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Rapid Automated Analysis of Skull Base Tumor Specimens Using Intraoperative Optical Imaging and Artificial Intelligence

Jiang, Cheng; Bhattacharya, Abhishek; Linzey, Joseph R; Joshi, Rushikesh S; Cha, Sung Jik; Srinivasan, Sudharsan; Alber, Daniel; Kondepudi, Akhil; Urias, Esteban; Pandian, Balaji; Al-Holou, Wajd N; Sullivan, Stephen E; Thompson, B Gregory; Heth, Jason A; Freudiger, Christian W; Khalsa, Siri Sahib S; Pacione, Donato R; Golfinos, John G; Camelo-Piragua, Sandra; Orringer, Daniel A; Lee, Honglak; Hollon, Todd C
BACKGROUND:Accurate specimen analysis of skull base tumors is essential for providing personalized surgical treatment strategies. Intraoperative specimen interpretation can be challenging because of the wide range of skull base pathologies and lack of intraoperative pathology resources. OBJECTIVE:To develop an independent and parallel intraoperative workflow that can provide rapid and accurate skull base tumor specimen analysis using label-free optical imaging and artificial intelligence. METHODS:We used a fiber laser-based, label-free, nonconsumptive, high-resolution microscopy method (<60 seconds per 1 × 1 mm2), called stimulated Raman histology (SRH), to image a consecutive, multicenter cohort of patients with skull base tumor. SRH images were then used to train a convolutional neural network model using 3 representation learning strategies: cross-entropy, self-supervised contrastive learning, and supervised contrastive learning. Our trained convolutional neural network models were tested on a held-out, multicenter SRH data set. RESULTS:SRH was able to image the diagnostic features of both benign and malignant skull base tumors. Of the 3 representation learning strategies, supervised contrastive learning most effectively learned the distinctive and diagnostic SRH image features for each of the skull base tumor types. In our multicenter testing set, cross-entropy achieved an overall diagnostic accuracy of 91.5%, self-supervised contrastive learning 83.9%, and supervised contrastive learning 96.6%. Our trained model was able to segment tumor-normal margins and detect regions of microscopic tumor infiltration in meningioma SRH images. CONCLUSION/CONCLUSIONS:SRH with trained artificial intelligence models can provide rapid and accurate intraoperative analysis of skull base tumor specimens to inform surgical decision-making.
PMID: 35343469
ISSN: 1524-4040
CID: 5205942

Long-term Natural History and Patterns of Sporadic Vestibular Schwannoma Growth: A Multi-institutional Volumetric Analysis of 952 Patients

Marinelli, John P; Schnurman, Zane; Killeen, Daniel E; Nassiri, Ashley M; Hunter, Jacob B; Lees, Katherine A; Lohse, Christine M; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas; Link, Michael J; Carlson, Matthew L
BACKGROUND:The current study aims to characterize the natural history of sporadic vestibular schwannoma volumetric tumor growth, including long-term growth patterns following initial detection of growth. METHODS:Volumetric tumor measurements from 3,505 serial MRI studies were analyzed from unselected consecutive patients undergoing wait-and-scan management at three tertiary referral centers between 1998 and 2018. Volumetric tumor growth was defined as a change in volume ≥20%. RESULTS:Among 952 patients undergoing observation, 622 experienced tumor growth with initial growth-free survival rates (95% CI) at 1, 3, and 5 years following diagnosis of 66% (63-69), 30% (27-34), and 20% (17-24). Among 405 patients who continued to be observed despite demonstrating initial growth, 210 experienced subsequent tumor growth with subsequent growth-free survival rates at 1, 3, and 5 years following initial growth of 77% (72-81), 37% (31-43), and 24% (18-31). Larger tumor volume at initial growth (HR 1.13, p=0.02) and increasing tumor growth rate (HR 1.31; p<0.001) were significantly associated with an increased likelihood of subsequent growth, whereas a longer duration of time between diagnosis and detection of initial growth was protective (HR 0.69; p<0.001). CONCLUSIONS:While most vestibular schwannomas exhibit an overall propensity for volumetric growth following diagnosis, prior tumor growth does not perfectly predict future growth. Tumors can subsequently grow faster, slower, or demonstrate quiescence and stability. Larger tumor size and increasing tumor growth rate portend a higher likelihood of continued growth. These findings can inform timing of intervention: whether upfront at initial diagnosis, after detection of initial growth, or only after continued growth is observed.
PMID: 34964894
ISSN: 1523-5866
CID: 5108222

The incidence and predictors of new brain metastases in patients with non-small cell lung cancer following discontinuation of systemic therapy

London, Dennis; Patel, Dev N; Donahue, Bernadine; Navarro, Ralph E; Gurewitz, Jason; Silverman, Joshua S; Sulman, Erik; Bernstein, Kenneth; Palermo, Amy; Golfinos, John G; Sabari, Joshua K; Shum, Elaine; Velcheti, Vamsidhar; Chachoua, Abraham; Kondziolka, Douglas
OBJECTIVE:Patients with non-small cell lung cancer (NSCLC) metastatic to the brain are living longer. The risk of new brain metastases when these patients stop systemic therapy is unknown. The authors hypothesized that the risk of new brain metastases remains constant for as long as patients are off systemic therapy. METHODS:A prospectively collected registry of patients undergoing radiosurgery for brain metastases was analyzed. Of 606 patients with NSCLC, 63 met the inclusion criteria of discontinuing systemic therapy for at least 90 days and undergoing active surveillance. The risk factors for the development of new tumors were determined using Cox proportional hazards and recurrent events models. RESULTS:The median duration to new brain metastases off systemic therapy was 16.0 months. The probability of developing an additional new tumor at 6, 12, and 18 months was 26%, 40%, and 53%, respectively. There were no additional new tumors 22 months after stopping therapy. Patients who discontinued therapy due to intolerance or progression of the disease and those with mutations in RAS or receptor tyrosine kinase (RTK) pathways (e.g., KRAS, EGFR) were more likely to develop new tumors (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.81, p = 2.5 × 10-3; HR 2.51, 95% CI 1.45-4.34, p = 9.8 × 10-4, respectively). CONCLUSIONS:The rate of new brain metastases from NSCLC in patients off systemic therapy decreases over time and is uncommon 2 years after cessation of cancer therapy. Patients who stop therapy due to toxicity or who have RAS or RTK pathway mutations have a higher rate of new metastases and should be followed more closely.
PMID: 34891140
ISSN: 1933-0693
CID: 5110502

Integrated Molecular-Morphologic Meningioma Classification: A Multicenter Retrospective Analysis, Retrospectively and Prospectively Validated

Maas, Sybren L N; Stichel, Damian; Hielscher, Thomas; Sievers, Philipp; Berghoff, Anna S; Schrimpf, Daniel; Sill, Martin; Euskirchen, Philipp; Blume, Christina; Patel, Areeba; Dogan, Helin; Reuss, David; Dohmen, Hildegard; Stein, Marco; Reinhardt, Annekathrin; Suwala, Abigail K; Wefers, Annika K; Baumgarten, Peter; Ricklefs, Franz; Rushing, Elisabeth J; Bewerunge-Hudler, Melanie; Ketter, Ralf; Schittenhelm, Jens; Jaunmuktane, Zane; Leu, Severina; Greenway, Fay E A; Bridges, Leslie R; Jones, Timothy; Grady, Conor; Serrano, Jonathan; Golfinos, John; Sen, Chandra; Mawrin, Christian; Jungk, Christine; Hänggi, Daniel; Westphal, Manfred; Lamszus, Katrin; Etminan, Nima; Jungwirth, Gerhard; Herold-Mende, Christel; Unterberg, Andreas; Harter, Patrick N; Wirsching, Hans-Georg; Neidert, Marian C; Ratliff, Miriam; Platten, Michael; Snuderl, Matija; Aldape, Kenneth D; Brandner, Sebastian; Hench, Jürgen; Frank, Stephan; Pfister, Stefan M; Jones, David T W; Reifenberger, Guido; Acker, Till; Wick, Wolfgang; Weller, Michael; Preusser, Matthias; von Deimling, Andreas; Sahm, Felix
PURPOSE:), whereas no molecularly based stratification exists for the broad spectrum of patients with low- and intermediate-risk meningioma. METHODS:DNA methylation data and copy-number information were generated for 3,031 meningiomas (2,868 patients), and mutation data for 858 samples. DNA methylation subgroups, copy-number variations (CNVs), mutations, and WHO grading were analyzed. Prediction power for outcome was assessed in a retrospective cohort of 514 patients, validated on a retrospective cohort of 184, and on a prospective cohort of 287 multicenter cases. RESULTS:= .005). Besides the overall stratification advantage, the integrated score separates more precisely for risk of progression at the diagnostically challenging interface of WHO grade 1 and grade 2 tumors (hazard ratio 4.34 [2.48-7.57] and 3.34 [1.28-8.72] retrospective and prospective validation cohorts, respectively). CONCLUSION:Merging these layers of histologic and molecular data into an integrated, three-tiered score significantly improves the precision in meningioma stratification. Implementation into diagnostic routine informs clinical decision making for patients with meningioma on the basis of robust outcome prediction.
PMCID:8713596
PMID: 34618539
ISSN: 1527-7755
CID: 5103732

Perioperative team communication through a mobile app for improving coordination and education in neurosurgery cases

Ber, Roee; London, Dennis; Senan, Samya; Youssefi, Yasmin; Harter, David H; Golfinos, John G; Pacione, Donato
OBJECTIVE:Miscommunication and poor coordination among surgical teams are known causes of preventable medical harms and operating room inefficiencies and inhibit surgical training. Technology may help overcome these challenges. This study used the personal experience of one of the authors as a former Air Force F-15 pilot to design a combat aviation pre- and postoperative communication workflow in the neurosurgery department and tested its effect on safety, efficiency, and education. The authors hypothesized that the adoption of this workflow through a tailored technological platform will increase compliance and improve the chances of sustainability. METHODS:Data were prospectively collected from neurosurgery cases before (January-May 2020) and after (June-October 2020) implementation of this workflow. Briefing and debriefing were executed using a custom mobile platform and were defined as nonmandatory for all participants. All faculty and residents who operated at NYU Langone Medical Center (Tisch campus) during the intervention period were enrolled on the platform. Primary outcomes were morbidity and mortality per the department's criteria, and intraoperative last-minute requests as reported by operating room staff in a double-blinded fashion. Secondary outcomes were user responses on the subjective questionnaires. RESULTS:Data were collected from 637 and 893 cases during the preintervention and intervention periods, respectively. The average briefing rates for residents and surgeons were 71% and 81%, respectively, and the average debriefing rates for residents and surgeons were 67% and 88%. There was no significant difference in preoperative risk score between the preintervention and intervention patient populations (p = 0.24). The rate of intraoperative last-minute requests significantly decreased from 16.6% (35/211) to 10.5% (35/334, p = 0.048). There was no significant change in morbidity and mortality between the preintervention and intervention periods. On subjective questionnaires there was a statistically significant improvement in safety, efficiency, and educational aspects of the cases during the intervention period. CONCLUSIONS:Implementation of aviation-like structured team communication practices in the neurosurgery department through a technological platform improved education and communication between surgical teams and led to a reduction in last-minute surgical requests that could impact costs.
PMID: 34560644
ISSN: 1933-0693
CID: 5178422

Outcomes of Salvage Resection and Radiosurgery Following Failed Primary Treatment of Vestibular Schwannomas

Kay-Rivest, Emily; Golfinos, John G; McMenomey, Sean O; Friedmann, David R; Jethanamest, Daniel; Kondziolka, Douglas; Roland, J Thomas
OBJECTIVE:To evaluate outcomes following salvage microsurgery (MS) and salvage stereotactic radiosurgery (SRS) after failure of primary treatment for vestibular schwannomas (VS). STUDY DESIGN/METHODS:Retrospective chart review. SETTING/METHODS:Tertiary referral center. METHODS:Patients with more than 1 intervention for their VS were divided into 4 groups: MS followed by SRS (n = 61), MS followed by MS (n = 9), SRS followed by MS (n = 7), and SRS followed by SRS (n = 7), and outcomes were evaluated. RESULTS:A total of 77 patients were included (84 procedures). In group 1 (MS then SRS), 3% developed a decline in facial function, 3% developed trigeminal sensory loss, and 13% patients had gradual improvement of facial nerve function following SRS. Group 2 (MS then MS) had the highest rates of facial nerve deterioration, although all but 1 patient achieved a House-Brackmann score of II or III. Gross-total resection (GTR) was achieved in 56% of patients. When a different approach was used for salvage resection, GTR occurred more commonly, and facial nerve outcomes were similar. In group 3 (SRS then MS), GTR occurred in 43% of cases, and 2 of 7 patients developed worsened facial function. In group 4 (SRS then SRS), no patient developed facial weakness after reirradiation, and 1 developed a trigeminal nerve deficit. CONCLUSIONS:For MS recurrences/residuals, SRS is the mainstay of treatment and does not preclude facial function recovery. If salvage microsurgery is required, an alternate approach should be considered. For SRS failures, when MS is required, less-than GTR may be preferable, and reirradiation is a potential safe alternative.
PMID: 34488519
ISSN: 1097-6817
CID: 5067092

Phase 0 Clinical Trial of Everolimus in Patients with Vestibular Schwannoma or Meningioma

Karajannis, Matthias A; Mauguen, Audrey; Maloku, Ekrem; Xu, Qingwen; Dunbar, Erin M; Plotkin, Scott R; Yaffee, Anna; Wang, Shiyang; Roland, J Thomas; Sen, Chandranath; Placantonakis, Dimitris G; Golfinos, John G; Allen, Jeffrey C; Vitanza, Nicholas A; Chiriboga, Luis A; Schneider, Robert J; Deng, Jingjing; Neubert, Thomas A; Goldberg, Judith D; Zagzag, David; Giancotti, Filippo G; Blakeley, Jaishri O
Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of NF2 patients with vestibular schwannoma (VS). To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for VS or meningiomas. Eligible patients with meningioma or VS requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. Ten patients completed protocol therapy. Median pre- and post-operative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to control tissues from untreated patients (p=0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and will inform the design of future pre-clinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.
PMID: 34224367
ISSN: 1538-8514
CID: 4932142

Volumetric growth rates of untreated cavernous sinus meningiomas

Benjamin, Carolina Gesteira; Schnurman, Zane; Ashayeri, Kimberly; Kazi, Eman; Mullen, Reed; Gurewitz, Jason; Golfinos, John G; Sen, Chandranath; Placantonakis, Dimitris G; Pacione, Donato; Kondziolka, Douglas
OBJECTIVE:Meningiomas that arise primarily within the cavernous sinus are often believed to be more indolent in their growth pattern. Despite this perceived growth pattern, disabling symptoms can arise even with small tumors. While research has been done on cavernous sinus meningiomas (CSMs) and their treatment, very little is known about their natural growth rates. With a better understanding of the growth rate of CSM, patient treatment and guidance can be can optimized and individualized. The goal of this study was to determine volumetric growth rates of untreated CSMs. METHODS:Thirty-seven patients with 166 MR images obtained between May 2004 and September 2019 were reviewed, with a range of 2-13 MR images per patient (average of 4.5 MR images per patient). These scans were obtained over an average follow-up period of 45.9 months (median 33.8, range 2.8-136.9 months). All imaging prior to any intervention was included in this analysis. Volumetric measurements were performed and assessed over time. RESULTS:The estimated volumetric growth rate was 23.3% per year (95% CI 10.2%-38.0%, p < 0.001), which is equivalent to an estimated volume doubling time (VDT) of 3.3 years (95% CI 2.1-7.1 years). There was no significant relationship between growth rate and patient age (p = 0.09) or between growth rate and patient sex (p = 0.78). The median absolute growth rate was 41% with a range of -1% to 1793%. With a definition of "growth" as an increase of greater than 20% during the observed period, 65% of tumors demonstrated growth within their observation interval. Growth rates for each tumor were calculated and tumors were segmented based on growth rate. Of 37 patients, 22% (8) demonstrated no growth (< 5% annual growth, equivalent to a VDT > 13.9 years), 32% (12) were designated as slow growth (annual growth rate 5%-20%, VDT 3.5-13.9 years), 38% (14) were found to have medium growth (annual growth rate 20%-100%, VDT 0.7-3.5 years), and 8% were considered fast growing (annual growth rate > 100%, VDT < 0.7 years). CONCLUSIONS:This study evaluated CSM volumetric growth rates. A deeper understanding of the natural history of untreated CSMs allows for better counseling and management of patients.
PMID: 34416713
ISSN: 1933-0693
CID: 5091952

Hearing loss and volumetric growth rate in untreated vestibular schwannoma

Gurewitz, Jason; Schnurman, Zane; Nakamura, Aya; Navarro, Ralph E; Patel, Dev N; McMenomey, Sean O; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas
OBJECTIVE:In this study, the authors aimed to clarify the relationship between hearing loss and tumor volumetric growth rates in patients with untreated vestibular schwannoma (VS). METHODS:Records of 128 treatment-naive patients diagnosed with unilateral VS between 2012 and 2018 with serial audiometric assessment and MRI were reviewed. Tumor growth rates were determined from initial and final tumor volumes, with a median follow-up of 24.3 months (IQR 8.5-48.8 months). Hearing changes were based on pure tone averages, speech discrimination scores, and American Academy of Otolaryngology-Head and Neck Surgery hearing class. Primary outcomes were the loss of class A hearing and loss of serviceable hearing, estimated using the Kaplan-Meier method and with associations estimated from Cox proportional hazards models and reported as hazard ratios. RESULTS:Larger initial tumor size was associated with an increased risk of losing class A (HR 1.5 for a 1-cm3 increase; p = 0.047) and serviceable (HR 1.3; p < 0.001) hearing. Additionally, increasing volumetric tumor growth rate was associated with elevated risk of loss of class A hearing (HR 1.2 for increase of 100% per year; p = 0.031) and serviceable hearing (HR 1.2; p = 0.014). Hazard ratios increased linearly with increasing growth rates, without any evident threshold growth rate that resulted in a large, sudden increased risk of hearing loss. CONCLUSIONS:Larger initial tumor size and faster tumor growth rates were associated with an elevated risk of loss of class A and serviceable hearing.
PMID: 34416729
ISSN: 1933-0693
CID: 5092022

Stereotactic Radiosurgery for Atypical (World Health Organization II) and Anaplastic (World Health Organization III) Meningiomas: Results From a Multicenter, International Cohort Study

Shepard, Matthew J; Xu, Zhiyuan; Kearns, Kathryn; Li, Chelsea; Chatrath, Ajay; Sheehan, Kimball; Sheehan, Darrah; Faramand, Andrew; Niranjan, Ajay; Kano, Hideyuki; Gurewitz, Jason; Bernstein, Kenneth; Liscak, Roman; Guseynova, Khumar; Grills, Inga S; Parzen, Jacob S; Cifarelli, Christopher P; Rehman, Azeem A; Atik, Ahmet; Bakhsheshian, Joshua; Zada, Gabriel; Chang, Eric; Giannotta, Steven; Speckter, Herwin; Wu, Hsiu-Mei; Kondziolka, Douglas; Golfinos, John G; Mathieu, David; Lee, Cheng-Chia; Warnick, Ronald E; Lunsford, L Dade; Sheehan, Jason P
BACKGROUND:Atypical and anaplastic meningiomas have reduced progression-free/overall survival (PFS/OS) compared to benign meningiomas. Stereotactic radiosurgery (SRS) for atypical meningiomas (AMs) and anaplastic meningiomas (malignant meningiomas, MMs) has not been adequately described. OBJECTIVE:To define clinical/radiographic outcomes for patients undergoing SRS for AM/MMs. METHODS:An international, multicenter, retrospective cohort study was performed to define clinical/imaging outcomes for patients receiving SRS for AM/MMs. Tumor progression was assessed with response assessment in neuro-oncology (RANO) criteria. Factors associated with PFS/OS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. RESULTS:A total of 271 patients received SRS for AMs (n = 233, 85.9%) or MMs (n = 38, 14.0%). Single-fraction SRS was most commonly employed (n = 264, 97.4%) with a mean target dose of 14.8 Gy. SRS was used as adjuvant treatment (n = 85, 31.4%), salvage therapy (n = 182, 67.2%), or primary therapy (1.5%). The 5-yr PFS/OS rate was 33.6% and 77.0%, respectively. Increasing age (hazard ratio (HR) = 1.01, P < .05) and a Ki-67 index > 15% (HR = 1.66, P < .03) negatively correlated with PFS. MMs (HR = 3.21, P < .05), increased age (HR = 1.04, P = .04), and reduced KPS (HR = 0.95, P = .04) were associated with shortened OS. Adjuvant versus salvage SRS did not impact PFS/OS. A shortened interval between surgery and SRS improved PFS for AMs (HR = 0.99, P = .02) on subgroup analysis. Radiation necrosis occurred in 34 (12.5%) patients. Five-year rates of repeat surgery/radiation were 33.8% and 60.4%, respectively. CONCLUSION/CONCLUSIONS:AM/MMs remain challenging tumors to treat. Elevated proliferative indices are associated with tumor recurrence, while MMs have worse survival. SRS can control AM/MMs in the short term, but the 5-yr PFS rates are low, underscoring the need for improved treatment options for these patients.
PMID: 33469655
ISSN: 1524-4040
CID: 4861842