Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival.

The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00-1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03-1.59). Among females, anemia was not associated with median-OS using hemoglobin (HR 1.00; 95% CI 0.78-1.27) or hematocrit-based cutoffs (HR: 1.10; 95% CI 0.85-1.41). Iron supplementation of anemic females trended toward increased median-OS (HR 0.61; 95% CI 0.32-1.19) although failing to reach statistical significance whereas no significant association was found in anemic males (HR 0.85; 95% CI 0.41-1.75). Functional transferrin-binding assays confirmed sexually dimorphic binding in resected patient samples indicating underlying differences in iron biology. Anemia among glioblastoma patients exhibits a sex-specific association with survival.

Impact of Peritumoral Edema During Tumor Treatment Field Therapy: A Computational Modelling Study.

BACKGROUND: Tumor treatment fields (TTFie-lds) are an approved adjuvant therapy for glioblastoma (GBM). The magnitude of applied electrical field has been shown to be related to the anti-tumoral response. However, peritumoral edema may result in shunting of electrical current around the tumor, thereby reducing the intra-tumoral electric field. In this study, we systematically address this issue with computational simulations. METHODS: Finite element models are created of a human head with varying amounts of peritumoral edema surrounding a virtual tumor. The electric field distribution was simulated using the standard TTFields electrode montage. Electric field magnitude was extracted from the tumor and related to edema thickness. Two patient specific models were created to confirm these results. RESULTS: The inclusion of peritumoral edema decreased the average magnitude of the electric field within the tumor. In the model considering a frontal tumor and an anterior-posterior electrode configuration, ≥6 mm of peritumoral edema decreased the electric field by 52%. In the patient specific models, peritumoral edema decreased the electric field magnitude within the tumor by an average of 26%. The effect of peritumoral edema on the electric field distribution was spatially heterogenous, being most significant at the tissue interface between edema and tumor. CONCLUSIONS: The inclusion of peritumoral edema during TTFields modelling may have a dramatic effect on the predicted electric field magnitude within the tumor. Given the importance of electric field magnitude for the anti-tumoral effects of TTFields, the presence of edema should be considered both in future modelling studies and when planning TTField therapy.

Interventions to Reduce Neurological Symptoms in Patients with GBM Receiving Radiotherapy: From Theory to Clinical Practice.

BACKGROUND: Patients affected by glioblastoma often develop cerebral oedema as a life-threatening complication. Although there is no approved pharmacological intervention, such cerebral oedema is usually treated with dexamethasone. Dexamethasone has been shown in experimental studies to reduce cerebral oedema with only few mineralocorticoid side-effects. The goal of our study was to examine its efficacy in reducing the emergence of neurological deficits during the Stupp protocol. PATIENTS AND METHODS: We studied a retrospective cohort of 459 patients, assigned in controlled groups: in group A, patients received radiochemotherapy followed by adjuvant chemotherapy; in group B, patients received an equivalent combined treatment with dexamethasone. RESULTS: The frequency of neurological symptoms was significantly lower in dexamethasone-treated patients. CONCLUSION: Early diagnosis and prevention of cerebral oedema are important because functional consequences can be anticipated with an appropriate medical treatment. Thus, our study reveals that dexamethasone acts to prevent the appearance of neurological symptoms in patients with brain tumour.

Mecanismos moleculares da interação entre betalaínas cumarínicas fluorescentes e células de glioma humano / Molecular mechanisms of interaction between fluorescent coumarinic betalains and human glioma cells

Moléculas orgânicas fluorescentes são uma importante ferramenta para biologia celular. Compostos ideais para esta aplicação devem ter alto brilho (produto do coeficiente de atenuação molar e do rendimento quântico de fluorescência), ser fotoestáveis e internalizáveis, não comprometer a viabilidade celular e interagir com biomoléculas com algum grau de especificidade. Nesta Tese de Doutorado é apresentado o estudo do uso de cBeet120, uma betalaína cumarínica artificial, e células de glioma humano da linhagem U87-MG. Betalaínas são pigmentos de plantas que apresentam alta biocompatibilidade que servem como material de partida para o desenvolvimento de derivados funcionais. A sonda se acumula principalmente no núcleo das células U87- MG e marca principalmente nucléolos via interação com proteínas. A presença de DNAse ou RNAase elimina a marcação nuclear, sem afetar a fraca marcação citoplasmática de fundo. Estudos de inibição de transporte sugerem que cBeet120 é internalizada por transportadores de L-glutamato da família de transportadores de amino ácidos excitatórios (EAAT). O uso de artemisinina para inibição Ca2+-ATPases aumenta a velocidade de internalização de cBeet120 em células U87-MG. Quando irradiada com luz de cor ciano, cBeet120 no interior do núcleo de células vivas é fotoativada, resultando em um aumento da intensidade de fluorescência com o tempo (monitorado por 90 min) e o deslocamento hipsocrômico do máximo de emissão. Em células fixadas com paraformaldeído, o padrão de marcação da célula se torna mais difuso e a sonda emite fluorescência sem fotoativação. Medidas de tempo de vida de fluorescência em solução e imageamento por microscopia de tempo de vida de fluorescência permitem inferir a ocorrência da formação de um complexo proteína-cBeet120 ou um produto de transiminação que pode estar sujeito a isomerização cis/trans

Fluorescent organic molecules are an important tool for cell biology. Ideal compounds for this application must have high brightness (product of the molar attenuation coefficient and fluorescence quantum yield), be photostable and internalizable by cells, do not compromise cellular viability and interact with biomolecules with some degree of specificity. In this Doctorate Thesis, we describe the interaction of cBeet120, an artificial coumarinic betalain, and human glioma cells of line U87-MG. Betalains are plant pigments that exhibit high biocompatibility that serve as starting material for the development of functional derivatives. The probe accumulates mainly in the nucleus of the U87-MG cells and mainly marks nucleoli via interaction with proteins. The presence of DNAse or RNAase eliminates nuclear labeling, without affecting the poor background cytoplasmic labeling. Transport inhibition studies suggest that cBeet120 is internalized by L-glutamate transporters from the excitatory amino acid transporter (EAAT) family. The use of artemisinin for inhibition Ca2+-ATPases increases the rate of cBeet120 internalization in U87-MG cells. When irradiated with cyan colored light, cBeet120 within the nucleus of living cells is photoactivated, resulting in an increase in fluorescence intensity over time (monitored for 90 min) and the hypochromic shift of the emission maximum. In cells fixed with paraformaldehyde, the labeling pattern of the cell becomes more diffuse and the probe emits fluorescence without photoactivation. Fluorescence life-time measurements in solution and fluorescence life-time imaging microscopy allows to infer the occurrence of the formation of a protein-cBeet120 complex or the formation of a transimination product that may be subject to cis/trans isomerization

Prognostic relevance of epilepsy at presentation in glioblastoma patients.

BACKGROUND: Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients. METHODS: Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment. RESULTS: Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61-0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment. CONCLUSION: Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.

Further evidence for a pain pathway involving the cingulate gyrus: a case of chronic cluster headache cured by glioblastoma.

The authors report a case of a 49-year-old man with long-standing, chronic cluster headache (CH) refractory to medical therapy and occipital nerve stimulation that resolved a few weeks prior to the diagnosis of glioblastoma involving primarily the right cingulate gyrus. An attempt to explore the underlying role of the cingulate cortex in pain modulation by appraising the current literature is presented. This report suggests that the cingulate gyri could be a potential target for neuromodulation in patients with medically refractory chronic CH.

Haematological toxicity of Valproic acid compared to Levetiracetam in patients with glioblastoma multiforme undergoing concomitant radio-chemotherapy: a retrospective cohort study.

Patients with glioblastoma multiforme (GBM) and symptomatic seizures are in need of a sufficient antiepileptic treatment. Haematological toxicity is a limiting side effect of both, first line radio-chemotherapy with temozolomide (TMZ) and co-medication with antiepileptic drugs. Valproic acid (VPA) and levetiracetam (LEV) are considered favourable agents in brain tumor patients with seizures, but are commonly reported to induce haematological side effects on their own. We hypothesized, that antiepileptic treatment with these agents has no increased impact on haematological side effects during radio-chemotherapy in the first line setting. We included 104 patients from two neuro-oncologic centres with GBM and standard radio-chemotherapy in a retrospective cohort study. Patients were divided according to their antiepileptic treatment with either VPA, LEV or without antiepileptic drug therapy (control group). Declines in haemoglobin levels and absolute blood cell counts for neutrophil granulocytes, lymphocytes and thrombocytes were analyzed twice during concomitant and once during adjuvant phase. A comparison between the examined groups was performed, using a linear mixed model. Neutrophil granulocytes, lymphocytes and thrombocytes significantly decreased over time in all three groups (all p < 0.012), but there was no significant difference between the compared groups. A significant decline in haemoglobin was observed in the LEV treated group (p = 0.044), but did not differ between the compared groups. As a novel finding, this study demonstrates that co-medication either with VPA or LEV in GBM patients undergoing first line radio-chemotherapy with TMZ has no additional impact on medium-term haematological toxicity.

Pediatric thalamic glioblastoma associated with Ollier disease (multiple enchondromatosis): a rare case of concurrence.

Ollier disease and Maffucci syndrome are rare syndromes in which there is deforming dysplasia of cartilage, primarily but not exclusively involving the metaphyses and diaphyses of long bones. In a minority of patients, dysplasia can lead to sarcomatous degeneration, producing chondrosarcomas. There also appears to be an association with other neoplasms. Little has been written about the association between Ollier disease and intracranial tumors, and these papers have largely consisted of case reports in adults. The authors present the case of a 6-year-old girl with left arm osseous changes consistent with Ollier disease and a biopsy-proven thalamic glioblastoma multiforme. They then examine the co-occurrence of brain tumors in conjunction with a dyschondroplasia syndrome in children and adolescents to assess the presentation, treatment offered, and disease course of similar cases. Eight other such cases were identified, 6 in patients with Ollier disease (ranging in age from 7 to 18 years), and 2 with Maffucci syndrome (both in late adolescence). Including our own patient, 7 of the 9 cases of comorbid dyschondroplasia and intracranial malignancy occurred in girls. Some patients presented soon after the acute onset of symptoms, and others had a more subtle, protracted course over as many as 2 years. Some tumors were deemed resectable and others not. In only 1 instance was follow-up beyond 1 year reported.

Bimedial rectus hypermetabolism in convergence spasm as observed on positron emission tomography.

A 52-year-old man developed vertical gaze palsy, convergence spasm, and convergence-retraction nystagmus due to glioblastoma of the right thalamus. 18F-fluorodeoxyglucose positron emission tomography (PET) inadvertently demonstrated markedly increased metabolism in the medial rectus muscles. The hypermetabolism indicates active contraction of these extraocular muscles due to excessive convergence drive attributed to inappropriate activation or disrupted inhibition of convergence neurons by the diencephalic lesion.

Acquired long QT syndrome and monomorphic ventricular tachycardia after alternative treatment with cesium chloride for brain cancer.

Individuals searching for symptomatic relief or a potential cure are increasingly seeking and using nontraditional therapies for their various diseases. Little is known about the potential adverse effects that patients may encounter while undergoing these alternative treatments. Cesium chloride is an unregulated agent that has been reported to have antineoplastic properties. Cesium chloride is advertised as an alternative agent for many different types of cancers and can be purchased easily on the Internet. Recently, QT prolongation and polymorphic ventricular tachycardia were reported in several patients taking cesium chloride as alternative treatment for cancer. We report acquired QT prolongation and sustained monomorphic ventricular tachycardia in a patient who self-initiated and completed a course of cesium chloride as adjunctive treatment for brain cancer.

[Cross-hypersensitivity syndrome between antiepileptic drugs: report of a case]. / Síndrome de hipersensibilidad cruzado entre antiepilépticos: a propósito de un caso.

Antiepileptic hypersensitivity syndrome (SHA) is a rare (1/1.000 to 1/10.000 in new exposures) but potentially life-threatening syndrome that occurs after exposure to an anticonvulsant, most commonly the aromatic ones such as phenytoin, carbamazepine or phenobarbital. Clinical features of this syndrome include cutaneous reactions, fever, lymphadenopaties, eosinophilia and internal organ involvement (mainly liver, but also kidney, CNS, heart or lung). We present a case report of a 61-year-old woman treated with phenobarbital who developed a cutaneous eruption attributed to this drug. Treatment was changed to phenytoin and after 17 days the patient developed cutaneous rash, eosinophilia and an increase in transaminase levels. The high rate of cross-sensitivity between aromatic anticonvulsants (40-80%) suggests a link between a hypersensitivity reaction to phenytoin and the previous reaction to phenobarbital.

Subarachnoid hemorrhage from brain tumors in childhood.

Six children are reported in whom subarachnoid hemorrhage was an initial symptom of brain tumor. In our neurosurgical clinics, this represented 3.6% of pediatric brain tumors and showed a frequency equal to aneurysmal rupture among nontraumatic subarachnoid hemorrhage of children. In pediatric patients, hemorrhages from brain tumors occur predominantly in the posterior fossa. The medulloblastoma, which had been believed to bleed rarely, is now realized to be a common source of tumor hemorrhages in such cases. The introduction of CT scan facilitates early recognition of hemorrhagic stroke from brain tumors and prompt management for acute intracranial hypertension and brainstem dysfunction. Although the patients achieve favorable recovery from their initial catastrophic condition, the ultimate prognosis, in the majority of cases, is still rather poor because such hemorrhages usually develop from a malignant tumor. The present and other recent reports indicate that the incidence of hemorrhagic stroke from brain tumors in pediatric patients is much higher than has been thought and is an important cause of subarachnoid hemorrhage in this age group.

Hyperphagia and obesity. Relationship to medial hypothalamic lesions.

Progressive left hemiparesis followed by face and trunk cutaneous vasodilation and hyperphagia developed in a 28-year-old man. He began eating five to six meals a day and gained 16 kg in 60 days. Computed tomography disclosed a neoplastic lesion involving the midline via the hypothalamus and reaching the contralateral lenticular nucleus. Findings from endocrine studies, including thyroid-stimulating hormone, growth hormone, prolactin, and cortisol serum levels, were normal. Hyperphagia and consequent obesity were associated with bilateral destruction of the ventromedial hypothalamic area; cutaneous vasodilation was related to involvement of the preoptic area.

Abrupt memory loss associated with thalamic tumor.

We report a case in which glioma with apparent major involvement of the right thalamus was manifested initially solely by abrupt onset of severe impairment of both recent and moderately remote memory. Distracting stimuli plays a role in prevention of consolidation of memory.