Stereotactic radiosurgery for idiopathic glossopharyngeal neuralgia: A systematic review.

Background: Stereotactic radiosurgery (SRS) has recently gained space as an accepted non-invasive alternative treatment option for drug resistant Glossopharyngeal neuralgia (GPN). The purpose of this systematic review was to provide an overview of the outcomes of SRS treatment in patients with GPN. Methods: A literature review until March 2023 was performed. Data about patient's demographics, complications and recurrence rates, additional treatment post procedure as well as pain outcomes in the short and long term were collected. Studies without reported pain outcomes were excluded. Results: Sixteen studies with a total of 97 patients diagnosed with GPN who had undergone SRS were identified. The mean reported maximal radiation dose ranged from 70 to 88.7 Gy with the glossopharyngeal meatus (GPM) being the most common target in 12/16 studies. The median time from SRS till pain response was between 2 and 120 days. The mean proportion of patients requiring further treatment after SRS ranged from 11.1 to 57.14% in a time frame between 2 and 36 months post procedure. Favourable pain response rates after SRS (BNI-IIIb) ranged from 60% to 100% and 57.1%-100% in short and long term respectively. Conclusion: SRS for GPN remains a safe alternative to surgery with low complication rates and favourable pain outcomes in both short and long term.

Antitumor activity of 5-hydroxy-3',4',6,7-tetramethoxyflavone in glioblastoma cell lines and its antagonism with radiotherapy.

5-Hydroxy-3',4',6,7-tetramethoxyflavone (TMF) is a plant-origin flavone known for its anti-cancer properties. In the present study, the cytotoxic effect of TMF was evaluated in the U87MG and T98G glioblastoma (GBM) cell lines. The effect of TMF on cell viability was assessed with trypan blue exclusion assay and crystal violet staining. In addition, flow cytometry was performed to examine its effect on the different phases of the cell cycle, and in vitro scratch wound assay assessed the migratory capacity of the treated cells. Furthermore, the effect of in vitro radiotherapy was also evaluated with a combination of TMF and radiation. In both cell lines, TMF treatment resulted in G0/G1 cell cycle arrest, reduced cell viability, and reduced cell migratory capacity. In contrast, there was an antagonistic property of TMF treatment with radiotherapy. These results demonstrated the antineoplastic effect of TMF in GBM cells in vitro, but the antagonistic effect with radiotherapy indicated that TMF should be further evaluated for its possible antitumor role post-radiotherapy.

Therapeutic Hypothermia in Treating Glioblastoma: A Review.

Glioblastoma (GBM) is the most commonly occurring of all malignant central nervous system (CNS) tumors in adults. Considering the low median survival of only ∼15 months and poor prognosis in GBM patients, despite surgical resection with adjuvant radiation and chemotherapy, it is vital to seek brand new and innovative treatment in combination with already existing methods. Hypothermia participates in many metabolic pathways, inflammatory responses, and apoptotic processes, while also promoting the integrity of neurons. Following the successful application of therapeutic hypothermia across a spectrum of disorders such as traumatic CNS injury, cardiac arrest, and epilepsy, several clinical trials have set to evaluate the potency of hypothermia in treating a variety of cancers, including breast and ovaries cancer. In regard to primary neoplasms and more specifically, GBM, hypothermia has recently shown promising results as an auxiliary treatment, reinforcing chemotherapy's efficacy. In this review, we discuss the recent advances in utilizing hypothermia as treatment for GBM and other cancers.

Nuclear Medicine and Cancer Theragnostics: Basic Concepts.

Cancer theragnostics is a novel approach that combines diagnostic imaging and radionuclide therapy. It is based on the use of a pair of radiopharmaceuticals, one optimized for positron emission tomography imaging through linkage to a proper radionuclide, and the other bearing an alpha- or beta-emitter isotope that can induce significant damage to cancer cells. In recent years, the use of theragnostics in nuclear medicine clinical practice has increased considerably, and thus investigation has focused on the identification of novel radionuclides that can bind to molecular targets that are typically dysregulated in different cancers. The major advantages of the theragnostic approach include the elimination of multi-step procedures, reduced adverse effects to normal tissues, early diagnosis, better predictive responses, and personalized patient care. This review aims to discuss emerging theragnostic molecules that have been investigated in a series of human malignancies, including gliomas, thyroid cancer, neuroendocrine tumors, cholangiocarcinoma, and prostate cancer, as well as potent and recently introduced molecular targets, like cell-surface receptors, kinases, and cell adhesion proteins. Furthermore, special reference has been made to copper radionuclides as theragnostic agents and their radiopharmaceutical applications since they present promising alternatives to the well-studied gallium-68 and lutetium-177.

Ependymomas in Children and Adults.

Ependymomas account for approximately 5% of all CNS tumors in adults and around 10% in the pediatric population. Contrary to traditional theories supporting that ependymomas arise from ependymal cells, recent studies propose radial glial cells as the cells of origin. In adults, half of the ependymomas arise in the spinal cord, whereas in the pediatric population, almost 90% of ependymomas are located intracranially. Most of the ependymomas are usually low-grade tumors except anaplastic variants and some cases of RELA-fusion-positive ependymomas, a molecular variant consisting the most recent addition to the 2016 World Health Organization (WHO) classification. Of note, the recently described molecular classification of ependymomas into nine distinct subgroups appears to be of greater clinical utility and prognostic value compared to the traditional histopathological classification, and parts of it are expected to be adopted by the WHO in the near future. Clinical manifestations depend on the location of the tumor with infratentorial ependymomas presenting with acute hydrocephalus. Gross total resection should be the goal of treatment. The prognostic factors of patients with ependymomas include age, grade, and location of the tumor, with children with intracranial, anaplastic ependymomas having the worst prognosis. In general, the 5-year overall survival of patients with ependymomas is around 60-70%.

Brain and Spinal Cord Tumors of Embryonic Origin.

Embryonal tumors (ETs) of the central nervous system (CNS) comprise a large heterogeneous group of highly malignant tumors that predominantly affect children and adolescents. Currently, the neoplasms classified as ET are the medulloblastoma (MB), embryonal tumors with multilayered rosettes (ETMR), medulloepithelioma (ME), CNS neuroblastoma (NB), CNS ganglioneuroblastoma (GNB), atypical teratoid/rhabdoid tumors (AT/RT), and CNS embryonal tumors with rhabdoid features. All these tumors are classified as malignant-grade IV neoplasms, and the prognosis of patients with these neoplasms is very poor. Currently, except for the histological classification of MB, the recently utilized WHO classification accepts a novel molecular classification of MBs into four distinct molecular subgroups: wingless/integrated (WNT)-activated, sonic hedgehog (Shh), and the numerical Group3 and Group 4. The combination of both histological and genetic classifications has substantial prognostic significance, and patients are categorized as low risk with over 90% survival, the standard risk with 75-90% survival, high risk with 50-75% survival, and very high risk with survival rate lower than 50%. Children under three years are predominantly affected by AT/RT and represent about 20% of all CNS tumors in this age group. AT/RT is typically located in the posterior fossa (mainly in cerebellopontine angle) in 50-60% of the cases. The pathogenesis of this neoplasm is strongly associated with loss of function of the SMARCB1 (INI1, hSNF5) gene located at the 22q11.23 chromosome, or very rarely with alterations in (SMARCA4) BRG1 gene. The cells of this neoplasm resemble those of other neuronal tumors, and hence, immunochemistry markers have been utilized, such as smooth muscle actin, epithelial membrane antigen, vimentin, and lately antibodies for INI1. ETMRs are characterized by the presence of ependymoblastic rosettes formed by undifferentiated neuroepithelial cells and neuropil. The tumorigenesis of ETMRs is strongly related to the amplification of the pluripotency factor Chr19q13.41 miRNA cluster (C19MC) present in around 90% of the cases. Additionally, the expression of LIN28A is a highly sensitive and specific marker of ETMR diagnosis, as it is overexpressed in almost all cases of ETMR and is related to poor patient outcomes. The treatment of patients with ETs includes a combination of surgical resection, radiotherapy (focal or craniospinal), and chemotherapeutic agents. Currently, there is a trend to reduce the dose of craniospinal irradiation in the treatment of low-risk MBs. Novel targeted therapies are expected in the treatment of patients with MBs due to the identification of the main driver genes. Survival rates vary between ET types and their subtypes, with ganglioneuroblastoma having over 95% 5-year survival rate, while ATRT is probably linked with the worst prognosis with a 30% 5-year survival rate.

Assessment of Gliomas' Grade of Malignancy and Extent of Resection Using Intraoperative Flow Cytometry.

BACKGROUND: Intraoperative Flow Cytometry (iFC) is a novel technique for the assessment of the grade of malignancy and the diagnosis of tumor type and resection margins during solid tumor surgery. Herein, we set out to analyze the role of iFC in the grading of gliomas and the evaluation of resection margins. MATERIAL AND METHODS: iFC uses a fast cell cycle analysis protocol (Ioannina Protocol) that permits the analysis of tissue samples within 5-6 min. Cell cycle analysis evaluated the G0/G1 phase, S-phase, mitosis, and tumor index (S + mitosis phase fraction) and ploidy status. In the current study, we evaluated tumor samples and samples from the peripheral borders from patients with gliomas who underwent surgery over an 8-year period. RESULTS: Eighty-one patients were included in the study. There were sixty-eight glioblastoma cases, five anaplastic astrocytomas, two anaplastic oligodendrogliomas, one pilocytic astrocytoma, three oligodendrogliomas and two diffuse astrocytomas. High-grade gliomas had a significantly higher tumor index than low grade gliomas (median value 22 vs. 7.5, respectively, p = 0.002). Using ROC curve analysis, a cut-off value of 17% in the tumor index could differentiate low- from high-grade gliomas with a 61.4% sensitivity and 100% specificity. All low-grade gliomas were diploid. From the high-grade gliomas, 22 tumors were aneuploid. In glioblastomas, aneuploid tumors had a significantly higher tumor index (p = 0.0018). Twenty-three samples from glioma margins were evaluated. iFC verified the presence of malignant tissue in every case, using histology as the gold standard. CONCLUSION: iFC constitutes a promising intraoperative technique for glioma grading and resection margin assessment. Comparative studies with additional intraoperative adjuncts are necessary.

Meningioma grading based on positron emission tomography: A systematic review and meta-analysis.

Introduction: Meningiomas are the most common central nervous system tumor in adults. Knowledge of the tumor grade can guide optimal treatment timing and shape personalized follow-up strategies. Positron emission tomography (PET) has been utilized for the metabolic assessment of various intracranial space-occupying lesions. Herewith, we set out to evaluate the diagnostic accuracy of PET for the noninvasive assessment of meningioma's grade. Materials and methods: The Medline, Scopus and Cochrane databases were systematically searched in March 2022 for studies that evaluated the sensitivity and specificity of PET compared to the gold standard of histological diagnosis in the grading of meningiomas. Summary statistics will be calculated and scatter plots, summary curve from the HSROC model and posterior predictions by empirical Bayes estimates will be presented. Results: Five studies consisting of 242 patients with a total of 196 low-grade (Grade 1) and 46 high grade (Grade 2/3) meningiomas were included in our analysis. Three of the included studies used 18F-FDG, one study used 18F-FLT and one used(Whiting et al., 2011) 18 F-FET as PET tracers. The pooled sensitivity was 76% (95% CI: 52%-91%) and the pooled specificity was 89% (95% CI: 83%-93%). The diagnostic odds ratio was 27.17 (95% CI: 9.22-80.06), the positive likelihood ratio was 7.18 (95% CI: 4.54-11.34) and the negative likelihood ratio was 0.26 (95% CI: 0.11-0.61). Conclusion: PET is a promising and viable option as a noninvasive imaging tool to differentiate the meningioma grades. However, currently it cannot overtake the gold standard of histological grade confirmation. More studies are required for further validation and refinement of this imaging technique and assessment of other radiotracers as well.

Stereotactic radiosurgery versus whole-brain radiotherapy after resection of solitary brain metastasis: A systematic review and meta-analysis.

Objective: The standard of care in patients with solitary brain metastasis involves surgical resection and postoperative whole-brain radiotherapy (WBRT). However, WBRT is associated with adverse effects, mainly neurocognitive deterioration. Stereotactic radiosurgery (SRS) is a more targeted form of radiation therapy that could be as effective as WBRT without the detrimental neurocognitive decline. Methods: We performed the first systematic review and meta-analysis comparing postoperative SRS versus postoperative WBRT in patients with one resected brain metastasis. PubMed, Scopus, and Cochrane library were systematically searched for studies comparing the efficacy of the two radiation modalities in terms of local and distant brain control, leptomeningeal disease control, and overall survival. Additionally, we extracted patients' neurocognitive function and quality of life after each postoperative radiation form. Results: Four studies with 248 patients (128: WBRT, 120: SRS) were included in our analysis. There was no difference between SRS and WBRT in the risk of local recurrence (RR = 0.92, CI = 0.51-1.66, p = 0.78, I2 = 0%) and leptomeningeal disease (RR = 1.21, CI = 0.49-2.98, p = 0.67, I2 = 18%), neither in the patients' overall survival (HR = 1.06, CI = 0.61-1.85, p = 0.83, I2 = 63%). Nevertheless, SRS appeared to increase the risk of distant brain failure (RR = 2.03, CI = 0.94-4.40, p = 0.07, I2 = 61%). Neurocognitive function and quality of life in the SRS group were equal or superior to the WBRT group. Conclusions: Although SRS may increase the risk of distant brain failure, it appears to be as effective as WBRT in terms of local control, risk of leptomeningeal disease, and overall survival while sparing the patients of the detrimental, WBRT-associated cognitive deterioration.

Therapeutic Potential of Linearol in Combination with Radiotherapy for the Treatment of Glioblastoma In Vitro.

Glioblastoma is one of the most malignant and lethal forms of primary brain tumors in adults. Linearol, a kaurane diterpene isolated from different medicinal plants, including those of the genus Sideritis, has been found to possess significant anti-oxidant, anti-inflammatory and anti-microbial properties. In this study, we aimed to determine whether linearol could exhibit anti-glioma effects when given alone or in combination with radiotherapy in two human glioma cell lines, U87 and T98. Cell viability was examined with the Trypan Blue Exclusion assay, cell cycle distribution was tested with flow cytometry, and the synergistic effects of the combination treatment were analyzed with CompuSyn software. Linearol significantly suppressed cell proliferation and blocked cell cycle at the S phase. Furthermore, pretreatment of T98 cells with increasing linearol concentrations before exposure to 2 Gy irradiation decreased cell viability to a higher extent than linearol or radiation treatment alone, whereas in the U87 cells, an antagonistic relationship was observed between radiation and linearol. Moreover, linearol inhibited cell migration in both tested cell lines. Our results demonstrate for the first time that linearol is a promising anti-glioma agent and further studies are needed to fully understand the underlying mechanism of this effect.

Intraoperative Flow Cytometry for the Evaluation of Meningioma Grade.

Meningiomas are the most frequent central nervous system tumors in adults. The majority of these tumors are benign. Nevertheless, the intraoperative identification of meningioma grade is important for modifying surgical strategy in order to reduce postoperative complications. Here, we set out to investigate the role of intraoperative flow cytometry for the differentiation of low-grade (grade 1) from high-grade (grade 2-3) meningiomas. The study included 59 patients. Intraoperative flow cytometry analysis was performed using the 'Ioannina Protocol' which evaluates the G0/G1 phase, S-phase, mitosis and tumor index (S + mitosis phase fraction) of a tumor sample. The results are available within 5 min of sample receipt. There were 41 grade 1, 15 grade 2 and 3 grade 3 meningiomas. High-grade meningiomas had significantly higher S-phase fraction, mitosis fraction and tumor index compared to low-grade meningiomas. High-grade meningiomas had significantly lower G0/G1 phase fraction compared to low-grade meningiomas. Thirty-eight tumors were diploids and twenty-one were aneuploids. No significant difference was found between ploidy status and meningioma grade. ROC analysis indicated 11.4% of tumor index as the optimal cutoff value thresholding the discrimination between low- and high-grade meningiomas with 90.2% sensitivity and 72.2% specificity. In conclusion, intraoperative flow cytometry permits the detection of high-grade meningiomas within 5 min. Thus, surgeons may modify tumor removal strategy.

Radiological assessment and surgical management of cervical spine involvement in patients with rheumatoid arthritis.

The purpose of the present systematic review was to describe the diagnostic evaluation of rheumatoid arthritis in the cervical spine to provide a better understanding of the indications and options of surgical intervention. We performed a literature review of Pub-med, Embase, and Scopus database. Upon implementing specific inclusion and exclusion criteria, all eligible articles were identified. A total of 1878 patients with Rheumatoid Arthritis (RA) were evaluated for cervical spine involvement with plain radiographs. Atlantoaxial subluxation (AAS) ranged from 16.4 to 95.7% in plain radiographs while sub-axial subluxation ranged from 10 to 43.6% of cases. Anterior atlantodental interval (AADI) was found to between 2.5 mm and 4.61 mm in neutral and flexion position respectively, while Posterior Atlantodental Interval (PADI) was between 20.4 and 24.92 mm. 660 patients with RA had undergone an MRI. A pannus diagnosis ranged from 13.33 to 85.36% while spinal cord compression was reported in 0-13% of cases. When it comes to surgical outcomes, Atlanto-axial joint (AAJ) fusion success rates ranged from 45.16 to 100% of cases. Furthermore, the incidence of postoperative subluxation ranged from 0 to 77.7%. With regards to AADI it is evident that its value decreased in all studies. Furthermore, an improvement in Ranawat classification was variable between studies with a report improvement frequency by at least one class ranging from 0 to 54.5%. In conclusion, through careful radiographic and clinical evaluation, cervical spine involvement in patients with RA can be detected. Surgery is a valuable option for these patients and can lead to improvement in their symptoms.

Surgical oncology during the post-COVID-19 era: What is next?

During first outburst of COVID-19, several strategies had been applied for surgical oncology patients to minimize COVID-19 transmission. COVID-19 infection seemed to compromise survival and major complication rates of surgical oncology patients. However, survival, tumor progression and recurrence rates of surgical oncology patients were associated to the consequences of COVID-19 pandemic on their management. In addition, the severity of COVID-19 infections has been downgraded. Therefore, management of surgical oncology patients should be reconsidered.

Siderol Inhibits Proliferation of Glioblastoma Cells and Acts Synergistically with Temozolomide.

Glioblastoma (GBM) is the most aggressive primary central nervous system (CNS) tumor in adults with dismal prognosis. Currently, the therapeutic interventions include gross total resection, when possible, followed by radiotherapy and chemotherapy. However, despite treatment, tumor usually recurs within 7-9 months. The presence of glioma cells with stem-like properties and tumor's heterogeneity have been identified as the most important factors driving recurrence. Recently, research efforts have been focused on the use of natural substances as treatment for GBM. Siderol is an ent-kaurane diterpenoid, isolated from the genus Sideritis. Sideritis extracts have already been investigated for their anti-inflammatory, antioxidant, and anticancer effects. In this study, we investigated the antitumoral effects of siderol in GBM T98 and U87 cell lines, as well as the effects of combined treatment with temozolomide (TMZ). Cell viability was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. Different concentrations of siderol were used in order to calculate the IC50 values at 72 h after treatment. Flow cytometry used for the DNA cell cycle analysis after treatment with siderol in concentrations of IC50 and twice the IC50 values for 72 h. Furthermore, the effect of siderol in cell's migratory ability was tested using wound healing assay. Cell viability and proliferation, after combined treatment with siderol and TMZ, also were evaluated with the trypan blue exclusion assay and the effects of the combination treatment were analyzed with CompuSyn software. Treatment with siderol significantly reduced cell viability in T98 and U87 cell lines in a dose-dependent manner and IC50 values were calculated, 18 µM and 13 µM, respectively. Moreover, siderol induced G0/G1 cell cycle arrest in a dose-dependent manner and inhibited the migration in both cell lines. In addition, siderol and TMZ seem to have synergistic action in the majority of tested concentrations in both T98 and U87 cells. In conclusion, siderol may represent an innovative strategy for the treatment of GBM, and further studies are needed on siderol's efficacy and mode of action.

Accurate Characterization of Bladder Cancer Cells with Intraoperative Flow Cytometry.

Bladder cancer represents a major health issue. Transurethral resection is the first line treatment and an accurate assessment of tumor margins might warrant complete tumor removal. Genomic instability and proliferative potential are common hallmarks of cancer cells. We have previously demonstrated the utility of intraoperative flow cytometry (iFC), a next-generation margin evaluation methodology for assessment of DNA content, in the detection of several types of malignancy. In the current study we investigated the possible value of iFC in the characterization of bladder cancer during surgery. Samples from a population of 52 people with urothelial cancer were included in the study. The total time for iFC evaluation is 3-5 min per sample and included a two-step analysis, including DNA-index and Tumor-index calculation. First, DNA-index calculation revealed 24 hyperploid and one hypoploid tumor. Second, cell cycle analysis and Tumor-index calculation revealed that tumor samples are distinguished from normal cells based on their significantly higher proliferative potential. The standard for iFC evaluation was pathology assessment and revealed that our protocol exhibits an accuracy of 98% in defining the presence of cancer cells in a given sample. Our results support the further assessment of iFC value towards its use as a novel malignancy evaluation tool in transurethral resections.