First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. CONCLUSIONS: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1 ; initially registered 19 September 2002.

Correction to: First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

The preliminary radiogenomics association between MR perfusion imaging parameters and genomic biomarkers, and their predictive performance of overall survival in patients with glioblastoma.

The radiogenomics association of neovascularization is important for overall survival (OS) in glioblastoma patients and remains unclear. The purpose of this study is to assess the association between MR perfusion imaging derived parameters and genomic biomarkers of glioblastoma, and to evaluate their prognostic value. This retrospective study enrolled 41 patients with newly diagnosed glioblastoma. The mean and maximal relative cerebral blood volume (rCBV) ratio (rCBVmean and rCBVmax), derived from MR perfusion weighted imaging, of the enhancing tumor, as well as maximal rCBV ratio of peri-enhancing tumor area (rCBVperi-tumor) were measured. The ki-67 labeling index, mammalian target of rapamycin (mTOR) activation, epidermal growth factor receptor (EGFR) amplification, isocitrate dehydrogenase (IDH) mutation and TP53 were assessed. There was a significant correlation between rCBVmax and mTOR based on Pearson's correlations with Benjamini-Hochberg adjustment for controlling false discovery rate, p = 0.047. The rCBVperi-tumor showed significant correlation with mTOR (p = 0.0183) after adjustment of gender and EGFR status. The mean rCBVperi-tumor value of the patients with OS shorter than 14 months was significantly higher than patients with OS longer than 14 months, p = 0.002. The rCBVperi-tumor and age were the two strongest predictors of OS (hazard ratio = 1.29 and 1.063 respectively) by Cox regression analysis. This study showed that hemodynamic abnormalities of glioblastoma were associated with genomics activation status of mTOR-EGFR pathway, however, the radiogenomics associations are different in enhancing and peri-enhancing area of glioblastoma. The rCBVperi-tumor has better prognostic value than genomic biomarkers alone.

Brain metastasis from melanoma: the prognostic value of varying sites of extracranial disease.

Patients with brain metastasis from melanoma have poor outcomes. Radiation is used both for prognostic and symptomatic value. We aimed to further clarify the role of stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT) as well as the prognostic implication of various sites of extracranial disease. The records of 73 consecutive patients treated at the University of Rochester Medical Center for brain-metastatic melanoma from January 2004 to October 2013 were reviewed. The median overall survival (OS) was 3.0 months. Patients treated with WBRT alone had decreased OS compared to those treated with SRS alone (HR = 0.38, p = 0.001) or WBRT and SRS (HR = 0.51, p = 0.039). The mean number of brain metastasis differed (p = 0.002) in patients in patients who received WBRT (4.0) compared to those who did not (2.0). Among patients with extracranial disease (n = 63), bone metastasis (HR = 1.86, p = 0.047, n = 15) was a negative prognostic factor; liver (HR = 1.59, p = 0.113, n = 17), lung (HR = 1.51, p = 0.23, n = 51) and adrenal metastasis (HR = 1.70, p = 0.15, n = 10) were not. In patients with concurrent brain and lung metastasis, those with disease limited to those two sites (OS = 8.7 mo, n = 13) had improved OS (HR = 0.44, p = 0.014) compared to those with additional disease (OS = 1.8 mo, n = 50). Based on this hypothesis-generating retrospective analysis, SRS may offer survival benefit compared to WBRT alone in patients with brain metastatic melanoma. Bone metastasis appears to confer a particularly poor prognosis. Those with disease confined to the lung and brain may represent a population with improved prognosis.

Risk factors for venous thromboembolism in patients undergoing craniotomy for neoplastic disease.

Patients undergoing neurosurgical procedures for neoplasia have historically been considered at higher risk for developing venous thromboembolism (VTE). We sought to identify risk factors associated with VTE in patients undergoing craniotomy for tumor resection. We reviewed a national surgical quality database (American College of Surgeons National Surgical Quality Improvement Project, ACS-NSQIP, http://site.acsnsqip.org/ ). Patients undergoing non-emergent craniotomy for neoplastic indications were identified based on current procedural terminology codes. Clinical factors were identified that were associated with VTE events. 3,098 patients who underwent non-emergent craniotomy were identified. 1,741 patients underwent procedures for neoplastic disease (56.2 %). The rate of DVT in these patients was 3.2 % compared to 1.4 % in other neurosurgical patients (OR 2.30, CI 2.29-2.30). The rate of pulmonary embolism was 1.8 % compared to 0.5 % (OR 3.61, CI 3.60-3.62). Univariate analysis identified several factors correlated with VTE. Pre-operative characteristics associated with VTE were the presence of impaired sensorium, dependent functional status, and age > 60 years. Total operative time > 4 h was associated with VTE. Post-operative events associated with VTE included pneumonia, unplanned intubation, fail to wean from ventilator, UTI, stroke, sepsis and septic shock. Age > 60, OR time > 4 h, UTI, and septic shock were significantly associated with VTE in multivariate analysis. Patients undergoing craniotomy for neoplasm are at increased risk of VTE. This risk appears to be modified by pre-operative medical comorbidities, longer operative time, and post-operative complications.

Correlation between progression free survival and dynamic susceptibility contrast MRI perfusion in WHO grade III glioma subtypes.

The purpose of this study was to determine whether dynamic susceptibility contrast MR perfusion relative cerebral blood volume (rCBV) correlates with prognosis of World Health Organization (WHO) grade III glial tumors and their different subtypes. Retrospective evaluation of pre-treatment tumor rCBV derived from dynamic susceptibility contrast MR perfusion was performed in 34 patients with histopathologically diagnosed WHO grade III glial tumors (anaplastic astrocytomas (n = 20), oligodendrogliomas (n = 4), and oligoastrocytomas (n = 10)). Progression free survival was correlated with rCBV using Spearman rank analysis. ROC curve analysis was performed to determine the operating point for rCBV in patients with anaplastic astrocytomas dichotomized at the median progression free survival time. For all grade III tumors (n = 34) the mean rCBV was 2.51 with a progression free survival of 705.5 days. The mean rCBV of anaplastic astrocytomas was 2.47 with progression free survival 495.2 days. In contrast, the mean rCBV for oligodendroglial tumors was 2.56 with a progression free survival of 1005.6 days. Although there was no significant correlation between rCBV and progression free survival among all types of grade III gliomas (P = 0.12), among anaplastic astrocytomas there was a significant correlation between pretreatment rCBV and progression free survival with correlation coefficient of -0.51 (P = 0.02). The operating point for rCBV in patients with anaplastic astrocytomas dichotomized at the median progression free survival time (446.5 days) was 2.86 with 78 % accuracy and there was a significant difference between the survival of patients with anaplastic astrocytomas in the dichotomized groups (P = 0.0009). Pre-treatment rCBV may serve as a prognostic imaging biomarker for anaplastic astrocytomas, but not grade III oligodendroglioma tumors.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

Primary spinal cord glioma: a Surveillance, Epidemiology, and End Results database study.

To characterize the overall survival (OS) and cause specific survival (CSS), and variables affecting outcome, in patients with primary spinal cord astrocytoma (SCA) and ependymoma (SCE). About 664 patients with SCA and 1,057 patients with SCE were analyzed using the Surveillance, Epidemiology, and End Results database. For grade 1, 2, 3 and 4 SCA, the 5-year OS was 82, 70, 28 and 14%; the 5-year CSS was 89, 77, 36 and 20%. For SCA, lower grade, younger age, and undergoing resection significantly improved OS and CSS; treatment without radiotherapy was favorable for CSS. Smaller tumor size also improved survival. For grade 1, 2, and 3 SCE, the 5-year OS was 92, 97 and 58%; the 5-year CSS was 100, 98 and 64%. For SCE, lower grade, younger age, and undergoing resection significantly improved OS and CSS; treatment without radiotherapy was favorable for OS. Smaller tumor size did not confer a survival benefit. Patients with resected grade 2 spinal cord glioma who did not receive radiotherapy fared well with respect to OS and CSS. For patients with spinal cord glioma, the variables of histology, grade, age and undergoing resection are significant predictors of outcome. Though treatment with radiotherapy was associated with worse outcomes, this may reflect a bias in that patients who underwent radiotherapy were perhaps more likely to have had adverse risk factors. Given the retrospective nature of this study, specific recommendations about which situations warrant radiotherapy cannot be determined.

Vascular gene expression patterns are conserved in primary and metastatic brain tumors.

Malignant primary glial and secondary metastatic brain tumors represent distinct pathological entities. Nevertheless, both tumor types induce profound angiogenic responses in the host brain microvasculature that promote tumor growth. We hypothesized that primary and metastatic tumors induce similar microvascular changes that could function as conserved angiogenesis based therapeutic targets. We previously isolated glioma endothelial marker genes (GEMs) that were selectively upregulated in the microvasculature of proliferating glioblastomas. We sought to determine whether these genes were similarly induced in the microvasculature of metastatic brain tumors. RT-PCR and quantitative RT-PCR were used to screen expression levels of 20 candidate GEMs in primary and metastatic clinical brain tumor specimens. Differentially regulated GEMs were further evaluated by immunohistochemistry or in situ hybridization to localize gene expression using clinical tissue microarrays. Thirteen GEMs were upregulated to a similar degree in both primary and metastatic brain tumors. Most of these genes localize to the cell surface (CXCR7, PV1) or extracellular matrix (COL1A1, COL3A1, COL4A1, COL6A2, MMP14, PXDN) and were selectively expressed by the microvasculature. The shared expression profile between primary and metastatic brain tumors suggests that the molecular pathways driving the angiogenic response are conserved, despite differences in the tumor cells themselves. Anti-angiogenic therapies currently in development for primary brain tumors may prove beneficial for brain metastases and vice versa.

Contralateral acute subdural hematoma after surgical evacuation of acute subdural hematoma.

We present a case of an 81-year-old woman who developed an acute left-sided subdural hematoma with midline shift shortly after craniotomy for evacuation of a traumatic right-sided acute subdural hematoma. She was immediately taken back to the operating room for evacuation of the left-sided clot and her neurologic outcome was excellent. Believed to be caused by rapid brain decompression, bleeding far from the operative site, such as a within the contralateral subdural space, can occur after a craniotomy and must be promptly recognized.

Risk factors associated with early adverse outcomes following craniotomy for malignant glioma in older adults.

INTRODUCTION: Craniotomy for tumor resection improves survival in adults aged ≥65 years with malignant glioma. However, the decision to attempt resection must be weighed against the near-term risks of surgery. This study examined risk factors associated with unfavorable 30-day outcomes following craniotomy for malignant glioma resection in older adult patients. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2016 was queried for patients aged 65-89 years undergoing craniotomy for primary, supratentorial, malignant, intra-axial tumor resection. 30-day outcomes included mortality, life-threatening complication, unplanned readmission, reoperation, and change in living disposition. Independent risk factors were identified through multiple logistic regression. RESULTS: In total, 1016 cases met eligibility criteria. Death occurred in 35 cases (3.4%). 58 patients (5.7%) suffered at least one life-threatening complication. Risk factors for morbidity and mortality included frontal lobe tumor, corticosteroid use, dependent functional status, and underweight body mass index (BMI). Among 816 patients admitted from home, 33.9% experienced a change in living disposition, which was associated with advanced age, female sex, frontal lobe tumor, underweight BMI, and diabetes mellitus (among others). Readmission (11.8%) was most frequently attributed to altered mental status, seizure, or venous thromboembolism. Reoperation was rare (4.5%). DISCUSSION: Death and life-threatening morbidity were rare early outcomes for older adult patients undergoing malignant glioma resection. However, one in three patients admitted from home experienced a change in living disposition. Factors related to baseline state of health, tumor location, and corticosteroid regimen should be considered when anticipating the immediate postoperative course.

Clinical Efficacy of Tumor Treating Fields for Newly Diagnosed Glioblastoma.

BACKGROUND/AIM: Whether adding tumor treating fields (TTF) to the Stupp protocol increases survival for glioblastoma (GBM) patients in routine clinical care remains unknown. PATIENTS AND METHODS: We retrospectively identified adult patients with newly diagnosed GBM (n=104) treated with the Stupp protocol or TTF at our Institution. RESULTS: Thirty-six percent (37/104) of patients received TTF in conjunction with the Stupp protocol and these patients had increased 6-month (p=0.006) and 1-year (p=0.170), but not 2-year survival rates compared to the 67-patients who received Stupp alone. The improvement of survival rate at 6-month was further confirmed by a modified Poisson model (p=0.010). However, we did not observe any improvement in overall survival (OS) with a Cox model. CONCLUSION: While adding TTF to the Stupp protocol appeared to benefit patients with newly diagnosed GBM, this effect was mild and may be largely due to selection bias.

Time to treatment initiation and outcomes in high-grade glioma patients in rehabilitation: a retrospective cohort study.

Aims: To investigate wait time (WT) for chemoradiation and survival in post-op high-grade glioma (HGG) patients admitted to inpatient rehabilitation compared with those discharged home. Materials & methods: A total of 291 HGG patients (14.4% grade III and 84.9% grade IV) were included in this retrospective cohort study. Patients were grouped by disposition following surgery. Results: Median length of stay was longer in acute inpatient rehabilitation facility (AIRF) patients (10d) compared with patients discharged home (3d). AIRF admission was associated with higher odds of excessive treatment delay. Median survival for AIRF patients less than for patients discharged home (42.9 vs 72.71 weeks). WT was not associated with survival even after adjusting for prognostic factors. Conclusion: HGG patients discharged to rehabilitation facilities have longer length of stay, longer WT and shorter survival compared with patients discharged home.

The correlation of fractional anisotropy parameters with Ki-67 index, and the clinical implication in grading of non-enhancing gliomas and neuronal-glial tumors.

PURPOSE: To investigate the correlation between the FA parameters and Ki-67 labeling index, and their diagnostic performance in grading supratentorial non-enhancing gliomas and neuronal-glial tumors (GNGT). METHODS: This institutional review board-approved, Health Insurance Portability and Accountability (HIPAA) compliant retrospective study enrolled 35 patients, including 19 with low grade GNGT and 16 with high grade GNGT. The mean FA, maximal FA and mean maximal FA values derived from diffusion tensor imaging were measured. The correlation between the FA parameters and the Ki-67 labeling index was assessed by Spearman rank test. The receiver operating characteristic curve analysis and multivariate logistic regression analysis were performed to detect the optimal imaging parameters in grading GNGT. RESULTS: The three FA parameters of low grade GNGT were significantly lower than the high grade GNGT (p < 0.001). The mean FA, maximal FA and mean maximal FA had significant positive correlation with Ki-67 labeling index (p = 0.001, p < 0.001, p < 0.001 respectively). The maximal FA showed a higher sensitivity and specificity in grading of non-enhancing GNGT with specificity of 78.9%, sensitivity of 100.0%, respectively. CONCLUSIONS: The FA parameters correlated with Ki-67 labeling index, and were useful surrogates in preoperative grading supratentorial non-enhancing GNGT.

Characterization of TEM1/endosialin in human and murine brain tumors.

BACKGROUND: TEM1/endosialin is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of TEM1/endosialin in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models. METHODS: In situ hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize TEM1/endosialin expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in TEM1/endosialin expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown in vitro. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude TEM1/endosialin knockout (KO) and wildtype (WT) mice. RESULTS: TEM1/endosialin was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated TEM1/endosialin expression in 79% of tumors. Robust TEM1/endosialin expression occurred in 31% of glioblastomas (grade IV astroctyomas). TEM1/endosialin expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, alphaSMA and fibronectin in clinical specimens. In vitro, TEM1/endosialin was upregulated in human endothelial cells cultured in matrigel. Vascular Tem1/endosialin was induced in intracranial U87MG GBM xenografts grown in mice. Tem1/endosialin KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although Tem1/endosialin KO tumors were significantly more vascular than the WT counterparts. CONCLUSION: TEM1/endosialin was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of TEM1/endosialin did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of TEM1/endosialin and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies.

Healthcare Costs for High-grade Glioma.

BACKGROUND/AIM: Data on verified healthcare costs for high-grade gliomas (HGGs) are limited. This study aimed to determine the healthcare costs for HGGs. MATERIALS AND METHODS: A total of 88 primary HGGs patients diagnosed and treated at our Institution between 2011 and 2017 who had insurance plans administered with Excellus BCBS were retrospectively identified. Patient clinical information was linked with all verified insurance payment data. RESULTS: Median insurance payments for clinical management of HGGs were $184,159.83. The leading cost was therapeutic radiation oncology. Patients under commercial insurance had a longer survival time, and higher healthcare expenditures in total and in each phase of clinical care. Healthcare costs were higher during therapy initiation and at disease recurrence and lower during the interim. A generalized linear model showed that patients with commercial insurance, better Karnofsky Performance Status, and longer survival time had higher healthcare expenditures. CONCLUSION: Healthcare payments for HGGs patients were substantial and such high healthcare expenditures were positively associated with patient survival and commercial insurance.

The Impact of Timing of Concurrent Chemoradiation in Patients With High-Grade Glioma in the Era of the Stupp Protocol.

Background: The purpose of this study is to provide a critical review of current evidence for the impact of time to initiation of chemoradiation on overall survival in patients with newly diagnosed high-grade gliomas treated with radiation and concurrent temozolomide chemotherapy. Methods: A literature search was conducted using PubMed/MEDLINE and EMBASE databases. Studies were included if they provided separate analysis for patients treated with current standard of care: radiation and concurrent temozolomide. Bias assessment was performed for each included study using the Newcastle-Ottawa Assessment Scale, with Karnofsky Performance Status (KPS) and extent of resection used for comparability. Results: The initial search yielded 575 citations. Based on the inclusion/exclusion criteria, a total of 10 retrospective cohort studies were included in this review for a total of 30,298 patients. Of these, one study described an indirect relationship between time to initiation of treatment and overall survival. One study found decreased survival only with patients with significantly longer time to treatment. Four studies found no significant effect of time to treatment on overall survival. The four remaining studies found that patients with moderate time to initiation had the best overall survival. Conclusion: This review provides evidence that moderate time to initiation of chemoradiotherapy in patients with high-grade gliomas does not lead to a significant decrease in overall survival, though the effect of significant delays in treatment initiation remains unclear.

Plasmalemmal vesicle associated protein-1 (PV-1) is a marker of blood-brain barrier disruption in rodent models.

BACKGROUND: Plasmalemmal vesicle associated protein-1 (PV-1) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state. RESULTS: We demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated. CONCLUSION: Our results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.

Systematic Review of Safety and Cost-Effectiveness of Venous Thromboembolism Prophylaxis Strategies in Patients Undergoing Craniotomy for Brain Tumor.

BACKGROUND: Studies have evaluated various strategies to prevent venous thromboembolism (VTE) in neuro-oncology patients, without consensus. OBJECTIVE: To perform a systematic review with cost-effectiveness analysis (CEA) of various prophylaxis strategies in tumor patients undergoing craniotomy to determine the safest and most cost-effective prophylaxis regimen. METHODS: A literature search was conducted for VTE prophylaxis in brain tumor patients. Articles reporting the type of surgery, choice of VTE prophylaxis, and outcomes were included. Safety of prophylaxis strategies was determined by measuring rates of VTE and intracranial hemorrhage. Cost estimates were collected based on institutional data and existing literature. CEA was performed at 30 d after craniotomy, comparing the following strategies: mechanical prophylaxis (MP), low molecular weight heparin with MP (MP+LMWH), and unfractionated heparin with MP (MP+UFH) to prevent symptomatic VTE. All costs were reported in 2016 US dollars. RESULTS: A total of 34 studies were reviewed (8 studies evaluated LMWH, 12 for MP, and 7 for UFH individually or in combination; 4 studies used LMWH and UFH preoperatively). Overall probability of VTE was 1.49% (95% confidence interval (CI) 0.42-3.72) for MP+UFH, 2.72% [95% CI 1.23-5.15] for MP+LMWH, and 2.59% (95% CI 1.31-4.58) for MP, which were not statistically significant. Compared to a control of MP alone, the number needed to treat for MP+UFH is 91 and 769 for MP+LMWH. The risk of intracranial hemorrhage was 0.26% (95% CI 0.01-1.34) for MP, 0.74% (95% CI 0.09-2.61) for MP+UFH, and 2.72% (95% CI 1.23-5.15) for MP+LMWH, which were also not statistically significant. Compared to MP, the number needed to harm for MP+UFH was 208 and for MP+LMWH was 41. Fifteen studies were included in the final CEA. The estimated cost of treatment was $127.47 for MP, $142.20 for MP+UFH, and $169.40 for MP+LMWH. The average cost per quality-adjusted life-year for different strategies was $284.14 for MP+UFH, $338.39 for MP, and $722.87 for MP+LMWH. CONCLUSION: Although MP+LMWH is frequently considered the optimal prophylaxis for VTE risk reduction, our model suggests that MP+UFH is the safest and most cost-effective measure to balance VTE and hemorrhage risks in brain tumor patients at lower risk of hemorrhage. MP+LMWH may be more effective for patients at higher risk of VTE.

Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas.

BACKGROUND: The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts. METHODS: In University of Pittsburgh Cancer Institute (UPCI) protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) received gross total resection (GTR) of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC) loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging. RESULTS AND DISCUSSION: In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4+ as well as CD8+ T cells. Interferon (IFN)-gamma Enzyme-Linked Immuno-SPOT (ELISPOT) assay in another human leukocyte antigen (HLA)-A2+ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA) epitope EphA2883-891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants received scheduled vaccinations with no incidence of major adverse events. Monocyte-derived DCs produced high levels of IL-12 p70. Treatment was well tolerated; however, we were unable to observe detectable IFN-gamma post-vaccine responses or prolonged progression-free survival in these participants. CONCLUSION: Feasibility challenges inherent in the generation of a patient-specific gene transfection-based vaccine strongly suggests the need for more practical formulations that would allow for the timely administration of vaccines. Nevertheless, successful generation of type-1 DCs and preliminary safety in the current study provide a strong rationale for further efforts to develop novel glioma vaccines.