TRAIL  and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL–based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies. Several therapeutic strategies are currently subjected to testing with the aim to trigger the antitumor immune responses . TRAIL . MoreoveTRAIL exists in two forms: the membrane-bound TRAIL (mTRAIL) and the soluble TRAIL (sTRAIL). Both forms can be found in different leukocyte subpopulations . The binWithin the cytoplasm, a number of inhibitors are recruited depending on the cellular context. The inhibitors, such as c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 (B-cell lymphoma 2), or DcR1/DcR2 can restrain the caspase activation and lead to the TRAIL-mediated apoptosis resistance, in vitro and in vivo .TRAIL-R agonistic monoclonal antibodies bind specifically to either TRAIL-R1 (DR4) or TRAIL-R2 (DR5) with high affinity. The mechanism of action via TRAIL-R agonistic antibodies has been shown in preclinical models to induce also the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytolysis (CDC) . HoweverWhile different agonistic TRAIL-R1 antibodies have been developed, such as HS101, 4HS, or 4G7, only HGS-ETR1 antibody, also known as mapatumumab, has entered clinical trials in humans and has reached the second phase of clinical testing . MapatumThe efficacy of combination therapies with mapatumumab was assessed throughout various malignancies . Most ofin vitro, tigatuzumab and conatumumab treatment results in vivo were rather disappointing . Currently, an open-label, multicenter, phase I study with a novel recombinant humanized tetravalent antibody targeting TRAIL-R2 is recruiting patients with locally advanced or metastatic solid tumors, including sarcomas (NCT03715933).in vitro . The efficacy and safety of SCB-313, therefore, remains to be determined.SCB-313 is a recombinant fully-human TRAIL-trimer fusion protein administered to patients for the first time at the end of 2019 (NCT04123886). Five clinical trials with SCB-313 are currently recruiting patients with the following indications: malignant ascites, peritoneal carcinomatosis, and malignant pleural effusions  were described to increase the tumor-killing efficiency and were initially divided into two major groups. The first group of molecules allows dual targeting by construction of scFv-TRAIL associated with a tumor-associated antigen, such as epidermal growth factor (EGFR), multidrug resistance protein (MRP3), mesothelin and others . The secIn the case of scFv-PD-L1:TRAIL derivate, the TRAIL-mediated apoptosis is accompanied by a checkpoint inhibition leading to an increased T cell activation . Novel TTo overcome TRAIL resistance, several attempts to conjugate TRAIL with cytotoxic drugs were carried out. So far, a TRAIL conjugate with monomethyl auristatin E (MMAE), the TRAIL-MMAE, was shown to deliver a potent antitumor response in breast carcinoma xenograft animal models . MoreoveRecently, a fusion protein ABBV-621 composed of three TRAIL receptor binding domains and an Fc domain of a human immunoglobulin G (IgG) entered a phase I clinical trial both in monotherapy and in combination therapies (NTC03082209). Multiple study arms evaluated the ABBV-621 efficacy in the treatment of solid or hematological malignancies . The preAnother novel approach with targeted stem cells expressing TRAIL, MSCTRAIL, has been introduced in a study initiated in 2019 (NCT03298763). The results of the second phase are eagerly awaited.in vitro setting (Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of advanced B cell leukaemias and lymphomas . This no setting . In this setting .It has been reported that some cancers are TRAIL-therapy resistant for various reasons . In suchBoth TRAIL agonistic antibodies and recombinant TRAIL have proven good safety profiles and, therefore, can be easily combined with chemotherapy and/or radiotherapy.In cervical cancer cell lines, mapatumumab in combination with irradiation enhanced the cell apoptosis from 51to 83%, compared to mapatumumab alone (NCT01088347). The initial studies indicated that even though some tumors are primary TRAIL-resistant, chemotherapy or radiotherapy may overcome the resistance . This waImmunotherapy, biological therapy, and targeted therapy have significantly improved the OS in various malignancies and were shown to largely affect the tumor microenvironment . Therefoin vivo and to sensitize the tumor to TRAIL-induced apoptosis. For that purpose, sulforaphane, melittin, resveratrol, wogonin, and multiple other components were tested .Researchers highlighted that the activation of the TRAIL apoptotic pathway could be achieved by administering TRAIL therapy together with other agents increasing the expression of TRAIL and/or its receptors DR4 and DR5 . As it ie tested . Six cliin vitro and in vivo studies (TRAIL and its death receptors TRAIL-R1 and TRAIL-R2 trigger the apoptotic cell death in tumor cells without damaging non-malignant cells. This phenomenon has been illustrated in a number of  studies .The mechanism underlying the selective induction of apoptosis in tumor cells has not yet been elucidated, even though the significantly higher expression of TRAIL’s decoy receptors in non-malignant cells may provide some answers .Because the gene encoding protein p53 is often mutated in cancers, TRAIL's ability to activate apoptosis independently of the p53, together with its tumor-selectivity, made TRAIL an attractive therapeutic target . Yet, owIn spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The TRAIL-R’s agonistic antibodies seem to rather elicit a limited agonistic potential, and only a few drugs have entered the phase II clinical trials. The main reason for the clinical failure of the first generation of antibodies was their weak ability to induce the receptor aggregation which is necessary for triggering the downstream apoptotic pathway . Multiva-induced apoptosis in primary TRAIL-resistant tumor cells (The antitumor activity of soluble TRAIL agents was mostly seen in the treatment of NSCLC, where the recombinant protein dulanermin has reached clinical phase III . It is por cells .Therefore, to understand mechanisms that drive the expression of TRAIL-Rs, the extensive analysis of the expression status prior- and post- chemotherapy/targeted therapy/immunotherapy should be conducted.The so-far modest efficacy of the TRAIL-agonistic antibodies and recombinant TRAIL, the therapies could still show unexpected efficacy upon combining with other treatment approaches that promise to condition the cancer cells to the TRAIL-induced apoptosis.


The use of positron emission tomography (PET) imaging in neuro-oncological surgery is an exciting field with thriving perspectives. Increasing evidence exists for amino acid-based PET to facilitate interpretation of imaging findings following therapeutic interventions in patients with glioma and brain metastases. In meningioma patients, radiolabeled somatostatin receptor ligands provide an improved tumor tissue visualization in lesions located in the vicinity of the skull base and differentiate between scar tissue and tumor recurrence. Moreover, they can be applied as an individual treatment option in recurrent atypical and anaplastic meningioma not eligible for further surgery and radiotherapy. With a focus on its clinical application, this review provides an overview of the emerging field of PET imaging in neuro-oncological surgery.O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET). The thematic scope includes surgical resection planning, prognostication, non-invasive prediction of molecular tumor characteristics, depiction of intratumoral heterogeneity, response assessment, differentiation between tumor progression and treatment-related changes, and emerging new tracers. Furthermore, the role of PET using specific somatostatin receptor ligands for the management of patients with meningioma is discussed. Further advances in neuro-oncological imaging can be expected from promising new techniques, such as hybrid PET/MR scanners and the implementation of artificial intelligence methods, such as radiomics.This review provides an overview of current applications and perspectives of PET imaging in neuro-oncological surgery. The past and future of PET imaging in the management of patients with glioma and brain metastases are elucidated with an emphasis on amino acid tracers, such as  In the evolving field of neuro-oncology, the management of both primary and secondary brain tumors can be improved by advanced imaging techniques. While conventional magnetic resonance imaging (MRI) reflects anatomical features, such as size and number of lesions, mass effect, perifocal edema, and contrast enhancement patterns, it cannot define the extent of metabolically active tumor tissue and intratumoral heterogeneity of the respective brain tumor. Both the increasing availability of elaborated tumor genetic analyses, such as next-generation sequencing as well as emerging new treatment options for primary and secondary brain tumors, including refined radiotherapy techniques and immunotherapeutic approaches, have led to a rising necessity of additional metabolic imaging techniques.Positron emission tomography (PET) has proven to be a valuable tool in oncological settings since its propagation in the late 1970s. The basic principle of PET imaging relies on the so-called annihilation coincidence detection: while an intravenously injected isotope passes through the tissue, it emits positrons, annihilating with electrons; the reaction leading to a simultaneous emission of two photons heading in exactly opposite directions. A ring of detectors around the patient registers this reaction, respectively a projection of the line between the two photons. The resulting data of several projections from various coincidence lines are then reconstructed into three-dimensional images . The maj18F]fluoro-2-deoxy-D-glucose (18F-FDG). However, it has only limited clinical value in neuro-oncology due to the poor contrast between neoplastic and normal brain tissue. In contrast to 18F-FDG uptake, protein metabolism is clearly elevated in brain tumor cells compared to healthy brain tissue, making radiolabeled amino acids, such as [11C]-methyl-L-methionine (11C-MET), O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET), 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA), or 18F-fluciclovine (18F-FACBC) important targets for brain tumor imaging DOTA-Tyr3-octreotide (68Ga-DOTATOC) and [68Ga]DOTA-D-Phe1-Tyr-3-octreotide (68Ga-DOTATATE), targeting somatostatin receptors are increasingly gaining importance in the management of recurrent or surgically poorly accessible tumors, both for the diagnostic and therapeutic use [In patients with meningioma, chelator-based tracers, such as [utic use .This review provides an overview of the current literature for using PET imaging in neuro-oncological neurosurgery. The first part focuses on using PET in patients with glioma and brain metastases, and the second part deals with applying PET in patients with meningioma.18F-FET uptake was shown to be more sensitive to detect tumor tissue than intraoperative 5-ALA [18F-FET PET volume was associated with the overall survival [Resection planning in glioma surgery involves two main goals: achieving maximal tumor removal while preserving functional tissue. Whereas advanced MRI techniques, such as diffusion tensor imaging and functional MRI (fMRI), allow for the evaluation of structural and functional connectivity in eloquent regions due to the infiltrative nature of glioma growth, the delineation of non-enhancing glioma tissue in areas with signal hyperintensity in T2-weighted MR images may be difficult based on conventional MRI alone. Visualization of areas with tumor infiltration using 5-aminolevulinic acid (5-ALA) is of value for intraoperative decision-making and has been repeatedly shown to increase the extent of resection rates . While msurvival . However18F-FET PET has been shown to detect aggressive tumor sub-volumes, and dynamic 18F-FET uptake parameters calculated from time–activity curves have shown to be an independent biomarker for clinical outcome [In eloquently localized tumors without clear contrast enhancement and not eligible for complete resection, identifying the most malignant tumor parts representing intratumoral heterogeneity is essential for the planning of the surgical procedure . Here, P outcome ,21,22.IDH mutation and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, have shown a homogeneous distribution within glial tumors [IDH mutant gliomas seem not only to evolve in less eloquent brain regions, but the affected patients also may have a greater benefit from maximal tumor resection [Furthermore, the refinement of molecular sequencing techniques has, not only since the revision of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) in 2016, prompted increasing research interest in metabolic and genetic properties in brain tumors . In partl tumors . Thus, tl tumors . WHO graesection . This apIDH wild-type status in patients with newly diagnosed WHO II-IV glioma using dynamic 18F-FET PET data [18F-FET PET/MRI radiomics study in glioma patients identified an IDH mutation with an accuracy of 93% when combining static, dynamic, and textural 18F-FET PET data [18F-FET PET analysis have additionally shown to be an independent predictor for overall survival in patients with astrocytic IDH mutant glioma, but not in oligodendrogliomas or IDH wild-type gliomas [IDH wild-type glioma [18F-FET PET for distinct tumor subgroups must be re-evaluated in further studies.It has been reported that parameters obtained from dynamic AA-PET acquisition are of clinical value for predicting molecular markers and the estimation of prognosis in patients with newly diagnosed glioma. A recent study identified a positive predictive value of 87% for the prediction of an PET data . SimilarPET data . Paramet gliomas . Subseque glioma . NeverthThe calculation of biological tumor volume (BTV) in PET images, especially the uptake volume of radiolabeled amino acids, also seems to be of clinical value. Several studies have suggested that in most patients with newly diagnosed glioma, the BTV is considerably larger than the contrast-enhancing volume on MRI, which is valuable for neurosurgical resection planning .18F-FET PET-based target volume definition compared to conventional MRI before re-irradiation of patients with glioblastoma relapse is currently evaluated within the NOA-10/GLIAA trial [Furthermore, another study highlighted the prognostic value of the BTV after resection in newly diagnosed glioblastoma patients . SeveralAA trial .18F-FET PET for response assessment has provided a more accurate evaluation of metabolic response or failure to alkylating chemotherapy, allowing for a timely adjustment of treatment. Furthermore, both decrease in metabolically active tumor volume and absolute tracer uptake, as well as a combination of both values, were predictive for a prolonged progression-free survival [Additionally, BTVs calculated from AA-PET seem to be of value for the assessment of response to temozolomide chemoradiation and maintenance temozolomide chemotherapy in glioblastoma patients and in patients with predominantly non-enhancing WHO grade II glioma undergoing alkylating chemotherapy ,37,38. F18F-FDG PET (21%). Nevertheless, it should be considered that its sensitivity in lesions smaller than 1 cm in diameter is diminished due to the lower spatial resolution of PET scanners [The incidence of brain metastases occurring in approximately up to 20% of cancer patients is supposed to increase due to improved systemic treatment options and monitoring in patients with extracranial tumors. Apart from local treatment options, including microsurgery, external beam radiotherapy, and radiosurgery, there is increasing evidence for the efficacy of systemic treatment in brain metastases . Due to scanners ,43. Furt18F-FET uptake improved the diagnostic performance [With increasing incidence and availability of treatment strategies, including the heightened use of radiosurgical techniques, the differentiation between treatment-related changes, such as radionecrosis and brain metastases relapse, remains still challenging. However, this differentiation based on structural imaging alone is limited due to its low specificity for neoplastic tissue . Severalformance ,45,48.18F-FET PET radiomics features was slightly higher (83%). Notably, the best discriminative power with an accuracy of 89% was achieved when the information of both modalities was combined [It has been demonstrated that radiomics using textural features obtained from metabolic imaging  provides additional diagnostic information. Textural features extracted from MRI alone had a diagnostic accuracy for predicting radiation-induced changes versus tumor recurrence in previously irradiated brain metastases of 81%, while the accuracy of combined .Systemic treatment options based on immunotherapeutic approaches, such as checkpoint inhibitors used in patients with lung cancer or melanoma brain metastases, may impose the problem of treatment-related changes related to inflammation ,50. As a18F-FET can identify checkpoint inhibitor-related pseudoprogression [n = 40) with more than 100 brain metastases secondary to melanoma or non-small cell lung carcinoma treated with checkpoint inhibitors or targeted therapy combined with radiosurgery reported that 18F-FET PET provides important diagnostic information in terms of response assessment [18F-FET PET had a significantly longer progression-free survival in contrast to response determination based on contrast-enhanced MRI.An initial pilot study in patients with melanoma brain metastases treated with ipilimumab suggested that amino acid PET using gression . A subsegression . A recensessment . Moreove18F-FLT. The principle of 18F-FLT is based on phosphorylation of the fluorinated thymidine analog by the enzyme thymidine kinase 1 (TK1) and its consecutive entrapment within the tumor cell [18F-FLT uptake within the cell reflects an increased TK1 activity. A pilot study assessing the role of 18F-FLT PET imaging for treatment response assessment in patients with melanoma brain metastases treated with either targeted therapy or immunotherapy has shown a considerable reduction of 18F-FLT uptake in treatment responders compared to only minimal or no changes on the corresponding MR images [Another promising approach for the inclusion of metabolic imaging data for the response evaluation of checkpoint inhibitors and targeted therapies is using PET tracers designed to assess proliferation, such as mor cell ,54. TK1 R images .Meningiomas constitute most primary brain tumors, about 80% being classified as WHO grade I, whereas WHO grade II and III meningioma are less common . If indi3-octreotate (TATE) or the octapeptide octreotide (TOC) and a chelator, e.g., tetraxetane (DOTA), coupled to the short-lived radionuclide gallium (Ga-68) [On the molecular level, meningiomas may express various hormonal receptors for progesterone and estrogen, as well as specific somatostatin receptors (SSTR) ,59. SSTR (Ga-68) . Recentl (Ga-68) .68Ga-DOTATATE PET was able to identify meningioma out of 13 intraorbital symptomatic lesions with both specificity and sensitivity of 100% [Since their development in the 1990s, SSTR agonists have been increasingly used in meningioma imaging . The mai of 100% .68Ga-DOTATATE PET revealing additional tumor tissue is shown in Exact tumor delineation in complex anatomical regions, such as the skull base, is not only crucial for surgical considerations but also of crucial importance for radiotherapy planning. Inclusion of PET imaging for stereotactic radiotherapy planning was not only able to identify infiltrated tissue and provide information beyond bone windowing on CT and contrast enhancement on MRI, but also has led to a preservation of critical areas, such as the pituitary gland and the optic chiasm ,67. An e68Ga-DOTATATE PET was able to differentiate between scar tissue and vital remnants or tumor recurrence with a specificity of 74% and a sensitivity of 90%, outperforming contrast-enhanced MRI [68Ga-DOTATATE PET for differentiation between tumor progression and treatment-related changes was even higher in these lesions with a specificity of 100% and a sensitivity of 97% [Following treatment, nced MRI . Interesy of 97% . A receny of 97% .Predominantly in patients with recurrent atypical and anaplastic meningioma not eligible for further surgical or radiotherapeutic interventions, the exchange of the radiolabeled isotope gallium-68 to lutetium-177 or yttrium-90 allows for peptide receptor-based radionuclide therapy (PRRT) . SimilarMagnetic resonance imaging, being widely accessibleand easy to interpret due to standardized protocols and assessment criteria, still remains the method of choice in neuro-oncology imaging. However, increasing evidence exists for amino acid-based PET to facilitate interpretation of imaging findings following therapeutic interventions in patients with glioma and brain metastases. In meningioma patients, radiolabeled somatostatin receptor ligands provide an improved tumor tissue visualization in lesions located in the vicinity of the skull base as well as for differentiation between scar tissue and tumor recurrence. Moreover, they can be applied as an individual treatment option in recurrent atypical and anaplastic meningioma not eligible for further surgery and radiotherapy. Further advances in neuro-oncological imaging can be expected from promising newer techniques, such as a combination of PET/MR imaging using hybrid scanners and the implementation of methods from the field of artificial intelligence.