed. RESULTS: Patients with unresectable tumor or with tumor spillage (surgical high-risk group) more frequently demonstrated displacement of great vessels and contralateral tumor extension. Operative time and blood loss were also significantly related to tumor size, area, volume, displacement of great vessels and contralateral extension. CONCLUSION: Besides tumor size, displacement of great vessels and contralateral extension were significantly associated with surgical risks. These factors are easily determined using CT images and are, therefore, useful to decide whether preoperative chemotherapy should be started instead of primary tumor resection for large localized WTs.

Clinicopathological features of neuroblastic tumors with opsoclonus-myoclonus-ataxia syndrome: Follicular structure predicts a better neurological outcome.

Neuroblastic tumors (NT) with opsoclonus-myoclonus syndrome (OMS) display characteristic histological features, such as lymphocytic infiltration with lymphoid follicles, indicating an underlying immune response. We retrospectively assessed NT patients from 2001 to 2016. Five cases of NT with OMS and 76 cases of NT without OMS were histopathologically reviewed in this study. The grade of lymphocytic infiltration was evaluated. The number of follicles was counted and the presence or absence of lymphoid follicles was recorded for each case. We also confirmed the presence or absence of follicular dendritic cells (FDCs). We investigated the relationship between the histopathological and clinical findings of NT with OMS. Lymphocytic infiltration was observed in all cases; however, the precise follicular structure was occasionally unclear. Patients with clear follicular structures displayed germinal centers including tingible body macrophages and FDCs. All patients without neurological sequelae demonstrated a clear follicular structure with a FDC meshwork pattern. The interval between OMS onset and the detection and initial treatment of NT was typically longer in patients with neurological sequelae compared to those without neurological sequelae. Early detection and treatment of NT with OMS at the phase of a clear follicular formation with multiple FDC may provide favorable neurological outcomes.

Magnetic compression anastomosis for postoperative biliary atresia.

We report a case of successful magnetic compression anastomosis (MCA) for obstructed cyst-jejunostomy in a young woman who had undergone surgery for type 1 biliary atresia (BA) on day 78 of life. A 16-year-old girl was admitted with obstructive jaundice. Jaundice resolved with percutaneous trans-hepatic cholangiodrainage (PTCD) but contrast medium injected from the PTCD tube did not flow through the anastomosis. Magnets were placed on each side of the anastomosis, in the cyst and the jejunum, to compress the partition. On postoperative day (POD) 6, the anastomosis was recanalized and the PTCD tube placed trans-anastomotically until POD 245. The patient remained free from jaundice after removal of the PTCD tube. MCA can be a useful and less invasive procedure for treating biliary tract anastomotic obstruction in patients with BA.

Long-term morbidity in adolescents and young adults with surgically treated esophageal atresia.

PURPOSE: To investigate the long-term morbidity of surgically treated esophageal atresia (EA) in adolescents and young adults and establish whether these long-term morbidities are affected by the type of EA. PATIENTS AND METHODS: We reviewed the medical records, including backgrounds and associated conditions, of 69 long-term survivors of EA, aged >15 years. The long-term morbidities included neurodevelopmental abnormality, nutritional impairment (short height <-2SD, low BMI <18.5), subjective symptoms, and musculoskeletal deformities. Comparisons of the results were made between Gross A-type EA (n = 6) and Gross C-type EA (n = 63). RESULTS: All patients underwent esophageal anastomosis without esophageal replacement. Cardiac anomalies and long gap were present in 26 and 18%, respectively. Esophageal dilatation, fundoplication, and aortopexy were performed in 40, 34, and 18%, respectively. The incidence of long gap and esophageal stenosis was higher in Gross A-type EA than in Gross C-type EA. The long-term morbidities included neurodevelopmental abnormality (13%), nutritional impairment (62%: as short height in 34% and as low BMI in 46%), subjective symptoms (14%), and musculoskeletal deformities (59%). There were no differences in the long-term morbidities between Gross A and Gross C. CONCLUSIONS: The incidence of the long-term morbidities is high in adolescents and young adults, regardless of the type of EA. Early detection of morbidity is important to improve the long-term outcomes of EA.

Onset ages of hepatopulmonary syndrome and pulmonary hypertension in patients with biliary atresia.

PURPOSE: Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PoPH) are extrahepatic complications of biliary atresia (BA). Their detection is sometimes delayed, which may result in missed opportunities for liver transplantation. The aim of this study was to determine the onset ages of HPS and PoPH in BA patients. METHODS: BA patients followed at our institution were identified. Patients visited our clinic for routine blood work, as well as regular electrocardiography, chest X-rays, and arterial blood gas tests. Lung perfusion scintigraphy and cardiac ultrasound were performed to diagnose HPS. Cardiac catheterization was conducted to diagnose PoPH. RESULTS: The study population consisted of 88 BA patients. The median follow-up duration was 11.6 years (range 0.8-26.0 years). Six patients (6.8%) developed HPS and three patients (3.4%) developed PoPH. The median age of onset of HPS was significantly younger than that of PoPH (HPS: 4 years, PoPH: 15 years, P < 0.019). Two patients (66%) with PoPH died, while all patients with HPS survivied. CONCLUSION: The onset of HPS was significantly earlier than that of PoPH. The mortality rate was high in patients with PoPH. Teenagers with BA should receive routine cardiac echocardiograms to detect PH in its early stages.

Implantable central venous access device in infants: Long-term results.

BACKGROUND: The management of central venous access device (CVAD) is extremely difficult in babies and small infants (BSI). We therefore compared the long-term results and complications of CVAD in BSI with those in children. METHODS: One hundred and twenty patients were divided into two groups as follows: age <1 year or weight <10 kg (group A; 25 patients); and age ≧1 year and weight ≧10 kg (group B; 95 patients). The clinical results were retrospectively compared between the groups. RESULTS: Mean age and weight were 12.5 ± 5.9 months and 8.2 ± 1.2 kg in group A, and 78.8 ± 58.9 months and 20.9 ± 13.6 kg in group B. Operation time was 57 ± 29 min in group A and 52 ± 21 min in group B (P = 0.38). The catheter was advanced with difficulty into the central vein in five and in 16 patients (P = 0.77), and surgical complications occurred in one and in seven patients in groups A and B, respectively (P > 0.99). The CVAD remained in place for 627 ± 494 and 550 ± 414 days (P = 0.47) and was removed before treatment completion in five and in 14 patients in groups A and B, respectively (P = 0.54). CONCLUSION: The clinical results for CVAD in BSI did not differ from those in children. CVAD are useful and safe for the treatment of BSI with serious diseases.

Fibroadenoma in Beckwith-Wiedemann syndrome with paternal uniparental disomy of chromosome 11p15.5.

Herein is described a case of breast fibroadenomas in a 16-year-old girl with Beckwith-Wiedemann syndrome (BWS) and uniparental disomy (UPD) of chromosome 11p15.5. She was clinically diagnosed with BWS and direct closure was performed for an omphalocele at birth. Subtotal and 90% pancreatectomy were performed for nesidioblastosis at the ages 2 months and 8 years, respectively. Bilateral multiple breast fibroadenomas were noted at the age of 16 and 17 years. In this case, paternal UPD of chromosome 11p15.5 was identified on microsatellite marker analysis. The relevant imprinted chromosomal region in BWS is 11p15.5, and UPD of chromosome 11p15 is a risk factor for BWS-associated tumorigenicity. Chromosome 11p15.5 consists of imprinting domains of IGF2, the expression of which is associated with the tumorigenesis of various breast cancers. This case suggests that fibroadenomas occurred in association with BWS.