Biomedical subjects
Publications and source records attributed to K Mokhtari.
Interleukin-6 (IL-6) is known to promote tumour growth and survival. We evaluated IL-6 gene amplification in tumours from 53 glioma patients using fluorescence in situ hybridisation. Amplification events were detected only in glioblastomas (15 out of 36 cases), the most malignant tumours, and were significantly associated with decreased patient survival.
A wild common dolphin was found stranded on the French Atlantic coast. At necropsy, an intracranial grey- to tan-coloured mass (7 x 5 x 4 cm) was found at the right cerebellopontine angle, compressing the right cerebellar hemisphere, the brainstem and the occipital lobe of the right cerebral hemisphere. Microscopically, the tumour was composed of small lobules of polygonal to elongated neoplastic cells with multifocal areas of stellate and vacuolated cells. Neoplastic cells strongly expressed vimentin, S-100 protein and neuron-specific enolase. They were rarely positive for cytokeratin. Ultrastructurally, the neoplastic cells displayed all the diagnostic features of meningiomas and in some areas showed long cytoplasmic processes delimiting extracellular spaces. The immunohistochemical and ultrastructural features were consistent with the histopathological diagnosis of a microcystic meningioma. This is the first report of a meningioma in dolphins or in any other cetacean species.
INTRODUCTION: Optic pathways cavernomas are rare vascular hamartomas that can present either with an acute chiasmal syndrome or slowly progressive visual loss. OBSERVATION: A 29-year-old patient presented with mild unilateral visual loss of rapid onset and monocular left temporal hemianopia. MRI disclosed a heterogenous enhancing optochiasmal lesion. Work-up found no evidence for an inflammatory, infectious or tumoral disease and therefore a neurosurgical approach of the lesion allowed diagnosis of cavernoma, confirmed by pathological examination. Successful resection resulted in partial recovery of the visual field. CONCLUSION: Optochiasmal cavernomas are rare, removal can improve visual outcome.
The expression of Olig2, a basic helix-loop-helix (bHLH) transcription factor involved in oligodendroglial specification, was investigated by immunohistochemistry in a series of 146 tumours and control samples. Olig2 expression was restricted to glial tumours and nontumoral oligodendrocytes. It was higher in oligodendrogliomas as compared to astrocytomas and oligoastrocytomas, and in grade III as compared to grade II tumours. Olig 2 was absent or weakly expressed in glioblastoma (GBM), whereas strong expression was found in the oligodendroglial foci of GBM with oligodendroglial component (GBMO). Double labelling was performed on a subset of the most typical tumours, according to the WHO classification. It showed a mutual exclusion, at cell level, of Olig2 and GFAP expression. In pure oligodendrogliomas, tumour cells were Olig2+/GFAP-. In contrast, two main tumour populations, Olig2+/GFAP- and Olig2-/GFAP+, were found in both oligoastrocytomas and astrocytomas. Based on these data from selected samples, two separate entities can be established, corresponding to 'pure oligodendrogliomas' and 'astrocytomas and oligoastrocytomas'. The relevance of this subdivision is further supported by the association with 1p loss and a trend to better survival for pure oligodendrogliomas and with p53 expression and a trend to shorter survival for astrocytomas and oligoastrocytomas. Combined testing of Olig2, 1p status, GFAP and p53 expression may therefore be helpful in refining current classification and providing more homogeneous sets of gliomas for clinical studies.
OBJECTIVE: To investigate possible correlations between tumor location and genetic alterations in a series of oligodendrogliomas. METHODS: A series of 158 consecutive oligodendrogliomas were retrospectively reviewed. In each case, the radiologic picture and the chromosome 1p (chr 1p) status of the tumor detected by the loss of heterozygosity technique were analyzed. Correlation between tumor location and molecular profile was made by chi2 tests. RESULTS: Eighty-eight of the 158 patients had low-grade oligodendrogliomas, and 70 had anaplastic oligodendrogliomas. Overall, oligodendrogliomas with chr 1p loss were located preferentially in the anterior part of the brain, whereas tumors with intact chr 1p affected mainly the posterior part of the brain (p = 0.0038). In terms of lobar involvement, a preferential location of oligodendrogliomas with chr 1p loss was found in the frontal lobes as compared with the temporal, parietal, and occipital tumors (p < 0.01). CONCLUSION: There is a significant correlation between loss of heterozygosity on chromosome 1p and tumor location in oligodendrogliomas, suggesting that subtypes of oligodendrogliomas could derive from site-specific precursors.
PURPOSE: To determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response. PATIENTS AND METHODS: Adult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique. RESULTS: Sixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004). CONCLUSION: TMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.
BACKGROUND: Because of the diffuse nature of gliomatosis cerebri (GC), surgery is not suitable, and large field radiotherapy carries the risk of severe toxicity. In this setting, initial chemotherapy warrants further investigation. METHODS: The authors treated 63 consecutive patients with GC with initial chemotherapy consisting of either PCV (procarbazine, 60 mg/m2 on days 8 to 21; CCNU, 110 mg/m2 on day 1; and vincristine, 1.4 mg/m2 on days 8 and 29) or temozolomide (TMZ; 150 to 200 mg/m2 for 5 days every 4 weeks). There were 40 men and 23 women, with a median age of 48 years (range, 17 to 74 years) and a median Karnofsky performance status of 90 (range, 50 to 100). GC was initially present at diagnosis in 49 patients (primary GC), whereas 14 patients with a circumscribed glioma at onset developed secondary GC after a median follow-up period of 5.11 years. GC was classified based on the predominant tumor cells as astrocytic, oligodendroglial, or mixed GC. RESULTS: Seventeen patients received 1 to 6 cycles (median, 5) of PCV, and 46 received 2 to 24 courses (median, 13) of TMZ. Grade 3 to 4 hematologic toxicity was seen in 4 of 17 (23.5%) patients treated with PCV and in 4 of 46 (8.6%) of those treated with TMZ. Clinical objective responses were observed in 21 of 63 (33%) patients, and radiologic responses were seen in 16 of 62 (26%), with no significant difference between the two regimens. For all patients combined, the median progression-free survival (PFS) and overall survival (OS) were 16 months and 29 months, respectively. Regardless of the chemotherapeutic regimen, oligodendroglial GC had a better prognosis than astrocytic and oligoastrocytic GC in terms of PFS (p < 0.02) and OS (p < 0.0001). CONCLUSION: Initial chemotherapy is useful for some patients with gliomatosis cerebri. Temozolomide is well tolerated and appears to be a valuable alternative to procarbazine-CCNU-vincristine, especially for those with slow-growing, low-grade GC.
The 190 kDa multidrug resistance protein MRP1 is likely to be involved in the multidrug resistance phenotype of human gliomas. MRP1 expression was evaluated in surgical tumor samples from 17 patients with gliomas. In addition, the impact of the MRP's inhibitor, indomethacin, on the chemosensitivity to etoposide (VP16) and vincristine (VCR) of two glioblastoma cell lines expressing MRP1 (GL15 and 8MG) was investigated. When evaluated in tumor samples, MRP1 expression was observed in all of them with more than 90% of stained tumor cells in 14/15 high-grade gliomas. MRP1 was also strongly expressed at the membrane of the vascular endothelial cells in the same 14 tumor samples, suggesting that the permeability to anticancer drugs could be also limited across brain tumor vessels. At concentrations comprised between 5 and 50 microM, indomethacin significantly increased the cytotoxic effect of etoposide in both cell lines but it was more efficient in increasing the cytotoxicity of VCR on GL15 cells, as compared with 8MG cells. These results suggest that the association of indomethacin to VCR or etoposide could be of interest in the clinical management of gliomas.
Intravascular malignant lymphomatosis is a rare and probably often overlooked disease characterised by massive intravascular proliferation of lymphoid cells, usually with a poor prognosis. CT and MRI appearances are nonspecific; the most suggestive finding being both asymmetrical, bilateral, contrast enhancing high-signal areas on T2 weighting and infarct-like lesions of the cortex and basal ganglia. We report two patients with previously unreported dural and spinal cord involvement.
OLIG 1/2 genes encode basic helix-loop-helix transcription factors that play a critical role in motor neurone and oligodendrocyte fate specification during development. Two recent studies in which OLIG transcripts were detected by in situ hybridization have reported a high expression of the OLIG genes in oligodendrogliomas. This suggests that the detection of these lineage markers could become an adjunct to the classic morphological diagnosis of these tumours. There are problems in the diagnosis of oligodendroglioma. To date, all other known oligodendrocyte lineage markers have failed to label specifically neoplastic oligodendrocytes. Deletions on chromosome 1p and 19q are much more frequent in oligodendrogliomas than in astrocytomas but these molecular alterations are not constant. For the future, when routinely available, immunohistochemical techniques using anti-OLIG antibodies on paraffin embedded tissues will allow a systematic study of a large series of tumours so that we will know the specificity and sensitivity of this investigation in diagnosis. At another level, it is possible that expression of OLIG in neoplastic oligodendrocyte might participate in the oncogenesis of oligodendrogliomas. Initial work suggests that this is probably not the case. However further in vitro and in vivo studies analysing the functional consequence of OLIG overexpression in terms of proliferation and tumour progression are needed.
INTRODUCTION: Extra-axial cavernous hemangiomas or angiomas [(hem)angiomas] are relatively rare lesions. They usually arise in relation to the dura mater intracranially or at the spinal level. Most of these lesions have been described in the middle cranial fossa at level of the cavernous sinus. Controversy still exists regarding the exact nature of these extra-axial cavernous angiomas: vascular tumor versus vascular malformation similar to intra-axial cavernomas. It has been suggested that they could represent an adult form of the hemangioma of infancy. Extra-axial cavernous (hem)angiomas often mimic meningiomas and their clinical behavior and imaging appearance are quite different than those of intra-axial cavernous angiomas. SUBJECTS AND METHODS: Five patients ranging in age from 24 to 63 years with a histologically proven dural cavernous angioma were retrospectively included. The lesions were located at level of the cavernous sinus (4 cases) and falx. CT and MR scans were performed in all cases and angiography in three patients. Four patients underwent surgery and a biopsy was performed in one case. One lesion was embolized before biopsy. Histology was available in all patients. RESULTS: In the operated patients, the lesion was totally resected in 2 cases and partially in the other 2. No postsurgical complication was noted. Histology revealed a vascular malformation composed of large vascular channels lined by flat endothelium and separated by fibroconnective tissue stroma. The pathological diagnosis was cavernous angioma. CONCLUSION: On the basis of the analysis of the literature and of our cases, intra-cranial extra-cerebral so-called cavernous (hem)angiomas present findings suggesting that they are vascular malformative lesions, analogous to the intra-axial cavernous angioma. A relationship with the hemangiomas of infancy seems unlikely. Correct terms for extra-cerebral cavernous (hem)angiomas are cavernoma, cavernous angioma, or venous vascular malformation of cavernous type . The term hemangioma should be avoided and reserved for the common vascular tumor of infancy.
HIV infection is associated with a high incidence of AIDS-related lymphomas (ARLs). Since the use of highly active antiretroviral therapy (HAART), the incidence of AIDS-defining illnesses has decreased, leading to a significant improvement in survival of HIV-infected patients. The consequences of HAART use on ARL are under debate. This study compared the incidence and the characteristics of ARL before and after the use of HAART in a large population of HIV-infected patients in the French Hospital Database on HIV (FHDH) and particularly in 3 centers including 145 patients with proven lymphoma. Within the FHDH, the incidence of systemic ARL has decreased between 1993-1994 and 1997-1998, from 86.0 per 10 000 to 42.9 per 10 000 person-years (P < 10(-30)). The incidence of primary brain lymphoma has also fallen dramatically between the periods, from 27.8 per 10 000 to 9.7 per 10 000 person-years (P < 10(-11)). The analysis of 145 cases of ARL in 3 hospitals showed that known HIV history was longer in the second period than in the first period among patients with systemic ARL (98 versus 75 months; P <.01). Patients had a higher number of CD4 cells at diagnosis during the second period (191 versus 63/microL, P = 10(-3)). Survival of patients with systemic ARL also increased between the periods (from 6 to 20 months; P =.004). Therefore, the profile of ARL has changed since the era of HAART, with a lower incidence of systemic and brain ARL. The prognosis of systemic ARL has improved.
OBJECTIVE: To identify different genetic molecular profiles in oligodendrogliomas and to evaluate their prognostic significance. METHODS: The main genetic alterations reported in glial tumors were investigated in 26 oligodendrogliomas (10 World Health Organization grade II and 16 World Health Organization grade III). Correlation between identified molecular changes and pathologic grade or clinical course was subsequently analyzed using univariate and multivariate statistical analyses. RESULTS: Loss of heterozygosity (LOH) on chromosome 1p, 19q, and 10; P16/CDKN2A homozygous deletion; EGFR (epidermal growth factor receptor) amplification; and TP53 and PTEN mutations were observed in 14 (54%), 15 (58%), 9 (35%), 7 (27%), 5 (19%), 1 (4%), and 0 cases. LOH 1p and 19q were tightly associated (p < 0.0001). A mutual exclusion was found between LOH 1p/19q and EGFR amplification (p = 0.01), P16/CDKN2A deletions (p = 0.001), or LOH on 10q (p = 0.03), suggesting the existence of distinct genetic subsets in oligodendrogliomas. On univariate analysis, age <50 years (p = 0.002) and LOH 1p (p = 0.01) were associated with a longer progression-free survival (PFS) whereas LOH 10q (p = 0.03) and EGFR amplification (p = 0.007) were associated with a worse PFS. In multivariate analyses, age <50 years (p = 0.001) and LOH 1p (p = 0.006) remained independent predictive factors for PFS. CONCLUSION: These results provide evidence for two alternative molecular pathways of progression in oligodendrogliomas. The first one is associated with loss of 1p and 19q and the second one with P16/CDKN2A deletion, 10q loss, and EGFR amplification. The findings confirm the value of loss of 1p as predictor of longer progression-free survival; in addition, the study demonstrates the unfavorable impact of 10q loss and EGFR amplification on the prognosis.
Because of the increasing incidence of primary central nervous system lymphoma (PCNSL), it is essential to recognize this disease in order to start appropriate treatment. We present the characteristic CT and MRI features of this tumour. The findings of 32 CT and 31 MR of 37 immunocompetent patients with biopsy-proved PCNSL are reviewed. The main features are presented and analysed, and are discussed in comparison with proven literature data. Primary central nervous system lymphoma presents as supratentorial solitary lesions in approximately 80% of the patients and multiple lesions in 20%. In contrast to classical data, the lesions are located in deep structures only in one-third of the cases, and involve posterior fossa in 10% of cases. Most of the lesions are hyperdense or isodense (92%) on CT, hypointense or isointense on T1-weighted images, and only about 40% are hyperintense on T2-weighted images. Nearly all the lesions enhance, except after corticosteroid administration. They produce mild oedema and mass effect. Meningeal or ventricular enhancement are rare but suggestive. Calcification, haemorrhage or necrosis are scarce. Although PCNSL in immunocompetent patients have a variable CT and MR appearance, the imaging data often suggest the diagnosis.
OLIG2 is a recently identified transcription factor involved in the specification of cells in the oligodendroglial lineage. We investigated the expression of OLIG2 by in-situ hybridisation in 21 brain tumours: nine grade II and III oligodendrogliomas, three grade II oligoastrocytomas, and nine non-oligodendroglial tumours (four grade IV astrocytomas, two meningiomas, a dysembryoplastic neuroepithelial tumour, and two metastases). OLIG2-positive cells corresponding to neoplastic oligodendrocytes were present in all oligodendrogliomas and oligoastrocytomas. By contrast, OLIG2 expression was not detected in the non-oligodendroglial tumours. Thus, oligodendroglioma probably arise from oligodendrocyte precursor cells. OLIG2 should prove a useful marker for the diagnosis of oligodendroglial tumours.
Cerebral meningiomas account for 15-20% of all cerebral tumours. Although seldom malignant, they frequently recur in spite of complete surgery, which remains the cornerstone of the treatment. In order to decrease the probability of local recurrence, radiotherapy has often been recommended in atypical or malignant meningioma as well as in benign meningioma which was incompletely resected. However, this treatment never was the subject of prospective studies, randomized or not. The purpose of this review of the literature was to give a progress report on the results of different published series in the field of methodology as well as in the techniques of radiotherapy. Proposals for a therapeutic choice are made according to this analysis. For grade I or grade II-III meningiomas, limits of gross tumor volume (GTV) include the tumour in place or the residual tumour after surgery; clinical target volume (CTV) limits include gross tumour volume before surgery with a GTV-CTV distance of 1 and 2 cm respectively. Delivered doses are 55 Gy into CTV and 55-60 Gy and 70 Gy into GTV for grade I and grade II-III meningiomas respectively.
Glioblastoma (GBM) is considered by the WHO classification to represent the most malignant grade of the astrocytic tumors. However, a subset of GBM includes recognizable areas with oligodendroglial features, suggesting that some GBM may also have an oligodendroglial origin. The aim of this study was to analyze the molecular profile of GBM associated with an oligodendroglial component (GBMO). We analyzed a series of 25 GBMO. Loss of heterozygosity (LOH) on 1p and 19q, known as common markers of oligodendroglial tumors, were observed in 40% and 60% of cases, respectively; 72% of the tumors displayed one or both of these markers. All but 4 tumors (84%) showed alterations known to be preferentially involved in the progression of astrocytic tumors to GBM, such as EGFR amplification (44%), P16 deletion (48%), LOH on 10q (64%), PTEN (20%), and TP53 (24%) mutations. Therefore, GBMO displayed all the genetic aberrations found in "standard" GBM with a comparable incidence, but differed from GBM by having a higher rate of LOH on 1p and 19q. These results suggest that GBMO might represent a subgroup of tumors of oligodendroglial origin that is distinct from the "standard" GBM in terms of tumorigenesis pathway.
OBJECT: Tumor size is one of the features commonly used in oncology to predict disease evolution. However, for most primary brain tumors it is not predictive of outcome. Taking advantage of a gene therapy trial in which recurrences of glioblastoma were targeted with suicide genes, the authors developed a new parameter: the extent of tumor-brain interface--also called surface of tumor volume (STV)--to better describe three-dimensional conformation and the relationship between tumors and the surrounding normal tissue. Correlations between the STV and the usual clinical parameters were analyzed. METHODS: Between 1995 and 1998, 16 patients presenting with recurrent glioblastomas were enrolled in this study. Preoperative magnetic resonance images were analyzed on a separate workstation; the interface between tumor and normal brain tissue was measured on each 3-mm-thick section to assess STV. The mean STV was 29.2 cm2, and the mean tumor volume (TV) was 23.8 cm3. The STV was significantly correlated with survival (Spearman test: r = -0.54, p = 0.03), but TV was not (Spearman test: r = -0.39, p = 0.15). A separate analysis of responding and nonresponding patients showed that, as expected, STV was negatively correlated with survival among nonresponding patients (p = 0.04), but that among responding patients there was a positive tendency between STV and survival. CONCLUSIONS: These findings indicate that STV may be a useful tool for predicting the evolution of malignant glioma. Moreover, in future gene therapy trials in which such in situ approaches are used, increasing density and improved distribution of transfer cells should be taken into consideration as an important issue for efficacy.