Predictive factors of human cytomegalovirus reactivation in newly diagnosed glioblastoma patients treated with chemoradiotherapy.

The human cytomegalovirus (HCMV) is a ubiquitous herpes virus which infects 40 to 99% of the population. HCMV reactivation may occur in the context of immunosuppression and can induce significant morbidities. Several cases of HCMV infections or HCMV reactivation have thus been reported in glioblastoma (GBM) patients treated with radio(chemo)therapy. With the aim to identify the main risk factors associated with HCMV reactivation, we reviewed all patients treated for a newly diagnosed GBM in our institution from October 2013 to December 2015. Age, sex, Karnofsky performance status (KPS), absolute lymphocyte count (ALC), serological HCMV status, and steroid doses were recorded at the start and 1 month after the end of radiotherapy (RT). Within the 103 patients analyzed, 34 patients (33%) had an initial negative serology for HCMV, and none of them developed a seroconversion after treatment. Among patients with positive HCMV IgG (n = 69), 16 patients (23%) developed a viremia at one point during treatment. Age (> 60 years), steroid intake, and ALC (< 1500/mm3) before RT were correlated with HCMV reactivation. HCMV viremia was associated with neurological decline 1 month after chemoradiotherapy but progression-free survival was not impacted. A shorter overall survival was seen in these patients when compared with the others, but this could be biased by the older age in this subgroup. HCMV reactivation needs to be sought in case of a neurological decline during RT especially in older patients treated with steroids and low lymphocytes counts.

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.

Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature.

Immune checkpoint inhibitors (ICIs) targeting CTLA4 and PD1 constitute a promising class of cancer treatment but are associated with several immune-related disorders. We here review the literature reporting neurological adverse events (nAEs) associated with ICIs. A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with ICIs was conducted. Eligible studies included case reports and prospective trials. One case seen in our ward was also added. Within the 59 clinical trials (totalling 9208 patients) analysed, the overall incidence of nAEs was 3.8% with anti-CTLA4 antibodies, 6.1% with anti-PD1 antibodies, and 12.0% with the combination of both. The clinical spectrum of neurological disorders was highly heterogeneous. Most of these nAEs were grade 1-2 and consisted of non-specific symptoms such as headache (55%). The incidence of high grade nAEs was below 1% for all types of treatment. Headaches, encephalopathies and meningitis were the most commonly reported (21%, 19% and 15%, respectively). Among the 27 case reports, the most common nAEs were encephalopathies, meningoradiculoneuritis, Guillain-Barré like syndromes and myasthenic syndromes. The median time of nAEs onset was 6 weeks. In most cases, drug interruption and steroids led to neurological recovery, even in conditions where steroids are not usually recommended such as Guillain-Barré syndrome.

Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma.

BACKGROUND AND PURPOSE: Despite surgery, radiotherapy (RT) and temozolomide (TMZ), the prognosis of glioblastoma (GBM) patients remains dismal. Normally prescribed with the aim to lower blood pressure, angiotensin-II (Ang-II) inhibitors were reported to reduce angiogenesis and tumour growth in several tumour models including one glioma. Thus whether treatment with Ang-II inhibitors could be associated with a better clinical outcome in GBM patients was investigated. METHODS: A series of 81 consecutive patients, homogeneously treated with RT and TMZ for a newly diagnosed, supratentorial GBM, were analysed. The objective of this retrospective study was to assess the impact of angiotensin-converting enzyme inhibitors (ACEIs) and Ang-II receptor 1 blockers (ARBs) on functional independence, progression-free survival (PFS) and overall survival (OS). RESULTS: Amongst the 81 GBM patients analysed, 26 were already treated for high blood pressure (seven with ACEIs and 19 with ARBs). The number of patients who remained functionally independent at 6 months after RT was higher in the group of patients treated with Ang-II inhibitors compared to the other patients (85% vs. 56%, P = 0.01). In patients treated with Ang-II inhibitors, PFS was 8.7 months (vs. 7.2 months in the other patients) and OS was 16.7 months (vs. 12.9 months). The use of Ang-II inhibitors was a significant prognostic factor for both PFS (P = 0.04) and OS (P = 0.04) in multivariate analysis. CONCLUSION: Treatment with Ang-II inhibitors in combination with RT and TMZ might improve clinical outcome in GBMs. Prospective trials are needed to test this hypothesis.

[Systemic treatment of brain metastases from lung cancer]. / Traitement systémique des métastases cérébrales de cancer bronchique.

Systemic treatment of lung cancer patients with brain metastases is based on clinical (presence of symptomatic intracranial lesions), pathological and molecular characteristics of the disease. The efficacy of standard platinum-based chemotherapy is comparable inside and outside the brain, justifying its use as front-line therapy. The intracranial efficacy of targeted therapies (EGFR tyrosine kinase inhibitors, ALK inhibitors) is demonstrated, and is globally superior to the efficacy of standard chemotherapy, justifying their use as front-line therapy in case of EGFR activating mutation or ALK rearrangement (providing the change in the crizotinib label in France). The concomitant use of whole brain radiotherapy and a systemic treatment (chemotherapy or targeted therapy) is not recommended in the absence of a demonstrated better efficacy and/or acceptable safety profile. Several trials are ongoing to assess new whole brain radiotherapy modalities, new targeted therapies alone or in combination, especially exploring immunotherapy.

Seronegative paraneoplastic cerebellar degeneration: the PNS Euronetwork experience.

BACKGROUND AND PURPOSE: To describe the characteristics of patients presenting a paraneoplastic cerebellar degeneration without classical onconeural antibodies (seronegative PCD). METHODS: Thirty-nine seronegative PCD patients from the Paraneoplastic Neurological Syndrome Euronetwork were retrospectively analyzed and compared with 180 patients with PCD associated with classical onconeural antibodies (seropositive PCD). RESULTS: No patient had anti-CASPR2 or anti-mGluR1 antibodies. No significant difference between the clinical characteristics of seronegative and seropositive PCD patients was observed. Yet the frequency of associated tumors was different. Lymphoma was more frequent in seronegative than in seropositive women (24% vs. 2%, P = 0.002) whilst gynecological cancer were less frequent (38% vs. 74%, P = 0.002). In comparison with seropositive men, seronegative men more frequently had a non-small-cell lung cancer (27% vs. 6%, P = 0.08) or a genitourinary cancer (22% vs. 0%, P = 0.04) but less frequently a small-cell lung cancer (23% vs. 74%, P = 0.002). Seronegative and seropositive PCD patients with similar tumors had a similar overall survival. CONCLUSION: The clinical characteristics of seronegative and seropositive PCD are similar but the spectrum of associated tumors is different. The immunological scenario of seronegative PCD seems to be different from that of limbic encephalitis with only few patients harboring anti-neuropile antibodies.

Steroid-sparing effects of angiotensin-II inhibitors in glioblastoma patients.

BACKGROUND: The standard of care in patients with glioblastoma (GBM) relies on surgical resection, radiation therapy (RT), and temozolomide. Steroids are required in almost all patients to reduce peritumoral edema, but are associated with numerous side effects. Vascular endothelial growth factor (VEGF) is a key driver of peritumoral edema and angiogenesis in human GBM. Recently, angiotensin-II inhibitors were reported to reduce VEGF secretion and tumor growth in some animal models. METHODS: To investigate whether angiotensin-II inhibitors might have a similar effect in humans and before undertaking a prospective study, we retrospectively investigated a series of 87 consecutive, newly diagnosed GBM patients, treated in a single center. Amongst these patients, 29 (33%) were already treated before RT for high blood pressure (HBP), 18 of them (21%) with an angiotensin-II inhibitor. In all patients, performance status, surgical procedures, and steroid dosages were documented. RESULTS: Patients treated with angiotensin-II inhibitors, but not other antihypertensive drugs, required half of the steroids of the other patients during radiotherapy (P = 0.005 in multivariate analysis, considering other antihypertensive treatments, surgical resection, and performance status). This effect of angiotensin-II inhibitors was also significant at the beginning of radiotherapy (P = 0.03 in multivariate analysis). Treatment with angiotensin-II inhibitors had no effect on survival (16.2 vs. 17.9 months for the treated and the non-treated group, respectively, P = 0.77). CONCLUSION: Angiotensin-II inhibitors might display significant steroid-sparing effects in brain tumor patients. Given the morbidity associated with steroids, this finding might have important practical consequences in these patients and warrants a randomized study.

Immunotherapy in human glioblastoma.

Glioblastoma patients spontaneously develop anti-tumour immune responses. However, the tumour itself develops several mechanisms that allow the tumor to escape the immune system. Clinical trials using infusion of activated autologous immune cells, or active immunotherapy with tumor antigens and dendritic cells have successfully induced anti-tumour immunity and some radiological responses. More recently, approaches targeting the mechanisms of tolerance have shown promising data in melanoma, and are currently under investigations in gliomas. However, large randomised trials are still needed to prove the usefulness of cancer vaccines in brain tumors.

[Management of brain metastases from non-small cell lung carcinoma]. / Les métastases cérébrales des cancers bronchiques non à petites cellules : vers une prise en charge homogène.

INTRODUCTION: In France, approximately 30,000 new patients per year develop brain metastases (BM), most of them resulting from a lung cancer. STATE OF THE ART: Surgery and radiosurgery of all the BM must be considered when possible. In other cases, whole brain radiotherapy remains the standard of care. PERSPECTIVES: The role of chemotherapy, poorly investigated so far, should be revisited. CONCLUSION: This review focused on BM secondary to a non-small cell lung carcinoma.

[Atypical progressive multifocal leukoencephalopathy (PML) in a patient with pulmonary sarcoidosis]. / Leucoencéphalopathie multifocale progressive atypique chez un patient atteint de sarcoïdose médiastinopulmonaire.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of central nervous system due to the JC virus. PML generally occurs in immunocompromised hosts and has a fatal outcome. OBSERVATION: We report a case of an atypical PML in a patient with pulmonary sarcoidosis: MRI showed multifocal and punctate contrast enhancements. The diagnostic was made by brain biopsy. CONCLUSION: The pathophysiology of this association is probably related to the immunodepression induced by sarcoidosis.

Cerebrospinal fluid study in paraneoplastic syndromes.

OBJECTIVE: Paraneoplastic neurological syndromes (PNS) probably result from an immune reaction against antigens shared by the nervous system and tumour cells. To characterise CSF alterations in these syndromes, we studied a large series of paraneoplastic patients. METHODS: Using the PNS European database which includes patients diagnosed with PNS in Europe, we reviewed the clinical data of all patients included between 2000 and 2007 for which information on CSF was available. Patients were studied if they met the following inclusions criteria: (1) definite paraneoplastic disease with anti-Hu, anti-Yo, anti-CV2, anti-Ri anti-Ma/Ta and anti-Tr antibodies; (2) clinical information available; and (3) at least one CSF study. RESULTS: 295 patients met the inclusion criteria. Abnormal CSF (pleiocytosis and/or high protein level and/or oligoclonal bands) was found in 93% of patients. Pleiocytosis, but not hyperproteinorachia, was more frequently seen in patients in whom the CSF study was done early in the evolution. In 24 patients, oligoclonal bands were the only abnormality found in the CSF (10%). Elevated numbers of cells were found in 47% of patients before the third month compared with 28% after the third month (p<0.01). This evolution might suggest a subacute inflammation phase within the nervous system, followed by a non-inflammatory phase. The inflammation profile was similar in all antibody types, cancers or neurological syndromes of the PNS. Surprisingly, anti-Hu patients with high pleiocytosis at the time of diagnostic had a better survival in this study than those without pleiocytosis (572 days vs 365 days; p = 0.05). CONCLUSION: CSF inflammation is a common finding in PNS patients and can be a helpful tool for diagnosis, especially if this analysis is done within 3 months after neurological onset.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.

OBJECTIVE: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. METHODS: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. RESULTS: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. INTERPRETATION: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

[New therapeutic approaches in glioblastomas]. / Actualités dans les nouvelles approches thérapeutiques dans les glioblastomes.

Current treatment of glioblastomas relies on surgical resection, radiotherapy and chemotherapy. However, the efficacy of these therapeutics is still limited and new therapeutic approaches based on the understanding of brain tumor biology are emerging. High expression of the EGF receptor by tumor cells, activation of the PI3K/Akt and the Ras/Raf pathways represent interesting targets for new selective drugs under development. The most promising drugs are currently antiangiogenic agents. This article reviews these emerging therapies currently under clinical trials in glioblastomas.

Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer.

BACKGROUND: The clinical and immunological profiles of patients with paraneoplastic cerebellar degeneration (PCD) and non-small-cell lung cancer (NSCLC) are not well known. OBJECTIVE: To review the clinical and immunological features of patients with PCD, NSCLC and without well-characterised onconeural antibodies. METHODS: The clinical features of nine patients with the diagnosis of classical PCD and NSCLC, included in our archives, were retrospectively reviewed. The presence of antibodies to cerebellar components was determined by immunohistochemistry and immunoblot of rat cerebellum. A cDNA library of human cerebellum was screened with the positive sera to identify the antigen. RESULTS: Nine patients with PCD and NSCLC were identified. Six patients were men, and the median age at diagnosis of PCD was 63 (range 47-73) years. PCD was completely reversed in two patients, and partially in one, after treatment of the tumour. The serum of one of the patients with PCD showed a unique reactivity with Purkinje cells. The screening of a cerebellar-expression library resulted in the isolation of protein kinase Cgamma (PKCgamma). PKCgamma immunoreactivity was not observed in the serum of 170 patients with non-paraneoplastic neurological syndromes, 27 patients with PCD, no onconeural antibodies and small-cell lung cancer, and 52 patients with NSCLC without paraneoplastic neurological syndromes. The NSCLC from 11 patients without PCD did not express PKCgamma at either the RNA or protein level. However, many cells of the NSCLC of the patient with PKCgamma antibodies expressed PKCgamma. CONCLUSION: PCD occurs in patients with NSCLC without typical onconeural antibodies and is associated with immune reactions against key proteins of the Purkinje cells.

[New therapeutic approaches in glioblastomas]. / Nouvelles approches thérapeutiques dans les glioblastomes.

INTRODUCTION: Current treatment of glioblastomas relies on surgical resection, radiotherapy and chemotherapy. However, the efficacy of these therapeutics is still limited and new therapeutic approaches based on the understanding of brain tumor biology are emerging. STATE OF ART: High expression of the EGF receptor by tumor cells, activation of the PI3K/Akt and the Ras/Raf pathways represent interesting targets for new selective drugs under development. Proteases inhibitors and antiangiogenic agents are also under investigations in clinical trials. Perspectives. In addition, the recent development of convection-enhanced delivery technique allows the administration of drugs which do not cross the blood-brain-barrier, such as selective toxins or immunostimulating oligonucleotides. CONCLUSION: Though the results of clinical trials have been somewhat disappointing, using different drug combinations or drug-radiotherapy associations will probably enable an improvement in the prognosis for these patients in the future.

EGFR tyrosine kinase domain mutations in human gliomas.

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor effective in patients with lung cancer with mutations in exons 19 and 21 of the EGFR tyrosine kinase domain. In this study, the authors tested the presence of such mutations in 95 gliomas including glioblastomas, anaplastic oligodendrogliomas, and low-grade gliomas. No mutation was found, which suggests that the biology of EGFR in gliomas is different from lung cancer and that this may be a factor in the resistance of glioblastomas to gefitinib.

Value of Hu antibody determinations in the follow-up of paraneoplastic neurologic syndromes.

The long-term evolution of Hu antibody (Hu-Ab) titers in patients with paraneoplastic neurologic syndromes (PNSs) is not known. Described is the evolution of Hu-Ab titers in 35 patients with PNS with a median follow-up of 32 months (range 6 to 108 months). No correlation was observed between Hu-Ab titers and neurologic outcome, tumor evolution, or type of treatment. Serial Hu-Ab determinations are not useful for monitoring the clinical outcome of patients with PNS.