Increasing evidence indicates that extracellular vesicles (EVs) secreted from tumor cells play a key role in the overall progression of the disease state. EVs such as exosomes are secreted by a wide variety of cells and transport a varied population of proteins, lipids, DNA, and RNA species within the body. Gliomas constitute a significant proportion of all primary brain tumors and majority of brain malignancies. Glioblastoma multiforme (GBM) represents grade IV glioma and is associated with very poor prognosis despite (...) the cumulative advances in diagnostic procedures and treatment strategies. Here, the authors describe the progress in understanding the role of EVs, especially exosomes, in overall glioma progression, and how new research is unraveling the utilities of exosomes in glioma diagnostics and development of next‐generation therapeutic systems. Finally, based on an understanding of the latest scientific literature, a model for the possible working of therapeutic exosomes in glioma treatment is proposed. (shrink)

WHO II low grade glioma evolves inevitably to anaplastic transformation. Magnetic resonance imaging is a good non-invasive way to watch it, by hemodynamic and metabolic modifications, thanks to multinuclear spectroscopy 1H/31P. In this work we study a multi-scale minimal model of hemodynamics and metabolism applied to the study of gliomas. This mathematical analysis leads us to a fast-slow system. The control of the position of the stationary point brings to the concept of domain of viability. Starting from this system, (...) the equations bring to light the parameters that push glioma cells out of their domain of viability. Four fundamental factors are highlighted. The first two are cerebral blood flow and the rate of lactate transport through monocarboxylate transporters, which must be reduced in order to push glioma out of its domain of viability. Another factor is the intra arterial lactate, which must be increased. The last factor is pH, indeed a decrease of intra cellular pH could interfere with glioma growth. These reflections suggest that these four parameters could lead to new therapeutic strategies for the management of low grade gliomas. (shrink)

Hydroxycamptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro. eww140918dxn This is the first study to investigate the release, distribution, and efficacy of hydroxycamptothecin which was incorporated into the biodegradable polymer Polylactic Acid (PLA), and implant into brain directly. In vitro release curve generated showed that a large initial release occurred over the first three days and was followed by a steady, but considerably slower rate of release over the next 25 days. After (...) implanting the discs into 40 male SD rats, the animals were followed up to 28 days, where the concentration in brain tissue was far higher than that in peripheral blood at the each of the eight time-points evaluated, and it was also within the therapeutic range for C6 cells tested in vitro. The in vivoefficacy of the discs was evaluated with rats inoculated intracranially with C6 glioma and treated with hydroxycamptothecin polymer compared to intravenous as well as intratumoral injections; the median survival is 21.1, 13.9, 14.9 days, respectively. Given these data, we conclude that the biodegradable polymer PLA releases hydroxycamptothecin, producing tumoricidal levels in brain tissues and prolonging survival in a rat glioma model. (shrink)

Using fMRI, we investigated how right temporal lobe gliomas affecting the posterior superior temporal sulcus alter neural processing observed during speech perception and production tasks. Behavioural language testing showed that three pre-operative neurosurgical patients with grade 2, grade 3 or grade 4 tumours had the same pattern of mild language impairment in the domains of object naming and written word comprehension. When matching heard words for semantic relatedness (a speech perception task), these patients showed under-activation in the tumour infiltrated right (...) superior temporal lobe compared to 61 neurotypical participants and 16 patients with tumours that preserved the right postero-superior temporal lobe, with enhanced activation within the (tumour-free) contralateral left superior temporal lobe. In contrast, when correctly naming objects (a speech production task), the patients with right postero-superior temporal lobe tumours showed higher activation than both control groups in the same right postero-superior temporal lobe region that was under-activated during auditory semantic matching. The task dependent pattern of under-activation during the auditory speech task and over-activation during object naming was also observed in eight stroke patients with right hemisphere infarcts that affected the right postero-superior temporal lobe compared to eight stroke patients with right hemisphere infarcts that spared it. These task-specific and site-specific cross-pathology effects highlight the importance of the right temporal lobe for language processing and motivate further study of how right temporal lobe tumours affect language performance and neural reorganisation. These findings may have important implications for surgical management of these patients, as knowledge of the regions showing functional reorganisation may help to avoid their inadvertent damage during neurosurgery. (shrink)

IntroductionBrain tumours frequently cause language impairments and are also likely to co-occur with localised abnormal slow-wave brain activity. However, it is unclear whether this applies specifically to low-grade brain tumours. We investigate slow-wave activity in resting-state electroencephalography in low-grade glioma and meningioma patients, and its relation to pre- and postoperative language functioning.MethodPatients with a glioma infiltrating the language-dominant hemisphere and patients with a meningioma with mass effect on this hemisphere underwent extensive language testing before and 1 year after (...) surgery. EEG was registered preoperatively, postoperatively, and once in healthy individuals. Slow-wave activity in delta- and theta- frequency bands was evaluated visually and quantitatively by spectral power at three levels over the scalp: the whole brain, the affected hemisphere, and the affected region.ResultsGlioma patients had increased delta activity and increased theta activity before and after surgery. In these patients, increased preoperative theta activity was related to the presence of language impairment, especially to poor word retrieval and grammatical performance. Preoperative slow-wave activity was also related to postoperative language outcomes. Meningioma patients showed no significant increase in EEG slow-wave activity compared to healthy individuals, but they presented with word retrieval, grammatical, and writing problems preoperatively, as well as with writing impairments postoperatively.DiscussionAlthough the brain-tumour pathology in low-grade gliomas and meningiomas has a different effect on resting-state brain activity, patients with low-grade gliomas and meningiomas both suffer from language impairments. Increased theta activity in glioma patients can be considered as a language-impairment marker, with prognostic value for language outcome after surgery. (shrink)

Neurofibromatosis type 1 is associated with peripheral and central nervous system tumors. It is noteworthy that the regions in which these tumors frequently arise are the optic pathways and the brainstem. Thus, we decided to trace the procedure of diffusion Magnetic Resonance Imaging alterations along with Short-Wavelength Automated Perimetry examinations of the OPs after surgery and chemotherapy over 1 year, which enabled us to evaluate chemotherapy's efficacy in an NF1 patient with an OP tumor. In this study, a 25-year-old woman (...) with NF1 and left optic radiation glioma underwent surgery to remove the glioma. Immunohistochemistry revealed a Pilocytic Astrocytoma WHO grade I. Post-operation chemotherapy done using nine treatment cycles of administering Temozolomide for 5 days every 4 weeks. Applying the region of interest differential tractography method and SWAP four times every 3 months allowed us to follow the patient's visual acuity alterations longitudinally. The differential deterministic tractography method and statistical analyses enabled us to discover the white matter tracts anisotropy alterations over time. Furthermore, statistical analyses on the SWAP results along time illustrated possible alterations in visual acuity. Then, we could compare and associate the findings with the SWAP examinations and patient symptoms longitudinally. Statistical analyses of SWAP tests revealed a significant improvement in visual fields, and longitudinal differential tractography showed myelination and dense axonal packing in the left OR after 1 year of treatment. In this study, we examined an old hypothesis suggesting that chemotherapy is more effective than radiotherapy for NF1 patients with OP gliomas because of the radiation side effects on the visual field, cognition, and cerebrovascular complications. Our longitudinal clinical case study involving dMRI and SWAP on a single NF1-OPG patient showed that chemotherapy did not suppress the OP myelination over time. However, it should be noted that this is a clinical case study, and, therefore, the generalization of results is limited. Future investigations might focus on genetic-based imaging, particularly in more cases. Further, meta-analyses are recommended for giving a proper Field Of View to researchers as a subtle clue regarding precision medicine. (shrink)

Highly malignant neuroepithelial tumors are known for their extensive tissue invasion. Investigating the relationship between their spatial behavior and temporal patterns by employing detrended fluctuation analysis (DFA), we report here that faster glioma cell motility is accompanied by both greater predictability of the cells' migration velocity and concomitantly, more directionality in the cells' migration paths. Implications of this finding for both experimental and clinical cancer research are discussed.

High-resolution neuroimaging modalities are used often in studies involving healthy volunteers. Subsequently, a significant increase in the incidental discovery of asymptomatic intracranial abnormalities raised the important ethical issues of when follow-up and treatment may be necessary. We examined the literature to establish a practical set of criteria for approaching incidental findings. Our objective is to develop an algorithm for when follow-up may be important and to provide recommendations that would increase the likelihood of follow-up. A systematic literature search was performed (...) using the PubMed and MEDLINE databases to identify articles describing brain tumors and intracranial aneurysms. The treatment algorithm we present suggests that incidental intracranial masses suspicious for glioma should be biopsied or resected, while other masses are to be followed with serial imaging based on the expected growth pattern. Lack of follow-up can result in adverse outcomes that can be mitigated by using technology to facilitate communication and improve follow-up care. The importance of training physicians to be good communicators is also stressed. New technology including automated telephone systems, texting and email will improve access to patients and hopefully encourage compliance and follow-up. (shrink)

Gliomas are diffuse and invasive brain tumors with the nefarious ability to evade even seemingly draconian treatment measures. Here we introduce a simple mathematical model for drug delivery of chemotherapeutic agents to treat such a tumor. The model predicts that heterogeneity in drug delivery related to variability in vascular density throughout the brain results in an apparent tumor reduction based on imaging studies despite continual spread beyond the resolution of the imaging modality. We discuss a clinical example for which the (...) model-predicted scenario is relevant. The analysis and results suggest an explanation for the clinical problem of the long-standing confounding observation of shrinkage of the lesion in certain areas of the brain with continued growth in other areas. (shrink)

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt a previously (...) developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to (...) disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity. -/- . (shrink)

While primary malignant brain tumors account for only two percent of all adult cancers, these neoplasms cause a disproportionate amount of cancer-related disabilities and death. The five-year survival rates for brain tumors are the third lowest among all types of cancer. Malignant gliomas comprise the most common types of primary central nervous system tumors and have a combined incidence of five to eight cases per 100,000 people. The median survival rate of conservatively treated patients with malignant gliomas is 14 weeks; (...) with surgical resection alone, 20 weeks; with surgery and radiation, 36 weeks; and with the addition of newer biochemotherapies such as temozolomide and bevacizumab, upward of 14-18 months.The profound cost of caring for terminally ill patients with primary malignant brain tumors raises ethical considerations for the American public; the stewardship of health care dollars for the population at large maintains a juxtaposed tension against a dynamic, necessary balance of hope, care, rehabilitation and research efforts for affected patients and their advocates. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Ice Cream for BreakfastMichelle MethvenIn June of 2011, on a warm sunny day in Toronto, Canada, my partner and I brought our daughter Stella into the local hospital emergency room for what we believed would be a routine check–up. She had been exhibiting worsening clumsiness and limping for the previous two weeks and we thought it would be easier just to get her seen and have whatever it was (...) dealt with rather than wait two months to see a specialist. My partner and I believed it was likely a severe ear infection, or maybe Lyme disease from a recent camping trip. We each called our workplaces and said we would be an hour or so late. Nothing could have prepared us for the news 22 hours after arriving at the hospital, that Stella had a cancerous mass in her brain. After a biopsy three days later to confirm the diagnosis, Stella was diagnosed with Diffuse Intrinsic Pontine Glioma (DIPG), and given less than a year to live.Parents most often describe DIPG as “a monster.” The tumour saturates the pons and shuts down nerve pathways one at a time. In no particular order, and in no particular time, sufferers (most often young children) lose the ability to walk, sit up, hold up their head, speak and see. The pons is also responsible for breathing, swallowing and regulating the heartbeat, so death can come in many forms at any given time. Though it destroys the brain’s ability to command, the person continues to think and understand as the main part of the brain is untouched. Different from most cancers, chemotherapy and radiation have almost no effect on DIPG; even trials with the most toxic chemotherapies do not slow its progress.My partner and I were shaken to the core at this diagnosis. Looking at our energetic, redheaded [End Page 31] mop–topped little imp, it was impossible to fathom that she had just been given a fatal diagnosis. Yet we knew the doctors at the hospital were among the best and most sought–after in the world, so denial was never a part of our mantra.A week after Stella was diagnosed, we met with a neuro–oncologist to discuss our plans. The only treatment that is slightly effective for DIPG is focal radiation, which can stall the tumor’s growth, granting what is known as a “honeymoon period” of no new symptoms. The honeymoon lasts approximately six months, but there are no guarantees. Twenty percent of children get no honeymoon whatsoever after radiation, and others get only weeks. The doctor we met with confirmed radiation would not be curative, but would “buy time”. He explained that radiation involved six weeks of treatment, seven days a week. Following the six weeks of treatment, there would be a period of anywhere from one to six months in which Stella would likely be asymptomatic. However, at some point, the symptoms generally return and when they do, children deteriorate relatively quickly. Sometimes it takes a month or two, but on occasion there is as little as two weeks between progression and death.As Stella’s parents, we were not convinced that the prescribed radiation was something we wanted to subject Stella to. Because she was only two, and a very spirited and energetic child, it would have been virtually impossible to have her lie quietly on the table in hospital each day for six weeks while radiation was put behind her ear. The neuro–oncologists’ solution was that Stella be sedated for each daily radiation treatment, which would make her groggy for a big part of the day and necessitate needles and IV. As parents, we were presented with an impossible gamble. Do we risk taking away six weeks of her still somewhat symptom–free life for a possible extra three to six months later? And the timing was difficult as well. It was late June. If we chose to radiate it would mean spending the entire summer shuttling her between hospital and home with no weeks at the cottage, and much less time to attend neighbourhood BBQ’s, parties, trips to the park, the library, science centre and zoo... (shrink)

Objective: To investigate the differences between patients returning to work and those who did not after brain tumor surgery.Methods: Patients were evaluated before surgery and after 3 months. The Montreal Cognitive Assessment test, Trail-Making Test, 15-word Rey–Osterrieth Word List, F-A-S tests, and Karnosfky Performance Status were used to assess cognitive status, attention, executive functions, memory, word fluency, and functional status. Patient-reported outcome measures used to evaluate emotional distress and disability were the Hospital Anxiety and Depression Scale and World Health Organization (...) Disability Assessment Schedule. Clinical and work-related variables, PROMs, and cognitive tests were compared using chi-squared, t-test or Mann–Whitney U test.Results: Sixty patients were included. Patients returning to work were 61.3 and 31.0% among people with meningioma and glioma, respectively. They reported lower postoperative disability and lesser home-to-work travel time. Patients with meningioma also showed better preoperative and postoperative attention and executive functions, better postoperative functional and cognitive status, and lower frequency of treatments.Conclusions: These variables should be considered in a clinical context to plan interventions for people who need support during return to work and in future research to investigate preoperative and postoperative predictive factors of going back to work. (shrink)

Background: Maximum safe resection of infiltrative brain tumors in eloquent area is the primary objective in surgical neuro-oncology. This goal can be achieved with direct electrical stimulation to perform a functional mapping of the brain in patients awake intraoperatively. When awake surgery is not possible, we propose a pipeline procedure that combines advanced techniques aiming at performing a dissection that respects the anatomo-functional connectivity of the peritumoral region. This procedure can benefit from intraoperative monitoring with computerized tomography scan and brain (...) shift correction. Associated with this intraoperative monitoring, the additional value of preoperative investigation combining brain mapping by navigated transcranial magnetic stimulation with various neuroimaging modalities has not yet been reported.Case Report: A 42-year-old left-handed man had increased intracranial pressure, left hand muscle deficit, and dysarthria, related to an infiltrative tumor of the right frontal lobe with large mass effect and circumscribed contrast enhancement in motor and premotor cortical areas. Spectroscopy profile and intratumoral calcifications on CT-scan suggested an WHO grade III glioma, later confirmed by histology. The aforementioned surgical procedure was considered, since standard awake surgery was not appropriate for this patient. In preoperative time, nTMS mapping of motor function was performed, combined with magnetic resonance imaging -based tractography reconstruction of 6 neural tracts and resting-state functional MRI connectivity of sensorimotor and language networks. In intraoperative time, DES mapping was performed with motor evoked response recording and tumor resection was optimized using non-rigid image transformation of the preoperative data to iCT data. Image guidance was updated with correction for brain shift and tissue deformation using biomechanical modeling taking into account brain elastic properties. This correction was done at crucial surgical steps, i.e., when tumor bulged through the craniotomy after dura mater opening and when approaching the presumed eloquent brain regions. This procedure allowed a total resection of the tumor region with contrast enhancement as well as a complete regression of IICP and dysarthria. Hand paresis remained stable with no additional deficit. Postoperative nTMS mapping confirmed the good functional outcome.Conclusion: This case report and technical note highlights the value of preoperative functional evaluation by nTMS updated intraoperatively with correction of brain deformation by iCT. This multimodal approach may become the optimized technique of reference for patients with brain tumors in eloquent areas that are unsuitable for awake brain surgery. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:An Encounter with the Art and Science of MedicineAnonymous Five“Let Nothing Upset YouLet Nothing Frighten YouEverything is ChangingOnly God is Changeless”—St. Theresa of AvilaSt. Teresa’s prayer is on the front cover of each of four binders dedicated to storing insurance authorizations, studies, references, and reports about our daughter’s brain tumor treatment. They represent our experience, what we learned, the information we were given, and the information we sought out. (...) I kept them in case our daughter ever wanted to understand how my husband and I arrived at a decision for her treatment that was in direct opposition to the strong recommendation of her primary treatment team of physicians.On December 10, 2003, I received an urgent call from our daughter’s neurologist requesting that we meet with the doctor late that afternoon. For six months prior to that appointment, our daughter had been telling us about odd sensations with breathing, nausea, and balance. Sometimes she would seem extremely distressed for a short period of time or report that her friends told her about doing or saying things that didn’t make sense and that she didn’t remember. We consulted a series of physicians as her symptoms became steadily more intense and more prevalent. Our family practice physician referred us to an allergy specialist and a pulmonologist. There were a number of tests for allergies and lung problems. As the tests and treatments did not help, our daughter became increasingly unwilling to go to doctor’s appointments. My husband and I were confused and deeply concerned about the lack of progress. The next series of referrals included a gastroenterologist and a neurologist. The gastroenterologist suggested our daughter had partial–complex epilepsy, concurred with our plan to see a neurologist, and mentioned she should have an MRI.I remember the neurologist putting the MRI scans up, pointing to the large dark spot which he called a “large mass” (5 cm), that could be either a cluster of blood vessels or a neoplasm. He said his office had arranged for us to meet a neurosurgeon the following day. We all remember the same thing about that visit—the image of the large dark mass on the scan—and the neurologists flat, brisk tone. We met with the neuro-surgeon the next day. Her team was kind and sympathetic—she was positive, up beat and direct. She did not think this mass was blood vessels. She thought it was a large tumor that needed to be removed right away. Our daughters surgery was scheduled for the following Friday—December 19, 2003. She had turned 15 on November 5.Four and a half hours after our daughter was wheeled into the operating room, her surgeon told us they had removed 98% of the tumor. She said there was no cure, but there was a good prognosis based on the surgical outcome. Several days later, she called us and said she had more data, and it looked like the resection was closer to 90%. The first pathology report, a “first impression” directly after surgery, described our daughter’s tumor as an astrocytoma, probably high grade. Three weeks after surgery, we met with a panel of doctors—two oncologists and radiologist—who explained that based on the final pathology report, our daughter’s tumor was classified as an ependymoma, grade 2. We were dismayed. First, there had been the change in the estimated success of the resection and now a complete shift in both grade and tumor type.The team recommended radiation to follow her surgery, which they said was standard treatment. We began to try to inform ourselves about her tumor. Her father, an agronomist, did an extensive search in PubMed to evaluate and sort through the literature on low–grade gliomas and radiation. What he could find was inconclusive and grim. Most reports in the literature suggested at best delayed mortality at five years after radiation. [End Page E7] Meanwhile, our daughter went through a spinal MRI and the preparatory “fitting” of the mask to immobilize her head during radiation.E7I consulted with a friend who had worked as an EKG tech. She urged... (shrink)

Basic emotions such as happiness, sadness, and anger are universal, regardless of the human species, and are governed by specific brain regions. A recent report revealed that mentalizing, which is the ability to estimate other individuals’ emotional states via facial expressions, can be preserved with the help of awake surgery. However, it is still questionable whether we can maintain the ability to understand others’ emotions by preserving the positive mapping sites of intraoperative assessment. Here, we demonstrated the cortical regions related (...) to basic emotions via awake surgery for patients with frontal glioma and investigated the usefulness of functional mapping in preserving basic emotion. Of the 56 consecutive patients with right cerebral hemispheric glioma who underwent awake surgery at our hospital, intraoperative assessment of basic emotion could be successfully performed in 22 patients with frontal glioma and were included in our study. During surgery, positive responses were found in 18 points in 12 patients. Of these, 15 points from 11 patients were found at the cortical level, mainly the premotor and posterior part of the prefrontal cortices. Then, we focused on cortical 15 positive mappings with 40 stimulations and investigated the types of emotions that showed errors by every stimulation. There was no specific rule for the region-emotional type, which was beyond our expectations. In the postoperative acute phase, the test score of basic emotion declined in nine patients, and of these, it decreased under the cut-off value in three patients. Although the total score declined significantly just after surgery, it recovered within 3 months postoperatively. Our study revealed that through direct electrical stimulation, the premotor and posterior parts of the prefrontal cortices are related to various kinds of basic emotion, but not a single one. When the region with a positive mapping site is preserved during operation, basic emotion function might be maintained although it declines transiently after surgery. (shrink)

The transcriptional co‐activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD‐family co‐activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP‐TEAD cooperates with the RAS‐induced AP‐1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF‐SRF to (...) promote activation of cancer‐associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2‐LATS1/2) pathway and the key upstream activators are mechanically induced Integrin‐SRC and E‐cadherin‐AJUBA/TRIP6/LIMD1, growth factor induced PI3K‐AKT, and inflammation‐induced G‐protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy. (shrink)

Background: The risk of surgery in eloquent areas is related to neuropsychological dysfunctions. Maximizing the extent of resection increases the overall survival. The onco-functional balance is mandatory when surgery involves cognitive areas, and maximal information on the cognitive status of patients during awake surgery is needed. This can be achieved using direct cortical stimulation mapping and, in addition to this, a neuropsychological monitoring technique called real-time neuropsychological testing. The RTNT includes testing protocols based on the area where the surgery is (...) performed. We reported on tests used for left temporal lobe surgery and our RTNT decision tree.Case Report: We reported our RTNT experience with a 25-year-old right-handed man with 13 years of schooling. He reported daily partial seizures. MRI revealed the presence of a low-grade glioma involving the temporo-insular cortex. The neuropsychological status presurgery which was within the normal range was combined with functional magnetic resonance imaging and diffusion tensor imaging information. Awake surgery plus RTNT was performed. Direct electrical stimulation during object naming elicited a motor speech arrest. Resection was continuously accompanied by the RTNT. The RTNT provided enriched information to the surgeon. Performance never dropped. A slight decrement in accuracy emerged for pseudoword repetition, short-term memory and working memory, phonological processing, and verbal comprehension. Total resection was performed, and the histological examination confirmed the nature of the lesion. Immediate postsurgery performance was within the normal range as it was the fMRI and DTI assessment.Conclusion: The RTNT provides essential information that can be used online, during surgery, for clinical aims to provide the surgeon with useful feedback on the cognitive status of patients. (shrink)

We examine the consequences of long-range effects on tumour cell migration. Our starting point are previous results of ours where we have shown that the migration patterns of glioma cells are best interpreted if one assumes attractive interactions between cells. Here we complement the cellular automaton model previously introduced by the assumption of the existence of a chemorepellent produced by the main bulk of large spheroids (in the hypoxic/necrotic areas). Visible effects due to the presence of such a substance (...) can be found in the density profiles of cells migrating out of a single spheroid as well as in the angular distribution of cells coming from two close-lying spheroids. These effects depend crucially on the diffusion speed of the chemorepellent. A comparison of the simulation results to experimental data of Werbowetski et al. allows to draw (tentative) conclusions on the existence of a chemorepellent and its properties. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Ethan’s GiftMichelle BurgessEthan was your average boy next door. He loved everything most 8–year–old boys do including playing baseball, swimming, and watching his favorite baseball team, the Philadelphia Phillies.On December 3rd 2008, life for our family changed forever when Ethan was diagnosed with Diffuse Intrinsic Pontine Glioma, a rare inoperable brainstem tumor. DIPG is in essence a death sentence. There are no survivors and life expectancy after diagnosis (...) is only 9–12 months. Our family was devastated.For the next 14 months, we lived life to the fullest, never taking a single moment or day for granted. As Ethan’s condition worsened, and it became clear that he was close to passing, I spoke with Ethan’s doctor about my desire to be able to donate Ethan’s corneas and his brain tumor for research. He informed me that because of Ethan’s type of tumor that he may be a candidate for donation of other organs as well if that is something we wanted to do.Knowing that there was nothing we could do to save Ethan, it was something that we felt we could do to help others so we decided to explore the option of donating Ethan’s other organs. We were put in contact with the Gift of Life.Two representatives from Gift of Life came to our home and discussed at length with us what would have to happen to make organ donation possible at the time of Ethan’s passing. Specifically that Ethan would have to pass away at the hospital and in the operating room. This was very different than the hospice environment that we had planned. They also had told us that Ethan was only the second young person that they had ever dealt with that the families had planned ahead of time to donate organs. The other person was a teenager who planned his own organ donation.On January 26th 2010, Ethan’s pain had become unmanageable at home and his breathing had become very labored. I spoke with his oncologist and he advised me to bring Ethan to the hospital to try and get his pain under control.We loaded Ethan up in the car for the one–hour car ride to the hospital. On the way to the hospital Ethan fell asleep while being cuddled by me in the backseat. When we arrived at the hospital we noticed that his fingers and toes had turned purple. The nurses immediately checked his oxygen and it had fallen to only 10 %.The doctors advised that he had slipped into a coma in the car, one that he would never awake from. He was immediately placed on life support. A scan was done and it was evident that the progressing tumor was placing pressure on the areas of the brain that controlled basic life functions such as breathing. Ethan could not recover.The decision was made to begin to look for recipients for Ethan’s organs. Because Ethan had not reached the point of brain death, his donation would have to be a post cardiac death transplant, meaning, life support would be removed, when his heart stopped beating and he passed away, the organ procurement would begin. However, he [End Page E1] would not be able to donate his heart. This was very sad for us, knowing how strong his little heart was, but we did understand the process.On January 28th 2010, our family spent the day saying goodbye to Ethan. Even though he could not respond, we know that he could hear us. The nurse was wonderful, doing everything possible to accommodate our large family and despite all the tubes and machines, make it so that I could cuddle with my little boy one last time.Ethan was moved to the operating room and with his stepfather and I on one side and his father and stepmother on the other, life support was removed. Watching my son take his last breath, while I held his hand, kissed his cheeks, told him I loved him and that it was okay to let go and go to Heaven was the hardest moment of... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Life in LimboM. ChiuWhen my son was 7 years old, he began complaining of headaches. They were frequent, but never seemed severe. “I have a headache!” was always followed by “Can I watch TV?” I didn’t believe the pain was real until it woke him up in the middle of the night. I knew then that something must be wrong. I approached our pediatrician, who said it sounded like (...) migraines, but we should order an MRI to rule anything out. The appointment was scheduled several months in advance, and I always had the urge to cancel it. I was pretty sure my son just wanted to watch TV. The pediatrician told me I might as well do the MRI. He told me that if we skipped it and something was wrong, I would never be able to live with the regret. We kept the Monday morning appointment, and went to the MRI expecting reassurance that nothing was wrong. Instead, we got a phone call later that day. They needed to see us on immediately, but wouldn’t tell me why. Of course, I knew something was wrong. “Is it a tumor?” I asked. “This isn’t something we can discuss on the phone” was the answer I got. An appointment was scheduled for Wednesday. Two days might be “immediately” to medical professionals, but to a parent who just heard that her child had an abnormal MRI, it was an eternity. I planned my son’s funeral in those two days.Our meeting with the Neurologist began with reviewing the MRI. “See this spot here? It shouldn’t be there”. A tumor. 1 ½ × 1 ½ × 2 ½ cm tumor, in the right thalamus. Small, they said. Looks like a Low Grade Glioma they said. The kind of tumor you want to have, if you have to have a brain tumor. A biopsy was scheduled for two weeks later. The [End Page E2] biopsy confirmed it was a Juvenile Pilocytic Astrocytoma (JPA). The neurosurgeon was confident she could remove all of the tumor. We were at one of the best Children’s Hospitals in the world. We were in good hands.A few days before the surgery, a friend who is a medical doctor suggested we get a second opinion. “It couldn’t hurt, it could help”, my husband said. Fortunately, he just sold a start–up company, and was planning to take a few months off from work before starting his next venture. He had time to research, talk to friends in the medical field and make phone calls.Our second opinion from another leading hospital reviewed the MRI’s with us. The neurosurgeon asked, “Did they say tumor? One?” Yes, they did. “See this here?” he said, pointing to a second spot on the MRI. He said it was possibly a second tumor, or more likely, an extension of the first. It was in inoperable location. Surgery wasn’t an option. Chemo would be our best choice. Why would we cut into our son’s brain to remove part of the tumor when he would need to do chemo anyway? Why not try chemo first?I would like to say that we do not fault our original neuro–oncology team for missing this second abnormality. It is hard to notice an ant in the room when there is an elephant staring at you. People make mistakes, and tumors don’t always look the same. That’s what second opinions are for. That is why doctors should encourage patients to get second opinions.We scheduled the surgery for port implantation, and got busy educating ourselves about chemo regimes. It was going to be a long journey. 18 months of transfusions with a pretty low success rate and a high rate of secondary complications. Unsure if we were doing the right thing, we got a third opinion. I am so grateful that my husband was between jobs and had time to devote to finding the best possible treatment for our son. We were financially stable and had great insurance. What do people do when they don’t have this luxury?By now, several months had passed since our first MRI. Our... (shrink)

We provide a mathematical study of a model of energy metabolism and hemodynamics of glioma allowing a better understanding of metabolic modifications leading to anaplastic transformation from low grade glioma.This mathematical analysis allows ultimately to unveil the solution to a viability problem which seems quite pertinent for applications to medecine.

This paper discusses the evidence for the role of CREB in neural stem/progenitor cell (NSPC) function and oncogenesis and how these functions may be important for the development and growth of brain tumours. The cyclic‐AMP response element binding (CREB) protein has many roles in neurons, ranging from neuronal survival to higher order brain functions such as memory and drug addiction behaviours. Recent studies have revealed that CREB also has a role in NSPC survival, differentiation and proliferation. Recent work has shown (...) that over‐expression of CREB in transgenic animals can impart oncogenic properties on cells in various tissues and that aberrant CREB expression is associated with tumours in patients. It is the central position of CREB, downstream of key developmental and growth signalling pathways, which give CREB the ability to influence a spectrum of cell activities, such as cell survival, growth and differentiation in both normal and cancer cells. (shrink)