Glioblastoma and Internal Carotid Artery Calcium Score: A Possible Novel Prognostic Partnership?

Purpose: Clinical evidence suggests an association between comorbidities and outcome in patients with glioblastoma (GBM). We hypothesised that the internal carotid artery (ICA) calcium score could represent a promising prognostic biomarker in a competing risk analysis in patients diagnosed with GBM. Methods: We validated the use of the ICA calcium score as a surrogate marker of the coronary calcium score in 32 patients with lung cancer. Subsequently, we assessed the impact of the ICA calcium score on overall survival in GBM patients treated with radio-chemotherapy. Results: We analysed 50 GBM patients. At the univariate analysis, methyl-guanine-methyltransferase gene (MGMT) promoter methylation (p = 0.048), gross total tumour resection (p = 0.017), and calcium score (p = 0.011) were significant prognostic predictors in patients with GBM. These three variables also maintained statistical significance in the multivariate analysis. Conclusions: the ICA calcium score could be a promising prognostic biomarker in GBM patients.

Electron FLASH radiotherapy in vivo studies. A systematic review.

FLASH-radiotherapy delivers a radiation beam a thousand times faster compared to conventional radiotherapy, reducing radiation damage in healthy tissues with an equivalent tumor response. Although not completely understood, this radiobiological phenomenon has been proved in several animal models with a spectrum of all kinds of particles currently used in contemporary radiotherapy, especially electrons. However, all the research teams have performed FLASH preclinical studies using industrial linear accelerator or LINAC commonly employed in conventional radiotherapy and modified for the delivery of ultra-high-dose-rate (UHDRs). Unfortunately, the delivering and measuring of UHDR beams have been proved not to be completely reliable with such devices. Concerns arise regarding the accuracy of beam monitoring and dosimetry systems. Additionally, this LINAC totally lacks an integrated and dedicated Treatment Planning System (TPS) able to evaluate the internal dose distribution in the case of in vivo experiments. Finally, these devices cannot modify dose-time parameters of the beam relevant to the flash effect, such as average dose rate; dose per pulse; and instantaneous dose rate. This aspect also precludes the exploration of the quantitative relationship with biological phenomena. The dependence on these parameters need to be further investigated. A promising advancement is represented by a new generation of electron LINAC that has successfully overcome some of these technological challenges. In this review, we aim to provide a comprehensive summary of the existing literature on in vivo experiments using electron FLASH radiotherapy and explore the promising clinical perspectives associated with this technology.

New insights on clinical perspectives of FLASH radiotherapy: from low- to very high electron energy.

Radiotherapy (RT) is performed in approximately 75% of patients with cancer, and its efficacy is often hampered by the low tolerance of the surrounding normal tissues. Recent advancements have demonstrated the potential to widen the therapeutic window using "very short" radiation treatment delivery (from a conventional dose rate between 0.5 Gy/min and 2 Gy/min to more than 40 Gy/s) causing a significant increase of normal tissue tolerance without varying the tumor effect. This phenomenon is called "FLASH Effect (FE)" and has been discovered by using electrons. Although several physical, dosimetric, and radiobiological aspects need to be clarified, current preclinical "in vivo" studies have reported a significant protective effect of FLASH RT on neurocognitive function, skin toxicity, lung fibrosis, and bowel injury. Therefore, the current radiobiological premises lay the foundation for groundbreaking potentials in clinical translation, which could be addressed to an initial application of Low Energy Electron FLASH (LEE) for the treatment of superficial tumors to a subsequent Very High Energy Electron FLASH (VHEE) for the treatment of deep tumors. Herein, we report a clinical investigational scenario that, if supported by preclinical studies, could be drawn in the near future.

Cancer Stem Cells and Glioblastoma: Time for Innovative Biomarkers of Radio-Resistance?

Despite countless papers in the field of radioresistance, researchers are still far from clearly understanding the mechanisms triggered in glioblastoma. Cancer stem cells (CSC) are important to the growth and spread of cancer, according to many studies. In addition, more recently, it has been suggested that CSCs have an impact on glioblastoma patients' prognosis, tumor aggressiveness, and treatment outcomes. In reviewing this new area of biology, we will provide a summary of the most recent research on CSCs and their role in the response to radio-chemotherapy in GB. In this review, we will examine the radiosensitivity of stem cells. Moreover, we summarize the current knowledge of the biomarkers of stemness and evaluate their potential function in the study of radiosensitivity.

A predictive model of polymetastatic disease from a multicenter large retrospectIve database on colorectal lung metastases treated with stereotactic ablative radiotherapy: The RED LaIT-SABR study.

Aim: Stereotactic ablative radiotherapy (SABR) showed increasing survival in oligometastatic patients. Few studies actually depicted oligometastatic disease (OMD) evolution and which patient will remain disease-free and which will rapidly develop a polymetastatic disease (PMD) after SABR. Therefore, apart from the number of active metastases, there are no clues on which proven factor should be considered for prescribing local treatment in OMD. The study aims to identify predictive factors of polymetastatic evolution in lung oligometastatic colorectal cancer patients. Methods: This international Ethical Committee approved trial (Prot. Negrar 2019-ZT) involved 23 Centers and 450 lung oligometastatic patients. Primary end-point was time to the polymetastatic conversion (tPMC). Additionally, oligometastases number and cumulative gross tumor volume (cumGTV) were used as combined predictive factors of tPMC. Oligometastases number was stratified as 1, 2-3, and 4-5; cumGTV was dichotomized to the value of 10 cc. Results: The median tPMC in the overall population was 26 months. Population was classified in the following tPMC risk classes: low-risk (1-3 oligometastases and cumGTV ≤ 10 cc) with median tPMC of 35.1 months; intermediate-risk (1-3 oligometastases and cumGTV > 10 cc), with median tPMC of 13.9 months, and high-risk (4-5 oligometastases, any cumGTV) with median tPMC of 9.4 months (p = 0.000). Conclusion: The present study identified predictive factors of polymetastatic evolution after SABR in lung oligometastatic colorectal cancer. The results demonstrated that the sole metastases number is not sufficient to define the OMD since patients defined oligometastatic from a numerical point of view might rapidly progress to PMD when the cumulative tumor volume is high. A tailored approach in SABR prescription should be pursued considering the expected disease evolution after SABR, with the aim to avoid unnecessary treatment and toxicity in those at high risk of polymetastatic spread, and maximize local treatment in those with a favorable disease evolution.

Impact of temporalis muscle thickness in elderly patients with newly diagnosed glioblastoma treated with radio or radio-chemotherapy.

BACKGROUND: There is an unmet need for new biomarkers able to predict both the outcomes of up-front therapy and the compliance of elderly patients diagnosed with glioblastoma. For this purpose, temporal muscle thickness is a promising tool to be investigated. METHODS: Data from 52 glioblastoma patients older than 65 years, treated with post-operative radio or radio-chemotherapy and referred to Pisa University Hospital, were retrieved. The thickness of temporal muscle (TMT) was divided into quartiles and correlated with overall survival (Our primary endpoint). Survival curves were calculated using Kaplan-Meier method, and log-rank test was used to evaluate the differences between curves. RESULTS: Patients in the lower quartile of TMT, with TMT thinner than 7 mm, have survived longer; both univariate and multivariate analyses showed a statistically significant correlation between TMT and overall survival (P = 0.012 and P = 0.003, respectively). CONCLUSION: Future prospective and more extensive studies focused on elderly glioblastoma patients are needed to confirm the role of TMT as prognostic value on OS and to help explaining this association.

Old and New Systemic Immune-Inflammation Indexes Are Associated with Overall Survival of Glioblastoma Patients Treated with Radio-Chemotherapy.

Background. Systemic immunity and inflammation indexes (SI) derived from blood cells have gained increasing attention in clinical oncology as potential biomarkers that are associated with survival. Materials and methods. We tested 12 different SI using blood tests from patients with isocitrate dehydrogenase 1 and 2 wild-type glioblastomas, treated with radio-chemotherapy. The primary endpoint was their overall survival. Results. A total of 77 patients, comprising 43 males and 34 females, with a median age of 64 years (age range 26-84), who were treated between October 2010 and July 2020, were included in the present analysis (approved by a local ethics committee). In the univariate Cox regression analysis, all the indexes except two showed a statistically significant impact on OS. In the multivariate Cox regression analysis, neutrophil × platelet × leukocyte/(lymphocyte × monocyte) (NPW/LM) and neutrophil × platelet × monocyte/lymphocyte (NPM/L) maintained their statistically significant impact value. Conclusions. This univariate analysis confirms the potential of systemic inflammation indexes in patients with glioblastoma, while the multivariate analysis verifies the prognostic value of NPW/LM and NPM/L.

Role of magnetic resonance imaging following postoperative radiotherapy in clinical decision-making of patients with high-grade glioma.

OBJECTIVES: The present study aims to investigate the role of the first magnetic resonances (MRI) following radio-chemotherapy (RT-CT) in patients diagnosed with high-grade glioma. METHODS: We retrospectively recorded radiological evaluations following RT-CT, symptoms related to disease progression (avoiding any sign due to radiotherapy or chemotherapy) and the change of therapeutic strategy. RESULTS: In March 2021, at data analysis, the data of 149 patients diagnosed with high-grade glioma and treated between May 2013 and July 2020 were retrieved for the present analysis. Two out of 122 (1.6%), 5 out of 106 (4.7%) and 8 out of 92 (8.6%) asymptomatic patients received the diagnosis of disease recurrence at the time of the first, second and third MRI, respectively. Otherwise, 16 out of 27 (59.2%), 16 out of 24 (66.6%) and 13 out of 16 (82.2%) symptomatic patients changed their therapy after the first, second and third MRI, respectively. Among patients that experienced radiological signs of distant progression, 10 out of 14 were symptomatic and changed their therapy. CONCLUSIONS: MRIs performed by 6 months after the end of RT-CT lead to change treatment strategy mostly in symptomatic patients.

Impact of recurrence pattern in patients undergoing a second surgery for recurrent glioblastoma.

The impact of different patterns of glioblastoma (GBM) recurrence has not yet been fully established in patients suitable for a second surgery. Through the present observational study carried out at Pisa University Hospital, we aimed to investigate how different patterns of GBM failure influence second surgery outcomes. Overall survival (OS) and post-recurrence survival (PRS) were assessed according to clinical characteristics, including pattern of recurrence, in a prospective cohort of recurrent GBM patients. Survival curves were calculated using the Kaplan-Meier method and the log-rank test was applied to evaluate the differences between curves. Patients with local recurrence had better OS than patients with non-local one, 24.1 versus 18.2 months, respectively [P = 0.015, HR = 1.856 (1.130-3.050)]. The second surgery conferred an advantage in OS respect to non-operated patients, however, this advantage was more evident in patients with local recurrence [P = 0.002 with HR 0.212 (95% CI 0.081-0.552) and P = 0.029 with HR = 0.522 (95% CI 0.291-0.936), respectively]. The recurrence pattern can influence the outcome of patients with recurrent GBM suitable for a second surgery.

Adjuvant Radiotherapy in Patients With Pancreatic Adenocarcinoma. Is It Still Appealing in Clinical Trials? A Meta-analysis and Review of the Literature.

AIM: Pancreatic adenocarcinoma is a life-threatening disease with a rising frequency and the fourth leading cause of cancer death. This review aimed to assess the impact of postoperative radiotherapy through a meta-analysis of prospective randomized studies. MATERIALS AND METHODS: Six studies met the inclusion criteria and were analyzed to calculate the cumulative risk of death (hazard ratio) in patients affected by pancreatic cancer treated with or without radiotherapy. Higgins' index was used to determine heterogeneity in between-study variability and, subsequently, the random-effects model was applied according to DerSimonian and Laird. RESULTS: Eight hundred and thirty-seven patients were analyzed (418 in the control arm and 419 in the treatment one), the hazard ratio for death after randomization was 0.92 (p=0.560, 95% confidence interval=0.70-1.22). When scrutinizing these studies, only one out of six showed a statistically significant benefit due to the addition of radiotherapy in the postoperative setting. CONCLUSION: We conclude that the use of adjuvant radiotherapy is not beneficial in treating all patients affected by pancreatic cancer but only for a subset of cases with potential residual local disease.

Association of XRCC3 rs1799794 polymorphism with survival of glioblastoma multiforme patients treated with combined radio-chemotherapy.

This study reports the results of a monocentric prospective analysis conducted with the aim of evaluating the impact of XRCC1 rs25487, XRCC3 rs861539, XRCC3 rs1799794, RAD51 rs1801320 and GSTP-1 rs1695 single nucleotide polymorphisms (SNP) on patients with high-grade glioma treated with concomitant radio-chemotherapy. From October 2010 to August 2019, a total of 75 patients aged ≥18 years, with histological diagnosis of high-grade glioma, isocitrate dehydrogenase (IDH) 1/2 wild type and treated with radio-chemotherapy and sequential chemotherapy with temozolomide (TMZ) were prospectively recruited. The local ethic committee approved this study (Comitato Etico di Area Vasta Nord Ovest [CEAVNO]; protocol 3304/2011). After a median follow up of 25 months (range: 7-98 months), median progression-free survival (PFS) and overall survival (OS) were 11 months (CI95%: 8-14 months) and 18 months (CI95%: 15-21 months), respectively. In univariate and multivariate Cox regression analysis, a statistically significant association with PFS and OS was found with XRCC3 rs1799794 SNP. The study suggests that XRCC3 rs1799794 SNP can be associated with different PFS and OS in glioblastoma patients treated with radio-chemotherapy.