Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report

<p>Abstract</p> <p>Background</p> <p>Management of glioblastoma multiforme (GBM) has been difficult using standard therapy (radiation with temozolomide chemotherapy). The ketogenic diet is used commonly to treat refractory epilepsy in children and, when administered in restricted amounts, can also target energy metabolism in brain tumors. We report the case of a 65-year-old woman who presented with progressive memory loss, chronic headaches, nausea, and a right hemisphere multi-centric tumor seen with magnetic resonance imaging (MRI). Following incomplete surgical resection, the patient was diagnosed with glioblastoma multiforme expressing hypermethylation of the <it>MGMT </it>gene promoter.</p> <p>Methods</p> <p>Prior to initiation of the standard therapy, the patient conducted water-only therapeutic fasting and a restricted 4:1 (fat: carbohydrate + protein) ketogenic diet that delivered about 600 kcal/day. The patient also received the restricted ketogenic diet concomitantly during the standard treatment period. The diet was supplemented with vitamins and minerals. Steroid medication (dexamethasone) was removed during the course of the treatment. The patient was followed using MRI and positron emission tomography with fluoro-deoxy-glucose (FDG-PET).</p> <p>Results</p> <p>After two months treatment, the patient's body weight was reduced by about 20% and no discernable brain tumor tissue was detected using either FDG-PET or MRI imaging. Biomarker changes showed reduced levels of blood glucose and elevated levels of urinary ketones. MRI evidence of tumor recurrence was found 10 weeks after suspension of strict diet therapy.</p> <p>Conclusion</p> <p>This is the first report of confirmed GBM treated with standard therapy together with a restricted ketogenic diet. As rapid regression of GBM is rare in older patients following incomplete surgical resection and standard therapy alone, the response observed in this case could result in part from the action of the calorie restricted ketogenic diet. Further studies are needed to evaluate the efficacy of restricted ketogenic diets, administered alone or together with standard treatment, as a therapy for GBM and possibly other malignant brain tumors.</p

Epileptogenesis and Tumorigenesis in Glioblastoma: Which Relationship?

Epilepsy is reported in 29–52% of patients with glioblastoma (GBM) and has an important role in the natural history of this tumor and patients’ life quality. Although GBM is less epileptogenic than lower-grade gliomas, seizures are usually more difficult to control with common antiseizure medications; drug resistance is found in 20% of cases. Recent studies suggest that seizures at the onset of GBM could be a possible favorable independent prognostic factor in patients. Moreover, a growing body of evidence shows that many molecular mechanisms that influence epileptogenesis often regulate GBM growth and invasiveness, sometimes favoring or counteracting the tumor, respectively. The better-characterized players include glutamate, gamma-aminobutyric acid, aquaporin-4, and hypoxia-activated molecules. However, currently available data on the molecular basis of epileptogenesis, tumorigenesis, and their relationship is incomplete or discordant and further research is urgently needed on this topic

Efficacy and Tolerability of Perampanel in Brain Tumor-Related Epilepsy: A Systematic Review

(1) Background: Epilepsy is a frequent comorbidity in patients with brain tumors, in whom seizures are often drug-resistant. Current evidence suggests that excess of glutamatergic activity in the tumor microenvironment may favor epileptogenesis, but also tumor growth and invasiveness. The selective non-competitive -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel (PER) was demonstrated to be efficacious and well-tolerated in patients with focal seizures. Moreover, preclinical in vitro studies suggested a potential anti-tumor activity of this drug. In this systematic review, the clinical evidence on the efficacy and tolerability of PER in brain tumor-related epilepsy (BTRE) is summarized. (2) Methods: Five databases and two clinical trial registries were searched from inception to December 2022. (3) Results: Seven studies and six clinical trials were included. Sample size ranged from 8 to 36 patients, who received add-on PER (mean dosage from 4 to 7 mg/day) for BTRE. After a 6–12 month follow-up, the responder rate (% of patients achieving seizure freedom or reduction 50% of seizure frequency) ranged from 75% to 95%, with a seizure freedom rate of up to 94%. Regarding tolerability, 11–52% of patients experienced non-severe adverse effects (most frequent: dizziness, vertigo, anxiety, irritability). The retention rate ranged from 56% to 83%. However, only up to 12.5% of patients discontinued the drug because of the adverse events. (4) Conclusions: PER seems to be efficacious, safe, and well-tolerated in patients with BTRE. Further randomized studies should be conducted in more homogeneous and larger populations, also evaluating the effect of PER on tumor progression, overall survival, and progression-free survival

Insights into healthcare professionals’ perceptions and attitudes toward nanotechnological device application: What is the current situation in glioblastoma research?

Nanotechnology application in cancer treatment is promising and is likely to quickly spread worldwide in the near future. To date, most scientific studies on nanomaterial development have focused on deepening the attitudes of end users and experts, leaving clinical practice implications unexplored. Neuro-oncology might be a promising field for the application of nanotechnologies, especially for malignant brain tumors with a low-survival rate such as glioblastoma (GBM). As to improving patients’ quality of life and life expectancy, innovative treatments are worth being explored. Indeed, it is important to explore clinicians’ intention to use experimental technologies in clinical practice. In the present study, we conducted an exploratory review of the literature about healthcare workers’ knowledge and personal opinions toward nanomedicine. Our search (i) gives evidence for disagreement between self-reported and factual knowledge about nanomedicine and (ii) suggests the internet and television as main sources of information about current trends in nanomedicine applications, over scientific journals and formal education. Current models of risk assessment suggest time-saving cognitive and affective shortcuts, i.e., heuristics support both laypeople and experts in the decision-making process under uncertainty, whereas they might be a source of error. Whether the knowledge is poor, heuristics are more likely to occur and thus clinicians’ opinions and perspectives toward new technologies might be biased

How the First Year of the COVID-19 Pandemic Impacted Patients’ Hospital Admission and Care in the Vascular Surgery Divisions of the Southern Regions of the Italian Peninsula

Background: To investigate the effects of the COVID-19 lockdowns on the vasculopathic population. Methods: The Divisions of Vascular Surgery of the southern Italian peninsula joined this multicenter retrospective study. Each received a 13-point questionnaire investigating the hospitalization rate of vascular patients in the first 11 months of the COVID-19 pandemic and in the preceding 11 months. Results: 27 out of 29 Centers were enrolled. April-December 2020 (7092 patients) vs. 2019 (9161 patients): post-EVAR surveillance, hospitalization for Rutherford category 3 peripheral arterial disease, and asymptomatic carotid stenosis revascularization significantly decreased (1484 (16.2%) vs. 1014 (14.3%), p = 0.0009; 1401 (15.29%) vs. 959 (13.52%), p = 0.0006; and 1558 (17.01%) vs. 934 (13.17%), p &lt; 0.0001, respectively), while admissions for revascularization or major amputations for chronic limb-threatening ischemia and urgent revascularization for symptomatic carotid stenosis significantly increased (1204 (16.98%) vs. 1245 (13.59%), p &lt; 0.0001; 355 (5.01%) vs. 358 (3.91%), p = 0.0007; and 153 (2.16%) vs. 140 (1.53%), p = 0.0009, respectively). Conclusions: The suspension of elective procedures during the COVID-19 pandemic caused a significant reduction in post-EVAR surveillance, and in the hospitalization of asymptomatic carotid stenosis revascularization and Rutherford 3 peripheral arterial disease. Consequentially, we observed a significant increase in admissions for urgent revascularization for symptomatic carotid stenosis, as well as for revascularization or major amputations for chronic limb-threatening ischemia

Pattern of care and effectiveness of treatment for glioblastoma patients in the real world: Results from a prospective population-based registry. Could survival differ in a high-volume center?

BACKGROUND: As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. METHODS: Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. RESULTS: Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients 64aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388-0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). CONCLUSIONS: The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged 6470 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor

Prognostic value of MGMT promoter status in non-resectable glioblastoma after adjuvant therapy

Background Methylation of MGMT promoter has been identified as a favourable predictive factor of benefit from XRT/TMZ → TMZ. Patients with non-resectable glioblastoma (GBM) generally exhibit a poor prognosis, even after XRT/TMZ. Few data are available concerning the predictive value of MGMT promoter methylation in this population. Methods This is an observational retrospective study in patients with malignant brain glioma, treated between June 2008 and October 2011 and followed up until April 2012 at the Neurosurgery-Neurotraumatology Unit of the University Hospital of Parma and at the Neurosurgery Unit of IRCCS "ASMN" of Reggio Emilia, Italy. The medical records of an overall number of 174 patients with a newly diagnosed GBM were reviewed. Volumetry analysis of the lesions was performed on pre- and post-operative neuroimaging by Voxar 3D Ebit AET software. The genetic characterization was performed on paraffin embedded tissue from all resected tumours. Isolation of nucleic acids, bisulfite modification of DNA, methylation-specific PCR and sequencing analyses were done mainly on fresh tissue from biopsy withdrawals. Within 3-4 weeks after either biopsy or surgery, patients were assigned to receive XRT/TMZ → TMZ: treatment included XRT (60 Gy in 30 fractions)/TMZ (daily dose of 75 mg/m2)/TMZ (150-200 mg/m2 per day for 5 days of every 28-day cycle). Results and discussion A total of 55 consecutive patients (23 men, 22 women) fulfilled inclusion criteria consisting of age over 18 years, supratentorial histologically proven primary malignant glioma, complete determination of the MGMT methylation status, no prior history of surgery, XRT and/or chemotherapy, adequate clinical and radiological follow-up no lesser than 6 months. Twenty-three patients underwent neuronavigation needle biopsy (B Group) and thirty-two patients were operated with craniotomy for tumour resection (R Group). The pre-operative mean age was similar between groups (61.7 ± 10.7 vs 60.3 ± 11.8 years in the B and R groups respectively; p > 0.05). The B groups showed a slightly lower KPS than the R Group (82.1 ± 17.3 vs 90.3 ± 14.1 respectively; p > 0.05). The mean pre-operative volume of the tumour did not differ between groups (46.2 ± 40.2 cm3 vs 44.1 ± 33.2 cm3 in the R Group and B Group respectively; p > 0.05). The MGMT promoter was methylated in 12 patients (51.2%) of B Group and in 17 patients (53.1%) of R Group. XRT/TMZ → TMZ was accomplished in 11 patients (47.8%) of B Group and in 24 patients (75%) of R Group; in 24/29 methylated patients (82.8%) and in 11/26 unmethylated patients (42.3%). Survival analysis of methylated vs unmethylated tumours was statistically significant (Log Rank Mantel Cox: 0.019 in B Group and 0.023 in R Group). In B Group the mean overall survival (OS) of methylated patients was 11.4 months (IC 95% 6.5-16.4) vs 4.8 months (95% IC, 2.6-7.0) of unmethylated patients. In R Group the mean OS was 21.7 months (95% IC, 16.9-26.6) for methylated patients and 14.0 months (95% IC, 8.5-19.4) for unmethylated patients. At the multivariate Cox regression analysis conducted on the total population (55 patients), XRT and TMZ were found to be predictive of OS. In the R Group, KPS, XRT and TMZ correlated with a better outcome. In the B Group, XRT and MGMT promoter methylation were favourably related with OS. Conclusion MGMT promoter unmethylation has a predominant unfavourable impact on clinical outcomes even in the subpopulation of patients with non-resectable GBM. The unmethylated MGMT promoter status could be considered the main predictor of poor prognosis in biopsied GBM, due to the greater probability of patients not having benefits from adjuvant therapies and not being able to accomplish XRT/TMZ → TMZ. The frameless neuronavigation biopsy technique is safe and effective for predictive evaluation and could help in treatment decision making

Alexithymia, Burnout, and Hopelessness in a Large Sample of Healthcare Workers during the Third Wave of COVID-19 in Italy

In the present study, we aimed to assess the frequency of and the relationships between alexithymia, burnout, and hopelessness in a large sample of healthcare workers (HCWs) during the third wave of COVID-19 in Italy. Alexithymia was evaluated by the Italian version of the 20-item Toronto Alexithymia Scale (TAS-20) and its subscales Difficulty in Identifying Feelings (DIF), Difficulty in Describing Feelings (DDF), and Externally Oriented Thinking (EOT), burnout was measured with the scales emotional exhaustion (EE), depersonalisation (DP), and personal accomplishment (PA) of the Maslach Burnout Test (MBI), hopelessness was measured using the Beck Hopelessness Scale (BHS), and irritability (IRR), depression (DEP), and anxiety (ANX) were evaluated with the Italian version of the Irritability‚ Depression‚ Anxiety Scale (IDA). This cross-sectional study recruited a sample of 1445 HCWs from a large urban healthcare facility in Italy from 1 May to 31 June 2021. The comparison between individuals that were positive (n = 214, 14.8%) or not for alexithymia (n = 1231, 85.2%), controlling for age, gender, and working seniority, revealed that positive subjects showed higher scores on BHS, EE, DP IRR, DEP, ANX, DIF, DDF, and EOT and lower on PA than the not positive ones (p < 0.001). In the linear regression model, higher working seniority as well as higher EE, IRR, DEP, ANX, and DDF scores and lower PA were associated with higher hopelessness. In conclusion, increased hopelessness was associated with higher burnout and alexithymia. Comprehensive strategies should be implemented to support HCWs’ mental health and mitigate the negative consequences of alexithymia, burnout, and hopelessness

Safety of Inhomogeneous Dose Distribution IMRT for High-Grade Glioma Reirradiation: A Prospective Phase I/II Trial (GLIORAD TRIAL)

Glioblastoma multiforme (GBM) is the most aggressive astrocytic primary brain tumor, and concurrent temozolomide (TMZ) and radiotherapy (RT) followed by maintenance of adjuvant TMZ is the current standard of care. Despite advances in imaging techniques and multi-modal treatment options, the median overall survival (OS) remains poor. As an alternative to surgery, re-irradiation (re-RT) can be a therapeutic option in recurrent GBM. Re-irradiation for brain tumors is increasingly used today, and several studies have demonstrated its feasibility. Besides differing techniques, the published data include a wide range of doses, emphasizing that no standard approach exists. The current study aimed to investigate the safety of moderate&ndash;high-voxel-based dose escalation in recurrent GBM. From 2016 to 2019, 12 patients met the inclusion criteria and were enrolled in this prospective single-center study. Retreatment consisted of re-irradiation with a total dose of 30 Gy (up to 50 Gy) over 5 days using the IMRT (arc VMAT) technique. A dose painting by numbers (DPBN)/dose escalation plan were performed, and a continuous relation between the voxel intensity of the functional image set and the risk of recurrence in that voxel were used to define target and dose distribution. Re-irradiation was well tolerated in all treated patients. No toxicities greater than G3 were recorded; only one patient had severe G3 acute toxicity, characterized by muscle weakness and fatigue. Median overall survival (OS2) and progression-free survival (PFS2) from the time of re-irradiation were 10.4 months and 5.7 months, respectively; 3-, 6-, and 12-month OS2 were 92%, 75%, and 42%, respectively; and 3-, 6-, and 12-month PFS2 were 83%, 42%, and 8%, respectively. Our work demonstrated a tolerable tolerance profile of this approach, and the future prospective phase II study will analyze the efficacy in terms of PFS and OS