Pulsed reduced-dose rate re-irradiation for patients with recurrent grade 2 gliomas.

Background: Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced-dose rate (PRDR) radiation for patients with recurrent grade 2 glioma. Methods: A retrospective analysis of 58 patients treated with PRDR from 2000 to 2021 was performed. Radiation was delivered in 0.2 Gy pulses every 3 minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan-Meier and Cox regression analyses. Results: The median survival from the date of initial surgery was 8.6 years (95% CI: 5.5-11.8 years). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI: 8.3-17.0 months) and progression-free survival was 6.2 months (95% CI: 3.8-8.6 months). Overall response rate based on post-PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with 5 patients remaining disease-free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated. Conclusions: To the best of our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q codeletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.

Tumor Volume Growth Rates and Doubling Times during Active Surveillance of IDH-mutant Low-Grade Glioma.

PURPOSE: Isocitrate dehydrogenase-mutant (IDH-mt) gliomas are incurable primary brain tumors characterized by a slow-growing phase over several years followed by a rapid-growing malignant phase. We hypothesized that tumor volume growth rate (TVGR) on MRI may act as an earlier measure of clinical benefit during the active surveillance period. EXPERIMENTAL DESIGN: We integrated three-dimensional volumetric measurements with clinical, radiologic, and molecular data in a retrospective cohort of IDH-mt gliomas that were observed after surgical resection in order to understand tumor growth kinetics and the impact of molecular genetics. RESULTS: Using log-linear mixed modeling, the entire cohort (n = 128) had a continuous %TVGR per 6 months of 10.46% [95% confidence interval (CI), 9.11%-11.83%] and a doubling time of 3.5 years (95% CI, 3.10-3.98). High molecular grade IDH-mt gliomas, defined by the presence of homozygous deletion of CDKN2A/B, had %TVGR per 6 months of 19.17% (95% CI, 15.57%-22.89%) which was significantly different from low molecular grade IDH-mt gliomas with a growth rate per 6 months of 9.54% (95% CI, 7.32%-11.80%; P < 0.0001). Using joint modeling to comodel the longitudinal course of TVGR and overall survival, we found each one natural logarithm tumor volume increase resulted in more than a 3-fold increase in risk of death (HR = 3.83; 95% CI, 2.32-6.30; P < 0.0001). CONCLUSIONS: TVGR may be used as an earlier measure of clinical benefit and correlates well with the WHO 2021 molecular classification of gliomas and survival. Incorporation of TVGR as a surrogate endpoint into future prospective studies of IDH-mt gliomas may accelerate drug development.

Leptomeningeal Carcinomatosis from Solid Tumor Malignancies: Treatment Strategies and Biomarkers.

Leptomeningeal metastases/diseases (LMDs) are a late-stage complication of solid tumor or hematologic malignancies. LMD is spread of cancer cells to the layers of the leptomeninges (pia and arachnoid maters) and subarachnoid space seen in 3 to 5% of cancer patients. It is a disseminated disease which carries with it significant neurologic morbidity and mortality. Our understanding of disease pathophysiology is currently lacking; however, advances are being made. As our knowledge of disease pathogenesis has improved, treatment strategies have evolved. Mainstays of treatment such as radiotherapy have changed from involved-field radiotherapy strategies to proton craniospinal irradiation which has demonstrated promising results in recent clinical trials. Systemic treatment strategies have also improved from more traditional chemotherapeutics with limited central nervous system (CNS) penetration to more targeted therapies with better CNS tumor response. Many challenges remain from earlier clinical detection of disease through improvement of active treatment options, but we are getting closer to meaningful treatment.

Cerebrospinal fluid-administered therapies for leptomeningeal metastases from solid tumors.

Aims/purpose: Leptomeningeal metastases (LM) are associated with substantial morbidity and mortality. Several approaches are used to treat LM, including intrathecally administered therapies. We consolidated current studies exploring intrathecal therapies for LM treatment. Patients & methods: A review of clinical trials using intrathecal agents was conducted with outcomes tabulated and trends described. 48 trials met the inclusion criteria. Initial investigations began with cytotoxic agents; following this were formulations with longer cerebrospinal fluid half-lives, targeted antibodies and radionucleotides. Results & conclusion: Outcomes were not reported consistently. Survival, when reported, remained poor. Intrathecal therapies for LM remain a viable option. Their use can be informed by an understanding of efficacy, safety and toxicity. They may be an important component of future LM treatments.

This paper summarizes the findings from 48 clinical trials conducted since the 1970s about the treatment of leptomeningeal metastases through an intrathecal approach (administering drugs directly into the cerebrospinal fluid ­ a fluid that surrounds the brain and spinal cord). The results of these studies suggest that although these therapies show promise for the future, they currently do not clearly and consistently report a benefit. Further work is needed to explore the possible use of these treatments.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Hemangioblastoma and mosaic von Hippel Lindau disease: rare presentation and review of the literature.

Hemangioblastomas are benign vascular tumors that can occur throughout the central nervous system (CNS) sporadically or in association with von Hippel-Lindau (VHL) disease. We present a case of an 11-year-old girl with a hemangioblastoma that tested negative for germline mutation of VHL disease at the time of diagnosis. Our patient went on to have multiple recurrences and further areas of concern for disease within the CNS. Repeat VHL testing was pursued many years later and remained negative for germline mutations. However, next-generation sequencing (NGS) testing on prior tumor tissue returned positive for VHL somatic mutations. The diagnosis of VHL mosaicism has important implications on management and risk of recurrence of hemangioblastoma, along with the need for close follow-up with surveillance imaging.

In Situ Liquid Electrochemical TEM Investigation of LiMn1.5 Ni0.5 O4 Thin Film Cathode for Micro-Battery Applications.

Micro-batteries are attractive miniaturized energy devices for new Internet of Things applications, but the lack of understanding of their degradation process during cycling hinders improving their performance. Here focused ion beam (FIB)-lamella from LiMn1.5 Ni0.5 O4 (LMNO) thin-film cathode is in situ cycled in a liquid electrolyte inside an electrochemical transmission electron microscope (TEM) holder to analyze structural and morphology changes upon (de)lithiation processes. A high-quality electrical connection between the platinum (Pt) current collector of FIB-lamella and the microchip's Pt working electrode is established, as confirmed by local two-probe conductivity measurements. In situ cyclic voltammetry (CV) experiments show two redox activities at 4.41 and 4.58/4.54 V corresponding to the Ni2+/3+ and Ni3+/4+ couples, respectively. (S)TEM investigations of the cycled thin-film reveal formation of voids and cracks, loss of contact with current collector, and presence of organic decomposition products. The 4D STEM ASTAR technique highlights the emergence of an amorphization process and a decrease in average grain size from 20 to 10 nm in the in situ cycled electrode. The present findings, obtained for the first time through the liquid electrochemical TEM study, provide several insights explaining the capacity fade of the LMNO thin-film cathode typically observed upon cycling in a conventional liquid electrolyte.

IDH-Mutant Low-grade Glioma: Advances in Molecular Diagnosis, Management, and Future Directions.

PURPOSE OF REVIEW: IDH-mutant low-grade gliomas (LGG) have emerged as a distinct clinical and molecular entity with unique treatment considerations. Here, we review updates in IDH-mutant LGG diagnosis and classification, imaging biomarkers, therapies, and neurocognitive and patient-reported outcomes. RECENT FINDINGS: CDKN2A/B homozygous deletion in IDH-mutant astrocytoma is associated with shorter survival, similar to WHO grade 4. The T2-FLAIR mismatch, a highly specific but insensitive sign, is diagnostic of IDH-mutant astrocytoma. Maximal safe resection is currently indicated in all LGG cases. Radiotherapy with subsequent PCV (procarbazine, lomustine, vincristine) provides longer overall survival compared to radiotherapy alone. Temozolomide in place of PCV is reasonable, but high-level evidence is still lacking. LGG adjuvant treatment has important quality of life and neurocognitive side effects that should be considered. Although incurable, IDH-mutant LGG have a favorable survival compared to IDH-WT glioma. Recent advances in molecular-based classification, imaging, and targeted therapies will hopefully improve survival and quality of life.

Role of Ethnicity and Geographic Location on Glioblastoma IDH1/IDH2 Mutations.

BACKGROUND: Previous studies have demonstrated possible differences in glioblastoma (GBM) survival attributable to ethnicity. The goal of this study was to quantify oncogenic differences and evaluate the overall survival (OS) and progression-free survival (PFS) differences in GBM patients across race/ethnicity using both population-based surveillance and institutional data sets from the United States (US) and Mexico. METHODS: Retrospective cohort study comprising the Texas Cancer Registry (TCR, n = 4134) and referral institutions located in US (n = 254) and Mexico (n = 47) were evaluated. Primary outcomes include OS and PFS. Oncogenic differences attributable to ethnicity were assessed. IDH1/IDH2 status was evaluated by sequencing in US and Mexico samples. Kaplan-Meier and Cox proportional hazards regression for survival analysis. RESULTS: A total of 4134 GBM patients were identified from the TCR data set, ethnicity comparison demonstrated that Hispanic patients were diagnosed at a significantly younger age compared to non-Hispanic white patients (NHW) (median: 58 vs. 62, P < 0.001) and had improved OS (hazard ratio: 0.82, P < 0.001). In the oncogenic analysis, we observed a significant enrichment of IDH1/IDH2 mutations in Mexican Hispanic patients compared to US Hispanic patients (29.8% vs. 7.9%, P = 0.012); IDH2 mutations drove this difference. Post-progression survival was significantly shorter in patients from Mexico than US (3.0 vs. 11.4 months; P < 0.001), while OS remained similar. CONCLUSIONS: IDH2 mutations are more prevalent in Mexican Hispanic individuals compared to US individuals and may be a crucial contributor to the previously reported survival benefit of Hispanic individuals in large population databases. These findings are critical for both screening of IDH2 mutations and targeted interventions in GBM.

Rethinking the need for a platelet transfusion threshold of 50 × 109 /L for lumbar puncture in cancer patients.

BACKGROUND: Lumbar puncture (LP) is a frequently performed diagnostic and therapeutic procedure in oncology patients. Transfusing to a minimum preprocedural platelet threshold of 50 × 109 /L is widely upheld without good quality evidence. The objective was to compare the outcomes of LPs performed with platelets above and below this threshold. An increased risk of adverse events in patients with lower platelet counts was not expected. As a corollary, transfusion reaction rates incurred by transfusing to this recommended threshold are also reported. METHODS: A total of 2259 LPs performed on 1137 oncology patients (adult, n = 871, and pediatric, n = 266) were retrospectively analyzed between February 2011 and December 2017. The incidence of LP-related complications for groups above and below the minimum platelet threshold was compared. Traumatic tap was defined as 500 or more red blood cells per high-power field in the cerebral spinal fluid. Groups were compared using the 2-Proportion Z-test and Fisher exact test. RESULTS: At time of LP, the total number of events with platelets less than 50 × 109 /L and 50 × 109 /L or greater were 110 and 2149, respectively. There were no significant differences in LP-associated complications between patients with platelet counts above or below 50 × 109 /L (P = .29). Patients with a pre-LP platelet count of less than 50 × 109 /L had a higher proportion of traumatic taps (P < .001). Three patients developed transfusion-related adverse events. CONCLUSION: Patients with platelet counts less than 50 × 109 /L did not have a higher incidence of clinically significant post-lumbar puncture complications (P = .29).

Neurologic and oncologic features of Erdheim-Chester disease: a 30-patient series.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the MAPK (mitogen-activating protein kinase) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. METHODS: We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. RESULTS: Median age was 52 years (range, 7-77), and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 patients (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%). Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and 2 fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppressants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 patients (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%), and complete metabolic response in 1/16 (6%) by 18F-fluorodeoxyglucose (FDG)-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. CONCLUSIONS: These data highlight underrecognized symptomatology, heterogeneous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

MRI radiomic features are associated with survival in melanoma brain metastases treated with immune checkpoint inhibitors.

BACKGROUND: Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival. METHODS: Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis. RESULTS: Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19-91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort. CONCLUSION: Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS.

Staging identifies non-CNS malignancies in a large cohort with newly diagnosed lymphomatous brain lesions.

Lymphomatous brain lesions can represent primary central nervous system (CNS) lymphoma or secondary involvement as part of systemic disease (SCNSL). In this study, we characterize staging evaluations in a large patient cohort with newly-diagnosed brain lymphomas, to determine the frequency of SCNSL and secondary malignancies. This retrospective review includes 262 patients with newly-diagnosed lymphomatous CNS lesions evaluated at Memorial Sloan Kettering Cancer Center between 2006 and 2018. Staging procedures included PET scans in 180 (69%) patients, CT scans of chest/abdomen/pelvis (CAP) in 195 (74%) and bone marrow biopsies (BMB) in 177 (68%). PET scans were reported as abnormal in 34 of 180 (19%), CT in 50 of 195 (26%) and BMB in 15 of 177 (8.5%). A total of 24 non-CNS malignancies were identified (11.8%; 19 systemic lymphomas and 5 secondary malignancies). Thus, in patients with new lymphomatous brain lesions, performing initial systemic staging procedures can identify systemic lymphoma and additional malignancies, highlighting the importance of staging evaluations, in particular PET and BMB.

Distinctive Infectious Complications in Patients with Central Nervous System Lymphoma Undergoing Thiotepa, Busulfan, and Cyclophosphamide-conditioned Autologous Stem Cell Transplantation.

We investigated the incidence of viral, fungal, bacterial, and parasitic infections observed in 57 patients with central nervous system lymphoma after thiotepa, busulfan, and cyclophosphamide-conditioned autologous stem cell transplantation (TBC-ASCT) and 79 patients with systemic non-Hodgkin lymphoma after traditional carmustine, etoposide, cytarabine, and melphalan-conditioned ASCT (BEAM-ASCT). Twenty of 57 (35%) TBC-ASCT patients had detectable viremia with human herpesvirus 6, cytomegalovirus, adenovirus, or BK virus, versus 9 of 79 (11%) BEAM-ASCT patients. Eight TBC-ASCT patients had clinically relevant viral infections (4 human herpesvirus 6, 2 cytomegalovirus, 1 adenovirus, 2 BK virus), versus 0 in the BEAM-ASCT group. Four TBC-ASCT patients suffered infections from either a fungal or parasitic pathogen versus 1 BEAM-ASCT patient. TBC was associated with greater risk of viral reactivation compared with BEAM, independent of other factors (hazard ratio, 4.42; 95% confidence interval, 1.9 to 11.3; P < .001). Prolonged lymphopenia and steroid use in the peri- and post-ASCT period did not explain these observed differences. The pathogenesis of these unusual infections in TBC-ASCT patients remains incompletely understood, and may involve more potent immune suppression with TBC conditioning. Clinicians should be aware of these differences in infection risk in TBC-ASCT patients, which more closely parallel those seen in allogenic hematopoietic cell transplantation recipients. New prophylactic approaches to help minimize these infections should be considered in this population.

Overexpression of DMP1 accelerates mineralization and alters cortical bone biomechanical properties in vivo.

Dentin matrix protein-1 (DMP1) is a key regulator of biomineralization. Here, we examine changes in structural, geometric, and material properties of cortical bone in a transgenic mouse model overexpressing DMP1. Micro-computed tomography and three-point bending were performed on 90 femora of wild type and transgenic mice at 1, 2, 4, and 6 months. Fourier transform infrared imaging was performed at 2 months. We found that the transgenic femurs were longer (p<0.01), more robust in cross-section (p<0.05), stronger (p<0.05), but had less post-yield strain and displacement (p<0.01), and higher tissue mineral density (p<0.01) than the wild type femurs at 1 and 2 months. At 2 months, the transgenic femurs also had a higher mineral-to-matrix ratio (p<0.05) and lower carbonate substitution (p<0.05) compared to wild type femurs. These findings indicate that increased mineralization caused by overexpressing DMP1 led to increased structural cortical bone properties associated with decreased ductility during the early post-natal period.

TNF-alpha knockout and minocycline treatment attenuates blood-brain barrier leakage in MPTP-treated mice.

Following intraparenchymal injection of the dopamine (DA) neurotoxin 6-hydroxydopamine, we previously demonstrated passage of fluoresceinisothiocyanate-labeled albumin (FITC-LA) from blood into the substantia nigra (SN) and striatum suggesting damage to the blood-brain barrier (BBB). The factors contributing to the BBB leakage could have included neuroinflammation, loss of DA neuron control of barrier function, or a combination of both. In order to determine which factor(s) was responsible, we assessed BBB integrity using the FITC-LA technique in wild-type (WT), tumor necrosis factor alpha (TNF-alpha) knockout (KO), and minocycline (an inhibitor of microglia activation) treated mice 72 h following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Compared with WT mice, TNF-alpha KO mice treated with MPTP showed reduced FITC-LA leakage, decreased numbers of activated microglia, and reduced proinflammatory cytokines (TNF-alpha and interleukin 1beta) associated with significant MPTP-induced DA neuron loss. In contrast, minocycline treated animals did not exhibit significant MPTP-induced DA neuron loss although their FITC-LA leakage, numbers of activated microglia, and MPTP-induced cytokines were markedly attenuated. Since both TNF-alpha KO and minocycline treatment attenuated MPTP-induced BBB dysfunction, microglial activation, and cytokine increases, but had differential effects on DA neuron loss, it appears that neuroinflammation and not DA neuron loss was responsible for disrupting the blood-brain barrier integrity.