Intrathecal drug delivery systems for cancer pain

Introduction: A substantial number of patients with cancer suffer considerable pain at some point during their disease, and approximately 25% of cancer patients die in pain. In cases of uncontrolled pain or intolerable side effects, intrathecal drug delivery system (IDDS) is a recognised management option. Indeed, IDDS offer rapid and effective pain relief with less drug side effects compared to oral or parenteral administration. The aim of this study is to retrospectively review our series of cancer patients treated with IDDS. Method: Data was extracted from the institutional neuromodulation registry. Patients with cancer pain treated with IDDS from 01.01.1997 to 30.12.2009 were analysed for subjective improvement, changes in pain intensity (VAS) and survival time after implantation. Measurements were available for a decreasing number of patients as time since baseline increased. Results: During the studied period, 78 patients were implanted with IDDS for cancer pain. The mean survival time was 11.1 months (median: 3.8 months) and 14 patients (18%) were still alive at the end of the studied period. Subjective improvement was graded between 55 and 83% during the first year. Mean VAS during the first year remained lower than VAS at baseline. Discussion: IDDS has been shown to be cost-effective in several studies. Although initial costs of implantation are high, the cost benefits favour analgesia with implanted intrathecal pumps over epidural external systems after 3 to 6 months in cancer patients. Improved survival has been associated with IDDS and in this series both the mean and median survival times were above the cut-off value of three months. The mean subjective improvement was above 50% during the whole first year, suggesting a good efficacy of the treatment, a finding that is consistent with the results from other groups. Changes in pain intensity are difficult to interpret in the context of rapidly progressive disease such as in terminal cancer. However, mean VAS from 1 thru12 months were lower than baseline, suggesting improved pain control with IDDS, or at least a stabilisation of the pain symptoms. Conclusion: Our retrospective series suggests IDDS is effective in intractable cancer pain and we believe it should be considered even in terminally ill patients with limited life expectancies.

MGMT methylation status: the advent of stratified therapy in glioblastoma?

Glioblastomas are the most malignant gliomas with median survival times of only 15 months despite modern therapies. All standard treatments are palliative. Pathogenetic factors are diverse, hence, stratified treatment plans are warranted considering the molecular heterogeneity among these tumors. However, most patients are treated with "one fits all" standard therapies, many of them with minor response and major toxicities. The integration of clinical and molecular information, now becoming available using new tools such as gene arrays, proteomics, and molecular imaging, will take us to an era where more targeted and effective treatments may be implemented. A first step towards the design of such therapies is the identification of relevant molecular mechanisms driving the aggressive biological behavior of glioblastoma. The accumulation of diverse aberrations in regulatory processes enables tumor cells to bypass the effects of most classical therapies available. Molecular alterations underlying such mechanisms comprise aberrations on the genetic level, such as point mutations of distinct genes, or amplifications and deletions, while others result from epigenetic modifications such as aberrant methylation of CpG islands in the regulatory sequence of genes. Epigenetic silencing of the MGMT gene encoding a DNA repair enzyme was recently found to be of predictive value in a randomized clinical trial for newly diagnosed glioblastoma testing the addition of the alkylating agent temozolomide to standard radiotherapy. Determination of the methylation status of the MGMT promoter may become the first molecular diagnostic tool to identify patients most likely to respond that will allow individually tailored therapy in glioblastoma. To date, the test for the MGMT-methylation status is the only tool available that may direct the choice for alkylating agents in glioblastoma patients, but many others may hopefully become part of an arsenal to stratify patients to respective targeted therapies within the next years.

Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial.

PURPOSE: The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide (TMZ) and radiotherapy (RT) in glioblastoma (GBM) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone. We evaluated in this trial whether the recursive partitioning analysis (RPA) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class. PATIENTS AND METHODS: Five hundred seventy-three patients with newly diagnosed GBM were randomly assigned to standard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ. The primary end point was overall survival. The European Organisation for Research and Treatment of Cancer RPA used accounts for age, WHO performance status, extent of surgery, and the Mini-Mental Status Examination. RESULTS: Overall survival was statistically different among RPA classes III, IV, and V, with median survival times of 17, 15, and 10 months, respectively, and 2-year survival rates of 32%, 19%, and 11%, respectively (P < .0001). Survival with combined TMZ/RT was higher in RPA class III, with 21 months median survival time and a 43% 2-year survival rate, versus 15 months and 20% for RT alone (P = .006). In RPA class IV, the survival advantage remained significant, with median survival times of 16 v 13 months, respectively, and 2-year survival rates of 28% v 11%, respectively (P = .0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (P = .054). CONCLUSION: RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM, particularly in classes III and IV.

Progress of soybean charcoal rot under tillage and no-tillage systems in Brazil

The increase in incidence of charcoal rot caused by Macrophomina phaseolina on soybeans (Glycine max) was followed four seasons in conventional and no-till cropping systems. In the 1997/98 and 2000/01 seasons, total precipitation between sowing and harvest reached 876.3 and 846.9 mm, respectively. For these seasons, disease incidence did not differ significantly between the no-till and conventional systems. In 1998/99 and 1999/00 precipitation totaled 689.9 and 478.3 mm, respectively. In 1998/99, in the no-till system, the disease incidence was 43.7% and 53.1% in the conventional system. In 1999/00 the final incidence was 68.7% and 81.2% for the no-till and conventional systems, respectively. For these two seasons, precipitation was lower than that required for soybean crops (840 mm), and the averages of disease incidence were significantly higher in the conventional system. The concentration of microsclerotia in soil samples was higher in samples collected in conventional system at 0 - 10 cm depth. However, analysis of microsclerotia in roots showed that in years with adequate rain no difference was detected. In dry years, however, roots from plants developed under the conventional system had significantly more microsclerotia. Because of the wide host range of M. phaseolina and the long survival times of the microsclerotia, crop rotation would probably have little benefit in reducing charcoal rot. Under these study conditions it may be a better alternative to suppress charcoal rot by using the no-till cropping system to conserve soil moisture and reduce disease progress.

Hyperthermia induced after recirculation triggers chronic neurodegeneration in the penumbra zone of focal ischemia in the rat brain

Chronic neurodegenerative processes have been identified in the rat forebrain after prolonged survival following hyperthermia (HT) initiated a few hours after transient global ischemia. Since transient global ischemia and ischemic penumbra share pathophysiological similarities, this study addressed the effects of HT induced after recirculation of focal brain ischemia on infarct size during long survival times. Adult male Wistar rats underwent intra-luminal occlusion of the left middle cerebral artery for 60 min followed by HT (39.0-39.5°C) or normothermia. Control procedures included none and sham surgery with and without HT, and middle cerebral artery occlusion alone. Part I: 6-h HT induced at recirculation. Part II: 2-h HT induced at 2-, 6-, or 24-h recirculation. Part III: 2-h HT initiated at recirculation or 6-h HT initiated at 2-, 6- or 24-h recirculation. Survival periods were 7 days, 2 or 6 months. The effects of post-ischemic HT on cortex and striatum were evaluated histopathologically by measuring the area of remaining tissue in the infarcted hemisphere at -0.30 mm from bregma. Six-hour HT initiated from 6-h recirculation caused a significant decrease in the remaining cortical tissue between 7-day (N = 8) and 2-month (N = 8) survivals (98.46 ± 1.14 to 73.62 ± 8.99%, respectively). When induced from 24-h recirculation, 6-h HT caused a significant reduction of the remaining cortical tissue between 2- (N = 8) and 6-month (N = 9) survivals (94.97 ± 5.02 vs 63.26 ± 11.97%, respectively). These data indicate that post-ischemic HT triggers chronic neurodegenerative processes in ischemic penumbra, suggesting that similar fever-triggered effects may annul the benefit of early recirculation in stroke patients over the long-term.

Contribuição para o estudo do linfoma no cão em Portugal : análise da casuística em dois centros de referência

O linfoma é um grupo heterogéneo de neoplasias que apresentam morfologia variável e apresentações clínicas diversas, exigindo diferentes abordagens diagnósticas e terapêuticas. O prognóstico difere bastante entre os canídeos afectados. A presente dissertação refere-se a um estudo retrospectivo (2008-2012), de 50 canídeos com linfoma, com o objectivo de comparar os resultados obtidos com a bibliografia publicada, determinando ainda o impacto do imunofenótipo (B ou T) na sobrevida de cães com linfoma. Foi registado o mesmo número de machos e fêmeas e as raças mais frequentes foram o Boxer, Rottweiller e Cocker Spaniel. O diagnóstico da doença foi realizado maioritariamente por histopatologia de linfonodo (56%), revelando 84% de linfomas da forma multicêntrica. Quando determinado, o imunofenótipo mais frequente foi o de células B (69%). A maioria dos canídeos estava em estadios avançados da doença (III-V) (98%) no momento do diagnóstico, revelando 54% dos casos sub-estadio "b" segundo a OMS. O tratamento quimioterápico mais utilizado foi o protocolo CHOP (n=26) seguido do COP (n=9). A toxicidade hematológica e gastrointestinal secundárias à quimioterapia estiveram em igual número (22% cada), não se observando efeitos adversos em 56% dos cães com linfoma. Por último, o tempo médio de sobrevivência registado foi de 393 dias. Não foi encontrada uma relação estatísticamente significativa entre as variáveis (raça, sub-estadio e sexo) e o imunofenótipo de linfoma, sendo os tempos médios de sobrevivência de linfomas T e B semelhantes, 388 e 463 dias, respectivamente. No nosso caso, as principais diferenças encontradas, relativamente à bibliografia publicada, foram uma quantidade elevada de pacientes em sub-estadio "b" e os tempos médios de sobrevivência semelhantes para os diferentes imunofenótipos.

Bayesian analysis of an inverse Gaussian correlated frailty model

In survival analysis frailty is often used to model heterogeneity between individuals or correlation within clusters. Typically frailty is taken to be a continuous random effect, yielding a continuous mixture distribution for survival times. A Bayesian analysis of a correlated frailty model is discussed in the context of inverse Gaussian frailty. An MCMC approach is adopted and the deviance information criterion is used to compare models. As an illustration of the approach a bivariate data set of corneal graft survival times is analysed. (C) 2006 Elsevier B.V. All rights reserved.

Competition and dispersal in the pea aphid: clonal variation and correlations across traits

1. The presence of an across-species trade-off between dispersal ability and competitive ability has been proposed as a mechanism that facilitates coexistence. It is not clear if a similar trade-off exists within species. Such a trade-off would constrain the evolution of either trait and, given appropriate selection pressures, promote local adaptation in these traits. 2. This study found substantial levels of heritable variation in competitive ability of the pea aphid, Acyrthosiphon pisum Harris (Homoptera: Aphididae), measured in terms of relative survival when reared with a single clone of the vetch aphid, Megoura viciae Buckton (Homoptera: Aphididae). 3. Pea aphids can move to new patches by either flying (longer distance dispersal) or walking (local dispersal) from plant to plant. There was considerable clonal variation in dispersal ability, measured in terms of the proportion of winged offspring produced, and ability to survive away from their host plant. 4. Winged individuals showed longer off-plant survival times than wingless forms of the same pea aphid clone. 5. There was no evidence of a relationship between clonal competitive ability and either measure of dispersal ability, although the power of the test is limited by the number of pea aphid clones used in the trial. 6. However, there was a positive correlation between clonal fecundity and the proportion of winged offspring produced. Although speculative, it is suggested that clones that are more likely to either overwhelm their host plant or attract higher numbers of natural enemies as a result of having higher fecundity are more likely to produce winged morphs.

Supplementary feeding of wild birds indirectly affects the local abundance of arthropod prey

Providing supplementary food for wild birds is a globally popular past-time; almost half of the households in many developed countries participate and billions of US dollars are spent annually. Although the direct influence of this additional resource on bird survivorship and fecundity has been studied, there is little understanding of the wider ecological consequences of this massive perturbation to (what are usually) urban ecosystems. We investigated the possible effects of wild bird feeding on the size and survivorship of colonies of a widespread arthropod prey species of many small passerine birds, the pea aphid [Acyrthosiphon pisum (Harris); Hemiptera: Aphididae], in suburban gardens in a large town in southern England. We found significantly fewer aphids and shorter colony survival times in colonies exposed to avian predation compared to protected controls in gardens with a bird feeder but no such differences between exposed and protected colonies in gardens that did not feed birds. Our work therefore suggests that supplementary feeding of wild birds in gardens may indirectly influence population sizes and survivorship of their arthropod prey and highlights the need for further research into the potential effects on other species.

Retinal removal up-regulates cannabinoid CB1 receptors in the chick optic tectum

The endocannabinoid system has been implicated in several neurobiological processes, including neurodegeneration and neuro protection. The aim of this study was to evaluate the effects of unilateral retinal ablation on the expression of the cannabinoid receptor subtype 1 (CB1) at both protein and mRNA levels in the optic tectum of the adult chick brain. After different survival times postlesion (2-30 days), the chick brains were subjected to immunohistochemical, immunoblotting, and real-time PCR procedures to evaluate CB1 expression. TUNEL and Fluoro-Jade B were used to verify the possible occurrence of cell death, and immunostaining for the microtubule-associated protein MAP-2 was performed to verify possible dendritic remodeling after lesions. No cell death could be observed in the deafferented tectum, at least up to 30 days postlesion, although Fluoro-Jade B could reveal degenerating axons and terminals. Retinal ablation seems to generate an increase of CB1 protein in the optic tectum and other retinorecipient visual areas, which paralleled an increase in MAP-2 staining. On the other hand, CB, mRNA levels were not changed after retinal ablation. Our results reveal that CB, expression in visual structures of the adult chick brain may be negatively regulated by the retinal innervation. The increase of CB1 receptor expression observed after retinal removal indicates that these receptors are not presynaptic in retinal axons projecting to the tectum and suggests a role of the cannabinoid system in plasticity processes ensuing after lesions. (c) 2008 Wiley-Liss, Inc.

An orthotopic skull base model of malignant meningioma

Meningioma tumor growth involves the subarachnoid space that contains the cerebrospinal fluid. Modeling tumor growth in this microenvironment has been associated with widespread leptomeningeal dissemination, which is uncharacteristic of human meningiomas. Consequently, survival times and tumor properties are varied, limiting their utility in testing experimental therapies. We report the development and characterization of a reproducible orthotopic skull-base meningioma model in athymic mice using the IOMM-Lee cell line. Localized tumor growth was obtained by using optimal cell densities and matrigel as the implantation medium. Survival times were within a narrow range of 17-21 days. The xenografts grew locally compressing surrounding brain tissue. These tumors had histopathologic characteristics of anaplastic meningiomas including high cellularity, nuclear pleomorphism, cellular pattern loss, necrosis and conspicuous mitosis. Similar to human meningiomas, considerable invasion of the dura and skull and some invasion of adjacent brain along perivascular tracts were observed. The pattern of hypoxia was also similar to human malignant meningiomas. We use bioluminescent imaging to non-invasively monitor the growth of the xenografts and determine the survival benefit from temozolomide treatment. Thus, we describe a malignant meningioma model system that will be useful for investigating the biology of meningiomas and for preclinical assessment of therapeutic agents.

TLR2 Is a Negative Regulator of Th17 Cells and Tissue Pathology in a Pulmonary Model of Fungal Infection

To study the role of TLR2 in a experimental model of chronic pulmonary infection, TLR2-deficient and wild-type mice were intratracheally infected with Paracoccidioides brasiliensis, a primary fungal pathogen. Compared with control, TLR2(-/-) mice developed a less severe pulmonary infection and decreased NO synthesis. Equivalent results were detected with in vitro-infected macrophages. Unexpectedly, despite the differences in fungal loads both mouse strains showed equivalent survival times and severe pulmonary inflammatory reactions. Studies on lung-infiltrating leukocytes of TLR2(-/-) mice demonstrated an increased presence of polymorphonuclear neutrophils that control fungal loads but were associated with diminished numbers of activated CD4(+) and CD8(+) T lymphocytes. TLR2 deficiency leads to minor differences in the levels of pulmonary type 1 and type 2 cytokines, but results in increased production of KC, a CXC chemokine involved in neutrophils chemotaxis, as well as TGF-beta, IL-6, IL-23, and IL-17 skewing T cell immunity to a Th17 pattern. In addition, the preferential Th17 immunity of TLR2(-/-) mice was associated with impaired expansion of regulatory CD4(+)CD25(+)FoxP3(+) T cells. This is the first study to show that TLR2 activation controls innate and adaptive immunity to P. brasiliensis infection. TLR2 deficiency results in increased Th17 immunity associated with diminished expansion of regulatory T cells and increased lung pathology due to unrestrained inflammatory reactions. The Journal of Immunology, 2009, 183: 1279-1290.

Atividade antiplasmódica e toxicológica de plantas medicinais usadas popularmente no Brasil : uma abordagem etnobotânica

Malaria is a disease of global distribution, recognized by governments around the world as a serious public health problem, affecting more than 109 countries and territories and endangering more than 3.3 billion people. The economic costs of this disease are also relevant: the African continent itself has malaria-related costs of about $ 12 billion annually. Nowadays, in addition to chloroquine, Plasmodium falciparum is resistant to many drugs used in the treatment of malaria, such as amodiaquine, mefloquine, quinine and sulfadoxine-pyrimethamine; resistance of Plasmodium vivax to treatments, although less studied, is also reported. Nature, in general, is responsible for the production of most known organic substances, and the plant kingdom is responsible for the most of the chemical diversity known and reported in the literature. Most medicinal plants commercialized in Brazil, however, are of exotic origin, which makes the search for endemic medicinal plants, besides a patent necessity, a fascinating subject of academic research and development. This study aimed to: (i) verify the antimalarial activity of ethanolic and hydroalcoholic extracts of Boerhavia paniculata Rich. And acetonic extract of Clethra scabra Pers. in Swiss albino mice infected by Plasmodium berghei NK65, (ii) observe possible combined effects between the course of infection by P. berghei NK65 and administration of these extracts in Swiss albino mice, and (iii) conduct a preliminary study of the acute toxicity of these extracts in Swiss albino mice. All extracts notable pharmacological activities - with parasite infections inhibitions ranging from 22% to 54%.These characteristics suggest that the activities are relevant, although comparatively lower than the activity displayed by the positive control group (always above 90%). The general framework of survival analysis demonstrates an overall reduction in survival times for all groups. Necroscopy has not pointed no change in color, shape, size and/or consistency in the evaluated organs - the only exception was the livers of rats submitted to treatment to hydroalcoholic extracts: these organs have been presented in a slightly congestive aspect with mass increasing roughly 28% higher than the other two groups and a p-value of 0.0365. The 250 mg/Kg ethanolic group has been pointed out by the Dunn s post test, as the only class with simultaneous inequalities (p<0.05) between positive and negative control groups. The extracts, notably ethanol extract, have, in fact, a vestigial antimalarial activity, although well below from the ones perceived to chloroquine-treated groups; nevertheless, the survival times of the animals fed with the extracts do not rise by presence of such therapy. Both the toxicopharmacological studies of the synergism between the clinical course of malaria and administration of extracts and the isolated evaluation of toxicity allow us to affirm the absence of toxicity of the extracts at the level of CNS and ANS, as well as their non-influence on food and water consumption patterns, until dosages of 500 mg/Kg. Necroscopic analysis leads us to deduct a possible hepatotoxic effect of hydroalcoholic extract at dosages of 500 mg/Kg, and an innocuous tissue activity of the ethanol extract, in the same dosage. We propose a continuation of the studies of these extracts, with protocol modifications capable of addressing more clearly and objectively their pharmacological and toxicological aspects

Hypertrophy and neuron loss: structural changes in sheep SCG induced by unilateral sympathectomy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Outcome of superficial squamous cell carcinoma of the esophagus: a clinicopathological study

PURPOSE: To analyze the clinicopathological features and outcome of patients with pathologically proven superficial squamous cell carcinoma of the esophagus. METHODS: A total of 234 consecutive cases of esophageal carcinoma in a 15-year period were reviewed. RESULTS: Superficial esophageal cancer was found in five patients (2.1%). They were four men and one woman and the mean age was 52.5 years. Smoking and alcohol were the main risk factors. Achalasia due to Chagas disease occurred in one patient and a second primary tumor developed in the larynx in another patient. Four patients underwent esophagectomy and one patient received chemoradiotherapy. The histopathologic diagnosis was of squamous cell carcinoma in all cases. Intramucosal tumor (Tis) was identified in three cases and superficially invasive carcinoma in two cases. Four patients are free of disease with survival times of two, four, six and nine years. The patient who developed laryngeal cancer died six years after esophagectomy. CONCLUSION: Long-term survival in patients with esophageal cancer is related to early diagnosis. Therefore, a less aggressive surgical approach, such as endoscopic resection, may be a good option for these patients, if depth of tumor invasion can be accurately predicted by the new imaging tools.