Prognostic value of circulating lymphocyte subsets in primary central nervous system lymphoma.

BACKGROUND: Immunity plays an important role in CNS-DLBCL development. CNS-DLBCL predictive factors need to be improved. OBJECTIVE: To evaluate the predictive value of circulating lymphocyte subsets in PCNSL patients. METHODS: We prospectively analyzed blood lymphocyte immunophenotyping (LIP) in newly CNS-DLBCL referred to our institution between December 2013 and January 2020. LIP analysis was performed before rituximab and chemotherapy administration. The clinical, radiological, histological, biological and treatment data were retrospectively collected. RESULTS: Fifty-three patients were included with a median age of 69.7 (range 21.7-87.5). Median KPS was 60 (range 30-100). Thirty-three patients (64%) presented with one or several lymphopenias: 21 (40%), 24 (46%) and 9 (17%) NK, T and B lymphopenias respectively. Only 11 patients (21%) had normal LIP. Median CD4+/CD8+ ratio was 2.11 (range 0.54-9.11). This ratio was normal, low or high in 27%, 28% and 44% of patients respectively. The presence of steroids did not impact LIP results. Complete, partial responses, stable and progressive disease (PD) were observed in 24 (50%), 10 (21%), 4 (8%), and 10 (21%) patients respectively. CD4+/CD8+ ratio tended to be different between refractory (PD patients) and non-refractory patients (p = 0.077, ROC AUC: 0.684). Median progression-free survival (PFS) and overall survival (OS) were 14.7 (95%CI 6.5-22.9) and 43.2 (95%CI 21.6-64.9) months, respectively. In multivariate analyses, adjusted by KPS, a CD4+/CD8+ ratio > 1.97 was associated with poor PFS [p = 0.043, HR = 3.32 (1.02-4.88)] and tended to be associated with worse OS (p = 0.064). CONCLUSION: LIP at baseline may predict refractory disease and exhibits a prognostic value in CNS-DLBCL patients.

Adult H3K27M mutated thalamic glioma patients display a better prognosis than unmutated patients.

BACKGROUND: Adult thalamic gliomas are a rare entity whose management is challenging for physicians. The aim of this study is to describe the characteristics and prognostic factors of thalamic gliomas in adult patients. METHODS: We retrospectively analyzed the clinical, neuro-radiological, histological, and molecular characteristics of all cases of adult thalamic glioma in our regional center. RESULTS: We included 38 adult patients. Median age at diagnosis was 56.5 years old (range, 24-80). Median KPS at diagnosis was 70%. Two-thirds of patients presented with tumor necrosis on MRI. Bithalamic lesions were present in four patients. The median volume of enhancement associated with lesions was relatively small (14 mm3). Two patients had undergone partial surgical resection. All other patients underwent biopsy. Median PFS was 7.1 months (95% CI [3.7-10.5]) and median OS was 15.6 months (95% CI [11.7-19.6]). Among 20 patients with available tumor samples for molecular analyses, only 4 (20%) presented with H3K27M mutation. Patients with H3K27M mutation had longer survival compared to those without. Finally, we identified a long-term survivor population characterized by a younger age, no cognitive impairment, low steroid dose treatment and the presence of H3K27M mutation. CONCLUSION: Thalamic adult glioma differs from bithalamic glioma in children with regards to its clinical, radiological and molecular profiles. Long-term survival is observed in young patients with limited symptoms and H3K27M mutation. A larger prospective cohort is needed to validate these findings.

Coping strategies and quality of life: a longitudinal study of high-grade glioma patient-caregiver dyads.

BACKGROUND: Among a sample of patient-informal caregiver dyads in the specific context of new diagnoses of high-grade glioma in the time-frame between diagnosis and the third month following diagnosis, we examine whether the coping strategies implemented by the patients and their caregivers influenced their own quality of life (QoL) and the QoL of their relatives. METHODS: Thirty-eight dyads with patients having recent diagnoses of high-grade glioma were involved in this longitudinal study. The self-reported data include QoL (Patient-Generated Index, EORTC QLQ-C30, and CareGiver Oncology Quality of Life), and coping strategies (BriefCope). Data were collected at T1 corresponding to the time-frame between diagnosis and postsurgical treatment initiation and T2 corresponding to the 3-month post-inclusion follow-up. RESULTS: Coping strategies based on social support and avoidance were the least used at baseline and the 3-month follow-up, both for patients and caregivers. At the 3-month follow-up, the use of social support at baseline was significantly related to lower scores of QoL for the patients and with higher QoL for the caregivers. For the patient, the use of problem-solving or positive thinking at baseline was not related to his/her QoL, while it was related to more satisfactory QoL scores for the caregiver. The use of avoidance at baseline was linked to a higher 3-month QoL for the patients and a lower 3-month QoL for the caregivers. Using the specific dyadic analyses (actor-partner interdependence model), the 3-month patient's QoL was lower (ß = - 0.322; p = 0.03) when the patient mobilized the social support strategy at baseline, but was higher(ß = 0.631; p < 10- 3) when his/her informal caregiver used this strategy. After adjustment for sex, age, and baseline PGI score, the link between high use of the social support strategy at baseline by the caregiver and the patient's 3-month QoL, remained present (positive partner effect; ß =0.675; p < 10- 3). CONCLUSION: The QoL for patients and their informal caregivers since the time of diagnosis is directly related to the use of coping strategies based on social support at time of diagnosis.

Relationship between magnetic resonance imaging characteristics and plasmatic levels of MMP2 and MMP9 in patients with recurrent high-grade gliomas treated by Bevacizumab and Irinotecan.

Matrix metalloproteases MMP2 and MMP9 are involved in cancer angiogenesis and invasion. We recently demonstrated that plasma MMP2 and MMP9 levels could both predict response to bevacizumab in patients with recurrent high-grade glioma (HGG). We examined the potential relationship between MMP2/MMP9 plasma levels and glioma imaging characteristics. In this retrospective, monocentric study, MRI before bevacizumab administration for HGG patients was independently analyzed for contrast enhancement (CE) and FLAIR sequences. Contemporary MMP2 and MMP9 plasma levels were assessed using ELISA kits. We analyzed 28 patients with a median Karnofsky Performance Status of 70 (range 50-80). A diffuse pattern was observed in 14 patients (50%). We did not observe any correlation between baseline imaging features and plasma levels of MMP2 or MMP9. We found no association between baseline MMP levels and diffuse MRI patterns. In univariate analyses, diffuse pattern, multi-focal disease, tumor diameter, surface area, and volume had no impact on outcome, while the number of lobes involved in CE and crossing of the midline by CE were associated with a worse progression-free survival (p = 0.072 and p = 0.012, respectively) and overall survival (p = 0.012 and p < 0.001, respectively). In patients with recurrent high-grade glioma treated with a bevacizumab-based regimen, our exploratory analysis of multiple MRI tumor characteristics at baseline failed to detect a relationship between imaging feature and plasma levels of MMP2 and MMP9. Our results suggests that number of lobes involved in CE and crossing of the midline by CE are associated with outcome although the potential prognostic versus predictive role of these markers warrant further investigation.

Radio-chemotherapy feasibility for biopsy-only unresectable IDH wild-type glioblastomas (BO-GBM).

Background: "Biopsy-only" glioblastoma (BO-GBM) is a heterogeneous, understudied group of patients associated with a poor outcome. Our objective was to explore the pattern of care and prognosis associated with BO-GBM in our center. Methods: Patients with IDH wild-type BO-GBM included in a prospective regional cohort initiated in 2014 and closed in 2017 were retrospectively reviewed for patient characteristics, MRI findings, treatment allocation, and delivery. Results: Of 535 patients included in the cohort, 137 patients were included in the present analysis. The median age was 66 years old and the median KPS was 70. Forty-six patients (33.6%) were referred to radiotherapy and chemotherapy (RT-TMZ) regimen, 75 (54.7%), considered unfitted for RT, received chemotherapy upfront (CT) and 16 (11.7%) were referred to palliative care (PC). Regarding the first group, 91% of patients completed the RT-TMZ. In the CT group, 11 of 75 patients (14.7%) underwent radiotherapy after chemotherapy upfront. Median overall survival was 12.3 months (95% CI, 15.30-24.16), 5.7 months (95% CI, 6.22-9.20), and 1.9 months (95% CI, 1.43-5.08) in RT-TMZ, CT, and PC groups, respectively. In multivariate analyses, progression-free survival was impacted by baseline KPS (P < .001) and MGMT status (P = .004). Overall survival was impacted by baseline KPS (P < .001) and age (P = .030). Conclusion: BO-GBM constitute a large and heterogeneous population in which one-third of patients is amenable to the standard of care, with survival outcome close to one of the patients who underwent surgery. Reliable criteria are needed to help select patients for adequate treatment while new strategies are warranted for BO-GBM unfit for RT.

Advances in PET imaging of brain tumors: a referring physician's perspective.

PURPOSE OF REVIEW: To highlight the most recent advances in PET imaging of brain tumors, aiming at expanding the referring physician's knowledge in the field, the sine qua non for translating PET into the practice of neuro-oncology. RECENT FINDINGS: The role of PET with amino acid tracers in the setting of brain lesions of unknown significance has been better defined, reducing the need for invasive procedures. The impact of PET-guided resection of high-grade glioma using ¹¹C-methionine (¹¹C-MET) has been strongly documented. [¹8F]Fluoroethyl-L-tyrosine is currently available for glioma management; advances in targeting glial tumor biopsy and monitoring response to standard chemoradiation of malignant glioma have been remarkable. 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-penta-fluoropropyl)-acetamide is a rationally designed radiotracer with potential for imaging hypoxia in glioblastoma. New insights regarding the predictive value of 3-deoxy-3-[¹8F]fluorothymidine in outcome of recurrent malignant glioma treated with bevacizumab/irinotecan have been provided. First steps are being made toward apoptosis PET imaging for early assessment of radiotherapy response in brain metastases. SUMMARY: The use of ¹¹C-MET and ¹8F-labeled PET tracers is getting a more precise position in the management of brain tumors. Advances hold promises in routine decision-making and in the design and conduct of clinical trials.

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. METHODS: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. RESULTS: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). CONCLUSIONS: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.

Leptomeningeal Gliomatosis: A Single Institution Study of 31 Patients.

BACKGROUND/AIM: Secondary leptomeningeal gliomatosis (LG) is a rare and severe progression pattern of glioma. Our objective was to evaluate the characteristics and outcome of patients with LG. PATIENTS AND METHODS: We retrospectively reviewed 31 patients diagnosed with secondary LG. At the time of LG diagnosis, the median age of patients was 45 years. The histological grade was IV in 20 patients and II to III in 11 patients. As a first-line of therapy for LG, 22 patients received an oncological treatment: i) BCNU-temozolomide (TMZ) (n=15), ii) other type of chemotherapy (n=7), and iii) no treatment (supportive care) (n=9). RESULTS: Following LG diagnosis, the median progression-free survival (PFS) and overall survival (OS) were 1.8 months [95% confidence interval (CI)=0.9-2.7] and 2.1 months (95%CI=1.3-3), respectively. The univariate analyses showed an improved OS with age of less than 45 years (p<0.001), a prolonged interval from the initial glioma diagnosis (IGD) to LG diagnosis (p=0.003), BCNU-TMZ as the preferred first-line treatment for LG out of the three options (p=0.008), and Karnofsky performance status (KPS) ≥70 (p=0.012). Prolonged interval from IGD to LG diagnosis (HR=5.839) and BCNU-TMZ as the chosen first-line treatment for LG (HR=6.635) remained significant in the multivariate analyses as well. Among the 22 treated patients, the median OS was significantly higher (p=0.008) with the BCNU-TMZ treatment (5.7 months; 95%CI=4.2-7.1), compared to other types of treatment offered (2 months; 95%CI=1.1-2.9). CONCLUSION: The time interval from the IGD to the LG diagnosis is a potential prognostic factor for LG. BCNU-TMZ may be a therapeutic option in the present setting.

Negative Survival Impact of High Radiation Doses to Neural Stem Cells Niches in an IDH-Wild-Type Glioblastoma Population.

Aims: Assess the impact of radiation doses to neural stem cell (NSC) niches in patients with IDH-wild-type glioblastoma. Materials and Methods: Fifty patients were included in the study. NSC niches [SubVentricular Zone (SVZ) and Sub Granular Zone (SGZ)] were contoured by fusing CT scans and pre-therapy MRI, Tumor location defined ipsilateral and contralateral SVZ and SGZ. Prognostic significance of clinical, biological and dosimetric parameters were examined. We generated a Recursive Partitioning Analysis (RPA) model with independent prognostic classes. Results: Median follow-up: 23.8 months. Event free and overall survival (OS): 10 and 19.1 months. Incomplete surgery, PTV (planning target volume), ipsilateral SVZ or NSC niche mean dose > 57.4 Gy, contralateral NSC niche mean dose > 35 Gy and bilateral NSC niche mean dose > 44 Gy were significantly correlated with reduced OS. Only EGFR amplification was an independent prognostic factor (p = 0.019) for OS. RPA generated independent risk groups: 1 (low risk): [ipsilateral NSC mean dose (INMD) < 58.01 Gy and methylated MGMT promoter], 2: (INMD < 58.01 Gy and unmethylated MGMT promoter and contralateral SVZ mean dose < 18.6 Gy; p = 0.43), 3: (INMD < 58.01 Gy and unmethylated MGMT promoter and contralateral SVZ mean dose > 18.6 Gy; p = 0.002) and 4: (very high risk) (INMD > 58.01 Gy; p < 0.001). Conclusion: High radiation doses to ipsilateral NSC and contralateral SVZ could have a negative impact on overall survival in IDH-wild-type glioblastoma population.

Recurrent extraneural sonic hedgehog medulloblastoma exhibiting sustained response to vismodegib and temozolomide monotherapies and inter-metastatic molecular heterogeneity at progression.

BACKGROUND: Response to targeting and non-targeting agents is variable and molecular information remains poorly described in patients with recurrent sonic-hedgehog-driven medulloblastoma (SHH-MB). MATERIALS AND METHODS: Clinical and PET/CT findings during treatment with successive hedgehog antagonists and temozolomide monotherapies are described in a heavily pre-treated patient with recurrent extraneural metastases from PTCH1 mutated/ wild type smoothened (SMO) CNS SHH-MB. Molecular tests were prospectively performed in tissue from two extraneural sites at progression. RESULTS: Sustained clinical/metabolic response was obtained to vismodegib. At progression, itraconazole was ineffective, but salvage temozolomide treatment results in a response similar to vismodegib. At further progression, acquired SMO and PIK3CA mutations were identified in bone (G477L and H1047A, respectively) and epidural (L412P and H1065L, respectively) metastases. No response was observed with subsequent sonidegib treatment. CONCLUSIONS: This is the first clinical report of recurrent extraneural PTCH1 mutated SHH-MB exhibiting: 1) a sustained response to vismodegib and temozolomide, and 2) inter-metastatic molecular heterogeneity and acquired SMO-G477L, SMO-L412P, and PIK3CA-H1065L mutations at progression, highlighting the need for a multitarget treatment approach.

Relationships Between Dose Intensity, Toxicity, and Outcome in Patients with Oligodendroglial Tumors Treated with the PCV Regimen.

BACKGROUND/AIM: The drug combination of procarbazine, lomustine (CCNU) and vincristine (PCV) has been associated with efficacy in oligodendroglial gliomas (OG) when added to radiotherapy as the first line of treatment, despite the important toxicity of this treatment schedule. The aim of the present study was to analyze the tolerance, feasibility and impact of the dose intensity of the PCV regimen on outcome for patients with OG. PATIENTS AND METHODS: We retrospectively reviewed all patients with OG receiving PCV (CCNU=110 mg/m(2)) who were referred to our two Institutions. The total dose and dose adaptation, cycle delay, dose intensity, toxicity and discontinuation of CCNU were analyzed. Impacts on the outcome were evaluated. RESULTS: Between 2007 and 2011, 89 patients received PCV. PCV was administered at relapse in 73% of patients. Only 37% completed six cycles, 13.4% discontinued PCV because of toxicity, the other patients discontinued due to tumor progression. Cycle delay and dose reduction were observed for 62% and 70% patients, respectively. Grade 3 and 4 toxicities were observed in 38% and 8% patients, respectively. Among patients whose disease did not progress under the PCV regimen, discontinuation due to toxicity was significantly correlated to poor progression-free survival (PFS: p=0.023, hazard ratio=2.354) and poor overall survival (OS: p=0.021, hazard ratio=5.093). A factor that negatively impacted PFS was the absence of CCNU dose adaptation (p=0.001), while OS was negatively impacted by the absence of cycle delay (p=0.049) and grade 3/4 toxicities (p=0.045). CONCLUSION: Despite the efficacy of the PCV regimen, significant toxicity is associated with this schedule, which appears to impact its feasibility and efficacy. The optimal PCV schedule with the appropriate CCNU dose-intensity adaptation should be redefined taking into account this finding.

An efficient strategy based on an individualized selection of registration methods. Application to the coregistration of MR and SPECT images in neuro-oncology.

An efficient registration strategy is described that aims to help solve delicate medical imaging registration problems. It consists of running several registration methods for each dataset and selecting the best one for each specific dataset, according to an evaluation criterion. Finally, the quality of the registration results, obtained with the best method, is visually scored by an expert as excellent, correct or poor. The strategy was applied to coregister Technetium-99m Sestamibi SPECT and MRI data in the framework of a follow-up protocol in patients with high grade gliomas receiving antiangiogenic therapy. To adapt the strategy to this clinical context, a robust semi-automatic evaluation criterion based on the physiological uptake of the Sestamibi tracer was defined. A panel of eighteen multimodal registration algorithms issued from BrainVisa, SPM or AIR software environments was systematically applied to the clinical database composed of sixty-two datasets. According to the expert visual validation, this new strategy provides 85% excellent registrations, 12% correct ones and only 3% poor ones. These results compare favorably to the ones obtained by the globally most efficient registration method over the whole database, for which only 61% of excellent registration results have been reported. Thus the registration strategy in its current implementation proves to be suitable for clinical application.

A framework using multimodal imaging for longitudinal monitoring of patients in neuro-oncology. Application to a SPECT/MRI study.

This paper proposes a framework to assess the potential value of 99mTc Sestamibi SPECT in addition to Gadolinium-enhanced MRI for the monitoring of patients with high grade gliomas under antiangiogenic treatment. It includes: 1) multimodal and monomodal high precision registration steps achieved thanks to a registration strategy which selects the best method among several ones for each dataset, 2) tumor segmentation steps dedicated to each modality and 3) a tumor comparison step which consists in the computation of some global (volume, intensity) and local (matching and mismatching) quantitative indices to analyze the tumor using different imaging modalities and at different times during the treatment. Each step is checked via 2D and 3D visualization. This framework was applied to a database of fifteen patients. For all patients, except one, the tumor volumes decrease globally and locally. Furthermore, a high correlation (r=0.77) was observed between MRI and Sestamibi tumor volumes. Finally, local indices show some possible mismatches between MRI Gadolinium uptake and Sestamibi uptake, which need to be further investigated.

A new strategy to improve coregistration of SPECT and MR images in patients with high grade glioma.

This paper proposes a new strategy to optimize the coregistration of Technetium-99m Sestamibi SPECT and MRI data in case of patients with high grade glioma. It consists in a personalized approach which selects, for each data set, the best registration method among several ones. To achieve this selection, a quantitative dedicated evaluation criterion based on the average intensities within specific anatomical structures corresponding to physiological areas of uptake of Sestamibi was defined. The strategy was applied to sixty-two data sets using nine registration methods based on mutual information and chamfer distance registration approaches, with different settings. It was implemented within the Anatomist/Brainvisa environment, using its basic registration functions. The visual evaluation by experts indicated that this strategy provides 60% good quality registrations, and 26% intermediate quality ones. Compared to the single use of the best global registration method, the number of registrations of good quality was multiplied by 1.4 when using the data specific strategy.

Response assessment in recurrent glioblastoma treated with irinotecan-bevacizumab: comparative analysis of the Macdonald, RECIST, RANO, and RECIST + F criteria.

Traditionally, the most widely used criteria for response assessment in glioblastoma have been Macdonald and the Response Evaluation Criteria In Solid Tumors (RECIST). Recently, new criteria addressing contrast enhancement and fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity have been defined (the Response Assessment in Neuro-Oncology criteria) to better evaluate the effect of antiangiogenic therapy. Whether FLAIR/T2 imaging could also be helpful to refine RECIST criteria remains unresolved. This study proposed the RECIST + F criteria and compared the 4 methods (Macdonald, RECIST, RANO, and RECIST + F) to determine their agreement in identifying response and progression of recurrent glioblastomas to irinotecan-bevacizumab. Patients with recurrent glioblastoma treated with second-line irinotecan-bevacizumab were eligible. Clinical status, corticosteroid dose, and 1-dimensional and 2-dimensional measurements of tumor contrast enhancement and FLAIR hyperintensity were retrospectively assessed. Response and progression were determined according to each set of criteria. Seventy-eight patients were included. Response rates ranged from 34.2% with RECIST + F to 44.7% with Macdonald criteria. Agreement among the 4 methods in determining response and type of progression was high (kappa statistic > 0.75). One-third of patients exhibited nonenhancing progression with stable or improved contrast enhancement. Median progression-free survival was predicted by RECIST, at 13.6 weeks; RECIST + F, 12.3; Macdonald, 12.7; and RANO, 11.7 (P = .840). Intra- and interobserver correlations were high for both contrast enhancement and FLAIR hyperintensity measurements. There was a strong concordance among the different methods in determining response and progression to irinotecan-bevacizumab. Criteria integrating FLAIR hyperintensity tended, however, to reduce response rates and progression-free survival compared with criteria considering only contrast enhancement. The 1-dimensional approach appeared to be as valid as the 2-dimensional approach.