Functional prediction of response to therapy prior to therapeutic intervention is associated with improved survival in patients with high-grade glioma.

Patients with high-grade glioma (HGG) have an extremely poor prognosis compounded by a lack of advancement in clinical care over the past few decades. Regardless of classification, most newly diagnosed patients receive the same treatment, radiation and temozolomide (RT/TMZ). We developed a functional precision oncology test that prospectively identifies individual patient's response to this treatment regimen. Tumor tissues isolated from patients with newly diagnosed HGG enrolled in 3D PREDICT REGISTRY were evaluated for response to chemotherapeutic agents using the 3D Predict™ Glioma test. Patients receiving RT/TMZ were followed for 2 years. Clinical outcomes including imaging, assessments, and biomarker measurements were compared to patient matched test-predicted therapy response. Median survival between test-predicted temozolomide responders and test-predicted temozolomide non-responders revealed a statistically significant increase in progression-free survival when using the test to predict response across multiple subgroups including HGG (5.8 months), glioblastoma (4.7 months), and MGMT unmethylated glioblastoma (4.7 months). Overall survival was also positively separated across the subgroups at 7.6, 5.1, and 6.3 months respectively. The strong correlation of 3D Predict Glioma test results with clinical outcomes demonstrates that this functional test is prognostic in patients treated with RT/TMZ and supports aligning clinical treatment to test-predicted response across varying HGG subgroups.

Histopathological correlation of brain tumor recurrence vs. radiation effect post-radiosurgery as detected by MRI contrast clearance analysis: a validation study.

PURPOSE: The differentiation between adverse radiation effects (ARE) and tumor recurrence or progression (TRP) is a major decision-making point in the follow-up of patients with brain tumors. The advent of immunotherapy, targeted therapy and radiosurgery has made this distinction difficult to achieve in several clinical situations. Contrast clearance analysis (CCA) is a useful technique that can inform clinical decisions but has so far only been histologically validated in the context of high-grade gliomas. METHODS: This is a series of 7 patients, treated between 2018 and 2023, for various brain pathologies including brain metastasis, atypical meningioma, and high-grade glioma. MRI with contrast clearance analysis was used to inform clinical decisions and patients underwent surgical resection as indicated. The histopathology findings were compared with the CCA findings in all cases. RESULTS: All seven patients had been treated with gamma knife radiosurgery and were followed up with periodic MR imaging. All patients underwent CCA when the necessity to distinguish tumor recurrence from radiation necrosis arose, and subsequently underwent surgery as indicated. Concordance of CCA findings with histological findings was found in all cases (100%). CONCLUSIONS: Based on prior studies on GBM and the surgical findings in our series, delayed contrast extravasation MRI findings correlate well with histopathology across a wide spectrum of brain tumor pathologies. CCA can provide a quick diagnosis and have a direct impact on patients' treatment and outcomes.

Expected motor function change following decompressive surgery for spinal metastatic disease.

Background: Motor function in patients with spinal metastatic disease (SMD) directly impacts a patient's ability to receive systemic therapy and overall survival. Spine surgeons may be in the challenging position to advise a patient on expected motor function outcomes and determine a patient's suitability as a surgical candidate. We present this study to provide this critical information on anticipated motor function change to spine surgeons. Methods: Consecutive patients undergoing spinal surgery for SMD at a National Cancer Institute-designated cancer institute were prospectively enrolled. Patient motor function status before and after surgery was assessed using the standard 0 to 5 five-point muscle strength grading scale. The difference in presurgical and postsurgical motor function (proximal and distal) was used to assess motor function changes following surgery. Results: A total of 171 patients were included. The mean age was 62.7±10.46 years and 40.9% (70) were female. Common primary malignancy types were lung (49), kidney (28), breast (25), and prostate (23). The average proximal and distal motor function difference was 0.38 (standard deviation=1.02, p<.0001) and 0.32 (standard deviation=0.91, p<.0001) respectively showing an improvement following surgery. Patients with proximal presurgical motor function of 2, 3, and 4 had an improved motor function in 73%, 77%, and 73% of the patients. Patients with distal presurgical motor function of 2, 3, and 4 had an improved motor function in 80%, 89%, and 70% of the patients. Conclusions: Most patients undergoing surgery for SMD have a modest improvement in motor function following surgery. The degree of improvement in most instances is less than 1 point on a 0 to 5 motor function scale. This is critical knowledge for a spinal surgeon when evaluating SMD patients with significant preoperative motor function deficits. These results aid spinal surgeons in setting expectations and evaluating the need for rapid spinal decompression.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Postoperative Restrictive Opioid Protocols and Durable Changes in Opioid Prescribing and Chronic Opioid Use.

Importance: Changes in postsurgical opioid prescribing practices may help reduce chronic opioid use in surgical patients. Objective: To investigate whether postsurgical acute pain across different surgical subspecialties can be managed effectively after hospital discharge with an opioid supply of 3 or fewer days and whether this reduction in prescribed opioids is associated with reduced new, persistent opioid use. Design, Setting, and Participants: In this prospective cohort study with a case-control design, a restrictive opioid prescription protocol (ROPP) specifying an opioid supply of 3 or fewer days after discharge from surgery along with standardized patient education was implemented across all surgical services at a tertiary-care comprehensive cancer center. Participants were all patients who underwent surgery from August 1, 2018, to July 31, 2019. Main Outcomes and Measures: Main outcomes were the rate of compliance with the ROPP in each surgical service, the mean number of prescription days and refill requests, type of opioid prescribed, and rate of conversion to chronic opioid use determined via a state-run opioid prescription program. Postsurgical complications were also measured. Results: A total of 4068 patients (mean [SD] age, 61.0 [13.8] years; 2528 women [62.1%]) were included, with 2017 in the pre-ROPP group (August 1, 2018, to January 31, 2019) and 2051 in the post-ROPP group (February 1, 2019, to July 31, 2019). The rate of compliance with the protocol was 95%. After implementation of the ROPP, mean opioid prescription days decreased from a mean (SD) of 3.9 (4.5) days in the pre-ROPP group to 1.9 (3.6) days in the post-ROPP group (P < .001). The ROPP implementation led to a 45% decrease in prescribed opioids after surgery (mean [SD], 157.22 [338.06] mean morphine milligram equivalents [MME] before ROPP vs 83.54 [395.70] MME after ROPP; P < .001). Patients in the post-ROPP cohort requested fewer refills (367 of 2051 [17.9%] vs 422 of 2017 [20.9%] in the pre-ROPP cohort; P = .02). There was no statistically significant difference in surgical complications. The conversion rate to chronic opioid use decreased following ROPP implementation among both opioid-naive patients with cancer (11.3% [143 of 1267] to 4.5% [118 of 2645]; P < .001) and those without cancer (6.1% [19 of 310] to 2.7% [16 of 600]; P = .02). Conclusions and Relevance: In this cohort study, prescribing an opioid supply of 3 or fewer days to surgical patients after hospital discharge was feasible for most patients, led to a significant decrease in the number of opioids prescribed after surgery, and was associated with a significantly decreased conversion to long-term opioid use without concomitant increases in refill requests or significant compromises in surgical recovery.

Prospective prediction of clinical drug response in high-grade gliomas using an ex vivo 3D cell culture assay.

BACKGROUND: Clinical outcomes in high-grade glioma (HGG) have remained relatively unchanged over the last 3 decades with only modest increases in overall survival. Despite the validation of biomarkers to classify treatment response, most newly diagnosed (ND) patients receive the same treatment regimen. This study aimed to determine whether a prospective functional assay that provides a direct, live tumor cell-based drug response prediction specific for each patient could accurately predict clinical drug response prior to treatment. METHODS: A modified 3D cell culture assay was validated to establish baseline parameters including drug concentrations, timing, and reproducibility. Live tumor tissue from HGG patients were tested in the assay to establish response parameters. Clinical correlation was determined between prospective ex vivo response and clinical response in ND HGG patients enrolled in 3D-PREDICT (ClinicalTrials.gov Identifier: NCT03561207). Clinical case studies were examined for relapsed HGG patients enrolled on 3D-PREDICT, prospectively assayed for ex vivo drug response, and monitored for follow-up. RESULTS: Absent biomarker stratification, the test accurately predicted clinical response/nonresponse to temozolomide in 17/20 (85%, P = .007) ND patients within 7 days of their surgery, prior to treatment initiation. Test-predicted responders had a median overall survival post-surgery of 11.6 months compared to 5.9 months for test-predicted nonresponders (P = .0376). Case studies provided examples of the clinical utility of the assay predictions and their impact upon treatment decisions resulting in positive clinical outcomes. CONCLUSION: This study both validates the developed assay analytically and clinically and provides case studies of its implementation in clinical practice.

Lateral Temporal Approach for Image-Guided Stereotactic Biopsy of Pineal Region Tumors.

BACKGROUND: Biopsy of pineal region neoplasms is frequently accomplished by way of endoscopic transventricular access or using an image-guided, computer-assisted stereotactic approach. METHODS: We evaluated a nonorthogonal lateral temporal approach for stereotactic biopsy of pineal region tumors as a variation of previously described stereotactic methods. Magnetic resonance imaging-guided frameless stereotaxy was used to plan and perform biopsies of pineal region tumors using a nonorthogonal trajectory extending from the superior or middle temporal gyri through the temporal stem, anterior to the atrium of the lateral ventricle, and posterior to the corticospinal tract. RESULTS: All patients had an uncomplicated postoperative course and remained at neurologic baseline. No parenchymal or ventricular hemorrhage was present on postoperative scans. A tissue diagnosis was obtained in all patients. CONCLUSIONS: This method appears to be a safe alternative to stereotactic biopsy using other trajectories and provides adequate tissue for definitive diagnosis.

Central Nervous System Cancers, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

The case for radiosurgery for brainstem metastases.

PURPOSE: To challenge the prevalent pessimism regarding the outcome of patients with metastases in the brainstem resulting in the use of whole brain radiation for palliation rather than stereotactic radiosurgery for definitive control and preservation of quality of life. We present our single institution review of the efficacy and safety of treating brainstem metastases aggressively with GKRS. METHODS: Forty-one patients with 45 total lesions treated with GKRS were included. Mean age was 58.7 years, ranging from 22 to 82. Tumor volumes were objectively calculated, treatment effects assessed on imaging and clinical data collected and correlated to the radiosurgical response. RESULTS: Mean survival after diagnosis of BSM was 11.6 months, ranging from 1.4 to 58.8 months. Margin dose ranged from 12 to 20 Gy. At first follow up, 11 (27%) patients had complete resolution of the treated lesion. At the second follow up 15 (37%) and third follow up 19 (46%) patients had a complete response. On average, there was a 64% decrease in tumor size at first follow up after treatment. 25 (61%) patients received WBRT in addition to radiosurgery; 16 (39%) received radiosurgery alone. There was no difference in overall survival between the two groups (p = 0.1324). ARE was seen in one patient who received  16 Gy to the margin of a 2.06 cm3 pontine tumor, but without correlative symptoms. One patient was treated with Bevacizumab® for progressive, but asymptomatic, edema following treatment that was not controlled by corticosteroids. CONCLUSIONS: Location in brainstem should not be a deterrent to the use of radiosurgery for these patients. The addition or exclusion of WBRT should be based on the clinical progression of the patient and within the limits of this study does not seem to impact overall survival. With improved survival as a result of better systemic therapy, these patients can benefit from better preservation of cognitive function by this strategy.

Fusarium species intramedullary spinal cord fungus ball: case report.

The Fusarium species are one of the most common opportunistic fungal infections occurring in immunocompromised patients and are associated with high morbidity and mortality. Common sites of infection include blood, skin, nasal passages, lungs, bone, and other visceral organs. There is a paucity of literature on Fusarium infections in the brain, and the true nature and extent of central nervous system involvement is not well described. To the authors' knowledge, there have been no reported cases of Fusarium infection of the spine. The authors report the case of a man with acute myeloblastic leukemia and resultant pancytopenia who presented with fungal sinusitis, upper- and lower-extremity weakness, and cardiopulmonary arrest. Imaging studies revealed a spinal cervical intramedullary ring-enhancing lesion. Because of the progressive nature of his symptoms, neurosurgical intervention involving a C2-3 laminectomy and drainage of the lesion was performed. Intraoperative cultures and histopathology results were positive for Fusarium species and, along with intraoperative findings, were consistent with a fungus ball. The patient was placed on a regimen of intravenous and intrathecal antifungal therapy. Unfortunately, his clinical condition declined postoperatively, and he ultimately died of disseminated infection.

Intracranial stereotactic radiosurgery.

Stereotactic radiosurgery (SRS) is the use of a single high dose of radiation, stereotactically directed to an intracranial region of interest, in order to create a lesion or obliterate a preexisting one. This technology has evolved over the years into the use of multiple radiation sources oriented at a variety of angles, thus permitting the creation of various treatment target shapes. This allows for non-open surgical treatment of intracranial pathologies, which significantly decreases the risk of morbidity. The destruction of pathological tissue following radiosurgery is a stepwise process that involves a number of different stages, beginning with the necrotic stage, followed by the resorption stage, and concluding with the glial scar formation stage. There are currently a number of different delivery methods of SRS, including linear accelerators, Gamma Knife units, and charged particle methods (Bragg-peak and plateau-beam). Various intracranial lesions exhibit different responses to radiosurgery; however, most lesions of appropriate size tend to respond favorably. Radiosurgery is used today in the treatment of brain metastases, meningiomas, vestibular schwannomas, sellar and suprasellar lesions, and arteriovenous malformations. SRS is widely used to treat functional conditions, such as trigeminal neuralgia and intractable tremor. The treatment of intracranial lesions with radiosurgery can result in undesirable effects on the adjacent normal brain, resulting in adverse radiation effects. The distinction between tumor progression and adverse radiation effects can be challenging but is aided by various imaging modalities. Treatment options for this condition include observation, corticosteroids, pentoxifylline and vitamin E, bevacizumab, laser-interstitial thermal therapy, and surgical resection.

The C7 pedicle as a superior fixation point in spinal stabilization for spinal metastatic disease.

Spinal metastatic disease (SMD) often requires spinal stabilization; however, the cervicothoracic junction can be a challenging area to instrument. An anterior approach may require division of the sternum. A posterior or posterolateral approach may rely on cervical lateral mass screws for superior construct fixation that are more prone to pullout than screws placed in a pedicle. The C7 pedicle is able to support pedicle screw fixation in most instances based on morphological features of the vertebra. When the C7 pedicle is used as a superior fixation point, it aligns with the thoracic pedicles below to create a streamlined posterior construct. In this study, patients undergoing posterior stabilization with C7 pedicle superior fixation were examined. One hundred and thirty-nine consecutive spinal operations at a National Cancer Institute designated cancer center were retrospectively reviewed to identify patients who underwent spinal stabilization for SMD with a C7 pedicle screw placed as the superior fixation point of a posterior construct. Patient age, the primary disease, and clinical and radiographic information were identified. Follow-up duration was noted, and follow-up outcomes were recorded on the basis of the clinical history and the findings on computed tomography (CT) spinal imaging. Three patients were identified who underwent separation surgery for SMD that included posterior spinal stabilization with C7 pedicle screws as the superior fixation point. The average patient age was 70 years and one patient was a woman. The average follow-up time was 20.7 months. There were no occurrences of hardware failure, neurologic deterioration, or protracted pain in the cases analyzed. Overall, there were good surgical outcomes with improvement in pain without neurovascular injury or evidence of hardware failure during follow-up evaluation. These findings add to a small but notable number of studies showing the effectiveness of C7 pedicle screws as a superior fixation point in spinal oncology, specifically in metastatic lesions. In our experience the C7 pedicle has provided a useful superior fixation point solution for the posterior stabilization of high thoracic vertebral body metastases. This surgical option may help spinal surgeons address the stabilization of SMD in the cervicothoracic region.

The effects of extinction-aroused attention on context conditioning.

Two experiments assessed the effects of extinguishing a conditioned cue on subsequent context conditioning. Each experiment used a different video-game method where sensors predicted attacking spaceships and participants responded to the sensor in a way that prepared them for the upcoming attack. In Experiment 1 extinction of a cue which signaled a spaceship-attack outcome facilitated subsequent learning when the attack occurred unsignaled. In Experiment 2 extinction of a cue facilitated subsequent learning, regardless of whether the spaceship outcome was the same or different as used in the earlier training. In neither experiment did the extinction context become inhibitory. Results are discussed in terms of current associative theories of attention and conditioning.

Instrumented Spinal Stabilization without Fusion for Spinal Metastatic Disease.

OBJECTIVES: Spinal stabilization surgery is an integral part of the treatment of spinal metastatic disease. Bony fusion is the hallmark of spinal stabilization in non-oncology patients. Spinal oncology patients are unlikely to achieve bony fusion because of their overall prognosis and concurrent therapies. Stabilization surgery without fusion may be a reasonable approach for these patients. Literature evaluating the effectiveness of this approach is limited. The object of this study was to investigate the rate of instrumentation failure in patients undergoing posterior spinal instrumented stabilization without fusion for spinal metastatic disease. METHODS: Data from consecutive cases of spinal surgery at our institution during an 81-month period were reviewed. Demographics, clinical notes, and computed tomography findings were recorded and used to evaluate instrumentation failures. Patients who underwent separation surgery that included laminectomy and posterior spinal instrumentation without fusion for spinal metastatic disease and had follow-up computed tomography scans >3 months postoperatively were selected for the study. RESULTS: Twenty-seven patients were included in the study. Mean age was 64.85 ± 6.53 years. Nine patients were women. A mean of 1.61 ± 0.96 laminectomy levels was performed. A mean of 8.26 ± 1.48 screws was inserted. The mean postoperative discharge date was 5.07 ± 1.47 days. Mean follow-up duration was 12.17 ± 11.73 months. None of the patients had a change in instrumentation position, pedicle screw pullout, change in spinal alignment, or progressive deformity. No patient required reoperation or instrumentation revision or replacement. CONCLUSIONS: Our experience suggests that instrumented spinal stabilization without fusion is an acceptable approach for patients with spinal metastatic disease.

Impact of the Number of Metastatic Tumors Treated by Stereotactic Radiosurgery on the Dose to Normal Brain: Implications for Brain Protection.

PURPOSE/OBJECTIVES: The purpose of this study was to evaluate the effect of the number of brain lesions for which stereotactic radiosurgery (SRS) was performed on the dose volume relationships in normal brain. MATERIALS AND METHODS: Brain tissue was segmented using the patient's pre-SRS MRI. For each plan, the following data points were recorded: total brain volume, number of lesions treated, volume of brain receiving 8 Gy (V8), V10, V12, and V15. RESULTS: A total of 225 Gamma Knife® treatments were included in this retrospective analysis. The number of lesions treated ranged from 1 to 29. The isodose for prescription ranged from 40 to 95% (mean 55%). The mean prescription dose to tumor edge was 18 Gy. The mean coverage, selectivity, conformity, and gradient index were 97.5%, 0.63, 0.56, and 3.5, respectively. The mean V12 was 9.5 cm3 (ranging from 0.5 to 59.29). There was no correlation between the number of lesions and brain V8, V12, V10, or V15. There was a direct and statistically significant relationship between the brain volume treated (V8, V10, V12, and V15) and total volume of tumors treated (p < 0.001). In our study, the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3. CONCLUSIONS: The number of metastatic brain lesions treated bears no significant relationship to total brain tissue volume treated when using SRS. The fact that the integral dose to the brain exceeded 3 J when the total tumor volume exceeded 25 cm3 is useful for establishing guidelines. Although standard practice has favored using whole brain radiation therapy in patients with more than 4 lesions, a significant amount of normal brain tissue may be spared by treating these patients with SRS. SRS should be carefully considered in patients with multiple brain lesions, with the emphasis on total brain volume involved rather than the number of lesions to be treated.

Comparison of Operative Time with Conventional Fluoroscopy Versus Spinal Neuronavigation in Instrumented Spinal Tumor Surgery.

OBJECTIVE: Spinal neuronavigation improves accuracy of pedicle screw placement but may increase operative time, and its use in oncologic operations remains relatively unstudied. We compared the use of two-dimensional (2D) fluoroscopy and three-dimensional (3D) spinal neuronavigation relative to operative time in instrumented oncology procedures. METHODS: Consecutive instrumented oncologic spinal operations for multiple myeloma or metastatic disease performed between 2012 and 2014 were retrospectively reviewed. Patients were placed in 2 groups based on the method used for pedicle screw placement: 2D fluoroscopy versus spinal neuronavigation with 3D imaging. These groups were compared by age, number of screws placed, number of laminectomy levels, operative time, estimated blood loss, length of hospital stay after surgery, and rate of reoperation as a result of screw misplacement. RESULTS: Fourteen operations used 2D fluoroscopy and 25 used spinal neuronavigation. In the fluoroscopy and neuronavigation groups, respectively, patient ages were 64.71 ± 7.21 years and 63.24 ± 6.95 years (P = 0.534), number of screws was 8.07 ± 1.98 and 7.84 ± 1.34 (P = 0.667), laminectomy levels were 2.18 ± 1.25 and 1.60 ± 1.02 (P = 0.126), operative time was 200.79 ± 34.99 minutes and 193.48 ± 43.77 minutes (P = 0.596), estimated blood loss was 790.00 ± 769.61 mL and 389.80 ± 551.43 mL (P = 0.068), and length of stay after the operation was 7.64 ± 4.63 days and 6.40 ± 3.23 days (P = 0.331). One patient in the 2D fluoroscopy group and no patients in the spinal neuronavigation group required a reoperation for screw misplacement. CONCLUSIONS: There was no significant difference in length of operative time when neuronavigation was compared with fluoroscopy for instrumented oncologic spinal surgery. There was a trend toward a decrease in estimated blood loss in the neuronavigation cases.