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Advancements in the treatment of traumatic spinal cord injury during military conflicts

Andrew M. Hersh, A. Daniel Davidar, Carly Weber-Levine, Divyaansh Raj, Safwan Alomari, Brendan F. Judy, and Nicholas Theodore

Significant advancements in the treatment of spinal cord injury (SCI) were developed in the setting of military conflicts, partly due to the large numbers of injuries sustained by service members. No effective SCI treatment options existed into the early 20th century, and soldiers who sustained these injuries were usually considered untreatable. Extensive progress was made in SCI treatment during and after World War II, as physical therapy was increasingly encouraged for patients with SCI, multidisciplinary teams oversaw care, pathophysiology was better understood, and strategies were devised to prevent wound infection and pressure sores. Recent conflicts in Iraq and Afghanistan have caused a substantial rise in the proportion of SCIs among causes of casualties and wounds, largely due to new forms of war and weapons, such as improvised explosive devices. Modern military SCIs resulting from blast mechanisms are substantively different from traumatic SCIs sustained by civilians. The treatment paradigms developed over the past 100 years have increased survival rates and outcomes of soldiers with SCI. In this paper, the authors review the role of military conflicts in the development of therapeutic interventions for SCI and discuss how these interventions have improved outcomes for soldiers and civilians alike.

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Targeting of cyclin-dependent kinases in atypical teratoid rhabdoid tumors with multikinase inhibitor TG02

Andy S. Ding, Sakibul Huq, Joshua Casaos, Divyaansh Raj, Manuel Morales, Tianna Zhao, Timothy Kim, Siddhartha Srivastava, Ayush Pant, Riccardo Serra, Noah L. Gorelick, Henry Brem, and Betty Tyler

OBJECTIVE

Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors with no current standard of care and an estimated median patient survival of 12 to 18 months. Previous genetic analyses have implicated cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that is implicated in many cancers, as key drivers of tumorigenicity in ATRTs. Since the effects of EZH2 and cyclin D1 are facilitated by a host of cyclin-dependent kinases (CDKs), the authors sought to investigate the potential therapeutic effects of targeting CDKs in ATRTs with the multi–CDK inhibitor, TG02.

METHODS

Human ATRT cell lines BT12, BT37, CHLA05, and CHLA06 were selected for investigation. The effects of TG02 on cell viability, proliferation, clonogenicity, and apoptosis were assessed via Cell Counting Kit-8 assays, cell counting, clonogenic assays, and flow cytometry, respectively. Similar methods were used to determine the effects of TG02 combined with radiation therapy (RT) or cisplatin. Synergism indices for TG02-cisplatin combination therapy were calculated using CompuSyn software.

RESULTS

TG02 was observed to significantly impair ATRT cell growth in vitro by limiting cell proliferation and clonogenicity, and by inducing apoptosis. TG02 inhibited ATRT cell proliferation and decreased cell viability in a dose-dependent manner with nanomolar half maximal effective concentration (EC50) values (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). TG02 (150 nM) dramatically increased the proportion of apoptotic ATRT cells 72 hours posttreatment (TG02 8.50% vs control 1.52% apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs control 15.36%, p < 0.0001). Combination therapy studies revealed that TG02 acted as a potent radiosensitizer in ATRT cells (BT12 surviving fraction, RT 51.2% vs RT + TG02 21.7%). Finally, CompuSyn analysis demonstrated that TG02 acted synergistically with cisplatin against ATRT cells at virtually all therapeutic doses. These findings were consistent in cell lines that cover all three molecular subgroups of ATRTs.

CONCLUSIONS

The results of this investigation have established that TG02 is an effective therapeutic against ATRTs in vitro. Given the lack of standard therapy for ATRTs, these findings help fill an unmet need and support further study of TG02 as a potential therapeutic option for patients with this deadly disease.

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Automated prediction of the Thoracolumbar Injury Classification and Severity Score from CT using a novel deep learning algorithm

Sophia A. Doerr, Carly Weber-Levine, Andrew M. Hersh, Tolulope Awosika, Brendan Judy, Yike Jin, Divyaansh Raj, Ann Liu, Daniel Lubelski, Craig K. Jones, Haris I. Sair, and Nicholas Theodore

OBJECTIVE

Damage to the thoracolumbar spine can confer significant morbidity and mortality. The Thoracolumbar Injury Classification and Severity Score (TLICS) is used to categorize injuries and determine patients at risk of spinal instability for whom surgical intervention is warranted. However, calculating this score can constitute a bottleneck in triaging and treating patients, as it relies on multiple imaging studies and a neurological examination. Therefore, the authors sought to develop and validate a deep learning model that can automatically categorize vertebral morphology and determine posterior ligamentous complex (PLC) integrity, two critical features of TLICS, using only CT scans.

METHODS

All patients who underwent neurosurgical consultation for traumatic spine injury or degenerative pathology resulting in spine injury at a single tertiary center from January 2018 to December 2019 were retrospectively evaluated for inclusion. The morphology of injury and integrity of the PLC were categorized on CT scans. A state-of-the-art object detection region-based convolutional neural network (R-CNN), Faster R-CNN, was leveraged to predict both vertebral locations and the corresponding TLICS. The network was trained with patient CT scans, manually labeled vertebral bounding boxes, TLICS morphology, and PLC annotations, thus allowing the model to output the location of vertebrae, categorize their morphology, and determine the status of PLC integrity.

RESULTS

A total of 111 patients were included (mean ± SD age 62 ± 20 years) with a total of 129 separate injury classifications. Vertebral localization and PLC integrity classification achieved Dice scores of 0.92 and 0.88, respectively. Binary classification between noninjured and injured morphological scores demonstrated 95.1% accuracy. TLICS morphology accuracy, the true positive rate, and positive injury mismatch classification rate were 86.3%, 76.2%, and 22.7%, respectively. Classification accuracy between no injury and suspected PLC injury was 86.8%, while true positive, false negative, and false positive rates were 90.0%, 10.0%, and 21.8%, respectively.

CONCLUSIONS

In this study, the authors demonstrate a novel deep learning method to automatically predict injury morphology and PLC disruption with high accuracy. This model may streamline and improve diagnostic decision support for patients with thoracolumbar spinal trauma.

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Internal neurolysis versus intraoperative glycerin rhizotomy for trigeminal neuralgia

Risheng Xu, Joshua Materi, Divyaansh Raj, Safwan Alomari, Yuanxuan Xia, Sumil K. Nair, Pavan P. Shah, Nivedha Kannapadi, Timothy Kim, Judy Huang, Chetan Bettegowda, and Michael Lim

OBJECTIVE

Internal neurolysis (IN) and intraoperative glycerin rhizotomy (ioGR) are emerging surgical options for patients with trigeminal neuralgia without neurovascular contact. The objective of this study was to compare the neurological outcomes of patients who underwent IN with those of patients who underwent ioGR.

METHODS

The authors retrospectively reviewed all patients who underwent IN or ioGR for trigeminal neuralgia at our institution. Patient demographic characteristics and immediate postoperative outcomes, as well as long-term neurological outcomes, were compared.

RESULTS

Of 1044 patients who underwent open surgical treatment for trigeminal neuralgia, 56 patients underwent IN and 91 underwent ioGR. Of these 147 patients, 37 had no evidence of intraoperative neurovascular conflict. All patients who underwent IN and 96.7% of patients who underwent ioGR had immediate postoperative pain relief. At last follow-up, patients who underwent IN had lower Barrow Neurological Institute (BNI) pain intensity scores (p = 0.05), better BNI facial numbness scores (p < 0.01), and a greater degree of pain improvement (p = 0.05) compared with those who underwent ioGR. Patients who underwent IN also had significantly lower rates of symptomatic pain recurrence (p < 0.01) at last follow-up over an average of 9.5 months.

CONCLUSIONS

IN appears to provide patients with a greater degree of pain relief, lower rates of facial numbness, and lower rates of pain recurrence compared with ioGR. Future prospective studies will better characterize long-term pain recurrence and outcomes.