Meningeal Disease Research Articles

Fluorescent Pdots Facilitate High-Resolution Mapping of the Intact Meningeal Vascular Network and Eye-Brain Connections.

Meningeal vascular network is significant in neurology and neurosurgery. However, high-resolution imaging of intact meningeal vascular network is lacking. In this work, we develop a practical experimental method to ensure that the intact meninges are morphologically unfolded and fixed in an agarose gel. With the help of high-brightness polymer dots (Pdots) as probe, macroscopic and detailed imaging of the vascular network on the intact dorsal meninges can be performed. Meningeal vessels are symmetrically distributed along the superior sagittal sinus, and the distribution of meningeal vessels had a certain degree of hierarchy. The meninges are thicker blood vessels and capillary networks from the outside to the inside. Moreover, the diameter of the capillaries is 3.96 ± 0.89 μm. Interestingly, meningeal primo vessels in the central nervous system of mice is imaged with the diameter of 4.18 ± 1.18 μm, which has not been reported previously. It is worth mentioning that we found that orthotopic xenografts of brain tumors caused the appearance of corneal neovascularization and morphological changes in optic nerve microvessels. In conclusion, our work provides an effective Pdots-based imaging method for follow-up research on meningeal vascular-related diseases, and illustrates that the eye can serve as a window for the prevention and diagnosis of brain diseases.

Clinical characteristics and factors affecting disease severity in hospitalized tick-borne encephalitis patients in Norway from 2018 to 2022

PurposeTo describe the clinical characteristics and factors associated with disease severity in a Norwegian cohort of hospitalized patients with tick-borne encephalitis (TBE).MethodsThis observational multicenter study included hospitalized patients with TBE in the endemic area in the southeastern region of Norway from 2018 to 2022. Clinical signs and findings from laboratory tests, EEG, CT and MRI scans were recorded. Patient characteristics were compared among those with mild, moderate, and severe TBE, and factors associated with disease severity were identified.ResultsNearly all eligible patients were included in the final cohort (153/189 participants, 81%). The median age was 56 years, 63% were men, and 7% were vaccinated against TBE; no participants were fully vaccinated. TBE presented as mild (meningeal) disease in 31% of patients and as moderate or severe (encephalitic) disease in 54% and 14% of patients, respectively. We found that 46% of the patients had a monophasic course, 64% had hyponatremia, and 7% presented with central nervous system (CNS) symptoms without pleocytosis in cerebrospinal fluid (CSF). Dysesthesia, a symptom previously not described, was reported in 10% of the patients. Most objective findings were related to the CNS. Preexisting comorbidities, CRP and CSF protein levels were predictors of more severe disease.ConclusionThis novel presentation of a large Norwegian cohort supports TBE as a serious disease in the southeastern region of Norway. The majority of hospitalized patients presented with encephalitis, and fewer presented with meningitis. Comorbidities, CRP and CSF protein levels were associated with more severe disease.Trial registrationProsjekt #2,296,959 – The Norwegian Tick-borne Encephalitis Study – NOTES. Acute phase characteristics and long-term outcomes. – Cristin.

Endoscopic Endonasal Internal Carotid Artery Transposition Technique in Tumor With Parasellar Extension: A Single-Center Experience.

Lateralization or mobilization of the internal carotid artery (ICA) during a midline approach is required to expose lesions behind or lateral to the ICA. However, there have been no published data regarding the surgical outcomes of the endoscopic endonasal internal carotid transposition technique (EEITT). This study aimed to analyze the relevant surgical anatomy around the ICA and propose a grading scheme of EEITT. A retrospective review of patients who underwent EEITT at a single institution was performed. Based on structures that limited the ICA and intraoperative findings, an anatomically surgical grading scheme of EEITT was proposed. Forty-two patients (mean age 45.6 years, 57.1% female patients) were included. Of them, 29 cases (69.0%) were Knosp grade 4 pituitary adenoma, 6 cases (14.3%) were chordoma, 6 cases (14.3%) were meningioma, and a single case (2.4%) was meningeal IgG4-related disease. The EEITT was categorized into Grades 1, 2 and 3, which was used in 24 (57.1%), 12 (28.6%), and 6 (14.3%) cases, respectively. The most common symptom was visual disturbance (45.2%). The gross total resection rate in Grade 1 (79.2%) and Grade 2 (83.3%) was much higher than that in Grade 3 (66.6%). The overall rate of visual function improvement, preoperative cranial nerve (CN) palsy improvement, and postoperative hormonal remission was 89.4%, 85.7%, and 88.9%, respectively. The rate for the following morbidities was cerebrospinal fluid leakage, 2.4%; permanent diabetes insipidus, 4.8%; new transient CN palsy, 9.5%; permanent CN palsy, 4.7%; panhypopituitarism, 7.1%; and ICA injury, 2.4%. The EEITT is technically feasible and could be graded according to the extent of disconnection of limiting structures. For complex tumor with parasellar extensions, the distinction into Grades 1, 2, and 3 will be of benefit to clinicians in predicting risks, avoiding complications, and generating tailored individualized surgical strategies.

Abstract PO2-06-03: Meta-Analysis of Clinical Characteristics and Outcomes in Breast Cancer Patients with Visceral Crisis

Abstract Background: Recent advancements in novel therapeutics have resulted in improved survival over the last decade for patients with metastatic breast cancer, but there remain subsets of patients who experience disproportionately poor outcomes. Patients with visceral crisis (VC), defined by the 5th ESO ESMO as the presence of visceral metastasis with severe organ compromise and/or rapid progression, are often excluded from clinical trials of novel therapeutics. This is despite patients with VC having poorer clinical outcomes and a lack of guidelines consensus on best therapeutic practices. Thus, we sought to better characterize this patient cohort via a meta-analysis to elucidate clinical characteristics and treatment options. Methods: We searched MEDLINE, Embase, Cochrane, Scopus and other sources, from each database's inception to March 2023. The search strategy was designed and conducted by an experienced librarian with input from the study's principal investigator. Controlled vocabulary supplemented with keywords was used to search for patients with breast cancer in visceral crisis. Outcomes of interest included mortality and progression at different time points. Meta-analysis was conducted using the random-effects model. Results: The studies matching our initial inquiry was 154. After evaluation for patient number, and VC related outcomes, 16 studies (12 abstract only) met initial criteria. After data extraction, 12 studies were excluded due to insufficient outcomes delineated by VC. The treatment period was 01/2008 until 01/2022. The mean age at diagnosis of VC was 53.9 with a total of 6404 patients, 6259 were hormone positive, 41 Her2 positive and 87 triple negative. The type of VC included 212 liver dysfunction, 84 respiratory dysfunction, 40 with bone marrow dysfunction, 4 with SVC syndrome, and 43 with meningeal disease (VC type is not reported in every study). The treatments were varied and included multiple platinum doublets, CDK4/6 with endocrine therapy, platinum with bevacizumab, endocrine monotherapy and Her-2 targeted agents. Unfortunately, the number of patients per treatment group or VC type is not enough for targeted outcome analysis. The proportion of patients who progressed at 1, 6, 12 and 18 months were 0.17, 0.64, 0.95 and 0.91 respectively (2 studies Yang et al and Funasaka et al). Mortality assessed as proportion who expired at 1, 6, 12 and 18 months at 0.07, 0.44, 0.64 and 0.77 respectively (3 studies Yang et al, Funasaka et al and Franzoi et al) and at 24 months 0.89 in 4 studies (Yang et al, Funasaka et al, Dawood et al and Franzoi et al) (Table 1). Conclusions In this systematic review, we clearly demonstrate a lack of clinical trial data available to demonstrate specific outcomes based on chemotherapy, visceral crisis type or targeted treatment. The prognosis, however, is consistently poor with mortality at 64 percent by 12 months. Thus, further studies are needed to guide best treatment strategies that address both the poor clinical outcomes and therapeutic toxicities for patients with VC. Clinical trial groups and regulatory bodies overseeing new drug development for breast cancer should consider specific arms for patients with VC, instead of targeted exclusion from trials, as this strategy has proven effective in expansion of therapeutics for other challenging breast cancer subtypes. Table 1 Table 1: Proportion of progression and mortality. Progression studies include Yang et al 2022, Funasaka et al 2021. Mortality studies at 1, 6 and 12 months Yang et al 2022, Funasaka et al 2021 and Franzoi et al 2021. Mortality studies at 24 months Yang et al 2022, Funasaka et al 2021, Franzoi et al 2021, Dawood et al 2021. Citation Format: Michael Auster, Raed Benkhadra, Sophia Lee, Tamarah Aldawoodi, Larry Prokop, Tarek Nayfeh, Paromita Datta, Kate Lathrop. Meta-Analysis of Clinical Characteristics and Outcomes in Breast Cancer Patients with Visceral Crisis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-03.

P027 Infliximab in the treatment of cerebral tuberculosis paradoxical reactions with vasculitis

Abstract Background/Aims Tuberculosis meningitis (TBM) is associated with high morbidity and mortality. Up to 25% of patients may experience paradoxical reactions (PR) after commencing anti-TB therapy, which are exaggerated inflammatory reactions resulting in parenchymal inflammation, tuberculomas and secondary vasculitis. PR are minimised with steroid co-treatment, and relapsing disease often requires escalating steroid therapy. High levels of CSF TNFα have been shown in TBM with PR and immunosuppressants such as thalidomide, azathioprine and mycophenolate have been used with limited success. Herewith we describe a patient with TBM and PR with secondary vasculitis and consequent stroke treated successfully with infliximab. Methods A 55-year-old man presented with collapse, drowsiness, anergia and lateral gaze nystagmus. He was diagnosed with MDR TB-meningitis 3 months earlier and treated with cycloserine, clofazimine, moxifloxacin, bedaquiline, linezolid and dexamthasone. Results Prior to this presentation there had been recurring headaches after weaning dexamathasone to cessation. Two days into admission, he developed an unsteady gait with bilateral intention tremor, bi-directional nystagmus and left upper limb dysdiadochokinesia. An MRI brain showed new intraparenchymal and meningeal lesions suggestive of tuberculomas with acute infarcts involving both thalami and the left external capsule with hydrocephalus. Intracranial CT angiogram showed irregular posterior cerebral arteries indicative of arteritis. Findings were characteristic for TB paradoxical reactions with a secondary vasculitis. Dexamethasone was recommenced at 6mg BD and weaned to 3mg over a one month period. Mycophenolate was commenced as a steroid sparing agent for PR and up-titrated to 1000mg BD over four weeks. There was minimal improvement in the patient’s neurological state and repeat MRI showed some improvement in tuberculomas, but new infarcts within the right globus pallidus and left thalamus. As there was minimal progress and high steroid dependence the patient was loaded with infliximab (5mg/kg) over the next 8 weeks. An MRI done after three infusions showed significant improvement in tuberculomas, resolution of arteritis and residual meningeal disease which correlated with clinical improvement. As progress was improving infliximab was stopped after six infusions, and both mycophenolate and prednisolone weaned to cessation. At six months of follow-up the patient has made a full neurological recovery. Conclusion TBM and PR are associated with significant morbidity and disability. There are no evidence based treatments for PR and corticosteroids remain the mainstay of treatment. Several case series have suggested a role for anti-TNF agents and our described case contributes to the role of anti-TNF in treating patients with TB PR with secondary vasculitis. Disclosure H. Ko: None. A. Fatima: None. A. Sivagnanaratnam: None. A. McGregor: None. S. Hamdulay: None.

Magnetic resonance imaging subtraction vs. pre- and post-contrast 3D gradient recalled echo fat suppressed imaging for evaluation of the canine and feline brain.

Subtraction magnetic resonance imaging (MRI) has been reported to increase accuracy in the diagnosis of meningeal and inflammatory brain diseases in small animals. 3D T1W gradient recalled echo (GRE) techniques have been proposed as a suitable alternative to conventional spin echo sequences in imaging the canine brain. The aim of this study was to compare subtraction images and paired pre- and post-contrast 3D T1W GRE fat suppressed (FS) images in canine and feline MRI studies using clinical diagnosis as the gold standard. Paired pre- and post-contrast T1W 3D FS GRE images and individual subtraction images of 100 small animal patients were randomized and independently evaluated by 2 blinded observers. Diagnosis categories were "normal," "inflammatory," "neoplastic," and "other." Clinical diagnosis was made in the same categories and served as the gold standard. Image interpretation results were compared to the clinical diagnosis. Interobserver agreement was determined. Clinically, 41 studies were categorized as "normal," 18 as "inflammatory," 28 as "neoplastic," and 13 as "other." The agreement of the pre- and post-contrast GRE images with the gold standard was significantly higher than that of the subtraction images (k = 0.7491 vs. k = 0.5924; p = 0.0075). The largest sources of error were misinterpretation of "other" as "normal" and "normal" as "inflammatory." There was no significant difference between the two observers (p = 0.8820). Based on this study, subtraction images do not provide an advantage to paired pre- and post-contrast FS GRE images when evaluating the canine and feline brain.

A Retrospective Study on Outcomes of Secondary CNS Lymphoma: Pattern of Relapse, Prognostic Factors, and Role of Consolidation Therapy

Introduction Secondary CNS lymphoma (SCNSL) remains a treatment challenge in patients (pts) with aggressive lymphoma. Outcome of SCNSL is poor. Pts are often treated with high dose Methotrexate (HD-MTX) based regimens followed by autologous stem cell transplant (auto SCT). However, the benefit of consolidation therapy is not well established. There is limited data on the treatments and outcomes of SCNSL. In this single institution study, we aim to analyze the role of consolidation therapy and potential prognostic factors of outcomes in SCNSL. Method All pts with a diagnosis SCNSL who presented to Moffitt Cancer Center, FL, USA between 2017 and 2022 were included. The hazard ratios (HRs) were evaluated in the univariate and multivariate analysis using the cox proportional hazard mode. All analyses were done using SAS 9.4. Results A total of 60 pts with SCNSL were identified. The median age was 63 years (range 26-83 years); 27 (45%) were female; 13 (21.7%) had Eastern cooperative oncology group performance status (ECOG) ≥2. Entire cohort was divided in 3 subgroups: pts with concurrent CNS involvement at the time of initial diagnosis with systemic lymphoma (Sys-CNS) [22 (36.7%)]; pts with isolated CNS relapse (R-SCNS) [30 (50.0%)]; and pts with simultaneous CNS and systemic relapse (R-Sys-CNS) [8 (13.3%)]. 31 (51.7%) pts had brain parenchymal involvement, 24 (40%) had leptomeningeal disease, 4 (6.7%) had both leptomeningeal and parenchymal involvement, and 1 (1.7%) had ocular disease. 58(96.6%) pts had diffuse large B cell lymphoma (DLBCL) histology; 9 (15%) had DLBCL with MYC and BCL2 rearrangement; 10 (16.7%) had DLBCL MYC and BCL2 expression. For induction therapy of SCNSL, 53 (88.3%) of pts received HD MTX-based chemotherapy; 2 (3.3%) received Bruton tyrosine kinase inhibitor (BTKi), and 5 (8.3%) with meningeal disease alone received IT chemotherapy and/or rituximab(R). Sys-CNS pts also received R-CHOP or DA-R-EPOCH while R-Sys-CNS pts received R-Polatuzumab or Polatuzumab-R-Bendamustine. 20 (33.3%) received consolidation either by WBRT [13 (21.7%)] or auto SCT [4 (6.7%)]; 3 (5.0%) proceeded with chimeric antigen receptor (CAR-T) therapy. The overall response rate (ORR) for entire cohort was 55.2% (34.5% complete response CR and 20.7% partial response PR). However, improved ORR and CR were observed with 14(73.68%) and 9 (47.37%) respectively in pts who received consolidation. ORR and CR for pts with Sys-CNS, R-SCNS, R-Sys-CNS were 13 (61.9%)/ 10 (47.6%), 14 (48.3%)/9 (31%) and 2 (25%)/ 2 (25%), respectively. After a median follow up of 33.6 months, median OS was 8.3 months with a 2-year survival probability of 33.8% (95% CI: 21.7-46.3%); the PFS was 6.5 months with a 2-year PFS probability of 32.9% (95% CI: 20.7-45.6%). Consolidation therapy with either auto SCT or WBRT had significant survival benefit. In this subgroup, median OS is not reached (NR) and the 2-year OS probability was 59.6% (95% CI: 32.9-78.7%); median PFS was 25.6 months and 2-year PFS probability was 53.3% (95% CI: 27.5-73.6%). After the first-line therapy for CNS disease, 21(35%) pts experienced relapsed. However, relapse rate in consolidation group [7 (36.8%)] was almost similar to those who did not receive consolidation [14 (34.2%)] (table 1). 39 (65%) pts died; 29 (48.33%) from disease progression, 3 (5%) from therapy related side effect and 7(11.7%) from other causes. In the univariate analysis, ECOG PS ≥2 [HR 3.60 (CI:1.80-7.20), p<0.001], lack of consolidation therapy [2.45 (CI:1.12-5.36), p=0.024], <3 cycles of HD-MTX containing regimen [2.85 (CI: 1.47-5.520), p=0.002] and double hit lymphoma [2.27 (CI: 1.02-5.06), p=0.045] were associated with worse OS. In the multivariate analysis, R-SYS-CNS, <3 cycles of HD-MTX, ECOG ≥2 and lack of consolidation remained significant. Lack of consolidation and receiving <3 cycles of HD-MTX were associated with inferior PFS in both univariate and multivariate analysis (figure 1). Conclusion Outcomes of aggressive B cell lymphoma with CNS involvement remain poor. The median OS was 8.3 months in our cohort. After adjusting for confounding factors, receiving >3 cycles of HD-MTX based regimen and consolidation with either WBRT or auto SCT were associated with improved outcomes. Pts with simultaneous CNS and systemic relapse had worse OS. Prospective studies are needed to evaluate optimal treatment for SCNSL.

Predictors of Middle Meningeal Artery-Related Vascular Diseases Associated with Blunt Head Trauma

Traumatic middle meningeal artery (MMA)-middle meningeal vein (MMV) fistula (MMA-MMV fistula) and MMA pseudoaneurysm are the 2 main MMA-related vascular diseases occurring after blunt head trauma. These are rare but known causes of delayed intracranial hemorrhage. This study investigated predictors that may aid in the diagnosis of these diseases. In our department, screening digital subtraction angiography (DSA) is performed for patients with blunt head trauma accompanied by intracranial hemorrhage and skull or facial bone fracture. This study included 87 patients who underwent screening DSA without craniotomy from January 2019 to June 2023. The patients' clinical characteristics were retrospectively collected from the database. Statistical analysis was performed to examine the associations of various evaluation items with MMA-related vascular diseases. The first DSA examination revealed 34 MMA-MMV fistulas and 1 MMA pseudoaneurysm. The second follow-up DSA examination revealed 13 MMA-MMV fistulas and four MMA pseudoaneurysms. Temporal/parietal bone fracture (odds ratio, 5.33; P=0.0005; 95% confidence interval, 1.95-14.60) was significantly associated with MMA-related vascular diseases. Endovascular treatments were performed in 9 patients. All procedures were successfully completed without complications; no delayed bleeding was observed. Temporal/parietal bone fracture in patients with blunt head trauma is a likely predictor of MMA-related vascular diseases. When initial head computed tomography reveals this pathology, we recommend careful imaging follow-up (e.g., DSA) and treatment as needed, while considering the possibility of MMA-related vascular diseases.

Pachymeningeal disease: a systematic review and metanalysis.

Pachymeningeal disease (PMD) is a newly recognized pattern of brain metastasis (BrM) failure that specifically occurs following surgery with adjuvant stereotactic radiosurgery (SRS) and has unique prognostic implications relative to leptomeningeal disease (LMD). Here, we report its prevalence, prognostic implications, and associated risk factors. A literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses on PUBMED and Cochrane from January 2000 to June 2023. We identified 12 studies that included a total of 3992 BrM patients, 659 (16.5%) of whom developed meningeal disease (MD) following surgery plus adjuvant SRS, including either PMD or LMD. The mean prevalence of MD across studies was 20.9% (7.9-38.0%), with PMD accounting for 54.6% of this prevalence and LMD comprising the remaining 45.4%. Mean of the median overall survivals following diagnosis of PMD and LMD was 10.6 months and 3.7 months p = 0.007, respectively, a significant difference. Only 2 risk factors for PMD were reported in ≥ 2 studies and also identified as statistically significant per our meta-analysis: infratentorial location and controlled systemic disease status. While PMD has a superior prognosis to LMD, it is nevertheless a critical oncologic event associated with significant mortality and remains poorly recognized. PMD is predominantly observed in patients with controlled systemic disease status and infratentorial location. Future treatment strategies should focus on reducing surgical seeding and sterilizing surgical cavities.

P10 Collapse, confusion and acute kidney injury presenting in the context of bullous skin disease in a young male patient

P10 Collapse, confusion and acute kidney injury presenting in the context of bullous skin disease in a young male patient

Single-Fraction Versus Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM International Multicenter Cohort Study

Preoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS for resected brain metastases (BM). Most reported studies of preoperative SRS used single-fraction SRS (SF-SRS). The goal of this study was to compare outcomes and toxicity of preoperative SF-SRS with multifraction (3-5 fractions) SRS (MF-SRS) in a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). Patients with BM from solid cancers, of which at least 1 lesion was treated with preoperative SRS followed by planned resection, were included from 8 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included prior or planned whole brain radiation therapy. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. The study cohort included 404 patients with 416 resected index lesions, of which SF-SRS and MF-SRS were used for 317 (78.5%) and 87 patients (21.5%), respectively. Median dose was 15 Gy in 1 fraction for SF-SRS and 24 Gy in 3 fractions for MF-SRS. Univariable analysis demonstrated that SF-SRS was associated with higher cavity local recurrence (LR) compared with MF-SRS (2-year: 16.3% vs 2.9%; P=.004), which was also demonstrated in multivariable analysis. PSM yielded 81 matched pairs (n=162). PSM analysis also demonstrated significantly higher rate of cavity LR with SF-SRS (2-year: 19.8% vs 3.3%; P=.003). There was no difference in adverse radiation effect, meningeal disease, or overall survival between cohorts in either analysis. Preoperative MF-SRS was associated with significantly reduced risk of cavity LR in both the unmatched and PSM analyses. There was no difference in adverse radiation effect, meningeal disease, or overall survival based on fractionation. MF-SRS may be a preferred option for neoadjuvant radiation therapy of resected BMs. Additional confirmatory studies are needed. A phase 3 randomized trial of single-fraction preoperative versus postoperative SRS (NRG-BN012) is ongoing (NCT05438212).

Risk Factors for Progression and Toxic Effects After Preoperative Stereotactic Radiosurgery for Patients With Resected Brain Metastases

Preoperative stereotactic radiosurgery (SRS) has been demonstrated as a feasible alternative to postoperative SRS for resectable brain metastases (BMs) with potential benefits in adverse radiation effects (AREs) and meningeal disease (MD). However, mature large-cohort multicenter data are lacking. To evaluate preoperative SRS outcomes and prognostic factors from a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). This multicenter cohort study included patients with BMs from solid cancers, of which at least 1 lesion received preoperative SRS and a planned resection, from 8 institutions. Radiosurgery to synchronous intact BMs was allowed. Exclusion criteria included prior or planned whole-brain radiotherapy and no cranial imaging follow-up. Patients were treated between 2005 and 2021, with most treated between 2017 and 2021. Preoperative SRS to a median dose to 15 Gy in 1 fraction or 24 Gy in 3 fractions delivered at a median (IQR) of 2 (1-4) days before resection. The primary end points were cavity local recurrence (LR), MD, ARE, overall survival (OS), and multivariable analysis of prognostic factors associated with these outcomes. The study cohort included 404 patients (214 women [53%]; median [IQR] age, 60.6 [54.0-69.6] years) with 416 resected index lesions. The 2-year cavity LR rate was 13.7%. Systemic disease status, extent of resection, SRS fractionation, type of surgery (piecemeal vs en bloc), and primary tumor type were associated with cavity LR risk. The 2-year MD rate was 5.8%, with extent of resection, primary tumor type, and posterior fossa location being associated with MD risk. The 2-year any-grade ARE rate was 7.4%, with target margin expansion greater than 1 mm and melanoma primary being associated with ARE risk. Median OS was 17.2 months (95% CI, 14.1-21.3 months), with systemic disease status, extent of resection, and primary tumor type being the strongest prognostic factors associated with OS. In this cohort study, the rates of cavity LR, ARE, and MD after preoperative SRS were found to be notably low. Several tumor and treatment factors were identified that are associated with risk of cavity LR, ARE, MD, and OS after treatment with preoperative SRS. A phase 3 randomized clinical trial of preoperative vs postoperative SRS (NRG BN012) has began enrolling (NCT05438212).

CAR T-cell-associated neurotoxicity in central nervous system hematologic disease: Is it still a concern?

Chimeric antigen receptor (CAR) T-cell systemic immunotherapy has revolutionized how clinicians treat several refractory and relapsed hematologic malignancies. Due to its peculiar mechanism of action, CAR T-cell-based therapy has enlarged the spectrum of neurological toxicities. CAR T-cell-associated neurotoxicity-initially defined as CAR T-cell-related encephalopathy syndrome (CRES) and currently coined within the acronym ICANS (immune effector cell-associated neurotoxicity syndrome)-is perhaps the most concerning toxicity of CAR T-cell therapy. Importantly, hematologic malignancies (especially lymphoid malignancies) may originate in or spread to the central nervous system (CNS) in the form of parenchymal and/or meningeal disease. Due to the emergence of deadly and neurological adverse events, such as fatal brain edema in some patients included in early CAR T-cell trials, safety concerns for those with CNS primary or secondary infiltration arose and contributed to the routine exclusion of individuals with pre-existing or active CNS involvement from pivotal trials. However, based primarily on the lack of evidence, it remains unknown whether CNS involvement increases the risk and/or severity of CAR T-cell-related neurotoxicity. Given the limited treatment options available for patients once they relapse with CNS involvement, it is of high interest to explore the role of novel clinical strategies including CAR T cells to treat leukemias/lymphomas and myeloma with CNS involvement. The purpose of this review was to summarize currently available neurological safety data of CAR T-cell-based immunotherapy from the clinical trials and real-world experiences in adult patients with CNS disease due to lymphoma, leukemia, or myeloma. Increasing evidence supports that CNS involvement in hematologic disease should no longer be considered per se as an absolute contraindication to CAR T-cell-based therapy. While the incidence may be high, severity does not appear to be impacted significantly by pre-existing CNS status. Close monitoring by trained neurologists is recommended.

In Vitro Activity of Ceftolozane-Tazobactam against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa Obtained from Blood Cultures from Sentinel Public Hospitals in South Africa.

Multidrug-resistant (MDR) Gram-negative bacteria are responsible for the majority of healthcare-associated infections and pose a serious threat as they complicate and prolong clinical care. A novel cephalosporin-β-lactamase-inhibitor combination, ceftolozane-tazobactam (C/T) was introduced in 2014, which improved the treatment of MDR pathogens. This study aimed to evaluate the activity of C/T against Escherichia coli (n = 100), Klebsiella pneumoniae (n = 100), and Pseudomonas aeruginosa (n = 100) blood culture isolates in South Africa (SA). Isolates were sequentially selected (2010 to 2020) from the Group for Enteric, Respiratory, and Meningeal Diseases Surveillance (GERMS) programme in SA. Organism identification was performed using the matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS) instrument (Microflex, Bruker Daltonics, Bremen, Germany), and antibiotic susceptibility was performed using the Sensititre instrument (Trek Diagnostic Systems, East Grinstead, UK). C/T resistance was reported in 16 E. coli, 28 K. pneumoniae and 13 P. aeruginosa isolates. Fifty percent of the C/T resistant isolates were subjected to whole-genome sequencing (WGS). According to the whole genome multilocus sequence typing (MLST) analysis, the E. coli isolates (n = 8) belonged to sequence type (ST)10, ST131, ST405, and ST410, the K. pneumoniae isolates (n = 14) belonged to ST1, ST37, ST73, ST101, ST231, ST307, ST336 and ST6065 (novel ST), and the P. aeruginosa isolates (n = 7) belonged to ST111, ST233, ST273, and ST815. The WGS data also showed that all the E. coli isolates harboured aminoglycoside (aph (3'')-Ib, aph (6)-Id), macrolide (mdfA, mphA), and sulphonamide (sul2) antibiotic resistance genes, all the K. pneumoniae isolates harboured β-lactam (blaCTX-M-15), and sulphonamide (sul2) antibiotic resistance genes, and all the P. aeruginosa isolates harboured aminoglycoside (aph (3')-IIb), β-lactam (PAO), fosfomycin (fosA), phenicol (catB7), quinolone (crpP), and disinfectant (qacE) antibiotic resistance genes. It is evident that E. coli, K. pneumoniae and P. aeruginosa can adapt pre-existing resistance mechanisms to resist newer β-lactam molecules and inhibitors, since these isolates were not exposed to ceftolozane-tazobactam previously.

RADT-12. PRE- AND POST-OPERATIVE RADIATION TREATMENT PLANNING FOR PATIENTS RECEIVING STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: A VOLUMETRIC ANALYSIS

Abstract BACKGROUND Pre-operative stereotactic radiosurgery (SRS) has emerged as a recent treatment option to treat large or symptomatic brain metastases. Compared to post-operative SRS, pre-operative treatment may reduce rates of radiation necrosis (RN) and meningeal disease through treating a smaller treatment volume and by preventing post-operative tumor seeding. We hypothesize that pre-operative radiation volumes will be smaller than post-operative volumes, which in turn may lead to a decreased treatment morbidity. METHODS A retrospective analysis was conducted and patients who had surgical resection and post-operative SRS or fractionated stereotactic radiosurgery (FSRT) for a posterior fossa brain metastasis were eligible for inclusion. Both pre-operative and post-operative MRIs were required to allow for accurate radiation target delineation. A pre-operative tumor volume was added for each patient, and the post-operative clinical treatment volume (CTV) used for radiation treatment was included. Pre-operative tumor and post-operative cavity volumes were compared using Wilcoxon signed rank test. RESULTS 28 patients who received post-operative SRS or FSRT from 1/1/2016-12/31/2020 were included in this analysis. The mean pre-operative tumor volume was 14.9 ccs, and the mean post-operative CTV was 21.0 ccs (p < 0.01). 75% of patients had a smaller initial tumor size compared to the post-operative CTV used for radiation treatment planning. For patients with at least 4 follow up MRIs (n = 8), the size of the post-operative cavity progressively decreased with a mean initial cavity volume of 18.9 ccs and mean follow up volumes of 8.1, 7.1, 6.9, and 6.2 ccs. CONCLUSIONS In this study evaluating patients who received post-operative SRS, the pre-operative tumor volume was lower than the post-operative CTV for most patients. Previous studies including PROPS-BM have shown how pre-operative treatment may reduce the risk of RN because smaller radiation volumes are used. Pre-operative radiosurgery for patients with brain metastases requires prospective validation.

Comparing pre-operative versus post-operative single and multi-fraction stereotactic radiotherapy for patients with resectable brain metastases

BackgroundThe standard treatment for patients with large brain metastases and limited intracranial disease is surgical resection and post-operative stereotactic radiosurgery (SRS). However, post-operative SRS still has elevated rates of local failure (LF) and is complicated by radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated therapy may improve local control through delivering a higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) will have less toxicity compared to patients who receive post-operative SRS or FSRT. MethodsA multi-institutional analysis was conducted and included patients who had surgical resection and stereotactic radiation therapy to treat at least one brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. The primary outcome was a composite endpoint defined as patients with one of the following adverse events: 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. Results279 patients were eligible for analysis. The median follow-up time was 9 months. 87 % of patients received fractionated treatment. 29 % of patients received pre-operative treatment. The composite endpoint incidences for post-operative SRS (n = 10), post-operative FSRT (n = 189), pre-operative SRS (n = 27), and pre-operative FSRT (n = 53) were 0 %, 17 %, 15 %, and 7.5 %, respectively. ConclusionsIn our study, the composite endpoint of 7.5% for pre-operative FSRT compares favorably to our post-operative FSRT rate of 17%. Pre-operative FSRT was observed to have low rates of LF, MD, and RN. Prospective validation is needed.

Risk Factors for Progression and Toxicity after Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease (MD) compared to postop SRS. The goal of this study was to determine risk factors for progression and toxicity after preop SRS in an expanded multicenter cohort. <h3>Materials/Methods</h3> Patients with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy (WBRT). SRS dose, fractionation, and interval between preop SRS and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Radiographic MD was categorized as nodular (nMD) or classical "sugarcoating" (cMD). <h3>Results</h3> The cohort consisted of 378 patients with 389 preop SRS treated index lesions. Most patients (61.1%) had a single BM, underwent gross total resection (GTR, 95.4%), and had non-small cell lung (NSCLC, 47.9%), breast (16.1%), or melanoma (11.4%) cancer. Median dose was 15 Gy in 1 fraction to a median gross tumor volume (GTV) of 10.1 cc. Median interval between preop SRS and surgery was 2 days. Median cranial imaging follow-up interval was 9.5 months overall and 17.5 months for alive patients. The 2-year cavity local recurrence (LR) rate was 14.5%. Multivariable analysis (MVA) for LR demonstrated subtotal resection (STR, vs. GTR), single fraction SRS (vs. fractionated), larger GTV, gastrointestinal (GI) primary (vs. NSCLC), active systemic disease, and piecemeal resection (vs. en bloc) to be associated with higher risk of LR. Of note, interval between preop SRS and surgery was not significant. The 2-year any grade ARE rate was 7.7%. MVA for ARE demonstrated only larger planning target volume (PTV) margin expansion as associated with higher risk of ARE. The 2-year rate of MD was 5.6%. Most MD (76%) was classical type, with the remainder being nodular type. MVA for MD demonstrated STR (vs. GTR) and breast or melanoma histology (vs. NSCLC) as associated with higher risk of MD. Of note, posterior fossa location and type of surgical resection were not significant. <h3>Conclusion</h3> Preop SRS demonstrates overall excellent rates of cavity LR, ARE, and MD in this expanded multicenter cohort study. We have identified several tumor and treatment factors that are significantly associated with risk of cavity LR, ARE, and MD after treatment with preop SRS. Minimizing likelihood of STR and treating with fractionated preop SRS for larger higher risk tumors may lead to improved outcomes. A randomized trial of preop versus postop SRS is currently being designed (NRG BN012).

Pre-Operative vs. Post-Operative Fractionated Stereotactic Radiotherapy for Patients with Brain Metastases: A Multi-Institutional Analysis

<h3>Purpose/Objective(s)</h3> The standard treatment for patients with large brain metastases and limited intracranial disease is surgical resection and post-operative stereotactic radiosurgery (SRS). However, post-operative SRS still has elevated rates of local failure (LF), radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated treatments may improve local control by allowing delivery of higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) will have lower rates of RN, MD, and LF compared to patients who receive post-operative SRS or FSRT. <h3>Materials/Methods</h3> A retrospective, multi-institutional analysis was conducted and included patients who had surgical resection and radiation to treat at least one brain metastasis. Pre- and post-operative patients were eligible for inclusion. Single fraction and fractionated radiation treatments were allowed. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. The primary outcome was a composite endpoint defined by the events of 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. <h3>Results</h3> 279 patients were eligible for analysis. The median follow up was 8 months. 87% of patients received fractionated treatment. 29% of patients received pre-operative treatment. Patients receiving post-operative radiation had a significantly larger planning treatment volume (PTV) compared to pre-operative patients (38 vs. 14 ccs, p<0.001). The composite endpoint incidences for post-operative SRS (n = 10), post-operative FSRT (n = 189), pre-operative SRS (n = 27), and pre-operative FSRT (n = 53) were 0%, 17%, 15%, and 8%, respectively. <h3>Conclusion</h3> In our study, the composite endpoint of 8% for pre-operative FSRT was improved compared to our post-operative FSRT rate of 17% and compares favorably to historical post-operative SRS endpoints of 49-60% (N107C, Mahajan et. al, JCOG0504) and pre-operative SRS endpoints of 20.6% (PROPS-BM). Pre-operative FSRT appears to be safe and effective due to reduced incidence of LF, MD, and RN. Prospective validation is needed.

Single Fraction vs. Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease compared to postop SRS. Most reported studies of preop SRS utilized single fraction (fx) SRS. The goal of this study was to compare outcomes and toxicity of single fraction preop SRS with fractionated (3-5 fx) preop stereotactic radiotherapy (FSRT). <h3>Materials/Methods</h3> Patients (pts) with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS or FSRT and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy. RT dose, fractionation, and interval between preop RT and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. <h3>Results</h3> The cohort included 378 pts with 389 preop RT treated index lesions. Most pts had non-small cell lung (47.9%), breast (16.1%), or melanoma (11.4%) cancer. The majority of pts (61.1%) had a single BM and 95.4% underwent gross total resection (GTR). SRS was used for 328 (84.3%) lesions with FSRT used for 61 (15.7%). Most FSRT (93.4%) was 3 fx, with the remainder being 5 fx. Median prescribed dose for FSRT and SRS was 24 Gy and 15 Gy, respectively. There were baseline imbalances between cohorts. The FSRT cohort had significantly more use of planning target volume (PTV) margin expansion > 1 mm (64% vs. 5.2%), more pts with multiple BM (54% vs. 38%), and larger median gross tumor volume (GTV, 12.3 cc vs. 9.7 cc). In univariate analysis, preop FSRT was associated with significantly lower rate of cavity local recurrence (LR) than SRS (1-year: 2.8% vs. 14.1%, p=0.02). PSM yielded 57 matched pairs. There were no significant residual imbalances in the PSM cohorts. Median imaging FU period was 8 months for both groups. FSRT was associated with significantly lower cavity LR compared with SRS (1-year: 3% vs. 17.9%, p=0.02). There were no differences in ≥ grade 2 ARE (7.4% vs. 4.9%, p=0.34), meningeal disease (2% vs. 4%, p=0.81), or distant brain failure (21.8% vs. 37.4%, p=0.25). No grade 3 - 5 ARE events occurred. Overall survival (OS) was significantly higher with FSRT in PSM analysis as well (1-year: 71.2% vs. 52.1%, p=0.04). <h3>Conclusion</h3> Preop FSRT (3-5 fx) is associated with significantly reduced risk of cavity LR and improved OS compared with preop single fx SRS. Both preop FSRT and SRS show notably low rates of ARE and meningeal disease. Three fx preop FSRT may be a preferred option for neoadjuvant RT of larger or higher risk lesions. Additional confirmatory studies are needed. A randomized trial of preop SRS versus postop SRS is currently being designed (NRG BN012).

Meningo-cortical manifestations of myelin oligodendrocyte glycoprotein antibody-associated disease: Review of a novel clinico-radiographic spectrum

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disease that is distinct from multiple sclerosis. Initial manifestations of MOGAD that were reported in the literature included optic neuritis, myelitis, brainstem demyelination and encephalitis, with emphasis placed on acute disseminated encephalomyelitis (ADEM) as the primary encephalitic presentation. In 2017, however, Ogawa et al. described four patients with seizures, unilateral cortical hyperintensities on brain magnetic resonance imaging T2-fluid-attenuated inversion recovery sequences, and anti-MOG positivity, indicating a potentially novel form of encephalitis in MOGAD. In 2019, we systematically reviewed the literature to better characterize this unique syndrome, which we referred to as unilateral cortical FLAIR-hyperintense Lesions in Anti-MOG-associated Encephalitis with Seizures (FLAMES). Subsequently, anti-MOG positivity in patients with a variety of cortical and meningeal disease presentations has been reported, indicating a broader spectrum of meningo-cortical manifestations in MOGAD that we review herein.