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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 17148

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Dr. Marco Russo

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Guest Editor

Neurology Unit, Neuromotor & Rehabilitation Department, Azienda USL-IRCCS Reggio Emilia, 42121 Emilia, Italy
Interests: neuro-oncology; epilepsy; headache; clinical neurophysiology; EEG

Dr. Jessica Rossi

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Guest Editor

1. Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, 41121 Modena, Italy
2. Neurology Unit, Neuromotor& Rehabilitation Department, Azienda USL-IRCCS Reggio Emilia, 42121 Emilia, Italy
Interests: neuro-oncology; epilepsy; sleep medicine; clinical neurophysiology; EEG

Special Issue Information

Dear Colleagues,

Glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults, and is characterized by rapid progression and poor prognosis. In addition to high mortality, glioblastoma is associated with high morbidity. Symptoms like seizures, headache, and cognitive decline may occur from the earliest stages of the disease, causing a rapid deterioration of independence in activities of daily living. Despite multimodal treatment efforts, the survival rate for patients with glioblastoma has not significantly improved over the last several decades. Current research is aimed at studying new molecular markers that could allow the early identification of GBM, as well as prompt therapeutic and prognostic definition. However, the field still lacks in-depth knowledge on pathological mechanisms underlying tumor growth and invasiveness.

Moreover, the 2021 World Health Organization Classification of Central Nervous System tumors has defined new molecular entities, including IDH-mutant grade 4 astrocytoma and IDH-wild type molecularly defined glioblastoma, whose behavior and response to standardized GBM treatments remain to be defined.

The aim of this Special Issue is to discuss current knowledge on the mechanisms of glioblastoma development and progression, as well as research on the early diagnosis and management of GBM and GBM-associated symptoms.

In this Special Issue, original research articles and reviews are welcome.

We look forward to receiving your contributions.

Dr. Marco Russo
Dr. Jessica Rossi
Guest Editors

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Keywords

glioblastoma
biology
management
mortality
prognosis
markers
early diagnosis
targeted therapy
overall survival (OS)
progression-free survival (PFS)

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Published Papers (8 papers)

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10 pages, 759 KiB

Open AccessArticle

Influence of MRI Follow-Up on Treatment Decisions during Standard Concomitant and Adjuvant Chemotherapy in Patients with Glioblastoma: Is Less More?

by Bart R. J. van Dijken, Annerieke R. Doff, Roelien H. Enting, Peter Jan van Laar, Hanne-Rinck Jeltema, Rudi A. J. O. Dierckx and Anouk van der Hoorn

Cancers 2023, 15(20), 4973; https://doi.org/10.3390/cancers15204973 - 13 Oct 2023

Cited by 1 | Viewed by 1335

Abstract

MRI is the gold standard for treatment response assessments for glioblastoma. However, there is no consensus regarding the optimal interval for MRI follow-up during standard treatment. Moreover, a reliable assessment of treatment response is hindered by the occurrence of pseudoprogression. It is unknown if a radiological follow-up strategy at 2–3 month intervals actually benefits patients and how it influences clinical decision making about the continuation or discontinuation of treatment. This study assessed the consequences of scheduled follow-up scans post-chemoradiotherapy (post-CCRT), after three cycles of adjuvant chemotherapy [TMZ3/6], and after the completion of treatment [TMZ6/6]), and of unscheduled scans on treatment decisions during standard concomitant and adjuvant treatment in glioblastoma patients. Additionally, we evaluated how often follow-up scans resulted in diagnostic uncertainty (tumor progression versus pseudoprogression), and whether perfusion MRI improved clinical decision making. Scheduled follow-up scans during standard treatment in glioblastoma patients rarely resulted in an early termination of treatment (2.3% post-CCRT, 3.2% TMZ3/6, and 7.8% TMZ6/6), but introduced diagnostic uncertainty in 27.7% of cases. Unscheduled scans resulted in more major treatment consequences (30%; p < 0.001). Perfusion MRI caused less diagnostic uncertainty (p = 0.021) but did not influence treatment consequences (p = 0.871). This study does not support the current pragmatic follow-up strategy and suggests a more tailored follow-up approach. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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12 pages, 1858 KiB

Open AccessArticle

Intraoperative Neuromonitoring of the Visual Pathway in Asleep Neuro-Oncology Surgery

by Christos Soumpasis, Alba Díaz-Baamonde, Prajwal Ghimire, Asfand Baig Mirza, Marco Borri, Josef Jarosz, Richard Gullan, Keyoumars Ashkan, Ranjeev Bhangoo, Francesco Vergani, Jose Pedro Lavrador and Ana Mirallave Pescador

Cancers 2023, 15(15), 3943; https://doi.org/10.3390/cancers15153943 - 3 Aug 2023

Cited by 2 | Viewed by 1416

Abstract

Brain tumour surgery in visual eloquent areas poses significant challenges to neurosurgeons and has reported inconsistent results. This is a single-centre prospective cohort study of patients admitted for asleep surgery of intra-axial lesions in visual eloquent areas. Demographic and clinical information, data from tractography and visual evoked potentials (VEPs) monitoring were recorded and correlated with visual outcomes. Thirty-nine patients were included (20 females, 19 males; mean age 52.51 ± 14.08 years). Diffuse intrinsic glioma was noted in 61.54% of patients. There was even distribution between the temporal, occipital and parietal lobes, while 55.26% were right hemispheric lesions. Postoperatively, 74.4% remained stable in terms of visual function, 23.1% deteriorated and 2.6% improved. The tumour infiltration of the optic radiation on tractography was significantly related to the visual field deficit after surgery (p = 0.016). Higher N75 (p = 0.036) and P100 (p = 0.023) amplitudes at closure on direct cortical VEP recordings were associated with no new postoperative visual deficit. A threshold of 40% deterioration of the N75 (p = 0.035) and P100 (p = 0.020) amplitudes correlated with a risk of visual field deterioration. To conclude, direct cortical VEP recordings demonstrated a strong correlation with visual outcomes, contrary to transcranial recordings. Invasion of the optic radiation is related to worse visual field outcomes. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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17 pages, 2327 KiB

Open AccessArticle

Perifocal Zone of Brain Gliomas: Application of Diffusion Kurtosis and Perfusion MRI Values for Tumor Invasion Border Determination

by Natalia E. Zakharova, Artem I. Batalov, Eduard L. Pogosbekian, Ivan V. Chekhonin, Sergey A. Goryaynov, Andrey E. Bykanov, Anastasia N. Tyurina, Suzanna A. Galstyan, Pavel V. Nikitin, Lyudmila M. Fadeeva, Dmitry Yu. Usachev and Igor N. Pronin

Cancers 2023, 15(10), 2760; https://doi.org/10.3390/cancers15102760 - 15 May 2023

Cited by 4 | Viewed by 1769

Abstract

(1) Purpose: To determine the borders of malignant gliomas with diffusion kurtosis and perfusion MRI biomarkers. (2) Methods: In 50 high-grade glioma patients, diffusion kurtosis and pseudo-continuous arterial spin labeling (pCASL) cerebral blood flow (CBF) values were determined in contrast-enhancing area, in perifocal infiltrative edema zone, in the normal-appearing peritumoral white matter of the affected cerebral hemisphere, and in the unaffected contralateral hemisphere. Neuronavigation-guided biopsy was performed from all affected hemisphere regions. (3) Results: We showed significant differences between the DKI values in normal-appearing peritumoral white matter and unaffected contralateral hemisphere white matter. We also established significant (p < 0.05) correlations of DKI with Ki-67 labeling index and Bcl-2 expression activity in highly perfused enhancing tumor core and in perifocal infiltrative edema zone. CBF correlated with Ki-67 LI in highly perfused enhancing tumor core. One hundred percent of perifocal infiltrative edema tissue samples contained tumor cells. All glioblastoma samples expressed CD133. In the glioblastoma group, several normal-appearing white matter specimens were infiltrated by tumor cells and expressed CD133. (4) Conclusions: DKI parameters reveal changes in brain microstructure invisible on conventional MRI, e.g., possible infiltration of normal-appearing peritumoral white matter by glioma cells. Our results may be useful for plotting individual tumor invasion maps for brain glioma surgery or radiotherapy planning. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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23 pages, 2986 KiB

Open AccessArticle

Sphingosine-1-Phosphate Recruits Macrophages and Microglia and Induces a Pro-Tumorigenic Phenotype That Favors Glioma Progression

by Lavinia Arseni, Rakesh Sharma, Norman Mack, Deepthi Nagalla, Sibylle Ohl, Thomas Hielscher, Mahak Singhal, Robert Pilz, Hellmut Augustin, Roger Sandhoff, Christel Herold-Mende, Björn Tews, Peter Lichter and Martina Seiffert

Cancers 2023, 15(2), 479; https://doi.org/10.3390/cancers15020479 - 12 Jan 2023

Cited by 8 | Viewed by 3070

Abstract

Glioblastoma is the most aggressive brain tumor in adults. Treatment failure is predominantly caused by its high invasiveness and its ability to induce a supportive microenvironment. As part of this, a major role for tumor-associated macrophages/microglia (TAMs) in glioblastoma development was recognized. Phospholipids are important players in various fundamental biological processes, including tumor–stroma crosstalk, and the bioactive lipid sphingosine-1-phosphate (S1P) has been linked to glioblastoma cell proliferation, invasion, and survival. Despite the urgent need for better therapeutic approaches, novel strategies targeting sphingolipids in glioblastoma are still poorly explored. Here, we showed that higher amounts of S1P secreted by glioma cells are responsible for an active recruitment of TAMs, mediated by S1P receptor (S1PR) signaling through the modulation of Rac1/RhoA. This resulted in increased infiltration of TAMs in the tumor, which, in turn, triggered their pro-tumorigenic phenotype through the inhibition of NFkB-mediated inflammation. Gene set enrichment analyses showed that such an anti-inflammatory microenvironment correlated with shorter survival of glioblastoma patients. Inhibition of S1P restored a pro-inflammatory phenotype in TAMs and resulted in increased survival of tumor-bearing mice. Taken together, our results establish a crucial role for S1P in fine-tuning the crosstalk between glioma and infiltrating TAMs, thus pointing to the S1P–S1PR axis as an attractive target for glioma treatment. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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9 pages, 1201 KiB

Open AccessArticle

Sequential and Hybrid PET/MRI Acquisition in Follow-Up Examination of Glioblastoma Show Similar Diagnostic Performance

by Julian Ziegenfeuter, Claire Delbridge, Denise Bernhardt, Jens Gempt, Friederike Schmidt-Graf, Michael Griessmair, Marie Thomas, Hanno S. Meyer, Claus Zimmer, Bernhard Meyer, Stephanie E. Combs, Igor Yakushev, Benedikt Wiestler and Marie-Christin Metz

Cancers 2023, 15(1), 83; https://doi.org/10.3390/cancers15010083 - 23 Dec 2022

Cited by 5 | Viewed by 2302

Abstract

Both positron emission tomography (PET) and magnetic resonance imaging (MRI), including dynamic susceptibility contrast perfusion (DSC-PWI), are crucial for treatment monitoring of patients with high-grade gliomas. In clinical practice, they are usually conducted at separate time points. Whether this affects their diagnostic performance is presently unclear. To this end, we retrospectively reviewed 38 patients with pathologically confirmed glioblastoma (IDH wild-type) and suspected tumor recurrence after radiotherapy. Only patients who received both a PET–MRI (where DSC perfusion was acquired simultaneously with a FET-PET) and a separate MRI exam (including DSC perfusion) were included. Tumors were automatically segmented into contrast-enhancing tumor (CET), necrosis, and edema. To compare the simultaneous as well as the sequential DSC perfusion to the FET-PET, we calculated Dice overlap, global mutual information as well as voxel-wise Spearman correlation of hotspot areas. For the joint assessment of PET and MRI, we computed logistic regression models for the differentiation between true progression (PD) and treatment-related changes (TRC) using simultaneously or sequentially acquired images as input data. We observed no significant differences between Dice overlap (p = 0.17; paired t-test), mutual information (p = 0.18; paired t-test) and Spearman correlation (p = 0.90; paired t-test) when comparing simultaneous PET–MRI and sequential PET/MRI acquisition. This also held true for the subgroup of patients with >14 days between exams. Importantly, for the diagnostic performance, ROC analysis showed similar AUCs for differentiation of PD and TRC (AUC simultaneous PET: 0.77; AUC sequential PET: 0.78; p = 0.83, DeLong’s test). We found no relevant differences between simultaneous and sequential acquisition of FET-PET and DSC perfusion, also regarding their diagnostic performance. Given the increasing attention to multi-parametric assessment of glioma treatment response, our results reassuringly suggest that sequential acquisition is clinically and scientifically acceptable. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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21 pages, 1574 KiB

Open AccessArticle

Management of Recurrent Glioblastomas: What Can We Learn from the French Glioblastoma Biobank?

by Anne Clavreul, Lila Autier, Jean-Michel Lemée, Paule Augereau, Gwénaëlle Soulard, Luc Bauchet, Dominique Figarella-Branger, Philippe Menei and FGB Network

Cancers 2022, 14(22), 5510; https://doi.org/10.3390/cancers14225510 - 9 Nov 2022

Cited by 4 | Viewed by 2113

Abstract

Safe maximal resection followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ) is universally accepted as the first-line treatment for glioblastoma (GB), but no standard of care has yet been defined for managing recurrent GB (rGB). We used the French GB biobank (FGB) to evaluate the second-line options currently used, with a view to defining the optimal approach and future directions in GB research. We retrospectively analyzed data for 338 patients with de novo isocitrate dehydrogenase (IDH)-wildtype GB recurring after TMZ chemoradiotherapy. Cox proportional hazards models and Kaplan–Meier analyses were used to investigate survival outcomes. Median overall survival after first surgery (OS1) was 19.8 months (95% CI: 18.5–22.0) and median OS after first progression (OS2) was 9.9 months (95% CI: 8.8–10.8). Two second-line options were noted for rGB patients in the FGB: supportive care and treatments, with systemic treatment being the treatment most frequently used. The supportive care option was independently associated with a shorter OS2 (p < 0.001). None of the systemic treatment regimens was unequivocally better than the others for rGB patients. An analysis of survival outcomes based on time to first recurrence (TFR) after chemoradiotherapy indicated that survival was best for patients with a long TFR (≥18 months; median OS1: 44.3 months (95% CI: 41.7–56.4) and median OS2: 13.0 months (95% CI: 11.2–17.7), but that such patients constituted only a small proportion of the total patient population (13.0%). This better survival appeared to be more strongly associated with response to first-line treatment than with response to second-line treatment, indicating that the recurring tumors were more aggressive and/or resistant than the initial tumors in these patients. In the face of high rates of treatment failure for GB, the establishment of well-designed large cohorts of primary and rGB samples, with the help of biobanks, such as the FGB, taking into account the TFR and survival outcomes of GB patients, is urgently required for solid comparative biological analyses to drive the discovery of novel prognostic and/or therapeutic clinical markers for GB. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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17 pages, 6793 KiB

Open AccessSystematic Review

Prognostic Values of Systemic Inflammatory Immunological Markers in Glioblastoma: A Systematic Review and Meta-Analysis

by Pawel Jarmuzek, Klaudia Kozlowska, Piotr Defort, Marcin Kot and Agnieszka Zembron-Lacny

Cancers 2023, 15(13), 3339; https://doi.org/10.3390/cancers15133339 - 25 Jun 2023

Cited by 22 | Viewed by 2396

Abstract

Background. Neutrophils are an important part of the tumor microenvironment, which stimulates inflammatory processes through phagocytosis, degranulation, release of small DNA fragments (cell-free DNA), and presentation of antigens. Since neutrophils accumulate in peripheral blood in patients with advanced-stage cancer, a high neutrophil-to-lymphocyte ratio can be a biomarker of a poor prognosis in patients with glioblastoma. The present study aimed to explore the prognostic value of the preoperative levels of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and cell-free DNA (cfDNA) to better predict prognostic implications in the survival rate of glioblastoma patients. Methods. The meta-analysis was carried out according to the recommendations and standards established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Databases of PubMed, EBSCO, and Medline were systematically searched to select all the relevant studies published up to December 2022. Results. Poorer prognoses were recorded in patients with a high NLR or PLR when compared with the patients with a low NLR or PLR (HR 1.51, 95% CI 1.24–1.83, p < 0.0001 and HR 1.34, 95% CI 1.10–1.63, p < 0.01, respectively). Similarly, a worse prognosis was reported for patients with a higher cfDNA (HR 2.35, 95% CI 1.27–4.36, p < 0.01). The SII and SIRI values were not related to glioblastoma survival (p = 0.0533 and p = 0.482, respectively). Conclusions. Thus, NLR, PLR, and cfDNA, unlike SII and SIRI, appeared to be useful and convenient peripheral inflammatory markers to assess the prognosis in glioblastoma. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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14 pages, 676 KiB

Open AccessSystematic Review

A Systematic Review of Amino Acid PET Imaging in Adult-Type High-Grade Glioma Surgery: A Neurosurgeon’s Perspective

by Raffaele De Marco, Alessandro Pesaresi, Andrea Bianconi, Michela Zotta, Désirée Deandreis, Giovanni Morana, Pietro Zeppa, Antonio Melcarne, Diego Garbossa and Fabio Cofano

Cancers 2023, 15(1), 90; https://doi.org/10.3390/cancers15010090 - 23 Dec 2022

Cited by 14 | Viewed by 1999

Abstract

Amino acid PET imaging has been used for a few years in the clinical and surgical management of gliomas with satisfactory results in diagnosis and grading for surgical and radiotherapy planning and to differentiate recurrences. Biological tumor volume (BTV) provides more meaningful information than standard MR imaging alone and often exceeds the boundary of the contrast-enhanced nodule seen in MRI. Since a gross total resection reflects the resection of the contrast-enhanced nodule and the majority of recurrences are at a tumor’s margins, an integration of PET imaging during resection could increase PFS and OS. A systematic review of the literature searching for “PET” [All fields] AND “glioma” [All fields] AND “resection” [All fields] was performed in order to investigate the diffusion of integration of PET imaging in surgical practice. Integration in a neuronavigation system and intraoperative use of PET imaging in the primary diagnosis of adult high-grade gliomas were among the criteria for article selection. Only one study has satisfied the inclusion criteria, and a few more (13) have declared to use multimodal imaging techniques with the integration of PET imaging to intentionally perform a biopsy of the PET uptake area. Despite few pieces of evidence, targeting a biologically active area in addition to other tools, which can help intraoperatively the neurosurgeon to increase the amount of resected tumor, has the potential to provide incremental and complementary information in the management of brain gliomas. Since supramaximal resection based on the extent of MRI FLAIR hyperintensity resulted in an advantage in terms of PFS and OS, PET-based biological tumor volume, avoiding new neurological deficits, deserves further investigation. Full article

(This article belongs to the Special Issue Management of Glioblastomas)

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