RESUMEN

OBJECTIVE: The aim of this study was to investigate the outcomes and prognostic factors of patients with metastatic gastrointestinal neuroendocrine tumor (mGI-NET) who were treated with capecitabine and temozolomide (CAPTEM) and somatostatin receptor ligand (octreotide or lanreotide). METHODS: Clinicopathological characteristics and treatment outcomes of 43 patients with mGI-NET were retrospectively evaluated. Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier curve. Cox-regression analysis was used to assess prognostic variables. RESULTS: There were 23 (53.5%) men and 20 women (46.5%) with a median age of 59 years (range 27-85 y). Patients were given octreotide (86.0%) or lanreotide (14.0%) with CAPTEM. In patients with well-differentiated mGI-NET, median PFS was 17.4 months, and the disease control rate was 71.1%. Patients with poorly differentiated mGI-NET showed no response, and the median PFS was 4.5 months. Four (9.3%) discontinued the medication due to toxicity. Anemia (37.2%), thrombocytopenia (25.6%), and fatigue (16.3%) were the most prevalent adverse events. The 5-year OS rate was 61.0% in all patients during a median follow-up of 33.8 months. In multivariate analysis, age (P = 0.014) and tumor differentiation (P < 0.001) were statistically significant factors for OS. CONCLUSIONS: CAPTEM plus somatostatin receptor ligands were efficacious and well tolerated in individuals with well-differentiated mGI-NET. However, it was ineffective for those with poorly differentiated tumors. Age of 60 years or elder and poorly differentiated tumors were related to a poor patient prognosis.

Asunto(s)

Capecitabina , Tumores Neuroendocrinos , Temozolomida , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Octreótido/uso terapéutico , Estudios Retrospectivos , Temozolomida/uso terapéutico , Resultado del Tratamiento

RESUMEN

The described work entails the development of a simple, sensitive, green, and robust high-performance liquid chromatographic (HPLC) method for simultaneous estimation of temozolomide (TMZ) and γ-linolenic acid (GLA). The chemometric factor screening study helped identify the critical method parameters optimized using Box-Behnken design for improved understanding and enhancing the method performance. Chromatographic separation was performed on a Kinetex® C18 column (150 × 4.6 mm, 5 µm particle size) using methanol: water (pH adjusted to 3.5 using 0.5% v/v O-phosphoric acid) as the mobile phase at 0.5 mL/min flow rate and diode array detection between 210 and 360 nm. The linearity of the method was observed for concentrations of TMZ and GLA ranging between 1 and 100 µg.mL-1 (R2 = 0.999, p < 0.05). Accuracy evaluation showed good percent recovery within 97.9-100%, while intra- and inter-day precision showed RSD values within 0.37%-1.01%. The limit of detection and quantification for TMZ was found to be 0.75 and 1.0 µg.mL-1, respectively, while the values 0.55 and 1.0 µg.mL-1, respectively, were observed for GLA. System suitability (96.9-102.8%), its limits, and robustness evaluation indicated good percent recovery within, while RSD values were found to be within the acceptable limit of less than 2%. The method was specific for its ability to detect the analytes and their degradation products during forced degradation studies, which also indicated that TMZ was highly prone to alkaline conditions while GLA showed mild degradation in all the studied conditions. The estimation of both the analytes from lipid nanoparticles formulation showed good values for total drug content (82.6-85.3%), entrapment efficiency (95.4 to 98.7%), and drug loading (25.2 to 38.4%). Overall, the results indicated that the developed method was reliable for its accuracy, precision, sensitivity, and specificity for simultaneous estimation of the analytes. The method was found to be stability-indicating in nature and suitable for simultaneous estimation of TMZ and GLA from the developed nanoparticles formulation. Further, employing a greenness assessment approach established the method greenness.

Asunto(s)

Nanopartículas , Ácido gammalinolénico , Quimiometría , Cromatografía Líquida de Alta Presión/métodos , Liposomas , Reproducibilidad de los Resultados , Temozolomida

RESUMEN

Glioblastoma (GBM) remains a cancer of high unmet clinical need. Current standard of care for GBM, consisting of maximal surgical resection, followed by ionisation radiation (IR) plus concomitant and adjuvant temozolomide (TMZ), provides less than 15-month survival benefit. Efforts by conventional drug discovery to improve overall survival have failed to overcome challenges presented by inherent tumor heterogeneity, therapeutic resistance attributed to GBM stem cells, and tumor niches supporting self-renewal. In this review we describe the steps academic researchers are taking to address these limitations in high throughput screening programs to identify novel GBM combinatorial targets. We detail how they are implementing more physiologically relevant phenotypic assays which better recapitulate key areas of disease biology coupled with more focussed libraries of small compounds, such as drug repurposing, target discovery, pharmacologically active and novel, more comprehensive anti-cancer target-annotated compound libraries. Herein, we discuss the rationale for current GBM combination trials and the need for more systematic and transparent strategies for identification, validation and prioritisation of combinations that lead to clinical trials. Finally, we make specific recommendations to the preclinical, small compound screening paradigm that could increase the likelihood of identifying tractable, combinatorial, small molecule inhibitors and better drug targets specific to GBM.

RESUMEN

Glioblastoma multiforme is a malignant neoplasm of the brain with poor prognosis. The first-line drug against glioblastoma is the alkylating agent temozolamide (TMZ); unfortunately, treatment resistance and tumor re-incidence are common. In some cases, immunogenic cell death (ICD) inducers can decrease treatment resistance and tumor recurrence by stimulating an antitumor specific immune response. Not all ICD inducers, however, are suitable for glioma patients because of the low permeability of the blood-brain barrier (BBB). Panobinostat (PAN), a histone deacetylase inhibitor and Lophophora williamsii (LW) extract can pass through the BBB and have antitumor properties. The aim of this study is to evaluate the cytotoxic potential of TMZ, PAN and LW extract against the glioma C6 cell line, and its role in the release of damage-associated molecular patterns (DAMPs), which is a hallmark of ICD. Our results indicate that all treatments induce cellular death in a time- and concentration-dependent manner, and that PAN and LW extract induce apoptosis, whereas TMZ induces apoptosis and necrosis. Also, that some of the treatments and their sequential administration induce the release of DAMPs. Furthermore, in a rat glioma model, we observed that all treatments decreased tumor volume, but the in vivo cell death mechanism was not ICD. Our findings indicate that TMZ, PAN, and LW combination have a cytotoxic effect against glioma cells but do not induce ICD.

RESUMEN

Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3 µM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC50 values of 324 nM and 48.6 nM, respectively, against MNK1 and MNK2 kinases; osimertinib (0.3-3 µM) dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). In GBM patient-derived xenografts mice, oral administration of osimertinib (40 mg· kg-1 ·d-1, for 18 days) significantly suppressed the tumor growth (TGI = 74.5%) and inhibited eIF4E phosphorylation in tumor cells. Given the fact that osimertinib could cross the blood-brain barrier and its toxicity was well tolerated in patients, our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.

Asunto(s)

Acrilamidas/uso terapéutico , Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Glioblastoma/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Niño , Receptores ErbB/deficiencia , Factor 4E Eucariótico de Iniciación/química , Factor 4E Eucariótico de Iniciación/metabolismo , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Masculino , Ratones , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto Joven

RESUMEN

The clinical presentation of glioblastomas is varied, and definitive diagnosis requires pathologic examination and study of the tissue. Management of glioblastomas includes surgery and adjuvant chemotherapy and radiotherapy, with surgery playing an important role in the prognosis of these patients. Awake craniotomy plays a crucial role in tumors in or adjacent to eloquent areas, allowing surgeons to maximize resection, while minimizing iatrogenic deficits. However, the prognosis remains dismal. This article presents the perioperative management of patients with glioblastoma including tools and surgical adjuncts to maximize extent of resection and minimize poor outcomes.

Asunto(s)

Neoplasias Encefálicas/diagnóstico , Glioblastoma/diagnóstico , Glioblastoma/cirugía , Procedimientos Neuroquirúrgicos/métodos , Atención Perioperativa/métodos , Humanos , Monitoreo Intraoperatorio , Periodo Perioperatorio , Resultado del Tratamiento

RESUMEN

Glioblastoma is the most aggressive tumor of the central nervous system. Prognosis is poor, even in the presence of a methylated state of MGMT gene promoter, which represents the biomarker with the highest prognostic/predictive value for the standard treatment of patients. Among patients with a methylated MGMT status, we identified an intermediate range of methylation above the standard 9% cut-off (gray zone) in which the predictive strength of the marker was lost. In an effort to improve the evaluation of the biomarker in clinical decision-making, we are carrying out a retrospective study, performing an in-depth analysis of samples used for diagnosis to understand how molecular heterogeneity, a hallmark of glioblastoma, impacts the evaluation of MGMT gene promoter methylation. Preliminary data from samples belonging to the "gray zone" tend to confirm the hypothesis of a mismatch between methylation values used for clinical decision-making and those included in our in-depth analysis. Confirmation of these data would help to better define the predictive power of MGMT promoter methylation status and greatly facilitate clinical decision-making.

RESUMEN

OBJECTIVE: To evaluate the efficacy of combining an oral chemotherapeutic agent temozolamide with radiotherapy in the management of the un-resectable non-metastatic soft tissue sarcomas compared with radiotherapy alone. METHODS: The randomised controlled phase 3, double-arm study was conducted at King Edward Medical University/Mayo Hospital, Lahore, Pakistan, from December 2012 to July 2017. Patients with all sub-types of locally advanced un-resectable soft tissue sarcomas were randomised into two groups. Group-A received radiotherapy alone while Group-B received concomitant chemoradiotherapy with temozolamide after receiving two cycles of standard chemotherapy. Response was evaluated according to response evaluation criteria in solid tumours through computed tomography scan or magnetic resonance imaging after 6 weeks following completion of radiotherapy. SPSS 21 was used for data analysis. RESULTS: Of the 64 patients, 32(50%) were assigned to each group. The mean age of Group-A was 36.25±20.31 and of Group-B 37.84±15.79 years .There were 18(56.3%) males in Group-A and 20(62.5%) in Group-B. Improvement in trends of overall response rate was observed in Group-B 24(75%) compared to 18(56.3%) in Group-A (p=0.12).. CONCLUSIONS: Though not statistically significant, there was improvement in response rate with the addition of temozolamide to standard radiation therapy.

Asunto(s)

Quimioradioterapia/métodos , Radioterapia/métodos , Sarcoma , Temozolomida , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Estadificación de Neoplasias , Sarcoma/diagnóstico por imagen , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Sarcoma/radioterapia , Temozolomida/administración & dosificación , Temozolomida/efectos adversos , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento

RESUMEN

Carcinoid brain metastases are extremely rare and are associated with a poor prognosis. Treatment options are variable, ranging from surgery, radiation, or chemotherapy alone or combined. We report on a case of rectal carcinoid metastatic to the cerebellum and review chemotherapeutic regimens for carcinoid tumor treatment, focusing on the potential role of temozolomide or stereotactic radiosurgery.

RESUMEN

Objective: To perform a retrospective analysis of the prognosis and influence factors of radiotherapy concurrent with che-motherapy and adjuvant temozolomide therapy in adult patients with high-grade brainstem glioma. Methods: Twenty-nine patients with pathological diagnosis of high-grade glioma (World Health Organization [WHO] Ⅲ and Ⅳ) from June 2012 to December 2013 were eligible for inclusion in the analysis. Demographic and clinical characteristics including age, gender, the time from morbidity to operation, the size of the lesion, the method of operation, the Karnofsky Performance Status (KPS) score, and the pathological grade were examined. The significance of related prognostic factors was evaluated via univariate and multivariate Logistic regression analy-sis. A P-value of<0.05 was considered to be statistically significant. Results: The median overall survival (OS) was 11.5 months. Univari-ate analysis showed that low WHO grade index was associated with better outcome (P<0.05). Multivariate analysis suggested that high KPS score (>60) and low WHO grade were associated with better survival. Conclusions: In this study, low pathological grade and high KPS score were independently associated with better survival among patients with high-grade brainstem glioma.

RESUMEN

The development of local recurrence and metastatic disease, most probably attributable to the intrinsic or acquired resistance of tumor cells to standard therapy, still constitute the major clinical problem preventing the cure of cancer patients. Despite progress in the research of new therapeutic targets and compounds, resistant cells displaying stem-like properties seem to play a leading role in therapeutic failures and to be the culprit cells responsible for associated tumor recurrence. A whole new plethora of research studies suggest that drug-tolerant cancer stem cells may be induced by conventional cancer chemotherapeutics such as doxorubicin, cisplatinum and ionizing radiation. This phenotypic plasticity and transition from a differentiated to stem-like cell state associates with the activation of diverse stem cell self-renewal (e.g. Notch, Hedgehog, Wnt), drug efflux (e.g. ABC transporters) and survival-related pathways (e.g. TGF-ß, ERK, AKT), which may confer resistance and treatment failures in solid tumors. Therefore, combined therapeutic strategies aiming to simultaneously target drug-sensitive tumor cells and their capacity of phenotypic switching may lead to survival benefits and meaningful disease remissions. This knowledge can be applicable to the clinic and contribute to better therapeutic outcomes and prevent tumor recurrence.

Asunto(s)

Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Animales , Plasticidad de la Célula/efectos de los fármacos , Humanos

RESUMEN

INTRODUCTION: Non-functioning pituitary adenomas (NFPAs) are in general large tumors that present with symptoms secondary to local pressure on adjacent structures. Transsphenoidal surgery is the first line of treatment but residual tumor mass is often detected post-operatively. Medical therapy, in any stage of tumor management, is not well established. METHODS: A literature search was performed to review the available data on medical treatment of NFPAs. RESULTS: Medications investigated for the treatment of NFPAs include dopamine receptor agonists (DA) and somatostatin receptor ligands. Randomized controlled trials are lacking, but available data suggest that DA have a positive effect on tumor remnant stabilization after surgery and could be considered in this setting. Temozolomide is reserved for aggressive tumors, although future studies are required. CONCLUSIONS: NFPA are often not amenable to complete surgical resection. Conservative follow-up after surgery is associated with a high prevalence of tumor remnant progression. DA therapy may prevent residual tumor enlargement in over 85% of these patients, with a substantial consequent reduction in the need for repeat surgery or radiation therapy. It is our view that DA treatment should be routinely considered for the management of NFPA patients with incompletely resected tumors.

Asunto(s)

Neoplasias Hipofisarias/cirugía , Adenoma/tratamiento farmacológico , Adenoma/cirugía , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Femenino , Humanos , Masculino , Neoplasias Hipofisarias/tratamiento farmacológico , Temozolomida

RESUMEN

OBJECTIVE: To assess the efficacy and cost-effectiveness of modulated electrohyperthermia (mEHT) concurrent to dose-dense temozolomide (ddTMZ) 21/28 days regimen versus ddTMZ 21/28 days alone in patients with recurrent glioblastoma (GBM). DESIGN: A cohort of 54 patients with recurrent GBM treated with ddTMZ+mEHT in 2000-2005 was systematically retrospectively compared with five pooled ddTMZ 21/28 days cohorts (114 patients) enrolled in 2008-2013. RESULTS: The ddTMZ+mEHT cohort had a not significantly improved mean survival time (mST) versus the comparator (p=0.531) after a significantly less mean number of cycles (1.56 vs 3.98, p<0.001). Effect-to-treatment analysis (ETA) suggests that mEHT significantly enhances the efficacy of the ddTMZ 21/28 days regimen (p=0.011), with significantly less toxicity (no grade III-IV toxicity vs 45%-92%, p<0.0001). An estimated maximal attainable median survival time is 10.10 months (9.10-11.10). Cost-effectiveness analysis suggests that, unlike ddTMZ 21/28 days alone, ddTMZ+mEHT is cost-effective versus the applicable cost-effectiveness thresholds €US$25 000-50 000/quality-adjusted life year (QALY). Budget impact analysis suggests a significant saving of €8 577 947/$11 201 761 with 29.1-38.5 QALY gained per 1000 patients per year. Cost-benefit analysis suggests that mEHT is profitable and will generate revenues between €3 124 574 and $6 458 400, with a total economic effect (saving+revenues) of €5 700 034 to $8 237 432 per mEHT device over an 8-year period. CONCLUSIONS: Our ETA suggests that mEHT significantly improves survival of patients receiving the ddTMZ 21/28 days regimen. Economic evaluation suggests that ddTMZ+mEHT is cost-effective, budget-saving and profitable. After confirmation of the results, mEHT could be recommended for the treatment of recurrent GBM as a cost-effective enhancer of ddTMZ regimens, and, probably, of the regular 5/28 days regimen. mEHT is applicable also as a single treatment if chemotherapy is impossible, and as a salvage treatment after the failure of chemotherapy.

Asunto(s)

Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Glioblastoma/terapia , Hipertermia Inducida/economía , Adulto , Anciano , Antineoplásicos Alquilantes/economía , Neoplasias Encefálicas/economía , Análisis Costo-Beneficio , Dacarbazina/economía , Dacarbazina/uso terapéutico , Femenino , Alemania , Glioblastoma/economía , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/terapia , Años de Vida Ajustados por Calidad de Vida , Análisis de Regresión , Estudios Retrospectivos , Temozolomida

RESUMEN

We present a retrospective review of 55 Stereotactic Radiosurgery (SRS) procedures performed in 47 consecutive patients with high-grade glioma (HGG). Thirty-three (70.2%) patients were diagnosed with glioblastoma and 14 (29.8%) with grade III glioma. The indications for SRS were small (up to 30 mm in diameter) locally progressing lesions in 32/47 (68%) or new distant lesions in 15/47 (32%) patients. The median target volume was 2.2 cc (0.2-9.5 cc) and the median prescription dose was 18 Gy (14-24 Gy). Three patients (5.5% incidence in 55 treatments) developed radiation necrosis. In eight cases (17%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0%) patients received concurrent chemo- or biological therapy, including temozolamide (TMZ) (15 patients), bevacizumab (BVZ) (6 patients) and carboplatin in one patient. Median time to progression after SRS was 5.0 months (1.0-96.4). Median survival time after SRS was 15.9 months (2.3-109.3) overall median survival (since diagnosis) was 37.4 months (9.6-193.6 months). Long-lasting responses (>12 months) after SRS were observed in 25/46 (54.3%) patients. We compared a matched (histology, age, KPS) cohort of patients with recurrent HGG treated with BVZ alone with the current study group. Median survival was significantly longer for SRS treated patients compared to the BVZ only cohort (12.6 vs. 7.3 months, p = 0.0102). SRS may be considered an effective salvage procedure for selected patients with small volume, recurrent high-grade gliomas. Long-term radiological control was observed in more than 50% of the patients.

Asunto(s)

Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Glioma/patología , Glioma/cirugía , Radiocirugia , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Carga Tumoral , Adulto Joven

RESUMEN

The impressive but sad list of over forty clinical studies using various cytotoxic chemotherapies published in the last few years has failed to increase median survival of glioblastoma beyond two years after diagnosis. In view of this apparent brick wall, adjunctive non-cytotoxic growth factor blocking drugs are being tried, as in the CUSP9* protocol. A related theme is searching for agonists at growth inhibiting receptors. One such dataset is that of melatonin agonism at M1 or M2 receptors found on glioblastoma cells, being a negative regulator of these cells' growth. Melatonin itself is an endogenous hormone, but when used as an exogenously administered drug it has many disadvantages. Agomelatine, marketed as an antidepressant, and ramelteon, marketed as a treatment for insomnia, are currently-available melatonin receptor agonists. These melatonin receptor agonists have significant advantages over the natural ligand: longer half-life, better oral absorption, and higher affinity to melatonin receptors. They have an eminently benign side effect profile. As full agonists they should function to inhibit glioblastoma growth, as demonstrated for melatonin. A potentially helpful ancillary attribute of melatonergic agonists in glioblastoma treatment is an increase in interleukin-2 synthesis, expected, at least partially, to reverse some of the immunosuppression associated with glioblastoma.

RESUMEN

Temozolomide (TMZ) is an alkylating drug used usually in glioma treatment by inducing the apoptosis in glioma cell. The aim of the study is to investigate the anticancer mechanism of TMZ in SH-SY5Y human neuroblastoma cell line. Cytotoxic effects of TMZ were determined by using XTT assay. IC50 doses in the SH-SY5Y were detected as 5 mM. Expression profiles of novel genes URG4/URGCP, CCND1, CCND2, CDK4, and BCL2 were determined by real-time PCR. The apoptotic effects of TMZ were evaluated with TUNEL method. Furthermore, effects of TMZ on colony formation and invasion were investigated in this study. It was observed that TMZ in SH-SY5Y cell line caused a significant decrease in the gene expressions of URG4/URGCP, CCND1, CCND2, CDK4, and BCL2. According to TUNEL assay results, TMZ markedly induced apoptosis in SH-SY5Y cell line. It was found that TMZ in SH-SY5Y cell line suppressed invasion and colony formation using matrigel invasion chamber and colony formation assay, respectively. To conclude, it is thought that TMZ demonstrates anticarcinogenesis activity by affecting cell cycle arrest, apoptosis, invasion, and colony formation on SH-SY5Y cells. TMZ may be an effective agent for treatment of neuroblastoma as a single or in combination with other drugs.

Asunto(s)

Dacarbazina/análogos & derivados , Proteínas de Neoplasias/biosíntesis , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Dacarbazina/administración & dosificación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas de Neoplasias/genética , Neuroblastoma/patología , Temozolomida

RESUMEN

BACKGROUND: Methylation of MGMT promoter has been identified as a favourable predictive factor of benefit from XRT/TMZ → TMZ. Patients with non-resectable glioblastoma (GBM) generally exhibit a poor prognosis, even after XRT/TMZ. Few data are available concerning the predictive value of MGMT promoter methylation in this population. METHODS: This is an observational retrospective study in patients with malignant brain glioma, treated between June 2008 and October 2011 and followed up until April 2012 at the Neurosurgery-Neurotraumatology Unit of the University Hospital of Parma and at the Neurosurgery Unit of IRCCS "ASMN" of Reggio Emilia, Italy. The medical records of an overall number of 174 patients with a newly diagnosed GBM were reviewed. Volumetry analysis of the lesions was performed on pre- and post-operative neuroimaging by Voxar 3D Ebit AET software. The genetic characterization was performed on paraffin embedded tissue from all resected tumours. Isolation of nucleic acids, bisulfite modification of DNA, methylation-specific PCR and sequencing analyses were done mainly on fresh tissue from biopsy withdrawals. Within 3-4 weeks after either biopsy or surgery, patients were assigned to receive XRT/TMZ→TMZ: treatment included XRT (60 Gy in 30 fractions)/TMZ (daily dose of 75 mg/m(2))/TMZ (150-200mg/m(2) per day for 5 days of every 28-day cycle). RESULTS AND DISCUSSION: A total of 55 consecutive patients (23 men, 22 women) fulfilled inclusion criteria consisting of age over 18 years, supratentorial histologically proven primary malignant glioma, complete determination of the MGMT methylation status, no prior history of surgery, XRT and/or chemotherapy, adequate clinical and radiological follow-up no lesser than 6 months. Twenty-three patients underwent neuronavigation needle biopsy (B Group) and thirty-two patients were operated with craniotomy for tumour resection (R Group). The pre-operative mean age was similar between groups (61.7 ± 10.7 vs 60.3 ± 11.8 years in the B and R groups respectively; p>0.05). The B groups showed a slightly lower KPS than the R Group (82.1 ± 17.3 vs 90.3 ± 14.1 respectively; p>0.05). The mean pre-operative volume of the tumour did not differ between groups (46.2 ± 40.2 cm(3) vs 44.1 ± 33.2 cm(3) in the R Group and B Group respectively; p>0.05). The MGMT promoter was methylated in 12 patients (51.2%) of B Group and in 17 patients (53.1%) of R Group. XRT/TMZ → TMZ was accomplished in 11 patients (47.8%) of B Group and in 24 patients (75%) of R Group; in 24/29 methylated patients (82.8%) and in 11/26 unmethylated patients (42.3%). Survival analysis of methylated vs unmethylated tumours was statistically significant (Log Rank Mantel Cox: 0.019 in B Group and 0.023 in R Group). In B Group the mean overall survival (OS) of methylated patients was 11.4 months (IC 95% 6.5-16.4) vs 4.8 months (95% IC, 2.6-7.0) of unmethylated patients. In R Group the mean OS was 21.7 months (95% IC, 16.9-26.6) for methylated patients and 14.0 months (95% IC, 8.5-19.4) for unmethylated patients. At the multivariate Cox regression analysis conducted on the total population (55 patients), XRT and TMZ were found to be predictive of OS. In the R Group, KPS, XRT and TMZ correlated with a better outcome. In the B Group, XRT and MGMT promoter methylation were favourably related with OS. CONCLUSION: MGMT promoter unmethylation has a predominant unfavourable impact on clinical outcomes even in the subpopulation of patients with non-resectable GBM. The unmethylated MGMT promoter status could be considered the main predictor of poor prognosis in biopsied GBM, due to the greater probability of patients not having benefits from adjuvant therapies and not being able to accomplish XRT/TMZ → TMZ. The frameless neuronavigation biopsy technique is safe and effective for predictive evaluation and could help in treatment decision making.

Asunto(s)

Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirugía , Quimioterapia Adyuvante/métodos , Glioblastoma/genética , Glioblastoma/cirugía , O(6)-Metilguanina-ADN Metiltransferasa/genética , Regiones Promotoras Genéticas/genética , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores de Tumor/análisis , Biopsia con Aguja , Neoplasias Encefálicas/terapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Femenino , Glioblastoma/terapia , Humanos , Masculino , Persona de Mediana Edad , Neuronavegación , Procedimientos Neuroquirúrgicos , O(6)-Metilguanina-ADN Metiltransferasa/análisis , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Análisis de Supervivencia , Temozolomida , Resultado del Tratamiento

RESUMEN

Significant gaps exist in our understanding of the causes and clinical management of glioma. One of the biggest gaps is how best to manage low-grade (World Health Organization [WHO] Grade II) glioma. Low-grade glioma (LGG) is a uniformly fatal disease of young adults (mean age 41 years), with survival averaging approximately 7 years. Although LGG patients have better survival than patients with high-grade (WHO Grade III or IV) glioma, all LGGs eventually progress to high-grade glioma and death. Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute suggest that for the majority of LGG patients, overall survival has not significantly improved over the past 3 decades, highlighting the need for intensified study of this tumor. Recently published research suggests that historically used clinical variables are not sufficient (and are likely inferior) prognostic and predictive indicators relative to information provided by recently discovered tumor markers (e.g., 1p/19q deletion and IDH1 or IDH2 mutation status), tumor expression profiles (e.g., the proneural profile) and/or constitutive genotype (e.g., rs55705857 on 8q24.21). Discovery of such tumor and constitutive variation may identify variables needed to improve randomization in clinical trials as well as identify patients more sensitive to current treatments and targets for improved treatment in the future. This article reports on survival trends for patients diagnosed with LGG within the United States from 1973 through 2011 and reviews the emerging role of tumor and constitutive genetics in refining risk stratification, defining targeted therapy, and improving survival for this group of relatively young patients.

Asunto(s)

Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioma/diagnóstico , Glioma/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/cirugía , Supervivencia sin Enfermedad , Femenino , Glioma/mortalidad , Glioma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Riesgo , Adulto Joven

RESUMEN

Long-term survival in relapsed Ewing sarcoma (ES) is less than 20%. Encouraging results have been reported with irinotecan and temozolomide combinations (IRN/TMZ). We aimed to share our experience and compare it with previously published studies using this combination to treat relapsed ES. We retrospectively evaluated 20 patients treated with a combination of IRN (20 mg/m(2)/d × 5 for 2 weeks) and temozolomide (100 mg/m(2)/d × 5). Patients received a total of 97 courses. An objective response was achieved in 11 patients (55%) and maintained for a median of 12 months. Five patients were alive for a median of 12 months. Median time to progression was 5.5 (2-57) months. After the IRN/TMZ treatment, 1-year overall and event-free survival rates were 54.2% and 44.4%, respectively. Grade 3-4 toxicities included diarrhea (9.2%), neutropenia (11.3%), and thrombocytopenia (6.2%). Three retrospective trials were found in our literature review, which used an IRN/TMZ combination to treat ES. There was one other study which retrospectively evaluated the efficacy of vincristine, IRN, and TMZ combination in relapsed ES. A total of 81 patients were treated with IRN/TMZ in four studies including ours. The objective response rate was 55.1%, and median time to progression ranged from 5.5 to 8.3 months. Twenty-six (7.5%) of a total of 346 courses were associated with grade 3-4 diarrhea. Grade 3-4 neutropenia and thrombocytopenia were reported in 9.2% and 7.2% of the courses, respectively. Results showed that an IRN/TMZ combination is effective and tolerable in patients with relapsed ES.

Asunto(s)

Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/mortalidad , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Niño , Preescolar , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Irinotecán , Masculino , Estudios Retrospectivos , Tasa de Supervivencia , Temozolomida

RESUMEN

Objetivos: conocer la sobrevida a dos años de pacientes con diagnóstico de Glioblastoma multiforme (GBM) tratados con Temozolamida con cobertura del Fondo Nacional de Recursos (FNR), evaluar la seguridad del tratamiento y los factores pronósticos. Metodología: cohorte de pacientes portadores de GBM, tratados con Temozolamida entre mayo de 2009 y diciembre 2011. Fuente de información: base de datos del FNR. Resultados: Se incluyeron 81 pacientes. La mediana de sobrevida global fue de 18 meses. Vivos a dos años: 33 de los pacientes. El análisis multivariado encontró a la edad y al peor estado funcional del paciente como los factores de riesgo para mortalidad. 8 pacientes tuvieron efectos adversos severos. Discusión: Se presentan los primeros resultados nacionales vinculados al tratamiento combinado de los GBM. La sobrevida fue similar a la reportada en los estudios de referencia internacionales y mayor que la descripta para el tratamiento radiante exclusivo. El beneficio es mayor en aquellos pacientes jóvenes con buena capacidad funcional previa al inicio del tratamiento. Su seguridad fue considerada como aceptable.

---

Objectives: find out the two-year survival of patients diagnosed with Multiform Glioblastoma (MGB) treated with Temozolamide funded by the National Resource Fund (FNR), and evaluate the safety of therapy and prognostic factors. Methodology: cohort of patients with MGB, treated with Temozolamide between May 2009 and December 2011. Data source: database of the FNR. Results: the 81 patients included had a median overall survival of 18 months; 33 of them were still alive at two years. The multivariate analysis found that the patient’s age and functional status were the risk factors for mortality. Eight patients had severe adverse effects. Discussion: Presentation of the first national results related to the combined therapy of MGB. Survival was similar to that reported in the international reference studies and greater than that described for radiation therapy alone. Benefits were greater in young patients presenting with a good functional capacity before starting therapy. The safety of therapy was deemed acceptable.

Asunto(s)

Humanos , Masculino , Femenino , Antineoplásicos Alquilantes/uso terapéutico , Glioblastoma/radioterapia , Glioblastoma/terapia , Estudios de Cohortes