Search

OBJECTIVE The purpose of this study was to analyze risk factors for sacral fracture following noninstrumented partial sacral amputation for en bloc chordoma resection. METHODS A multicenter retrospective chart review identified patients who underwent noninstrumented partial sacral amputation for en bloc chordoma resection with pre- and postoperative imaging. Hounsfield units (HU) were measured in the S1 level. Sacral amputation level nomenclature was based on the highest sacral level with bone removed (e.g., S1 foramen amputation at the S1–2 vestigial disc is an S2 sacral amputation). Variables collected included basic demographics, patient comorbidities, surgical approach, preoperative radiographic details, neoadjuvant and adjuvant radiation therapy, and postoperative sacral fracture data. RESULTS A total of 101 patients (60 men, 41 women) were included; they had an average age of 69 years, BMI of 29 kg/m2, and follow-up of 60 months. The sacral amputation level was S1 (2%), S2 (37%), S3 (44%), S4 (9%), and S5 (9%). Patients had a posterior-only approach (77%) or a combined anterior–posterior approach (23%), with 10 patients (10%) having partial sacroiliac (SI) joint resection. Twenty-seven patients (27%) suffered a postoperative sacral fracture, all occurring between 1 and 7 months after the index surgery. Multivariable logistic regression analysis demonstrated S1 or S2 sacral amputation level (p = 0.001), combined anterior–posterior approach (p = 0.0064), and low superior S1 HU (p = 0.027) to be independent predictors of sacral fracture. The fracture rate for patients with superior S1 HU < 225, 225–300, and > 300 was 38%, 15%, and 9%, respectively. An optimal superior S1 HU cutoff of 300 was found to maximize sensitivity (89%) and specificity (42%) in predicting postamputation sacral fracture. In addition, the fracture rate for patients who underwent partial SI joint resection was 100%. CONCLUSIONS Patients with S1 or S2 partial sacral amputations, a combined anterior–posterior surgical approach, low superior S1 HU, and partial SI joint resection are at higher risk for postoperative sacral fracture following en bloc chordoma resection and should be considered for spinopelvic instrumentation at the index procedure.

Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes.

Brain metastasis (BrM) is a devastating complication of solid tumors associated with poor outcomes. Immune-checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, but determinants of response are incompletely understood. Given the rising incidence of BrM, improved understanding of immunobiologic principles unique to the central nervous system (CNS) and dissection of those that govern the activity of ICIs are paramount toward unlocking BrM-specific antitumor immunity. In this review, we seek to discuss the current clinical landscape of ICI activity in the CNS and CNS immunobiology, and we focus, in particular, on the role of glial cells in the CNS immune response to BrM.Significance:There is an urgent need to improve patient selection for and clinical activity of ICIs in patients with cancer with concomitant BrM. Increased understanding of the unique immunobiologic principles that govern response to ICIs in the CNS is critical toward identifying targets in the tumor microenvironment that may potentiate antitumor immunity.

The diagnosis of brain metastases has historically been a dreaded, end-stage complication of systemic disease. Additionally, with the increasing effectiveness of systemic therapies that prolong life expectancy and improved imaging tools, the incidence of intracranial progression is becoming more common. Within this context, there has been increasing attention directed at understanding the molecular underpinnings of intracranial progression. Exploring the unique features of brain metastases compared with their extracranial counterparts to identify aberrant signaling pathways, which can be targeted pharmacologically, may help lead to new treatments for this patient population. Additionally, critical discoveries outside the sphere of the central nervous system are increasingly being applied to brain metastases with the emergence of immune checkpoint inhibition, becoming a prevalent treatment option for patients with brain metastases across multiple histologies. As novel treatment strategies are considered, they require thoughtful incorporation of agents that can cross the blood-brain barrier and can synergize with pre-existing agents through rational combinations. Lastly, as clinicians and scientists continue to understand key molecular features of these tumors, they will continue to influence the treatment algorithms that are developing for the management of these patients. Due to the complexity of treatment decisions for patients with brain metastases, an emerging tool is the utilization of multidisciplinary brain metastasis tumor boards to ensure optimal treatment decisions are made and that patients are provided access to applicable clinical trials. Looking to the future, the collective effort to understand the various tumor-intrinsic and tumor-extrinsic factors that promote central nervous system seeding and propagation will have the potential to change the clinical trajectory for these patients.

Despite advances, glioblastoma is characterized by exceptionally high rates of recurrence and resistance to therapy. This commentary remarks on the recently published article by Maruyama et al, which reports the PMDA review of G47Δ injection for malignant glioma, in which the efficacy and safety results of G47Δ were evaluated and approval conditions clarified.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Supplementary Figure from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Supplementary Data from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Co-culture model of endogenous Vstat120 impact on microglia response to oHSV-infected glioma.

Ewing sarcoma subcutaneous tumors stained for CD68+ macrophages, with hematoxylin counterstain.

List of genes differentially induced ({greater than or equal to} 1.5 fold) in macrophages cultured with rHSVQ1 (Q) vs. RAMBO (R) infected glioma cells (UI, uninfected).

List of genes significantly up-regulated (>1.5 fold) in macrophages upon culture with glioma cells infected with RAMBO (R) or rHSVQ1 (Q) relative to uninfected (UI) cells.

Despite initial responses1-3, most melanoma patients develop resistance4 to immune checkpoint blockade (ICB). To understand the evolution of resistance, we studied 37 tumor samples over 9 years from a patient with metastatic melanoma with complete clinical response to ICB followed by delayed recurrence and death. Phylogenetic analysis revealed co-evolution of seven lineages with multiple convergent, but independent resistance-associated alterations. All recurrent tumors emerged from a lineage characterized by loss of chromosome 15q, with post-treatment clones acquiring additional genomic driver events. Deconvolution of bulk RNA sequencing and highly multiplexed immunofluorescence (t-CyCIF) revealed differences in immune composition among different lineages. Imaging revealed a vasculogenic mimicry phenotype in NGFRhi tumor cells with high PD-L1 expression in close proximity to immune cells. Rapid autopsy demonstrated two distinct NGFR spatial patterns with high polarity and proximity to immune cells in subcutaneous tumors versus a diffuse spatial pattern in lung tumors, suggesting different roles of this neural-crest-like program in different tumor microenvironments. Broadly, this study establishes a high-resolution map of the evolutionary dynamics of resistance to ICB, characterizes a de-differentiated neural-crest tumor population in melanoma immunotherapy resistance and describes site-specific differences in tumor-immune interactions via longitudinal analysis of a patient with melanoma with an unusual clinical course.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

BackgroundOncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials. Results from these studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we assess the extent to which targeting specific mechanisms underlying the immunosuppressive tumor microenvironment optimizes viroimmunotherapy.MethodsWe used RNA-seq analyses to analyze the transcriptome, and validated the results using Q-PCR, flow cytometry, and immunofluorescence. Viral activity was analyzed by replication assays and viral titration. Kyn and Trp metabolite levels were quantified using liquid chromatography–mass spectrometry. Aryl hydrocarbon receptor (AhR) activation was analyzed by examination of promoter activity. Therapeutic efficacy was assessed by tumor histopathology and survival in syngeneic murine models of gliomas, including Indoleamine 2,3-dioxygenase (IDO)-/- mice. Flow cytometry was used for immunophenotyping and quantification of cell populations. Immune activation was examined in co-cultures of immune and cancer cells. T-cell depletion was used to identify the role played by specific cell populations. Rechallenge experiments were performed to identify the development of anti-tumor memory.ResultsBulk RNA-seq analyses showed the activation of the immunosuppressive IDO-kynurenine-AhR circuitry in response to Delta-24-RGDOX infection of tumors. To overcome the effect of this pivotal pathway, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. The combination therapy increased the frequency of CD8+ T cells and decreased the rate of myeloid-derived suppressor cell and immunosupressive Treg tumor populations in animal models of solid tumors. Functional studies demonstrated that IDO-blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of the effectors and suppressors of the tumor immune landscape significantly prolonged the survival in animal models of orthotopic gliomas.ConclusionsOur data identified for the first time the in vivo role of IDO-dependent immunosuppressive pathways in the resistance of solid tumors to oncolytic adenoviruses. Specifically, the IDO-Kyn-AhR activity was responsible for the resurface of local immunosuppression and resistance to therapy, which was ablated through IDO inhibition. Our data indicate that combined molecular and immune therapy may improve outcomes in human gliomas and other cancers treated with virotherapy.

OBJECTIVEAlthough several prognostic scores for spinal metastatic disease have been developed in the past 2 decades, the applicability and validity of these models to specific cancer types are not yet clear. Most of the data used for model formation are from small population sets and have not been updated or externally validated to assess their performance. Developing predictive models is clinically relevant as prognostic assessment is crucial to optimal decision-making, particularly the decision for or against spine surgery. In this study, the authors investigated the performance of various spinal metastatic disease risk models in predicting prognosis for spine surgery to treat metastatic renal cell carcinoma (RCC).METHODSData of patients who underwent surgery for RCC metastatic to the spine at 2 tertiary centers between 2010 and 2019 were retrospectively retrieved. The authors determined the prognostic value associated with the following scoring systems: the Tomita score, original and revised Tokuhashi scores, original and modified Bauer scores, Katagiri score, the Skeletal Oncology Research Group (SORG) classic algorithm and nomogram, and the New England Spinal Metastasis Score (NESMS). Regression analysis of patient variables in association with 1-year survival after surgery was assessed using Cox proportional hazard models. Calibration and time-dependent discrimination analysis were tested to quantify the accuracy of each scoring system at 3 months, 6 months, and 1 year.RESULTSA total of 86 metastatic RCC patients were included (median age 64 years [range 29–84 years]; 63 males [73.26%]). The 1-year survival rate was 72%. The 1-year survival group had a good performance status (Karnofsky Performance Scale [KPS] score 80%–100%) and an albumin level > 3.5 g/dL (p < 0.05). Multivariable-adjusted Cox regression analysis showed that poor performance status (KPS score < 70%), neurological deficit (Frankel grade A–D), and hypoalbuminemia (< 3.5 g/dL) were associated with a higher risk of death before 1 year (p < 0.05). The SORG nomogram, SORG classic, original Tokuhashi, and original Bauer demonstrated fair performance (0.7 < area under the curve < 0.8). The NESMS differentiates survival among the prognostic categories with the highest accuracy (area under the curve > 0.8).CONCLUSIONSThe present study shows that the most cited and commonly used scoring systems have a fair performance predicting survival for patients undergoing spine surgery for metastatic RCC. The NESMS had the best performance at predicting 1-year survival after surgery.

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1–3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients—17 with breast cancer, two with lung cancer and one with ovarian cancer—were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2–12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39–0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab. In a phase 2 clinical trial cohort of patients with leptomeningeal disease, anti-PD-1 monotherapy was safe and associated with a 3-month overall survival of 60%.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

The aim of this study is to evaluate the outcomes and tolerance of immune checkpoint inhibitors (ICIs) for patients with recurrent chordoma. We reviewed the records of 17 patients with recurrent chordomas who received ICIs for progressing disease as part of their treatment between 2016 and 2020. Response was assessed using response evaluation criteria in solid tumors 1.1 criteria. The Kaplan-Meier method was used to estimate the duration of response, progression-free survival (PFS), and overall survival (OS). Clinical benefit was defined as having stable disease (SD), a partial response, or a complete response. The median follow-up from the start of ICIs was 29 months [interquartile range (IQR): 13-35 m]. The majority received pembrolizumab (n=9, 53%), and the median number of cycles delivered was 8 (IQR: 7-12). The 1-year OS was 87%, and the 1-year PFS was 56% with a median PFS of 14 months (95% CI, 5-17 mo). After ICI initiation, most patients (n=15, 88%) had clinical benefit consisting of a complete response (n=1, 6%), partial response (n=3, 18%), and stable disease (n=11, 65%). Among all responders (n=15), the median duration of response was 12 months. Toxicities were limited: 2 (12%) patients having grade 3/4 immune-related toxicities (colitis, grade 3; myocarditis, grade 4). We observed a high rate of clinical benefit and favorable durability from ICI use for patients with recurrent chordoma. These data provide support for the integration of ICIs as a standard first-line systemic therapy option for patients with recurrent chordoma. Prospective studies are warranted to further evaluate efficacy and enhance response rates.

Introduction: Tumor treating fields (TTF) are used for treatment of glioblastoma. Its utilization for spinal metastasis has never been described. We investigate the anti-mitotic effect of TTF to inhibit the growth of human cancer cells in vitro and in vivo models of spinal metastasis. Methods: In vitro: human derived osteosarcoma (Krib-luc-1) and lung adenocarcinoma (A549-luc) cells were seeded in 5 × 3mm human demineralized bone grafts kept in culture while treated with 0kHz (control) or 150kHZ of TTF for 14 days. Bioluminescence images (BLI) were obtained at baseline and 14 days. In vivo: Krib-Luc-1 cells were surgically implanted via transperitoneal approach to L3 vertebra in nude mice. Animals were treated with 0kHz or 150kHz for 30 days or until death. BLI were obtained at day 0 and every 7 days. MRI was obtained at day 22. Histological analysis was performed at the end of the experiment. Control and TTF-treated groups were compared with two-tailed t-tests. Results: In vitro: BLI of the control groups demonstrated 5-fold and 34-fold higher tumor signal (photons/sec) than corresponding 150 kHz TTF treatment groups at 14 days (A549 p=0.0289; KRIB p=0.00895). In vivo: All mice receiving 0 kHz treatment displayed hind limb paralysis by day 30, while mice treated with 150 kHz TTF displayed tail drop or no signs of paralysis. MRI and histology confirmed smaller tumors corroborating to BLI (3.67-fold change in photons/sec) (p=0.0212) when the 150 kHz TTF treatment group was compared to controls. Conclusions: Application of TTF at 150kHz reduced cellular proliferation in both in vitro and in vivo models of spinal metastasis. This is the first report of utilization of TTF for treatment of bony tumors and represents the first evidence that TTF could become a revolutionary therapy for spinal metastasis. Citation Format: Claudio Esteves Tatsui, Daniel Ledbetter, Christopher Alvarez-Breckenridge. In vitro and in vivo investigation of tumor treating fields for treatment of spinal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 20.

Background Primary spinal high-grade gliomas (S-HGG) are rare aggressive tumors; radiation therapy (RT) often plays a dominant role in management. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs. Methods Patients with biopsy-proven S-HGG who received RT from 2001 to 2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan–Meier estimates were used for survival analyses. Results Twenty-nine patients were identified with a median age of 25.9 years (range 1–74 y). Four patients had GTR while 25 underwent subtotal resection or biopsy. All patients were IDH wildtype and MGMT-promoter unmethylated, where available. H3K27M mutation was present in 5 out of 10 patients tested, while one patient harbored p53 mutation. Median RT dose was 50.4 Gy (range 39.6–54 Gy) and 65% received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) of patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8 had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS was 9.7 months. On univariate analysis, age, gender, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer PFS compared to those without mutation (10.1 m vs 45.1 m) but the difference did not reach statistical significance (P = .26). Conclusions The prognosis of patients with spinal HGGs remains poor with two-thirds of the patients developing distant recurrence despite chemoradiation. Survival outcomes were similar in patients ≤ 29 years compared to adults > 29 years. A better understanding of the molecular drivers of spinal HGGs is needed to develop more effective treatment options.

Immune-related therapies have revolutionized the management of cancer. Oncolytic viruses are now considered part of the immunotherapy armamentarium and have shown promise in clinical trials of patients with glioblastoma. These studies have suggested that tumor microenvironment remodeling is required to achieve an effective response in solid tumors. Here, we showed that Delta-24-RGDOX (DNX-2440), an oncolytic adenovirus expressing the T cell activator OX40L, triggered antitumor immune responses. However, Delta-24-RGDOX also elicited paradoxical activation of the cytokine-driven immunosuppressive IDO-kynurenine-AhR circuitry. The IDO-kynurenine-AhR cascade had the dual effects of preventing optimum viral replication and decreasing the virus-initiated antitumor immune response. To enhance virotherapy, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors. This combination therapy increased the frequency of activated CD8+ T cells and decreased the frequencies of immunosuppressive MDSC and Treg populations in animal models of gliomas and melanoma. Functional studies demonstrated that the IDO blockade-dependent activation of immune cells against tumor antigens could be reversed by the oncometabolite kynurenine. The concurrent targeting of effectors and suppressors in the tumor immune landscape significantly prolonged the survival of glioma- and melanoma-bearing mice. Our data identified the striking role of immunosuppressive pathways in the resistance of solid tumors to oncolytic virotherapy. Specifically, the activity of the tumor microenvironment IDO circuitry was responsible, at least partially, for the remodeling of local immunosuppression after tumor infection. Combining molecular and immune-related therapies may improve outcomes in human gliomas and other cancers treated with virotherapy.

Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research., Leptomeningeal disease (LMD) is a serious complication of metastatic solid tumors with a poor prognosis. Here, by using single-cell RNA sequencing of cerebrospinal fluid, the authors report genomic and immune correlates of response to immunotherapy in two cohorts of patients with LMD treated with immune checkpoint inhibitors.

The potential of big data analytics to improve the quality of care for patients with spine tumors is significant. At this moment, the application of big data analytics to oncology and spine surgery is at a nascent stage. As such, efforts are underway to advance data-driven oncologic care, improve patient outcomes, and guide clinical decision making. This is both relevant and critical in the practice of spine oncology as clinical decision making is often made in isolation looking at select variables deemed relevant by the physician. With rapidly evolving therapeutics in surgery, radiation, interventional radiology, and oncology, there is a need to better develop decision-making algorithms utilizing the vast data available for each patient. The challenges and limitations inherent to big data analyses are presented with an eye towards future directions.

Oncolytic viruses are considered part of immunotherapy and have shown promise in preclinical experiments and clinical trials in a small fraction of patients. To improve the response rate, it is necessary to reshape the tumor microenvironment that shields the tumor from the immune system of the patient. We engineered Delta-24-RGDOX (DNX-2440), an oncolytic adenovirus to express the T-cell activator OX40L, which triggered, in murine glioblastoma models, a dramatic reshaping of the tumor microenvironment dominated by changes in immune processes in an RNA-seq analysis of ingenuity pathways. Paradoxically, network analyses also revealed that Delta-24-RGDOX induced robust activation of the cytokine-driven immunosuppressive IDO-Kynurenine-AhR circuitry, indicating a potential mechanism of resistance of gliomas to oncolytic virotherapy. To reverse this immunosuppression, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors to treat glioma-bearing mice. The combined therapy decreased the activation of the IDO network without affecting viral activity. Flow cytometry assays revealed a decrease in the presence of the immunosuppressive cell populations, MDSCs and Tregs, which presence was higher in Delta-24-RGDOX-treated tumors. These data were further confirmed in gene set enrichment analyses. Functional co-culture studies showed that the combined therapy activated splenocytes against tumor antigens and that this activation was reversed by Kynurenine. Importantly, the combination treatment eradicated the tumors in a CD4-dependent manner and significantly prolonged the survival of glioma-bearing mice. Altogether, these studies indicate that the combination treatment promotes an adaptive immune response while decreasing the immunosuppression caused by the virus-induced IDO activation. Furthermore, our data identified the striking role of immunosuppressive pathways in the resistance of gliomas to oncolytic virotherapy. Specifically, the activity of the tumor microenvironment IDO circuitry was responsible, at least partially, for the remodeling of local immunosuppression after tumor infection. Combining molecular and immune-related therapies may improve outcomes in human gliomas treated with virotherapy.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need due to central nervous system (CNS) progression as a frequent, end-stage site of disease. Immune checkpoint inhibition (ICI) represents a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique MBM-TME elements and correlates of MBM-ICI response, we collected 32 fresh MBM and performed single cell RNA sequencing of the MBM-TME and T cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity, most notably multiple distinct neutrophil states including an IL-8 expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observe significant relationships between intracranial T cell phenotypes and the distribution of T cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data demonstrate unique features of the MBM-TME, which may represent potential targets to improve clinical outcomes for patients with MBM.

Key Points Question Can cell-free DNA analysis of cerebrospinal fluid provide additional diagnostic utility beyond cytologic assessment? Findings In this diagnostic study of 43 cerebrospinal fluid samples from 22 patients with leptomeningeal disease confirmed by cytologic assessment who did not have parenchymal tumors abutting their cerebrospinal fluid, tumor-derived cell-free DNA was detected in the cerebrospinal fluid of 40 (93%) samples, whereas 31 (72%) of the samples were positive for malignant neoplasm as determined by cytologic analysis, a significant difference. Meaning These findings suggest that cerebrospinal fluid cell-free DNA analysis may be more sensitive than cytologic analysis for diagnosing leptomeningeal disease., Importance Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions. Objective To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis. Design, Setting, and Participants This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018. Main Outcomes and Measures The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection. Results In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients. Conclusions and Relevance This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted., This diagnostic study compares the sensitivity and accuracy for detecting leptomeningeal disease via genomic sequencing of cell-free DNA with that of cytologic assessment of cerebrospinal fluid obtained from patients with suspected or cytologically confirmed leptomeningeal disease.

Viroimmunotherapy aims to infect cancer cells to elicit anti-tumor immune responses. In clinical trials, glioma treatment with oncolytic viruses induced durable clinical responses in a small fraction of patients. To improve the percentage of responders, it is necessary to reshape the tumor microenvironment that shields the tumor from the immune system of the patient. Thus, we engineered Delta-24-RGDOX (DNX-2440), an oncolytic adenovirus that carries the cDNA of the T-cell activator, OX40L. In this work, we observed that Delta-24-RGDOX triggered a dramatic reshaping of the tumor microenvironment dominated by strong changes in immune processes as indicated by RNA-sequencing via ingenuity pathway analyses in a murine glioblastoma model. Paradoxically, network analyses revealed that Delta-24-RGDOX also induced robust activation of the cytokine-driven immunosuppressive IDO-Kynurenine-AhR circuitry, indicating a potential mechanism of resistance of the cancer cells to oncolytic virotherapy. To reverse this immunosuppression, we combined Delta-24-RGDOX with clinically relevant IDO inhibitors to treat glioma bearing mice. Importantly, addition of the IDO inhibitor to Delta-24-RGDOX decreased the activation of the IDO network. IDO inhibition did not affect virus infection or replication in human or murine glioma cells. Flow cytometry assays revealed that the combination therapy increased the frequency of activated CD8+ T cells and decreased the presence of the immunosuppressive cell populations, MDSCs and Tregs. Gene set enrichment analyses confirmed the decrease of MDSCs and Tregs in the combination treated glioma-bearing mice compared to the virus alone. Functional co-culture studies showed that the combined therapy activated splenocytes against tumor antigens, and that this activation was reversed by kynurenine. Importantly, the combination treatment eradicated the tumors in a CD4-dependent manner and significantly prolonged the survival of glioma-bearing mice. Altogether, these studies indicate that the combination treatment promotes an adaptive immune response while decreasing immunosuppression caused by virus-induced IDO activation. Furthermore, our data identified the striking role of immunosuppressive pathways in the resistance of gliomas to oncolytic virotherapy. Specifically, the activity of the tumor microenvironment IDO circuitry was responsible, at least partially, for the remodeling of local immunosuppression after tumor infection. Combining molecular and immune-related therapies may improve outcomes in human gliomas treated with virotherapy. Citation Format: Teresa T. Nguyen, Dong Ho Shin, Sagar Sohoni, Sanjay K. Singh, Yisel Rivera-Molina, Hong Jiang, Xuejun Fan, Joy Gumin, Frederick F. Lang, Christopher Alvarez-Breckenridge, Marta M. Alonso, Filipa Godoy-Vitorino, Lijie Zhai, Erik Ladomersky, Kristen L. Lauing, Derek A. Wainwright, Juan Fueyo, Candelaria Gomez-Manzano. RNA-seq analyses reveal remodeling of tumor microenvironment and reversal of glioma resistance to oncolytic viruses by targeting immunometabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4184.

Management of chordoma along the cranial-spinal axis is a major challenge for both skull base and spinal surgeons. Although chordoma remains a rare tumor, occurring in approximately 1 per 1 million individuals, its treatment poses several challenges. These tumors are generally poorly responsive to radiation and chemotherapy, leading to surgical resection as the mainstay of treatment. Due to anatomic constraints and unique challenges associated with each primary site of disease, gross total resection is often not feasible and is associated with high rates of morbidity. Additionally, chordoma is associated with high rates of recurrence due to the tumor's aggressive biologic features, and postoperative radiation is increasingly incorporated as a treatment option for these patients. Despite these challenges, modern-day surgical techniques in both skull base and spinal surgery have facilitated improved patient outcomes. For example, endoscopic endonasal techniques have become the mainstay in resection of skull base chordomas, improving the ability to achieve gross total resection, while reducing associated morbidity of open transfacial techniques. Resection of spinal chordomas has been facilitated by emerging techniques in preoperative imaging, intraoperative navigation, spinal reconstruction, and radiotherapy. Taken collectively, the treatment of chordoma affecting the skull base and spinal requires a multidisciplinary team of surgeons, radiation oncologists, and medical oncologists who specialize in the treatment of this challenging disease.

Background With the advent of intraoperative computed tomography (CT) for image guidance, numerous examples of accurate navigation being applied to cranial and spinal pathology have come to light. For spinal disorders, the utilization of image guidance for the placement of percutaneous spinal instrumentation, complex osteotomies, and minimally invasive approaches are frequently utilized in trauma, degenerative, and oncological pathologies. The use of intraoperative CT for navigation, however, requires a low target registration error that must be verified throughout the procedure to confirm the accuracy of image guidance. Objective To present the use of skin staples as a sterile, economical fiducial marker for minimally invasive spinal procedures requiring intraoperative CT navigation. Methods Staples are applied to the skin prior to obtaining the registration CT scan and maintained throughout the remainder of the surgery to facilitate confirmation of image guidance accuracy. Results This low-cost, simple, sterile approach provides surface landmarks that allow reliable verification of navigation accuracy during percutaneous spinal procedures using intraoperative CT scan image guidance. Conclusion The utilization of staples as a fiducial marker represents an economical and easily adaptable technique for ensuring accuracy of image guidance with intraoperative CT navigation.

Brain metastases are the most common intracranial tumor in adults, with increasing incidence owing to prolonged survival times. Roughly half of patients diagnosed with new brain metastases have greater than 1 brain metastasis at the time of diagnosis, raising the question of how to optimize patient care with multiple brain metastases. The authors review studies relevant to the care of patients with brain metastasis, with emphasis on those relevant to the care of patients with multiple brain metastases. They discuss evolving strategies involving multiple modalities and the benefit of surgical management in patients with a large symptomatic brain metastasis.

Background Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy-induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy. Material and methods An institutional review board-approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS. Results The 2-year overall survival for patients treated with cytotoxic T-lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy-naive melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6-39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8-16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞; p = .12). On multivariate analysis, immunotherapy-naive brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00-2.99) compared with immunotherapy-naive brain metastases treated with surgery followed by immunotherapy. Conclusion In treatment-naive patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naive melanoma brain metastases is warranted. Implications for practice In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy-naive brain metastases. The benefit of surgical intervention was seen in immunotherapy-naive brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy-naive melanoma brain metastasis may provide a bridge toward immunotherapy-mediated systemic control.

Please see the full-text version of this guideline https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2) for the target population of each recommendation listed below. SURGERY FOR METASTATIC BRAIN TUMORS AT NEW DIAGNOSIS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT)? Recommendations Level 1: Surgery + WBRT is recommended as first-line treatment in patients with single brain metastases with favorable performance status and limited extracranial disease to extend overall survival, median survival, and local control. Level 3: Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors Level 3: Multimodal treatments including either surgery + WBRT + SRS boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits. SURGERY AND RADIATION FOR METASTATIC BRAIN TUMORS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgical resection followed by WBRT, SRS, or another combination of these modalities? Recommendations Level 1: Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases. Level 3: Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival. Level 3: It is recommended that SRS alone be considered equivalent to surgery + WBRT. SURGERY FOR RECURRENT METASTATIC BRAIN TUMORS QUESTION: Should patients with recurrent metastatic brain tumors undergo surgical resection? Recommendations Level 3: Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS. SURGICAL TECHNIQUE AND RECURRENCE QUESTION A: Does the surgical technique (en bloc resection or piecemeal resection) affect recurrence? Recommendation Level 3: En bloc tumor resection, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases. Question b Does the extent of surgical resection (gross total resection or subtotal resection) affect recurrence? Recommendation Level 3: Gross total resection is recommended over subtotal resection in recursive partitioning analysis class I patients to improve overall survival and prolong time to recurrence. The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2.

With the increasing prevalence of obesity, there is a need to understand the impact of body mass index (BMI) on spine surgery outcomes. Previous literature has reported the influence of obesity in thoracolumbar surgery; however, the impact of obesity on postoperative complications after posterior cervical fusion (PCF) is unknown.Consecutive patients who underwent cervical laminectomy and multi-level instrumented fusion for degenerative spinal conditions at an academic tertiary care hospital between 2012 and 2019 were evaluated. Patients were categorized into groups with a BMI ≥30.0 kg/mA total of 275 patients were included, with 80 obese (29.1%) and 195 nonobese (70.9%) patients. At baseline, obesity was associated with worse myelopathy (mJOA score: 10.2 vs. 13.1, P = 0.04 and Nurick grading: 3.2 vs. 1.1, P = 0.05) and abnormal cervical radiographic alignment (C2-7 sagittal vertical axis: 43.9 vs. 38.1 mm, P = 0.04). The intraoperative estimated blood loss was higher among obese patients (561.1 vs. 391.2 mL, P0.001). There was no significant difference in absolute scores for neurologic outcomes and radiographic alignment at 12 months after surgery. However, obese patients had significantly more complications than nonobese patients in terms of mechanical failure (6.3% vs. 0.5%, P = 0.05) and wound infection (8.7% vs. 0.0%, P = 0.04).Our results corroborate that PCF surgery provides significant improvement in neurologic and radiographic outcomes at 12 months after surgery for degenerative cervical spinal disorders. Obesity is a factor to consider in the pre-operative risk assessment.

Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials utilizing either Pembrolizumab alone or the combination of Ipilimumab and Nivolumab. We investigated the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We isolated and sequenced 34,742 cells from both the malignant and immune compartment within CSF. Amongst the 19 patients included in the cohort, there were 13 pre-treatment and 24 post-treatment samples, and 9 patients were sampled across multiple timepoints. We detected dynamic changes in immune cell recruitment into the CSF and activation within 30 days of ICI, including increased effector T cell activation and IFN-gamma response pathways within T cells. Moreover, the overall level of IFN-gamma response and antigen processing within 30 days of ICI in malignant cells correlated with survival past clinical trial primary endpoint. Lastly, we observed evidence of longitudinal outgrowth of distinct immunogenic clones over the course of ICI. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and provides unique insights into the compartmental and temporal variation during the course of ICI. Moreover, our findings demonstrate the clinical utility of cell- free and single-cell genomic measurements for LMD research.

Although several prognostic scores for spinal metastatic disease have been developed in the past 2 decades, the applicability and validity of these models to specific cancer types are not yet clear. Most of the data used for model formation are from small population sets and have not been updated or externally validated to assess their performance. Developing predictive models is clinically relevant as prognostic assessment is crucial to optimal decision-making, particularly the decision for or against spine surgery. In this study, the authors investigated the performance of various spinal metastatic disease risk models in predicting prognosis for spine surgery to treat metastatic renal cell carcinoma (RCC).Data of patients who underwent surgery for RCC metastatic to the spine at 2 tertiary centers between 2010 and 2019 were retrospectively retrieved. The authors determined the prognostic value associated with the following scoring systems: the Tomita score, original and revised Tokuhashi scores, original and modified Bauer scores, Katagiri score, the Skeletal Oncology Research Group (SORG) classic algorithm and nomogram, and the New England Spinal Metastasis Score (NESMS). Regression analysis of patient variables in association with 1-year survival after surgery was assessed using Cox proportional hazard models. Calibration and time-dependent discrimination analysis were tested to quantify the accuracy of each scoring system at 3 months, 6 months, and 1 year.A total of 86 metastatic RCC patients were included (median age 64 years [range 29-84 years]; 63 males [73.26%]). The 1-year survival rate was 72%. The 1-year survival group had a good performance status (Karnofsky Performance Scale [KPS] score 80%-100%) and an albumin level3.5 g/dL (p0.05). Multivariable-adjusted Cox regression analysis showed that poor performance status (KPS score70%), neurological deficit (Frankel grade A-D), and hypoalbuminemia (3.5 g/dL) were associated with a higher risk of death before 1 year (p0.05). The SORG nomogram, SORG classic, original Tokuhashi, and original Bauer demonstrated fair performance (0.7area under the curve0.8). The NESMS differentiates survival among the prognostic categories with the highest accuracy (area under the curve0.8).The present study shows that the most cited and commonly used scoring systems have a fair performance predicting survival for patients undergoing spine surgery for metastatic RCC. The NESMS had the best performance at predicting 1-year survival after surgery.

Although lung adenocarcinomas frequently metastasize to the brain, treatment options for lung adenocarcinoma brain metastases are limited. We discovered novel candidate drivers of progression by using case-control analyses to compare whole-exome sequencing data from a cohort of 73 lung adenocarcinoma brain metastases to a control cohort of 503 primary lung adenocarcinomas. We identified 3 genomic regions with significantly more frequent amplifications in brain metastases compared to the control cohort: MYC (12% vs 6%), YAP1 (7% vs 0.8%) and MMP13 (10% vs 0.6%). We also identified CDKN2A/B as a region deleted at a significantly greater frequency in brain metastases compared to primary lung adenocarcinomas (27% vs 13%, respectively). We confirmed frequent amplifications of MYC and YAP1/MMP13 in an independent validation cohort of 105 lung adenocarcinoma brain metastasis samples using fluorescence in situ hybridization. We further validated that MYC, YAP1 and MMP13 can drive brain metastases in a patient-derived xenograft mouse model. We found a higher incidence of metastases to the brain in mice receiving intracardiac injections of tumor cells expressing the candidate drivers compared to tumor cells expressing LacZ as a control. These results indicate that somatic alterations can drive lung adenocarcinomas to metastasize to the brain. The candidate brain metastasis drivers that we identified may serve as therapeutic targets in patients with lung adenocarcinomas who develop this devastating complication.