Instructive cross-talk between neural progenitor cells and gliomas

Gliomas are the most common primary brain tumors and offer a poor prognosis in patients because of their infiltrative and treatment-resistant nature. The median survival time after diagnosis is approximately 11-12 months. There is a strong need for novel treatment modalities in targeting gliomas, and recent advances use neural progenitor cells as delivery systems for different therapeutic strategies. In this study, we show that rat embryonic neural progenitor cell (NPC) lines, transplanted at a distant site from a 3-day-preestablished glioma in the striatum, were able to migrate toward and colocalize with tumor isles without general spread into the brain parenchyma. Upon encounter with tumor, neural progenitor cells changed phenotype and became vimentin positive. These results demonstrate that transplanted neural progenitor cells respond to queues from a tumor and home to and exert an antitumor effect on the preestablished glioma, significantly decreasing the tumor volume with approximately 67% compared with control tumors after 1-2 weeks. Moreover, these early effects could be translated into increased survival times of animals treated with neural progenitor cell grafts 3 days after intrastriatal tumor inoculation. In contrast, there was no activation or migration of endogenous subventricular zone (SVZ) neuroblasts in response to an intrastriatal syngeneic tumor. In conclusion, NPC possess the ability to influence tumor growth as well as respond to queues from the tumor or tumor microenvironment, demonstrating a cross-talk between the cells.     

Interstitial stereotactic radiosurgery of pilocytic astrocytomas in paediatric patients

Summary Objective. To evaluate the clinical presentation, tumour response, clinical improvement and complications in 12 children and young people with a pilocytic astrocytoma, WHO I grade 1, who were treated with interstitial radiosurgery using Iodine-125 seed implants. Patients and Methods. Retrospective analysis of 12 patients aged under 18 years (mean 8.4 years, ranging from 8 months to 17 years of age) with a pilocytic astrocytoma treated between 1993 and 2006. Iodine-125 seeds were used as temporary implants with low-dose rate (≤10 cGy/h) and a calculated reference dose of 60 and 100 Gy to the outer ring of the tumour. Results. There was no perioperative mortality. Two patients worsened transiently, but thereafter each patient improved clinically. Eleven out of 12 tumours shrank after the treatment. The mean volume of the tumours before implantation was 17.9 cm³. and was reduced to 60% of this volume at 6 months, to 26.5% at 12 months, to 8% at 24 months, and was less than 1% at 30–36 months One patient underwent a reimplantation to treat a recurrence 3 years after the initial treatment. Ten patients were alive 2 years after the first intervention. In the longest surving patient, there was no evidence of progression after 13.4 years of follow up.     

MRI apparent diffusion coefficient reflects histopathologic subtype, axonal disruption, and tumor fraction in diffuse-type grade II gliomas

The apparent diffusion coefficient (ADC) determined from MR diffusion tensor imaging (DTI) has shown promise for distinguishing World Health Organization grade II astrocytoma (AS) from the more prognostically favorable grade II oligodendroglioma (OD). Since mixed oligoastrocytomas (OAs) with codeletions in chromosomes 1p and 19q confer prognoses similar to those of OD, we questioned whether a previously determined ADC-based criterion for distinguishing OD and AS would hold on an independent set of gliomas that included OA with codeleted or intact 1p/19q chromosomes. We also questioned whether the ADC is associated with the tumor microstructure. ADC colormaps generated from presurgical DTI scans were used to guide the collection of biopsies from each tumor. The median normalized ADC distinguished OD from AS with 91% sensitivity and 92% specificity. 1p/19q codeleted OAs were always classified as ODs, while 1p/19q intact OAs were always classified as ASs. There were positive associations between the ADC and both the SMI-31 score of axonal disruption and the fraction of tumor cells in the biopsies. The ADC of OD and 1p/19q codeleted OA was more associated with tumor fraction, while the ADC of AS and 1p/19q intact OA was more associated with SMI-31 score. We conclude that our previously determined threshold median ADC can distinguish grade II OD and AS on a new patient cohort and that the distinctions extend to OA with codeleted and intact 1p/19q chromosomes. Further, the ADC in grade II gliomas is associated with the fraction of tumor cells and degree of axonal disruption in tumor subregions.     

First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1–5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.     

Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy.

OBJECTIVE: Diabetic nephropathy is associated with low-grade inflammation and activation of the complement system. Defensins, as part of the innate immune system, may play a regulatory role in the complement cascade and may also augment the production of proinflammatory cytokines. The aim of this study was therefore to elucidate whether alpha-defensin is associated with diabetic nephropathy, low-grade inflammation and lipid profiles. RESEARCH DESIGN AND METHODS: Data were obtained from 189 patients with type 1 diabetes selected from the FinnDiane Study. Patients were divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: normoalbuminuria (AER <20 microg/min or <30 mg/24 h), microalbuminuria (20 200 microg/min or >300 mg/24 h). Alpha-defensin was determined by a novel, solid-phase radioimmunoassay (RIA) based on a monoclonal antibody, which recognizes alpha-defensin isoforms 1-3. RESULTS: Total serum alpha-defensin (-1, -2 and -3) concentrations were higher (P < 0.001) in patients with macroalbuminuria compared to micro- and normoalbuminuria, but no difference was observed between normoalbuminuria and microalbuminuria. In multiple linear regression analysis alpha-defensin was associated with systolic blood pressure (P = 0.032), HDL-cholesterol (P = 0.013), total cholesterol (P = 0.008), age (P = 0.001) and estimated glomerular filtration rate (P = 0.001), but not with low-grade inflammatory markers. CONCLUSIONS; Serum alpha-defensin (-1, -2 and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy.     

Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease

This study defined the clinical features and assessed the prognosis of 47 patients (17 males, 30 females, median age 63 years) with primary nodal marginal zone B-cell lymphoma. Forty-five per cent had stage IV disease. Hepatitis C virus serology was positive in 24%. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 33% were classified as low-risk, 34% as intermediate-risk, and 33% as high-risk. The 5-year overall survival (OS) was 69%. In univariate analysis worse OS was associated with: FLIPI (P = 0.02), age > 60 years (P = 0.05) and raised lactate dehydrogenase (P = 0.05). In multivariate analysis, only FLIPI predicted a worse OS (P = 0.02).     

ACNU和三尖杉酯碱分别联合MTX超选择性脑动脉灌注治疗恶性脑瘤的疗效比较

比较超选择性脑动脉灌注嘧啶亚硝脲（ＡＣＮＵ）加氨甲喋呤（ＭＴＸ）（Ａ组）以及三尖杉酯碱加ＭＴＸ（Ｂ组）治疗恶性脑胶质细胞瘤的疗效。方法将ＡＣＮＵ２～３ｍｇ／ｋｇ，三尖杉酯碱０１～０５ｍｇ／ｋｇ，ＭＴＸ０１～０２ｍｇ／ｋｇ按Ａ、Ｂ两组各１２例方案，采用超选择性脑动脉联合灌注化疗，并于化疗后１～１５个月以ＣＴ检查评定疗效。结果Ａ组肿瘤体积缩小４８３２％，Ｂ组缩小４６２１％；Ａ组有效者占４／１２，Ｂ组占３／１２；平均生存期分别为２５３个月和２３３个月；两组治疗前后肿瘤体积变化均有显著性差异，但两组疗效则无明显差异；并均无眼部及严重脑部并发症。结论ＡＣＮＵ加ＭＴＸ以及三尖杉酯碱加ＭＴＸ超选择性脑动脉灌注对恶性脑胶质细胞瘤的疗效相似，毒副作用小。     

Low level of microsatellite instability in paediatric malignant astrocytomas

Aim: Microsatellite instability (MSI) has been proposed as a possible mechanism in the development of cancer. The aim of the current study was to determine whether MSI is involved in the pathogenesis of paediatric malignant astrocytomas. Methods: We screened a cohort of 126 high‐grade astrocytoma samples for MSI using a sensitive and precise method of DNA analysis including a panel of five mononucleotide repeats, in combination with immunohistochemistry for DNA mismatch repair (MMR) proteins. Results: We identified low level of MSI (MSI‐L) in four of 126 (3.2%) paediatric malignant astrocytic tumours. To analyse the molecular profile associated with MSI‐L positive tumours, we performed immunohistochemistry for protein expression of hMSH6 and p53 as well as mutational analysis of the K‐ras gene. In MSI‐L paediatric malignant astrocytic tumours we detected retained nuclear expression of hMSH6 protein and strong nuclear accumulation of p53 protein indicating possible mutations of TP53. There was no correlation between K‐ras mutational status and frequency of MSI in this patient population. Conclusion: Our results suggest that the MSI‐L phenotype is associated with p53 accumulation and/or mutations. However, this represents only a small subgroup of paediatric gliomas with possible distinct biological features, and the deficiencies of DNA MMR genes do not play a main role in the tumourigenesis of the majority of paediatric malignant astrocytomas.     

Molecular biology of adult gliomas: some landmarks for neurosurgeons

BACKGROUND AND PURPOSE: Recent developments in molecular biology have provided the clinician with opportunities to investigate a number of new biomarkers. This has led to an abundant literature reporting the biological role, the relation to survival, and the predictive value of treatment responses in adult glioma patients. Consequently, the clinician must assimilate a large amount of information, raising the question of the genuine role of these biomarkers in the daily care of these patients. METHODS: The authors report the data on biomarkers from the literature relevant to this context. DISCUSSION: Molecular biology today sheds new and valuable light on the natural history of adult glioma, bringing to the forefront a number of therapeutic principles for glioma patients as a group. However, each of these biomarkers does not have sufficient power to amount to a criterion for individual patient therapeutics. CONCLUSIONS: Biomarkers are not pertinent today for decision making, but the authors believe that the principle of including this approach in adult glioma workups must be encouraged as a promising means of study in the years to come.     

Does high‐dose carmustine increase overall survival in supratentorial high‐grade malignant glioma? An EBMT retrospective study

Radiotherapy plus concomitant and adjuvant temozolomide have demonstrated improved survival for glioblastoma. However, prognosis remains poor. High-doses chemotherapy with carmustine is another way to improve response and survival by increasing the dose delivered. Myelotoxicity imposes autologous stem cell rescue. European Group for Blood and Marrow Transplantation experience of this treatment in patients with high-grade glioma was reported here. A retrospective analysis of 217 patients from European Group for Blood and Marrow Transplantation database was realized. Ninety-six patients underwent complete surgical resection while the 121 others had partial resection or only biopsy and were evaluable for an antitumor effect. Patients received 800 mg/m2 of carmustine intravenously at least 1 month after neurosurgery. Forty-eight to 72 hr after chemotherapy, 108 patients received autologous hematopoietic stem cells from bone marrow harvest and 109 patients autologous hematopoietic stem cells from peripheral blood. Radiotherapy was started approximately 40 days after transplantation. Ten deaths were related to the treatment. Of the 121 patients evaluable for tumor response, 64 (53%) presented an objective response. This protocol appear feasible, but with toxicity-related mortality of 4.5%. Median overall survival was 20 months and median time to treatment failure was 7 months. Overall survival and time to treatment were correlated with age, quality of resection and histological subtypes. In glioblastoma multiforme, age and surgery quality appeared to be prognostic factors. Compared with Stupp et al.'s recent study, this study did not favor high-dose carmustine for patients with glioblastoma multiforme with complete surgical resection.