Biomedical subjects

J M Kros

Publications and source records attributed to J M Kros.

At least 37 records · Page 2Linked to original sources

PubMed2001

Cyclin D1 (CCND1) genotype is associated with tumour grade in sporadic pituitary adenomas.

The cyclin D1 (CCND1) gene contains a frequent A/G polymorphism within the splice donor region of exon 4/intron 4. CCND1 genotype is associated with clinical outcome in a number of malignancies although prognostic significance varies with tumour type. We examined CCND1 allele frequencies and genotype distribution in 294 patients with sporadic pituitary adenomas of various histologies. CCND1 allele frequencies and distribution of genotypes were similar in the 294 cases compared with previously reported control populations. Analysis according to tumour subtype showed no statistical difference in allele frequencies compared with controls. However, CCND1 genotype distribution in the somatotrophinomas showed a significant difference compared with normal controls (P = 0.008). We next examined CCND1 allele frequencies and genotype distribution across the tumour grades. Within the total tumour cohort the CCND1 allele frequencies showed a significant inverse relationship across the tumour grades (P = 0.005). The CCND1 A allele progressively increased from grade 1 (0.37) through to grade 4 (0.62) tumours, whilst the CCND1 G allele frequency progressively decreased from grade 1 (0.63) through to grade 4 (0.38) tumours. Trend analysis of CCND1 genotypes showed a significant progressive increase in AA frequency from grade 1 (15%) through to grade 4 (46%) tumours (P = 0.005). The CCND1 GG genotype progressively decreased from grade 1 (41%) through to grade 4 (23%) tumours (P = 0.204). No statistical significance was observed between CCND1 AG genotype and tumour grades. While the functional significance of the observed segregation of the CCND1 A/G polymorphism and tumour grade is unclear, our data suggest that CCND1 allele frequencies and genotype distributions show significant differences between tumour grades in sporadic pituitary adenomas. Since CCND1 genotype may be determined by analysis of peripheral blood samples it may provide a useful predictive marker for those tumours likely to show invasive behaviour. This may be clinically useful in indicating which tumours should receive adjunctive treatment (e.g. radiotherapy) immediately after surgical resection.

Adenoma↗

PubMed2001

Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading.

Prognostic value of histological grading of oligodendroglial tumors is controversial and interobserver reproducibility in grading of these tumors is unknown. Seven neuropathologists and 6 surgical pathologists experienced in brain tumor-diagnosis assessed 124 oligodendroglial tumors operated at the Mayo Clinic (1960-1990). Among histologic parameters upon which current oligodendroglioma grading systems are based, only high cellularity, presence of mitoses, microcalcifications, endothelial hypertrophy, endothelial proliferation, and necrosis appeared to be reproducible. Reproducible histologic features, based on consensus ratings among neuropathologists (defined as > 60%), were evaluated for the association with cause-specific survival by fitting Cox regression models. By univariate analysis, a significant association with survival was found for age, high cellularity, presence of mitoses, endothelial hypertrophy and proliferation and necrosis. On multivariable analysis with a stepwise variable selection method, only age and presence of endothelial proliferation were found to be independently associated with survival with a discriminatory index of the model of 0.68. Mitotic index was significantly associated with survival based on the grading from each separate neuropathologist, but it was not based on consensus, most likely because this was classified as indeterminate in 54% of cases. Alternatively, "models fit" considering the assessment of single neuropathologists, identified a model based on age and on mitotic index with similar discriminatory indices of 0.69-0.7. Our study found few factors independently associated with cause specific-survival among morphological parameters. These findings are consistent with the present WHO stratification of oligodendrogliomas into low- and high-grade variants.

Adult↗

PubMed2000

Critical illness polyneuropathy and myopathy (CIPNM): evidence for local immune activation by cytokine-expression in the muscle tissue.

In a longitudinal prospective study a muscle biopsy was taken from 30/32 (33%) of the 98 patients who developed critical illness polyneuropathy and myopathy (CIPNM). Neuropathic changes were found in 37%, myopathic in 40%, and a combination in 23% of the biopsies. The immunohistopathology showed macrophages and Th-cells in 40% and 60% of the muscle biopsies respectively. Small mainly perivascular infiltrates contained macrophages and Th-cells. ICAM-1, VCAM and MAC were found on the vascular endothelium in 58%, 53% and 79% respectively. In all biopsies there was an upregulation of both HLA-I and HLA-DR. Proinflammatory cytokines and TNFalphaR75 were also produced locally (IL-1beta in 71%, IFN-gamma in 40%, IL-12 in 73%, TNFalphaR75 in 90%). The anti-inflammatory cytokine IL-10 was simultaneously expressed in 96% of the biopsies. HLA-DR, TNFalphaR75 and IL-10 differed significantly when compared with control muscle biopsies. Our data provide evidence that small numbers of activated leukocytes producing both pro- and anti-inflammatory cytokines infiltrate skeletal muscle of CIPNM patients. We propose that the local balance of leukocyte activities is of importance in the pathophysiology of muscle weakness in CIPNM.

Antigens, CD↗

PubMed2000

Papillary meningioma with pleural metastasis: case report and literature review.

Papillary meningiomas are rare meningeal tumors which are associated with a grim prognosis. These tumors usually recur locally and in some cases they metastasize. The clinical, radiological and histopathological features of a case of a papillary meningioma with a pleural metastasis in a 13-year-old boy are presented. The literature on metastasizing papillary meningiomas is reviewed. Up to now, 131 cases of papillary meningioma have been reported in the literature. Only 8 cases gave rise to metastases outside the central nervous system. The preferential site of metastasis appeared to be the lung. This is the first report of a papillary meningioma giving rise to a metastasis in the pleura.

Adolescent↗

PubMed2000

Intra-CSF administered recombinant adenovirus causes an immune response-mediated toxicity.

High doses of adenotk were injected into the cerebrospinal fluid of rats and nonhuman primates (Macaca mulatta). Vector administration was followed by ganciclovir administration for 14 days. Despite the absence of clinical symptoms, analysis of the cerebrospinal fluid (CSF) and histopathological examination of the central nervous system (CNS) of the monkeys (3 weeks after vector injection) were consistent with a viral meningitis. Immunohistochemical analysis of the inflammatory infiltrates in the monkeys revealed the presence of T and B lymphocytes, indicating a combined cellular and humoral immune response to the vector. This latter was supported by the finding of intrathecal anti-adenovirus antibody synthesis. Rats receiving high intrathecal adenotk doses showed a transient and dose-dependent clinical toxicity consisting of lethargy, hyperemic eyes and weight loss. Histopathological examination of the meninges showed a shift from polymorphonuclear infiltrates during the first post-injection days to clusters of mononuclear cells after 7 days. Acute toxicity is probably related to the early, innate immune response to the vector. In a separate experiment, high levels of IL-8 and IL-6, were measured during the first 2-3 post-injection days in the CSF of two monkeys which received intrathecal adenoLacZ. Therefore, these cytokines seem to play an important role in initiating the nonspecific immune response. In one monkey which received adenotk, recombinant adenovirus was cultured from serum samples obtained at the 7th post-injection day. At this time-point, no vector could be isolated from CSF samples. Based on these preclinical data, we recommend careful dose finding for clinical studies that aim to treat patients with leptomeningeal metastases.

Adenoviridae↗

PubMed2000

Cytogenetic analysis of gemistocytic cells in gliomas.

Gemistocytes are glial cells characterized by voluminous, eosinophilic cytoplasm and a peripherally positioned, often flattened nucleus. Gemistocytes, usually present in anoxic-ischemic brains, are regularly encountered in glial neoplasms. The presence of gemistocytes in gliomas has been associated with an unfavorable clinical course, notwithstanding the low proliferative potential of these cells. It is not known whether gemistocytes residing in gliomas are dormant tumor cells, or alternatively, represent interspersed reactive glial cells. Whereas gemistocytic astrocytomas have been subject to various genetic investigations, no genomic analysis comparing individual cells in gliomas has been reported so far. In the present study, 3 astrocytomas, 3 oligodendrogliomas, and 3 mixed oligoastrocytomas, all harboring gemistocytic cells, were genetically analyzed by DNA in situ hybridization to paraffin-embedded, formalin-fixed tissue samples with optimal preservation of cellular morphology. To this end, probes for the centromeric regions of chromosome 7 and 10, known to show copy number aberrations in gliomas, were used. In addition, probes for centromeric regions of chromosomes 1 and 17 were used for the ploidy status of the tumors. The spot counts for the various chromosomes were statistically compared. Gains of chromosome 7 were found in 1 anaplastic astrocytoma, 1 anaplastic oligodendroglioma, and 1 anaplastic oligoastrocytoma. Loss of chromosome 10 was seen in 2 anaplastic astrocytomas, in 1 anaplastic oligodendroglioma, and in 1 anaplastic oligoastrocytoma. In 3 cases, significant differences in spot distributions between gemistocytes and non-gemistocytes were found, but the other cases showed no difference in spot distribution. It is concluded that, although many gemistocytic cells in gliomas may be considered reactive cells, in a subset of tumors, part of the gemistocytic cells should be considered neoplastic.

Adult↗

PubMed2000

Right temporal lobe glioblastoma presenting in the left orbit. Case report.

Dissemination of gliomas outside the central nervous system without preceding neurosurgery is a rare phenomenon. Glial neoplasms presenting as bone lesions are even more rare. A case of glioblastoma multiforme (GBM) with initial presentation in the orbit following a single generalized seizure is described. Signs of intracranial hypertension resulted from subarachnoid tumor invasion. The patient was treated with whole-dose radiation therapy but survived for only 6 months following the initial presentation. An autopsy revealed a right temporal GBM with extensive subarachnoid spread and invasion in the left orbit and skull base. The literature on dissemination of primary tumors of the brain is reviewed.

Brain Neoplasms↗

PubMed1999

Distribution of recombinant adenovirus in the cerebrospinal fluid of nonhuman primates.

Gene therapy by administration of vectors into the cerebrospinal fluid (CSF) may be used in treatment of leptomeningeal metastases (cancer gene therapy) as well as in treatment of neurodegenerative disorders, traumatic injury, and chronic pain. Recombinant adenoviruses are attractive vectors for intra-CSF administration because they can efficiently transfer genes into the nonreplicating cells of the central nervous system (CNS). In addition, they can be produced in high titers and, because no producers cells are introduced, the risk of CSF obstruction by clustering cells is circumvented. However, successful application requires favorable distribution dynamics, high transduction efficiency, and long-lasting transgene expression. In this study we examined the distribution of a recombinant adenovirus containing the lacZ gene after administration into the CSF of nonhuman primates. After intraventricular and suboccipital administration, homogeneous distribution of the vector along the meninges covering the brain and spinal cord was obtained, as demonstrated by extensive and intense blue staining of cells, predominantly in the arachnoid and pia mater. In one animal we also found beta-galactosidase activity in the cervical paraspinal fat and in one of the deep cervical lymph nodes, indicating drainage of the vector or vector products with CSF into cervical lymph. This route of vector clearance from the CNS may result in antigenic presentation and an effective immune response and may explain the sixfold higher serum antibody titers after intrathecal injection of adenovirus as compared with intranasal application in Fischer rats. We conclude that distribution dynamics of recombinant adenovirus after intra-CSF administration are excellent. However, because of the immune response elicited by the virus, even after administration to the CNS, development of immunomodulating strategies remains a challenge.

Adenoviridae↗

PubMed1999

Genetic aberrations in oligodendroglial tumours: an analysis using comparative genomic hybridization (CGH).

Four low-grade oligodendrogliomas, nine anaplastic oligodendrogliomas and two mixed oligoastrocytomas were investigated for chromosomal aberrations by comparative genomic hybridization on formalin-fixed, paraffin-embedded tissue samples. The most frequent losses observed involved 1p, 9p, 10pq, 14q, 16p, 19q, while the most frequent gains were seen on 7pq, 11pq, 17p, 19pq, and Xp. In one oligodendroglioma, a highly specific amplification of 1q32.1 was seen. The frequent losses of 14q have not been reported previously. In the two cases of mixed oligoastrocytomas multiple gains and losses were found that did not show a clear overlap with the alterations found in the pure oligodendrogliomas.

Adult↗

PubMed1999

Expression of the neurofibromatosis type 2 gene in human tissues.

The neurofibromatosis Type 2 tumor suppressor gene is implicated in the hereditary tumor syndrome NF2, hallmarked by bilateral vestibular schwannomas, meningiomas, and ocular non-neoplastic features. The gene product has characteristics of a membrane cytoskeleton-linking protein but the mechanism of tumor suppression by the NF2 protein remains to be elucidated. The NF2 gene is widely expressed in mouse and rat tissues. In humans, most of the expression data have accumulated through Northern blot analysis, RT-PCR and, more recently, Western blot analysis, providing information on whole tissues and organs rather than on specific cell types. We report here an extensive survey of NF2 gene expression in human tissues using a combination of mRNA in situ hybridization (mRNA ISH) and immunohistochemistry (IH) with a panel of monoclonal antibodies (MAbs) supplemented by tissue immunoprecipitation experiments with affinity-purified polyclonal antibodies. Expression was observed in many different cell types, most of which appear functionally normal in individuals affected by NF2. Surprisingly, expression could not be consistently documented in Schwann cells and arachnoidal cells by IH or by mRNA ISH in formalin-fixed tissue. However, consistent immunostaining of Schwann cells was seen in frozen sections. (J Histochem Cytochem 47:1471-1479, 1999)

Animals↗

PubMed1998

Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation.

Mutations at codons 717 and 670/671 in the amyloid precursor protein (APP) are rare genetic causes of familial Alzheimer's disease (AD). A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). We have reported a APP692Ala-->Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem examination of two demented patients with the APP692 mutation. The neuropathological findings support the diagnosis of AD. Leptomeningial and parenchymal vessels showed extensive deposition of Abeta amyloid protein. Numerous senile plaques consisted of large Abeta amyloid cores, often measuring more than 30 microm in diameter and were surrounded by a fine meshwork of dystrophic neurites. In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites. Our findings show that the APP692 mutation leads to morphological abnormalities that are similar to AD, but the morphology of senile plaques is clearly distinct from that described in sporadic and chromosome 14-linked AD patients, in patients with APP717 mutations causing familial, presenile AD and in patients with the APP693 mutation causing HCHWA-D.

Alzheimer Disease↗

PubMed1998

Phase II study on cisplatin and ifosfamide in recurrent high grade gliomas.

27 patients with recurrent high grade glioma following surgery and radiation therapy were treated with 100 mg/m2 cisplatin and 6 g/m2 ifosfamide per cycle, administered on days 1-3 in 4 week cycles, for a maximum of six cycles. Toxicity was assessed after every cycle. Response was assessed following every second cycle, and a 50% decrease of the largest cross-sectional tumour area on contrast enhanced magnetic resonance imaging or computed tomography scan was considered a partial response (PR). A total of 95 cycles was administered; 26 patients were evaluable for response. In 5 patients (19%), a PR was obtained (median time to progression (TTP): 34 weeks). Stable disease was observed in 6 patients (23%, median TTP: 22 weeks). The most frequent toxicity was haematological: 37% of cycles were complicated by a grade 3 or 4 leucopenia. 1 patients died, probably as a consequence of increased cerebral oedema induced by the cisplatin hydration schedule. Determination of the cisplatin concentration in this patient showed a 10-fold increase in the tumour concentration as compared with that in normal brain tissue, demonstrating the absence of a blood-brain barrier in the tumour. In conclusion, generally this schedule was well tolerated, but it is of moderate activity for recurrent glioma.

Adult↗

PubMed1998

The effect of dexamethasone on the uptake of cisplatin in 9L glioma and the area of brain around tumor.

The negative influence of dexamethasone (Dex) on the uptake of cisplatin in brain tumors was investigated in rats bearing 9L glioma. Dex or saline was given intraperitoneally prior to intravenous administration of cisplatin 5 mg/kg. Total Platinum (Pt) concentration was quantified with atomic absorption spectroscopy (AAS) in tumor, brain around tumor (BAT), normal brain and plasma. In the second experiment DNA-adducts of cisplatin were determined in tumor and BAT by AAS. In tumor, there was no difference in the Pt concentration and in the DNA-adduct level between the two treatment groups. In BAT, the Pt level in the Dex group was 0.20 microg/g (SD=0.10 microg/g), which was significantly lower than in the controls (0.53 microg/g (SD=0.21 microg/g); p < 0.001). In addition, the DNA-adduct level in BAT was 23% lower in the Dex treated rats (p=0.05). In normal brain the Pt concentration was 10-fold lower than in tumor tissue. Thus, Dex did not significantly limit the uptake of cisplatin in brain tumor nor did it influence the uptake in normal brain parenchyma. In contrast, in BAT that has a partially disrupted BBB, the concentrations of Pt and DNA-adduct formation were significantly decreased following pretreatment with Dex. The influence of Dex on limiting the effects of chemotherapy for brain tumors needs further study.

Animals↗

PubMed1998

Intracerebral injection of adenovirus harboring the HSVtk gene combined with ganciclovir administration: toxicity study in nonhuman primates.

A high dose (1-2.5 x 10(10) infectious units) of recombinant adenovirus harboring the herpes simplex thymidine kinase gene (IG.Ad.MLPI.TK) was injected into the white matter of the right frontal lobe in two rhesus monkeys (M. mulatta). Injection of the vector was followed by systemic ganciclovir administration (10 mg/kg per day) for 14 days. During treatment no clinical symptoms were observed. Histopathological analysis of the brain at day 18 showed a 5 mm necrotic area at the site of the virus injection. This area was invaded and surrounded by inflammatory cells and activated astrocytes (gliosis). Immunohistochemical analysis of the infiltrates revealed the presence of predominantly mononuclear cells. In the vicinity of the lesion perivascular cuffs were seen containing T lymphocytes and clusters of B lymphocytes. From this preclinical study we conclude that the toxicity of adenotk/GCV is acceptable and treatment of patients with malignant gliomas using this kind of therapy is feasible. However, careful dose finding in clinical studies is recommended.

Adenoviridae↗

PubMed1998

Brain parenchyma/pO2 catheter interface: a histopathological study in the rat.

Local cerebral oxygenation can be monitored continuously using an intraparenchymal Clark-type pO2 sensitive catheter. Measured values of brain tissue pO2 (PbrO2) not only depend on the clinically interesting balance between oxygen offer and demand, but also on catheter properties and characteristics of the probe tissue interface. Microdamage surrounding pO2-sensitive needles, inserted into various tissues, has been reported; we evaluated histologic changes at the probe tissue interface after insertion of pO2 probes, suitable for clinical use, in the rat brain. The effect of insertion of the probe itself (mechanical damage), the application of micropotential during the measurements, and the effect of time was evaluated using digital image analysis of H&E-stained histological slices. Surrounding the probe tract, a zone of edema with an average radius of 126.8 microm was seen; microhemorrhages with an average surface area of 56.2 x 10(3) microm2 were observed in nearly all cases. The area of edema and the presence of microhemorrhages were not influenced by performed measurements or by time. Intraventricular blood was observed in 10 of 19 rats studied. Measured low PbrO2 values were related to the presence of a microhemorrhage in either probe tract or ventricles. Tissue damage due to the measurements is negligible, and the amount of edema itself does not influence the accuracy or response time of the pO2 probe. Low PbrO2 readings, however, could be caused by local microhemorrhages, undetectable on CT or MRI.

Analysis of Variance↗

PubMed1998

Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late surgery.

BACKGROUND: A retrospective study of patients with low grade astrocytoma was carried out because the best management of such patients remains controversial. Prognostic factors were identified by multivariate analysis. Special attention was paid to the effect of extent and timing of surgery. METHODS: Ninety patients with low grade astrocytoma were studied. Seventy two patients had resective surgery, 15 had a diagnostic biopsy only, and three patients had resective surgery after initial biopsy. RESULTS: Significant prognostic factors for survival were age, preoperative neurological condition, epilepsy as the single sign, extent of surgery, and histology. The extent of surgery was highly significant on univariate analysis (p=0.002); however, after correction for age and preoperative symptoms this was considerably reduced (p=0.04). A subgroup of 30 patients with epilepsy as their single presenting symptom was identified. Thirteen of these patients were treated immediately after diagnosis, whereas the other 17 patients were initially followed up and treated only after clinical or radiological progression. Survival in both groups was identical (63% survival rate after five years) and much better than survival for the whole group (27% survival rate after five years). Malignant dedifferentiation was observed in 25 (70%) of 36 patients who were reoperated, after a median period of 37 months. This period was 41 months for the subgroup of patients with epilepsy only and 28 months for the remaining patients. CONCLUSIONS: Due to the retrospective nature of the study only restricted conclusions can be drawn. Low grade glioma with epilepsy as the single symptom has a much better prognosis than if accompanied by other symptoms. This prognosis is not influenced by the timing of surgery. It seems, therefore, safe to defer surgery until clinical or radiological progression in low grade glioma with epilepsy only.

Adult↗

PubMed1998

Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy. Dutch Neuro-oncology Group.

OBJECTIVES: To determine the response rate and factors correlated with response of oligodendroglial tumors to procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy. DESIGN: Retrospective, observational multicenter study. METHODS: Patients treated with PCV or intensified PCV chemotherapy for a recurrent oligodendroglial tumor after surgery and radiation therapy with measurable disease were retrospectively evaluated for response. A 50% reduction in cross-sectional enhancing tumor area was considered a partial response. Stabilized or responding patients received six cycles of PCV unless unacceptable toxicity occurred. RESULTS: Fifty-two patients were included; median time to progression (MTP) for the entire group was 10 months. In 17% of patients a complete response (MTP, 25 months) was obtained, and in 46% a partial response (MTP, 12 months) was obtained. Median overall survival was 20 months. Although treatment was discontinued for toxicity in seven patients, it was generally well tolerated. The intensified PCV regimen was more toxic. Patients initially presenting with seizures and patients with tumor necrosis in histologic specimens had a better response rate in contrast to patients who had their first relapse within 1 year of first treatment (surgery and radiation therapy). CONCLUSIONS: Oligodendroglial tumors are chemosensitive, but most patients will have relapsed after 12 to 16 months. New studies must aim at improving initial treatment and second-line chemotherapy.

Adolescent↗

PubMed1997

Pleomorphic xanthoastrocytoma: DNA flow cytometry and outcome analysis of 12 patients.

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is an astrocytic tumor occurring primarily in childhood and adolescence with some malignant histologic features but a relatively slow clinical course. However, some tumors progress more rapidly and can undergo malignant degeneration. The authors attempted to determine whether various histologic features or tumor cell proliferative indices might help identify lesions at risk for early progression and distinguish PXAs from malignant gliomas. METHODS: In a retrospective study of 12 patients with PXA, the tumor's histologic features and DNA flow cytometric parameters were compared with their clinical course. DNA flow cytometry values for the S- and G2-phase of the PXAs also were compared with control group samples of malignant and low grade astrocytomas. RESULTS: Of the 12 tumors at initial diagnosis, 5 were considered typical PXAs whereas 7 had some atypical features (4 with paucity of reticulin fibers, 1 with focal necrosis, and 2 with both atypical reticulin and focal necrosis). During the follow-up period (range, 3.75-11 years; mean, 6.8 years), 2 patients had recurrences; 1 atypical reticulin PXA progressed to glioblastoma after 6.5 years and the 1 tumor with focal necrosis recurred at 6 months and again at 2 years with typical histologic features. DNA flow cytometry parameters of the typical PXA group were similar to values for malignant astrocytoma and significantly higher than values for control specimens of low grade astrocytomas. There were no distinctive DNA flow cytometric features that could distinguish this last tumor from others with a more benign clinical course. CONCLUSIONS: Measurements of the S-phase and G2-phase obtained from DNA flow cytometry and atypical histologic features cannot reliably identify PXA patients at risk for early progression and overall are significantly higher than values obtained for low grade gliomas. Therefore, frequent (i.e., two to three times per year) postoperative clinical and radiologic examinations are necessary to judge the appropriateness of adjuvant therapy in patients with PXA. The paradox of slow growth but DNA flow cytometry consistent with aggressive malignant lesions may represent a cell-cycle arrest mechanism in these lesions that could be verified in subsequent studies.

Adolescent↗