Monoclonal antibody T-199 directed against human medulloblastoma: characterization of a new antigenic system expressed on neuroectodermal tumors and natural killer cells.

A monoclonal antibody (mAb) (T-199) of IgG1 isotype was raised against medulloblastoma by immunizations of mice with the medulloblastoma cell line TE-671. Studies of the specificity of mAb T-199 on cell lines as well as fresh frozen sections of normal and malignant tissues revealed the antigen in high amounts on the cell surface of neuroectodermally derived tumors such as medulloblastoma, neuroblastoma, retinoblastoma, and astrocytoma. Some melanomas and a subgroup of rhabdomyosarcomas also expressed the antigen. In contrast, mesenchymal tumors, osteosarcomas, and Ewing's sarcomas did not bear the T-199 antigen. Reactivity of T-199 with normal tissues has not been found with few exceptions; in certain areas of the brain, especially in the cerebellum and part of the hypothalamus, in the adrenal glands, and in the pancreatic islet cells small amounts of antigen were detectable. Natural killer cells could also be demonstrated to express the T-199 antigen similar to the NKH-1 antigen. However, despite some striking similarities, the antigens or antigen epitopes recognized by mAbs T-199 and NKH-1 are not identical. Therefore, mAb T-199 seems to detect a unique differentiation antigen on neuroectodermal tumors, coexpressed in low amounts on normal neuroectodermally derived cells and natural killer cells. The pattern of reactivity and the biochemical properties of the T-199 antigen are different from other cell surface markers for neuroectodermal cells coexpressed on natural killer cells or T-cells (HNK-1, NKH-1, or Thy-1). Biochemical analysis of the T-199 antigen showed that it is a heat-labile protein.

Effectiveness of preoperative chemotherapy in Wilms' tumor: results of an International Society of Paediatric Oncology (SIOP) clinical trial.

The results of a controlled clinical trial of preoperative radiotherapy compared to chemotherapy in patients with nephroblastoma are presented. Of 397 histologically proven cases of Wilms' tumor registered at 34 centers between January 1977 and July 1979, 164 were eligible for the trial and were randomized to receive preoperative radiotherapy and chemotherapy (group R, 76 patients) or preoperative chemotherapy (group C, 88 patients). The results were evaluated in terms of the number of surgical tumor ruptures and of local tumor extent at pathologic examination, reflecting the effectiveness of the preoperative treatment. Survival and recurrence-free survival in the two treatment groups were also taken into account. The stage distribution was comparable in the two groups, with 52% stage I tumors in group R, and 43% in group C. Significant changes in the pathologic pattern were more frequent in group R than in group C (53% versus 17%). From these data it is concluded that preoperative chemotherapy is as good as preoperative radiotherapy in terms of prevention of tumor rupture. In addition, it was shown that 43% of an unselected population of patients with Wilms' tumor could be treated without any radiotherapy when chemotherapy had been given preoperatively.

Clinico-pathological criteria with prognostic relevance in hepatoblastoma.

We investigated clinical data and histological specimens of 46 patients with a hepatoblastoma (HB) for prognostic criteria. Disease-free survival (DFS) of 23 patients treated in the German Cooperative Study HB-89 (1988-1990) was 83%, in contrast to 40% in 10 children with other chemotherapy regimes (1977-1987) and 38% in 13 with only a tumour resection (P = 0.005). Tumour residence after resection (R category) correlated significantly with probability of DFS (P = 0.0001). This was also the case for pT status, according to the pTNM classification for liver carcinoma (P = 0.0007), involvement of one or both liver lobes (P = 0.004), multiplicity of tumour nodes (P = 0.001), vascular invasion (P = 0.0006) and expression of nucleolar organiser regions as an indicator for proliferation activity of tumour cells (P = 0.05). Patients' age and histopathological subtypes could only indicate outcome, while tumour size and serum alpha-fetoprotein values were not significantly related to prognosis. In multivariate analysis, pT status and R categories remained significant. These should be applied in all cooperative trials on HB.

Efficiency and toxicity of ifosfamide, cisplatin and doxorubicin in the treatment of childhood hepatoblastoma. Study Committee of the Cooperative Paediatric Liver Tumour Study HB89 of the German Society for Paediatric Oncology and Haematology.

The Cooperative German Paediatric Liver Tumour Study HB89 was conceived to evaluate the efficiency and toxicity of ifosfamide, cisplatin and doxorubicin (IPA) in children with resectable and non-resectable hepatoblastoma (HB) and to determine late sequelae including tubular nephropathy of tumour treatment. The study also assessed the results of a surgical strategy, which adapts the procedure at the initial operation to the tumour's extension in the liver. The relationship of the tumours' histological differentiation to response to chemotherapy was also examined. Patients with a HB restricted to one liver lobe underwent primary resection. Larger tumours were initially treated with IPA chemotherapy and resected at second-look surgery. All patients received IPA adjuvantly after tumour resection. The IPA regimen consisted of ifosfamide 3.5 g/m2 (over 72 h days 1-3), cisplatin 100 mg/m2 (over 5 days 4-8) and doxorubicin 60 mg/m2 (over 48 h, days 9-10). Median follow-up of survivors was 64 months (range 28-82). Long-term disease-free survival (DFS) was for stage I: 21/21; stage II: 3/6; stage III: 28/38; and stage IV: 2/7 (overall 75%). Severe surgical complications occurred in 15% (4/27) of primary and 21% (8/38) of secondary resections with no lethality. 44/45 stage III/IV HB displayed PR after two IPA courses. Drug resistance developed in 8/12 tumours after four or five chemotherapy courses. Acute toxicity was observed in 34/242 (14%) IPA courses. Late sequelae were found in 7/54 (13%) of survivors, and subclinical renal tubulopathy occurred in 7/41 investigated patients (17%). Despite a more favourable prognosis in pure fetal and predominantly fetal histology, statistical analysis revealed no relationship between tumour differentiation and response to chemotherapy. In conclusion, IPA chemotherapy in combination with delayed surgery was highly effective in the treatment of HB.

Posterior urethral duplication and triplication in the male.

This is a report of a case of urethral triplication in a male baby with two accessory urethral channels terminating at the perineum and a normally situated but partially strictured urethra. Classification of urethral duplications is discussed and an embryologic explanation of type III urethral duplications proposed.

Embryology of bladder exstrophy.

A hypothesis in respect to the teratogenesis of bladder exstrophy and its variants is offered. The central feature of this hypothesis is the abnormal persistence of the caudal position of the insertion of the body stalk on the embryo. As a consequence of this, the normal advance and interposition of mesenchymal tissue to the midline becomes impossible. The cloaca cannot be translocated backwards into the body cavity, and the cranial end of the cloacal membrane remains in contact with the inferior aspect of the low-set body stalk. This, in contrast to the previously proposed abnormal rostral extension of the cloacal membrane, causes a wedge-effect resulting in the lateralization of the abdominal wall structures and also in the prevention of the midline fusion of the genital hillocks (labioscrotal or genital folds). A cloacal membrane normally is an unstable structure lacking mesoderm, and it retains these characteristics in the superficial and infraumbilical position to be described. It has a strong tendency to disintegrate. It may rupture at variable times and to a variable extent. The consequence of such an embryonic event is either a typical bladder exstrophy or one of the variants of the exstrophy malformation. Three different variants are presented that the proposed embryologic hypothesis can readily explain.

Diagnosis and current management of penile agenesis.

Penile agenesis is a rare congenital anomaly in which early gender reassignment is recommended. In the past, multiple operations were carried out to form feminized external genitalia. The authors performed a definite genital reconstruction in a neonate using the posterior sagittal approach. Preoperatively, a magnetic resonance imaging (MRI) scan demonstrated erectile tissue, which was preserved and incorporated into the genital plasty. The operation included bilateral orchiectomy, urethral reconstruction, sigmoid vaginal replacement, and formation of the labia. The authors discuss the controversy around gender assessment. They emphasize the urethral hypotrophy to be a main challenge in this anomaly and conclude that immediate complete reconstruction is possible and should be performed in patients with this delicate condition.

Nephron-sparing surgery in synchronous bilateral Wilms' tumors.

BACKGROUND: Synchronous bilateral Wilms' tumor is rare and experience with renal salvage procedures and their limitations accumulates slowly at single institutions. The authors analyzed whether their growing experience with atypical renal resections and awareness of nephroblastomatosis had influenced the outcome of surgical procedures. METHODS: Retrospective analysis of patients treated from 1977 to 1995 was performed. Surgical reports, clinical sheets, and follow-up data were evaluated. All pathology slides were reviewed for histological classification and presence of nephroblastomatosis. Renal function was evaluated pre- and postoperatively and at final follow-up. RESULTS: Fourteen patients were treated. Two to 20 years after surgery, 13 patients are alive, and none has had renal failure. Five patients had unilateral nephrectomies, and a renal salvage procedure was performed on 22 kidneys. One patient with an anaplastic bilateral Wilms' tumor died of tumor progress 1 year after surgery. Several kidneys, which would have been sacrificed by application of traditional criteria, could be salvaged by atypical and unconventional tumor resections and by superficial dissection and enucleation of supposed nephroblastomatosis. Nephrectomy appeared unavoidable with hilar invasion by tumor. CONCLUSION: Atypical resections of localized lesions and superficial dissections of suspected nephroblastomatosis appeared as valid surgical treatment options for patients who would otherwise have been candidates for nephrectomy. In the case of hilar tumor invasion, however, nephrectomy seems unavoidable.

New aspects in a murine model for extrahepatic biliary atresia.

The cause of extrahepatic biliary atresia (EHBA) remains unknown, and even an animal model is still lacking. Observations in a murine infectious model (newborn Balb/c mice infected with rhesus rotavirus group A [RRV]) reported extrahepatic biliary obstruction similar to findings in children who have EHBA. In the present study, this animal experiment was repeated, and the clinical and histomorphologic changes were observed over 3 weeks. Eighty-nine newborn mice were infected with RRV, and 67% showed signs of cholestasis and delayed growth. Eight of these animals recovered spontaneously whereas the others remained icteric. Fourty-six pups were prepared for microscopic examination following a 2-day interval. From the fifth day, the whole biliary tract showed edematous swelling with cellular infiltration. Ten days later, in the extrahepatic bile duct, a transformation took place in which concentric infiltration led to complete obstruction, sometimes with prestenotic dilatation. The intrahepatic changes showed reactive necrosis and proliferation of the small bile ducts. In one 19-day-old mouse, a ballooning dilatation was observed, similar to a developing choledochal cyst. Infection with RRV induces in newborn Balb/c mice a cholestatic clinical picture with different courses of the disease leading mostly to complete biliary obstruction and secondary hepatic changes similar to EHBA in children. This is the first animal model for EHBA with complete obstruction of the extrahepatic bile duct induced by infection. These findings present a new basis for further studies.

Complete resection before development of drug resistance is essential for survival from advanced hepatoblastoma--a report from the German Cooperative Pediatric Liver Tumor Study HB-89.

Clinical data and tumor histology of 37 patients with advanced and/or metastatic hepatoblastoma (32 stage III and 5 stage IV) treated according to the protocol of the German Cooperative Pediatric Liver Tumor Study HB-89 from 1988 to 1992 were studied for prognostic factors. Twenty-three patients (73%) were free of tumor 9 months to 5 years (median, 36 months) after treatment, whereas 4 experienced progressive disease, 7 had local relapse, and 3 had recurrent metastases. None of 2 patients with primary lymph node involvement or 5 with primary metastases remained disease-free. Chemotherapy with ifosfamide, cisplatin, and adriamycin was effective in reduction of tumor to resectability in 33 (89%) patients. Drug resistance developed in 6 of 11 patients treated with four or more courses of chemotherapy as could be shown by monitoring of serum-alpha-fetoprotein (AFP) and serial investigations of tumor expansion with sonography and computed tomographic (CT) scan. Only 1 of these patients survived after a liver transplantation. Completeness of tumor resection at second- or third-look laparotomy was significantly related to disease-free survival (P < .0001). Patients with initial serum-AFP values < 100 ng/mL or > 1,000,000 ng/mL had a worse outcome than those with immediate levels (P = .044). The rate of decrease of serum-AFP during chemotherapy was significantly related to prognosis (P = .003). Growth pattern of tumor within the liver (ie, defined nodes versus diffusely disseminated) (P = .011) and vascular tumor invasion (P = .026) were valuable prognostic factors, whereas tumor volume, local infiltration of surrounding tissue, histological subtypes, and epithelial differentiation were not significantly related to the outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Urethral reconstruction using an autologous bladder mucosal graft.

Since 1988 twelve children underwent urethral reconstruction by using an autologous bladder mucosal graft. In 10 of these previous surgery for hypospadias or other penile anomalies had failed. Bladder mucosal graft was used in 2 cases for primary urethral reconstruction. Our results in using this method, mostly in hypospadias cripples, are satisfying, so that we are encouraged to use the autologous bladder mucosal graft for primary urethral reconstruction in selected cases with severe forms of hypospadias as well.

Feminizing genital reconstruction, sigmoid vaginal replacement and anorectoplasty as a one-stage procedure for anorectal atresia associated with ambiguous genitalia.

Anorectal atresia associated with male pseudohermaphroditism presents both diagnostic and surgical challenges. In the past, multiple operations were necessary for feminizing genitoplasty in gender-reassigned children with ambiguous genitalia. We combined the repair of an imperforate anus with a feminizing genitoplasty, including sigmoid vaginal replacement using the posterior sagittal approach in a 3-months-old infant. We conclude that a primary complete reconstruction is advantageous and should be performed in this condition.

Occlusion of liver veins (Budd-Chiari syndrome) in childhood: a case report.

The Budd-Chiari syndrome is a rare cause of portal hypertension during childhood. We report on a 2-year-old boy suffering from liver congestion and ascites. No cause for the occlusion of the liver veins was found. There was an almost complete occlusion of the subdiaphragmatic vena cava due to compression by a hypertrophic lobus caudatus. Normal venous pressure could be demonstrated below this subtotal occlusion while numerous venous collaterals into the areas of the venae azygos and hemiazygos were encountered. A mesocaval shunt operation, therefore, seemed to be appropriate. There was, however, no decrease in production of ascites postoperatively. Repeat cavography now showed an elevation of venous pressure caused by the additional inflow of portal blood which could not, as expected, be compensated by caval collaterals. Therefore, a mesoatrial shunt was performed eight days after the first operation. However, even this additional shunt did not decrease the enormous production of ascites, and the child finally died. Hemodynamic and lymphodynamic pathways of the Budd-Chiari syndrome are discussed. Possibly a mesoatrial shunt in the first place, followed by a mesocaval shunt, would have been the better operative strategy.

One-stage reconstruction of bladder exstrophy.

From 1984 to 1990 a primary one-stage reconstruction of bladder exstrophy was performed at our hospital on 15 consecutive infants. Reconstruction included Cohen's ureteral reimplantation, bladder neck reconstruction according to Young-Dees, bladder closure, symphyseal bone approximation, abdominal wall closure, and repair of epispadias in females. Postoperatively, all patients were immobilized by overhead extension. Iliac osteotomy was done in 9 children, but was abandoned in recent years for infants less than one month old Follow-up examinations included an interview with the parents, clinical examinations, blood and urine analyses, uroflowmetry, and ultrasound scan of the abdomen. Nuclear renal scan, i.v. pyelography, and cystography were carried out as indicated. At the time of last evaluation the children were between 3 and 9 years of age. The cosmetic results were satisfactory in all cases. Eight of 15 children were dry day and night with micturition intervals more than 3 hours during day time (complete continence). Five children were dry during day time with micturition intervals up to 3 hours, but occasionally wet their beds (partial continence). Two children were incontinent. Eleven of 15 children had a bladder capacity of more than 100 ml. Renal function was normal in all patients. Two children showed a mild VUR, and no other abnormalities of the upper urinary tracts were found. Iliac osteotomy did not influence the functional or cosmetic results, but in two patients asymmetry of pelvic bones with consecutive lumbar scoliosis was found. Comparing these results with reports on staged reconstructive procedures, we conclude that by primary complete one-stage reconstruction a well acceptable success rate is achieved, and that by this method possibly some advantages are offered to patients with bladder exstrophy.

Experience with repair of 120 hypospadias using Mathieu's procedure.

Between 1985 and 1993 120 boys with distal hypospadias (from distal penile shaft to glandular position) were treated using Mathieu's procedure at the department of pediatric surgery, Hannover Medical School, Germany. The outcome of these cases has been analysed. Fistula-rate was 12.5%. Results are compared with published reports, recent developments and changes in treatment are discussed.

Is laparatomy the first step in treatment of childhood liver tumors?--The experience from the German Cooperative Pediatric Liver Tumor Study HB-89.

In the cooperative study on childhood liver tumors (HB-89) of the German Society for Pediatric Oncology and Hematology an initial laparotomy was recommended for all children with a primary liver tumor. Now a more differentiated surgical strategy has been worked out on the basis of study data. Patient's age, alpha-fetoprotein or other tumor markers, imaging techniques and histological investigations were predictive for differential diagnosis in most, but not all cases. Surgical complications occurred infrequently, there was no perioperative mortality. Results of therapy were satisfactory in hepatoblastoma, but poor in hepatocellular carcinoma, since chemotherapy and radiation were not effective on this tumor. In conclusion, primary chemotherapy without histological confirmation is justified, if in children between six months and three years of age with a high serum-alpha-fetoprotein a hepatoblastoma is certain, and the tumor involves both lobes of the liver. All other patients should have an initial laparotomy for resection of small or biopsy of large tumors. In case of hepatocellular carcinoma a primary resection should be attempted on principle.

Liver tumors in neonates and very young infants: diagnostic pitfalls and therapeutic problems.

We report on 26 infants under 3 months of age with various liver tumors, who were treated in our hospital since 1977 and/or registered in the German Cooperative Pediatric Liver Tumor Study HB-89. 17 of these had an infantile hemangioendothelioma (inf HE), 7 a hepatoblastoma (HB), one a mesenchymal hamartoma (mes H) and one a neuroblastoma stage IV-S (Nbl). Polyhydramnios occurred in 5 cases of inf HE, in one associated with hydrops fetalis. This led to a preterm delivery of 4 infants. 7 infants with a large inf HE suffered from high output congestive heart insufficiency, 2 additionally from a Kasabach-Merritt-syndrome. Serum alpha-fetoprotein was within normal range of age in all infants except in one HB patient. Neuron-specific enolase was clearly elevated in the Nbl patient and slightly above normal range in one inf HE and 3 HB patients. Other tumor markers and platelet counts were not indicative of diagnosis. Also imaging techniques as ultrasonography, CT and angiography were not always reliable in differentiating the tumors. In 2 cases the initial histological diagnosis of an HB had to be corrected for an inf HE. In 6 children the tumors were initially treated under a wrong assumption: 4 tumors as an HB instead of an inf HE, one as an inf HE instead of a Nbl IV-S and one as a focal nodular hyperplasia of the liver instead of an HB. 7 not resected inf HEs (Dehner type I) showed spontaneous regression after 6 months to 3 years. One inf HE type II relapsed twice after resection.(ABSTRACT TRUNCATED AT 250 WORDS)

Retroperitoneal lymphangiomyoma in an infant.

Lymphangiomyomatosis (LAM) is a benign tumor-like lesion of lymphatic vessels with unknown etiology. 80 cases of LAM are presently described. So far, it appears that only women in their reproductive years seem to be affected. Here, we describe the first LAM in an 11-months-old infant with a presumably local form of LAM. This leads us to consider the possibility that this tumor-like lesion may originate from a hamartomateous malformation. The diagnosis is based on pre-operative sonography and CT, as well as on histological and immunohistochemical examination of the tumor.

The role of initial laparotomy and second-look surgery in the treatment of abdominal B-cell non-Hodgkin's lymphoma of childhood. A report of the BFM Group.

The aim of this study was to determine the role of surgery in the treatment of abdominal B-cell non-Hodgkin's lymphomas (B-NHL) in children. We analyzed the effect of surgical variables of initial laparotomy and second-look surgery on event-free survival (EFS) of 177 patients with abdominal B-NHL enrolled into the three consecutive multicenter trials NHL-BFM 81, NHL-BFM 83, and NHL-BFM 86. The therapy regimen was comparable in all 3 trials as well as the overall outcome of the patients. Patients with stage II and complete resection received 3 courses of therapy (4 in trial NHL-BFM 81), patients with stage II not resected, stage III, and stage IV received 6 courses of therapy (8 in trial NHL-BFM 81). An initial laparotomy was performed in 161 patients, in 59 of them as an urgent procedure. Complete resection of the abdominal primary was performed in 43 patients, 40 of them had a localized bowel tumor. The probability of EFS (pEFS) at 5 years is 95%, 69%, 62%, and 67% for patients with complete resection, subtotal resection (n = 36), partial resection (n = 21), or biopsy only (n = 61), respectively. Complete resection was achieved in 30 out of 40 patients with stage II, but only in 12 of 113 and 1 of 24 patients with stage III and IV, respectively. pEFS at 5 years according to stage and completeness of resection is as follows: stage II complete resected 97%; stage II not complete resected 100%; stage III/IV complete resected 92%; stage III/IV not complete resected 63%.(ABSTRACT TRUNCATED AT 250 WORDS)

Progress in developing animal models for biliary atresia.

Animal models for extrahepatic biliary atresia (EHBA) have failed to simulate the course of the disease. Until now only a few aspects of the entity could be investigated and no model was helpful in discovering the etiology of EHBA. Following the suspicion of a viral and hepatotropic infection, investigations in an infectious mouse model were continued. The results of previous and topical studies are summarized here. Infection of newborn Balb/c-mice with rhesus rotavirus (RRV) leads to cholestasis in 85% of the animals followed by a lethality of 90%. Preparation and histomorphological investigation of liver and ligamentum duodenale reveal EHBA of varying extent. Clinical course and morphological findings in mice are very similar to EHBA in newborn children and the results are presented in a chronological table. Hepatobiliary morbidity and lethality after RRV infection is higher in Balb/c-mice than in other mouse strains. This observation supports the suspicion that immunocompetence might be a determining factor in the etiology of EHBA. Initial therapeutic trials were made using this model by treating infected newborn mice with interferon-alpha (IFN). The prophylactic application of IFN protects the infected mice from cholestatic symptoms and appears to induce partial immunity. Their descendants are protected against the hepatotropic effect of RRV infection. Infected animals presenting with clinical signs of cholestasis can be treated successfully by IFN-therapy for one week. In the presented animal model. EHBA can be better induced and simulated than by any other method. As a first trial, a non-surgical and more etiologically orientated therapeutic method is tested in this model.