T2-FLAIR mismatch sign predicts DNA methylation subclass and CDKN2A/B status in IDH-mutant astrocytomas.

PURPOSE: DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low-grade and high-grade groups. We investigated the utility of the T2-FLAIR mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization (WHO) classification. EXPERIMENTAL DESIGN: Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n=71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed. RESULTS: The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (p<0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (p=0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for PFS (p=0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, CNV, and methylation grade, showed trends toward significance for DNA methylation grade with OS (p=0.045) and CDKN2A/B status with PFS (p=0.052). CONCLUSIONS: The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas.

Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

Evaluation of the SSTR2-targeted Radiopharmaceutical 177Lu-DOTATATE and SSTR2-specific 68Ga-DOTATATE PET as Imaging Biomarker in Patients with Intracranial Meningioma.

PURPOSE: There are no effective medical therapies for patients with meningioma who progress beyond surgical and radiotherapeutic interventions. Somatostatin receptor type 2 (SSTR2) represents a promising treatment target in meningiomas. In this multicenter, single-arm phase II clinical study (NCT03971461), the SSTR2-targeting radiopharmaceutical 177Lu-DOTATATE is evaluated for its feasibility, safety, and therapeutic efficacy in these patients. PATIENTS AND METHODS: Adult patients with progressive intracranial meningiomas received 177Lu-DOTATATE at a dose of 7.4 GBq (200 mCi) every eight weeks for four cycles. 68Ga-DOTATATE PET-MRI was performed before and six months after the start of the treatment. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Secondary endpoints were safety and tolerability, overall survival (OS) at 12 months (OS-12), median PFS, and median OS. RESULTS: Fourteen patients (female = 11, male = 3) with progressive meningiomas (WHO 1 = 3, 2 = 10, 3 = 1) were enrolled. Median age was 63.1 (range 49.7-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated. Seven patients (50%) achieved PFS-6. Best radiographic response by modified Macdonald criteria was stable disease (SD) in all seven patients. A >25% reduction in 68Ga-DOTATATE uptake (PET) was observed in five meningiomas and two patients. In one lesion, this corresponded to >50% reduction in bidirectional tumor measurements (MRI). CONCLUSIONS: Treatment with 177Lu-DOTATATE was well tolerated. The predefined PFS-6 threshold was met in this interim analysis, thereby allowing this multicenter clinical trial to continue enrollment. 68Ga-DOTATATE PET may be a useful imaging biomarker to assess therapeutic outcome in patients with meningioma.

Impact of Rare and Multiple Concurrent Gene Fusions on Diagnostic DNA Methylation Classifier in Brain Tumors.

DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions. IMPLICATIONS: DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.

Time interval from diagnosis to treatment of brain metastases with stereotactic radiosurgery is not associated with radionecrosis or local failure.

Introduction: Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear. Methods: This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure. Results: A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure. Discussion: An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

Corrigendum: Time interval from diagnosis to treatment of brain metastases with stereotactic radiosurgery is not associated with radionecrosis or local failure.

[This corrects the article DOI: 10.3389/fonc.2023.1132777.].

Newly Diagnosed Glioblastoma in Elderly Patients.

PURPOSE OF REVIEW: Elderly patients with newly diagnosed glioblastoma (eGBM) carry a worse prognosis compared with their younger counterparts. eGBM garners special attention due to the unique challenges, including increased treatment-associated toxicity, less relative benefit from aggressive therapy, medical comorbidities, and immunosuppression. The pivotal GBM trials excluded patients > 70 years old and the optimal treatment approach remains unsettled for eGBM. In this review, we analyze the historical evidence-based data for treating eGBM and discuss the future direction for managing this vulnerable population. RECENT FINDINGS: Treatment for eGBM continues to evolve. Therapy choice is guided by performance status and presence of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation. For eGBM with good performance status, combinatorial hypofractionated radiation therapy (hRT) and temozolomide should be recommended. For those with poor performance status, further stratification based on MGMT promoter methylation test result is recommended. Single-agent temozolomide is a viable treatment option for MGMT methylated tumors (mMGMT); in particular, those classified with receptor tyrosine kinase II methylation. hRT alone can be considered in MGMT unmethylated (uMGMT) eGBM patients. As precision oncology continues to advance, effective targeted and immunotherapy may emerge as new treatment options for eGBM. Management of elderly patients with newly diagnosed GBM carries a unique set of challenges. Progress has been made in defining the optimal therapeutic approach for these patients, but many questions remain to be answered.

Causes of Death and End-of-Life Care in Patients With Intracranial High-Grade Gliomas: A Retrospective Observational Study.

BACKGROUND AND OBJECTIVES: To understand patterns of care and circumstances surrounding end of life in patients with intracranial gliomas. METHODS: We retrospectively analyzed end-of-life circumstances in patients with intracranial high-grade gliomas at Columbia University Irving Medical Center who died from January 2014 to February 2019, including cause of death, location of death, and implementation of comfort measures and resuscitative efforts. RESULTS: There were 152 patients (95 men, 57 women; median age at death 61.5 years, range 24-87 years) who died from January 2014 to February 2019 with adequate data surrounding end-of-life circumstances. Clinical tumor progression (n = 117, 77.0%) was the most common cause of death, with all patients transitioned to comfort measures. Other causes included, but were not limited to, infection (19, 12.5%); intratumoral hemorrhage (5, 3.3%); seizures (8, 5.3%); cerebral edema (4, 2.6%); pulmonary embolism (4, 2.6%); autonomic failure (2, 1.3%); and hemorrhagic shock (2, 1.3%). Multiple mortal events were identified in 10 (8.5%). Seventy-three patients (48.0%) died at home with hospice. Other locations were inpatient hospice (40, 26.3%); acute care hospital (34, 22.4%), including 27 (17.8%) with and 7 (4.6%) without comfort measures; skilled nursing facility (4, 3.3%), including 3 (2.0%) with and 1 (0.7%) without comfort measures; or religious facility (1, 0.7%) with comfort measures. Acute cardiac or pulmonary resuscitation was performed in 20 patients (13.2%). DISCUSSION: Clinical tumor progression was the most common (77.0%) cause of death, followed by infection (12.5%). Hospice or comfort measures were ultimately implemented in 94.7% of patients, although resuscitation was performed in 13.2%. Improved understanding of circumstances surrounding death, frequency of use of hospice services, and frequency of resuscitative efforts in patients with gliomas may allow physicians to more accurately discuss end-of-life expectations with patients and caregivers, facilitating informed care planning.

Innovations in Neuro-Oncology.

Although outcomes for many brain tumors, especially glioblastomas, remain poor, there have been significant advances in clinical and scientific understanding of neuro-oncologic disease. Tumor molecular profiling has become a critical component of clinical practice, allowing more accurate pathologic diagnosis and enhanced clarity of the pathogenesis of both primary and metastatic brain tumors. The development of cerebral organoids carries exciting potential to provide representative models of tumor growth and potential drug efficacy, while new radiology techniques continue to improve clinical decision making. New adaptive trial platforms have been developed to rapidly test therapies and biomarkers with good scientific rationale. Lastly, growth and development of neuro-oncology clinical care teams aim to further improve patients' outcomes and symptoms, especially at the end of life.

Foundations of Neuro-Oncology: A Multidisciplinary Approach.

Neuro-oncology is a branch of medicine focused on the diagnosis and treatment of primary and secondary tumors of the nervous system as well as the neurologic complications of cancer and cancer treatments. In practice, neuro-oncologists require an intimate knowledge of the neurologic presentation and management of central nervous system tumors, including gliomas, meningiomas, primary central nervous system lymphoma, metastases to the nervous system, and others. The mainstays of treatment for most nervous system tumors include surgical intervention, radiation therapy, and medical treatment with chemotherapy, immunotherapy, and/or targeted therapy. Interdisciplinary collaboration is thus critical to neuro-oncology. The prognosis for many central nervous system tumors, including gliomas and brain metastases, is often poor despite the advent of novel medical therapies. Efforts to develop more effective therapies are ongoing, and patient enrollment in clinical trials assessing the efficacy of new treatments is crucial to improve outcomes.

Scientific and Clinical Challenges within Neuro-Oncology.

Both primary and metastatic brain tumors carry poor prognoses despite modern advances in medical therapy, radiation therapy, and surgical techniques. Gliomas, including glioblastoma (GBM), are particularly difficult to treat, and high-grade gliomas have poor outcomes. Treatment of brain tumors involves a unique set of scientific and clinical challenges, which are often not present in the treatment of systemic malignancies. With respect to scientific challenges, the anatomy and physiology of brain tumors (including the blood-brain barrier, blood-tumor barrier, and blood-cerebrospinal fluid barrier) prevent adequate drug delivery into the central nervous system. The unique nature of the immune system in the central nervous system as well as the immunosuppressive microenvironment of tumors such as GBM also create therapeutic roadblocks in the treatment of brain tumors. Tumor heterogeneity, particularly in GBM, has classically been believed to contribute to multitherapy resistance; however, recent data suggest that this may not be the case. Clinical challenges include neurologic and medical comorbidities of patients with brain tumor, as well as potential toxicity of tumor-directed treatment. Clinical trials investigating new treatment paradigms are needed, but several roadblocks exist to good and promising clinical trial availability.

[68Ga]-DOTATATE PET/CT and PET/MRI in the diagnosis and management of esthesioneuroblastoma: illustrative cases.

BACKGROUND: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare sinonasal neuroectodermal malignancy with a slow onset of symptoms, favorable 5-year survival, and a propensity for delayed locoregional recurrence. Current treatment options include resection, adjuvant radiotherapy, and/or chemotherapy; however, because of its rarity and location, determining the optimal treatment for ENB has been challenging. OBSERVATIONS: ENBs strongly express somatostatin receptors (SSTRs), particularly SSTR2, providing a molecular target for imaging and therapy. LESSONs: The authors present a case series of ENBs imaged with [68Ga]-DOTATATE PET/MRI and PET/CT and discuss the emerging role of [68Ga]-DOTATATE PET for ENB diagnosis, staging, and treatment response monitoring.

The influence of environmental factors on bone tissue engineering.

Bone repair and regeneration are dynamic processes that involve a complex interplay between the substrate, local and systemic cells, and the milieu. Although each constituent plays an integral role in faithfully recreating the skeleton, investigators have long focused their efforts on scaffold materials and design, cytokine and hormone administration, and cell-based therapies. Only recently have the intangible aspects of the milieu received their due attention. In this review, we highlight the important influence of environmental factors on bone tissue engineering.

Identification of chemosensory receptor genes in Manduca sexta and knockdown by RNA interference.

BACKGROUND: Insects detect environmental chemicals via a large and rapidly evolving family of chemosensory receptor proteins. Although our understanding of the molecular genetic basis for Drosophila chemoreception has increased enormously in the last decade, similar understanding in other insects remains limited. The tobacco hornworm, Manduca sexta, has long been an important model for insect chemosensation, particularly from ecological, behavioral, and physiological standpoints. It is also a major agricultural pest on solanaceous crops. However, little sequence information and lack of genetic tools has prevented molecular genetic analysis in this species. The ability to connect molecular genetic mechanisms, including potential lineage-specific changes in chemosensory genes, to ecologically relevant behaviors and specializations in M. sexta would be greatly beneficial. RESULTS: Here, we sequenced transcriptomes from adult and larval chemosensory tissues and identified chemosensory genes based on sequence homology. We also used dsRNA feeding as a method to induce RNA interference in larval chemosensory tissues. CONCLUSIONS: We report identification of new chemosensory receptor genes including 17 novel odorant receptors and one novel gustatory receptor. Further, we demonstrate that systemic RNA interference can be used in larval olfactory neurons to reduce expression of chemosensory receptor transcripts. Together, our results further the development of M. sexta as a model for functional analysis of insect chemosensation.

Bone tissue engineering: current strategies and techniques--part II: Cell types.

Bone repair and regeneration is a dynamic process that involves a complex interplay between the (1) ground substance; (2) cells; and (3) milieu. Each constituent is integral to the final product, but it is often helpful to consider each component individually. While bone tissue engineering has capitalized on a number of breakthrough technologies, one of the most valued advancements is the incorporation of mesenchymal stem cells (SCs) into bone tissue engineering applications. With this new idea, however, came new found problems of guiding SC differentiation. Moreover, investigators are still working to understand which SCs source produces optimal bone formation in vitro and in vivo. Bone marrow-derived mesenchymal SCs and adipose-derived SCs have been researched most extensively, but other SC sources, including dental pulp, blood, umbilical cord blood, epithelial cells reprogrammed to become induced pluripotent SCs, among others, are being investigated. In Part II of this review series, we discuss the variety of cell types (e.g., osteocytes, osteoblasts, osteoclasts, chondrocytes, mesenchymal SCs, and vasculogenic cells) important in bone tissue engineering.