Intradural extramedullary spinal metastasis of renal cell carcinoma: illustrative case report and comprehensive review of the literature.

STUDY DESIGN: Literature review. OBJECTIVES: Intradural metastasis of renal cell carcinoma (RCC) has rarely been reported. We describe a case of an intradural extramedullary spinal metastasis to the cervical spine in a 68-year-old male treated for RCC 22 years prior. Additionally, we review the known reports of both intradural extramedullary and intramedullary of RCC. METHODS: Case report and literature review. RESULTS: A 68-year-old male with a history of right-sided nephrectomy for RCC preformed 22 years prior now presents with a MRI of the cervical spine showing a 1.5 cm contrast enhancing intradural extramedullary lesion at the level of C3-C4. Surgical resection of the lesion was performed. The tumor's histological and immunohistochemical profile was consistent with metastatic RCC. There are 18 reported cases of intradural extramedullary metastases of sporadic RCC. The average age at diagnosis was 61.6 ± 14.3 years. The interval from diagnosis of primary RCC to diagnosis metastasis ranged from 0 to 264 months (mean 46.8 ± 74.0 months). Sixteen cases of intramedullary renal cell carcinoma metastasis are reported. The average age at time of diagnosis was 53.6 ± 10.2 years. The interval from diagnosis of primary RCC to diagnosis of metastasis ranged from 0 to 180 months (mean 20.9 ± 53.4 months). CONCLUSION: The 22-year interval from diagnosis of primary RCC to intradural metastasis is the longest latency reported in the literature. Intramedullary metastases tend to have a younger age at diagnosis and shorter interval from diagnosis of primary RCC compared to extramedullary lesions.

Radiographic Trends for Infield Recurrence After Radiosurgery for Cerebral Metastases.

Objective Recurrence following stereotactic radiosurgery (SRS) for the treatment of cerebral metastases is not uncommon. Recurrence can represent recurrent tumor and/or radiation necrosis. The radiographic response to Gamma Knife (GK) treatment is variable with some remaining stable, some decreasing in size, some increasing in size, while some may show a combination of all three. For tumors that demonstrate progression on MRI, the question to intervene with additional surgical or radiation therapy and the timing of such intervention remains debatable. In this study, we retrospectively reviewed surveillance MRIs of post-GK cerebral metastases to determine if radiographic trends are a predictor of infield progression. Methods A retrospective review of cerebral metastases treated with GK radiosurgery with at least two consecutive post-GK MRI scans was performed. Infield progression was defined by new enhancement increased by at least 25% in two out of three dimensions on two consecutive scans. Primary endpoints for infield recurrence were either continued observation, therapeutic intervention, or withdrawal of care.  Results A total of 579 cerebral metastases were treated with GK radiosurgery. A total of 123 metastases demonstrated radiographic progression on one follow-up MRI scan. Of those, 75% demonstrated continued progression follow-up imaging, while 25% stabilized or regressed. For post-GK metastases demonstrating progression on two consecutive MRI scans, 85% of lesions continued to progress, whereas only 15% demonstrated stabilization or regression. A total of 91% of lesions either require intervention or demonstrate continued progression with observation at this timepoint. Cumulatively 100% of metastases with radiographic progression on ≥3 consecutive MRIs went on to need further intervention. Conclusion Approximately one-fourth of infield recurrence demonstrating progression on the first surveillance MRI will stabilize or regress. Those demonstrating infield progression on two consecutive MRI scans should be considered treatment failures. Early interventions before tumor volume increases in size or patients require high-dose steroids maybe beneficial.

Teaching an Old Drug New Tricks: Dexamethasone as an In Vivo Inhibitor of Glioblastoma Dispersal.

Identifying drugs that can mitigate dispersal of glioblastoma cells, particularly after patients undergo radiotherapy and concomitant chemotherapy, may increase the length of time to recurrence and improve overall survival. Previous studies have shown that dexamethasone (Dex), a drug currently used to treat brain tumor-related edema, which is tapered immediately after the edema has resolved, induces fibronectin matrix assembly (FNMA) and reduces dispersal of primary human glioblastoma multiforme (GBM) cells in vitro and ex vivo. Here, we utilized an in vivo mouse retina dispersal assay to demonstrate that Dex also inhibits dispersal in vivo. We show that 1) Dex significantly reduces z-axis penetration of glioblastoma cells into mouse retina; 2) treatment alters the morphology of dispersal; 3) without Dex, the presence of fibronectin increases dispersal; 4) treatment activates in vivo FNMA by glioblastoma cells, leading to the containment of the tumor mass; and 5) Dex-mediated activation of FNMA is fibronectin dose-dependent. Dispersal inhibition could be achieved at human equivalent doses as low as 1 mg/day, a dose significantly lower than currently used to reduce edema. This is the first step towards future studies in which patients can be potentially maintained on low-dose dexamethasone therapy with the aim of increasing the time between initial resection and recurrence.

Delayed-Onset Cyst Formation After Laser Interstitial Thermal Therapy: Unreported Long-Term Complication.

BACKGROUND: The majority of complications following (LITT) therapy occur in the early postoperative period, with few long-term complications being reported. CASE DESCRIPTION: Here we present 2 cases of delayed-onset cyst formation occurring more than 1 year following ablation, a previously unreported complication. In the first case, a 59-year-old female who previously underwent LITT for a radiation-induced cavernoma developed a 2-cm cystic lesion 18 months after ablation, resulting in recurrent seizures. In the second case, a 53-year-old female with a recurrent left frontal cerebral metastasis developed a large cystic lesion 30 months post ablation. Both patients required craniotomies and resection of their cystic lesions. In both cases pathology demonstrated reactive gliosis and blood vessel sclerosis. CONCLUSIONS: We hypothesize chronic gliosis following LITT therapy results in blood vessel sclerosis leading to blood-brain barrier-breakdown and delayed cyst formation. These findings support the need for long-term surveillance of patients treated with LITT.

Magnetic Resonance-Guided Laser-Induced Thermal Therapy for the Treatment of Progressive Enhancing Inflammatory Reactions Following Stereotactic Radiosurgery, or PEIRs, for Metastatic Brain Disease.

BACKGROUND: In patients who have previously undergone maximum radiation for metastatic brain tumors, a progressive enhancing inflammatory reaction (PEIR) that represents either tumor recurrence or radiation necrosis, or a combination of both, can occur. Magnetic resonance-guided laser-induced thermal therapy (LITT) offers a minimally invasive treatment option for this problem. OBJECTIVE: To report our single-center experience using LITT to treat PEIRs after radiosurgery for brain metastases. METHODS: Patients with progressive, enhancing reactions at the site of prior radiosurgery for metastatic brain tumors and who had a Karnofsky performance status of ≥70 were eligible for LITT. The primary endpoint was local control. Secondary end points included dexamethasone use and procedure-related complications. RESULTS: Between 2010 and 2017, 59 patients who underwent 74 LITT procedures for 74 PEIRs met inclusion criteria. The mean pre-LITT PEIR size measured 3.4 ± 0.4 cm3. At a median follow-up of 44.6 wk post-LITT, the local control rate was 83.1%. Most patients were weaned off steroids post-LITT. Patients experiencing a post-LITT complication were more likely to remain on steroids indefinitely. The rate of new permanent neurological deficit was 3.4%. CONCLUSION: LITT is an effective treatment for local control of PEIRs after radiosurgery for metastatic brain disease. When possible, we recommend offering LITT once PEIRs are identified and prior to the initiation of high-dose steroids for symptom relief.

Isolated Abducens Nerve Palsy Associated with Ruptured Posterior Inferior Cerebellar Artery Aneurysm: Rare Neurologic Finding.

BACKGROUND: Isolated abducens nerve palsy can be the presenting sign of a ruptured PICA aneurysm. Few cases have been reported in the literature. In the majority of cases, cranial nerve VI resolved following microsurgical clipping. CASE DESCRIPTION: Here, we report a 56-year-old female who presented with a ruptured 4 mm × 3 mm left PICA aneurysm associated with a left abducens nerve palsy. The patient underwent endovascular coil embolization of the aneurysm and had complete resolution of her abducens nerve palsy. CONCLUSIONS: Here, we present the first case of an abducens nerve palsy associated with a ruptured PICA aneurysm to completely resolve following endovascular coil embolization. The direction and amount of subarachnoid hemorrhage extravasation from the ruptured aneurysm are most likely responsible for cranial nerve palsy.

Assessment of motion error for frame-based and noninvasive mask-based fixation using the Leksell Gamma Knife Icon radiosurgery system.

OBJECTIVEThe Leksell Gamma Knife Icon (GK Icon) radiosurgery system can utilize cone-beam computed tomography (CBCT) to evaluate motion error. This study compares the accuracy of frame-based and frameless mask-based fixation using the Icon system.METHODSA retrospective cohort study was conducted to evaluate patients who had undergone radiosurgery with the GK Icon system between June and December 2017. Patients were immobilized in either a stereotactic head frame or a noninvasive thermoplastic mask with stereotactic infrared (IR) camera monitoring. Setup error was defined as displacement of the skull in the stereotactic space upon setup as noted on pretreatment CBCT compared to its position in the stereotactic space defined by planning MRI for frame patients and defined as skull displacement on planning CBCT compared to its position on pretreatment CBCT for mask patients. For frame patients, the intrafractionation motion was measured by comparing pretreatment and posttreatment CBCT. For mask patients, the intrafractionation motion was evaluated by comparing pretreatment CBCT and additional CBCT obtained during the treatment. The translational and rotational errors were recorded.RESULTSData were collected from 77 patients undergoing SRS with the GK Icon. Sixty-four patients underwent frame fixation, with pre- and posttreatment CBCT studies obtained. Thirteen patients were treated using mask fixation to deliver a total of 33 treatment fractions. Mean setup and intrafraction translational and rotation errors were small for both fixation systems, within 1 mm and 1° in all axes. Yet mask fixation demonstrated significantly larger intrafraction errors than frame fixation. Also, there was greater variability in both setup and intrafraction errors for mask fixation than for frame fixation in all translational and rotational directions. Whether the GK treatment was for metastasis or nonmetastasis did not influence motion uncertainties between the two fixation types. Additionally, monitoring IR-based intrafraction motion for mask fixation-i.e., the number of treatment stoppages due to reaching the IR displacement threshold-correlated with increasing treatment time.CONCLUSIONSCompared to frame-based fixation, mask-based fixation demonstrated larger motion variations. The variability in motion error associated with mask fixation must be taken into account when planning for small lesions or lesions near critical structures.

Volumetric Trends Associated with MR-guided Stereotactic Laser Amygdalohippocampectomy in Mesial Temporal Lobe Epilepsy.

OBJECTIVE: Magnetic resonance (MR)-guided stereotactic laser amygdalohippocampectomy is a minimally invasive procedure for the treatment of refractory epilepsy in patients with mesial temporal sclerosis. Limited data exist on post-ablation volumetric trends associated with the procedure. METHODS: 10 patients with mesial temporal sclerosis underwent MR-guided stereotactic laser amygdalohippocampectomy. Three independent raters computed ablation volumes at the following time points: pre-ablation (PreA), immediate post-ablation (IPA), 24 hours post-ablation (24PA), first follow-up post-ablation (FPA), and greater than three months follow-up post-ablation (>3MPA), using OsiriX DICOM Viewer (Pixmeo, Bernex, Switzerland). Statistical trends in post-ablation volumes were determined for the time points. RESULTS: MR-guided stereotactic laser amygdalohippocampectomy produces a rapid rise and distinct peak in post-ablation volume immediately following the procedure. IPA volumes are significantly higher than all other time points. Comparing individual time points within each raters dataset (intra-rater), a significant difference was seen between the IPA time point and all others. There was no statistical difference between the 24PA, FPA, and >3MPA time points. A correlation analysis demonstrated the strongest correlations at the 24PA (r=0.97), FPA (r=0.95), and 3MPA time points (r=0.99), with a weaker correlation at IPA (r=0.92). CONCLUSION: MR-guided stereotactic laser amygdalohippocampectomy produces a maximal increase in post-ablation volume immediately following the procedure, which decreases and stabilizes at 24 hours post-procedure and beyond three months follow-up. Based on the correlation analysis, the lower inter-rater reliability at the IPA time point suggests it may be less accurate to assess volume at this time point. We recommend post-ablation volume assessments be made at least 24 hours post-selective ablation of the amygdalohippocampal complex (SLAH).

Direct Midline Posterior Corpectomy and Fusion of a Lumbar Burst Fracture with Retrospondyloptosis.

BACKGROUND: Traumatic burst fractures of the lumbar spine can result in significant neurologic injury and mechanical instability. The ideal surgical approach for the treatment of unstable lumbar spine burst fractures remains debatable. CASE DESCRIPTION: A 37-year-old man presented with severe neurologic injury including loss of motor function below the level of the iliopsoas muscles bilaterally, saddle anesthesia, and absent rectal tone, after a fall from 18.28 m (60 ft). Computed tomography showed an L4 vertebral body comminuted burst fracture with complete posterior translation of L4 over L5. The patient was taken to the operating room for an L4 corpectomy and L2-S1 posterior fusion. The L4 vertebral body was visualized posterior to the posterior elements of L5 and resected in a piecemeal fashion. Because the thecal sac had been completely transected, a visible path down the L3-L4 and L4-L5 disk spaces was apparent, allowing direct posterior discectomies at these levels and completion of the L4 segment resection. The use of a direct posterior approach resulted in minimal blood loss, correction of sagittal alignment, and satisfactory outcomes comparable with the standard posterior transpedicular approach. Construct stability and solid bony fusion have been maintained for 4 years postoperatively. CONCLUSIONS: The use of a direct midline posterior corpectomy approach may be considered for patients with lumbar burst fractures, high-grade neurologic injury, and transection of the thecal sac.

OUTCOME OF IMPLEMENTATION OF A MULTIDISCIPLINARY TEAM APPROACH TO THE CARE OF PATIENTS AFTER TRANSSPHENOIDAL SURGERY.

OBJECTIVE: Transsphenoidal surgery (TS) for sellar lesions is an established and safe procedure, but complications can occur, particularly involving the neuroendocrine system. We hypothesized that postoperative care of TS patients would be optimized when performed by a coordinated team including a pituitary neurosurgeon, endocrinologists, and a specialty nurse. METHODS: We implemented a formalized, multidisciplinary team approach and standardized postoperative protocols for the care of adult patients undergoing TS by a single surgeon (J.N.B.) at our institution beginning in July 2009. We retrospectively compared the outcomes of 214 consecutive TS-treated cases: 113 cases prior to and 101 following the initiation of the team approach and protocol implementation. Outcomes assessed included the incidence of neurosurgical and endocrine complications, length of stay (LOS), and rates of hospital readmission and unscheduled clinical visits. RESULTS: The median LOS decreased from 3 days preteam to 2 days postteam (P<.01). Discharge occurred on postoperative day 2 in 46% of the preteam group patients compared to 69% of the postteam group (P<.01). Rates of early postoperative diabetes insipidus (DI) and readmissions within 30 days for syndrome of inappropriate antidiuretic hormone (SIADH) or other complications did not differ between groups. CONCLUSION: Implementation of a multidisciplinary team approach was associated with a reduction of LOS. Despite earlier discharge, postoperative outcomes were not compromised. The endocrinologist is central to the success of this team approach, which could be successfully applied to care of patients undergoing TS, as well as other types of endocrine surgery at other centers.

Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma.

BACKGROUND: Glioblastoma subtypes have been defined based on transcriptional profiling, yet personalized care based on molecular classification remains unexploited. Topoisomerase II (TOP2) contributes to the transcriptional signature of the proneural glioma subtype. Thus, we targeted TOP2 pharmacologically with etoposide in proneural glioma models. METHODS: TOP2 gene expression was evaluated in mouse platelet derived growth factor (PDGF)(+)phosphatase and tensin homolog (PTEN)(-/-)p53(-/-) and PDGF(+)PTEN(-/-) proneural gliomas and cell lines, as well as human glioblastoma from The Cancer Genome Atlas. Correlation between TOP2 transcript levels and etoposide susceptibility was investigated in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia public dataset and in mouse proneural glioma cell lines. Convection-enhanced delivery (CED) of etoposide was tested on cell-based PDGF(+)PTEN(-/-)p53(-/-) and retroviral-based PDGF(+)PTEN(-/-) mouse proneural glioma models. RESULTS: TOP2 expression was significantly higher in human proneural glioblastoma and in mouse proneural tumors at early as well as late stages of development compared with normal brain. TOP2B transcript correlated with susceptibility to etoposide in mouse proneural cell lines and in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia. Intracranial etoposide CED treatment (680 µM) was well tolerated by mice and led to a significant survival benefit in the PDGF(+)PTEN(-/-)p53(-/-) glioma model. Moreover, etoposide CED treatment at 80 µM but not 4 µM led to a significant survival advantage in the PDGF(+)PTEN(-/-) glioma model. CONCLUSIONS: TOP2 is highly expressed in proneural gliomas, rendering its pharmacological targeting by intratumoral administration of etoposide by CED effective on murine proneural gliomas. We provide evidence supporting clinical testing of CED of etoposide with a molecular-based patient selection approach.

High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM): a case series.

BACKGROUND AND IMPORTANCE: Rarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors. CLINICAL PRESENTATION: We present a case series of 4 patients with aggressive, adrenocorticotrophic hormone--producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for > 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM. CONCLUSION: This is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.

Murine cell line model of proneural glioma for evaluation of anti-tumor therapies.

Molecular subtypes of glioblastoma (GBM) with distinct alterations have been identified. There is need for reproducible, versatile preclinical models that resemble specific GBM phenotypes to facilitate preclinical testing of novel therapies. We present a cell line-based murine proneural GBM model and characterize its response to radiation therapy. Proneural gliomas were generated by injecting PDGF-IRES-Cre retrovirus into the subcortical white matter of adult mice that harbor floxed tumor suppressors (Pten and p53) and stop-floxed reporters. Primary cell cultures were generated from the retrovirus induced tumors and maintained in vitro for multiple passages. RNA sequencing-based expression profiling of the resulting cell lines was performed. The tumorigenic potential of the cells was assessed by intracranial injection into adult naïve mice from different strains. Tumor growth was assessed by bioluminescence imaging (BLI). BLI for tumor cells and brain slices were obtained and compared to in vivo BLI. Response to whole-brain radiation was assessed in glioma-bearing animals. Intracranial injection of Pdgf(+)Pten(-/-)p53(-/-)luciferase(+) glioma cells led to formation of GBM-like tumors with 100 % efficiency (n = 48) and tumorigenesis was retained for more than 3 generations. The cell lines specifically resembled proneural GBM based on expression profiling by RNA-Seq. Pdgf(+)Pten(-/-)p53(-/-)luciferase(+) cell number correlated with BLI signal. Serial BLI measured tumor growth and correlated with size and location by ex vivo imaging. Moreover, BLI predicted tumor-related mortality with a 93 % risk of death within 5 days following a BLI signal between 1 × 10(8) and 5 × 10(8) photons/s cm(2). BLI signal had transient but significant response following radiotherapy, which corresponded to a modest survival benefit for radiated mice (p < 0.05). Intracranial injection of Pdgf(+)Pten(-/-)p53(-/-)luciferase(+) cells constitutes a novel and highly reproducible model, recapitulating key features of human proneural GBM, and can be used to evaluate tumor-growth and response to therapy.