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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.

Resume La maladie de Hirschsprung est la plus frequente des etiologies d’occlusion intestinale chez l’enfant. Cette maladie est caracterisee par l’absence de cellules ganglionnaires dans la sous-muqueuse et dans les plexus myenteriques du tube digestif a sa partie distale. A cote de la forme classique rectosigmoidienne (80 % des cas) sont decrites une forme colique totale (10 %), une forme etendue (1 %) et une forme courte rectale (9 %). Cette anomalie se traduit par une dilatation au-dessus de la zone pathologique. Actuellement, les formes sporadiques comme les formes familiales font l’objet d’etudes genetiques, avec la decouverte de trois regions chromosomiques connues pour etre liees a la maladie de Hirschsprung. L’expression clinique de cette maladie debute a la naissance avec un syndrome occlusif ou plus tardivement par une constipation opiniâtre du nourrisson. La complication principale est l’enterocolite aigue qui en fait toute la gravite et peut imposer une derivation intestinale en urgence. Le diagnostic de la maladie est a la fois clinique, radiologique et surtout anatomopathologique. En effet, c’est la biopsie rectale qui affirme le diagnostic en mettant en evidence l’association d’absence de cellules ganglionnaires et l’hypertrophie des filets nerveux. La prise en charge des enfants atteints de maladie de Hirschsprung a considerablement evolue ces dernieres annees, la chirurgie en un temps, sans colostomie initiale, devient a la fois le traitement de choix de la maladie de Hirschsprung rectosigmoidienne, mais aussi de plus en plus souvent de la maladie de Hirschsprung totale.

La enfermedad de Hirschsprung es la causa mas frecuente de oclusion intestinal infantil. Esta enfermedad se caracteriza por la ausencia de celulas ganglionares en la submucosa y en los plexos mientericos de la porcion distal del tubo digestivo. Ademas de la forma clasica rectosigmoidea (80% de los casos) se han descrito una forma colica total (10%), una forma extensa (1%) y una variante rectal corta (9%). Esta anomalia se traduce por una dilatacion proximal respecto a la zona patologica. En la actualidad se estan realizando estudios geneticos tanto en las formas esporadicas como en las de tipo familiar, y se han descubierto tres regiones cromosomicas relacionadas con la enfermedad de Hirschsprung. La expresion clinica de esta afeccion se inicia tras el nacimiento, con un sindrome oclusivo, o bien de forma mas tardia como un estrenimiento pertinaz del lactante. La complicacion principal es la enterocolitis aguda, de la que deriva toda la gravedad del trastorno, y que puede obligar a realizar una derivacion intestinal urgente. El diagnostico de la enfermedad es a la vez clinico, radiologico y, sobre todo, anatomopatologico. La biopsia rectal es la tecnica que confirma el diagnostico al demostrar la asociacion de ausencia de celulas ganglionares y la hipertrofia de los filetes nerviosos. El tratamiento de los ninos con enfermedad de Hirschsprung ha evolucionado de forma considerable en los ultimos anos. La cirugia en una sola intervencion, sin colostomia inicial, se ha convertido en el tratamiento de eleccion tanto de la enfermedad de Hirschsprung rectosigmoidea como (cada vez con mas frecuencia) de su forma total.

Resume La maladie de Hirschsprung est la plus frequente des etiologies d’occlusion intestinale chez l’enfant. Cette maladie est caracterisee par l’absence de cellules ganglionnaires dans la sous-muqueuse et dans les plexus myenteriques du tube digestif a sa partie distale. A cote de la forme classique rectosigmoidienne (80 % des cas) sont decrites une forme colique totale (10 %), une forme etendue (1 %) et une forme courte rectale (9 %). Cette anomalie se traduit par une dilatation au-dessus de la zone pathologique. Actuellement, les formes sporadiques comme les formes familiales font l’objet d’etudes genetiques, avec la decouverte de trois regions chromosomiques connues pour etre liees a la maladie de Hirschsprung. L’expression clinique de cette maladie debute a la naissance avec un syndrome occlusif ou plus tardivement par une constipation opiniâtre du nourrisson. La complication principale est l’enterocolite aigue qui en fait toute la gravite et peut imposer une derivation intestinale en urgence. Le diagnostic de la maladie est a la fois clinique, radiologique et surtout anatomopathologique. En effet, c’est la biopsie rectale qui affirme le diagnostic en mettant en evidence l’association d’absence de cellules ganglionnaires et l’hypertrophie des filets nerveux. La prise en charge des enfants atteints de maladie de Hirschsprung a considerablement evolue ces dernieres annees, la chirurgie en un temps, sans colostomie initiale, devient a la fois le traitement de choix de la maladie de Hirschsprung rectosigmoidienne, mais aussi de plus en plus souvent de la maladie de Hirschsprung totale.

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.

Resumen La enfermedad de Hirschsprung es la causa mas frecuente de oclusion intestinal en el nino y se caracteriza por la ausencia de celulas ganglionares mientericas en la parte distal del tubo digestivo. Ademas de la forma rectosigmoidea (el 80 % de los casos) se distinguen las siguientes formas: colica total (10 %), extendida (1 %) y rectal corta (9 %). Esta anomalia se manifiesta por una dilatacion del colon sano por encima de la zona patologica. Los antecedentes se remontan al momento del nacimiento a causa de un retraso en la evacuacion de meconio, oclusion neonatal o estrenimiento pertinaz del lactante. La principal complicacion en el periodo neonatal es la enterocolitis aguda. Esta ultima puede ser mortal y es responsable de la gravedad del cuadro, pudiendo requerir la realizacion de una derivacion intestinal de urgencia. El diagnostico es clinico, radiologico y sobre todo anatomopatologico. El diagnostico se confirma mediante biopsia rectal y examen histologico convencional con tinciones especificas, que pone de manifiesto la ausencia de celulas ganglionares en la submucosa y la capa muscular rectal y la hipertrofia de filetes nerviosos que puede alcanzar las vellosidades. El tratamiento de la enfermedad de Hirschsprung en el nino ha progresado considerablemente en los ultimos anos. Aunque las tecnicas descritas por Swenson, Duhamel, Soave y Boley no han perdido actualidad, cada vez se practica mas la cirugia en un solo tiempo, que se lleva a cabo en el primer mes de vida sin necesidad de efectuar una derivacion inicial de descarga. La tecnica laparoscopica y la via transanal se han convertido en el tratamiento de eleccion de la forma clasica rectosigmoidea.

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.

Cytokines play a role in alopecia areata. We used immunohistochemical and in situ hybridization studies to demonstrate the persistence of pro-inflammatory as well as apoptotic mechanisms in skin biopsies from patients with chronic alopecia areata. In situ hybridization allows the visualization of the distribution of immunocompetent cells in vivo. We studied skin biopsies from 11 untreated alopecia areata patients and two normal controls. In situ hybridization was performed on frozen sections using 35S-radio-labeled riboprobes, specific for IL-1beta, IL-2, IL-6, INFgamma, and granzyme B mRNA. Immunohistochemistry was carried out using an anti-IL-1beta monoclonal antibody, and a monoclonal antibody directed against the human Fas protein. We demonstrated the presence of cells labeled with IL-1beta, IL-6, INFgamma, and granzyme B antisense probes. Similarly, cells labeled with anti-IL-1beta were found in 10 of 11 cases. The labeled cells were located in the mononuclear peri- and intrafollicular infiltrate. Cells expressing granzyme B were found in close contact with the follicle. Fas positivity was demonstrated in four of four cases at the level of the cytoplasmic membrane of the hair follicle keratinocytes. These results, based on visualizing the labeled cells, demonstrate that pro-inflammatory cytokines are produced by the mononuclear cell infiltrate in close contact with follicles in alopecia areata. Furthermore, they demonstrate for the first time that apoptotic mechanisms involving granzyme B and Fas-Fas ligand pathways may play a major role in the persistence of chronic alopecia areata.

The role of vitamin D in ameloblasts and odontoblasts has been studied experimentally in rodents. Dental dysplasias have also been reported in clinical studies of children with rickets. Vitamin D acts via a nuclear receptor which binds the major metabolite, 1,25-dihydroxyvitamin D3, and positively or negatively controls the expression of specific genes. The most extensively studied markers of 1,25-dihydroxyvitamin D3 action are calbindin-D9k, calbindin-D28k, and osteocalcin. Therefore, to study in more detail the potential role of 1,25-dihydroxyvitamin D3 in human dental development, 1,25-dihydroxyvitamin D3 receptor (VDR) was localized by immunofluorescence in forming teeth (8-26 wk of gestation). Calbindin-D28k was also mapped by immunoperoxidase in antenatal and postnatal forming and formed teeth. VDR were detected in both dental epithelium and mesenchyme of bud, cap, and bell stages of tooth germs. Nuclei of overtly differentiated ameloblasts and odontoblasts were also immunostained. Calbindin-D28k was present in differentiated ameloblasts and odontoblasts. The presence of VDR and calbindin-D28k in ameloblasts and odontoblasts suggests that 1,25-dihydroxyvitamin D3 may contribute to the regulation of enamel and dentin formation, as classically reported for bone formation. Finally, the early appearance of VDR supports the concept that 1,25-dihydroxyvitamin D3 may also control forward stages of tooth crown development in humans.

Dominant megacolon (Dom) is one of four mutations in the mouse that can produce a phenotype similar to Hirschsprung disease in human. The Dom gene product is not known, and no candidate region has been defined for a possible human homolog. In this publication we report mapping the Dom locus with high definition, using several intra- and interspecific crosses and a set of 16 Chr 15-specific microsatellites flanking this locus.

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.

The number, distribution, and phenotype of mononuclear cells infiltrating the allograft lung transplant were determined immunohistochemically with monoclonal antibodies directed against cellular antigens (CD3, CD4, CD8, CD22, CD25, CD16, CD56, CD68, HLA-DR) on frozen sections of transbronchial biopsies. Seventy-two transbronchial biopsies from 21 patients undergoing lung or heart-lung transplantation were evaluated histologically and immunohistologically in a prospective study. Four major results were obtained in the graft lung parenchyma: (1) whatever the histological grading of rejection, T lymphocytes expressing CD3 were present and in a significantly higher number than in control subjects (P < 0.0005); (2) there was a positive correlation between histological rejection and the number of CD3+, CD8+, CD25+, CD16+ cells (P < 0.01); (3) the CD4/CD8 ratio was inverted (0.52 +/- 0.04), with no correlation with the histological rejection; and (4) the number and location of CD3+, CD25+ cells did not correlate with CMV identification in bronchoalveolar lavage. Immunohistochemical criteria could be used for diagnosis of rejection in the management of heart-lung transplantation.

The prognostic significance of phenotype in malignant lymphomas (ML) is a matter of controversy. Here we analyze the clinical presentation, response to treatment, and survival of the 361 phenotyped patients with ML who were treated by the LNH-84 regimen. Histologic subtypes were diffuse-small cell in 10 patients, diffuse mixed in 69, diffuse large-cell in 177, immunoblastic in 94, and anaplastic large-cell in 11. One hundred and eight patients (30%) had a peripheral T-cell ML and 253 (70%) a B-cell ML. Most of B-cell MLs were of diffuse large-cell type, and the T-cell MLs were distributed among diffuse mixed and immunoblastic subtypes. T-cell MLs had an aggressive presentation with more patients having advanced stage (21% versus 41% stage II, 53% versus 45% stage IV, p = .0002), and B symptoms (58% versus 42%, p less than .01). The only significant difference in clinical manifestations were the higher frequency of gastrointestinal involvement in B-cell MLs (20% versus 2%, p less than .0001) and the more frequent spleen (39% versus 21%, p = .0005) and skin (19% versus 3%, p less than .0001) involvement in T-cell MLs. There was no difference in response to the LNH-84 regiment between the two subgroups, but T-cell ML patients relapsed at a higher rate (43% versus 29%, p less than .001). T-cell ML patients have a significantly shorter freedom-from-relapse (FFR) survival (median: 34 months versus not reached, logrank test: p = .002) and a non-significant shorter overall survival (median: 42 versus 50 months).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Comparative investigations of odontogenic cells in normally forming teeth and tumors may provide insights into the mechanisms of the differentiation process. The present study is devoted to late phenotypic markers of ameloblast and odontoblast cells, i.e., proteins involved in biomineralization. The in situ expression of amelogenins, keratins, collagens type III and IV, vimentin, fibronectin, osteonectin, and osteocalcin was performed on normal and tumor odontogenic human cells. The pattern of protein expression showed some similarities between ameloblasts and odontoblasts present in normally developing human teeth and cells present in neoplastic tissues of ameloblastic fibroma, ameloblastic fibro-odontomas, and complex odontomas. Amelogenins (for ameloblasts) and osteocalcin (for odontoblasts) were detected in cells with well-organized enamel and dentin, respectively. In contrast, "mixed" cells located in epithelial zones of mixed odontogenic tumors co-expressed amelogenins and osteocalcin, as shown by immunostaining. The presence of osteocalcin transcripts was also demonstrated by in situ hybridization in these cells. Keratins and vimentin were detected in the same epithelial zones. Tumor epithelial cells were associated with various amounts of polymorphic matrix (amelogenin- and osteocalcin-immunoreactive), depending on the types of mixed tumors. No osteocalcin labeling was found in epithelial tumors. This study confirms that the differentiation of normal and tumor odontogenic cells is accompanied by the expression of some common molecules. Furthermore, the gene products present in normal mesenchymal cells were also shown in odontogenic tumor epithelium. These data may be related to a tumor-specific overexpression of the corresponding genes transcribed at an undetectable level during normal development and/or to an epithelial-mesenchymal transition proposed to occur during normal root formation. A plausible explanation for the results is that the odontogenic tumor epithelial cells are recapitulating genetic programs expressed during normal odontogenesis, but the tumor cells demonstrate abnormal expression patterns for these genes.

Review of a series of 90 renal transplantations performed in 86 children revealed 3 cases of early or late mortality and 28 cases of major surgical complications, predominantly vascular (13 cases) and urological complications (12 cases). The time to onset, the diagnosis and the management of these complications are reviewed. This study again emphasizes the importance of graft selection (donor age) and the value of living related donor renal transplantation.

Cytotoxic T lymphocytes (CTL) are potent effector cells that could provide long term antitumor immunity if induced by appropriate vaccines. CTL recognize 8-14 amino acid-long peptides processed intracellularly and presented by MHC class I molecules. A well-characterized example of a potential tumor antigen in childhood pre-B Acute Lymphoblastic Leukemia (ALL) results from the chromosomal translocation 12;21 leading to the fusion of the ETV6 and AML1 genes. This translocation is observed in > 25% of ALL-patients. In this study, we have examined whether the chimeric ETV6-AML1 protein could serve as a tumor specific antigen for CTL in HLA-A2.1 individuals. We have identified a nonapeptide (RIAECILGM), encoded by the fusion region of the ETV6-AML1 protein, that binds to HLA-A2.1 molecules and induces specific primary CTL in peripheral blood lymphocytes from healthy donors. These CTL specifically lysed HLA-A2.1 tumor cells endogeneously expressing the ETV6-AML fusion protein. CTL with similar functional capacities were found with high frequencies and cloned from one patient's bone marrow indicating that ETV6-AML1-specific anti-ALL CTL are, at least in some patients, spontaneously stimulated and might participate to host antileukemia defense.

It has previously been demonstrated that the overproduction of interleukin-6 (IL-6) is a key element in the clinical and biological abnormalities encountered in Castleman's disease (CD). The particular case of a male child with a localized form of CD is reported. In this patient, evidence was found of a correlation between systemic manifestations and circulating IL-6, and IL-6 gene overexpression in the germinal centers of hyperplastic lymph nodes. Circulating IL-6 levels were 10- to 100-fold higher than in all CD cases previously documented. This unique biological feature was closely associated with high levels of circulating IL-1 and tumor necrosis factor-alpha (TNF-alpha), which are known for their ability to induce and/or amplify IL-6 production. One month after surgical removal of the pathological lymph node, the clinical and biological abnormalities diminished, while circulating IL-6 levels dropped dramatically eight months later. It is worth noting that after resection, the time-course of the IL-6 decrease closely correlated with that of IL-1 and TNF-alpha. Considering that in various inflammatory diseases IL-1, TNF-alpha and IL-6 may act in a synergistic manner in inducing systemic manifestations, this case report raises new questions as to the nature of the systemic pathogenicity of cytokines in CD.

AIMS: To describe ticlopidine related microscopic colitis and to assess the occurrence of apoptosis in the colon epithelium. METHODS: A series of colorectal biopsy samples from nine patients with ticlopidine related chronic diarrhoea were analysed. Biopsies were also taken from five of these patients between two and four months after ticlopidine withdrawal. The number of apoptotic cells in the crypts/mm2 (apoptotic index) was calculated using in situ labelling by terminal deoxyribonucleotidyl transferase (TdT) mediated dUTP-biotin nick end labelling (TUNEL). All specimens were matched to normal colorectal specimens from a control group of comparable age and sex distribution. RESULTS: Histological examination of the colon biopsy specimens taken from all nine patients with ticlopidine related chronic diarrhoea showed characteristic features of microscopic colitis. The histology returned to normal when ticlopidine was withdrawn. Apoptotic cells were rarely found in controls, and the mean apoptotic index was 0.53. The apoptotic index was significantly higher (16.53) in ticlopidine related colitis, but decreased dramatically to control value when ticlopidine was withdrawn. CONCLUSION: Microscopic colitis can be induced by ticlopidine and is accompanied by an increase in epithelial apoptosis. Hence, increased apoptosis might be related to drug injury or might be part of microscopic colitis.

One hundred and five appendices removed at the time of surgical reduction of intussusception in children were studied by light microscopy after routine procedures to search for aetiological factors involved in intussusception. Normal pediatric appendix specimens served as controls (n = 30). Light microscopic examination showed viral inclusions in epithelial cells in 48 of 105 appendices (45%) from the cases of intussusception. No viral inclusion was observed in controls. Immunohistochemistry performed on 21 appendices from intussusception with a monoclonal antibody against adenovirus showed intranuclear positivity in all appendices with viral inclusions. Viral inclusions seen in epithelial cells of appendices from cases of intussusception are caused by virus and in particularly by adenovirus. The etiological factors involved in intussusception without viral inclusion in appendix remain unknown.

We report one case of Solitary infantile Myofibromatosis of Bone in a 14-year old girl. Radiologic features of the tibial lesion were consistent with the diagnosis of a benign bone tumor. The final diagnosis was made on a total resection of the tumor. Histologically, the tumor consisted of nodules, hyalinized or cellular, with spindle-shaped cells resembling fibroblasts or smooth-muscle cells. There were numerous vascular spaces in close contact with these nodules. The tumor cells were immunoreactive with anti-alpha-smooth muscle actin antibodies. These data were consistent with the diagnosis of Myofibromatosis. The histologic features were similar to those of Infantile Myofibromatosis of other sites such as skin and soft tissue. The case reported is rare and not yet published, due to the age and sex of the patient, and the location of the tumor.

An atypical case of a first branchial cleft presenting with a cutaneous fistula and an epidermoid cyst of the external auditory canal is reported. The relevant embryology of the branchial apparatus is summarized, and variations of first branchial anomalies are discussed. The relationship with a congenital cholesteatoma is discussed.

Interferon alfa and cytotoxic drugs have synergistic effects in patients with non-Hodgkin's lymphoma. In 1986, we designed a clinical trial to evaluate the benefit of concomitant administration of recombinant interferon alfa with a regimen containing doxorubicin in patients with follicular non-Hodgkin's lymphoma.The trial involved 242 patients with advanced low-grade follicular non-Hodgkin's lymphoma selected on the basis of clinical, radiographic, and biologic criteria. All patients were treated with a regimen consisting of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP), given monthly for six cycles and then every two months for one year. After randomization, 123 patients also received interferon alfa-2b at a dosage of 5 million units three times weekly for 18 months. The remaining 119 patients received chemotherapy alone.As compared with the patients treated with CHVP only, the patients treated with CHVP plus interferon alfa had a higher overall rate of response (85 percent vs. 69 percent, P = 0.006), a longer median event-free survival (34 months vs. 19 months, P0.001), and a higher rate of survival at 3 years (86 percent vs. 69 percent, P = 0.02). Granulocyte toxicity was greater in the patients treated with CHVP plus interferon alfa than in those treated with CHVP alone. There were no treatment-related deaths. Interferon alfa had to be stopped because of toxic effects (fatigue and hepatitis) in 13 patients (11 percent).The addition of interferon alfa to a regimen containing doxorubicin increased the rate of response, event-free survival, and overall survival in patients with advanced follicular non-Hodgkin's lymphoma, without serious toxicity, although some patients were unable to tolerate the side effects.

Granulocyte/macrophage-colony stimulating factor (GM-CSF) induces in vitro activation of Langerhans' cells. The association of GM-CSF and tumour necrosis factor alpha (TNF alpha) induces the differentiation of Langerhans' cells from CD34 positive haematopoietic progenitors. Intradermal administration of recombinant GM-CSF is associated with local accumulation of Langerhans' cells. We investigated the presence of GM-CSF in tissue samples of 10 patients with Langerhans' cell histiocytosis. Four patients had skin involvement, three had bone and three had diffuse disease. Eight normal skin samples were analysed as controls. Immunohistochemistry was performed on frozen tissue samples with two specific monoclonal antibodies directed against two different epitopes of GM-CSF. We detected GM-CSF in all the histiocytosis tissue samples. The GM-CSF was detected within the cytoplasm of all the tumoral Langerhans' cells. We did not find GM-CSF in any other cell type. These results suggest that GM-CSF may be implicated in the pathogenesis of Langerhans' cell histiocytosis.

Both cytokines produced by activated monocytes and T cells and direct cell-to-cell contact with antigen-primed T cells during inflammatory reactions are known to induce the expression of several adhesion proteins on endothelial cells. In this prospective longitudinal study, we analyzed the expression of ELAM-1, VCAM-1, and ICAM-1 on myocardial allograft biopsy specimens taken from 16 cardiac allograft recipients either for routine monitoring or for the investigation of suspected rejection. Infiltrating T cells were identified using anti-CD3 antibodies. Three to six sequential biopsies taken at one-week intervals were analyzed by means of conventional histology and immunohistochemistry. Seven patients did not develop rejection during the study; their biopsies were negative for VCAM-1 and ELAM-1, although faint ICAM-1 staining was present on capillaries, reflecting constitutive expression. Three patients entered the study with clear-cut clinical and histologic signs of acute rejection. Intense VCAM-1 and ICAM-1 expression was detected on capillary and postcapillary venules, together with a heavy CD3+ T cell infiltrate; VCAM-1 was also expressed on arteriolar endothelial cells. ELAM-1 was undetectable in all three cases. Six patients developed acute rejection during the course of the study. In four, ELAM-1 and VCAM-1 were expressed on both capillary and postcapillary venules one or two weeks before the histological diagnosis of rejection (heavy CD3+ cell infiltrate). Importantly, ELAM-1 expression was short-lived and had disappeared by the time CD3+ cellular infiltrate was detected, thus extending in vivo the finding that ELAM-1 expression is usually transient in vitro. Only VCAM-1 expression was observed in the other two patients, one week prior to the histological diagnosis of rejection. These results suggest that ELAM-1 and VCAM-1 might represent early predictive markers of acute cardiac allograft rejection. ELAM-1 expression is, however, usually transient, necessitating frequent testing.

A ten year nine month-old girl was admitted to hospital for a painful inflammatory tumour of the right popliteal area. There was a calcification on X-ray and computerised angiography showed a tumour. MRI showed a heterogenous irregular mass. This looked like a malignant tumour. At surgical biopsy: it was a circonscripta myositis ossificans. This benign tumour of soft tissues, rare in children (25 cases in the literature), had a spontaneous favourable evolution. Differential diagnosis with malignant tumour is well known, but is still difficult. Biopsy is necessary in doubtful cases. We had to remove the mass because of acute pain.

Twenty-four malignant mesenchymal tumour specimens were analysed for human multidrug resistance (MDRI) gene transcript levels using Northern and slot blot techniques. The presence of P-glycoprotein was assessed in 12 of the 24 samples by immunohistochemistry using the monoclonal antibody (MAb) C219. Increased MDRI transcript levels were found in 2 (8.3%), while, using immunohistochemistry, 2 samples were positive and 3 faintly positive (41.6%). Overall, elevated P-glycoprotein or MDRI transcript levels were found in tumours of 6 patients, 3 of whom are dead. The relationship to MDRI expression and subsequent resistance to chemotherapy has to be established.

Expression of bcl-2 protein was analyzed in 140 cases of follicular lymphoma by immunohistologic staining of paraffin-embedded tissue; 85% of cases were positive, the frequency being related to histologic grade (100% for the small-cleaved cell type, 86% for the mixed cell type, and 76% for the large cell group). There was striking heterogeneity of bcl-2 content in a number of cases and the smaller neoplastic cells (i.e., centrocytes) were usually the most strongly labeled. In most cases, bcl-2 protein staining was much weaker in normal lymphoid cells than in the neoplastic cells. In several cases, staining for bcl-2 revealed patterns of neoplastic cell spread into adjacent tissue (e.g., normal follicles, lymphoid sinuses), and bcl-2 protein expression tended to be highest in these migratory cells.

We recently demonstrated that IL-2 is produced by reactive T cells in CD25-positive malignant lymphomas (ML). Using in situ hybridization, we investigated IL-6 mRNA expression in these CD25-positive ML. The ML tested included 9 anaplastic large cell lymphomas and 3 B-diffuse large cell lymphomas. Five CD25-negative ML were studied as controls. We show that IL-6 producing cells are present in all these ML. The density of positive cells was heterogeneous from case to case. However 3 cases of CD25-positive ML showed a dramatically higher density of IL-6 producing cells (70, 50, 43 producing cells per 10,000 cells, respectively) as compared to the other 9 cases of CD25-positive ML (mean 6.03 +/- 2.1 per 10,000). Morphological and topographical data suggested that several types of cells including fibroblasts, lymphocytes, macrophages and endothelial cells may synthesize IL-6. A combination of immunohistochemistry and in situ hybridization showed that reactive T cells and endothelial cells express the IL-6 gene whereas CD30-positive ML cells do not express this gene. Previous studies showed that IL-6 was capable to induce IL-2 receptor expression as well as production of IL-2 and stimulation of lymphomatous cells growth. Our present results indicate that the paracrine production of this cytokine may play a role in the proliferation of malignant lymphomas.

Cytokine gene expression could be studied by both immunohistochemistry and in situ hybridization. These techniques allowed us to demonstrate the role of IL-6 and IL-2 in the pathophysiology of Castelman's disease and CD25 positive malignant lymphomas, respectively.

Three pediatric cases of parotid carcinoma are reported two are acinic cell carcinoma of relatively good prognosis. The third case is a cystic variety of salivary duct carcinoma, more exceptional, which prognosis remains uncertain. A review of the parotid tumors of this age range is done.

Expression of the IL-2 receptor (Tac antigen/CD25) is documented in malignant lymphomas. Because IL-2 is a major lymphocyte growth factor, an IL-2-dependent growth could be involved in the proliferation of Tac-positive lymphomas. Indeed such a mechanism has been demonstrated experimentally for the growth of T-cell lines. To investigate this point in human lymphomas, we used in situ hybridization to analyze the expression of the IL-2 gene in 20 non-Hodgkin's lymphomas, among which 12 expressed the IL-2 receptor. Nine of these were anaplastic large cell lymphomas expressing the Ki-1-related antigen. We here show that IL-2-producing cells are present in all the lymphomas we analyzed. As a mean, there is no significant difference in the percentage of IL-2-producing cells between Tac-positive and -negative lymphomas. However, the level of IL-2 production is highly heterogeneous in both groups, and the highest density of IL-2-producing cells was observed in 2 Tac-positive lymphomas. Simultaneous detection of cellular antigens and of IL-2 mRNA demonstrates that IL-2 is produced by reactive T cells rather than by tumor cells. These results suggest that if IL-2 is involved in the growth of Tac-positive lymphomas, it acts as a paracrine, rather than an autocrine, factor.

The authors report the results of a chemotherapy regimen of methyl-GAG, etoposide and prednimustine in 21 elderly patients (median age = 78 years) with aggressive non-Hodgkin's lymphoma. Sixteen patients responded (11 complete remissions, 5 partial remissions) with minor toxic side-effects. This regimen could be proposed for patients whose age and/or cardiovascular status prohibit treatment with usual anthracycline-containing chemotherapy programs.

The prognostic significance of phenotype in malignant lymphomas (ML) is a matter of controversy. Here we analyze the clinical presentation, response to treatment, and survival of the 361 phenotyped patients with ML who were treated by the LNH-84 regimen. Histologic subtypes were diffuse-small cell in 10 patients, diffuse mixed in 69, diffuse large-cell in 177, immunoblastic in 94, and anaplastic large-cell in 11. One hundred and eight patients (30%) had a peripheral T-cell ML and 253 (70%) a B-cell ML. Most of B-cell MLs were of diffuse large-cell type, and the T-cell MLs were distributed among diffuse mixed and immunoblastic subtypes. T-cell MLs had an aggressive presentation with more patients having advanced stage (21% versus 41% stage II, 53% versus 45% stage IV, p = .0002), and B symptoms (58% versus 42%, p less than .01). The only significant difference in clinical manifestations were the higher frequency of gastrointestinal involvement in B-cell MLs (20% versus 2%, p less than .0001) and the more frequent spleen (39% versus 21%, p = .0005) and skin (19% versus 3%, p less than .0001) involvement in T-cell MLs. There was no difference in response to the LNH-84 regiment between the two subgroups, but T-cell ML patients relapsed at a higher rate (43% versus 29%, p less than .001). T-cell ML patients have a significantly shorter freedom-from-relapse (FFR) survival (median: 34 months versus not reached, logrank test: p = .002) and a non-significant shorter overall survival (median: 42 versus 50 months).(ABSTRACT TRUNCATED AT 250 WORDS)

AFTER the successful results of experimental studies using cyclosporine A (CsA) in animals, we started small bowel transplantation (SBTx) in pediatric patients 10 years ago. During the period from 1987 to 1990, nine isolated SBTx have been performed in seven children aged 5 months to 9 years with short bowel syndrome. CsA was used as the main immunosuppressive agent associated with methylprednisolone and antilymphoglobulines. Two graft underwent early failure (1 death); five grafts were removed within 2 months after transplantation for uncontrolled acute graft rejection. One patient died after 6 months from sepsis and multiorgan failure. Two additional grafts were removed 6 and 17 months after transplantation for chronic rejection. Finally, only the youngest recipient having received a small bowel graft from ananencephalic neonate remains with a functioning graft 9 years later. She is enjoying normal life at home, free of TPN, growing normally. She is the longest isolated small bowel survival worldwide. Her current immunosuppression includes low doses of steroids and Neoral. Of the four patients who have survived after graft removal, three died within 2 years with end-stage liver cirrhosis. The last one is currently on long-term home parenteral nutrition (PN) waiting for isolated small bowel retransplantation.