Taizo Furukawa

Familial occurrence of intestinal obstruction in children with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)

The syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is an uncommon neuromuscular disorder caused by mitochondrial dysfunctions that result in headaches, seizures, and progressive dementia. The authors describe a clinical case study of gastrointestinal manifestations in a pedigree with MELAS, in which all three children, ages 11, 8, and 6, demonstrated acute onset of intestinal obstruction. They unexpectedly showed severe abdominal distension and vomiting. Their parents had no clinical manifestation. The first female sibling underwent an emergent laparotomy because she was diagnosed to have intestinal strangulation. She had postoperative complications caused by progressive lactic acidosis and died the next day. The second and third sisters had similar onsets of the disease and were treated with gastrointestinal decompression and intravenous administration of lactate-free fluid and coenzyme Q10. Genetic testing using blood samples showed an A-to-G point mutation at nucleotide position 3243 in the tRNALeu(UUR) region in the mitochondrial DNA. In MELAS children who demonstrate acute onset of gastrointestinal manifestations, a careful review of family history and an elevation of serum lactate and pyruvate levels may enable a differential diagnosis to be made of acute abdomen to avoid unnecessary surgical intervention.

Laparoscopic versus open abdominoperineal rectoplasty for infants with high-type anorectal malformation

BACKGROUND/PURPOSE There has not been any study comparing laparoscopic abdominoperineal rectoplasty (ARP) with open ARP. This study investigated the true benefits of the laparoscopic approach in infants with high anorectal malformation. PATIENTS AND METHODS A retrospective analysis was performed in 28 infants with high anorectal malformation treated between 1990 and 2007. Fifteen were treated by open ARP, and 13 were treated by laparoscopic ARP. Surgical durations, amount of bleeding, complications, anorectal pressure measurements, barium enema study, and clinical assessment were compared between the 2 groups. RESULTS The amount of intraoperative bleeding was significantly less in laparoscopic ARP (12 ± 11 g) than in open ARP (65 ± 44 g) (P = .003). Anal resting pressure was 34 ± 9 cm H(2)O after laparoscopic ARP and 31 ± 14 cm H(2)O after open ARP. Anorectal reflex was positive in 1 (7%) of 15 after open ARP and 3 (23%) of 13 after laparoscopic ARP. There was no significant difference in barium enema study and clinical assessment between the 2 groups. With regard to postoperative complications, mucosal prolapse occurred in 10 (67%) of 15 after open ARP and in none of 13 after laparoscopic ARP (P = .003). CONCLUSION Benefits of the laparoscopic approach were reduced intraoperative bleeding and a lower incidence of postoperative anal mucosal prolapse. These results indicate that minimal dissection of the mesorectum in laparoscopic ARP may provide those better outcomes.

Intralobar pulmonary sequestration diagnosed by MR angiography

A definitive diagnosis of pulmonary sequestration necessitates evidence of a systemic arterial supply to the sequestered lung segment by aortography. We report a case of intralobar pulmonary sequestration in an 11-month-old girl in whom the diagnosis was made by contrast-enhanced magnetic resonance (MR) angiography. Contrast-enhanced MR angiography is the most reliable noninvasive method for the definitive diagnosis of pulmonary sequestration in children.

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.

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.

Prenatal administration of neuropeptide bombesin promotes lung development in a rat model of nitrofen-induced congenital diaphragmatic hernia

BACKGROUND/PURPOSE Fetal medical treatment to improve lung hypoplasia in congenital diaphragmatic hernia (CDH) has yet to be established. The neuropeptide bombesin (BBS) might play an important role in lung development. The present study aims to determine whether prenatally administered BBS could be useful to promote fetal lung development in a rat model of nitrofen-induced CDH. METHODS Pregnant rats were administered with nitrofen (100mg) on gestation day 9.5 (E9.5). BBS (50mg/kg/day) was then daily infused intraperitoneally from E14, and fetal lungs were harvested on E21. The expression of PCNA was assessed by both immunohistochemical staining and RT-PCR to determine the amount of cell proliferation. Lung maturity was assessed as the expression of TTF-1, a marker of alveolar epithelial cell type II. RESULTS The lung-body-weight ratio was significantly increased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). The number of cells stained positive for PCNA and TTF-1 was significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.01). The TTF-1 mRNA expression levels were significantly decreased in CDH/BBS(+) compared with CDH/BBS(-) (p<0.05). CONCLUSIONS Prenatally administered BBS promotes lung development in a rat model of nitrofen-induced CDH. Neuropeptide BBS could help to rescue lung hypoplasia in fetal CDH.

Management strategies for infants with total intestinal aganglionosis

PURPOSE This study investigated appropriate management strategies for infants with total intestinal aganglionosis (TIA), focusing on surgical and medical managements. METHODS Six infants with TIA or near TIA treated in our institution between 1980 and 2007 were reviewed retrospectively. Surgery was performed as a simple jejunostomy, 65 to 70 cm below the ligament of Treitz (LOT) in 2 infants, and 30 cm below LOT in 1 without extended myectomy-myotomy (EMM). Jejunostomy with EMM 30 to 35 cm below LOT were performed in 3. RESULTS Two infants with jejunostomy 65 cm or 70 cm distal from LOT died of sepsis at 7 months and 8 months of age, respectively. One infant with jejunostomy 30 cm from LOT without EMM died of cholestatic liver failure at the age of 1 year and 8 months. To date, the remaining 3 infants with jejunostomy 30 cm or 35 cm distal from LOT in addition to EMM have survived 10 years, 3 years and 10 months, and 2 years of age, respectively. Nutritional managements such as parenteral nutrition with 80 to 100 kcal/kg/day and oral feeding with elemental diet (ED) were preferable to reduce the occurrence of enteritis, sepsis, and cholestatic liver dysfunction. CONCLUSION A good combination of cyclic parenteral nutrition and oral intake with elemental diet after short proximal jejunostomy with EMM may be a key for the survival of infants with TIA. In addition, in infants whose absorptive function was not ameliorated by EMM, medical management such as GH administration might be worth trying.

Tumor-homing effect of human mesenchymal stem cells in a TH-MYCN mouse model of neuroblastoma

BACKGROUND Human mesenchymal stem cells (hMSCs) are multipotent stem-like cells that are reported to have tumor-suppression effects and migration ability toward damaged tissues or tumors. The aim of this study was to analyze the tumor-homing ability of hMSCs and antitumor potency in a transgenic TH-MYCN mouse model of neuroblastoma (NB). METHODS hMSCs (3×106) labeled with DiR, a lipophilic near-infrared dye, were intraperitoneally (i.p.) or intravenously (i.v.) administered to the TH-MYCN mice. hMSC in vivo kinetics were assayed using the IVIS® imaging system for 24h after injection. Immunohistochemistry using human CD90 antibody was also performed to confirm the location of hMSCs in various organs and tumors. Furthermore, the survival curve of TH-MYCN mice treated with hMSCs was compared to a control group administered PBS. RESULTS i.p. hMSCs were recognized in the tumors of TH-MYCN mice by IVIS. hMSCs were also located inside the tumor tissue. Conversely, most of the i.v. hMSCs were captured by the lungs, and migration into the tumors was not noted. There was no significant difference in the survival between the hMSC and control groups. CONCLUSION The present study suggested that hMSCs may be potential tumor-specific therapeutic delivery vehicles in NB according to their homing potential to tumors.

Bombesin can minimize impairments of interstitial cells of Cajal induced by FK506 in small bowel transplantation

PURPOSE Interstitial cells of Cajal (ICC) are known as intestinal pacemaker cells and express c-kit on their membrane. Previously, we reported that FK506 had neurotoxicity to enteric ganglia, and bombesin (BBS) preserved them against FK506. The aim of this study was to investigate whether ICC was impaired by FK506 and whether ICC was preserved by BBS against FK506. METHODS Twelve rats underwent allogeneic SBTx heterotopically and were divided into 2 groups as follows: group A underwent SBTx with FK506 and group B with FK506/BBS. All rats were administered FK506 daily. Either BBS or normal saline was infused continuously from day 14 to 28. Analysis of ICC was performed immunohistochemically with c-kit. Interstitial cells of Cajal were evaluated by counting the number of c-kit-positive clusters in each graft. RESULTS The expression of c-kit accumulated around 60% of PGP9.5-positive enteric ganglia. The number of c-kit-positive clusters in group A was 22.3 +/- 5.5 clusters per cross section (C/CS) and that in group B was 36.3 +/- 5.1 C/CS. Interstitial cells of Cajal were well preserved in group B. There was a significant difference between groups A and B (P <.001). CONCLUSION Interstitial cells of Cajal were impaired by FK506 in allografts, and BBS could minimize the impairment of ICC against FK506.