Systemic management of malignant meningiomas: A comparative survival and molecular marker analysis between Octreotide in combination with Everolimus and Sunitinib.

PURPOSE: To compare the effectiveness of octreotide/everolimus vs. sunitinib for the systemic treatment of recurrent aggressive meningiomas. METHODS: 31 patients with recurrent or refractory WHO II or WHO III meningiomas were examined in two reference centers in Colombia. Patients who had systemic treatment (sunitinib, everolimus/octreotide) and a complete follow-up were included. Overall survival (OS), progression-free survival (PFS) and toxicities were evaluated. Additionally, tissue samples were examined for PDGFRß and VEGFR2, their expression was correlated with outcomes. RESULTS: Twenty-two patients (72%) were female with a median age of 55 years (SD±15.3). The most prevalent histology was anaplastic meningioma in 20 patients (65%) with 48% of patients suffering from three previous relapses before the start of systemic treatment. A total of 14 patients received combination therapy with octreotide/everolimus, 11 received sunitinib and the remaining 6 received other second-line agents. Median OS was 37.3 months (95%CI 28.5-42.1) and the PFS during the treatment with everolimus/octreotide (EO) and sunitinib (Su) was 12.1 months (95%CI 9.2-21.1) and 9.1 months (95%CI 6.8-16.8); p = 0.43), respectively. The OS of the group treated with the EO→Su→Bev sequence (1st/2nd/3rd line) was 6.5 months longer than the Su→EO→Bev sequence (36.0 vs. 29.5 months) (p = 0.0001). When analyzing molecular markers, the positive PDGFRß and negative VEGFR2 expression were associated with longer survival both in OS and PFS. CONCLUSION: Sunitinib and octreotide/everolimus have similar efficacy and safety in the systemic management of refractory meningioma. VEGFR2 and PDGFRß expression are associated with better outcomes.

Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma.

Epilepsy is a common symptom in patients with glioblastoma (GB). 213 patients with GB from RedLANO follow-up registry were included. All patients underwent surgery, if feasible, followed by chemoradiation based on temozolomide (Stupp platform). Information was recorded regarding demographics, seizure timing, anti-epileptic drugs (AEDs), dosage, time to next seizure, total seizures in 6 months, and main side effects of AEDs. The relationship between epilepsy treatment and overall survival (OS) was evaluated. Mean age was 53 years old and 56.8% were male. Seventy-eight patients (37%) were treated with levetiracetam (LEV), 27% were given another AED and 36% did not require any AED. Choice of AED was not associated with age (p = 0.67), performance status (p = 0.24) or anatomic tumor site (p = 0.34). Seizures and AED requirement were greater in those having primary GB (p = 0.04). After starting an AED, the mean time until next crisis was 9.9 days (SD ± 6.3), which was shorter in those receiving LEV (p = 0.03); mean number of seizures during the first 3 and 6 months were 2.9 and 4, respectively. Most patients treated with LEV (n = 46) required less than two medication adjustments compared to those treated with other AEDs (p = 0.02). Likewise, less patients exposed to LEV required a coadjuvant drug (p = 0.04). Additionally, patients receiving LEV had significantly less adverse effects compared to patients treated with another AED. OS was significantly higher in the group treated with LEV compared to other AEDs (25.5 vs. 17.9 months; p = 0.047). Patients treated with LEV had better seizure control and longer OS compared to other AEDs.

SEOM guideline for the treatment of malignant glioma.

High-grade gliomas are an infrequent disease diagnosed usually in the fifth or sixth decade. Careful histopathological diagnosis is essential because tumour grade and type condition the treatment. Magnetic resonance with gadolinium is considered the standard radiologic exploration and should be followed by tissue sampling. Treatment of these patients should be decided in a multidisciplinary committee. Surgery, radiotherapy and chemotherapy are the basis of patients' treatment, with the best results obtained when the three of them can be used.

Tumour and serum MGMT promoter methylation and protein expression in glioblastoma patients.

INTRODUCTION: Methylation of the promoter of the MGMT gene and MGMT protein expression are recognized as predictive markers for response to alkylating chemotherapy in glioblastoma (GB). MATERIAL AND METHODS: We have assessed MGMT methylation with the methylation-specific polymerase chain reaction (MSP) in tumor samples from 70 GB patients and in serum samples from 37 of these patients. We have also assessed MGMT protein expression by immunohistochemical (IHC) analysis in tissue samples from 63 of these patients. RESULTS: We found concordance between MGMT methylation status in tissue and serum (Cohen's Kappa = 0.586; p<0.0001). MSP for detection of non-methylated MGMT promoter in serum showed a sensitivity of 95.4% and a specificity of 60%, while the IHC methylation test showed a low specificity (8.9%). Patients whose MGMT promoter was methylated in tissue attained longer progression-free and overall survival. In the multivariate analysis, serum MGMT promoter methylation emerged as an independent factor for longer progression-free and overall survival. CONCLUSION: Serum-based MGMT methylation analysis offers a promising alternative to tumor-based MGMT analysis in cases where tissue samples are unavailable.

Update on the diagnosis of cancer of unknown primary (CUP) origin.

The cancer of unknown primary (CUP) concept encompasses a heterogeneous group of cancers that are difficult to diagnose and that show diverse clinical and histopathological features. Currently, CUP is the fifth most frequent cancer diagnosis in women and the eighth in men. The ongoing development of new therapies specific to the various cancer types makes mandatory the identification of the primary tumour in CUP patients, so that they may benefit from advances in therapy and improvements in prognosis. Molecular detection techniques provide very useful tools in the prediction of primary tumour types and must be used together with clinical, histopathological and IHC diagnostic techniques. Steady collaboration and fluid communication between oncologists and pathologists is of the utmost importance for the correct interpretation of tests and the personalised approach required by each individual case. Work in multidisciplinary teams will result in significant changes in the diagnosis and treatment of these patients.

Stem cells in brain tumorigenesis and their impact on therapy.

The concept that the genesis of new cells in the adult mammalian brain is negligible has long influenced our perception and understanding of the origin and development of central nervous system (CNS) tumors. The discovery that neurons and glia are produced throughout life from neural stem cells provides new possibilities for candidate precursor cells of CNS neoplasms. The emerging hypothesis is that alterations in the cellular and genetic mechanisms that control adult neurogenesis might contribute to brain tumorigenesis. As such, opportunities become available to identify new therapeutic strategies.

Neuropatía inducida por el tratamiento médico del cáncer: [revisión] / Neuropathy induced by medical cancer therapy: [review]

Los avances recientes en el tratamiento de las enfermedades neoplásicas han mejorado las tasas de supervivencia. Las intervenciones médicas generan diversos efectos adversos agudos que comprometen el tracto gastrointestinal y la medula ósea, mientras la neurotoxicidad tiende a ser tardía y evoluciona en el tiempo. En el sistema nervioso periférico es frecuente documentar la neuropatía inducida por el tratamiento médico del cáncer, hallazgo relacionado con la administración de agentes quimioterapéuticos utilizados para controlar los tumores hematológicos y sólidos. El tratamiento oncológico genera una gran variedad de cambios estructurales y funcionales en los nervios periféricos, incluyendo la afectación de los cuerpos neuronales del sistema de transporte axonal, del recubrimiento mielínico y de las estructuras de soporte glial. Cada agente presenta un espectro de toxicidad único que se relaciona con su mecanismo de acción, eventos que pueden mitigarse gracias a los resultados de múltiples estudios. Gracias al reconocimiento de los efectos devastadores de la neuropatía inducida por el tratamiento médico del cáncer en la calidad de vida, la investigación básica y clínica ha empezado a evaluar el papel de múltiples terapias para prevenir y tratar el daño neurológico. Esta revisión integra información seleccionada a partir de búsquedas estructuras realizadas en las bases de datos biomédicas más relevantes, haciendo énfasis en el diagnóstico y en las intervenciones farmacológicas y no farmacológicas descritas como parte del manejo de la neuropatía inducida por el tratamiento médico del cáncer, que con frecuencia es subvalorada. En conclusión, la información disponible hasta el momento permite establecer los mecanismos de la enfermedad y sugiere el desarrollo de un número mayor de estudios que permitan validar las estrategias descritas hasta el momento.

Recent advances in the development and administration of therapy for malignant diseases have been rewarded with prolonged survival rates. Unlike more immediate toxicities that affect the gastrointestinal tract and bone marrow, chemotherapy-induced neurotoxicity is frequently delayed in onset and may progress over time. In the peripheral nervous system, the major brunt of the toxicity is directed against the peripheral nerve, resulting in cancer therapy-induced peripheral neuropathy. Chemotherapeutic agents used to treat hematologic and solid tumors target a variety of structures and functions in the peripheral nervous system, including the neuronal cell body, the axonal transport system, the myelin sheath, and glial support structures. Each agent exhibits a spectrum of effects unique to its mechanism of action, and recent studies in this fi eld have yielded clearer ideas on how to mitigate injury. Combined with the call for a greater recognition of the devastating effects of cancer therapy-induced peripheral neuropathy on quality of life, basic and clinical researchers have begun to investigate therapy to prevent and treat neurologic damage. This review was made based on relevant information avaliable on international databases concerning cancer therapyinduced peripheral neuropathy and summarizes the evidence for diagnosis, pharmacologic and nonpharmacologic approaches to the management of this commonly unrecognized condition. In conclusion, the information avaliable in this moment establish the mechanisms of the disease and exposes the importance of the development of statistically stronger clinical trials that complement current data available in this moment.

Valor genómico de la isocitratodeshidrogenasa(IDH1/2) en el origen yprogresión de los gliomas (OncolGroup) / Genomic value of isocitrate-dehydrogenase (IDH1/2) in glioma origin and progression (ONCOLGroup)

Introduccción. Las mutaciones heterocigotas del gen que codifica la isocitrato deshidrogenasa (IDH) ocurren con relativa frecuencia en los gliomas; sin embargo, su relevancia durante el desarrollo tumoral es desconocida. Estas alteraciones provocan una pérdida en la afinidad de la enzima por el sustrato, inhibiendo la actividad de la isoforma silvestre de la IDH1 a través de la formación de heterodímeros inactivos. La expresión forzada de la mutación IDH1/2 en cultivos celulares reduce la formación del producto de la enzima, el α-ketoglutarato (α-KG), e incrementa los niveles del factor inducido por la hipoxia tipo 1 (HIF-1α, un elemento de transcrip¬ción que facilita el crecimiento tumoral en presencia de bajas concentraciones de oxígeno, hallazgo regulado en parte por el α-KG. La expresión del HIF-1α suele ser mayor entre los gliomas portadores de la mutación IDH, en los que la vía de señalización del HIF está implicada en su progresión. Varios grupos independientes han demostrado el papel que tienen las mutaciones del gen IDH1/2 como marcador pronóstico, especialmente para los pacientes con gliomas de bajo grado y con glioblastomas secundarios que presentan un patrón oligo¬dendroglial. Este conocimiento proporciona una clara oportunidad para mejorar las estrategias diagnósticas y terapéuticas para los pacientes con gliomas, que en la actualidad no se encuentran dirigidas contra alteraciones moleculares específicas. Este artículo presenta una revisión detallada del papel de las mutaciones del gen IDH en la progresión y el mantenimiento de los gliomas, y explora algunas opciones terapéuticas dirigidas contra este entorno.

Heterozygous mutations in the gene encoding isocitrate dehydrogenase (IDH) occur in gliomas, but theirmechanistic role in tumor development is unknown. Tumor-derived IDH mutations impair the enzyme’saffinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, α-ketoglutarate (α-KG), and increases the levels of hypoxia-inducible factor subunit 1 (HIF-1α, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by α-KG. HIF-1α levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation, thus, IDH1/2 contributes to tumor progression in part through induction of the HIF-1 pathway. Numerous independent research groups had demonstrated the role of IDH mutations as a prognostic marker, especially for those patients with low grade gliomas and secondary glioblastomas with oligodendroglial pattern. This knowledge indicates great opportunities to improve diagnostic and therapeutic strategies for gliomas, whichare not currently targeted at the specific molecular alterations. This paper presents a detailed review of the role of the IDH gene mutations in progression and manteinance of gliomas, and explores some therapeutic options directed against this environment.