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.

Temozolomide Plus Bevacizumab in Elderly Patients with Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial (ATAG).

LESSONS LEARNED: Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients with glioblastoma multiforme with poor performance status.Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study. BACKGROUND: The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70. MATERIALS AND METHODS: Patients aged ≥70 years with a KPS <70 and biopsy-proven GBM were eligible for this multicenter, prospective, nonrandomized, phase II trial of older patients with impaired performance status. Treatment consisted of TMZ administered at 130-150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeks. RESULTS: The trial included 66 patients (median age of 76 years; median KPS of 60). The median overall survival (OS) was 23.9 weeks (95% confidence interval [CI], 19-27.6), and the median progression-free survival (PFS) was 15.3 weeks (95% CI, 12.9-19.3). Twenty-two (33%) patients became transiently capable of self-care (i.e., KPS >70). Cognition and quality of life significantly improved over time during treatment. Grade ≥3 hematological adverse events occurred in 13 (20%) patients, high blood pressure in 16 (24%), venous thromboembolism in 3 (4.5%), cerebral hemorrhage in 2 (3%), and intestinal perforation in 2 (3%). CONCLUSION: This study suggests that TMZ + Bev treatment is active in elderly patients with GBM with low KPS and has an acceptable tolerance level.

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.

An MRI review of acquired corpus callosum lesions.

Lesions of the corpus callosum (CC) are seen in a multitude of disorders including vascular diseases, metabolic disorders, tumours, demyelinating diseases, trauma and infections. In some diseases, CC involvement is typical and sometimes isolated, while in other diseases CC lesions are seen only occasionally in the presence of other typical extra-callosal abnormalities. In this review, we will mainly discuss the MRI characteristics of acquired lesions involving the CC. Identification of the origin of the CC lesion depends on the exact localisation of the lesion(s) inside the CC, presence of other lesions seen outside the CC, signal changes on different MRI sequences, evolution over time of the radiological abnormalities, history and clinical state of the patient, and other radiological and non-radiological examinations.

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.

Combination of neoadjuvant chemotherapy followed by surgical resection as a new strategy for WHO grade II gliomas: a study of cognitive status and quality of life.

Diffuse WHO grade II (GIIG) may be unresectable when involving critical structures. To assess the feasibility and functional tolerance (cognition and quality of life) of an original therapeutic strategy combining neoadjuvant chemotherapy followed by surgical resection for initially inoperable GIIG. Ten patients underwent Temozolomide for unresectable GIIG, as initial treatment or at recurrence after previous partial resection, due to invasion of eloquent areas or bi-hemispheric diffusion preventing a total/subtotal removal. Functional outcome after both treatments was assessed, with evaluation of seven cognitive domains. Chemotherapy induced tumor shrinkage (median volume decrease 38.9%) in ipsilateral functional areas in six patients and in the contralateral hemisphere in four. Only four patients had a 1p19q codeletion. The tumor shrinkage made possible the resection (mean extent of resection 93.3%, 9 total or subtotal removals) of initially inoperable tumors. Postoperatively, three patients had no deficits, while verbal episodic memory and executive functions were slightly impaired in seven patients. However, global quality of life was roughly preserved on the EORTC QLQ C30 + BN 20 (median score: 66.7%). Role functioning score was relatively reduced (median score: 66.7%) whereas KPS was preserved (median score: 90, range 80-100). Seven patients became seizure-free while three improved. This combined treatment is feasible, efficient (surgery made possible by neoadjuvant chemotherapy) and well-tolerated (preservation of quality of life, no serious cognitive disturbances). Cognitive deficits seem mostly related to tumor location. Because KPS is not reliable enough, a detailed neuropsychological assessment should be systematically performed in GIIG.

Diploic epidermoid cyst associated with focal brain pseudohypertrophy.

We present an 82-year-old woman, admitted for generalized status epilepticus, showing an osteolytic lesion of the right parietal bone associated with underlying focal brain pseudohypertrophy. A radiological diagnosis of diploic epidermoid cyst based on MRI characteristics was made. The aspect of focal brain pseudohypertrophy was probably caused by direct involvement of the underlying meningeal structures preventing the brain parenchyma locally from being retracted (i.e., retraction due to age-related brain atrophy). This aspect of focal brain pseudohypertrophy can potentially be seen in all chronic primary cranial bone lesions associated with meningeal involvement.

Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial.

PURPOSE: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas. PATIENTS AND METHODS: Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1-28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety. RESULTS: A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%-73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%-97.4%) and 75% (95% CI, 50.0%-88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003). CONCLUSIONS: The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Management and outcome of primary CNS lymphoma in the modern era: An LOC network study.

OBJECTIVE: Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL. METHODS: The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed. RESULTS: We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients <60 years of age received consolidation treatment in 77% of cases, consisting of whole-brain radiotherapy (WBRT) (54%) or high-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) (23%). Among patients >60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (<60 years: not reached [NR], 70%, and 61%; >60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis. CONCLUSIONS: Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

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.

Prognostic value of health-related quality of life for death risk stratification in patients with unresectable glioblastoma.

Glioblastoma is the most common malignant brain tumor in adults. Baseline health-related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty-four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ-C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrel's C-index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials.

Thalamic lesions: a radiological review.

BACKGROUND: Thalamic lesions are seen in a multitude of disorders including vascular diseases, metabolic disorders, inflammatory diseases, trauma, tumours, and infections. In some diseases, thalamic involvement is typical and sometimes isolated, while in other diseases thalamic lesions are observed only occasionally (often in the presence of other typical extrathalamic lesions). SUMMARY: In this review, we will mainly discuss the MRI characteristics of thalamic lesions. Identification of the origin of the thalamic lesion depends on the exact localisation inside the thalamus, the presence of extrathalamic lesions, the signal changes on different MRI sequences, the evolution of the radiological abnormalities over time, the history and clinical state of the patient, and other radiological and nonradiological examinations.

Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: an ANOCEF phase II trial.

PURPOSE: The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken. PATIENTS AND METHODS: Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition. RESULTS: Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS ≥ 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03). CONCLUSION: Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter.

Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004.

This report, an audit requested by the French government, describes oncological patterns of care, prognostic factors, and survival for patients with newly diagnosed and histologically confirmed glioblastoma multiforme (GBM) in France. The French Brain Tumor DataBase, which is a national multidisciplinary (neurosurgeons, neuropathologists, radiotherapists, neurooncologists, epidemiologists, and biostatisticians) network, prospectively collected initial data for the cases of GBM in 2004, and a specific data card was used to retrospectively collect data on the management and follow-up care of these patients between January 1, 2004, and December 1, 2006. We recorded 952 cases of GBM (male/female ratio 1.6, median age 63.9 years, mean preoperative Karnofsky performance status [KPS] 79). Surgery consisted of resection (RS; n = 541) and biopsy (n = 411); 180 patients did not have subsequent oncological treatment. After surgery, first-line treatment (n = 772) consisted of radiotherapy (RT) and temozolomide (TMZ) concomitant +/- adjuvant in 314 patients, RT alone in 236 patients, chemotherapy (CT) alone in 157 patients, and other treatment modalities in 65 patients. Median overall survival was 286 days (95% CI, 266-314) and was significantly affected by age, KPS, and tumor location. Median survival (days, 95% CI) associated with these main strategies, when analyzed by a surgical group, were as follows: RS + RT-TMZ((n=224)): 476 (441-506), biopsy + RT-TMZ((n=90)): 329 (301-413), RS + RT((n=147)): 363 (331-431), biopsy + RT((n=89)): 178 (153-237), RS + CT((n=61)): 245 (190-361), biopsy + CT((n=96)): 244 (198-280), and biopsy only((n=118)): 55 (46-71). This study illustrates the usefulness of a national brain tumor database. To our knowledge, this work is the largest report of recent GBM management in Europe.