Shigehisa Fumino

Long-term outcomes after hepaticojejunostomy for choledochal cyst: a 10- to 27-year follow-up

INTRODUCTION Choledochal cyst (CC) is closely associated with anomalous arrangement of the pancreaticobiliary duct, which is considered a high-risk factor for biliary tract malignancy. Early diagnosis and early treatment for CC could lead to a good prognosis. This study investigated late complications and long-term outcomes after surgery for CC. PATIENTS AND METHODS Fifty-six patients with CC and over 10 years of postoperative follow-up were analyzed retrospectively. All patients had undergone total resection of the extrahepatic bile duct and hepaticojejunostomy. RESULTS Six patients showed liver dysfunction manifested in the first 10 years after surgery, but all returned to normal thereafter. Dilatation of intrahepatic bile ducts persisted in 6 postoperatively, and in 3, this was still apparent more than 10 years after. Recurrent abdominal pain was encountered in 3, 1 had pancreas divisum with a pancreatic stone, and 1 had adhesive small bowel obstruction. Two patients developed biliary tract malignancy. A 14-year-old girl died of recurrent common bile duct cancer 2 years after the initial resection of CC with adenocarcinoma. A 26-year-old man with repeated cholangitis owing to multiple intrahepatic bile stones developed cholangiocarcinoma 26 years after the initial resection of CC. Event-free survival rate and overall survival rate were 89% (50/56) and 96% (54/56), respectively. CONCLUSIONS Choledochal cyst generally has an excellent prognosis with early total resection and reconstruction. Long-term surveillance for the development of malignancy is still essential, especially if there is ongoing dilatation of the intrahepatic bile duct or biliary stones.

Diagnostic impact of computed tomography cholangiography and magnetic resonance cholangiopancreatography on pancreaticobiliary maljunction

BACKGROUND/PURPOSE The aim of this study was to investigate the diagnostic potential of computed tomography cholangiography (CTC) and magnetic resonance cholangiopancreatography (MRCP) in children with pancreaticobiliary maljunction (PBM). METHODS Fifty-three children with PBM were consecutively treated between 1997 and 2009. Among them, the patients who underwent CTC and/or MRCP preoperatively were enrolled in this study. Computed tomography cholangiography was examined after infusion of meglumine iodoxamate with subsequent 3-dimensional rendering. The visualization of the biliary and pancreatic duct systems was evaluated and compared with that visualized with MRCP. The findings of direct cholangiography were used as the standard of reference. RESULTS Of the 53 cases with PBM, 17 cases were examined by CTC, 10 cases by MRCP, and 17 with both. The extrahepatic bile tract was visualized in 32 (94.1%) of 34 patients in CTC and in all 27 patients in MRCP. The intrahepatic bile duct was more frequently demonstrated by MRCP than by CTC (96.3% vs 70.6%, P = .02). Pancreaticobiliary maljunction was noted in 13 (38.2%) of 34 with CTC and in 12 (44.4%) of 27 with MRCP. The minimum age for visualization of PBM was at 10 months in CTC and at 1 year and 11 months in MRCP, respectively. The main pancreatic duct was more frequently visualized by MRCP than by CTC (81.5% vs 8.8%, P < .001). CONCLUSIONS Magnetic resonance cholangiopancreatography provides superior visualization of the intrahepatic duct and the pancreatic system when compared with CTC. However, it is still challenging to perform a good-quality examination in young infant. The great advantage of CTC is its ability to produce high-quality images without respiratory artifacts and that it allows accurate assessment of the presence of PBM equivalent to MRCP.

Significance of ductal plate malformation in the postoperative clinical course of biliary atresia

PURPOSE Ductal plate malformation (DPM) is one of the etiologic theories for the development of biliary atresia (BA). In this study, we investigated the significance of DPM in the postoperative clinical course of BA, especially as a predictive factor of jaundice clearance. METHODS Between 1988 and 2005, 31 patients with uncorrectable BA underwent hepatoportoenterostomy and steroid therapy. Immunohistochemistry was used to characterize biliary structures using cytokeratin 19. Specimens were defined as DPM-positive if a concentric cellular arrangement was detected. This retrospective study included comparisons of preoperative characteristics, the postoperative jaundice period, and cumulative steroid doses between patients with and without DPM. RESULTS Of the 31 patients with uncorrectable BA, 25 (80.6%) became jaundice-free. Ductal plate malformation was detected in 11 (35.5%) of the 31. Between the 2 groups, there were no differences in preoperative characteristics or in the postoperative jaundice-free rate. Among those who became anicteric, the postoperative jaundice period was 145.3 +/- 69.9 days in the DPM-positive group (n = 9) and 81.8 +/- 44.7 days in the DPM-negative group (n = 16) (P < .05). The total administered steroids were 149.7 +/- 78.2 and 95.0 +/- 60.2 mg/kg, respectively (P = .09). CONCLUSION Ductal plate malformation may disturb bile flow and require more steroid to improve bile drainage. Therefore, the presence of DPM in the liver predicts poor bile flow after hepatoportoenterostomy in infants with BA.

Diagnosis and Treatment of Pancreaticobiliary Maljunction in Children

Pancreaticobiliary maljunction (PBM), which may be called by synonymous terms such as “anomalous arrangement of the pancreaticobiliary duct” or “anomalous union of biliopancreatic ducts,” is defined as an anatomical maljunction of the pancreatic duct and the biliary duct outside of the duodenal wall beyond the influence of the sphincter of Oddi. Pancreaticobiliary maljunction is classified into three groups according to the type of the pancreaticobiliary junction. Pancreaticobiliary maljunction is diagnosed mainly by endoscopic retrograde cholangiopancreatography; however, in pediatric patients, it may be diagnosed by intraoperative cholangiography, and more recently has been diagnosed by computed tomographic cholangiography or contrastenhanced helical computed tomography. Children with PBM without choledochal cysts usually do not show any symptoms except for abdominal pain and hyperamylasemia. Pancreaticobiliary maljunction is considered to be a major risk factor for biliary tract malignancy. In patients with PBM, free reflux of pancreatic juice into the biliary tract might induce biliary tract damage and biliary carcinogenesis. Thus, total resection of the extrahepatic bile duct and hepaticojejunostomy are recommended in children diagnosed with PBM with choledochal cyst. Early diagnosis and early surgical treatment provide a good prognosis with few complications. In addition, successive follow-up is necessary for early detection of biliary tract malignancy, especially in patients demonstrating postoperative complications.

Surgical treatment of anorectal malformations

The goal of surgery for anorectal malformations (ARM) is to achieve good bowel, urinary, and sexual functions, as well as the ability for children to become healthy adults. Various surgical procedures and surgical management protocols have been explored or devised by pediatric surgeons. These are described in this review. Making a correct type classification by invertography, fistelography and urethrography in the neonatal period allows pediatric surgeons to select an appropriate surgical strategy. Surgery for low-type malformations is principally neonatal perineoplasty, while that for intermediate- or high-type malformations is colostomy, followed by a pull-through operation during infancy. Posterior sagittal anorectoplasty or laparoscopy-assisted surgery has recently been accepted as alternative procedures. Fecal incontinence represents a devastating problem that often prevents a patient from becoming socially accepted and may cause serious psychological sequelae. One-third of adult patients with high- or intermediate-type malformations occasionally complain of fecal incontinence after surgery. Most patients with ARM have normal urinary function if they do not have urinary tract or sacral anomalies. These associated anomalies also influence the prognosis for sexual function, especially in males. Some female patients have experienced normal vaginal delivery and had children. In patients with cloacal malformation, however, fertility or sexual problems are also often present. Based on this information, it is clear that only well-planned and systemic treatments can provide a good functional prognosis after making a correct classification in the neonatal period.

Surgical strategies for unresectable hepatoblastomas

BACKGROUND The aim of this study was to assess the surgical strategies for unresectable hepatoblastomas at the initial diagnosis based on the experience of two institutions. METHODS The PRETEXT (Pretreatment evaluation of tumor extent) and POST-TEXT (Post treatment extent of disease) staging, surgical treatments, and clinical outcomes were retrospectively analyzed for 12 cases with PRETEXT III or IV and M(-) of 29 hepatoblastomas treated based on the JPLT-2 (The Japanese Study Group for Pediatric Liver Tumor-2) protocol at two institutions between 1998 and 2011. RESULTS Two of the 9 cases with PRETEXT III status were downstaged to POST-TEXT II. One of the 3 cases with PRETEXT IV showed downstaging to POST-TEXT III. Four of the 7 cases with P2 or V3 (indicated for liver transplantation) in the PRETEXT staging system showed P2 or V3 in POST-TEXT staging after 2 cycles of CITA (JPLT-2 standard regimen), and one case showed P2 or V3 in POST-TEXT staging at the initial operation and underwent primary liver transplantation. The initial surgical treatments were 1 lobectomy, 2 segmentectomies, 6 trisegmentectomies, 2 mesohepatectomies, and 1 primary liver transplantation. Both patients who underwent mesohepatectomies had bile leakage, and 1 of 5 trisegmentectomies had an acute obstruction of the right hepatic vein. Two patients underwent rescue living donor liver transplantation. Both of these patients showed P2 or V3 positive findings in POST-TEXT staging after 2 cycles of CITA. CONCLUSIONS POST-TEXT staging and P and V factors should be evaluated after 2 cycles of CITA for unresectable hepatoblastomas detected at the initial diagnosis. The patients should be referred to the transplantation center if the POST-TEXT IV, P2, or V3 is positive at that time. Liver resection by trisegmentectomy is recommended in view of the incidence of surgical complications. Careful treatment, such as back-up transplantation, should thus be considered for liver resection in the cases with POST-TEXT IV, P2, or V3 status after initial 2 cycles of CITA.

PCSK5 and GDF11 expression in the hindgut region of mouse embryos with anorectal malformations.

BACKGROUND/PURPOSE Retinoid-mediated signal transduction plays a crucial role in the embryonic development of various organs. We previously reported that retinoic acid induced anorectal malformations (ARM) in mice. GDF11 is a TGFβ superfamily molecule and is cleaved and activated by proprotein convertase subtilisin/kexin 5 (PCSK5). PCSK5 (PC5/6) mutations result in an abnormal expression of Hlxb9 and Hox genes, which include known GDF11 targets that are necessary for caudal development in vertebrate embryos. To determine a possible role of the retinoid-mediated signaling pathway in the pathogenesis of ARM, we investigated whether all-trans retinoic acid (ATRA) affected the expression patterns of PCSK5 and GDF11 in ARM-treated mouse embryos. METHODS Pregnant ICR-Slc mice were administered 100 mg/kg ATRA by gavage on embryonic day (E) 9.0. Embryos were harvested between days E12 and E18, and mid-sagittal sections of the hindgut region were prepared for immunohistochemistry using antibodies against PCSK5 (PC5/6) and GDF11 (GDF8/11). RESULTS Over 95% of the embryos treated with ATRA showed ARM, with rectourethral fistula or rectocloacal fistula, and a short tail. Furthermore, most of these embryos exhibited sacral malformations, tethered spinal cords, and presacral masses resembling those malformations found in caudal regression syndrome. By E14, normal mouse embryos formed a rectum and anus, and the somites behind the hindgut were positive for PC5/6 and GDF8/11. In contrast, in ARM embryos, the somites behind the hindgut were negative for PC5/6 and GDF8/11. CONCLUSION ATRA treatment affected the caudal development in mouse embryos, resulting in anorectal, sacral, and spinal malformations, and inhibited PCSK5 and GDF11 expression in the hindgut region. These findings indicate that the expression of PCSK5 and GDF11, which plays a crucial role in the organogenesis of the hindgut, was disturbed in the hindgut region when retinoid-mediated signaling was disrupted. This study offers a new insight into the pathogenesis of ARM in mice as affected by the interaction between ATRA and PCSK5/GDF11.

OK-432 therapy for chylous pleural effusion or ascites associated with lymphatic malformations

OK-432 therapy is effective for the treatment of macrocystic lymphatic malformations (LMs), but the optimal management of patients with microcystic LMs associated with large chylous pleural effusions or chylous ascites is not resolved. We performed thoracoscopic- or laparoscopic-guided injection of OK-432 for 2 patients with diffuse microcystic LMs accompanied by refractory chylous pleural effusion or chylous ascites. Both cases responded well to OK-432 therapy with improvement/resolution of fluid collections and associated symptoms. We recommend the use of OK-432 therapy as a promising treatment for microcystic LMs with functionally significant lymphatic fluid collections.

MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects and predicting their efficacy

BACKGROUND A recent study reported that relapsed neuroblastomas had frequent RAS-ERK pathway mutations. We herein investigated the effects and pathways of MEK inhibitors, which inhibit the RAS-ERK pathway, as a new molecular-targeted therapy for refractory neuroblastomas. METHOD Five neuroblastoma cell lines were treated with trametinib (MEK inhibitor) or CH5126766 (RAF/MEK inhibitor). Growth inhibition was analyzed using a cell viability assay. ERK phosphorylation and the MYCN expression were analyzed by immunoblotting or immunohistochemistry. RAS/RAF mutations were identified by direct sequencing or through the COSMIC database. RESULTS Both MEK inhibitors showed growth inhibition effects on cells with ERK phosphorylation, but almost no effect on cells without. In immunoblotting analyses, ERK phosphorylation and MYCN expression were suppressed in ERK active cells by these drugs. Furthermore, phosphorylated-ERK immunohistochemistry corresponded to the drug responses. Regarding the relationship between RAS/Raf mutations and ERK phosphorylation, ERK was phosphorylated in one cell line (NLF) without RAS/Raf mutations. CONCLUSION MEK inhibitors are a promising molecular-targeted therapeutic option for ERK active neuroblastomas. The efficacy of MEK inhibitors corresponds to ERK phosphorylation, while RAS/RAF mutations are not always detected in drug-sensitive cells. Phosphorylated-ERK immunohistochemistry is thus a useful method to analyze ERK activity and predict the therapeutic effects of MEK inhibitors.

Surgical intervention strategies for pediatric congenital cystic lesions of the lungs: A 20-year single-institution experience

BACKGROUND The aim of this study was to assess surgical intervention strategies for congenital cystic lesions of the lungs (CCL), focusing on the safety of lung resection. MATERIALS AND METHODS The clinical features of 27 children (CCAM, n=16; bronchial atresia, n=4; bronchogenic cyst, n=3; pulmonary sequestration, n=3; lobar emphysema, n=1) who were treated at our institution between 1995 and 2014 were analyzed. RESULTS Of the 27 patients, 14 were asymptomatic, and 13 were symptomatic. The youngest symptomatic patient presented with pneumonia at 9months of age. The mean age at surgery was 4months in the asymptomatic group and 4.1years in the symptomatic group. The mean operating time was 167minutes in the asymptomatic group and 275minutes in the symptomatic group (P<0.001). The mean amount of intraoperative bleeding was 15g in the asymptomatic group and 83.4g in the symptomatic group (P<0.05). All of the prenatally diagnosed patients underwent surgery within six months of birth. Three patients had remnant cystic lesions, all of which involved cystic lesions located over the lobulation anomalies of the lung. CONCLUSIONS To minimize surgical invasiveness, surgery for CCL should be performed during the asymptomatic period or within six months after birth.