Niklas Schäfer

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine–DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial

PURPOSE In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. PATIENTS AND METHODS In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). RESULTS In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. CONCLUSION BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Therapy of leptomeningeal metastasis in solid tumors.

Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection:

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0–3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

Systemic Thrombolysis for Ischemic Stroke after Antagonizing Dabigatran with Idarucizumab—A Case Report

We here describe our experience of systemic thrombolysis therapy for severe ischemic stroke in a patient taking dabigatran for atrial fibrillation. After administration of the monoclonal antibody fragment idarucizumab, the anticoagulative effects of dabigatran were efficiently antagonized and application of alteplase was safe and feasible in our patient. This case report may illustrate a novel treatment option in the neurological emergency setting.

Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex

Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to serine substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery.

Primary CNS lymphoma: a clinician's guide

Primary CNS lymphoma is a high malignant disease of the brain which can lead rapidly to death if diagnosis and/or the start of treatment is delayed. The age at time of diagnosis is a strong factor influencing prognosis so that in younger patients <65 years of age long-term survival may be achieved in a substantial percentage of patients, while in elderly patients long-term survival is seen much more rarely. First-line therapy consists of high-dose methotrexate-based (poly)chemotherapy. This review provides an overview of clinical presentation, steps to diagnosis, detailed information about current treatment concepts and specific information for particular clinical situations.

Ifosfamide, Carboplatin and Etoposide in Recurrent Malignant Glioma

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.

Carmustine (BCNU) plus Teniposide (VM26) in Recurrent Malignant Glioma

Background: After the failure of radiotherapy and temozolomide, there is no established standard therapy for patients with recurrent glioblastoma (GBM). Based on the promising data of a previous trial (NOA-01) for primary GBM and some retrospective case series for GBM recurrence, the combination of nimustine and teniposide (VM26) was commonly used in this setting. When nimustine was no longer available in Europe, we switched to intrvaveneous carmustine (BCNU). Data on the toxicity and efficacy of BCNU and VM26 in recurrent GBM are lacking. Methods: In our neurooncological center, all patients with recurrent GBM or with progressed glioma and a typical MRI lesion suggesting GBM treated with BCNU (130-150 mg/m2, day 1/42) and VM26 (45-60 mg/m2, days 1-3/42) were analyzed retrospectively for progression-free survival, overall survival and toxicity. Results: Fifteen patients (median age 52 years) were identified. Median progression-free survival was 2 months and median overall survival was 4 months. Two patients (14%) developed grade 3/4 hematotoxicity. Nonhematological toxicity ≥grade 3 was not observed. Conclusion: Our data do not support the application of BCNU/VM26 in patients with late stages of recurrent GBM.

FUNCTIONAL SUBCLONE PROFILING FOR PREDICTION OF TREATMENT-INDUCED INTRA-TUMOR POPULATION SHIFTS AND DISCOVERY OF RATIONAL DRUG COMBINATIONS IN HUMAN GLIOBLASTOMA

Purpose: Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design: Here, we used 33 single cell–derived subclones generated from five clinical glioblastoma specimens for exploring intra- and interindividual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacologic sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results: Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential antiglioblastoma compounds. A more comprehensive intratumoral analysis revealed that stable genetic and phenotypic characteristics of coexisting subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacologic profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions: Our data provide a previously unrecognized strategy for revealing functional consequences of intratumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. Clin Cancer Res; 23(2); 562–74. ©2016 AACR.

Intravascular CNS lymphoma: Successful therapy using high-dose methotrexate-based polychemotherapy.

Intravascular diffuse large B-cell lymphoma limited to the CNS (cIVL) is a very rare malignant disorder characterized by a selective accumulation of neoplastic lymphocytes (usually B cells) within the lumen of CNS blood vessels but not in the brain parenchyma. In the past, treatment of cIVL with anthracycline-based regimens was unsatisfactory with very short survival times. In the case of cIVL presented here, high-dose methotrexate-based polychemotherapy according to the Bonn protocol plus rituximab therapy was successful and led to a complete clinical and MRI remission which is ongoing 29 months after diagnosis.