Developing Implantable Scaffolds to Enhance Neural Stem Cell Therapy for Post-Operative Glioblastoma.

Pre-clinical and clinical studies have shown that engineered tumoricidal neural stem cells (tNSCs) are a promising treatment strategy for the aggressive brain cancer glioblastoma (GBM). Yet, stabilizing human tNSCs within the surgical cavity following GBM resection is a significant challenge. As a critical step toward advancing engineered human NSC therapy for GBM, we used a preclinical variant of the clinically utilized NSC line HB1.F3.CD and mouse models of human GBM resection/recurrence to identify a polymeric scaffold capable of maximizing the transplant, persistence, and tumor kill of NSC therapy for post-surgical GBM. Using kinetic bioluminescence imaging, we found that tNSCs delivered into the mouse surgical cavity wall by direct injection persisted only 3 days. We found that delivery of tNSCs into the cavity on nanofibrous electrospun poly-l-lactic acid scaffolds extended tNSC persistence to 8 days. Modifications to fiber surface coating, diameter, and morphology of the scaffold failed to significantly extend tNSC persistence in the cavity. In contrast, tNSCs delivered into the post-operative cavity on gelatin matrices (GEMs) persisted 8-fold longer as compared to direct injection. GEMs remained permissive to tumor-tropic homing, as tNSCs migrated off the scaffolds and into invasive tumor foci both in vitro and in vivo. To mirror envisioned human brain tumor trials, we engineered tNSCs to express the prodrug/enzyme thymidine kinase (tNSCstk) and transplanted the therapeutic cells in the post-operative cavity of mice bearing resected orthotopic patient-derived GBM xenografts. Following administration of the prodrug ganciclovir, residual tumor volumes in mice receiving GEM/tNSCs were reduced by 10-fold at day 35, and median survival was extended from 31 to 46 days. Taken together, these data begin to define design parameters for effective scaffold/tNSC composites and suggest a new approach to maximizing the efficacy of tNSC therapy in human patient trials.

Generation and Profiling of Tumor-Homing Induced Neural Stem Cells from the Skin of Cancer Patients.

The conversion of human fibroblasts into personalized induced neural stem cells (iNSCs) that actively seek out tumors and deliver cytotoxic agents is a highly promising approach for treating various types of cancer. However, the ability to generate iNSCs from the skin of cancer patients has not been explored. Here, we take an important step toward clinical application by generating iNSCs from skin biopsies of human patients undergoing treatment for the aggressive brain cancer, glioblastoma (GBM). We then utilized a panel of functional and genomic studies to investigate the efficacy and tumor-homing capacity of these patient-derived cells, as well as genomic analysis, to characterize the impact of interpatient variability on this personalized cell therapy. From the skin-tissue biopsies, we established fibroblasts and transdifferentiated the cells into iNSCs. Genomic and functional testing revealed marked variability in growth rates, therapeutic agent production, and gene expression during fibroblast-to-iNSC conversion among patient lines. In vivo testing showed patient-derived iNSCs home to tumors, yet rates and expression of homing-related pathways varied among patients. With the use of surgical-resection mouse models of invasive human cluster of differentiation 133+ (CD133+) GBM cells and serial kinetic imaging, we found that "high-performing" patient-derived iNSC lines reduced the volume of GBM cells 60-fold and extended survival from 28 to 45 days. Treatment with "low-performing" patient lines had minimal effect on tumor growth, but the anti-tumor effect could be rescued by increasing the intracavity dose. Together, these data show, for the first time, that tumor-homing iNSCs can be generated from the skin of cancer patients and efficaciously suppress tumor growth. We also begin to define genetic markers that could be used to identify cells that will contain the most effective attributes for tumor homing and kill in human patients, including high gene expression of the semaphorin-3B (SEMA3B), which is known to be involved in neuronal cell migration. These studies should serve as an important guide toward clinical GBM therapy, where the personalized nature of optimized iNSC therapy has the potential to avoid transplant rejection and maximize treatment durability.

Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases.

PURPOSE: Brain metastases (BM) are a complication of advanced breast cancer (BC). Histology of melanoma BM offers prognostic value; however, understanding the microenvironment of breast cancer brain metastases (BCBM) is less characterized. This study reports on four histological biomarkers, gliosis, immune infiltrate, hemorrhage, necrosis, and their prognostic significance in BCBM. METHODS: A biobank of 203 human tissues from patients who underwent craniotomy for BCBM was created across four academic institutions. Degree of gliosis, immune infiltrate, hemorrhage, and necrosis were identified and scored via representative H&E stain (0-3+). Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards regression evaluated prognostic value of the biomarkers in the context of standard clinical characteristics. RESULTS: BCBM subtype (available for n = 158) was 36% Her2+, 26% hormone receptor (HR)+/Her2- 38% HR-/Her2- (triple negative, TN). Gliosis was observed in 82% (116/141) of BCBM, with immune infiltrate 44% (90/201), hemorrhage 82% (166/141), and necrosis 87% (176/201). Necrosis was significantly higher in TNBC (p < 0.01). Presence of gliosis, immune infiltrate, and hemorrhage correlated with improved OS (p = 0.03, p = 0.03, p = 0.1), while necrosis correlated with inferior OS (p = 0.01). Improved OS was associated with gliosis in TN (p = 0.02), and immune infiltrate (p = 0.001) and hemorrhage (p = 0.07) in HER2+. In a multivariable model for OS, incorporating these biomarkers with traditional clinical variables improved the model fit (p < 0.001). CONCLUSION: Gliosis confers superior prognosis in TNBC BM; immune infiltrate and hemorrhage correlate with superior prognosis in HER2+ BCBM. Understanding the metastatic microenvironment of BCBM refines prognostic considerations and may unveil novel therapeutic strategies.

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.

Pediatric Auditory Brainstem Implantation: Surgical, Electrophysiologic, and Behavioral Outcomes.

OBJECTIVES: The objectives of this study were to demonstrate the safety of auditory brainstem implant (ABI) surgery and document the subsequent development of auditory and spoken language skills in children without neurofibromatosis type II (NFII). DESIGN: A prospective, single-subject observational study of ABI in children without NFII was undertaken at the University of North Carolina at Chapel Hill. Five children were enrolled under an investigational device exemption sponsored by the investigators. Over 3 years, patient demographics, medical/surgical findings, complications, device mapping, electrophysiologic measures, audiologic outcomes, and speech and language measures were collected. RESULTS: Five children without NFII have received ABIs to date without permanent medical sequelae, although 2 children required treatment after surgery for temporary complications. All children wear their device daily, and the benefits of sound awareness have developed slowly. Intra-and postoperative electrophysiologic measures augmented surgical placement and device programming. The slow development of audition skills precipitated limited changes in speech production but had little impact on growth in spoken language. CONCLUSIONS: ABI surgery is safe in young children without NFII. Benefits from device use develop slowly and include sound awareness and the use of pattern and timing aspects of sound. These skills may augment progress in speech production but progress in language development is dependent upon visual communication. Further monitoring of this cohort is needed to better delineate the benefits of this intervention in this patient population.

Longitudinal Changes in Electrically Evoked Auditory Event-Related Potentials in Children With Auditory Brainstem Implants: Preliminary Results Recorded Over 3 Years.

OBJECTIVES: This preliminary study aimed (1) to assess longitudinal changes in electrically evoked auditory event-related potentials (eERPs) in children with auditory brainstem implants (ABIs) and (2) to explore whether these changes could be accounted for by maturation in the central auditory system of these patients. DESIGN: Study participants included 5 children (S1 to S5) with an ABI in the affected ear. The stimulus was a train of electrical pulses delivered to individual ABI electrodes via a research interface. For each subject, the eERP was repeatedly measured in multiple test sessions scheduled over up to 41 months after initial device activation. Longitudinal changes in eERPs recorded for each ABI electrode were evaluated using intraclass correlation tests for each subject. RESULTS: eERPs recorded in S1 showed notable morphological changes for five ABI electrodes over 41 months. In parallel, signs or symptoms of nonauditory stimulation elicited by these electrodes were observed or reported at 41 months. eERPs could not be observed in S2 after 9 months of ABI use but were recorded at 12 months after initial stimulation. Repeatable eERPs were recorded in S3 in the first 9 months. However, these responses were either absent or showed remarkable morphological changes at 30 months. Longitudinal changes in eERP waveform morphology recorded in S4 and S5 were also observed. CONCLUSIONS: eERP responses in children with ABIs could change over a long period of time. Maturation of the central auditory system could not fully account for these observed changes. Children with ABIs need to be closely monitored for potential changes in auditory perception and unfavorable nonauditory sensations. Neuroimaging correlates are needed to better understand the emergence of nonauditory stimulation over time in these children.

The Electrically Evoked Auditory Change Complex Evoked by Temporal Gaps Using Cochlear Implants or Auditory Brainstem Implants in Children With Cochlear Nerve Deficiency.

OBJECTIVES: This study aimed to (1) establish the feasibility of measuring the electrically evoked auditory change complex (eACC) in response to temporal gaps in children with cochlear nerve deficiency (CND) who are using cochlear implants (CIs) and/or auditory brainstem implants (ABIs); and (2) explore the association between neural encoding of, and perceptual sensitivity to, temporal gaps in these patients. DESIGN: Study participants included 5 children (S1 to S5) ranging in age from 3.8 to 8.2 years (mean: 6.3 years) at the time of testing. All subjects were unilaterally implanted with a Nucleus 24M ABI due to CND. For each subject, two or more stimulating electrodes of the ABI were tested. S2, S3, and S5 previously received a CI in the contralateral ear. For these 3 subjects, at least two stimulating electrodes of their CIs were also tested. For electrophysiological measures, the stimulus was an 800-msec biphasic pulse train delivered to individual electrodes at the maximum comfortable level (C level). The electrically evoked responses, including the onset response and the eACC, were measured for two stimulation conditions. In the standard condition, the 800-msec pulse train was delivered uninterrupted to individual stimulating electrodes. In the gapped condition, a temporal gap was inserted into the pulse train after 400 msec of stimulation. Gap durations tested in this study ranged from 2 up to 128 msec. The shortest gap that could reliably evoke the eACC was defined as the objective gap detection threshold (GDT). For behavioral GDT measures, the stimulus was a 500-msec biphasic pulse train presented at the C level. The behavioral GDT was measured for individual stimulating electrodes using a one-interval, two-alternative forced-choice procedure. RESULTS: The eACCs to temporal gaps were recorded successfully in all subjects for at least one stimulating electrode using either the ABI or the CI. Objective GDTs showed intersubject variations, as well as variations across stimulating electrodes of the ABI or the CI within each subject. Behavioral GDTs were measured for one ABI electrode in S2 and for multiple ABI and CI electrodes in S5. All other subjects could not complete the task. S5 showed smaller behavioral GDTs for CI electrodes than those measured for ABI electrodes. One CI and two ABI electrodes in S5 showed comparable objective and behavioral GDTs. In contrast, one CI and two ABI electrodes in S5 and one ABI electrode in S2 showed measurable behavioral GDTs but no identifiable eACCs. CONCLUSIONS: The eACCs to temporal gaps were recorded in children with CND using either ABIs or CIs. Both objective and behavioral GDTs showed inter- and intrasubject variations. Consistency between results of eACC recordings and psychophysical measures of GDT was observed for some but not all ABI or CI electrodes in these subjects.

The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy.

Stereotactic radiotherapy (SRT) is the standard treatment for patients with limited number of brain metastases. In the past few years, newer immunotherapies (immune checkpoint inhibitors) have been proven to prolong survival in patients with metastatic melanoma. The safety of the combination of SRT and immunotherapy for brain metastases is unknown. We retrospectively identified patients with melanoma brain metastases treated with SRT between 2007 and 2015. Patients who did not have at least 3 months of follow-up with imaging after SRT were excluded from the analysis. Outcomes were compared between patients who were treated with or without immunotherapy. A total of 58 patients were included; of these, 29 were treated with SRT and immunotherapy. MAPK inhibitors (BRAF, MEK inhibitors) were used more often in the immunotherapy group (nine vs. two patients). There was a higher incidence of intracranial complications in patients treated with immunotherapy and SRT. Eight patients had radiation necrosis; all occurred in patients who were treated with immunotherapy. Nine patients had hemorrhage, of which seven occurred in patients who were treated with immunotherapy (P=0.08). However, patients treated with immunotherapy and SRT had a significant overall survival advantage compared with SRT without immunotherapy (15 vs. 6 months, P=0.0013). Patients treated with SRT and immunotherapy have a higher incidence/risk of intracranial complications, but a longer overall survival.

A Multidisciplinary Breast Cancer Brain Metastases Clinic: The University of North Carolina Experience.

BACKGROUND: Breast cancer brain metastasis (BCBM) confers a poor prognosis and is unusual in requiring multidisciplinary care in the metastatic setting. The University of North Carolina at Chapel Hill (UNC-CH) has created a BCBM clinic to provide medical and radiation oncology, neurosurgical, and supportive services to this complex patient population. We describe organization and design of the clinic as well as characteristics, treatments, and outcomes of the patients seen in its first 3 years. METHODS: Clinical and demographic data were collected from patients in a prospectively maintained database. Descriptive statistics are reported as percentages and means. The Kaplan-Meier method was used to estimate time-to-event outcomes. RESULTS: Sixty-five patients were seen between January 2012 and January 2015. At the time of presentation to the BCBM clinic, most patients (74%) had multiple (≥2) brain metastases and had received prior systemic (77%) and whole-brain radiation therapy and/or central nervous system stereotactic radiosurgery (65%) in the metastatic setting. Seventy-eight percent returned for a follow-up visit; 32% were enrolled in a clinical trial. Median time from diagnosis of brain metastasis to death was 2.11 years (95% confidence interval [CI] 1.31-2.47) for all patients, 1.15 years (95% CI 0.4-2.43) for triple-negative breast cancer, 1.31 years (95% CI 0.51-2.52) for hormone receptor-positive/HER2- breast cancer, and 3.03 years (95% CI lower limit 1.94, upper limit not estimable) for HER2+ breast cancer (p = .0037). CONCLUSION: Patients with BCBM have unique and complex needs that require input from several oncologic disciplines. The development of the UNC-CH multidisciplinary BCBM clinic is a model that can be adapted at other centers to provide coordinated care for patients with a challenging and complex disease. IMPLICATIONS FOR PRACTICE: Patients with breast cancer brain metastases often require unique multidisciplinary care to meet the numerous and uncommon challenges associated with their conditions. Here, the development and characteristics of a clinic designed specifically to provide for the multidisciplinary needs of patients with breast cancer brain metastases are described. This clinic may serve as a model for other institutions interested in creating specialty clinics with similar objectives.

Multidisciplinary Management of Breast Cancer Brain Metastases.

This review summarizes the most up-to-date approach to the multidisciplinary management of patients with breast cancer brain metastases. A brief overview of the epidemiology and biology of breast cancer brain metastasis is provided. The perspectives of radiation oncology, neurosurgery, and medical oncology-and landmark studies from each discipline-are all discussed. We also offer practical tips to help guide the treating physician, including data on antiseizure medications. Finally, we introduce the concept of a multidisciplinary clinic that combines input from medical and radiation oncology, neurosurgery, and support services, which we developed at the University of North Carolina as a coordinated and optimal approach to the management of patients with this complex disease.

Electrically Evoked Auditory Event-Related Responses in Patients with Auditory Brainstem Implants: Morphological Characteristics, Test-Retest Reliability, Effects of Stimulation Level, and Association with Auditory Detection.

OBJECTIVE: This study aimed to (1) characterize morphological characteristics of the electrically evoked cortical auditory event-related potentials (eERPs) and explore the potential association between onset eERP morphology and auditory versus nonauditory stimulation; (2) assess test-retest reliability of onset eERPs; (3) investigate effects of stimulation level on onset eERPs; and (4) explore the feasibility of using the onset eERP to estimate the lowest stimulation level that can be detected for individual stimulating electrodes in patients with auditory brainstem implants (ABIs). DESIGN: Study participants included 5 children (S1 to S5) and 2 adults (S6 to S7) with unilateral Cochlear Nucleus 24M ABIs. Pediatric ABI recipients ranged in age from 2.6 to 10.2 years (mean: 5.2 years) at the time of testing. S6 and S7 were 21.2 and 24.6 years of age at the time of testing, respectively. S6 and S7 were diagnosed with neurofibromatosis II (NF2) and implanted with an ABI after a surgical removal of the tumors. All pediatric subjects received ABIs after being diagnosed with cochlear nerve deficiency. The lowest stimulation level that could be detected (behavioral T level) and the estimated maximum comfortable level (C level) was measured for individual electrodes using clinical procedures. For electrophysiological measures, the stimulus was a 100-msec biphasic pulse train that was delivered to individual electrodes in a monopolar-coupled stimulation mode at stimulation levels ranging from subthreshold to C levels. Electrophysiological recordings of the onset eERP were obtained in all subjects. For studies evaluating the test-retest reliability of the onset eERP, responses were measured using the same set of parameters in two test sessions. The time interval between test sessions ranged from 2 to 6 months. The lowest stimulation level that could evoke the onset eERP was defined as the objective T level. RESULTS: Onset eERPs were recorded in all subjects tested in this study. Inter- and intrasubject variations in morphological characteristics of onset eERPs were observed. Onset eERPs with complex waveforms were recorded for electrodes that evoked nonauditory sensations, based on feedback from subjects, as well as for electrodes without any indications of nonauditory stimulations. Onset eERPs in patients with ABIs demonstrated good test-retest reliability. Increasing stimulation levels resulted in increased eERP amplitudes but showed inconsistent effects on response latencies in patients with ABIs. Objective and behavioral T levels were correlated. CONCLUSIONS: eERPs could be recorded in both non-NF2 and NF2 patients with ABIs. eERPs in both ABI patient groups show inter- and intrasubject variations in morphological characteristics. However, onset eERPs measured within the same subject in this study tended to be stable across study sessions. The onset eERP can potentially be used to estimate behavioral T levels in patients with ABIs. Further studies with more adult ABI recipients are warranted to investigate whether the onset eERP can be used to identify electrodes with nonauditory stimulations.

The electrically evoked cortical auditory event-related potential in children with auditory brainstem implants.

OBJECTIVE: This study explored the feasibility of measuring electrically evoked cortical auditory event-related potentials (eERPs) in children with auditory brainstem implants (ABIs). DESIGN: Five children with unilateral ABIs ranging in age from 2.8 to 10.2 years (mean: 5.2 years) participated in this study. The stimulus was a 100-msec biphasic pulse train that was delivered to individual electrodes in a monopolar stimulation mode. Electrophysiological recordings of the onset eERP were conducted in all subjects. RESULTS: The onset eERP was recorded in four subjects who demonstrated auditory perception. These eERP responses showed variations in waveform morphology across subjects and stimulating electrode locations. No eERPs were observed in one subject who received no auditory sensation from ABI stimulation. CONCLUSIONS: eERPs can be recorded in children with ABIs who develop auditory perception. The morphology of the eERP can vary across subjects and also across stimulating electrode locations within subjects.

Preservation of neurocognitive function and local control of 1 to 3 brain metastases treated with surgery and carmustine wafers.

BACKGROUND: Neurosurgical resection and whole-brain radiation therapy (WBRT) are accepted treatments for single and oligometastatic cancer to the brain. To avoid the decline in neurocognitive function (NCF) linked to WBRT, the authors conducted a prospective, multicenter, phase 2 study to determine whether surgery and carmustine wafers (CW), while deferring WBRT, could preserve NCF and achieve local control (LC). METHODS: NCF and LC were measured in 59 patients who underwent resection and received CW for a single (83%) or dominant (oligometastatic, 2 to 3 lesions) metastasis and received stereotactic radiosurgery (SRS) for tiny nodules not treated with resection plus CW. Preservation of NCF was defined as an improvement or a decline ≤ 1 standard deviation from baseline in 3 domains: memory, executive function, and fine motor skills, evaluated at 2-month intervals. RESULTS: Significant improvements in executive function and memory occurred throughout the 1-year follow-up. Preservation or improvement of NCF occurred in all 3 domains for the majority of patients at each of the 2-month intervals. NCF declined in only 1 patient. The chemowafers were well tolerated, and serious adverse events were reversible. There was local recurrence in 28% of the patients at 1-year follow-up. CONCLUSIONS: Patients with brain metastases had improvements in their cognitive trajectory, especially memory and executive function, after treatment with resection plus CW. The rate of LC (78%) was comparable to historic rates of surgery with WBRT and superior to reports of WBRT alone. For patients who undergo resection for symptomatic or large-volume metastasis or for tissue diagnosis, the addition of CW can be considered as an option.

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.

Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse.

The ability to predict metastatic potential could be of great clinical importance, however, it is uncertain if predicting metastasis to specific vital organs is feasible. As a first step in evaluating metastatic predictions, we analyzed multiple primary tumors and metastasis pairs and determined that >90% of 298 gene expression signatures were found to be similarly expressed between matched pairs of tumors and metastases; therefore, primary tumors may be a good predictor of metastatic propensity. Next, using a dataset of >1,000 human breast tumor gene expression microarrays we determined that HER2-enriched subtype tumors aggressively spread to the liver, while basal-like and claudin-low subtypes colonize the brain and lung. Correspondingly, brain and lung metastasis signatures, along with embryonic stem cell, tumor initiating cell, and hypoxia signatures, were also strongly expressed in the basal-like and claudin-low tumors. Interestingly, low "Differentiation Scores," or high expression of the aforementioned signatures, further predicted for brain and lung metastases. In total, these data identify that depending upon the organ of relapse, a combination of gene expression signatures most accurately predicts metastatic behavior.

Comparative Outcomes by Surgical Approach in Patients with Malignant Sinonasal Disease.

Objective There is a paucity of data on comparative outcomes for open versus endoscopic surgery for patients with malignant sinonasal pathology. Most of the available studies are limited by a sample size <100 patients. Design This is a retrospective cohort study. Setting The findings of this study come from a single-institution tertiary care center from 2008 to 2019. Participants In total, 199 patients who underwent surgery for malignant sinonasal disease participated in this study. Main Outcome Measures The main outcome measures were perioperative complications and reoperation. Results Patients in our sample had a mean age of 59.7 years (SD, 20.4). In total, 62% were male and 72% were white. An endoscopic-only approach was used in 41% of patients and an open or combined approach in 59% of patients. Squamous cell carcinoma was the most common pathology (43.0%), followed by sarcoma (9.5%), skin cancer (6.5%), sinonasal undifferentiated carcinoma (6.5%), and adenocarcinoma (5.5%). The all-cause complication rate was 14.6%. Patients with an open resection had a higher rate of intraoperative complications (5.9 vs. 0%; p = 0.043), postoperative complications (19.5 vs. 3.7%; p = 0.001), and all-cause complications (21.0 vs. 3.7%; p < 0.001). The likelihood of early reoperation (<6 months) or late reoperation (>6 months) did not significantly differ by surgical approach ( p = 1.000 and 0.741, respectively). Conclusion The endoscopic approach for resection of malignant sinonasal disease is viable for select patients and may be associated with a favorable complication rate compared with the open approach.

Tumor sound, auditory cues, and tissue pathology in glioma surgery: a proof-of-concept study.

OBJECTIVE: Visual, tactile, and auditory cues are used during surgery to differentiate tissue type. Auditory cues in glioma surgery have not been studied previously. The objectives of this study were 1) to evaluate the feasibility of recording sound generated by the suction device during glioma surgery in matched tissue samples, and 2) to characterize the acoustic variation that occurs in different tissue samples. METHODS: This was a prospective observational proof-of-concept study. Recordings were attempted in 20 patients in order meet the accrual target of 10 patients with matched sound and tissue data. For each patient, three 30- to 60-second recordings were made at these sites: normal white matter, infiltrative margin, and tumor. Tissue samples at each site were then reviewed by experienced neuropathologists, and agreement with surgical identification was estimated with the kappa statistic. Acoustic parameters were characterized for each sample. RESULTS: Data from 20 patients were analyzed. Patient-related or technical issues resulted in missing data for 10 patients, but the final 10 patients had both audio and tissue data for analysis. Among all tissue samples, fair agreement was observed between surgeon identification and actual pathology (κ = 0.24, standard error 0.096, p = 0.006). Acoustic data suggested that 1) the acoustic stimulus is broadband, 2) acoustic features are somewhat consistent within cases, 3) high-entropy values indicate irregularity of sound over time, and 4) bimodal pitch distributions could differentially reflect cues of interest. CONCLUSIONS: This study supports the feasibility of collecting intraoperative data on acoustic features during glioma surgery, and it provides an example of how an analysis could be performed to compare different types of tissues.

Disparities in Postoperative Endocrine Outcomes After Endoscopic-Assisted Transsphenoidal Pituitary Adenoma Resection.

Objectives Socioeconomic factors can influence morbidity in patients with pituitary adenoma. This study aims to identify associations between socioeconomic factors and postoperative outcomes in patients with pituitary adenomas. Methods A retrospective medical chart review was conducted on adult patients who underwent resection of purely sellar nonfunctional and functional pituitary adenomas between May 1, 2014, and May 31, 2020, at the University of North Carolina Medical Center. The main outcome measures included the incidence of postoperative diabetes insipidus (PDI), postoperative hyponatremia (PHN), and postoperative hypopituitarism (PHP). Outcome measures were analyzed using univariate and multivariate analyses against preoperative tumor volume as well as socioeconomic and demographic factors (self-identified race/ethnicity, age, gender, address assessed by the Area Deprivation Index (ADI), and insurance status). Results On univariate analysis, patients of Hispanic race/ethnicity and patients living in more disadvantaged neighborhoods had an increased incidence of postoperative diabetes insipidus. Patients who experienced PDI were significantly younger on average in both univariate and multivariate analyses. When analyzed further, patients of Hispanic race/ethnicity were significantly younger and more likely to be uninsured compared to their respective racial/ethnic counterparts. No significant correlations were found for PHN or PHP. Conclusions Patients of Hispanic race/ethnicity and patients living in more disadvantaged neighborhoods were more likely to experience PDI. This finding, when combined with findings regarding age and insurance status, suggests complex disparities in medical care that are confirmed or corroborated by prior literature. These results may enhance clinicians' management of patients from disadvantaged socioeconomic backgrounds through increased awareness of disparities and the provision of resources for assistance.