Case Of Anaplastic Astrocytoma Research Articles

P11.07 BRAF V600E mutation: has it a role in pediatric gliomas?

Abstract Introduction: Pediatric high-grade gliomas (HGGs) represent a malignancy with a low survival rate. The genetic analysis of these tumors has identified useful mutations for an improved prognostic framing, as well as potential targets for new generation drugs. Previous studies have shown that the presence of BRAF V600E mutation in 23% of all pediatric gliomas reaching about 10% in WHO-grades III and IV, suggesting this alteration is one of the most common gene alterations in pediatric gliomas. BRAF mutation may help to differentiate indolent cancer from aggressive ones; tumors with BRAF V600E have a strong trend toward an increased risk for progression, developing a second cancer with anaplastic evolution. Moreover, BRAF mutation is a possible target for improved adjuvant treatment of residual or recurrent tumors. Materials and Methods: We performed a retrospective analysis of a population of pediatric patients with HGGs. Mutation analysis was carried out on DNA from each tumor sample. Portions coding and their flanking regions were amplified by PCR. The data were obtained after the purification of the samples and analysis by means of specific software. Results: We retrospectively evaluated 41 cases of pediatric HGGs. The median age at diagnosis was 7 years (range 0-32). The histological samples included: 9 cases of glioblastoma multiforme, 28 cases of anaplastic astrocytoma (AA), 3 glioneuronal tumor with neuropil-like islands (GTNI) and 1 glioma with mist components (2,45%). BRAF V600E mutation was analyzed in 27 samples: 21 patients did not have the mutation (77.77%), 6 patients showed the mutation (22,22). Four of 6 AA patients derived from a previous low grade tumor (3LGGs, and 1 GTNI) (p: 0.001). The BRAF V600E mutation seems therefore associated with increased risk of anaplastic progression. Finally, we have valuated the correlation between the presence of BRAF mutation and the tumor histology without statistically significant results (p: 0.12). Conclusions: The genetic analysis of tumor samples from children with HGGs represents an essential contribution to the prognostic stratification for each new diagnosis. BRAFV600E mutation is a negative prognostic factor in pediatric gliomas and a potential target of specific inhibitors. Considering the high rate of recurrence of these tumors and the limited impact on disease control of the following treatments, BRAF V600E detection is essential for a new therapeutic approach of poor responsive diseases.

Coexistence of anaplastic astrocytoma and arteriovenous malformation

Coexistence of astrocytoma with cerebral vascular malformations is unusual, especially if both lesions occur separately. Preoperative angiogram will help us to identify any coexisting arteriovenous malformation (AVM). This will in turn change the treatment strategy for astrocytoma. Preoperative embolization for AVM may be done prior to the glioma excision. There is increased risk of bleeding if AVMs are not preoperatively diagnosed. AVMs coexisting with astrocytomas are rare. We report a case of anaplastic astrocytoma coexisting with an acquired AVM.

Survivin, caspase-3 and MIB-1 expression in astrocytic tumors of various grades

PurposeGliomas are the most common primary brain tumors. The etiology is still unclear and the progression from low to high-grade gliomas is frequent. The molecular mechanisms are quite established, however the heterogeneity of glioblastomas force the scientist to look for the new therapeutic targets. The aim of the study was to evaluate the caspase-3 and survivin expression in correlation with MIB-1 expression in gliomas of various grade to assess the apoptosis in gliomas and to determinate new possible targets for the future therapy. Material and methodsWe identified 131 patients with a histopathological diagnosis of astrocytic tumors (diffuse astrocytoma, anaplastic astrocytoma and glioblastoma). The evaluation of caspase-3, survivin and MIB-1 expression was done using immunohistochemical methods. ResultsCaspase-3 and survivin expression was observed both in low- and high-grade astrocytomas. The differences in expression were the most evident in glioblastoma group. All primary glioblastomas (31 cases) expressed caspase-3. In secondary glioblastoma group only 17 out of 30 specimens were positive for caspase-3. Survivin expression was observed in 80.6% primary glioblastomas and in all examined secondary glioblastomas and the staining was strong and diffuse in all cases. MIB-1 expression was low in diffuse astrocytomas (DA) and ranged between 1 and 5%. In anaplastic astrocytoma group it was ranged between 5 and 10% and the highest percentage of the positive cells was observed in glioblastoma cases and ranged from 10% even to 30%. The most evident MIB-1 expression was observed in the cells surrounding the pathological blood vessels and necrosis. ConclusionsThe high incidence of survivin and caspase-3 expression in diffuse and anaplastic astrocytoma cases may suggest, that the regulation between pro- and antiapoptotic proteins may play an important role in tumor growth and progression. The overexpression of survivin and MIB-1 expression in glioblastoma cases also may confirm the theory about the important role of anti-apoptotic and proliferation processes in glioblastoma progression and as such may be potential therapeutic targets.

Prognostic Value of ALDH1, EZH2 and Ki-67 in Astrocytic Gliomas.

Tumor stem cells have been found in a variety of neoplasms and stated to have a role in tumor progression. This study aimed to evaluate the prognostic significance of biomarkers which are said to be related to these cells, i.e., EZH2, ALDH1 and Ki-67, and their correlation with each other in astrocytic gliomas. Formalin-fixed, paraffin-embedded tissue specimens of 40 patients with astrocytic glioma who underwent initial surgery during the period from December 2011 to May 2014 at Zagazig University Hospitals were enrolled in the study. Consecutive 4-μm thick sections from formalin-fixed, paraffin-embedded tissue blocks were prepared and stained with hematoxylin and eosin for histopathological evaluation. Immunohistochemical analysis using ALDH1, EZH2 and Ki-67 antibodies were performed to examine the cases. A total of forty patients; 22 males and 18 females were studied. The lesions were classified as follows: 14 cases of low-grade astrocytoma (WHO grade I or II), 11 cases of anaplastic astrocytoma (WHO grade III), and 15 glioblastomas (WHO grade IV). There was a significant increase in ALDH1 immunoreactivity with increasing the grade of astrocytoma (mean ±SD = 0.2 ±0.4, 0.5 ±0.6, 1.1 ±1.3 and 2.95 ±2.97 in grade I to IV astrocytic gliomas, respectively). This expression was significantly correlated with overall survival (OS) and progression-free survival (PFS) (P=0.004). EZH2 expression was also significantly associated with advanced grades (mean ±SD =1.35 ±0.4, 3.1 ±2.6, 7.2 ±3.5 and 9.9 ±4.1, in grade I to IV astrocytic gliomas, respectively). EZH2 and Ki-67 expressions were found to be correlated with OS and PFS (P < 0.001). Increased expression of ALDH1, EZH2 and KI67 are found to be associated with unfavourable prognosis in patients with astrocytic gliomas and may predict therapeutic modalities.

RTRB-02EFFECTIVENESS OF MULTIPLE FRACTIONS GAMMA KNIFE THERAPY FOR RECURRENT MALIGNANT ASTROCYTIC TUMORS WITHOUT BEVACIZUMAB

INTRODUCTION: As temozolomide (TMZ) therapy has now become standard therapy for malignant glioma (MG), patients surviving for the long term have increased. However, use of gamma knife as second-line therapy for recurrent MG cases is not always effective. We therefore compared single- and multiple-fraction groups to clarify survival and outcomes for patients with recurrent MG. MATERIAL AND METHODS: A total of 16 consecutive cases of recurrent MG were given Gamma Knife therapy between April 2010 and September 2014 without bevacizumab, including 12 cases of glioblastoma, 1 case of anaplastic astrocytoma, and 3 cases of anaplastic oligoastrocytoma. Seven cases (total number, 8 cases) were single-fraction cases and 9 cases (total number, 13 cases) were multiple-fraction cases. RESULTS: The single-fraction group was given a 50% marginal dose of 21–24 Gy to a total of 15 lesions. The multiple-fraction group was given a 50% marginal dose of 7.5–14.5 Gy in two or three fractions, to a total of 36 lesions. Mean number of lesions treated, M-PFS, M-OS, and tumor control rate (CR, PR, SD) were 1.9, 2.3 months, 7.6 months, and 25% in the single-fraction group, and 2.8, 3.4 months, 10.0 months, and 67.2% in the in the multiple-fraction group, respectively. CONCLUSIONS: Although no significant differences in PFS, OS, or tumor control rate were evident between single- and multiple-fraction groups, the multiple-fraction group tended to show longer PFS and OS and better control rate compared to the single-fraction group.

Overexpression of Eg5 correlates with high grade astrocytic neoplasm.

To investigate the relationship between Eg5 and histopathological grade of astrocytoma, Eg5 expression was evaluated by immunohistochemical examination on 88 specimens including 25 cases of glioblastoma (WHO grade IV), 22 cases of anaplastic astrocytoma (WHO grade III), 20 cases of diffuse astrocytoma (WHO grade II), and 21 cases of pilocytic astrocytoma (WHO grade I). The histopathological characteristics and Eg5 expression level of each tumor were assessed and statistically analyzed. Astrocytic tumors exhibited significant correlation of expression of Eg5 with higher WHO histopathological grades (p < 0.001). Eg5 is expressed in 51-98% (mean 76.88%) of neoplastic cells in glioblastoma, 34-57% (mean 43.59%) of neoplastic cells in anaplastic astrocytoma, 6-36% (mean 18.60%) of neoplastic cells in diffuse astrocytoma, and 2-28% (mean 13.48%) of neoplastic cells in pilocytic astrocytoma. In conclusion, overexpression of Eg5 associates with high-grade astrocytic neoplasm, and it may represent an independent diagnostic and prognostic factor in grading astrocytic tumors and predicting prognosis of astrocytic tumor patients.

EG-08 * IDH MUTATIONS IN GLIOMAS ASSOCIATED WITH ENCHONDROMATOSIS

The enchondromatoses, Ollier's disease and Maffucci syndrome, are non-heritable developmental disorders characterized by multiple enchondromas (Olllier's) in association with hemangiomas (Maffucci). Glial neoplasms are reported in both disorders but a pathogenic mechanism underlying this association has not been identified. We report a case of anaplastic astrocytoma in a 23 year old man with Maffucci syndrome whose tumor carried a substitution mutation of arginine for cysteine at position 132 (R132C) of the isocitrate dehydrogenase 1 (IDH1) protein. This mutation, commonly found in Maffucci-associated enchondromas and hemangiomas, was not detected on routine immunohistochemical (IHC) analysis of the astrocytoma using the R132H mutation-specific antibody, commonly applied in clinical laboratories. The R132C mutation was detected by polymerase chain reaction (PCR) and subsequently confirmed using a SNaPshot assay. Because somatic mosaic IDH mutations are associated with enchondromas and hemangiomas in Maffucci syndrome, we looked for the R132C mutation in a hemangioma, peripheral blood mononuclear cells (PBMNC) and histologically normal brain surrounding the tumor from this patient. The mutation was present in the hemangioma, absent in PBMNC, and present in 2% of alleles in ‘normal’ brain. The low level in surrounding brain tissue is consistent with tumor cell infiltration, not mosaicism, as a S173T p53 mutation in the tumor showed similar results. Using IHC, we further demonstrated that the mutant IDH1 protein in this glioma functions as an oncometabolite. Two repressive histone trimethylation marks were strongly positive in the tumor, supporting a role for 2-hydroxyglutarate in the inhibition of histone demethylation. Together, these data demonstrate that an IDH1 mutation common in enchodromatoses underlies the association of glial tumors reported in both Ollier's disease and Maffucci syndrome.

Intraoperative rapid diagnosis of primary central nervous system lymphomas: advantages and pitfalls.

To study the advantages and pitfalls of intraoperative rapid diagnosis (IRD) of primary central nervous system lymphomas (PCNSL), pathology reports and frozen sections in our institution were reviewed. We examined 27 cases of PCNSL, one case of anaplastic glioma, and one case of metastatic brain tumor that were diagnosed on neuroimaging. Fifteen cases of intraoperative cytological preparations were also reviewed in a correlative manner. Among the 27 cases initially diagnosed as PCNSL, 18 were also diagnosed as PCNSL by IRD. However, IRD identified four of the 27 cases as gliosis, two as demyelination, one as atypical epithelial cells, one as malignant glioma and anaplastic astrocytoma. In addition, the case identified as metastatic brain tumor on neuroimaging was corrected to a diagnosis of PCNSL based on IRD. The final accuracy of IRD in the present study was 89.6% (26/29). After postoperative definitive diagnosis, two cases of anaplastic astrocytoma and one case of PCNSL by IRD were corrected to PCNSL, anaplastic oligodendroglioma and demyelination, respectively. PCNSL were sometimes histologically indistinguishable from malignant gliomas or demyelinating diseases in the present study, particularly in frozen sections. Notably, all cases for which both intraoperative cytology and frozen section were performed concomitantly were correctly diagnosed in the present study. In particular, lymphoglandular bodies were highly characteristic cytological findings of PCNSL. Both intraoperative cytology and frozen sections should therefore be performed concomitantly when PCNSL are suspected.

Perfusion magnetic resonance imaging for high grade astrocytomas: Can cerebral blood volume, peak height, and percentage of signal intensity recovery distinguish between progression and pseudoprogression?

ObjectivesTo study the usefulness of common MRI perfusion parameters for identifying pseudoprogression in high grade astrocytomas. Materials and methodsThis retrospective case–control study compared the relative cerebral blood volume (rCBV), the relative percentage of signal intensity recovery (rPSR), and the relative peak height (rPH) recorded in a sample of 17 cases of anaplastic astrocytomas and gliomas considered to be undergoing pseudoprogression by biopsy or follow-up with those recorded in a sample of histologically similar tumors that were treated and considered to be undergoing progression by histologic study or follow-up. We evaluated the accuracy of these parameters and the correlations among them. Statistical significance was set at p<.05. ResultsThe rCBV, rPSR, and rPH were significantly different between the two groups (p=.001). The cutoff values rPH=1.37, rCBV=0.9, and rPSR=99% yielded sensitivity (S)=88% and specificity (Sp)=82.2% for rPH, S=100% and Sp=100% for rCBV, and S=100% and Sp=70.6% for rPSR, respectively. We found negative correlations between rPRS and rPH (−0.76) and between rPRS and rCBV (−0.81) and a high positive correlation between rPH and rCBV (0.87). ConclusionThe variables rPH and rCBV were useful for differentiating between pseudoprogression and true progression in our sample. The variable rPRS was also very sensitive, although the overlap in the values between samples makes it less useful a priori.

Radiobiological Framework for the Evaluation of Stereotactic Radiosurgery Plans for Invasive Brain Tumours

This study presents a radiobiological formalism for the evaluation of the treatment plans with respect to the probability of controlling tumours treated with stereotactic radiosurgery accounting for possible infiltrations of malignant cells beyond the margins of the delineated target. Treatments plans devised for three anaplastic astrocytoma cases were assumed for this study representing cases with different difficulties for target coverage. Several scenarios were considered regarding the infiltration patterns. Tumour response was described in terms of tumour control probability (TCP) assuming a Poisson model taking into account the initial number of clonogenic cells and the cell survival. The results showed the strong impact of the pattern of infiltration of tumour clonogens outside the delineated target on the outcome of the treatment. The treatment plan has to take into account the existence of the possible microscopic disease around the visible lesion; otherwise the high gradients around the target effectively prevent the sterilisation of the microscopic spread leading to low probability of control, in spite of the high dose delivered to the target. From this perspective, the proposed framework offers a further criterion for the evaluation of stereotactic radiosurgery plans taking into account the possible infiltration of tumour cells around the visible target.

Resonancia magnética de perfusión en astrocitomas de alto grado: el volumen sanguíneo cerebral, la altura del pico y el porcentaje de recuperación de intensidad de señal ¿pueden discriminar entre progresión y seudoprogresión?

To study the usefulness of common MRI perfusion parameters for identifying pseudoprogression in high grade astrocytomas.This retrospective case-control study compared the relative cerebral blood volume (rCBV), the relative percentage of signal intensity recovery (rPSR), and the relative peak height (rPH) recorded in a sample of 17 cases of anaplastic astrocytomas and gliomas considered to be undergoing pseudoprogression by biopsy or follow-up with those recorded in a sample of histologically similar tumors that were treated and considered to be undergoing progression by histologic study or follow-up. We evaluated the accuracy of these parameters and the correlations among them. Statistical significance was set at P<.05.The rCBV, rPSR, and rPH were significantly different between the two groups (P=.001). The cutoff values rPH=1.37, rCBV=0.9, and rPSR=99% yielded sensitivity (S)=88% and specificity (Sp)=82.2% for rPH, S=100% and Sp=100% for rCBV, and S=100% and Sp=70.6% for rPSR, respectively. We found negative correlations between rPRS and rPH (-0.76) and between rPRS and rCBV (-0.81) and a high positive correlation between rPH and rCBV (0.87).The variables rPH and rCBV were useful for differentiating between pseudoprogression and true progression in our sample. The variable rPRS was also very sensitive, although the overlap in the values between samples make it less useful a priori.

Second primary brain tumors following cranial irradiation for pediatric solid brain tumors

We describe our institution's experience with seven patients who developed second brain tumors following cranial irradiation. The median age at first irradiation was 8 years (range, 3-20 years). Initial diagnoses were two cases of germinoma, one non-germinomatous germ cell tumor (NGGCT), three cases of medulloblastoma, and one pineal gland tumor (pathology undetermined). All patients received craniospinal irradiation followed by local boost and the median dose to the initial tumor area was 54.0 Gy (range, 49.8-60.6 Gy). Four patients (two medulloblastomas, one germinoma, and one NGGCT) received chemotherapy. Second brain tumors were diagnosed a median of 114 months (range, 64-203) after initial radiation. Pathologic diagnoses were one glioblastoma, two cases of anaplastic astrocytoma, one medulloblastoma, one low-grade glioma, one high-grade glial tumor, and one atypical meningioma. Five patients underwent surgical resection with subsequent radiotherapy. One anaplastic astrocytoma patient received chemotherapy only following stereotactic biopsy. The meningioma patient was alive 32 months after total resection and radiosurgery for subsequent recurrences. Six patients died within 18 months and most deaths were due to disease progression. Most patients diagnosed with second brain tumors had received high-dose, large-volume radiotherapy with chemotherapy at a young age. Further studies are required to determine the relationship between radiotherapy/chemotherapy and the development of secondary brain tumors.

Anaplastic astrocytomas with abundant Rosenthal fibers in elderly patients: A diagnostic pitfall of high‐grade gliomas

To investigate the clinicopathological features of anaplastic astrocytoma (AA) with abundant Rosenthal fibers (RFs), this study assessed four cases of AA (elderly patients; age ≥ 70 years). Histologically, these tumors were composed of diffusely infiltrating astrocytomas with brightly eosinophilic cytoplasmic granules or cork-screw or beaded bundles. Tumor cells showed pleomorphism, bizarre giant cells, and mitotic activity, but no necrosis. The cytoplasmic granules showed negativity on PAS staining. Immunohistochemically, the tumor cells with cytoplasmic granular cells showed a positive reaction for GFAP. The cytoplasmic eosinophilic granules or bundles were positive for αB-crystallin, ubiquitin and HSP27. In addition, tumor cells showed strong cytoplasmic positivity for isocitrate dehydrogenase 1 (IDH1)-R132H protein in all cases. The MIB-l labeling index of these cases ranged from 7% to 10%. In cases 1 and 2, ultrastructurally, the tumor cells had electron-dense, amorphous structures in the cytoplasm and in the processes. These structures were bound to glial intermediate filaments. Based on these microscopic, immunohistochemical and ultrastructural findings, case 1 was diagnosed as AA with abundant, mixed, common type of RFs and miniature (m) RFs, and cases 2,3, and 4 were diagnosed as AA with abundant mRFs. These results indicate that the presence of RFs in astrocytic tumors does not necessarily exclude a diagnosis of high-grade astrocytoma. In addition, AAs with abundant mRFs in elderly patients should be classified as a peculiar variant of AA.

Posterolateral Sulcus Approach for Spinal Intramedullary Tumor of Lateral Location: Technical Note

Posterolateral sulcus (PLS) approach of the spinal cord, being equivalent to the dorsal root entry zone myelotomy, may offer the satisfactory exposure of the spinal intramedullary tumor if applied appropriately. Eight consecutive patients with spinal intramedullary tumors of lateral location underwent the surgery of PLS approach in our institute. There were 6 male and 2 female patients, ranging in age from 34 to 72 years (mean, 57 years). PLS approach was indicated for the intramedullary tumor situated laterally in the spinal cord and that do not contact the posterior or lateral surfaces on magnetic resonance (MR) images before surgery. Total removal of the tumor was achieved in 6 cases except of 2 cases of anaplastic astrocytoma. All 6 patients with total removal of the tumor demonstrated the modest or mild deterioration of motor function on the approach side early after surgery, which resolved within 1 month after surgery. Average grade of the modified McCormick functional schema was 3.5 before surgery and improved to 3.0 at 3 months after surgery. These 6 patients demonstrated satisfactory pain relief early after surgery. Average grade of the sensory pain scale was 2.7 before surgery and improved to 1.7 at 3 months after surgery. PLS approach can be one of the surgical choices to the spinal intramedullary tumors, if applied appropriately. Better indication for PLS approach may be the tumors of the uneven location within the spinal cord associated with moderate or severe local pain.

Intraoperative direct electrical stimulations of central nervous system during surgery of gliomas near eloquent areas

Objective To report our experiences of direct cortical stimulation in surgery of gliomas located in eloquent areas. Methods Clinical data of 157 patients with gliomas underwent awake craniotomy with the direct electrical stimulation for functional mapping of the eloquent areas were analysed retrospectively. Results Negative cortical stimulation was found in 4 patients, and positive cortical stimulation was achieved in 153 patients (97.45% ). Four hundred and ninty ⁃ six cortical sites in 139 patients were detected for motor response by direct electrical stimulation, 70 sites in 21 patients for sensory, 112 sites in 91 patients for language (such as counting and naming). The positive areas of counting disturbance were mainly seen at the lower part of left precentral gyri operculum of left inferior frontal gyri, triangular part of left inferior frontal gyri, posterior part of left middle frontal gyri, and posterior part of left superior frontal gyri. Postoperative MRI showed 92 patients (58.60%) achieved total resection, 55 cases (35.03%) subtotal and 10 cases (6.37%) partial. One hundred and ten patients (70.06%) were diagnosed as having low grade glimas, including 71 cases of astrocytoma, 26 cases of oligodendroglioma, and 13 cases of mixed astro ⁃ oligodendroglioma, 47 patients (29.94% ) were high grade gliomas, including 19 cases of glioblastoma, 15 cases of anaplastic astrocytoma, and 13 cases of anaplastic oligodendroglioma. After operation 53 patients (33.76% ) occurred transient postoperative paralysis, 39 patients (24.84% ) transient language disturbance and 4 patients (2.55%) permanent neurological deficits. Conclusion Intraoperative direct electrical stimulation is a reliable, precise and safety method for functional mapping of the eloquent areas. This technique allows us to achieve 'maximal safety resection' in glioma surgery． DOI：10.3969/j.issn.1672⁃6731.2012.06.011

Astrocitoma anaplásico do cerebelo: relato de caso

ResumoAstrocitomas de alto grau são tumores de apresentação rara na fossa posterior, especialmente na idade adulta. A sobrevida média descrita na literatura é de cerca de 14 a 32 meses. A apresentação clínica mais frequente é na forma de síndrome de hipertensão intracraniana. Tende a evoluir com disseminação leptomeníngea e também pode estender-se ao tronco cerebral e à medula. Apresentamos um caso de astrocitoma anaplásico (grau III) da fossa posterior numa mulher de 62 anos, o único observado num adulto no nosso hospital num período de 10 anos. O diagnóstico foi confirmado com biópsia estereotáxica da lesão. A apresentação clínica está de acordo com o descrito na literatura, contudo a sobrevida observada foi significativamente mais curta.

J1‐31 protein expression in astrocytes and astrocytomas

J1-31 is one of the astrocytic proteins, the expression of which has not been evaluated in astrocytomas. In the present study, we studied the expression of J1-31 protein in astrocytes and astrocytomas in comparison with GFAP, p53 and Ki-67. Materials consisted of formalin-fixed paraffin-embedded tissue specimens that included five cases of normal brain, 17 of gliosis, 15 of pilocytic astrocytoma (WHO grade I), 26 of low-grade diffuse astrocytoma (WHO grade II), four of anaplastic astrocytoma (WHO grade III), and eight of glioblastoma (WHO grade IV). GFAP was highly expressed in all specimens examined. The anti-J1-31 antibody exhibited strong cytoplasmic staining of reactive gliosis in 17/17 (100%) cases with a higher intensity of staining than that observed in the adjacent normal astrocytes. The antibody showed reactivity with tumor cells in 12/15 (80%) cases of pilocytic astrocytoma, although intensity of staining was generally weaker and more focal than observed in reactive gliosis. J1-31-positive tumor cells were detected in only 9/26 (35%) cases of the low-grade diffuse astrocytoma and none of the cases of anaplastic astrocytoma and glioblastoma. Increasing Ki-67 indices paralleled advancing tumor grades. p53 protein was expressed more commonly in infiltrating astrocytomas compared to pilocytic astrocytoma. In conclusion, down-regulation of J1-31 expression correlates with advancing grade of astrocytomas. The result suggests this protein plays some role in astrocytes that is progressively lost in malignant progression. The anti-J1-31 antibody may help further our understanding of astrocytes in disease and may be useful as an aid in the pathologic diagnosis of astrocytic lesions.

High-grade gliomas in survivors of childhood acute lymphoblastic leukaemia

Dear Editor: We read with great interest the recent article by Bien et al. on high-grade gliomas that occurred in children cured of acute lymphoblastic leukaemia (ALL). In this study, the authors reported two cases of glioblastoma multiforme and one case of anaplastic astrocytoma with poor overall survival despite aggressive treatment. Cranial irradiation has been considered as the most important factor for the development of secondary brain tumours. The authors concluded that early detection followed by complete resection and chemoradiotherapy is of paramount importance; however, they do not warrant better prognosis [1]. We recently studied the secondary malignant brain tumours in children who were previously treated for ALL in our institute and we encountered one case of glioblastoma multiforme and two cases of anaplastic oligodendrogliomas. The tumours developed after a mean period of 6.8 years after ALL treatment. The occurrence of anaplastic oligodendrogliomas is exceedingly rare and only eight cases have been reported in the literature. For further investigation, we undertook a molecular cytogenetic study of the oligodendroglioma specimens obtained from the two patients using fluorescence in situ hybridization (FISH) with DNA probes mapping to chromosome 1p36, 19p13 and 19q13. FISH analysis demonstrated in both cases 1p36 deletions (unpublished data). Studies of oligodendroglioma patients indicated that a loss of chromosome 1p and 19q was associated with high sensitivity to chemotherapy and radiotherapy and a better probability of survival [2]. We believe that it would be interesting to investigate if the allelic loss differs from those observed in primary lesions. Further research is needed to clarify if certain underlying genetic characteristics may also be associated with an increased risk of radiation-induced brain tumours.

Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: Results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882)

BackgroundIn a previous randomised EORTC study on adjuvant dibromodulcitol (DBD) and bichloroethylnitrosourea (BCNU) in adults with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), a clinically significant trend towards a longer overall survival (OS) and a progression-free survival (PFS) was observed in the subgroup of AA. The aim of the present study was to test this adjuvant regimen in a larger number of AA patients. MethodsContinuation of the previous phase III trial for newly diagnosed AA according to the local pathologist. Patients were randomised to either radiotherapy only or to radiotherapy in combination with BCNU on day 2 and weekly DBD, followed by adjuvant DBD and BCNU in cycles of six weeks for a maximum total treatment duration of one year. OS was the primary end-point. ResultsPatients (193 ) with newly diagnosed AA according to local pathological assessment were randomised to radiotherapy (RT) alone (n=99), or to RT plus DBD/BCNU (n=94); 12 patients were considered not eligible. At central pathology review, over half (53%) of the locally diagnosed AA cases could not be confirmed. On intent-to-treat analysis, no statistically significant differences in OS (p=0.111) and PFS (p=0.087) were observed, median OS after RT was only 23.9 months 95% confidence interval (CI), [18.4–34.0] after RT plus DBD/BCNU 27.3 months 95% CI [21.4–46.8]. ConclusionNo statistically significant improvement in survival was observed after BCNU/DBD adjuvant chemotherapy in AA patients. The trend towards improved survival is consistent with previous reports. Central pathology review of grade 3 tumours remains crucial.

Multicentric anaplastic astrocytoma in a child

We report a rare case of anaplastic astrocytoma with multicentric central nervous system lesions in a 10-year-old girl presenting with a 1-month history of progressive headache and paraparesis. Neurological examination upon admission revealed papilloedema of both eyes and grade 2/5 weakness of both legs. Cranial and spinal magnetic resonance imaging revealed multiple tumour foci within the suprasellar region, cerebellar hemisphere, cervical and thoracic cords. After an uneventful laminectomy and excision of the tumour at the T8–9 level, a significant improvement of motor function was observed. The histological diagnosis was anaplastic astrocytoma based on the WHO classification. The patient received postoperative radiotherapy and chemotherapy, and was able to walk with the aid of auxiliary crutches. Despite being an uncommon disease in children and being associated with an unfavourable long-term outcome, early diagnosis and appropriate management of this condition may contribute to reduced patient morbidity.