A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is an important regulator of the chronic inflammation contributing to tumour progression. Infliximab, an anti-TNF-alpha monoclonal antibody was investigated in this trial of patients with advanced cancer. The primary objectives were to determine the safety profile and biological response of infliximab in a cancer population. Clinical response was a secondary objective. PATIENTS AND METHODS: Forty-one patients received infliximab at 5 mg/kg (n = 21) or 10 mg/kg (n = 20) i.v. at 0 and 2 weeks and then every 4 weeks. Post-treatment samples were measured for changes in plasma and serum TNF-alpha, CCL2, IL-6 and C-reactive protein (CRP). RESULTS: Infliximab was well tolerated with no dose-limiting toxic effects. At both doses of infliximab, neutralisation of serum TNF-alpha was observed after 1 h while plasma CCL2, IL-6 and serum CRP were decreased 24 and 48 h following infliximab administration. Seven patients experienced disease stablisation (range 10-50+ weeks). There was no evidence of disease acceleration in any patient. CONCLUSIONS: Infliximab treatment was safe and well tolerated in patients with advanced cancer. There was evidence of biological activity with baseline TNF-alpha and CCL2 being correlated with infliximab response.     

Olfactory and trigeminal thresholds and nasal resistance to airflow

Nasal congestion associated with the common cold or allergy is associated with a decreased sensitivity of the sense of smell. This study was designed to detect any relationship between nasal resistance to airflow and the ability to detect odors presented to the nose. In particular we were interested to determine if the asymmetrical nasal resistance to airflow associated with the nasal cycle influenced nasal thresholds to menthol which is detected by trigeminal nerves and vanillin which is detected by olfactory nerves. Nasal resistance to airflow and the thresholds for L-menthol and vanillin were measured for each nasal passage in 17 normal volunteer subjects. Nasal resistance to airflow was asymmetrical due to the nasal cycle with a resistance on the high side of 0.94 +/- 0.15 Pa/cm3 s (mean +/- S.E. n = 17). and 0.48 +/- 0.04 Pa/cm3 s on the low side. The range of unilateral nasal resistances varied from 0.31-2.55 Pa/cm3 s. Despite these variations in nasal resistance to airflow no relationship was found between nasal resistance to airflow and thresholds for menthol or vanillin. Since threshold and nasal resistance are not related in normal subjects this may indicate that it is not the level of nasal congestion that affects the sense of smell in nasal infection and allergy, but some other factor related to the inflammatory response of the nasal mucosa.     

Randomized controlled trial of dexamethasone treatment in very-low-birth-weight infants with ventilator-dependent chronic lung disease

This randomized controlled trial was designed to answer the question: does administration of dexamethasone to neonates with bronchopulmonary dysplasia decrease the need for assisted ventilation? Twenty-five infants with a birth weight < 1501 g, requiring mechanical ventilation and FiO₂ of ± 0.30 at 21-35 days of age, were randomized to treatment with iv dexamethasone or to sham injections for 12 days. The primary outcome criterion was extubation within seven days after study entry. Treatment (n= 12) and control (n= 13) groups were well matched at entry. Dexamethasone facilitated weaning from assisted ventilation (p= 0.0154). There was no increased incidence of infection. Dexamethasone treatment resulted in a significant increase in glucosuria (p= 0.0002) and in systolic blood pressure (p= 0.0034). There was a significant decrease in heart rate (p= 0.0001) and a significant weight loss (p= 0.0002) following dexamethasone treatment. Dexamethasone treatment facilitated weaning from assisted ventilation but several systemic effects were noted that deserve further evaluation before dexamethasone becomes routine treatment.     

Effects of positive and negative pressure ventilation on cerebral blood volume of newborn infants

The effects of intermittent positive airway and continuous negative extrathoracic pressure ventilation on cerebral blood volume in preterm infants were studied using near infrared spectroscopy. In 12 infants continuous negative extrathoracic pressure caused a median decrease in cerebral blood volume of 0.14ml/100ml brain (95% confidence intervals (CI) 0.035–0.280) compared with no respiratory support. Oxygenated and deoxygenated haemoglobin also decreased, implying increased venous drainage as the main effect. In 17 infants intermittent positive pressure ventilation also caused a median reduction in cerebral blood volume of 0.06 ml/100 ml brain (95% CI 0.010–0.115) compared with endotracheal positive airway pressure. Deoxygenated haemoglobin increased by 0.07 ml/100 ml brain (95% CI 0.010–0.100) while oxygenated haemoglobin decreased by O.lOml/lOOml brain (95% CI 0.005–0.175). The increase in deoxygenated haemoglobin implies decreased venous drainage and the decrease in oxygenated haemoglobin implies that other factors may also be significant. Heart rate, blood pressure and oxygen saturation were monitored continuously and remained stable.     

A synthetic matrix metalloproteinase inhibitor prevents squamous carcinoma cell proliferation by interfering with epidermal growth factor receptor autocrine loops

Head and neck squamous cell carcinoma (HNSCC) is characterized by its capacity to invade adjacent tissues and to metastasize locoregionally. Evidence suggests that matrix metalloproteinases (MMPs) may play a causal role in HNSCC progression. While evaluating the role of MMPs in the invasion process, we made the surprising observation that a broad-spectrum MMP inhibitor, (marimastat, BB2516), inhibited the growth in vitro of some HNSCC cell lines. This inhibitory effect was only found in HNSCC cell lines overexpressing epidermal growth factor receptors. The effects of the MMP inhibitor could be reversed by adding exogenous c-erbB ligands, suggesting that the phenomenon may be related to autocrine ligand processing. This hypothesis was supported by the finding that the growth-inhibitory effect of marimastat was directly related to its ability to prevent the release of major c-erbB ligands including transforming growth factor-alpha, betacellulin and heregulin beta1 from HNSCC. Marimastat was also found to potentiate the cytotoxic effects of cisplatin both in vitro and in vivo. Our results indicate that the cleavage of several c-erbB ligands from membrane-anchored precursors requires MMP activity. We conclude that MMP inhibitors could prevent tumor progression not only by inhibiting invasion and angiogenesis, as previously shown, but also by their ability to inhibit autocrine signaling through the c-erbB receptors. Clinical trials to test this hypothesis in HNSCC should be considered.     

血清SOD、MDA、NO与突发性聋的相关研究

目的：通过对突发性聋病人血中一氧化氮（NO）、丙二醛（MDA）、超氧化物歧化酶（SOD）含量的检洲，探讨突聋与血氧自由基和自由基的清除剂SOD之间的关系。方法：采用硝酸还原酶法测定了30例突聋病人血中NO含量，并以25例同期体检正常的健康人为对照组；同时还用硫代巴比妥酸比色法测定MDA含量，用黄嘌呤氧化酶法测定SOD含量。砖呆；应用金纳多、能量合剂、克林臭（即马来酸桂哌齐特，钙通道阻滞药）联合静脉输入，突聋各组的听力均有不同程度提高，有效率在78．57％以上。治疗后同对照组相比，血清NO、MDA水平明显低于患病之初，而SOD活性明显高于治疗之前，P〈0．01。结论；检测突聋病人血中N0、MDA、SOD的含量，能帮助我们探讨突聋的发病机理，估计预后。血氧自由基的升高可能是突聋发病因素之一，而SOD的含量可以帮助我们估计预后。     

Accurate prediction of BRCA1 and BRCA2 heterozygous genotype using expression profiling after induced DNA damage.

PURPOSE: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells. EXPERIMENTAL DESIGN: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used. RESULTS: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes. CONCLUSIONS: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.     

Primary osteosarcoma of the skull

Primary osteogenic sarcoma of the skull is an exceedingly rare condition. An adult male patient is described, who had a painless swelling in the right forehead that had rapidly enlarged in the previous 6 months. Radiological investigations showed a large destructive mass lesion involving the right side of the frontal bone with extension into the frontal sinus, causing marked extradural compression of brain parenchyma. Histopathological examination confirmed the lesion to be primary osteogenic sarcoma.