Prolo Lab Publications


  • CDC42BPA::BRAF represents a novel fusion in desmoplastic infantile ganglioglioma/desmoplastic infantile astrocytoma. Neuro-oncology advances Barros Guinle, M. I., Nirschl, J. J., Xing, Y. L., Nettnin, E. A., Arana, S., Feng, Z. P., Nasajpour, E., Pronina, A., Garcia, C. A., Grant, G. A., Vogel, H., Yeom, K. W., Prolo, L. M., Petritsch, C. K. 2024; 6 (1): vdae050

    View details for DOI 10.1093/noajnl/vdae050

    View details for PubMedID 38741773

    View details for PubMedCentralID PMC11089409

  • The Sensitivity of Limited-Sequence MRI in Identifying Pediatric Cervical Spine Injury: A Western Pediatric Surgery Research Consortium Multicenter Retrospective Cohort Study. The journal of trauma and acute care surgery Melhado, C., Durand, R., Russell, K. W., Polukoff, N. E., Rampton, J., Iyer, R. R., Acker, S. N., Koehler, R., Prendergast, C., Stence, N., O'Neill, B., Padilla, B. E., Jamshidi, R., Vaughn, J. A., Ronecker, J. S., Selesner, L., Lofberg, K., Regner, M., Thiessen, J., Sayama, C., Spurrier, R. G., Ross, E. E., Liu, C. J., Chu, J., McNevin, K., Beni, C., Robinson, B. R., Linnau, K., Buckley, R. T., Chao, S. D., Sabapaty, A., Tong, E., Prolo, L. M., Ignacio, R., Floan Sachs, G., Kruk, P., Gonda, D., Ryan, M., Pandya, S., Koral, K., Braga, B. P., Auguste, K., Jensen, A. R. 2024


    Clinical clearance of a child's cervical spine after trauma is often challenging due to impaired mental status or an unreliable neurologic examination. Magnetic resonance imaging (MRI) is the gold standard for excluding ligamentous injury in children but is constrained by long image acquisition times and frequent need for anesthesia. Limited-sequence MRI (LSMRI) is used in evaluating the evolution of traumatic brain injury and may also be useful for cervical spine clearance while potentially avoiding the need for anesthesia. The purpose of this study was to assess the sensitivity and negative predictive value of LSMRI as compared to gold standard full-sequence MRI as a screening tool to rule out clinically significant ligamentous cervical spine injury.We conducted a ten-center, five-year retrospective cohort study (2017-2021) of all children (0-18y) with a cervical spine MRI after blunt trauma. MRI images were re-reviewed by a study pediatric radiologist at each site to determine if the presence of an injury could be identified on limited sequences alone. Unstable cervical spine injury was determined by study neurosurgeon review at each site.We identified 2,663 children less than 18 years of age who underwent an MRI of the cervical spine with 1,008 injuries detected on full-sequence studies. The sensitivity and negative predictive value of LSMRI were both >99% for detecting any injury and 100% for detecting any unstable injury. Young children (age < 5 years) were more likely to be electively intubated or sedated for cervical spine MRI.LSMRI is reliably detects clinically significant ligamentous injury in children after blunt trauma. To decrease anesthesia use and minimize MRI time, trauma centers should develop LSMRI screening protocols for children without a reliable neurologic exam.2 (Diagnostic Tests or Criteria).

    View details for DOI 10.1097/TA.0000000000004271

    View details for PubMedID 38523120

  • Language-discordant care in pediatric neurosurgery: parent and provider perspectives on challenges and multilevel solutions to reduce disparities. Journal of neurosurgery. Pediatrics Ruiz Colon, G. D., Bereknyei Merrell, S., Poon, D. C., Mahaney, K. B., Maher, C. O., Prolo, L. M. 2024: 1-7


    OBJECTIVE: In the United States, Spanish is the second most spoken language, with nearly 42 million individuals speaking Spanish at home. Spanish speakers have been noted to have higher rates of unfavorable neurosurgical outcomes; however, to the authors' knowledge, no study has explored the experiences of patients, caregivers, and providers receiving or delivering neurosurgical care in language-discordant settings. In this study, the authors sought to identify challenges faced by pediatric neurosurgery providers and Spanish-speaking parents communicating with a language barrier and propose solutions to address those challenges.METHODS: Spanish-speaking parents and pediatric neurosurgery providers were invited to participate in semistructured interviews. Purposeful sampling was used to recruit Spanish-speaking parents whose child had recently undergone neurological surgery at the authors' institution and to identify pediatric neurosurgery clinical team members to interview, including physicians, advanced practice providers, and interpreters. Codes were inductively developed and applied to transcripts by two researchers. Thematic analysis was conducted to identify challenges faced by parents and providers.RESULTS: Twenty individuals were interviewed, including parents (n = 8), advanced practice providers (n = 5), physicians (n = 3), interpreters (n = 2), a social worker (n = 1), and a nurse (n = 1). Three challenges were identified. 1) Compared with English-speaking parents, providers noted that Spanish-speaking parents were less likely to ask questions or raise new concerns. Concurrently, Spanish-speaking parents expressed a desire to better understand their child's future medical needs, care, and development. 2) There is a dearth of high-quality resources available in the Spanish language to supplement patient and parent neurosurgical education. 3) Both parents and providers invariably prefer in-person interpreters; however, their availability is limited.CONCLUSIONS: Three challenges were identified by Spanish-speaking parents of pediatric neurosurgery patients and providers when receiving or delivering care through a language barrier. The authors discuss multilevel solutions that, if deployed, could directly address these shared challenges. Furthermore, optimizing communication may help mitigate the disparities experienced by non-English-speaking Hispanic/Latino individuals when receiving neurosurgical care.

    View details for DOI 10.3171/2024.1.PEDS23435

    View details for PubMedID 38518279

  • Neurosurgical Outcomes Among Non-English Speakers: A Systematic Review and a Framework for Future Research. World neurosurgery Ruiz Colon, G. D., Barros Guinle, M. I., Wu, A., Grant, G. A., Prolo, L. M. 2024


    OBJECTIVE: In 2019, 22% of adults in the United States reported speaking a language other than English at home, representing 52% growth since 2000. This diversity in languages - and resulting possible communication barriers - represents a potential challenge to effective care. In this manuscript, we summarize clinical outcomes and healthcare utilization patterns of adult and pediatric neurosurgical patients who are non-English primary language speakers (NEPLS).METHODS: We systematically queried five databases from inception through October 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to identify studies for inclusion. The Newcastle-Ottawa Scale was used to assess the quality of studies. Additionally, a retrospective chart review was conducted to assess differences in postoperative communication patterns in a cohort of English and Spanish speaking patients with craniosynostosis at our institution.RESULTS: Our search yielded 442 abstracts; ten were included in the final cohort. Outcomes for 973 unique NEPLS with a neurosurgical condition were included; Spanish was the most represented language. Delivery and timing of surgical treatment was the most frequently reported metric; 75% of studies demonstrated a statistically significant delay in time to surgery or decreased likelihood for NEPLS to receive surgical treatment. Length of stay (LOS) was reported in three studies; all demonstrated that NEPLS had longer LOS.CONCLUSION: There is a paucity of literature reporting outcomes among NEPLS. It is critical to examine NEPLS patients' outcomes and experiences, as language barriers are potentially modifiable demographic factors. We present a framework that demonstrates opportunities for further research to improve quality of care.

    View details for DOI 10.1016/j.wneu.2024.02.068

    View details for PubMedID 38387790

  • iSPAN: Explainable prediction of outcomes post thrombectomy with Machine Learning. European journal of radiology Kelly, B. S., Mathur, P., Vaca, S. D., Duignan, J., Power, S., Lee, E. H., Huang, Y., Prolo, L. M., Yeom, K. W., Lawlor, A., Killeen, R. P., Thornton, J. 2024; 173: 111357


    PURPOSE: This study aimed to develop and evaluate a machine learning model and a novel clinical score for predicting outcomes in stroke patients undergoing endovascular thrombectomy.MATERIALS AND METHODS: This retrospective study included all patients aged over 18years with an anterior circulation stroke treated at a thrombectomy centre from 2010 to 2020 with external validation. The primary outcome was day 90 mRS ≥3. Existing clinical scores (SPAN and PRE) and Machine Learning (ML) models were compared. A novel clinical score (iSPAN) was derived by adding an optimised weighting of the most important ML features to the SPAN.RESULTS: 812 patients were initially included (397 female, average age 73), 63 for external validation. The best performing clinical score and ML model were SPAN and XGB (sensitivity, specificity and accuracy 0.290, 0.967, 0.628 and 0.693, 0.783, 0.738 respectively). A significant difference was found overall and our XGB model was more accurate than SPAN (p<0.0018). The most important features were Age, mTICI and total number of passes. The addition of 11 points for mTICI of ≤2B and 3 points for ≥3 passes to the SPAN achieved the best accuracy and was used to create the iSPAN. iSPAN was not significantly less accurate than our XGB model (p>0.5). In the external validation set, iSPAN and SPAN achieved sensitivity, specificity, and accuracy of (0.735, 0.862, 0.79) and (0.471, 0.897, 0.67) respectively.CONCLUSION: iSPAN incorporates machine-derived features to achieve better predictions compared to existing clinical scores. It is not inferior to our XGB model and is externally generalisable.

    View details for DOI 10.1016/j.ejrad.2024.111357

    View details for PubMedID 38401408

  • Unraveling the Complexity of the Senescence-Associated Secretory Phenotype in Adamantinomatous Craniopharyngioma Using Multi-Modal Machine Learning Analysis. Neuro-oncology Prince, E. W., Apps, J. R., Jeang, J., Chee, K., Medlin, S., Jackson, E. M., Dudley, R., Limbrick, D., Naftel, R., Johnston, J., Feldstein, N., Prolo, L. M., Ginn, K., Niazi, T., Smith, A., Kilburn, L., Chern, J., Leonard, J., Lam, S., Hersh, D. S., Gonzalez-Meljem, J. M., Amani, V., Donson, A. M., Mitra, S. S., Bandohpadhayay, P., Martinez-Barbera, J. P., Hankinson, T. C. 2024


    Cellular senescence can have positive and negative effects on the body, including aiding in damage repair and facilitating tumor growth. Adamantinomatous Craniopharyngioma (ACP), the most common pediatric sellar/suprasellar brain tumor, poses significant treatment challenges. Recent studies suggest that senescent cells in ACP tumors may contribute to tumor growth and invasion by releasing a Senesecence-Associated Secretory Phenotype (SASP). However, a detailed analysis of these characteristics has yet to be completed.We analyzed primary tissue samples from ACP patients using single-cell, single-nuclei, and spatial RNA Sequencing. We performed various analyses, including gene expression clustering, inferred senescence cells from gene expression, and conducted cytokine signaling inference. We utilized LASSO to select essential gene expression pathways associated with senescence. Finally, we validated our findings through immunostaining.We observed significant diversity in gene expression and tissue structure. Key factors such as NFKB, RELA, and SP1 are essential in regulating gene expression, while senescence markers are present throughout the tissue. SPP1 is the most significant cytokine signaling network among ACP cells, while the Wnt signaling pathway predominantly occurs between epithelial and glial cells. Our research has identified links between senescence-associated features and pathways, such as PI3K/Akt/mTOR, MYC, FZD, and Hedgehog, with increased P53 expression associated with senescence in these cells.A complex interplay between cellular senescence, cytokine signaling, and gene expression pathways underlies ACP development. Further research is crucial to understand how these elements interact to create novel therapeutic approaches for patients with ACP.

    View details for DOI 10.1093/neuonc/noae015

    View details for PubMedID 38334125

  • Review: therapeutic approaches for circadian modulation of the glioma microenvironment. Frontiers in oncology Nettnin, E. A., Nguyen, T., Arana, S., Barros Guinle, M. I., Garcia, C. A., Gibson, E. M., Prolo, L. M. 2023; 13: 1295030


    High-grade gliomas are malignant brain tumors that are characteristically hard to treat because of their nature; they grow quickly and invasively through the brain tissue and develop chemoradiation resistance in adults. There is also a distinct lack of targeted treatment options in the pediatric population for this tumor type to date. Several approaches to overcome therapeutic resistance have been explored, including targeted therapy to growth pathways (ie. EGFR and VEGF inhibitors), epigenetic modulators, and immunotherapies such as Chimeric Antigen Receptor T-cell and vaccine therapies. One new promising approach relies on the timing of chemotherapy administration based on intrinsic circadian rhythms. Recent work in glioblastoma has demonstrated temporal variations in chemosensitivity and, thus, improved survival based on treatment time of day. This may be due to intrinsic rhythms of the glioma cells, permeability of the blood brain barrier to chemotherapy agents, the tumor immune microenvironment, or another unknown mechanism. We review the literature to discuss chronotherapeutic approaches to high-grade glioma treatment, circadian regulation of the immune system and tumor microenvironment in gliomas. We further discuss how these two areas may be combined to temporally regulate and/or improve the effectiveness of immunotherapies.

    View details for DOI 10.3389/fonc.2023.1295030

    View details for PubMedID 38173841

    View details for PubMedCentralID PMC10762863

  • Cervical Collar-Associated Pressure Injury in Pediatric Trauma Patients: A Western Pediatric Surgery Research Consortium Study. Journal of pediatric surgery Melhado, C., Russell, K. W., Acker, S. N., Padilla, B. E., Lofberg, K., Spurrier, R. G., Robinson, B., Chao, S., Ignacio, R. C., Ryan, M., Jensen, A. R. 2023


    Healthcare-associated pressure injuries (HAPI) are known to be associated with medical devices and are preventable. Cervical spine immobilization is commonly utilized in injured children prior to clinical clearance or for treatment of an unstable cervical spinal injury. The frequency of HAPI has been quantified in adults with cervical spine immobilization but has not been well-described in children. The aim of this study was to describe characteristics of children who developed HAPI associated with cervical immobilization.We analyzed a retrospective cohort of children (0-18 years) who developed a stage two or greater cervical HAPI. This cohort was drawn from an overall sample of 49,218 registry patients treated over a five-year period (2017-2021) at ten pediatric trauma centers. Patient demographics, injury characteristics, and cervical immobilization were tabulated to describe the population.The cohort included 32 children with stage two or greater cervical HAPI. The median age was 5 years (IQR 2-13) and 78% (n = 25) were admitted to the intensive care unit. The median (IQR) time to diagnosis of HAPI was 11 (7-21) days post-injury. The majority of cervical HAPI (78%, 25/32) occurred in children requiring immobilization for cervical injuries, with only four children developing HAPI after wearing a prophylactic cervical collar in the absence of a cervical spine injury.Advanced-stage HAPI associated with cervical collar use in pediatric trauma patients is rare and usually occurs in patients with cervical spine injuries requiring immobilization for treatment. More expedient cervical spine clearance with MRI is unlikely to substantially reduce cervical HAPI in injured children.Level III (Epidemiologic and Prognostic).

    View details for DOI 10.1016/j.jpedsurg.2023.10.021

    View details for PubMedID 38030530

  • Treatment Course and Outcomes of Intracranial Teratomas in Pediatric Patients: A Retrospective 15-Year Case Series Study. Pediatric neurosurgery Wu, A., Jin, M. C., Vogel, H., Hiniker, S., Campen, C., Prolo, L. M., Grant, G. A. 2023; 58 (6): 429-438


    There is no standard treatment paradigm for intracranial teratomas, a rare subset of primary intracranial non-germinomatous germ cell tumors (NGGCT), which comprise less than 1% of pediatric brain tumors. This case series retrospectively analyzes treatment and outcomes of pediatric intracranial teratomas from a single institution.Authors reviewed a comprehensive pathology database at Stanford's Lucile Packard Children's Hospital for intracranial teratomas in pediatric patients treated from 2006 to 2021; their demographics, treatment, and clinical course were analyzed.Among 14 patients, median follow-up time was 4.6 years and mean age at diagnosis was 10.5 years. Ten had elevated tumor markers and underwent chemotherapy as initial treatment for NGGCT. Ultimately, these patients all required surgery for progressive or residual disease. Two patients did not undergo radiation. After biopsy or resection, 8 patients had pure mature teratoma, five had mixed germ cell tumor with teratoma component, and one had immature teratoma. The patient with immature teratoma died during chemotherapy from septic shock. No patients experienced recurrence. Common sequelae were endocrine (42.8%) and eye movement (50.0%) abnormalities.We highlight the variable treatment course and outcome for pediatric patients with intracranial teratomas. Elevated tumor markers at presentation, along with imaging findings, favor chemotherapy initiation for presumed NGGCT. Resection of residual tumor is recommended even if tumor markers return to normal. Prognosis remains excellent; no patients had recurrence with a median follow-up of 4.6 years.

    View details for DOI 10.1159/000534721

    View details for PubMedID 37879310

  • Disparities in Postoperative Communication Patterns Among Spanish-Speaking Pediatric Patients with Hydrocephalus. The Journal of pediatrics Ruiz Colón, G. D., Pizzitola, R. J., Grant, G. A., Prolo, L. M. 2023: 113678


    To determine if differences exist in postoperative communication patterns or healthcare utilization among English-speaking patients (ESPs) and Spanish-speaking patients (SSPs) with childhood hydrocephalus.A single-institution, retrospective cohort study was conducted. Through simple random sampling, fifty ESPs and fifty SSPs (<18 years old) who underwent a ventriculoperitoneal shunt (VPS) or endoscopic third ventriculostomy (ETV) were identified. Demographics, communication with clinic (eg, number of calls/messages postoperatively), and healthcare utilization were collected. Multiple linear regressions assessed the significance of predictors on communication frequency and utilization.SSPs were more likely to have a comorbidity and VPS than ESPs. SSPs had longer median postoperative length of stay (p<0.01) and 30-day readmission (p<0.01) than ESPs. Only 18% of SSPs communicated with clinic; 11 total calls/messages from SSPs versus 57 from ESPs (p<0.01). The most common reason for outreach among both cohorts was a new symptom. ESP outreach most frequently resulted in reassurance or medical course changes on an outpatient basis (30% ESPs vs. 0% SSPs, p=0.04), whereas SSP outreach most frequently resulted in guidance to present to the emergency department (ED, 3% ESPs vs. 36% SSPs, p<0.01). Language remained a significant predictor for number of calls/messages even after adjusting for comorbidity, operation type, and insurance (p<0.01).Despite having more complex disease, only 18% of SSPs communicated with the neurosurgical team postoperatively and were more frequently sent to the ED for management. Future research will explore communication barriers and preferences to ensure postoperative care is timely and patient-centered.

    View details for DOI 10.1016/j.jpeds.2023.113678

    View details for PubMedID 37611737

  • Endoscopic Endonasal Transtuberculum Approach for Pediatric Tuberoinfundibular Craniopharyngioma: 2-Dimensional Operative Video. Operative neurosurgery (Hagerstown, Md.) Vigo, V., Chang, J. E., Nunez, M. A., Prolo, L. M., Hwang, P. H., Fernandez-Miranda, J. C. 2023


    INDICATIONS CORRIDOR AND LIMITS OF EXPOSURE: The endoscopic endonasal transtuberculum approach grants access to suprasellar and retrochiasmatic lesions with hypothalamic involvement. Here, we present a case of a 13-year-old boy with a history of stunted growth, decreased vision, headaches, and low energy with a tuberoinfundibular craniopharyngioma. The patient consented to the procedure.ANATOMIC ESSENTIALS NEED FOR PREOPERATIVE PLANNING AND ASSESSMENT: Evaluation of the sphenoid sinus pneumatization, internal carotid artery disposition, presence of clinoidal rings, variations of the infrachiasmatic corridor (optic chiasm location, height of dorsum sella), and location of the pituitary stalk are crucial for surgical strategy.ESSENTIALS STEPS OF THE PROCEDURE: Harvesting of nasoseptal flap and access to the sphenoid sinus; drilling the sella, tuberculum, and chiasmatic sulcus up to the limbus sphenoidalis and laterally exposing the clinoidal carotid artery segment; wide dural opening to the level of distal rings inferolaterally and falciform ligaments superolaterally; identification and coagulation of superior hypophyseal branches providing tumor supply; intracapsular dissection and debulking and subpial sharp dissection at the hypothalamic tumor interface to achieve complete removal; and reconstruction with inlay collagen, fascia lata, and nasoseptal flap.PITFALLS/AVOIDANCE OF COMPLICATIONS: Preservation of the superior hypophyseal arteries and stalk is essential for preventing pituitary dysfunction. Preoperative reckoning of hypothalamic invasion and identification of adequate interface aids in avoiding complications. To reduce CSF leak risk, multilayer reconstruction was performed and lumbar drain placed postoperatively.VARIANTS AND INDICATIONS FOR THEIR USE: For retroclival extension, intradural pituitary transposition should be considered to expand the corridor; in patients with preoperative hypopituitarism, pituitary sacrifice is most effective to increase retroclival access.

    View details for DOI 10.1227/ons.0000000000000726

    View details for PubMedID 37350589

  • TUMOR INFLAMMATION-ASSOCIATED NEUROTOXICITY (TIAN): A TOXICITY SYNDROME IN PATIENTS TREATED WITH IMMUNOTHERAPY FOR CENTRAL NERVOUS SYSTEM TUMORS Mahdi, J., Dietrich, J., Straathof, K., Roddie, C., Scott, B., Davidson, T., Prolo, L., Batchelor, T., Campen, C., Davis, K., Gust, J., Lim, M., Majzner, R., Park, J., Partap, S., Ramakrishna, S., Richards, R., Schultz, L., Vitanza, N., Wang, L., Mackall, C., Monje, M. OXFORD UNIV PRESS INC. 2023
  • BIOPROCESSING OF SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING Nasajpour, E., Tran, C., Garcia, C., Lyle, G., Guinle, M., Bagley, B. A., Lancero, H., Gibson, E. E., Schouten, T., Mahaney, K., Vogel, H., Learned, K., Vaske, O., Grant, G. A., Prolo, L. M., Petritsch, C. K. OXFORD UNIV PRESS INC. 2023
  • CHEK2 mutations in pediatric brain tumors. Neuro-oncology advances Tlais, D., Barros Guinle, M. I., Wheeler, J. R., Prolo, L. M., Vogel, H., Partap, S. 2023; 5 (1): vdad038

    View details for DOI 10.1093/noajnl/vdad038

    View details for PubMedID 37207118

    View details for PubMedCentralID PMC10191190

  • Tumor inflammation-associated neurotoxicity. Nature medicine Mahdi, J., Dietrich, J., Straathof, K., Roddie, C., Scott, B. J., Davidson, T. B., Prolo, L. M., Batchelor, T. T., Campen, C. J., Davis, K. L., Gust, J., Lim, M., Majzner, R. G., Park, J. R., Partap, S., Ramakrishna, S., Richards, R., Schultz, L., Vitanza, N. A., Wang, L. D., Mackall, C. L., Monje, M. 2023


    Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of 'pseudoprogression,' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.

    View details for DOI 10.1038/s41591-023-02276-w

    View details for PubMedID 37024595

    View details for PubMedCentralID 7238960

  • Quality and patient safety research in pediatric neurosurgery: a review. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery Ruiz Colón, G. D., Wu, A., Ratliff, J. K., Prolo, L. M. 2023


    In 2001, the National Academy of Medicine, formerly known as the Institute of Medicine (IOM), published their seminal work, Crossing the Quality Chasm: A New Health System for the 21st Century. In this work, the authors called for improved safety, effectiveness, patient-centeredness, timeliness, efficiency, and equity in the United States' healthcare system. Two decades after the publication of this work, healthcare costs continue to rise, but outcomes lag other nations. The objective of this narrative review is to describe research efforts in pediatric neurosurgery with respect to the six quality aims proposed by the IOM, and highlight additional research opportunities.PubMed, Google Scholar, and EBSCOhost were queried to identify studies in pediatric neurosurgery that have addressed the aims proposed by the IOM. Studies were summarized and synthesized to develop a set of research opportunities to advance quality of care.Twenty-three studies were reviewed which focused on the six quality aims proposed by the IOM. Out of these studies, five research opportunities emerged: (1) To examine performance of tools of care, (2) To understand processes surrounding care delivery, (3) To conduct cost-effectiveness analyses for a broader range of neurosurgical conditions, (4) To identify barriers driving healthcare disparities, and (5) To understand patients' and caregivers' experiences receiving care, and subsequently develop tools and programs to address their needs and preferences.There is a growing body of literature examining quality in pediatric neurosurgical care across all aims proposed by the IOM. However, there remains important gaps in the literature that, if addressed, will advance the quality of pediatric neurosurgical care delivery.

    View details for DOI 10.1007/s00381-022-05821-z

    View details for PubMedID 36695845

  • The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science. Neoplasia (New York, N.Y.) Lilly, J. V., Rokita, J. L., Mason, J. L., Patton, T., Stefankiewiz, S., Higgins, D., Trooskin, G., Larouci, C. A., Arya, K., Appert, E., Heath, A. P., Zhu, Y., Brown, M. A., Zhang, B., Farrow, B. K., Robins, S., Morgan, A. M., Nguyen, T. Q., Frenkel, E., Lehmann, K., Drake, E., Sullivan, C., Plisiewicz, A., Coleman, N., Patterson, L., Koptyra, M., Helili, Z., Van Kuren, N., Young, N., Kim, M. C., Friedman, C., Lubneuski, A., Blackden, C., Williams, M., Baubet, V., Tauhid, L., Galanaugh, J., Boucher, K., Ijaz, H., Cole, K. A., Choudhari, N., Santi, M., Moulder, R. W., Waller, J., Rife, W., Diskin, S. J., Mateos, M., Parsons, D. W., Pollack, I. F., Goldman, S., Leary, S., Caporalini, C., Buccoliero, A. M., Scagnet, M., Haussler, D., Hanson, D., Firestein, R., Cain, J., Phillips, J. J., Gupta, N., Mueller, S., Grant, G., Monje-Deisseroth, M., Partap, S., Greenfield, J. P., Hashizume, R., Smith, A., Zhu, S., Johnston, J. M., Fangusaro, J. R., Miller, M., Wood, M. D., Gardner, S., Carter, C. L., Prolo, L. M., Pisapia, J., Pehlivan, K., Franson, A., Niazi, T., Rubin, J., Abdelbaki, M., Ziegler, D. S., Lindsay, H. B., Stucklin, A. G., Gerber, N., Vaske, O. M., Quinsey, C., Rood, B. R., Nazarian, J., Raabe, E., Jackson, E. M., Stapleton, S., Lober, R. M., Kram, D. E., Koschmann, C., Storm, P. B., Lulla, R. R., Prados, M., Resnick, A. C., Waanders, A. J. 2022; 35: 100846


    Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents,and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

    View details for DOI 10.1016/j.neo.2022.100846

    View details for PubMedID 36335802

  • Stereotactic radiosurgery for recurrent pediatric brain tumors: clinical outcomes and toxicity. Neurosurgical focus Wang, E., Gutkin, P. M., Oh, J., Pollom, E., Soltys, S. G., Grant, G. A., Prolo, L. M., Chang, S., Li, G., Fisher, P. G., Partap, S., Campen, C. J., Gibbs, I. C., Hiniker, S. M. 2022; 53 (5): E2


    Recurrence of brain tumors in children after the initial course of treatment remains a problem. This study evaluated the efficacy and safety of reirradiation using stereotactic radiosurgery (SRS) in patients with recurrent pediatric primary brain tumors.This IRB-approved retrospective review included pediatric patients with recurrent primary brain tumors treated at Stanford University from 2000 to 2019 using frameless SRS. Time to local failure (LF) and distant intracranial failure (DIF) were measured from the date of SRS and analyzed using competing risk analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed with the Kaplan-Meier method.In total, 37 patients aged 2-24 years (median age 11 years at recurrence) were treated for 48 intracranial tumors. Ependymoma (38%) and medulloblastoma (22%) were the most common tumor types. The median (range) single fraction equivalent dose of SRS was 16.4 (12-24) Gy. The median (range) follow-up time was 22.9 (1.5-190) months. The median OS of all patients was 36.8 months. Eight of 40 (20%) lesions with follow-up imaging locally recurred. The 2-year cumulative incidence of LF after reirradiation with SRS was 12.8% (95% CI 4.6%-25.4%). The 2-year cumulative incidence of DIF was 25.3% (95% CI 12.9%-39.8%). The median PFS was 18 months (95% CI 8.9-44). Five (10.4%) patients developed toxicities potentially attributed to SRS, including cognitive effects and necrosis.Reirradiation using SRS for recurrent pediatric brain tumors appears safe with good local control. Innovations that improve overall disease control should continue because survival outcomes after relapse remain poor.

    View details for DOI 10.3171/2022.8.FOCUS22361

    View details for PubMedID 36321285

  • BIOPROCESSING OF SURGICAL PEDIATRIC BRAIN TUMOR SPECIMENS FOR GENOME-GUIDED PERSONALIZED DRUG TESTING Nasajpour, E., Lyle, G., Lancero, H., Garcia, C., Learned, K., Gibson, E., Tran, C., Schouten, T., Vogel, H., Mahaney, K., Prolo, L., Vaske, O., Grant, G., Petritsch, C. OXFORD UNIV PRESS INC. 2022: 232
  • Increased utilization of healthcare services in children with craniosynostosis. Journal of neurosurgery. Pediatrics Ruiz Colón, G. D., Jin, M. C., Grant, G. A., Prolo, L. M. 2022: 1-8


    Craniosynostosis is characterized by the premature fusion of at least one cranial suture. Although evidence suggests that patients with both syndromic and nonsyndromic craniosynostosis may benefit from developmental, behavioral, and mental health support, data on utilization of healthcare services are lacking. In this study the authors compared utilization of mental health care, rehabilitation therapies, and other specialty medical services among children with craniosynostosis, children with plagiocephaly, and healthy controls.The Optum Clinformatics Data Mart database was queried to identify 1340 patients with craniosynostosis, of whom 200 had syndromic craniosynostosis. Long-term utilization of mental health care, rehabilitation therapies, and other medical services up to the age of 6 years was calculated. Rates of utilization were compared to healthy controls (n = 1577) and children with plagiocephaly (n = 1249).Patients with syndromic and nonsyndromic craniosynostosis used mental health care, occupational therapy, speech-language pathology, and other medical services at similar rates (p = 0.1198, p > 0.9999, p = 0.1097, and p = 0.8119, respectively). Mental health services were used more frequently by patients with craniosynostosis (11.0% in patients with syndromic craniosynostosis and 7.5% in those with nonsyndromic craniosynostosis) compared to patients in the plagiocephaly (5.0%, p = 0.0020) and healthy control (2.9%, p < 0.0001) cohorts. Rehabilitation therapies were more frequently used by patients with syndromic craniosynostosis and plagiocephaly (16.0% and 14.1%, respectively), which was significantly higher than use by healthy controls (p < 0.0001). Other medical subspecialty services (developmental pediatrics, ophthalmology, optometry, and audiology) were used by 37.0% of patients with craniosynostosis, compared with 20.9% (p < 0.0001) and 15.1% (p < 0.0001) of patients with plagiocephaly and healthy controls, respectively. Among patients with craniosynostosis, utilization did not differ by race or household income, but it was not uniform by age. Whereas ophthalmology utilization did not differ by age (p = 0.1003), mental health care was most commonly used among older children (p = 0.0107).In this study, the authors demonstrate that rates of utilization of mental health care, rehabilitation therapies, and other medical subspecialty services are similar between patients with syndromic and those with nonsyndromic craniosynostosis, but higher than in healthy controls. Although surgical correction may be considered an isolated event, providers and parents need to monitor all children with craniosynostosis-syndromic and nonsyndromic-for developmental and mental health support longitudinally. Future work should explore risk factors driving utilization, including suture involvement, repair type, and comorbidities.

    View details for DOI 10.3171/2022.2.PEDS2253

    View details for PubMedID 35426826

  • Endoscopic Endonasal Approach for Suprasellar Mature Teratoma in Growing Teratoma Syndrome: 2-Dimensional Operative Video. Operative neurosurgery (Hagerstown, Md.) Vigo, V., Prolo, L. M., Nunez, M. A., Nayak, J. V., Fernandez-Miranda, J. C. 2022


    Intracranial growing teratoma syndrome is a rare phenomenon characterized by enlargement of a germ cell tumor during or after adjuvant therapy despite normalization of tumor markers.1,2 It has been suggested that chemotherapy acts on the nonteratomatous components or induces differentiation of the immature germ cells to mature teratomatous phenotype.3 An 8-year-old boy presented with headache, emesis, and blurry vision. Neuroimaging revealed hydrocephalus with multiple central nervous system masses: pineal gland, suprasellar region, and spine (T8). Elevated serum and cerebrospinal fluid levels of alpha-fetoprotein and beta-human chorionic gonadotropin were found. A ventriculoperitoneal shunt was placed. Despite chemotherapy and decreasing tumor markers, the pineal mass rapidly enlarged, and the patient became somnolent. He underwent microsurgical resection with the diagnosis of mixed germ cell tumor. During his second chemotherapy cycle, the patient endorsed worsening vision and panhypopituitarism. Imaging demonstrated enlargement and honeycomb appearance of the suprasellar mass. The patient and family consented to the procedure, and an endoscopic endonasal approach was performed to access the retroinfundibular region. Removal of the nonfunctional pituitary gland and dorsum sellae was performed. Careful dissection of the tumor from the optic apparatus, hypothalamus, and perforating arteries allowed total resection. Reconstruction with fascia lata and nasoseptal flap was performed. Mature teratoma was found histologically. Postoperative course was complicated by flap hemorrhage resolved by surgical revision. Postoperative imaging showed complete resection. The patient was discharged without other complications and was making excellent recovery. To the best of our knowledge, this is the first reported case of hypothalamic intracranial growing teratoma syndrome successfully treated using an endoscopic endonasal approach.

    View details for DOI 10.1227/ons.0000000000000166

    View details for PubMedID 35383719

  • Development of an Integrated Risk Scale for Prediction of Shunt Placement After Neonatal Intraventricular Hemorrhage Jin, M. C., Parker, J. J., Rodrigues, A., Colon, G. R., Garcia, C. A., Mahaney, K. B., Grant, G. A., Prolo, L. M. OXFORD UNIV PRESS INC. 2022: 37-38
  • An integrated risk model stratifying seizure risk following brain tumor resection among seizure-naive patients without antiepileptic prophylaxis. Neurosurgical focus Jin, M. C., Parker, J. J., Prolo, L. M., Wu, A., Halpern, C. H., Li, G., Ratliff, J. K., Han, S. S., Skirboll, S. L., Grant, G. A. 2022; 52 (4): E3


    The natural history of seizure risk after brain tumor resection is not well understood. Identifying seizure-naive patients at highest risk for postoperative seizure events remains a clinical need. In this study, the authors sought to develop a predictive modeling strategy for anticipating postcraniotomy seizures after brain tumor resection.The IBM Watson Health MarketScan Claims Database was canvassed for antiepileptic drug (AED)- and seizure-naive patients who underwent brain tumor resection (2007-2016). The primary event of interest was short-term seizure risk (within 90 days postdischarge). The secondary event of interest was long-term seizure risk during the follow-up period. To model early-onset and long-term postdischarge seizure risk, a penalized logistic regression classifier and multivariable Cox regression model, respectively, were built, which integrated patient-, tumor-, and hospitalization-specific features. To compare empirical seizure rates, equally sized cohort tertiles were created and labeled as low risk, medium risk, and high risk.Of 5470 patients, 983 (18.0%) had a postdischarge-coded seizure event. The integrated binary classification approach for predicting early-onset seizures outperformed models using feature subsets (area under the curve [AUC] = 0.751, hospitalization features only AUC = 0.667, patient features only AUC = 0.603, and tumor features only AUC = 0.694). Held-out validation patient cases that were predicted by the integrated model to have elevated short-term risk more frequently developed seizures within 90 days of discharge (24.1% high risk vs 3.8% low risk, p < 0.001). Compared with those in the low-risk tertile by the long-term seizure risk model, patients in the medium-risk and high-risk tertiles had 2.13 (95% CI 1.45-3.11) and 6.24 (95% CI 4.40-8.84) times higher long-term risk for postdischarge seizures. Only patients predicted as high risk developed status epilepticus within 90 days of discharge (1.7% high risk vs 0% low risk, p = 0.003).The authors have presented a risk-stratified model that accurately predicted short- and long-term seizure risk in patients who underwent brain tumor resection, which may be used to stratify future study of postoperative AED prophylaxis in highest-risk patient subpopulations.

    View details for DOI 10.3171/2022.1.FOCUS21751

    View details for PubMedID 35364580

  • Development of an integrated risk scale for prediction of shunt placement after neonatal intraventricular hemorrhage. Journal of neurosurgery. Pediatrics Jin, M. C., Parker, J. J., Rodrigues, A. J., Ruiz Colón, G. D., Garcia, C. A., Mahaney, K. B., Grant, G. A., Prolo, L. M. 2022: 1-10


    Neonatal intraventricular hemorrhage (IVH) is a major cause of mortality and morbidity, particularly following premature birth. Even after the acute phase, posthemorrhagic hydrocephalus is a long-term complication, frequently requiring permanent ventriculoperitoneal shunt (VPS) placement. Currently, there are no risk classification methods integrating the constellation of clinical data to predict short- and long-term prognosis in neonatal IVH. To address this need, the authors developed a two-part machine learning approach for predicting short- and long-term outcomes after diagnosis of neonatal IVH. Integrating both maternal and neonatal characteristics, they developed a binary classifier to predict short-term mortality risk and a clinical scale to predict the long-term risk of VPS placement.Neonates with IVH were identified from the Optum Clinformatics Data Mart administrative claims database. Matched maternal and childbirth characteristics were obtained for all patients. The primary endpoints of interest were short-term (30 day) mortality and long-term VPS placement. Classification of short-term mortality risk was evaluated using 5 different machine learning approaches and the best-performing method was validated using a withheld validation subset. Prediction of long-term shunt risk was performed using a multivariable Cox regression model with stepwise variable selection, which was subsequently converted to an easily applied integer risk scale.A total of 5926 neonates with IVH were identified. Most patients were born before 32 weeks' gestation (67.2%) and with low birth weight (81.2%). Empirical 30-day mortality risk was 10.9% across all IVH grades and highest among grade IV IVH (34.3%). Among the neonates who survived > 30 days, actuarial 12-month postdiagnosis risk of shunt placement was 5.4% across all IVH grades and 31.3% for grade IV IVH. The optimal short-term risk classifier was a random forest model achieving an area under the receiver operating characteristic curve of 0.882 with important predictors ranging from gestational age to diverse comorbid medical conditions. Selected features for long-term shunt risk stratification were IVH grade, respiratory distress syndrome, disseminated intravascular coagulation, and maternal preeclampsia or eclampsia. An integer risk scale, termed the Shunt Prediction After IVH in Neonates (SPAIN) scale, was developed from these 4 features, which, evaluated on withheld cases, demonstrated improved risk stratification compared with IVH grade alone (Harrell's concordance index 0.869 vs 0.852).In a large cohort of neonates with IVH, the authors developed a two-pronged, integrated, risk classification approach to anticipate short-term mortality and long-term shunt risk. The application of such approaches may improve the prognostication of outcomes and identification of higher-risk individuals who warrant careful surveillance and early intervention.

    View details for DOI 10.3171/2021.11.PEDS21390

    View details for PubMedID 35090135

  • Robot-assisted stereoelectroencephalography in young children: technical challenges and considerations. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery Boop, S., Barkley, A., Emerson, S., Prolo, L. M., Goldstein, H., Ojemann, J. G., Hauptman, J. S. 2021


    Robot-assisted stereoelectroencephalography (sEEG) is frequently employed to localize epileptogenic zones in patients with medically refractory epilepsy (MRE). Its methodology is well described in adults, but less so in children. Given the limited information available on pediatric applications, the objective is to describe the unique technical challenges and considerations of sEEG in the pediatric population. In this report, we describe our institutional experience with the technical aspects of robot-assisted sEEG in an exclusively pediatric epilepsy surgery unit, focusing on pre-, intra-, and post-operative nuances that are particular to the pediatric population. The pediatric population presents several unique challenges in sEEG, including reduced skull thickness relative to adults, incomplete neurologic development, and often special behavioral considerations. Pre-operative selection of putative epileptogenic zones requires careful multidisciplinary decision-making. Intraoperative attention to nuances in positioning, clamp selection, registration, and electrode placement are necessary. Activity considerations and electrode migration and removal are key post-operative considerations. Robot-assisted sEEG is a valuable tool in the armamentarium of techniques to characterize MRE. However, special considerations must be given to the pediatric population to optimize safety and efficacy.

    View details for DOI 10.1007/s00381-021-05384-5

    View details for PubMedID 34716458

  • Incorporating patient-centered quality-of-life measures for outcome assessment after Chiari malformation type I decompression in a pediatric population: a pilot study. Journal of neurosurgery. Pediatrics Savchuk, S., Jin, M. C., Choi, S., Kim, L. H., Quon, J. L., Bet, A., Prolo, L. M., Hong, D. S., Mahaney, K. B., Grant, G. A. 2021: 1-8


    OBJECTIVE: Optimal management of pediatric Chiari malformation type I (CM-I) is much debated, chiefly due to the lack of validated tools for outcome assessment, with very few tools incorporating patient-centered measures of health-related quality of life (HRQOL). Although posterior fossa decompression (PFD) benefits a subset of patients, prediction of its impact across patients is challenging. The primary aim of this study was to investigate the role of patient-centered HRQOL measures in the assessment and prediction of outcomes after PFD.METHODS: The authors collected HRQOL data from a cohort of 20 pediatric CM-I patients before and after PFD. The surveys included assessments of selected Patient-Reported Outcomes Measurement Information System (PROMIS) health domains and were used to generate the PROMIS preference (PROPr) score, which is a measure of HRQOL. PROMIS is a reliable standardized measure of HRQOL domains such as pain, fatigue, depression, and physical function, which are all relevant to CM-I. The authors then compared the PROPr scores with Chicago Chiari Outcome Scale (CCOS) scores derived from time-matched clinical documentation. Finally, the authors used the PROPr scores as an outcome measure to predict postsurgical HRQOL improvement at 1 year on the basis of patient demographic characteristics, comorbidities, and radiological and physical findings. The Wilcoxon signed-rank test, Mann-Whitney U-test, and Kendall's correlation were used for statistical analysis.RESULTS: Aggregate analysis revealed improvement of pain severity after PFD (p = 0.007) in anatomical patterns characteristic of CM-I. Most PROMIS domain scores trended toward improvement after surgery, with anxiety and pain interference reaching statistical significance (p < 0.002 and p < 0.03, respectively). PROPr scores also significantly improved after PFD (p < 0.008). Of the baseline patient characteristics, preexisting scoliosis was the most accurate negative predictor of HRQOL improvement after PFD (median -0.095 vs 0.106, p < 0.001). A correlation with modest magnitude (Kendall's tau range 0.19-0.47) was detected between the patient-centered measures and CCOS score.CONCLUSIONS: The authors observed moderate improvement of HRQOL, when measured using a modified panel of PROMIS question banks, in this pilot cohort of pediatric CM-I patients after PFD. Further investigations are necessary to validate this tool for children with CM-I and to determine whether these scores correlate with clinical and radiographic findings.

    View details for DOI 10.3171/2021.8.PEDS21228

    View details for PubMedID 34715646

  • Fluidic Considerations of Measuring Intracranial Pressure Using an Open External Ventricular Drain. Cureus Beidler, P. G., Novokhodko, A., Prolo, L. M., Browd, S., Lutz, B. R. 2021; 13 (5): e15324


    Measurement of intracranial pressure (ICP) during cerebrospinal fluid (CSF) drainage with an external ventricular drain (EVD) typically requires stopping the flow during measurement. However, there may be benefits to simultaneous ICP measurement and CSF drainage. Several studies have evaluated whether accurate ICP measurements can be obtained while the EVD is open. They report differing outcomes when it comes to error, and hypothesize several sources of error. This study presents an investigation into the fluidic sources of error for ICP measurement with concurrent drainage in an EVD. Our experiments and analytical model both show that the error in pressure measurement increases linearly with flow rate and is not clinically significant, regardless of drip chamber height. At physiologically relevant flow rates (40 mL/hr) and ICP set points (13.6 - 31.3 cmH2O or 10 - 23 mmHg), our model predicts an underestimation of 0.767 cmH2O (0.56 mmHg) with no observed data point showing error greater than 1.09 cmH2O (0.8 mmHg) in our experiment. We extrapolate our model to predict a realistic worst-case clinical scenario where we expect to see a mean maximum error of 1.06 cmH2O (0.78 mmHg) arising from fluidic effects within the drainage system for the most resistive catheter. Compared to other sources of error in current ICP monitoring, error in pressure measurement due to drainage flow is small and does not prohibit clinical use. However, other effects such as ventricular collapse or catheter obstruction could affect ICP measurement under continuous drainage and are not investigated in this study.

    View details for DOI 10.7759/cureus.15324

    View details for PubMedID 34221772

    View details for PubMedCentralID PMC8239198

  • Fluidic Considerations of Measuring Intracranial Pressure Using an Open External Ventricular Drain CUREUS Beidler, P. G., Novokhodko, A., Prolo, L. M., Browd, S., Lutz, B. R. 2021; 13 (5)
  • Acetazolamide-Challenged Arterial Spin Labeling Detects Augmented Cerebrovascular Reserve After Surgery for Moyamoya Stroke Rao, V. L., et al 2021
  • Resection of hip heterotrophic ossification leads to resolution of autonomic nervous system dysfunction in a patient with spinal Charcot arthropathy: a case report. Spinal cord series and cases Fatemi, P., Prolo, L. M., Giori, N. J., Tharin, S. 2020; 6 (1): 41


    INTRODUCTION: Patients with complete spinal cord injury (SCI) may develop concurrent sequalae that interact and share symptoms; thus, a careful approach to diagnosis and management of new symptoms is crucial.CASE PRESENTATION: A patient with prior T4 complete SCI presented with progressive autonomic nervous system (ANS) dysfunction. The initial differential diagnosis included syringomyelia and lumbar Charcot arthropathy. He had comorbid heterotopic ossification (HO) of the left hip. Surprisingly, his autonomic symptoms resolved following resection of the HO. In hindsight, loss of motion through the hip caused by HO may have led to hinging through a previously asymptomatic lumbar Charcot joint, causing dysautonomia.DISCUSSION: ANS dysfunction is a disabling sequela of complete SCI and has a broad differential diagnosis. Hip immobility may be an indirect and overlooked cause due to the mechanical relationship between the hip and the lumbar spine.

    View details for DOI 10.1038/s41394-020-0286-5

    View details for PubMedID 32404876

  • Evaluating Shunt Survival Following Ventriculoperitoneal Shunting with and without Stereotactic Navigation in Previously Shunt-Naïve Patients. World neurosurgery Jin, M. C., Wu, A. n., Azad, T. D., Feng, A. n., Prolo, L. M., Veeravagu, A. n., Grant, G. A., Ratliff, J. n., Li, G. n. 2020

    View details for DOI 10.1016/j.wneu.2020.01.138

    View details for PubMedID 31996335

  • Patterns of Care and Age-Specific Impact of Extent of Resection and Adjuvant Radiotherapy in Pediatric Pineoblastoma. Neurosurgery Jin, M. C., Prolo, L. M., Wu, A. n., Azad, T. D., Shi, S. n., Rodrigues, A. J., Soltys, S. G., Pollom, E. L., Li, G. n., Hiniker, S. M., Grant, G. A. 2020


    Pediatric pineoblastomas are highly aggressive tumors that portend poor outcomes despite multimodal management. Controversy remains regarding optimal disease management.To evaluate patterns of care and optimal clinical management of pediatric pineoblastoma.A total of 211 pediatric (age 0-17 yr) histologically confirmed pineoblastoma patients diagnosed between 2004 and 2015 were queried from the National Cancer Database. Wilcoxon rank-sum statistics and chi-squared analyses were used to compare continuous and categorical variables, respectively. Univariable and multivariable Cox regressions were used to evaluate prognostic impact of covariates. Propensity-score matching was used to balance baseline characteristics.Older patients (age ≥ 4 yr) experienced improved overall survival compared to younger patients (age < 4 yr) (hazard ratio [HR] = 0.41; 95% CI 0.25-0.66). Older patients (adjusted odds ratio [aOR] = 5.21; 95% CI 2.61-10.78) and those residing in high-income regions (aOR = 3.16; 95% CI 1.21-8.61) received radiotherapy more frequently. Radiotherapy was independently associated with improved survival in older (adjusted HR [aHR] = 0.31; 95% CI 0.12-0.87) but not younger (aHR = 0.64; 95% CI 0.20-1.90) patients. The benefits of radiotherapy were more pronounced in patients receiving surgery than in those not receiving surgery (aHR [surgical patients] = 0.23; 95% CI 0.08-0.65; aHR [nonsurgical patients] = 0.46; 95% CI 0.22-0.97). Older patients experienced improved outcomes associated with aggressive resection (P = .041); extent of resection was not associated with survival in younger patients (P = .880).Aggressive tumor resection was associated with improved survival only in older pediatric patients. Radiotherapy was more effective in patients receiving surgery. Age-stratified approaches might allow for improved disease management of pediatric pineoblastoma.

    View details for DOI 10.1093/neuros/nyaa023

    View details for PubMedID 32110805

  • Recurrence of cavernous malformations after surgery in childhood. Journal of neurosurgery. Pediatrics Prolo, L. M., Jin, M. C., Loven, T. n., Vogel, H. n., Edwards, M. S., Steinberg, G. K., Grant, G. A. 2020: 1–10


    Cavernous malformations (CMs) are commonly treated cerebrovascular anomalies in the pediatric population; however, the data on radiographic recurrence of pediatric CMs after surgery are limited. The authors aimed to study the clinical presentation, outcomes, and recurrence rate following surgery for a large cohort of CMs in children.Pediatric patients (≤ 18 years old) who had a CM resected at a single institution were identified and retrospectively reviewed. Fisher's exact test of independence was used to assess differences in categorical variables. Survival curves were evaluated using the Mantel-Cox method.Fifty-three patients aged 3 months to 18 years underwent resection of 74 symptomatic CMs between 1996 and 2018 at a single institution. The median length of follow-up was 5.65 years. Patients most commonly presented with seizures (45.3%, n = 24) and the majority of CMs were cortical (58.0%, n = 43). Acute radiographic hemorrhage was common at presentation (64.2%, n = 34). Forty-two percent (n = 22) of patients presented with multiple CMs, and they were more likely to develop de novo lesions (71%) compared to patients presenting with a single CM (3.4%). Both radiographic hemorrhage and multiple CMs were independently prognostic for a higher risk of the patient requiring subsequent surgery. Fifty percent (n = 6) of the 12 patients with both risk factors required additional surgery within 2.5 years of initial surgery compared to none of the patients with neither risk factor (n = 9).Patients with either acute radiographic hemorrhage or multiple CMs are at higher risk for subsequent surgery and require long-term MRI surveillance. In contrast, patients with a single CM are unlikely to require additional surgery and may require less frequent routine imaging.

    View details for DOI 10.3171/2020.2.PEDS19543

    View details for PubMedID 32357336

  • Targeted genomic CRISPR-Cas9 screen identifies MAP4K4 as essential for glioblastoma invasion. Scientific reports Prolo, L. M., Li, A. n., Owen, S. F., Parker, J. J., Foshay, K. n., Nitta, R. T., Morgens, D. W., Bolin, S. n., Wilson, C. M., Vega L, J. C., Luo, E. J., Nwagbo, G. n., Waziri, A. n., Li, G. n., Reimer, R. J., Bassik, M. C., Grant, G. A. 2019; 9 (1): 14020


    Among high-grade brain tumors, glioblastoma is particularly difficult to treat, in part due to its highly infiltrative nature which contributes to the malignant phenotype and high mortality in patients. In order to better understand the signaling pathways underlying glioblastoma invasion, we performed the first large-scale CRISPR-Cas9 loss of function screen specifically designed to identify genes that facilitate cell invasion. We tested 4,574 genes predicted to be involved in trafficking and motility. Using a transwell invasion assay, we discovered 33 genes essential for invasion. Of the 11 genes we selected for secondary testing using a wound healing assay, 6 demonstrated a significant decrease in migration. The strongest regulator of invasion was mitogen-activated protein kinase 4 (MAP4K4). Targeting of MAP4K4 with single guide RNAs or a MAP4K4 inhibitor reduced migration and invasion in vitro. This effect was consistent across three additional patient derived glioblastoma cell lines. Analysis of epithelial-mesenchymal transition markers in U138 cells with lack or inhibition of MAP4K4 demonstrated protein expression consistent with a non-invasive state. Importantly, MAP4K4 inhibition limited migration in a subset of human glioma organotypic slice cultures. Our results identify MAP4K4 as a novel potential therapeutic target to limit glioblastoma invasion.

    View details for DOI 10.1038/s41598-019-50160-w

    View details for PubMedID 31570734

  • Deep Brain Stimulation for Pediatric Neuropsychiatric Disorders NEUROTECHNOLOGY AND BRAIN STIMULATION IN PEDIATRIC PSYCHIATRIC AND NEURODEVELOPMENTAL DISORDERS Quon, J. L., Kim, L. H., Quon, C. A., Prolo, L. M., Grant, G. A., Halpern, C. H., Oberman, L. M., Enticott, P. G. 2019: 237–52
  • Uninstrumented Posterior Lumbar Interbody Fusion: Have Technological Advances in Stabilizing the Lumbar Spine Truly Improved Outcomes? WORLD NEUROSURGERY Prolo, L. M., Oklund, S. A., Zawadzki, N., Desai, M., Prolo, D. J. 2018; 115: 490–502
  • Uninstrumented Posterior Lumbar Interbody Fusion: Have Technological Advances in Stabilizing the Lumbar Spine Truly Improved Outcomes? World neurosurgery Prolo, L. M., Oklund, S. A., Zawadzki, N., Desai, M., Prolo, D. J. 2018


    BACKGROUND: Since the 1980s, numerous operations have replaced posterior lumbar interbody fusion (PLIF) with human bone. These operations often involve expensive implants and complex procedures. Escalating expenditures in lumbar fusion surgery warrant re-evaluation of classical PLIF with allogeneic ilium and without instrumentation. The purpose of this study was to determine the long-term fusion rate and clinical outcomes of PLIF with allogeneic bone (allo-PLIF).METHODS: Between 1981 and 2006, 321 patients aged 12-80 years underwent 339 1-level or 2-level allo-PLIFs for degenerative instability and were followed for 1-28 years. Fusion status was determined by radiographs and as available, by computed tomography scans. Clinical outcome was assessed by the Economic/Functional Outcome Scale.RESULTS: Of the 321 patients, 308 were followed postoperatively (average 6.7 years) and 297 (96%) fused. Fusion rates were lower for patients with substance abuse (89%, P= 0.007). Clinical outcomes in 87% of patients were excellent (52%) or good (35%). Economic/Functional Outcome Scale scores after initial allo-PLIF on average increased 5.2 points. Successful fusion correlated with nearly a 2-point gain in outcome score (P= 0.001). A positive association between a patient characteristic and outcome was observed only with age 65 years and greater, whereas negative associations in clinical outcomes were observed with mental illness, substance abuse, heavy stress to the low back, or industrial injuries. The total complication rate was7%.CONCLUSIONS: With 3 decades of follow-up, we found that successful clinical outcomes are highly correlated with solid fusion using only allogeneic iliac bone.

    View details for PubMedID 29631080

  • Occipital Dermal Sinus Tract JOURNAL OF PEDIATRICS Prolo, L. M., Grant, G. A. 2018; 193: 276

    View details for PubMedID 29174077

  • Anterolateral approach to the upper cervical spine: Case report and operative technique HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Song, Y., Tharin, S., Divi, V., Prolo, L. M., Sirjani, D. B. 2015; 37 (9): E115-E119


    Transcervical approaches to the upper cervical spine are challenging because several upper anterior neurovascular structures need to be displaced to provide access. Although various techniques have been described, the anterolateral approach is one of the safest and most effective methods available to access the anterior C2-C3 disc space. Despite the approach's efficacy, however, it can cause postoperative complications because of, at least partly, the inter-surgeon differences in the methods by which the larynx and hypopharynx are displaced medially.We present a case report of a patient treated with a modified anterolateral approach to C2-C3. The approach provided excellent visualization while protecting vital structures. The patient recovered without any postoperative dysphagia or other surgical complications.The anterolateral approach to C2-C3 described herein safely protects the contents of the submandibular triangle while providing a wide exposure for direct access to the C2-C3 disc space. © 2015 Wiley Periodicals, Inc. Head Neck 37: E115-E119, 2015.

    View details for DOI 10.1002/hed.23951

    View details for Web of Science ID 000359605700004

    View details for PubMedID 25522016

  • Anterolateral approach to the upper cervical spine: Case report and operative technique. Head & neck Song, Y., Tharin, S., Divi, V., Prolo, L. M., Sirjani, D. B. 2015; 37 (9): E115-9


    Transcervical approaches to the upper cervical spine are challenging because several upper anterior neurovascular structures need to be displaced to provide access. Although various techniques have been described, the anterolateral approach is one of the safest and most effective methods available to access the anterior C2-C3 disc space. Despite the approach's efficacy, however, it can cause postoperative complications because of, at least partly, the inter-surgeon differences in the methods by which the larynx and hypopharynx are displaced medially.We present a case report of a patient treated with a modified anterolateral approach to C2-C3. The approach provided excellent visualization while protecting vital structures. The patient recovered without any postoperative dysphagia or other surgical complications.The anterolateral approach to C2-C3 described herein safely protects the contents of the submandibular triangle while providing a wide exposure for direct access to the C2-C3 disc space. © 2015 Wiley Periodicals, Inc. Head Neck 37: E115-E119, 2015.

    View details for DOI 10.1002/hed.23951

    View details for PubMedID 25522016

  • Vesicular uptake and exocytosis of L-aspartate is independent of sialin FASEB JOURNAL Morland, C., Nordengen, K., Larsson, M., Prolo, L. M., Farzampour, Z., Reimer, R. J., Gundersen, V. 2013; 27 (3): 1264-1274


    The mechanism of release and the role of l-aspartate as a central neurotransmitter are controversial. A vesicular release mechanism for l-aspartate has been difficult to prove, as no vesicular l-aspartate transporter was identified until it was found that sialin could transport l-aspartate and l-glutamate when reconstituted into liposomes. We sought to clarify the release mechanism of l-aspartate and the role of sialin in this process by combining l-aspartate uptake studies in isolated synaptic vesicles with immunocyotchemical investigations of hippocampal slices. We found that radiolabeled l-aspartate was taken up into synaptic vesicles. The vesicular l-aspartate uptake, relative to the l-glutamate uptake, was twice as high in the hippocampus as in the whole brain, the striatum, and the entorhinal and frontal cortices and was not inhibited by l-glutamate. We further show that sialin is not essential for exocytosis of l-aspartate, as there was no difference in ATP-dependent l-aspartate uptake in synaptic vesicles from sialin-knockout and wild-type mice. In addition, expression of sialin in PC12 cells did not result in significant vesicle uptake of l-aspartate, and depolarization-induced depletion of l-aspartate from hippocampal nerve terminals was similar in hippocampal slices from sialin-knockout and wild-type mice. Further, there was no evidence for nonvesicular release of l-aspartate via volume-regulated anion channels or plasma membrane excitatory amino acid transporters. This suggests that l-aspartate is exocytotically released from nerve terminals after vesicular accumulation by a transporter other than sialin.

    View details for DOI 10.1096/fj.12-206300

    View details for Web of Science ID 000315585200038

    View details for PubMedID 23221336

    View details for PubMedCentralID PMC3574276

  • The Lysosomal Sialic Acid Transporter Sialin Is Required for Normal CNS Myelination JOURNAL OF NEUROSCIENCE Prolo, L. M., Vogel, H., Reimer, R. J. 2009; 29 (49): 15355-15365


    Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane protein that transports free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders, and the clinical phenotype is characterized by neurodevelopmental defects, including severe CNS hypomyelination. In this study, we used a sialin-deficient mouse to address how loss of sialin leads to the defect in myelination. Behavioral analysis of the sialin(-/-) mouse demonstrates poor coordination, seizures, and premature death. Analysis by histology, electron microscopy, and Western blotting reveals a decrease in myelination of the CNS but normal neuronal cytoarchitecture and normal myelination of the PNS. To investigate potential mechanisms underlying CNS hypomyelination, we studied myelination and oligodendrocyte development in optic nerves. We found reduced numbers of myelinated axons in optic nerves from sialin(-/-) mice, but the myelin that was present appeared grossly normal. Migration and density of oligodendrocyte precursor cells were normal; however, a marked decrease in the number of postmitotic oligodendrocytes and an associated increase in the number of apoptotic cells during the later stages of myelinogenesis were observed. These findings suggest that a defect in maturation of cells in the oligodendrocyte lineage leads to increased apoptosis and underlies the myelination defect associated with sialin loss.

    View details for DOI 10.1523/JNEUROSCI.3005-09.2009

    View details for PubMedID 20007460

  • Physiology - Keeping it regular with protons NATURE Prolo, L. M., Goodman, M. B. 2008; 452 (7183): 35-36

    View details for DOI 10.1038/452035a

    View details for Web of Science ID 000253671900033

    View details for PubMedID 18322516

  • Circadian rhythm generation and entrainment in astrocytes JOURNAL OF NEUROSCIENCE Prolo, L. M., Takahashi, J. S., Herzog, E. D. 2005; 25 (2): 404-408


    In mammals, the master circadian pacemaker is considered the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consists of a heterogeneous population of neurons and relatively understudied glia. We investigated whether glia, like neurons, rhythmically express circadian genes. We generated pure cultures of cortical astrocytes from Period2::luciferase (Per2::luc) knock-in mice and Period1::luciferase (Per1::luc) transgenic rats and recorded bioluminescence as a real-time reporter of gene activity. We found that rat Per1::luc and mouse Per2::luc astroglia express circadian rhythms with a genetically determined period. These rhythms damped out after several days but were reinitiated by a variety of treatments, including a full volume exchange of the medium. If cultures were treated before damping out, the phase of Per1::luc rhythmicity was shifted, depending on the time of the pulse relative to the peak of Per1 expression. Glial rhythms entrained to daily 1.5 degrees C temperature cycles and were significantly sustained when cocultured with explants of the adult SCN but not with cortical explants. Thus, multiple signals, including a diffusible factor(s) from the SCN, are sufficient to either entrain or restart circadian oscillations in cortical glia.

    View details for DOI 10.1523/JNEUROSCI.4133-04.2005

    View details for Web of Science ID 000226271400014

    View details for PubMedID 15647483

    View details for PubMedCentralID PMC3812245