MGMT promoter hypermethylation correlates with a survival benefit from temozolomide in patients with recurrent anaplastic astrocytoma but not glioblastoma

AimsTo investigate the correlation between O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and benefit from temozolomide in patients with recurrent high-grade glioma.Patients and methodsA real-time, quantitative, methylation-specific PCR assay was performed on archival tissue blocks from patients treated with temozolomide at the first recurrence.ResultsA subgroup of 38 patients who were chemotherapy-naive at recurrence was analysed (22 glioblastoma, 12 anaplastic astrocytoma [AA] and 4 anaplastic oligoastrocytoma [AOA]); none had 1p/19q loss. Among 10 (26%) patients with a hypermethylated MGMT promoter, none experienced disease progression within the first two treatment cycles compared with 12 of 28 (43%) patients with an unmethylated promoter (p = 0.016). By Cox multivariate analysis, tumour grade and MGMT promoter methylation correlated with time to progression (p < 0.05); MGMT promoter methylation correlated with superior overall survival in AA/AOA but not in glioblastoma.ConclusionsMGMT promoter methylation predicted a survival benefit in patients with 1p/19q intact AA/AOA treated with temozolomide at recurrence.     

IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy

Several molecular markers have been proposed as predictors of outcome in patients with high grade gliomas. We report a retrospective multicenter study of 97 consecutive adult patients with anaplastic astrocytoma (AA) treated with radiation therapy (RT) plus concomitant and adjuvant temozolomide (TMZ) between October 2004 and March 2012. Correlations between the isocitrate dehydrogenase 1 (IDH1) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation with survival outcomes have been analyzed. At a median follow-up time of 46 months (range 12–89 months), median and 5-year overall survival rates were 50.5 months (95 % CI, 37.8–63.2) and 38 % (95 % CI, 25.7–50.7 %), and median and 5-year progression-free survival rates were 36 months (95 % CI, 28.5–44.0) and 22 % (95 % CI, 10–34 %), respectively. IDH1 mutation and MGMT promoter methylation were present in 54 and 60 % of evaluable patients, respectively. Multivariate Cox proportional hazards regression analysis showed that IDH1 mutation (P = 0.001), MGMT methylation (P = 0.01), age < 50 years (P = 0.02), and extent of resection (P = 0.04) were significantly associated with longer survival. Our study confirms the favorable prognostic value of IDH1 mutation and MGMT methylation in patients with AA treated with RT plus concomitant and adjuvant TMZ. The superiority of combined radiochemotherapy over other treatment modalities remains to be demonstrated.     

Cerebellar anaplastic astrocytoma in a teenager with Ollier Disease

INTRODUCTION: Ollier Disease is a sporadic skeletal disorder with a predisposition to oncogenesis. It is estimated at around 1/100,000. We are presenting a young patient with Ollier Disease and high-grade astrocytoma. CASE REPORT: A 14-year-old, Caucasian male with Ollier Disease presented with a history of headaches, vomiting, blurred vision, and unsteady gait. Brain MRI with contrast showed a 41 x 55 mm mass in the posterior fossa with spotty enhancement, which pathology proved to be anaplastic astrocytoma. CONCLUSION: Despite the universal acceptance that Ollier Disease carries a high risk of developing malignancy there is very little in the literature about systematic screening. We recommended a cost-effective screening regime for these patients.     

Cerebrospinal fluid polyamines in patients with Glioblastoma multiforme and anaplastic astrocytoma

Eighteen cerebrospinal fluid polyamine determinations in 12 patients with glioblastoma multiforme and 76 determinations in 37 patients with anaplastic astrocytoma were evaluated. Cerebrospinal fluid polyamine levels showed no significant relationship to the degree of malignancy or to enhanced tumor volume or volume of tumor central low density as determined by contrast-enhanced computerized tomography. A significant correlation was found between polyamine levels and the proximity of the tumor to the cerebral ventricles. Polyamine levels were correlated with clinical status as determined by neurological examination, radionuclide scan, and computerized tomography. Compared with those of stable patients, cerebrospinal fluid polyamine levels were significantly elevated in patients with recurrent tumors; however, elevation of polyamine levels did not appear to precede tumor recurrence. A large fraction of the results were false-positive or false-negative results. In contrast to our findings in patients with medulloblastoma, it appears that cerebrospinal fluid polyamine levels determinations may be of little use for monitoring tumor progression in patients with glioblastoma multiforme and anaplastic astrocytoma.     

The genetic landscape of anaplastic astrocytoma

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.     

Histopathological predictors of progression-free survival in atypical meningioma: a single-center retrospective cohort and meta-analysis

Brain Tumor Pathology - To determine the prognostic significance of histopathological features included in the diagnostic criteria of atypical meningioma for progression-free survival (PFS). We...     

Minichromosome maintenance protein 3 elicits a cancer-restricted immune response in patients with brain malignancies and is a strong independent predictor of survival in patients with anaplastic astrocytoma.

PURPOSE: The identification of new molecular markers in astrocytic tumors may help to understand the biology of these tumors in more detail. Informative tumor markers may represent prognostic factors for response to therapy and outcome as well as potential targets for novel anticancer therapies. EXPERIMENTAL DESIGN: Tumor-associated antigens were identified by immunoscreening of a human glioma cDNA expression library with allogeneic sera from patients with diffuse astrocytoma (WHO grades 2-4). The expression of one of the identified antigens, the replication licensing factor minichromosome maintenance protein 3 (MCM3), was analyzed by immunohistochemistry in 142 primary and 27 recurrent astrocytomas (WHO grades 2-4). In addition, 98 serum specimens from patients with primary and secondary brain malignancies and 30 serum specimens from healthy controls were examined by serologic immunoscreening for immunoreactivity with MCM3. RESULTS: MCM3 is overexpressed in human astrocytic tumors and elicits a cancer-restricted humoral immune response in 9.3% (9 of 97) of patients with brain tumors (n = 95) and brain metastases (n = 2) but not in healthy controls. Expression of MCM3 in diffuse astrocytoma is significantly associated with age (P < 0.001), histologic grade (P < 0.001), time to recurrence (P = 0.01), and expression of the proliferation marker Ki-67 (P < 0.001) but not with sex (P = 0.800). Univariate and multivariate Cox regression analysis confirmed MCM3 expression as an independent predictor of poor outcome in astrocytoma patients (P < 0.001 for both). CONCLUSIONS: MCM3 may represent a glioma-associated antigen with significant prognostic role as well as have some potential as a target for cancer-directed therapy.     

Highly anaplastic astrocytoma: a review of 357 patients treated between 1977 and 1989.

Between May 1977 and August 1989, 357 patients (199 male, 158 female; median age 40 years) with highly anaplastic astrocytomas other than glioblastoma multiforme were treated according to any of several protocols used in studies by the University of California, San Francisco, and the Northern California Oncology Group. The data evaluated were age, Karnofsky Performance Score, survival, time to tumor progression, therapy, and the effect of treatment at the time of progression. The records of 219 patients were taken from the University of California database, and those of the other 138 were taken from the Northern California Oncology Group computer files. Their median Karnofsky Performance Score was 90% (range 40-100%), the overall median survival was projected as 170.9 weeks, and the median time to first tumor progression was 127.3 weeks. The median survival time measured after the first progression was 41.3 weeks. Age and Karnofsky Performance Score had a significant influence on survival and on time to the first tumor progression, whereas extent of surgery and the use of interstitial brachytherapy in the initial therapy did not. We conclude that these patients can expect a median survival of over 3 years, that young age and high Karnofsky Performance Score have a positive influence on survival, and that salvage therapies can extend survival after the onset of tumor progression for nearly a year. Although it did not lengthen survival when used in initial therapy, interstitial brachytherapy used at the time of tumor progression was associated with increased survival.     

FAK signaling in anaplastic astrocytoma and glioblastoma tumors

Focal adhesion kinase (FAK) is a non-receptor cytoplasmic-tyrosine kinase that is activated by several different cell surface receptors shown to be upregulated on glioblastoma cells (integrins alpha(v)beta3 and alpha(v)beta5, and the epidermal growth factor receptor). Activated FAK can signal through several different signaling pathways, which are reviewed here. Published data are summarized that have demonstrated 1) elevated FAK expression in anaplastic astrocytoma and glioblastoma tumor biopsy samples, 2) a role for FAK in the promotion of glioblastoma cell proliferation, survival and migration in vitro, and 3) a role for FAK in the promotion of glioblastoma cell proliferation in vivo in an animal model. The available data suggests that increased levels of FAK protein and activity may contribute to an increased ERK activity and cell proliferation in vivo in these tumors.     

Iatrogenic seeding of anaplastic astrocytoma following stereotactic biopsy

We present a case of probable tumor seeding along the needle tract following computer tomography-guided stereotactic biopsy of an anaplastic astrocytoma in a 23 year old male. Six months after the initial biopsy and 3 months following a second stereotactic procedure for cyst aspiration, a second lesion appeared directly along the biopsy trajectory at a distance from the primary tumor. This lesion is presumed to be recurrent tumor and appears to have been spread iatrogenically following the biopsy of the initial tumor and the subsequent cyst aspiration along the same tract.     

Predicting survival in patients with advanced disease

Prognostication is an important clinical skill for all clinicians, particularly those clinicians working with patients with advanced cancer. However, doctors can be hesitant about prognosticating without a fundamental understanding of how to formulate a prognosis more accurately and how to communicate the information with honesty and compassion. Irrespective of the underlying type of malignancy, most patients with advanced cancer experience a prolonged period of gradual decline (months/years) before a short phase of accelerated decline in the last month or two. The main indicators of this final phase are poor performance status, weight loss, symptoms such as anorexia, breathlessness or confusion and abnormalities on laboratory parameters (e.g. high white cell count, lymphopaenia, hyopalbuminaemia, elevated lactate dehydrogenase or C-reactive protein). The clinical estimate of survival remains a powerful independent prognostic indicator, often enhanced by experience, but research has only begun to understand the different biases affecting clinicians’ estimates. More recent research has shown probabilistic predictions to be more accurate than temporal predictions. Simple, reliable and valid prognostic tools have been developed in recent years that can be used readily at the bedside of terminally ill cancer patients. The greatest accuracy occurs with the use of a combination of subjective prognostic judgements and objective validated tools.Communicating survival predictions is an important part of cancer care and guidelines exist for improving delivery of such information. Important cultural differences may influence communication strategies and should be recognised in clinical encounters. More well-designed studies of prognosis and its impact on decision making are needed. The benefits and limitations of prognostication should be considered in many clinical decisions.     

Problems entailed in the definition and pathology of anaplastic astrocytoma

Three-tiered system dividing supratentorial astrocytic neoplasms into the astrocytoma, anaplastic (malignant) astrocytoma and the glioblastoma multiforme has been widely used. However, the pathology of anaplastic astrocytoma is defined in different ways according to different classifications. A total of 42 biopsy specimens from 35 cases diagnosed as anaplastic astrocytoma were reviewed pathologically and their features were correlated with a follow-up clinical study to discuss the prognostic usefulness of the subdivision of anaplastic astrocytoma. In WHO classification, anaplastic astrocytoma is defined as "astrocytoma containing areas of anaplasia". Follow-up study of 7 cases with the histology as such revealed that 5 cases had survived more than one year and seven months. The other 28 cases showed a varied histology and were subclassified into an astrocytoma in which moderately anaplastic cells are found throughout the tumor, an astrocytoma formed by anaplastic fusiform cells, an astrocytoma composed of predominantly rounded anaplastic cells, and a pleomorphic astrocytoma with or without intracytoplasmic hyaline inclusions. A follow-up study of cases with these types of astrocytoma disclosed death in 15 cases within one year and 7 months following the first surgery and that three cases displayed typical histological features of glioblastoma at autopsy. It is considered that there would be a considerable overlap between the group of anaplastic astrocytoma and that of glioblastoma, if we use the term "anaplastic astrocytoma" in a broader category.     

间变性星形细胞瘤中DR4及DR5的表达

目的研究肿瘤坏死因子相关凋亡诱导配体(TRAIL)的死亡受体(death receptor,DR)DR4和DR5在间变性星形细胞瘤中的表达,并探讨其临床意义.方法联合采用免疫组化和原位杂交方法检测24间变性星形细胞瘤和16例正常脑组织中DR的表达.结果免疫组化染色显示,24例间变性星形细胞瘤均大量表达死亡受体DR4和DR5,而16例正常脑组织中7例(43.8%)表达DR4,5例(31.3%)表达DR5.间变性星形细胞瘤组织中DR蛋白的表达显著高于正常脑组织中DR蛋白的表达,两者差异有显著性(P<0.01).原位杂交显示,DR在全部24例间变性星形细胞瘤组织和大部分正常脑组织中均呈强阳性表达,二者差异无显著性(P>0.05).结论间变性星形细胞瘤细胞中普遍存在DR的高表达,这可能为间变性星形细胞瘤的凋亡诱导治疗提供新的靶点.DR蛋白在正常脑组织和间变性星形细胞瘤中的表达差异,可能是TRAIL选择性诱导凋亡的机制之一.     

Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group.

PURPOSE: To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse. PATIENTS AND METHODS: This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m(2)/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m(2)/d; the dose could be increased to 200 mg/m(2)/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle. RESULTS: Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients. CONCLUSION: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.     

Th1/Th2 cytokine imbalance in meningioma, anaplastic astrocytoma and glioblastoma multiforme patients

The balance between Th1 and Th2 cytokines is thought to be an important factor in terms of tumour prognosis. Serum samples from 61 newly diagnosed patients with brain tumours and 50 age- and sex-matched non-tumour controls were analysed by ELISA for circulating levels of interleukin-12 (IL-12p70 and p40) and interleukin-10 (IL-10); pivotal Th1 and Th2 cytokines, respectively. Patients were divided into various groups depending on their histological diagnosis: meningioma (n=11), anaplastic astrocytoma (n=4) and glioblastoma multiforme (GBM; n=46). Significant reduction in serum IL-12 was seen in all groups as compared with the controls: meningioma, p=0.03; anaplastic astrocytoma, p<0.001; and GBM, p<0.001. Conversely, serum IL-10 was significantly increased in anaplastic astrocytoma, p=0.02, and GBM, p=0.03. The changes in the serum cytokines were not caused by the effects of steroids, as sequential analysis of patients pre- and post-steroid treatment commencement showed no difference. This study shows that patients with advanced primary intracranial malignancies have decreased circulating IL-12 and increased circulating IL-10, demonstrating that brain tumours have a major systemic effect on the immune system.     

Predicting survival in patients with hepatocellular carcinoma: a UK perspective.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a cancer of rising incidence in the UK. The aim of this study was to compare the Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer (BCLC) classifications as predictors of survival in UK patients with HCC. METHODS: Data were analysed from a prospective database maintained in a specialist hepatobiliary unit from 1998 to 2003. Each system was assessed for its discriminatory power, monotonicity of gradient, and independent contribution to prediction of mortality status based on a multivariate model. RESULTS: One hundred and two patients (77 males, 25 females) were identified with a median age of 65 (range, 14-87) years. The overall median survival time was 13 months and the one- and five-year survival rates were 52.9% (95% CI: 43.2%, 62.6%) and 35.3% (95% CI: 26.0%, 44.6%), respectively. All three classification systems had the capacity to differentiate between patient survival times across different stages. The Okuda system was superior in overall discriminatory power and in strength of monotonicity. The BCLC system, however, made the highest independent contribution of all three systems in predicting survival in the Cox regression model. CONCLUSIONS: All three classification systems were effective in predicting survival for patients with HCC in a UK population.     

A first feasibility study of temozolomide for Japanese patients with recurrent anaplastic astrocytoma and glioblastoma multiforme

Background. The efficacy of temozolomide has been evaluated in phase I and phase II trials in patients with recurrent malignant gliomas in the United States and the European Union. We report a feasibility study of the palliative efficacy of temozolomide for patients with recurrent anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Methods. Sixteen patients with at least two prior chemotherapy regimens were enrolled in the study. Nine patients were confirmed to have GBM and 7 patients were confirmed to have AA at the latest pathology review, and all had a Karnofsky performance status (KPS) of over 50%. The median age was 57 years (range, 31–65 years). Results. No cumulative toxicity was observed at any dose level when temozolomide was administered on a once-daily, 5-day schedule. Myelosuppression occurred, with the nadir being mid-late in the cycle (day 14 or 21). National Cancer Institute common toxicity criteria (NCI-CTC) grade 3 or 4 hematological toxicity did not occur. In the 9 GBM patients, the overall response rate (complete response + partial response [CR + PR]) was 0%. The median time to progression (TTP) was 3.5 months, and the rates of progression-free survival (PFS) at 6 and 12 months were 40% and 0%. In the 7 AA patients, the overall response rate (CR + PR) was 29% and median TTP was 9 months, while PFS rates at 6 and 12 months were 80% and 30%. Conclusion. The favorable safety profile and the efficacy of temozolomide in Japanese patients are not incompatible with the results seen with patients in the United States and the European Union.