Akiko Yokoi

Regression of established tumors and metastases by potent vascular endothelial growth factor blockade

Vascular endothelial growth factor (VEGF) is a critical promoter of blood vessel growth during embryonic development and tumorigenesis. To date, studies of VEGF antagonists have primarily focused on halting progression in models of minimal residual cancer. Consistent with this focus, recent clinical trials suggest that blockade of VEGF may impede cancer progression, presumably by preventing neoangiogenesis. However, VEGF is also a key mediator of endothelial–vascular mural cell interactions, a role that may contribute to the integrity of mature vessels in advanced tumors. Here, we report that high-affinity blockade of VEGF, using the recently described VEGF-Trap, abolishes mature, preexisting vasculature in established xenografts. Eradication of vasculature is followed by marked tumor regression, including regression of lung micrometastases. Thus, the contribution of relatively low levels of VEGF to vessel integrity may be critical to maintenance of even very small tumor masses. Potent blockade of VEGF may provide a new therapeutic option for patients with bulky, metastatic cancers.

Esophageal atresia: Prognostic classification revisited

BACKGROUND Although the Spitz classification is the most widely used prognostic classification for esophageal atresia and/or tracheoesophageal fistula (EA), its discrimination ability remains unclear. We sought to develop a more accurate prognostic classification for EA. METHODS The records of 121 consecutive infants with EA (1980-2005) were reviewed. The independent variables included 6 clinical characteristics, and the dependent variables were survival and mortality. Stepwise logistic regression analysis was used to construct models predicting mortality and create a revised prognostic classification. The discrimination abilities of the revised classification and the Spitz classification were compared using receiver-operating characteristic (ROC) curves. RESULTS Birth weight and the presence of major cardiac anomalies were significant prognostic factors for mortality, and major cardiac anomalies affected mortality more than birth weight. The ROC curve for birth weight suggested that 2,000 g was an appropriate cutoff point. The Spitz classification was revised as follows: the revised class I (low-risk group) consisted of patients without major cardiac anomalies and birth weight >2,000 g; class II (moderate-risk group) consisted of patients without major cardiac abnormalities and birth weight <2,000 g; class III (relatively high-risk group) consisted of patients with major cardiac anomalies and birth weight >2,000 g; and class IV (high-risk group) consisted of patients with major cardiac anomalies and birth weight <2,000 g. The ROC comparisons showed that the revised classification provided a significant improvement (P = .049). CONCLUSION This revised classification can improve the stratification of EA patients and be a useful predictor of survival.

Significance of serial real-time PCR monitoring of EBV genome load in living donor liver transplantation.

Background: Quantitative analysis of the Epstein–Barr virus (EBV) genome has been recently reported to be helpful for early identification of EBV viremia which could reduce the risk of post‐transplantation lymphoproliferative disorder (PTLD).

Monosegmental Living-Donor Liver Transplantation for Infantile Hepatic Hemangioendothelioma

Infantile hepatic hemangioendothelioma (IHHE) is a rare vascular tumor that presents before the age of 6 months. The patients with IHHE suffer from high-output congestive heart failure caused by major arteriovenous fisutulas in the liver, which leads to respiratory compromise and results in a high mortality rate despite medical treatments. A case of 4-month-old baby with liver failure caused by IHHE is reported. The baby received an urgent liver transplantation from a living donor. A monosegmental graft was used to mitigate graft-to- recipient size mismatching. The surgical procedure of monosegmental living donor liver transplantation also is discussed.

Risk Factors for the Recurrence of the Congenital Diaphragmatic Hernia—Report from the Long-Term Follow-Up Study of Japanese CDH Study Group

AIM OF THE STUDY Few follow-up studies focused on the recurrence regarding the postoperative course of congenital diaphragmatic hernia (CDH) survivors. The aim of this study was to report on risk factor for CDH patients who had the recurrence during the follow-up. MATERIALS AND METHODS A multicenter retrospective survey was conducted on neonates diagnosed to have CDH between January 2006 and December 2010. Follow-up survey was conducted between September 2013 and October 2013 (ethical approval: No. 25-222). Nine institutions agreed to participate in this survey. Out of 228, 182 (79.8%) patients were alive and 180 patients were included in this study. Two patients were excluded because the defect had not repaired at the primary operation. The patients were divided into the recurrence group (n=21) and the nonrecurrence group (n=159). Postnatal and postoperative variables were compared between these two groups. Baseline variables which showed significance in univariate analysis were entered into multiple logistic regression analysis for analyzing the recurrence. A value of p<0.05 was considered to be statistically significant by using the JMP software program (version 9; SAS Institute, Inc, Cary, North Carolina, United States). MAIN RESULTS Out of 180, 21 (11.7%) CDH neonates had the recurrence during the course of the follow-up. Five (2.8%) patients had the recurrence before primary discharge and 16 (8.9%) patients had the recurrence after discharge. Univariate analysis showed that liver herniation (crude odds ratio [OR], 7.4; 95% confidence interval [CI], 2.73-23.68), defect size C and D, proposed by the CDH Study Group (crude OR, 7.09; 95% CI, 2.73-19.99) and patch repair (crude OR, 5.00; 95% CI, 1.91-14.70) were risk factors. Multivariate logistic regression analysis showed liver herniation (adjusted OR, 3.96; 95% CI, 1.01-16.92) was the risk factor for the recurrence. CONCLUSION A wide spectrum of the disease severity and the rarity of the disease mask the risk of the recurrence for CDH patients. This study showed the only factor to predict the recurrence was the liver herniation. These data will be helpful for providing information for the long-term follow-up of the CDH patients.

Intracranial Hemorrhage and Vitamin K Deficiency Associated with Biliary Atresia: Summary of 15 Cases and Review of the Literature

Biliary atresia (BA) is a rare disease, characterized by progressive and obliterative cholangiopathy, and is one of the major causes of secondary vitamin K deficiency in infancy. We describe 15 infants (10 female, 5 male) with BA, presenting with intracranial hemorrhage (ICH), including 10 subdural hemorrhages, 4 subarachnoid hemorrhages, 2 intraventricular hemorrhages, and 1 intraparenchymal hemorrhage. The age at onset of ICH ranged from 26 to 79 (mean 54.2) days. Eight patients underwent successful surgical evacuation of ICH, following administration of vitamin K. All 15 patients underwent Kasai portoenterostomy for BA 8–30 days after onset. During a mean follow-up period of 86.8 (range 2–352) months, 4 patients died of liver failure despite lack of neurological sequelae. Two patients underwent living-related donor and 1 patient living-unrelated donor liver transplantation. Only 2 patients suffered neurological signs and symptoms, including mental retardation and epilepsy, whereas 3 were noted to have temporary hemiparesis which recovered completely during the follow-up period. The possibility of BA should be considered in the treatment of ICH due to vitamin K deficiency, since it is reported to be one of the major causes of secondary vitamin K deficiency. Urgent surgical intervention for ICH can be performed successfully following sufficient administration of vitamin K or fresh frozen human plasma. Moreover, early performance of Kasai portoenterostomy is possible even for patients who have undergone craniotomy.

Congenital tracheal stenosis: the prognostic significance of associated cardiovascular anomalies and the optimal timing of surgical treatment

BACKGROUND/PURPOSE Cardiovascular anomalies (CA) are frequently associated with congenital tracheal stenosis (CTS), but their prognostic impact on CTS and the optimal timing of surgical treatment remain uncertain. The aim of this study was to explore the prognostic factors and the optimal timing of surgical treatment in CTS patients with CA. METHODS After obtaining institutional review board approval, a retrospective review of 42 patients who underwent surgical repair of CTS between 1996 and 2006 was conducted. The patients were divided into 3 groups: CTS without CA (n = 10, group A), CTS with CA repaired simultaneously (n = 27, group B), and CTS with CA repaired in stages (n = 5, group C). Seven clinical characteristics, including gestational week and weight at birth, the age and body weight at operation, the length of tracheal stenosis (%), the duration of cardiopulmonary bypass (CPB) during surgery, and operation time were compared among the groups using analysis of variance, Fishers Exact test, and Students t test. RESULTS Although no operative mortalities occurred in groups A and C, there were 3 early deaths and 1 late death in group B. The deaths occurred in cases with associated complex CA (critical pulmonary stenosis, tetralogy of Fallot with an absent pulmonary valve, right ventricular outflow block, and cor triatrium). The duration of CPB was significantly different between groups A and B (P = .017), and furthermore, CPB time was significantly longer in early death cases than in surviving cases in group B (318.3 +/- .71.1 vs 204.0 +/- 67.8 minutes; P = .012). CONCLUSIONS Complex CA and long CPB duration would be prognostic factors for the outcome of surgical management for CTS and CA. Simultaneous reconstruction of CTS and simple CA appears to be a reasonable method of surgical intervention, but patients with long segment CTS with complex CA may still be difficult to cure using this strategy, and staged correction may be considered.

Aortopexy with tracheal reconstruction for postoperative tracheomalacia in congenital tracheal stenosis.

PURPOSE Congenital tracheal stenosis is a rare condition and can be difficult to manage. One source of difficulty is postoperative tracheomalacia requiring long-term tracheal stenting. To prevent symptomatic postoperative tracheomalacia, we have been adding aortopexy to tracheal reconstruction since 2008. The aim of this study was to evaluate efficacy of aortopexy for preventing postoperative tracheomalacia after reconstruction of congenital tracheal stenosis. METHODS Retrospective chart review was conducted. From October 2003 to March 2011, 24 had tracheal reconstruction without aortopexy (group A) and 8 with aortopexy (group B). Statistical analysis was performed using Fishers Exact test. RESULTS One had anastomotic leakage in group A, and 1, in group B (P = .44). Eleven patients required tracheostomy because of postoperative tracheomalacia confirmed by postoperative bronchoscopy in group A vs none in group B (P = .029). CONCLUSIONS We found that aortopexy with tracheal reconstruction reduced the need for postoperative tracheostomy in this patient group. Although there is a potential risk of anastomotic leakage because of the suspension suture on the anterior tracheal wall to aorta, we did not detect an increased incidence after aortopexy. Thus, aortic suspension may be a useful adjunct to prevent symptoms of tracheomalacia in these patients.

Pretransplant risk factors and optimal timing for living-related liver transplantation in biliary atresia : experience of one Japanese children's hospital and transplantation center

BACKGROUND/PURPOSE Although living-related liver transplantation (LRLT) is effective for patients with biliary atresia (BA) after a failed Kasai operation, the pretransplant factors affecting post-LRLT mortality and the optimal timing of the procedure remain unclear. METHOD A retrospective review of 27 patients with BA after a failed Kasai operation (median age, 22 months; range, 6-237 months) who received LRLT from 1994 to 2005 was done. The clinical characteristics at the time of the pre-LRLT assessment of those who did and did not survive were compared. A simple regression analysis and receiver operating characteristic analysis were done to correlate the clinical data. RESULTS Among the 27 patients, 4 patients died within 1 year post-LRLT. The significant factors affecting posttransplant death were hepatopulmonary syndrome (HPS), age at LRLT, and graft-to-recipient weight ratio. The arterial blood gas analysis of HPS patients showed that there was a significant negative correlation between the SaO(2) value on room air and the intrapulmonary shunt ratio. The receiver operating characteristic analysis of age at LRLT showed that the optimal cutoff point was 103 months of age. CONCLUSION Older children with HPS or a lower graft-to-recipient weight ratio are not ideal candidates for LRLT. The correlation between the shunt ratio and SaO(2) suggests that HPS could be detected early using pulse oximetry.

Treatment of postoperative tracheal granulation tissue with inhaled budesonide in congenital tracheal stenosis.

PURPOSE Tracheal obstruction by granulation tissue can compromise the postoperative course in congenital tracheal stenosis (CTS). Balloon dilatation and stenting may be required. Budesonide is a corticosteroid with topical anti-inflammatory effects. In 2008, we used inhaled budesonide for treatment of postoperative granulation tissue for the first time in CTS, resulting in significant improvement. The aim of this study was to evaluate the efficacy of inhaled budesonide for treatment of postoperative granulation tissue in CTS. METHODS Retrospective chart review was conducted. From 2004 through 2011, we performed 39 tracheoplasties. Forced stenting ± balloon dilatation (S/B) was required when airway obstruction with tissue granulation was life-threatening. We compared the requirement for S/B between the early group without budesonide (2004-Nov. 2008, Early) and the late group with budesonide (Dec. 2008-2011, Late). Statistical analysis was performed using Fishers Exact test. RESULTS Eleven of 22 in Early and 8 of 17 in Late were successfully extubated, never having had life-threatening tissue granulation. The remaining patients in each group (11 in Early and 9 in Late) required tracheostomies due to postoperative complication. Ten in Early and 5 in Late with tracheostomies developed granulation tissue. Of these patients, the 10 in Early required S/B, while none of the 5 in Late required S/B (P=.0003). Bronchoscopy demonstrated significant regression of granulation tissue in all cases treated with inhaled budesonide. CONCLUSION Inhaled budesonide is effective for treatment of tracheal granulation tissue in patients with tracheostomies after repair of CTS.