The First Application of Intraumbilical Longitudinal Incision to Pyloromyotomy for Hypertrophic Pyloric Stenosis.

OBJECTIVE: There are several approaches to pyloromyotomy for the treatment of hypertrophic pyloric stenosis including open transumbilical pyloromyotomy and laparoscopic pyloromyotomy. Beginning in 2012, we adopted intraumbilical longitudinal incision as a new transumbilical approach for pyloromyotomy. We describe details of the operative technique and results of this new approach. METHODS: We reviewed records of patients undergoing transumbilical pyloromyotomy from 2005 to 2018. Perioperative outcomes were compared between intraumbilical longitudinal incision and supraumbilical incision, the latter of which is the conventional incision for transumbilical pyloromyotomy. RESULTS: Twenty-four patients underwent pyloromyotomy with intraumbilical longitudinal incision (intraumbilical group) and 28 patients with supraumbilical incision (supraumbilical group). The median operative time was longer in the intraumbilical group (58.0 vs. 43.5 min, p = 0.002). However, the time to full feeding did not differ significantly between the two groups, and the median postoperative stay was shorter in the intraumbilical group (3 vs. 5.5 days, p = 0.003). There was no difference in the rate of complications (4.2% vs. 7.1%, p = 1.0). Scars after intraumbilical longitudinal incision were localized inside the umbilicus. CONCLUSION: Pyloromyotomy can be performed through intraumbilical longitudinal incision as safely as supraumbilical incision and intraumbilical longitudinal incision may improve cosmetic results. This approach can be an alternative technique for pyloromyotomy.

A case of secretory breast cancer in a 6 year-old girl: is it possible to make a correct preoperative diagnosis?

Secretory breast carcinoma constitutes the majority of breast cancers in children and young people less than 20 years of age. Noninvasive examination is particularly necessary for the diagnosis of breast carcinoma in children. Herein, we report a case of secretory breast carcinoma in a 6-year-old girl with psychomotor retardation. She was referred to our outpatient clinic for evaluation of a palpable mass in her left breast. A hard mass, rather than the increase in size typical of premature thelarche, was palpated. An excision biopsy was performed. Pathological findings revealed an invasive secretory breast carcinoma. We performed a retrospective review of the preoperative findings of this case, and compared it to the pathological diagnosis. Elastography, which can be performed without deep sedation or general anesthesia and without causing pain, resulted in a stiffness score of 4; however, the distinction between benign and malignant tumors on elastography, which is important to decide the intra-operative procedures, was not sufficient according to the Japanese breast cancer society clinical guidelines. This is the first report of secretory breast carcinoma in a child with a stiffness score determined by tissue elasticity imaging. A breast mass in a child with a high stiffness score of more than 4 on elastography should be referred for invasive diagnostic procedures, such as fine needle aspiration or excisional biopsy. According to our experience, an accurate preoperative diagnosis could be possible for malignant breast tumors in children. Such parameters as stiffness score on elastography are practical, noninvasive, and objective diagnostic tools for the accurate preoperative diagnosis of breast tumors in children.

Engineering and repair of diaphragm using biosheet (a collagenous connective tissue membrane) in rabbits.

BACKGROUND: Prosthetic patches can be used to repair large congenital diaphragmatic hernia defects but may be associated with infection, recurrence, and thoracic deformity. Biosheets (collagenous connective tissue membranes) have been used in regenerative medicine. We evaluated the efficacy of Biosheets in a rabbit model. METHODS: Biosheets were prepared by embedding silicone plates in dorsal subcutaneous pouches of rabbits for 4weeks. In group 1 (n=11), Gore-Tex® sheets (1.8×1.8cm) were implanted into a diaphragmatic defect. In group 2 (n=11), Seamdura®, a bioabsorbable artificial dural substitute, was implanted in the same manner. In group 3 (n=14), biosheets were autologously transplanted into the diaphragmatic defects. All rabbits were euthanized 3months after transplantation to evaluate their graft status. RESULTS: Herniation of liver was observed in 5 rabbits (45%) in group 1, 8 (73%) in group 2, and 3 (21%) in group 3. A significant difference was noted between groups 2 and 3 (P=0.017). Biosheets had equivalent burst strength and modulus of elasticity as native diaphragm. Muscular tissue regeneration in transplanted biosheets in group 3 was confirmed histologically. CONCLUSION: Biosheets may be applied to diaphragmatic repair and replacement of diaphragmatic muscular tissue. LEVEL OF EVIDENCE: Level III.

Mosapride for gastroesophageal reflux disease in neurologically impaired patients.

BACKGROUND: The prokinetic agent cisapride is effective for the treatment of gastroesophageal reflux disease (GERD) in infants and children, but is no longer used for this purpose because of safety concerns. Therefore, other pharmacological agents need to be investigated for efficacy in GERD treatment. In this study, we examined the effectiveness and safety of mosapride for the treatment of neurologically impaired children and adolescents with GERD. METHODS: Mosapride (0.3 mg/kg/day) was administered to 11 neurologically impaired patients with GERD (five male; median age, 12.3 years). Esophageal acid exposure was measured using esophageal pH monitoring before and at >5 days after the start of mosapride treatment. The pressure and length of the lower esophageal sphincter were compared before and after mosapride treatment. RESULTS: In the 11 patients, median reflux index (percentage of the total monitoring period during which recorded pH was <4.0) was 17.5% (range, 4.4-59%) before and 8.2% (range, 2.8-20.7%) after mosapride treatment (P = 0.02). Median esophageal clearance was 1.0 min/reflux (range, 0.5-2.1 min/reflux) before and 0.7 min/reflux (range, 0.4-1.2 min/reflux) after treatment with mosapride (P = 0.02). The median number of reflux episodes before (219) and after (122) drug treatment did not differ significantly. CONCLUSION: The decreased reflux index in neurologically impaired patients with GERD is due to mosapride, therefore mosapride may be a candidate for GERD treatment.

Patch tracheoplasty in body tissue engineering using collagenous connective tissue membranes (biosheets).

BACKGROUND: Collagenous connective tissue membranes (biosheets) are useful for engineering cardiovascular tissue in tissue engineering. The aim was to evaluate the use of biosheets as a potential tracheal substitute material in vivo in a rabbit model. METHODS: Group 1: Rectangular-shaped Gore-Tex (4×7mm) was implanted into a 3×6mm defect created in the midventral portion of the cervical trachea. Group 2: Rectangular-shaped dermis was implanted into a tracheotomy of similar size. Group 3: Biosheets were prepared by embedding silicone moulds in dorsal subcutaneous pouches in rabbits for 1month. Rectangular-shaped biosheets were implanted into a tracheotomy of similar size in an autologous fashion. All groups (each containing 10 animals) were sacrificed 4weeks after implantation. MAIN RESULTS: All materials maintained airway structure for up to 4weeks after implantation. Regenerative cartilage in implanted Biosheets in group 3 was confirmed by histological analysis. Tracheal epithelial regeneration occurred in the internal lumen of group 3. There were significant differences in the amounts of collagen type II and glycosaminoglycan between group 3 and group 1 or 2. CONCLUSION: We confirm that cartilage can self-regenerate onto an airway patch using Biosheets.

Tracheoplasty with cartilage-engineered esophagus environments.

PURPOSE: Our objective was to investigate the feasibility of engineering cartilage on the esophagus layer and outside the esophagus. Moreover, we investigated the feasibility of tracheoplasty with cartilage engineered on the esophagus in rabbits. METHODS: Chondrocytes were isolated from auricular cartilages. 1. Engineered cartilage formation by histological findings on/into the esophageal layer was compared with that of injectable scaffold and preformed scaffold with chondrocytes. 2. Chondrocytes adhered to gelatin+vicryl mesh™ and b-FGF, were implanted on the outer esophageal surface. Four weeks after seeding, we found that cartilage was implanted in the midposterior portion of the cervical trachea (n=5), and it was retrieved 8weeks after seeding. RESULTS: 1. A gelatin sponge incorporating ß-TCP with vicryl mesh™ showed the best performance for fabricating engineered cartilage on the outer side of the esophagus. 2. Two of 5 rabbits died due to obstructed esophagus. Cartilage engineered outside the esophagus by a composite scaffold as the main material in the gelatin sponge, maintained the airway structure for up to 1month after implantation. Tracheal epithelial regeneration occurred in the internal lumen of this engineered cartilage. CONCLUSION: Tracheoplasty with cartilage engineered outside the esophagus may be useful for reconstructing airways.

Slow release of basic fibroblast growth factor (b-FGF) promotes growth of tracheal cartilage.

PURPOSE: Tracheomalacia is a major cause of morbidity in conditions such as oesophageal atresia. However, symptoms usually improve with age. A more rapid growth of tracheal cartilage can be induced by basic-Fibroblast Growth Factor (b-FGF). This study aimed to investigate whether slow-release b-FGF could act as a novel treatment for tracheomalacia. METHODS: Biodegradable gelatin hydrogel sheets incorporating 0.5, 5, or 50 µg/20 µl of b-FGF solution were inserted between the cervical trachea and esophagus of rats. No intervention was performed in rats in a control group. All animals were sacrificed 4 weeks later, and the luminal area of the cervical trachea and the thickness of the cartilage were measured. RESULTS: The mean luminal areas in the control group and in the b-FGF groups were 3.1, 3.2, 3.8, and 2.6mm(2), respectively, and showed a peak area at 5 µg of b-FGF. A significant difference was seen only between the control group and the b-FGF 5 µg group (p<0.05). The mean thickness of the tracheal cartilage was 0.12, 0.13, 0.19, and 0.32 mm in the control and the b-FGF groups, respectively, and showed a dose-dependent increase, which was statistically significant between the b-FGF 5 µg or 50 µg groups and the control group (p<0.01). CONCLUSION: This study showed that slow-release b-FGF enlarges the tracheal lumen and thickens the cartilage in a dose-dependent fashion.

Plasma citrulline may be a good marker of intestinal functions in intestinal dysfunction.

BACKGROUND: Plasma citrulline has been reported to be a good indicator of intestinal functional volume in patients with intestinal dysfunction. We reconfirmed the facts and also investigated the dynamic changes of plasma citrulline in acute-phase patients with intestinal dysfunction. METHODS: We measured plasma citrulline in six patients with intestinal dysfunction who were in the acute and chronic phase for more than 6 months. RESULTS: Four patients out of six could be withdrawn from total parenteral nutrition, and their plasma citrulline level dynamically changed according to their intestinal states and finally increased up to 15 nmol/mL. Two patients, who could not be withdrawn from parenteral nutrition, showed very low levels of plasma citrulline throughout the treatment course (under 15 nmol/mL). CONCLUSION: The cut-off level of plasma citrulline indicating permanent intestinal dysfunction may be 15 nmol/mL in our data. In the acute phase, plasma citrulline changed dynamically according to the intestinal state and may be a good indicator of fluctuating intestinal functions. Thus, although only a few patients were enrolled in this study, plasma citrulline may be a good indicator of stable-state as well as acute-unstable-state intestinal functions.

Translumenal esophageal anastomosis for natural orifice translumenal endoscopic surgery: an ex vivo feasibility study.

AIM: This study aimed to develop a novel procedure for esophagoesophageal anastomosis for natural orifice translumenal endoscopic surgery (NOTES). MATERIALS AND METHODS: An ex vivo feasibility study was performed in eight porcine models. The procedure was as follows: (1) A BraceBar™ (Olympus Medical Systems Corp., Tokyo, Japan), a double T-bar suturing device, was placed endoscopically at the blind end of the upper esophagus (UE). (2) The blind end was incised, and the scope was advanced out of the esophagus. (3) A balloon catheter was inserted into the lower esophagus (LE). (4) The catheter and a thread on the BraceBar were withdrawn so that the end of the UE was inverted, and the LE was pulled into the UE. (5) After the catheter was removed, a short tube was placed inside the duplicated part of the esophagus via the transgastric route. (6) A double ligature was performed using a ligating device over the tube. A liquid leak test was performed after the procedure. RESULTS: All steps in this procedure were technically successful under the endoscopic visualization without any assistance from outside of the esophagus. The median time of this procedure was 31 (23-66) minutes. The median internal pressure of the UE was 122 (82-142) mm Hg when the anastomosed esophagus was separated into two specimens during the leak test. CONCLUSIONS: Translumenal esophagoesophageal anastomosis was feasible. The duration of the procedure was short, and the anastomoses appear to have sufficient strength for use in clinical practice. An in vivo survival study is needed to confirm the safety and reliability of this NOTES procedure.

Interleukin 6 and interleukin 8 play important roles in systemic inflammatory response syndrome of meconium peritonitis.

PURPOSE: Meconium peritonitis is caused by an intestinal perforation that may occur in the fetus, followed by severe chemical peritonitis, resulting in high morbidity. METHODS: We have experienced six patients with meconium peritonitis. Cystic drainage was performed soon after birth for all patients. We investigated the concentrations of several cytokines and a chemokine (interleukin 8) in the ascites from the six patients with meconium peritonitis. In two patients we also measured the serum cytokines and chemokine level just after birth. RESULTS: Interleukin 6 and interleukin 8 concentrations were very high in the cyst or ascites just after birth. In the serum taken from two patients, the levels of interleukin 6 and interleukin 8 were also high. In five patients who underwent drainage of cysts after birth, systemic inflammation could not be completely suppressed before curative surgery. CONCLUSIONS: Interleukin 6 and interleukin 8 play important roles in the inflammatory response syndrome associated with meconium peritonitis, and drainage of cystic fluid did not completely suppress this inflammation. To lessen the high morbidity of meconium peritonitis, efforts should be made to suppress the inflammatory response using new treatment strategies, such as administration of steroids or anti-cytokine therapy to supplement cystic drainage.

A pilot study of laparoscopic gastric pull-up by using the natural orifice translumenal endoscopic surgery technique: a novel procedure for treating long-gap esophageal atresia (type a).

AIM: This study aimed to develop a novel procedure for treating long-gap pure esophageal atresia. This procedure, which entails the combined use of laparoscopy and natural orifice translumenal endoscopic surgery (NOTES), would enable primary repair without cervical and thoracic incisions and prevent postoperative gastroesophageal reflux disease (GERD). METHODS: Nonsurvival experiments were conducted in 9 pigs to study the technical feasibility. The procedure comprised the following: (1) creation of the disease model by laparoscopic resection of the lower esophagus; (2) laparoscopic fundoplication, complete mobilization of the stomach, and enlargement of the esophageal hiatus; (3) formation of a peroral transesophageal entry site into either the postmediastinum or the right thoracic cavity followed by fashioning a tunnel to the peritoneal cavity; (4) gastric pull-up by using both laparoscopy and NOTES; (5) esophagoesophageal anastomosis using BraceBar™, a prototype of the double T-bar suturing device (Olympus Medical Systems Co., Tokyo, Japan). RESULTS: Laparoscopic procedures were performed without complications. The postmediastinal tunnel was successfully created three times with a complication of pleural injury. However, gastric pull-up via this route could not be completed due to porcine anatomical reasons. Gastric pull-up through the right thoracic route was achieved five times in six attempts. Two disorientations and a hemorrhagic death occurred during the procedures. CONCLUSIONS: This study showed that combined use of laparoscopy and NOTES enabled gastric pull-up without cervical and thoracic incisions. Our method has the potential of lowering the incidence of GERD and enabling primary repair of this disease.

Attenuated Th1 induction by dendritic cells from mice deficient in the leukotriene B4 receptor 1.

Dendritic cells (DCs) are important antigen-presenting cells that control Th1- and Th2-type immunological reactions by releasing cytokines and interacting directly with T cells. Leukotriene B4 (LTB4), a classical proinflammatory lipid mediator for phagocytes, was recently identified as an important attractant for effector CD4(+) and CD8(+) T cells. However, little information is available on the roles of LTB4 and its receptor BLT1 in DCs. Here we show that functional BLT1 expressed in mouse bone marrow-derived DCs (BMDCs) plays important role in initiating Th1-type immune response. Detailed analyses using BMDCs revealed that BLT1-deficient DCs produced less IL-12p70 than WT DCs, leading to attenuated IFN-gamma production in an allogeneic mixed lymphocyte reaction. Adoptive transfer of antigen-loaded BLT1-deficient DCs into naïve WT mice induced a weakened Th1- and enhanced Th2-response in vivo compared to WT DCs. BLT1-deficient mice consistently showed much attenuated delayed-type hypersensitivity (DTH), in which Th1-type cellular responses play a key role, and popliteal lymph node cells of BLT1-deficient mice showed reduced production of Th1 cytokines after DTH induction compared to cells from WT mice. Thus, in addition to its role in inflammation, the LTB4-BLT1 axis is important in initiating Th1-type immunological reactions mediated by DCs.

Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells.

There is strong evidence for a role of prostaglandin E(2) (PGE(2)) in cancer cell proliferation and tumor development. In PGE(2) biosynthesis, cyclooxygenases (COX-1/COX-2) convert arachidonic acid to PGH(2), which can be isomerized to PGE(2) by microsomal PGE-synthase-1 (MPGES-1). The human prostate cancer cell line DU145 expressed high amounts of MPGES-1 in a constitutive manner. MPGES-1 expression also was detectable in human prostate cancer tissues, where it appeared more abundant compared with benign hyperplasia. By using shRNA, we established stable and practically complete knockdown of MPGES-1, both in DU145 cells with high constitutive expression and in the non-small cell lung cancer cell line A549, where MPGES-1 is inducible. For microsomes prepared from knockdown clones, conversion of PGH(2) to PGE(2) was reduced by 85-90%. This resulted in clear phenotypic changes: MPGES-1 knockdown conferred decreased clonogenic capacity and slower growth of xenograft tumors (with disintegrated tissue structure) in nude mice. For DU145 cells, MPGES-1 knockdown gave increased apoptosis in response to genotoxic stress (adriamycin), which could be rescued by exogenous PGE(2). The results suggest that MPGES-1 is an alternative therapeutic target in cancer cells expressing this enzyme.

Long-term survival of a baby with body stalk anomaly: report of a case.

Body stalk anomaly is characterized by severe scoliosis, severe pulmonary hypoplasia, and giant omphalocele. The prognosis of the disease is poor and most obstetricians consider it fatal. Very few patients with body stalk anomaly survive. We report the case of a baby diagnosed with body stalk anomaly in fetal life, who was saved by intensive care after birth. We closed the giant omphalocele successfully by placing karaya gum sheets over it, which created a humidified environment and promoted natural skin epithelization over the skin defect.

Identification of the intracellular region of the leukotriene B4 receptor type 1 that is specifically involved in Gi activation.

Many G-protein-coupled receptors can activate more than one G-protein subfamily member. Leukotriene B4 receptor type 1 (BLT1) is a high affinity G-protein-coupled receptors for leukotriene B4 functioning in host defense, inflammation, and immunity. Previous studies have shown that BLT1 utilizes different G-proteins (the Gi family and G16 G-proteins) in mediating diverse cellular events and that truncation of the cytoplasmic tail of BLT1 does not impair activation of Gi and G16 proteins. To determine responsive regions of BLT1 for G-protein coupling, we performed an extensive mutagenesis study of its intracellular loops. Three intracellular loops (i1, i2, and i3) of BLT1 were found to be important for both Gi and G16 coupling, as judged by Gi-dependent guanosine 5'-(gamma-thio) triphosphate (GTPgammaS) binding and G16-dependent inositol phosphate accumulation assays. The i3-1 mutant, with a mutation at the i3 amino terminus, exhibited greatly reduced GTPgammaS binding but intact inositol phosphate accumulation triggered by leukotriene B4 stimulation. These results suggest that the i3-1 region is required only for Gi activation. Moreover, in the i3-1 mutant, the deficiency in Gi activation was accompanied by a loss of the high affinity leukotriene B4 binding state seen with the wild type receptor. A three-dimensional model of BLT1 constructed based on the structure of bovine rhodopsin suggests that the i3-1 region may consist of the cytoplasmic end of the transmembrane helix V, which protrudes the helix into the cytoplasm. From mutational studies and three-dimensional modeling, we propose that the extended cytoplasmic helix connected to the transmembrane helix V of BLT1 might be a key region for selective activation of Gi proteins.

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.

Absence of leukotriene B4 receptor 1 confers resistance to airway hyperresponsiveness and Th2-type immune responses.

Bronchial asthma is an increasingly common disorder that remains poorly understood and difficult to manage. The disease is characterized by airway hyperresponsiveness, chronic inflammation, and mucus overproduction. Based on the finding that leukotriene B4 receptor 1 (BLT1) is expressed highly in Th2 lymphocytes, we analyzed the roles of BLT1 using an OVA-induced bronchial asthma model. BLT1-null mice did not develop airway hyperresponsiveness, eosinophilic inflammation, and hyperplasia of goblet cells. Attenuated symptoms were accompanied by reduced IgE production, and accumulation of IL-5 and IL-13 in bronchoalveolar lavage fluid, suggesting attenuated Th2-type immune response in BLT1-null mice. Peribronchial lymph node cells of sensitized BLT1-null mice showed much attenuated proliferation and production of Th2 cytokines upon re-stimulation with Ag in vitro. Thus, LTB4-BLT1 axis is required for the development of Th2-type immune response, and blockade of LTB4 functions through BLT1 would be novel and useful in the effort to ameliorate bronchial asthma and related Th2-biased immune disorders.

Lethal gastric rupture caused by acute gastric ulcer in a 6-year-old girl.

Gastric rupture is extremely rare in childhood beyond the neonatal period. We describe a previously healthy 6-year-old girl with a large laceration along the greater curvature on the posterior wall of the stomach. The patient was admitted to a neighboring hospital because of vertigo with 1-day history of intractable vomiting and epigastric pain. Although abdominal distension was noticed during the physical examination, muscular rigidity was not detected on palpation. Laboratory data showed severe hypotonic dehydration and moderate metabolic acidosis with hyperkalemia. She suddenly developed cardiac arrest within an hour after admission. After resuscitation, surgical consultation was obtained. Abdominal X-ray and ultrasound revealed abdominal free air and massive cloudy ascites. At laparotomy, there was a large laceration on the greater curvature of the stomach. Pathology of the gastric wall showed mucosal necrosis while the musculature remained intact consistent with an acute gastric ulcer. Since clinical condition of gastric rupture deteriorates rapidly, early diagnosis and appropriate treatment is essential for good prognosis. One should consider that ulcer formation might cause gastric rupture in childhood.

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.