The intersection between immunotherapy and laser interstitial thermal therapy: a multipronged future of neuro-oncology.

The rise of immunotherapy (IT) in oncological treatment has greatly improved outcomes in a number of disease states. However, its use in tumors of the central nervous system (CNS) remains limited for multiple reasons related to the unique immunologic tumor microenvironment. As such, it is valuable to consider the intersection of IT with additional treatment methods that may improve access to the CNS and effectiveness of existing IT modalities. One such combination is the pairing of IT with localized hyperthermia (HT) generated through technologies such as laser interstitial thermal therapy (LITT). The wide-ranging immunomodulatory effects of localized and whole-body HT have been investigated for some time. Hyperthermia has demonstrated immunostimulatory effects at the level of tumor cells, immune cells, and the broader environment governing potential immune surveillance. A thorough understanding of these effects as well as the current and upcoming investigations of such in combination with IT is important in considering the future directions of neuro-oncology.

Subdural Extra-arachnoid Hygroma Because of Occult Distal Durotomy After Minimally Invasive Decompression: A Case Report.

CASE: We present the case of a 59-year-old man who had MIS L4-5 decompression. He presented the next day with intractable back and leg pain. Magnetic resonance imaging revealed ventral displacement of the cauda equina and a subdural collection on the right L3/L4 nerve roots. Revision decompression revealed occult durotomy caudal and contralateral to the index decompression. CONCLUSION: Minimally invasive spine (MIS) surgery leverages shorter operative time and reduced postoperative pain. Yet, decreased exposure can make identification and management complications challenging. This report highlights occult durotomy and spinal subdural extra-arachnoid hygroma in patients with postoperative nerve compression after seemingly uncomplicated MISS.

Automated segmentation of ablated lesions using deep convolutional neural networks: A basis for response assessment following laser interstitial thermal therapy.

BACKGROUND: Laser interstitial thermal therapy (LITT) of intracranial tumors or radiation necrosis enables tissue diagnosis, cytoreduction, and rapid return to systemic therapies. Ablated tissue remains in situ, resulting in characteristic post-LITT edema associated with transient clinical worsening and complicating post-LITT response assessment. METHODS: All patients receiving LITT at a single center for tumors or radiation necrosis from 2015 to 2023 with ≥9 months of MRI follow-up were included. An nnU-Net segmentation model was trained to automatically segment contrast-enhancing lesion volume (CeLV) of LITT-treated lesions on T1-weighted images. Response assessment was performed using volumetric measurements. RESULTS: Three hundred and eighty four unique MRI exams of 61 LITT-treated lesions and 6 control cases of medically managed radiation necrosis were analyzed. Automated segmentation was accurate in 367/384 (95.6%) images. CeLV increased to a median of 68.3% (IQR 35.1-109.2%) from baseline at 1-3 months from LITT (P = 0.0012) and returned to baseline thereafter. Overall survival (OS) for LITT-treated patients was 39.1 (9.2-93.4) months. Lesion expansion above 40% from volumetric nadir or baseline was considered volumetric progression. Twenty-one of 56 (37.5%) patients experienced progression for a volumetric progression-free survival of 21.4 (6.0-93.4) months. Patients with volumetric progression had worse OS (17.3 vs 62.1 months, P = 0.0015). CONCLUSIONS: Post-LITT CeLV expansion is quantifiable and resolves within 6 months of LITT. Development of response assessment criteria for LITT-treated lesions is feasible and should be considered for clinical trials. Automated lesion segmentation could speed the adoption of volumetric response criteria in clinical practice.

Laser ablation of a sphenoid wing meningioma: A case report and review of the literature.

Background: Meningiomas are the most common primary central nervous system neoplasm in the United States. While the majority of meningiomas are benign, the World Health Organization (WHO) Grade I tumors, a not-insignificant proportion of tumors are in anatomically complex locations or demonstrate more aggressive phenotypes, presenting a challenge for local disease control with surgery and radiation. Laser interstitial thermal therapy (LITT) consists of stereotactic delivery of laser light for tumor ablation and is minimally invasive, requiring implantation of a laser fiber through a cranial burr hole. Herein, we demonstrate the first use of this technology in a progressive atypical sphenoid wing meningioma for a previously resected and irradiated tumor. Case Description: A 47-year-old female was diagnosed with a left-sided atypical meningioma, the WHO 2, of the sphenoid wing following acute worsening of bitemporal headache and dizziness. Given neurovascular involvement, a subtotal resection was performed, followed by stereotactic radiosurgery. Following progression 9 months from resection, the patient elected to proceed with LITT. The patient's postoperative course was uncomplicated and she remains progression free at 24 months following LITT. Conclusion: We present the first use of LITT for a sphenoid wing meningioma documented in the literature, which demonstrated enhanced disease control for a lesion that was refractory to both surgery and radiation. LITT could represent an additional option for local control of progressive meningiomas, even in locations that are challenging to access surgically. More evidence is needed regarding the technical nuances of LITT for lesions of the skull base.

Risk of Tract Seeding Following Laser Interstitial Thermal Therapy for Brain Tumors.

BACKGROUND: The management of intracranial oncological disease remains a significant challenge despite advances in systemic cancer therapy. Laser interstitial thermal therapy (LITT) represents a novel treatment for local control of brain tumors through photocoagulation with a stereotactically implanted laser fiber. Because the use of laser interstitial thermal therapy continues to increase within neurosurgery, characterization of LITT is necessary to improve outcomes. OBJECTIVE: To quantify the risk of tumor seeding along the laser fiber tract in patients receiving LITT for primary or metastatic brain tumors at a high-volume treatment center. METHODS: We retrospectively reviewed all patients receiving LITT from 2015 to 2021 at our medical center. Patients with biopsy-confirmed tumors were included in this study. Tract seeding was identified as discontinuous, newly enhancing tumor along the LITT tract. RESULTS: Fifty-six patients received LITT for biopsy-confirmed tumors from 2015 to 2021, with tract seeding identified in 3 (5.4%). Twenty-nine (51.8%) patients had gliomas, while the remainder had metastases, of which lung was the most common histology (20 patients, 74%). Tract seeding was associated with ablation proceeding inward from superficial tumor margin closest to the cranial entry point ( P = .03). Patients with tract seeding had a shorter median time to progression of 1.1 (0.1-1.3) months vs 4.2 (2.2-8.6) months ( P = .03). CONCLUSION: Although the risk of tract seeding after LITT is reassuringly low, it is associated with decreased progression-free survival. This risk may be related to surgical technique or experience. Follow-up radiosurgery to the LITT tract has the potential to prevent this complication.

Instrument Tracking for Prone Lateral Surgery.

The prone lateral transpsoas approach for lumbar interbody fusion and posterior instrumentation enables a large surface area implant without disruption of the posterior spine musculature from a single position.1,2 The addition of virtual live fluoroscopy instrument tracking navigation to surgery provides multiple benefits, including a reduction in patient and surgeon radiation exposure, highly accurate and dynamic spatial tool localization, and flexible equipment and patient positioning.3,4 Here, we highlight the use of virtual live fluoroscopy in prone lateral spine surgery. A 75-year-old man presented with prior L3-L5 fusion and progressive lower extremity pain and weakness. Using the described techniques, the patient underwent a lateral retroperitoneal interbody fusion and posterior instrumentation at L2-L3. The operation proceeded without complication, and the patient reported improved ambulation at 6-week follow-up. The prone lateral transpsoas approach and minimally invasive posterior instrumentation for lumbar interbody fusion permits effective fusion without significant posterior muscle disruption from a single position. The integration of virtual live fluoroscopy enables real-time instrument tracking throughout the minimally invasive case, with reductions in patient and surgeon radiation exposure. Video 1 depicts the use and benefits of this technology in lateral spine surgery. Compared with computed tomography-guided navigation, virtual live fluoroscopy technology enables rapid remapping to iatrogenic anatomic changes for more fluid progression through the operation.5 Virtual live fluoroscopy instrument tracking is a valuable tool that increases the safety and efficiency of single-position lateral spine surgery.

Erratum to "E.C. Lerner, E.S. Srinivasan, G. Broadwater, et al. Factors Associated With New-Onset Seizures Following Stereotactic Radiosurgery for Newly Diagnosed Brain Metastases. Adv Radiat Oncol. 2022;7:101054."

[This corrects the article DOI: 10.1016/j.adro.2022.101054.].

Gold Nanostars Obviate Limitations to Laser Interstitial Thermal Therapy (LITT) for the Treatment of Intracranial Tumors.

PURPOSE: Laser interstitial thermal therapy (LITT) is an effective minimally invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT. EXPERIMENTAL DESIGN: The impact of GNS on LITT coverage capacity was tested in ex vivo models using clinical LITT equipment and agarose gel-based phantoms of control and GNS-infused central "tumors." In vivo accumulation of GNS and amplification of ablation were tested in murine intracranial and extracranial tumor models followed by intravenous GNS injection, PET/CT, two-photon photoluminescence, inductively coupled plasma mass spectrometry (ICP-MS), histopathology, and laser ablation. RESULTS: Monte Carlo simulations demonstrated the potential of GNS to accelerate and specify thermal distributions. In ex vivo cuboid tumor phantoms, the GNS-infused phantom heated 5.5× faster than the control. In a split-cylinder tumor phantom, the GNS-infused border heated 2× faster and the surrounding area was exposed to 30% lower temperatures, with margin conformation observed in a model of irregular GNS distribution. In vivo, GNS preferentially accumulated within intracranial tumors on PET/CT, two-photon photoluminescence, and ICP-MS at 24 and 72 hours and significantly expedited and increased the maximal temperature achieved in laser ablation compared with control. CONCLUSIONS: Our results provide evidence for use of GNS to improve the efficiency and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors and amplification of laser ablation, and the GNS-infused phantom experiments demonstrate increased rates of heating, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.

Dr. Ruth Jackson: the legacy of the first female spine surgeon.

Dr. Ruth Jackson, born in 1902, was the first female spine surgeon on record. Her story of remarkable resilience and sacrifice is even more relevant given the stark gender disparities in orthopedic surgery and neurosurgery that remain today. Dr. Jackson entered the field during the Great Depression and overcame significant barriers at each step along the process. In 1937, she became the first woman to pass the American Board of Orthopedic Surgery examination and join the American Academy of Orthopedic Surgeons as a full member. Her work in the cervical spine led to a notable lecture record and the publication of several articles, as well as a book, The Cervical Syndrome, in which she discussed the anatomy, etiology, and treatment of cervical pathologies. Additionally, Dr. Jackson developed the Jackson CerviPillo, a neck support that is still in use today. She left a legacy that continues to resonate through the work of the Ruth Jackson Orthopedic Society, which supports women at all levels of practice and training. From the story of Dr. Jackson's life, we can appreciate her single-minded determination that blazed a path for women in spine surgery, as well as consider the progress that remains to be made.

Posterior Cervical Decompression and Fusion With Exoscope: 2-Dimensional Operative Video.

Posterior cervical decompression and fusion is an effective strategy for correction of cervical spondylotic myelopathy. Here, we highlight the operative treatment of a 63-yr-old man entailing a 4-level posterior cervical laminectomy and fusion, with the use of an exoscope throughout. The patient initially presented with symptoms of gait dysfunction and loss of fine motor control in the upper extremities, without neck pain or radiculopathy. His imaging demonstrated a congenitally narrowed spinal canal with cervical stenosis at C3-C4, C5-C6, and C6-C7. The patient consented to the procedure and publication of his image, along with other participants and any identifiable individuals. The operation proceeded with the patient in a prone position with midline dissection to the posterior elements of C3-C6. Pilot holes were drilled in the lateral masses and C3-C4, C4-C5, C5-C6, and C6-C7 laminectomies performed using a high-speed drill, with removal of the laminae en bloc. Lateral mass screws were inserted and precontoured rods secured, with morselized autograft and allograft bone chips placed for arthrodesis. Postoperatively, the patient reported noted improvement in his symptoms.

Minimally invasive lateral retroperitoneal transpsoas approach for lumbar corpectomy and fusion with posterior instrumentation.

In this video, the authors highlight the operative treatment of a 55-year-old man with chronic osteomyelitis discitis. The operation entailed a minimally invasive lateral retroperitoneal transpsoas approach for L3 and L4 corpectomies, L2-5 interbody fusion, and L2-5 minimally invasive posterior instrumentation. The operation proceeded in two stages, beginning in the lateral position with corpectomy of the L3 and L4 vertebral bodies and placement of a corpectomy cage. After closure of this access wound, the patient was turned to a prone position for the posterior element of the operation. Posterior instrumentation was placed with pedicle screws at L2 and L5. The video can be found here: https://stream.cadmore.media/r10.3171/2022.3.FOCVID2210.

Time to Steroid Independence After Laser Interstitial Thermal Therapy vs Medical Management for Treatment of Biopsy-Proven Radiation Necrosis Secondary to Stereotactic Radiosurgery for Brain Metastasis.

BACKGROUND: Radiation necrosis (RN) after stereotactic radiosurgery (SRS) for brain metastases (BM) can result in significant morbidity, compounded by the effects of extended steroid therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive procedure that can offer definitive treatment for RN while potentially obviating the need for prolonged steroid use. OBJECTIVE: To compare LITT vs medical management (MM) in the treatment of RN. METHODS: A multicenter, retrospective study was performed of SRS-treated patients with BM who developed biopsy-proven RN and were treated with LITT or MM. Clinical outcome data were compared by treatment modality. RESULTS: Seventy-two patients met criteria with a median follow-up of 10.0 months (4.2-25.1), and 57 patients (79%) underwent LITT. Four MM (27%) and 3 LITT patients (5%) demonstrated radiographic progression (P = .031) at a median of 5.3 and 4.0 months (P = .40). There was no significant difference in overall survival (LITT median of 15.2 vs 11.6 months, P = .60) or freedom from local progression (13.6 vs 7.06 months, P = .40). Patients stopped steroid therapy earlier in the LITT cohort at a median of 37 days compared with 245 days (P < .001). When controlled for follow-up duration, patients treated with LITT were 3 times more likely to be weaned off steroids before the study end point (P = .003). CONCLUSION: These data suggest that LITT for treatment of biopsy-proven RN after SRS for BM significantly decreases time to steroid independence. Prospective trials should be designed to further validate the utility of LITT for RN and its impact on steroid-induced morbidity.

Factors Associated With New-Onset Seizures Following Stereotactic Radiosurgery for Newly Diagnosed Brain Metastases.

Purpose: Stereotactic radiosurgery (SRS) is a highly effective therapy for newly diagnosed brain metastases. Prophylactic antiepileptic drugs are no longer routinely used in current SRS practice, owing to a perceived low overall frequency of new-onset seizures and potential side effects of medications. It is nonetheless desirable to prevent unwanted side effects following SRS. Risk factors for new-onset seizures after SRS have not been well established. As such, we aimed to characterize variables associated with increased seizure risk. Methods and Materials: Patients treated with SRS for newly diagnosed brain metastases between 2013 and 2016 were retrospectively reviewed at a single institution. Data on baseline demographics, radiation parameters, and clinical courses were collected. Results: The cohort consisted of 305 patients treated with SRS without prior seizure history. Median age and baseline Karnofsky Performance Scale score were 64 years (interquartile range, 55-70) and 80 (interquartile range, 80-90), respectively. Twenty-six (8.5%) patients developed new-onset seizures within 3 months of SRS. There was no association between new-onset seizures and median baseline Karnofsky Performance Scale score, prior resection, or prior whole brain radiation therapy. There were significant differences in the combined total irradiated volume (12.5 vs 3.7 cm3, P < .001), maximum single lesion volume (8.8 vs 2.8 cm3, P = .003), lesion diameter (3.2 vs 2.0 cm, P = .003), and number of lesions treated (3 vs 1, P = .018) between patients with and without new-onset seizures, respectively. On multivariate logistic regression, total irradiated volume (odds ratio, 1.09 for every 1-cm1 increase in total volume; confidence interval, 1.02-1.17; P = .016) and pre-SRS neurologic symptoms (odds ratio, 3.08; 95% confidence interval, 1.19-7.99; P = .020) were both significantly correlated with odds of seizures following SRS. Conclusions: Our data suggest that larger total treatment volume and the presence of focal neurologic deficits at presentation are associated with new-onset seizures within 3 months of SRS. High-risk patients undergoing SRS may benefit from counseling or prophylactic antiseizure therapy.

Combination laser interstitial thermal therapy plus stereotactic radiotherapy increases time to progression for biopsy-proven recurrent brain metastases.

Background: Improved survival for patients with brain metastases has been accompanied by a rise in tumor recurrence after stereotactic radiotherapy (SRT). Laser interstitial thermal therapy (LITT) has emerged as an effective treatment for SRT failures as an alternative to open resection or repeat SRT. We aimed to evaluate the efficacy of LITT followed by SRT (LITT+SRT) in recurrent brain metastases. Methods: A multicenter, retrospective study was performed of patients who underwent treatment for biopsy-proven brain metastasis recurrence after SRT at an academic medical center. Patients were stratified by "planned LITT+SRT" versus "LITT alone" versus "repeat SRT alone." Index lesion progression was determined by modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Results: Fifty-five patients met inclusion criteria, with a median follow-up of 7.3 months (range: 1.0-30.5), age of 60 years (range: 37-86), Karnofsky Performance Status (KPS) of 80 (range: 60-100), and pre-LITT/biopsy contrast-enhancing volume of 5.7 cc (range: 0.7-19.4). Thirty-eight percent of patients underwent LITT+SRT, 45% LITT alone, and 16% SRT alone. Median time to index lesion progression (29.8, 7.5, and 3.7 months [P = .022]) was significantly improved with LITT+SRT. When controlling for age in a multivariate analysis, patients treated with LITT+SRT remained significantly less likely to have index lesion progression (P = .004). Conclusions: These data suggest that LITT+SRT is superior to LITT or repeat SRT alone for treatment of biopsy-proven brain metastasis recurrence after SRT failure. Prospective trials are warranted to validate the efficacy of using combination LITT+SRT for treatment of recurrent brain metastases.

The microenvironment of brain metastases from solid tumors.

Brain metastasis (BrM) is an area of unmet medical need that poses unique therapeutic challenges and heralds a dismal prognosis. The intracranial tumor microenvironment (TME) presents several challenges, including the therapy-resistant blood-brain barrier, a unique immune milieu, distinct intercellular interactions, and specific metabolic conditions, that are responsible for treatment failures and poor clinical outcomes. There is a complex interplay between malignant cells that metastasize to the central nervous system (CNS) and the native TME. Cancer cells take advantage of vascular, neuronal, immune, and anatomical vulnerabilities to proliferate with mechanisms specific to the CNS. In this review, we discuss unique aspects of the TME in the context of brain metastases and pathways through which the TME may hold the key to the discovery of new and effective therapies for patients with BrM.

Front-Back Cervical Deformity Correction by Anterior Cervical Discectomy and Fusion With Posterior Instrumentation: 2-Dimensional Operative Video.

Front-back procedures for cervical deformity permit the correction of cervical kyphosis in the setting of unfused facets. Here, we highlight the operative treatment of a 65-yr-old female entailing a 4-level anterior cervical discectomy and fusion (ACDF) at C3-C4, C4-C5, C5-C6, and C6-C7 with hyperlordotic interbody implants, supplemented by a posterior C2-T2 instrumented fusion. The patient initially presented with symptoms of treatment-refractory neck pain while neurologically intact on examination. Her imaging demonstrated significant cervical kyphosis measuring 46° as the Cobb angle between C2 and C7 without neural compression. The patient consented to the procedure and publication of their image. After 2 d of traction, the operation proceeded with the patient initially in a supine position with dissection medial to the sternocleidomastoid muscle down to the vertebral bodies. Discectomies were performed at each level followed by installation of the interbody implants. After closure of this access wound, the patient was turned to a prone position for the posterior element of the operation. The posterior bony elements were exposed and a C2-T2 instrumented fusion performed. Postoperative imaging demonstrated improvement of her sagittal cervical curvature and the patient described improvement in her neck pain.

Laser interstitial thermal therapy for brain metastases.

Laser interstitial thermal therapy (LITT) is a minimally invasive treatment for intracranial lesions entailing thermal ablation via a stereotactically placed laser probe. In metastatic disease, it has shown the most promise in the treatment of radiographically progressive lesions after initial stereotactic radiosurgery, whether due to recurrent metastatic disease or radiation necrosis. LITT has been demonstrated to provide clinical benefit in both cases, as discussed in the review below. With its minimal surgical footprint and short recovery period, LITT is further advantaged for patients who are otherwise high-risk surgical candidates or with lesions in difficult to access locations. Exploration of the current data on its use in metastatic disease will allow for a better understanding of the indications, benefits, and future directions of LITT for these patients.

Two-Level Minimally Invasive Lumbar Laminectomy and Foraminotomy: 2-Dimensional Operative Video.

Minimally invasive lumbar laminectomies utilize tubular retractors to minimize tissue disturbance, blood loss, and hospital length of stay compared to open operations. Here, we highlight the operative treatment of a 68-yr-old male entailing a 2-level minimally invasive lumbar laminectomy and foraminotomy at L2-L3 and L3-L4. The patient initially presented with symptoms of treatment-refractory lower extremity numbness and limited ambulation. His imaging demonstrated coronal scoliosis and severe lumbar central and foraminal stenosis at L2-L3 and L3-L4, with enlarged spinous processes, laminae, and facets. The patient consented to the procedure and publication of their image. The operation proceeded with the patient in a prone position with paramedian dissection to the lamina through a minimally invasive tubular retractor. Laminectomies and foraminotomies were performed at each level with high-speed drill and a Kerrison rongeur, with care to identify and protect the relevant spinal nerve roots. Postoperatively, the patient reported significantly reduced numbness and improved ambulation, with a well-healed surgical incision notably smaller than those produced in an open operation.

CD4 T-Cell Exhaustion: Does It Exist and What Are Its Roles in Cancer?

In chronic infections and in cancer, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion. Exhausted T cells are characterized by an increased expression of inhibitory markers and a progressive and hierarchical loss of function. Although cancer-induced exhaustion in CD8 T cells has been well-characterized and identified as a therapeutic target (i.e., via checkpoint inhibition), in-depth analyses of exhaustion in other immune cell types, including CD4 T cells, is wanting. While perhaps attributable to the contextual discovery of exhaustion amidst chronic viral infection, the lack of thorough inquiry into CD4 T-cell exhaustion is particularly surprising given their important role in orchestrating immune responses through T-helper and direct cytotoxic functions. Current work suggests that CD4 T-cell exhaustion may indeed be prevalent, and as CD4 T cells have been implicated in various disease pathologies, such exhaustion is likely to be clinically relevant. Defining phenotypic exhaustion in the various CD4 T-cell subsets and how it influences immune responses and disease severity will be crucial to understanding collective immune dysfunction in a variety of pathologies. In this review, we will discuss mechanistic and clinical evidence for CD4 T-cell exhaustion in cancer. Further insight into the derivation and manifestation of exhaustive processes in CD4 T cells could reveal novel therapeutic targets to abrogate CD4 T-cell exhaustion in cancer and induce a robust antitumor immune response.

Salting the Soil: Targeting the Microenvironment of Brain Metastases.

Paget's "seed and soil" hypothesis of metastatic spread has acted as a foundation of the field for over a century, with continued evolution as mechanisms of the process have been elucidated. The central nervous system (CNS) presents a unique soil through this lens, relatively isolated from peripheral circulation and immune surveillance with distinct cellular and structural composition. Research in primary and metastatic brain tumors has demonstrated that this tumor microenvironment (TME) plays an essential role in the growth of CNS tumors. In each case, the cancerous cells develop complex and bidirectional relationships that reorganize the local TME and reprogram the CNS cells, including endothelial cells, pericytes, astrocytes, microglia, infiltrating monocytes, and lymphocytes. These interactions create a structurally and immunologically permissive TME with malignant processes promoting positive feedback loops and systemic consequences. Strategies to interrupt interactions with the native CNS components, on "salting the soil," to create an inhospitable environment are promising in the preclinical setting. This review aims to examine the general and specific pathways thus far investigated in brain metastases and related work in glioma to identify targetable mechanisms that may have general application across the spectrum of intracranial tumors.