Role of TNFα in pulmonary pathophysiology

Tumor necrosis factor alpha (TNFα) is the most widely studied pleiotropic cytokine of the TNF superfamily. In pathophysiological conditions, generation of TNFα at high levels leads to the development of inflammatory responses that are hallmarks of many diseases. Of the various pulmonary diseases, TNFα is implicated in asthma, chronic bronchitis (CB), chronic obstructive pulmonary disease (COPD), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In addition to its underlying role in the inflammatory events, there is increasing evidence for involvement of TNFα in the cytotoxicity. Thus, pharmacological agents that can either suppress the production of TNFα or block its biological actions may have potential therapeutic value against a wide variety of diseases. Despite some immunological side effects, anti-TNFα therapeutic strategies represent an important breakthrough in the treatment of inflammatory diseases and may have a role in pulmonary diseases characterized by inflammation and cell death

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Abstract P1-12-06: Outcome of Frail Elderly Patients Treated with Letrozole Alone

Abstract Background There are no data on the rate of progression of infirm or elderly postmenopausal patients unfit for surgery who have been treated with aromatase inhibiors alone. The aim was to determine the rate of disease control in a series of patients treated in the Edinburgh Breast Unit. Patients 79 patients with a median age of 81 years (range 57 to 98) with ER rich breast cancers (Allred score 6-8) have been treated with letrozole alone. The median follow up is 2.06 years, range 0.34 to 7.64. Of 71 patients with HER2 results, 59 (83%) were negative and 12 (17%) were positive. Results At two years, 65% were progression-free. By five years, this was 43%. The median time to first progression was 3.1 years (95% CI 1.7 to 4.5). By the Log Rank test, there was evidence of a significant difference between HER2+ve and-ve cancers (p=0.014). Median time to first progression for HER2-ve patients was 3.1 years (95% CI 1.9 to 4.2) and for HER2+ve patients was 1.8 years (95% CI 0.7 to 2.8). By two years, 67% of HER2-ve patients were progression-free, while 34% of the HER2+ve patients remained progression-free. At five years, 32% of the HER2-ve patients were progression free, however HER2+ve patients had insufficient follow up to estimate the 5 year progression-free rate. At two years, 77% of patients were still alive. By five years, that number was 33%. The median survival time was only 3.2 years (95% CI 2.4 to 4.1). There was no evidence to suggest a difference in mortality rates between HER2+ve and HER2-ve patients (p=0.79). Median survival time for HER2- ve patients was 2.6 years (95% CI 1.6 to 3.7) and for HER2+ve patients it was 3.0 years (95% CI 2.5 to 3.5). Conclusions In an elderly unfit population with ER rich breast cancer two thirds of these women will have their cancer controlled at 2 years by letrozole alone. HER2+ve cancers have a significantly shorter progression free survival than HER2-ve cancers. For older or infirm women unfit for surgegy with ER rich breast cancers, letrozole will control their cancer in the majority to the time of their death which was from other causes in all patients in this series. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-06.</jats:p

Abstract P1-12-05: Factors Affecting Local Recurrence after Breast Conserving Surgery Following Neoadjuvant Endocrine Therapy with Letrozole

Abstract Background Few data exist on local recurrence rates after breast conserving surgery in post menopausal patients following neoadjuvant endocrine therapy with letrozole. The aim was to investigate the outcome of a large series of patients treated in the Edinburgh Breast Unit. Patients 208 patients underwent breast conserving surgery after at least a 3 month course of neoadjuvant letrozole. The median age was 77 years (range 51 to 93). Of these patients 73% (151/208) received postoperative radiotherapy. Median follow up was 2.95 years (range 0.28 to 8.43) Results At two years 97% were local recurrence free and by five years 95% were recurrence free. By the Log Rank (Mantel-Cox) non-parametric method of analysis, there was a significant difference between patients treated by postoperative whole breast radiotherapy (RT) compared with no radiotherapy (p=0.02). There were very small numbers of local recurrences (five in no RT group, two in RT group by the end of five years). At two years 93% of patients with no RT were recurrence-free, compared with 98% of those with RT, at five years this is 86% and 98% respectively There was a borderline significant difference between HER2 positive and negative breast cancers, (p=0.055). At two years 97% of HER2 negative patients were recurrence-free, compared with 91% of HER2 positive patients. At five years, it was 96% and 85% respectively. Death from other causes was very common in this elderly age group and the median survival time was 7.2 years (95% CI 5.8 to 8.5). 90% of patients survived to the end of two years (95% CI: 86% to 94%), while only 68% survived to the end of years (60% to 76%). By the Log Rank test, there was a significant difference between patients treated by radiotherapy and those who did not receive radiotherapy (p=0.004). The median survival with no RT was 4.7 years (95% CI: 3.7 to 5.8) and for patients following RT was 8.1 years (95% CI: 6.2 to 10.0). The reason for this was selection of fitter patients for radiotherapy and avoiding radiotherapy in frail patients. Conclusions Local recurrence after breast conserving therapy following neoadjuvant endocrine therapy with letrozole is uncommon in this group of patients. Following radiotherapy local recurrence is only 2% at 5 years. Rates of recurrence are over 10% at 5 years without radiotherapy. HER2 positive patients have a higher local recurrence rate than HER2 negative patients. Breast Conserving Surgery followed by whole breast radiotherapy produces excellent rates of local control in postmenopausal women following neoadjuvant endocrine therapy with letrozole. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-12-05.</jats:p

Effect of mild hyperglycemia +/- meta-iodo-benzylguanidine on the radiation response of R3230 Ac tumors.

The effects of glucose or meta-iodo-benzylguanidine (MIBG) on oxygen utilization (QO2) of several tumor cell lines were studied using a Clark-type electrode chamber. For in vivo studies, rats bearing R3230 Ac rat mammary adenocarcinomas were utilized. To evaluate changes in tumor oxygenation induced by glucose or MIBG, intratumoral pO2 and skeletal muscle pO2 were measured using Eppendorf Histography. To find the effect of mild hyperglycemia (i.p., 1 g/kg) +/- MIBG (i.p., 20 mg/kg) on the radiation response, a growth delay assay was used. Glucose alone produced a approximately 20% inhibition of QO2 in several tumor cells we tested except Q7 tumor cells. MIBG inhibited QO2 in R3230 Ac tumors. The median tumor pO2 for glucose + MIBG was increased from 5.3 mm Hg to 13.8 mm Hg. We hypothesized that combined treatment with glucose + MIBG significantly enhanced radiation-induced tumoricidal effects on R3230 Ac tumors, mainly due to reduction in QO2 and increase in tumor pO2