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.     

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.     

Modifiers of risk of hereditary breast and ovarian cancer

Hereditary breast and ovarian cancer is among the most commonly encountered adult genetic disease, and it is increasingly important that geneticists, oncologists, surgeons and gynaecologists are aware of the issues regarding risk assessment, prevention and management of women with inherited susceptibility to cancer. Genetic risk can be modified by external factors, but what are these factors, and how might our knowledge of them help us to better define the risks for individual women and to develop strategies for cancer prevention?     

Breast cancer risk perception among women who have undergone prophylactic bilateral mastectomy

BACKGROUND: Prophylactic bilateral mastectomy is a preventive option for women who are at high risk of developing breast cancer. We compared the perceptions of breast cancer risk among women who had previously undergone prophylactic bilateral mastectomy with objective estimates of their breast cancer risk. METHODS: We asked 75 women in the Canadian province of Ontario who had undergone prophylactic bilateral mastectomy between 1991 and 2000 to provide a complete family history of the cancers that had occurred by the time of their surgery and to indicate their BRCA1 and BRCA2 gene mutation status. This information was used to generate estimates of each woman's risk for breast cancer by using the Gail model, the Claus model, and the BRCAPRO model. Sixty of the women also provided their own estimates of their lifetime risks of developing breast cancer before and after they had prophylactic mastectomy. Risk estimates were compared using Wilcoxon's signed-rank test and Pearson's product-moment correlation analysis. All statistical tests were two-sided. RESULTS: The women estimated that their lifetime risk of developing breast cancer before surgery was, on average, 76% (range = 20%-100%) and after surgery was 11.4% (range = 0%-60%). The mean estimated absolute risk reduction the women attributed to prophylactic mastectomy was 64.8%. The average computer-generated risk estimates were 59% for the 14 women who reported that they carried a BRCA1 or BRCA2 gene mutation and 17% for the other women (of whom 43 had a strong family history of breast cancer and 18 had a limited family history). Breast cancer risk was statistically significantly overestimated by all women except for the known BRCA1 and BRCA2 gene mutation carriers. CONCLUSION: Women who undergo prophylactic bilateral mastectomy have an exaggerated perception of their breast cancer risk before surgery. Formal genetic counseling and genetic testing may result in more accurate risk perceptions to guide women in choosing other preventive options.     

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。     

CHEK2-positive breast cancers in young Polish women.

PURPOSE: To investigate the contribution of CHEK2 mutations to early-onset breast cancer in Poland and to establish the characteristic features of these cancers. EXPERIMENTAL DESIGN: We studied 3,228 women diagnosed with breast cancer under the age of 51 years and 5,496 population controls. CHEK2 mutations were detected by RFLP-PCR or allele-specific oligonucleotide-PCR assays. Clinical and pathologic features of CHEK2-positive cases and CHEK2-negative cases were compared. RESULTS: A truncating CHEK2 mutation (1100delC or IVS2+1G>A) was seen in 47 of 3,228 cases and in 34 of 5,496 controls (odds ratio, 2.4; P = 0.0001). The CHEK2 I157T missense mutation was present in 207 of 3,228 cases, compared with 264 of 5,496 controls (odds ratio, 1.4; P = 0.002). Breast cancers in women with a CHEK2 mutation were more commonly of lobular histology (21.5% versus 15.8%; P = 0.05), of size >2 cm (54.8% versus 43.5%; P = 0.01), or of multicentric origin (28.7% versus 19.5%; P = 0.01) than were cancers from women without a CHEK2 mutation. Bilateral cancers were equally common in both subgroups. CONCLUSION: Three founder alleles in CHEK2 contribute to early-onset breast cancer in Poland. Breast tumors which arise in carriers of CHEK2 mutations seem to be similar to those of breast cancers in the population at large.     

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.     

Cancer incidence in a population of Jewish women at risk of ovarian cancer.

PURPOSE: To evaluate the incidence and clinical characteristics of ovarian and other cancers in a cohort of women at risk of developing ovarian cancer. PATIENTS AND METHODS: The Gilda Radner Ovarian Cancer Detection Program in Los Angeles, CA, was established in 1991 to study the efficacy of screening in the early detection of ovarian cancer. We present findings from a historical cohort of 290 Jewish women who were offered BRCA testing for three common founder mutations (BRCA1 185delAG and 5382insC and BRCA2 6174delT). RESULTS: In 10 years, 17 cancers were observed (1,111 per 100,000 per year), including six breast and eight ovarian or related cancers. A high proportion of cancers of peritoneal origin was observed. The majority (86%) of women with incident breast or ovarian/peritoneal cancer carried a mutation in the BRCA1 gene. The overall cancer incidence among carriers of mutations in the BRCA1 gene was estimated to be 5,450 per 100,000 per year, corresponding to a cumulative incidence of 47.5% at 10 years. In contrast, the cumulative incidence of cancer among noncarriers was 2.5% (P < 10(-8)). After adjustment for sampling, the risks to BRCA1 mutation carriers at 10 years were estimated to be 21% for ovarian/peritoneal/tubal cancer, 16% for breast cancer, and 36% for all cancers. CONCLUSION: The excess risk of breast and ovarian cancer in Jewish women with a family history of ovarian cancer is largely attributable to mutations in BRCA1. Intensive surveillance by use of CA-125 and ultrasound does not seem to be an effective means of diagnosing early-stage ovarian cancer in this high-risk cohort.