Kelly H. Yoo, MD, PhD

All Publications

• Therapeutic approaches for spinal synovial sarcoma: a comprehensive review of the literature. Journal of neurosurgery. Spine Zamarud, A., Shahnoor, S., Maryyum, A., Khan, A. M., Hassan, K. M., Ijaz, A., Sayed, R., Yoo, K., Park, D. J., Chang, S. D. 2024: 1-8

  Abstract

  Synovial sarcoma (SS) is a relatively rare type of soft-tissue sarcoma that is commonly treated with surgery, radiation, chemotherapy, and palliative care. Stereotactic radiosurgery (SRS) is an emerging approach that shows promise in treating CNS conditions, but it has not been studied for SS. The authors present a systematic review that explores the effectiveness of different treatments, with a focus on SRS, for managing spinal SS.A systematic PubMed search was conducted that covered studies from 1964 to 2022, yielding 70 relevant studies. Inclusion criteria encompassed primary and metastatic spinal SS, various treatment modalities, patient age 17 years or older, English-language studies, retrospective series, and case reports. Based on these criteria, 26 studies were included in this review and 44 were excluded.Of the included studies, 15 patients from 9 studies were treated with surgical intervention followed by both conventional radiotherapy (RT) and chemotherapy, 10 patients from 10 studies were treated with surgery followed by RT, 5 studies comprising 8 patients were exclusively treated with surgery, 5 cases in 3 studies were treated with surgery plus concomitant chemotherapy, 4 patients in 2 studies were treated with SRS, and only 1 study reported treatment without surgery and with chemotherapy and RT. The median progression-free survival and overall survival periods observed in the SRS-treated patients were 37 months and 60 months, respectively, which were higher than those of any other treatment method or combination used.The authors' study offers a thorough review of spinal SS treatments. They are hopeful that this will aid clinicians in informed decision-making for better patient outcomes.

  View details for DOI 10.3171/2024.1.SPINE231184

  View details for PubMedID 38489819

• Evaluating Computer Vision, Large Language, and Genome-Wide Association Models in a Limited Sized Patient Cohort for Pre-Operative Risk Stratification in Adult Spinal Deformity Surgery. Journal of clinical medicine Schonfeld, E., Pant, A., Shah, A., Sadeghzadeh, S., Pangal, D., Rodrigues, A., Yoo, K., Marianayagam, N., Haider, G., Veeravagu, A. 2024; 13 (3)

  Abstract

  Background: Adult spinal deformities (ASD) are varied spinal abnormalities, often necessitating surgical intervention when associated with pain, worsening deformity, or worsening function. Predicting post-operative complications and revision surgery is critical for surgical planning and patient counseling. Due to the relatively small number of cases of ASD surgery, machine learning applications have been limited to traditional models (e.g., logistic regression or standard neural networks) and coarse clinical variables. We present the novel application of advanced models (CNN, LLM, GWAS) using complex data types (radiographs, clinical notes, genomics) for ASD outcome prediction. Methods: We developed a CNN trained on 209 ASD patients (1549 radiographs) from the Stanford Research Repository, a CNN pre-trained on VinDr-SpineXR (10,468 spine radiographs), and an LLM using free-text clinical notes from the same 209 patients, trained via Gatortron. Additionally, we conducted a GWAS using the UK Biobank, contrasting 540 surgical ASD patients with 7355 non-surgical ASD patients. Results: The LLM notably outperformed the CNN in predicting pulmonary complications (F1: 0.545 vs. 0.2881), neurological complications (F1: 0.250 vs. 0.224), and sepsis (F1: 0.382 vs. 0.132). The pre-trained CNN showed improved sepsis prediction (AUC: 0.638 vs. 0.534) but reduced performance for neurological complication prediction (AUC: 0.545 vs. 0.619). The LLM demonstrated high specificity (0.946) and positive predictive value (0.467) for neurological complications. The GWAS identified 21 significant (p < 10-5) SNPs associated with ASD surgery risk (OR: mean: 3.17, SD: 1.92, median: 2.78), with the highest odds ratio (8.06) for the LDB2 gene, which is implicated in ectoderm differentiation. Conclusions: This study exemplifies the innovative application of cutting-edge models to forecast outcomes in ASD, underscoring the utility of complex data in outcome prediction for neurosurgical conditions. It demonstrates the promise of genetic models when identifying surgical risks and supports the integration of complex machine learning tools for informed surgical decision-making in ASD.

  View details for DOI 10.3390/jcm13030656

  View details for PubMedID 38337352

• Timing of Lumbar ESIs: Do Pre-operative Epidural Injections Effect Lumbar Spine Surgery Outcomes Journal of Neurology and Neuroscience Yoo, K. H., Sadeghzadeh, S., Shah, A., Veeravagu, A. 2024; 14
• Surgery and stereotactic radiosurgery for spinal leiomyosarcoma: a single-institution retrospective series and systematic review. Journal of neurosurgery. Spine Zamarud, A., Marianayagam, N. J., Sekar, V., Testa, S., Park, D. J., Yener, U., McCleary, T. L., Yoo, K. H., Emrich, S., Tayag, A., Ustrzynski, L., Pollom, E., Soltys, S., Wang, L., Charville, G., Ganjoo, K., Chang, S. D., Meola, A. 2023: 1-13

  Abstract

  Leiomyosarcoma (LMS) is a rare, aggressive soft-tissue sarcoma that seldom spreads to the bone. The spine can be either the site of LMS osseous metastases or the primary tumor site. The optimal treatment option for spinal LMS is still unclear. The authors present a cohort of patients with spinal LMS treated with either upfront surgery or upfront CyberKnife stereotactic radiosurgery (SRS).The authors retrospectively studied the clinical and radiological outcomes of 17 patients with spinal LMS treated at their institution between 2004 and 2020. Either surgery or SRS was used as the upfront treatment. The clinical and radiological outcomes were assessed. A systematic review of the literature was also conducted.Of the 17 patients (20 spinal lesions), 12 (70.6%) were female. The median patient age was 61 years (range 41-80 years). Ten patients had upfront surgery for their spinal lesions, and 7 had upfront CyberKnife radiosurgery. The median follow-up was 11 months (range 0.3-130 months). The median overall survival (OS) for the entire cohort was 13 months (range 0.3-97 months). In subgroup analysis, the median OS was lower for the surgical group (13 months, range 0.3-50 months), while the median OS for the SRS group was 15 months (range 5-97 months) (p = 0.5). Forty percent (n = 4) of those treated with surgery presented with local recurrence at a median of 6.7 months (range 0.3-36 months), while only 14% (n = 1) of those treated with CyberKnife radiosurgery had local recurrence after 5 months. Local tumor control (LTC) rates at the 6-, 12-, and 18-month follow-ups were 72%, 58%, and 43%, respectively, for the SRS group and 40%, 30%, and 20%, respectively, for the surgery group (p < 0.05). The literature review included 35 papers with 70 patients harboring spinal LMS; only 2 patients were treated with SRS. The literature review confirms the clinical and radiological outcomes of the surgical group, while data on SRS are anecdotal.The authors present the largest series in the literature of spinal LMS and the first on SRS for spinal LMS. This study shows that LTC is statistically significantly better in patients receiving upfront SRS instead of surgery. The OS does not appear different between the two groups.

  View details for DOI 10.3171/2023.10.SPINE23666

  View details for PubMedID 38157539

• CyberKnife Radiosurgery for Extracranial Metastases of Oligodendroglioma: A Clinical Case Report. Cureus Shaghaghian, E., Park, D. J., Yoo, K. H., Meola, A., Chang, S. D. 2023; 15 (12): e51035

  Abstract

  Oligodendroglioma is an uncommon glial tumor known for its extremely rare tendency to metastasize to extracranial areas, particularly to the spinal region. We present a rare case of oligodendroglioma that metastasizes to the spinal cord 14 years after resection of the initial tumor. Furthermore, a systematic review of the relevant literature is conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, encompassing oligodendroglioma cases with extracranial metastases. Our PRISMA-guided systematic review fills a critical knowledge gap in neurosurgery by consolidating scattered data on oligodendroglioma metastases, offering pivotal insights for clinical practice and future research. A 50-year-old male patient exhibited severe headaches and dizziness, with MRI findings revealing a significant brain mass suggestive of oligodendroglioma. Consequently, the patient underwent a craniotomy procedure. After 14 years, the patient presented with weakness in both lower extremities and bladder as well as bowel dysfunction. A lumbosacral MRI of the patient revealed two intradural enhancing masses in the lumbosacral spine. Surgical resection was performed, and the characteristics were identical to those of the primary tumor. The systemic review encompassed 52 articles, covering 67 cases of extracranial metastases from oligodendroglioma. Only three cases in the literature review fulfilled the inclusion criteria, demonstrating the required molecular genetic profiles of isocitrate dehydrogenase​​​ (IDH)-mutation and chromosome 1p/19q-codeletion. The inclusion criteria encompassed cases of oligodendroglioma with confirmed extracranial metastases, focusing on those with documented molecular genetic profiles indicating IDH-mutation and 1p/19q-codeletion. Our emphasis was on identifying cases with this specific genetic profile to ensure consistency and relevance in the literature review. Interestingly, our case was the first to exhibit intradural spinal metastases, while the other cases involved metastasis to the spinal bone marrow. Our case and literature review demonstrate that oligodendrogliomas, although exceptionally rare, can metastasize not only to the extracranial area but also to the spinal cord. To improve survival in oligodendroglioma cases, it is recommended to implement regular radiological screening and monitoring to enable early detection and treatment of extracranial metastases.

  View details for DOI 10.7759/cureus.51035

  View details for PubMedID 38264380

  View details for PubMedCentralID PMC10805176

• The outcome of central nervous system hemangioblastomas in Von Hippel-Lindau (VHL) disease treated with belzutifan: a single-institution retrospective experience. Journal of neuro-oncology Zamarud, A., Marianayagam, N. J., Park, D. J., Yener, U., Yoo, K. H., Meola, A., Chang, S. D. 2023

  Abstract

  Belzutifan is a Hypoxia Inducible Factor 2-alpha inhibitor approved in 2021 by the FDA for the treatment of renal cell carcinoma (RCC) in patients with Von-Hippel Landau (VHL) disease. These patients can also present with central nervous system (CNS) hemangioblastomas (HBs). We aim to study the effectiveness and adverse effects of belzutifan for CNS HBs, by reporting our preliminary institutional experience.We present a series of VHL patients with CNS HBs undergoing treatment with belzutifan for RCC. All the included patients met the RECIST inclusion criteria. The clinical and radiological outcome measures included: Objective response rate (ORR), time-to-response (TTR), adverse events (AE), and patient response. Patient response was classified as partial response (PR), complete response (CR), progressive disease (PD), or stable disease (SD).Seven patients with 25 HBs were included in our study. A belzutifan dose of 120 mg/day PO was administered for a median of 13 months (range 10-17). Median follow up time was 15 months (range 10-24). An ORR of 71% was observed. The median TTR was 5 months (range: 1-10). None of the patients showed CR, while 5 patients (71.4%) showed PR and 2 (28.5%) showed SD. Among patients with SD the maximum tumor response was 20% [increase/decrease] of the lesion diameter. All the patients experienced decreased hemoglobin concentration, fatigue, and dizziness. None of the patients experienced severe anemia (grade 3-4 CTCAE).Belzutifan appears to be an effective and safe treatment for CNS hemangioblastoma in VHL patients. Further clinical trials to assess the long-term effectiveness of the medication are required.

  View details for DOI 10.1007/s11060-023-04496-z

  View details for PubMedID 37955759

  View details for PubMedCentralID 5573741

• STEREOTACTIC RADIOSURGERY FOR RESIDUAL, RECURRENT, AND METASTATIC HEMANGIOPERICYTOMAS: A SINGLE INSTITUTION EXPERIENCE Yoo, K., Park, D., Veeravagu, A., Lee, M., Marianayagam, N., Zamarud, A., Gu, X., Pollom, E., Soltys, S., Chang, S., Meola, A. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400225

• STEREOTACTIC RADIOSURGERY FOR CYSTIC AND SOLID INTRACRANIAL HEMANGIOBLASTOMAS: A SINGLE-INSTITUTION RETROSPECTIVE SERIES Yoo, K., Park, D., Marianayagam, N., Pollom, E., Soltys, S., Meola, A., Chang, S. OXFORD UNIV PRESS INC. 2023

  View details for Web of Science ID 001115245400236

• Stereotactic Radiosurgery for Cranial and Spinal Hemangioblastomas: A Single-Institution Retrospective Series. Neurosurgery Yoo, K. H., Park, D. J., Marianayagam, N. J., Gu, X., Pollom, E. L., Soltys, S. G., Chang, S. D., Meola, A. 2023

  Abstract

  Stereotactic radiosurgery (SRS) has been an attractive treatment modality for both cranial and spinal hemangioblastomas, especially for multiple lesions commonly associated with von Hippel-Lindau (VHL) disease. This study aims to provide the largest long-term analysis of treatment efficacy and adverse effects of SRS for cranial and spinal hemangioblastomas at a single institution.We evaluated the clinical and radiological outcomes of patients with hemangioblastomas treated with CyberKnife SRS at our institute from 1998 to 2022. The follow-up data were available for 135 hemangioblastomas in 35 patients. Twenty-eight patients had 123 hemangioblastomas associated with VHL, and 7 had 12 sporadic hemangioblastomas. The median age was 36 years, and the median tumor volume accounted for 0.4 cc. The SRS was administered with the median single-fraction equivalent dose of 18 Gy to the 77% median isodose line.At a median follow-up of 57 months (range: 3-260), only 20 (16.2%) of the VHL-associated and 1 (8.3%) sporadic hemangioblastomas progressed. The 5-year local tumor control rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in patients with VHL. SRS improved tumor-associated symptoms of 98 (74.8%) of 131 symptomatic hemangioblastomas, including headache, neck pain, dizziness, visual disturbances, dysesthesia, ataxia, motor impairment, seizures, and dysphagia. Two patients developed radiation necrosis (5.7%), and 1 of them required surgical resection.SRS is a safe and effective treatment option for patients with hemangioblastomas in critical locations, such as the brainstem, cervicomedullary junction, and spinal cord, and in patients with multiple hemangioblastomas associated with VHL disease.

  View details for DOI 10.1227/neu.0000000000002728

  View details for PubMedID 37967154

• Stereotactic Radiosurgery for Medically Refractory Trigeminal Neuralgia Secondary to Stroke: A Systematic Review and Clinical Case Presentation. World neurosurgery Zamarud, A., Park, D. J., Ung, T. H., McCleary, T. L., Yoo, K. H., Soltys, S. G., Lim, M., Chang, S. D., Meola, A. 2023

  View details for DOI 10.1016/j.wneu.2023.08.092

  View details for PubMedID 37640262

• Optimizing the synergy between stereotactic radiosurgery and immunotherapy for brain metastases. Frontiers in oncology Yoo, K. H., Park, D. J., Choi, J. H., Marianayagam, N. J., Lim, M., Meola, A., Chang, S. D. 2023; 13: 1223599

  Abstract

  Solid tumors metastasizing to the brain are a frequent occurrence with an estimated incidence of approximately 30% of all cases. The longstanding conventional standard of care comprises surgical resection and whole-brain radiotherapy (WBRT); however, this approach is associated with limited long-term survival and local control outcomes. Consequently, stereotactic radiosurgery (SRS) has emerged as a potential alternative approach. The primary aim of SRS has been to improve long-term control rates. Nevertheless, rare observations of abscopal or out-of-field effects have sparked interest in the potential to elicit antitumor immunity via the administration of high-dose radiation. The blood-brain barrier (BBB) has traditionally posed a significant challenge to the efficacy of systemic therapy in managing intracranial metastasis. However, recent insights into the immune-brain interface and the development of immunotherapeutic agents have shown promise in preclinical and early-phase clinical trials. Researchers have investigated combining immunotherapy with SRS to enhance treatment outcomes in patients with brain metastasis. The combination approach aims to optimize long-term control and overall survival (OS) outcomes by leveraging the synergistic effects of both therapies. Initial findings have been encouraging in the management of various intracranial metastases, while further studies are required to determine the optimal order of administration, radiation doses, and fractionation regimens that have the potential for the best tumor response. Currently, several clinical trials are underway to assess the safety and efficacy of administering immunotherapeutic agents concurrently or consecutively with SRS. In this review, we conduct a comprehensive analysis of the advantages and drawbacks of integrating immunotherapy into conventional SRS protocols for the treatment of intracranial metastasis.

  View details for DOI 10.3389/fonc.2023.1223599

  View details for PubMedID 37637032

  View details for PubMedCentralID PMC10456862

• Stereotactic radiosurgery for sarcoma metastases to the brain: a single-institution experience. Neurosurgical focus Zamarud, A., Park, D. J., Dadey, D. Y., Yoo, K. H., Marianayagam, N. J., Yener, U., Szalkowski, G. A., Pollom, E., Soltys, S., Chang, S. D., Meola, A. 2023; 55 (2): E7

  Abstract

  Brain metastases (BMs) secondary to sarcoma are rare, and their incidence ranges from 1% to 8% of all bone and soft tissue sarcomas. Although stereotactic radiosurgery (SRS) is widely used for BMs, only a few papers have reported on SRS for sarcoma metastasizing to the brain. The purpose of this study was to evaluate the safety and effectiveness of SRS for sarcoma BM.The authors retrospectively reviewed the clinical and radiological outcomes of patients with BM secondary to histopathologically confirmed sarcoma treated with SRS, either as primary treatment or as adjuvant therapy after surgery, at their institution between January 2005 and September 2022. They also compared the outcomes of patients with hemorrhagic lesions and of those without.Twenty-three patients (9 females) with 150 BMs secondary to sarcoma were treated with CyberKnife SRS. Median age at the time of treatment was 48.22 years (range 4-76 years). The most common primary tumor sites were the heart, lungs, uterus, upper extremities, chest wall, and head and neck. The median Karnofsky Performance Status on presentation was 73.28 (range 40-100). Eight patients underwent SRS as a primary treatment and 15 as adjuvant therapy to the resection cavity. The median tumor volume was 24.1 cm3 (range 0.1-150.3 cm3), the median marginal dose was 24 Gy (range 18-30 Gy) delivered in a median of 1 fraction (range 1-5) to a median isodose line of 76%. The median follow-up was 8 months (range 2-40 months). Median progression-free survival and overall survival were 5.3 months (range 0.4-32 months) and 8.2 months (range 0.1-40), respectively. The 3-, 6-, and 12-month local tumor control (LTC) rates for all lesions were respectively 78%, 52%, and 30%. There were no radiation-induced adverse effects. LTC at the 3-, 6-, and 12-month follow-ups was better in patients without hemorrhagic lesions (100%, 70%, and 40%, respectively) than in those with hemorrhagic lesions (68%, 38%, and 23%, respectively).SRS, both as a primary treatment and as adjuvant therapy to the resection cavity after surgery, is a safe and relatively effective treatment modality for sarcoma BMs. Nonhemorrhagic lesions show better LTC than hemorrhagic lesions. Larger studies aiming to validate these results are encouraged.

  View details for DOI 10.3171/2023.5.FOCUS23168

  View details for PubMedID 37527671

• Stereotactic Radiosurgery for Contrast-Enhancing Satellite Nodules in Recurrent Glioblastoma: A Rare Case Series From a Single Institution. Cureus Park, D. J., Persad, A. R., Yoo, K. H., Marianayagam, N. J., Yener, U., Tayag, A., Ustrzynski, L., Emrich, S. C., Chuang, C., Pollom, E., Soltys, S. G., Meola, A., Chang, S. D. 2023; 15 (8): e44455

  Abstract

  Introduction Glioblastoma (GBM) is the most common malignant adult brain tumor and is invariably fatal. The standard treatment for GBM involves resection where possible, followed by chemoradiation per Stupp's protocol. We frequently use stereotactic radiosurgery (SRS) as a single-fraction treatment for small (volume ≤ 1cc) nodular recurrent GBM to the contrast-enhancing target on T1 MRI scan. In this paper, we aimed to evaluate the safety and efficacy of SRS for patients with contrast-enhancing satellite nodules in recurrent GBM. Methods This retrospective study analyzed the clinical and radiological outcomes of five patients who underwent CyberKnife (Accuray Inc., Sunnyvale, California) SRS at the institute between 2013 and 2022. Results From 96 patients receiving SRS for GBM, five (four males, one female; median age 53) had nine distinct new satellite lesions on MRI, separate from their primary tumor beds. Those nine lesions were treated with a median margin dose of 20 Gy in a single fraction. The three-, six, and 12-month local tumor control rates were 77.8%, 66.7%, and 26.7%, respectively. Median progression-free survival (PFS) was seven months, median overall survival following SRS was 10 months, and median overall survival (OS) was 35 months. Interestingly, the only lesion that did not show radiological progression was separate from the T2-fluid attenuated inversion recovery (FLAIR) signal of the main tumor. Conclusion Our SRS treatment outcomes for recurrent GBM satellite lesions are consistent with existing findings. However, in a unique case, a satellite nodule distinct from the primary tumor's T2-FLAIR signal and treated with an enlarged target volume showed promising control until the patient's demise. This observation suggests potential research avenues, given the limited strategies for 'multicentric' GBM lesions.

  View details for DOI 10.7759/cureus.44455

  View details for PubMedID 37664337

  View details for PubMedCentralID PMC10470661

• Stereotactic radiosurgery for distant brain metastases secondary to esthesioneuroblastoma: a single-institution series. Neurosurgical focus Zamarud, A., Yener, U., Yoo, K. H., Park, D. J., Marianayagam, N. J., Ho, Q. A., Pollom, E., Soltys, S., Wang, L., Chang, S. D., Meola, A. 2023; 55 (2): E6

  Abstract

  Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare, malignant tumor of neuroectodermal origin that arises from the olfactory neuroepithelium. In this study the authors present the first series in the literature on distant brain metastases (BMs) secondary to ENB that were treated with stereotactic radiosurgery (SRS), to evaluate the safety and effectiveness of SRS for this indication.A retrospective analysis of clinical and radiological outcomes of patients with ENB who underwent CyberKnife (CK) SRS at a single center was conducted. The clinical and radiological outcomes of patients, including progression-free survival, overall survival, and local tumor control (LTC) were reported.Between 2003 and 2022, 32 distant BMs in 8 patients were treated with CK SRS at Stanford University. The median patient age at BM diagnosis was 62 years (range 47-75 years). Among 32 lesions, 2 (6%) had previously been treated with surgery, whereas for all other lesions (30 [94%]), CK SRS was used as their primary treatment modality. The median target volume was 1.5 cm3 (range 0.09-21.54 cm3). CK SRS was delivered by a median marginal dose of 23 Gy (range 15-30 Gy) and a median of 3 fractions (range 1-5 fractions) to a median isodose line of 77% (range 70%-88%). The median biologically effective dose was 48 Gy (range 21-99.9 Gy) and the median follow-up was 30 months (range 3-95 months). The LTC at 1-, 2-, and 3-year follow-up was 86%, 65%, and 50%, respectively. The median progression-free survival and overall survival were 29 months (range 11-79 months) and 51 months (range 15-79 months), respectively. None of the patients presented adverse radiation effects.In the authors' experience, SRS provided excellent LTC without any adverse radiation effects for BMs secondary to ENB.

  View details for DOI 10.3171/2023.5.FOCUS23216

  View details for PubMedID 37527675

• CyberKnife Radiosurgery for Extracranial Metastases of Oligodendroglioma: A Clinical Case Report Cureus Shaghaghian, E., Park, D. J., Yoo, K. H., Meola, A., Chang, S. D. 2023

  View details for DOI 10.7759/cureus.51035

• Chimeric antigen receptor (CAR) immunotherapy: basic principles, current advances, and future prospects in neuro-oncology. Immunologic research Yoo, H. J., Harapan, B. N. 2021; 69 (6): 471-486

  Abstract

  With recent advances, chimeric antigen receptor (CAR) immunotherapy has become a promising modality for patients with refractory cancer diseases. The successful results of CAR T cell therapy in relapsed and refractory B-cell malignancies shifted the paradigm of cancer immunotherapy by awakening the scientific, clinical, and commercial interest in translating this technology for the treatment of solid cancers. This review elaborates on fundamental principles of CAR T cell therapy (development of CAR construct, challenges of CAR T cell therapy) and its application on solid tumors as well as CAR T cell therapy potential in the field of neuro-oncology. Glioblastoma (GBM) is identified as one of the most challenging solid tumors with a permissive immunological milieu and dismal prognosis. Standard multimodal treatment using maximal safe resection, radiochemotherapy, and maintenance chemotherapy extends the overall survival beyond a year. Recurrence is, however, inevitable. GBM holds several unique features including its vast intratumoral heterogeneity, immunosuppressive environment, and a partially permissive anatomic blood-brain barrier, which offers a unique opportunity to investigate new treatment approaches. Tremendous efforts have been made in recent years to investigate novel CAR targets and target combinations with standard modalities for solid tumors and GBM to improve treatment efficacy. In this review, we outline the history of CAR immunotherapy development, relevant CAR target antigens validated with CAR T cells as well as preclinical approaches in combination with adjunct approaches via checkpoint inhibition, bispecific antibodies, and second-line systemic therapies that enhance anticancer efficacy of the CAR-based cancer immunotherapy.

  View details for DOI 10.1007/s12026-021-09236-x

  View details for PubMedID 34554405

  View details for PubMedCentralID PMC8580929

• Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). Journal of neurology Harapan, B. N., Yoo, H. J. 2021; 268 (9): 3059-3071

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, is responsible for the outbreak of coronavirus disease 19 (COVID-19) and was first identified in Wuhan, China in December 2019. It is evident that the COVID-19 pandemic has become a challenging world issue. Although most COVID-19 patients primarily develop respiratory symptoms, an increasing number of neurological symptoms and manifestations associated with COVID-19 have been observed. In this narrative review, we elaborate on proposed neurotropic mechanisms and various neurological symptoms, manifestations, and complications of COVID-19 reported in the present literature. For this purpose, a review of all current published literature (studies, case reports, case series, reviews, editorials, and other articles) was conducted and neurological sequelae of COVID-19 were summarized. Essential and common neurological symptoms including gustatory and olfactory dysfunctions, myalgia, headache, altered mental status, confusion, delirium, and dizziness are presented separately in sections. Moreover, neurological manifestations and complications that are of great concern such as stroke, cerebral (sinus) venous thrombosis, seizures, meningoencephalitis, Guillain-Barré syndrome, Miller Fisher syndrome, acute myelitis, and posterior reversible encephalopathy syndrome (PRES) are also addressed systematically. Future studies that examine the impact of neurological symptoms and manifestations on the course of the disease are needed to further clarify and assess the link between neurological complications and the clinical outcome of patients with COVID-19. To limit long-term consequences, it is crucial that healthcare professionals can early detect possible neurological symptoms and are well versed in the increasingly common neurological manifestations and complications of COVID-19.

  View details for DOI 10.1007/s00415-021-10406-y

  View details for PubMedID 33486564

  View details for PubMedCentralID PMC7826147

• Leukemic stem cell phenotype is associated with mutational profile in acute myeloid leukemia. The Korean journal of internal medicine Han, H., Byun, J. M., Shin, D. Y., Yoon, S. S., Koh, Y., Hong, J., Kim, I., Lee, C., Yoo, H., Yun, H., Kim, M. J., Cho, S. I., Seong, M. W., Park, S. S. 2021; 36 (2): 401-412

  Abstract

  Understanding leukemic stem cell (LSC) is important for acute myeloid leukemia (AML) treatment. However, association of LSC with patient prognosis and genetic information in AML patients is unclear.Here we investigated the associations between genetic information and the various LSC phenotypes, namely multipotent progenitor (MPP)-like, lymphoid primed multipotent progenitor (LMPP)-like and granulocyte-macrophage progenitors (GMP)-like LSC in 52 AML patients.In secondary AML patients, MPP-like LSC was significantly higher than de novo AML (p = 0.0037). The proportion of MPP-like LSC was especially high in post-myeloproliferative neoplasm AML (p = 0.0485). There was no correlation between age and LSC phenotype. Mutations of KRAS and NRAS were observed in MPP-like LSC dominant patients, TP53 and ASXL1 mutations in LMPP-like LSC dominant patients, and CEBPA, DNMT3A and IDH1 mutations in GMP-like LSC dominant patients. Furthermore, KRAS mutation was significantly associated with MPP-like LSC expression (p = 0.0540), and TP53 mutation with LMPP-like LSC expression (p = 0.0276). When the patients were separated according to the combined risk including next generation sequencing data, the poorer the prognosis, the higher the LMPP-like LSC expression (p = 0.0052). This suggests that the dominant phenotype of LSC is one of the important factors in predicting the prognosis and treatment of AML.LSC phenotype in AML is closely associated with the recurrent mutations which has prognostic implication. Further research to confirm the meaning of LSC phenotype in the context of genetic aberration is warranted.

  View details for DOI 10.3904/kjim.2020.014

  View details for PubMedID 32811132

  View details for PubMedCentralID PMC7969060

• Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. International journal of cancer Fan, F., Yoo, H. J., Stock, S., Wang, L., Liu, Y., Schubert, M. L., Wang, S., Neuber, B., Hückelhoven-Krauss, A., Gern, U., Schmitt, A., Müller-Tidow, C., Dreger, P., Schmitt, M., Sellner, L. 2021; 148 (2): 419-428

  Abstract

  Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naïve-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naïve-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.

  View details for DOI 10.1002/ijc.33212

  View details for PubMedID 32683672

• Ibrutinib for improved chimeric antigen receptor T cell production for chronic lymphocytic leukemia patients Schmitt, M., Fan, F., Hyeon, J. Y., Stock, S., Wang, L., Liu, Y., Schubert, M., Wang, S., Neuber, B., Hueckelhoven-Krauss, A., Gern, U., Schmitt, A., Mueller-Tidow, C., Dreger, P., Sellner, L. KARGER. 2020: 239

  View details for Web of Science ID 000575955000539

• Tumor-Specific Reactive Oxygen Species Accelerators Improve Chimeric Antigen Receptor T Cell Therapy in B Cell Malignancies. International journal of molecular sciences Yoo, H. J., Liu, Y., Wang, L., Schubert, M. L., Hoffmann, J. M., Wang, S., Neuber, B., Hückelhoven-Krauss, A., Gern, U., Schmitt, A., Müller-Tidow, C., Dreger, P., Mokhir, A., Schmitt, M., Sellner, L. 2019; 20 (10)

  Abstract

  Chimeric antigen receptor T cell (CART) therapy is currently one of the most promising treatment approaches in cancer immunotherapy. However, the immunosuppressive nature of the tumor microenvironment, in particular increased reactive oxygen species (ROS) levels, provides considerable limitations. In this study, we aimed to exploit increased ROS levels in the tumor microenvironment with prodrugs of ROS accelerators, which are specifically activated in cancer cells. Upon activation, ROS accelerators induce further generation of ROS. This leads to an accumulation of ROS in tumor cells. We hypothesized that the latter cells will be more susceptible to CARTs. CD19-specific CARTs were generated with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Cytotoxicity was determined by chromium-51 release assay. Influence of the ROS accelerators on viability and phenotype of CARTs was determined by flow cytometry. The combination of CARTs with the ROS accelerator PipFcB significantly increased their cytotoxicity in the Burkitt lymphoma cell lines Raji and Daudi, as well as primary chronic lymphocytic leukemia cells. Exposure of CARTs to PipFcB for 48 h did not influence T cell exhaustion, viability, or T cell subpopulations. In summary, the combination of CARTs with ROS accelerators may improve adoptive immunotherapy and help to overcome tumor microenvironment-mediated treatment resistance.

  View details for DOI 10.3390/ijms20102469

  View details for PubMedID 31109083

  View details for PubMedCentralID PMC6566309

• Association analysis identifies 65 new breast cancer risk loci NATURE Michailidou, K., Lindstrom, S., Dennis, J., Beesley, J., Hui, S., Kar, S., Lemacon, A., Soucy, P., Glubb, D., Rostamianfar, A., Bolla, M. K., Wang, Q., Tyrer, J., Dicks, E., Lee, A., Wang, Z., Allen, J., Keeman, R., Eilber, U., French, J. D., Chen, X., Fachal, L., McCue, K., McCart, A. E., Reed, A., Ghoussaini, M., Carroll, J. S., Jiang, X., Finucane, H., Adams, M., Adank, M. A., Ahsan, H., Aittomaki, K., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Arun, B., Auer, P. L., Bacot, F., Barrdahl, M., Baynes, C., Beckmann, M. W., Behrens, S., Benitez, J., Bermisheva, M., Bernstein, L., Blomqvist, C., Bogdanova, N. V., Bojesen, S. E., Bonanni, B., Borresen-Dale, A., Brand, J. S., Brauch, H., Brennan, P., Brenner, H., Brinton, L., Broberg, P., Brock, I. W., Broeks, A., Brooks-Wilson, A., Brucker, S. Y., Bruening, T., Burwinkel, B., Butterbach, K., Cai, Q., Cai, H., Caldes, T., Canzian, F., Carracedo, A., Carter, B. D., Castelao, J. E., Chan, T. L., Cheng, T., Chia, K., Choi, J., Christiansen, H., Clarke, C. L., Collee, M., Conroy, D. M., Cordina-Duverger, E., Cornelissen, S., Cox, D. G., Cox, A., Cross, S. S., Cunningham, J. M., Czene, K., Daly, M. B., Devilee, P., Doheny, K. F., Doerk, T., dos-Santos-Silva, I., Dumont, M., Durcan, L., Dwek, M., Eccles, D. M., Ekici, A. B., Eliassen, A., Ellberg, C., Elvira, M., Engel, C., Eriksson, M., Fasching, P. A., Figueroa, J., Flesch-Janys, D., Fletcher, O., Flyger, H., Fritschi, L., Gaborieau, V., Gabrielson, M., Gago-Dominguez, M., Gao, Y., Gapstur, S. M., Garcia-Saenz, J. A., Gaudet, M. M., Georgoulias, V., Giles, G. G., Glendon, G., Goldberg, M. S., Goldgar, D. E., Gonzalez-Neira, A., Alnaes, G., Grip, M., Gronwald, J., Grundy, A., Guenel, P., Haeberle, L., Hahnen, E., Haiman, C. A., Hakansson, N., Hamann, U., Hamel, N., Hankinson, S., Harrington, P., Hart, S. N., Hartikainen, J. M., Hartman, M., Hein, A., Heyworth, J., Hicks, B., Hillemanns, P., Ho, D. N., Hollestelle, A., Hooning, M. J., Hoover, R. N., Hopper, J. L., Hou, M., Hsiung, C., Huang, G., Humphreys, K., Ishiguro, J., Ito, H., Iwasaki, M., Iwata, H., Jakubowska, A., Janni, W., John, E. M., Johnson, N., Jones, K., Jones, M., Jukkola-Vuorinen, A., Kaaks, R., Kabisch, M., Kaczmarek, K., Kang, D., Kasuga, Y., Kerin, M. J., Khan, S., Khusnutdinova, E., Kiiski, J. I., Kim, S., Knight, J. A., Kosma, V., Kristensen, V. N., Kruger, U., Kwong, A., Lambrechts, D., Le Marchand, L., Lee, E., Lee, M., Lee, J., Lee, C., Lejbkowicz, F., Li, J., Lilyquist, J., Lindblom, A., Lissowska, J., Lo, W., Loibl, S., Long, J., Lophatananon, A., Lubinski, J., Luccarini, C., Lux, M. P., Ma, E. K., MacInnis, R. J., Maishman, T., Makalic, E., Malone, K. E., Kostovska, I., Mannermaa, A., Manoukian, S., Manson, J. E., Margolin, S., Mariapun, S., Martinez, M., Matsuo, K., Mavroudis, D., McKay, J., McLean, C., Meijers-Heijboer, H., Meindl, A., Menendez, P., Menon, U., Meyer, J., Miao, H., Miller, N., Taib, N., Muir, K., Mulligan, A., Mulot, C., Neuhausen, S. L., Nevanlinna, H., Neven, P., Nielsen, S. F., Noh, D., Nordestgaard, B. G., Norman, A., Olopade, O. I., Olson, J. E., Olsson, H., Olswold, C., Orr, N., Pankratz, V., Park, S. K., Park-Simon, T., Lloyd, R., Perez, J. A., Peterlongo, P., Peto, J., Phillips, K., Pinchev, M., Plaseska-Karanfilska, D., Prentice, R., Presneau, N., Prokofyeva, D., Pugh, E., Pylkas, K., Rack, B., Radice, P., Rahman, N., Rennert, G., Rennert, H. S., Rhenius, V., Romero, A., Romm, J., Ruddy, K. J., Ruediger, T., Rudolph, A., Ruebner, M., Rutgers, E. T., Saloustros, E., Sandler, D. P., Sangrajrang, S., Sawyer, E. J., Schmidt, D. F., Schmutzler, R. K., Schneeweiss, A., Schoemaker, M. J., Schumacher, F., Schuermann, P., Scott, R. J., Scott, C., Seal, S., Seynaeve, C., Shah, M., Sharma, P., Shen, C., Sheng, G., Sherman, M. E., Shrubsole, M. J., Shu, X., Smeets, A., Sohn, C., Southey, M. C., Spinelli, J. J., Stegmaier, C., Stewart-Brown, S., Stone, J., Stram, D. O., Surowy, H., Swerdlow, A., Tamimi, R., Taylor, J. A., Tengstrom, M., Teo, S. H., Terry, M., Tessier, D. C., Thanasitthichai, S., Thoene, K., Tollenaar, R. M., Tomlinson, I., Tong, L., Torres, D., Truong, T., Tseng, C., Tsugane, S., Ulmer, H., Ursin, G., Untch, M., Vachon, C., van Asperen, C. J., Van Den Berg, D., van den Ouweland, A. W., van der Kolk, L., van der Luijt, R. B., Vincent, D., Vollenweider, J., Waisfisz, Q., Wang-Gohrke, S., Weinberg, C. R., Wendt, C., Whittemore, A. S., Wildiers, H., Willett, W., Winqvist, R., Wolk, A., Wu, A. H., Xia, L., Yamaji, T., Yang, X. R., Yip, C., Yoo, K., Yu, J., Zheng, W., Zheng, Y., Zhu, B., Ziogas, A., Ziv, E., Lakhani, S. R., Antoniou, A. C., Droit, A., Andrulis, I. L., Amos, C. I., Couch, F. J., Pharoah, P. P., Chang-Claude, J., Hall, P., Hunter, D. J., Milne, R. L., Garcia-Closas, M., Schmidt, M. K., Chanock, S. J., Dunning, A. M., Edwards, S. L., Bader, G. D., Chenevix-Trench, G., Simard, J., Kraft, P., Easton, D. F., NBCS Collaborators, ABCTB Investigators, KConFab AOCS Investigators 2017; 551 (7678): 92-+

  Abstract

  Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

  View details for PubMedID 29059683

  View details for PubMedCentralID PMC5798588

• Marked Impact of Different Cytokines on Phenotype and Cytotoxic Activity of CD19-Specific CAR T Cells Hoffmann, J., Wang, L., Huckelhoven, A., Schmitt, A., Gern, U., Sellner, L., Kleist, C., Wenthe, J., Wuchter, P., Schubert, M., Yoo, H., Ni, M., Hofmann, S., Dreger, P., Ho, A. D., Loskog, A., Schmitt, M. AMER SOC HEMATOLOGY. 2016

  View details for DOI 10.1182/blood.V128.22.3509.3509

  View details for Web of Science ID 000394452508015