Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09.

OBJECTIVE: The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced non-small-cell lung cancer are promising for further investigation. METHODS: We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated. RESULTS: A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16 cycles. PFS at 6 months was 70%, median PFS was 14 months, and ORR was 70%. Biopsy at progression was safe and successful in 71% of the cases. CONCLUSIONS: Both combination therapies were promising for further studies. Biopsy at progression was feasible and will be part of future SAKK studies to investigate molecular mechanisms of resistance.

Gamma oscillations in V1 are correlated with GABAA receptor density: A multi-modal MEG and Flumazenil-PET study.

High-frequency oscillations in the gamma-band reflect rhythmic synchronization of spike timing in active neural networks. The modulation of gamma oscillations is a widely established mechanism in a variety of neurobiological processes, yet its neurochemical basis is not fully understood. Modeling, in-vitro and in-vivo animal studies suggest that gamma oscillation properties depend on GABAergic inhibition. In humans, search for evidence linking total GABA concentration to gamma oscillations has led to promising -but also to partly diverging- observations. Here, we provide the first evidence of a direct relationship between the density of GABAA receptors and gamma oscillatory gamma responses in human primary visual cortex (V1). By combining Flumazenil-PET (to measure resting-levels of GABAA receptor density) and MEG (to measure visually-induced gamma oscillations), we found that GABAA receptor densities correlated positively with the frequency and negatively with amplitude of visually-induced gamma oscillations in V1. Our findings demonstrate that gamma-band response profiles of primary visual cortex across healthy individuals are shaped by GABAA-receptor-mediated inhibitory neurotransmission. These results bridge the gap with in-vitro and animal studies and may have future clinical implications given that altered GABAergic function, including dysregulation of GABAA receptors, has been related to psychiatric disorders including schizophrenia and depression.

Angiotensin receptor blockers are not associated with reduced inflammatory markers in the general population.

OBJECTIVE: Angiotensin receptor blockers (ARBs) have been suggested to reduce inflammation in randomized controlled trials. We assessed the association between ARBs and inflammatory markers in a general population setting. METHODS: This is a population-based prospective study conducted in Lausanne, Switzerland. Baseline data from 933 participants on antihypertensive drugs (424 on ARBs) was collected in 2003-2006. Follow-up data from 1120 participants (572 on ARBs) was collected in 2009-2012. C-reactive protein (CRP), interleukins 1β and 6 and tumor necrosis factor alpha (TNF-α) were assessed and categorized in quartiles. RESULTS: At baseline, no differences were found between participants taking or not taking ARBs for all inflammatory markers studied, and this association persisted after multivariate adjustment: odds ratios (ORs) and (95% confidence interval) for being in the highest quartile of interleukin-1β, interleukin-6, TNF-α and CRP for participants on ARB compared to participants not on ARB were 1.23 (0.89-1.70), 1.26 (0.93-1.70), 1.14 (0.85-1.53) and 1.27 (0.96-1.69) respectively (P > 0.05). These findings were further replicated in the follow-up study: OR and (95% CI) of 1.10 (0.78-1.55), 0.87 (0.64-1.19), 0.83 (0.61-1.14) and 0.91 (0.68-1.22) for interleukin-1β, interleukin-6, TNF-α and CRP respectively (P > 0.05). Finally, no effect of ARBs was found when comparing participants who received ARBs throughout the 5.4-year follow-up with participants on other antihypertensive drugs: OR and (95% CI) of 0.93 (0.61-1.42), 0.80 (0.54-1.17), 0.86 (0.59-1.25) and 0.95 (0.67-1.35) for interleukin-1β, interleukin-6, TNF-α and CRP respectively (P > 0.05). CONCLUSION: ARBs are not associated with reduced levels of inflammatory markers in the general population.

Simultaneous determination of moxifloxacin and H2 receptor antagonist in pharmaceutical dosage formulations by RP-HPLC: application to in vitro drug interactions

Simultaneous determination of moxifloxacin (MOX) and H2-antagonists was first time developed in bulk and formulations. Purospher STAR C18 (250 x 4.6 mm, 5 μm) column was used. The mobile phase (methanol: water: ACN, 60:45:5 v/v/v, pH 2.7) was delivered at a flow rate of 1.0 mL min-1, eluent was monitored at 236, 270 and 310 nm for cimetidine, famotidine and ranitidine, respectively. The proposed method is specific, accurate (98-103%), precise (intra-day and inter-day variation 0.098-1.970%) and linear (r>0.998). The LOD and LOQ were 0.006-0.018 and 0.019-0.005 μg mL-1, respectively. The statistical parameters were applied to verify the results. The method is applicable to routine analysis of formulations and interaction of MOX with H2-antagonist.

Indicadores de Prognóstico em Câncer de Mama com Axila Negativa: Receptor de Estrógeno e Expressão de P53 e de c-erbB-2

Objetivo: avaliar o valor prognóstico do receptor de estrógeno e da expressão das proteínas p53 e c-erbB-2 no câncer de mama com axila negativa. Métodos: foi realizado estudo imuno-histoquímico em material incluido em parafina, do arquivo do Instituto de Pesquisas Cito-Oncológicas (IPCO) da Fundação Faculdade Federal de Ciências Médicas de Porto Alegre (FFFCMPA), de 50 casos de câncer de mama sem comprometimento dos linfonodos axilares, em mulheres menopausadas, tratadas na Irmandade da Santa Casa de Porto Alegre (ISCMPA) e no Hospital Santa Rita de Porto Alegre (HSR) de janeiro 1990 a dezembro de 1994. Para análise estatística foram utilizados os testes de c² com correção de Yates, teste exato de Fisher e curvas de sobrevida pelo método de Kaplan-Meier comparados pelo teste log rank. O seguimento médio das pacientes foi de 3,6 anos (3,1-4,5). Dos 50 casos, 14 apresentaram recidiva no período observado. Resultados: a média de idade foi 61 anos (variação de 46 a 78 anos). A mastectomia radical modificada (MRM) foi realizada em 35 pacientes (70%) e 15 (30%) foram submetidas a setorectomia com esvaziamento axilar e posterior radioterapia. Metade das pacientes que apresentaram recidiva apresentaram-na nos três primeiros anos após o diagnóstico. O tamanho médio do tumor foi 2,8 cm (1,98-3,13) e o tipo histológico mais freqüente foi o carcinoma ductal infiltrante de tipo histológico não-especial (92%), conforme a graduação histológica de Bloom e Richardson, sendo 3 grau I (6,6%), 35 grau II (76%) e 8 grau III (17,4%); nos tumores que recidivaram não houve nenhum grau I, 9 (25,7%) eram grau II e 3 (37,5%) eram grau III. Em relação ao prognóstico, a taxa de intervalo livre de doença foi menor quando da associação de tumor pouco diferenciado (grau III) com receptor de estrógeno negativo (p = 0,006), p53 positivo (p = 0,006) e c-erbB-2 positivo (p = 0,001). Conclusão: mulheres menopausadas com câncer de mama sem comprometimento dos linfonodos axilares tem pior prognóstico, em relação ao intervalo livre de doença, quando apresentam associação de tumor pouco diferenciado com RE negativo, p53 positivo e c-erbB-2 positivo.

Relação entre polimorfismo do gene do receptor de progesterona, raça, paridade e ocorrência de leiomioma uterino

OBJETIVOS: analisamos raça, paridade e presença do polimorfismo do gene do receptor de progesterona, denominado PROGINS, como fatores relacionados à ocorrência de leiomioma uterino em mulheres brasileiras. MÉTODOS: realizamos estudo caso-controle, no qual foram incluídas 122 pacientes com diagnóstico de leiomioma e 125 mulheres sem a doença. Após registro dos dados clínicos, coletamos material biológico para extração de DNA, reação em cadeia da polimerase e eletroforese em gel de agarose, a fim de identificar a presença do polimorfismo PROGINS. A análise estatística foi feita pelo teste não paramétrico de Mann-Whitney ou pelo teste do chi2, a depender da variável estudada. O risco para ocorrência da doença foi calculado pelo modelo de regressão logística, com obtenção da odds ratio (OR) (razão de chances). O nível de significância adotado foi de 5% (p<0,05) e o intervalo de confiança foi de 95% (IC 95%). RESULTADOS: observamos maior prevalência de "não-brancas"- pardas e negras - (50 vs 22,4%) e de nulíparas (23,8 vs 11,2%) nos casos, ao passo que o genótipo do receptor de progesterona foi mais freqüentemente PROGINS positivo - heterozigoto ou homozigoto mutante - entre os controles (21,6 vs 10,7%). A razão de chances indicou elevação do risco para leiomioma relacionada à raça "não branca"(OR=3,46; IC 95%: 2,0-6,0) e à nuliparidade (OR=3,30; IC 95%: 1,9-5,6), com redução na presença de genótipos PROGINS positivo (OR=0,43; IC 95%: 0,2-0,9). CONCLUSÕES: a raça "não branca"e a nuliparidade foram consideradas fatores de risco para a ocorrência de leiomioma uterino em mulheres da população estudada, ao passo que o polimorfismo PROGINS demonstrou ser fator protetor.

Associação entre os polimorfismos HaeIII e MspI do gene para o receptor alfa de estrogênio e densidade mamográfica em mulheres após a menopausa

OBJETIVO: Avaliar a presença dos polimorfismos HaeIII e MspI do gene para o receptor de estrogênio alfa, bem como fatores clínicos e suas possíveis associações com a densidade mamográfica em mulheres após a menopausa. MÉTODOS: Foram avaliadas 115 mulheres após a menopausa, não usuárias de terapia hormonal e sem lesão mamária clínica ou mamograficamente identificada. A densidade mamográfica foi determinada por três observadores independentes, tomando-se como base a classificação dos padrões mamográficos do ACR-BIRADS®, 2003 (duas avaliações subjetivas e uma computadorizada - Adobe Photoshop® 7.0). Amostras de raspado bucal foram obtidas para extração de DNA e em seguida foi realizada uma PCR-RFLP (Polymerase Chain Reation - Restriction Fragment Length Polymorphism) para análise de polimorfismos presentes no íntron 1 e éxon 1 do gene do REalfa (HaeIII e MspI). RESULTADOS: O polimorfismo HaeIII foi encontrado em 43 (37,4%) das 115 mulheres, ao passo que o MspI estava presente em 96 (83,5%) das mesmas. Houve alto grau de concordância entre os três observadores na determinação da densidade mamográfica. Trinta e quatro (29,6%) mulheres tinham mamas densas, e 81 (70,4%), mamas lipossubstituídas. CONCLUSÃO: Não houve associação entre o polimorfismo HaeIII do gene para o receptor de estrogênio alfa e densidade mamográfica (Fisher = 0,712). Houve associação próxima à significância estatística entre o polimorfismo MspI e densidade (Fisher = 0,098). Idade, paridade e índice de massa corporal mostraram-se associados com densidade mamográfica.

Distribution of AMPA-type glutamate receptor subunits in the chick visual system

Several glutamate receptor (GluR) subunits have been characterized during the past few years. In the present study, subunit-specific antisera were used to determine the distribution of the AMPA-type glutamate receptor subunits GluR1-4 in retinorecipient areas of the chick brain. Six white leghorn chicks (Gallus gallus, 7-15 days old, unknown sex) were deeply anesthetized and perfused with 4% buffered paraformaldehyde and brain sections were stained using immunoperoxidase techniques. The AMPA-type glutamate receptor subunits GluR1, GluR2/3 and GluR4 were present in several retinorecipient areas, with varying degrees of colocalization. For example, perikarya in layers 2, 3, and 5 of the optic tectum contained GluR1, whereas GluR2/3 subunits appeared mainly in neurons of layer 13. The GluR4 subunit was only detected in a few cells of the tectal layer 13. GluR1 and GluR2/3 were observed in neurons of the nucleus geniculatus lateralis ventralis, whereas GluR4 was only present in its neuropil. Somata in the accessory optic nucleus appeared to contain GluR2/3 and GluR4, whereas GluR1 was the dominant subunit in the neuropil of this nucleus. These results suggest that different subpopulations of visual neurons might express different combinations of AMPA-type GluR subunits, which in turn might generate different synaptic responses to glutamate derived from retinal ganglion cell axons

Hyperalgesic effect induced by barbiturates, midazolam and ethanol: pharmacological evidence for GABA-A receptor involvement

The involvement of GABA-A receptors in the control of nociception was studied using the tail-flick test in rats. Non-hypnotic doses of the barbiturates phenobarbital (5-50 mg/kg), pentobarbital (17-33 mg/kg), and thiopental (7.5-30 mg/kg), of the benzodiazepine midazolam (10 mg/kg) or of ethanol (0.4-1.6 g/kg) administered by the systemic route reduced the latency for the tail-flick response, thus inducing a 'hyperalgesic' state in the animals. In contrast, non-convulsant doses of the GABA-A antagonist picrotoxin (0.12-1.0 mg/kg) administered systemically induced an increase in the latency for the tail-flick response, therefore characterizing an 'antinociceptive' state. Previous picrotoxin (0.12 mg/kg) treatment abolished the hyperalgesic state induced by effective doses of the barbiturates, midazolam or ethanol. Since phenobarbital, midazolam and ethanol reproduced the described hyperalgesic effect of GABA-A-specific agonists (muscimol, THIP), which is specifically antagonized by the GABA-A antagonist picrotoxin, our results suggest that GABA-A receptors are tonically involved in the modulation of nociception in the rat central nervous system

Distribution of the a2, a3, and a5 nicotinic acetylcholine receptor subunits in the chick brain

Nicotinic acetylcholine receptors (nAChRs) are ionotropic receptors comprised of a and ß subunits. These receptors are widely distributed in the central nervous system, and previous studies have revealed specific patterns of localization for some nAChR subunits in the vertebrate brain. In the present study we used immunohistochemical methods and monoclonal antibodies to localize the a2, a3, and a5 nAChR subunits in the chick mesencephalon and diencephalon. We observed a differential distribution of these three subunits in the chick brain, and showed that the somata and neuropil of many central structures contain the a5 nAChR subunit. The a2 and a3 subunits, on the other hand, exhibited a more restricted distribution than a5 and other subunits previously studied, namely a7, a8 and ß2. The patterns of distribution of the different nAChR subunits suggest that neurons in many brain structures may contain several subtypes of nAChRs and that in a few regions one particular subtype may determine the cholinergic nicotinic responses

Fractures of the proximal femur: correlation with vitamin D receptor gene polymorphism

Fractures are the feared consequences of osteoporosis and fractures of the proximal femur (FPF) are those that involve the highest morbidity and mortality. Thus far, evaluation of bone mineral density (BMD) is the best way to determine the risk of fracture. Genetic inheritance, in turn, is one of the major determinants of BMD. A correlation between different genotypes of the vitamin D receptor (VDR) and BMD has been recently reported. On this basis, we decided to determine the importance of the determination of VDR genotype in the presence of an osteoporotic FPF in a Brazilian population. We studied three groups: group I consisted of 73 elderly subjects older than 65 years (78.5 ± 7.2 years) hospitalized for nonpathological FPF; group II consisted of 50 individuals older than 65 years (72.9 ± 5.2 years) without FPF and group III consisted of 98 young normal Brazilian individuals aged 32.6 ± 6.6 years (mean ± SD). Analysis of VDR gene polymorphism by restriction fragment length polymorphism (RFLP) was performed by PCR amplification followed by BsmI digestion of DNA isolated from peripheral leukocytes. The genotype distribution in group I was 20.5% BB, 42.5% Bb and 37% bb and did not differ significantly from the values obtained for group II (16% BB, 36% Bb and 48% bb) or for group III (10.2% BB, 47.6% Bb and 41.8% bb). No differences in genotype distribution were observed between sexes or between the young and elderly groups. We conclude that determination of VDR polymorphism is of no practical use for the prediction of FPF. Other nongenetic factors probably start to affect bone mass, the risk to fall and consequently the occurrence of osteoporotic fractures with advancing age.

Increased training prevents the impairing effect of intra-amygdala infusion of the non-NMDA receptor antagonist CNQX on inhibitory avoidance expression

Intra-amygdala infusion of the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) prior to testing impairs inhibitory avoidance retention test performance. Increased training attenuates the impairing effects of amygdala lesions and intra-amygdala infusions of CNQX. The objective of the present study was to determine the effects of additional training on the impairing effects of intra-amygdala CNQX on expression of the inhibitory avoidance task. Adult female Wistar rats bilaterally implanted with cannulae into the border between the central and the basolateral nuclei of the amygdala were submitted to a single session or to three training sessions (0.2 mA, 24-h interval between sessions) in a step-down inhibitory avoidance task. A retention test session was held 48 h after the last training. Ten minutes prior to the retention test session, the animals received a 0.5-µl infusion of CNQX (0.5 µg) or its vehicle (25% dimethylsulfoxide in saline). The CNQX infusion impaired, but did not block, retention test performance in animals submitted to a single training session. Additional training prevented the impairing effect of CNQX. The results suggest that amygdaloid non-NMDA receptors may not be critical for memory expression in animals given increased training.

Effect of SX-3228, a selective ligand for the BZ1 receptor, on sleep and waking during the light-dark cycle in the rat

The effects of the benzodiazepine1 (BZ1) receptor agonist SX-3228 were studied in rats (N = 12) implanted for chronic sleep procedures. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228, sc, to rats 1 h after the beginning of the light phase of the light-dark cycle induced a significant reduction of rapid-eye-movement sleep (REMS) during the third recording hour. Moreover, slow wave sleep (SWS) was increased during the fourth recording hour after the two largest doses of the compound. Administration of 0.5, 1.0 and 2.5 mg/kg SX-3228 one hour after the beginning of the dark period of the light-dark cycle caused a significant and maintained (6-h recording period) reduction of waking (W), whereas SWS and light sleep (LS) were increased. REMS values tended to increase during the entire recording period; however, the increase was statistically significant only for the 1.0 mg/kg dose during the first recording hour. In addition, a significant and dose-related increase of power density in the delta and the theta regions was found during nonREM sleep (LS and SWS) in the dark period. Our results indicate that SX-3228 is a potent hypnotic when given to the rat during the dark period of the light-dark cycle. Moreover, the sleep induced by SX-3228 during the dark phase closely resembles the physiological sleep of the rat.