Deep-learning-based reconstruction of undersampled MRI to reduce scan times: a multicentre, retrospective, cohort study.

BACKGROUND: The extended acquisition times required for MRI limit its availability in resource-constrained settings. Consequently, accelerating MRI by undersampling k-space data, which is necessary to reconstruct an image, has been a long-standing but important challenge. We aimed to develop a deep convolutional neural network (dCNN) optimisation method for MRI reconstruction and to reduce scan times and evaluate its effect on image quality and accuracy of oncological imaging biomarkers. METHODS: In this multicentre, retrospective, cohort study, MRI data from patients with glioblastoma treated at Heidelberg University Hospital (775 patients and 775 examinations) and from the phase 2 CORE trial (260 patients, 1083 examinations, and 58 institutions) and the phase 3 CENTRIC trial (505 patients, 3147 examinations, and 139 institutions) were used to develop, train, and test dCNN for reconstructing MRI from highly undersampled single-coil k-space data with various acceleration rates (R=2, 4, 6, 8, 10, and 15). Independent testing was performed with MRIs from the phase 2/3 EORTC-26101 trial (528 patients with glioblastoma, 1974 examinations, and 32 institutions). The similarity between undersampled dCNN-reconstructed and original MRIs was quantified with various image quality metrics, including structural similarity index measure (SSIM) and the accuracy of undersampled dCNN-reconstructed MRI on downstream radiological assessment of imaging biomarkers in oncology (automated artificial intelligence-based quantification of tumour burden and treatment response) was performed in the EORTC-26101 test dataset. The public NYU Langone Health fastMRI brain test dataset (558 patients and 558 examinations) was used to validate the generalisability and robustness of the dCNN for reconstructing MRIs from available multi-coil (parallel imaging) k-space data. FINDINGS: In the EORTC-26101 test dataset, the median SSIM of undersampled dCNN-reconstructed MRI ranged from 0·88 to 0·99 across different acceleration rates, with 0·92 (95% CI 0·92-0·93) for 10-times acceleration (R=10). The 10-times undersampled dCNN-reconstructed MRI yielded excellent agreement with original MRI when assessing volumes of contrast-enhancing tumour (median DICE for spatial agreement of 0·89 [95% CI 0·88 to 0·89]; median volume difference of 0·01 cm3 [95% CI 0·00 to 0·03] equalling 0·21%; p=0·0036 for equivalence) or non-enhancing tumour or oedema (median DICE of 0·94 [95% CI 0·94 to 0·95]; median volume difference of -0·79 cm3 [95% CI -0·87 to -0·72] equalling -1·77%; p=0·023 for equivalence) in the EORTC-26101 test dataset. Automated volumetric tumour response assessment in the EORTC-26101 test dataset yielded an identical median time to progression of 4·27 months (95% CI 4·14 to 4·57) when using 10-times-undersampled dCNN-reconstructed or original MRI (log-rank p=0·80) and agreement in the time to progression in 374 (95·2%) of 393 patients with data. The dCNN generalised well to the fastMRI brain dataset, with significant improvements in the median SSIM when using multi-coil compared with single-coil k-space data (p<0·0001). INTERPRETATION: Deep-learning-based reconstruction of undersampled MRI allows for a substantial reduction of scan times, with a 10-times acceleration demonstrating excellent image quality while preserving the accuracy of derived imaging biomarkers for the assessment of oncological treatment response. Our developments are available as open source software and hold considerable promise for increasing the accessibility to MRI, pending further prospective validation. FUNDING: Deutsche Forschungsgemeinschaft (German Research Foundation) and an Else Kröner Clinician Scientist Endowed Professorship by the Else Kröner Fresenius Foundation.

Brain expression profiles of two SCN1A antisense RNAs in children and adolescents with epilepsy.

Objective: Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches. Methods: We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested. Results: The SCN1A related antisense RNAs SCN1A-dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A-usAS (upstream AS, SCN1A-AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A-usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A-dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A-dsAS transcripts. Conclusion: These findings support the role of SCN1A-dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A-dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

Injury-specific factors in the cerebrospinal fluid regulate astrocyte plasticity in the human brain.

The glial environment influences neurological disease progression, yet much of our knowledge still relies on preclinical animal studies, especially regarding astrocyte heterogeneity. In murine models of traumatic brain injury, beneficial functions of proliferating reactive astrocytes on disease outcome have been unraveled, but little is known regarding if and when they are present in human brain pathology. Here we examined a broad spectrum of pathologies with and without intracerebral hemorrhage and found a striking correlation between lesions involving blood-brain barrier rupture and astrocyte proliferation that was further corroborated in an assay probing for neural stem cell potential. Most importantly, proteomic analysis unraveled a crucial signaling pathway regulating this astrocyte plasticity with GALECTIN3 as a novel marker for proliferating astrocytes and the GALECTIN3-binding protein LGALS3BP as a functional hub mediating astrocyte proliferation and neurosphere formation. Taken together, this work identifies a therapeutically relevant astrocyte response and their molecular regulators in different pathologies affecting the human cerebral cortex.

Neurosurgical Interventions for Cerebral Metastases of Solid Tumors.

BACKGROUND: Metastases are the most common malignant tumors affecting the central nervous system and occur in 20-40 percent of patients with solid systemic tumors. The aim of this review is to discuss the role of neurosurgical procedures in a modern, multidisciplinary treatment approach. METHODS: An expert panel of neurosurgeons, neurologists, and radio-oncologists conducted a selective literature review on neu - rosurgical interventions for the diagnosis and treatment of cerebral metastases. Original articles, meta-analyses, and systematic reviews were included. RESULTS: There is a lack of prospective randomized studies. Based on retrospective case series, international guidelines recommend the harvesting (if required, stereotactically guided) of tissue for histological and molecular diagnosis in cases of unknown or possibly competing underlying systemic malignant diseases, in cases of suspected tumor recurrence, and with regard to the evaluation of targeted therapies taking into account molecular heterogeneity of primary and secondary tumors. Surgical resection is particularly valuable for the treatment of up to three space-occupying cerebral metastases, especially to achieve clinical stabilization to allow further non-surgical treatment. For cystic metastasis, a combination of stereotactic puncture and radiotherapy may be useful. Meningeal carcinomatosis can be treated with intrathecal medication via an intraventricular catheter system. Ventriculo-peritoneal shunts represents an effective treatment option for patients with tumor-associated hydrocephalus. CONCLUSION: Neurosurgical procedures are of central importance in the multimodal treatment of cerebral metastases. The indications for neurosurgical interventions will be refined in the light of more effective radiation techniques and systemic treatments with new targeted therapeutic approaches and immunotherapies on the horizon.

Spinal Tuberculosis within the Vertebral Arch Mimicking a Malignant Tumor: Case Report.

BACKGROUND: Spinal tuberculosis is a manifestation of extrapulmonary tuberculosis. The incidence of tuberculosis is low in high-income countries; however, globally, it still remains one of the most frequent fatal infectious diseases. Because of its rarity in developed countries, spinal tuberculosis can be mistaken for malignant tumors of the spine, especially in case of an atypical radiologic manifestation and without pulmonary affection. METHODS: We present the case of a 39-year-old man from South India with quickly progressing gait disturbance and hypesthesia below the Th10 level. Magnetic resonance imaging revealed an osteolytic lesion of the vertebral arch Th2 with central necrosis and compression of the spinal cord altogether highly suspicious for spinal metastasis. RESULTS: After surgical removal of the mass by laminectomy, the patient regained normal neurologic function. Histology revealed a severe granulomatous inflammation and DNAhybridization of polymerase chain reaction (PCR) products detected Mycobacterium tuberculosis-specific DNA in the sample. Biopsy of an enlarged hilar lymphnode allowed us to obtain material to successfully perform a drug resistance test to start specific antimicrobial therapy. CONCLUSION: Spinal tuberculosis, even with atypical radiologic appearance, has to be considered a differential diagnosis in patients with provenance from endemic countries. A multidisciplinary diagnostic approach helps perform antimicrobial susceptibility testing to avoid delaying the start of antibiotic therapy.

The Role of Stereotactic Radiosurgery in the Management of Foramen Magnum Meningiomas-A Multicenter Analysis and Review of the Literature.

BACKGROUND: Foramen magnum meningiomas (FMMs) represent a considerable neurosurgical challenge given their location and potential morbidity. Stereotactic radiosurgery (SRS) is an established non-invasive treatment modality for various benign and malignant brain tumors. However, reports on single-session or multisession SRS for the management and treatment of FMMs are exceedingly rare. We report the largest FMM SRS series to date and describe our multicenter treatment experience utilizing robotic radiosurgery. METHODS: Patients who underwent SRS between 2005 and 2020 as a treatment for a FMM at six different centers were eligible for analysis. RESULTS: Sixty-two patients met the inclusion criteria. The median follow-up was 28.9 months. The median prescription dose and isodose line were 14 Gy and 70%, respectively. Single-session SRS accounted for 81% of treatments. The remaining patients received three to five fractions, with doses ranging from 19.5 to 25 Gy. Ten (16%) patients were treated for a tumor recurrence after surgery, and thirteen (21%) underwent adjuvant treatment. The remaining 39 FMMs (63%) received SRS as their primary treatment. For patients with an upfront surgical resection, histopathological examination revealed 22 World Health Organization grade I tumors and one grade II FMM. The median tumor volume was 2.6 cubic centimeters. No local failures were observed throughout the available follow-up, including patients with a follow-up ≥ five years (16 patients), leading to an overall local control of 100%. Tumor volume significantly decreased after treatment, with a median volume reduction of 21% at the last available follow-up (p < 0.01). The one-, three-, and five-year progression-free survival were 100%, 96.6%, and 93.0%, respectively. Most patients showed stable (47%) or improved (21%) neurological deficits at the last follow-up. No high-grade adverse events were observed. CONCLUSIONS: SRS is an effective and safe treatment modality for FMMs. Despite the paucity of available data and previous reports, SRS should be considered for selected patients, especially those with subtotal tumor resections, recurrences, and patients not suitable for surgery.

Neurofilament light chain serum levels correlate with the severity of neurotoxicity after CAR T-cell treatment.

Antitumor therapy with CD19-targeted chimeric antigen receptor (CAR) modified T cells is highly efficient. However, treatment is often complicated by a unique profile of unpredictable neurotoxic adverse effects of varying degrees known as immune effector cell-associated neurotoxicity syndrome (ICANS). We examined 96 patients receiving CAR T cells for refractory B-cell malignancies at 2 major CAR T-cell treatment centers to determine whether serum levels of neurofilament light chain (NfL), a marker of neuroaxonal injury, correlate with the severity of ICANS. Serum NfL levels were measured before and after infusion of CAR T cells using a single-molecule enzyme-linked immunosorbent assay and correlated with the severity of ICANS. Elevated NfL serum levels before treatment were associated with more severe ICANS in both unadjusted and adjusted analyses. Multivariable statistical models revealed a significant increase in NfL levels after CAR T-cell infusion, which correlated with the severity of ICANS. Preexisting neuroaxonal injury. which was characterized by higher NfL levels before CAR T-cell treatment, correlated with the severity of subsequent ICANS. Thus, serum NfL level might serve as a predictive biomarker for assessing the severity of ICANS and for improving patient monitoring after CAR T-cell transfusion. However, these preliminary results should be validated in a larger prospective cohort of patients.

Implementation of TERT promoter mutations improve prognostication of the WHO classification in meningioma.

TERT promoter mutations have been associated with increased risk of recurrence in meningioma cohorts, thus a potential biomarker for aggressive phenotypes. A main purpose of refining tumour classification is better predictions on the patient level. We compiled data from previous published cohorts to investigate patient-level predictions of recurrence based on TERTp-mut status. Implementation of TERTp-mut into the WHO grading led to better patient prognostication by improved prediction of recurrence. Our results support implementation of TERTp-mut into diagnostics and classification of meningiomas.

L-type amino acid transporter (LAT) 1 expression in 18F-FET-negative gliomas.

BACKGROUND: O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30% of low- and 5% of high-grade gliomas do not present enhanced 18F-FET uptake at primary diagnosis ("18F-FET-negative gliomas") and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed 18F-FET-negative gliomas and to compare them to a matched group of 18F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 18F-FET-negative (tumour-to-background ratio (TBR) < 1.6), n = 20 18F-FET-positive gliomas (TBR > 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells (%) and the staining intensity (range 0-2) were multiplied to an overall score (H-score; range 0-200) and correlated to PET findings as well as progression-free survival (PFS). RESULTS: IHC staining of LAT1 expression was positive in both, 18F-FET-positive as well as 18F-FET-negative gliomas. No differences were found between the 18F-FET-negative and 18F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBRmax, neither in the overall group nor in the 18F-FET-positive group only (p = 0.651 and p = 0.140). CONCLUSION: Although LAT1 is reported to mediate the uptake of 18F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in 18F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of 18F-FET are necessary.

Bilateral and Optimistic Warning Paradigms Improve the Predictive Power of Intraoperative Facial Motor Evoked Potentials during Vestibular Schwannoma Surgery.

Facial muscle corticobulbar motor evoked potentials (FMcoMEPs) are used to monitor facial nerve integrity during vestibular schwannoma resections to increase maximal safe tumor resection. Established warning criteria, based on ipsilateral amplitude reduction, have the limitation that the rate of false positive alarms is high, in part because FMcoMEP changes occur on both sides, e.g., due to brain shift or pneumocephalus. We retrospectively compared the predictive value of ipsilateral-only warning criteria and actual intraoperative warnings with a novel candidate warning criterion, based on "ipsilateral versus contralateral difference in relative stimulation threshold increase, from baseline to end of resection" (BilatMT ≥ 20%), combined with an optimistic approach in which a warning would be triggered only if all facial muscles on the affected side deteriorated. We included 60 patients who underwent resection of vestibular schwannoma. The outcome variable was postoperative facial muscle function. Retrospectively applying BilatMT, with the optimistic approach, was found to have a significantly better false positive rate, which was much lower (9% at day 90) than the traditionally used ipsilateral warning criteria (>20%) and was also lower than actual intraoperative warnings. This is the first report combining the threshold method with an optimistic approach in a bilateral multi-facial muscle setup. This method could substantially reduce the rate of false positive alarms in FMcoMEP monitoring.

Detection of impending perfusion deficits by intraoperative computed tomography (iCT) in aneurysm surgery of the anterior circulation.

BACKGROUND: The aim of our study was to evaluate the additional benefit of intraoperative computed tomography (iCT), intraoperative computed tomography angiography (iCTA), and intraoperative computed tomography perfusion (iCTP) in the intraoperative detection of impending ischemia to established methods (indocyanine green videoangiography (ICGVA), microDoppler, intraoperative neuromonitoring (IONM)) for initiating timely therapeutic measures. METHODS: Patients with primary aneurysms of the anterior circulation between October 2016 and December 2019 were included. Data of iCT modalities compared to other techniques (ICGVA, microDoppler, IONM) was recorded with emphasis on resulting operative conclusions leading to inspection of clip position, repositioning, or immediate initiation of conservative treatment strategies. Additional variables analyzed included patient demographics, aneurysm-specific characteristics, and clinical outcome. RESULTS: Of 194 consecutive patients, 93 patients with 100 aneurysms received iCT imaging. While IONM and ICGVA were normal, an altered vessel patency in iCTA was detected in 5 (5.4%) and a mismatch in iCTP in 7 patients (7.5%). Repositioning was considered appropriate in 2 patients (2.2%), where immediate improvement in iCTP could be documented. In a further 5 cases (5.4%), intensified conservative therapy was immediately initiated treating the reduced CBP as clip repositioning was not considered causal. In terms of clinical outcome at last FU, mRS0 was achieved in 85 (91.4%) and mRS1-2 in 7 (7.5%) and remained mRS4 in one patient with SAH (1.1%). CONCLUSIONS: Especially iCTP can reveal signs of impending ischemia in selected cases and enable the surgeon to promptly initiate therapeutic measures such as clip repositioning or intraoperative onset of maximum conservative treatment, while established tools might fail to detect those intraoperative pathologic changes.

Multimodal therapy of cavernous sinus meningioma: Impact of surgery and 68Ga-DOTATATE PET-guided radiation therapy on tumor control and functional outcome.

BACKGROUND: Functional preservation in patients with WHO grade I meningioma involving the cavernous sinus (CSM) is crucial for long-term tumor control. Concise data on the functional outcome of an interdisciplinary, multimodal treatment are scarce. We analyzed functional outcome and tumor control in CSM patients following maximal safe resection (MSR), fractionated stereotactic radiotherapy (FSRT), or combination of them, retrospectively. METHODS: Patients with WHO grade I CSM treated between 2003 and 2017 were included. Prior to FSRT, a 68Ga-DOTATATE PET/CT was performed for radiation planning. Progression-free survival (PFS) was analyzed using Kaplan-Meier method and log-rank test was performed to test differences between groups. Visual function was analyzed at baseline and follow-up. RESULTS: Eighty-five patients were included. MSR alone was performed in 48 patients (group A), MSR followed by FSRT in 25 patients (group B), and FSRT alone in 12 patients (group C). Intracranial tumor volumes were higher in A and B compared to C (median 9.2/10.8/4.3 ccm for A/B/C, P = .023). Median follow-up was 47/46/45 months and PFS at 5 years 55.7%, 100%, and 100% in A/B/C, respectively (P < .001). Optic nerve compression was more common in A (91.7%) and B (84.0%) than C (16.7%), P < .001. Post-therapeutic new onset or deterioration of double vision was observed in 29% (A), 17% (B), and 0% (C). CONCLUSION: Personalized treatment strategies for CSM are essential to control space-occupying or functionally compromising lesions. The additional potential side effect of radiotherapy seems to be justified under the aspect of longer tumor control with low functional risk. Without space-occupying effect of CSM, FSRT alone is reasonably possible.

Deep-learning-based synthesis of post-contrast T1-weighted MRI for tumour response assessment in neuro-oncology: a multicentre, retrospective cohort study.

BACKGROUND: Gadolinium-based contrast agents (GBCAs) are widely used to enhance tissue contrast during MRI scans and play a crucial role in the management of patients with cancer. However, studies have shown gadolinium deposition in the brain after repeated GBCA administration with yet unknown clinical significance. We aimed to assess the feasibility and diagnostic value of synthetic post-contrast T1-weighted MRI generated from pre-contrast MRI sequences through deep convolutional neural networks (dCNN) for tumour response assessment in neuro-oncology. METHODS: In this multicentre, retrospective cohort study, we used MRI examinations to train and validate a dCNN for synthesising post-contrast T1-weighted sequences from pre-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences. We used MRI scans with availability of these sequences from 775 patients with glioblastoma treated at Heidelberg University Hospital, Heidelberg, Germany (775 MRI examinations); 260 patients who participated in the phase 2 CORE trial (1083 MRI examinations, 59 institutions); and 505 patients who participated in the phase 3 CENTRIC trial (3147 MRI examinations, 149 institutions). Separate training runs to rank the importance of individual sequences and (for a subset) diffusion-weighted imaging were conducted. Independent testing was performed on MRI data from the phase 2 and phase 3 EORTC-26101 trial (521 patients, 1924 MRI examinations, 32 institutions). The similarity between synthetic and true contrast enhancement on post-contrast T1-weighted MRI was quantified using the structural similarity index measure (SSIM). Automated tumour segmentation and volumetric tumour response assessment based on synthetic versus true post-contrast T1-weighted sequences was performed in the EORTC-26101 trial and agreement was assessed with Kaplan-Meier plots. FINDINGS: The median SSIM score for predicting contrast enhancement on synthetic post-contrast T1-weighted sequences in the EORTC-26101 test set was 0·818 (95% CI 0·817-0·820). Segmentation of the contrast-enhancing tumour from synthetic post-contrast T1-weighted sequences yielded a median tumour volume of 6·31 cm3 (5·60 to 7·14), thereby underestimating the true tumour volume by a median of -0·48 cm3 (-0·37 to -0·76) with the concordance correlation coefficient suggesting a strong linear association between tumour volumes derived from synthetic versus true post-contrast T1-weighted sequences (0·782, 0·751-0·807, p<0·0001). Volumetric tumour response assessment in the EORTC-26101 trial showed a median time to progression of 4·2 months (95% CI 4·1-5·2) with synthetic post-contrast T1-weighted and 4·3 months (4·1-5·5) with true post-contrast T1-weighted sequences (p=0·33). The strength of the association between the time to progression as a surrogate endpoint for predicting the patients' overall survival in the EORTC-26101 cohort was similar when derived from synthetic post-contrast T1-weighted sequences (hazard ratio of 1·749, 95% CI 1·282-2·387, p=0·0004) and model C-index (0·667, 0·622-0·708) versus true post-contrast T1-weighted MRI (1·799, 95% CI 1·314-2·464, p=0·0003) and model C-index (0·673, 95% CI 0·626-0·711). INTERPRETATION: Generating synthetic post-contrast T1-weighted MRI from pre-contrast MRI using dCNN is feasible and quantification of the contrast-enhancing tumour burden from synthetic post-contrast T1-weighted MRI allows assessment of the patient's response to treatment with no significant difference by comparison with true post-contrast T1-weighted sequences with administration of GBCAs. This finding could guide the application of dCNN in radiology to potentially reduce the necessity of GBCA administration. FUNDING: Deutsche Forschungsgemeinschaft.

Prediction of TERTp-mutation status in IDH-wildtype high-grade gliomas using pre-treatment dynamic [18F]FET PET radiomics.

PURPOSE: To evaluate radiomic features extracted from standard static images (20-40 min p.i.), early summation images (5-15 min p.i.), and dynamic [18F]FET PET images for the prediction of TERTp-mutation status in patients with IDH-wildtype high-grade glioma. METHODS: A total of 159 patients (median age 60.2 years, range 19-82 years) with newly diagnosed IDH-wildtype diffuse astrocytic glioma (WHO grade III or IV) and dynamic [18F]FET PET prior to surgical intervention were enrolled and divided into a training (n = 112) and a testing cohort (n = 47) randomly. First-order, shape, and texture radiomic features were extracted from standard static (20-40 min summation images; TBR20-40), early static (5-15 min summation images; TBR5-15), and dynamic (time-to-peak; TTP) images, respectively. Recursive feature elimination was used for feature selection by 10-fold cross-validation in the training cohort after normalization, and logistic regression models were generated using the radiomic features extracted from each image to differentiate TERTp-mutation status. The areas under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive value were calculated to illustrate diagnostic power in both the training and testing cohort. RESULTS: The TTP model comprised nine selected features and achieved highest predictability of TERTp-mutation with an AUC of 0.82 (95% confidence interval 0.71-0.92) and sensitivity of 92.1% in the independent testing cohort. Weak predictive capability was obtained in the TBR5-15 model, with an AUC of 0.61 (95% CI 0.42-0.80) in the testing cohort, while no predictive power was observed in the TBR20-40 model. CONCLUSIONS: Radiomics based on TTP images extracted from dynamic [18F]FET PET can predict the TERTp-mutation status of IDH-wildtype diffuse astrocytic high-grade gliomas with high accuracy preoperatively.

Chemotherapy for adult patients with spinal cord gliomas.

BACKGROUND: The incidence of spinal cord gliomas, particularly in adults is low, and the role of chemotherapy has remained unclear. METHODS: We performed a multicenter, retrospective study of 21 patients diagnosed with spinal cord glioma who received chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by magnetic resonance imaging. Data on radiotherapy were taken into consideration. RESULTS: Thirteen patients were diagnosed with astrocytic gliomas World Health Organization (WHO) grades 1-4, the remaining eight patients with ependymomas WHO grades 1 or 3. Most patients had more than one neurosurgical intervention. Median age at time of first chemotherapy was 33 years (range 21-67 years). Seven patients had chemotherapy combined with radiotherapy as first-line treatment. Two patients had chemoradiotherapy at recurrence, without prior tumor-specific treatment beyond surgery. One patient received chemotherapy alone as first-line treatment and 2 patients had chemotherapy alone at recurrence, without prior treatment. Nine patients had received radiation therapy at an earlier time and chemotherapy was given at time of further recurrences. Best responses in astrocytomas were as follows: chemotherapy alone-2 stable disease (SD) and 3 progressive disease (PD); chemoradiotherapy-1 complete response, 3 SD, and 4 PD. Best responses in ependymomas were as follows: chemotherapy alone-1 partial response, 5 SD, and 1 PD; chemoradiotherapy-1 SD. CONCLUSIONS: Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal cord glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.

Comparing Tumor Cell Invasion and Myeloid Cell Composition in Compatible Primary and Relapsing Glioblastoma.

Glioblastoma (GBM) recurrence after treatment is almost inevitable but addressing this issue with adequate preclinical models has remained challenging. Here, we introduce a GBM mouse model allowing non-invasive and scalable de-bulking of a tumor mass located deeply in the brain, which can be combined with conventional therapeutic approaches. Strong reduction of the GBM volume is achieved after pharmacologically inducing a tumor-specific cell death mechanism. This is followed by GBM re-growth over a predictable timeframe. Pharmacological de-bulking followed by tumor relapse was accomplished with an orthotopic mouse glioma model. Relapsing experimental tumors recapitulated pathological features often observed in recurrent human GBM, like increased invasiveness or altered immune cell composition. Orthotopic implantation of GBM cells originating from biopsies of one patient at initial or follow-up treatment reproduced these findings. Interestingly, relapsing GBM of both models contained a much higher ratio of monocyte-derived macrophages (MDM) versus microglia than primary GBM. This was not altered when combining pharmacological de-bulking with invasive surgery. We interpret that factors released from viable primary GBM cells preferentially attract microglia whereas relapsing tumors preponderantly release chemoattractants for MDM. All in all, this relapse model has the capacity to provide novel insights into clinically highly relevant aspects of GBM treatment.

Image-Guided Robotic Radiosurgery for the Treatment of Same Site Spinal Metastasis Recurrences.

BACKGROUND: Due to recent medical advancements, patients suffering from metastatic spinal disease have a prolonged life expectancy than several decades ago, and some will eventually experience relapses. Data for the retreatment of spinal metastasis recurrences occurring at the very same macroscopic spot as the initially treated lesion are limited. Previous studies mainly included recurrences in the boundary areas as well as other macroscopic parts of the initially affected vertebrae. This study exclusively analyzes the efficacy and safety of spinal reirradiation for recurrences on the same site utilizing single-session robotic radiosurgery. MATERIALS AND METHODS: Patients between 2005 and 2020 who received radiotherapy for a spinal metastasis suffering from a local recurrence were eligible for analysis. Only patients undergoing a single-session reirradiation were included. All recurrences must have been occurred in the same location as the initial lesion. This was defined as a macroscopic recurrence on computed tomography occurring at the same site as the initial spinal metastasis. All other lesions, including those in the boundary areas or other parts of the initially affected vertebrae, were excluded. RESULTS: Fifty-three patients with fifty-three lesions were retreated for spinal metastases. The median dose and number of fractions for the initial radiotherapy were 36 Gy and 15, respectively. Eleven patients were initially treated with stereotactic body radiotherapy. Retreatment was performed with a median dose of 18 Gy prescribed to a median isodose of 70%. The local control was 77% after a median follow-up of 22.2 months. Patients experiencing a second recurrence received a lower dose (p = 0.04), mostly below 18 Gy, and had a worse coverage (p = 0.01) than those showing local tumor control. 51% of patients experienced an improvement in pain control after treatment delivery. Besides, four vertebral compression fractures (7% of patients) but no other adverse events higher than grade 2 were observed. CONCLUSION: Single-session robotic radiosurgery appears to be a safe, time-saving, and effective treatment modality for spinal metastasis recurrences occurring in the same initial location if a considerable dose and coverage can be applied. Treatment results are comparable to reirradiated metastases in the boundary areas.

Image-Guided Robotic Radiosurgery for the Management of Spinal Ependymomas.

BACKGROUND: Ependymomas are rare neoplasms of the central nervous system (CNS), usually localized intracranially and most commonly diagnosed in children. Spinal ependymomas are more frequent in young adults. They are either primary lesions or manifest as disseminated seeding of cranial tumors. Data on the management of spinal ependymoma lesions remain scarce, especially concerning stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). The purpose of this study is to report the treatment outcomes of two institutions using robotic radiosurgery (RRS) for the treatment of spinal ependymomas. MATERIALS AND METHODS: All patients with a histopathologically confirmed diagnosis of an ependymoma WHO grade II or III who were treated with RRS for one or more spinal lesions were included in this analysis. RESULTS: Twelve patients underwent RRS for the treatment of 32 spinal ependymoma lesions between 2005 and 2020. Two patients were below the age of 18 when treated, whereas nine patients (75%) suffered from a primary spinal ependymoma. The median dose was 15 Gy prescribed to a median isodose of 70%, with 27 lesions (84%) receiving a single-session treatment. The local control (LC) after a median follow-up of 56.7 months was 84%. LC rates at 1, 3, and 5 years were 92, 85, and 77%, respectively. The Kaplan-Meier estimated overall survival after 1, 3, and 5 years were 75, 75, and 64%, respectively. Five patients died, all of them suffering from an anaplastic ependymoma, with widespread CNS tumor progression being the reason for death in four patients. The majority of patients (58%) showed a stable neurological status at the last available follow-up. Overall, the treatment was well tolerated. CONCLUSION: RRS appears to be a safe and efficient treatment modality for managing primary and secondary spinal ependymal tumors in patients with multiple lesions and local recurrences.