Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases.

Challenges in obtaining tissue specimens from patients with brain tumours limit the diagnosis and molecular characterisation and impair the development of better therapeutic approaches. The analysis of cell-free tumour DNA in plasma (considered a liquid biopsy) has facilitated the characterisation of extra-cranial tumours. However, cell-free tumour DNA in plasma is limited in quantity and may not reliably capture the landscape of genomic alterations of brain tumours. Here, we review recent work assessing the relevance of cell-free tumour DNA from cerebrospinal fluid in the characterisation of brain cancer. We focus on the advances in the use of the cerebrospinal fluid as a source of cell-free tumour DNA to facilitate diagnosis, reveal actionable genomic alterations, monitor responses to therapy, and capture tumour heterogeneity in patients with primary brain tumours and brain and leptomeningeal metastases. Profiling cerebrospinal fluid cell-free tumour DNA provides the opportunity to precisely acquire and monitor genomic information in real time and guide precision therapies.

Combined irradiation and targeted therapy or immune checkpoint blockade in brain metastases: toxicities and efficacy.

BACKGROUND: Targeted therapies (TT) and immune checkpoint inhibitors (ICI) are currently modifying the landscape of metastatic cancer management and are increasingly used over the course of many cancers treatment. They allow long-term survival with controlled extra-cerebral disease, contributing to the increasing incidence of brain metastases (BMs). Radiation therapy remains the cornerstone of BMs treatment (either whole brain irradiation or stereotactic radiosurgery), and investigating the safety profile of radiation therapy combined with TT or ICI is of high interest. Discontinuing an efficient systemic therapy, when BMs irradiation is considered, might allow systemic disease progression and, on the other hand, the mechanisms of action of these two therapeutic modalities might lead to unexpected toxicities and/or greater efficacy, when combined. PATIENTS AND METHODS: We carried out a systematic literature review focusing on the safety profile and the efficacy of BMs radiation therapy combined with targeted agents or ICI, emphasizing on the role (if any) of the sequence of combination scheme (drug given before, during, and/or after radiation therapy). RESULTS: Whereas no relevant toxicity has been noticed with most of these drugs, the concomitant use of some other drugs with brain irradiation requires caution. CONCLUSION: Most of available studies appear to advocate for TT or ICI combination with radiation therapy, without altering the clinical safety profiles, allowing the maintenance of systemic treatments when stereotactic radiation therapy is considered. Cognitive functions, health-related quality of life and radiation necrosis risk remain to be assessed. The results of prospective studies are awaited in order to complete and validate the above discussed retrospective data.

REBECA: a phase I study of bevacizumab and whole-brain radiation therapy for the treatment of brain metastasis from solid tumours.

BACKGROUND: Brain metastases (BMs) are associated with a poor prognosis. Standard treatment comprises whole-brain radiation therapy (WBRT). As neo-angiogenesis is crucial in BM growth, combining angiogenesis inhibitors such as bevacizumab with radiotherapy is of interest. We aimed to identify the optimal regimen of bevacizumab combined with WBRT for BM for phase II evaluation and provide preliminary efficacy data. PATIENTS AND METHODS: In this multicentre single-arm phase I study with a 3 + 3 dose-escalation design, patients with unresectable BM from solid tumours received three cycles of bevacizumab at escalating doses [5, 10 and 15 mg/kg every 2 weeks at dose levels (DL) 0, 1 and 2, respectively] and WBRT (30 Gy/15 fractions/3 weeks) administered from day 15. DL3 consisted of bevacizumab 15 mg/kg with WBRT from day 15 in 30 Gy/10 fractions/2 weeks. Safety was evaluated using NCI-CTCAE version 3. BM response (RECIST 1.1) was assessed by magnetic resonance imaging at 6 weeks and 3 months after WBRT. RESULTS: Nineteen patients were treated, of whom 13 had breast cancer. There were no DLTs. Grade 1-2 in-field and out-field toxicities occurred for five and nine patients across all DLs, respectively, including three and six patients (including one patient with both, so eight patients overall) of nine patients in DL3. One patient experienced BM progression during treatment (DL0). At the 3-month post-treatment assessment, 10 patients showed a BM response: one of three treated at DL0, one of three at DL1, two of three at DL2 and six of seven at DL3, including one complete response. BM progression occurred in five patients, resulting in two deaths. The remaining patient died from extracranial disease progression. CONCLUSION: Bevacizumab combined with WBRT appears to be a tolerable treatment of BM. DL3 warrants further efficacy evaluation based on the favourable safety/efficacy balance. ClinicalTrials.gov Identifier: NCT01332929.

Circulating tumor cells and brain metastasis outcome in patients with HER2-positive breast cancer: the LANDSCAPE trial.

BACKGROUND: Decrease of circulating tumor cells (CTC) during treatment is an independent prognostic factor in metastatic breast cancer (MBC). We specifically evaluated the impact of CTC on brain metastasis outcome. METHODS: HER2-positive MBC with brain metastasis not previously treated with whole-brain radiotherapy received first-line combination of lapatinib and capecitabine in a phase II study. CTC were detected at baseline and day 21 (CellSearch). RESULTS: Median follow-up of the 44 analyzed patients was 21.2 months. The central nervous system objective response (CNS-OR) rate was 66%. At baseline, 20 of 41 assessable patients for CTC (49%) had ≥1 CTC (range 1-301, median 3) and 9 (22%) had ≥5 CTC. At day 21, 7 of 38 patients (18%) had ≥1 CTC (P = 0.006, versus baseline), and CTC had disappeared in 11 patients. CNS-OR rate was significantly higher in patients with no CTC at day 21 [25 of 31 (80%) versus 2 of 7 (29%), P = 0.01]. The 1-year overall survival rate was 83.9% in patients with no CTC at day 21 versus 42.9% in patients with ≥1 CTC (P = 0.02). CONCLUSIONS: This is the first report showing a correlation between CNS metastasis response, outcome and early CTC clearance under targeted treatment of HER2+ MBC. CLINICAL TRIALS NUMBER: NCT00967031.

A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer.

Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.

[Limbic encephalitis: a new paraneoplastic auto-immune manifestation associated with metastatic melanoma?]. / Encéphalite limbique : une nouvelle manifestation auto-immune paranéoplasique associée au mélanome métastatique ?

BACKGROUND: Several studies indicate an association between immune-related manifestations and prolonged survival in metastatic melanoma. Limbic encephalitis driven by immune-mediated disorders may also be observed during the course of certain cancers. PATIENTS AND METHODS: In November 2009, a 60-year-old woman followed up for metastatic melanoma since July 2005 developed rapidly progressive cognitive disorder. Clinical, biological, MRI and electroencephalogram abnormalities resulted in diagnosis of probably paraneoplastic limbic encephalitis in a context of immune-related manifestations although chemotoxicity could not be ruled out. Auto-immunity with hypothyroidism and thrombocytopenia were seen concomitantly. DISCUSSION: To the best of our knowledge, this is the first reported case of probably paraneoplastic limbic encephalitis associated with melanoma, a new example of an immune-related condition associated with prolonged survival in metastatic melanoma.

Supportive care in neurooncology.

The quality of life of patients treated for brain tumor is, in all cases, deeply altered by the tumor and the treatments. Optimizing the symptomatic management is a key objective for all care givers. We present in this paper a very pragmatic focus concerning the management of intracranial hypertension (and/or neurological deficits), venous thromboembolism, confusion, epilepsy and symptoms more directly associated with the end of life.

[Cognitive disorders and adult grade II and III gliomas: analysis of a series of 15 patients]. / Troubles cognitifs dans les gliomes de grade II et III de l'adulte : à propos d'une série de 15 patients.

BACKGROUND AND PURPOSE: Correlated with better follow-up of gliomas, cognitive disorders are increasingly studied. The aim of this study was to describe the cognitive disorders presented by these patients at baseline, before any treatment, and to evaluate the relations between cognitive disorders and return to work. METHODS: A detailed neuropsychological evaluation was administrated to 15 newly diagnosed patients with a grade II or III glial tumor before any treatment. Patients also completed the quality of life and depression scales. RESULTS: All patients in our study presented with at least one failed cognitive domain during the detailed examination, while the scores on the MMSE scale were within the norm. The most deteriorated functions were divided attention and episodic verbal and nonverbal memory. Moreover, a significant link was found between the number of failed cognitive functions and quality of life. CONCLUSION: Cognitive disorders are frequent with glial tumors and impact patients' quality of life. Simple tests of global cognitive status are not sufficient to detect cognitive difficulties in these patients. Consequently, detailed and adapted neuropsychological assessment is necessary, especially to detect deteriorated problems with memory, divided attention, or processing speed in this population.

Angiotensin II receptor blockers, steroids and radiotherapy in glioblastoma-a randomised multicentre trial (ASTER trial). An ANOCEF study.

BACKGROUND: Glioblastomas (GBMs) induce a peritumoural vasogenic oedema impairing functional status and quality of life. Steroids reduce brain tumour-related oedema but are associated with numerous side-effects. It was reported in a retrospective series that angiotensin receptor blockers might be associated with reduced peritumoural oedema. The ASTER study is a randomised, placebo-controlled trial to assess whether or not the addition of Losartan to standard of care (SOC) can reduce steroid requirement during radiotherapy (RT) in patients with newly diagnosed GBM. PATIENTS AND METHODS: Patients with a histologically confirmed GBM after biopsy or partial surgical resection were randomised between Losartan or placebo in addition to SOC with RT and temozolomide (TMZ). The primary objective was to investigate the steroid dosage required to control brain oedema on the last day of RT in each arm. The secondary outcomes were steroids dosage 1 month after the end of RT, assessment of cerebral oedema on magnetic resonance imaging, tolerance and survival. RESULTS: Seventy-five patients were randomly assigned to receive Losartan (37 patients) or placebo (38 patients). No difference in the steroid dosage required to control brain oedema on the last day of RT, or one month after completion of RT, was seen between both arms. The incidence of adverse events was similar in both arms. Median overall survival was similar in both arms. CONCLUSIONS: Losartan, although well tolerated, does not reduce the steroid requirement in newly diagnosed GBM patients treated with concomitant RT and TMZ. Trial registration number NCT01805453 with ClinicalTrials.gov.

[Superficial hemosiderosis of the central nervous system improved by corticosteroids]. / Hémosidérose marginale du névraxe d'évolution favorable sous corticoïdes.

INTRODUCTION: Superficial siderosis is of the Central Nervous System (CNS) is an uncommon and often disabling disorder. There is no evidence that any treatment, including removal of an identified source of bleeding, affects disease progression. OBSERVATION: We report the case of a 49-year-old woman exhibiting progressive and various neurological disorders associating chorea, pyramidal syndrome, cerebellar ataxia, cognitive disorders and cranial nerve deficits. She had a prior history of right occipital arterioveinous malformation (AVM) revealed four years before by ventricular hemorrhage. The AVM was treated by radiosurgery. Because of a pronounced progression of the symptoms, treatment with steroid therapy was initiated before the diagnosis of siderosis of the central nervous system was asserted by magnetic resonance imaging (rim of hypo-intensity due to hemosiderin around the brainstem, the cerebellum and the spinal cord on T-2 weighted and gradient echo T-2* imaging) and cerebrospinal fluid (CSF) examination (high CSF levels of iron and ferritin). Over the next months the neurological condition improved under steroid therapy. CONCLUSION: Our observation is interesting because of the chorea movement disorders which are rarely reported in the disease and because of the improvement of the neurological condition after steroid therapy which is described in only another case in the literature. Steroid therapy could constitute a new track for the treatment of siderosis of CNS.

High-field intraoperative MRI in glioma surgery: A prospective study with volumetric analysis of extent of resection and functional outcome.

BACKGROUND: High-field intraoperative MRI (IoMRI) is a useful tool to improve the extent of glioma resection (EOR). OBJECTIVE: To compare the interest of 1.5T IoMRI in glioma surgery between enhancing and non-enhancing tumors, based on volumetric analysis. METHODS: A prospective single-center study included consecutive adult patients undergoing glioma surgery with IoMRI. Volumetric evaluation was based on FLAIR hypersignal after gadolinium injection in non-enhancing tumors and T1 hypersignal after gadolinium injection in enhancing tumors. Endpoints comprised: residual tumor volume (RTV), EOR, workflow and clinical outcome on Karnofsky performance score (KPS). RESULTS: Fifty-three surgeries were performed from July 2014 to January 2016. Thirty-four patients underwent one IoMRI, and 19 two IoMRIs. In non-enhancing tumors, intraoperative RTV on 1st IoMRI T2/FLAIR was higher than in enhancing tumors on T1 sequences (7.25cm3 vs. 0.74cm3, respectively; P=0.008), whereas the RTV on 2nd IoMRIs and final RTV were no longer significantly different. After IoMRI, 72% of patients underwent additional resection. In non-enhancing tumors, EOR increased from 77.3% on 1st IoMRI to 97.4% on last MRI (P<0.001). Taking all tumors together, final RTV values were: median=0cm3, mean=3.9cm3. Mean final EOR was 94%. In 25% of patients, KPS was reduced during early postoperative course; at 3 and 6 months postoperatively, median KPS was 90. CONCLUSION: Intraoperative MRI guidance significantly enhanced the extent of glioma resection, especially for non- or minimally enhancing tumors, while preserving patient autonomy.

Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era.

Leptomeningeal metastasis is a fatal manifestation seen in advanced cancer patients. Its incidence is increasing, reaching 3.8% in molecularly unselected non-small cell lung cancer patients and up to 5% and 9% in ALK-rearranged and EGFR-mutant lung cancer patients, respectively. The prognosis remains poor despite systemic treatment, intrathecal chemotherapy, radiation therapy and personalized treatments in molecularly selected patients. However, new therapies with improved cerebral-spinal fluid penetration have been developed for subgroups of molecular selected patients indicating they could be promising therapeutic options for managing leptomeningeal disease. Systemic chemotherapy, which may be combined with intrathecal chemotherapy, remains standard treatment for lung cancer patients with leptomeningeal disease and a good-risk profile. We summarize evidence reported in the literature for managing this complication in lung cancer patients. Based on this, we have selected potential therapeutic strategies that could be used in daily clinical practice.

Intraoperative MRI for the management of brain lesions adjacent to eloquent areas.

BACKGROUND: The aim of our study was to report the usefulness of intraoperative MRI guidance in the resection of brain lesions adjacent to eloquent areas. PATIENTS AND METHODS: A single center prospective series of gliomas amenable to optimized resection with intraoperative MRI between September 2014 and December 2015. RESULTS: The study included 56 patients. The median duration of the first intraoperative MRI was 38min, interquartile range (IQR 30-46). Fourteen patients (40%) underwent a second intraoperative MRI, which had a median duration of 26min (IQR, 18-30). The median total operative time was 265min (IQR, 242-337). After the first intraoperative MRI, the median residual glioma volume of the 35 gliomas adjacent to eloquent areas was 7.04cm3 (IQR, 2.22-13.8), which did not significantly differ from the other gliomas (P=0.07). After the second intraoperative MRI, the median residual glioma volume was 3.86cm3 (IQR, 0.82-6.99), which did not significantly differ from the other patients (P=0.700). On the postoperative MRI, the median extent of the glioma resections adjacent to eloquent areas was 99.78% (IQR, 88.9-100), which was not significantly different from the rest of the population (P=0.290). At 6 months after surgery, the median Karnofsky Performance Score was 90, and 2.8% of the patients presented a permanent new neurological deficit. CONCLUSION: Our results suggest that intraoperative MRI is an effective and safe technique to improve the extent of brain lesion resections close to eloquent areas.

Different patterns of Mini Mental Status Examination responses in primary progressive aphasia and Alzheimer's disease.

Primary progressive aphasia (PPA) syndrome is frequently misdiagnosed--particularly in favour of Alzheimer's disease (AD). Misdiagnosis is related to the heterogeneity of language disorders at onset, variability in the rate of clinical progression and the low prevalence of PPA syndrome, compared with AD. The aim of this study was to determine whether a patient's first Mini Mental Status Examination (MMSE) might provide insight into differentiating between PPA and AD. We compared item scores for the first, complete MMSE in consecutive patients with PPA versus matched patients with AD. Word recall and constructional praxis were significantly better in patients subsequently diagnosed as suffering from PPA. Patients with AD performed significantly better in terms of word registration, object naming, repetition and verbal direction. Our findings indicate that the various MMSE item scores may be helpful in differentiating PPA and AD in the first few years of the disease.