Quantifying intra-tumoral genetic heterogeneity of glioblastoma toward precision medicine using MRI and a data-inclusive machine learning algorithm.

BACKGROUND AND OBJECTIVE: Glioblastoma (GBM) is one of the most aggressive and lethal human cancers. Intra-tumoral genetic heterogeneity poses a significant challenge for treatment. Biopsy is invasive, which motivates the development of non-invasive, MRI-based machine learning (ML) models to quantify intra-tumoral genetic heterogeneity for each patient. This capability holds great promise for enabling better therapeutic selection to improve patient outcome. METHODS: We proposed a novel Weakly Supervised Ordinal Support Vector Machine (WSO-SVM) to predict regional genetic alteration status within each GBM tumor using MRI. WSO-SVM was applied to a unique dataset of 318 image-localized biopsies with spatially matched multiparametric MRI from 74 GBM patients. The model was trained to predict the regional genetic alteration of three GBM driver genes (EGFR, PDGFRA and PTEN) based on features extracted from the corresponding region of five MRI contrast images. For comparison, a variety of existing ML algorithms were also applied. Classification accuracy of each gene were compared between the different algorithms. The SHapley Additive exPlanations (SHAP) method was further applied to compute contribution scores of different contrast images. Finally, the trained WSO-SVM was used to generate prediction maps within the tumoral area of each patient to help visualize the intra-tumoral genetic heterogeneity. RESULTS: WSO-SVM achieved 0.80 accuracy, 0.79 sensitivity, and 0.81 specificity for classifying EGFR; 0.71 accuracy, 0.70 sensitivity, and 0.72 specificity for classifying PDGFRA; 0.80 accuracy, 0.78 sensitivity, and 0.83 specificity for classifying PTEN; these results significantly outperformed the existing ML algorithms. Using SHAP, we found that the relative contributions of the five contrast images differ between genes, which are consistent with findings in the literature. The prediction maps revealed extensive intra-tumoral region-to-region heterogeneity within each individual tumor in terms of the alteration status of the three genes. CONCLUSIONS: This study demonstrated the feasibility of using MRI and WSO-SVM to enable non-invasive prediction of intra-tumoral regional genetic alteration for each GBM patient, which can inform future adaptive therapies for individualized oncology.

68Ga-DOTATATE and 18F-FDG PET Imaging of a Rare Chordoid Meningioma With Intracranial Recurrence and Extracranial Metastases.

ABSTRACT: Chordoid meningiomas, rare meningioma variants, are characterized by their histopathological features and clinical behavior resembling that of other chondroid/myxoid neoplasms. We present a case of pathology-proven chordoid meningioma imaged with both 68Ga-DOTATATE and 18F-FDG PET images during a complicated postoperative course with multiple episodes of local recurrence and, ultimately, extracranial metastasis. This case underscores the aggressive behavior of chordoid meningiomas while highlighting how molecular imaging plays an important role in clinical monitoring and guidance of management.

Alfred Washington Adson: Perspectives on Intracranial Neurosurgery and the Responsibilities of the Neurosurgeon.

In a period when the budding field of neurosurgery was believed to have little promise, Dr Alfred Washington Adson founded and led the first neurosurgical department at Mayo Clinic. He was not without reservations-surgical intervention for neurological conditions was rarely pursued because of poor outcomes and high complication rates, and Dr Adson acknowledged his early concerns about the future of neurosurgery in his memoirs. However, his education, mentorship, his training, and his first neurosurgical cases helped to shape the impact he ultimately had on the field and his legacy as a neurosurgeon. Dr Adson trained with several renowned Mayo general surgeons, notably his mentor Dr Emil Beckman, whose desire for operative precision shaped Dr Adson's drive to develop his own skills as a surgeon. Two years into his residency, he became the youngest staff surgeon and was tasked with managing the neurosurgical cases at Mayo. The five neurosurgical cases overseen by Dr Adson in the next year illuminated the opportunity for neurosurgery to drastically improve the lives of patients. Dr Adson, given the option of continuing as either a general surgeon or a neurosurgeon, ultimately chose to pursue neurosurgery. This article seeks to provide a historical perspective on the neurosurgeon Dr Alfred Washington Adson using primary and secondary accounts from the Mayo archives, highlighting his contributions to the early understanding of intracranial pathology and how his early experiences as a trainee developed into a personal passion for self-improvement, education, and advocacy for health care in America.

Virtual Planning and Augmented Reality-Guided Microsurgical Resection of a Frontal Arteriovenous Malformation.

Arteriovenous malformations (AVMs) are complex vascular lesions that can pose significant risk for spontaneous hemorrhage, seizures, and symptoms related to ischemia and venous hypertension.1 Microsurgical management of AVMs requires a deep understanding of the surrounding anatomy and precise identification of the lesion characteristics. We demonstrate the use of augmented reality in the localization of arterial feeders and draining veins in relation to bordering normal structures (Video 1). A 66-year-old man presented with several episodes of severe right frontal headaches. Magnetic resonance imaging revealed an AVM along the right frontal pole. Subsequent computed tomography angiography demonstrated arterial supply from the right anterior cerebral artery with venous drainage to the superior sagittal sinus. Due to the size, noneloquent location, and superficial pattern of venous drainage, the patient elected to proceed with microsurgery. A virtual planning platform was used in preparation for surgery. Augmented reality integrated with neuronavigation was used during microsurgical resection. Postoperative angiography showed complete resection of the AVM. The patient was discharged home on postoperative day 3 with no complications. He remains neurologically well at 4 months of follow-up.

The use of Microsurgical Exploration of the External Carotid Artery for Removal of a Retained Microcatheter After Middle Meningeal Artery Embolization Using Live Fluoroscopy: A Technical Note.

BACKGROUND: Fragmentation, disconnection, or entrapment of an in-use microcatheter during neuro-endovascular procedures is a known risk. Often a benign entity, retained catheters are not infrequently observed, but severe complications including thrombus, thromboembolic events, pseudoaneurysm, and limb ischemia have been described, necessitating retrieval. This technical case report demonstrates the safe use of an external carotid artery (ECA) approach for ligation and removal of a retained microcatheter after middle meningeal artery (MMA) embolization. This article also demonstrates the use of live intraoperative fluoroscopy as a surgical adjunct to ensure that the catheter is fully removed without any injury, shearing, or breakage during removal. METHODS: A 66-year-old male patient presented with bilateral subdural hematomas to an outside hospital. He subsequently underwent evacuation of the hematomas followed by a right-sided MMA embolization, complicated by Onyx (Medtronic, Minneapolis, MN) entrapment of the microcatheter in the MMA. The patient was asymptomatic, but there was significant concern about continuing antiplatelet/anticoagulation therapy in the presence of the subdural hematoma. We proceeded with an open surgical approach for catheter retrieval. As the catheter was withdrawn, intraoperative fluoroscopy demonstrated complete removal without any retained fragments. RESULTS: The patient recovered without event and was discharged on postoperative day 1. On follow-up the patient continued to do well without any complications from the fragment that remained in the external carotid circulation. CONCLUSIONS: This case and accompanying video demonstrates the effective use of open ECA surgical approach to retrieve the retained microcatheter after an MMA embolization. This approach allowed for safe and effective removal of the microcatheter while significantly reducing complication risks.

Remote magnetic navigation enables precision telesurgery.

Medical devices actuated by external magnetic fields can create opportunities for clinical adoption of precision telesurgery.

Microsurgical Treatment of Pineal Tumors: Anatomy and Techniques.

Pineal region tumors are challenging lesions in terms of surgical accessibility and removal.1 The complexity is compounded by the infrequency and heterogeneity of pineal neoplasms.2,3 In Video 1, we present the case of a 39-year-old woman who presented with progressive headaches and vision impairment. She underwent microsurgical resection for a pineal parenchymal tumor of intermediate differentiation. We discuss the rationale, risks, and benefits of treatment for this patient, as well as provide a detailed overview of the alternative approaches that may be considered. Additionally, we discuss the unique anatomic considerations for each approach and include a virtual reality-compatible 3-dimensional fly-through to highlight the relationship between the tumor and relevant venous anatomy. The patient tolerated the procedure well with excellent neurologic outcome, and her follow-up imaging showed no evidence of tumor recurrence.

Extent of Surgical Resection as a Predictor of Tumor Progression in Skull Base Chordomas: A Multicenter Volumetric Analysis.

INTRODUCTION: Skull-base chordomas are aggressive tumors with a propensity for recurrence/progression. Even with standard of care (SoC), 5-year recurrence rates are variable (19%-54%). This high recurrence/progression rate correlates with increased morbidity and mortality. We sought to analyze a multicenter cohort of skull base chordomas to identify predictors of progression in patients receiving SoC. METHODS: The [Blinded]-Neurosurgery data registry was queried for skull base chordomas treated from 2008-2020. Patients with the histopathologic diagnosis of chordoma were included. The cohort was composed of patients with preoperative and postoperative magnetic resonance imaging. Tumor volume and radiologic characteristics were obtained from axial T2 sequences using a Digital Imaging and Communications in Medicine viewer. Survival analysis was performed using Kaplan-Meier method, and time-to-event multivariate regression was performed to identify independent predictors of progression. RESULTS: The cohort included 195 patients, of which 66 patients met inclusion criteria; median age was 44, and 28 (42%) were females. Fifty-four (82%) received SoC, 7 (11%) resection only, and 5 (8%) radiotherapy only. Median preoperative and postoperative tumor volumes were 11.55 cm3 (0.33-54.89) and 0.34 cm3 (0-42.52), respectively. Recurrence rate with SoC was 37%. Postoperative tumor volume (P = 0.010) correlated with progression. A postoperative volume of >4.9 cm3 (P = 0.044), ≤81.3% of tumor resection (P = 0.02), and lower-clivus location (P < 0.005) correlated with decreased time to progression. CONCLUSIONS: Skull base chordomas can be challenging to resect. Even though maximal resection and radiotherapy improve rate of tumor progression, many of these lesions eventually recur. We have identified a postoperative tumor volume of ≥4.9 cm3 and extent of resection of ≤81.3% in this cohort as predictors of progression in patients receiving SoC.

The clinical presentation of PIT1 positive pituitary neuroendocrine tumor immunonegative for growth hormone, prolactin, and thyroid stimulating hormone with analysis of clinical and immunostaining dissociation.

BACKGROUND: PIT1 is a pituitary transcription factor that is associated with either growth hormone (GH), prolactin (PRL), or thyroid-stimulating hormone (TSH) production. However, PIT1-positive pituitary neuroendocrine tumors (PitNETs) are occasionally immunonegative for GH, PRL, and TSH. This paper describes the clinical presentation of PIT1 positive however immunonegative PitNETs. METHODS: We conducted a retrospective analysis, identifying 228 PIT1-positive PitNET patients between 2017 and 2022. Out of these, ten (4%) tested negative for GH, PRL, and TSH. Functioning PitNETs were defined as those causing hormonal excess symptoms or hormonal overproduction. RESULTS: As for 10 patients immunonegative for all three hormones however PIT1-positive, the mean ( ± standard deviation) age was 46 ± 13 years with 70% women. Six patients exhibited signs of excess GH or PRL, and three had visual problems. Additionally, one patient had secondary hypothyroidism and adrenal insufficiency resulting from the mass effect. All tumors were macroadenoma, with a median volume of 2.1 cm3 (range, 0.8-17.5 cm3). Gross total resection was attained in six patients by trans-sphenoidal surgery. Postoperatively, eight patients experienced clinical improvement: three in vision, two in amenorrhea, two in headache, and one in acromegaly symptoms. Biochemical improvement was observed in six patients, with all experiencing remission in hormonal excess and one showing improvement in secondary hypothyroidism. Stereotactic radiosurgery was performed in three patients. CONCLUSIONS: Patients with functioning PitNETs may exhibit PIT1 staining without GH, PRL, or TSH staining. Hormonally active tumors exist in this patient population; therefore, close endocrine follow-up is necessary despite the lack of staining for GH, PRL, and TSH.

Extracranial-Intracranial Bypass for Moyamoya Disease: The Influence of Racial and Socioeconomic Disparities on Outcomes - A National Inpatient Sample Analysis.

BACKGROUND: Extracranial-intracranial (EC-IC) bypass is an established therapeutic option for Moyamoya disease (MMD). However, little is known about the effects of racial and ethnic disparities on outcomes. This study assessed trends in EC-IC bypass outcomes among MMD patients stratified by race and ethnicity. METHODS: Utilizing the US National Inpatient Sample, we identified MMD patients undergoing EC-IC bypass between 2002 and 2020. Demographic and hospital-level data were collected. Multivariable analysis was conducted to identify independent factors associated with outcomes. Trend analysis was performed using piecewise joinpoint regression. RESULTS: Out of 14,062 patients with MMD, 1771 underwent EC-IC bypass. Of these, 60.59% were White, 17.56% were Black, 12.36% were Asians, 8.47% were Hispanic, and 1.02% were Native Americans. Nonhome discharge was noted in 21.7% of cases, with a 6.7% death and 3.8% postoperative neurologic complications rates. EC-IC bypass was more commonly performed in Native Americans (23.38%) and Asians (17.76%). Hispanics had the longest mean length of stay (8.4 days) and lower odds of nonhome discharge compared to Whites (odds ratio: 0.64; 95% confidence interval: 0.40-1.03; P = 0.04). Patients with Medicaid, private insurance, self-payers, and insurance paid by other governments had lower odds of nonhome discharge than those with Medicare. CONCLUSION: This study highlights racial and socioeconomic disparities in EC-IC bypass for patients with MMD. Despite these disparities, we did not find any significant difference in the quality of care. Addressing these disparities is essential for optimizing MMD outcomes.

Image-localized biopsy mapping of brain tumor heterogeneity: A single-center study protocol.

Brain cancers pose a novel set of difficulties due to the limited accessibility of human brain tumor tissue. For this reason, clinical decision-making relies heavily on MR imaging interpretation, yet the mapping between MRI features and underlying biology remains ambiguous. Standard (clinical) tissue sampling fails to capture the full heterogeneity of the disease. Biopsies are required to obtain a pathological diagnosis and are predominantly taken from the tumor core, which often has different traits to the surrounding invasive tumor that typically leads to recurrent disease. One approach to solving this issue is to characterize the spatial heterogeneity of molecular, genetic, and cellular features of glioma through the intraoperative collection of multiple image-localized biopsy samples paired with multi-parametric MRIs. We have adopted this approach and are currently actively enrolling patients for our 'Image-Based Mapping of Brain Tumors' study. Patients are eligible for this research study (IRB #16-002424) if they are 18 years or older and undergoing surgical intervention for a brain lesion. Once identified, candidate patients receive dynamic susceptibility contrast (DSC) perfusion MRI and diffusion tensor imaging (DTI), in addition to standard sequences (T1, T1Gd, T2, T2-FLAIR) at their presurgical scan. During surgery, sample anatomical locations are tracked using neuronavigation. The collected specimens from this research study are used to capture the intra-tumoral heterogeneity across brain tumors including quantification of genetic aberrations through whole-exome and RNA sequencing as well as other tissue analysis techniques. To date, these data (made available through a public portal) have been used to generate, test, and validate predictive regional maps of the spatial distribution of tumor cell density and/or treatment-related key genetic marker status to identify biopsy and/or treatment targets based on insight from the entire tumor makeup. This type of methodology, when delivered within clinically feasible time frames, has the potential to further inform medical decision-making by improving surgical intervention, radiation, and targeted drug therapy for patients with glioma.

Safety and efficacy of the pipeline embolization device for treatment of small vs. large aneurysms: a systematic review and meta-analysis.

Flow diversion with the pipeline embolization device (PED) is increasingly used to treat intracranial aneurysms with high obliteration rates and low morbidity. However, long-term (≥ 1 year) angiographic and clinical outcomes still require further investigation. The aim of this study was to compare the occlusion and complication rates for small (< 10 mm) versus large (10-25 mm) aneurysms at long-term following treatment with PED. A systematic review and meta-analysis were performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We conducted a comprehensive search of English language databases including Ovid MEDLINE and Epub Ahead of Print, In-Process, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. Our studies included a minimum of 10 patients treated with PED for small vs. large aneurysms and with at least 12 months of follow-up. The primary safety endpoint was the rate of clinical complications measured by the occurrence of symptomatic stroke (confirmed clinically and radiographically), intracranial hemorrhage, or aneurysmal rupture. The primary efficacy endpoint was the complete aneurysm occlusion rate. Our analysis included 19 studies with 1277 patients and 1493 aneurysms. Of those, 1378 aneurysms met our inclusion criteria. The mean age was 53.9 years, and most aneurysms were small (89.75%; N = 1340) in women (79.1%; N = 1010). The long-term occlusion rate was 73% (95%, CI 65 to 80%) in small compared to 84% (95%, CI 76 to 90%) in large aneurysms (p < 0.01). The symptomatic thromboembolic complication rate was 5% (95%, CI 3 to 9%) in small compared to 7% (95%, CI 4 to 13%) in large aneurysms (p = 0.01). The rupture rate was 2% vs. 4% (p = 0.92), and the rate of intracranial hemorrhage was 2% vs. 4% (p = 0.96) for small vs. large aneurysms, respectively; however, these differences were not statistically significant. The long-term occlusion rate after PED treatment is higher in large vs. small aneurysms. Symptomatic thromboembolic rates with stroke are also higher in large vs. small aneurysms. The difference in the rates of aneurysm rupture and intracranial hemorrhage was insignificant. Although the PED seems a safe and effective treatment for small and large aneurysms, further studies are required to clarify how occlusion rate and morbidity are affected by aneurysm size.

Outcomes following surgical and endovascular treatment of extracranial vertebral artery aneurysms (VAA): a systematic evaluation of the literature.

Extracranial vertebral artery aneurysms are rare complications resulting from trauma and multiple different diseases. However, the difference between clinical and surgical profiles is well understood. To investigate the clinical and interventional outcomes following extracranial vertebral artery aneurysms (VAA) treatment through a systematic review of the literature to date, an electronic database search for full-text English articles was conducted following PRISMA guidelines. The search yielded results on clinical and surgical outcomes for extracranial VAAs. These results included patient-specific risk factors, indications, and techniques. Our literature search resulted in 561 articles, of which 36 studies were qualified to be included in the analysis. A total of 55 patients with multiple various extracranial VAA incidents were included. The mean age of subjects was 42 years (ranging from 13.0 to 76.0 years), and the majority of patients were males (71%, n =39). Blunt trauma was the most frequent risk factor for extracranial VAA formation (35%, n = 19). The majority of aneurysms (60%) were dissected in nature. The most common form of treatment for extracranial VAAs was the use of a flow diverter (24%, n=13). Overall, five (9%) patients had long-term adverse neurological complications following intervention with 5% (n=3) mortality, 2% (n=1) resulting in unilateral vocal cord paralysis, and 2% (n=1) resulted in a positive Romberg sign. The mortality rate is 15.7% in the surgical group, whereas the endovascular treatment did not result in any mortality. The endovascular approach is a safe and effective treatment of extracranial VAAs due to its relatively low overall complication rate and lack of resulting mortality. This is in contrast to the surgical approach which results in a higher rate of complications, recurrence, and mortality outcomes. An understanding of the factors and clinical outcomes associated with the incidence of extracranial VAAs is essential for the future improvement of patient outcomes.

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures.

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

Immunohistochemical markers predicting long-term recurrence following clival and spinal chordoma resection: a multicenter study.

OBJECTIVE: Chordomas are rare tumors from notochordal remnants and account for 1%-4% of all primary bone malignancies, often arising from the clivus and sacrum. Despite margin-negative resection and postoperative radiotherapy, chordomas often recur. Further, immunohistochemical (IHC) markers have not been assessed as predictive of chordoma recurrence. The authors aimed to identify the IHC markers that are predictive of postoperative long-term (≥ 1 year) chordoma recurrence by using trained multiple tree-based machine learning (ML) algorithms. METHODS: The authors reviewed the records of patients who had undergone treatment for clival and spinal chordomas between January 2017 and June 2021 across the Mayo Clinic enterprise (Minnesota, Florida, and Arizona). Demographics, type of treatment, histopathology, and other relevant clinical factors were abstracted from each patient record. Decision tree and random forest classifiers were trained and tested to predict long-term recurrence based on unseen data using an 80/20 split. RESULTS: One hundred fifty-one patients diagnosed and treated for chordomas were identified: 58 chordomas of the clivus, 48 chordomas of the mobile spine, and 45 chordomas sacrococcygeal in origin. Patients diagnosed with cervical chordomas were the oldest among all groups (58 ± 14 years, p = 0.009). Most patients were male (n = 91, 60.3%) and White (n = 139, 92.1%). Most patients underwent resection with or without radiation therapy (n = 129, 85.4%). Subtotal resection followed by radiation therapy (n = 51, 33.8%) was the most common treatment modality, followed by gross-total resection then radiation therapy (n = 43, 28.5%). Multivariate analysis showed that S100 and pan-cytokeratin are more likely to predict the increase in the risk of postoperative recurrence (OR 3.67, 95% CI 1.09-12.42, p= 0.03; and OR 3.74, 95% CI 0.05-2.21, p = 0.02, respectively). In the decision tree analysis, a clinical follow-up > 1897 days was found in 37% of encounters and a 90% chance of being classified for recurrence (accuracy = 77%). Random forest analysis (n = 500 trees) showed that patient age, type of surgical treatment, location of tumor, S100, pan-cytokeratin, and EMA are the factors predicting long-term recurrence. CONCLUSIONS: The IHC and clinicopathological variables combined with tree-based ML tools successfully demonstrated a high capacity to identify recurrence patterns with an accuracy of 77%. S100, pan-cytokeratin, and EMA were the IHC drivers of recurrence. This shows the power of ML algorithms in analyzing and predicting outcomes of rare conditions of a small sample size.