Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy.

BACKGROUND AND PURPOSE: Emerging data suggest immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) or radiotherapy (SRT) may work synergistically, potentially increasing both efficacy and toxicity. This manuscript characterizes factors associated with intracranial control and radiation necrosis in this group. MATERIALS AND METHODS: All patients had non-small cell lung cancer, renal cell carcinoma, or melanoma and were treated from 2013 to 2021 at two institutions with ICI and SRS/SRT. Univariate and multivariate analysis were used to analyze factors associated with local failure (LF) and grade 2+ (G2 + ) radiation necrosis. RESULTS: There were 179 patients with 549 metastases. The median follow up from SRS/SRT was 14.7 months and the median tumor size was 7 mm (46 tumors ≥ 20 mm). Rates of LF and G2 + radiation necrosis per metastasis were 5.8% (32/549) and 6.9% (38/549), respectively. LF rates for ICI +/- 1 month from time of radiation versus not were 3% (8/264) and 8% (24/285) (p = 0.01), respectively. G2 + radiation necrosis rates for PD-L1 ≥ 50% versus < 50% were 17% (11/65) and 3% (5/203) (p=<0.001), respectively. PD-L1 ≥ 50% remained significantly associated with G2 + radiation necrosis on multivariate analysis (p = 0.03). Rates of intracranial failure were 54% (80/147) and 17% (4/23) (p = 0.001) for those without and with G2 + radiation necrosis, respectively. CONCLUSIONS: PD-L1 expression (≥50%) may be associated with higher rates of G2 + radiation necrosis, and there may be improved intracranial control following the development of radiation necrosis. Administration of ICIs with SRS/SRT is overall safe, and there may be some local control benefit to delivering these concurrently.

Machine learning for automated and real-time two-dimensional to three-dimensional registration of the spine using a single radiograph.

OBJECTIVE: The goal of this work was to methodically evaluate, optimize, and validate a self-supervised machine learning algorithm capable of real-time automatic registration and fluoroscopic localization of the spine using a single radiograph or fluoroscopic frame. METHODS: The authors propose a two-dimensional to three-dimensional (2D-3D) registration algorithm that maximizes an image similarity metric between radiographic images to identify the position of a C-arm relative to a 3D volume. This work utilizes digitally reconstructed radiographs (DRRs), which are synthetic radiographic images generated by simulating the x-ray projections as they would pass through a CT volume. To evaluate the algorithm, the authors used cone-beam CT data for 127 patients obtained from an open-source de-identified registry of cervical, thoracic, and lumbar scans. They systematically evaluated and tuned the algorithm, then quantified the convergence rate of the model by simulating C-arm registrations with 80 randomly simulated DRRs for each CT volume. The endpoints of this study were time to convergence, accuracy of convergence for each of the C-arm's degrees of freedom, and overall registration accuracy based on a voxel-by-voxel measurement. RESULTS: A total of 10,160 unique radiographic images were simulated from 127 CT scans. The algorithm successfully converged to the correct solution 82% of the time with an average of 1.96 seconds of computation. The radiographic images for which the algorithm converged to the solution demonstrated 99.9% registration accuracy despite utilizing only single-precision computation for speed. The algorithm was found to be optimized for convergence when the search space was limited to a ± 45° offset in the right anterior oblique/left anterior oblique, cranial/caudal, and receiver rotation angles with the radiographic isocenter contained within 8000 cm3 of the volumetric center of the CT volume. CONCLUSIONS: The investigated machine learning algorithm has the potential to aid surgeons in level localization, surgical planning, and intraoperative navigation through a completely automated 2D-3D registration process. Future work will focus on algorithmic optimizations to improve the convergence rate and speed profile.

Tumor sound, auditory cues, and tissue pathology in glioma surgery: a proof-of-concept study.

OBJECTIVE: Visual, tactile, and auditory cues are used during surgery to differentiate tissue type. Auditory cues in glioma surgery have not been studied previously. The objectives of this study were 1) to evaluate the feasibility of recording sound generated by the suction device during glioma surgery in matched tissue samples, and 2) to characterize the acoustic variation that occurs in different tissue samples. METHODS: This was a prospective observational proof-of-concept study. Recordings were attempted in 20 patients in order meet the accrual target of 10 patients with matched sound and tissue data. For each patient, three 30- to 60-second recordings were made at these sites: normal white matter, infiltrative margin, and tumor. Tissue samples at each site were then reviewed by experienced neuropathologists, and agreement with surgical identification was estimated with the kappa statistic. Acoustic parameters were characterized for each sample. RESULTS: Data from 20 patients were analyzed. Patient-related or technical issues resulted in missing data for 10 patients, but the final 10 patients had both audio and tissue data for analysis. Among all tissue samples, fair agreement was observed between surgeon identification and actual pathology (κ = 0.24, standard error 0.096, p = 0.006). Acoustic data suggested that 1) the acoustic stimulus is broadband, 2) acoustic features are somewhat consistent within cases, 3) high-entropy values indicate irregularity of sound over time, and 4) bimodal pitch distributions could differentially reflect cues of interest. CONCLUSIONS: This study supports the feasibility of collecting intraoperative data on acoustic features during glioma surgery, and it provides an example of how an analysis could be performed to compare different types of tissues.

Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report.

We report the neuroimaging and histopathologic findings of a 12-year-old female patient with a disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural metastatic disease. These tumors may represent distinct pathology primarily seen in pediatric patients. Neuroimaging demonstrates diffuse, progressive enhancement of the leptomeninges often with interval development of intraparenchymal lesions on follow-up. Disease is typically confined to the central nervous system, though diffuse peritoneal disease was seen in our case, possibly through metastatic seeding of the abdomen via ventriculoperitoneal shunt.

Primary paraspinal leiomyosarcoma invading the cervical spinal canal successfully treated with surgery, radiotherapy, and chemotherapy. Case report.

A primary paraspinal leiomyosarcoma invading the spine is an exceedingly rare neoplasm that may clinically mimic a schwannoma. The authors report a case involving a 45-year-old man with a primary leiomyosarcoma of the cervical paraspinal musculature that invaded the spinal canal at C1-2 and subsequently metastasized to the lungs and pancreas. Aggressive treatment consisting of resection of the primary tumor, adjunctive radiation therapy and chemotherapy, and surgical debulking of metastatic disease resulted in local tumor control at the primary site and long-term survival of the patient.

Aminophylline for the treatment of symptomatic bradycardia and asystole secondary to cervical spine injury.

INTRODUCTION: Bradycardia is a common complication of cervical spine damage in the weeks following injury, occurring in up to 100% of patients in some studies. Cardiac arrest and asystole have been reported in as many as 15% of these patients and cardiac events are the main cause of death within the first year. We describe the case of a 25-year-old African-American male involved in a motor vehicle collision who suffered C6-C7 subluxation. METHODS: Following cervical discectomy and spinal fusion the patient began to develop progressive bradycardia culminating on hospital day 20 with two asystolic events requiring atropine administration. In an attempt to prevent further events and generate hemodynamic stability, aminophylline therapy was initiated. RESULTS: Following day two of therapy, the patient's bradycardia resolved, and no further asystolic events occurred. CONCLUSION: There is limited evidence for the use of methylxanthines in the treatment of bradycardia associated with spinal cord injury. In patients with recurrent asystolic events or symptomatic bradycardia the use of these agents should be considered.

Interspecies comparative genomic hybridization (I-CGH): a new twist to study animal tumor models.

Animal models of human diseases are widely used to address questions of tumor development. Selection of a particular animal model depends upon a variety of factors, among them: animal cost, species lifespan and hardiness; availability of biomolecular and genetic tools for that species; and evolutionary distance from humans. In spite of the growth in genomic data in the past several years, many animal models cannot yet be studied extensively due to gaps in genetic mapping, sequencing and functional analyses. Thus, alternative molecular genetic approaches are needed. We have designed an interspecies comparative genomic hybridization approach to analyze genetic changes in radiation-induced brain tumors in the non-human primate, Macaca mulatta. Using homologies between the primate and human genomes, we adapted widely-available CGH techniques to generate cytogenetic profiles of malignant gliomas in four monkey tumors. Losses and gains were projected onto the corresponding homologous chromosomal regions in the human genome, thus directly translating the status of the monkey gliomas into human gene content. This represents a novel method of comparative interspecies cytogenetic mapping that permits simultaneous analysis of genomic imbalances of unknown sequences in disparate species and correlation with potential or known human disease-related genes.

Common genetic changes in hereditary and sporadic pituitary adenomas detected by comparative genomic hybridization.

Twenty-four pituitary adenomas, both the sporadic type (n = 18) and the type arising in association with either multiple endocrine neoplasia, type 1 (MEN1; n = 2), or Carney complex (CNC, n = 4) were analyzed by comparative genomic hybridization. Twenty-one (88%) tumors displayed chromosomal alterations. The number of chromosomal aberrations in each tumor varied from 2 to greater than 10. Several recurrent chromosomal abnormalities were identified in this study. The most frequently detected losses of chromosomal material involved 1p (14 of 24, 58%), 11p (11 of 24, 46%), 17 (10 of 24, 42%), 16p (9 of 24, 38%), 4 (8 of 24, 33%), 10p (6 of 24, 25%), 12 (6 of 24, 25%), 20 (6 of 24, 25%), 22q (6 of 24, 25%), 13q (5 of 24, 21%), and 9p (4 of 24, 17%). Copy number increases were detected on 4q (7 of 24, 29%), 17 (8 of 24, 33%), 19 (7 of 24, 29%), 1p (6 of 24, 25%), 5 (6 of 24, 25%), 20 (6 of 24, 25%), 6q (5 of 24, 21%), 13q21-qter (5 of 24, 21%), and 16p (5 of 24, 21%). Chromosome 11 loss, which involved 11p in all cases, was the most significant finding and was common to tumors arising sporadically and in association with MEN1 and CNC. In addition, the majority of the tumors (18 of 24, 75% overall and 86% of all tumors with chromosomal abnormalities) showed involvement of chromosome 1. Tumors had either loss (14 of 24, 58%) or gain (6 of 24, 25%) in the 1p32-1pter region. Finally, changes on chromosome 17, either loss or gain, occurred in 71% (17) of all 24 patients. In summary, all the tumors with chromosomal rearrangements (21 of 24, 88%), whether sporadic pituitary adenomas or those associated with MEN1 or CNC, had alteration(s) of 1p32, 11p, or 17.

History of minimally invasive spine surgery.

Patients prefer minimally invasive techniques because such techniques reduce recovery times and provide cosmetic benefits. Reviewing the history of minimally invasive surgery helps us understand the advances in spine surgery. Minimally invasive spine surgery has adopted techniques from several fields to better treat spinal disorders. Minimally invasive spine surgery has been influenced by advances in lasers, endoscopy, and image guidance systems. Discogenic disorders have been treated by using chemonucleolysis, automated percutaneous discectomy, and intradiscal thermoablation. Endoscopic techniques have been used to treat spinal disorders. Thoracoscopes and laparoscopes have been used to perform anterior release of scoliotic or kyphotic deformities and to perform transthoracic microsurgical discectomies. The role of spinal thoracoscopy has expanded to include corpectomy, vertebral reconstruction with internal fixation, hardware application, and resection of neurogenic, spinal, and paraspinal tumors. Advances in interbody fusion cage technology have generated a great deal of interest in laparoscopic techniques. Image-guided systems are widely used in intracranial surgery and have been adapted to facilitate screw placement since the middle 1990s. The use of image-guided systems for pedicle screw placement has improved placement accuracy. The system relies on precise localization of the pedicles with computed tomography. Minimally invasive surgery is designed for "conventional" operations involving extensive anatomic dissections performed via small incisions; it yields shorter recovery times and less morbidity.

Minimally invasive spine instrumentation.

OBJECTIVE: We discuss the instrumentation used with minimally invasive spine surgery. METHODS: Minimally invasive surgery has revolutionized all areas of surgery. The use of endoscopes permits surgical maneuvers to be performed through small incisions. RESULTS: Video-assisted thoracoscopic surgery can be used for a variety of spinal indications. The nerve roots and the spinal cord can be decompressed, bone grafts can be placed for interbody fusion and vertebral body reconstruction, and internal fixation devices can be applied to stabilize the spine. Thoracoscopy can be used to perform thoracic sympathectomies, to resect thoracic disk herniations, to biopsy thoracic vertebral body lesions, to release complex spinal curvatures for the reduction of scoliosis, to perform vertebrectomies, to resect tumors, to debride infections, and to treat spinal fractures. Laparoscopic techniques have been applied to the lumbar spine. Laparoscopic procedures have been used for anterior and posterior approaches to the lumbar spine. Anterior arthrodesis has been performed by laparoscopic insertion of the Bagby and Kuslich cages into the L4-5 and the L5-S1 intervertebral disc spaces. Laparoscopic retroperitoneal techniques have been used for anterior plating to fixate the anterior column rigidly to restore stability. In addition, the posterolateral approach has been used for pedicle screw fixation of the lumbar spine using endoscopic techniques. CONCLUSION: Minimally invasive techniques have been used successfully for treating spinal disorders. With the use of endoscopic techniques, a spine surgeon can perform complex spinal instrumentation through small portals, thus reducing morbidity for the patient.