Treatment of children over the age of one year with unresectable localised neuroblastoma without MYCN amplification: results of the SIOPEN study.

BACKGROUND: In children older than 1 year with localised unresectable neuroblastoma (NB), treatment strategies are heterogeneous according to the national groups. The objective of this phase III non-randomised study was to evaluate the efficacy of conventional chemotherapy followed by surgery. PATIENTS AND METHODS: In the presence of surgical risk factors (SRF), six courses of chemotherapy alternating Carboplatin-Etoposide and Vincristin-Cyclophosphamide-Doxorubicin were given, and surgical resection was attempted after four. Survival analyses were performed using an intention-to-treat approach. The main objective was to achieve a 5-year survival over 80%. RESULTS: Out of 191 registered children, 160 were evaluable. There were 62.5% older than 18 months and 52.5% had unfavourable histology according to International Neuroblastoma Pathology Classification (INPC). Chemotherapy reduced the number of SRFs by one third. Delayed surgery was attempted in 86.3% of patients and was complete or nearly complete in 74%. The 5-year EFS and OS were 76.4% and 87.6% respectively, with significant better results for patients younger than 18 months or with favourable histology. CONCLUSION: This strategy provides encouraging results in children older than 1 year or 12 months with localised unresectable NB without MYCN amplification. However, in children older than 18 months and with unfavourable histology, additional treatment is recommended.

[Epidemiology and management of rare paediatric tumours within the framework of the French Society for Children Cancer]. / Tumeurs rares en pédiatrie : particularités épidémiologiques et organisation de leur prise en charge dans le cadre de la Société française des cancers et des leucémies de l'enfant et de l'adolescent (SFCE).

Less than 1% of cancer occurs in children. With the progress made by national and international cooperative groups 75% of them are actually cured. However some entities have an incidence so weak that we can't actually establish standardized therapeutics guidelines. To improve our knowledge on these rare tumours a national organisation become necessary as well as an international collaboration. A French rare tumour committee was created within the French Society for Children Cancer (SFCE). Others European countries have such organisation. The objectives of these tasks groups are to enhance our knowledge of the real incidence of these rare tumours, their evolution, and to propose therapeutic recommendations for each of them. This article focuses on the specific French organization for rare tumours treatment. It also describes the draft for the creation of a new data base for prospective registry of clinical, therapeutics and follow up data. To provide a better understanding of these pathologies, the "Bulletin du Cancer's" editorial board decided to regularly publish an update on a rare paediatric tumour in a specific section.

Sialoblastoma of salivary glands in children: chemotherapy should be discussed as an alternative to mutilating surgery.

Sialoblastoma is a very rare congenital salivary gland tumor. No consensus has been reached concerning the treatment of this tumor due to its rarity. The treatment of reference is surgery, which can be mutilating, in the case of a locally invasive tumor. The treatment of metastatic disease is also controversial. The authors report a new case of a 6-year-old girl with a progressively growing left parotid mass since birth. The first cytological diagnosis was that of pleomorphic adenoma. Due to local progression, superficial parotidectomy was performed at the age of 3.5 years and revealed a diagnosis of sialoblastoma. Six months later, local recurrence and lung metastasis were treated by neoadjuvant chemotherapy with a very good partial response on the local recurrence and the lung metastasis, allowing complete parotidectomy with sacrifice of the facial nerve. Bilateral lung biopsies after adjuvant chemotherapy showed total necrosis. No recurrence was observed with a follow-up of 1 year. This case and a review of the literature confirm the very good chemosensitivity of this tumor and argue in favor of neoadjuvant chemotherapy for locally invasive tumors rather than extensive mutilating surgery.

Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B.

CONTEXT: Early prophylactic thyroidectomy in patients with multiple endocrine neoplasia (MEN) type 2 offers the best chance for a normal life expectancy. OBJECTIVE: To analyze the results of thyroidectomy performed during the first year of life in six patients with MEN 2A (codon 634) or MEN 2B (codon 918) syndrome. DESIGN AND SETTING: A university hospital-based prospective study from 2001 to 2008. SUBJECTS AND METHODS: Six family members affected either by MEN 2A (n=3) or MEN 2B (n=3) syndrome were identified through neonatal genetic screening. RESULTS: Total thyroidectomy was performed at a median age of 0.8 year in the six patients, with central lymph node dissection in five. Bilateral millimetric medullary thyroid carcinoma (MTC) was found in all patients, with a unilateral lymph node micrometastasis in two of the three MEN 2B patients. Before thyroidectomy, MEN 2B patients had much higher basal serum calcitonin levels than those with MEN 2A and controls. After thyroidectomy, with a median follow-up of 3.3 years, the six patients had no evidence of persistent MTC. CONCLUSION: Bilateral millimetric MTC may be present during the first year of life in these patients, with lymph node metastases also occurring in MEN 2B patients. These results support a total thyroidectomy at the age of about one year in MEN 2A (codon 634) children with an abnormal serum calcitonin level, and a total thyroidectomy with central neck dissection within the first weeks of life in MEN 2B patients.

In neuroblastic tumours, Schwann cells do not harbour the genetic alterations of neuroblasts but may nevertheless share the same clonal origin.

Neuroblastic tumours are composed of variable proportions of neuroblasts and Schwann cells. Whether both components share a common neoplastic origin is highly debated and discrepant results have been reported about the presence of tumour-related genetic alterations in Schwann cells. We have used X-methylation analysis and array-CGH to investigate contiguous Schwannian and neuroblastic areas in tumours with a nodular pattern. A skewed X inactivation was observed in four out of five stromal components. Interestingly, in these four cases, the X-inactivation profiles of the neuroblastic components were identical to the matched stromal areas. However, whereas all neuroblastic areas displayed chromosomal imbalances, no alteration was found in any Schwann cell components. Similarly, no alteration was observed in a series of 19 tumours with a single stroma-rich component, which occasionally exhibited a skewed X-inactivation pattern (3/17 informative tumours). Altogether, this indicates that most stroma-rich tumours display a polyclonal proliferation and that Schwann cells do not derive from neuroblasts. However, in tumours with both stroma-rich and -poor components, our results suggest that cells from both areas share a common progenitor.

Leukocytes and the kidney contribute to interstitial inflammation in lupus nephritis.

Interstitial leucocyte infiltration, a prominent feature of lupus nephritis, predicts deterioration of renal function. We used two models of lupus nephritis in mice, one with chronic spontaneous disease and the other with acute interferon-alpha (IFN alpha)-mediated disease. The latter is characterized by the virtual absence of interstitial infiltration. In vivo migration assays showed that splenic leukocytes from spontaneously nephritic mice tended to migrate into non-inflamed syngeneic kidneys. This was enhanced if the recipient kidneys were already inflamed. Kidneys from both chronically and acutely nephritic mice showed similar ability to recruit splenic leukocytes from chronically diseased mice. Leukocytes from acutely diseased mice, however, failed to migrate into chronically inflamed kidney. Compared with those with chronic nephritis, the kidneys of acute nephritic mice expressed less of the inflammatory chemokine CXCL13/BLC. Moreover, leukocytes from acute nephritic mice displayed impaired migration, in vitro, to T-cell chemokine attractants. This study links leukocyte infiltration to both kidney chemokine expression, and leukocyte chemotaxis to kidney-expressed chemokines.

A transient microenvironment loaded mainly with macrophages in the early developing human pancreas.

We have previously shown that the human developing pancreas, as a tissue under construction and remodeling, is composed of epithelial ducts and differentiated endocrine cells surrounded by mesenchyme. The physiologic importance of resident tissue leukocytes, expected to enter through the mesenchyme in remodeling functions, prompted us to investigate human developing pancreases for the presence of leukocyte lineages and for expression of cytokines and receptors involved in their recruitment and differentiation. Immunohistochemistry studies were performed on 69 human, paraffin-embedded pancreases at 6-12 weeks of development (WD). Cytokines and receptor transcripts were monitored by reverse transcription (RT)-PCR, by immunohistochemistry when antibodies were available or by in situ hybridization (ISH). We show that numerous cells expressing CD45RA, HLADR and CD68 antigens are cellular components of the mesenchyme of all the pancreases at 6-12 WD. So-called constitutive chemokines (SLC (CCL19), stromal-derived factor 1 (SDF1) (CXCL12)) and a macrophage-specific growth/survival factor, colony-stimulating factor 1 (CSF1), were detected in epithelial duct cells. Both epithelial and mesenchymal cells expressed chemokine receptors, suggesting a role in leukocyte recruitment and possibly in early pancreatic development. In conclusion, we demonstrated the presence of CD45RA resident leukocyte-derived lineages, mostly macrophages, in the early human pancreatic mesenchyme. These cells may have migrated in the tissue through the vascular system, attracted by constitutively expressed chemokines, and locally surviving through CSF1 signaling. The role of macrophages in epithelium/mesenchyme interaction-mediated pancreatic development remains to be demonstrated.

[Peripheral neuroblastic tumors: anatomo pathological classification]. / Les tumeurs neuroblastiques périphériques, classification anatomo-pathologique.

Peripheral Neuroblastic Tumors are classified according to the recommendations of the INPC into four categories and their subtypes: 1/Neuroblastoma stroma poor, undifferentiated, poorly differentiated, and differentiating, 2/ganglioneuroblastoma stroma composite, nodular, 3/ganglioneuroblastoma stroma composite, intermixed and 4/ganglioneuromas stroma dominant, maturing and mature. The classification is based on age and morphologic features of PNT, including the differentiation grade of the neuroblasts and the mitosis-karyorrhexis index. Histopathological classification has prognostic impact in predicting overall and event-free survival allowing the categorisation of PNT into two groups: favorable subset and unfavorable subset.

Cytokines, chemokine receptors, and homing molecule distribution in the rectum and stomach of pediatric patients with ulcerative colitis.

BACKGROUND: Cytokines appear to play a significant role in the pathogenesis of inflammatory bowel disease (IBD) with a predominant Th2 pattern in colonic mucosa of patients with ulcerative colitis (UC). Chemokines and their receptors also regulate the migration of Th1 or Th2 lymphocytes to inflammatory tissues during the immune response. Although adult UC is usually confined to the colon, pediatric UC not uncommonly affects the stomach. AIMS: The aim of this study was to compare expression of cytokines, chemokine receptors, and homing molecules in the rectal and the histologically characterized gastric mucosa of pediatric patients with UC. SUBJECTS Sixteen patients (11 girls and 5 boys; median age, 9 years) having all the features of UC were included in the study. METHODS: Rectal and gastric mucosa obtained from UC cases were immunostained with antibodies against L-selectin, beta 7 integrin, CXCR3, CCR3, and CCR5. IL-4 and IL-12 p40 transcript expression was studied by in situ hybridization. RESULTS: Chronic gastritis was found in 93.7% of cases and Helicobacter pylori (Hp) was found in 2 (13.3%) cases. In the rectal and gastric mucosa, CXCR3 was found in perivascular lymphocytes and CCR5 in a subset of CXCR3+ cells in the lamina propria. CCR3+ lymphocytes and IL-4-positive cells were always found, but there was no evidence of IL-12 production. Most of the lymphocytes infiltrating the gastric mucosa expressed beta 7 but not CD62L. In contrast, beta 7-positive cells were randomly dispersed in the rectal lamina propria, and the fraction of CD3+beta 7+ was low. CONCLUSIONS: The authors conclude that gastritis is common in pediatric UC. The presence of CCR3+ lymphocytes, IL-4 transcript expression, without IL-12 p40 production in the stomach and in the rectum suggests a Th2 immune response. The presence of CCR3+, CD62L- activated Th2 cells may suggest that these gastric cells are recruited from colorectal primary lesions.

Laparoscopic adrenal surgery for neuroblastomas in children.

PURPOSE: The role of laparoscopy in children with neuroblastomas has not been fully defined. The laparoscopic approach to the adrenal gland is already largely used in adults and a few cases have been reported in children. We report the experience of a single surgical team center with laparoscopic adrenal surgery for neuroblastomas in children. MATERIALS AND METHODS: Between September 2000 and October 2002 laparoscopic adrenalectomy for neuroblastoma was performed in 9 patients (6 girls and 3 boys) with a mean age of 38 months (range 2 months to 9 years). Two tumors were detected prenatally and 7 postnatally. Preoperative diagnosis was neuroblastoma stage I in 4 cases and stage IV in 3 cases, and nondetermined suprarenal calcified masses in 2 cases. A 4 or 5-trocar transperitoneal approach was used in all cases. The adrenal tumors were completely excised, placed into a plastic bag and removed through the umbilical trocar site. RESULTS: All of the adrenal tumors were well encapsulated and completely excised. One of the 9 procedures was converted to open surgery because of adhesions to renal vessels. In 1 case a second hepatic localization was removed simultaneously, and in 3 cases 1 or more lymph nodes were resected. Average operative time was 85 minutes (range 45 to 170). There were no deaths. There were no postoperative complications, except 1 port site infection that was treated locally. Blood transfusion was not required. Average hospital stay was 4.5 days (range 2 to 10). Histological analysis of the 9 specimens (maximum length 6 cm) confirmed the diagnosis of neuroblastoma. N-myc status was studied in 8 of the 9 resected neuroblastomas and was amplified in 2 cases (both stage IV with preoperative biopsy). Average postoperative followup was 15 months (range 1 to 25). There was no local recurrence or metastasis, except in the case that required conversion to open surgery (local recurrence 7 months later). CONCLUSIONS: Laparoscopic adrenalectomy for neuroblastoma is safe and feasible in children, with good results. Experience with advanced laparoscopic surgery is required to achieve this result in optimal oncological conditions. Our short-term results must be reevaluated at long term, and further studies are needed to compare laparoscopy to open surgical techniques.

Card15 gene overexpression in mononuclear and epithelial cells of the inflamed Crohn's disease colon.

BACKGROUND: Crohn's disease is one of the principal human chronic inflammatory bowel diseases. Although its aetiology is still unknown, its complex pathogenesis has environmental, immunological, and genetic determinants. CARD15 is the first susceptibility gene implicated in the predisposition to Crohn's disease and is known to be expressed only in monocytes. However, its expression in situ has not yet been studied. AIMS: To analyse the tissue distribution of CARD15 and identify cells producing CARD15 in samples of colon from patients with Crohn's disease and control subjects. PATIENTS AND METHODS: We analysed CARD15 gene expression in surgical specimens of colon from eight children with Crohn's disease and nine controls by immunohistochemistry, in situ hybridisation, and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: We showed that CARD15 was present only in the cytoplasm of macrophages in the normal colon. Increased CARD15 expression was detected in Crohn's disease lesions. There were more CARD15 positive cells in Crohn's disease lesions than in uninvolved areas. Both intestinal epithelial cells, macrophages, and their derivatives overproduced CARD15 in Crohn's disease. To further assess CARD15 expression by intestinal epithelial cells, we performed RT-PCR on freshly isolated intestinal epithelial cells, and showed that these cells isolated from Crohn's disease samples contained more CARD15 mRNA than intestinal epithelial cells from controls. CONCLUSIONS: We have demonstrated that colonic involvement in active Crohn's disease is associated with increased CARD15 gene expression in both macrophages and intestinal epithelial cells. Therefore, this deregulation can affect the host-environment interaction and thus contribute to the pathogenesis of this disease.

Esophageal ligature in experimental gastroschisis.

BACKGROUND/PURPOSE: Recently, the authors have shown that in human fetuses suffering from gastroschisis, there is an amniotic fluid inflammatory response and that amniotic fluid exchange designed to disrupt the inflammatory loop seems to have a favorable impact on outcome. The authors, therefore, designed in the fetal sheep a model of gastroschisis in which amnioinfusion significantly improved the deleterious process. They hypothesized that regurgitation and presence of digestive enzyme in the amniotic fluid triggers and maintains the process of inflammation. METHODS: To test this hypothesis, the authors used their model of gastroschisis in the fetal lamb combined with esophageal ligation and compared it with gastroschisis with or without amnioinfusion. RESULTS: Of 34 fetuses operated on at midgestation (days 70 through 80), 11 died in utero or were stillborn, 8 had gastroschisis and amnioinfusion, 8 had gastroschisis and no amnioinfusion, and 7 had gastroschisis and esophageal ligation. There were 9 control fetuses. Fetuses were killed at day 145 by cesarean section. Extraabdominal bowels with fibrous peel were processed for histologic examination. Thickness of bowel muscularis (micrometers) was 82.7 +/- 19 for controls, 159 +/- 56 for the nonamnioinfused fetuses, 126 +/- 21 for the amnioinfused fetuses (P =.001), and 240 +/- 225.8 for fetuses with esophageal ligature combined with gastroschisis. The same results were obtained for thickness of serous fibrosis and plasma cell infiltration. Assay of amniotic fluid ferritin, lipase, and protein showed that only amnioinfusion lowered ferritin and protein to levels similar to those of controls, thus, illustrating its preventive effect on inflammation and that esophageal ligature did not prevent digestive enzyme presence in the amniotic fluid. CONCLUSION: In this model of gastroschisis in the fetal sheep, ligature of the esophagus, which was supposed to protect the extruded bowel by preventing oral regurgitation of digestive enzymes and by creating a relative hydramnios, did not improve the inflammatory and deleterious process, which is best prevented by amnioinfusion.

The IGF system in neuroblastoma xenografts: focus on IGF-binding protein-6.

With a view to investigating the implication of IGF-binding protein-6 (IGFBP-6) in the growth of neuroblastomas, nude mice were injected with IGFBP-6-expressing or control IGR-N-91 human neuroblastoma cells and the resulting xenografts examined. Expression of IGFBP-3, IGFBP-4 and type 1 and type 2 IGF receptor messengers was similar in control tumours and equal-sized IGFBP-6-expressing tumours that had developed. IGF-II was more strongly expressed in control tumours, and IGFBP-6-expressing tumours contained less IGFBP-2 than controls. In both populations, there was a significant positive correlation between IGF-II and IGFBP-2 expression. In small IGFBP-6-expressing xenografts where tumour development had apparently been arrested, haematoxylin--eosin and TUNEL staining revealed numerous apoptotic cells. In situ hybridization indicated homogeneous distribution of the IGFBP-6 signal in test tumours. In cell culture, IGFBP-6-expressing cells expressed similar amounts of IGFBP-2, IGF-II and N-myc mRNAs as control cells; but media conditioned by IGFBP-6-expressing cells contained less intact IGFBP-2 protein, with no increase in its proteolytic fragment. In media treated with plasminogen, in which IGFBP-2 was proteolysed, IGFBP-6 was increased. With its especially strong affinity for IGF-II and its resistance to proteolysis, IGFBP-6 would act by sequestering IGF-II, hence inhibiting its mitogenic and anti-apoptotic effects. In excess, IGFBP-6 would displace IGF-II from IGFBP-2 whose potentiation of IGF-II action would cease and whose susceptibility to degradation would be increased. This study therefore shows that IGFBP-6 plays a role in neuroblastoma cell growth in vivo and in vitro and that stable overexpression of IGFBP-6 leads to alteration of the initial balance between the IGFBPs.

Investigation of osteocalcin, osteonectin, and dentin sialophosphoprotein in developing human teeth.

Biochemical investigations in rodents have shown that numerous mineralized matrix proteins share expression in bone, dentin, and cementum. Little information is available regarding the expression pattern of these proteins in human tissues, particularly during tooth formation. The aim of this study was to identify the expression pattern of the two major noncollagenous proteins of bone and dentin, osteocalcin (OC) and osteonectin (ON), in comparison to the dentin-specific protein, dentin sialophosphoprotein (DSPP). Mandibles from fetuses (5-26 weeks), neonate autopsies, forming teeth from 10-12-year-old patients, third molars extracted for orthodontic reasons, and bone tumors were collected with approval from the National Ethics Committee. Human OC, ON, and DSPP mRNAs were detected by reverse transcription-polymerase chain reaction (RT-PCR) in fetal mandibles (5-11 weeks) and in primary cell cultures of dental pulp. In addition, OC, ON, and DSPP proteins were localized in forming human mineralized tissues using immunohistochemistry. In vivo, DSPP expression was associated with tooth terminal epithelial-mesenchymal interaction events, amelogenesis and dentinogenesis. Transient DSPP expression was seen in the presecretory ameloblasts with continuous expression in the odontoblasts. In contrast, both osteoblasts and odontoblasts showed a temporal gap between OC and ON expression in early development. ON was expressed in the initial stages of cytodifferentiation, whereas OC was expressed only during the later stages, especially in the teeth. At the maturation stage of enamel formation, both proteins were detected in odontoblasts and their processes within the extracellular matrix. In contrast to bone, OC was not localized extracellularly within the collagen-rich dentin matrix (predentin or intertubular dentin), but was found in the mature enamel. ON was present mostly in the nonmineralized predentin. These results demonstrate for the first time that both OC and ON are produced by human odontoblasts and determine the expression pattern of DSPP in human teeth, and suggest that OC and ON move inside the canalicule via odontoblast cell processes becoming localized to specific extracellular compartments during dentin and enamel formation. These distinct extracellular patterns may be related to the nature of DSPP, OC, and ON interactions with other matrix-specific macromolecules (i.e., amelogenin, dentin matrix protein-1) and/or to the polarized organization of odontoblast secretion as compared with osteoblasts.

Chimaeric anti-CD20 monoclonal antibody (rituximab) in post-transplant B-lymphoproliferative disorder following stem cell transplantation in children.

Post-transplant lymphoproliferative disorder (PTLD) after haemopoietic stem cell transplantation is a serious complication that occurs in 8-22% of patients with high-risk factors. We retrospectively investigated tolerance and efficacy of humanized anti-CD20 monoclonal antibody (rituximab) as first-line treatment in 12 children with B-cell PTLD. At diagnosis, eight patients had tumoral involvement. The other four patients had fever, associated with raised Epstein-Barr virus (EBV) viral load and monoclonal gammopathy. Rituximab was given at the dose of 375 mg/m2 once a week by intravenous infusion (1-9 infusions). Only 1/48 infusions was associated with a grade 2 clinical adverse event. Eight out of 12 (66%) patients responded to the treatment and were in complete remission. All patients without tumoral involvement responded to the treatment. A rapid decrease in fever within 1 week was observed in all responders. Non-responders did not show any clinical response during the first week. Tumoral involvement and immunodepression seemed to be more marked in non-responders. Rituximab was an effective and well-tolerated treatment of B-cell PTLD. Early treatment before tumoral involvement seemed to be the most effective approach. Lack of rapid response should lead to intensification of PTLD treatment. Pre-emptive treatment should be considered and evaluated in further longitudinal multicentre studies.

Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene.

Autosomal dominant polycystic kidney disease (ADPKD) is common and is a major cause of renal failure. Although the genetics of ADPKD are well known and have led to the discovery of polycystins, a new protein family, the pathogenesis of the disease remains largely unknown. Recent studies have indicated that the beta-catenin signaling pathway is one of the targets of the transduction pathway controlled by the polycystins. We have generated transgenic mice that overproduce an oncogenic form of beta-catenin in the epithelial cells of the kidney. These mice developed severe polycystic lesions soon after birth that affected the glomeruli, proximal, distal tubules and collecting ducts. The phenotype of these mice mimicked the human ADPKD phenotype. Cyst formation was associated with an increase in cell proliferation and apoptosis. The cell proliferation and apoptotic indexes was increased 4-5-fold and 3-4-fold, respectively, in cystic tubules of the transgenic mice compared to that of littermate controls. Our findings provide experimental genetic evidence that activation of the Wnt/beta-catenin signaling pathway causes polycystic kidney disease and support the view that dysregulation of the Wnt/beta-catenin signaling is involved in its pathogenesis.

GDNF expression in Wilms tumor.

PURPOSE: Wilms tumor or nephroblastoma is a developmental tumor of the kidney and one of the most frequent solid tumors in childhood. It derives from metanephrotic blastema and mimics nephrogenesis in a disorganized manner, offering an adequate model for study of human nephrogenesis. GDNF (glial cell line derived neurotrophic factor), a potent proliferation and survival factor of dopaminergic neurons, has recently been shown to have an early and major role in nephrogenesis. We studied the expression of GDNF in Wilms tumor. MATERIALS AND METHODS: The study included 20 patients with nephroblastoma whose age at surgery ranged from 2 months to 13 years. Expression of GDNF protein was analyzed by an immunohistochemical technique using anti-GDNF antibody. Presence of GDNF-messenger (m)RNA and receptors GFRalpha1 and GFRalpha2-mRNA was analyzed by reverse transcription polymerase chain reaction. Specimens were also studied to evaluate apoptosis, proliferation index and Bcl-2 expression. RESULTS: GDNF expression was mainly found in the epithelial cells of the most differentiated tubes, GDNF and co-receptors mRNA were found in specimens and proliferative activity was found on the same tubes as GDNF expression. Bcl-2 was expressed strongly in epithelial cells, in an intermediate fashion in the blastema and faintly in mesenchyma. Apoptosis was of low frequency in structures strongly expressing GDNF. CONCLUSIONS: We have shown that GDNF is expressed by nephroblastoma tissue of human kidneys. This expression is mainly in the differentiated epithelial component of the nephroblastoma. We have also shown that tissue strongly expressing GDNF is positively proliferative and has less apoptotic activity. We speculate that the role of GDNF may not be limited to normal nephrogenesis but may interact with other factors in the process of proliferation and apoptosis involved in nephroblastoma tumorigenesis.

Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.

The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.