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.

Meta-analysis of overall survival and postoperative neurologic deficits after resection or biopsy of butterfly glioblastoma.

Butterfly glioblastoma (bGBM) is a grade 4 glioma with a poor prognosis. Surgical treatment of these cancers has been reviewed in the literature with some recent studies supporting resection as a safe and effective treatment instead of biopsy and adjuvant therapy. This meta-analysis was designed to determine whether there are significant differences in overall survival (OS) and postoperative neurologic deficits (motor, speech, and cranial nerve) following intervention in patients who underwent tumor resection as part of their treatment, compared to patients who underwent biopsy without surgical resection. A literature search was conducted using PubMed (National Library of Medicine) and Embase (Elsevier) to identify articles from each database's earliest records to May 25, 2021, that directly compared the outcomes of biopsy and resection in bGBM patients and met predetermined inclusion criteria. A meta-analysis was conducted to compare the effects of the two management strategies on OS and postoperative neurologic deficits. Six articles met our study inclusion criteria. OS was found to be significantly longer for the resection group at 6 months (odds ratio [OR] 2.94, 95% confidence interval [CI] 1.23-7.05) and 12 months (OR 3.75, 95% CI 1.10-12.76) than for the biopsy group. No statistically significant differences were found in OS at 18 and 24 months. Resection was associated with an increased rate of postoperative neurologic deficit (OR 2.05, 95% CI 1.02-4.09). Resection offers greater OS up to 1 year postintervention than biopsy alone; however, this comes at the cost of higher rates of postoperative neurologic deficits.

Incidence trends and survival analysis of atypical meningiomas: a population-based study from 2004 to 2018.

PURPOSE: Atypical meningiomas have histologic and clinical features that fall between those for benign and malignant meningiomas. The incidence of atypical meningiomas has not been well studied with respect to changes in the World Health Organization (WHO) classification scheme over time. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was queried to obtain data from 2004 to 2018 for patients with all meningiomas, including atypical. Age-adjusted incidence rates were generated and annual percent change (APC) in the incidence rates was calculated with joinpoint regression. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A total of 4476 patients diagnosed with meningioma were identified from the SEER 18 registries. The incidence of atypical meningioma increased at an APC of 5.6% [95% confidence interval [CI], 3.4-7.8]; significantly faster than all meningiomas, which rose at an APC of 2.5% (95%CI 1.8-3.1;p = 0.008). For atypical meningiomas, the 1, 3, 5, and 10-year survival rates were 91.9%, 81.3%, 68.8%, and 34.3%, respectively. Male sex, older age (≥ 60 years), and large tumor size (> 5 cm) were independent risk factors for an unfavorable prognosis. CONCLUSIONS: The incidence of atypical meningioma was observed to be increasing relative to all meningiomas. It is important to diligently monitor atypical meningioma incidence and mortality rates over time to see whether observed uptrends persist. Continued effort toward improving outcomes in patients with atypical meningiomas is warranted, especially in light of an apparent rise in incidence.

Intrathecal Baclofen for Severe Spasticity: Longitudinal Data From the Product Surveillance Registry.

OBJECTIVE: To assist in the assessment of intrathecal baclofen (ITB) therapy risks and benefits by providing surgical intervention rate, safety, and elective device replacement rate data. MATERIALS AND METHODS: An ongoing prospective, long-term, multicenter Product Surveillance Registry (PSR) (NCT01524276) enrolled consented patients implanted with the SynchroMed II infusion system. Pump and catheter performance data were collected, with patients followed prospectively for events related to the device, procedure, and therapy. Investigators provided event descriptions, patient symptoms, and patient outcomes. RESULTS: We analyzed registry data from 1743 patients (77% adult, 46.8% female) treated with ITB for severe spasticity at 53 registry sites between August 2003 and October 2017, for an accumulated 6481 patient-years. Discontinuation from the registry was largely (58.6% of discontinued patients) due to study site closure and patient relocation; exit due to an adverse event was limited to 0.3%. After 10 years, 87.2% of adult and 76.3% of pediatric patients continued with ITB. Overall, 99.1% of pumps reaching end of battery life were replaced at the time of explant. CONCLUSIONS: ITB therapy for the treatment of severe spasticity requires surgical implantation of a programmable infusion system for chronic drug delivery. If complications arise, many necessitate surgical intervention for correction. For spinal and cerebral spasticity in pediatric and adult patients, discontinuation rates due to an adverse event were low (0.3%), and there was high acceptance (99.1%) of surgical intervention for therapy continuation. Patient/caregiver willingness to accept surgical and other risks for therapy continuation was extremely high.

Do brain mets grow while you wait? A volumetric natural history assessment of brain metastases from time of diagnosis to gamma knife treatment.

Brain metastasis (BM) is a common neurologic complication of cancers such as lung, breast, and melanoma. Recently, there has been a shift in treatment of BM from whole brain radiation therapy to stereotactic radiosurgery (SRS) and the success is dependent on tumor volume. While most metastases grow over time, data on growth rate is lacking. Therefore, we document volume changes of metastases before treatment. We retrospectively reviewed MRI imaging records of 82 patients with a total of 294 BMs, treated in our cancer center by one neurosurgeon and one radiation oncologist with Gamma Knife SRS over a three-year period. We measured tumor volume at the time of diagnosis and compared with tumor volume on the day of treatment. Volumes were compared using the Wilcoxon signed-rank test. Lung, melanoma and breast made up the majority of metastases diagnosed. More than 75% of tumors grew and these changes in volume and percent changes in volume were statistically significant. Thirty percent of tumors doubled in size before treatment. Patients with the largest mean pretreatment tumor size were urgently treated within 6 days, yet still demonstrated the largest change in volume. This study is one of the first to document volume changes of brain metastases from the time of diagnosis to SRS treatment. Our results indicate that brain metastases can grow rapidly and it is imperative that we streamline patient management processes to minimize delays in treating patients with SRS, since outcomes are dependent on tumor size.

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.

An Evaluation of the ICON® Mask Fixation: Curing Characteristics of the Thermoplastic Fixation and Implications for Patient Workflow.

BACKGROUND: Thermoplastic mask immobilization is used to perform hypo-fractionated treatments with the Gamma Knife ICON®. MATERIALS AND METHODS: We evaluated the curing characteristics of the ICON® Nanor mask using force sensing resistors coupled with a data logging tool designed by us. RESULTS: For patients being treated with masks made the same day as the treatment, often in the same sitting with no removal and replacement of the patient from the treatment cradle, based on the curves 80% of the force of fixation is reached at 30 minutes. CONCLUSIONS: Allowing for curing over 10-15 minutes and the subsequent localizing and delivery Cone beam CT (CBCT)s as well as the plan evaluation this is a reasonable time to start of therapy. For more exacting targets that are still requiring hypo-fractionation a cure period of 15 hours or greater will ensure that maximum rigidity of fixation is achieved.

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.

Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma.

Background: The survival rate for patients with glioblastoma (GBM) remains dismal. New therapies targeting molecular pathways dysregulated in GBM are needed. One such clinical-stage drug candidate, CBL0137, is a curaxin, small molecules which simultaneously downregulate nuclear factor-kappaB (NF-ĸB) and activate p53 by inactivating the chromatin remodeling complex, Facilitates Chromatin Transcription (FACT). Methods: We used publicly available databases to establish levels of FACT subunit expression in GBM. In vitro, we evaluated the toxicity and effect of CBL0137 on FACT, p53, and NF-ĸB on U87MG and A1207 human GBM cells. In vivo, we implanted the cells orthotopically in nude mice and administered CBL0137 in various dosing regimens to assess brain and tumor accumulation of CBL0137, its effect on tumor cell proliferation and apoptosis, and on survival of mice with and without temozolomide (TMZ). Results: FACT subunit expression was elevated in GBM compared with normal brain. CBL0137 induced loss of chromatin-unbound FACT, activated p53, inhibited NF-ĸB-dependent transcription, and was toxic to GBM cells. The drug penetrated the blood-brain barrier and accumulated in orthotopic tumors significantly more than normal brain tissue. It increased apoptosis and suppressed proliferation in both U87MG and A1207 tumors. Intravenous administration of CBL0137 significantly increased survival in models of early- through late-stage TMZ-responsive and -resistant GBM, with a trend toward significantly increasing the effect of TMZ in TMZ-responsive U87MG tumors. Conclusion: CBL0137 targets GBM according to its proposed mechanism of action, crosses the blood-brain barrier, and is efficacious in both TMZ-responsive and -resistant orthotopic models, making it an attractive new therapy for GBM.

Clinical outcomes in patients with brain metastases from breast cancer treated with single-session radiosurgery or whole brain radiotherapy.

OBJECTIVE Gamma Knife radiosurgery (GKRS) is used to treat brain metastases from breast cancer (BMB) as the sole treatment or in conjunction with tumor resection and/or whole brain radiotherapy (WBRT). This study evaluates outcomes in BMB based on treatment techniques and tumor biological features. METHODS The authors reviewed all patients treated with BMB between 2004 and 2014. Patients were identified from a prospectively collected radiosurgery database and institutional tumor registry; 214 patients were identified. Data were collected from aforementioned sources and supplemented with chart review where needed. Independent radiological review was performed for all available brain imaging in those treated with GKRS. Survival analyses are reported using Kaplan-Meier estimates. RESULTS During the 10-year study period, 214 patients with BMB were treated; 23% underwent GKRS alone, 46% underwent a combination of GKRS and WBRT, and 31% underwent WBRT alone. Median survival after diagnosis of BMB in those treated with GKRS alone was 21 months, and in those who received WBRT alone it was 3 months. In those treated with GKRS plus WBRT, no significant difference in median survival was observed between those receiving WBRT upfront or in a salvage setting following GKRS (19 months vs 14 months, p = 0.63). The median survival of patients with total metastatic tumor volume of ≤ 7 cm3 versus > 7 cm3 was 20 months vs 7 months (p < 0.001). Human epidermal growth factor receptor-2 (Her-2) positively impacted survival after diagnosis of BMB (19 months vs 12 months, p = 0.03). Estrogen receptor status did not influence survival after diagnosis of BMB. No difference was observed in survival after diagnosis of BMB based on receptor status in those who received WBRT alone. CONCLUSIONS In this single-institution series of BMB, the addition of WBRT to GKRS did not significantly influence survival, nor did the number of lesions treated with GKRS. Survival after the diagnosis of BMB was most strongly affected by Her-2 positivity and total metastatic tumor volume.

Intrathecal Drug Delivery Systems (IDDS): The Implantable Systems Performance Registry (ISPR).

OBJECTIVES: The ISPR was initially created to monitor the product performance of Medtronic implanted intrathecal drug infusion and spinal cord systems available in the United States. MATERIALS AND METHODS: Data were collected from 50 representative sites implanting and following patients with intrathecal drug delivery systems across the United States between August 7, 2003 and January 31, 2014. Device performance over time was estimated using life table survival methods. RESULTS: Of the 6093 patients enrolled in the ISPR, 3405 (55.9%) were female and 2675 (43.9%) were male, and 13 (0.2%) did not provide gender data. The average age at enrollment was 52.9 years (SD =17.6 years) and average follow-up time was 29.6 months. Currently, the estimates of device survival from pump-related events exceed 90% for all pump models across the applicable follow-up time points. The majority of product performance events were catheter-related. At 5 years of follow-up, all applicable catheter models, with the exception of revised not as designed or grafted not as designed catheters, had greater than 81% survival from catheter-related events. CONCLUSIONS: The ISPR is designed to serve as an ongoing source of system and device-related information with a focus on "real-world" safety and product performance. ISPR data continue to be used to guide future product development efforts aimed at improving product reliability and quality.

A murine model of targeted infusion for intracranial tumors.

Historically, intra-arterial (IA) drug administration for malignant brain tumors including glioblastoma multiforme (GBM) was performed as an attempt to improve drug delivery. With the advent of percutaneous neuorovascular techniques and modern microcatheters, intracranial drug delivery is readily feasible; however, the question remains whether IA administration is safe and more effective compared to other delivery modalities such as intravenous (IV) or oral administrations. Preclinical large animal models allow for comparisons between treatment routes and to test novel agents, but can be expensive and difficult to generate large numbers and rapid results. Accordingly, we developed a murine model of IA drug delivery for GBM that is reproducible with clear readouts of tumor response and neurotoxicities. Herein, we describe a novel mouse model of IA drug delivery accessing the internal carotid artery to treat ipsilateral implanted GBM tumors that is consistent and reproducible with minimal experience. The intent of establishing this unique platform is to efficiently interrogate targeted anti-tumor agents that may be designed to take advantage of a directed, regional therapy approach for brain tumors.

Intrathecal baclofen in multiple sclerosis: too little, too late?

The majority of patients with multiple sclerosis (MS) have symptoms of spasticity that increasingly impair function as the disease progresses. With appropriate treatment, however, quality of life can be improved. Oral antispasticity medications are useful in managing mild spasticity but are frequently ineffective in controlling moderate to severe spasticity, because patients often cannot tolerate the adverse effects of increasing doses. Intrathecal baclofen (ITB) therapy can be an effective alternative to oral medications in patients who have a suboptimal response to oral medications or who cannot tolerate dose escalation or multidrug oral regimens. ITB therapy may be underutilized in the MS population because clinicians (a) are more focused on disease-modifying therapies rather than symptom control, (b) underestimate the impact of spasticity on quality of life, and (c) have concerns about the cost and safety of ITB therapy. Delivery of ITB therapy requires expertly trained staff and proper facilities for pump management. This article summarizes the findings and recommendations of an expert panel on the use of ITB therapy in the MS population and the role of the physician and comprehensive care team in patient selection, screening, and management.

Experimental model and immunohistochemical comparison of U87 human glioblastoma cell xenografts on the chicken chorioallantoic membrane and in rat brains.

BACKGROUND: To study the neuropathology and selected tumour markers of malignant gliomas, an animal glioma model was developed using the implantation of U87 human glioblastoma cells into chick chorioallantoic membrane. The immunohistochemical characteristics were studied and compared with an orthotopic rodent model. MATERIALS AND METHODS: The U87 cell suspension was inoculated onto the chick chorioallantoic membrane on embryonic day seven and into the brain of nude rats. Brain tumour sections were examined for various known tumour markers by routine haematoxylin and eosin staining and immunohistochemical analyses. RESULTS: The immunohistochemical analyses showed that S100 protein, glial fibrillary acidic protein and synaptophysin expressions, initially present in tissue culture, were lost in both models. Persistent kallikrein, CD68 and vimentin expressions in U87 cells, as well as in both animal tumour models, were detected. The percentage of p53-positive nuclei, which was higher in the tumours grown on the chick chorioallantoic membrane than in rats, did not correlate with the Ki-67 labelling index. Strong cathepsin expression was maintained from the cell culture to both tumour models. CD3-positive cells and numerous leukocytes, but no CD20-positive cells were detected in any of the animal samples, indicating the immunological response of the host to be primarily cellular. Stronger immune reaction for vascular endothelial growth factor in rats correlated with an observed increase in vascular proliferation in these tumours. CONCLUSION: A simple, fast-growing, cheap and well-defined chick chorioallantoic membrane model of glioma was established, providing a basis for further experimental studies of genetic and protein expression during human glioma tumourigenesis. This model may possibly replace some rodent models for selective studies.

Neurite outgrowth from PC12 cells is enhanced by an inhibitor of mechanical channels.

GsMTx4, a peptide inhibitor for mechanosensitive ion channels (MSCs), promoted neurite outgrowth from PC12 cells in the presence of NGF in a dose-dependent manner between 5 and 100 microM peptide. Enhanced neurite growth required >12 h of peptide exposure in cells grown with NGF. Adsorption of GsMTx4 to serum proteins in the media lowered the free peptide concentration of 100 microM to a free concentration of 5 microM, a concentration shown to completely inhibit MSCs in the patch clamp assay. Outside-out patches from PC12 cells grown in NGF had mechanically activated cation channels that were reversibly inhibited by GsMTx4. These results are similar to those observed by Gomez and co-workers in Xenopus spinal cord. The inhibition of mechanosensitive channels by GsMTx4 may be a useful approach to accelerate regeneration of neurons in neurodegenerative diseases and spinal cord injury.

Approach for tunneling the lead in deep brain stimulation.

The implantation of a deep brain stimulator (DBS) is often a staged procedure that involves stereotactic placement of the neurostimulator electrode, followed by connection of the electrode to a pulse generator during a separate operation. The authors describe a practical technique for the retrograde tunneling of the stimulator lead during the initial electrode implantation procedure. After DBS electrode placement and securing of the lead, the lead is covered with a protective cap and boot, which are then folded back to tunnel a redundant loop of the lead in a retrograde fashion into a subgaleal pocket. This technique facilitates connection of the lead to the pulse generator connecting wire at the subsequent operation and may reduce lead damage.

Estrogen increases survival in an orthotopic model of glioblastoma.

Despite the male preponderance for developing glial tumors and a body of published literature that suggests a female gender advantage for long term survival in both human and animal studies, there have been relatively few rigorous investigations into the hormonal effects on glial tumor growth. In a previous study, we concluded that estrogen played a major role in the female survival bias seen in an intracerebral nude rat model of glioblastoma multiforme. Here we explore the potential therapeutic effect of exogenous estradiol delivery in nude rats with orthotopic glioblastoma tumors and examine the mechanism of action of estradiol on reducing tumor growth in this animal model. We administered estradiol, in several dosing regimens, to male, female and ovariectomized nude rats in a survival study. Brain sections, taken at various time points in tumor progression, were analyzed for estrogen receptor protein, proliferative index and apoptotic index. Estradiol increased survival of male, female and ovariectomized nude rats with intracerebral U87MG tumors, in a gender specific manner. The estradiol mediated effect occurred early in tumor progression, and appeared to be caused in-part by an increase in apoptotic activity. It remains unclear if estradiol's effect is direct or indirect and if it is estrogen receptor mediated. Estradiol-based or adjunctive therapy may be beneficial in treating GBM and further study is clearly warranted.

Distal baclofen pump catheter migration associated with far-lateral paraspinal surgical placement.

Objectives. The increased rigidity and spasms implicit to patients being treated with baclofen provide a potential source of drug delivery system-related complications. Placement of the intrathecal catheter from the far-lateral paraspinal approach has been advocated to avoid catheter fracture as previously reported with a midline approach. A thin fascial layer and increased muscle bulk laterally could increase motion of catheters placed in this position. The authors report on a series of patients found to have spinal catheter migration out from the thecal sac following a far-lateral paraspinal surgical approach. Materials and Methods. The medical records of six consecutive patients who required revision of an intrathecal baclofen infusion system secondary to spinal catheter migration were included in this retrospective review. Each patient failed to respond to oral antispasmodic therapy and showed a positive response to a trial of intrathecal baclofen before initial pump implantation. Clinical notes and operative reports were reviewed. Results. All patients had a baclofen pump inserted with the intrathecal catheter placed through the far-lateral portion of the paraspinal musculature entering above the lumbar vertebral pedicle. In all cases, the spinal catheter migrated and was found coiled outside of the thecal sac. In two patients, this occurred on two separate occasions. Mean time to catheter revision following implantation was 7 ± 2 months. Conclusions. Spinal catheter migration from the subarachnoid space can occur with intrathecal baclofen infusion systems. Alternative methods for spinal catheter placement warrant further study.