LRIG1 Enhances Chemosensitivity by Modulating BCL-2 Expression and Receptor Tyrosine Kinase Signaling in Glioma Cells

PURPOSE: Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) are an inhibitor of receptor tyrosine kinases (RTKs) that was discovered in recent years, and many studies showed that LRIG1 is a tumor suppressor gene and may be related to tumor drug resistance. In this study, we explored whether LRIG1 protein expression can improve the chemosensitivity of glioma cells and what was its mechanism. MATERIALS AND METHODS: We collected 93 cases of glioma tissues and detected the expression of LRIG1 and BCL-2. We constructed a multidrug resistance cell line U251/multidrug resistance (MDR) and examined the change of LRIG1 and BCL-2 at mRNA and protein expression levels. LRIG1 expression was upregulated in U251/MDR cells and we detected the change of multidrug resistance. Meanwhile, we changed the expression of LRIG1 and BCL-2 and explored the relationship between LRIG1 and BCL-2. Finally, we also explored the relationship between LRIG1 and RTKs. RESULTS: LRIG1 was negatively correlated with BCL-2 expression in glioma tissue and U251/MDR cells, and upregulation of LRIG1 can enhance chemosensitivity and inhibit BCL-2 expression. Furthermore, LRIG1 was negatively correlated with RTKs in U251/MDR cells. CONCLUSION: These results demonstrated that LRIG1 can improve chemosensitivity by modulating BCL-2 expression and RTK signaling in glioma cells.

Transient increased exudation after photodynamic therapy of intraocular tumors

To report transient increased exudation after photodynamic therapy [PDT] of three different intraocular tumors [retinal hemangioblastoma, retinal astrocytoma, amelanotic choroidal melanoma]. PDT with verteporfin [6 mg/m[2] body surface area] was delivered at a dose of 50 J/cm[2] and intensity of 600 mW/cm[2] over 83 s. All patients experienced decreased vision within a few days following PDT. Optical coherence tomography showed development of subfoveal fluid in all cases and noncystoid intraretinal edema in the eye with juxtapapillary retinal hemangioblastoma. There was complete absorption of retinal/subretinal fluid with improvement of visual acuity to 20/20 in all cases between 3 weeks to 4 months after PDT

Everolimo para o tratamento de astrocitoma subependimário de células gigantes (SEGA) associado à Esclerose Tuberosa / Everolimo for the treatment of subependymal giant cell astrocytoma (SEGA) associated with Tuberous Sclerosis

O astrocitoma subependimário de células gigantes (SEGA) é um tumor cerebral que se desenvolve em 5% a 20% dos pacientes com esclerose tuberosa, predominantemente em crianças e adolescentes. A esclerose tuberosa é uma condição de herança autossômica dominante que causa mutações nos genes TSC1 ou TSC2, levando ao surgimento de hamartomas (tumores benignos) em vários órgãos. A prevalência aproximada da esclerose tuberosa é de aproximadamente 1 em 6.000/10.000 nascidos vivos. Estima-se que 1 milhão de pessoas no mundo possuam a doença. A expressão da doença é variável, sendo os três principais sintomas convulsões, retardo mental e acometimentos cutâneos que podem surgir nos primeiros anos de vida. São poucos os acometimentos responsáveis pela diminuição da expectativa de vida: distúrbios neurológicos (SEGA e convulsões), doença renal (linfangioleiomiomatose e broncopneumonia) e doença cardiovascular (rabdomioma e aneurisma). Os SEGAs são tumores glioneuronais originados na zona subventricular perto do forame de Monro, causando hidrocefalia (quanto maior o volume do tumor, maior é o risco de hidrocefalia) e aumento da pressão intracraniana. Até o momento, não há tratamento de cura para a esclerose tuberosa, sendo indicada a ressecção cirúrgica dos tumores (terapia padrão-ouro) e o tratamento sintomático, como o uso de anticonvulsivantes. A ressecção cirúrgica deve ser realizada após a demonstração sequencial do crescimento tumoral por técnicas de imagem (ressonância nuclear magnética) e possui o inconveniente de alguns tumores não ser ressecáveis, devido a sua localização, e a possibilidade de sequelas em consequência da perda de massa cerebral. A TECNOLOGIA: Everolimo - Indicação proposta: tratamento de pacientes com astrocitoma subependimário de células gigantes (SEGA) associado à esclerose tuberosa. EVIDÊNCIAS CIENTÍFICAS: Além da análise dos estudos apresentados pelo demandante, a Secretaria-Executiva da CONITEC realizou busca na literatura por artigos científicos, com o objetivo de encontrar Revisões Sistemáticas e Ensaios Clínicos Randomizados (ECR), considerados a melhor evidência para avaliar a eficácia de uma tecnologia usada para tratamento. As bases pesquisadas foram Medline (via PubMed)7, The Cochrane Library (via Bireme) 8 e CRD (Centre for Reviews and Dissemination)9. Os termos utilizados na busca foram "tuberous sclerose", "subependymal giant-cell astrocytomas", "everolimus". Foram considerados os estudos publicados até o dia 15/02/2012, nos idiomas inglês, português ou espanhol. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 4ª reunião ordinária do plenário do dia 10/05/2012, por unanimidade, ratificaram a deliberação por não recomendar a incorporação do medicamento everolimo para o tratamento de Astrocitoma Subependimário de Células Gigantes (SEGA) associado à Esclerose Tuberosa. DECISÃO: PORTARIA SCTIE/MS N° 26, de 13 de setembro de 2012 - Torna pública a decisão de não incorporar o medicamento everolimo para o tratamento do Astrocitoma Subependimário de Células Gigantes (SEGA) associado à Esclerose Tuberosa no Sistema Único de Saúde (SUS).

H magnetic resonance spectroscopy assessment of the temozolomide response in peaditric pilocytic astrocytomas

Pilocytic Astrocytomas (PA) treatment and prognosis is variable depending on location. ¹H Magnetic Resonance Spectroscopy (MRS) is used to characterize tumor metabolism providing additional information to the Magnetic Resonance Imaging (MRI) evaluation assessing the therapy response. This study was designed to evaluate brain metabolic changes that result from Temozolomide (TMZ) administration on pediatric PA using MRS. Twenty children with PA were studied. We performed MRI and MRS pretreatment and after 12 months of therapy on a 3.0 Tesla scanner in order to monitor the chemotherapy response to 5-day treatment with oral TMZ (200 mg/mt² x day) given every 28 days for 12 cycles. Multivoxel Proton Spectroscopic Imaging was performed using a Point Resolved Spectroscopy sequence (PRESS). Analysis of Variance (ANOVA) was applied to the results in order to evaluate the possible statistical differences. Pairwise comparisons with Bonferroni correction test were assessed in order to verify the differences among ratio means. It was observed a significant decrease in Cho/Cr ratio (p<0.05) and a significant increase in NAA/Cr ratio (p<0.05) while TMZ therapy was taking place. These results are linked with tumor size reduction (r = 0.95, p< 0.05) detected by MRI. Results show MRS can detect early tumor reaction to therapy prior to MRI. Therefore, MRS could provide a useful tool to monitor the answer of pediatric PA to TMZ. The link between metabolic markers changes due to TMZ treatment assessed by MRS and the tumor volume reduction may also provide a fertile ground to developa TMZ-based therapy for pediatric PA and to predict its efficacy to improve PA’s response to treatment.

Evidence-based adjuvant therapy for gliomas: current concepts and newer developments.

The incidence of gliomas is increasing worldwide, including India. Of the 18,820 new cases of primary central nervous system (CNS) tumors diagnosed annually in the United States, gliomas account for over 60% with 30-40% of them being glioblastoma multiforme (GBM), 10% being anaplastic astrocytoma (AA), and 10% being low grade gliomas (LGGs). This is in contrast to one study from West Bengal, India, in which only 7.9% of the brain tumors were GBMs, while 46.8% were astrocytomas. Of all adult primary CNS tumors, GBM is the most common and the most malignant with about 7,000 to 8,000 new cases annually in the United States. Given poor outcomes, a number of treatment approaches have been investigated. Common to these approaches is the use of adjuvant radiation therapy, even as surgery alone, with or without chemotherapy, may be the mainstay for some lower grade and low-risk gliomas. Today, treatment typically involves external beam radiation, with concurrent and adjuvant chemotherapy for more aggressive histologies. Although gliomas are relatively uncommon, active research is ongoing. Results of landmark trials along with some of the recently published trials are presented. These trials and management strategies as well as evolving concepts are found by reviewing over 200 articles in the National Library Medical (NLM) database, PubMed, more than 60 of which are refrenced. Specifically, the database is searched using the following keywords, with various combinations: glioma, low-grade, anaplastic, astrocytoma, oligodendroglioma, oligoastrocytoma, glioblastoma multiforme, chemotherapy, radiation, new concepts, phase III, MGMT, CDX-110 (Celldex), temozolomide, 1p/19q deletion, and bevacizumab.

O tratamento do astrocitoma de baixo grau: um desafio à neurocirurgia contemporânea / The treatment of astrocytoma: a challenge to the neurosurgery contemporary

Os autores realizam uma revisão bibliográfica abrangendo as controvérsias, dúvidas e definições a respeito do(s) tratamento(s) mais indicado(s) para o Astrocitoma de baixo grau (astrocitoma WHO grau I e II). As abordagens que sustentam a terapia tumoral aliadas aos novos tratamentos de vanguarda são vistas por foco imparcial e descritivo, baseadas na literatura médica atual

Effect of Ketamine on Apoptosis by Energy Deprivation in Astroglioma Cells using Flow Cytometry System

Apoptosis is a programmed, physiologic mode of cell death that plays an important role in tissue homeostasis. As for the central nervous system, ischemic insults can induce pathophysiologic cascade of apoptosis in neurophils. Impairment of astroctye functions during brain ischemia can critically influence neuron survival by neuronglia interactions. We aimed to elucidate the protective effect of ketamine on apoptosis by energy deprivation in astrocytes. Ischemic insults was induced with iodoacetate/ carbonylcyanide mchlorophenylhydrazone (IAA/CCCP) 1.5 mM/ 20 micrometer or 150 micrometer/2 micrometer for 1 hr in the HTB-15 and CRL-1690 astrocytoma cells. Then these cells were reperfused with normal media or ketamine (0.1 mM) containing media for 1 hr or 24 hr. FITC-annexin-V staining and propidium iodide binding were determined by using flow cytometry. Cell size and granularity were measured by forward and side light scattering properties of flow cytometry system, respectively. An addition of keta-mine during reperfusion increased the proportion of viable cells. Ketamine alleviated cell shrinkage and increased granularity during the early period, and ameliorated cell swelling during the late reperfusion period. Ketamine may have a valuable effect on amelioration of early and late apoptosis in the astrocytoma cells, even though the exact mechanism remains to be verified.

Concurrent temozolomide [TMZ] and irradiation for the management of high grade malignant glioma

This pilot study was conducted on 18 newly diagnosed patients with malignant glioma [11 patients with glioblastoma multiforme [GBM] and 7 patients with anaplastic astrocytoma [AA]] to assess the safety, tolerability and efficacy of concurrent administration of temozolomide [TMZ] and radiation. The eligible patients received 40 Gy [1.8 Gy/fraction, 1 fraction/day, 5 days/week] to the computed tomography [CT] or magnetic resonance imaging [MRI] enhancing lesion and surrounding edema with a 3 cm margin, then 20 Gy to a smaller volume including the contrast enhancing lesion plus 1-2 cm margin. Starting from the first day of radiation, the patients received oral TMZ [150 mg/m2] daily for 5 days and repeated every 28 days for two cycles. The study demonstrated the safety and efficacy of concurrent TMZ with radiation in newly diagnosed high grade gliomas and supported a further continued investigation of low daily dose TMZ with concurrent radiation, preferably with some cycles of TMZ as an adjuvant to radiation, in a multicenter phase III randomized trial containing a large number of patients and comparing this regimen with radiotherapy alone in newly diagnosed high-grade astrocytomas

The observation of immunosuppressor(s) derived from cultured tumor cells and its partial neutralization with OK-432.

Malignant tumors such as brain tumors have been reported to be associated with immunosuppression caused by certain tumor-secreted cytokines. The reversion of tumor-derived immunosuppression has not been described. The use of OK-432, an immunomodulatory agent prepared from Su-strain of Streptococcus pyogenes A3, to activate peripheral blood mononuclear cells from a patient with glioblastoma multiforme has demonstrated a sharp rise in proliferative response. This proliferative response was compromised in the presence of living and irradiated autogeneic cancer cells. The conditioned media from cultured cells of glioblastoma multiforme, astrocytoma, and cholangiocarcinoma were tested for immunosuppressive ability. We found that conditioned media from 3 of 4 cases of glioblastoma, all 3 cases of astrocytoma, and 1 case of cholangiocarcinoma exhibited immunosuppressive activity toward the proliferative response of allogeneic peripheral blood mononuclear cells to phytohemagglutinin. This is the first report that cholangiocarcinoma produces soluble immunosuppressor(s). Our finding suggested that soluble substance(s) as well as direct cell-cell contact between tumor cells and mononuclear cells play roles in the observed tumor-derived immunosuppression.

Successful combination chemotherapy (vincristine, procarbazine, etoposide, and prednisolone) in the treatment of inoperable, radioresistant low grade astrocytoma: a case report.

A case of successful combination chemotherapy using vincristine, procarbazine, VP-16 and prednisolone to treat an inoperable low grade astrocytoma is presented. This patient, whose tumor was also resistant to radiotherapy, had well controlled symptoms after the initiation of chemotherapy. A brain CT scan demonstrated disappearance of the tumor mass after eight courses of a combination chemotherapy regimen. She is at present symptom-free 80 months after diagnosis. This result suggests that combination chemotherapy may offer treatment modalities for low grade astrocytoma.

Brain astrocytomas: a study of epidemiological finding, treatment results and prognostic factors in Tehran cancer institute's radiotherapy patients

Astrocytomas, including glioblastoma muttiforme [GBM], are the most common brain tumors. Post-operative radiotherapy plays an important role in their treatment. Records of all patients with a pathologic diagnosis of astrocytoma referred for radiotherapy from 1987-1992 were reviewed and prognostic factors with regard to recurrences were analyzed. During the study period, 162 astrocytoma patients were treated by radiation in our department. Male to female ratio was 1.4:1. The disease was most prevalent in the 3rd and 4th decades of life. Most tumors were in cerebral hemispheres and grade IV. In nearly all patients only CT scan had been used for diagnosis, and total resection had been performed. Radiation dose was mostly 5,000-5,500 cGy by standard fractionation. Follow-up was available for 91 patients, and in these patients CCNU [lomustine] chemotherapy was prescribed for high-grade tumors. Three-year local control was 77%. Grade, extent of surgery, and use of CCNU were statistically significant as prognostic factors. Also 4 GBM long-term survivors were found. Treatment of brain astrocytomas by radiation in our department was concluded to be reasonably successful

Análisis estadístico de los astrocitomas cerebrales

Presentamos los resultados del tratamiento de 120 casos de astrocitomas supratentoriales operados en el Instituto de Enfermedades Neoplásicas entre 1984-1994. El objetivo del presente estudio fue determinar si existen factores pronósticos relacionados con los parámetros clínicos y tratamiento. La población de estudio estuvo conformada por 61 mujeres y 59 hombres; de los cuales 23 fueron niños y 97 adultos; con una edad media de 39,4 años; los síntomas y signos más frecuentes fueron: cefalea en 109 casos (90,8 por ciento) déficit motor en 51 pacientes (42,5 por ciento), convulsiones en 50 casos (41,6 por ciento), papiledodema en 85 casos (70,8 por ciento), diversos grados de hemiparesia en 70 pacientes (58,3 por ciento), afasia en nueve casos (7,5 por ciento). Localización: en el lóbulo parietal; 24, frontal: 18, temporal: 12, compromiso de dos o más lóbulos: 31, cuerpo calloso: 14, área quiasmática: 5, ganglios basales e hipotálamos: 14. Se realizó biopsia en 36 casos, resección subtotal en 69 y total en 15 casos. Se dió radioterapia en 85 casos (en 77 con rango 50-60 Gy). Histología (Kernohan): 29 casos con astrocitomas grado I y II, 42 pacientes con astrocitomas grado III y 49 casos con astrocitomas grado IV. Mortalidad operatoria: 13 casos (10,8 por ciento. La media global de sobrevida en 23 niños fue 44,5 meses y en 84 adultos fue 22,9 meses, con diferencias estadísticamente significativas. Las mejores condiciones de Karnofski en el preoperatorio, dieron los mejores resultados en el postoperatorio. La media de sobrevida en astrocitomas grado II fue de 50.8 meses y la sobrevida a tres años fue 69 por ciento. En astrocitomas grado III, la media de sobrevida fue 24,8 meses y la sobrevida a 12 meses fue 54 por ciento....