Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).

Hirschsprung disease (HSCR) and Waardenburg sundrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells. The WS-HSCR association (Shah-Waardenburg syndrome) is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype, the EDN3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDN3 gene in a WS-HSCR patient. EDN3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.

Pancreatic resections for solid or cystic pancreatic masses in children.

OBJECTIVES: The aim of the study was to assess the diagnosis and management of solid pancreatic neoplasm in children and the type of surgical treatment, focusing on short- and long-term outcomes. METHODS: We retrospectively reviewed the charts of all children who had undergone pancreatic resection for suspicion of pancreatic tumor in Kremlin Bicêtre Hospital, Paris, between 1986 and 2008. We studied the symptoms at diagnosis, the type of surgery, and the short- and long-term morbidity and mortality. RESULTS: Of 18 patients identified, there were 7 pseudopapillary tumors, 3 neuroblastomas, 2 rhabdomyosarcomas, 1 acinar cell carcinoma, 1 endocrine cell carcinoma, 1 renal angiomyolipoma, and 3 pancreatic cysts. Symptoms at diagnosis were abdominal trauma, abdominal mass, and jaundice. Operative procedures were duodenopancreatectomy (11), mid-pancreatic resections (2), splenopancreatectomy (2), distal pancreatectomy (1), and tumorectomy (2). There were no deaths related to surgery. The postoperative morbidity rate was 45%, including 2 cases of fistula (11%) occurring after a mid-pancreatic resection and a pancreaticoduodenectomy. The median follow-up was 4.2 years (range 2-11). There was no diabetes mellitus, but there was 1 case of fat diet intolerance requiring pancreatic enzyme substitution. All of the children had a growth curve within normal limits. CONCLUSIONS: In this experience, pancreatic resections have proven to be a safe and efficient procedure, with low long-term morbidity, for the treatment of tumoral and selected nontumoral pancreatic masses.

Use of an intravaginal spacer in young girls treated with brachytherapy for bladder neck rhabdomyosarcoma: Dosimetric impact for organs at risk sparing and acute tolerance.

PURPOSE: Interstitial brachytherapy is indicated as part of a conservative strategy for children with bladder and/or prostate rhabdomyosarcoma (RMS), providing high local control probability with acceptable functional results. Vaginal and/or rectal complications were however reported, due to the close proximity to the implanted volume. We investigated the dosimetric impact of a vaginal spacer in terms of rectal and vaginal doses. METHODS AND PATIENTS: Medical records of 12 consecutive female patients with bladder neck RMS, median age 32 months (range: 1.3-6 years), were reviewed. Five patients were treated prior to 2017 without a vaginal spacer and seven patients treated after 2017 had their brachytherapy delivered with a vaginal spacer placed at time of implant. RESULTS: Minimal doses delivered to the most exposed 2cm3, 1cm3, and 0.5cm3 of the rectum were all statistically significantly lower among patients treated with a vaginal spacer, as compared to those treated without a spacer. Median rectal D2cm3 was 22GyEQD2 versus 38GyEQD2 (P=0.02), D1cm3 was 29GyEQD2 versus 51GyEQD2 (P=0.013), and D0.5cm3 was 32GyEQD2 versus 61GyEQD2 (P=0.017), with and without the vaginal spacer, respectively. The posterior vaginal wall D0.5cm3 dose was also significantly decreased, with median D0.5cm3 of 92GyEQD2 versus 54GyEQD2 (P<0.0001), with and without the spacer, respectively. Acute tolerance was excellent in all patients, with no need for replanning and no acute complication. CONCLUSIONS: The use of vaginal spacers in brachytherapy of female pediatric patients with bladder neck RMS resulted in significantly decreased doses to the rectum and the posterior vaginal wall. Though the clinical impact of such dose reduction remains undemonstrated, routine utilization of a vaginal spacer could be a method to decrease long-term morbidity in these patients.

In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study.

In-transit metastases (ITM) are defined as metastatic lymph nodes or deposits occurring between the primary tumor and proximal draining lymph node basin. In extremity rhabdomyosarcoma (RMS), they have rarely been reported. This study evaluates the frequency, staging and survival of patients with ITM in distal extremity RMS. METHODS: Patients with extremity RMS distal to the elbow or knee, enrolled in the EpSSG RMS 2005 trial between 2005 and 2016 were eligible for this study. RESULTS: One hundred and nine distal extremity RMS patients, with a median age of 6.2 years (range 0-21 years) were included. Thirty seven of 109 (34%) had lymph node metastases at diagnosis, 19 of them (51%) had ITM, especially in lower extremity RMS. 18F-FDG-PET/CT detected involved lymph nodes in 47% of patients. In patients not undergoing 18F-FDG-PET/CT lymph node involvement was detected in 22%. The 5-yr EFS of patients with ITM vs proximal lymph nodes vs combined proximal and ITM was 88.9% vs 21.4% vs 20%, respectively (p = 0.01) and 5-yr OS was 100% vs 25.2% vs 15%, respectively (p = 0.003). CONCLUSION: Our study showed that in-transit metastases constituted more than 50% of all lymph node metastases in distal extremity RMS. 18F-FDG-PET/CT improved nodal staging by detecting more regional and in-transit metastases. Popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of in-transit metastases. Biopsy of these nodes is recommended especially in distal extremity RMS of the lower limb. Patients with proximal (axillary or inguinal) lymph node involvement have a worse prognosis.

Idiopathic gingival fibromatosis: description of two cases.

Gingival fibromatosis is an enlargement localized or generalized of the gingival tissue characterized by an expansion and accumulation of the connective tissue, predominantly type I collagen, with occasional presence of increased number of cells, supposed fibroblastic proliferation. Gingival fibromatosis can be induced as a side effect of systemic drugs, such as phenytoin, cyclosporin, and nifedipine, or due to hereditary factors. However, in some cases, the gingival overgrowth is idiopathic. This paper reports two cases of idiopathic gingival fibromatosis and discusses the diagnosis, histopathological features, treatment and immunohistochemical evaluation of myofibroblasts of this condition. The tissues removed were fixed in formalin, and sections used for hematoxylin and eosin and Masson tricromic stain. To determine the presence of myofibroblasts, we performed immunohistochemistry against a-SMA protein. Histological examination revealed epithelial hyperplasia with long rete pegs and increase in the dense fibrous connective tissue. The Masson tricromic stain revealed wide bundles of collagen strongly stained. It was showed negative labeling to a-SMA. These results strongly suggest that myofibroblasts are not involved in gingival overgrowth in the cases of IGF reported. Future studies will be necessary to determine the pathogenesis of idiopathic gingival fibromatosis.

[Management of antenatal fetal abdominal tumors. Clues for the diagnosis of a congenital mesoblastic nephroma]. / Conduite à tenir obstétricopédiatrique devant la découverte anténatale d'une masse hyperéchogène rétropéritonéale. Arguments en faveur d'un néphrome mésoblastique congénital.

The prenatal diagnosis of abdominal mass poses the problem of its origin. Renal tumors are rarer than neuroblastoma but they are most often congenital mesoblastic nephroma. The congenital mesoblastic nephroma has a good forecast in spite of a sonographic impressive aspect. MRI can help to locate tumor but cannot tell difference between the different kinds of renal tumor. Prenatal forecast is especially linked with hydramnios and hydrops fetalis. Histolological study of the tumor is important for the prognosis. Two morphological subtypes are currently distinguished: the classic type with a good forecast and the atypical or cellular type. Distant metastases have been related only to the cellular form but especially in infants aged more than 3 months and never in the newborns. The diagnosis of the tumor does not change the mode of delivery except in case of an important volume. Complications are searched during the first days of life: hypertension, hypercalcemia, vomiting, hyperreninemia. Radical nephrectomy is performed after the end of the first week. In case of a classic form, the healing is always obtained. In case of cellular form, distant metastases are searched. In any rate, the follow-up is recommended until the end of the growth.

Fracture resistance of structurally compromised root filled bovine teeth restored with accessory glass fibre posts.

AIM: To evaluate the mechanical behaviour of structurally compromised root filled bovine roots after restoration with accessory glass fibre posts. METHODOLOGY: Fifty roots of bovine teeth received conventional post preparations with a cervical diameter of 3.5 mm. The roots were assigned to five groups (n = 10): group MP - cast metal post, group GP - glass fibre post and group AGP - glass fibre post plus accessory glass fibre posts. In groups GP-R and AGP-R (similar to groups GP and AGP), 2 mm of coronal tooth structure were left intact. All groups were subjected to an elastic limit assay and tested in an universal machine for fracture resistance. Repeated measures anova were performed to examine differences in fracture resistance; fracture modes were analysed by Fischer's exact test. RESULTS: The mean fracture resistance values (kgf) were 61.8 (MP), 63.1 (GP), 55.5 (AGP), 56 (GP-R) and (53.1) AGP-R. No statistically significant difference was found between groups. The Fisher's exact test indicated significant differences (P < 0.05) in the fracture mode amongst groups MP, GP and AGP, indicating 100%, 50% and 10% of catastrophic fractures, respectively. CONCLUSIONS: The use of accessory glass fibre posts affected the fracture mode favorably: 90% of fractures in group AGP were in the coronal third.

[Swallowing magnets: a dangerous game. A case report]. / Avaler des aimants : un jeu dangereux. A propos d'une observation.

Complications related to the ingestion of magnetic foreign bodies by children represents an affirmed health hazard in the United States. In France, an alert has been announced. We report the 1st case in France. Our aim is to alert pediatricians and emergency physicians and to draw attention to the particularities of this type of foreign body. Responsible for complications is the ingestion of at least 2 magnets, or 1 magnet and a metallic foreign body, with a time interval between ingestions. In these cases, it is strongly recommended to extract the foreign bodies with endoscopy if they have not yet passed the pylorus. For those further advanced in the intestinal tract, continuous observation is warranted and surgical extraction is indicated on apparition of 1st clinical symptoms.

Multinodular neurilemmoma of the tongue: a case report with differential immunohistochemical profile.

Neurilemmoma is a distinctive, encapsulated, benign tumor, derived from Schwann cells. It is the most common neurogenic tumor, eventually occurring in the mouth, particularly the tongue. It occurs most often during the second or third decades of life, with predilection in females. Clinically, neurilemmomas present as a solitary circumscribed nodule, rarely being multinodular. We report a case of a 46 year-old female who presented a multinodular neurilemmoma of the tongue. She had a sessile nodule with two months of evolution. The presumptive diagnosis was of a benign mesenchymal neoplasm and an excisional biopsy was performed. During the excision it was found that the lesion was formed by two well-delimitated firm yellowish-white nodules. Histopathologic evaluation revealed an encapsulated benign tissue, formed by spindle cells forming irregular Antoni A and Antoni B patterns, not easily recognizable. Immunostaining was strongly positive for S-100 protein and negative for neurofilament. The lesion was excised and after 12 months of follow-up there was no recurrence.

Preservation of future fertility in pediatric patients with cancer.

The cure rate for childhood and adolescent patients with cancer has currently reached almost 80% and protecting future fertility and thereby promoting quality of life have become a major challenge in the care of these patients (Bioethics Law, 2004). Age, sex and associated treatments influence the risk of future subfertility. Certain chemotherapies (particularly alkylating agents) and radiotherapy fields that include the gonads or hypothalamopituitary axis may negatively impact the future fertility of patients. Evaluation of the gonadotoxic potential of therapeutic measures and the utilization of appropriate methods to preserve fertility require the combined efforts of a multidisciplinary team that includes pediatric oncologists, radiotherapists, surgeons, reproductive physicians and biologists and psychologists. Techniques for fertility preservation vary depending on the age of the child and range from surgical transposition of the gonads for pelvic radiotherapy to cryopreservation of the ovary or testicle in case of sterilizing chemotherapy. While scientists still do not yet fully understand the maturation of immature germ cells, these children will be seeking the assistance of Medically Assisted Procreation (MAP) in 20-30 years. In the meanwhile, it is to be hoped that many more advances will be achieved in the utilization of harvested germinal tissue.

Is alpha-fetoprotein decline a prognostic factor of childhood non-seminomatous germ cell tumours? Results of the French TGM95 study.

PURPOSE: In adults' non-seminomatous germ cell tumours (NS-GCT), alpha-fetoprotein (AFP) decline was identified as an important prognostic factor. We investigated its prognostic value in the French TGM95 study for childhood NS-GCT. PATIENTS AND METHODS: Three risk groups were defined: low risk (LR: localised and completely resected pS1, AFP<15000 ng/ml), with a 'wait-and-see' strategy; intermediate-risk (IR: localised incompletely resected, AFP<15000 ng/ml) with 3-5 vinblastine-bleomycine-cisplatin courses; high risk (HiR: AFP≥15000 ng/ml and/or metastatic) with 4-6 etoposide-ifosfamide-cisplatin courses. The multivariable prognostic analysis for progression-free survival (PFS) included age (±10 years), primary tumour site (1-testis, 2-ovary, 3-extragonadal), extent of disease (1-pS1, 2-loco-regional dissemination, 3-metastasis) and AFP (±10,000 ng/ml). AFP decline prognostic value was investigated in IR + HiR groups using predicted time to normalisation (TTN), AFP change, and difference between observed and expected (based on AFP half-life) area under the curve (O-E AUC). RESULTS: From January 1995 to December 2005, 239 patients (median age = 3years, 60 LR, 65 IR, 114 HiR) were included. Main sites were testis (n = 66), ovary (n = 77) and sacrococcygeal (n = 57). Five-year PFS and OS were 85% (95% confidence interval [CI] = 80-89%) and 93% (89-95%), respectively. Age ≥ 10 years (hazard ratio [HR] = 4.6, 95% CI = 2.1-10.1, p = 0.0001) and extragonadal primary (HR = 6.3, 95% CI = 2.0-19.9, p = 0.005) were significant prognostic factors. In AFP decline analysis (n = 151, 17 events), TTN (p = 0.61) and AFP change (p = 0.10) were not prognostic, whereas we showed a significant effect of O-E AUC (HR = 2.1, 95% CI = 1.0-4.2, p = 0.05). CONCLUSION: Age ≥ 10 years and extragonadal tumours remain as poor prognostic factors. Contrary to adults, TTN is not reliable in paediatric NS-GCT. The prognostic value of O-E AUC should be investigated in larger studies.

Abdominal desmoplastic small round cell tumor without extraperitoneal metastases: Is there a benefit for HIPEC after macroscopically complete cytoreductive surgery?

BACKGROUND: Desmoplastic Small Round Cell Tumor (DSRCT) is a rare disease affecting predominantly children and young adults and for which the benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) after complete cytoreductive surgery (CCRS) remains unknown. METHODS: To identify patients with DSRCT without extraperitoneal metastases (EPM) who underwent CCRS between 1991 and 2015, a retrospective nation-wide survey was conducted by crossing the prospective and retrospective databases of the French Network for Rare Peritoneal Malignancies, French Reference Network in Sarcoma Pathology, French Sarcoma Clinical Network and French Pediatric Cancer Society. RESULTS: Among the 107 patients with DSRCT, 48 had no EPM and underwent CCRS. The median peritoneal cancer index (PCI) was 9 (range: 2-27). Among these 48 patients, 38 (79%) had pre- and/or postoperative chemotherapy and 23 (48%) postoperative whole abdominopelvic radiotherapy (WAP-RT). Intraperitoneal chemotherapy was administered to 11 patients (23%): two received early postoperative intraperitoneal chemotherapy (EPIC) and nine HIPEC. After a median follow-up of 30 months, the median overall survival (OS) of the entire cohort was 42 months. The 2-y and 5-y OS were 72% and 19%. The 2-y and 5-y disease-free survival (DFS) were 30% and 12%. WAP-RT was the only variable associated with longer peritoneal recurrence-free survival and DFS after CCRS. The influence of HIPEC/EPIC on OS and DFS was not statistically conclusive. CONCLUSION: The benefit of HIPEC is still unknown and should be evaluated in a prospective trial. The value of postoperative WAP-RT seems to be confirmed.

Conservative treatment for girls with nonmetastatic rhabdomyosarcoma of the genital tract: A report from the Study Committee of the International Society of Pediatric Oncology.

PURPOSE: To report the results of a conservative multimodal approach in girls with nonmetastatic rhabdomyosarcoma (RMS) of the genital tract, treated in International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors 84 and 89 protocols. PATIENTS AND METHODS: From 1984 to 1994, 38 girls with RMS of the genital tract (vulva, vagina, uterus) were treated in SIOP protocols. With the exception of patients with rare small tumors, which were resected at the start of the studies, all patients received initial chemotherapy (CHT) (ifosfamide, vincristine, and actinomycin D). Local treatment including surgery, brachytherapy (BT), and external-beam radiotherapy (ERT) was given only to girls who did not achieve complete remission (CR) with CHT or who subsequently relapsed. RESULTS: The primary tumor originated in the vulva or vagina in 27 girls and in the uterus in 11. The overall survival rate (+/- SE) was 91% +/- 6% at 5 years, and the event-free survival rate was 78% +/- 7%. At a median follow-up of 5 years, 30 girls were alive and in first CR and five were alive and in second CR. Four patients treated with complete resection of the tumor at diagnosis received less CHT. Thirteen patients were treated with CHT alone. In 17 patients, local treatment was necessary to achieve complete local control, for a residual mass after initial CHT (10 patients), for viable tumor on biopsy (three patients), or for local relapse (four patients). The local treatment used was radiotherapy (RT) (ERT in three patients, BT in seven), radical surgery with uterine ablation (three patients), RT and radical surgery (three patients), and conservative surgery with RT (one patient). CONCLUSION: Girls with nonmetastatic RMS of the genital tract have an excellent prognosis. We found no difference in outcome between uterine and vulvovaginal RMS. Local treatment does not seem necessary in patients who have a complete response to CHT. When a local treatment is needed, BT may be an alternative to radical surgery or ERT.

[Ovarian tissue cryopreservation for prepubertal girls: indications and feasibility]. / Cryoconservation de cortex ovarien chez la fille prépubère: indications et faisabilité.

OBJECTIVE: Survival improvement of children, adolescents and young women with cancer has led to consider with more cautiousness the long time iatrogenic side effects of treatments. Among those, premature ovarian failure has been described even for children. The aim of the study was to evaluate the indications and the feasibility of ovarian tissue cryopreservation for prepubertal girls. PATIENTS AND METHODS: From September 2000 to December 2004, 47 prepubertal girls were referred by oncologists for ovarian tissue cryopreservation. After informed consent, the ovarian tissue was collected and frozen by a slow cooling protocol until the temperature of liquid nitrogen. A histological analysis and a follicular account were performed. RESULTS: The harvest of ovarian tissue was performed for 45 patients. No surgical side effect occurred. The younger girls had a follicular density higher than the older. No metastatic ovarian tumour was found. DISCUSSION AND CONCLUSIONS: Numerous arguments as the follicular density in the ovary, the age of the patient, no surgical side effect, no metastatic ovarian tumour and recent progress in term of birth after ovarian tissue autografting allowed to think it is very important and ethical to propose an ovarian tissue cryopreservation even for children before sterilising treatment.

Ovarian tumors in children and adolescents: a series of 41 cases.

OBJECTIVE: Pictorial review with a detailed semiological analysis of ovarian tumors in children and adolescents to provide a relevant diagnostic approach. PATIENTS AND METHODS: Retrospective study (2001-2011) of 41 patients under the age of 15 who underwent surgery for an ovarian mass with a definite pathological diagnosis. RESULTS: Sixty-two percent of the lesions were benign, 33% were malignant and 5% were borderline. Germ cell tumors were most frequent (77.5%), followed by sex cord stromal tumors (12.5%) and epithelial tumors (7.5%). Malignant tumors were more frequent in children between 0 and 2 years old. On imaging, calcifications and fat were specific for germ cell tumors; the presence of a mural nodule was predictive of a mature teratoma (P<0.001). Predictive factors for malignancy were clinical, including abdominal distension (P<0.01) or a palpable mass (P=0.05), biological, including increased hCG and/or AFP levels (P<0.001) and radiological, including tumors larger than 12 cm (P<0.05), tumoral hypervascularity (P<0.01) and voluminous ascites (P<0.01). CONCLUSION: This semiological analysis confirms the role of imaging in diagnosing the etiology of ovarian lesions in children and adolescents and emphasizes the importance identifying tumoral hypervascularity, which, in addition to classic criteria, is highly predictive of malignancy.

Does aggressive local treatment have an impact on survival in children with metastatic rhabdomyosarcoma?

PURPOSE: Due to the extensive initial distant tumour spread in metastatic rhabdomyosarcoma, the importance of local treatment is sometimes underestimated. A retrospective study was conducted to identify the prognostic value of aggressive local treatment in paediatric metastatic rhabdomyosarcoma. PATIENTS: Patients with metastatic rhabdomyosarcoma aged 1-21 years treated in France from 1998 to 2011 according to European protocols MMT-4-89, 4-91, 98 and recent national guidelines were selected. Survival comparison were performed between patients with 'aggressive local treatment' (surgery and radiotherapy) and exclusive surgery or radiotherapy, after exclusion of patients with early progression. End-points were event-free and overall survival (OS). RESULTS: A total of 101 children, median age 9 years, with majority of primaries in unfavourable sites (73 patients, pts), T2 tumours (66 pts), alveolar subtypes (65 pts) and large tumours (>5 cm, 83 pts) received various chemotherapy regimens. On univariate and multivariate analyses, OS was better after 'aggressive local treatment' (49 pts; 44.3 ± 8%), than after exclusive surgery (10 pts; 18.8% ± 15.5%) or exclusive radiotherapy (29 pts; 16.1 ± 7.2%, P < 0.006). Moreover, OS was better in the case of surgery with complete resection (41.1 ± 10.2%) or microscopic residue (56.4 ± 14.9%) than macroscopic residue (20.0 ± 12.6%; P < 0.03). CONCLUSIONS: In this large retrospective analysis, OS appeared to be better for patients receiving 'aggressive local treatment' even after adjustment for the initial patient and tumour characteristics. Isolated debulking surgery is associated with a very poor outcome and should be avoided. Aggressive local treatment in patients with rhabdomyosarcoma, even with metastasis, should be seriously considered.

Treatment of non-metastatic rhabdomyosarcomas in childhood and adolescence. Results of the second study of the International Society of Paediatric Oncology: MMT84.

The second International Society of Paediatric Oncology (SIOP) study for rhabdomyosarcoma (MMT84) had several goals. The two principal aims were: (1) to improve the survival of children with rhabdomyosarcoma; and (2) to reduce the late effects from therapy by restricting the indications for surgery and/or radiotherapy after good response to initial chemotherapy. A further aim was to investigate the role of high-dose chemotherapy in young patients with parameningeal primary tumours. 186 previously untreated eligible patients entered the study. Patients with completely resected primary tumour received three courses of IVA (ifosfamide, vincristine and actinomycin D). Patients with incompletely resected tumour received six to 10 courses of IVA according to stage. Patients achieving complete remission with chemotherapy alone did not usually receive radiotherapy or undergo extensive surgery, but patients remaining in partial remission received local therapy with surgery and/or radiotherapy. Only patients over 5 years of age with parameningeal disease and patients over 12 years with tumours at any site were given systematic irradiation. Complete remission was achieved in 91% (170/186) of all patients. With a median follow-up of 8 years, the 5-year overall survival was 68% (+/- 3% standard error of the mean (SEM) and the 5-year event-free survival 53% (+/- 4% SEM). These results show an improvement over previous SIOP study (RMS75) in which survival was 52% and event-free survival was 47%. Among the 54 patients who exhibited isolated local relapse, 35% (19/54) survived in further remission longer than 2 years after retreatment, including local therapy (surgery +/- radiotherapy). Analysis of the overall burden of therapy received by all surviving children (including primary treatment and treatment for relapse if required) showed that 24% (28/116) were treated by limited surgery followed by three courses of IVA, 29% (34/116) were treated by chemotherapy alone (after initial biopsy) and 13% (15/116) received chemotherapy plus conservative local treatment (limited surgery or radiotherapy for residual disease). Only 34% (39/116) received intensive local therapy defined as radical wide field radiotherapy or radical surgery or both. Compared with the results obtained in the previous SIOP study, treatment in MMT84 was based on response to initial chemotherapy and, despite an overall reduction of the use of local therapy, significantly improved survival for patients with non-metastatic disease. This trial, also for the first time, provides evidence that retreatment after local relapse can achieve long-term second remissions.

Intraoperative localization of neuroblastoma in children with 123I- or 125I-radiolabeled metaiodobenzylguanidine.

BACKGROUND: This study describes a novel method of intraoperative localization of neuroblastoma with a gamma-detecting probe, to detect in situ tumor binding of radiolabeled 123I- or 125I-metaiodobenzylguanidine (MIBG) and improve the quality of tumor resection. METHODS: Fifty-eight children underwent 66 surgical procedures with intraoperative detection of radiolabeled MIBG. All patients with positive MIBG scintiscans at diagnosis were included in the study. A tumor/background ratio exceeding 2:1 at the time of operation was considered positive, indicating a significant uptake of MIBG, compatible with the presence of malignant cells. The surgeons were requested to evaluate the contribution of the method to the surgical procedure. Sensitivity and specificity of the method with either 123I-labeled MIBG or 125I-labeled MIBG, on the basis of correlations between probe findings and pathologic analysis of 288 resected specimens, were determined. RESULTS: Intraoperative detection was helpful in 65% of surgical procedures, allowing a better definition of tumor limits and extension to locoregional nodes or detection of small and nonpalpable tumors in sites with difficult surgical access, especially during operation for relapse. The detection was not contributory in 35% of the procedures (well-localized tumors, thoracic neuroblastoma for technical reasons, highly differentiated tumors as ganglioneuroma, and tumors with mainly necrosis or fibrosis). The sensitivity of 123I and 125I was the same (91% and 92%), but the specificity of 125I (85%) was significantly higher than that of 123I (55%) (p < 0.005). CONCLUSIONS: First, this study demonstrates the feasibility of intraoperative detection, with radiolabeled MIBG, of neuroblastoma in children. We advocate the use of 125I rather than 123I. Second, the method is useful to improve the quality of macroscopic resection in widespread neuroblastoma with nodal involvement, in sites with difficult access, and in operations for relapse.

Comparison between vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide levels in neuroblastoma tumour tissues.

Vasoactive intestinal polypeptide (VIP) is reported to exert an autocrine control on neuroblastoma cell tumours: VIP is produced by the tumour and stimulates cell differentiation. This study tested the hypothesis that the parent peptide; the pituitary adenylate cyclase activating polypeptide (PACAP) may have a similar role. It was found that PACAP mRNA and PACAP were expressed in 12/12 tumours; it was also observed that PACAP receptor mRNA and functional PACAP receptors were expressed in 12/12 and 5/9 tumours, respectively. VIP mRNA and VIP were detected in 9/12 tumours. VIP receptor mRNA was expressed in 5/12 tumours and functional VIP receptors were never demonstrated. The tumours having the highest VIP levels also had the highest PACAP contents and were associated with a watery diarrhoea syndrome due to activation of intestinal VIP receptors. As PACAP recognizes the PACAP receptors and the VIP receptors with the same high affinity it may contribute to the syndrome and is a likely candidate for an autocrine control of neuroblastoma cell growth and differentiation.

Total colonic aganglionosis (with or without ileal involvement): a review of 27 cases.

From 1960 to 1984, 27 cases of total colonic aganglionosis were treated at the Sick Children's Hospital in Paris; in 19 cases there was ileal involvement, 16 of them extending more than 15 cm above the ileocecal valve. Five had a family history of Hirschsprung's disease. Nine infants died without having had definitive surgery, because of delayed diagnosis, or intractable malabsorption in extensive ileal aganglionosis. Two cases were diagnosed only at the ages of 6 and 13 years. Eleven children had Martin's modification of the Duhamel operation, the oldest of these being now 13 years old; and one girl aged 13 underwent a Swenson operation with ileoanal anastomosis, and one child has had a Kimura procedure. Four infants still have a diverting ileostomy. One out of the 14 operated children died 3 years after operation with fulminating enterocolitis. Late surgical nutritional results are analyzed with regard to the length of the side-to-side ileocolorectal anastomosis, and to the size of the ileorectal anastomosis, on which adequate pouch emptying depends. The essential problem in total colonic aganglionosis is not the surgical management of the condition, but rather its prompt diagnosis and the handling of the neonatal intestinal obstruction.