Biomedical subjects

W Feiden

Publications and source records attributed to W Feiden.

At least 37 records · Page 2Linked to original sources

PubMed2001

Novel tankyrase-related gene detected with meningioma-specific sera.

In many meningiomas, alterations of chromosome 22 can be found, and the NF2 (neurofibromatosis type 2) gene, in particular, is of great interest as a putative gene involved in meningioma. Because the NF2 gene is not mutated in all meningiomas, additional genes may be involved. Instead of looking for alterations directly at the DNA level, we used the immune response of meningioma patients to identify immunogenic antigens that may be associated with the disease. We screened a fetal brain cDNA expression library with sera pools from different patients bearing meningioma classified according to the three WHO grades, using the serological identification of antigens by recombinant expression cloning immunological screening method. Here, we report the finding of a new tankyrase-related protein. We found 16 overlapping clones with homologies to tankyrase when we screened the library with the common-type meningioma sera pool and 2 such clones when we screened the library with the atypical meningioma sera. The anaplastic meningioma sera did not identify any tankyrase-related clones. We tested some of the newly identified clones with 13 single sera, 6 of which (37.5%) reacted positively with the tankyrase-related clones. In addition, we screened the tankyrase-related clone with six sera pools from individuals without obvious disease. Although 1 of 24 (4.2%) normal sera reacted with the tankyrase-related clone, we found a striking difference in the frequency of reactivity to this clone by sera from patients bearing tumors corresponding to the three WHO meningioma grades; common-type sera was the most frequently reactive. Northern blot analysis demonstrates expression of the novel tankyrase gene in two common-type meningiomas from patients with immune response.

Amino Acid Sequence↗

PubMed2001

Amplification and expression of splice variants of the gene encoding the P450 cytochrome 25-hydroxyvitamin D(3) 1,alpha-hydroxylase (CYP 27B1) in human malignant glioma.

PURPOSE: Recently, we reported the isolation of six novel genes termed glioma-amplified sequences (GASs) from the glioblastoma cell line TX3868 using microdissected mediated cDNA capture (U. Fischer et al., HUM: MOL: GENET:, 5: 595-600, 1996). The aim of this study was to further characterize the gene GAS89. EXPERIMENTAL DESIGN: To determine the amplification frequency, we performed comparative PCR studies and Southern blot hybridization experiments. To identify full-length clones of GAS89 we screened a HybriZAP library. Reverse transcription-PCR was performed to isolate splice variants and to determine expression levels. RESULTS: We identified for the gene GAS89 an amplification frequency of 25% in 28 examined glioblastoma multiforme samples. Screening a HybriZAP library, we isolated an incomplete gene sequence showing identity with the gene for 25-hydroxyvitamin D(3) 1,alpha-hydroxylase. Different full-length clones were then isolated using PCR primers chosen from the 3'- and 5'-untranslated regions. As determined by sequencing, the clones represent various splice variants of the 25-hydroxyvitamin D(3) 1,alpha-hydroxylase gene. The clones encode truncated proteins but also one potentially functional enzyme variant. Reverse transcription-PCR studies revealed overexpression of several variants in glioblastoma samples with GAS89 amplification in comparison with normal brain RNA and glioblastoma without GAS89 amplification. CONCLUSIONS: This is the first report of gene amplification for 25-hydroxyvitamin D(3) 1,alpha-hydroxylase and the appearance of mRNA splice variants in glioblastoma multiforme. The endogenous expression of the 25-hydroxyvitamin D(3) 1,alpha-hydroxylase gene and the appearance of alternative splice variants reveal a new feature of the molecular pathogenesis of glioblastoma and may represent a new target for glioma therapy.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed2000

[Neuropathological and neuroradiological aspects of acute disseminated encephalomyelitis (ADEM)].

Among non-neoplastic lesions of the central nervous system, demyelinating pseudotumors of the group of acute disseminated encephalomyelitis (ADEM) most frequently occasion neurosurgical intervention for purposes of definitive diagnosis and thus enter the domain of the surgical pathologist. Typically, ADEM presents with multifocal, bilateral lesions in an asymmetrical distribution. Especially monolocular manifestations may be diagnostically challenging. Due to the acuteness of clinical symptoms and the expansive, space-occupying character of the lesions a diffuse glioma, a metastatic disease, a primary cerebral Non-Hodgkin's lymphoma, brain abscess, a parasitosis or an ischemic brain tissue necrosis may be suspected. This impression is supported by uptake of contrast-medium most pronounced at the periphery of the lesion and the subcortical location. The histomorphologic feature of relative axonal preservation in areas with acute myelin breakdown and lymphocytic infiltrates make the diagnosis of an acute primary demyelinating disease probable. A diagnosis of glioma may be prompted by the florid, cytologically atypical astrogliosis especially in intraoperative request. Based on a series of 14 cases of radiologically and bioptically documented cases of ADEM typical examples will be demonstrated and discussed.

Adult↗

PubMed2000

Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats.

In developing iodine-123-labelled amino acid derivatives for imaging cerebral gliomas by single-photon emission tomography (SPET), we compared p-[123I]iodo-L-phenylalanine (IPA), L-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T3868 cells, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the 123I-iodinated agents for use as SPET radiopharmaceuticals was evaluated in healthy experimental rats as well as in rats with stereotactically implanted C6 gliomas. The radiopharmaceutical uptake into glioblastoma cells was rapid, temperature and pH dependent, and linear during the first 5 min. Equilibrium was reached after 15-20 min, except in the case of ITIC, the initial uptake of which gradually decreased from 15 min onwards. The radioactivity concentration in glioma cells following 30-min incubation at 37 degrees C (pH 7.4) varied from 11% to 35% of the total activity per million cells (ITIC < IMT < or = IPA). Competitive inhibition experiments using alpha-(methylamino)-isobutyric acid and 2-amino-2-norbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transported by system ASC, indicated that IPA, like IMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of the A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analysis of uptake under conditions that change the cell membrane potential, i.e. in high K+ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of valinomycin or nigericin induces a slight increase or decrease in the radiopharmaceutical uptake, suggesting a minor contribution of the mitochondria in the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereafter showed efflux from the brain. The radioactivity concentration in healthy rat brain 15 min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactically implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15 min p.i.), with tumour-to-background ratios greater than 4. These data indicate that IPA and ITIC, like IMT, exhibit interesting biological characteristics which hold promise for in vivo brain tumour investigations by SPET.

Alanine↗

PubMed2000

[Granulocytic sarcoma (so-called chloroma) as a possible cause of spinal cord compression. Case report and differential diagnosis].

Granulocytic sarcomas (so-called chloromas) are rare extramedullary tumorlike proliferates of myelogenous precursor cells that may de novo precede acute leukemia or coincide with the first manifestation or relapse of acute myeloid leukemia. Rarely, such tumors represent the initial manifestation of a blast crisis in the course of a chronic myeloproliferative disease, such as chronic myeloid leukemia. If they occur in aleukemic patients incorrect diagnoses may result. Differential diagnostic considerations are being discussed by presenting the case of a 58-year-old man who experienced spinal cord compression by an isolated epidural mass lesion.

Biopsy↗

PubMed2000

Expression of cancer testis genes in human brain tumors.

Cancer-testis (CT) genes are expressed in a variety of human cancers but not in normal tissues, except for testis tissue, and represent promising targets for immunotherapeutic and gene therapeutic approaches. Because little is known about their composite expression in human brain tumors, we investigated the expression of seven CT genes (MAGE-3, NY-ESO-1, HOM-MEL-40/SSX-2, SSX-1, SSX-4,HOM-TES-14/SCP-1, and HOM-TES-85) in 88 human brain tumor specimens. Meningiomas expressed only HOM-TES-14/SCP-1 (18% of meningiomas were HOM-TES-14/SCP-1 positive) and did not express any other CT genes. One ependymoma was negative for all CT genes tested. SSX-4 was the only CT gene expressed in oligodendrogliomas (2 of 5 cases), and it was also expressed in oligoastrocytomas (3 of 4 cases) and astrocytomas (10 of 37 cases). Astrocytomas were most frequently positive for HOM-TES-14/SCP-1 (40%) and SSX-4 (27%), followed by HOM-TES-85 (13%), SSX-2 (11%), and MAGE-3 (7%). Whereas MAGE-3 was detected only in grade IV astrocytomas, the expression of the other CT genes showed no clear correlation with histological grade. Of 39 astrocytomas, 60% expressed at least one CT gene, 21% expressed two CT genes, and 8% coexpressed three CT genes of the seven CT genes investigated. We conclude that a majority of oligoastrocytomas and astrocytomas might be amenable to specific immunotherapeutic interventions. However, the identification of additional tu-mor-specific antigens with a frequent expression in gliomas is warranted to allow for the development of widely applicable polyvalent glioma vaccines.

Antigens, Neoplasm↗

PubMed1999

[Spontaneous intracerebral hemorrhages. Neuropathologic aspects].

Non-traumatic so-called spontaneous intracerebral hemorrhages can occur in the supra- and infratentorial compartment. Taking into account their different etiologies, hemorrhages within the cerebral hemispheres are commonly divided into two categories, deep and lobar ones, with the first ones being frequently related to hypertensive vasculopathy. Lobar hemorrhages that are usually larger than their counterparts in the basal ganglia or thalamus, may be associated with arterio-venous malformations, leukemia or, especially in the elderly, with cerebral amyloid angiopathy (CAA) that is histopathologically characterized by deposits of betaA4-protein exclusively within the walls of medium-sized and small arteries of the leptomeninges and cerebral cortex.

Brain Neoplasms↗

PubMed1999

[Histopathologic findings in cerebral artery aneurysms after embolization with Guglielmi detachable platinum coils (GDC): report of two cases].

UNLABELLED: Following embolization with Guglielmi detachable coils the histomorphological findings and tissue reactions of two cerebral artery aneurysms were examined. METHODS: In order to study GDCs in situ a giant wide-necked aneurysm of the basilar artery (autopsy case; 14 days after embolization) and a resected aneurysm of the middle cerebral artery (resection; 6.5 months after embolization) were embedded in acrylate, cut in thin sections glued on acrylic slides, then grounded to about 10 microm thickness and finally stained with toluidine blue. RESULTS: With the above-described method GDCs became amenable to histopathologic studies. The coils were more densely packed within the dome than the central lumen. In the resected aneurysm this feature was particularly prominent in that the GDCs were embedded in scarred connective tissue. Few giant cells of the foreign body type were found intimately associated with the GDCs.

Adult↗

PubMed1999

Evaluation of l-3-[123I]iodo-alpha-methyltyrosine SPET and [18F]fluorodeoxyglucose PET in the detection and grading of recurrences in patients pretreated for gliomas at follow-up: a comparative study with stereotactic biopsy.

Based on the results of stereotactic biopsy, we evaluated in a prospective fashion the efficiency of l-3-[123I]iodo-alpha-methyltyrosine-single-photon emission tomography (SPET) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection and grading of recurrences in patients previously treated for gliomas. The patient population comprised 30 individuals, nine with astrocytomas of grade II, ten with astrocytomas of grade IV, three with oligoastrocytomas of grade II, six with oligodendrogliomas of grade II and two with anaplastic oligodendrogliomas of grade III) suspected of recurrence and scheduled for further treatment. IMT SPET data were acquired using either by dual-or a triple-headed SPET camera, Multispect 2/3. FDG uptake was measured with an ECAT ART PET camera. Two independent observers classified PET and SPET images as positive or negative for tumour tissue. Uptake of FDG and IMT was evaluated visually and, in the case of IMT, also quantitatively by calculating the ratios between tracer accumulation in the lesion and the unaffected contralateral regions of reference using the region of interest (ROI) technique. The PET and SPET results were compared with the histopathological findings obtained either by stereotactic biopsy or in one case by open surgery. Glucose metabolism and amino acid uptake of recurrences of brain tumours as assessed by FDG-PET and IMT-SPET correlated highly with the histopathological findings. Based on the histopathological data, FDG-PET and IMT-SPET findings confirmed recurrence in all cases of high-grade gliomas (IV). A difference could be demonstrated in low-grade (II-III) tumour recurrences. True-positive IMT-SPET results were found in 86% of grade III and 75% of grade II recurrences, whereas FDG-PET yielded a sensitivity of 71% in tumours of grade III and 50% in those of grade II. With respect to the grade of malignancy of brain tumours at recurrence, IMT-SPET, in contrast to FDG-PET, does not permit adequate in vivo grading of non-mixed brain tumours of astrocytic or oligodendroglial origin. However, in this study FDG-PET did not permit discrimination between upgrading of low-grade oligoastrocytomas (II) into anaplastic oligodendrogliomas (III) and upgrading into glioblastomas (IV) The results of this study indicate that FDG-PET and IMT-SPET are equivalent to stereotactic biopsy in their ability to identify high-grade tumours at recurrence. IMT-SPET proved to be superior to FDG-PET in confirming low-grade recurrences. In the case of suspected progression of the grade of malignancy in ordinary gliomas, FDG-PET correlated significantly with the histopathological grading, whereas IMT-SPET did not. However, tumour grading by FDG-PET has a limitation in mixed brain tumours in that it is not possible to discriminate between progression of the oligo- versus the astrocytic tumour entity. In this case histopathological evaluation of the tumour grade remains necessary.

Adult↗

PubMed1999

Genetic heterogeneity in human astrocytomas: spatial distribution of P16 and TP53 deletions in biopsies.

Smear preparations of 23 fresh astrocytoma biopsies were analyzed by two-color fluorescence in situ hybridization with cosmids specific for the P16 and the TP53 genes. Additionally, tissue sections of the same tumors were immunostained with the use of a monoclonal antibody that recognizes both wild-type and mutant TP53 protein. In 21 astrocytomas, loss of P16 was observed in a significant proportion of cells. Cells with homozygous P16 loss were present in 13 astrocytomas; 14 astrocytomas showed cells with heterozygous loss of P16. Remarkably, 5 astrocytomas showed a scattered mosaic pattern of cells with homozygous and, respectively, heterozygous p16 loss. Homozygous deletion of TP53 was not observed. Cells with heterozygous TP53 loss were detected in 12 tumors, in 7 of them in association with P16 loss. One tumor showed aberrant cells for neither TP53 nor P16 but strong immunostaining for TP53. Positive TP53 immunostaining was found in 16 astrocytomas. Heterozygous loss of TP53 was significantly correlated with TP53 protein expression. We conclude that, unlike typical tumor suppressor genes, P16 might enhance cellular proliferation after heterozygous loss through a dosage effect and that the distribution of cells with homozygous loss of P16 speaks in favor of a polyclonal loss of the second copy of this gene.

Astrocytoma↗

PubMed1999

Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation and alpha-interferon immunotherapy.

A patient with a stage IV mantle cell lymphoma (according to the REAL classification) was treated with high-dose chemotherapy and autologous bone marrow transplantation. One year later while on alpha-interferon immunotherapy she suffered from progressive loss of short-term memory and reported difficulties in recognizing objects. Magnetic resonance imaging (MRI) showed a vast ring-enhancing lesion of the left postcentral parietal area. Serial stereotactic biopsies disclosed progressive multifocal leukoencephalopathy without JC-virus in the cerebrospinal fluid. Therapy with subcutaneous interleukin-2 (IL-2) every other day and intrathecal cytarabine once a week was started. After 4 weeks the patient refused further treatment. Nevertheless her condition improved over the next 8 months and MRI scans showed a marked improvement in the lesions.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Evidence of focal genetic microheterogeneity in glioblastoma multiforme by area-specific CGH on microdissected tumor cells.

The term "multiforme" in glioblastoma multiforme (GBM) indicates the highly variable histomorphology that cannot be addressed by studies on homogenized tissue probes. In order to relate genetic findings with histomorphologically distinct areas we used microdissection to procure defined cell populations from microscopic tissue sections under direct visualization. Formalin-fixed and paraffin-embedded tissue sections of 10 GBM were evaluated for intratumoral genetic heterogeneity by microdissection of multiple areas of 20-50 tumor cells and DOP-PCR of DNA isolated from the dissected cell groups, followed by comparative genomic hybridization (CGH). Microdissected cells from histomorphologically normal extratumoral blood vessels from the same slides served as controls. The individual tumors showed variable combinations of primary chromosomal gains and losses common to all studied areas of a given case along with secondary, area-specific additional aberrations. CGH displayed a wider variety of chromosomal aberrations than metaphase cytogenetics of cell cultures from the same tumors. The most frequent aberrations observed were previously unperceived gains on chromosomes 4q (8/10) and 5q (5/10). Other nonrandom aberrations were gains on 12q (6/10), 13q (6/10), and 7 (5/10), and losses of 22 (5/10). Amplifications on 7p were intratumorally heterogeneous and only found in single areas of 2 tumors. In contrast to normal extratumoral vessels, vascular proliferates in most cases demonstrated chromosomal aberrations (CGH) which were partially different from the aberrations observed in the tumor itself. The described method gives evidence of considerable intratumoral genetic heterogeneity in GBM and provides a sensitive tool for the detection of quantitative chromosomal changes that are present only regionally within a given tumor.

Adult↗

PubMed1999

Radiomyelopathy after conventionally fractionated and hyperfractionated radiotherapy--experimental data and clinical consequences.

Explore the source record for details and available documents.

Animals↗

PubMed1999

Unbalanced translocation t(1;3)(p12-13;q11) in meningiomas as the unique feature of chordoid differentiation.

Chordoid meningioma is a rare histological subtype of meningiomas. Cytogenetic analysis of three cases revealed the unique feature of an unbalanced translocation der(1)t(1;3)(p12-13;q11) that was ascertained by chromosome microdissection and reverse fluorescence in situ hybridization. As the t(1;3) has not been observed in other subtypes of meningioma, it may represent a specific cytogenetic marker of chordoid meningiomas. It is not yet clear whether a fusion gene or the combined loss of genes from chromosome arms 1p and 3p is the pathogenetically important outcome of the translocation.

Aged↗

PubMed1999

Deletion of chromosome 1p and loss of expression of alkaline phosphatase indicate progression of meningiomas.

Meningiomas are cytogenetically characterized by loss of one chromosome 22 as a typical primary aberration and progression-associated secondary chromosome changes, of which monosomy 1p is the most common. The aim of this study was to evaluate the significance of monosomy 1p and enzyme activity loss of tissue nonspecific alkaline phosphatase (ALPL), whose gene maps to chromosome 1p36.1-p34, as parameters for the diagnosis of progression-prone meningiomas. We analyzed smear preparations of 56 meningiomas and additional paraffin sections of 17 of the cases by two-color fluorescence in situ hybridization (FISH) using the D1Z1 and D1Z2 probes and by a metaphase cytogenetic analysis of 30 of these tumors. The results were compared to clinical and morphological parameters and the expression of ALPL. Smear preparations showed deletion of 1p36 in 27% of common-type, 70% of atypical (intermediate-type), and 100% of anaplastic meningiomas. Monosomy 1p, as detected by FISH or the karyotype, was strongly associated with complete loss of ALPL activity. Intermediate-type and anaplastic meningiomas of younger patients displayed an increasing rate of cells with trisomy 1q and relative loss of 1p. The highly significant correlation of FISH results and ALPL histochemistry with clinical parameters gives evidence of their strong prognostic relevance. The complete activity loss of ALPL and the immunologically detected loss of ALPL protein in areas of meningiomas with monosomy 1p indicate a cytogenetically undetectable inactivation of the homologous Alpl allele. The apparently homozygous loss of expression of ALPL supports the notion that Alpl is a candidate tumor suppressor gene in meningiomas.

Alkaline Phosphatase↗

PubMed1998

Multivariate logistic analysis of dose-effect relationship and latency of radiomyelopathy after hyperfractionated and conventionally fractionated radiotherapy in animal experiments.

PURPOSE: We examined in rats whether the radiation tolerance of spinal cord is enhanced by using hyperfractionated radiotherapy compared to a conventional schedule. Higher tolerable doses to the spinal cord would allow dose escalation to the tumor and thus possibly lead to higher cure rates, especially in tumors with high cell proliferation. METHODS AND MATERIALS: Cervical spinal cord of 276 healthy rats was irradiated over 6 weeks hyperfractionally with single doses ranging from 0.75-2.5 Gy up to total doses ranging from 45-150 Gy (60 fractions) and conventionally with single doses of 1.5-4.0 Gy up to total doses of 45-120 Gy (30 fractions). The rats were examined neurologically and sacrificed when paralysis of the hind legs occurred. After fixation, spinal cord was removed and examined histologically. Dose-effect relationship and latency from the beginning of radiotherapy to the onset of paralysis were computed and analyzed using a multivariate logistic regression model. RESULTS: The model fitted the observed data excellently. There were highly significant effects both for the dose level and for the treatment regimen. Latency analysis showed earlier and more intense acute side effects after hyperfractionation but radiomyelopathy occurred markedly later. CONCLUSIONS: The sparing effect of hyperfractionation on spinal cord as predicted by radiobiologists could be confirmed in our experiments. Thus, it seems possible to escalate tumor doses using hyperfractionation without enhanced risk to spinal cord but with higher probability of tumor cure.

Animals↗

PubMed1998

[Classification and grading of gliomas and meningiomas].

GLIOMAS: As we demonstrated for supratentorial, diffuse gliomas in adults, a stratification into just two grades of malignancy, 'low' and 'high grade,' proved reliable and prognostically relevant. The discriminating histomorphological criterion for high-grade astrocytoma (WHO glioblastoma) as well as anaplastic oligodendroglioma and anaplastic oligoastrocytoma is endothelial hyperplasia/proliferation, which is usually associated with uptake of contrast medium in computed tomography and magnetic resonance imaging. As neoangiogenesis indicates glioma progression, it is worthwhile considering these radiographic features to judge the representativeness of the tumor samples critically. MENINGIOMAS: The revised edition of the WHO classification of brain tumors now includes the 'atypical' meningioma (WHO 'grade' II): Based on both its histomorphological features and prognosis, it should be placed between the common type and anaplastic meningioma. Nuclear area related Ki-67 proliferation indices, as determined by morphometry, were the prerequisite for outlining its histomorphological spectrum better. Cytogenetically, the most consistent progression-associated feature was loss of the distal part of the short arm of one chromosome 1 (1p-). Thus, a screening method using the tissue non-specific form of alkaline phosphatase (ALPL) as the respective marker enzyme was established. Diagnosing a meningioma of the intermediate type implies careful clinical and radiological patient follow-ups to detect tumor recurrences early.

Adult↗

PubMed1998

[Contribution of nuclear medicine to the diagnosis of recurrent brain tumors and cerebral radionecrosis].

The evaluation of brain tumor recurrence and therapy-induced benign changes following surgery and/or irradiation is a diagnostic challenge for imaging methods based on either morphology (cCT/MRI) or function (SPECT/PET). Current literature and the present data of our own patients demonstrate the diagnostic efficiency of IMT-SPECT and FDG-PET in the detection of recurrence and in-vivo grading. Thirty-nine patients suspected of brain tumor recurrence at follow-up were studied by FDG-PET and IMT-SPECT. Thirty-four of 39 patients showed recurrences; in 12 cases even a change in the grade of malignancy was observed. All high-grade recurrences could be confirmed by either methods. IMT-SPECT showed a higher sensitivity in detecting low-grade tumors at recurrence. In contrast to IMT-SPECT, FDG-PET supports sufficient in-vivo grading. Both methods can be used to differentiate between tumor recurrence and radionecrosis. In conclusion the results of our study demonstrate the efficiency of IMT-SPECT and FDG-PET in confirming recurrences and determining the actual tumor grade.

Adult↗