Prognostic significance of circulating tumor cells and bone marrow micrometastasis in advanced neuroblastoma.

PURPOSE: The aim of this study was to study the prognostic significance of circulating tumor cells (CTC) and the appropriate indications for aggressive surgery in advanced neuroblastoma. MATERIALS AND METHODS: Micrometastasis was sequentially explored using our reverse transcriptase-polymerase chain reaction method in 29 neuroblastoma patients (International Neuroblastoma Staging System stage 4, n = 24; stage 3, n = 5) who treated at our department with the united chemotherapeutic regimen since 1991. Their medical records and detection of CTC and/or the bone marrow micrometastasis were retrospectively reviewed then analyzed statistically. RESULTS: The overall survival rate was 58.6% (17/29). Circulating tumor cells were detected in 55.6% of the stage 4 patients, and all deaths were related to systemic metastases in the CTC-positive patients. The detection of CTC scarcely associated with MYCN amplification. In the patients showing MYCN amplification but no CTC, all deaths were related to local relapse or chemotherapy-associated complications. The survival rate was not significantly different between the patients with and without MYCN amplification (56.8% vs 52.7%). However, it was significantly lower in the patients with CTC and/or persistent bone marrow micrometastasis compared to those without detectable micrometastasis (33.8% vs 87.5%; P < .05). CONCLUSIONS: The presence of CTC and/or persistent micrometastasis may indicate a significantly high risk, regardless of MYCN amplification. Patients with MYCN amplification but no micrometastasis would be most benefited by highly intensive surgery.

Management of adult biliary atresia patients: should hard work and pregnancy be discouraged?

PURPOSE: The purpose of the paper was to study the potential risk and management of adult biliary atresia (BA) patients. MATERIALS AND METHODS: Clinical courses and biochemical data were retrospectively analyzed in 52 BA patients who were operated in our department and are now older than 15 years, with special emphasis on 47 patients who survived beyond the age of 20 years. RESULTS: Of these 47 patients, 45 (95.7%) are employed, receiving higher education, and/or married. Thirty-three patients showed favorable liver function at the age of 20 years with their native liver. Thereafter, 6 (18.2%) developed liver dysfunction after working hard or pregnancy. In these 6 patients, cholinesterase levels were significantly lower at the age of 20 years than those in the 27 stable patients (239.5 +/- 42.6 vs 285.8 +/- 47.5, P = .0216), whereas no significant difference was found in alanine aminotransferase, aspartate aminotransferase, or total protein levels at the age of 20 years or in any biochemical parameters at the age of 15 years. Of the 14 transplanted patients, 5 who underwent transplantation after the age of 20 years had relatively uneventful courses until the age of 20 years; however, their biochemical data already showed significant deterioration at puberty. CONCLUSION: Social activities and pregnancy should be managed individually according to the risk assessment for potential hepatic failure even in stable adult BA patients. A falling cholinesterase level after the age of 20 years may predict the risk for the late hepatic dysfunction.

Clinicopathologic assessment of prenatally diagnosed lung diseases.

PURPOSE: To investigate the clinical features and pathologic diagnosis of prenatally diagnosed lung diseases. MATERIALS AND METHODS: The medical records of 28 fetuses with prenatally diagnosed lung diseases were reviewed with regard to perinatal courses, ultrasonographic measurement of the lesion volume ratio, and the histopathology of lung tissue. RESULTS: Of the 23 fetuses with a prenatal diagnosis of congenital cystic adenomatoid malformation (CCAM), 4 required an emergency lobectomy (1 prenatally and 3 postnatally), whereas the other 14 showed uneventful courses after birth. The pathologic diagnosis of the resected lungs included CCAM (n = 4), lobar emphysema (n = 2), intralobar sequestration (n = 2), and bronchial atresia (n = 1). The peak value of the lesion volume ratio was significantly higher in the CCAM cases that required urgent surgery than in the non-CCAM cases (2.29 +/- 0.46 vs 1.20 +/- 0.21, P < .001). The ratio decreased after the 25th to the 30th week to less than 1.0 in the 5 non-CCAM cases, but remained higher than 2.0 in the 4 CCAM cases. Prenatally diagnosed extralobar pulmonary sequestration caused massive pleural effusion requiring a fetal intervention in 4 of the 5 fetuses. CONCLUSIONS: The prenatally diagnosed lung lesions include various kinds of pulmonary diseases. Regardless of the diseases, sequential ultrasonographic assessment may predict perinatal risks.

Late complications after surgery in patients with neuroblastoma.

PURPOSE: The purpose of this study was 2-fold: to study the complications of neuroblastoma treatment and to establish surgical guidelines. MATERIALS AND METHODS: The medical records of 92 patients with neuroblastoma (stage 1 or 2, n = 33; stage 3, n = 21; stage 4, n = 31; stage 4S, n = 7) who had undergone surgery in our department between 1985 and 2001 were reviewed, with an emphasis on treatments and late complications. RESULTS: The disease-free survival rate was 98.3% (58/59) in infantile patients, whereas it was 36.4% (12/33) in advanced patients older than 1 year. The rate was improved up to greater than 50% after the introduction of intensive local therapy with intraoperative radiation (IOR). The treatment-associated morbidity rate was 15.0% in nonadvanced infantile patients, was 42.1% in advanced infantile patients, and was 33.3% in advanced older patients. In the advanced cases, renovascular problems were most frequently seen especially after IOR. Furthermore, pulmonary problems, cardiac problems, and second cancer were highlighted as fatal problems; thyroid dysfunction, vertebral deformity, and growth retardation were also noted. CONCLUSIONS: Higher incidences of late morbidity and treatment-associated mortality appeared to be more strongly related to disease stage rather than to patient age. Appropriate surgery and IOR with lower doses should be recommended as a surgical strategy for high-risk patients.

Current role of liver transplantation for methylmalonic acidemia: a review of the literature.

To evaluate the current role of liver transplantation (LT) for methylmalonic acidemia (MMA), we reviewed the literature on outcomes of this treatment, and describe three of our own cases of living-donor liver transplantation (LDLT). The total number of LT cases identified was 18. Transplantation mode was deceased donor LT in 12, including five combined liver-kidney transplantations (CLKT) from deceased donors, and LDLT in six. Three hospital mortalities were noted, because of metabolic decompensation, sepsis and aspergillosis. Although mean postoperative serum MMA level decreased to 13.8% +/- 9.2% (range 1.25-26.1%) of preoperative levels, four patients (22.2%) had renal insufficiency after isolated LT and three (16.7%) had postoperative neurological disability. Continuing metabolic damage to the kidney and brain may occur even after successful LT. Further evaluation is required to determine the long-term suitability of this treatment modality.

Congenital bronchial atresia in infants and children.

BACKGROUND/PURPOSE: Congenital bronchial atresia (CBA) usually presents incidentally in asymptomatic young male adults but is rarely diagnosed in children. The aim of this study was to clarify the clinical characteristics of CBA in childhood and to describe the spectrum of this condition. METHODS: The clinical features in 29 patients with CBA, aged from 1 day to 13 years (median, 4 years), were reviewed retrospectively. Diagnosis was confirmed by pathological findings of a blind-ending bronchus associated with distal mucous-filled bronchocele surrounded by hyperinflated lung parenchyma. RESULTS: All but 1 patient were symptomatic. The most frequent symptom was productive cough and fever owing to recurrent pneumonia found in 26 children. Two infants suffered from respiratory distress. Chest x-ray showed various findings of infiltrative pneumonia, emphysema, and a large cyst. Computed tomography, bronchography, and bronchoscopy were useful modalities for demonstrating bronchocele associated with hyperinflated lung or proximal blind-ending bronchus even in infected cases. The right lower lobe was predominantly affected in 12 cases, followed by left or right upper lobe in 7 cases. Lobectomy or segmentectomy resulted in remarkable clinical improvement. CONCLUSIONS: Congenital bronchial atresia presents differently in children than in young adults. Modern imaging techniques and careful pathological analyses lead to an accurate diagnosis of bronchial atresia, which may be misdiagnosed as intralobar sequestration or pulmonary bronchial cysts. Bronchial atresia is a distinct pathological entity that accounts for recurrent pneumonia or respiratory distress in childhood, requiring surgical treatment.

Biliary atresia and pregnancy: puberty may be an important point for predicting the outcome.

PURPOSE: The aim of this study was to study the late clinical features of biliary atresia in relation to pregnancy. MATERIALS AND METHODS: Of the 175 patients with biliary atresia operated on at our department, the data for 49 patients (18 males, 31 females) older than 15 years were reviewed and analyzed. RESULTS: Six patients delivered 7 newborns (5 with their native liver and 1 with a transplanted liver). Although one of the patients delivered twice after transplantation, another underwent transplantation after delivery. None of the 7 newborns showed any congenital anomalies; however, 6 were small-for-date newborns. Their birth weight tended to be inversely related to the mothers' age at delivery. An additional 13 patients required liver transplantation, of whom 1 died after transplantation and 1 died before transplantation. The remaining 30 patients showed uneventful courses without transplantation. The age at Kasai operation was significantly higher in the 5 patients who delivered babies with their native liver compared with that in these 30 patients (88.0 vs 68.6 days). A significant difference between these 5 patients and those who died or required transplantation before pregnancy was recognized even at the age of puberty in the alanine aminotransferase (36.5 +/- 26.5 vs 126.4 +/- 56.1 IU/L), aspartate aminotransferase (36.2 +/- 26.5 vs 114.2 +/- 48.9 IU/L), and choline esterase (249.7 +/- 64.8 vs 163.5 +/- 40.2 IU/L). CONCLUSIONS: The age at Kasai operation may not necessarily impact the late clinical course; however, liver function at puberty may predict the subsequent clinical course, including the safety of pregnancy. The management strategies should be revised after puberty.

Tumor cell dynamics and metastasis in advanced neuroblastoma.

This study deals with the advancement process of neuroblastoma through clinical observations and circulating tumor cell exploration. Clinical feature, tumor biology, and circulating tumor cell detected by the previously described polymerase chain reaction (PCR) method were analyzed in 31 patients with advanced neuroblastoma treated in our department since 1991 through 2004. Treatment was completed in 28 patients, of whom 17 are alive without the disease and 11 died. The primary lesion was not confirmed in 2 patients with disseminated metastasis, both of whom showed positive circulating tumor cell. Circulating tumor cell was positive in 6 of 9 examined at their first appearance at the hospital, all had stage 4 disease, and 4 of the 6 (66.7%) died of systemic spread of the disease. N-myc was amplified in 15 patients, of whom only 2 (13.3%) died of systemic metastasis. N-myc amplification did not correlate with positive circulating tumor cell. A certain population of neuroblastoma may provide circulating tumor cells from the early period of the disease to form metastatic lesions independently of the primary lesion, which must be regulated by factors other than N-myc. Circulating tumor cells may suggest higher risk for systemic dissemination and poor prognosis.

Prenatal diagnosis and management of abdominal diseases in pediatric surgery.

PURPOSE: The aim of this study was to investigate the prenatal courses and management of abdominal surgical diseases. METHODS: Of the 327 patients registered with our fetal treatment board since March 2002, 83 fetuses referred to the surgical department were enrolled for the current study. The prenatal diagnosis, sequential fetal images, and perinatal courses of these cases were reviewed retrospectively. RESULTS: Of the 83 cases, abdominal diseases were suspected in 34, lung and thoracic diseases in 25, genitourinary diseases in 12, and other anomalies in 12. Meconium peritonitis (MP), intestinal obstruction, and abdominal wall defects accounted for approximately 65% of the abdominal diseases. Five patients with prenatally diagnosed lung diseases underwent fetal surgical intervention, and 17 of the 22 liveborn patients survived. In contrast, none of the patients with prenatally diagnosed abdominal anomalies underwent fetal surgical intervention, yet, 23 of the 24 liveborn patients survived. However, preterm labor and hydrops were seen frequently in the patients with giant cystic MP, suggesting a fetal critical condition. CONCLUSIONS: Although the clinical outcome of abdominal diseases seemed favorable with postnatal treatment, the current results suggested the occurrence of hidden mortality in utero and the potential need for fetal intervention for some abdominal conditions, such as MP.

Clinical significance of intensive surgery with intraoperative radiation for advanced neuroblastoma: does it really make sense?

PURPOSE: The aim of this study was to evaluate the significance of intensive surgery combined with intraoperative radiation therapy (IORT) in advanced neuroblastoma. METHODS: Clinical features and outcome were reviewed in 33 advanced neuroblastoma patients (24 with INSS stage 4, 9 with stage 3), who had surgery (total excision 29, subtotal excision 4) with IORT (10 to 15 Gy) against the primary tumor site. RESULTS: Three patients (8.8%) had relapse at the primary site, all of which arose from the unirradiated area after stem cell transplantation. Among 29 patients with total excision, disease-free survival was obtained in 15 (51.7%) for an average of 6.9 years, which included 5 survivors of 9 patients (55.9%) with amplified N-myc. In contrast, none of 4 patients with macroscopic residual survived. The Kaplan-Meier analysis showed significantly longer survival rates in the patients with total resection compared with those with macroscopic remnants. CONCLUSIONS: The intensive surgery with IORT dramatically increased the local eradication and improved the outcome even in advanced neuroblastoma with N-myc amplification. However, long-term survival was not obtained in patients with unresectable residual disease. These results may indicate the key role of surgical eradication in advanced neuroblastoma.

Five- and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry.

PURPOSE: The aim of this study was to elucidate the epidemiology and short- and long-term results of biliary atresia in Japan analyzing the data of the Japanese Biliary Atresia Registry (JBAR). METHODS: In 1989, the Japanese Biliary Atresia Society started a nationwide registry, JBAR, to investigate all aspects of biliary atresia. A total of 1,381 patients, 863 girls, 507 boys, and 11 unknown, were registered between 1989 and 1999. JBAR includes an initial and follow-up questionnaires. Using these patients' data, the incidence, sex distribution, associated anomalies, the type of obstruction, the type of operation, and the surgical results were evaluated. The 5- and the 10-year results of 735 patients who were registered initially in or before 1994 also were analyzed. RESULTS: The incidence of biliary atresia was 1 in 9,640 live births. One hundred sixty-four patients (11.9%) had type I atresia of the common bile duct, 34 (2.5%) had type II atresia of the hepatic ducts, and 1,162 (84.1%) had type III atresia at the porta hepatis. Congenital associated anomalies were found in 19.6% of the patients including 33 cases associated with polysplenia. Impact of the age at operation on bile flow was not clear until 90 days of age, and after 90 days the bile flow rate worsened. The original Roux-en-Y procedure had been used in more than 50% of the patients since 1995. In 1999, 96% of the patients underwent the original Roux-en-Y procedure or the Roux-en-Y with an intestinal valve, and only 3 patients (3.5%) underwent other modifications. There were no significant differences in either the rate of disappearance of jaundice or the incidence of cholangitis among these 3 procedures. Of the 735 patients registered in or before 1994, 19 patients (2.6%) were lost to follow-up. The 5-year survival rates of patients registered in 1989, 1990, 1991, 1992, 1993, and 1994 were 62%, 64.5%, 61.3%, 59.0%, 58.7%, and 52.7% without liver transplantation (LTx), and 69.4%, 74.2%, 75.2%, 79.5%, 78%, and 78.3% with LTx, respectively. Although the overall 5-year survival rate changed from 69.4% to 78.3%, the difference was not statistically significant. According to the 10-year follow-up results of the 108 patients initially registered in 1989, 72 (66.7%) and 57 (52.8%) survived with and without the aid of LTx, respectively. CONCLUSIONS: The overall 5- and 10-year survival rates were 75.3% (553 of 734) and 66.7% (72 of 108), respectively. In spite of the increasing number of survivors after LTx, there was no significant improvement in the 5-year survival rate. It was shown that the JBAR system was functioning well with only 19 patients lost to follow-up among the 743 patients registered from 1989 to 1994.

Biliary atresia, the next generation: a review of liver function, social activity, and sexual development in the late postoperative period.

PURPOSE: The current study aimed to establish the management for biliary atresia (BA) patients in the late postoperative period. METHODS: Of 165 BA patients operated on in the authors' department, 44 patients (16 boys, 28 girls) with a follow-up period of more than 15 years were reviewed retrospectively. RESULTS: Forty-one of 44 patients (93.2%) currently are employed or highly educated, 7 are married, whereas 2 (4.5%) died, and 10 (22.7%) required liver transplantation after puberty. Four babies have been born from BA parents without congenital anomalies. Four girls conceived 5 times and delivered 3 newborns weighing 2,330 to 2,474 g including one delivered after transplantation. Maternal portal hypertension uniformly deteriorated during pregnancy, and one pregnancy was terminated. Menstrual disorder correlated significantly with the biochemical data related to liver function at puberty such as serum choline esterase (266 +/- 70.4 in 19 normal patients v 159 +/- 34.3 IU/L in 9 abnormal patients, P =.00057), asparate aminotransferase (42 +/- 30.8 v 96.0 +/- 63.6 IU/L; P =.0031), and serum albumin (4.6 +/- 0.4 v 3.9 +/- 0.6 g/dL; P =.013). CONCLUSIONS: The long-term survivors of Kasai's operation, with or without liver transplantation, have reached the next generation. Transgenerational follow-up and management including conception and perinatal care should be required for BA patients.

Expression of cyclin-dependent kinase inhibitor p27/Kip1 and AP-1 coactivator p38/Jab1 correlates with differentiation of embryonal rhabdomyosarcoma.

Cyclin-dependent kinase (CDK) inhibitor p27/Kip1 (p27) is a diagnostic and prognostic marker of various malignancies. Low expression of p27 reflects poor differentiation and poor prognosis, and an inverse correlation between the expression of p27 and degree of tumor malignancy has been reported. Because p27 mutation is extremely rare in human tumors, it is important to study the expression of p27 and its inactivator, p38/Jab1 (JAB1). Here we analyzed the expression of p27 and JAB1 by immunohistochemistry in embryonal rhabdomyosarcoma (E-RMS). We first confirmed the expression of p27 and JAB1 in normal human tonsillar epithelium, and observed a coordinated expression pattern depending on cell differentiation. Subsequently, specimens of eight poorly- and three well-differentiated E-RMS were examined for the expression of p27 and JAB1. The analyses revealed that four out of eight poorly-differentiated E-RMS were negative for p27, with positivity for nuclear JAB (NJAB) (- / + for p27/NJAB) in three and negativity for any JAB-1 expression ( - / -) in one. The remaining four poorly-differentiated E-RMS expressed p27 in the nuclei, together with predominant NJAB (+ / +). In three well-differentiated E-RMS, only one expressed nuclear p27 and all of these three expressed no NJAB (+ / - for p27/NJAB), but expressed predominant cytoplasmic JAB1 (CJAB). These findings suggest that JAB1 may play an important role in determining the differentiation stage of rhabdomyosarcoma cells by modulating the activity of CDK inhibitor p27.

Two novel transcripts for human endothelin B receptor produced by RNA editing/alternative splicing from a single gene.

Hirschsprung disease is a heterogeneous genetic disorder, causative genes of which include the endothelin B receptor (ETB). To investigate the mutations of ETB in Hirschsprung disease, expression of the ETB gene in lymphoblastoid cells from patients and normal healthy adults was examined, and novel mutant transcripts were found. The mutant ETB gene transcripts lacked a 134-bp nucleotide sequence corresponding to exon 5, and some also contained a substitution from A to G at position 950 in exon 4, resulting in an amino acid substitution from glutamine (Q) to arginine (R). This substitution was suspected to be the result of RNA editing because it was not present in the genomic sequence. Transfection experiments using ETB minigenes containing the editing site with or without the gene for double-strand RNA deaminases (ADAR1 and ADAR2) revealed that the deaminases were involved in RNA editing. Furthermore, a c-Myc-tagged mutant ETB protein was not detected by Western blot analysis. The present results show that the mutant ETB transcripts were novel splice variants, which might not be translated, or that the products translated from splice variants might be quickly degraded, presumably because of their instability. The preferential production of this null function ETB by RNA editing/splicing could be involved in the etiology of some cases of Hirschsprung disease.