Neurosurgery

Alpha-internexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy (Article)

Mokhtari, K. — 2011-07-01T00:00:00Z

BACKGROUND: Although it has been demonstrated that the neuronal intermediate filament alpha-internexin (INA) is closely related to 1p19q codeletion in gliomas, its prognostic and predictive value has not yet been confirmed in a prospective trial. The authors of this report assessed the prognostic significance of INA expression and its correlation with relevant clinical and molecular characteristics in the prospective, randomized European Organization for Research and Treatment of Cancer (EORTC) 26951 trial of adjuvant procarbazine, lomustine, and vincristine (PCV) in patients with anaplastic oligodendroglial tumors (AOTs). METHODS: INA immunohistochemistry expression in tumors from 92 patients who were included in the EORTC 26951 trial was analyzed independently by 2 observers and was correlated with relevant clinical characteristics, including progression-free survival (PFS) and overall survival (OS), and with molecular features, including 1p/19q codeletion, isocitrate dehydrogenase 1 and 2 gene (IDH1/IDH2) mutation, and O-6 methylguanine-DNA methyltransferase (MGMT) promoter methylation status. RESULTS: INA expression was observed in 33 tumors and was strongly correlated with 1p/19q codeletion, IDH1 mutations, and MGMT promoter methylation. It was associated with significantly better PFS and OS independent of the treatment received. By using Cox proportional hazard modeling for OS with stepwise selection, INA expression, patient age, and performance status were identified as independent prognostic factors. The results indicated that INA expression may have an impact on the efficacy of combined radiotherapy plus PCV. CONCLUSIONS: In a homogeneously treated group of patients with grade III AOTs, INA expression had strong favorable prognostic significance for OS and may have predictive value for sensitivity to chemotherapy. Copyright

Evaluation of an early detection tool for social-emotional and behavioral problems in toddlers: The Brief Infant Toddler Social and Emotional Assessment - A cluster randomized trial (Article)

Kruizinga, I. — 2011-06-24T00:00:00Z

Background: The prevalence of social-emotional and behavioral problems is estimated to be 8 to 9% among preschool children. Effective early detection tools are needed to promote the provision of adequate care at an early stage. The Brief Infant-Toddler Social and Emotional Assessment (BITSEA) was developed for this purpose. This study evaluates the effectiveness of the BITSEA to enhance social-emotional and behavioral health of preschool children.Methods and design: A cluster randomized controlled trial is set up in youth health care centers in the larger Rotterdam area in the Netherlands, to evaluate the BITSEA. The 31 youth health care centers are randomly allocated to either the control group or the intervention group. The intervention group uses the scores on the BITSEA and cut-off points to evaluate a child's social-emotional and behavioral health and to decide whether or not the child should be referred. The control group provides care as usual, which involves administering a questionnaire that structures the conversation between child health professionals and parents. At a one year follow-up measurement the social-emotional and behavioral health of all children included in the study population will be evaluated. Discussion: It is hypothesized that better results will be found, in terms of social-emotional and behavioral health in the intervention group, compared to the control group, due to more adequate early detection, referral and more appropriate and timely care. Trial registration: Current Controlled Trials NTR2035.

Response assessment in neuro-oncology (a report of the RANO group): Assessment of outcome in trials of diffuse low-grade gliomas (Article)

Bent, M.J. van den — 2011-06-01T00:00:00Z

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Cytoreductive surgery of glioblastoma as the key to successful adjuvant therapies: New arguments in an old discussion (Article)

Stummer, W. — 2011-06-01T00:00:00Z

Background: This article discusses data from 3 randomized phase 3 trials, supporting a role for surgery in glioblastoma. Methods: Data were reviewed by extent of resection during primary surgery from the ALA-Glioma Study (fluorescence-guided versus conventional resection), the BCNU wafer study (BCNU wafer versus placebo), and the EORTC Study 26981-22981 (radiotherapy versus chemoradiotherapy with temozolomide). Results: For glioblastoma patients in the ALA study, median survival was 16.7 and 11.8 months for complete versus partial resection, respectively (P<0.0001). Survival effects were maintained after correction for differences in age and tumor location. For glioblastoma patients who received ≥90% resection in the BCNU wafer study, median survival increased for BCNU wafer versus placebo (14.5 versus 12.4 months, respectively; P=0.02), but no survival increase was found for <90% resection (11.7 versus 10.6 months, respectively; P=0.98). In the EORTC study, absolute median gain in survival with chemoradiotherapy versus radiotherapy was greatest for complete resections (+4.1 months; P=0.0001), compared with partial resections (+1.8 months; P=0.0001), or biopsies (+1.5 months; P=0.088), suggesting surgery enhanced adjuvant treatment. Conclusion: Complete resection appears to improve survival and may increase the efficacy of adjunct/adjuvant therapies. If safely achievable, complete resection should be the surgical goal for glioblastoma.

What if I don't treat my PSA-detected prostate cancer? Answers from three natural history models (Article)

Gulati, R. — 2011-05-01T00:00:00Z

Background: Making an informed decision about treating a prostate cancer detected after a routine prostate-specific antigen (PSA) test requires knowledge about disease natural history, such as the chances that it would have been clinically diagnosed in the absence of screening and that it would metastasize or lead to death in the absence of treatment. Methods: We use three independently developed models of prostate cancer natural history to project risks of clinical progression events and disease-specific deaths for PSA-detected cases assuming they receive no primary treatment. Results: The three models project that 20%-33% of men have preclinical onset; of these 38%-50% would be clinically diagnosed and 12%-25% would die of the disease in the absence of screening and primary treatment. The risk that men age less than 60 at PSA detection with Gleason score 2-7 would be clinically diagnosed in the absence of screening is 67%-93% and would die of the disease in the absence of primary treatment is 23%-34%. For Gleason score 8 to 10 these risks are 90%-96% and 63%-83%. Conclusions: Risks of disease progression among untreated PSA-detected cases can be nontrivial, particularly for younger men and men with high Gleason scores. Model projections can be useful for informing decisions about treatment. Impact: This is the first study to project population-based natural history summaries in the absence of screening or primary treatment and risks of clinical progression events following PSA detection in the absence of primary treatment.

Truncating the i-leader open reading frame enhances release of human adenovirus type 5 in glioma cells (Article)

Hengel, S.K. — 2011-04-13T00:00:00Z

Background: The survival of glioma patients with the current treatments is poor. Early clinical trails with replicating adenoviruses demonstrated the feasibility and safety of the use of adenoviruses as oncolytic agents. Antitumor efficacy has been moderate due to inefficient virus replication and spread. Previous studies have shown that truncation of the adenovirus i-leader open reading frame enhanced cytopathic activity of HAdV-5 in several tumor cell lines. Here we report the effect of an i-leader mutation on the cytopathic activity in glioma cell lines and in primary high-grade glioma cell cultures. Results: A mutation truncating the i-leader open reading frame was created in a molecular clone of replication-competent wild-type HAdV-5 by site-directed mutagenesis. We analyzed the cytopathic activity of this RL-07 mutant virus. A cell-viability assay showed increased cytopathic activity of the RL-07 mutant virus on U251 and SNB19 glioma cell lines. The plaque sizes of RL-07 on U251 monolayers were seven times larger than those of isogenic control viruses. Similarly, the cytopathic activity of the RL-07 viruses was strongly increased in six primary high-grade glioma cell cultures. In glioma cell lines the RL-07 virus was found to be released earlier into the culture medium. This was not due to enhanced viral protein synthesis, as was evident from equivalent E1A, Fiber and Adenovirus Death Protein amounts, nor to higher virus yields. Conclusion: The cytopathic activity of replicating adenovirus in glioblastoma cells is increased by truncating the i-leader open reading frame. Such mutations may help enhancing the antitumor cytopathic efficacy of oncolytic adenoviruses in the treatment of glioblastoma.

Reply to A.A. Brandes et al (Article)

Wen, P.Y. — 2011-03-20T00:00:00Z

Addition of serum-containing medium to cerebrospinal fluid prevents cellular loss over time (Article)

Graaf, M.T. de — 2011-03-12T00:00:00Z

Immediately after sampling, leukocyte counts in native cerebrospinal fluid (CSF) start to decrease rapidly. As the time lapse between CSF collection to analysis is not routinely registered, the clinical significance of decreasing cell counts in native CSF is not known. Earlier data suggest that addition of serum-containing medium to CSF directly after sampling prevents this rapid decrease in leukocyte counts and, thus, may improve the accuracy of CSF cell counting and cell characterization. Here, we prospectively examined the effect of storage time after lumbar puncture on counts of leukocytes and their major subsets in both native CSF and after immediate addition of serum-containing medium, measured by flow cytometry and microscopy. We collected CSF samples of 69 patients in tubes with and tubes without serum-containing medium and determined counts of leukocytes and subsets at 30 minutes, 1 hour, and 5 hours after sampling. Compared to cell counts at 30 minutes, no significant decrease in cell number was observed in CSF with serum-containing medium 1 and 5 hours after sampling, except for the granulocytes at 1 hour. In native CSF, approximately 50% of leukocytes and all their subsets were lost after 1 hour, both in flow cytometric and microscopic counting. In 6/7 (86%) samples with mild pleocytosis (5-15 × 10(6) leukocytes/l), native CSF at 1 hour was incorrectly diagnosed as normocellular. In conclusion, addition of serum-containing medium to CSF directly after sampling prevents cell loss and allows longer preservation of CSF cells prior to analysis, both for microscopic and flow cytometric enumeration. We suggest that this protocol results in more accurate CSF cell counts and may prevent incorrect conclusions based on underestimated CSF cell counts.

Clinical trial end points for high-grade glioma: The evolving landscape (Article)

Reardon, D.A. — 2011-03-01T00:00:00Z

To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome. Growing recognition of limitations weakening the reliability of traditional clinical trial primary end points has generated increasing uncertainty of how best to evaluate promising therapeutics for patients with HGG. The phenomena of pseudoprogression and pseudoresponse have made imaging-based end points, including overall radiographic response and progression-free survival, problematic. Although overall survival is considered the "gold-standard" end point, recently identified active salvage therapies such as bevacizumab may diminish the association between presalvage therapy and overall survival. Finally, advances in imaging as well as the assessment of patient function and well being have strengthened interest in auxiliary end points assessing these aspects of patient care and outcome. Better appreciation of the strengths and limitations of primary end points will lead to more effective clinical trial strategies. Technical advances in imaging as well as improved survival for patients with HGG support the further development of auxiliary end points evaluating novel imaging approaches as well as measures of patient function and well being.

EBV related cerebral lymphoma in a leukemia patient treated with alemtuzumab (Article)

Langerijt, B. — 2010-12-10T00:00:00Z

Human chorionic gonadotropin treatment of anti-Hu-associated paraneoplastic neurological syndromes (Article)

Broekhoven, F. — 2010-12-01T00:00:00Z

Objective: Paraneoplastic neurological syndromes associated with anti-Hu antibodies (Hu-PNS) are mediated by a T-cell immune response that is directed against the Hu antigens. In pregnancy, many Th1-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis regress. We hypothesised that this decreased disease activity during pregnancy may be related to high human chorionic gonadotropin (hCG) levels. Methods: 15 Hu-PNS patients were treated in a prospective, uncontrolled and unblinded trial with 10 000 IU daily of hCG administered by intramuscular injection during 12 weeks. Primary outcome measures were functional improvement defined as a decrease of one or more points on the modified Rankin Scale (mRS) or stabilisation in patients with mRS score ≤3 and improvement of neurological impairment assessed with the Edinburgh Functional Impairment Tests (EFIT). Secondary end points included the change in activities of daily living as evaluated using the Barthel Index. Results: Seven of 15 patients (47%) improved on the mRS or stabilised at mRS score ≤3. Four patients (27%) showed significant improvement of neurological impairment as indicated by an overall Edinburgh Functional Impairment Tests score of ≥1 point. Five patients improved on the Barthel Index (33%). Conclusion: Comparison with previous studies suggests that hCG may have immunomodulatory activity and may modify the course of Hu-PNS, although well-established confounding factors may have contributed in this uncontrolled trial.

What to do when a competent ICU patient does not want to live anymore but is dependent on life-sustaining treatment? Experience from the Netherlands (Article)

Hoven, B. van der — 2010-12-01T00:00:00Z

If patients on the intensive care unit (ICU) are awake and life-sustaining treatment is suspended because of the patients' request, because of recovering from the disease, or because independence from organ function supportive or replacement therapy outside the ICU can no longer be achieved, these patients can suffer before they inevitably die. In The Netherlands, two scenarios are possible for these patients: (1) deep palliative (terminal) sedation through ongoing administration of barbiturates or benzodiazepines before withdrawal of treatment, or (2) deliberate termination of life (euthanasia) before termination of treatment. In this article we describe two awake patients who asked for withdrawal of life-sustaining measures, but who were dependent on mechanical ventilation. We discuss the doctrine of double effect in relation to palliative sedation on the ICU. Administration of sedatives and analgesics before withdrawal of treatment is seen as normal palliative care. We conclude that the doctrine of the double effect is not applicable in this situation, and mentioning it criminalised the practice unnecessarily and wrongfully.

A primary extraosseous ewing sarcoma in the cerebellopontine angle of a child: Review of relevant literature and case report (Article)

Dos Santos Rubio, E.J. — 2010-12-01T00:00:00Z

BACKGROUND AND IMPORTANCE: We report the occurrence of a primary intracranial extraosseous Ewing sarcoma/peripheral primitive neuroectodermal tumor (EES/pPNET) in the cerebellopontine angle in a child. CLINICAL PRESENTATION: A 10-year-old girl presented with symptoms and signs of an infratentorial space-occupying lesion that was confirmed by magnetic resonance imaging and followed up by subtotal surgical resection. Tumor cells displayed membranous expression of CD99, and one of the typical translocations of EES/pPNET (chromosome 22) was demonstrated by cytogenetic analysis. CONCLUSION: The literature regarding the histopathological, molecular, radiological, prognostic, and therapeutic features of intracranial EES/pPNET is reviewed, emphasizing the distinction of this entity from the central PNET. Although exceptionally rare, intracranial EES/pPNET should be considered in the differential diagnosis of lesions in the cerebellopontine angle.

Agreement between maternal cannabis use during pregnancy according to self-report and urinalysis in a population-based cohort: The generation R study (Article)

El Marroun, H. — 2010-12-01T00:00:00Z

Aim: To verify self-reported information on prenatal drug use in urine because reporting in pregnancy is sensitive to stigma and might lead to misclassification. Methods: Using semiquantitative immunochemical analysis, the presence of the urinary metabolite (11-nor-Δ9-tetrahydrocannabinol- 9-carboxylic acid) was compared to self-reported prenatal cannabis use. Sensitivity and specificity for self-report and urinalysis outcomes were calculated and Yule's Y was used as an agreement measure. Results: Urine samples were available for 3,997 pregnant women. Of these women, 92 reported having used cannabis during pregnancy (2.3%) and 71 had positive urine screens (1.8%). In total 35% of the 92 women with self-reported cannabis use also had a positive urine screen. Positive urines were relatively frequent in women reporting cannabis use before pregnancy only (7.6%) and in women with missing information (2.6%). Sensitivity and specificity of urinalysis compared to self-report were 0.46 and 0.98. Sensitivity and specificity of self-report compared to urinalysis were 0.36 and 0.99. Yule's Y amounted to 0.77, indicating substantial agreement between the measures. Conclusions: Our findings illustrate the difficulties in obtaining valid information on prenatal cannabis use. To improve the quality of cannabis use data, we suggest a 2-step approach starting with self-report. Copyright

Effect of early dysphoric response and cannabis use on discontinuation of olanzapine or risperidone in patients with early psychosis (Letter To Editor)

Nimwegen-Campailla, L. — 2010-11-09T00:00:00Z

Molecular diagnostics of gliomas: The clinical perspective (Article)

Tabatabai, G. — 2010-11-01T00:00:00Z

Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast to the classical molecular markers in this field, p53 and epidermal growth factor receptor (EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical implications have now been identified: 1p/19q codeletion, O6-methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma. Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel treatments, too.

Towards improving the safety and diagnostic yield of stereotactic biopsy in a single centre (Article)

Dammers, R. — 2010-11-01T00:00:00Z

Background: Previously, we reported on our single centre results regarding the diagnostic yield of stereotactic needle biopsies of brain lesions. The yield then (1996-2006) was 89.4%. In the present study, we review and evaluate our experience with intraoperative frozen-section histopathologic diagnosis on-demand in order to improve the diagnostic yield. Methods: One hundred sixty-four consecutive frameless biopsy procedures in 160 patients (group 1, 2006-2010) were compared with the historic control group (group 2, n∈=∈164 frameless biopsy procedures). Diagnostic yield, as well as demographics, morbidity and mortality, was compared. Statistical analysis was performed by Student's t, Mann-Whitney U, Chi-square test and backward logistic regression when appropriate. Results: Demographics were comparable. In group 1, a non-diagnostic tissue specimen was obtained in 1.8%, compared to 11.0% in group 2 (p∈=∈0.001). Also, both the operating time and the number of biopsies needed were decreased significantly. Procedure-related mortality decreased from 3.7% to 0.6% (p∈=∈0.121). Multivariate analysis only proved operating time (odds ratio (OR), 1.012; 95% confidence interval (CI), 1.000-1.025; p∈=∈0.043), a right-sided lesion (OR, 3.183; 95% CI, 1.217-8.322; p∈=∈0.018) and on-demand intraoperative histology (OR, 0.175; 95% CI, 0.050-0.618; p∈=∈0.007) important factors predicting non-diagnostic biopsies. Conclusions: The importance of a reliable pathological diagnosis as obtained by biopsy must not be underestimated. We believe that when performing stereotactic biopsy for intracranial lesions, next to minimising morbidity, one should strive for as high a positive yield as possible. In the present single centre retrospective series, we have shown that using a standardised procedure and careful on-demand intraoperative frozen-section analysis can improve the diagnostic yield of stereotactic brain biopsy procedures as compared to a historical series.

Towards Raman-based epidemiological typing of Pseudomonas aeruginosa (Article)

Willemse-Erix, H.F.M — 2010-10-08T00:00:00Z

Raman spectra of bacteria can be used as highly specific fingerprints, enabling discrimination at strain level. Pseudomonas aeruginosa strains can be strongly pigmented, making it difficult to obtain high quality spectra of such isolates due to high fluorescent spectral backgrounds. Furthermore, the spectra that could be measured with acceptable quality often showed large spectral variations limiting the reproducibility required for strain level discrimination. P. aeruginosa produces a characteristic yellowish green fluorescent pigment, called pyoverdin. Applying a washing procedure to reduce the amount of fluorescent pigment, enabled the highly pigmented isolates to be measured with sufficient spectral quality. Isolation of the pigment/pyoverdin spectral features, together with spectral scaling methods improved reproducibility. It will be important to analyze the range of the spectral variations that can occur and ensure the correction of all of these factors to obtain the highest reproducibility required for strain level typing.

Primary central nervous system lymphoma in the elderly: A multicentre retrospective analysis (Article)

Schuurmans, M. — 2010-10-01T00:00:00Z

Elderly patients with primary central nervous ystem lymphoma (PCNSL) do not tolerate treatment with combined radio-chemotherapy well because of leuco-encephalopathy; they are usually treated initially with chemotherapy or radiotherapy alone. Little is known about the efficacy and toxicity of these treatments outside clinical studies. This study was a retrospective analysis of all patients aged 60 years or over who were admitted with PCNSL to one of five Dutch centers between 1998 and 2007. A total of 74 patients were identified. Twenty-nine were treated with radiotherapy only (Group A), in 36 the intended treatment was chemotherapy alone (Group B), and nine were planned to receive chemotherapy followed by radiotherapy (Group C). Median overall survival was 20 months; 4 months in patients with a Karnofsky performance status (KPS) <70, 25 months in patients with a KPS ≥ 70 (P < 0·001). Treatment modality was not an independent prognostic factor. Forty patients were treated with methotrexate 3 g/m2: there were two toxic deaths. Ten patients discontinued chemotherapy because of toxicity. Delayed encephalopathy was reported in 10 patients. In conclusion, community hospitals still frequently utilize whole brain radiotherapy in elderly PCNSL patients, though a majority tolerates chemotherapy well. Performance status was the most important variable determining prognosis. Short and long term toxicities must be weighed against possible clinical benefits of each treatment, making treatment decisions a highly individualized process.

Antiepileptic drug therapy in the perioperative course of neurosurgical patients (Article)

Klimek, M. — 2010-10-01T00:00:00Z

Purpose of review: Antiepileptic agents are widely used in the perioperative course of neurosurgical patients - for prophylactic and therapeutic reasons. However, the evidence supporting their use is extremely small and adverse events are common. This review highlights the current controversies. Recent findings: Prophylactic use of antiepileptic agents is unfavorable for patients with subarachnoid hemorrhage. In patients with brain tumors, prophylactic use is not recommended. If the drugs are used nevertheless, stopping after the first postoperative week must be strongly recommended. After traumatic brain injury, early prophylactic use might prevent late post-traumatic seizures. The new antiepileptic drug levetiracetam seems to have a better safety profile, which makes it more suitable for prophylactic use. However, in all groups, evidence concerning the choice of drugs and duration of prophylaxis is lacking. Current research is focusing on prevention of epileptogenesis. Therapeutic use of antiepileptic drugs is supported by evidence. These drugs should be continued perioperatively. However, they might induce severe adverse events during adjuvant treatments like radiotherapy or chemotherapy in patients with brain tumors. Summary: Despite lacking evidence, prophylactic antiepileptic drug use is common in the perioperative course of neurosurgical patients. More research is needed to deal better with epileptogenesis and to define the right drug for the right patient at the right time.