Should We Reject Donated Organs on Moral Grounds or Permit Allocation Using Non-Medical Criteria?:A Qualitative Study

Conditional and directed deceased organ donations occur when donors (or often their next of kin) attempt to influence the allocation of their donated organs. This can include asking that the organs are given to or withheld from certain types of people, or that they are given to specified individuals. Donations of these types have raised ethical concerns, and have been prohibited in many countries, including the UK. In this article we report the findings from a qualitative study involving interviews with potential donors (n = 20), potential recipients (n = 9) and transplant staff (n = 11), and use these results as a springboard for further ethical commentary. We argue that although participants favoured unconditional donation, this preference was grounded in a false distinction between ‘medical’ and ‘non-medical’ allocation criteria. Although there are good reasons to maintain organ allocation based primarily upon the existing ‘medical’ criteria, it may be premature to reject all other potential criteria as being unacceptable. Part of participants' justification for allocating organs using ‘medical’ criteria was to make the best use of available organs and avoid wasting their potential benefit, but this can also justify accepting conditional donations in some circumstances. We draw a distinction between two types of waste – absolute and relative – and argue that accepting conditional donations may offer a balance between these forms of waste

A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer

Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor. Recent advances in conventional chemotherapy and the development of novel ‘molecular’ treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies. This randomised study in pancreatic cancer compares marimastat (orally administered matrix metalloproteinase inhibitor) in combination with gemcitabine to gemcitabine alone. Two hundred and thirty-nine patients with unresectable pancreatic cancer were randomised to receive gemcitabine (1000 mg m−2) in combination with either marimastat or placebo. The primary end-point was survival. Objective tumour response and duration of response, time to treatment failure and disease progression, quality of life and safety were also assessed. There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo (P=0.95 log-rank test). Median survival times were 165.5 and 164 days and 1-year survival was 18% and 17% respectively. There were no significant differences in overall response rates (11 and 16% respectively), progression-free survival (P=0.68 log-rank test) or time to treatment failure (P=0.70 log-rank test) between the treatment arms. The gemcitabine and marimastat combination was well tolerated with only 2.5% of patients withdrawn due to presumed marimastat toxicity. Grade 3 or 4 musculoskeletal toxicities were reported in only 4% of the marimastat treated patients, although 59% of marimastat treated patients reported some musculoskeletal events. The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer. The combination of marimastat with gemcitabine was well tolerated. Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified

Acute liver failure due to primary angiosarcoma: A case report and review of literature

<p>Abstract</p> <p>Background</p> <p>Hepatic angiosarcoma is a primary sarcoma of the liver, accounting for only 2% of all primary hepatic malignancies. Acute liver failure is an extremely rare presentation of a primary liver tumour.</p> <p>Case presentation</p> <p>We report a case of a seventy year-old man who presented with a very short period of jaundice leading to fulminant hepatic failure (FHF). On further investigation he was found to have primary angiosarcoma of liver.</p> <p>Conclusion</p> <p>The treatment outcomes for hepatic angiosarcoma are poor, we discuss the options available and the need for prompt investigation and establishment of a diagnosis</p

Expression of collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of the metalloproteinases (TIMP1) in pancreatic and ampullary disease.

It is now recognised that epithelial-stromal interactions are important in a wide range of disease processes including neoplasia and inflammation. Metalloproteinases are central to matrix degradation and remodelling, which are key events in tumour invasion and metastasis and may also be involved in tissue changes occurring in chronic inflammation. Immunohistochemistry was performed on sections from 50 patients with pancreatic cancer (n = 27), ampullary cancer (n = 12), low bile duct cancer (n = 3), neuroendocrine tumours (n = 3) and chronic pancreatitis (n = 5), using antibodies raised against collagenase (MMP2), stromelysin (MMP3) and tissue inhibitor of metalloproteinase (TIMP1) and developed using the avidin-biotin complex method. Abundance of MMP2, MMP3 and TIMP1 was greater in pancreatic and ampullary cancer than any other pathology and immunoreactivity in the malignant epithelial cells in pancreatic and ampullary cancer was greater than in the stromal tissues (in pancreatic cancer: MMP2 100% vs 37%, MMP3 93% vs 15%, TIMP1 93% vs 4%, P < 0.0001). There were strong correlations between the immunoreactivity of the two antibodies for MMP2 (P < 0.0001), between MMP2 and TIMP1 (P < 0.0001) and between MMP3 and TIMP1 (P < 0.0001). The immunoreactivity for TIMP1 in pancreatic and ampullary cancers with lymph node metastases was significantly less compared with those cases without lymph node metastases (P < 0.02) and there was an association between increased immunoreactivity for MMP2 and the degree of tumour differentiation (P < 0.01). The results implicate MMP2, MMP3 and TIMP1 in the invasive phenotype of pancreatic and ampullary cancer

A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB-3644 in patients with solid tumours.

BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal DLT by day 84, defining the MTD as 5 mg bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended

Application of Portsmouth modification of physiological and operative severity scoring system for enumeration of morbidity and mortality (P-POSSUM) in pancreatic surgery

<p>Abstract</p> <p>Background</p> <p>Pancreatoduodenectomy (PD) is associated with high incidence of morbidity and mortality. We have applied P-POSSUM in predicting the incidence of outcome after PD to identify those who are at the highest risk of developing complications.</p> <p>Method</p> <p>A prospective database of 241 consecutive patients who had PD from January 2002 to September 2005 was retrospectively updated and analysed. P-POSSUM score was calculated for each patient and correlated with observed morbidity and mortality.</p> <p>Results</p> <p>30 days mortality was 7.8% and morbidity was 44.8%. Mean physiological score was 16.07 ± 3.30. Mean operative score was 13.67 ± 3.42. Mean operative score rose to 20.28 ± 2.52 for the complex major operation (p < 0.001) with 2 fold increase in morbidity and 3.5 fold increase in mortality. For groups of patients with a physiological score of (less than or equal to) 18, the O:P (observed to Predicted) morbidity ratio was 1.3–1.4 and, with a physiological score of >18, the O:P ratio was nearer to 1. Physiological score and white cell count were significant in a multivariate model.</p> <p>Conclusion</p> <p>P-POSSUM underestimated the mortality rate. While P-POSSUM analysis gave a truer prediction of morbidity, underestimation of morbidity and potential for systematic inaccuracy in prediction of complications at lower risk levels is a significant issue for pancreatic surgery</p

A preoperative predictive score of pancreatic fistula following pancreatoduodenectomy

AbstractBackgroundVarious factors are related to the occurrence of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD). Some of the strongest are identified intra- or postoperatively, which limits their utility in predicting this complication. The preoperative prediction of POPF permits an individualized approach to patient consent and selection, and may influence postoperative management. This study sought to develop and test a score to predict POPF.MethodsA post hoc analysis of a prospectively maintained database was conducted. Consecutive patients were randomly selected to modelling and validation sets at a ratio of 2:1, respectively. Patient data, preoperative blood tests and physical characteristics of the gland (assessed from preoperative computed tomography images) were subjected to univariate and multivariate analysis in the modelling set of patients. A score predictive of POPF was designed and tested in the validation set.ResultsPostoperative pancreatic fistula occurred in 77 of 325 (23.7%) patients. The occurrence of POPF was associated with 12 factors. On multivariate analysis, body mass index and pancreatic duct width were independently associated with POPF. A risk score to predict POPF was designed (area under the receiver operating characteristic curve: 0.832, 95% confidence interval 0.768–0.897; P < 0.001) and successfully tested upon the validation set.ConclusionsPreoperative assessment of a patient's risk for POPF is possible using simple measurements. The present risk score is a valid tool with which to predict POPF in patients undergoing PD

Rheology of magmas with bimodal crystal size and shape distributions: insights from analog experiments

Magmas in volcanic conduits commonly contain microlites in association with preexisting phenocrysts, as often indicated by volcanic rock textures. In this study, we present two different experiments that inves- tigate the flow behavior of these bidisperse systems. In the first experiments, rotational rheometric methods are used to determine the rheology of monodisperse and polydisperse suspensions consisting of smaller, prolate particles (microlites) and larger, equant particles (phenocrysts) in a bubble‐free Newtonian liquid (silicate melt). Our data show that increasing the relative proportion of prolate microlites to equant pheno- crysts in a magma at constant total particle content can increase the relative viscosity by up to three orders of magnitude. Consequently, the rheological effect of particles in magmas cannot be modeled by assuming a monodisperse population of particles. We propose a new model that uses interpolated parameters based on the relative proportions of small and large particles and produces a considerably improved fit to the data than earlier models. In a second series of experiments we investigate the textures produced by shearing bimodal suspensions in gradually solidifying epoxy resin in a concentric cylinder setup. The resulting textures show the prolate particles are aligned with the flow lines and spherical particles are found in well‐organized strings, with sphere‐depleted shear bands in high‐shear regions. These observations may explain the measured variation in the shear thinning and yield stress behavior with increasing solid fraction and particle aspect ratio. The implications for magma flow are discussed, and rheological results and tex- tural observations are compared with observations on natural samples