The Father of Wisdom: "The Influence of Surgical Experience on Overall Survival in Patients with Malignant Gliomas".

BACKGROUND: The role of surgery in the management of malignant gliomas has been feverishly deliberated after the publication of the first expansive case series, the last two decades reinvigorating the discussion regarding the value of total removal in improving survivability. Despite numerous technologies being implemented to increase the resection rates of malignant gliomas, the role of surgical experience has been largely overlooked. This article aims to discuss the importance of a single surgeon's experience in treating high-grade gliomas over a period of 20 years. MATERIAL AND METHODS: In order to demonstrate the role of surgical experience, we divided the patients operated by a single neurosurgeon into two distinct intervals: between 2000 and 2009 and between 2012 and 2020, respectively. Only cases with subsequent adjuvant radio-chemotherapy were included. For objective reasons, no technologies that could assist the extent of resection (EOR) such as intraoperative MRI (iMRI) or 5-ALA could be used in the country of our study. Gross total resection was the main goal whenever possible, whereas subtotal removal was defined as a clear remnant on contrasted MRI or CT performed 24-48 h postoperatively. Using the Kaplan-Meier method, we analyzed the survival and disease-free interval of our patients according to age, pathology, and degree of resection. RESULTS: In the 20-year interval of our retrospective study, the main author (ISF) operated 1591 cases of gliomas in a total of 1878 surgeries, including recurrences. The number of high-grade glioma (HGG) patients was 909 (57.10%), 495 of which were male (54.5%) and 414 (45.5%) female. The mean age of the HGG population was 51.9 years. The most common type of HGG subtype were glioblastomas with a total number 620 cases (68.2%). Regarding overall survival (OS), average survival at 12 months was better by 1.6%, and 12.1% improved at 18 months and 17.8% longer at 24 months in the 2012-2020 interval. The mean OS in the earlier interval was 11.00 months compared to the second when it reached 13.441 months (CI, 12.642-14.24). CONCLUSION: Surgical treatment represents a critical step in the multimodal treatment of malignant gliomas. According to our results, surgical experience improves not only overall survival in a manner equivalent to adjuvant chemotherapy but also the quality of life. As such, a special qualification in neurooncology may prove necessary in offering these patients a second chance at life.

Ventriculorenal shunts in the treatment of pediatric and adult hydrocephalus-historical perspective and analysis of current practice.

Hydrocephalus is a complex pathology that can have a significant impact on the quality of life in all age groups. Cerebrospinal fluid (CSF) diversions from the lateral ventricle to the peritoneal cavity are regarded as the treatment of first intent, but they have a high revision rate, and there are multiple factors which can impair their proper insertion and function. One of the many alternatives to peritoneal shunting is redirecting the CSF towards the renal system. A literature search was conducted to identify the particularities of these types of shunts and what clinical context rendered them feasible in pediatric and adult patient populations. Twenty-eight studies were found to meet the selection criteria. The shunts were classified into ventriculopyeloureteral, ventriculoureteral, and ventriculovesical. Their main advantage was that they did not depend on absorption properties of the tissues, like in the case of the peritoneum. However, several issues with ascending infections, bladder pressure imbalance, distal shunt migration, and calculus formation were noted. Literature suggests that the urinary tract can have the potential of diverting CSF when the peritoneum or atrium is not available, but further research is required to establish their proper role in current practice.

Ruptured AComA aneurysm and asymptomatic bilateral ACA vasospasm in an infant: surgical case report.

Intracranial aneurysms (IAs) are localized dilations of the cerebral vasculature, representing the leading cause for non-traumatic subarachnoid hemorrhage and an important source of morbidity and mortality. Despite it being a frequent pathology and most often diagnosed incidentally, IAs in infants are a very rare occurrence, and the ruptured variant is exceptional. A 4-month-old boy with a negative family history was brought to our department because of several episodes of incoercible vomiting and fever. Upon examination, the child was somnolent, without any noticeable deficit. Transfontanellar ultrasonography and CT angiography revealed a ruptured aneurysm of the anterior communicating artery (AComA), whereas the pre-clipping MRI showed thin, almost angiographically invisible anterior cerebral arteries (ACAs) on both sides due to vasospasm. We intervened surgically by placing an external ventricular shunt in an emergency setting, followed by clipping of the IA in a delayed manner. The child was discharged a month after admission with no deficit, despite the paradoxical aspect of the ACA. Ruptured IAs can be safely treated via microsurgery, even in infants. However, this requires a great amount of experience and surgical expertise. Furthermore, the lack of proper management would most likely result in a severe deficit in the long term. Lastly, the lack of visibility of the ACA on angiographic studies may not have neurological consequences if they occur in this age group.

External Validation of a Convolutional Neural Network for IDH Mutation Prediction.

Background and Objectives: The IDH (isocitrate dehydrogenase) status represents one of the main prognosis factors for gliomas. However, determining it requires invasive procedures and specialized surgical skills. Medical imaging such as MRI is essential in glioma diagnosis and management. Lately, fields such as Radiomics and Radiogenomics emerged as pertinent prediction tools for extracting molecular information out of medical images. These fields are based on Artificial Intelligence algorithms that require external validation in order to evaluate their general performance. The aim of this study was to provide an external validation for the algorithm formulated by Yoon Choi et al. of IDH status prediction using preoperative common MRI sequences and patient age. Material and Methods: We applied Choi's IDH status prediction algorithm on T1c, T2 and FLAIR preoperative MRI images of gliomas (grades WHO II-IV) of 21 operated adult patients from the Neurosurgery clinic of the Cluj County Emergency Clinical Hospital (CCECH), Cluj-Napoca Romania. We created a script to automate the testing process with DICOM format MRI sequences as input and IDH predicted status as output. Results: In terms of patient characteristics, the mean age was 48.6 ± 15.6; 57% were female and 43% male; 43% were IDH positive and 57% IDH negative. The proportions of WHO grades were 24%, 14% and 62% for II, III and IV, respectively. The validation test achieved a relative accuracy of 76% with 95% CI of (53%, 92%) and an Area Under the Curve (AUC) through DeLong et al. method of 0.74 with 95% CI of (0.53, 0.91) and a p of 0.021. Sensitivity and Specificity were 0.78 with 95% CI of (0.45, 0.96) and 0.75 with 95% CI of (0.47, 0.91), respectively. Conclusions: Although our results match the external test the author made on The Cancer Imaging Archive (TCIA) online dataset, performance of the algorithm on external data is still not high enough for clinical application. Radiogenomic approaches remain a high interest research field that may provide a rapid and accurate diagnosis and prognosis of patients with intracranial glioma.

Interlayer dural split technique for Chiari I malformation treatment in adult-Technical note.

OBJECTIVE: To present an alternative surgical technique in treating cases of Chiari I Malformation with mild-to-moderate syringomyelia after decompressive suboccipital craniectomy: incising only the outer layer of the dura mater, then dissecting it from the inner layer without opening the latter. PATIENTS AND METHODS: We utilized this technique in a short series of three cases who were admitted to our department for mild symptoms such as intermittent headache and dissociated sensory loss in the upper limbs, caused by a Chiari Malformation Type I. The patients were placed in the sitting position. We performed a reduced median suboccipital craniectomy and resection of the posterior arch of C1 adapted to the level of tonsil descent, from a limited superior half to complete resection. Afterward, we incised the outer dural layer, while sparing the inner one. Using a fine dissector, we then split apart the outer and inner layers to the margin of the craniectomy. Through the transparency of the inner layer and the arachnoid, the cerebellum and the medulla were visible and pulsating. An autologous fascia duraplasty was then performed. RESULTS: The postoperative course was favorable in all cases, the patients being discharged without any deficits and with complete symptom resolution. Follow-up at 3, 6, and 12 months after surgery revealed a significant reduction in brainstem compression and syringomyelia. CONCLUSIONS: Interlayer dural split technique can be used effectively in treating symptomatic cases of type I Chiari malformation in adults, with mild-to-moderate syringomyelia. It is less invasive than opening the dura and possibly more effective than decompressive craniectomy and C1 laminectomy alone. This technique must be validated in a larger case-control series.

Ruptured pontine cavernomas in infants: a report of two cases.

BACKGROUND: Cavernous malformations (CMs) are either congenital or acquired vascular lesions comprised of sinusoid spaces filled with either blood or its breakdown products. They possess a relatively reduced risk of hemorrhage, yet placement within the posterior fossa and especially the brainstem heightens their likelihood to rupture, making them a likely cause of permanent and debilitating neurological deficit, as well as a veritable surgical challenge. Although the incidence of rupture varies with age among reported case series, it is undoubtable that the severity of this occurrence is the highest while the brain is as its most vulnerable period, i.e. during infancy. CASE PRESENTATIONS: We present two patients, both female, 6.5- and 5-months-old respectively, who presented with brainstem hemorrhage from CM. They suffered from a sudden onset of hemiparesis and were subjected to surgical removal of their lesions and resulting hematomas. Both patients were discharged in a favorable neurological status and are currently alive and in good health. CONCLUSION: Microsurgical treatment of brainstem CMs in infants is not only possible with minimal deficit, but also advisable if the lesions are symptomatic. Nevertheless, this requires substantial patience and experience to prevent significant loss of blood and injury to the structures of the posterior fossa. We argue that the safest method to prevent further damage from brainstem CM rebleed is to remove these lesions shortly after the initial hemorrhage.

Evaluation of the ventriculocholecystic shunt-an overview of present practice in adult and pediatric hydrocephalus.

In the context of hydrocephalus, there are a multitude of therapeutic options that can be explored in order to improve patient outcomes. Although the peritoneum is the current elected clinical solution, various receptacles have been utilized when experiencing contraindications. Along with the ventriculoatrial or ventriculopleural, the ventriculocholecystic shunt was also described as an alternative. In order to make a decision on a place for drainage, the surgeon must be knowledgeable on details from modern literature. The main target of this review was to summarize the currently available information on this topic and assess the status of the gallbladder as a viable option for cerebrospinal fluid diversion.

Involvement of Microglia in the Pathophysiology of Intracranial Aneurysms and Vascular Malformations-A Short Overview.

Aneurysms and vascular malformations of the brain represent an important source of intracranial hemorrhage and subsequent mortality and morbidity. We are only beginning to discern the involvement of microglia, the resident immune cell of the central nervous system, in these pathologies and their outcomes. Recent evidence suggests that activated proinflammatory microglia are implicated in the expansion of brain injury following subarachnoid hemorrhage (SAH) in both the acute and chronic phases, being also a main actor in vasospasm, considerably the most severe complication of SAH. On the other hand, anti-inflammatory microglia may be involved in the resolution of cerebral injury and hemorrhage. These immune cells have also been observed in high numbers in brain arteriovenous malformations (bAVM) and cerebral cavernomas (CCM), although their roles in these lesions are currently incompletely ascertained. The following review aims to shed a light on the most significant findings related to microglia and their roles in intracranial aneurysms and vascular malformations, as well as possibly establish the course for future research.

'De Novo' Brain AVMs-Hypotheses for Development and a Systematic Review of Reported Cases.

Background and Objectives: Brain arteriovenous malformations AVMs have been consistently regarded as congenital malformations of the cerebral vasculature. However, recent case reports describing "de novo AVMs" have sparked a growing debate on the nature of these lesions. Materials and Methods: We have performed a systematic review of the literature concerning de novo AVMs utilizing the PubMed and Google Academic databases. Termes used in the search were "AVM," "arteriovenous," "de novo," and "acquired," in all possible combinations. Results: 53 articles including a total of 58 patients harboring allegedly acquired AVMs were identified by researching the literature. Of these, 32 were male (55.17%), and 25 were female (43.10%). Mean age at de novo AVM diagnosis was 27.833 years (standard deviation (SD) of 21.215 years and a 95% confidence interval (CI) of 22.3 to 33.3). Most de novo AVMs were managed via microsurgical resection (20 out of 58, 34.48%), followed by radiosurgery and conservative treatment for 11 patients (18.97%) each, endovascular embolization combined with resection for five patients (8.62%), and embolization alone for three (5.17%), the remaining eight cases (13.79%) having an unspecified therapy. Conclusions: Increasing evidence suggests that some of the AVMs discovered develop some time after birth. We are still a long way from finally elucidating their true nature, though there is reason to believe that they can also appear after birth. Thus, we reason that the de novo AVMs are the result of a 'second hit' of a variable type, such as a previous intracranial hemorrhage or vascular pathology. The congenital or acquired characteristic of AVMs may have a tremendous impact on prognosis, risk of hemorrhage, and short and long-term management.

From the heart to the bladder-particularities of ventricular shunt topography and the current status of cerebrospinal fluid diversion sites.

Hydrocephalus represents the pathological elevation of cerebrospinal fluid (CSF) levels as a consequence of various embryological or acquired defects. Although the classic method of treatment is by means of diverting the CSF from the ventricular system towards the peritoneum, there are other sites of diversion that have proven their efficiency through time, in the context of complications related to the more common option of intraperitoneal insertion. The aim of the review is to assess and organize a database of all the types of shunt locations from the oldest shunt attempts until present, using Pubmed and Medline and to underline the particularities related to technique, indications, complications and associated epidemiological background. Current literature reveals up to 36 sites of diversion of CSF with a diverse topography varying from cephalic regions such as venous sinuses or mastoid bone, thoracic elements such as the heart or the pleura and abdominopelvic segments such as the peritoneum or the urinary bladder. Several atypical locations were studied such as the fallopian and intestinal shunts. Although ventriculoperitoneal and ventriculoatrial shunts are the most commonly used shunts today, there are some systems such as the ventriculosinusal and ventriculolymphatic shunts that prove to be equally as efficient. The successful treatment of hydrocephalus requires a complete comprehension of the indications and therapeutic options and a reliable evaluation of the risks and possible complications. The profile of cerebral ventricular shunts is highly dynamic and the spectrum of cerebrospinal fluid diversion offers multiple solutions in the benefit of the patient.

Strategies for Complex Scalp Reconstruction in Patients With Poor Recipient Vessels.

Complex scalp defects with poor recipient vessels represent a challenge for plastic surgeons. In these cases, free flaps are the last resort for solving the problem. The authors present 5 difficult cases with complex large scalp and calvarium defects with unsuitable small recipient vessels for anastomoses. For these cases, the lesser saphenous vein was harvested and used as an interposition graft between the external carotid artery, the jugular vein, and the flap. Latissimus Dorsi, Anterolateral Thigh, and serratus anterior were the flaps used for reconstruction. Cranioplasty was simultaneously performed in 4 cases. The scalp defects varied from 83 to 288 cm. All flaps survived. In 1 case (extended Latissimus Dorsi) there was local infection and wound dehiscence with marginal flap necrosis that required flap readvancement. In conclusion, end-to-end anastomosis to the external carotid artery offers strong outflow through the vein graft and flap. A large vein graft allows good outflow and is more resistant to the pressure of the skin envelope. Anastomosis to large neck vessels (internal or external jugular) facilitates drainage since there is also an aspiration effect due to the venous flow circulation through it.

Neurosurgical cadaveric and in vivo large animal training models for cranial and spinal approaches and techniques - a systematic review of the current literature.

INTRODUCTION: Due to its high complexity, neurosurgery consists of a demanding learning curve that requires intense training and a deep knowledge of neuroanatomy. Microsurgical skill development can be achieved through various models of simulation, but as human cadaveric models are not always accessible, cadaveric animal models can provide a reliable environment in which to enhance the acquisition of surgical dexterity. The aim of this review was to analyse the current role of animal brains in laboratory training and to assess their correspondence to the procedures performed in humans. MATERIAL AND METHODS: A Pubmed literature search was performed to identify all the articles concerning training cranial and spinal techniques on large animal heads. The search terms were 'training model', and 'neurosurgery' in association with 'animal', 'sheep', 'cow', and 'swine'. The exclusion criteria were articles that were on human brains, experimental fundamental research, or on virtual simulators. RESULTS: The search retrieved 119 articles, of which 25 were relevant to the purpose of this review. Owing to their similar neuroanatomy, bovine, porcine and ovine models prove to be reliable structures in simulating neurosurgical procedures. On bovine skulls, an interhemispheric transcalosal and retrosigmoid approach along with different approaches to the Circle of Willis can be recreated. Ovine model procedures have varied from lumbar discectomies on sheep spines to craniosynostosis surgery, whereas in ex vivo swine models, cadaveric dissections of lateral sulcus, median and posterior fossa have been achieved. CONCLUSIONS: Laboratory training models enhance surgical advancements by familiarising trainee surgeons with certain neuroanatomical structures and promoting greater surgical dexterity. The accessibility of animal brains allows trainee surgeons to exercise techniques outside the operating theatre, thus optimising outcomes in human surgical procedures.

Optical coherence tomography as a marker of vision in children with optic pathway gliomas.

PURPOSE: Optic pathway gliomas (OPG) represent an important cause of visual loss in pediatric population. The indication of treatment is based on clinical or neuroimaging progression. Visual acuity loss is the most important symptom of disease progression, but children with OPG are frequently unable to complete the testing of visual function. Optical coherence tomography (OCT) was suggested as an objective tool for visual assessment. A literature review was performed in order to determine the role of retinal OCT as a surrogate marker of vision in children with OPG. METHODS: The search was performed using PubMed, Embase, and Web of Science databases and was restricted to articles published in English between 2000 and 2016, with a minimum of ten participants enrolled. RESULTS: Eleven studies met the eligibility criteria and were included in the present review. Both neurofibromatosis-1 associated and sporadic OPG were investigated. CONCLUSIONS: Retinal OCT is a promising tool to be considered as a screening or follow-up test in children with OPG, and further multicenter research is encouraged.

Optical coherence tomography impacts the evaluation of visual pathway tumors.

The objective of this systematic literature review is to assess the role of retinal optical coherence tomography (OCT) in the evaluation of patients with tumors of the visual pathway. We performed a PubMed database search according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The search was restricted to articles published in English between 2000 and 2016, with at least 10 human adult participants enrolled. Twenty-seven articles met the eligibility criteria. All studies investigated tumors of the anterior visual pathway. Both time-domain and spectral-domain OCT technologies were used and the role of OCT as diagnostic and/or prognostic tool was studied. Retinal OCT provides structural information about ganglion cell axon integrity and is complementary to visual function examination. OCT is a prognostic factor for post-operative visual outcome.

Our initial experience with ventriculo-epiplooic shunt in treatment of hydrocephalus in two centers.

INTRODUCTION: Hydrocephalus represents impairment in cerebrospinal fluid (CSF) dynamics. If the treatment of hydrocephalus is considered difficult, the repeated revisions of ventriculo-peritoneal (VP) shunts are even more challenging. OBJECTIVE: The aim of this article is to evaluate the efficiency of ventriculo-epiplooic (VEp) shunt as a feasible alternative in hydrocephalic patients. MATERIAL AND METHODS: A technical modification regarding the insertion of peritoneal catheter was imagined: midline laparotomy 8-10cm long was performed in order to open the peritoneal cavity; the great omentum was dissected between its two layers; we placed the distal end of the catheter between the two epiplooic layers; a fenestration of 4cm in diameter into the visceral layer was also performed. A retrospective study of medical records of 15 consecutive patients with hydrocephalus treated with VEp shunt is also presented. RESULTS: Between 2008 and 2014 we performed VEp shunt in 15 patients: 5 with congenital hydrocephalus, 8 with secondary hydrocephalus and 2 with normal pressure hydrocephalus. There were 7 men and 8 women. VEp shunt was performed in 13 patients with multiple distal shunt failures and in 2 patients, with history of abdominal surgery, as de novo extracranial drainage procedure. The outcome was favorable in all cases, with no significant postoperative complications. CONCLUSIONS: VEp shunt is a new, safe and efficient surgical technique for the treatment of hydrocephalus. VEp shunt is indicated in patients with history of recurrent distal shunt failures, and in patients with history of open abdominal surgery and high risk for developing abdominal complications.

Nanoparticles for Targeting Intratumoral Hypoxia: Exploiting a Potential Weakness of Glioblastoma.

Extensive hypoxic regions are the daunting hallmark of glioblastoma, as they host aggressive stem-like cells, hinder drug delivery and shield cancer cells from the effects of radiotherapy. Nanotechnology could address most of these issues, as it employs nanoparticles (NPs) carrying drugs that selectively accumulate and achieve controlled drug release in tumor tissues. Methods overcoming the stiff interstitium and scarce vascularity within hypoxic zones include the incorporation of collagenases to degrade the collagen-rich tumor extracellular matrix, the use of multistage systems that progressively reduce NP size or of NP-loaded cells that display inherent hypoxia-targeting abilities. The unfavorable hypoxia-induced low pH could be converted into a therapeutical advantage by pH-responsive NPs or multilayer NPs, while overexpressed markers of hypoxic cells could be specifically targeted for an enhanced preferential drug delivery. Finally, promising new gene therapeutics could also be incorporated into nanovehicles, which could lead to silencing of hypoxia-specific genes that are overexpressed in cancer cells. In this review, we highlight NPs which have shown promising results in targeting cancer hypoxia and we discuss their applicability in glioblastoma, as well as possible limitations. Novel research directions in this field are also considered.

Repositioning metformin in cancer: genetics, drug targets, and new ways of delivery.

After sitting many years on the shelves of drug stores as a harmless antidiabetic drug, metformin comes back in the spotlight of the scientific community as a surprisingly effective antineoplastic drug. Metformin targets multiple pathways that play pivotal roles in cancer progression, impacting various cellular processes, such as proliferation, cell death, metabolism, and even the cancer stemness features. The biomolecular characteristics of tumors, such as appropriate expression of organic cation transporters or genetic alterations including p53, K-ras, LKB1, and PI3K may impact metformin's anticancer efficiency. This could indicate a need for tumor genetic profiling in order to identify patients most likely to benefit from metformin treatment. Considering that the majority of experimental models suggest that higher, supra-clinical doses of metformin should be used in order to obtain an antineoplastic effect, new ways of drug delivery could be developed, such as metformin-loaded nanoparticles or incorporation of metformin into microparticles used in transarterial chemoembolization, with the aim of obtaining higher intratumoral drug concentrations and a targeted therapy which will ultimately maximize metformin's efficacy.

Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells.

PURPOSE: Glioblastoma stem cells (GSCs), responsible for the dismal disease prognosis after conventional treatments, are driven by overactive signaling pathways, such as PI3K/ AKT/mTOR and RAS/RAF/MAPK. The objective of our study was to target in vitro-GSCs by combining metformin (Met) as a mTOR inhibitor, with sorafenib (Soraf) as a RAF inhibitor. METHODS: GSCs cultured under basal conditions were treated with Met, temozolomide (TMZ), Soraf, Met+TMZ and Met+Soraf; as untreated arm served as control. At 4 hrs of drug exposure, we measured the level of reactive oxygen species (ROS) by 2',7'-dichlorofluorescein diacetate (DCFDA) assay, apoptosis by prodium iodide (PI)-V Annexin staining and efflux pump activity by using the fluorescent dye rhodamine 123. At 24 hrs, we measured cell proliferation by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and malondialdehyde (MDA) levels. MTT results were compared with corresponding measurements on cultures of non-stem glioblastoma cells and osteoblasts. RESULTS: Met+Soraf exerted the highest antiproliferative effects in GSCs and non-stem glioblastoma cells (p<0.001). Both Met and Soraf monotherapy exhibited a selective cytotoxic effect on GSCs (p<0.001), while no effect was detected on non-stem glioblastoma cells (p>0.05). Soraf, but not Met, impacted the proliferation of normal cells. Soraf displayed synergism with Met in producing high levels of ROS, decreasing efflux pump activity and generating the highest apoptotic rates when compared to either drug alone (p<0.001). CONCLUSION: GSCs were highly sensitive to the combination of Met and Soraf which reduced cell proliferation, increased oxidative stress, inhibited efflux pump activity and ultimately killed GSCs. We strongly believe that these results warrant further in vivo exploration.