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Background Initial learning curves are potentially shorter in robotic-assisted surgery (RAS) than in conventional laparoscopic surgery (LS). There is little evidence to support this claim. Furthermore, there is limited evidence how skills from LS transfer to RAS. Methods A randomized controlled, assessor blinded crossover study to compare how RAS naïve surgeons (n = 40) performed linear-stapled side-to-side bowel anastomoses in an in vivo porcine model with LS and RAS. Technique was rated using the validated anastomosis objective structured assessment of skills (A-OSATS) score and the conventional OSATS score. Skill transfer from LS to RAS was measured by comparing the RAS performance of LS novices and LS experienced surgeons. Mental and physical workload was measured with the NASA-task load index (NASA-Tlx) and the Borg-scale. Outcomes In the overall cohort, there were no differences between RAS and LS for surgical performance (A-OSATS, time, OSATS). Surgeons that were naïve in both LS and RAS had significantly higher A-OSATS scores in RAS (Mean (Standard deviation (SD)): LS: 48.0 ± 12.1; RAS: 52.0 ± 7.5); p = 0.044) mainly deriving from better bowel positioning (LS: 8.7 ± 1.4; RAS: 9.3 ± 1.0; p = 0.045) and closure of enterotomy (LS: 12.8 ± 5.5; RAS: 15.6 ± 4.7; p = 0.010). There was no statistically significant difference in how LS novices and LS experienced surgeons performed in RAS [Mean (SD): novices: 48.9 ± 9.0; experienced surgeons: 55.9 ± 11.0; p = 0.540]. Mental and physical demand was significantly higher after LS. Conclusion The initial performance was improved for RAS versus LS for linear stapled bowel anastomosis, whereas workload was higher for LS. There was limited transfer of skills from LS to RAS.

After esophagectomy, the postoperative rate of anastomotic leakage is between 5 and 30% and is the main driver of morbidity and mortality. Complication management is often based on endoluminal vacuum therapy (EndoVAC) with good success rates. Vacuum therapy has been shown to improve tissue perfusion in superficial wounds but this has not been shown for gastric conduits. The present study aimed to assess changes in gastric conduit perfusion in a porcine model for esophagectomy. Porcine model (n = 18) underwent gastric conduit formation and induction of partial conduit ischemia. In three experimental groups EndoVAC therapy was used in the gastric conduit (−40 mmHg, −125 mmHg and − 200 mmHg) with continuous suction. The changes in tissue perfusion and edema were assessed using hyperspectral imaging (HSI). During EndoVAC treatment with −125 mmHg a significant and stable increase in the oxygenation index from 44.9 ± 7.6% to 61.9 ± 5.5% and 62.9 ± 9.4%. (p = 0.02) was seen after 60 minutes and 120 minutes respectively. A similar trend was seen during EndoVAC treatment with −200 mmHg. There was a non-significant increase in tissue oxygenation during treatment with −40 mmHg. A significant increase of tissue water content from 40.8 ± 7.4 to 59.5 ± 10.3 (p = 0.004) was observed after 60 minutes of EndoVAC therapy with −200 mmHg. There were no significant differences in tissue water content during EndoVAC therapy with −40 mmHg and − 125 mmHg. EndoVAC treatment with a pressure of at least −125 mmHg significantly increases perfusion of partial ischemic gastric conduit. With better understanding of underlying physiology, the optimal use of EndoVac treatment can be guided and determined including a possible preemptive use for gastric conduits with impaired arterial perfusion or venous congestion. This can potentially be translated into clinical practice.

Intraoperative imaging assists surgeons during minimally invasive procedures. Hyperspectral imaging (HSI) is a noninvasive and noncontact optical technique with great diagnostic potential in medicine. The combination with artificial intelligence (AI) approaches to analyze HSI data is called intelligent HSI in this article.What are the medical applications and advantages of intelligent HSI for minimally invasive visceral surgery?Within various clinical studies HSI data from multiple in vivo tissue types and oncological resections were acquired using an HSI camera system. Different AI algorithms were evaluated for detection and discrimination of organs, risk structures and tumors.In an experimental animal study 20 different organs could be differentiated with high precision ( 95%) using AI. In vivo, the parathyroid glands could be discriminated from surrounding tissue with an F1 score of 47% and sensitivity of 75%, and the bile duct with an F1 score of 79% and sensitivity of 90%. Furthermore, ex vivo tumor tissue could be successfully detected with an area under the receiver operating characteristic (ROC) curve (AUC) larger than 0.91.This study demonstrates that intelligent HSI can automatically and accurately detect different tissue types. Despite great progress in the last decade intelligent HSI still has limitations. Thus, accurate AI algorithms that are easier to understand for the user and an extensive standardized and continuously growing database are needed. Further clinical studies should support the various medical applications and lead to the adoption of intelligent HSI in the clinical routine practice.HINTERGRUND: Intraoperative Bildgebung unterstützt Chirurgen bei minimal-invasiven Eingriffen. Die hyperspektrale Bildgebung („hyperspectral imaging“, HSI) ist ein nichtinvasives und kontaktloses optisches Verfahren mit großem diagnostischem Potenzial in der Medizin. Die Kombination mit Ansätzen der künstlichen Intelligenz (KI) für die Analyse der HSI-Daten wird in diesem Artikel intelligente HSI genannt.Wie kann intelligente HSI in der minimal-invasiven Viszeralchirurgie eingesetzt werden und wo liegen die Vorteile?Innerhalb verschiedener klinischer Studien wurden HSI-Daten mehrerer In-vivo-Gewebearten und onkologischer Resektate mit einer HSI-Kamera aufgenommen. Verschiedene KI-Algorithmen wurden zur Identifikation und Diskriminierung von Organen, Risikostrukturen und Tumoren evaluiert.Im Tierversuch konnten 20 verschiedene Organe mit hoher Genauigkeit ( 95 %) mittels KI differenziert werden. In-vivo konnten die Nebenschilddrüse mit einem F1-Score von 47 % und einer Sensitivität von 75 % sowie der Gallengang mit einem F1-Score von 79 % und einer Sensitivität von 90 % vom umliegenden Gewebe diskriminiert werden. Des Weiteren konnte Ex-vivo-Tumorgewebe mit einer Fläche unter der „Receiver-operating-characteristic“(ROC)-Kurve (AUC) größer als 0,91 erfolgreich erkannt werden.Die vorliegenden Arbeiten zeigen die Eignung intelligenter HSI zur automatischen Gewebeerkennung. Trotz großer Fortschritte in den letzten zehn Jahren zeigt intelligentes HSI noch Einschränkungen. So sind genauere und für den Benutzer verständlichere KI-Algorithmen sowie umfangreiche standardisierte und kontinuierlich wachsende Datenbanken notwendig. Weitere klinische Studien sollten die vielseitigen Anwendungen stützen und den Einsatz im klinischen Alltag fest etablieren.

Visual discrimination of tissue during surgery can be challenging since different tissues appear similar to the human eye. Hyperspectral imaging (HSI) removes this limitation by associating each pixel with high-dimensional spectral information. While previous work has shown its general potential to discriminate tissue, clinical translation has been limited due to the method’s current lack of robustness and generalizability. Specifically, it had been unknown whether variability in spectral reflectance is primarily explained by tissue type rather than the recorded individual or specific acquisition conditions. The contribution of this work is threefold: (1) Based on an annotated medical HSI data set (9,059 images from 46 pigs), we present a tissue atlas featuring spectral fingerprints of 20 different porcine organs and tissue types. (2) Using the principle of mixed model analysis, we show that the greatest source of variability related to HSI images is the organ under observation. (3) We show that HSI-based fully-automatic tissue differentiation of 20 organ classes with deep neural networks is possible with high accuracy (> 95 %). We conclude from our study that automatic tissue discrimination based on HSI data is feasible and could thus aid in intraoperative decision making and pave the way for context-aware computer-assisted surgery systems and autonomous robotics.Category for submissionExperimental studyLevel of EvidenceNot applicable. Translational animal science. Original article.

Semantic image segmentation is an important prerequisite for context-awareness and autonomous robotics in surgery. The state of the art has focused on conventional RGB video data acquired during minimally invasive surgery, but full-scene semantic segmentation based on spectral imaging data and obtained during open surgery has received almost no attention to date. To address this gap in the literature, we are investigating the following research questions based on hyperspectral imaging (HSI) data of pigs acquired in an open surgery setting: (1) What is an adequate representation of HSI data for neural network-based fully automated organ segmentation, especially with respect to the spatial granularity of the data (pixels vs. superpixels vs. patches vs. full images)? (2) Is there a benefit of using HSI data compared to other modalities, namely RGB data and processed HSI data (e.g. tissue parameters like oxygenation), when performing semantic organ segmentation? According to a comprehensive validation study based on 506 HSI images from 20 pigs, annotated with a total of 19 classes, deep learning-based segmentation performance increases, consistently across modalities, with the spatial context of the input data. Unprocessed HSI data offers an advantage over RGB data or processed data from the camera provider, with the advantage increasing with decreasing size of the input to the neural network. Maximum performance (HSI applied to whole images) yielded a mean DSC of 0.90 ((standard deviation (SD)) 0.04), which is in the range of the inter-rater variability (DSC of 0.89 ((standard deviation (SD)) 0.07)). We conclude that HSI could become a powerful image modality for fully-automatic surgical scene understanding with many advantages over traditional imaging, including the ability to recover additional functional tissue information. Code and pre-trained models: https://github.com/IMSY-DKFZ/htc., Comment: The first two authors (Silvia Seidlitz and Jan Sellner) contributed equally to this paper

Background Hyperspectral imaging (HSI) could provide extended haemodynamic monitoring of perioperative tissue oxygenation and tissue water content to visualize effects of haemodynamic therapy and surgical trauma. The objective of this study was to assess the capacity of HSI to monitor skin microcirculation and possible relations to perioperative organ dysfunction in patients undergoing pancreatic surgery. Methods The hyperspectral imaging TIVITA® Tissue System was used to evaluate superficial tissue oxygenation (StO2), deeper layer tissue oxygenation (near-infrared perfusion index (NPI)), haemoglobin distribution (tissue haemoglobin index (THI)) and tissue water content (tissue water index (TWI)) in 25 patients undergoing pancreatic surgery. HSI parameters were measured before induction of anaesthesia (t1), after induction of anaesthesia (t2), postoperatively before anaesthesia emergence (t3), 6 h after emergence of anaesthesia (t4) and three times daily (08:00, 14:00, 20:00 ± 1 h) at the palm and the fingertips until the second postoperative day (t5–t10). Primary outcome was the correlation of HSI with perioperative organ dysfunction assessed with the perioperative change of SOFA score. Results Two hundred and fifty HSI measurements were performed in 25 patients. Anaesthetic induction led to a significant increase of tissue oxygenation parameters StO2 and NPI (t1–t2). StO2 and NPI decreased significantly from t2 until the end of surgery (t3). THI of the palm showed a strong correlation with haemoglobin levels preoperatively (t2:r = 0.83, p < 0.001) and 6 h postoperatively (t4: r = 0.71, p = 0.001) but not before anaesthesia emergence (t3: r = 0.35, p = 0.10). TWI of the palm and the fingertip rose significantly between pre- and postoperative measurements (t2–t3). Higher blood loss, syndecan level and duration of surgery were associated with a higher increase of TWI. The perioperative change of HSI parameters (∆t1–t3) did not correlate with the perioperative change of the SOFA score. Conclusion This is the first study using HSI skin measurements to visualize tissue oxygenation and tissue water content in patients undergoing pancreatic surgery. HSI was able to measure short-term changes of tissue oxygenation during anaesthetic induction and pre- to postoperatively. TWI indicated a perioperative increase of tissue water content. Perioperative use of HSI could be a useful extension of haemodynamic monitoring to assess the microcirculatory response during haemodynamic therapy and major surgery. Trial registration German Clinical Trial Register, DRKS00017313 on 5 June 2019

ObjectiveTo optimize anastomotic technique and gastric conduit perfusion with hyperspectral imaging (HSI) for total minimally invasive esophagectomy (MIE) with linear stapled anastomosis.Summary Background DataEsophagectomy is the mainstay of esophageal cancer treatment but anastomotic insufficiency related morbidity and mortality remain challenging for patient outcome.MethodsA live porcine model (n=50) for MIE was used with gastric conduit formation and linear stapled side-to-side esophagogastrostomy. Four main experimental groups differed in stapling length (3 vs. 6 cm) and anastomotic position on the conduit (cranial vs. caudal). Tissue oxygenation around the anastomotic site was evaluated using HSI and was validated with histopathology.ResultsThe tissue oxygenation (ΔStO2) after the anastomosis remained constant only for the short stapler in caudal position (−0.4± 4.4%, n.s.) while it dropped markedly in the other groups (short-cranial: -15.6± 11.5%, p=0.0002; long-cranial: -20.4± 7.6%, p=0.0126; long-caudal: -16.1± 9.4%, pConclusionsTissue oxygenation at the anastomotic site of the gastric conduit during MIE is influenced by stapling technique. Optimal oxygenation was achieved with a short stapler (3 cm) and sufficient distance of the anastomosis to the cranial end of the gastric conduit. HSI tissue deoxygenation corresponded to histopathologic necrotic tissue changes. These findings allow for optimization of gastric conduit perfusion and anastomotic technique in MIE.Level of EvidenceNot applicable. Translational animal science. Original article.

IntroductionThe only curative treatment for most gastric cancer is radical gastrectomy with D2 lymphadenectomy (LAD). Minimally invasive total gastrectomy (MIG) aims to reduce postoperative morbidity, but its use has not yet been widely established in Western countries. Minimally invasivE versus open total GAstrectomy is the first Western multicentre randomised controlled trial (RCT) to compare postoperative morbidity following MIG vs open total gastrectomy (OG).Methods and analysisThis superiority multicentre RCT compares MIG (intervention) to OG (control) for oncological total gastrectomy with D2 or D2+LAD. Recruitment is expected to last for 2 years. Inclusion criteria comprise age between 18 and 84 years and planned total gastrectomy after initial diagnosis of gastric carcinoma. Exclusion criteria include Eastern Co-operative Oncology Group (ECOG) performance status >2, tumours requiring extended gastrectomy or less than total gastrectomy, previous abdominal surgery or extensive adhesions seriously complicating MIG, other active oncological disease, advanced stages (T4 or M1), emergency setting and pregnancy.The sample size was calculated at 80 participants per group. The primary endpoint is 30-day postoperative morbidity as measured by the Comprehensive Complications Index. Secondary endpoints include postoperative morbidity and mortality, adherence to a fast-track protocol and patient-reported quality of life (QoL) scores (QoR-15, EUROQOL EuroQol-5 Dimensions-5 Levels (EQ-5D), EORTC QLQ-C30, EORTC QLQ-STO22, activities of daily living and Body Image Scale). Oncological endpoints include rate of R0 resection, lymph node yield, disease-free survival and overall survival at 60-month follow-up.Ethics and disseminationEthical approval has been received by the independent Ethics Committee of the Medical Faculty, University of Heidelberg (S-816/2021) and will be received from each responsible ethics committee for each individual participating centre prior to recruitment. Results will be published open access.Trial registration numberDRKS00025765., publishedVersion

Background/purpose The dissemination of laparoscopic liver resection (LLR) has been based on non-randomized studies and reviews of these. Aim of this study was to evaluate if the randomized evidence comparing LLR to open liver resection (OLR) supports these findings. Methods A prospectively registered (reviewregistry866) systematic review and meta-analysis following Cochrane and PRISMA guidelines comparing LLR to OLR for benign and malignant diseases was performed via Medline, Web of Science, CENTRAL up to 31.12.2020. The main outcome was postoperative complications. Risk of bias was assessed with the Cochrane Risk of Bias tool 2.0, certainty of evidence was assessed using the GRADE approach. Results The search yielded 2080 results. 13 RCTs assessing mostly minor liver resections with 1457 patients were included. There were reduced odds of experiencing any complication (Odds ratio (OR) [95% confidence interval (CI)]: 0·42 [0·30, 0·58]) and severe complications (OR[CI]: 0·51 [0·31, 0·84]) for patients undergoing LLR. LOS was shorter (Mean difference (MD) [CI]: −2·90 [-3·88, −1·92] days), blood loss was lower (MD: [CI]: −115·41 [-146·08, −84·75] ml), and functional recovery was better for LLR. All other outcomes showed no significant differences. Conclusions LLR shows significant postoperative benefits. RCTs assessing long-term outcomes and major resections are needed.

Introduction Microcirculatory alterations are key mechanisms in sepsis pathophysiology leading to tissue hypoxia, edema formation, and organ dysfunction. Hyperspectral imaging (HSI) is an emerging imaging technology that uses tissue-light interactions to evaluate biochemical tissue characteristics including tissue oxygenation, hemoglobin content and water content. Currently, clinical data for HSI technologies in critical ill patients are still limited. Methods and analysis TIVITA® Tissue System was used to measure Tissue oxygenation (StO2), Tissue Hemoglobin Index (THI), Near Infrared Perfusion Index (NPI) and Tissue Water Index (TWI) in 25 healthy volunteers and 25 septic patients. HSI measurement sites were the palm, the fingertip, and a suprapatellar knee area. Septic patients were evaluated on admission to the ICU (E), 6 h afterwards (E+6) and three times a day (t3-t9) within a total observation period of 72 h. Primary outcome was the correlation of HSI results with daily SOFA-scores. Results Serial HSI at the three measurement sites in healthy volunteers showed a low mean variance expressing high retest reliability. HSI at E demonstrated significantly lower StO2 and NPI as well as higher TWI at the palm and fingertip in septic patients compared to healthy volunteers. StO2 and TWI showed corresponding results at the suprapatellar knee area. In septic patients, palm and fingertip THI identified survivors (E-t4) and revealed predictivity for 28-day mortality (E). Fingertip StO2 and THI correlated to SOFA-score on day 2. TWI was consistently increased in relation to the TWI range of healthy controls during the observation time. Palm TWI correlated positively with SOFA scores on day 3. Discussion HSI results in septic patients point to a distinctive microcirculatory pattern indicative of reduced skin oxygenation and perfusion quality combined with increased blood pooling and tissue water content. THI might possess risk-stratification properties and TWI could allow tissue edema evaluation in critically ill patients. Conclusion HSI technologies could open new perspectives in microcirculatory monitoring by visualizing oxygenation and perfusion quality combined with tissue water content in critically ill patients – a prerequisite for future tissue perfusion guided therapy concepts in intensive care medicine.

Background:The only curative treatment for most esophageal cancers is radical esophagectomy. Minimally invasive esophagectomy (MIE) aims to reduce postoperative morbidity, but is not yet widely established. Linear stapled anastomosis is a promising technique for MIE because it is quite feasible even without robotic assistance. Aim of the present study is to compare total MIE with linear stapled anastomosis to open esophagectomy (OE) with circular stapled anastomosis with special regard to postoperative morbidity in an expertise-based randomized controlled trial (RCT).Methods/design:This superiority RCT compares MIE with linear stapled anastomosis (intervention) to OE with circular stapled anastomosis (control) for Ivor-Lewis esophagectomy. It was initiated in February 2019 and recruitment is expected to last for 3 years. For inclusion, patients must be 18 years of age or more with a resectable primary malignancy in the distal esophagus. Participants with tumor localizations above the azygos vein, metastasis or infiltration into adjacent tissue will be excluded. In an expertise-based approach the allocated treatment will only be carried out by the single most experienced surgeon of the surgical center for each respective technique. The sample size was calculated with 20 participants per group for the primary endpoint postoperative morbidity according to comprehensive complication index (CCI) within 30 postoperative days. Secondary endpoints include anastomotic insufficiency, pulmonary complications, other intra- and postoperative outcome parameters such as estimated blood loss, operative time, length of stay, short-term oncologic endpoints, adherence to a standardized fast-track protocol, postoperative pain, and postoperative recovery (QoR-15). Quality of life (SF-36, CAT EORTC QLQ-C30, CAT EORTC QLQ-OES18) and oncological outcomes are evaluated with 60 months follow-up.Discussion:MIVATE is the first RCT to compare OE with circular stapled anastomosis to total MIE with linear stapled anastomosis exclusively for intrathoracic anastomosis. The expertise-based approach limits bias due to heterogeneity of surgical expertise. The use of a dedicated fast-track protocol in both OE and MIE will shed light on the role of the access strategy alone in this setting. The findings of this study will serve to define which approach has the best perioperative outcome for patients requiring esophagectomy.Trial registration: German Clinical Trials Register DRKS00016773. Registered on February 18th, 2019.

Background: The only curative treatment for most esophageal cancers is radical esophagectomy. Minimally invasive esophagectomy (MIE) aims to reduce postoperative morbidity, but is not yet widely established. Linear stapled anastomosis is a promising technique for MIE because it is quite feasible even without robotic assistance. Aim of the present study is to compare total MIE with linear stapled anastomosis to open esophagectomy (OE) with circular stapled anastomosis with special regard to postoperative morbidity in an expertise-based randomized controlled trial (RCT). Methods/design: This superiority RCT compares MIE with linear stapled anastomosis (intervention) to OE with circular stapled anastomosis (control) for Ivor-Lewis esophagectomy. It was initiated in February 2019 and recruitment is expected to last for 3 years. For inclusion, patients must be 18 years of age or more with a resectable primary malignancy in the distal esophagus. Participants with tumor localizations above the azygos vein, metastasis or infiltration into adjacent tissue will be excluded. In an expertise-based approach the allocated treatment will only be carried out by the single most experienced surgeon of the surgical center for each respective technique. The sample size was calculated with 20 participants per group for the primary endpoint postoperative morbidity according to comprehensive complication index (CCI) within 30 postoperative days. Secondary endpoints include anastomotic insufficiency, pulmonary complications, other intra- and postoperative outcome parameters such as estimated blood loss, operative time, length of stay, short-term oncologic endpoints, adherence to a standardized fast-track protocol, postoperative pain, and postoperative recovery (QoR-15). Quality of life (SF-36, CAT EORTC QLQ-C30, CAT EORTC QLQ-OES18) and oncological outcomes are evaluated with 60 months follow-up. Discussion: MIVATE is the first RCT to compare OE with circular stapled anastomosis to total MIE with linear stapled anastomosis exclusively for intrathoracic anastomosis. The expertise-based approach limits bias due to heterogeneity of surgical expertise. The use of a dedicated fast-track protocol in both OE and MIE will shed light on the role of the access strategy alone in this setting. The findings of this study will serve to define which approach has the best perioperative outcome for patients requiring esophagectomy. Trial registration: German Clinical Trials Register DRKS00016773. Registered on February 18th, 2019.

A network of communicating tumour cells established by tumour microtubes (TMs) is supposed to mediate relevant aspects of progression and resistance of incurable gliomas. Moreover, neuronal activity has been shown to foster malignant behavior of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here, we report an unexpected direct communication channel between neurons and glioma cells in multiple disease models as well as in astrocytomas and glioblastomas (GBs) of adult patients: functional bona fide chemical synapses formed between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses (NGS) show a typical synaptic ultrastructure, are located on TM networks, and produce depolarizing postsynaptic currents mediated by glutamate receptors of the AMPA subtype. AMPA-type glutamate receptors (AMPAR) are expressed by a molecularly and morphologically distinct subpopulation of network-integrated glioma cells. Increased neuronal activity under epileptic conditions ex vivo or neuronal optogenetic stimulation in vivo enhanced, while general anesthesia diminished synchronized calcium transients in TM-connected glioma networks. Accordingly, anesthesia reduced invasiveness of TM-positive tumour cells in mice. Genetic perturbation of AMPAR or chronic AMPAR inhibition by perampanel decreased glioma invasion and proliferation in mice and deletion of GluRII in Drosophila glioma increased survival. These findings reveal a hitherto unappreciated direct synaptic communication between neurons and glioma cells that appears relevant for brain tumour biology, implying new avenues for glioma treatment.

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.