Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study.

Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.

[Pseudoprogression or pseudoresponse: a challenge for the diagnostic imaging in Glioblastoma multiforme]. / Pseudoprogression oder Pseudorespons: Herausforderung an die Bildgebung des Glioblastoma multiforme.

This methodological paper on magnetic resonance tomography imaging recalls the assessment criteria on therapy response of Glioblastoma multiforme as defined by David Macdonald in 1990 that have remained State of the Art since their first publication. It defines the terms "pseudoprogression", "radiation induced necrosis" and "pseudoresponse". These phenomena are seen increasingly since the introduction of radiochemotherapy with Temozolomide as treatment standard in glioblastoma and since the use of antiangiogenetic therapy in malignant gliomas. Therefore, the assessment criteria have been recently updated with the newly proposed "RANO criteria (Response assessment in Neuro-Oncology)". Furthermore, the potential of additional information to conventional MR by MR perfusion, MR diffusion and MR spectroscopy is briefly discussed.

Paraneoplastic limbic encephalitis in a patient with extragonadal choriocarcinoma--significance of onconeural antibodies.

BACKGROUND: Paraneoplastic limbic or brainstem encephalitis is considered to be an autoimmune-mediated disorder of the nervous system associated with different types of cancer including germ cell tumors. CASE REPORT: We report on a 31-year-old patient presenting with eye motility dysfunction, dysarthrophonia, lethargy, depression, slow mentation, disorientation, dysgraphia, and retarded motion sequence. Neurologic tests, brain imaging, and blood chemistry tests failed to determine the cause of the symptoms. Further examinations including ultrasound of the abdomen led to the detection of a retroperitoneal mass. The biopsy of this mass showed fractions of a choriocarcinoma. The patient underwent curative chemotherapy, but although the cancer therapy was successful, the neurologic disorders did not improve. Concurrent examination for anti-Ma2 antibodies in the serum was positive and confirmed the paraneoplastic origin of these symptoms. CONCLUSIONS: Patients with symptoms of limbic or brainstem encephalitis, especially young men, should be tested for anti-Ma2 antibodies in the serum to elucidate their origin. The detection of these antibodies supports the diagnosis of a paraneoplastic syndrome, and may lead to the earlier identification of an otherwise hidden extragonadal germ cell tumor.

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space.

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

Symmetry of the arcuate fasciculus and its impact on language performance of patients with brain tumors in the language-dominant hemisphere.

OBJECTIVE Cerebral damage in frontal, parietal, and temporal brain areas and, probably more importantly, their interconnections can lead to deficits in language. However, neural plasticity and repair allow the brain to partly compensate for neural injury, mediated by both functional and structural changes. In this study, the authors sought to systematically investigate the relationship between language performance in brain tumor patients and structural perisylvian pathways (i.e., the arcuate fasciculus [AF]) using probabilistic fiber tracking on diffusion tensor imaging. The authors used a previously proposed model in which the AF is divided into anterior, long, and posterior segments. The authors hypothesized that right-handed patients with gliomas in the language-dominant (left) hemisphere would benefit from a more symmetrical or right-lateralized language pathway in terms of better preservation of language abilities. Furthermore, they investigated to what extent specific tumor characteristics, including proximity to the AF, affect language outcome in such patients. METHODS Twenty-seven right-handed patients (12 males and 15 females; mean age 52 ± 16 years) with 11 low-grade and 16 high-grade gliomas of the left hemisphere underwent 3-T diffusion-weighted MRI (30 directions) and language assessment as part of presurgical planning. For a systematic quantitative evaluation of the AF, probabilistic fiber tracking with a 2 regions of interest approach was carried out. Volumes of the 3 segments of both hemispheric AFs were evaluated by quantifying normalized and thresholded pathways. Resulting values served to generate the laterality index of the AFs. RESULTS Patients without language deficits tended to have an AF that was symmetric or lateralized to the right, whereas patients with deficits in language significantly more often demonstrated a left-lateralized posterior segment of the AF. Patients with high-grade gliomas had more severe language deficits than those with low-grade gliomas. Backward logistic regression revealed the laterality index of the posterior AF segment and tumor grade as the only independent statistically significant predictors for language deficits in this cohort. CONCLUSIONS In addition to the well-known fact that tumor entity influences behavioral outcome, the authors' findings suggest that the right homologs of structural language-associated pathways could be supportive for language function and facilitate compensation mechanisms after brain damage in functionally eloquent areas. This further indicates that knowledge about preoperative functional redistribution (identified by neurofunctional imaging) increases the chance for total or near-total resections of tumors in eloquent areas. In the future, longitudinal studies with larger groups are mandatory to overcome the methodological limitations of this cross-sectional study and to map neuroplastic changes associated with language performance and rehabilitation in brain tumor patients.

Temozolomide for recurrent or progressive high-grade malignant glioma: results of an Austrian multicenter observational study.

BACKGROUND: The use of chemotherapy in patients with malignant gliomas has remained a controversial issue even after the publication of favorable study data and a meta-analysis. The present study was initiated to support the use of chemotherapy in patients with relapsed high-grade gliomas (HGG). PATIENTS AND METHODS: Six Austrian centers recruited 43 patients with histologically confirmed HGG at first recurrence. Twelve chemotherapy-naïve patients received oral temozolomide at a dose of 200 mg/m(2) once a day for five consecutive days and 26 patients a dose of 150 mg/m(2) also for five days after various first-line chemotherapies. TMZ treatment was repeated every four weeks for a total of six cycles. RESULTS: Twenty-one patients (52.5 %) received at least six cycles of therapy. Two patients experienced complete remission and eight patients a partial response. Twenty patients survived at one year after enrolment in the study; eight patients survived beyond three years of follow-up. Hematological toxicities consisted of three thrombocytopenias G4 and 35 lymphocytopenias G3 and G4; these did not cause interstitial pneumonia or require inpatient treatment. Non-hematological toxicities were rare and without clinical relevance. Patients' quality of life was maintained during treatment. CONCLUSION: The study data confirm the feasibility and efficacy of chemotherapy with temozolomide in patients with relapsed/progressive HGG.

Poor short-term outcome in patients with ischaemic stroke and active cancer.

Stroke risk is increased in cancer patients and cancer activity has been claimed to play a role in the development of ischaemic stroke (IS). We wanted to further test these assumptions and to explore the impact of such relation on short-term prognosis. We identified all IS patients that were admitted to the neurological department of our primary and tertiary care university hospital between 2008 and 2014 (n = 4918) and reviewed their medical records for an additional diagnosis of cancer. Cancer patients were categorized into those with "active cancer" (AC: recurrent malignant tumour, metastases, ongoing chemo-/radiotherapy) and "non-active cancer" (NAC). We compared demographic, clinical and neuroimaging features of both patient groups and assessed their association with in-hospital mortality. 300 IS patients with known cancer were identified (AC: n = 73; NAC: n = 227). IS patients with AC were significantly younger (70.3 ± 10.6 vs. 74.9 ± 9.9 years), had more severe strokes at admission (NIHSS: median 5 vs. 3), more frequently cryptogenic strokes (50.7 vs. 32.5 %) and more often infarcts in multiple vascular territories of the brain (26 vs. 5.2 %) compared to IS patients with NAC. In-hospital mortality was significantly higher in AC patients (21.9 vs. 6.2 %). Multivariate analysis identified AC (odds ratio [OR] 3.70, 95 % confidence interval [CI] 1.50-9.30), NIHSS at admission (OR 1.10, CI 1.10-1.20) and C-reactive protein level (OR 1.01, CI 1.00-1.02) as factors significantly and independently associated with in-hospital death. Our findings support a direct role of AC in the pathogenesis and prognosis of acute IS. This needs to be considered in the management and counselling of such patients.

Treatment results and outcome in elderly patients with glioblastoma multiforme--a retrospective single institution analysis.

OBJECTIVE: Although glioblastoma multiforme is more common in patients older than 65 years, the elderly population is often excluded from clinical studies. Decision making in this subgroup can be challenging due to the lack of evidence for different neurosurgical and adjuvant treatment strategies. METHODS: In this retrospective study, we evaluated clinical, treatment and survival data of 124 consecutive patients over 65 years of age with supratentorial glioblastoma multiforme. RESULTS: Median OS was 6.0 months (std. error 0.783, 95% CI 4.456-7.535). Mean OS was 9.7 months (std. error 0.830, 95% CI 8.073-11.327). In univariate regression analysis, low KPS was of negative prognostic value (p < 0.006 for KPS ≤ 80), while greater advanced age did not have any impact on survival (p = 0.591 for differences between groups). Gross total resection and subtotal resection led to significantly improved overall survival (median 15.0 and 11.0 months; p < 0.02) compared to partial resection or biopsy (both 4.0 months), but complications were more common in subtotal and partial resections. The last observation did not reach statistical significance (p = 0.06). Combinations of irradiation and Temozolomide chemotherapy proved to be more effective than other adjuvant therapies. Extent of resection (gross total resection vs. all others) and form of adjuvant treatment were the only factors of independent prognostic value in multivariate analysis (p = 0.031 and p < 0.001, respectively). CONCLUSIONS: It appears that more aggressive treatment regimens can lead to longer overall survival in elderly glioblastoma multiforme patients. Gross total resection should be offered whenever safely possible; otherwise, biopsy may be preferred. Non-surgical treatment should consist of postoperative radiotherapy and concomitant and/or adjuvant chemotherapy. Possibly higher rates of hematological side effects in concomitant chemotherapy need to be further investigated.

Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma.

PURPOSE: A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recent in in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. PATIENTS AND METHODS: Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m(2)); (3) lomustine (110 mg/m(2)) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. RESULTS: The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. CONCLUSION: This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.

PURPOSE: NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS: Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS: Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS: This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.