Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m−2) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5½ weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m−2) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35–79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control

Au-Ag template stripped pattern for scanning probe investigations of DNA arrays produced by Dip Pen Nanolithography

We report on DNA arrays produced by Dip Pen Nanolithography (DPN) on a novel Au-Ag micro patterned template stripped surface. DNA arrays have been investigated by atomic force microscopy (AFM) and scanning tunnelling microscopy (STM) showing that the patterned template stripped substrate enables easy retrieval of the DPN-functionalized zone with a standard optical microscope permitting a multi-instrument and multi-technique local detection and analysis. Moreover the smooth surface of the Au squares (abput 5-10 angstrom roughness) allows to be sensitive to the hybridization of the oligonucleotide array with label-free target DNA. Our Au-Ag substrates, combining the retrieving capabilities of the patterned surface with the smoothness of the template stripped technique, are candidates for the investigation of DPN nanostructures and for the development of label free detection methods for DNA nanoarrays based on the use of scanning probes.Comment: Langmuir (accepted

Cross-scale analysis of social-ecological systems:Policy options appraisal for delivering NetZero and other environmental objectives in Scotland

Public policy confronts complex, contested, wicked problems such as climate and biodiversity crises with challenges of how issues are framed, analysed, codified, and interpreted. Social-ecological systems provide an analytical framework that couples the biosphere and technosphere, recognising biophysical limits and emphasising the importance of critical reflection within policy decision-making. Conducting policy-options appraisals is increasingly seen as a transdisciplinary research-policy endeavour with researchers engaging policy actors in an extended peer community (post-normal science). This paper presents a case study of analysis undertaken with researchers, policy analysts, policy makers and other stakeholders to support decisions on how to implement future agriculture support in Scotland, so that the policy programme better delivers across social, economic and environmental objectives. The key change being considered in the future agricultural support programme is Enhanced Conditionality (EC) where the level of financial support provided to farm-businesses will depend on their undertaking agri-environmental measures that deliver against the key priorities of reducing greenhouse gas emissions and reversing biodiversity losses. The paper outlines the policy context within which the EC options appraisal takes place – highlighting how EC is a crucial component in making the wider suite of policy measures work. The transdisciplinary approach, Quantitative Story Telling (QST) is presented, emerging from decision support, participatory research, and post-normal science for policy domains. The stages of QST highlight the importance of analysis that underpins any quantification (decision on how issues are framed and what it included in the analysis) and the expectation that research outputs with be deliberated on with, and interpreted from, stakeholder perspectives. The project specific analyses are outlined, combining top-down options appraisal of how macro-policy decisions could constrain EC and bottom-up analysis of potential uptake and effectiveness of EC measures, undertaken in inter-disciplinary workshops with domain experts from biodiversity, soils and waters. The paper highlights challenges for implementation and evaluation at meso-scale with interactions between farm-businesses and catchment, landscape and regional objectives. The conclusions of the analysis, in policy terms, are that EC presents an opportunity to significantly realign how agricultural land management is conducted in Scotland, so that it is more effective in delivering climate change and biodiversity objectives, but there are formidable challenges in resolving the policy “sudoku”. Meso-scale issues are likely to mean the need to integrate alternative modelling paradigms such as spatial, empirical agent-based modelling (ABM) into policy option appraisals. By taking multi-scale, social-ecological systems perspectives on EC it has been possible to identify key policy decisions at a range of scales on which the success of EC will depend, to have a realistic understanding of how effective the EC measures might be in heterogenous Scottish environments and what are the likely barriers to uptake. The analysis also highlighted where outcomes of the policy change are likely to be challenging to monitor-evaluate; and where there are dependencies between farm-businesses that mean EC measures need to be supplemented with mechanisms that (1) promote cooperation between land managers and (2) identify and respond to agreed local priorities. The value of the participatory QST process was in making sure the analyses being undertaken were salient and the outputs seen as credible – but the challenges of interpreting necessarily complex outputs remain. The greatest value of QST may be that it provides a structured way to navigate complexity with policy makers rather than seeking to control or eliminate it.</p

Cross-scale analysis of social-ecological systems:Policy options appraisal for delivering NetZero and other environmental objectives in Scotland

Public policy confronts complex, contested, wicked problems such as climate and biodiversity crises with challenges of how issues are framed, analysed, codified, and interpreted. Social-ecological systems provide an analytical framework that couples the biosphere and technosphere, recognising biophysical limits and emphasising the importance of critical reflection within policy decision-making. Conducting policy-options appraisals is increasingly seen as a transdisciplinary research-policy endeavour with researchers engaging policy actors in an extended peer community (post-normal science). This paper presents a case study of analysis undertaken with researchers, policy analysts, policy makers and other stakeholders to support decisions on how to implement future agriculture support in Scotland, so that the policy programme better delivers across social, economic and environmental objectives. The key change being considered in the future agricultural support programme is Enhanced Conditionality (EC) where the level of financial support provided to farm-businesses will depend on their undertaking agri-environmental measures that deliver against the key priorities of reducing greenhouse gas emissions and reversing biodiversity losses. The paper outlines the policy context within which the EC options appraisal takes place – highlighting how EC is a crucial component in making the wider suite of policy measures work. The transdisciplinary approach, Quantitative Story Telling (QST) is presented, emerging from decision support, participatory research, and post-normal science for policy domains. The stages of QST highlight the importance of analysis that underpins any quantification (decision on how issues are framed and what it included in the analysis) and the expectation that research outputs with be deliberated on with, and interpreted from, stakeholder perspectives. The project specific analyses are outlined, combining top-down options appraisal of how macro-policy decisions could constrain EC and bottom-up analysis of potential uptake and effectiveness of EC measures, undertaken in inter-disciplinary workshops with domain experts from biodiversity, soils and waters. The paper highlights challenges for implementation and evaluation at meso-scale with interactions between farm-businesses and catchment, landscape and regional objectives. The conclusions of the analysis, in policy terms, are that EC presents an opportunity to significantly realign how agricultural land management is conducted in Scotland, so that it is more effective in delivering climate change and biodiversity objectives, but there are formidable challenges in resolving the policy “sudoku”. Meso-scale issues are likely to mean the need to integrate alternative modelling paradigms such as spatial, empirical agent-based modelling (ABM) into policy option appraisals. By taking multi-scale, social-ecological systems perspectives on EC it has been possible to identify key policy decisions at a range of scales on which the success of EC will depend, to have a realistic understanding of how effective the EC measures might be in heterogenous Scottish environments and what are the likely barriers to uptake. The analysis also highlighted where outcomes of the policy change are likely to be challenging to monitor-evaluate; and where there are dependencies between farm-businesses that mean EC measures need to be supplemented with mechanisms that (1) promote cooperation between land managers and (2) identify and respond to agreed local priorities. The value of the participatory QST process was in making sure the analyses being undertaken were salient and the outputs seen as credible – but the challenges of interpreting necessarily complex outputs remain. The greatest value of QST may be that it provides a structured way to navigate complexity with policy makers rather than seeking to control or eliminate it.</p

A phase I/II study of oxaliplatin when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group (CCOG) study

The purpose of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of oxaliplatin given synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation for primary unresectable, locally advanced, rectal cancer. Preoperative pelvic radiotherapy using a three- or four-field technique and megavoltage photons comprised 45 Gy given in 25 fractions, 1.8 Gy per fraction, and delivered with escalating doses of oxaliplatin in combination with low-dose LV and 5FU. Chemotherapy was given synchronously with radiotherapy in weeks 1 and 5. Escalating doses of oxaliplatin (85, 130 and 150 mg m−2) were given on days 2 and 30, followed by low-dose LV (20 mg m−2) and 5FU (350 mg m−2), both given on days 1–5 and 29–33. Surgery was performed 6–10 weeks later. The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT). Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In all, 32 patients received oxaliplatin at the three dose levels, median age 60 years (range 31–79), 24 males and eight females. The MTD was reached at 150 mg m−2 when four out of six patients experienced DLT. Dose-limiting grade 3 or 4 diarrhoea was reported in two out of six patients at 85 mg m−2, 5 out of 20 at 130 mg m−2 and four out of 6 at 150 mg m−2. Grade 3 neuropathy was reported at 130 mg m−2 (1 out of 20) and at 150 mg m−2 (two out of six), and serious haematological toxicity was minimal; one grade 3 anaemia at 150 mg m−2. In all, 28 out of 32 patients completed all treatments as planned; three had radiotherapy interrupted and three a chemotherapy dose reduction. Four patients did not proceed to surgery due to the presence of metastatic disease (two), unfitness (one) or patient refusal (one). Also, 28 patients underwent surgical resection. Histopathology demonstrated histopathological complete response (pCR) 2 out of 27 (7%), Tmic 3 out of 27 (11%), pCR+Tmic 5 out of 27 (19%), pT0–2 6 out of 27 (22%) and histologically confirmed clear circumferential resection margins in 22 out of 27 (81%). Dose-limiting toxicity with oxaliplatin is 150 mg m−2 given days 2 and 30 when added to the described 5FU LV and 45 Gy radiation preoperatively. The acceptable toxicity and compliance at 130 mg m−2 recommend testing this dose in future phase II studies. The tumour downstaging and complete resection rates are encouragingly high for this very locally advanced group

Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study

The safety and efficacy of gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with resected pancreatic cancer was determined. Patients with resected adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice-weekly (40 mg m−2) for 5 weeks concurrent with upper abdominal radiation (50.4 Gy in 5½ weeks). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg m−2) weekly for two cycles. Each cycle consisted of 3 weeks of treatment followed by 1 week without treatment. Forty-seven patients were entered, 46 of whom are included in this analysis. Characteristics: median age 61 years (range 35–79); 24 females (58%); 73% stage T3/T4; and 70% lymph node positive. Grade III/IV gastrointestinal or haematologic toxicities were infrequent. The median survival was 18.3 months, while the median time to disease recurrence was 10.3 months. Twenty-four percent of patients were alive at 3 years. Only six of 34 patients with progression experienced local regional relapse as a component of the first site of failure. These results confirm the feasibility of delivering adjuvant concurrent gemcitabine and radiation to the upper abdomen. This strategy produced good local regional tumour control

Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study

Background Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. Methodology/Principal findings We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children’s homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08–0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02–0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0–1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5–37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2–12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Conclusions and significance Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents

In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients

The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-1 (hENT1), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENT1 had better response. Moreover, human nucleoside concentrative transporter-1 was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization

Gemcitabine with a specific conformal 3D 5FU radiochemotherapy technique is safe and effective in the definitive management of locally advanced pancreatic cancer

The aim of this phase II study was to assess the feasibility and efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-fluorouracil (CI 5FU) sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. Patients with inoperable cancer in the pancreatic head or body without metastases were given gemcitabine at 1000 mg m−2 weekly for 3 weeks followed by a 1-week rest and a 6-week period of radiotherapy and concurrent CI 5FU (200 mg m−2 day−1). The defined target volume was treated to 54 Gy in 30 daily fractions of 1.8 Gy. After 4 weeks' rest, gemcitabine treatment was re-initiated for three cycles (days 1, 8, 15, q28). Forty-one patients were enrolled. At the end of radiotherapy, one patient (2.4%) had a complete response and four patients (9.6%) had a partial response; at the end of treatment, three patients (7.3%) had a complete response and two patients (4.9%) had a partial response. Median survival time was 11.7 months, median time to progression was 7.1 months, and median time to failure of local control was 11.9 months. The 1- and 2-year survival rates were 46.3 and 9.8%, respectively. Treatment-related grade 3 and 4 toxicities were reported by 16 (39.0%) and four (9.8%) patients, respectively. Sixteen out of 41 patients did not complete the planned treatment and nine due to disease progression. This approach to treatment of locally advanced pancreatic cancer is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomised trial

Governance Conditions for Improving Quality Drinking Water Resources: the Need for Enhancing Connectivity

Realising the water quality objectives of the European Water Framework Directive have appeared to stagnate over the last decade all across Europe because of their highly complex nature. In the literature, interactive governance approaches tend to be regarded as the best way of dealing with complex water issues, but so far little empirical evidence has been reported on this perspective in regard to water quality issues. In this paper we have analysed how conditions of governance contribute to the realisation of water quality objectives at different types of drinking water resources in the Netherlands. The analysis demonstrates the importance of addressing different hydrological scales, institutional levels and sectors and thus enhance connectivity in order to improve water quality. The two other important conditions of governance approaches for water quality improvement which were identified are the use of joint fact-finding to gain a shared perception of risks, and the use of explicit decision-making and close monitoring of outcomes (re. water quality improvement), both of which contribute to this enhanced connectivity