Effect of Platform Type on Clinical Efficacy of SARS-CoV-2 Vaccines in Prime Vaccination Settings: A Systematic Review and Meta-Regression of Randomized Controlled Trials.

This systematic review investigated the association between platform type and the clinical efficacy of SARS-CoV-2 vaccines using the meta-regression of randomized controlled trials to compare the rates of the first appearance of symptomatic COVID-19 on the platforms. The trial search was conducted using PubMed, ClinicalTrials.gov, and the EU Clinical Trials Register. The main selection criteria included: non-active control, immunocompetent individuals without previous vaccination, and a low risk of bias. The platform effect was summarized with an incidence rate ratio (IRR) and a 95% confidence interval for every platform category against the reference. IRR was obtained by random-effect meta-regression with adjustment for confounding by effect modifiers. The analysis was conducted in per-protocol (PP) and modified intention-to-treat (mITT) sets. Six vaccine types with 35 trials were included. Vector vaccines were a reference category. In the PP set, rates of symptomatic COVID-19 on mRNA and protein subunit vaccines were significantly lower than on the vector: IRR = 0.30 [0.19; 0.46], p = 0.001 and 0.63 [0.46; 0.86], p = 0.012, respectively. There was no difference for inactivated and virus-like particle vaccines compared to the vector: IRR = 0.98 [0.71; 1.36], p = 0.913 and 0.70 [0.41; 1.20], p = 0.197, respectively. The rate of cases on DNA vaccines was significantly higher than that on the vector: IRR = 2.58 [1.17; 5.68], p = 0.034. Results for the mITT set were consistent. Platform type is an effect modifier of the clinical efficacy of SARS-CoV-2 vaccines.

Optical Differentiation of Brain Tumors Based on Raman Spectroscopy and Cluster Analysis Methods.

In the present study, various combinations of dimensionality reduction methods with data clustering methods for the analysis of biopsy samples of intracranial tumors were investigated. Fresh biopsies of intracranial tumors were studied in the Laboratory of Neurosurgical Anatomy and Preservation of Biological Materials of N.N. Burdenko Neurosurgery Medical Center no later than 4 h after surgery. The spectra of Protoporphyrin IX (Pp IX) fluorescence, diffuse reflectance (DR) and Raman scattering (RS) of biopsy samples were recorded. Diffuse reflectance studies were carried out using a white light source in the visible region. Raman scattering spectra were obtained using a 785 nm laser. Patients diagnosed with meningioma, glioblastoma, oligodendroglioma, and astrocytoma were studied. We used the cluster analysis method to detect natural clusters in the data sample presented in the feature space formed based on the spectrum analysis. For data analysis, four clustering algorithms with eight dimensionality reduction algorithms were considered.

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

(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.

Meningeosis Neoplastica in Patients with Glioblastoma: Analysis of 36 Cases.

BACKGROUND: Meningeosis neoplastica is a rare manifestation of high-grade gliomas and is usually associated with a devastating outcome. The aim of this bicenter series was to investigate the clinical course and outcome of patients with meningiosis neoplastica. METHODS: This case series included patients in whom surgery was performed for World Health Organization grade IV primary and secondary glioblastoma (GBM) at the University Medical Center Göttingen, Göttingen, Germany between 2009 and 2021 and Burdenko Institute of Neurosurgery, Moscow, Russia between 2012 and 2018. Inclusion criteria were manifestation of clinical and neuroradiologic signs of leptomeningeal, ependymal, or spinal dissemination of GBM at various time points during the course of the disease. RESULTS: Meningeosis neoplastica was found in 36 patients. Nine patients developed spinal metastases and 12 ependymal dissemination and 15 patients had a leptomeningeal manifestation of high-grade glioma. The median age of patients at first diagnosis of primary tumor was 56 years. Typical symptoms were headache, nausea, vomiting, and acute paraplegia. The median overall survival was 11 months and progression-free survival was 8 months. Meningeosis neoplastica developed a median 2 months after the initial tumor diagnosis. Salvage therapies included ventriculoperitoneal shunting, decompression of spinal metastases, and spinal radiation therapy. The median time between meningeosis manifestation and death was 3 months. CONCLUSIONS: Meningeosis neoplastica is a rare manifestation of GBM. It has a poor prognosis. The overall survival after the manifestation of meningeosis was barely longer than 3 months. Salvage therapies did not improve the outcome in our patient cohort.

5-ALA-guided tumor resection during awake speech mapping in gliomas located in eloquent speech areas: Single-center experience.

Background: Achieving maximal functionally safe resection of gliomas located within the eloquent speech areas is challenging, and there is a lack of literature on the combined use of 5-aminolevulinic acid (5-ALA) guidance and awake craniotomy. Objective: The aim of this study was to describe our experience with the simultaneous use of 5-ALA fluorescence and awake speech mapping in patients with left frontal gliomas located within the vicinity of eloquent speech areas. Materials and methods: A prospectively collected database of patients was reviewed. 5-ALA was administered at a dose of 20 mg/kg 2 h prior to operation, and an operating microscope in BLUE400 mode was used to visualize fluorescence. All patients underwent surgery using the "asleep-awake-asleep" protocol with monopolar and bipolar electrical stimulation to identify the proximity of eloquent cortex and white matter tracts and to guide safe limits of resection along with fluorescence guidance. Speech function was assessed by a trained neuropsychologist before, during, and after surgery. Results: In 28 patients operated with cortical mapping and 5-ALA guidance (12 Grade 4, 6 Grade 3, and 10 Grade 2 gliomas), Broca's area was identified in 23 cases and Wernicke's area was identified in 5 cases. Fluorescence was present in 14 cases. Six tumors had residual fluorescence due to the positive speech mapping in the tumor bed. Transient aphasia developed in 14 patients, and permanent aphasia developed in 4 patients. In 6 patients operated with cortical and subcortical speech mapping and 5-ALA guidance (4 Grade 4, 1 Grade 3, and 1 Grade 2 gliomas), cortical speech areas were mapped in 5 patients and subcortical tracts were encountered in all cases. In all cases, resection was stopped despite the presence of residual fluorescence due to speech mapping findings. Transient aphasia developed in 6 patients and permanent aphasia developed in 4 patients. In patients with Grade 2-3 gliomas, targeted biopsy of focal fluorescence areas led to upgrading the grade and thus more accurate diagnosis. Conclusion: 5-ALA guidance during awake speech mapping is useful in augmenting the extent of resection for infiltrative high-grade gliomas and identifying foci of anaplasia in non-enhancing gliomas, while maintaining safe limits of functional resection based on speech mapping. Positive 5-ALA fluorescence in diffuse Grade 2 gliomas may be predictive of a more aggressive disease course.

Differentiation of glioblastoma tissues using spontaneous Raman scattering with dimensionality reduction and data classification.

The neurosurgery of intracranial tumors is often complicated by the difficulty of distinguishing tumor center, infiltration area, and normal tissue. The current standard for intraoperative navigation is fluorescent diagnostics with a fluorescent agent. This approach can be further enhanced by measuring the Raman spectrum of the tissue, which would provide additional information on its composition even in the absence of fluorescence. However, for the Raman spectra to be immediately helpful for a neurosurgeon, they must be additionally processed. In this work, we analyzed the Raman spectra of human brain glioblastoma multiforme tissue samples obtained during the surgery and investigated several approaches to dimensionality reduction and data classificatin to distinguish different types of tissues. In our study two approaches to Raman spectra dimensionality reduction were approbated and as a result we formulated new technique combining both of them: feature filtering based on the selection of those shifts which correspond to the biochemical components providing the statistically significant differences between groups of examined tissues (center of glioblastoma multiforme, tissues from infiltration area and normally appeared white matter) and principal component analysis. We applied the support vector machine to classify tissues after dimensionality reduction of registered Raman spectra. The accuracy of the classification of malignant tissues (tumor edge and center) and normal ones using the principal component analysis alone was 83% with sensitivity of 96% and specificity of 44%. With a combined technique of dimensionality reduction we obtained 83% accuracy with 77% sensitivity and 92% specificity of tumor tissues classification.

The Role of 3D-pCASL MRI in the Differential Diagnosis of Glioblastoma and Brain Metastases.

Purpose: The first aim of this study was to compare the intratumoral and peritumoral blood flow parameters in glioblastomas and brain metastases measured by pseudocontinuous arterial spin labeling MRI (3D pCASL). The second aim of this study was to determine whether pCASL could aid in identifying the source of brain metastases. Materials and Methods: This study included 173 patients aged 12 to 83 years (median age-61 years), who were observed at the National Medical Research Center for Neurosurgery. All patients underwent preoperative MRI with pCASL perfusion. Thereafter patients were operated on and received histological diagnosis. No patients received preoperative chemo or radiotherapy. Results: The values of maximum and normalized intratumoral blood flow were significantly higher in the group with gliblastoma than in the group with brain metastases: 168.98 + -91.96 versus 152.1 + -173.32 and 7.6 + -8.4 versus 9.3 + -5.33 respectively (p <0.01). However, ROC analysis showed low AUC specificity and sensitivity (0.64, 70%, 60% for mTBF and 0.66, 77%, 62% for nTBF). Peritumoral blood flow parameters were also higher in the glioblastoma group (29.61 + -22.89 versus 16.58 + -6.46 for mTBF and 1.63 + -1.14 versus 0.88 + -0.38 for nTBF, respectively; p <0.01). ROC analysis showed the following measurements of AUC, specificity, and sensitivity (0.75, 68%, 73% for mTBF and 0.77, 58%, 91% for nTBF). Regarding pCASL and various histological subsets of brain metastases, the study found statistically significant differences between the lung and melanoma metastases and the lung and kidney metastases. ROC analysis gave the following values for lung and melanoma metastases: AUC-0.76, specificity-75%, and sensitivity-73% for mTBF; 0.83, 67%, and 93% respectively, for nTBF. For lung and kidney metastases: AUC-0.74, specificity-70%, and sensitivity-93% for mTBF; 0.75, 70%, and 93% respectively, for nTBF. Conclusions: pCASL could aid in differential diagnosis between glioblastoma and brain metastases. Measurement of peritumoral blood flow demonstrates higher specificity and sensitivity than with intratumoral blood flow. Moreover, pCASL provides the ability to distinguish lung metastases from kidney and melanoma metastases.

Prediction of Intraoperative Fluorescence of Brain Gliomas: Correlation between Tumor Blood Flow and the Fluorescence.

INTRODUCTION: The prediction of the fluorescent effect of 5-aminolevulinic acid (5-ALA) in patients with diffuse gliomas can improve the selection of patients. The degree of enhancement of gliomas has been reported to predict 5-ALA fluorescence, while, at the same time, rarer cases of fluorescence have been described in non-enhancing gliomas. Perfusion studies, in particular arterial spin labeling perfusion, have demonstrated high efficiency in determining the degree of malignancy of brain gliomas and may be better for predicting fluorescence than contrast enhancement. The aim of the study was to investigate the relationship between tumor blood flow, measured by ASL, and intraoperative fluorescent glow of gliomas of different grades. MATERIALS AND METHODS: Tumoral blood flow was assessed in 75 patients by pCASL (pseudo-continuous arterial spin labeling) within 1 week prior to surgery. In all cases of tumor removal, 5-ALA had been administered preoperatively. Maximum values of tumoral blood flow (TBF max) were measured, and normalized tumor blood flow (nTBF) was calculated. RESULTS: A total of 76% of patients had significant contrast enhancement, while 24% were non-enhancing. The histopathology revealed 17 WHO grade II gliomas, 12 WHO grade III gliomas and 46 glioblastomas. Overall, there was a relationship between the degree of intraoperative tumor fluorescence and ASL-TBF (Rs = 0.28, p = 0.02 or the TBF; Rs = 0.34, p = 0.003 for nTBF). Non-enhancing gliomas were fluorescent in 9/18 patients, with nTBF in fluorescent gliomas being 54.58 ± 32.34 mL/100 mg/s and in non-fluorescent gliomas being 52.99 ± 53.61 mL/100 g/s (p > 0.05). Enhancing gliomas were fluorescent in 53/57 patients, with nTBF being 170.17 ± 107.65 mL/100 g/s in fluorescent and 165.52 ± 141.71 in non-fluorescent gliomas (p > 0.05). CONCLUSION: Tumoral blood flow levels measured by non-contrast ASL perfusion method predict the fluorescence by 5-ALA; however, the additional value beyond contrast enhancement is not clear. ASL is, however, useful in cases with contraindication to contrast.

Fluorescence Diagnosis in Neurooncology: Retrospective Analysis of 653 Cases.

Objective: This study is to analyze fluorescence sensitivity in the diagnosis of brain and spinal cord tumors. Material and methods: The authors conducted a multicenter retrospective analysis of data on 653 cases in 641 patients: 553 of them had brain tumors and 88 spinal cord tumors. Brain tumor resection was performed in 523 patients, of whom 484 were adults and 39 children. The analyzed series was presented by 320 gliomas, 101 meningiomas, and 72 metastases. A stereotactic biopsy was performed in 20 patients and endoscopic surgery in 10 patients. In all cases, 20 mg/kg of 5-Aminolaevulinic acid was administered orally 2-h before surgery. All surgical interventions were performed with a microscope BLUE 400 to visualize fluorescence, while endoscopic surgery-with an endoscope equipped with a fluorescent module. Fluorescence spectroscopy was conducted in 20 cases of stereotactic biopsies and in 88 cases of spinal cord tumors. Results: Among adult brain tumors operated by microsurgical techniques, meningiomas showed the highest 5-ALA fluorescence sensitivity 94% (n = 95/101), brain metastases 84.7% (n = 61/72), low-grade gliomas 46.4% (n = 26/56), and high-grade gliomas 90.2% (n = 238/264). In children the highest 5-ALA visible fluorescence was observed in anaplastic astrocytomas 100% (n = 4/4) and in anaplastic ependymomas 100% (n = 4/4); in low-grade gliomas it made up 31.8% (n = 7/22). As for the spinal cord tumors in adults, the highest sensitivity was demonstrated by glioblastomas 100% (n = 4/4) and by meningiomas 100% (n = 4/4); Fluorescence was not found in gemangioblastomas (n = 0/6) and neurinomas (n = 0/4). Fluorescence intensity reached 60% (n = 6/10) in endoscopic surgery and 90% (n = 18/20) in stereotactic biopsy. Conclusion: 5-ALA fluorescence diagnosis proved to be most sensitive in surgery of HGG and meningioma (90.2 and 94.1%, respectively). Sensitivity in surgery of intracranial metastases and spinal cord tumors was slightly lower (84.7 and 63.6%, correspondingly). The lowest fluorescence sensitivity was marked in pediatric tumors and LGG (50 and 46.4%, correspondingly). Fluorescence diagnosis can also be used in transnasal endoscopic surgery of skull base tumors and in stereotactic biopsy.

The Role of 5-ALA in Low-Grade Gliomas and the Influence of Antiepileptic Drugs on Intraoperative Fluorescence.

Objectives: Intraoperative tumor visualization with 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX (PpIX) fluorescence is widely applied for improved resection of high-grade gliomas. However, visible fluorescence is present only in a minority of low-grade gliomas (LGGs) according to current literature. Nowadays, antiepileptic drugs (AEDs) are frequently administered to LGG patients prior to surgery. A recent in-vitro study demonstrated that AEDs result in significant reduction of PpIX synthesis in glioma cells. The aim of this study was thus to investigate the role of 5-ALA fluorescence in LGG surgery and the influence of AEDs on visible fluorescence. Patients and Methods: Patients with resection of a newly diagnosed suspected LGG after 5-ALA (25 mg/kg) administration were initially included. During surgery, the presence of visible fluorescence (none, mild, moderate, or bright) within the tumor and intratumoral fluorescence homogeneity (diffuse or focal) were analyzed. Tissue samples from fluorescing and/or non-fluorescing areas within the tumor and/or the assumed tumor border were collected for histopathological analysis (WHO tumor diagnosis, cell density, and proliferation rate). Only patients with diagnosis of LGG after surgery remained in the final study cohort. In each patient, the potential preoperative intake of AEDs was investigated. Results: Altogether, 27 patients with a histopathologically confirmed LGG (14 diffuse astrocytomas, 6 oligodendrogliomas, 4 pilocytic astrocytomas, 2 gemistocytic astrocytomas, and one desmoplastic infantile ganglioglioma) were finally included. Visible fluorescence was detected in 14 (52%) of 27. In terms of fluorescence homogeneity (n = 14), 7 tumors showed diffuse fluorescence, while in 7 gliomas focal fluorescence was noted. Cell density (p = 0.03) and proliferation rate (p = 0.04) was significantly higher in fluorescence-positive than in fluorescence-negative samples. Furthermore, 15 (56%) of 27 patients were taking AEDs before surgery. Of these, 11 patients (73%) showed no visible fluorescence. In contrast, 10 (83%) of 12 patients without prior AEDs intake showed visible fluorescence. Thus, visible fluorescence was significantly more common in patients without AEDs compared to patients with preoperative AED intake (OR = 0,15 (CI 95% 0.012-1.07), p = 0.046). Conclusions: Our study shows a markedly higher rate of visible fluorescence in a series of LGGs compared to current literature. According to our preliminary data, preoperative intake of AEDs seems to reduce the presence of visible fluorescence in such tumors and should thus be taken into account in the clinical setting.

Preoperative Stereotactic Radiosurgery of Brain Metastases: Preliminary Results.

INTRODUCTION:  Preoperative stereotactic radiosurgery (pre-SRS) is a recent advancement in the strategy for brain metastasis (BM) management, and available data demonstrate the advantages of pre-SRS before postoperative radiation treatment, including lower rates of local toxicity, leptomeningeal progression, and a high percentage of local control. The authors presented the results of pre-SRS in patients with BM. MATERIALS AND METHODS: Nineteen patients with BM (11 female and eight male) have been treated at N.N. Burdenko Medical Research Center for Neurosurgery (Moscow, Russia) and Gamma-Knife Center (Moscow, Russia) using pre-SRS. A total of 22 symptomatic metastatic lesions were preoperatively irradiated in the series. Eight patients had multiple BM (number of metastases ranged between two and seven). The median target volume for combined treatment was 14.131 cc (volumes varied between 2.995 and 57.098 cc; mean - 19.986 cc). The median of the mean target dose was 18 Gy, ranging between 12.58 and 24.36 Gy.  Results: All patients tolerated pre-SRS well, without any neurological deterioration, and surgical treatment was performed as scheduled. The median follow-up period was 6.3 months (ranging between five weeks and 22.9 months). In 17 out of 19 patients, follow-up magnetic resonance (MR) images obtained two or three months after the combined treatment demonstrated the postoperative cavity without any signs of postradiation alterations in the perifocal tissues. In two observations, peritumoral edema was present. Local recurrences were found in two cases, 5.5 and 17.4 months after treatment. Radionecrosis was present in one observation after 4.6 months of follow-up. Two patients died of disease progression and are presented as illustrative cases. CONCLUSION: The combined treatment of secondary brain tumors has proved to be the best treatment option. Preoperative stereotactic radiosurgery may decrease radiation-induced toxicity and rates of local tumor progression. The potential hazards of pre-SRS associated with the postoperative healing of irradiated soft tissues of the head were not confirmed in our study. The decision of pre-SRS should be made by the tumor board, including specialists in neurosurgery, neuro-oncology, and radiation oncology, if the diagnosis of BM is based on oncological history and visualization data.

Hiding in the Shadows: CPOX Expression and 5-ALA Induced Fluorescence in Human Glioma Cells.

Protoporphyrin IX (PpIX) is widely used in photodynamic diagnosis. To date, the details of molecular mechanisms underlying PpIX accumulation in malignant cells after 5-ALA administration remain unclear. The fluorescence of PpIX was studied in human glioma cells. Several cell cultures were established from glioma tumor tissue to study the differences between fluorescence-positive and fluorescence-negative human glioma tumors. The cell cultures demonstrated fluorescence profiles similar to those of source tumor tissues, which allows us to use these cultures in experimental research. Dynamics of the rates of synthesis and degradation of fluorescent protoporphyrin IX was studied in the cultures obtained. In addition, the expression of CPOX, an enzyme involved in PpIX synthesis, was evaluated. mRNA levels of heme biosynthesis enzymes were analyzed, and PpIX fluorescence proved to correlate with the CPOX protein level, whereas no such correlation was observed at the mRNA level. Fluorescence intensity decreased at low levels of the enzyme, which indicates its critical role in PpIX fluorescence. Finally, the fluorescence intensity proved to correlate with the proliferative activity.