Search

Glioblastoma is the most common and aggressive primary malignant brain tumour. The prognosis of patients with glioblastoma is poor, and their overall survival averages at 1 year, despite advances made in cancer therapy. The emergence of immunotherapy, a strategy that targets the natural mechanisms of immune evasion by cancerous cells, has revolutionised the treatment of melanoma, lung cancer and other solid tumours; however, immunotherapy failed to improve the prognosis of patients with glioblastoma. This is attributed to the fact that glioblastoma is endowed with numerous mechanisms of resistance that include the intrinsic resistance, which refers to the location of the tumour within the brain and the nature of the blood-brain barrier, as well as the adaptive and acquired resistance that result from the tumour heterogeneity and its immunosuppressive microenvironment. Glioblastoma is notorious for its inter and intratumoral heterogeneity, which, coupled with its spatial and temporal evolution, limits its immunogenicity. In addition, the tumour microenvironment is enriched with immunosuppressive cells and molecules that hinder the reactivity of cytotoxic immune cells and the success of immunotherapies. In this article, we review the mechanisms of resistance of glioblastoma to immunotherapy and discuss treatment strategies to overcome them worthy of further exploration.

Purpose Subependymomas located within the 4th ventricle are rare, and the literature describing imaging characteristics is sparse. Here, we describe the clinical and radiological characteristics of 29 patients with 4th ventricle subependymoma. Methods This is a retrospective multi-center study performed after Institutional Review Board (IRB) approval. Patients diagnosed with suspected 4th ventricle subependymoma were identified. A review of clinical, radiology, and pathology reports along with magnetic resonance imaging (MRI) images was performed. Results Twenty-nine patients, including 6 females, were identified. Eighteen patients underwent surgery with histopathological confirmation of subependymoma. The median age at diagnosis was 52 years. Median tumor volume for the operative cohort was 9.87 cm3, while for the non-operative cohort, it was 0.96 cm3. Thirteen patients in the operative group exhibited symptoms at diagnosis. For the total cohort, the majority of subependymomas (n = 22) were isointense on T1, hyperintense (n = 22) on T2, and enhanced (n = 24). All tumors were located just below the body of the 4th ventricle, terminating near the level of the obex. Fourteen cases demonstrated extension of tumor into foramen of Magendie or Luschka. Conclusion To the best of our knowledge, this is the largest collection of 4th ventricular subependymomas with imaging findings reported to date. All patients in this cohort had tumors originating between the bottom of the body of the 4th ventricle and the obex. This uniform and specific site of origin aids with imaging diagnosis and may infer possible theories of origin.

Supplementary Figure 1

Supplementary Figure 4

Supplementary Figure 3

Supplementary Figure 2

Supplementary Figure 5

Supplementary Figure 1

Supplementary Figure 6

Supplementary Figure 7

Purpose: Cytomegalovirus (CMV) has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited.Experimental Design: Glioblastoma multiforme (GBM) tumors were analyzed by flow cytometry to determine CMV antigen expression within various glioma-associated immune populations. The glioma cancer stem cell (gCSC) CMV interleukin (IL)-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF (vascular endothelial growth factor), TGF-β, viral IE1, and pp65 were determined by flow cytometry. The influence of CMV IL-10–treated monocytes on gCSC biology was ascertained by functional assays.Results: CMV showed a tropism for macrophages (MΦ)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the central nervous system MΦs/microglia) to assume an M2 immunosuppressive phenotype (as manifested by downmodulation of the major histocompatibility complex and costimulatory molecules) while upregulating immunoinhibitory B7-H1. CMV IL-10 also induces expression of viral IE1, a modulator of viral replication and transcription in the monocytes. Finally, the CMV IL-10–treated monocytes produced angiogenic VEGF, immunosuppressive TGF-β, and enhanced migration of gCSCs.Conclusions: CMV triggers a feedforward mechanism of gliomagenesis by inducing tumor-supportive monocytes. Clin Cancer Res; 17(14); 4642–9. ©2011 AACR.

Supplementary Figure Legends and Methods

Supplementary Figure 4

Supplementary Figure 2

Purpose:Radiomics is the extraction of multidimensional imaging features, which when correlated with genomics, is termed radiogenomics. However, radiogenomic biological validation is not sufficiently described in the literature. We seek to establish causality between differential gene expression status and MRI-extracted radiomic-features in glioblastoma.Experimental Design:Radiogenomic predictions and validation were done using the Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data glioblastoma patients (n = 93) and orthotopic xenografts (OX; n = 40). Tumor phenotypes were segmented, and radiomic-features extracted using the developed radiome-sequencing pipeline. Patients and animals were dichotomized on the basis of Periostin (POSTN) expression levels. RNA and protein levels confirmed RNAi-mediated POSTN knockdown in OX. Total RNA of tumor cells isolated from mouse brains (knockdown and control) was used for microarray-based expression profiling. Radiomic-features were utilized to predict POSTN expression status in patient, mouse, and interspecies.Results:Our robust pipeline consists of segmentation, radiomic-feature extraction, feature normalization/selection, and predictive modeling. The combination of skull stripping, brain-tissue focused normalization, and patient-specific normalization are unique to this study, providing comparable cross-platform, cross-institution radiomic features. POSTN expression status was not associated with qualitative or volumetric MRI parameters. Radiomic features significantly predicted POSTN expression status in patients (AUC: 76.56%; sensitivity/specificity: 73.91/78.26%) and OX (AUC: 92.26%; sensitivity/specificity: 92.86%/91.67%). Furthermore, radiomic features in OX were significantly associated with patients with similar POSTN expression levels (AUC: 93.36%; sensitivity/specificity: 82.61%/95.74%; P = 02.021E−15).Conclusions:We determined causality between radiomic texture features and POSTN expression levels in a preclinical model with clinical validation. Our biologically validated radiomic pipeline also showed the potential application for human–mouse matched coclinical trials.

Supplementary Figure S1; Supplementary Table S1.

Purpose:Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets.Patients and Methods:Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106–1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment.Results:We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0–8.3 months]; 6-month PFS was 19% (95% CI, 7%–52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas.Conclusions:Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

Supplementary Tables

Supplementary Figure 3

Supplementary Table 1 from Activation of Stat3 in Human Melanoma Promotes Brain Metastasis

Supplementary Figures 1 and 2 from Activation of Stat3 in Human Melanoma Promotes Brain Metastasis

Supplementary Figure 1 from FoxM1B Transcriptionally Regulates Vascular Endothelial Growth Factor Expression and Promotes the Angiogenesis and Growth of Glioma Cells

Supplementary Figures 1-6 from Molecular Basis for the Critical Role of Suppressor of Cytokine Signaling-1 in Melanoma Brain Metastasis

Brain metastasis is a major cause of morbidity and mortality in patients with melanoma. The molecular changes that lead to brain metastasis remain poorly understood. In this study, we developed a model to study human melanoma brain metastasis and found that Stat3 activity was increased in human brain metastatic melanoma cells when compared with that in cutaneous melanoma cells. The expression of activated Stat3 is also increased in human brain metastasis specimens when compared with that in the primary melanoma specimens. Increased Stat3 activation by transfection with a constitutively activated Stat3 enhanced brain metastasis, whereas blockade of Stat3 activation by transfection with a dominant-negative Stat3 suppressed brain metastasis of human melanoma cells in animal models. Furthermore, altered Stat3 activity profoundly affected melanoma angiogenesis in vivo and melanoma cell invasion in vitro and significantly affected the expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2) in vivo and in vitro. Finally, Stat3 activity transcriptionally regulated the promoter activity of bFGF in addition to VEGF and MMP-2 in human melanoma cells. These results indicated that Stat3 activation plays an important role in dysregulated expression of bFGF, VEGF, and MMP-2 as well as angiogenesis and invasion of melanoma cells and contributes to brain metastasis of melanoma. Therefore, Stat3 activation might be a new potential target for therapy of human melanoma brain metastases. (Cancer Res 2006; 66(6): 3188-96)

Thalamic gliomas are rare neoplasms that pose significant surgical challenges. The literature is limited to single-institution retrospective case series. We systematically review the literature and describe the clinical characteristics, treatment strategies, and survival outcomes of adult thalamic gliomas. Relevant articles were identified on PubMed, Scopus, and Cochrane databases. Papers containing cases of adult thalamic gliomas with clinical outcome data were included. A comprehensive review of clinical characteristics and survival analysis was conducted. We included 25 studies comprising 617 patients. The median age was 45 years (male = 58.6%). Glioblastoma was the most frequent histological type (47.2%), and 82 tumors were H3 K27M-mutant. Motor deficit was the most common presenting symptom (51.8%). Surgical resection was performed in 69.1% of cases while adjuvant chemotherapy and radiotherapy were administered in 56.3% and 72.6%, respectively. Other treatments included laser interstitial thermal therapy, which was performed in 15 patients (2.4%). The lesion laterality (P = 0.754) and the surgical approach (P = 0.111) did not correlate with overall survival. The median progression-free survival was 9 months, and the overall two-year survival rate was 19.7%. The two-year survival rates of low-grade and high-grade thalamic gliomas were 31.0% and 16.5%, respectively. H3 K27M-mutant gliomas showed worse overall survival (P = 0.017). Adult thalamic gliomas are associated with poor survival. Complete surgical resection is associated with improved survival rates but is not always feasible. H3 K27M mutation is associated with worse survival and a more aggressive approach should be considered for mutant neoplasms.

BACKGROUND Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma. OBJECTIVE To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR. METHODS A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P

The development of neurosurgery at Baylor College of Medicine began with the medical school’s relocation to the new Texas Medical Center in Houston in 1943. An academic service was organized in 1949 as a section of neurosurgery within Baylor’s Department of Surgery. Soon the practice, led by Dr. George Ehni, evolved to include clinical services at Methodist, Jefferson Davis (forerunner of Ben Taub), Texas Children’s, the Veterans Affairs, and the University of Texas MD Anderson Cancer Center hospitals. A neurosurgery residency program was established in 1954. As the clinical practice expanded, neurosurgery was upgraded from a section to a division and then to a department. It has been led by four chiefs/chairs over the past 60 years—Dr. George Ehni (1959–1979), Dr. Robert Grossman (1980–2004), Dr. Raymond Sawaya (2005–2014), and Dr. Daniel Yoshor (2015–2020). Since the 1950s, the department has drawn strength from its robust residency program, its research base in the medical school, and its five major hospital affiliates, which have largely remained unchanged (with the exception of Baylor St. Luke’s Medical Center replacing Methodist in 2004). The recent expansion of the residency program to 25 accredited positions and the growing strength of relationships with the “Baylor five” hospitals affiliated with Baylor College of Medicine portend a bright future.

Aim: To ascertain the maximum tolerated dose (MTD)/maximum feasible dose (MFD) of WP1066 and p-STAT3 target engagement within recurrent glioblastoma (GBM) patients. Patients & methods: In a first-in-human open-label, single-center, single-arm 3 + 3 design Phase I clinical trial, eight patients were treated with WP1066 until disease progression or unacceptable toxicities. Results: In the absence of significant toxicity, the MFD was identified to be 8 mg/kg. The most common adverse event was grade 1 nausea and diarrhea in 50% of patients. No treatment-related deaths occurred; 6 of 8 patients died from disease progression and one was lost to follow-up. Of 8 patients with radiographic follow-up, all had progressive disease. The longest response duration exceeded 3.25 months. The median progression-free survival (PFS) time was 2.3 months (95% CI: 1.7 months-NA months), and 6-month PFS (PFS6) rate was 0%. The median overall survival (OS) rate was 25 months (95% CI: 22.5 months-NA months), with an estimated 1-year OS rate of 100%. Pharmacokinetic (PK) data demonstrated that at 8 mg/kg, the T1/2was 2–3 h with a dose dependent increase in the Cmax. Immune monitoring of the peripheral blood demonstrated that there was p-STAT3 suppression starting at a dose of 1 mg/kg. Conclusion: Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.

Outcomes of treatments for patients with breast cancer brain metastasis (BCBM) remain suboptimal, especially for systemic therapy. To evaluate the effectiveness of systemic and local therapy (surgery [S], stereotactic radiosurgery [SRS] and whole brain radiotherapy [WBRT]) in BCBM patients, we analyzed the data of 873 BCBM patients from 1999 to 2012. The median overall survival (OS) and time to progression in the brain (TTP-b) after diagnosis of brain metastases (BM) were 9.1 and 7.1 months, respectively. WBRT prolonged OS in patients with multiple BM (hazard ratio [HR], 0.68; 95% CI, 0.52-0.88; P = .004). SRS alone, and surgery or SRS followed by WBRT (S/SRS + WBRT), were equivalent in OS and TTP-b (median OS, 14.9 vs 17.2 months; median TTP-b, 8.2 vs 8.6 months). Continued chemotherapy prolonged OS (HR, 0.35; 95% CI, 0.30-0.41; P

Pineal region tumors are surgically demanding tumors to resect. Long term neuro-oncologic outcomes following surgical excision of tumors from this region have been underreported. We sought to define the long term outcomes of patients undergoing resection of pineal region tumors.A retrospective analysis of a prospectively maintained database was performed on patients who underwent intended surgical excision of pineal region tumors. Overall survival (OS) and progression free survival (PFS) were the primary endpoints of this study. Factors associated with OS, PFS and the degree of resection were analyzed, along with 30-day complication rates and dependence on CSF diversion.Sixty-eight patients with a mean age of 30.9 ± 15.3 years were analyzed. The median clinical and radiographic follow-up was 95.7 and 48.2 months, respectively. The supracerebellar infratentorial and the occipital transtentorial corridors were utilized in the majority of cases (80.9%). The gross total resection (GTR) rate was 52.9% (n=36). The 5-year OS and PFS rates were 70.2% and 58.5%, respectively. Achieving GTR was associated with improved OS (HR 0.39, p = 0.03) and PFS (HR 0.4, p = 0.006). The 30-day mortality rate was 5.9%. The need for CSF diversion was high with 77.9% of patients requiring a shunt or ETV by last follow-up.This is the first modern surgical series providing long term follow-up for patients undergoing surgical resection of pineal region tumors. Obtaining a GTR of these challenging tumors is beneficial with regards to PFS/OS. Higher grade tumors have diminished PFS/OS and are treated with adjuvant chemotherapy and/or radiotherapy.

Thalamic gliomas are rare neoplasms that pose significant surgical challenges. The literature is limited to single-institution retrospective case series. We systematically review the literature and describe the clinical characteristics, treatment strategies, and survival outcomes of adult thalamic gliomas.Relevant articles were identified on PubMed, Scopus, and Cochrane databases. Papers containing cases of adult thalamic gliomas with clinical outcome data were included. A comprehensive review of clinical characteristics and survival analysis was conducted.We included 25 studies comprising 617 patients. The median age was 45 years (male = 58.6%). Glioblastoma was the most frequent histological type (47.2%), and 82 tumors were H3 K27M-mutant. Motor deficit was the most common presenting symptom (51.8%). Surgical resection was performed in 69.1% of cases while adjuvant chemotherapy and radiotherapy were administered in 56.3% and 72.6%, respectively. Other treatments included laser interstitial thermal therapy, which was performed in 15 patients (2.4%). The lesion laterality (P = 0.754) and the surgical approach (P = 0.111) did not correlate with overall survival. The median progression-free survival was 9 months, and the overall two-year survival rate was 19.7%. The two-year survival rates of low-grade and high-grade thalamic gliomas were 31.0% and 16.5%, respectively. H3 K27M-mutant gliomas showed worse overall survival (P = 0.017).Adult thalamic gliomas are associated with poor survival. Complete surgical resection is associated with improved survival rates but is not always feasible. H3 K27M mutation is associated with worse survival and a more aggressive approach should be considered for mutant neoplasms.

Background We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window. Methods In an open-label, single-center, single-arm phase II “window-of-opportunity” trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor. Results No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients’ recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages. Conclusions Immune analyses indicated that pembrolizumab anti–programmed cell death 1 (PD-1) monotherapy alone can’t induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.

OBJECTIVE Many neurosurgeons resect nonenhancing low-grade gliomas (LGGs) by using an inside-out piecemeal resection (PMR) technique. At the authors’ institution they have increasingly used a circumferential, perilesional, sulcus-guided resection (SGR) technique. This technique has not been well described and there are limited data on its effectiveness. The authors describe the SGR technique and assess the extent to which SGR correlates with extent of resection and neurological outcome. METHODS The authors identified all patients with newly diagnosed LGGs who underwent resection at their institution over a 22-year period. Demographics, presenting symptoms, intraoperative data, method of resection (SGR or PMR), volumetric imaging data, and postoperative outcomes were obtained. Univariate analyses used ANOVA and Fisher’s exact test. Multivariate analyses were performed using multivariate logistic regression. RESULTS Newly diagnosed LGGs were resected in 519 patients, 208 (40%) using an SGR technique and 311 (60%) using a PMR technique. The median extent of resection in the SGR group was 84%, compared with 77% in the PMR group (p = 0.019). In multivariate analysis, SGR was independently associated with a higher rate of complete (100%) resection (27% vs 18%) (OR 1.7, 95% CI 1.1–2.6; p = 0.03). SGR was also associated with a statistical trend toward lower rates of postoperative neurological complications (11% vs 16%, p = 0.09). A subset analysis of tumors located specifically in eloquent brain demonstrated SGR to be as safe as PMR. CONCLUSIONS The authors describe the SGR technique used to resect LGGs and show that SGR is independently associated with statistically significantly higher rates of complete resection, without an increase in neurological complications, than with PMR. SGR technique should be considered when resecting LGGs.

Gross total resection (GTR) of contrast-enhancing tumor is associated with significantly increased overall survival in primary glioblastoma (GBM). Even when achieved, recurrence is likely, in part due to malignant cells infiltrating outside enhanced regions. Subsequently, there has been increasing interest in performing supratotal resections (SpTRs) for GBM. Published results have varied in part due to a lack of consensus on the definition of SpTR in GBM and its appropriate use. A crowdsourcing approach was used to survey 21 academic neurosurgical oncologists representing 13 health systems nationwide. Participants’ demographics including fellowship training status, years of experience, and operative volume with various techniques was collected. Participants were presented with 11 definitions of SpTR from published, peer-reviewed studies and asked to rate the appropriateness of each definition. Subsequently, participants reviewed T1-weighed post-contrast and FLAIR MR imaging videos in the axial, coronal, and sagittal planes for 22 GBMs. Participants were asked to assess eloquence of the tumor’s location, perceived equipoise of enrolling patients in a randomized clinical trial comparing GTR to SpTR, and their own personal surgical treatment plans. Most neurosurgeons surveyed (n=18, 85.7%) agree or strongly agree that GTR plus resection of some non-contrast enhancement is an appropriate definition for SpTR. Overall, there was only moderate inter-rater agreement, measured using sample variance and the index of qualitative variation, regarding eloquence, equipoise, and personal treatment plans. Neurosurgeons who performed more than 10 SpTRs for GBMs in the past year were more likely than counterparts to recommend it as their personal treatment plan (p< 0.005). Anterior temporal and right frontal GBMs were considered the best randomization candidates. We established a consensus definition for SpTR of GBM and identified anatomically distinct locations deemed most amenable to SpTR. These results will be used to plan prospective trials further investigating the potential clinical utility of SpTR for GBMs.

Background Glioblastoma (GBM) is the most common primary malignant brain tumor in adulthood. Despite multimodality treatments, including maximal safe resection followed by irradiation and chemotherapy, the median overall survival times range from 14 to 16 months. However, a small subset of GBM patients live beyond 5 years and are thus considered long-term survivors. Methods A retrospective analysis of the clinical, radiographic, and molecular features of patients with newly diagnosed primary GBM who underwent treatment at The University of Texas MD Anderson Cancer Center was conducted. Eighty patients had sufficient quantity and quality of tissue available for next-generation sequencing and immunohistochemical analysis. Factors associated with survival time were identified using proportional odds ordinal regression. We constructed a survival-predictive nomogram using a forward stepwise model that we subsequently validated using The Cancer Genome Atlas. Results Univariate analysis revealed 3 pivotal genetic alterations associated with GBM survival: both high tumor mutational burden (P = .0055) and PTEN mutations (P = .0235) negatively impacted survival, whereas IDH1 mutations positively impacted survival (P < .0001). Clinical factors significantly associated with GBM survival included age (P < .0001), preoperative Karnofsky Performance Scale score (P = .0001), sex (P = .0164), and clinical trial participation (P < .0001). Higher preoperative T1-enhancing volume (P = .0497) was associated with shorter survival. The ratio of TI-enhancing to nonenhancing disease (T1/T2 ratio) also significantly impacted survival (P = .0022). Conclusions Our newly devised long-term survival-predictive nomogram based on clinical and genomic data can be used to advise patients regarding their potential outcomes and account for confounding factors in nonrandomized clinical trials.

Texas Children’s Hospital opened its doors in 1954, and since that time the institution has remained dedicated to a three-part mission: patient care, education, and research. Dr. William R. Cheek developed an early interest in pediatric neurosurgery, which led to his efforts in building and developing a service at Texas Children’s Hospital at a time when the field was just emerging. His work with other early pioneers in the field led to the establishment of organized societies, educational texts, and governing bodies that have led to significant advances in the field over the past 50 years.

In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted, followed by preclinical determinations of therapeutic effect in immune-competent mice harboring gliomas. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent’s ability to restore immunological function in the context of intended use., Immune profiling of glioma patients reveals that the immune suppressive adenosine axis predominates but is refractory to modulation.

Purpose: Cytomegalovirus (CMV) antigens occur in glioblastoma but not in normal brains, making them desirable immunologic targets. Patients and Methods: Highly functional autologous polyclonal CMV pp65-specific T cells from patients with glioblastoma were numerically expanded under good manufacturing practice compliant conditions and administered after 3 weeks of lymphodepleting dose-dense temozolomide (100 mg/m2) treatment. The phase I component used a 3+3 design, ascending through four dose levels (5 × 106–1 × 108 cells). Treatment occurred every 6 weeks for four cycles. In vivo persistence and effector function of CMV-specific T cells was determined by dextramer staining and multiparameter flow cytometry in serially sampled peripheral blood and in the tumor microenvironment. Results: We screened 65 patients; 41 were seropositive for CMV; 25 underwent leukapheresis; and 20 completed ≥1 cycle. No dose-limiting toxicities were observed. Radiographic response was complete in 1 patient, partial in 2. Median progression-free survival (PFS) time was 1.3 months [95% confidence interval (CI), 0–8.3 months]; 6-month PFS was 19% (95% CI, 7%–52%); and median overall survival time was 12 months (95% CI, 6 months to not reached). Repeated infusions of CMV-T cells paralleled significant increases in circulating CMV+ CD8+ T cells, but cytokine production showing effector activity was suppressed, especially from T cells obtained directly from glioblastomas. Conclusions: Adoptive infusion of CMV-specific T cells after lymphodepletion with dose-dense temozolomide was well tolerated. But apparently CMV seropositivity does not guarantee tumor susceptibility to CMV-specific T cells, suggesting heterogeneity in CMV antigen expression. Moreover, effector function of these T cells was attenuated, indicating a requirement for further T-cell modulation to prevent their dysfunction before conducting large-scale clinical studies.

We sought to compare the tumor profiles of brain metastases from common cancers with those of primary tumors and extracranial metastases in order to identify potential targets and prioritize rational treatment strategies. Tumor samples were collected from both the primary and metastatic sites of nonsmall cell lung cancer, breast cancer and melanoma from patients in locations worldwide, and these were submitted to Caris Life Sciences for tumor multiplatform analysis, including gene sequencing (Sanger and next-generation sequencing with a targeted 47-gene panel), protein expression (assayed by immunohistochemistry) and gene amplification (assayed by in situ hybridization). The data analysis considered differential protein expression, gene amplification and mutations among brain metastases, extracranial metastases and primary tumors. The analyzed population included: 16,999 unmatched primary tumor and/or metastasis samples: 8,178 nonsmall cell lung cancers (5,098 primaries; 2,787 systemic metastases; 293 brain metastases), 7,064 breast cancers (3,496 primaries; 3,469 systemic metastases; 99 brain metastases) and 1,757 melanomas (660 primaries; 996 systemic metastases; 101 brain metastases). TOP2A expression was increased in brain metastases from all 3 cancers, and brain metastases overexpressed multiple proteins clustering around functions critical to DNA synthesis and repair and implicated in chemotherapy resistance, including RRM1, TS, ERCC1 and TOPO1. cMET was overexpressed in melanoma brain metastases relative to primary skin specimens. Brain metastasis patients may particularly benefit from therapeutic targeting of enzymes associated with DNA synthesis, replication and/or repair.

As metástases cerebrais são complicações comuns do câncer sistêmico, sendo os tumores intracranianos mais freqüentes e com incidência crescente. Os autores discutem algumas características epidemiológicas e as novas técnicas neurocirúrgicas como modalidade terapêutica, enfatizando seus resultados, independentemente da proximidade das lesões com áreas eloqüentes cerebrais.

OBJECTIVEFourth ventricle tumors are rare, and surgical series are typically small, comprising a single pathology, or focused exclusively on pediatric populations. This study investigated surgical outcome and complications following fourth ventricle tumor resection in a diverse patient population. This is the largest cohort of fourth ventricle tumors described in the literature to date.METHODSThis is an 18-year (1993–2010) retrospective review of 55 cases involving patients undergoing surgery for tumors of the fourth ventricle. Data included patient demographic characteristics, pathological and radiographic tumor characteristics, and surgical factors (approach, surgical adjuncts, extent of resection, etc.). The neurological and medical complications following resection were collected and outcomes at 30 days, 90 days, 6 months, and 1 year were reviewed to determine patient recovery. Patient, tumor, and surgical factors were analyzed to determine factors associated with the frequently encountered postoperative neurological complications.RESULTSThere were no postoperative deaths. Gross-total resection was achieved in 75% of cases. Forty-five percent of patients experienced at least 1 major neurological complication, while 31% had minor complications only. New or worsening gait/focal motor disturbance (56%), speech/swallowing deficits (38%), and cranial nerve deficits (31%) were the most common neurological deficits in the immediate postoperative period. Of these, cranial nerve deficits were the least likely to resolve at follow-up. Multivariate analysis showed that patients undergoing a transvermian approach had a higher incidence of postoperative cranial nerve deficits, gait disturbance, and speech/swallowing deficits than those treated with a telovelar approach. The use of surgical adjuncts (intraoperative navigation, neurophysiological monitoring) did not significantly affect neurological outcome. Twenty-two percent of patients required postoperative CSF diversion following tumor resection. Patients who required intraoperative ventriculostomy, those undergoing a transvermian approach, and pediatric patients (< 18 years old) were all more likely to require postoperative CSF diversion. Twenty percent of patients suffered at least 1 medical complication following tumor resection. Most complications were respiratory, with the most common being postoperative respiratory failure (14%), followed by pneumonia (13%).CONCLUSIONSThe occurrence of complications after fourth ventricle tumor surgery is not rare. Postoperative neurological sequelae were frequent, but a substantial number of patients had neurological improvement at long-term followup. Of the neurological complications analyzed, postoperative cranial nerve deficits were the least likely to completely resolve at follow-up. Of all the patient, tumor, and surgical variables included in the analysis, surgical approach had the most significant impact on neurological morbidity, with the telovelar approach being associated with less morbidity.

Background There is recognition that breast cancer is a collection of heterogeneous diseases divided in subtypes based on combined molecular features such as hormonal receptors (HR) and human epidermal growth factor receptor 2 (HER2) status. We aimed to study clinical differences among biological subtypes in brain metastasis from breast cancer after targeted therapy introduction. Methods This was a retrospective study with 406 consecutive patients with brain metastasis from breast cancer treated at MD Anderson Cancer Center from 1998 to 2013. Overall, 315 of these patients met the study criteria and were analyzed. Subtypes were classified as HER2-/HR+ (96 patients), HER2+/HR+ (57 patients), HER2+/HR- (63 patients), and triple negative (HER2-/HR-) (99 patients). End points were time to development of brain metastasis (TDBM), brain metastasis-free survival (BMFS), and overall survival from start of treatment of brain metastasis (OSBM). Univariate and multivariate Cox proportional hazard regression models were used to analyze the data. Results TDBM was 41 months for HER2-/HR+; 58 months for HER2+/HR+; 30 months for HER2+/HR-; and 27 months for triple negative (P < .001). BMFS was 9 months for HER2-/HR+; 24 months for HER2+/HR+; 9 months for HER2+/HR-; and 7 months for triple negative (P = .06). OSBM was 20 months for HER2-/HR+; 22 months for HER2+/HR+; 24 months for HER2+/HR-; and 9 months for triple negative (P < .001). On multivariate analyses, triple negative showed lower OSBM compared with other subtypes, with a hazard ratio of 1.9 (P < .001). Conclusion Comparing all breast cancer subgroups we noticed that HR and HER2 are the most significant biomarkers in brain metastasis behavior. Patients who received targeted therapy had better outcomes, but not in the triple negative group. Prospective studies with different treatment modalities for each subgroup are recommended.

Preoperative mapping of language areas using fMRI greatly depends on the paradigms used, as different tasks harness distinct capabilities to activate speech processing areas. In this study, we compared the ability of 3 covert speech paradigms: Silent Sentence Completion (SSC), category naming (CAT) and verbal fluency (FAS), in localizing the Wernicke’s area and studied the association between genomic markers and functional activation. Fifteen right-handed healthy volunteers and 35 mixed-handed patients were included. We focused on the anatomical areas of posterosuperior, middle temporal and angular gyri corresponding to Wernicke’s area. Activity was deemed significant in a region of interest if P

Background MicroRNAs (miRs) are promising new therapeutics for glioblastoma. However, which miRs are most effective against glioblastomas and how these miRs should be delivered are major unanswered problems. Methods To identify potent antiglioma miRs, we selected 8 miRs based on a literature search and screened them against a panel of glioma stem cell (GSC) lines, representing all of the glioblastoma subtypes defined by The Cancer Genome Atlas. To address delivery, we tested the hypothesis that ex vivo cultured bone marrow-derived mesenchymal stem cells (MSCs) can package miRs into exosomes and that these engineered exosomes can systemically deliver antiglioma miRs to glioblastomas. Results Of the screened miRs, we identified miR-124a as the most effective antiglioma agent against GSCs. We then transduced MSCs with lentivirus vectors containing miR-124a and isolated vesicles from the medium. Electron microscopy, western blotting, and Nanosight proved that the isolated vesicles were exosomes. Quantitative PCR documented that these exosomes contained high levels of miR-124a, which was not present in control exosomes. In vitro treatment of GSCs with exosomes containing miR-124a (Exo-miR124) resulted in a significant reduction in viability and clonogenicity of GSCs compared with controls. In vivo treatment of mice harboring intracranial GSC267 with systemically delivered Exo-miR124 resulted in 50% of animals living long term. No evidence of tumor was present on histological analysis of the survivors. Mechanistic studies showed that miR-124a acts by silencing Forkhead box (FOX)A2, resulting in aberrant intracellular lipid accumulation. Conclusion MSCs can be used as natural biofactories to produce Exo-miR124, which is an effective antiglioma agent worthy of further clinical evaluation.

Summary Background After brain metastasis resection, whole brain radiotherapy decreases local recurrence, but might cause cognitive decline. We did this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved time to local recurrence compared with that for surgical resection alone. Methods In this randomised, controlled, phase 3 trial, we recruited patients at a single tertiary cancer centre in the USA. Eligible patients were older than 3 years, had a Karnofsky Performance Score of 70 or higher, were able to have an MRI scan, and had a complete resection of one to three brain metastases (with a maximum diameter of the resection cavity ≤4 cm). Patients were randomly assigned (1:1) with a block size of four to either SRS of the resection cavity (within 30 days of surgery) or observation. Patients were stratified by histology of the primary tumour, metastatic tumour size, and number of metastases. The primary endpoint was time to local recurrence in the resection cavity, assessed by blinded central review of brain MRI scans by the study neuroradiologist in the modified intention-to-treat population that analysed patients by randomised allocation but excluded patients found ineligible after randomisation. Participants and other members of the treatment team (excluding the neuroradiologist) were not masked to treatment allocation. The trial is registered with ClinicalTrials.gov, number NCT00950001, and is closed to new participants. Findings Between Aug 13, 2009, and Feb 16, 2016, 132 patients were randomly assigned to the observation group (n=68) or SRS group (n=64), with 128 patients available for analysis; four patients were ineligible (three from the SRS group and one from the observation group). Median follow-up was 11·1 months (IQR 4·8–20·4). 12-month freedom from local recurrence was 43% (95% CI 31–59) in the observation group and 72% (60–87) in the SRS group (hazard ratio 0·46 [95% CI 0·24–0·88]; p=0·015). There were no adverse events or treatment-related deaths in either group. Interpretation SRS of the surgical cavity in patients who have had complete resection of one, two, or three brain metastases significantly lowers local recurrence compared with that noted for observation alone. Thus, the use of SRS after brain metastasis resection could be an alternative to whole-brain radiotherapy. Funding National Institutes of Health.