A Wearable Fluorescence Imaging Device for Intraoperative Identification of Human Brain Tumors.

Malignant glioma (MG) is the most common type of primary malignant brain tumors. Surgical resection of MG remains the cornerstone of therapy and the extent of resection correlates with patient survival. A limiting factor for resection, however, is the difficulty in differentiating the tumor from normal tissue during surgery. Fluorescence imaging is an emerging technique for real-time intraoperative visualization of MGs and their boundaries. However, most clinical grade neurosurgical operative microscopes with fluorescence imaging ability are hampered by low adoption rates due to high cost, limited portability, limited operation flexibility, and lack of skilled professionals with technical knowledge. To overcome the limitations, we innovatively integrated miniaturized light sources, flippable filters, and a recording camera to the surgical eye loupes to generate a wearable fluorescence eye loupe (FLoupe) device for intraoperative imaging of fluorescent MGs. Two FLoupe prototypes were constructed for imaging of Fluorescein and 5-aminolevulinic acid (5-ALA), respectively. The wearable FLoupe devices were tested on tumor-simulating phantoms and patients with MGs. Comparable results were observed against the standard neurosurgical operative microscope (PENTERO® 900) with fluorescence kits. The affordable and wearable FLoupe devices enable visualization of both color and fluorescence images with the same quality as the large and expensive stationary operative microscopes. The wearable FLoupe device allows for a greater range of movement, less obstruction, and faster/easier operation. Thus, it reduces surgery time and is more easily adapted to the surgical environment than unwieldy neurosurgical operative microscopes. Clinical and Translational Impact Statement-The affordable and wearable fluorescence imaging device developed in this study enables neurosurgeons to observe brain tumors with the same clarity and greater flexibility compared to bulky and costly operative microscopes.

Case report: A unique presentation of a high-grade neuroepithelial tumor with EWSR1::PATZ1 fusion with diagnostic, molecular, and therapeutic insights.

Background: EWSR1::PATZ1 fusion tumors are exceedingly rare in the central nervous system with only 14 prior cases documented. PATZ1 fusion neuroepithelial tumors are beginning to be recognized as a distinct molecular class of neoplasms that most often occur in children and young adults. These tumors are polyphenotypic, show diverse morphologic features, may be low- or high-grade, and tend to have an intermediate prognosis. Case presentation: Herein, we present an unusual case of a high-grade neuroepithelial tumor in a young man with an EWSR1::PATZ1 fusion. This case is unique because the tumor appears to have undergone high-grade transformation from a persistent low-grade glioma, which has yet to be reported. Furthermore, this case is the first to document concurrent RB1 loss, SMAD4 loss, and TP53 inactivation in this tumor type, which correlates with high-grade transformation. Fortunately, this patient is alive 2.5 years after treatment and 18.5 years after initial presentation, which provides a unique window into how these tumors clinically behave over a long follow-up period. Finally, we discuss the altered molecular pathways that are a result of the EWSR1::PATZ1 fusion and discuss potential therapeutic targets. Conclusion: Awareness of the emerging entity of PATZ1 fusion neuroepithelial tumors is important not only for accurate diagnostic and prognostic purposes but also for predicting response to therapy.

Comparison of Glioblastoma Outcomes in Two Geographically and Ethnically Distinct Patient Populations in Disparate Health Care Systems.

Introduction Variations in glioblastoma (GBM) outcomes between geographically and ethnically distinct patient populations has been rarely studied. To explore the possible similarities and differences, we performed a comparative analysis of GBM patients at the University of Kentucky (UK) in the United States and the Aga Khan University Hospital (AKUH) in Pakistan. Methods A retrospective review was conducted of consecutive patients who underwent surgery for GBM between January 2013 and December 2016 at UK, and July 2014 and December 2017 at AKUH. Patients with recurrent or multifocal disease on presentation and those who underwent only a biopsy were excluded. SPSS (v.25 IBM, Armonk, New York, United States) was used to collect and analyze data. Results Eighty-six patients at UK (mean age: 58.8 years; 37 [43%] < 60 years and 49 [57%] > 60 years) and 38 patients at AKUH (mean age: 49.1 years; 30 (79%) < 60 years and 8 (21%) > 60 years) with confirmed GBM were studied. At UK, median overall survival (OS) was 11.5 (95% confidence interval [CI]: 8.9-14) months, while at AKUH, median OS was 18 (95% CI: 13.9-22) months ( p = 0.002). With gross-total resection (GTR), median OS at UK was 16 (95% CI: 9.5-22.4) months, whereas at AKUH, it was 24 (95% CI: 17.6-30.3) months ( p = 0.011). Conclusion Median OS at UK was consistent with U.S. data but was noted to be longer at AKUH, likely due to a younger patient cohort and higher preoperative Karnofsky's performance scale (KPS). GTR, particularly in patients younger than 60 years of age and a higher preoperative KPS had a significant positive impact on OS and progression-free survival (PFS) at both institutions.

Innate immune activation by checkpoint inhibition in human patient-derived lung cancer tissues.

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug's action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients' TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients' native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with 13C6-Glc/13C5,15N2-Gln, multiplex immunofluorescence, and digital spatial profiling (DSP) were employed to interrogate metabolic and functional responses to Pembrolizumab and/or WGP. Primary and BM PD-1+ lung cancer OTC responded to Pembrolizumab and Pembrolizumab + WGP treatments, respectively. Pembrolizumab activated innate immune metabolism and functions in primary OTC, which were accompanied by tissue damage. DSP analysis indicated an overall decrease in immunosuppressive macrophages and T cells but revealed microheterogeneity in immune responses and tissue damage. Two TMEs with altered cancer cell properties showed resistance. Pembrolizumab or WGP alone had negligible effects on BM-lung cancer OTC but Pembrolizumab + WGP blocked central metabolism with increased pro-inflammatory effector release and tissue damage. In-depth metabolic analysis and multiplex TME imaging of lung cancer OTC demonstrated overall innate immune activation by Pembrolizumab but heterogeneous responses in the native TME of a patient with primary NSCLC. Metabolic and functional analysis also revealed synergistic action of Pembrolizumab and WGP in OTC of metastatic NSCLC.

ACGME Operative Case Log Accuracy Varies Among Surgical Programs.

OBJECTIVE: This study evaluates the accuracy of reported the Accreditation Council for Graduate Medical Education (ACGME) operative case logs from graduated residents compared to institutional operating room electronic records (ORER). We hope this will help guide review committees and institutions develop complete, accurate resident case logs. DESIGN: This is a retrospective, cross-sectional study of general surgery (GS), neurosurgery (NS), and orthopedic surgery (OS) resident physicians. ACGME and ORER cases from 2009 to 2010 were analyzed and each case and current procedural terminology (CPT) code directly compared (ORER vs. ACGME). SETTING: Single academic tertiary-care medical center (University of Kentucky, Lexington, KY). PARTICIPANTS: Eleven thousand nine hundred and twenty-three cases for 46 residents among the 3 residency programs were analyzed. RESULTS: There was an overall logging accuracy of 72% for ORER cases reflected in the ACGME case logs. OS residents had a higher rate of logging accuracy (OS 91%, GS 69%, NS 58%, chi-square p = 0.014) and mean annual number of cases compared to the other 2 programs (OS 452, GS 183, NS 237, ANOVA p = 0.001). NS residents had higher accuracy of CPT codes than post-graduate years 2 to 5 in other programs (p < 0.017). There was a strong positive correlation between the number of cases completed per resident and case logging accuracy, (rho = 0.769, p < 0.001) consistent for NS and GS, but not OS. CONCLUSIONS: This study shows only 72% of a residents' operative experience is captured in the ACGME case log across 3 surgical programs. There is significant variability among surgical programs and among post-graduate year cohorts regarding case log and CPT code accuracy. There is a strong correlation with the total number of cases performed and increasing case log accuracy. Low case log accuracy may reflect individual resident behavior instead of program operative exposure. Further studies are needed to determine if ORER may serve as a more complete assessment of the operative experience of a resident and program.

Initial management of meningiomas: Analysis of the National Cancer Database.

BACKGROUND: Meningiomas are the most common central nervous system tumor. We describe current trends in treatment and survival using the largest cancer dataset in the United States. METHODS: We analyzed the National Cancer Database from 2004 to 2014, for all patients with diagnosis of meningioma. RESULTS: 201,765 cases were analyzed. Patients were most commonly White (81.9%) females (73.2%) with a median age of 64 years. Fifty percent of patients were diagnosed by imaging. Patients were reported as grade I (24.9%), grade II (5.0%), grade III (0.7%), or unknown WHO grade (69.4%). Patients diagnosed by imaging were older, received treatment in community facilities, had higher Charlson-Deyo score, and a lower rate of private insurance. Watchful waiting was the most common treatment modality (46.7%), followed by surgery only (40%). Grade II and III patients were more likely to receive therapy. Watchful waiting increased from 35.2% in 2004 to 51.4% in 2014. Younger age, male gender, private insurance, and treatment in academic facilities were determinants for receipt of surgery and/or radiation. Median survival was 12.6 years, higher in histologically confirmed cases (13.1 years). Older patients, Blacks, males, those that received radiation plus surgery, and were treated in community facilities had an increased risk of mortality. CONCLUSIONS: Over half of patients were diagnosed by imaging, suggesting a higher role of clinical determinants over histological confirmation in treatment decisions. Watchful waiting as initial management is increasing. Our survival analysis favored histological confirmation. Patients receiving radiation and surgery had an increased risk of mortality.

Patterns and disparities of care in glioblastoma.

BACKGROUND: Glioblastoma is an aggressive disease with a defined standard of care offering crucial survival benefits. Disparities in care may influence treatment decisions. This study seeks to evaluate potential patterns in care delivery using the National Cancer Database (NCDB). METHODS: We evaluated the NCDB from 1998 to 2011 for patients diagnosed with glioblastoma older than 20 years of age in order to describe current hospital-based demographics, rates of treatment modality by age, race, gender, likelihood of receiving treatment, and survival probabilities. RESULTS: From 1998 to 2011, 100672 patients were diagnosed with glioblastoma in the United States. Of these, 54% were younger than 65 years of age, while 20% were 75 years of age or older. The most common type of treatment was surgery (73%), followed by radiation (69%) and chemotherapy (50%). Eleven percent of patients did not receive any form of therapy. Patients receiving no form of treatment were more likely to be older, female, black, or Hispanic. Tumors that did not involve brainstem, ventricles, or the cerebellum were associated with more aggressive treatment and better overall survival. The median survival was 7.5 months. The use of concomitant surgical resection, chemotherapy, and radiation demonstrated greater survival benefit. CONCLUSIONS: Median survival for glioblastoma is significantly less than reported in clinical trials. Sociodemographic factors such as age, gender, race, and socioeconomic status affect treatment decisions for glioblastoma. The elderly are greatly undertreated, as many elderly patients receive no treatment or significantly less than standard of care.

Comprehensive evaluation of treatment and outcomes of low-grade diffuse gliomas.

BACKGROUND: Low-grade gliomas affect younger adults and carry a favorable prognosis. They include a variety of biological features affecting clinical behavior and treatment. Having no guidelines on treatment established, we aim to describe clinical and treatment patterns of low-grade gliomas across the largest cancer database in the United States. METHODS: We analyzed the National Cancer Database from 2004 to 2015, for adult patients with a diagnosis of World Health Organization grade II diffuse glioma. RESULTS: We analyzed 13,621 cases with median age of 41 years. Over 56% were male, 88.4% were white, 6.1% were black, and 7.6% Hispanic. The most common primary site location was the cerebrum (79.9%). Overall, 72.2% received surgery, 36.0% radiation, and 27.3% chemotherapy. Treatment combinations included surgery only (41.5%), chemotherapy + surgery (6.6%), chemotherapy only (3.1%), radiation + chemotherapy + surgery (10.7%), radiation + surgery (11.5%), radiation only (6.1%), and radiotherapy + chemotherapy (6.7%). Radiation was more common in treatment of elderly patients, 1p/19q co-deletion (37.3% versus 24.3%, p<0.01), and tumors with midline location. Median survival was 11 years with younger age, 1p/19q co-deletion, and cerebrum location offered survival advantage. CONCLUSIONS: Tumor location, 1p/19q co-deletion, and age were the main determinants of treatment received and survival, likely reflecting tumor biology differences. Any form of treatment was preferred over watchful waiting in the majority of the patients (86.1% versus 8.1%). Survival of low-grade gliomas is higher than previously reported in the majority of clinical trials and population-based analyses. Our analysis provides a real world estimation of treatment decisions, use of molecular data, and outcomes.

Novel Temporary Treatment for a Severe Case of Syndrome of Trephined.

BACKGROUND: Syndrome of the trephined is a unique neurosurgical condition that is seen in patients that have undergone craniectomy. While the symptoms of the condition range from mild to severe, the only definitive treatment for the condition is replacement of the bone flap. This article presents a novel, temporary treatment for syndrome of the trephined in a patient with severe symptoms who was unable to undergo immediate cranioplasty due to infection. CASE DESCRIPTION: A 25-year-old gentleman with a history of trauma resulting in hydrocephalus, craniectomy, and eventually ventriculoperitoneal shunt placement presented with a cranial wound infection requiring removal of his bone flap. While being treated with antibiotics, with his bone flap removed, he developed severe syndrome of the trephined. An emergency bedside procedure was developed and executed to treat his condition. CONCLUSIONS: Treating syndrome of the trephined with an external suction device proved useful and lifesaving fort the patient presented. Such a device can be made with common supplies found within any hospital. The technique used to treat the patient is novel and may be useful for others to consider if ever faced with a similar situation.

Characteristics and survival outcomes associated with the lack of radiation in the treatment of glioblastoma.

Radiation increases survival in glioblastoma (GBM); however, 30% do not receive this treatment. We sought to identify characteristics associated with not receiving radiation and the impact on outcomes. We analyzed the Surveillance, Epidemiology, and End Results program (SEER) 18 registries 2000-2013 research database on 30,479 GBM cases that were aged 20 years and older. In total, 21,179 received radiation as first course of therapy, while 8218 did not with 5178 (63%) being 65 years and older. Early decisions on surgery often predicted radiation therapy with 61% having only a biopsy or no surgery at diagnosis. Radiation use as upfront therapy has slowly increased over time at a rate of 0.4% per year; still 25% did not receive radiation in 2013. Cases treated with radiation were more likely to be younger, underwent surgery, lived in a metropolitan area, had higher socioeconomic status, and were in a couple-based relationship. An increased survival in GBM was associated with the use of upfront radiation along with younger age, being of race other than white, undergoing surgery, and a more recent diagnosis. Not receiving radiation therapy adversely affects survival. A trend toward an increased use of radiation was observed although many young adults still do not receive this treatment. Decreased usage of radiation in the elderly and in biopsy-only surgeries was anticipated, but race, gender, and poverty were also statistically significant. Clinicians should be aware of this underutilization, and an increased usage of radiation should improve outcomes for glioblastoma.

Can patients safely be admitted to a ward after craniotomy for resection of intra-axial brain tumors?

OBJECTIVE: We reviewed the safety of our practice of admitting patients who have undergone a craniotomy for resection of an intra-axial brain tumor to a floor bed instead of an ICU. We also tried to quantify the risk that patients electively admitted to the ICU would develop a problem that could not have been effectively managed on the ward. METHODS: A retrospective chart review was performed of both adult and pediatric patients who underwent craniotomy by the senior author for resection of an intra-axial brain tumor between January 2012 and December 2015. 413 patient charts were reviewed; 16 patients were omitted due to incomplete records. RESULTS: Four hundred twenty-one craniotomies (393 supratentorial, 28 infratentorial) were performed in 397 patients, 35 of whom were <18 years of age. Three hundred fifty-five patients (83%) were admitted to floor beds; 4 (1.1%) developed complications that required transfer to an ICU. None of the 4 died or had lasting disability. Sixty-six patients, 51 adults and 15 children, were admitted to the ICU after their operation. Twenty-five of these patients had an absolute indication for ICU admission: 9 required a ventilator, 14 had an EVD and 2 were medically unstable. Of the remaining 41, none developed a complication that would have required transfer to an ICU had they been on the ward. CONCLUSION: It is safe to admit almost all patients to a floor bed after craniotomy for intra-axial brain tumor resection. The risk of a catastrophic problem occurring after a 4 hour stay in the post anesthesia care unit is extremely low. Furthermore, even patients who are electively managed in an ICU are unlikely to develop problems that would lead to a worse outcome had they been in a floor bed.

Polyubiquitination of apurinic/apyrimidinic endonuclease 1 by Parkin.

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein crucial for repair of oxidized DNA damage not only in genomic DNA but also in mitochondrial DNA. Parkin, a tumor suppressor and Parkinson's disease (PD) associated gene, is an E3 ubiquitin ligase crucial for mitophagy. Although DNA damage is known to induce mitochondrial stress, Parkin's role in regulating DNA repair proteins has not been elucidated. In this study, we examined the possibility of Parkin-dependent ubiquitination of APE1. Ectopically expressed APE1 was degraded by Parkin and PINK1 via polyubiquitination in mouse embryonic fibroblast cells. PD-causing mutations in Parkin and PINK1 abrogated APE1 ubiquitination. Interaction of APE1 with Parkin was observed by co-immunoprecipitation, proximity ligation assay, and co-localization in the cytoplasm. N-terminal deletion of 41 amino acid residues in APE1 significantly reduced the Parkin-dependent APE1 degradation. These results suggested that Parkin directly ubiquitinated N-terminal Lys residues in APE1 in the cytoplasm. Modulation of Parkin and PINK1 activities under mitochondrial or oxidative stress caused moderate but statistically significant decrease of endogenous APE1 in human cell lines including SH-SY5Y, HEK293, and A549 cells. Analyses of glioblastoma tissues showed an inverse relation between the expression levels of APE1 and Parkin. These results suggest that degradation of endogenous APE1 by Parkin occur when cells are stressed to activate Parkin, and imply a role of Parkin in maintaining the quality of APE1, and loss of Parkin may contribute to elevated APE1 levels in glioblastoma. © 2016 Wiley Periodicals, Inc.

Use of dermal regeneration template to close a giant myelomeningocele in a newborn.

Many techniques are available to close a myelomeningocele, but large lesions can be particularly difficult to close given the absence of surrounding tissue. The authors present the case of a 2-day-old girl with a large lumbosacral myelomeningocele who underwent a staged repair using dermal regeneration template (DRT; Integra) followed by split-thickness skin grafting. The results demonstrated that the combined use of myofascial turnover flaps and DRT with delayed skin grafting is a safe, effective option for this challenging reconstructive dilemma.

Alternating magnetic field-induced hyperthermia increases iron oxide nanoparticle cell association/uptake and flux in blood-brain barrier models.

PURPOSE: Superparamagnetic iron oxide nanoparticles (IONPs) are being investigated for brain cancer therapy because alternating magnetic field (AMF) activates them to produce hyperthermia. For central nervous system applications, brain entry of diagnostic and therapeutic agents is usually essential. We hypothesized that AMF-induced hyperthermia significantly increases IONP blood-brain barrier (BBB) association/uptake and flux. METHODS: Cross-linked nanoassemblies loaded with IONPs (CNA-IONPs) and conventional citrate-coated IONPs (citrate-IONPs) were synthesized and characterized in house. CNA-IONP and citrate-IONP BBB cell association/uptake and flux were studied using two BBB Transwell(®) models (bEnd.3 and MDCKII cells) after conventional and AMF-induced hyperthermia exposure. RESULTS: AMF-induced hyperthermia for 0.5 h did not alter CNA-IONP size but accelerated citrate-IONP agglomeration. AMF-induced hyperthermia for 0.5 h enhanced CNA-IONP and citrate-IONP BBB cell association/uptake. It also enhanced the flux of CNA-IONPs across the two in vitro BBB models compared to conventional hyperthermia and normothermia, in the absence of cell death. Citrate-IONP flux was not observed under these conditions. AMF-induced hyperthermia also significantly enhanced paracellular pathway flux. The mechanism appears to involve more than the increased temperature surrounding the CNA-IONPs. CONCLUSIONS: Hyperthermia induced by AMF activation of CNA-IONPs has potential to increase the BBB permeability of therapeutics for the diagnosis and therapy of various brain diseases.

Refractory anaplastic astrocytoma responsive to PCV in combination with bevacizumab.

We present a patient with anaplastic astrocytoma who had recurrent disease after treatment with surgery, radiation, procarbazine, lomustine (CCNU) and vincristine (PCV) over one year followed by poor response to second line treatment with temozolomide, irinotecan with bevacizumab, Novocure TTF therapy successively over a four year period after her initial treatment who then responded to PCV in combination with bevacizumab as third line therapy. This is the first report demonstrating benefit of concurrent PCV and bevacizumab treatment in a highly treatment refractory tumor.

Long-term treatment with temozolomide in malignant glioma.

Six months of maintenance temozolomide (TMZ) following concurrent TMZ chemotherapy and radiation therapy has become the standard of care in the treatment of glioblastoma. In addition, TMZ has also been used to treat other forms of glioma although less evidence of efficacy exists. TMZ administration longer than 6months is common in clinical practice, but it is unusual for the drug to be administered longer than 1 to 2years. We report five patients who received long-term treatment with TMZ chemotherapy at normal dosing levels. One of these patients was diagnosed with glioblastoma, two with anaplastic astrocytoma, one with gliosarcoma, and one with oligo-astrocytoma. The length of treatment in our group of patients ranged from 45 to 85 cycles of TMZ. Common Terminology Criteria for Adverse Events (CTCAE) developed by The National Cancer Institute was used to classify toxicity. Two patients experienced no toxicity per CTCAE guidelines. One patient experienced grade I thrombocytopenia, one developed grade I leukopenia, and one experienced both grade I thrombocytopenia and grade I nausea, all which resolved with either withholding TMZ for 1month or supportive treatment. Our report provides evidence that long-term TMZ chemotherapy is a therapeutic option when appropriately monitored.

Autophagy and oxidative stress in gliomas with IDH1 mutations.

IDH1 mutations in gliomas associate with longer survival. Prooxidant and antiproliferative effects of IDH1 mutations and its D-2-hydroxyglutarate (2-HG) product have been described in vitro, but inconsistently observed. It is also unclear whether overexpression of mutant IDH1 in wild-type cells accurately phenocopies the effects of endogenous IDH1-mutations on tumor apoptosis and autophagy. Herein we investigated the effects of 2-HG and mutant IDH1 overexpression on proliferation, apoptosis, oxidative stress, and autophagy in IDH1 wild-type glioma cells, and compared those results with patient-derived tumors. 2-HG reduced viability and proliferation of U87MG and LN18 cells, triggered apoptosis in LN18 cells, and autophagy in U87MG cells. In vitro studies and flank xenografts of U87MG cells overexpressing R132H IDH1 exhibited increased oxidative stress, including increases of both manganese superoxide dismutase (MnSOD) and p62. Patient-derived IDH1-mutant tumors showed no significant differences in apoptosis or autophagy, but showed p62 accumulation and actually trended toward reduced MnSOD expression. These data indicate that mutant IDH1 and 2-HG can induce oxidative stress, autophagy, and apoptosis, but these effects vary greatly according to cell type.