Response assessment of GBM during immunotherapy by delayed contrast treatment response assessment maps.

Introduction: Assessing the treatment response of glioblastoma multiforme during immunotherapy (IT) is an open issue. Treatment response assessment maps (TRAMs) might help distinguish true tumor progression (TTP) and pseudoprogression (PsP) in this setting. Methods: We recruited 16 naïve glioblastoma patients enrolled in a phase II trial consisting of the Stupp protocol (a standardized treatment for glioblastoma involving combined radiotherapy and chemotherapy with temozolomide, followed by adjuvant temozolomide) plus IT with dendritic cells. Patients were followed up till progression or death; seven underwent a second surgery for suspected progression. Clinical, immunological, and MRI data were collected from all patients and histology in case of second surgery. Patients were classified as responders (progression-free survival, PFS > 12 months), and non-responders (PFS ≤ 12), HIGH-NK (natural killer cells, i.e., immunological responders), and LOW-NK (immunological non-responders) based on immune cell counts in peripheral blood. TRAMs differentiate contrast-enhancing lesions with different washout dynamics into hypothesized tumoral (conventionally blue-colored) vs. treatment-related (red-colored). Results: Using receiver operating characteristic (ROC) curves, a threshold of -0.066 in VBlue/VCE (volume of the blue portion of tumoral area/volume of contrast enhancement) variation between values obtained in the MRI performed before PsP/TTP and at TTP/PSP allowed to discriminate TTP from PsP with a sensitivity of 71.4% and a specificity of 100%. Among HIGH-NK patients, at month 6 there was a significant reduction compared to baseline and month 2 in median "blue" volumes. Discussion: In conclusion, in our pilot study TRAMs support the discrimination between tumoral and treatment-related enhancing features in immunological responders vs. non-responders, the distinction between PsP and TTP, and might provide surrogate markers of immunological response.

Extra-Neural Metastases of Glioblastoma: A Case Series.

Glioblastoma (GBM) is the most common brain tumor and has a median survival of less than two years. The current standard of care consists of surgery followed by concomitant radio and chemotherapy with temozolomide. Although it is an aggressive tumor, distant metastases are extremely rare. The dissemination mechanisms are not fully understood and currently there is no standard of care for its treatment. In this study, the authors present a comprehensive analysis of all the existing cases of extra-neural metastases of GBM in a tertiary care center over the last five years, along with the procedures carried out in each case.

Outcome of glioblastoma resection in patients 80 years of age and older.

OBJECTIVE: To evaluate the role and possible complications of tumor resection in the management of glioblastoma (GBM) in a series of patients 80 years of age and older with review of literature. METHODS: The authors retrospectively analyzed cases involving patients 80 years or older who underwent biopsy or initial resection of GBM at their hospital between 2007 and 2018. A total of 117 patients (mean age 82 years) met the inclusion criteria; 57 had resection (group A) and 60 had biopsy (group B). Functional outcomes and survival at follow-up were analyzed. RESULTS: Group A differed significantly from group B at baseline in having better WHO performance status, better ASA scores, more right-sided tumors, and no basal ganglia or "butterfly" gliomas. Nevertheless, 56% of group A patients had an ASA score of 3. Median survival was 9.5 months (95% CI 8-17 months) in group A, 4 months (95% CI 3.5-6 months) in group B, and 17.5 months (95% CI 12-24 months) in the 56% of group A patients treated with resection and Stupp protocol. Rates of postoperative neurologic and medical complications were almost identical in the 2 groups, but the rate of surgical site complications was substantially greater in group A (12% vs 5%). There was no significant difference in mean preoperative and postoperative KPS scores (group A). CONCLUSIONS: In selected patients 80 years or older, radical removal of GBM was associated with acceptable survival and a low perioperative complication rate which is comparable to that of a biopsy. Although the median survival of the whole group was lower than reported for younger patients, a subgroup amenable to radical surgery and Stupp protocol achieved a median survival of 17.5 months.

A Systematic Review and Meta-Analysis on the Number of Adjuvant Temozolomide Cycles in Newly Diagnosed Glioblastoma.

BACKGROUND: In newly diagnosed glioblastoma, radiation with concurrent and adjuvant (six cycles) temozolomide (TMZ) is the established standard of postsurgical care. However, the benefit of extending adjuvant TMZ therapy beyond six cycles has remained unknown. METHODS: We searched PubMed, Web of Science, Scopus, and Embase up to October 1, 2021. The search keywords were "glioblastoma," "adjuvant chemotherapy," and their synonyms. The data of randomized clinical trials were extracted and included in this meta-analysis if they had reported patients' median overall survival (OS) or median progression-free survival (PFS). The standard and extended chemotherapy regimens were considered as adjuvant TMZ up to six cycles and beyond six cycles (up to a total of 12 cycles), respectively. The median OS and median PFS were pooled and compared. RESULTS: Four studies consisting of 882 patients (461 patients for the standard chemotherapy group and 421 patients for the extended chemotherapy group) were included in this meta-analysis. The extended TMZ regimen was associated with a nonsignificant improvement in PFS [12.0 months (95% CI 9.0 to 15.0) vs. 10.0 months (95% CI 7.0 to 12.0), P = 0.27] without corresponding improvement in OS [23.0 months (95% CI 19.0 to 27.0) and 24.0 months (95% CI 20.0 to 28.0), P = 0.73]. CONCLUSIONS: In newly diagnosed glioblastoma, continuing adjuvant TMZ beyond six cycles did not shown an increase neither in PFS nor OS.

Expression Analysis of α5 Integrin Subunit Reveals Its Upregulation as a Negative Prognostic Biomarker for Glioblastoma.

Integrin α5ß1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031-2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168-4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance.

Impact of Immunohistochemical profiling of Glioblastoma multiforme on clinical outcomes: Real-world scenario in resource limited setting.

OBJECTIVE: Intuition into the molecular pathways of glioblastoma multiforme (GBM) has changed the diagnostic, prognostic, and therapeutic approaches. We investigated the influence of various clinical and molecular prognostic factors on survival outcomes in radically treated GBM patients. METHODS: Medical records of 160 GBM patients treated between January-2012 and December-2018 with surgery followed by post-operative external beam radiotherapy (EBRT) with/without temozolomide (TMZ) were reviewed. Immunohistochemical (IHC) assays were performed for IDH1mutation, ATRX loss, TP53 overexpression and Ki-67% index. Apart from disease and treatment-related factors' influence on clinical outcomes, the impact of IHC markers in prognostication was analyzed using appropriate statistical tests. RESULTS: The median overall survival (OS) was 14 months. EBRT with concurrent TMZ was given to 60% of patients and 42.5% completed the standard Stupp-protocol. Significant improvements in OS was observed in patients aged ≤ 50years (2-year OS: 22.1% vs. 12.5%, p = 0.001), those who underwent gross total resection (2-year OS: 21.8% vs. 12.8%, p = 0.002), received concurrent TMZ (21.9% vs. 12.5%, p = 0.005), completed the entire Stupp-protocol (2-year OS: 23.4% vs. 6.5%, p = 0.000), and with Ki-67 index <20% (2-year OS: 23.3% vs. 11.6%, p = 0.015). On multivariate analysis, IDH1 mutation, ATRX loss, TP53 expression, and Ki-67 ≤ 20% were significant prognosticators of outcomes. CONCLUSION: GBM patients treated with concurrent chemoradiation and those who completed the full Stupp-protocol experienced better survival outcomes. Molecular biology significantly impacts clinical outcomes and plays a key deterministic role in newer management strategies.

Clinical Efficacy of Tumor Treating Fields for Newly Diagnosed Glioblastoma.

BACKGROUND/AIM: Whether adding tumor treating fields (TTF) to the Stupp protocol increases survival for glioblastoma (GBM) patients in routine clinical care remains unknown. PATIENTS AND METHODS: We retrospectively identified adult patients with newly diagnosed GBM (n=104) treated with the Stupp protocol or TTF at our Institution. RESULTS: Thirty-six percent (37/104) of patients received TTF in conjunction with the Stupp protocol and these patients had increased 6-month (p=0.006) and 1-year (p=0.170), but not 2-year survival rates compared to the 67-patients who received Stupp alone. The improvement of survival rate at 6-month was further confirmed by a modified Poisson model (p=0.010). However, we did not observe any improvement in overall survival (OS) with a Cox model. CONCLUSION: While adding TTF to the Stupp protocol appeared to benefit patients with newly diagnosed GBM, this effect was mild and may be largely due to selection bias.

Aggressive Pituitary Adenomas and Carcinomas.

A subset of pituitary tumors present an aggressive behavior that remains difficult to predict, and in rare cases they metastasize. The current European Society for Endocrinology (ESE) guidelines for the management of aggressive pituitary tumors and carcinomas provide valuable guidance, but several issues remain unaddressed because of the scarcity of data in the literature. This article presents key clinical aspects regarding aggressive pituitary tumors and carcinomas, and also discusses some of the unanswered questions of the ESE guidelines, focusing on both diagnosis and treatment.

High-grade Glioma - A decade of care in Christchurch.

INTRODUCTION: High-grade glioma (HGG) is a devastating illness. Our study aimed to investigate outcomes for patients with HGG treated in Christchurch focussing particularly on those diagnosed with glioblastoma mulitforme (GBM); compare GBM survival with international standards; examine factors associated with better prognosis; and assess the involvement of various allied health disciplines. METHODS: A 10-year retrospective study of patients who were diagnosed and treated for HGG at Christchurch Hospital. Kaplan-Meier method was used to estimate survival. Predefined multivariate analysis was performed to investigate potential prognostic and predictive factors. RESULTS: A total of 363 patients were diagnosed with HGG at a median age of 64 years with a 5-year overall survival of 6.1%. Patients with grade IV tumours had a poorer outcome than grade III patients (P = 0.0002, log-rank test). Eighty-two per cent of patients had a surgical resection or biopsy of the tumour. For those patients with GBM, gross tumour resection followed by radical chemoradiation was associated with better survival compared with needle biopsy (HR = 1.93, P = 0.018); increasing age was negatively associated with survival (HR = 1.02 per additional age year, P = 0.037); however, waiting time between neurosurgery and radiation did not affect survival. Six per cent of patients received formal psychological input. CONCLUSION: Our survival outcomes were comparable with internationally published series. More research is required to improve survival in HGG, including molecular guided treatment, and better define treatment paradigms, such as for the elderly and frail.

Temozolomide-induced Aplastic Anemia Treated with Eltrombopag and Granulocyte Colony Stimulating Factor: A Report of a Rare Complication.

Temozolomide is an alkylating agent used in the treatment for glioblastoma multiforme (GBM), the most frequent primary malignant brain tumor in adults. Temozolomide was approved in March 2005 for treatment of GBM, with the Stupp protocol (radiotherapy and concomitant use of temozolomide). Despite initial studies demonstrating mild and well-tolerated side effects, several recent reports describe severe hematologic adverse effects associated with temozolomide use. We report the case of a 51-year-old female diagnosed with GBM who received the standard treatment protocol of radiotherapy and concomitant temozolomide. The patient developed prolonged pancytopenia. Bone marrow biopsy demonstrated hypocellular bone marrow with diminished trilineage hematopoiesis, suggestive of drug-induced aplastic anemia. Although temozolomide is regarded as a safe drug with few side effects, severe hematologic toxicities have been reported.

Memory and attention recovery in patients with High Grade Glioma who completed the Stupp protocol: A before-after study.

OBJECTIVES: Advances in therapeutic schemes for High Grade Gliomas, such as the introduction of Stupp protocol, have raised interest in elucidating its effects on quality of life and cognitive function. This study aims to examine executive functions, memory and attention in patients with High Grade Gliomas, before initiation and after completion of Stupp protocol. PATIENTS AND METHODS: A before-after study was executed. Patients were selected from a consecutive sample of subjects with High Grade Gliomas who had not initiated Stupp protocol. Neuropsi - Attention and Memory test (Second edition) was employed to evaluate subjects. Inferential analysis was conducted with Bayesian Mixed Effects Model for repeated measures, using a contrast coding scheme for estimating the change between mean neurocognitive scores obtained before and after Stupp protocol. Model was fitted employing random-effect predictors accounting for concomitant administration of bevacizumab and anticonvulsants, and by-subject performance variability. As excluding patients who did not complete Stupp protocol might bias results, complementary analyses were conducted for determining if those were consistent in alternative scenarios. RESULTS: Twenty-nine patients were included; 17 (58.6%) completed Stupp protocol and both neuropsychological evaluations. Inside Fixed Effects Model, 95% credible intervals for all cognitive functions crossed the zero threshold (No change); however, in all Mixed Effects Models, credible intervals for memory and attention did not cross zero. CONCLUSION: Results showed significant recovery in memory and attention functions after treatment and suggest a confounding role for co-administered treatments and other factors related to subject cognitive performance variability. Nevertheless, these findings need to be corroborated with additional studies including more representative samples.

Glioblastoma Survival Outcomes at a Tertiary Hospital in Appalachia: Factors Impacting the Survival of Patients Following Implementation of the Stupp Protocol.

BACKGROUND: Glioblastoma is a fatal brain cancer with low median and yearly survival rates. Standard of care for treating glioblastoma is gross total resection (GTR) coupled with the Stupp protocol, but various factors influence the interventions undertaken and survival achieved. As health disparities exist in rural areas, survival in these areas needs to be assessed to understand which factors detract from the successes of these standard medical interventions. METHODS: We retrospectively determined impact of age at diagnosis, number of lesions, the molecular marker O6-methylguanine methyltransferase (MGMT), extent of surgery, and completion of the Stupp protocol on survival in patients treated at West Virginia University Hospitals. We also compared our findings with a pre-Stupp protocol study done in West Virginia in 1996. RESULTS: Age <60 years at diagnosis, having the MGMT gene methylated, having a unifocal tumor, receiving GTR, adhering to the Stupp protocol, and undergoing a treatment course of GTR followed by the Stupp protocol significantly increased survival. Comparison with the 1996 study showed that although overall median survival has not increased, all interventions involving GTR have resulted in a significantly higher survival. CONCLUSIONS: We can serve our patient population by offering GTR to all adult patients with glioblastoma when no contraindications exist and ensuring that patients follow the Stupp protocol. After discharge, the Stupp protocol may not be followed or completed for a variety of reasons. In the future, we aim to assess these reasons and analyze other significant interventional and socioeconomic factors that influence survival.

Early initiation of chemoradiation following index craniotomy is associated with decreased survival in high-grade glioma.

The Stupp protocol of post-resection external beam radiation therapy and concomitant temozolomide is the standard of care for patients with newly-diagnosed glioblastoma, with expanded use in anaplastic astrocytoma. However, the optimal interval between surgery and these adjuvant therapies, and its impact on survival, is unknown. To investigate this, de-identified claims from a large, private health insurance database were queried to identify adult patients who underwent index craniotomy for resection of a supratentorial neoplasm during the period 2005-2014 and began postoperative radiation and temozolomide within 13 weeks of surgery. A total of 2535 patients were assigned to groups based on interval from surgery to first radiation treatment of up to 4 weeks, 4-6 weeks, or 6-13 weeks. Of these, 1098 patients began radiation treatment within 4 weeks of craniotomy, 1019 between 4 and 6 weeks, and 418 between 6 and 13 weeks. There was significant regional variation in treatment schedule in the United States. Survival was calculated based on time from first craniotomy to death. Kaplan-Meier plot and multivariate Cox proportional hazard regression demonstrated a statistically significant association between earliest postoperative radiation and decreased survival (hazard ratio 1.31), along with older age and male sex. Earlier initiation of postoperative radiation for high-grade glioma is not associated with increased survival. Rather, beginning radiation treatment within 4 weeks of craniotomy was associated with significantly worse survival compared to initiation of treatment 4-13 weeks after craniotomy. This is the largest population-based study to date regarding timing of Stupp protocol initiation.

A survival analysis of GBM patients in the West of Scotland pre- and post-introduction of the Stupp regime.

OBJECTIVE: It is now accepted that the concomitant administration of temozolomide with radiotherapy (Stupp regime), in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM), significantly improves survival and this practice has been adopted locally since 2004. However, survival outcomes in cancer can vary in different population groups, and outcomes can be affected by a number of local factors including socioeconomic status. In the West of Scotland, we have one of the worse socioeconomic status and overall health record for a western European country. With the ongoing reorganisation and rationalisation in the National Health Service, the addition of prolonged courses of chemotherapy to patients' management significantly adds to the financial burden of a cash stripped NHS. A survival analysis in patients with GBM was therefore performed, comparing outcomes of pre- and post-introduction of the Stupp regime, to justify the current practice. MATERIALS AND METHODS: Prospectively collected clinical data were analysed in 105 consecutive patients receiving concurrent chemoradiotherapy (Stupp regime) following surgical treatment of GBM between December 2004 and February 2009. This was compared to those of 106 consecutive GBM patients who had radical radiotherapy (pre-Stupp regime) post-surgery between January 2001 and February 2006. RESULTS: The median overall survival for the post-Stupp cohort was 15.3 months (range, 2.83-50.5 months), with 1-year and 2-year overall survival rates of 65.7% and 19%, respectively. This was in comparison with the median overall pre-Stupp survival of 10.7 months, with 1-year and 2-year survival rates of 42.6% and 12%, respectively (log-rank test, p < 0.001). Multivariate Cox regression analysis showed that independent prognostic factors for better survival were younger age, greater extent of surgical resection and a post-operative chemoradiotherapy regime. CONCLUSION: Significant survival benefit has been achieved, following the introduction of the Stupp regime, in GBM patients in the West of Scotland.