Neoadjuvant continuous infusion of weekly 5-fluorouracil and escalating doses of oxaliplatin plus concurrent radiation in locally advanced oesophageal squamous cell carcinoma: results of a phase I/II trial

Oxaliplatin and 5-fluorouracil have a significant activity in locally advanced oesophageal squamous cell cancer (OSCC). However, their optimal dosage and efficacy when combined with concurrent radiotherapy as neoadjuvant treatment are unknown. This non-randomised, phase I/II study aimed to define the maximum tolerated dose (MTD) and assessed the histopathological tumour response rate to neoadjuvant oxaliplatin in weekly escalating doses (40, 45, 50 mg m−2) and continuous infusional 5-fluorouracil (CI-5FU; 225 mg m−2) plus concurrent radiotherapy. Patients had resectable OSCC. Resection was scheduled for 4–6 weeks after chemoradiotherapy. During phase I (dose escalation; n=19), weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 was established as the MTD and was the recommended dosage for phase II. Oesophageal mucositis was the dose-limiting toxicity at higher doses. During phase II, histopathological responses (<10% residual tumour cells within the specimen) were observed in 10 of 16 patients (63%; 95% confidence interval: 39–82%). Overall, 16 of the 25 patients (64%) who underwent resection had a histopathological response; tumour-free resection (R0) was achieved in 80%. Neoadjuvant weekly oxaliplatin 45 mg m−2 plus CI-5FU 225 mg m−2 with concurrent radiotherapy provides promising histological response rates and R0 resection rates in locally advanced OSCC

IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection

Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised people. Previously we showed that mice succumb to intranasal infection by induction of pulmonary interleukin (IL)-4Rα-dependent type 2 immune responses, whereas IL-12-dependent type 1 responses confer resistance. In the experiments presented here, IL-4Rα −/− mice unexpectedly show decreased fungal control early upon infection with C. neoformans , whereas wild-type mice are able to control fungal growth accompanied by enhanced macrophage and dendritic cell recruitment to the site of infection. Lower pulmonary recruitment of macrophages and dendritic cells in IL-4Rα −/− mice is associated with reduced pulmonary expression of CCL2 and CCL20 chemokines. Moreover, IFN-γ and nitric oxide production are diminished in IL-4Rα −/− mice compared to wild-type mice. To directly study the potential mechanism(s) responsible for reduced production of IFN-γ, conventional dendritic cells were stimulated with C. neoformans in the presence of IL-4 which results in increased IL-12 production and reduced IL-10 production. Together, a beneficial role of early IL-4Rα signaling is demonstrated in pulmonary cryptococcosis, which contrasts with the well-known IL-4Rα-mediated detrimental effects in the late phase

A collaboratively-derived science-policy research agenda

The need for policy makers to understand science and for scientists to understand policy processes is widely recognised. However, the science-policy relationship is sometimes difficult and occasionally dysfunctional; it is also increasingly visible, because it must deal with contentious issues, or itself becomes a matter of public controversy, or both. We suggest that identifying key unanswered questions on the relationship between science and policy will catalyse and focus research in this field. To identify these questions, a collaborative procedure was employed with 52 participants selected to cover a wide range of experience in both science and policy, including people from government, non-governmental organisations, academia and industry. These participants consulted with colleagues and submitted 239 questions. An initial round of voting was followed by a workshop in which 40 of the most important questions were identified by further discussion and voting. The resulting list includes questions about the effectiveness of science-based decision-making structures; the nature and legitimacy of expertise; the consequences of changes such as increasing transparency; choices among different sources of evidence; the implications of new means of characterising and representing uncertainties; and ways in which policy and political processes affect what counts as authoritative evidence. We expect this exercise to identify important theoretical questions and to help improve the mutual understanding and effectiveness of those working at the interface of science and policy

Optimization of in-vacuo template-stripped Pt surfaces via UHV STM

A recently demonstrated [1] in-vacuo template-stripping process is applied to the study of platinum films stripped from ultra-flat silicon-oxide surfaces. Template-stripped (TS) Pt surfaces, prepared with a range of post-deposition annealing times prior to being stripped from the templating surface in an ultra-high vacuum (UHV) environment, are examined by UHV scanning tunneling microscopy (STM). These studies reveal that without post-deposition annealing, TS Pt surfaces are largely made up of poorly-ordered, granular nanostructures undesirable for many applications. The post-deposition annealing treatments explored in the study result in the emergence and continuous growth of large smooth crystallites. Issues with crystallite orientation relative to the TS surface and artefacts arising as a result of the epoxy used in the template-stripping process are presented and discussed in relation to optimizing the template-stripping procedure for specific applications such as self-assembled monolayer (SAM) formation for molecular electronics. © Springer-Verlag 2005

Predictors of pulmonary toxicity in limited stage small cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70Gy daily radiotherapy: CALGB 30904

Introduction: Standard therapy for limited stage small cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy followed by prophylactic cranial radiotherapy. Predictors of post chemoradiotherapy pulmonary toxicity in limited stage (LS) small cell lung cancer (SCLC) patients are not well defined. Current guidelines are derived from non-small cell lung cancer regimens, and do not account for the unique biology of this disease. Therefore, we analyzed patients on three consecutive CALGB LS-SCLC trials treated with concurrent chemotherapy and daily high dose radiotherapy (70. Gy) to determine patient and treatment related factors predicting for post-treatment pulmonary toxicity. Methods: Patients treated on CALGB protocols 39808, 30002, 30206 investigating two cycles of chemotherapy followed by concurrent chemotherapy and 70. Gy daily thoracic radiation therapy were pooled. Patient, tumor, and treatment related factors were evaluated to determine predictors of grade 3-5 pulmonary toxicities after concurrent chemoradiotherapy. Results: 100 patients were included. No patient experienced grade 4-5 post-treatment pulmonary toxicity. Patients who experienced post-treatment pulmonary toxicity were more likely to be older (median age 69 vs 60, p= 0.09) and have smaller total lung volumes (2565 cc vs 3530 cc, p= 0.05).). Furthermore, exposure of larger volumes of lung to lower (median V5. = 70%, p= 0.09, median V10. = 63%, p= 0.07), intermediate (median V20. = 50, p= 0.04) and high (median V60. = 25%, p= 0.01) doses of radiation were all associated with post-treatment grade 3 pulmonary toxicity, as was a larger mean lung radiation dose (median 31. Gy) p= 0.019. Conclusion: Post-treatment pulmonary toxicity following the completion of 2 cycles of chemotherapy followed by concurrent chemotherapy and high dose daily radiation therapy was uncommon. Care should be taken to minimize mean lung radiation exposure, as well as volumes of low, intermediate and high doses of radiation. © 2013 Elsevier Ireland Ltd.link_to_subscribed_fulltex

A pooled analysis of limited-stage small-cell lung cancer patients treated with induction chemotherapy followed by concurrent platinum-based chemotherapy and 70 Gy daily radiotherapy: CALGB 30904

INTRODUCTION: Standard therapy for limited-stage small-cell lung cancer (L-SCLC) is concurrent chemotherapy and radiotherapy (RT) followed by prophylactic cranial radiotherapy. Although many consider the standard RT regimen to be 45 Gy in 1.5 Gy twice-daily fractions, this has failed to gain widespread acceptance. We pooled data of patients assigned to receive daily RT of 70 Gy from three, consecutive prospective Cancer and Leukemia Group B L-SCLC cancer trials and report the results here. METHODS: All patients from consecutive Cancer and Leukemia Group B L-SCLC trials (39808, 30002, and 30206) using high-dosage daily RT with concurrent chemotherapy were included, and analyzed for toxicity, disease control, and survival. Overall survival (OS) and progression-free survival (PFS) were modeled using Cox proportional hazards models. Prognostic variables for OS-rate and PFS-rate were assessed using logistic regression model. RESULTS: Two hundred patients were included. The median follow-up was 78 months. Grade 3 or greater esophagitis was 23%. The median OS for pooled population was 19.9 months (95% confidence interval [CI]: 16.7-22.3), and 5-year OS rate was 20% (95% CI: 16-27%). The 2-year PFS was 26% (95% CI: 21-32%). Multivariate analysis found younger age (p = 0.02; hazard ratio [HR]: 1.023; 95% CI: 21-32), and female sex (p = 0.02; HR:0.69; 95% CI: 0.50-0.94) independently associated with improved overall survival. CONCLUSION: Two-Gy daily RT to a total dosage of 70 Gy was well tolerated with similar survival to 45 Gy (1.5 Gy twice-daily). This experience may aid practitioners decide whether high-dosage daily RT with platinum-based chemotherapy is appropriate outside of a clinical trial. © 2013 by the International Association for the Study of Lung Cancer.link_to_subscribed_fulltex

On the binding energies and configurations of vacancy and copper-vacancy clusters in bcc Fe-Cu: A computational study

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