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Raf Sciot

Publications and source records attributed to Raf Sciot.

At least 55 records · Page 3Linked to original sources
PubMed2004

Molecular analysis of the INK4A/INK4A-ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression.

Loss of heterozygosity (LOH) at chromosomal band 9p21 is one of the few consistent genetic aberrations found in conventional chondrosarcoma. This locus harbours two cell-cycle regulators, CDKN2A/p16/INK4A and INK4A-p14ARF, which are inactivated in various human malignancies. It was therefore hypothesized that this locus also plays a role in the development of chondrosarcoma and this locus was investigated at protein, genetic, and epigenetic levels. Loss of p16 protein expression was detected by immunohistochemistry in 12 of 73 central chondrosarcomas and it correlated with increasing histological grade (p = 0.001). Loss of p16 protein expression was not found in 51 enchondromas, which are presumed to be potential precursors of conventional central chondrosarcoma. LOH at 9p21 was found in 15 of 39 chondrosarcomas (38%) but it did not correlate with loss of p16 protein expression. SSCP analysis of p16 did not reveal any mutations in 47 cases. Also, p14 was not the target of LOH, since it gave no aberrant bands on SSCP. To investigate whether an epigenetic mechanism was operating, methylation-specific PCR was used to look at p16 promotor methylation, which was identified in 5 of 30 tumours. However, this did not correlate with protein expression, or with LOH at 9p21. Cytogenetic data were available in a subset of cases. All tumours that showed chromosome 9 alterations also showed LOH and loss of INK4A/p16 protein expression. It is concluded that although some alterations were found at the DNA level and at the promoter expression level, the lack of correlation between LOH, promotor methylation, and protein expression indicates that a locus other than CDKN2A/p16 must be the target of LOH at 9p21. The correlation between INK4A/p16 protein expression and tumour grade, and the retention of expression in enchondromas, indicates that loss of INK4A/p16 protein expression may be an important event during tumour progression from enchondroma to conventional central chondrosarcoma, and in the progression in grade after recurrence of chondrosarcoma.

Adolescent↗
PubMed2004

Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity.

Gastrointestinal stromal tumours (GISTs) are currently defined as mesenchymal tumours of the gastrointestinal tract that express KIT receptor tyrosine kinase. However, a small subgroup of tumours that fulfil the clinical and morphological criteria for GISTs lack KIT expression. So far, the biological features of these tumours have rarely been addressed. The present study describes seven gastrointestinal stromal neoplasms that presented clinicopathological features typical of GISTs but showed absence of CD117 expression as detected by immunohistochemistry. The tumours originated from the stomach (n = 5), duodenum (n = 1), and colon (n = 1), showing histologically either predominantly epithelioid (n = 3), mixed spindled and epithelioid (n = 2), or anaplastic/spindle cell (n = 2) type features. CD34 and alpha-smooth muscle actin (alpha-SMA) positivity was present in four and three tumours, respectively. Chromosomal analysis was performed in two cases, both showing losses of chromosomes 14, 22, and 1p, which is the characteristic feature of GISTs. Dual-colour interphase fluorescence in situ hybridization (FISH) analysis, utilizing chromosome 1p-, 14-, and 22-specific probes, revealed a similar cytogenetic profile in the remaining five tumour specimens. Mutational analysis of exons 9, 11, 13, and 17 of KIT, and exons 12 and 18 of PDGFRA was performed in all cases by denaturing high-pressure liquid chromatography (DHPLC) pre-screening, followed by direct sequencing. None of the tumours showed KIT mutant isoforms. Three tumours harboured PDGFRA exon 18 activating mutations; two were Asp --> Val(842) missense substitutions and one was a DIM842-844 amino acid deletion. KIT and PKC theta (protein activated in interstitial cells of Cajal and GISTs) expression was determined by western immunoblotting of the total cell lysates from three tumour biopsies. None of these three tumours expressed KIT, while all specimens showed expression of PKC theta protein. These findings indicate that there is a subgroup of KIT-negative GISTs that exhibit the same morphological, cytogenetic, and molecular features as KIT-positive tumours. While intragenic PDGFRA activating mutations are present in some of these tumours, the oncogenic events underlying the pathogenesis of the others remain unknown.

Adult↗
PubMed2004

Pericardial synovial sarcoma: 14-year survival with multimodality therapy.

We report a case of recurrent primary synovial sarcoma of the pericardium. Reverse transcriptase-polymerase chain reaction analysis for t(X,18) demonstrated the presence of the chimeric transcript SYT/SSX. Because of the rarity of this entity, optimal therapy is unknown. The prognosis of this tumor is very poor in previous reports. In this report, we present a case with five recurrences treated by a combination of surgery, chemotherapy, and radiotherapy. The patient survives now for more than 14 years, the longest reported survival of a primary synovial sarcoma of the pericardium.

Adult↗
PubMed2004

Changing concepts in the pathological basis of soft tissue and bone sarcoma treatment.

Though soft tissue sarcomas are rare considerable progress has been made in the clinical and biological understanding of these neoplasms. This has led to the launch of a new WHO classification of soft tissue tumours in 2002, which integrate morphological data with tumour specific (cyto-) genetics. Moreover worldwide consensus has grown how to predict clinical behaviour based on a specific grading system and which specific types of tumours seem not to obey these rules. As a consequence entry criteria for multi-institute prospective trials have changed over the last few years. The recent identification of tumour specific drug targets by immunohistochemistry has had impact on specimen requirements and handling as well as laboratory standards. These changes in concepts, classification, and processing of soft tissue sarcomas have had impact on patient selection and treatment and formats of multi-institute trials.

Biomarkers, Tumor↗
PubMed2004

Benign renal mesenchymoma in the pediatric age group: a novel pathologic and karyotype entity.

Benign mesenchymal renal tumors are extremely rare in the pediatric age group. We report a case of a benign renal tumor composed of smooth muscle cells, adipose tissue, and areas of cartilaginous differentiation and expressing a 46,XX, t(8;10)(q21;q24) karyotype in a 13-year-old girl. Although some pediatric renal tumors show a degree of heterologous differentiation, none of them exclusively consist of these three well-differentiated mesenchymal components. The unique features of the present case were further confirmed by the karyotype changes, which to our knowledge, have never been described before in a pediatric renal tumor.

Adolescent↗
PubMed2004

Activation of the GLI oncogene through fusion with the beta-actin gene (ACTB) in a group of distinctive pericytic neoplasms: pericytoma with t(7;12).

Activation of the GLI oncogene is an important step in the sonic hedgehog signaling pathway, and leads to, eg, tissue-specific cell proliferation during embryogenesis. GLI activity in adult tissues is restricted, but has been identified in various neoplasms, as a result of mutations in the PTCH (patched) or SMOH (smoothened) genes, encoding components of the sonic hedgehog pathway, or by amplification of GLI. Herein, we present a new mechanism of GLI activation through fusion with the beta-actin gene (ACTB) in five histologically distinctive soft tissue tumors showing a t(7;12)(p21-22;q13-15) and a pericytic phenotype. Each was composed of a perivascular proliferation of monomorphic short spindle cells that stained positively for smooth muscle actin and laminin and that showed pericytic features by electron microscopy. To date, with a median follow-up of 24 months, none has behaved in an aggressive manner. Molecular genetic analysis showed that the translocation in all cases resulted in a fusion transcript including the 5'-part of ACTB and the 3'-part of GLI. The DNA-binding zinc finger domains of GLI were retained in the fusion transcripts and it is likely that the replacement of the promoter region of GLI with that of the ubiquitously expressed ACTB gene leads to deregulation of GLI expression and its downstream target genes.

Actins↗
PubMed2004

Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site.

Gastrointestinal stromal tumors (GISTs) form a distinctive group of mesenchymal neoplasms, showing differentiation towards the interstitial cells of Cajal. Morphologically, GISTs vary from cellular spindle cell tumors to epithelioid or mixed, epithelioid and spindle cell variants. The genotypic features underlying the morphologic differences of GISTs with vs without epithelioid components are not well defined. Acquisition of activating mutations in KIT and PDGFRA has been reported as alternative oncogenic events in the pathogenesis of GISTs. In this study, a comprehensive KIT and PDGFRA mutational analysis was performed in a group of 28 epithelioid/mixed type tumors, in order to explore whether a specific KIT/PDGFRA mutational status segregates these neoplasms from spindle cell variant GISTs. All GISTs were primary neoplasms, 16 (57.1%) originated from the stomach and 12 (42.8%) from other locations. Histomorphologically, 14 GISTs showed an epithelioid and 14 a mixed cell type pattern. Mutational analysis included KIT exons 9, 11, 13, and 17, and PDGFRA exons 12 and 18 prescreening by denaturing high-performance liquid chromatography, followed by direct sequencing. Activating mutations of KIT were found in 14 (50%) GISTs, the majority being within exon 11 (n=11; 39.2%), and the other comprised exon 9 AY 502-503 duplications (n=2; 7.2%) and exon 17 Lys --> Aln822 missense mutations (n=1; 3.6%). Most of the KIT mutant tumors (n=11; 78.6%) originated from nongastric sites. Seven (25.0%) GISTs with no detectable KIT mutations demonstrated PDGFRA mutant isoforms, carrying either D842 V mutations (n=5) or exon 18 deletions (n=2). All GISTs harboring PDGFRA mutant isoforms originated from the stomach. In seven tumors, no detectable mutations were found; all but one of nonmutant tumors initiated from the stomach and exhibited an epithelioid morphology. These findings indicate that the mutational status of epithelioid/mixed GISTs associates with the anatomical site of the tumor.

Adult↗
PubMed2004

Transient local response and persistent tumor control in a child with recurrent malignant glioma: treatment with combination therapy including dendritic cell therapy. Case report.

Treatment of malignant glioma is difficult and discouraging. Even after resection and maximal adjuvant therapy, the prognosis remains poor. The authors sought a novel form of treatment, such as stimulating the patient's own immune response against the tumor, and developed a protocol of tumor vaccination in which autologous dendritic cells (DCs) were used in patients with recurrent malignant glioma. A 4-year-old girl was treated by means of biopsy sampling and radiotherapy for a rolandic low-grade glioma. Ten years later, a Grade III recurrence was discovered and treated with subtotal resection, interstitial radiation, six courses of oral temozolomide, and 12 courses of oral VP 16. At the end of the chemotherapy cycle, a new rapidly growing recurrence was diagnosed. A macroscopically complete resection was performed. Afterward, the girl was vaccinated with autologous DCs that had been pulsed ex vivo with the homogenate of the resection specimen. She received six vaccines in total. The efficacy of immunization was checked by a positive delayed-type hypersensitivity skin reaction after the second injection. After the fifth vaccine, a transient contrast enhancement without mass effect was visualized on magnetic resonance imaging. Simultaneously, positron emission tomography imaging revealed a transient increase of metabolic activity around the resection cavity, but the metabolic uptake ratio remained below 1.8. The patient's disease is still in complete remission 24 months after the last surgery. She is clinically well with minor and stable left hemiparesis. This case report illustrates the potential of vaccination with DCs loaded with crude tumor homogenate as adjuvant therapy to induce prolonged tumor control of malignant glioma and the objective noninvasively monitored immune response against infiltrating tumor cells.

Astrocytoma↗
PubMed2003

MAPK phosphatase DUSP16/MKP-7, a candidate tumor suppressor for chromosome region 12p12-13, reduces BCR-ABL-induced transformation.

Recurrent chromosome 12p deletions are associated with distinct tumor types and suggest the presence of a tumor suppressor gene (TSG). Previously, we mapped an EST with similarity to a protein tyrosine phosphatase to the minimally deleted region for all these neoplasms. The corresponding gene, DUSP16/MKP-7, was recently shown to code for a mitogen-activated protein kinase phosphatase, suggestive for a function as tumor suppressor. Overexpression of DUSP16 in BCR-ABL-transformed Rat-1 fibroblasts reduces their transforming capacity in vitro and in vivo via downregulation of BCR-ABL-induced JNK activation. A role for DUSP16 as a regulator of JNK signaling was further demonstrated via overexpression in Ba/F3 cells, which increased their antiapoptosis. However, no inactivating mutations could be detected in leukemia patients hemizygous for DUSP16, and the effect of hemizygosity on DUSP16 expression level could not be assessed due to the variability of DUSP16 transcript levels observed in leukaemia cell lines and in patients. Taken together, the functional data point to a context-dependent role for DUSP16 on cell transformation and apoptosis, reflecting the dual role of JNK, and therefore suggest that DUSP16 might be haploinsufficient for tumor suppression.

Animals↗
PubMed2003

Late-Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo A syndrome.

Sanfilippo A syndrome, mucopolysaccharidosis type IIIA, is caused by a deficiency of heparan sulphamidase activity, and usually presents in childhood with neurodegeneration leading to death in teenage years. Visceral symptoms are limited to coarsening and diarrhea. We now describe an adult patient who presented with cardiomyopathy. At age 45 years she had hypertension, and the next year she developed a progressively worsening cardiomyopathy with prominent apical hypertrophy and atrial fibrillation. At age 53, she had severe concentric hypertrophic nonobstructive cardiomyopathy in both ventricles. There was no coarsening of features. Neurologic function, skeleton, cornea, liver, and spleen were normal. Percutaneous endomyocardial biopsy showed ballooned cardiomyocytes with storage vacuoles, containing acid mucopolysaccharides. Leucocytes, uterus, and brain biopsy did not show this storage material. There was a slight increase in total urine mucopolysaccharides, with an increased proportion of heparan sulfates. Heparan sulphamidase activity was deficient in leukocytes and heparan sulphamidase protein and activity were reduced in cultured fibroblasts. No mutations were identified after sequencing of the heparan sulphamidase gene at the cDNA and the genomic level. This new clinical presentation expands the clinical spectrum of Sanfilippo A syndrome to include a primary visceral presentation of cardiomyopathy without neurologic symptoms in the adult. The late onset may be related to the residual heparan sulphamidase activity. The genetic basis of this new variant is still unclear. Physicians evaluating adults must remain aware of possible new adult presentations of storage conditions.

Cardiomyopathies↗
PubMed2003

Lipoblastoma in a 23-year-old male: distinction from atypical lipomatous tumor using cytogenetic and fluorescence in-situ hybridization analysis.

Lipoblastoma is a rare benign tumor that occurs primarily in infancy and early childhood. We present the rare presentation of a 12 cm sized intramuscular lipoblastoma of the thigh in a 23-year-old patient. On histology, the tumor strongly resembled an atypical lipomatous tumor due to the presence of lipoblasts and atypical stromal nuclei. The very focal lobulation and myxoid change presented the only histological hint towards a lipoblastoma. Cytogenetic and subsequent FISH evaluation of the tumor cells showed a 46,XY, t(8;15) (q12;q25) as chromosomal change with rearrangement of the PLAG1 gene. The present case indicates that lipoblastoma should enter the differential diagnosis of an 'atypical' deep seated fatty tumor in adults. The diagnostic value of cytogenetic/molecular analysis in the differential diagnosis of lipomatous tumors is underscored as well.

Adult↗
PubMed2003

Clustering of deletions on chromosome 13 in benign and low-malignant lipomatous tumors.

Deletions and structural rearrangements of the long arm of chromosome 13 are frequently observed in benign and low-malignant lipomatous tumors, but nothing is known about their molecular genetic consequences. We assessed the karyotypes of 40 new and 22 previously published cases (35 ordinary lipomas, 15 spindle cell/pleomorphic lipomas, 2 myxolipomas, 1 angiomyxolipoma and 9 atypical lipomatous tumors) with chromosome 13-abnormalities, and found bands 13q12-22 to be frequently affected. Twenty-seven cases with structural abnormalities within this region were selected for breakpoint and deletion mapping by metaphase fluorescence in situ hybridization (FISH), using a set of 20 probes. Deletions were found in 23 of 27 cases. The remaining 4 cases had seemingly balanced rearrangements. The breakpoints were scattered but clustered to band 13q14, and in all cases with unbalanced abnormalities, a limited region within band 13q14 was partially or completely deleted. A deletion within band 13q14 was found together with a breakpoint on the other homologue in 5 cases, 4 of which could be tested further with regard to the status of the retinoblastoma (RB1)-gene. In all 4 cases, only 1 copy of the gene was deleted. In addition to the breaks and deletions in the vicinity of the RB1-locus, several other regions of 13q were recurrently affected, e.g., in the vicinity of the hereditary breast cancer (BRCA2; 13q12)- and lipoma HMGIC fusion partner (LHFP; 13q13)- genes. Our findings strongly indicate that deletion of a limited region (approximately 2.5 Mbp) within 13q14, distal to the RB1-locus, is of importance in the development of a subset of lipomatous tumors.

Adult↗
PubMed2003

Spindle-cell rhabdomyosarcoma with 2q36 approximately q37 involvement.

The cytogenetic analysis of a spindle-cell variant of embryonal rhabdomyosarcoma (RMS), presenting as a cheek mass in an 18-year-old girl, is reported. The tumor cells showed an abnormal karyotype 46,XX,der(2)t(2;7)(q36 approximately q37;q3?),del(14)(q24),der(16)t(1;16)(q21;q13), with a tetraploid range of chromosome number in a subpopulation of cells. By fluorescence in situ hybridization analysis, the tumor cells were negative for FKHR-disrupting translocations specific for alveolar type of RMS and for NMYC gene amplification.

Adolescent↗
PubMed2003

Accuracy of diffusion-weighted MR imaging in the diagnosis of sporadic Creutzfeldt-Jakob disease.

The definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is based on brain autopsy. The 14-3-3 analysis in the CSF is considered a highly sensitive and specific procedure. Sensitivity, specificity and accuracy of EEG, the 14-3-3 assay and MR imaging in 12 patients referred for suspected sCJD were calculated. We suggest that diffusion-weighted MR imaging (DWI) should be included in the array of diagnostic tests because of the 100 % sensitivity and specificity.

Aged↗
PubMed2003

Complex genomic rearrangement of ALK loci associated with integrated human Epstein-Barr virus in a post-transplant myogenic liver tumor.

Epstein-Barr virus (EBV) is a ubiquitous viral agent, well known to be associated with lymphoid, epithelial, and smooth-muscle malignancies in immunocompromised individuals. This report describes a 10-year-old patient with an EBV-related liver tumor occurring after kidney transplantation. The neoplasm presented a phenotypic spectrum, ranging from a smooth-muscle tumor to an inflammatory pseudotumor (IPT). The neoplastic cells failed to disclose CD21, CD35, or ALK expression, the latter confirmed by reverse-transcription polymerase chain reaction. Cytogenetic analysis revealed a single clonal cell population showing 46,XY,del (2)(p23),der(3)t (2;3)(p23;q29),der(21) t(Y;21)(q12;p13) karyotype. By metaphase FISH analysis, the neoplastic cells demonstrated the presence of two molecularly different but related aberrant clones, one with the loss of one ALK allele and the second with translocation of the 3'end of ALK kinase domain on the der(3) chromosome. Using FISH with an EBV-specific and 3'end ALK DNA probes, a co-localization of the viral DNA and the ALK sequences was found on the der(3) chromosome. Metaphases with loss of rearranged ALK did not show integrated virus; instead, viral particles together with an associated 3'end ALK domain formed an ex-chromosomal, episomal-like type configuration. The interphase study, using dual-color 5'/3' end ALK FISH assay, revealed 30% of nuclei with only one fused signal, confirming the total loss of one ALK allele in the subset of tumor cells. A combined immunofluorescence and FISH study indicated this separate clonal variant to correspond to desmin-positive smooth-muscle cells. In contrast, desmin-negative myofibroblasts showed the presence of both normal and rearranged ALK alleles. Our results indicate that ALK locus may be a target of EBV integration, a hitherto unreported finding. Although the sustained clonal expansion in EBV-related smooth-muscle tumors/IPTs may depend on functions provided by the EBV oncogenic proteins, the tumor phenotype may be further modified by the secondary genomic rearrangements imposed by the virus during and/or after the integration event. In this respect, the observed phenotypic heterogeneity most likely reflects divergence during neoplastic progression, with the subsequent expansion of morphologically and molecularly distinct but cytogenetically related clones.

Anaplastic Lymphoma Kinase↗
PubMed2003

Segmental spinal cord hypoplasia and meningocele with preservation of medullary function: case report.

BACKGROUND: In very rare dysraphic cases, it is not clear whether the primary abnormalities are in the neural elements, or in the bony elements. CASE DESCRIPTION: We describe a case of segmental hypoplasia of the spinal cord, with absent nerve roots in the afflicted segments, and associated meningocele and vertebral abnormalities. We illustrate the arguments for and against the classification of this lesion either as an atypical case of myelomeningocele (MMC) or as a mild case of segmental spinal dysgenesis (SSD). CONCLUSIONS: Possibly, in this exceptional case, the primary defect is in the neural tissue like in more usual cases of MMC and not in the spine, like in segmental spinal dysgenesis.

Child↗
PubMed2003

Evidence for involvement of a tumor suppressor gene on 1p in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNST) are rare soft-tissue malignancies. The genetic basis of these tumors is still poorly understood. Cytogenetic analyses predominantly revealed complex karyotypes, precluding the identification of recurrent chromosomal changes. We report loss of 1p material in a near-diploid karyotype with few or no additional structural chromosome changes in two sporadic cases of MPNST, indicating an important role of 1p loss in MPNST development. In one of these two tumors, a distal 1p deletion (1p31.2 approximately pter) was detected suggesting involvement of a tumor suppressor gene located within this distal region of 1p. Further evidence for recurrent 1p loss in MPNST was obtained by interphase fluorescence in situ hybridization, which showed loss of 1p material in 3 out of 13 tumors. These findings together with data from the literature suggest that loss of a tumor suppressor gene located within distal 1p is implicated in the pathogenesis of MPNST.

Child↗