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Evaluation of the SSTR2-targeted radiopharmaceutical 177Lu-DOTATATE and SSTR2-specific 68Ga-DOTATATE PET as imaging biomarker in patients with intracranial meningioma

Kurz, Sylvia C; Zan, Elcin; Cordova, Christine; Troxel, Andrea B; Barbaro, Marissa; Silverman, Joshua S; Snuderl, Matija; Zagzag, David; Kondziolka, Douglas; Golfinos, John G; Chi, Andrew S; Sulman, Erik P
BACKGROUND: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/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 begin of 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 (F=11, M=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 (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.
PMID: 38048045
ISSN: 1557-3265
CID: 5595302

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

Galbraith, Kristyn; Serrano, Jonathan; Shen, Guomiao; Tran, Ivy; Slocum, Cheyanne C; Ketchum, Courtney; Abdullaev, Zied; Turakulov, Rust; Bale, Tejus; Ladanyi, Marc; Sukhadia, Purvil; Zaidinski, Michael; Mullaney, Kerry; DiNapoli, Sara; Liechty, Benjamin L; Barbaro, Marissa; Allen, Jeffrey C; Gardner, Sharon L; Wisoff, Jeffrey; Harter, David; Hidalgo, Eveline Teresa; Golfinos, John G; Orringer, Daniel A; Aldape, Kenneth; Benhamida, Jamal; Wrzeszczynski, Kazimierz O; Jour, George; Snuderl, Matija
UNLABELLED: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/UNASSIGNED:DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.
PMID: 37870438
ISSN: 1557-3125
CID: 5625782

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

Leu, Justin; Akerman, Meredith; Mendez, Christopher; Lischalk, Jonathan W; Carpenter, Todd; Ebling, David; Haas, Jonathan A; Witten, Matthew; Barbaro, Marissa; Duic, Paul; Tessler, Lee; Repka, Michael C
[This corrects the article DOI: 10.3389/fonc.2023.1132777.].
PMID: 37093946
ISSN: 2234-943x
CID: 5465052

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

Leu, Justin; Akerman, Meredith; Mendez, Christopher; Lischalk, Jonathan W; Carpenter, Todd; Ebling, David; Haas, Jonathan A; Witten, Matthew; Barbaro, Marissa; Duic, Paul; Tessler, Lee; Repka, Michael C
INTRODUCTION/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.
PMID: 37091181
ISSN: 2234-943x
CID: 5464962

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing

Galbraith, Kristyn; Vasudevaraja, Varshini; Serrano, Jonathan; Shen, Guomiao; Tran, Ivy; Abdallat, Nancy; Wen, Mandisa; Patel, Seema; Movahed-Ezazi, Misha; Faustin, Arline; Spino-Keeton, Marissa; Roberts, Leah Geiser; Maloku, Ekrem; Drexler, Steven A; Liechty, Benjamin L; Pisapia, David; Krasnozhen-Ratush, Olga; Rosenblum, Marc; Shroff, Seema; Boué, Daniel R; Davidson, Christian; Mao, Qinwen; Suchi, Mariko; North, Paula; Hopp, Amanda; Segura, Annette; Jarzembowski, Jason A; Parsons, Lauren; Johnson, Mahlon D; Mobley, Bret; Samore, Wesley; McGuone, Declan; Gopal, Pallavi P; Canoll, Peter D; Horbinski, Craig; Fullmer, Joseph M; Farooqui, Midhat S; Gokden, Murat; Wadhwani, Nitin R; Richardson, Timothy E; Umphlett, Melissa; Tsankova, Nadejda M; DeWitt, John C; Sen, Chandra; Placantonakis, Dimitris G; Pacione, Donato; Wisoff, Jeffrey H; Teresa Hidalgo, Eveline; Harter, David; William, Christopher M; Cordova, Christine; Kurz, Sylvia C; Barbaro, Marissa; Orringer, Daniel A; Karajannis, Matthias A; Sulman, Erik P; Gardner, Sharon L; Zagzag, David; Tsirigos, Aristotelis; Allen, Jeffrey C; Golfinos, John G; Snuderl, Matija
BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.
PMID: 37476329
ISSN: 2632-2498
CID: 5536102


Kurz, S; Zan, E; Cordova, C; Barbaro, M; Troxel, A; Silverman, J; Snuderl, M; Zagzag, D; Golfinos, J; Kondziolka, D; Sulman, E
BACKGROUND: While most meningiomas are considered benign tumors, a subset of these tumors are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgical and radiotherapeutic options, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in neuroendocrine tumors. Here we report the results of the interim analysis of an ongoing clinical trial (NCT03971461) that is evaluating the effect of 177Lu-DOTATATE in treating progressive intracranial meningiomas.
METHOD(S): In this Simon two-stage design phase II study, adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every eight weeks for four doses. 68Ga-DOTATATE PET-MRI was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass.
RESULT(S): Fourteen patients (F = 11, M = 3) with progressive meningiomas (WHO I = 3, II = 10, III = 1) have been enrolled. Median age was 63.1 (range 49-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, no treatment-limiting toxicities were observed. Six of 14 patients (42%) achieved PFS-6. Radiographically, all six patients had achieved Stable Disease. A functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging was observed in three patients.
CONCLUSION(S): Treatment with SSTR2- targeting 177Lu-DOTATATE is well tolerated. In this interim analysis, six of 14 patients achieved PFS-6. This exceeds the predefined threshold to continue to stage two of this study. This clinical trial is now open to patient enrollment at two study sites in the US
ISSN: 1523-5866
CID: 5513302

Newly Diagnosed Glioblastoma in Elderly Patients

Yuen, Carlen A; Barbaro, Marissa; Haggiagi, Aya
PURPOSE OF REVIEW/OBJECTIVE: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/RESULTS: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.
PMID: 35122621
ISSN: 1534-6269
CID: 5154052

Correction: Newly Diagnosed Glioblastoma in Elderly Patients

Yuen, Carlen A; Barbaro, Marissa; Haggiagi, Aya
PMID: 35199296
ISSN: 1534-6269
CID: 5172252

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

Barbaro, Marissa; Blinderman, Craig D; Iwamoto, Fabio M; Kreisl, Teri N; Welch, Mary R; Odia, Yazmin; Donovan, Laura E; Joanta-Gomez, Adela E; Evans, Katharine A; Lassman, Andrew B
BACKGROUND AND OBJECTIVES/OBJECTIVE: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 through 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 1/2014-2/2019 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 and/or pulmonary resuscitation was performed in 20 patients (13.2%). DISCUSSION/CONCLUSIONS: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, though 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.
PMID: 34795049
ISSN: 1526-632x
CID: 5049622

Scientific and Clinical Challenges within Neuro-Oncology

Barbaro, Marissa; Fine, Howard A; Magge, Rajiv S
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.
PMID: 33610863
ISSN: 1878-8769
CID: 5032862