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Specialist Neuro-Oncology Associations
Recent Research Publications
Brain and Spinal Cord Tumours
Childhood Brain Tumours

Specialist Neuro-Oncology Associations (8 links)

Recent Research Publications

Cortinovis D, Chiari R, Catino A, et al.
Italian Cohort of the Nivolumab EAP in Squamous NSCLC: Efficacy and Safety in Patients With CNS Metastases.
Anticancer Res. 2019; 39(8):4265-4271 [PubMed] Related Publications
BACKGROUND/AIM: Brain metastases are an additional challenge in patients with non-small-cell lung cancer (NSCLC) because most chemotherapy agents cannot cross the blood-brain barrier. Nivolumab has demonstrated efficacy in patients with advanced squamous NSCLC, but because patients with central nervous system (CNS) metastases are typically excluded from registration trials, 'field-practice' data are needed.
PATIENTS AND METHODS: Patients in the Italian cohort of the Expanded Access Program (EAP) who had CNS metastases at baseline were analyzed.
RESULTS: Thirty-seven patients with CNS metastases received a median of six doses of nivolumab. Three patients (8%) had grade 3-4 adverse events and one patient discontinued due to an adverse event. The objective response rate was 19%. Median overall survival was 5.8 (95% confidence interval=1.9-9.8) months and median progression-free survival was 4.9 (95% confidence interval=2.7-7.1) months.
CONCLUSION: The safety and efficacy of nivolumab in patients with CNS metastases appear to be similar to those seen in the overall EAP cohort in Italy.

Antonopoulos M, VAN Gool SW, Dionysiou D, et al.
Immune Phenotype Correlates With Survival in Patients With GBM Treated With Standard Temozolomide-based Therapy and Immunotherapy.
Anticancer Res. 2019; 39(4):2043-2051 [PubMed] Related Publications
BACKGROUND/AIM: The need for more effective treatment modalities that can improve the clinical outcome of patients with glioblastoma multiforme remains imperative. Dendritic cell vaccination is a fast-developing treatment modality, currently under exploration. Functional immune cell subpopulations may play a role in the final outcome.
MATERIALS AND METHODS: Data from 101 patients drawn from the HGG-2010 trial, including baseline patient characteristics and fluorescence-activated cell sorting of immune cell subpopulations, were analyzed by statistical and machine-learning methods.
RESULTS: The analysis revealed strong correlations between immune profiles and overall survival, when the extent of resection and the vaccination schedule were used as stratification variables.
CONCLUSION: A systematic, in silico workflow detecting strong and statistically significant correlations between overall survival and immune profile-derived quantities obtained at the start of dendritic cell vaccination was devised. The derived correlations could serve as a basis for the identification of prognostic markers discriminating between potential long- and short-term survivors of patients with glioblastoma multiforme.

Byun HK, Kim N, Yoon HI, et al.
Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era.
Radiat Oncol. 2019; 14(1):51 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Immunotherapy is currently being examined as a treatment modality for glioblastoma. Maintaining an optimal total lymphocyte count (TLC) after radiotherapy (RT) and using temozolomide may be beneficial in optimizing immunotherapy. However, conventional temozolomide-based chemoradiation is known to induce immunosuppressive effects, including lymphopenia. Therefore, this study aimed to identify potential clinical predictors of acute severe lymphopenia (ASL) in patients receiving chemoradiation for glioblastoma.
METHODS: We identified patients with glioblastoma treated with RT plus temozolomide from 2006 to 2017. ASL was defined as a TLC of < 500/μL within 3 months after initiating RT. Independent predictors of ASL were determined using logistic regression.
RESULTS: A total of 336 patients were evaluated. Three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) were used in 186 (55.4%) and 150 patients (44.6%), respectively. TLC decreased during RT and remained persistently low during the 1-year follow-up, whereas the levels of other blood cell types recovered. In total, 118 patients (35.1%) developed ASL. During a median follow-up of 19.3 months, patients with ASL showed significantly worse overall survival than did those without ASL (median, 18.2 vs. 22.0 months; P = .028). Multivariable analysis revealed that increased planning target volume (PTV) was independently associated with increased ASL incidence (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00-1.03; P = .042), while IMRT was independently associated with decreased ASL incidence (HR, 0.48; 95% CI, 0.27-0.87; P = .015). A propensity-matched comparison showed that the incidence of ASL was lower with IMRT than with 3D-CRT (20% vs. 37%; P = .005).
CONCLUSIONS: IMRT and low PTV were significantly associated with decreased ASL incidence after RT plus temozolomide for glioblastoma. An IMRT-based strategy is necessary to enhance treatment outcomes in the immune-oncology era.

Bachmann N, Leiser D, Ermis E, et al.
Impact of regular magnetic resonance imaging follow-up after stereotactic radiotherapy to the surgical cavity in patients with one to three brain metastases.
Radiat Oncol. 2019; 14(1):45 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Administering stereotactic radiotherapy to the surgical cavity and thus omitting postoperative whole brain radiotherapy (WBRT) is a favored strategy in limited metastatic brain disease. Little is known about the impact of regular magnetic resonance imaging follow-up (MRI FU) in such patient cohorts. The aim of this study is to examine the impact of regular MRI FU and to report the oncological outcomes of patients with one to three brain metastases (BMs) treated with stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic radiotherapy (HFSRT) to the surgical cavity.
METHODS: We retrospectively analyzed patients who received SRS or HFSRT to the surgical cavity after resection of one to two BMs. Additional, non-resected BMs were managed with SRS alone. Survival was estimated by the Kaplan-Meier method. Prognostic factors were examined with the log-rank test and Cox proportional hazards model. Regular MRI FU was defined as performing a brain MRI 3 months after radiotherapy (RT) and/or performing ≥1 brain MRI per 180 days. Primary endpoint was local control (LC). Secondary endpoints were distant brain control (DBC), overall survival (OS) and the correlation between regular MRI FU and overall survival (OS), symptom-free survival (SFS), deferment of WBRT and WBRT-free survival (WFS).
RESULTS: Overall, 75 patients were enrolled. One, 2 and 3 BMs were seen in 63 (84%), 11 (15%) and 1 (1%) patients, respectively. Forty (53%) patients underwent MRI FU 3 months after RT and 38 (51%) patients received ≥1 brain MRI per 180 days. Median OS was 19.4 months (95% CI: 13.2-25.6 months). Actuarial LC, DBC and OS at 1 year were 72% (95% CI: 60-83%), 60% (95% CI: 48-72%) and 66% (95% CI: 53-76%), respectively. A planning target volume > 15 cm
CONCLUSION: Our results regarding oncological outcomes consist with the current data from the literature. Surprisingly, regular MRI FU did not result in increased OS, SFS, WFS or deferment of WBRT in our cohort consisting mainly of patients with a single and resected BM. Therefore, the impact of regular MRI FU needs prospective evaluation.
TRIAL REGISTRATION: Project ID: 2017-00033, retrospectively registered.

Buecker R, Hong ZY, Liu XM, et al.
Risk factors to identify patients who may not benefit from whole brain irradiation for brain metastases - a single institution analysis.
Radiat Oncol. 2019; 14(1):41 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Radiotherapy plays a major role in the management of brain metastases. This study aimed to identify the subset of patients with multiple brain metastases who may not benefit from whole brain irradiation (WBI) due to a short survival time regardless of treatment.
METHODS: We analyzed a total of 339 patient records with brain metastases treated with whole brain radiotherapy from January 2009 to January 2016. External beam radiotherapy techniques were used to deliver 33 Gy in 11 fractions (4 fractions per week) to the whole brain. Eight clinical factors with a potential influence on survival were investigated using the Kaplan-Meier method. All factors with a P < 0.05 in univariate analysis were entered into multivariate analysis using Cox regression.
RESULTS: In the present series of 339 patients, median survival time was 2.5 months (M; range, 0-61 months). Four risk factors Karnofsky Performance Score (KPS) < 70, age > 70, > 3 of metastases intracranial, uncontrolled primary tumor) were identified that were significant and negatively correlated with median survival time. Patients with no risk factors had a median survival of 4.7 M; one risk factor, 2.5 M; two risk factors, 2.3 M; and 3-4 risk factors, 0.4 M (p < 0.00001).
CONCLUSIONS: Patients with identified risk factors might have a negatively impacted overall survival after WBI. Accordingly, patients who will not benefit from WBI can be easily predicted if they have 3-4 of these risk factors.

Hui CY, Rudra S, Ma S, et al.
Impact of overall corticosteroid exposure during chemoradiotherapy on lymphopenia and survival of glioblastoma patients.
J Neurooncol. 2019; 143(1):129-136 [PubMed] Related Publications
PURPOSE: Corticosteroids are commonly used to alleviate symptoms from cerebral vasogenic edema in glioblastoma (GBM) patients. This study evaluated the impact of overall corticosteroid exposure during chemoradiotherapy (CRT) on acute severe lymphopenia (ASL) and survival outcomes of GBM patients.
METHODS: GBM patients treated with CRT from 2007 to 2016 were retrospectively analyzed. Overall corticosteroid exposure was estimated as the average daily dexamethasone dose during 6 weeks of CRT. ASL was defined as grade 3 or higher lymphopenia within 3 months of starting CRT. ASL rates, overall survival (OS), and progression-free survival (PFS) were analyzed using Kaplan-Meier method. Multivariable analysis (MVA) was performed using logistic and Cox regression to identify independent predictors of ASL and survival outcomes, respectively.
RESULTS: Of the 319 eligible patients, the median daily dexamethasone use was 2 mg/day. The high-dose dexamethasone cohort (> 2 mg/day) had significantly higher ASL and worse OS than the low-dose dexamethasone cohort: 3-month ASL of 43.7% versus 19.8% (p < 0.003) and median OS of 12.6 months versus 17.9 months (p < 0.001), respectively. On MVA, higher dexamethasone use was independently associated with higher ASL and worse OS, but not worse PFS. A subset analysis of patients with gross-total resection found that higher dexamethasone use was significantly associated with ASL, but not OS.
CONCLUSION: Increased corticosteroid use among GBM patients during CRT appears to be an independent risk factor for developing subsequent ASL. Its apparent association with worse OS may be influenced by other confounding factors and would need to be validated through prospective investigations.

Kuskucu A, Tuysuz EC, Gurkan S, et al.
Co-polysomy of 1p/19q in glial tumors: Retrospective analysis of 221 cases from single center.
Gene. 2019; 701:161-168 [PubMed] Related Publications
Glial tumors are malignant brain tumors that arise from glial cells of brain or spine and have genetic aberrations in their genome. 1p/19q co-deletion is associated with increased Overall Survival (OS) time with enhanced response to chemo- and radio-therapy in oligodendrogliomas. However, prognostic significance of 1p/19q co-polysomy is still unclear. We evaluated 1p/19q status of 221 patients with glial tumor by Fluorescent in situ Hybridization (FISH). Records of the patients were collected retrospectively. Our results demonstrated that 1p/19q co-polysomy was associated with decreased OS time, high P53 expression and frequently located in temporal lobe, whereas 1p/19q co-deletion was associated with increased overall survival time, low P53 expression and frontal lobe location. Furthermore, classification of patients based on both 1p/19q status and P53 expression revealed that patients with 1p/19q co-polysomy and high P53 expression had the worst prognosis. Lastly, our bioinformatic survival analysis revealed that high expression of SRM, ICMT, and FTL located in 1p36.13-p36.31 and 19q13.2-q13.33 region were related with decreased OS time in patients with Low Grade Glioma (LGG). The study demonstrated that 1p/19q co-polysomy is a poor prognostic marker for glial tumor.

Richard NM, Bernstein LJ, Mason WP, et al.
Cognitive rehabilitation for executive dysfunction in brain tumor patients: a pilot randomized controlled trial.
J Neurooncol. 2019; 142(3):565-575 [PubMed] Related Publications
PURPOSE: Patients with brain tumors face unique quality of life challenges. Executive dysfunction is common and functionally limiting, with no established treatments as standard care. This pilot study evaluated the efficacy of Goal Management Training (GMT), a behavioral intervention combining mindfulness and strategy training, for improving executive and real-life functioning in this population.
METHODS: Twenty-five primary brain tumor survivors were randomized to GMT, an active control (Brain Health Program, BHP), or a wait-list (WAIT) control group. The BHP was a supportive care intervention offering education and activities to promote general brain health, without cognitive strategy training. Participants in GMT and BHP completed eight individual sessions and homework between sessions; those in WAIT received usual care. Assessments at baseline, immediately post-training, and 4-month follow-up used a battery of objective and subjective measures, including functional goal attainment.
RESULTS: Adherence (% sessions completed) was high for both GMT (98.9%) and BHP (84.4%). Executive functions improved with GMT but not BHP or WAIT (repeated measures analysis of variance, time-by-group interaction, post-training P = 0.077, follow-up P = 0.046). Both intervention groups reported fewer cognitive concerns at post-training (P = 0.049) and follow-up (P < 0.001). Functional goal attainment was greatest with GMT (post-training P = 0.027, follow-up P = 0.064).
CONCLUSIONS: GMT improved executive and real-life functioning in brain tumor survivors, with gains maintained at 4-month follow-up. Clinical implementation of this adaptable program merits consideration for clinically stable patients with cognitive dysfunction. Further development and larger prospective cognitive rehabilitation trials appear warranted.

Lesueur P, Lequesne J, Grellard JM, et al.
Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol.
BMC Cancer. 2019; 19(1):198 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Despite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM.
METHODS: The OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa.
DISCUSSION: Combining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer.
TRIAL REGISTRATION: NCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Fleischhack G, Massimino M, Warmuth-Metz M, et al.
Nimotuzumab and radiotherapy for treatment of newly diagnosed diffuse intrinsic pontine glioma (DIPG): a phase III clinical study.
J Neurooncol. 2019; 143(1):107-113 [PubMed] Related Publications
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence.
METHODS: The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m
RESULTS: All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression.
CONCLUSIONS: Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

Quillien V, Carpentier AF, Gey A, et al.
Absolute numbers of regulatory T cells and neutrophils in corticosteroid-free patients are predictive for response to bevacizumab in recurrent glioblastoma patients.
Cancer Immunol Immunother. 2019; 68(6):871-882 [PubMed] Free Access to Full Article Related Publications
Bevacizumab (Bv) remains frequently prescribed in glioblastoma (GBM) patients, especially at recurrence. We conducted a prospective clinical trial with 29 recurrent GBM patients treated with Bv alone with a longitudinal follow-up of different circulating immune cells [complete blood count, myeloid-derived suppressor cells (MDSCs), classical, intermediate, non-classical and Tie2 monocytes, VEGFR1+ and regulatory T cells (Treg)]. We observed a significant increase for leucocytes, neutrophils, eosinophils and classical monocytes and a decrease for the fraction of Treg during the treatment. The best prognostic values for survival under Bv were obtained for basal neutrophils and Treg. Counts below 3.9 G/L for neutrophils and above 0.011 G/L for Treg were associated with an overall survival of 17.5 and 19.9 months, respectively, as compared with 5.4 and 5.6 months, respectively, for counts above and below these cutoffs (p = 0.004 and p < 0.001). No prognostic impact was observed for neutrophils in a retrospective cohort of 26 patients treated with nitrosoureas alone. In another retrospective validation cohort of 61 GBM patients treated at recurrence with a Bv-containing regimen, an interaction was observed between neutrophils and corticosteroid intake. The predictive value of neutrophils on survival under Bv was lost in patients treated with corticosteroids, when steroid-free patients with a low neutrophil count had a particularly long median survival of 3.4 years. These two simply accessible criteria (basal neutrophils and steroid intake) could be used to reserve this relatively costly treatment for patients likely to be the most responsive to Bv and prevent unnecessary side effects in others.

Ceschin R, Kocak M, Vajapeyam S, et al.
Quantifying radiation therapy response using apparent diffusion coefficient (ADC) parametric mapping of pediatric diffuse intrinsic pontine glioma: a report from the pediatric brain tumor consortium.
J Neurooncol. 2019; 143(1):79-86 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND AND PURPOSE: Baseline diffusion or apparent diffusion coefficient (ADC) characteristics have been shown to predict outcome related to DIPG, but the predictive value of post-radiation ADC is less well understood. ADC parametric mapping (FDM) was used to measure radiation-related changes in ADC and compared these metrics to baseline ADC in predicting progression-free survival and overall survival using a large multi-center cohort of DIPG patients (Pediatric Brain Tumor Consortium-PBTC).
MATERIALS AND METHODS: MR studies at baseline and post-RT in 95 DIPG patients were obtained and serial quantitative ADC parametric maps were generated from diffusion-weighted imaging based on T2/FLAIR and enhancement regions of interest (ROIs). Metrics assessed included total voxels with: increase in ADC (iADC); decrease in ADC (dADC), no change in ADC (nADC), fraction of voxels with increased ADC (fiADC), fraction of voxels with decreased ADC (fdADC), and the ratio of fiADC and fdADC (fDM Ratio).
RESULTS: A total of 72 patients were included in the final analysis. Tumors with higher fiADC between baseline and the first RT time point showed a trend toward shorter PFS with a hazard ratio of 6.44 (CI 0.79, 52.79, p = 0.083). In contrast, tumors with higher log mean ADC at baseline had longer PFS, with a hazard ratio of 0.27 (CI 0.09, 0.82, p = 0.022). There was no significant association between fDM derived metrics and overall survival.
CONCLUSIONS: Baseline ADC values are a stronger predictor of outcome compared to radiation related ADC changes in pediatric DIPG. We show the feasibility of employing parametric mapping techniques in multi-center studies to quantitate spatially heterogeneous treatment response in pediatric tumors, including DIPG.

Laprie A, Ken S, Filleron T, et al.
Dose-painting multicenter phase III trial in newly diagnosed glioblastoma: the SPECTRO-GLIO trial comparing arm A standard radiochemotherapy to arm B radiochemotherapy with simultaneous integrated boost guided by MR spectroscopic imaging.
BMC Cancer. 2019; 19(1):167 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival.
METHODS/DESIGN: In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status.
DISCUSSION: This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging.
TRIAL REGISTRATION: NCT01507506 , registration date December 20, 2011.

Huang J, Chaudhary R, Cohen AL, et al.
A multicenter phase II study of temozolomide plus disulfiram and copper for recurrent temozolomide-resistant glioblastoma.
J Neurooncol. 2019; 142(3):537-544 [PubMed] Related Publications
PURPOSE: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ.
METHODS: This open-label, single-arm phase II study treated recurrent TMZ-resistant GBM patients with standard monthly TMZ plus concurrent daily DSF 80 mg PO TID and Cu 1.5 mg PO TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known isocitrate dehydrogenase (IDH) mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit (response or stable disease for at least 6 months), and safety.
RESULTS: From March 2017 to January 2018, 23 recurrent TMZ-resistant GBM patients were enrolled across seven centers, and 21 patients were evaluable for response. The median duration of DSF/Cu was 1.6 cycles (range: 0.1-12.0). The ORR was 0%, but 14% had clinical benefit. Median PFS was 1.7 months, and median OS was 7.1 months. Only one patient (4%) had dose-limiting toxicity (grade three elevated alanine transaminase).
CONCLUSIONS: Addition of DSF/Cu to TMZ for TMZ-resistant IDH-wild type GBM appears well tolerated but has limited activity for unselected population.

Xie YH, Xie HT, Wang TS, et al.
Perioperative holistic care more significantly reduces levels of anxiety and depression of pituitary tumor patients versus conventional care.
Medicine (Baltimore). 2019; 98(7):e14411 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
To compare the effect of perioperative holistic care versus conventional care on the levels of anxiety and depression of pituitary tumor patients at a single tertiary care center in China.We enrolled 100 patients who underwent transnaso-sphenoidal microsurgical resection of pituitary tumor at our institution between January 2017 and December 2017. The patients were assigned to the conventional care group (n = 50) and the holistic care group by the order of admission. Patients were evaluated by staff nurses at admission and upon discharge from the hospital using the self-rating anxiety scale (SAS), and the self-rating depression scale (SDS). QoL was assessed using EORTC QLQ-C30.The 2 groups were comparable in the demographic and baseline variables including baseline SDS and SAS scores (P > .05). A significantly greater reduction in SAS score was observed in the holistic care group versus the conventional care group (-19.14% vs -11.60%; P < .05). Moreover, we observed a significantly greater reduction in SDS score in the holistic care group versus the conventional care group (-40.4% vs -18.79%, P < .05). The QoL functional domain scores at discharge were significantly higher in the holistic care group than the conventional care group (P < .05).Perioperative holistic care significantly alleviates the levels of anxiety and depression and improves QoL of pituitary adenoma patients.

Cloughesy TF, Mochizuki AY, Orpilla JR, et al.
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.
Nat Med. 2019; 25(3):477-486 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

Schalper KA, Rodriguez-Ruiz ME, Diez-Valle R, et al.
Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma.
Nat Med. 2019; 25(3):470-476 [PubMed] Related Publications
Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival

Liebenow B, Tatter A, Dezarn WA, et al.
Gamma Knife Stereotactic Radiosurgery favorably changes the clinical course of hemangioblastoma growth in von Hippel-Lindau and sporadic patients.
J Neurooncol. 2019; 142(3):471-478 [PubMed] Related Publications
PURPOSE: This is the first single-institution study of its size to characterize the treatment impact and to address the question of whether hemangioblastoma treatment with Gamma Knife Stereotactic Radiosurgery (GKRS) in both sporadic and VHL patients changes the characteristic saltatory hemangioblastoma growth pattern.
METHODS: The authors reviewed a single-institution tumor registry to identify patients who had received GKRS for hemangioblastomas between January 1st, 1999, and December 31st, 2017.
RESULTS: 15 patients with 101 lesions met search criteria with a median age of first GKRS of 39.2 years (interquartile range [IQR] of 25.7-57.4 years), including 96 VHL and 5 sporadic lesions. The median time from GKRS to last follow-up was 5.4 years (IQR 2.3-11.5 years). 4 lesions (4%) and 3 patients (20%) experienced a local failure. The 1-year, 3-year, and 5-year freedom from new hemangioblastoma formation rates were 97%, 80%, and 46% respectively. Multivariate analysis revealed a reduction in tumor volume after GKRS. Several variables associated with a greater percent reduction in volume from GKRS to last follow-up: non-cystic status (p = .01), no prior craniotomy (p = .04), and follow-up time from GKRS (p < .0001).
CONCLUSIONS: GKRS is a successful long-term treatment option for hemangioblastomas changing the clinical course from saltatory growth to reduction in tumor volume. Non-cystic tumors and those without prior craniotomy were associated with a greater percent reduction in volume from GKRS at last follow-up.

Wu T, Kang H, Zhuang D, et al.
The role of ABCB1 polymorphism as a prognostic marker for primary central nervous system lymphoma.
Ann Hematol. 2019; 98(4):923-930 [PubMed] Related Publications
To investigate the possible role of functional single nucleotide polymorphism (SNP) in circadian genes as prognostic markers of primary central nervous system lymphoma (PCNSL). We conducted a prospective study using data from Huashan Hospital 2006-2015 and followed up 91 PCNSL patients until June 30, 2016. The survival of patients with different prognostic factors was compared by log-rank test. Univariate and multivariate analyses were performed by Cox regression. During a long-term follow-up (6-110 months), overall survival (OS) was 32 months (95% CI, 13.3-91.1) and progression-free survival (PFS) was 23 months (95% CI, 9.0-41.0) for the entire cohort. Age (P = 0.046, P = 0.001) and performance status (PS) score (P = 0.013, P = 0.003) showed differences in OS and PFS. ABCB1 rs1045642 variant showed significant difference in PFS between patients with CC genotype and those with CT/TT genotypes (P = 0.020). In multivariate analysis, age (HR = 2.3; 95% CI, 1.2-4.2, P = 0.008), PS (HR = 2.4; 95% CI, 1.3-4.4, P = 0.007), and ABCB1 rs1045642 (HR = 1.9; 95% CI, 1.0-3.3, P = 0.036) were the independent risk factors for PFS. In our results, the most important prognostic factors associated with higher risk of progression were ABCB1 rs1045642 CC genotype, PS > 2, and older age.

Murphy M, Dowling A, Thien C, et al.
A feasibility study of the Nativis Voyager
CNS Oncol. 2019; 8(1):CNS31 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
AIM: Evaluation of the Nativis Voyager
MATERIALS & METHODS: A total of 15 patients with rGBM were treated with one of two Voyager ultra-low radio frequency energy cognates: A1A or A2HU. Safety and clinical utility were assessed every 2-4 months.
RESULTS: Median overall survival was 8.04 months in the A1A arm and 6.89 months in the A2HU arm. No serious adverse events associated with Voyager were reported. No clinically relevant trends were noted in clinical laboratory parameters or physical exams.
CONCLUSION: The data suggest that the Voyager is safe and feasible for the treatment of rGBM.

Silvani A, De Simone I, Fregoni V, et al.
Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma.
J Neurooncol. 2019; 142(3):455-462 [PubMed] Related Publications
BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment.
METHODS: In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m
RESULTS: Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients.
CONCLUSION: Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time.
TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT01989884.

Na K, Kim HS, Shim HS, et al.
Targeted next-generation sequencing panel (TruSight Tumor 170) in diffuse glioma: a single institutional experience of 135 cases.
J Neurooncol. 2019; 142(3):445-454 [PubMed] Related Publications
PURPOSE: The TruSight Tumor 170 (TST-170) panel consists of a DNA workflow for the identification of single-nucleotide variants, small insertions and deletions, and copy number variation, as well as a panel of 55 genes for a RNA workflow for the identification of splice variants and gene fusions. To date, the application of TST-170 in diffuse gliomas (DGs) has not been described.
METHODS: We analyzed 135 samples of DG, which were diagnosed by WHO criteria based on histological features and conventional molecular tests including immunostaining, 1p/19q FISH, and analysis of MGMT methylation and TERT promoter mutation.
RESULTS: A total of 135 cases consisted of 38 IDH-mutant [17 astrocytoma (AC), 13 oligodendroglioma (OD) and eight glioblastoma (GBM)], 87 IDH-wildtype (six AC, three OD and 78 GBM), and 10 diffuse midline glioma, H3K27M-mutant. DNA analysis enabled the detection of all mutations identified in these samples by conventional techniques, and the results were highly comparable to the known mutations in each subtype. RNA analysis detected four fusion genes including PTPRZ1-MET, FGFR3-TACC3, FAM131B-BRAF, and RET-CCDC6 and one splicing variant (EGFR vIII mutant). Clustered copy number loss in 1p and 19q loci genes were detected in 1p/19q-codeleted OD.
CONCLUSIONS: The application of TST-170 panel based NGS in clinical and laboratory setting is expected to improve diagnostic accuracy and prognostication. Most benefits are expected in IDH-wildtype DG, a group of genetically heterogenous tumors harboring DNA sequence changes, copy number alterations, and fusions in a large number of oncogenes and tumor suppressor genes.

Su M, Gao YJ, Pan C, et al.
Outcome of children with Langerhans cell histiocytosis and single-system involvement: A retrospective study at a single center in Shanghai, China.
Pediatr Hematol Oncol. 2018 Oct - Nov; 35(7-8):385-392 [PubMed] Related Publications
BACKGROUND: This is a descriptive review of the clinical patterns and outcomes of children with Langerhans cell histiocytosis and single-system involvement (SS-LCH) treated at Shanghai Children's Medical Center.
PROCEDURE: 60 evaluable newly diagnosed patients (37 boys, 23 girls) with a median age of 3.9 years (range: 0.3-15.3 years) and histiopathology-confirmed SS-LCH were enrolled from 2010 to 2014. All patients received systemic chemotherapy using either the DAL HX-83 or LCH-II protocol as determined by the physician.
RESULTS: Bone was the most frequently affected organ (56/60, 93.3%). Of the 56 patients suffering from SS-bone disease, 35 (62.5%) had unifocal disease and 21 (37.5%) had multifocal disease. CNS-risk lesions were seen in nine patients (16.1%, 9/56) at diagnosis. Thirty-two patients were treated with the LCH-II protocol and 28 received the DAL HX-83 protocol. No patient received intralesional steroid injection at the time of surgery. CNS-risk lesion correlated with an inferior event-free survival (EFS) for patients with bone disease (62.5 ± 17.1% vs. 90.7 ± 4.5%; p = 0.039). The difference in the 5-year EFS between patients with unifocal and multifocal SS-bone LCH did not reach the statistical significance (93.8 ± 4.3% vs. 75.0 ± 9.7%; p = 0.074). No deaths were observed, leading to a 5-year OS of 100% in the present cohort of patients. Permanent consequences and secondary malignancies were not observed but were also limited by short follow-up.
CONCLUSIONS: Optimal therapy for patients with SS-bone LCH has not been established. Less toxic therapeutic approaches should be considered for these patients and tested in prospective trials.

Michael AP, Watson VL, Ryan D, et al.
Effects of 5-ALA dose on resection of glioblastoma.
J Neurooncol. 2019; 141(3):523-531 [PubMed] Related Publications
PURPOSE: Fluorescence-guided surgery (FGS) with the use of 5-aminolevulinic acid (5-ALA) leads to more extensive resection of high-grade glioma (HGG) and longer overall survival (OS) of patients compared to conventional resection. The purpose of this study is to investigate the effect of 5-ALA dosages on residual tumor volume (RTV) and OS in patients with glioblastoma.
METHODS: A retrospective cohort study for patients who participated in a phase I and II dose-escalation clinical trial on 5-ALA for resection of HGG. A total of 25 patients were found to have newly diagnosed glioblastoma on histology and enrolled in our study. Patients receiving low doses of 5-ALA (10-30 mg/kg) (n = 6) were compared to those receiving high doses (40-50 mg/kg) (n = 19). Pre- and post-operative contrast enhanced T1W MRI were evaluated with volumetric analysis.
RESULTS: Median RTV was 0.69 cm
CONCLUSIONS: High doses of 5-ALA FGS are associated with less RTV and greater probability of GTR. 5-ALA dose was not associated with OS. Further studies with a larger patient cohort are warranted.

Kazda T, Misove A, Burkon P, et al.
Incidence of Hippocampal Metastases: Laterality and Implications for Unilateral Hippocampal Avoiding Whole Brain Radiotherapy.
Biomed Res Int. 2018; 2018:2459608 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Introduction: Hippocampi sparing whole brain radiotherapy (WBRT) is an evolving approach in the treatment of patients with multiple brain metastases, pursuing mitigation of verbal memory decline as a consequence of hippocampal radiation injury. Accumulating data are showing different postradiotherapy changes in the left and right hippocampus with a theoretical proposal of only unilateral (dominant, left) hippocampal sparing during WBRT.
Method: The aim of this retrospective study is to describe spatial distribution of brain metastases on MRI in a cohort of 260 patients (2595 metastases) and to evaluate distribution separately in the left and right hippocampus and in respective hippocampal avoiding zones (HAZ, region with subtherapeutic radiation dose), including evaluation of location of metastatic mass centre.
Results: The median number of brain metastases was three, with lung cancer being the most common type of primary tumour; 36% had single metastasis. Almost 8% of patients had metastasis within hippocampus (1.1% of all metastases) and 18.1% of patients within HAZ (3.3% of all metastases). No statistically significant difference was observed in the laterality of hippocampal involvement, also when the location of centre of metastases was analyzed. There were more patients presenting the centre of metastasis within left (15) versus right (6) HAZ approaching the borderline of statistical significance.
Conclusion: No significant difference in the laterality of BM seeding within hippocampal structures was observed. The hypothesized unilateral sparing WBRT would have theoretical advantage in about 50% reduction in the risk of subsequent recurrence within spared regions.

Humbert O, Bourg V, Mondot L, et al.
Eur J Nucl Med Mol Imaging. 2019; 46(3):558-568 [PubMed] Related Publications
PURPOSE: This study aimed to assess the therapeutic impact and diagnostic accuracy of
METHODS: Patients with histologically proven glioblastoma or brain metastases were prospectively included in this monocentric clinical trial (IMOTEP). Patients were included either due to a clinical suspicion of relapse or to assess residual tumor infiltration after treatment. Multimodality brain MRI and
RESULTS: One hundred six cases were prospectively investigated by the MNTB. All patients with brain metastases (N = 41) had a clinical suspicion of recurrence. The addition of

Suzuki R, Wei X, Allen PK, et al.
Outcomes of re-irradiation for brain recurrence after prophylactic or therapeutic whole-brain irradiation for small cell lung Cancer: a retrospective analysis.
Radiat Oncol. 2018; 13(1):258 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Small cell lung cancer (SCLC) can recur in the brain after whole-brain irradiation (WBI). We documented outcomes after treatment of such recurrences and sought predictors of local control and overall survival (OS).
MATERIALS AND METHODS: Eighty-five patients with SCLC and brain recurrence after prophylactic or therapeutic WBI in 1998-2015 were identified and data were extracted from the medical records. Survival was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards modeling was used to identify factors associated with OS or further brain progression.
RESULTS: Brain recurrence was treated by stereotactic radiosurgery (SRS) in 33 patients (39%), repeat WBI in 14 (16%), chemotherapy-only in 16 (19%), and observation in 22 (26%). Median OS time after brain recurrence (OSrec) was 4.3 months for all patients; 6-month OSrec rates were 58% after SRS, 21% after repeat WBI, 50% after chemotherapy-only, and 5% after observation (P < 0.001). Inferior OSrec was associated with poor performance status (ECOG score ≥ 3) and uncontrolled extracranial disease. Superior OSrec was associated with receipt of ≥4 chemotherapy cycles before brain recurrence and receipt of chemotherapy, SRS, or repeat WBI afterward. Receipt of chemotherapy after brain recurrence correlated with brain progression.
CONCLUSIONS: Some patients with brain recurrence after WBI for SCLC can survive for extended periods with appropriate intervention, especially those with adequate performance status or controlled extracranial disease.

Huff WX, Agrawal N, Shapiro S, et al.
Efficacy of pre-operative stereotactic radiosurgery followed by surgical resection and correlative radiobiological analysis for patients with 1-4 brain metastases: study protocol for a phase II trial.
Radiat Oncol. 2018; 13(1):252 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Stereotactic radiosurgery (SRS) has emerged as a common adjuvant modality used with surgery for resectable brain metastases (BMs). However, the optimal sequence of the multi-modality therapy has not been established. The goal of the study is to evaluate 6-month local control utilizing pre-operative SRS followed by surgical resection for patients with 1-4 brain metastases.
METHODS: This prospective, single arm, phase II trial will recruit patients with up to 4 brain metastases and at least one resectable lesion. All lesions will be treated with SRS and symptomatic lesions will be resected within 1-4 days after SRS. Patients will be monitored for 6-month local control, in-brain progression free survival, distant in-brain failure, rate of leptomeningeal spread, radiation necrosis and overall survival. Additionally, we will also perform correlative radiobiological molecular studies to assess the effect of radiation dosing on the tumor tissue and clinical outcomes. We expect that pre-operative SRS to the gross tumor prior to surgical resection will improve local control and decrease leptomeningeal failure.
DISCUSSION: Our study is the second prospective trial to investigate the efficacy of pre-operative SRS in the treatment of multiple BMs. In addition, the correlative molecular studies will be the first to investigate early response of BMs at a cellular and genetic level in response to radiation doses and potentially provide molecular prognostic markers for local control and overall survival.
TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03398694 (registration date: January 12, 2018).

Sun H, Xu L, Wang Y, et al.
Additional radiation boost to whole brain radiation therapy may improve the survival of patients with brain metastases in small cell lung cancer.
Radiat Oncol. 2018; 13(1):250 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: The role of the dose escalation strategy in brain radiotherapy for small cell lung cancer (SCLC) patients with brain metastases (BMs) has not been identified. This study aims to determine whether an additional radiation boost to whole brain radiation therapy (WBRT) has beneficial effects on overall survival (OS) compared with WBRT-alone.
METHODS: A total of 82 SCLC patients who were found to have BMs treated with WBRT plus a radiation boost (n = 33) or WBRT-alone (n = 49) from January 2008 to December 2015 were retrospectively analyzed. All patients were limited-stage (LS) SCLC at the time of the initial diagnosis, and none of them had extracranial metastases prior to detection of BMs. The primary end point was OS.
RESULTS: The median OS for all of the patients was 9.6 months and the 6-, 12- and 24-months OS rates were 69.1, 42.2 and 12.8%, respectively. At baseline, the proportion of more than 3 BMs was significantly higher in the WBRT group than in the WBRT plus boost group (p = 0.0001). WBRT plus a radiation boost was significantly associated with improved OS in these patients when compared with WBRT-alone (13.4 vs. 8.5 months; p = 0.004). Further, the survival benefit still remained significant in WBRT plus boost group among patients with 1 to 3 BMs (13.4 vs. 9.6 months; p = 0.022).
CONCLUSION: Compared with WBRT-alone, the use of WBRT plus a radiation boost may prolong survival in SCLC patients with BMs. The dose escalation strategy in brain radiotherapy for selected BMs patients with SCLC should be considered.

Cobbs C, McClay E, Duic JP, et al.
An early feasibility study of the Nativis Voyager
CNS Oncol. 2019; 8(1):CNS30 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
AIM: Evaluation of the Nativis Voyager
MATERIALS & METHODS: Voyager is a noninvasive, nonthermal, nonionizing and portable investigational device which delivers ultra-low radio frequency energy (ulRFE
RESULTS: Data from the first 11 patients treated are reported here. Median progression-free survival was 10 weeks in the V arm and 16 weeks in the V + SoC arm. Median overall survival was 16 months in V arm and 11 months in the V + SoC arm. No serious adverse events associated with the device were reported.
CONCLUSION: These data suggest that the Voyager is safe and feasible for the treatment of rGBM.

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