Intraoperative recording of laryngeal adductor reflex and cortical motor evoked potentials during jugular foramen schwannoma surgery: a case report and literature review.

PURPOSE: Schwannoma, a tumor originating from the peripheral nervous system, may arise from the vagus nerve, although it is not very often. Injury of the vagus nerve by surgical attempts may have consequences that will seriously affect the patient's quality of life. In recent years, continuous monitoring of the laryngeal adductor reflex (LAR) has become a promising methodology for evaluating vagus nerve function intraoperatively. We refer to our experience changing our surgical strategy due to concurrent deterioration in LAR and CoMEPs intraoperatively. We also provide a literature review and summarize the current knowledge of this technique. METHODS: The LAR was elicited and recorded by an electromyographic endotracheal tube in a 36-year-old man diagnosed with vagal nerve schwannoma. Subdermal needle electrodes were placed in both cricothyroid (CTHY) muscles for corticobulbar motor evoked potentials (CoMEPs) recording. RESULTS: Recordings of ipsilateral LAR and CTHY CoMEPs were obtained despite preoperative ipsilateral cord vocalis weakness. The surgical strategy was altered after the simultaneous decrease of CTHY CoMEPs and LAR amplitudes, and the surgery was completed with subtotal resection. No additional neurological deficit was observed in the patient except dysphonia, which resolved within a few weeks after the surgery. CONCLUSIONS: We conclude that LAR with vagal nerve CoMEPs are two complementary methods and provide reliable information about the functional status of the vagus nerve during surgery.

Treatment Strategies for Dopamine Agonist-Resistant and Aggressive Prolactinomas: A Comprehensive Analysis of the Literature.

Despite most of the prolactinomas can be treated with endocrine therapy and/or surgery, a significant percentage of these tumors can be resistant to endocrine treatments and/or recur with prominent invasion into the surrounding anatomical structures. Hence, clinical, pathological, and molecular definitions of aggressive prolactinomas are important to guide for classical and novel treatment modalities. In this review, we aimed to define molecular endocrinological features of dopamine agonist-resistant and aggressive prolactinomas for designing future multimodality treatments. Besides surgery, temozolomide chemotherapy and radiotherapy, peptide receptor radionuclide therapy, estrogen pathway modulators, progesterone antagonists or agonists, mTOR/akt inhibitors, pasireotide, gefitinib/lapatinib, everolimus, and metformin are tested in preclinical models, anecdotal cases, and in small case series. Moreover, chorionic gonadotropin, gonadotropin releasing hormone, TGFß and PRDM2 may seem like possible future targets for managing aggressive prolactinomas. Lastly, we discussed our management of a unique prolactinoma case by asking which tumors' proliferative index (Ki67) increased from 5-6% to 26% in two subsequent surgeries performed in a 2-year period, exerted massive invasive growth, and secreted huge levels of prolactin leading up to levels of 1 605 671 ng/dl in blood.

Caprylic acid ameliorates rotenone induced inflammation and oxidative stress in the gut-brain axis in Zebrafish.

BACKGROUND: Dysfunction of the gastrointestinal tract (GIT) is one of the most common non-motor symptom of Parkinson's Disease (PD). Pathological processes causing PD were suggested to initiate in the enteric nervous system (ENS) and proceed to the central nervous system (CNS). There are studies showing that low-carbohydrate ketogenic diets can improve motor symptoms of PD. Caprylic acid (C8) is the principal fatty acid component of the medium-chain triglycerides in the ketogenic diets. In this study, we aimed to evaluate the effects of caprylic acid, in neurotoxin exposed zebrafish focusing on the relationship between intestinal and brain oxidative stress and inflammation. METHODS: Adult zebrafish were exposed to rotenone (5 µg/L) (R group) and caprylic acid (20 and 60 mg/mL) (L + HDCA and R + HDCA groups) for 30 days. At the end of 30 days locomotor activities were determined. Levels of lipid peroxidation (LPO), nitric oxide, glutathione and superoxide dismutase and glutathione S-transferase activities were determined by spectrophotometric methods and gene expressions of tnf⍺, il1, il6, il21, ifnÉ£ and bdnf were evaluated by RT-PCR in the brain and intestinal tissues of zebrafish. RESULTS: Caprylic acid ameliorated LPO, NO, SOD and the expressions of tnf⍺, il1, il6, il21, ifnÉ£ and bdnf in brain and intestines. Locomotor activities were only ameliorated in high dose R + HDCA group. CONCLUSIONS: Caprylic acid ameliorated the neurotoxin-induced oxidative stress and inflammation both in the brain and intestines and enhanced locomotor activity in zebrafish.

Polymorphous low-grade neuroepithelial tumor of the young: A detailed pathomolecular analysis and discussion of a case.

AIM: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare entity with a diffuse, infiltrative pattern, awaiting to be included in the WHO CNS tumor classification; it occurs in pediatric and young patients with seizures and harbors mutually exclusive BRAFV600E or FGFR mutations. Nonetheless, the presence of these mutations may not be obligatory for diagnosis. The conventional histology of these tumors resembles that of oligodendrogliomas. We aimed to discuss a PLNTY case in a young woman presenting with seizures due to a parietal brain tumor and to provide an analysis of the literature. Histopathologically the tumor was consistent of oligodendroglioma-like neoplastic cells showing almost diffuse CD34 and olig-2 staining, retained ATRX expression, p53-negativity, and a low Ki67 index with no necrosis or microvascular proliferation. MATERIALS AND METHODS: 1p/19q statuswas analyzed with FISH; IDH1 and IDH2 mutations were analyzed with minisequence analysis. Translocations, mutations, and expression analyses were studied for 18, 19, and 21 genes via targeted new-generation deep RNA sequencing, respectively. RESULTS: The tumor did not carry 1p/19q codeletion, was IDH wild-type, and had radiological features compatible with the diagnosis of PLNTY. The tumor did not show BRAF or FGFR alterations but had an EGFR c.2342A>G (p.Asn781Ser) mutation which was likely a non-driver mutation due to its low allele frequency of 4%. CONCLUSION: PLNTYs are rare brain tumors, and their accurate diagnosis is important to avoid improper management. Their prognosis shall be stratified according to their mutations.

A pediatric cerebral tumor with MN1 alteration and pathological features mimicking carcinoma metastasis: may the terminology "high grade neuroepithelial tumor with MN1 alteration" still be relevant?

INTRODUCTION: Astroblastoma, MN1-altered (old name: high-grade neuroepithelial tumor/HGNET with MN1 alteration) is a recently described central nervous system tumor mostly affecting pediatric patients and profoundly young girls. Differential pathological diagnoses of these tumors include ependymoma, pleomorphic xanthoastrocytoma, embryonal tumor with multilayered rosettes, meningioma, and even glioblastoma. As the treatment approaches to these tumors differ, it is essential to increase the awareness about these tumors in the neurosurgical community. CLINICAL PRESENTATION: A 7-year-old female patient admitted with a 7-day history of headache, nausea, and vomiting. A contrasted MRI scan revealed a left parietal 4 × 4 × 5 cm mass with central necrosis and peripheral contrast enhancement. The tumor's histopathological findings were suggestive of a metastatic carcinoma with unknown primary, yet further genetic analysis revealed MN1 alteration. Peculiarly, the tumor pathomorphological features were not compatible with astroblastomas and exerted features strongly indicating a metastatic cancer; however, systemic PET and whole-body MRI failed to detect a primary malignancy. OUTCOME AND CONCLUSIONS: Eighteen months after gross-total tumor resection, an in-field and out-field multifocal recurrence developed which required a second surgery and subsequent chemo-radiotherapy. The patient is doing well for 1 year after the second treatment regimen at the time of this report. Despite the final cIMPACT6 classification in 2020 advised to define all MN1 altered brain tumors as astroblastomas, there exist prognostic differences in MN1-altered tumors with and without morphological features of astroblastoma. Rare morphological variants of MN1-altered tumors shall be recognized for their future prognostic and clinical classification. HGNET with MN1 alteration seems still be a more proper definition of such malignancies as an umbrella term.

Benign leiomyoma with multiple metastases to vertebrae and calvarium: An index case with comprehensive review of endocrine targets.

"Benign" metastatic leiomyomas (BML) are indolently growing metastatic tumors which mostly associate with uterine leiomyomas in women in reproductive ages. The reason to define these lesions as "benign" despite metastasis is their pathological features with low mitotic counts, lack of or minimal nuclear atypia, pseudocyst formation, and coagulative necrosis unlike leiomyosarcomas. Despite lack of pathological malignant features, they may cause significant morbidity and even mortality. Here, we describe a BML case with metastases to vertebrae and skull bones. Vertebral and skull metastases of BMLs were very rarely reported. In treatment of these tumors, hysterectomy and GnRH modifier treatments are widely employed. GnRH agonists act by desensitization and downregulation of the GnRH receptors, while GnRH antagonists act via the canonical competitive blockage. These treatments reduce FSH and LH levels, thereby reducing the systemic levels of sex steroids which stimulate leiomyoma growth. However, leiomyomas inherently harbor aromatase activity and synthesize their own estrogen; hence, treatment with systemic estrogen antagonists may provide better tumor control. Another important factor in BML pathogenesis is progesterone, and both progesterone receptor antagonists and high-dose progesterone receptor agonists may reduce BML growth. Following surgical treatment of the calvarial mass and radiotherapy of the vertebral metastatic foci, our BML case was successfully managed with hysterectomy and anastrozole treatment. Higher awareness of BML cases and their molecular endocrinological features in the neurosurgical community may pave to develop better strategies for treatment of these tumors causing high morbidity.

Neuroprotective effects of mitoquinone and oleandrin on Parkinson's disease model in zebrafish.

Aim: The aim of this study is to investigate the possible protective effects of mitoquinone and oleandrin on rotenone induced Parkinson's disease in zebrafish. Materials and methods: Adult zebrafish were exposed to rotenone and mitoquinone for 30 days. Biochemical parameters were determined by spectrophotometric method and Parkinson's disease-related gene expressions were determined by reverse transcription polymerase chain reaction method. Measurement of neurotransmitters was performed by liquid chromatography tandem-mass spectrometry instrument. The accumulation of synuclein was demonstrated by immunohistochemical staining. In vitro thiazolyl blue tetrazolium bromide method was applied to determine the mitochondrial function of synaptosomal brain fractions using rotenone as a neurotoxic agent and mitoquinone and oleandrin as neuroprotective agents. Results: Mitoquinone improved the oxidant-antioxidant balance and neurotransmitter levels that were disrupted by rotenone. Mitoquinone also ameliorated the expressions of Parkinson's disease-related gene expressions that were disrupted by rotenone. According to thiazolyl blue tetrazolium bromide assay results, mitoquinone and oleandrin increased mitochondrial function which was decreased due to rotenone exposure. Conclusion: Based on the results of our study, positive effects of mitoquinone were observed in Parkinson's disease model induced by rotenone in zebrafish.

Noscapine, a Non-addictive Opioid and Microtubule-Inhibitor in Potential Treatment of Glioblastoma.

Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks significant hypnotic and euphoric effects rendering it safe in terms of addictive potential. In 1954, Hans Lettré first described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960's, yet no effect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not affect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apoptosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood-brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy.

Could hepatitis B vaccine act as an adjuvant to lower risk and relapses of cancer?

In this review article, we hypothesize that Hepatitis B Virus Vaccine (HBV-V) and certain antigens of Hepatitis B Virus (HBV) could act as anticancer immunoadjuvants in addition to their role of preventing HBV-associated liver cancer. Evidence suggests that in animal breast cancer and melanoma models, combining hepatitis B-surface antigen (HBsAg) with other cancer antigens resulted in enhanced antitumour activity. HBsAg shares antigenic mimicry with healthy and malignant cells including squamous epithelia, thymic epithelia, bladder- and colon cancer cells. There exist anecdotal reports and small case series about spontaneous remission of leukaemias and neuroblastoma following acute HBV-infection. Recent studies also exist showing HBV-carrier state is a good prognostic factor for intrahepatic cholangiocarcinoma. Further epidemiological studies and animal experiments are necessary whether HBV-Vs exert additional immunoadjuvant benefits besides lowering the risk of liver cancer.

Methenamine's journey of 160 years: Repurposal of an old urinary antiseptic for treatment and hypoxic radiosensitization of cancers and glioblastoma.

Methenamine (hexamethylenetetramine, hexamine, urotropine) is a compound discovered in 1859, which is still currently being used as a urinary antiseptic. Methenamine is highly soluble in water and polar solvents, and its molecular constitution is similar to adamantane compounds with tetrahedral cage like structure. In acidic conditions, methenamine decomposes to formaldehyde and ammonia. Recently, methenamine has gained a renewal of interest due to antibiotic-resistant bacteria urinary tract infections; interestingly, bacteria cannot gain resistance to formaldehyde. In 1968, David and Burkitt reported remarkable regression of four Burkitt Lymphoma patients in eight subjects who were treated with septicemine (a solution containing 6.3 g of methenamine iodomethylate and 1 g of methenamine sodium benzoate in 100 cc distilled water). Unfortunately, these striking observations did not gain interest in the medical community; despite experimental models that showed that methenamine synergized with hyperthermia, radiation, and chemotherapy to block cancer growth. As the hypoxic core of tumours have an acidic pH, it would be plausible to expect that methenamine would selectively target dormant, non-proliferative, and treatment-resistant cancer clones in large tumours. Moreover, previous data suggests that methenamine can be safely used intravenously and for treatment of infections of the central nervous system. It may therefore be an effective adjuvant in treatment of systemic cancers and glioblastoma.

From epidemiology and neurometabolism to treatment: Vitamin D in pathogenesis of glioblastoma Multiforme (GBM) and a proposal for Vitamin D + all-trans retinoic acid + Temozolomide combination in treatment of GBM.

Here we review tumoricidal efficacy of Vitamin D analogues in glioblastoma multiforme (GBM) and potential synergisms with retinoic acid and temozolomide based on epidemiological and cellular studies. Epidemiological data suggest that winter birth is associated with higher risk of GBM, and GBM debulking in the winter enhanced mortality, which may relate with lower exposure to sunlight essential to convert cholecalciferol to Vitamin D. Comparative studies on blood bank specimens revealed that higher prediagnosis levels of calcidiol are associated with lower risk of GBM in elderly men. Supplemental Vitamin D reduced mortality in GBM patients in comparison to nonusers. Expression of Vitamin D Receptor is associated with a good prognosis in GBM. Conversely, Vitamin D increases glial tumor synthesis of neutrophins NGF and NT-3, the low affinity neurotrophin receptor p75NTR, IL-6 and VEGF, which may enhance glioma growth. Antitumor synergisms between temozolomide and Vitamin D and Vitamin D with Vitamin A derivatives were observed. Hence, we hypothesize that Calcitriol + ATRA (All-Trans Retinoic Acid) + Temozolomide - CAT combination might be a safer approach to benefit from Vitamin D in the management of high-grade glial tumors. Adding acetazolomide to this protocol may reduce the risk of pseudotumor cerebri, as both Vitamin D and Vitamin A excess may cause intracranial hypertension; this approach may provide further benefit as acetazolomide also exhibits anticancer activity.

Reproductive epidemiology of glial tumors may reveal novel treatments: high-dose progestins or progesterone antagonists as endocrino-immune modifiers against glioma.

Female gender, contraceptives, and menopausal hormone replacement treatments containing progesterone analogues associate with higher risk of meningiomas yet with lower risk of gliomas. Progesterone receptor (PR) expression and mifepristone treatment was highly discussed for meningiomas. However, much less is known in regard to progesterone actions in gliomas despite PR expression strongly correlates with their grade. Meningiomas and gliomas may grow faster during gestation; but paradoxically, parousity reduces lifetime risk of gliomas which can be explained with dichotomous cell growth-stimulating and inhibitory actions of progesterone at low versus high levels. Progesterone levels gradually increase in gestation up to 200-fold and the incidence of highly angiogenic brain tumors decreases in the last trimester. Indeed, progesterone stimulates glial tumor cell growth at low doses (10 nM) while induces cell kill at higher doses. During gestation, some immune pathways are activated to protect the mother and the fetus against microbial pathogens. In parallel, high-dose medroxyprogesterone acetate (MPA) used in treatment of endometrial carcinoma decreases tumoral expression of PR-B and increases infiltration of cytotoxic T lymphocytes and natural killer cells. MPA also synergies with IL-2 in clinical treatment of renal cancer. In both glioma and meningioma, the dominant cytosolic PR is PR-B which increases cell growth, while PR-A limits cell growth. This seems also paradoxical at the first glance due to opposite behavior of these tumors in diverse endocrine conditions. High-dose progestins may inhibit brain tumor growth by downregulating PR-B, yet the dosage thresholds may differ between glial and meningeal tumors due to higher total PR expression in meningiomas. Supporting this proposal, certain progestins were reported to stimulate meningioma growth in anecdotal reports, but same agents at much higher doses reduced meningioma cell proliferation in pilot clinical studies. PR antagonist mifepristone reduced meningioma growth in some clinical studies, but lacked efficacy in others. In fact, mifepristone also has partial PR agonist efficacy and acts in synergy with MPA to block EC growth. Hence, a similar mechanism of receptor downregulation may also account for mifepristone. Both MPA and mifepristone also harbor myeloprotective features against chemotherapy. Ulipristal is another contraceptive PR antagonist and exerts promising anticancer activity on drug-resistant ovarian cancer and BRCA1-mutant breast cancer cells, which can be tested in animal glioblastoma models. We propose that progestins strongly deserve to be investigated in experimental models of glioblastoma alone and in combination with immunostimulating agents.

Boron's neurophysiological effects and tumoricidal activity on glioblastoma cells with implications for clinical treatment.

Purpose: To define the actions of boron on normal neurophysiology and glioblastoma growth. Materials and Methods: PubMed and other relevant databases were searched. Results: Discovery of novel boron compounds in treatment of glioblastoma is being actively investigated, but the majority of such studies is focused on the synthesis of boron compounds as sensitizers to Boron Neutron Capture Therapy (BNCT). Nonetheless, the translational functionality of boron compounds is not limited to BNCT as many boron compounds possess direct tumoricidal activity and there is substantial evidence that certain boron compounds can cross the blood-brain barrier. Moreover, boron-containing compounds interfere with several tumorigenic pathways including intratumoral IGF-I levels, molybdenum Fe-S containing flavin hydroxylases, glycolysis, Transient Receptor Potential (TRP) and Store Operated Calcium Entry (SOCE) channels. Conclusions: Boron compounds deserve to be studied further in treatment of systemic cancers and glioblastoma due to their versatile antineoplastic functions.

Targeting nitric oxide and NMDA receptor-associated pathways in treatment of high grade glial tumors. Hypotheses for nitro-memantine and nitrones.

Glioblastoma multiforme (GBM) is a devastating brain cancer with no curative treatment. Targeting Nitric Oxide (NO) and glutamatergic pathways may help as adjunctive treatments in GBM. NO at low doses promotes tumorigenesis, while at higher levels (above 300 nM) triggers apoptosis. Gliomas actively secrete high amounts of glutamate which activates EGR signaling and mediates degradation of peritumoral tissues via excitotoxic injury. Memantine inhibits NMDA-subtype of glutamate receptors (NMDARs) and induces autophagic death of glioma cells in vitro and blocks glioma growth in vivo. Nitro-memantines may exert further benefits by limiting NMDAR signaling and by delivery of NO to the areas of excessive NMDAR activity leading NO-accumulation at tumoricidal levels within gliomas. Due to the duality of NO in tumorigenesis, agents which attenuate NO levels may also act beneficial in treatment of GBM. Nitrone compounds including N-tert-Butyl-α-phenylnitrone (PBN) and its disulfonyl-phenyl derivative, OKN-007 suppress free radical formation in experimental cerebral ischemia. OKN-007 failed to show clinical efficacy in stroke, but trials demonstrated its high biosafety in humans including elderly subjects. PBN inhibits the signaling pathways of NF-κB, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX). In animal models of liver cancer and glioblastoma, OKN-007 seemed more efficient than PBN in suppression of cell proliferation, microvascular density and in induction of apoptosis. OKN-007 also inhibits SULF2 enzyme, which promotes tumor growth via versatile pathways. We assume that nitromemantines may be more beneficial concomitant with chemo-radiotherapy while nitrones alone may act useful in suppressing basal tumor growth and angiogenesis.

Neuroprotective and tumoricidal activities of cardiac glycosides. Could oleandrin be a new weapon against stroke and glioblastoma?

Cardiac glycosides induce a strong immunological cancer cell cytotoxicity, in which the released intracellular components of dying tumor cells (e.g. calreticulin, HMGB1 and ATP) stimulate immunity and help in eradicating cancer. Among the cardiac glycosides, oleandrin is an inhibitor of P-glycoprotein expression and exerts excellent penetration through the blood-brain barrier which also harbors neuroprotective and anti-glioma efficacies. Cardiac glycosides also exert neuroprotective activities, one explanation for such an action is the metabolic arrest as a defense strategy against hypoxia. Recently, it was also shown that oleandrin increases survival of glioma-implanted mice alone and in synergy with temozolomide, which also associated with the release of brain derived neurotrophic factor and activation of its receptor TrkB. In conclusion, oleandrin strongly deserves to be studied as a candidate molecule in treatment of neurodegenerative and neurooncological diseases.

Paradoxical results obtained with Ki67-labeling and PHH3-mitosis index in glial tumors: a literature analysis.

Precise tiered tumor grading is essential for predicting prognosis, selecting different treatment options and for follow-up of brain tumor patients. Ki67 labeling index (LI) is widely employed in assessing aggressiveness of glial brain tumors. However, Ki67 is subject to interlaboratory variability, and its antigen is expressed on all cell cycle phases except G0, which hinders its usage as a precise criterion for assessing cell proliferation. Indeed, there exist peculiar observations pertinent to increases of Ki67 index in glial tumors following radiotherapy or treatment with tyrosine kinase inhibitors. Moreover, we have witnessed a reduced Ki67 labeling in a gemistocytic glioma during its rapid recurrence under temozolomide treatment. Therefore, we reviewed pitfalls in employing Ki67 indices for predicting glial tumor biology and tried to answer whether the mitotic marker PHH3 (phosphorylated histone H3) could provide additional information in predicting glial tumor biology. PHH3-based assessment of proliferating cell fraction provides novel potentials, but it has also its own weaknesses. It has not yet been determined whether it would be more advantageous to report: a mitotic count (MC) per unit-area (e.g., 10 high power fields (HPF)) or a mitotic index (MI) (per 1,000 tumor cells). Further, there exist peculiarities in terms of unexpectedly low or high PHH3 values in pilocytic astrocytomas and angiocentric gliomas, respectively. Indeed, we encountered almost no staining with PHH3 in our unique gemistocytic astrocytoma case. Hence, at least in some glial malignancies, PHH3 may not be necessary for cell proliferation. Awareness of the weaknesses of proliferation markers in brain tumors may improve patient monitoring and treatment.
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A Metabolic Inhibitory Cocktail for Grave Cancers: Metformin, Pioglitazone and Lithium Combination in Treatment of Pancreatic Cancer and Glioblastoma Multiforme.

Pancreatic cancer (PC) and glioblastoma multiforme (GBM) are among the human cancers with worst prognosis which require an urgent need for efficient therapies. Here, we propose to apply to treat both malignancies with a triple combination of drugs, which are already in use for different indications. Recent studies demonstrated a considerable link between risk of PC and diabetes. In experimental models, anti-diabetogenic agents suppress growth of PC, including metformin (M), pioglitazone (P) and lithium (L). L is used in psychiatric practice, yet also bears anti-diabetic potential and selectively inhibits glycogen synthase kinase-3 beta (GSK-3ß). M, a biguanide class anti-diabetic agent shows anticancer activity via activating AMP-activated protein kinase (AMPK). Glitazones bind to PPAR-γ and inhibit NF-κB, triggering cell proliferation, apoptosis resistance and synthesis of inflammatory cytokines in cancer cells. Inhibition of inflammatory cytokines could simultaneously decrease tumor growth and alleviate cancer cachexia, having a major role in PC mortality. Furthermore, mutual synergistic interactions exist between PPAR-γ and GSK-3ß, between AMPK and GSK-3ß and between AMPK and PPAR-γ. In GBM, M blocks angiogenesis and migration in experimental models. Very noteworthy, among GBM patients with type 2 diabetes, usage of M significantly correlates with better survival while reverse is true for sulfonylureas. In experimental models, P synergies with ligands of RAR, RXR and statins in reducing growth of GBM. Further, usage of P was found to be lesser in anaplastic astrocytoma and GBM patients, indicating a protective effect of P against high-grade gliomas. L is accumulated in GBM cells faster and higher than in neuroblastoma cells, and its levels further increase with chronic exposure. Recent studies revealed anti-invasive potential of L in GBM cell lines. Here, we propose that a triple-agent regime including drugs already in clinical usage may provide a metabolic adjuvant therapy for PC and GBM.

Impact of 1p/19q codeletion on the diagnosis and prognosis of different grades of meningioma.

BACKGROUND: Meningiomas are one of the most common tumours to affect the central nervous system. Genetic mutations are important in meningeal tumourigenesis, progression and prognosis. In this study, we aimed to examine the effect of 1p/19q deletion on the diagnosis and prognosis of meningioma subtypes using the fluorescence in situ hybridization (FISH) method. METHODS: Twenty-four patients with meningioma were retrospectively studied. Tumour samples were obtained from 10 typical, 11 atypical and three anaplastic malignant meningiomas. The most representative tumour sections were screened for 1p/19q deletion using the FISH method. RESULTS: Of the 24 patients, eight were women (33.3%) and 16 (66.7%) were men. The mean age was 56.6 years. The higher-grade meningioma was usually seen in males and had a higher rate of deletion on 1p (p = 0.001). There was a statistically significant difference between the grades and the rate of deletion on 19q (p = 0.042) and between the grades and the rates of polysomy, monosomy and amplification on 19q (p = 0.002; p = 0.001; p = 0.002, respectively). There was no statistical difference between 1p/19q codeletion and the grades of meningioma (p > 0.05). We detected higher level of Ki-67 in the condition of codeletion but did not find a statistical difference (p = 0.0553). CONCLUSION: Deletion on 1p, as well as deletion, polysomy, monosomy and amplification on 19q, are detected more frequently in high grade meningiomas. This amplification is most likely due to the amplification of oncogenes.

Microsurgical fenestration and cystoperitoneal shunt through preauricular subtemporal keyhole craniotomy for the treatment of symptomatic middle fossa arachnoid cysts in children.

INTRODUCTION: The optimal surgical treatment for symptomatic middle fossa arachnoid cyst is still controversial. The most leading therapeutic options include cyst shunting and fenestration (endoscopic, microsurgical). We present our experience on surgical treatments of arachnoid cysts. PATIENTS AND METHODS: A retrospective data review of 16 children who underwent keyhole craniotomy for microsurgical fenestration and shunting of middle fossa arachnoid cysts between 1999 and 2012 was performed after institutional review board approval. The average patient age was 6.1 years. The average follow-up period was 36.5 months. There were ten male and six female patients in the series. Indications for surgery included intractable headaches (50%), increasing in cyst size (18.75%), and seizures (31.25%). All patient records were reviewed for their clinical presentation, classification, cyst resolution, symptom resolution, and cyst outcomes. After surgery, all patients underwent assessments of clinical and radiological improvement. RESULTS: Postoperative complications were observed in two cases: progressively resolving monoparesia in one case and resolving epileptic seizure with monotherapy in the other. All patients had a satisfactory clinical outcome, and in 87.5%, there was either a decrease in the size or a complete disappearance of the MFAC. Nevertheless, three (18.75%) of all patients needed shunt revision because of shunt dysfunction. Complication related to surgical technique was cerebrospinal fluid leak which spontaneously resolved in one patient. CONCLUSION: Microsurgical fenestration with keyhole craniotomy to provide passage between cysts to basal cisterns together with cystoperitoneal shunting during the same operation is still an effective and safe method in cases with symptomatic middle fossa arachnoid cysts in children.

A Simple Technique for Bone Storage after Decompressive Craniectomy in Children.

Cranial vault reconstruction in the pediatric population is a specialized procedure, which requires additional considerations. Generally, inherent difficulties of bone storage and cranioplasty are neglected in the literature. We present a simple method of bone storage and autologous cranioplasty in a small child with severe head injury. The child underwent surgical treatment with decompressive craniectomy. A bone flap was transversally divided into two pieces and stored under the galea. Bone storage and reconstruction of the cranial vault with our surgical technique is a safe, easy and cost-effective choice excluding the surgical trauma to obtain a new subcutanous pocket for bone storage in pediatric decompressive craniectomy patients.