Outpatient neurosurgery in neuro-oncology.

Technological breakthroughs along with modern application of awake craniotomy and new neuroanesthesia protocols have led to a progressive development in outpatient brain tumor surgery and improved surgical outcomes. As a result, outpatient neurosurgery has become a standard of care at the authors' center due to its clinical benefits and impact on patient recovery and overall satisfaction. On the other hand, the financial savings derived from its application is also another favorable factor exerting influence on patients, health care systems, and society. Although validated several years ago and with recent data supporting its application, outpatient brain tumor surgery has not gained the traction that it deserves, based on scientific skepticism and perceived potential for medicolegal issues. The goal of this review, based on the available literature and the senior author's experience in outpatient brain tumor surgery, was to evaluate the most important aspects regarding indications, clinical outcomes, economic burden, and patient perceptions.

Global neurosurgery: models for international surgical education and collaboration at one university.

OBJECTIVE: International collaborations between high-income (HICs) and low- and middle-income countries (LMICs) have been developed as an attempt to reduce the inequalities in surgical care around the world. In this paper the authors review different models for international surgical education and describe projects developed by the Division of Neurosurgery at the University of Toronto in this field. METHODS: The authors conducted a review of models of international surgical education reported in the literature in the last 15 years. Previous publications on global neurosurgery reported by the Division of Neurosurgery at the University of Toronto were reviewed to exemplify the applications and challenges of international surgical collaborations. RESULTS: The most common models for international surgical education and collaboration include international surgical missions, long-term international partnerships, fellowship training models, and online surgical education. Development of such collaborations involves different challenges, including limited time availability, scarce funding/resources, sociocultural barriers, ethical challenges, and lack of organizational support. Of note, evaluation of outcomes of international surgical projects remains limited, and the development and application of assessment tools, such as the recently proposed Framework for the Assessment of International Surgical Success (FAIRNeSS), is encouraged. CONCLUSIONS: Actions to reduce inequality in surgical care should be implemented around the world. Different models can be used for bilateral exchange of knowledge and improvement of surgical care delivery in regions where there is poor access to surgical care. Implementation of global neurosurgery initiatives faces multiple limitations that can be ameliorated if systematic changes occur, such as the development of academic positions in global surgery, careful selection of participant centers, governmental and nongovernmental financial support, and routine application of outcome evaluation for international surgical collaborations.

[Neuroprotective subthalamotomy in Parkinson's disease. The role of magnetic resonance-guided focused ultrasound in early surgery]. / Subtalamotomía como neuroprotección en la enfermedad de Parkinson. El papel de los ultrasonidos guiados por resonancia como cirugía temprana.

Subthalamic nucleus hyperactivity in Parkinson's disease may be a very early phenomenon. Its start is not well known, and it may occur during the pre-symptomatic disease stage. Glutamatergic hyperactivity may be neurotoxic over the substantia nigra compacta dopaminergic neurons. If this occurred, the excitatory neurotransmitter, glutamate, should affect the neurons that maintain a high turnover as a compensatory mechanism. Would a subthalamic nucleus lesion decrease this hyperactivity and thus be considered as a neuroprotective mechanism for dopaminergic neurons? The authors hypothesise about the possibility to perform surgery on a subthalamic nucleus lesion at a very early stage in order to avoid the neurotoxic glutamatergic effect over the dopaminergic neurons, and therefore be considered as a neuroprotective surgery able to alter the progress of the disease during early motor symptoms. In this regard, magnetic resonance-guided focused ultrasound techniques open a new window in the stereotactic armamentarium.

Factors associated with a higher rate of distant failure after primary treatment for glioblastoma.

Our purpose was to analyze the pattern of failure in glioblastoma (GBM) patients at first recurrence after radiotherapy and temozolomide and its relationship with different factors. From 77 consecutive GBM patients treated at our institution with fluorescence guided surgery and standard radiochemotherapy, 58 first recurrences were identified and included in a retrospective review. Clinical data including age, Karnofsky performance score, preoperative tumor volume and location, extend of resection, MGMT promoter methylation status, time to progression (PFS), overall survival (OS) and adjuvant therapies were reviewed for every patient. Recurrent tumor location respect the original lesion was the end point of the study. The recurrence pattern was local only in 65.5% of patients and non-local in 34.5%. The univariate and multivariate analysis showed that greater preoperative tumor volume in T1 gadolinium enhanced sequences, was the only variable with statistical signification (p < 0.001) for increased rate of non-local recurrences, although patients with MGMT methylation and complete resection of enhancing tumor presented non-local recurrences more frequently. PFS was longer in patients with non-local recurrences (13.8 vs. 6.4 months; p = 0.019, log-rank). However, OS was not significantly different in both groups (24.0 non-local vs. 19.3 local; p = 0.9). Rate of non-local recurrences in our series of patients treated with fluorescence guided surgery and standard radiochemotherapy was higher than previously published in GBM, especially in patients with longer PFS. Greater preoperative enhancing tumor volume was associated with increased rate of non-local recurrences.

Spectrum of gluten-sensitive enteropathy in patients with dysmotility-like dyspepsia.

BACKGROUND: Dysmotility-like dyspepsia symptoms are frequent in patients with gluten-sensitive enteropathy (GSE). Current data suggest that patients with mild enteropathy may be present with gluten-sensitive symptoms and complications. AIM: To investigate the prevalence of GSE, including mild enteropathy, in patients with dysmotility-like dyspepsia symptoms. METHODS: We retrospectively studied 142 patients who presented dysmotility-like dyspepsia symptoms and normal upper gastrointestinal endoscopy. Endoscopic duodenal biopsies were taken and processed using hematoxylin-eosin staining and CD3 immunophenotyping. In patients with enteropathy (number of intraepithelial lymphocytes greater than 25 per 100 enterocytes) we also performed coeliac serology (anti-tissue transglutaminase IgA) and HLA-DQ2/DQ8 genotyping. A gluten-free diet was offered if one of these markers was positive. The final GSE diagnosis was established based on clinical and histopathological response to the gluten-free diet after 18 months of follow-up. RESULTS: Fifty-one patients (35.9%) had enteropathy; 4 (2.8%) Marsh type 3b, 24 (16.9%) Marsh type 3a, 3 (2.1%) Marsh type 2, and 20 (14.1%) Marsh type 1. A positive serology result was extremely low (6.7%) in mild enteropathy (Marsh type 1-3a) in contrast with Marsh type 3b patients (50%). Most patients with enteropathy had positive HLA DQ2 or -DQ8 genotyping (84.1%). Out of the 37 patients who started a gluten-free diet, 34 (91.9%) improved their symptoms, and 28 of 32 (87.5%) had a histopathological or serological response. A final GSE diagnosis was established in 28 of the 142 patients (19.7%). CONCLUSION: Gluten-sensitive enteropathy can be a frequent and unsuspected cause of dysmotility-like dyspepsia.

[Lymphocytic duodenosis: etiological study and clinical presentations]. / Duodenosis linfocítica: estudio etiológico y formas de presentación clínica.

INTRODUCTION: Lymphocytic duodenosis (LD) is a characteristic lesion in the initial phases of celiac disease (CD) but can be associated with many other entities. The aim of this study was to evaluate the prevalence of distinct causes of LD and possible differences in clinical presentation according to etiology. METHODS: A retrospective study was performed that included 194 patients diagnosed with LD (more than 25 intraepithelial lymphocytes per 100 epithelial cells). A preestablished strategy to evaluate the cause of the disease was followed that included celiac serology (antitransglutaminase antibodies), HLA-DQ2/DQ8 genotypes, diagnosis of Helicobacter pylori and small intestinal bacterial overgrowth (SIBO). Diagnosis of CD was established on the basis of clinical and histological response to a gluten-free diet in patients with positive serology or compatible findings on HLA-DQ2 (at least one of the alleles) or -DQ8 (both alleles) study. RESULTS: The most frequent cause of LD was CD (39%), followed by SBBO (22%), H.pylori (14%), CD and SIBO (12%), and other causes (13%). Most of the patients (83%) had a compatible HLA-DQ2 or -DQ8 genotype. In these patients, the most frequent diagnosis was CD (46%), while in the absence of HLA-DQ2/DQ8, the most frequent diagnoses were SIBO (44%) and H. pylori (22%). CD was the most frequent diagnosis in patients referred for dyspepsia, diarrhea and anemia, while H. pylori was the most frequent diagnosis in patients with abdominal pain. CONCLUSIONS: The most common causes of LD in our environment are CD, followed by SIBO and H. pylori infection.

RNU6-1 in circulating exosomes differentiates GBM from non-neoplastic brain lesions and PCNSL but not from brain metastases.

BACKGROUND: Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Circulating biomarkers may assist in the processes of differential diagnosis and response assessment. GBM cells release extracellular vesicles containing a subset of proteins and nucleic acids. We previously demonstrated that exosomes isolated from the serum of GBM patients had an increased expression of RNU6-1 compared to healthy subjects. In this exploratory study, we investigated the role of this small noncoding RNA as a diagnostic biomarker for GBM versus other brain lesions with some potential radiological similarities. METHODS: We analyzed the expression of RNU6-1 in circulating exosomes of GBM patients (n = 18), healthy controls (n = 30), and patients with subacute stroke (n = 30), acute/subacute hemorrhage (n = 30), acute demyelinating lesions (n = 18), brain metastases (n = 21), and primary central nervous system lymphoma (PCNSL; n = 12) using digital droplet PCR. RESULTS: Expression of RNU6-1 was significantly higher in GBM patients than in healthy controls (P = .002). RNU6-1 levels were also significantly higher in exosomes from GBM patients than from patients with non-neoplastic lesions (stroke [P = .05], hemorrhage [P = .01], demyelinating lesions [P = .019]) and PCNSL (P = .004). In contrast, no significant differences were found between patients with GBM and brain metastases (P = .573). Receiver operator characteristic curve analyses supported the role of this biomarker in differentiating GBM from subacute stroke, acute/subacute hemorrhage, acute demyelinating lesions, and PCNSL (P < .05), but again not from brain metastases (P = .575). CONCLUSIONS: Our data suggest that the expression of RNU6-1 in circulating exosomes could be useful for the differentiation of GBM from non-neoplastic brain lesions and PCNSL, but not from brain metastases.

Conditional KCa3.1-transgene induction in murine skin produces pruritic eczematous dermatitis with severe epidermal hyperplasia and hyperkeratosis.

Ion channels have recently attracted attention as potential mediators of skin disease. Here, we explored the consequences of genetically encoded induction of the cell volume-regulating Ca2+-activated KCa3.1 channel (Kcnn4) for murine epidermal homeostasis. Doxycycline-treated mice harboring the KCa3.1+-transgene under the control of the reverse tetracycline-sensitive transactivator (rtTA) showed 800-fold channel overexpression above basal levels in the skin and solid KCa3.1-currents in keratinocytes. This overexpression resulted in epidermal spongiosis, progressive epidermal hyperplasia and hyperkeratosis, itch and ulcers. The condition was accompanied by production of the pro-proliferative and pro-inflammatory cytokines, IL-ß1 (60-fold), IL-6 (33-fold), and TNFα (26-fold) in the skin. Treatment of mice with the KCa3.1-selective blocker, Senicapoc, significantly suppressed spongiosis and hyperplasia, as well as induction of IL-ß1 (-88%) and IL-6 (-90%). In conclusion, KCa3.1-induction in the epidermis caused expression of pro-proliferative cytokines leading to spongiosis, hyperplasia and hyperkeratosis. This skin condition resembles pathological features of eczematous dermatitis and identifies KCa3.1 as a regulator of epidermal homeostasis and spongiosis, and as a potential therapeutic target.

Minimally invasive system to reliably characterize ventricular electrophysiology from living donors.

Cardiac tissue slices preserve the heterogeneous structure and multicellularity of the myocardium and allow its functional characterization. However, access to human ventricular samples is scarce. We aim to demonstrate that slices from small transmural core biopsies collected from living donors during routine cardiac surgery preserve structural and functional properties of larger myocardial specimens, allowing accurate electrophysiological characterization. In pigs, we compared left ventricular transmural core biopsies with transmural tissue blocks from the same ventricular region. In humans, we analyzed transmural biopsies and papillary muscles from living donors. All tissues were vibratome-sliced. By histological analysis of the transmural biopsies, we showed that tissue architecture and cellular organization were preserved. Enzymatic and vital staining methods verified viability. Optically mapped transmembrane potentials confirmed that action potential duration and morphology were similar in pig biopsies and tissue blocks. Action potential morphology and duration in human biopsies and papillary muscles agreed with published ranges. In both pigs and humans, responses to increasing pacing frequencies and ß-adrenergic stimulation were similar in transmural biopsies and larger tissues. We show that it is possible to successfully collect and characterize tissue slices from human myocardial biopsies routinely extracted from living donors, whose behavior mimics that of larger myocardial preparations both structurally and electrophysiologically.

Expanded Endoscopic Endonasal Approach for Resection of Intradural Chordoma: Surgical and Anatomic Nuances: 2-Dimensional Operative Video.

The expanded endoscopic endonasal approach (EEA) has been growing as a surgical alternative for the treatment of clival chordomas because of their frequent midline location and bone erosion. The endoscopic transclival approach provides with a safer and more direct anatomic route for tumors located predominantly in the midline contributing to minimize postoperative comorbidities. In this video, we demonstrate the step-by-step technique for resection of such challenging clival pathology. This is an operative video of an extended endoscopic resection of a clival chordoma with stepwise description of the surgical technique. We present the case of a 49-yr-old man in whom, incidentally in the context of low testosterone level, a clival lesion with purely midline location with intradural extension into the ventral brainstem and occupation of the left cerebellopontine angle was discovered. The patient was submitted to an expanded endoscopic transclival approach and a macroscopic gross total resection was successfully achieved. The final pathology was compatible with a conventional chordoma. This video details the surgical anatomy of the clival region to facilitate the identification of surgical landmarks and anatomic boundaries with the goal of avoiding injury to the neurovascular structures involved in this approach. Extended endoscopic transclival surgery is a useful and safer option for the management of midline chordomas because it provides with a dissection corridor free of major neurovascular structures. Endoscopic techniques are associated with good outcomes in terms of macroscopic gross total resection and low surgical risks in these selected tumors.

Characterisation of resistance mechanisms developed by basal cell carcinoma cells in response to repeated cycles of Photodynamic Therapy.

Photodynamic Therapy (PDT) with methyl-aminolevulinate acid (MAL-PDT) is being used for the treatment of Basal cell carcinoma (BCC), but recurrences have been reported. In this work, we have evaluated resistance mechanisms to MAL-PDT developed by three BCC cell lines (ASZ, BSZ and CSZ), derived from mice on a ptch+/- background and with or without p53 expression, subjected to 10 cycles of PDT (10thG). The resistant populations showed mesenchymal-like structure and diminished proliferative capacity and size compared to the parental (P) cells. The resistance was dependent on the production of the endogenous photosensitiser protoporphyrin IX in the CSZ cell line and on its cellular localisation in ASZ and BSZ cells. Moreover, resistant cells expressing the p53 gene presented lower proliferation rate and increased expression levels of N-cadherin and Gsk3ß (a component of the Wnt/ß-catenin pathway) than P cells. In contrast, 10thG cells lacking the p53 gene showed lower levels of expression of Gsk3ß in the cytoplasm and of E-cadherin and ß-catenin in the membrane. In addition, resistant cells presented higher tumorigenic ability in immunosuppressed mice. Altogether, these results shed light on resistance mechanisms of BCC to PDT and may help to improve the use of this therapeutic approach.

Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models.

Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome. Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement. Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models. Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy. Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments. In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors. Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors. SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.

The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models.

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).

The aberrant splicing of BAF45d links splicing regulation and transcription in glioblastoma.

Background: Glioblastoma, the most aggressive primary brain tumor, is genetically heterogeneous. Alternative splicing (AS) plays a key role in numerous pathologies, including cancer. The objectives of our study were to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation. Methods: We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma. Results: BAF45d is part of the switch/sucrose nonfermentable complex and plays a key role in the development of the CNS. The BAF45d/6A isoform is present in 85% of over 200 glioma samples that have been analyzed and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription. Conclusions: Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.

Development of a DIPG Orthotopic Model in Mice Using an Implantable Guide-Screw System.

OBJECTIVE: In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. METHODS: It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. RESULTS: The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. CONCLUSION: Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.

Biphasic synovial sarcoma of the abdominal wall.

Synovial sarcoma arising in the abdominal wall is a rare tumor. We report a case of a 38-year-old man who complained of abdominal pain. Physical examination revealed a firm mobile mass, 25 cm in diameter, in the left lower abdominal wall. The tumor was first thought to be a sarcoma arising from the omentum or mesentery. During surgery, a large tumor was found attached to the inner surface of the abdominal wall and compressing the gastrointestinal tract. On microscopic examination the tumor corresponded to a biphasic synovial sarcoma immunoreactive for cytokeratins (AE1/AE3, 7 and 19), epithelial membrane antigen and carcinoembryonic antigen in the epithelial tumor cells, for E-cadherin especially in their glandular structure, vimentin, CD99, and CD56 in the spindle cell component and for bcl-2 protein. The tumor recurred at the same site, and clinical course progressed to death 3 months after the initial diagnosis.

Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic Acid-guided surgery.

BACKGROUND: There is evidence in the literature supporting that fluorescent tissue signal in fluorescence-guided surgery extends farther than tissue highlighted in gadolinium in T1 sequence magnetic resonance imaging (MRI), which is the standard to quantify the extent of resection. OBJECTIVE: To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) cases with complete resection confirmed by MRI. METHODS: A retrospective review in our center found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5-aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy. RESULTS: The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267). CONCLUSION: GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue.