Long-term survivors of advanced neuroblastoma with MYCN amplification: A report of 19 patients surviving disease-free for more than 66 months.

PURPOSE: According to initial reports, stage 4 neuroblastoma patients with amplification of the MYCN proto-oncogene developed progressive disease within 8 months. The prognosis for such patients, however, should now be reevaluated in light of recent results achieved with up-to-date combination chemotherapy. PATIENTS AND METHODS: Patients with stage 3, 4, and 4S neuroblastoma and more than 10 copies of MYCN received induction chemotherapy, which from January 1985 to February 1991 consisted of regimen A(1 )(cyclophosphamide 1,200 mg/m(2) on day 1, vincristine 1.5 mg/m(2) on day 1, pirarubicin 40 mg/m(2) on day 3, and cisplatin 90 mg/m(2) on day 5) and from March 1991 to September 1993 consisted of regimen A(3 )(cyclophosphamide 1,200 mg/m(2) on days 1 and 2, pirarubicin 40 mg/m(2) on day 3, etoposide 100 mg/m(2) on days 1 through 5, and continuous infusion cisplatin 25 mg/m(2) on days 1 through 5). Most of these patients underwent radical surgery to remove the original tumor and local metastases, irradiation, and supralethal preconditioning regimens, followed by blood stem-cell transplantation (SCT). Data on the patients were collected in December 1998, and the factors contributing to disease-free survival were analyzed. RESULTS: During the study period, 66 patients with more than 10 copies of MYCN were treated. Five of nine patients with stage 3 disease, 13 of 55 with stage 4, and one of two with stage 4S survived for at least 66 months. It is interesting that all but one patient who survived for more than 66 months underwent SCT, in contrast with only five of 45 patients who died. CONCLUSION: Not all patients with advanced neuroblastoma who have more than 10 copies of MYCN will die. The requisites for survival in such patients seem to be intensive induction chemotherapy, effective surgery, irradiation, and the use of SCT.

Primary benign histiocytosis X of the stomach. A report of a case showing spontaneous remission after 5 1/2 years.

A 49-year-old Japanese woman was found to have innumerable, small sessile elevations throughout the stomach as revealed by radiographic and endoscopic examination. Endoscopic biopsy showed that the elevations were formed by a diffuse proliferation of histiocytes in the lamina propria mucosae. The histiocytes were characterized by abundant interdigitating cytoplasmic projections, Birbeck granules, an oval or indented nucleus, and an absence of phagocytosis. They stained for S-100 protein but not for lysozyme, alpha-1-antitrypsin, or nonspecific antigen cross-reacting with carcinoembryonic antigen. Five and a half years after the first diagnosis, most of the elevated lesions disappeared, but a few histiocytoid cells were noted microscopically. Systemic examination showed no abnormalities outside the stomach. The patient has continued to be well. This case was diagnosed as primary benign histiocytosis X of the stomach. Four similar cases have been reported. This is the first case that was diagnosed using biopsy techniques and in which the natural history--i.e., from multiple polypoid extension throughout the stomach to spontaneous remission--was observed.

Immunohistochemical and ultrastructural studies of twelve argentaffin and six argyrophil carcinoids of the appendix vermiformis.

Endocrine cell types in 12 argentaffin and six argyrophil carcinoids and in nonneoplastic epithelia of the appendix vermiformis were investigated histochemically, immunohistochemically, and ultrastructurally. The nonneoplastic epithelia contained serotonin (Ser), peptide YY (PYY), glicentin (Gli), neurotensin (Neu), and somatostatin (So) cells in decreasing frequency. Out of 30 nonneoplastic Ser cells examined ultrastructurally, 28 cells were EC1 cells and two were non-EC cells. Eleven of 12 argentaffin carcinoids could be immunostained with anti-Ser serum and all of those 11 were composed almost totally of Ser cells. One of the 11 contained a small number of Neu cells. Ultrastructurally, 11 argentaffin carcinoids were composed predominantly of EC1 and/or ECn cells, and one was composed primarily of non-EC cells. Out of the six argyrophil carcinoids, five were argyrophil, non-argentaffin carcinoids; three consisted almost totally of PYY cells; one consisted of 60% PYY cells, 40% So cells and a few Gli cells; and one consisted of Ser cells alone. Ultrastructurally, the first four of those tumors were composed of D1 and/or L cells and the latter tumor was composed of ECn cells. The remaining one argyrophil carcinoid contained a few Ser-positive argentaffin cells and consisted almost totally of ECn cells which were found in both parts, with and without argentaffinity. It is concluded that the appendiceal carcinoids comprise two distinct groups on the basis of the main constituting cell type: Ser-positive, argentaffin carcinoids, composed of EC cells and peptide (especially of PYY)-positive, and Ser-negative, argyrophil non-argentaffin carcinoids of D1 and/or L cells.

Neoplastic endocrine cells in carcinomas of the small intestine: histochemical and immunohistochemical studies of 24 tumors.

Endocrine cells in 24 primary carcinomas and in the nonneoplastic mucosa of the small intestine were investigated histochemically and immunohistochemically with antisera against serotonin and 10 kinds of peptide hormones. Argyrophil-positive endocrine cells were found in four of eight duodenal, all of eight jejunal, and six of eight ileal carcinomas. The density of the positive cells was higher in the ileal tumors than in the duodenal and jejunal ones. Immunoreactive endocrine cells were detected in three duodenal, six jejunal, and five ileal carcinomas. Immunoreactive serotonin cells were present most frequently and most densely without respect to the site of origin of the carcinomas. In general, the population of endocrine cells among the tumor cells was higher in the ileal carcinomas than in the duodenal and jejunal ones. The ileal carcinomas frequently and densely demonstrated somatostatin, peptide YY, neurotensin, glucagon, and glicentin cells in addition to serotonin cells. The kinds of endocrine cells and the relative frequency of each kind of endocrine cell in carcinomas of the small intestine were similar to those in the nonneoplastic mucosa from which the carcinomas originated. This is the first systematic immunohistochemical study on endocrine cells in carcinoma of the small intestine.

Peptide YY immunoreactive cells in gastrointestinal carcinoids: immunohistochemical and ultrastructural studies of 60 tumors.

The distribution and frequency of peptide YY (PYY) cells in 60 gastrointestinal carcinoids and in the nonneoplastic mucosa around the carcinoids were studied by an indirect immunoperoxidase method with anti-PYY serum. Additionally, the endocrine cell type of the PYY cells in appendiceal and rectal carcinoids was assessed by transmission electron microscopy. A few PYY cells were present in specimens of nonneoplastic mucosa from stomach, duodenum, jejunum, ileum, and appendix, with an abundance of these cells in rectal mucosa. Peptide YY cells were found in one of 13 gastric, one of 13 duodenal, one of one jejunal, zero of two ileal, three of 11 appendiceal, and 16 of 20 rectal carcinoids. All but one of the PYY-positive carcinoids were argyrophil carcinoids. Peptide YY cells in the gastric, duodenal, and jujunal carcinoids were present in small numbers. The three PYY-positive carcinoids of the appendix were composed almost totally of PYY cells, whereas those of the rectum generally contained only sporadic PYY cells. The peptide YY cells observed ultrastructurally contained almost round secretory granules (about 160 nm in average diameter), which were most consistent with D1(H) cell type granules with respect to shape and average diameter. This is the first systematic immunohistochemical and ultrastructural study of PYY cells in gastrointestinal carcinoids.

IGF-II-like immunoreactivity in human tissues, neuroendocrine tumors, and PC12 cells.

We looked for cells that reacted with monoclonal antibodies against rat insulin-like growth factor II (IGF-II). We found them in human fetal kidneys in the 14th week of gestation and in adult adrenal medullas but not in human liver, pancreas, pituitary gland, or thymus. Every pheochromocytoma in a group of 20 had IGF-II-like immunoreactive cells, as did three out of four ganglioneuroblastomas (one of which was heterotransplantable in athymic nude mice) and one carotid body tumor. Using the electron microscope we localized the immunoreactivity in pheochromocytoma cells to their neurosecretory granules of the non-catecholamine type. We failed to find any IGF-II-reactive cells among the pancreatic islet cell tumors, neuroblastomas, medullary carcinomas of the thyroid, retinoblastomas, and Wilms' tumor we studied. One line of human neuroblastoma cells did show some immunoreactivity after treatment with dbcAMP. Additionally, the rat pheochromocytoma cell line PC12 and its subline PC12h occasionally produced a few immunostained cells. These results strongly indicate that human IGF-II is primarily produced in paraganglionic tissues and tumors.

Effects of trimebutine on intestinal motility after massive small bowel resection.

Effects of trimebutine maleate (TM) on intestinal motility in short bowel syndrome (SBS) were studied in conscious canines in both acute and chronic phases following 80% massive distal small bowel resection (MSBR). TM was administered orally to beagles with MSBR or as controls in the postprandial and fasting states, and given simultaneously with meals. Intestinal motility was measured using bipolar electrodes for approximately 1 month after the electrodes were implanted in each beagle and the data compared between treatment groups. When TM was given with meals, the postprandial period without duodenal migrating myoelectric (or motor) complexes (MMCs) was shorter than in those given meals only. When TM was given in the postprandial state in short bowel beagles, the initial duodenal MMCs occurred earlier, i.e. the postprandial period was shorter. Diarrhea did not occur in these beagles. When TM was given in the fasting state, duodenal MMCs occurred and propagated to the distal intestine. In conclusion, oral TM administration can produce a more appropriate intestinal condition for the next food intake and make enteral nutrition possible even in the acute phase after MSBR. Such feeding can be carried out without overloading gut function as a result of the modulation of gastrointestinal motility by TM.

Effects of intestinal muscular wrapping on remnant intestinal motility after massive small bowel resection in conscious canines.

We searched the effect of the muscular valve on the management of short bowel syndrome. The motility of the remnant intestine with a special muscular valve after 80% massive distal small bowel resection (MSBR) was evaluated in conscious dogs. The valve (muscular ring) was made by the autointestinal muscle layer holding vascular pedicle. Interdigestive and postprandial bowel motility using bipolar electrodes and/or contractile strain gauge force transducers 2-4 weeks after the surgery, and data of this group (Group I) were compared to the motility in dogs after MSBR without valve construction (Group II) and in controls (Control). Results; Fasting duodenal migrating myoelectric (or motor) complexes (MMCs) in Group I occurred at longer intervals than in Control and almost similarly to those in Group II. MMCs arising from the duodenum were often interrupted before the jejunum above the valve and the anastomosis. The velocity of duodenal MMC propagation was slowed in every intestinal segment including that from the duodenum to the proximal jejunum, and to the jejunum above the anastomosis. Transit time in MSBR group (I and II) from the duodenum to the terminal ileum was extremely shorter than in Control, but there were no differences between in Groups I and II. The duration of the postprandial period without duodenal MMCs in Group I was significantly prolonged than in Control, but was shorter than that in Group II. The muscular valve was frequently activated, and the jejunum covered with the valve was contracted frequently which synchronized with the valve activity. It seemed the valve worked as sphincter. However, intestinal obstruction was not occurred through the jejunum covered by the valve. In conclusion, changes in gut motility after MSBR with the valve construction compensate for the shortened intestine and maintain the bowel content earlier postoperatively in comparison with the MSBR alone, and also contribute to the adaptive increase in the remnant intestinal absorption.

[Intestinal motility after massive small bowel resection].

To evaluate intestinal motility after 80% massive distal small bowel resection (MSBR), we continuously monitored interdigestive and postprandial bowel motility using bipolar electrodes and/or contractile strain gage force transducers in conscious beagle dogs before, and at 0-4 weeks and 8-13 months after the surgery. Fasting duodenal migrating myoelectric (or motor) complexes (MMCs) occurred at longer intervals in the short-term after 80% MSBR than in controls, and were simulated in long-term that in controls. MMCs arising from the duodenum were often migrated to the proximal jejunum, the jejunum above the anastomosis, and to the terminal ileum beyond the anastomosis. The velocity of duodenal MMC propagation was slowed in every intestinal segment in the short-term, and had not recovered even long after the operation. The duration of the postprandial period without duodenal MMCs was prolonged significantly in the short-term, and still remained longer in the long-term than in controls. These findings suggest that changes in gut motility after MSBR tend to compensate for the shorter intestine and maintain small bowel absorption early postoperatively, and adaptations of motility would occur over the long-term to increased intestinal absorption.

[Changes in intestinal motility after massive small bowel resection with a reversed jejunal segment].

To evaluate the functioning and effectiveness of a 20-cm reversed jejunal segment after 75-80% massive small bowel resection (MSBR), and whether migrating polarity changes or not, we continuously measured the postoperative bowel motility (using bipolar electrodes and/or contractile strain gage force transducers) in interdigestive and postprandial conscious dogs in short- (2-5 weeks) and long-term (6-10 months) after surgery. The fasting migrating myoelectric (or motor) complex (MMC) arising from the duodenum was often interrupted at the jejunum above the proximal anastomosis and did not migrate smoothly to the reversed segment or terminal ileum. In addition, brief small discordant contractions were frequent in the jejunum above the proximal anastomosis and the proximal part of the reversed segment. The duodenal MMCs predominantly propagated to the ileum through the inherent anatomic continuity of the bowel. These findings of the MMC propagation pattern are very similar in short- and in long-term after surgery. The duration of the postprandial period without duodenal MMC activity was markedly longer in short-term, but shorter in long-term (both were significantly longer than in controls). Marked dilatation of the jejunum and reversed jejunal segment was noted across the proximal anastomosis. These results suggest that the transit time and passage of intestinal contents can be delayed and stagnated for at least 10 months after MSBR with a 20-cm reversed jejunal segment. Although, reports on the polarity of peristalsis in the reversed segment in long-term followup have been contradictory in both experimental and clinical studies, this results support the conclusion that the reversed jejunal segment maintains its inherent propagative polarity and pattern over a long postoperative period.

Development of the motor activity of the rat gastrointestinal tract by in vitro measurement.

To clarify the postnatal developmental changes of the motor activity of the gastrointestinal tract, the frequency and amplitude of spontaneous intraluminal pressure of the isolated stomach, duodenum, jejunum, and ileum of the 1- to 5-week-old rat and adult (over 12 weeks old) were examined in vitro. The spectral frequencies of the spontaneous motor activity of 1- to 2-week-old rat were significantly lower than those of the adult. They became similar to the values of the adult at 3-4 weeks after birth. The amplitudes of spontaneous motor activity of 1- to 3-week-old rats were significantly smaller than those of adults. They became similar to the values of adults at 4 weeks after birth. Body weight, stomach wet weight and the length of the total intestine increased gradually and they were still below the values of the adult even at 5 weeks after birth. The stomach was filled with just milk until the end of 2 weeks. However, by the end of 3-4 weeks, milk and solid food were found in the stomach. By the end of 5 weeks, just solid food was seen in the stomach. Therefore, the motor activity of the gastrointestinal tract at birth seems immature and gradually develops postnatally. It seems to be mature by the end of 3-4 weeks after birth. Interestingly, the time of the pacemaker or motor maturity of the gastrointestinal tract according to spontaneous frequency or pacemaker activity and amplitude seemed almost consistent with the weaning time.

Familial occurrence of congenital bile duct dilatation.

The occurrence of congenital bile duct dilatation (CBD) in both a mother and her daughter was recently experienced at Niigata University Hospital and Niigata Shimin Hospital. Bile duct dilatation with anomalous pancreaticobiliary ductal junction (AP-BDJ) was disclosed in both. Intrahepatic bile duct dilatation was only in the mother. Removal of dilated bile duct, cholecystectomy, and hepaticojejunostomy were performed in both. Fourteen cases of CBD from seven families were collected from literature and discussed.

Evaluation of lower esophageal sphincter function in infants and children following esophageal surgery.

Esophageal manometry was performed before and after the operations for esophageal disorders in children to evaluate lower esophageal sphincter (LES) function and motility of the esophagocardiac region in each disease. Patients who underwent radical operations for gross C-type esophageal atresia (EA) and those with hiatal hernias considered to have gastroesophageal reflux (GER) showed reduction in LESP and LESL and eosphagocardiac motor abnormalities. Lower esophageal sphincter pressure and length, and motility of the esophagocardiac region improved in six patients who underwent an antireflux operation. Abnormal esophageal waves in EA patients persisted even after improvements in LES function by the antireflux operation and were considered to be a congenital problem, as the literature suggests. Effects of surgical intervention on the esophagus on the LES function were studied. Lower esophageal sphincter and esophagocardiac function were preserved, and GER did not develop after Livaditis' procedure for EA or esophageal transection and sectioning the esophageal branch of the vagus nerve for esophageal varices. Anatomic abnormalities that lead to LES dysfunction are considered to cause GER.

Resulting long-term intestinal motility in dogs following construction of a reversed jejunal segment after extensive small bowel resection.

To evaluate the long-term function and effective motility of a reversed jejunal segment after extensive small bowel resection, the authors continuously measured postoperative bowel motility during interdigestive and postprandial periods in conscious dogs 6 to 10 months after surgery. The long-term findings were compared with previously reported short-term results measured 2 to 4 weeks after the operation. In the long-term follow-up dogs with a 20-cm reversed jejunal segment constructed after extensive (75% to 80%) small bowel resection, the fasting duodenal migrating myoelectric (or motor) complex (MMC) was often interrupted in the jejunum above the reversed segment, and did not migrate smoothly to the reversed segment or terminal ileum. The MMCs arising from the duodenum predominantly propagated to the ileum through the inherent anatomic continuity of the bowel. In addition, brief small discordant contractions were frequent in the reversed segment and the jejunum, above the proximal anastomosis. These findings are similar to those of the MMC propagation pattern noted 2 to 4 weeks after surgery. However, the postprandial duration without duodenal MMC activity was significantly shorter in the dogs with long-term follow-up than in those with short-term follow-up (both were longer than in control dogs). Marked dilatation of the jejunum and reversed jejunal segment was noted across the proximal anastomosis. These results suggest that the transit time and passage of intestinal contents can be delayed and stagnated for at least 10 months after extensive small bowel resection with a 20-cm reversed jejunal segment.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term results after nonshunt operations for esophageal varices in children.

The clinical results of nonshunt operations for esophageal varices in 15 children were evaluated. The varices were caused by congenital extrahepatic portal obstruction (EHPO) in 10, liver cirrhosis or fibrosis (C/F) in 3, and idiopathic portal hypertension (IPH) in 2. The operative procedures were transthoracic esophageal transection with paraesophageal devascularization (TR) for 2 EHPO patients under 5 years of age, TR combined with splenectomy and paragastric devascularization (Sugiura procedure) for 11 (8 EHPO, 3 C/F), and splenectomy with devascularization (SP) or splenectomy for the 2 IPH patients. In the EHPO patient under 5 years of age, TR is associated with a likelihood of gastric or esophageal hemorrhage resulting from hypersplenism, gastric congestion, or persistent distal esophageal varices, which can be treated with partial splenic arterial embolization (PSE), endosclerotherapy, or an additional abdominal procedure. The Sugiura procedure has provided satisfactory long-term results, without rebleeding from esophageal varices, in patients with EHPO and C/F for 1 to 20 years. But EHPO patients who undergo the Sugiura procedure before age 6 can have gastric hemorrhage, because of mucosal congestion, for more than 10 years after the procedure, and selective gastric arterial embolization (GAE) might be necessary. In some EHPO patients, especially young ones who have variceal bleeding, a significant increase in hepatopetal portal flow may not develop, but hepatofugal natural shunts may progress. Therefore we recommend direct operative procedures, ie, TR for patients < or = 6 years of age and a one- or two-stage Sugiura procedure for those over 7 years old.(ABSTRACT TRUNCATED AT 250 WORDS)

A case of congenital colonic atresia associated with atresia ani.

The association of atresia ani with congenital colonic atresia is extremely rare, with only one such case having been reported up to date. We have recently treated a female infant with atresia ani (covered anus complete) accompanied by atresia of the sigmoid colon, who was managed by three stage surgery.

Intestinal myoelectric activity and contractile motility in dogs with a reversed jejunal segment after extensive small bowel resection.

To evaluate the functioning and effectiveness of a reversed jejunal segment after extensive small bowel resection, we continuously measured the postoperative bowel motility (using bipolar electrodes and/or contractile strain gage force transducers) in interdigestive and postprandial conscious dogs at 2 to 5 weeks after surgery. The fasting duodenal migrating myoelectric (or motor) complex (MMC) occurred at markedly longer intervals in dogs with a 20-cm reversed jejunal segment created after 75% to 80% extensive small bowel resection (group 3) than in dogs that received extensive resection alone (group 2) or dogs that underwent construction of a reversed jejunal segment without bowel resection (group 1). The MMC arising from the duodenum was often interrupted at the jejunum above the proximal anastomosis and did not migrate smoothly to the reversed segment or terminal ileum in group 3. In addition, brief small discordant contractions were frequent in the reversed segment and the jejunum above the proximal anastomosis in group 3. The duration of the postprandial period without duodenal MMC activity was significantly prolonged in groups 2 and 3. These results suggest that the transit time and passage of intestinal contents were delayed and that the periodical MMC was disturbed in group 3. The delay of transit time was due to prolongation of the interval between duodenal MMCs, the interruption of MMC propagation at the jejunum above the proximal anastomosis, the dominance of MMCs that followed the inherent anatomical continuity of the bowel, and discordant movements across the proximal anastomosis. Functional obstruction could be a potential problem in a 20-cm reversed jejunal segment inserted after extensive small bowel resection.

Studies on intestinal motility and mechanism of cholangitis after biliary reconstruction.

Cholangitis is a serious complication of biliary reconstruction for congenital biliary atresia. To observe the effect of intestinal motility on the mechanism of cholangitis, we studied intestinal motility in dogs after experimental common duct ligation and reconstruction by Roux-en-Y or interposition cholecystojejunostomy. One year after operation, bipolar electrodes were implanted in the canine intestine and electromyograms were performed. Distinct patterns of propagation and the direction of intestinal motility characteristic of each procedure were observed. The animals with Roux-en-Y loops showed a decrease in motility of the duodenum and upper jejunum. Those with an interposed segment demonstrated stagnation in both the duodenum and jejunum, and poor coordination of intestinal movement. The myoelectric activity of the Roux-en-Y loop suggests that it is the reconstruction technique most likely to prevent reflux cholangitis.

Flow cytometric DNA analysis of neuroblastoma: prognostic significance of DNA ploidy in unfavorable group.

Flow cytometric DNA content analyses were performed on samples of 54 patients with neuroblastoma. DNA aneuploidy was detected in 55.6% of the 54 patients. A high incidence of DNA aneuploidy was observed in patients with prognostically favorable variables such as age (less than 1 year), clinical stage (I, II, or IVs), and primary site (extraadrenal sites). DNA aneuploidy was predominant in surviving patients, even in those with unfavorable variables. In patients 1 year old or more, the survival rate among those with DNA aneuploidy was 58.8% compared with 28.6% in patients with diploidy. Likewise, in patients with advanced stage (III or IV) neuroblastoma, the survival rate among those with DNA aneuploidy was 63.2% compared with 30.4% in patients with DNA diploidy. It is concluded that DNA content analysis is of value in predicting the prognosis of patients with neuroblastoma.

Mediastinal yolk sac tumor in a young girl: case report and review of the literature.

The authors report a rare case of a female infant who underwent successful treatment of a mediastinal yolk sac tumor. Therapy included four cycles of preoperative PVB (cisplatinum, vinblastine, bleomycin), complete surgical resection of the tumor, and one postoperative cycle of PVB and four cycles of VAC (vincristine, actinomycine, cyclophosphamide) chemotherapy. The successful treatment of this tumor depends on preoperative chemotherapy to reduce the size, followed by complete surgical excision with subsequent postoperative chemotherapy. Recent improvements in the treatment of mediastinal yolk sac tumors are discussed.