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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

Neuropathological Applications of Microscopy with Ultraviolet Surface Excitation (MUSE): A Concordance Study of Human Primary and Metastatic Brain Tumors

Lechpammer, Mirna; Todd, Austin; Tang, Vivian; Morningstar, Taryn; Borowsky, Alexander; Shahlaie, Kiarash; Kintner, John A; McPherson, John D; Bishop, John W; Fereidouni, Farzad; Harmany, Zachary T; Coley, Nicholas; Zagzag, David; Wong, Jason W H; Tao, Jiang; Hesson, Luke B; Burnett, Leslie; Levenson, Richard
Whereas traditional histology and light microscopy require multiple steps of formalin fixation, paraffin embedding, and sectioning to generate images for pathologic diagnosis, Microscopy using Ultraviolet Surface Excitation (MUSE) operates through UV excitation on the cut surface of tissue, generating images of high resolution without the need to fix or section tissue and allowing for potential use for downstream molecular tests. Here, we present the first study of the use and suitability of MUSE microscopy for neuropathological samples. MUSE images were generated from surgical biopsy samples of primary and metastatic brain tumor biopsy samples (n = 27), and blinded assessments of diagnoses, tumor grades, and cellular features were compared to corresponding hematoxylin and eosin (H&E) images. A set of MUSE-treated samples subsequently underwent exome and targeted sequencing, and quality metrics were compared to those from fresh frozen specimens. Diagnostic accuracy was relatively high, and DNA and RNA integrity appeared to be preserved for this cohort. This suggests that MUSE may be a reliable method of generating high-quality diagnostic-grade histologic images for neuropathology on a rapid and sample-sparing basis and for subsequent molecular analysis of DNA and RNA.
PMCID:10813539
PMID: 38275528
ISSN: 2076-3425
CID: 5625372

Neuropathological Applications of Microscopy with Ultraviolet Surface Excitation (MUSE): A Concordance Study of Human Primary and Metastatic Brain Tumors

Lechpammer, Mirna; Todd, Austin; Tang, Vivian; Morningstar, Taryn; Borowsky, Alexander; Shahlaie, Kiarash; Kintner, John A.; McPherson, John D.; Bishop, John W.; Fereidouni, Farzad; Harmany, Zachary T.; Coley, Nicholas; Zagzag, David; Wong, Jason W.H.; Tao, Jiang; Hesson, Luke B.; Burnett, Leslie; Levenson, Richard
Whereas traditional histology and light microscopy require multiple steps of formalin fixation, paraffin embedding, and sectioning to generate images for pathologic diagnosis, Microscopy using Ultraviolet Surface Excitation (MUSE) operates through UV excitation on the cut surface of tissue, generating images of high resolution without the need to fix or section tissue and allowing for potential use for downstream molecular tests. Here, we present the first study of the use and suitability of MUSE microscopy for neuropathological samples. MUSE images were generated from surgical biopsy samples of primary and metastatic brain tumor biopsy samples (n = 27), and blinded assessments of diagnoses, tumor grades, and cellular features were compared to corresponding hematoxylin and eosin (H&E) images. A set of MUSE-treated samples subsequently underwent exome and targeted sequencing, and quality metrics were compared to those from fresh frozen specimens. Diagnostic accuracy was relatively high, and DNA and RNA integrity appeared to be preserved for this cohort. This suggests that MUSE may be a reliable method of generating high-quality diagnostic-grade histologic images for neuropathology on a rapid and sample-sparing basis and for subsequent molecular analysis of DNA and RNA.
SCOPUS:85183133975
ISSN: 2076-3425
CID: 5629222

The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability

Ravn-Boess, Niklas; Roy, Nainita; Hattori, Takamitsu; Bready, Devin; Donaldson, Hayley; Lawson, Christopher; Lapierre, Cathryn; Korman, Aryeh; Rodrick, Tori; Liu, Enze; Frenster, Joshua D; Stephan, Gabriele; Wilcox, Jordan; Corrado, Alexis D; Cai, Julia; Ronnen, Rebecca; Wang, Shuai; Haddock, Sara; Sabio Ortiz, Jonathan; Mishkit, Orin; Khodadadi-Jamayran, Alireza; Tsirigos, Aris; Fenyö, David; Zagzag, David; Drube, Julia; Hoffmann, Carsten; Perna, Fabiana; Jones, Drew R; Possemato, Richard; Koide, Akiko; Koide, Shohei; Park, Christopher Y; Placantonakis, Dimitris G
Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.
PMID: 37938973
ISSN: 2211-1247
CID: 5590372

Long-Term Follow-up of Multinodular and Vacuolating Neuronal Tumors and Implications for Surveillance Imaging

Dogra, S; Zagzag, D; Young, M; Golfinos, J; Orringer, D; Jain, R
BACKGROUND AND PURPOSE:Most multinodular and vacuolating neuronal tumors (MVNTs) are diagnosed and followed radiologically without any change across time. There are no surveillance guidelines or quantitative volumetric assessments of these tumors. We evaluated MVNT volumes during long follow-up periods using segmentation tools with the aim of quantitative assessment. MATERIALS AND METHODS:All patients with MVNTs in a brain MR imaging report in our system were reviewed. Patients with only 1 brain MR imaging or in whom MVNT was not clearly the most likely diagnosis were excluded. All MVNTs were manually segmented. For all follow-up examinations, absolute and percentage volume change from immediately prior and initial examinations were calculated. RESULTS:= .67), respectively. CONCLUSIONS:MVNT segmentation across follow-up brain MR imaging examinations did not demonstrate significant volume differences, suggesting that these tumors do not enlarge with time. Hence, frequent surveillance imaging of newly diagnosed MVNTs may not be necessary.
PMCID:10494952
PMID: 37500290
ISSN: 1936-959x
CID: 5593842

Recurrent TRAK1::RAF1 Fusions in pediatric low-grade gliomas

Benhamida, Jamal K; Harmsen, Hannah J; Ma, Deqin; William, Christopher M; Li, Bryan K; Villafania, Liliana; Sukhadia, Purvil; Mullaney, Kerry A; Dewan, Michael C; Vakiani, Efsevia; Karajannis, Matthias A; Snuderl, Matija; Zagzag, David; Ladanyi, Marc; Rosenblum, Marc K; Bale, Tejus A
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
PMID: 37399073
ISSN: 1750-3639
CID: 5539042

Clinical Validation of Stimulated Raman Histology for Rapid Intraoperative Diagnosis of Central Nervous System Tumors

Movahed-Ezazi, Misha; Nasir-Moin, Mustafa; Fang, Camila; Pizzillo, Isabella; Galbraith, Kristyn; Drexler, Steven; Krasnozhen-Ratush, Olga A; Shroff, Seema; Zagzag, David; William, Christopher; Orringer, Daniel; Snuderl, Matija
Stimulated Raman histology (SRH) is an ex vivo optical imaging method that enables microscopic examination of fresh tissue intraoperatively. The conventional intraoperative method uses frozen section analysis, which is labor and time intensive, introduces artifacts that limit diagnostic accuracy, and consumes tissue. SRH imaging allows rapid microscopic imaging of fresh tissue, avoids tissue loss, and enables remote telepathology review. This improves access to expert neuropathology consultation in both low- and high-resource practices. We clinically validated SRH by performing a blinded, retrospective two-arm telepathology study to clinically validate SRH for telepathology at our institution. Using surgical specimens from 47 subjects, we generated a data set composed of 47 SRH images and 47 matched whole slide images (WSIs) of formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin, with associated intraoperative clinicoradiologic information and structured diagnostic questions. We compared diagnostic concordance between WSI and SRH-rendered diagnoses. Also, we compared the 1-year median turnaround time (TAT) of intraoperative conventional neuropathology frozen sections with prospectively rendered SRH-telepathology TAT. All SRH images were of sufficient quality for diagnostic review. A review of SRH images showed high accuracy in distinguishing glial from nonglial tumors (96.5% SRH vs 98% WSIs) and predicting final diagnosis (85.9% SRH vs 93.1% WSIs). SRH-based diagnosis and WSI-permanent section diagnosis had high concordance (κ = 0.76). The median TAT for prospectively SRH-rendered diagnosis was 3.7 minutes, approximately 10-fold shorter than the median frozen section TAT (31 minutes). The SRH-imaging procedure did not affect ancillary studies. SRH generates diagnostic virtual histologic images with accuracy comparable to conventional hematoxylin and eosin-based methods in a rapid manner. Our study represents the largest and most rigorous clinical validation of SRH to date. It supports the feasibility of implementing SRH as a rapid method for intraoperative diagnosis complementary to conventional pathology laboratory methods.
PMID: 37201685
ISSN: 1530-0285
CID: 5508102

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.
PMCID:10355794
PMID: 37476329
ISSN: 2632-2498
CID: 5536102

RADIONUCLIDE THERAPY WITH 177LU-DOTATATE (LUTATHERA) IN ADULTS WITH ADVANCED INTRACRANIAL MENINGIO [Meeting Abstract]

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
EMBASE:639939893
ISSN: 1523-5866
CID: 5513302

Clinical, Pathological, and Molecular Characteristics of Diffuse Spinal Cord Gliomas

Garcia, Mekka R; Feng, Yang; Vasudevaraja, Varshini; Galbraith, Kristyn; Serrano, Jonathan; Thomas, Cheddhi; Radmanesh, Alireza; Hidalgo, Eveline T; Harter, David H; Allen, Jeffrey C; Gardner, Sharon L; Osorio, Diana S; William, Christopher M; Zagzag, David; Boué, Daniel R; Snuderl, Matija
Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.
PMID: 35997552
ISSN: 1554-6578
CID: 5338172