Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma.

PURPOSE: The monoterpene perillyl alcohol (POH) a Ras inhibitor with potential capacity to arrest gliomagenesis is being used in a phase I/II clinical trial in adults with recurrent malignant glioma. The present study aimed to investigate the efficacy of intranasal administration of monoterpene POH upon survival rate of patients with recurrent glioblastoma (GBM) in comparison with historical control group of GBM patients. PATIENTS AND METHODS: It was included 89 adults with recurrent GBM receiving daily intranasal administration of 440 mg POH and 52 matched GBM patients as historical control untreated group only with supportive treatment. RESULTS: Patients with recurrent primary GBM treated with POH survived significantly longer (log rank test, P < 0.0001) than untreated group. Patients with recurrent primary GBM in deep location survived significantly longer than with lobar location (log rank test, P < 0.0001). Median survival rate of secondary GBM was 11.2 months, longer (log rank test, P = 0.0366) than primary GBM (5.9 months). Radiographic improvement and reduction of corticosteroid dosage (36%) further associated with a delay towards progression. CONCLUSION: Intranasal administration of POH increased the overall survival of patients with recurrent GBM in comparison with historical untreated controls, but especially patients with secondary GBM and primary GBM with tumor localized in deep regions of the brain. The side effects of POH treatment were almost nonexistent, even in patients treated for over 4 years.

Successful treatment of lipoid pneumonia associated with bowel obstruction by Ascaris lumbricoides.

Partial bowel obstruction is a serious complication of ascariasis infestation generally treated with mineral oil. This prospective study aimed to evaluate the efficacy of multiple bronchoalveolar lavages (BAL) as a therapeutic strategy for reducing lung inflammation of lipoid pneumonia associated with ascariasis. The study included five children (mean age 25 months) with partial small-bowel obstruction by Ascaris lumbricoides, who underwent diagnostic bronchoalveolar lavage for assessment of refractory pneumonia. Routine biochemical, microbiological and cytological analysis were carried out in the BAL. Protein, lactate dehydrogenase and tumor necrosis factor-alpha (TNF-α) cytokine levels were determined in the serum before and after treatment. At admission, children consistently had respiratory symptoms, altered hematological function, increased immunoglobulin E serum level and peripheral blood eosinophilia. Chest tomography showed consolidation with air bronchogram (4/4), ground-glass infiltration (3/4) and decreased attenuation in the consolidation areas (2/4). Presence of marked pleocytosis with Sudan positive foamy alveolar macrophages, high protein and lactate dehydrogenase levels in the BAL indicated presence of mixed alveolitis. One child with extensive consolidation and air bronchogram in both lungs died before treatment. Multiple bronchoalveolar lavages efficiently removed alveolar oil deposits, restored BAL cellularity, improved clinical symptoms, radiological parameters and further reduced inflammatory reaction evidenced by marked decrease of the inflammatory cytokine, TNF-α. This study presents a therapeutic strategy for management of lung complications caused by mineral oil administration to treat intestinal bowel obstruction associated with ascariasis.

Evolution of exogenous lipoid pneumonia in children: clinical aspects, radiological aspects and the role of bronchoalveolar lavage.

OBJECTIVE: To present aspects of the evolution of lipoid pneumonia in children, based on clinical, radiological and bronchoalveolar lavage fluid findings, emphasizing the importance of bronchoalveolar lavage for the diagnosis and treatment. METHODS: We included 28 children, with a mean age of 20 months (range, 1-108 months), diagnosed with chronic pneumonia refractory to antimicrobial therapy, with TB or with a combination of the two. Most of the children had at least one risk factor for aspiration, and all of them had a history of mineral oil ingestion for intestinal constipation (23/28) or complicated ascaridiasis (5/28). Clinical evaluations, tomographic evaluations and analyses of bronchoalveolar lavage fluid were carried out at the beginning of treatment and throughout a follow-up period of 24 months. RESULTS: Tachypnea and cough were the most common symptoms. The most common radiological alterations were areas of consolidation (23/28), perihilar infiltrates (13/28) and hyperinflation (11/28). Chest CT scans showed areas of consolidation with air bronchogram (24/28), decreased attenuation in the areas of consolidation (16/28), ground-glass opacities (3/28) and crazy-paving pattern (1/28). In the analysis of the bronchoalveolar lavage fluid, Sudan staining revealed foamy macrophages, confirming the diagnosis of lipoid pneumonia. After treatment with multiple bronchoalveolar lavages (mean = 9.6), 20 children became asymptomatic, 18 of those presenting normal tomographic images. CONCLUSIONS: A diagnosis of lipoid pneumonia should be considered in patients with chronic refractory pneumonia or TB, especially if there is a history of mineral oil ingestion. Bronchoscopy with multiple bronchoalveolar lavages was an efficient treatment for the clearance of mineral oil from the lung parenchyma and the prevention of fibrosis. This strategy contributed to reducing the morbidity of lipoid pneumonia, which remains a rare diagnosis.

Evolução da pneumonia lipoide exógena em crianças: aspectos clínicos e radiológicos e o papel da lavagem broncoalveolar / Evolution of exogenous lipoid pneumonia in children: clinical aspects, radiological aspects and the role of bronchoalveolar lavage

OBJETIVO: Descrever os aspectos da evolução da pneumonia lipoide em crianças, com base em aspectos clínicos, radiológicos e de achados no lavado broncoalveolar, enfatizando a importância diagnóstica e terapêutica da lavagem broncoalveolar. MÉTODOS: Foram incluídas 28 crianças, com idade média de 20 meses (1-108 meses) e diagnóstico de pneumonia crônica refratária a antimicrobianos e/ou TB. A maioria apresentava um fator de risco para aspiração, e todas apresentavam história de ingestão de óleo mineral para o tratamento de constipação intestinal (23/28) ou de ascaridíase complicada (5/28). A avaliação clínica e tomográfica e análises do lavado broncoalveolar foram realizadas no início do tratamento e em até 24 meses. RESULTADOS: Os sintomas mais frequentes foram taquipneia e tosse. As principais alterações radiológicas foram consolidações (23/28), infiltrado peri-hilar (13/28) e hiperinsuflação (11/28). A TC de tórax mostrou consolidações com broncograma aéreo (24/28), diminuição de atenuação nas áreas de consolidação (16/28), opacidade em vidro fosco (3/28) e padrão em mosaico (1/28). O estudo do lavado broncoalveolar apresentava macrófagos espumosos corados por Sudan, confirmando o diagnóstico da pneumonia lipoide. Após tratamento com múltiplas lavagens broncoalveolares (média = 9,6), 20 crianças tornaram-se assintomáticas, havendo normalização tomográfica em 18. CONCLUSÕES: O diagnóstico de pneumonia lipoide deve ser considerado na pneumonia crônica ou TB refratárias ao tratamento, especialmente se houver história de ingestão de óleo mineral. A broncoscopia com múltiplas lavagens broncoalveolares mostrou-se eficiente para a depuração do óleo aspirado do parênquima pulmonar e a prevenção da fibrose, contribuindo para a redução da morbidade dessa doença, que ainda é pouco diagnosticada.

OBJECTIVE: To present aspects of the evolution of lipoid pneumonia in children, based on clinical, radiological and bronchoalveolar lavage fluid findings, emphasizing the importance of bronchoalveolar lavage for the diagnosis and treatment. METHODS: We included 28 children, with a mean age of 20 months (range, 1-108 months), diagnosed with chronic pneumonia refractory to antimicrobial therapy, with TB or with a combination of the two. Most of the children had at least one risk factor for aspiration, and all of them had a history of mineral oil ingestion for intestinal constipation (23/28) or complicated ascaridiasis (5/28). Clinical evaluations, tomographic evaluations and analyses of bronchoalveolar lavage fluid were carried out at the beginning of treatment and throughout a follow-up period of 24 months. RESULTS: Tachypnea and cough were the most common symptoms. The most common radiological alterations were areas of consolidation (23/28), perihilar infiltrates (13/28) and hyperinflation (11/28). Chest CT scans showed areas of consolidation with air bronchogram (24/28), decreased attenuation in the areas of consolidation (16/28), ground-glass opacities (3/28) and crazy-paving pattern (1/28). In the analysis of the bronchoalveolar lavage fluid, Sudan staining revealed foamy macrophages, confirming the diagnosis of lipoid pneumonia. After treatment with multiple bronchoalveolar lavages (mean = 9.6), 20 children became asymptomatic, 18 of those presenting normal tomographic images. CONCLUSIONS: A diagnosis of lipoid pneumonia should be considered in patients with chronic refractory pneumonia or TB, especially if there is a history of mineral oil ingestion. Bronchoscopy with multiple bronchoalveolar lavages was an efficient treatment for the clearance of mineral oil from the lung parenchyma and the prevention of fibrosis. This strategy contributed to reducing the morbidity of lipoid pneumonia, which remains a rare diagnosis.

Clinic and radiological improvement of lipoid pneumonia with multiple bronchoalveolar lavages.

OBJECTIVE: To assess the potential role of multiple bronchoalveolar lavages (BALs) in the treatment of children with lipoid pneumonia (LP). MATERIALS AND METHODS: This prospective study included 10 children (7 female, 3 male) with LP secondary to mineral oil aspiration. The age ranged from 3 months to 7 years and 1-60 days history of mineral oil intake, with a 6 months clinic follow-up. High-resolution computer tomography (CT) was performed 1-7 days prior to treatment and 2-20 days after the last therapeutic BAL, and reviewed by two experienced chest radiologists. Oxygen saturation was measured with digital oximetry. Therapeutic BAL was performed weekly until BAL fluid was nearly transparent and the cell count returned to normal range values. RESULTS: In all children, the initial CT scans showed multifocal bilateral consolidation involving mainly the dorsal and central regions. The areas of consolidation had foci of decreased attenuation in eight patients. Following a total of 4-10 therapeutic BALs, the CT scans returned to normal in 3 patients, improved considerably in 5, and showed only slight improvement in 2. Oxygen saturation increased from 88.8 +/- 3.4% at presentation to 96.2 +/- 0.8% after treatment (P < 0.0001). Multiple lavages reduced (P < 0.003) numbers of lipid-laden macrophages and restored BAL cellularity to normal range values. CONCLUSION: Multiple therapeutic BAL of children with LP results in significant improvement of CT findings, oxygen saturation, restoration of BAL fluid cellularity and clinical recover without any evidence of respiratory distress at the end of treatment and 6 months after the last BAL.

Análise de metaloproteases de matriz extracelular como indicador prognóstico nos gliomas malignos / Analysis of matrix metalloproteinase as prognostic indicator in malignant gliomas

Introdução: Metaloproteases de matriz extracelular(MMP) são enzimas proteolíticas sintetizadas na fase de fenótipo mais agressivo dos gliomas malignos, degradando proteínas da matriz extracelular,ocasionando ruptura da barreira hematoencefálica e contribuindo para a resposta neuroinflamatória,angiogênese e migração.Estudos mostram expressão de gelatinase A(MMP-2)proeminentemente nas células gliais tumorais,com pouca expressão na microvasculatura,enquanto expressão de gelatinase B(MMP-9)é proeminente na microvasculatrua, com porco sinal nas células tumorais.Objetivo:Neste estudo analisamos amostras de soro de 34 pacientes com gliomas malignos recidivos,antes e durante o tratamento com álcool perílico por via inalatória para determinar se a expressão de MMP poderia ser usada como indicador prognóstico.Métodos:A atividade gelatinade (MMP-2, MMP-9)nas amostras de soro foi determinada por zimografia e a atividade enzimática relativa foi determinada utilizando-se programa de análise densitométrica.Os valores foram correlacionados com exames de imagem e sobrevida dos pacientes. Resultados:Os resultados obtidos em nosso estudo evidenciaram que os pacientes com gliomas malignos apresentaram aumento da expressão de MMP-2 e MMP-9 quando comparados com pacientes saudáveis.Expressão aumentada de MMP-2 foi proporcional à progressão tumoral,sobrevida desfavorável e área de edema peritumoral.Conclusão:Esses resultados indicam proporcionalidade entre a expressão de MMP-2 e a malignidade dos gliomas, sugerindo seu emprego como indicador prognóstico para recorrência tumoral pós-operatória e sobrevida desfavorável dos pacientes.

Study of polymorphisms in the interleukin-4 and IL-4 receptor genes in a population of Brazilian patients with multiple sclerosis.

This study aimed to investigate in a population of Brazilian patients with multiple sclerosis (MS) single-nucleotide polymorphisms (SNP) in the promoter region of IL4 (*33C-T) and receptor IL4R (*Q551R A-G) genes proposed to interfere with disease progression. No significant differences were observed in either of the SNPs investigated between healthy controls (n=135) and MS patients (n=129). However, the IL4+33 TT genotype was significantly (p=0.039) higher in African descendants MS (AF-MS= 9.09%) than in Caucasian MS (CA-MS= 1.35%). It was also observed a significant (p=0.016) increase for the IL4R* Q551R CC genotype in AF-MS compared to those of Caucasian ethnicity (AF-MS= 21.62%; CA-MS= 4.35%). These results suggest that IL4+33 and IL4R*Q551 polymorphisms may have a disease-promoting role of TH2 mediators in African MS descendants. Additionally neither IL4 nor IL4R genes are susceptibility factors for Brazilian MS but may be able to modify ethnicity-dependent disease risk and penetrance of susceptibility factors.

Oligodendrogliomas: a genética molecular e o desenvolvimento estratégia terapêutica adjuvante / Oligodendrogliomas: molecular genetics and development of adjuvant therapeutic strategies

A incidência dos oligodendrogliomas tem aumentado provavelmente em razão do progresso na precisão de diagnóstico. Aproximadamente dois terços dos pacientes com a forma mais agressiva, oligodendroglioma anaplásico, mostram resposta substancial à quimioterapia com a associação procarbazina/lomustina/vincristina (PCV). Entretanto, os resultados da quimuiterapia anaplásica dos oligodendrogliomas resulta em grande número de células com ERK/MAPK ativadas. O monoterpeno álcool perílico demonstra atividades quimiopreventiva e quimioterápica em diversos modelos de tumores e sugere-se que estas possam estar associadas com a capacidade de inibir a farmesilação pós-traducional e a sinalização da Ras, assim como a cascata de sinalização por meio da RAF-MEK-ERK. Estudo do nosso grupo observou que pode estar atuando mediante a inibição da fosforilação da extracellular regulated kinase (ERK), uma proteína envolvida na cascata de transdução de sinal através da membrana e proliferação celular induzida pela proteína Ras. Este artigo discute a redução de oligodendroglioma anaplásico recidivado em paciente tratado durante nove meses com álcool perílico por via intranasal.

Study of polymorphisms in the interleukin-4 and IL-4 receptor genes in a population of Brazilian patients with multiple sclerosis

This study aimed to investigate in a population of Brazilian patients with multiple sclerosis (MS) single-nucleotide polymorphisms (SNP) in the promoter region of IL4 (*33C-T) and receptor IL4R (*Q551R A-G) genes proposed to interfere with disease progression. No significant differences were observed in either of the SNPs investigated between healthy controls (n=135) and MS patients (n=129). However, the IL4+33 TT genotype was significantly (p=0.039) higher in African descendants MS (AF-MS= 9.09 percent) than in Caucasian MS (CA-MS= 1.35 percent). It was also observed a significant (p=0.016) increase for the IL4R* Q551R CC genotype in AF-MS compared to those of Caucasian ethnicity (AF-MS= 21.62 percent; CA-MS= 4.35 percent). These results suggest that IL4+33 and IL4R*Q551 polymorphisms may have a disease-promoting role of TH2 mediators in African MS descendants. Additionally neither IL4 nor IL4R genes are susceptibility factors for Brazilian MS but may be able to modify ethnicity-dependent disease risk and penetrance of susceptibility factors.

Este é um estudo inédito realizado numa população brasileira de pacientes portadores de esclerose múltipla (EM) visando determinar uma possível associação na expressão de polimorfismo (SNP) nos genes da citocina reguladora IL4 (*33C-T) e do seu respectivo receptor IL4R (*Q551R A-G) capazes de modificar a evolução da doença. Não foi observada diferença significativa em ambos SNPs analisados entre o grupo controle de indivíduos saudáveis (n=135) e os pacientes com EM (n=129). Contudo, o genotipo IL4+33 TT apresentava percentual mais elevado (9,09 por cento) nos pacientes EM com descendência africana (AF-EM) do que nos descendentes caucasianos (CA-EM=1,35 por cento) sendo esta diferença significativa (p=0,039). Também foi observado um aumento significativo (p=0,016) para o genotipo IL4R* Q551R CC nos pacientes AF-EM (21,62 por cento) comparando-se com CA-EM (4,35 por cento). Estes resultados indicam que polimorfismos nos genes da citocina IL4 (*33C-T) e respectivo receptor IL4R (*Q551R A-G) influenciam na produção de citocinas do tipo TH2 e evolução da doença nos pacientes EM com descendência africana. Embora polimorfismo nos genes IL4 (*33C-T) e respectivo receptor IL4R (*Q551R A-G) não sejam fatores indutores de susceptibilidade para EM podem modificar o risco e evolução da EM numa população com alto grau de miscigenação étnica.

Anaplastic oligodendroglioma responding favorably to intranasal delivery of perillyl alcohol: a case report and literature review.

BACKGROUND: In recent years, molecular genetics and biology are exerting significant influence on the practice of neuro-oncology, with oligodendrogliomas being the most prominent example. To explore therapeutic strategies and evaluate the clinical results, we report a case of a patient with anaplastic oligodendroglioma managed with intranasal delivery of POH. CASE DESCRIPTION: A 62 year-old white woman presented with complaints of seizures and frontal headache in June 1999. Nervous system examination was normal. Her Karnofsky performance score was 90. A contrast-enhanced MRI scan of the brain revealed a regular space-occupying lesion in the right frontal lobe that enhanced with gadolinium. A radical surgical excision of the tumor was carried out, and the histopathological diagnosis was an anaplastic oligodendroglioma. Subsequently, there were 2 recurrent/progressive lesions, in July 2002 and October 2004, despite combination treatment using surgery, radiotherapy, and chemotherapy. Intranasal delivery of 0.3% concentration of POH 4 times daily was performed. A follow-up MRI scan after 5 months of treatment revealed reduction in size of the enhancing lesion. CONCLUSION: Whereas surgery continues to be the primary treatment for oligodendroglioma, the scheme for postoperative therapy has shifted primarily because of the lesion's relative chemosensitivity. This article evaluates the effects of intranasal delivery of POH in a case of regression of anaplastic oligodendroglioma.

Administração intranasal do agente antitumoral álcool perílico: estratégia terapêutica para pacientes com glioblastoma recidivado / Intranasal delivery of anti-tumor agent perillyl alcohol: potential therapeutic alternative for patients with relapsed glioblastoma

Álcool perílico (AP) é um monoterpeno com ação antitumoral comprovada, em estudos pré-clínicos, sobre diferentes tipos de tumores induzidos em animais. Fase I e II de ensaios clínicos estão correntemente em desenvolvimento. O mecanismo de ação da atividade antitumoral do AP envolve a inibição da isoprenilação pós-traducional de proteinas G, incluindo a p21-Ras, bloqueando a transdução do sinal. A desregulação da função da p21-Ras, como resultado de mutação, superexpressão ou superativação dos fatores de crescimento, contribui para o crescimento de glioblastoma. A administração intranasal é uma abordagem prática e não-invasiva que permite que agentes terpêuticos que não cruzam a barreira hemato-encefálica alcancem o sistema nervoso central, reduzindo os efeitos colaterais provenientes da administração sistêmica. Este artigo discute a administração intranasal do AP, como potencial estratégia terapêutica multimodal para estas neoplasias e apresenta resultado preliminar em um caso.

Caracterizaçäo imunofetípica das subpopulaçöes de linfócitos do lavado broncoalveolar de pacientes com silicose / Phenotypic characterization of lymphocyte subsets in bronchoalveolar lavage of patients with silicosis

A lavagem broncoalveolar é um procedimento simples e seguro, na avaliaçäo das pneumopatias relacionadas à exposiçäo a poeiras minerais. O objetivo do estudo foi caracterizar as subpopulaçöes celulares no lavado broncoalveolar (LBA) de pacientes silicóticos. A lavagem broncoalveolar foi realizada em 26 trabalhadores com diferentes formas de silicose: forma simples ( n=12 ), complicada ( n=13 ) e sadios. Os pacientes com silicose apresentam intensa pleocitose com predomínio de macrófagos alveolares e tendência à linfocitose. As subpopulaçöes de linfócitos presentes no lavado broncoalveolar (LBA) dos indivíduos sadios apresentaram fenótipo de células maduras. A grande maioria era constituída por células CD2+TCR alfa beta ( 87,3 por cento ) e somente 2,9 por cento das células T apresentam marcaçäo CD2+TCR. A relaçäo CD2/CD8 foi de 1.8, com poucas (16 por cento) células T imaturas duplo-negativas CD4-CD8. Em contraste, pacientes com silicose apresentaram reduçäo acentuada das subpopulaçöes dos linfócitos maduros CD2+CD4, CD2+CD8 e aumento marcantes (47 por cento) de células imaturas (DN) duplo-negativas (CD4-CD8). Näo foi observado aumento das céluas NK (CD56+). A análise do conteúdo protéico e a determinaçäo da relaçäo Ig/ albumina permitiram caracterizar produçäo local de imunoglobulinas no microambiente pulmonar. Como näo foi observado aumento percentual de plasmócitos e linfócitos B (CD19+) no LBA desses pacientes, é possível concluir que as células produtoras de imunoglobulinas estäo possivelmente localizadas no interstício pulmonar. Estes resultados sugerem que, durante a evoluçäo da silicose, ocorre o desenvolvimento de linfopoese extratímica e surgimento de órgäo linfóide terciário, no microambiente pulmonar desses pacientes