Impact of Frailty on Surgical Outcomes of Patients With Cushing Disease Using the Multicenter Registry of Adenomas of the Pituitary and Related Disorders Registry.

BACKGROUND AND OBJECTIVES: Despite growing interest in how patient frailty affects outcomes (eg, in neuro-oncology), its role after transsphenoidal surgery for Cushing disease (CD) remains unclear. We evaluated the effect of frailty on CD outcomes using the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) data set from a collaboration of US academic pituitary centers. METHODS: Data on consecutive surgically treated patients with CD (2011-2023) were compiled using the 11-factor modified frailty index. Patients were classified as fit (score, 0-1), managing well (score, 2-3), and mildly frail (score, 4-5). Univariable and multivariable analyses were conducted to examine outcomes. RESULTS: Data were analyzed for 318 patients (193 fit, 113 managing well, 12 mildly frail). Compared with fit and managing well patients, mildly frail patients were older (mean ± SD 39.7 ± 14.2 and 48.9 ± 12.2 vs 49.4 ± 8.9 years, P < .001) but did not different by sex, race, and other factors. They had significantly longer hospitalizations (3.7 ± 2.0 and 4.5 ± 3.5 vs 5.3 ± 3.5 days, P = .02), even after multivariable analysis (ß = 1.01, P = .007) adjusted for known predictors of prolonged hospitalization (age, Knosp grade, surgeon experience, American Society of Anesthesiologists grade, complications, frailty). Patients with mild frailty were more commonly discharged to skilled nursing facilities (0.5% [1/192] and 4.5% [5/112] vs 25% [3/12], P < .001). Most patients underwent gross total resection (84.4% [163/193] and 79.6% [90/113] vs 83% [10/12]). No difference in overall complications was observed; however, venous thromboembolism was more common in mildly frail (8%, 1/12) than in fit (0.5%, 1/193) and managing well (2.7%, 3/113) patients (P = .04). No difference was found in 90-day readmission rates. CONCLUSION: These results demonstrate that mild frailty predicts CD surgical outcomes and may inform preoperative risk stratification. Frailty-influenced outcomes other than age and tumor characteristics may be useful for prognostication. Future studies can help identify strategies to reduce disease burden for frail patients with hypercortisolemia.

Multicenter Registry of Adenomas of the Pituitary and Related Disorders: Initial Description of Cushing Disease Cohort, Surgical Outcomes, and Surgeon Characteristics.

BACKGROUND AND OBJECTIVES: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies. METHODS: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission. RESULTS: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years. CONCLUSION: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD.

Tumor-informed deep sequencing of ctDNA detects minimal residual disease and predicts relapse in osteosarcoma.

Background: Current surveillance modalities of osteosarcoma relapse exhibit limited sensitivity and specificity. Although circulating tumor DNA (ctDNA) has been established as a biomarker of minimal residual disease (MRD) in many solid tumors, a sensitive ctDNA detection technique has not been thoroughly explored for longitudinal MRD detection in osteosarcoma. Methods: From August 2019 to June 2023, 59 patients diagnosed with osteosarcoma at the First Affiliated Hospital of Sun Yat-sen University were evaluated in this study. Tumor-informed MRD panels were developed through whole exome sequencing (WES) of tumor tissues. Longitudinal blood samples were collected during treatment and subjected to multiplex PCR-based next-generation sequencing (NGS). Kaplan-Meier curves and Log-rank tests were used to compare outcomes, and Cox regression analysis was performed to identify prognostic factors. Findings: WES analysis of 83 patients revealed substantial mutational heterogeneity, with non-recurrent mutated genes accounting for 58.1%. Tumor-informed MRD panels were successfully obtained for 85.5% of patients (71/83). Among 59 patients with successful MRD panel customization and available blood samples, 13 patients exhibited positive ctDNA detection after surgery. Patients with negative post-operative ctDNA had better event-free survival (EFS) compared to those with positive ctDNA, at 1-6 months after surgery, after adjuvant chemotherapy, and more than 6 months after surgery (p < 0.05). In both univariate and multivariate Cox regression analysis, ctDNA results emerged as a significant predictor of EFS (p < 0.05). ctDNA detection preceded positive imaging in 5 patients, with an average lead time of 92.6 days. Thirty-nine patients remained disease-free, with ctDNA results consistently negative or turning negative during follow-up. Interpretation: Our study underscores the applicability of tumor-informed deep sequencing of ctDNA in osteosarcoma MRD surveillance and, to our knowledge, represents the largest cohort to date. ctDNA detection is a significant prognostic factor, enabling the early identification of tumor relapse and progression compared to standard imaging, thus offering valuable insights in guiding osteosarcoma patient management. Funding: The Grants of National Natural Science Foundation of China (No. 82072964, 82072965, 82203798, 82203026), the Natural Science Foundation of Guangdong (No. 2023A1515012659, 2023A1515010302), and the Regional Combination Project of Basic and Applied Basic Research Foundation of Guangdong (No. 2020A1515110010).

A Phase 1/2 Study of Disulfiram and Copper With Concurrent Radiation Therapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma.

PURPOSE: This phase 1/2 study aimed to evaluate the safety and preliminary efficacy of combining disulfiram and copper (DSF/Cu) with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Patients received standard RT and TMZ with DSF (250-375 mg/d) and Cu, followed by adjuvant TMZ plus DSF (500 mg/d) and Cu. Pharmacokinetic analyses determined drug concentrations in plasma and tumors using high-performance liquid chromatography-mass spectrometry. RESULTS: Thirty-three patients, with a median follow-up of 26.0 months, were treated, including 12 IDH-mutant, 9 NF1-mutant, 3 BRAF-mutant, and 9 other IDH-wild-type cases. In the phase 1 arm, 18 patients were treated; dose-limiting toxicity probabilities were 10% (95% CI, 3%-29%) at 250 mg/d and 21% (95% CI, 7%-42%) at 375 mg/d. The phase 2 arm treated 15 additional patients at 250 mg/d. No significant difference in overall survival or progression-free survival was noted between IDH- and NF1-mutant cohorts compared with institutional counterparts treated without DSF/Cu. However, extended remission occurred in 3 BRAF-mutant patients. Diethyl-dithiocarbamate-copper, the proposed active metabolite of DSF/Cu, was detected in plasma but not in tumors. CONCLUSIONS: The maximum tolerated dose of DSF with RT and TMZ is 375 mg/d. DSF/Cu showed limited clinical efficacy for most patients. However, promising efficacy was observed in BRAF-mutant GBM, warranting further investigation.

Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM.

Laser interstitial thermal therapy for new and recurrent meningioma: a prospective and retrospective case series.

OBJECTIVE: Meningiomas are the most common primary brain tumors in adults and a subset are aggressive lesions resistant to standard therapies. Laser interstitial thermal therapy (LITT) has been successfully applied to other brain tumors, and recent work aims to explore the safety and long-term outcome experiences of LITT for both new and recurrent meningiomas. The authors' objective was to report safety and outcomes data of the largest cohort of LITT-treated meningioma patients to date. METHODS: Eight United States-based hospitals enrolled patients with meningioma in the Laser Ablation of Abnormal Neurological Tissue Using Robotic NeuroBlate System (LAANTERN) prospective multicenter registry and/or contributed additional retrospective enrollments for this cohort study. Demographic, procedural, safety, and outcomes data were collected and analyzed using standard statistical methods. RESULTS: Twenty adult patients (12 prospective and 8 retrospective) with LITT-targeted meningiomas were accrued. Patients underwent LITT for new (6 patients) and recurrent (14 patients) tumors (ranging from the 1st to 12th recurrence). The 30-day complication rate was 10%. Twenty percent of patients (4/20) had exhausted all other treatment options. Median length of follow-up was 1.3 years. One-third of new (2/6) and one-half of recurrent (7/14) meningiomas had disease progression during follow-up. One-year estimated local control (LC), progression-free survival, and overall survival rates were 55.3%, 48.4%, and 86.3%, respectively. In the 12 patients who had ≥ 91% ablative coverage, 1-year estimated LC was 61.4%. The complication rate was 10% (2/20), with 1 complication being transient and resolving postoperatively. CONCLUSIONS: This cohort study supports the safety of the procedure for this tumor type. LITT can offer a much-needed treatment option, especially for patients with multiply recurrent meningiomas who have limited remaining alternatives.

Glioblastoma-Infiltrating CD8+ T Cells Are Predominantly a Clonally Expanded GZMK+ Effector Population.

Recent clinical trials have highlighted the limited efficacy of T cell-based immunotherapy in patients with glioblastoma (GBM). To better understand the characteristics of tumor-infiltrating lymphocytes (TIL) in GBM, we performed cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing with paired V(D)J sequencing, respectively, on TILs from two cohorts of patients totaling 15 patients with high-grade glioma, including GBM or astrocytoma, IDH-mutant, grade 4 (G4A). Analysis of the CD8+ TIL landscape reveals an enrichment of clonally expanded GZMK+ effector T cells in the tumor compared with matched blood, which was validated at the protein level. Furthermore, integration with other cancer types highlights the lack of a canonically exhausted CD8+ T-cell population in GBM TIL. These data suggest that GZMK+ effector T cells represent an important T-cell subset within the GBM microenvironment and may harbor potential therapeutic implications. SIGNIFICANCE: To understand the limited efficacy of immune-checkpoint blockade in GBM, we applied a multiomics approach to understand the TIL landscape. By highlighting the enrichment of GZMK+ effector T cells and the lack of exhausted T cells, we provide a new potential mechanism of resistance to immunotherapy in GBM. This article is featured in Selected Articles from This Issue, p. 897.

Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy.

Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating anti-tumor immune memory while minimizing multi-mechanistic immune suppression. A critical aspect of these therapies is the controlled, spatiotemporal delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME). Architectures such as spherical nucleic acids or poly(beta-amino ester)/dendrimer-based nanoparticles have shown promising results in preclinical models due to their multivalency and abilities to activate antigen-presenting cells and prime antigen-specific T cells. These nanostructures also permit systematic variation to optimize their distribution, TME accumulation, cellular uptake, and overall immunostimulatory effects. Delving deeper into the relationships between nanotherapeutic structures and their performance will accelerate nano-drug development and pave the way for the rapid clinical translation of advanced nanomedicines. In addition, the efficacy of nanotechnology-based immunotherapies may be enhanced when integrated with emerging precision surgical techniques, such as laser interstitial thermal therapy, and when combined with systemic immunotherapies, particularly inhibitors of immune-mediated checkpoints and immunosuppressive adenosine signaling. In this perspective, we highlight the potential of emerging treatment modalities, combining advances in biomedical engineering and neurotechnology development with existing immunotherapies to overcome treatment resistance and transform the management of GBM. We conclude with a call to action for researchers to leverage these technologies and accelerate their translation into the clinic.

Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state.

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted.

The Hao-Fountain syndrome protein USP7 regulates neuronal connectivity in the brain via a novel p53-independent ubiquitin signaling pathway.

Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics analysis reveals that the neuronal USP7 interactome is enriched for proteins implicated in neurodevelopmental disorders and specifically identifies the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.

Indiana Pouch Continent Cutaneous Urinary Diversion After Robotic-assisted Radical Cystectomy: A 16-Year Experience.

BACKGROUND: Population-based practice patterns in the United States reveal continent diversions are only performed in 8%-10.4% of patients.1-4 Ideally, for patients undergoing radical cystectomy the choice of urinary diversion should be influenced by clinical factors and patient preference, with discussions surrounding quality of life. Unfortunately, receipt of continent diversion has been shown to be influenced by a plethora of other factors such as surgeon preference/training, geography, socioeconomic status, gender, and hospital volume.1-3 Thus, by providing detailed instruction and long-term follow-up, we hope to mitigate some of these disparities by changing the perceptions regarding feasibility and complications of continent diversions. OBJECTIVE: To provide step-by-step instruction and to report long-term clinical outcomes in bladder cancer patients receiving an Indiana pouch continent cutaneous urinary diversion (CCUD) after robot-assisted radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS: After Institutional Review Board approval, a prospectively maintained bladder cancer database was queried for patients with T1-T4, N0-N1, M0 bladder cancer undergoing radical cystectomy with CCUD at a tertiary referral center from 2004 to 2020. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complications at 30- and 90-day were recorded according to the Clavien-Dindo classification. Continence rates were recorded by chart review. RESULTS AND LIMITATIONS: A total of 97 patients were included with a median follow-up of 93months. Clinically, 91.8% had ≤T2 disease and 29.9% received neoadjuvant chemotherapy. The median length of surgery was 8.0 hours, length of hospital stay was 8.3days, and urinary continence rate was 99.0%. The overall complication rate was 73.2% and 76.5% at 30- and 90-day, respectively. The major complication rate (Clavien III-V) was 17.5% at 30-day and 22.7% at 90-day. The most common major complications were abdominal infection and uretero-colonic stricture. The readmission rate was 21.4% and median overall survival was 108months. CONCLUSION: CCUD provides exceptional functional outcomes with acceptable complication rates compared to other diversion types. CCUD is a reliable reconstructive option and with this step-by-step video as a reference, we hope it will be offered to more patients.

Association of county-level socioeconomic status with meningioma incidence and outcomes.

BACKGROUND: Prior literature suggests that individual socioeconomic status (SES) may influence incidence, treatments, and survival of brain tumor cases. We aim to conduct the first national study to evaluate the association between US county-level SES and incidence, treatment, and survival in meningioma. METHODS: The Central Brain Tumor Registry of the United States analytic dataset, which combines data from CDC's National Program of Cancer Registries (NPCR) and National Cancer Institute's Surveillance, Epidemiology, and End Results Program, was used to identify meningioma cases from 2006 to 2019. SES quintiles were created using American Community Survey data. Logistic regression models were used to evaluate associations between SES and meningioma. Cox proportional hazard models were constructed to assess the effect of SES on survival using the NPCR analytic dataset. RESULTS: A total of 409 681 meningioma cases were identified. Meningioma incidence increased with higher county-level SES with Q5 (highest quintile) having a 12% higher incidence than Q1 (incidence rate ratios (IRR) = 1.12, 95%CI: 1.10-1.14; P < .0001). The Hispanic group was the only racial-ethnic group that had lower SES associated with increased meningioma incidence (Q5: age-adjusted incidence ratio (AAIR) = 9.02, 95%CI: 8.87-9.17 vs. Q1: AAIR = 9.33, 95%CI: 9.08-9.59; IRR = 0.97, 95%CI: 0.94-1.00; P = .0409). Increased likelihood of surgical treatment was associated with Asian or Pacific Islander non-Hispanic individuals (compared to White non-Hispanic (WNH)) (OR = 1.28, 95%CI: 1.23-1.33, P < .001) and males (OR = 1.31, 95%CI: 1.29-1.33, P < .001). Black non-Hispanic individuals (OR = 0.90, 95%CI: 0.88-0.92, P < .001) and those residing in metropolitan areas (OR = 0.96, 95%CI: 0.96-0.96, P < .001) were less likely to receive surgical treatment compared to WNH individuals. Overall median survival was 137 months, and survival was higher in higher SES counties (Q5 median survival = 142 months). CONCLUSIONS: Higher county-level SES was associated with increased meningioma incidence, surgical treatment, and overall survival. Racial-ethnic stratification identified potential disparities within the meningioma population. Further work is needed to understand the underpinnings of socioeconomic and racial disparities for meningioma patients.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Predicting survival in glioblastoma with multimodal neuroimaging and machine learning.

PURPOSE: Glioblastoma (GBM) is the most common and aggressive malignant glioma, with an overall median survival of less than two years. The ability to predict survival before treatment in GBM patients would lead to improved disease management, clinical trial enrollment, and patient care. METHODS: GBM patients (N = 133, mean age 60.8 years, median survival 14.1 months, 57.9% male) were retrospectively recruited from the neurosurgery brain tumor service at Washington University Medical Center. All patients completed structural neuroimaging and resting state functional MRI (RS-fMRI) before surgery. Demographics, measures of cortical thickness (CT), and resting state functional network connectivity (FC) were used to train a deep neural network to classify patients based on survival (< 1y, 1-2y, >2y). Permutation feature importance identified the strongest predictors of survival based on the trained models. RESULTS: The models achieved a combined cross-validation and hold out accuracy of 90.6% in classifying survival (< 1y, 1-2y, >2y). The strongest demographic predictors were age at diagnosis and sex. The strongest CT predictors of survival included the superior temporal sulcus, parahippocampal gyrus, pericalcarine, pars triangularis, and middle temporal regions. The strongest FC features primarily involved dorsal and inferior somatomotor, visual, and cingulo-opercular networks. CONCLUSION: We demonstrate that machine learning can accurately classify survival in GBM patients based on multimodal neuroimaging before any surgical or medical intervention. These results were achieved without information regarding presentation symptoms, treatments, postsurgical outcomes, or tumor genomic information. Our results suggest GBMs have a global effect on the brain's structural and functional organization, which is predictive of survival.

A pilot phase Ib study to evaluate tadalafil to overcome immunosuppression during chemoradiotherapy for IDH-wild-type glioblastoma.

Background: Myeloid-derived suppressor cells (MDSCs) are critical regulators of immunosuppression and radioresistance in glioblastoma (GBM). The primary objective of this pilot phase Ib study was to validate the on-target effect of tadalafil on inhibiting MDSCs in peripheral blood and its safety when combined with chemoradiotherapy in GBM patients. Methods: Patients with newly diagnosed IDH-wild-type GBM received radiation therapy (RT) and temozolomide (TMZ) combined with oral tadalafil for 2 months. A historical cohort of 12 GBM patients treated with RT and TMZ was used as the comparison group. The ratio of MDSCs, T cells, and cytokines at week 6 of RT compared to baseline were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Tadalafil was well tolerated with no dose-limiting toxicity among 16 evaluable patients. The tadalafil cohort had a significantly lower ratio of circulating MDSCs than the control: granulocytic-MDSCs (mean 0.78 versus 3.21, respectively, P = 0.01) and monocytic-MDSCs (1.02 versus 1.96, respectively, P = 0.006). Tadalafil increased the CD8 ratio compared to the control (1.99 versus 0.70, respectively, P < 0.001), especially the PD-1-CD8 T cells expressing Ki-67, CD38, HLA-DR, CD28, and granzyme B. Proinflammatory cytokine IL-1ß was also significantly increased after tadalafil compared to the control. The tadalafil cohort did not have significantly different PFS and OS than the historical control. Conclusions: Concurrent tadalafil is well tolerated during chemoradiotherapy for GBM. Tadalafil is associated with a reduction of peripheral MDSCs after chemoradiotherapy and increased CD8 T-cell proliferation and activation.

The function of histone methylation and acetylation regulators in GBM pathophysiology.

Glioblastoma (GBM) is the most common and lethal primary brain malignancy and is characterized by a high degree of intra and intertumor cellular heterogeneity, a starkly immunosuppressive tumor microenvironment, and nearly universal recurrence. The application of various genomic approaches has allowed us to understand the core molecular signatures, transcriptional states, and DNA methylation patterns that define GBM. Histone posttranslational modifications (PTMs) have been shown to influence oncogenesis in a variety of malignancies, including other forms of glioma, yet comparatively less effort has been placed on understanding the transcriptional impact and regulation of histone PTMs in the context of GBM. In this review we discuss work that investigates the role of histone acetylating and methylating enzymes in GBM pathogenesis, as well as the effects of targeted inhibition of these enzymes. We then synthesize broader genomic and epigenomic approaches to understand the influence of histone PTMs on chromatin architecture and transcription within GBM and finally, explore the limitations of current research in this field before proposing future directions for this area of research.

Diffusion basis spectrum imaging as an adjunct to conventional MRI leads to earlier diagnosis of high-grade glioma tumor progression versus treatment effect.

Background: Following chemoradiotherapy for high-grade glioma (HGG), it is often challenging to distinguish treatment changes from true tumor progression using conventional MRI. The diffusion basis spectrum imaging (DBSI) hindered fraction is associated with tissue edema or necrosis, which are common treatment-related changes. We hypothesized that DBSI hindered fraction may augment conventional imaging for earlier diagnosis of progression versus treatment effect. Methods: Adult patients were prospectively recruited if they had a known histologic diagnosis of HGG and completed standard-of-care chemoradiotherapy. DBSI and conventional MRI data were acquired longitudinally beginning 4 weeks post-radiation. Conventional MRI and DBSI metrics were compared with respect to their ability to diagnose progression versus treatment effect. Results: Twelve HGG patients were enrolled between August 2019 and February 2020, and 9 were ultimately analyzed (5 progression, 4 treatment effect). Within new or enlarging contrast-enhancing regions, DBSI hindered fraction was significantly higher in the treatment effect group compared to progression group (P = .0004). Compared to serial conventional MRI alone, inclusion of DBSI would have led to earlier diagnosis of either progression or treatment effect in 6 (66.7%) patients by a median of 7.7 (interquartile range = 0-20.1) weeks. Conclusions: In the first longitudinal prospective study of DBSI in adult HGG patients, we found that in new or enlarging contrast-enhancing regions following therapy, DBSI hindered fraction is elevated in cases of treatment effect compared to those with progression. Hindered fraction map may be a valuable adjunct to conventional MRI to distinguish tumor progression from treatment effect.

TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ-induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased tumor growth and increased survival. Trem2 inhibition reprogrammed myeloid phenotypes and increased programmed cell death protein 1 (PD-1)+CD8+ T cells in the TME. Last, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment, which may represent a therapeutic strategy for patients with GBM.

Efficacy of laser interstitial thermal therapy for biopsy-proven radiation necrosis in radiographically recurrent brain metastases.

Background: Laser interstitial thermal therapy (LITT) in the setting of post-SRS radiation necrosis (RN) for patients with brain metastases has growing evidence for efficacy. However, questions remain regarding hospitalization, local control, symptom control, and concurrent use of therapies. Methods: Demographics, intraprocedural data, safety, Karnofsky performance status (KPS), and survival data were prospectively collected and then analyzed on patients who consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 US centers. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan-Meier estimated survival. Results: Ninety patients met the inclusion criteria. Four patients underwent 2 ablations on the same day. Median hospitalization time was 32.5 hours. The median time to corticosteroid cessation after LITT was 13.0 days (0.0, 1229.0) and cumulative incidence of lesional progression was 19% at 1 year. Median post-procedure overall survival was 2.55 years [1.66, infinity] and 77.1% at one year as estimated by KaplanMeier. Median KPS remained at 80 through 2-year follow-up. Seizure prevalence was 12% within 1-month post-LITT and 7.9% at 3 months; down from 34.4% within 60-day prior to procedure. Conclusions: LITT for RN was not only again found to be safe with low patient morbidity but was also a highly effective treatment for RN for both local control and symptom management (including seizures). In addition to averting expected neurological death, LITT facilitates ongoing systemic therapy (in particular immunotherapy) by enabling the rapid cessation of steroids, thereby facilitating maximal possible survival for these patients.