Reducing uncertainty in health-care resource allocation

A key task for health policymakers is to optimise the outcome of health care interventions. The pricing of a new generation of cancer drugs, in combination with limited health care resources, has highlighted the need for improved methodology to estimate outcomes of different treatment options. Here we introduce new general methodology, which for the first time employs continuous hazard functions for analysis of survival data. Access to continuous hazard functions allows more precise estimations of survival outcomes for different treatment options. We illustrate the methodology by calculating outcomes for adjuvant treatment of gastrointestinal stromal tumours with imatinib mesylate, which selectively inhibits the activity of a cancer-causing enzyme and is a hallmark representative for the new generation of cancer drugs. The calculations reveal that optimal drug pricing can generate all win situations that improve drug availability to patients, make the most of public expenditure on drugs and increase pharmaceutical company gross profits. The use of continuous hazard functions for analysis of survival data may reduce uncertainty in health care resource allocation, and the methodology can be used for drug price negotiations and to investigate health care intervention thresholds. Health policy makers, pharmaceutical industry, reimbursement authorities and insurance companies, as well as clinicians and patient organisations, should find the methodology useful

Prognostic value of the neutrophil/lymphocyte ratio in enteropancreatic neuroendocrine tumors

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1–2, Ki-674; n=25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/ depot 120mg was independent of NLRs (P>0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis

Dysregulation of Mitochondrial Dynamics and the Muscle Transcriptome in ICU Patients Suffering from Sepsis Induced Multiple Organ Failure

BACKGROUND: Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patient's protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients impairing cellular energy balance, which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments and the molecular consequences. METHODOLOGY/PRINCIPAL FINDINGS: Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2alpha/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. CONCLUSIONS/SIGNIFICANCE: This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments

The loss of P2X7 receptor expression leads to increase intestinal glucose transit and hepatic steatosis

In intestinal epithelial cells (IEC), it was reported that the activation of the P2X7 receptor leads to the internalization of the glucose transporter GLUT2, which is accompanied by a reduction of IEC capacity to transport glucose. In this study, we used P2rx7−/− mice to decipher P2X7 functions in intestinal glucose transport and to evaluate the impacts on metabolism. Immunohistochemistry analyses revealed the presence of GLUT2 at the apical domain of P2rx7−/− jejunum enterocytes. Positron emission tomography and biodistribution studies demonstrated that glucose was more efciently delivered to the circulation of knockout animals. These fndings correlated with increase blood glucose, insulin, triglycerides and cholesterol levels. In fact, P2rx7−/− mice had increased serum triglyceride and cholesterol levels and displayed glucose intolerance and resistance to insulin. Finally, P2rx7−/− mice developed a hepatic steatosis characterized by a reduction of Acaca, Acacb, Fasn and Acox1 mRNA expression, as well as for ACC and FAS protein expression. Our study suggests that P2X7 could play a central role in metabolic diseases

Lung shunt fraction calculation using 99mTc-MAA SPECT/CT imaging for 90Y microsphere selective internal radiation therapy of liver tumors

Background 99m Tc-macroaggregated albumin ( 99m Tc-MAA) scintigraphy is utilized in treatment planning for Yttrium-90 ( 90 Y) Selective Internal Radiation Therapy (SIRT) of liver tumors to evaluate hepatopulmonary shunting by calculating the lung shunt fraction (LSF). The purpose of this study was to evaluate if LSF calculation using SPECT/CT instead of planar gamma camera imaging is more accurate and if this can potentially lead to more effective treatment planning of hepatic lesions while avoiding excessive pulmonary irradiation. Results LSF calculation was obtained using two different methodologies in 85 cases from consecutive patients intended to receive 90 Y SIRT. The first method was based on planar gamma camera imaging in the anterior and posterior views with geometric mean calculation of the LSF from regions of interest of the liver and lungs. The second method was based on segmentation of the liver and lungs from SPECT/CT images of the thorax and abdomen. The differences in planar imaging versus SPECT/CT derived LSF values along with the estimated absorbed lung mean dose (LMD) were evaluated. The LSF values were higher in planar imaging versus SPECT/CT in 81/85 cases, with a mean value of 8.5% vs. 4.6% respectively; the difference was statistically significant using a paired t-test (alpha = 0.05). In those patients who received SIRT, the estimated absorbed LMD calculated with planar imaging was significantly higher than with SPECT/CT (t-test, P  < 0.005). Repeated phantom experiments using an anthropomorphic torso phantom with variable 99m Tc activity concentrations for the liver and lungs were performed with the standard patient protocol, demonstrated improved accuracy of the LSF calculation based on SPECT/CT than planar imaging (mean overestimated value of 6% vs. 26%). Conclusions This study demonstrates that LSF calculation using planar imaging can be significantly overestimated while calculation using SPECT/CT imaging and appropriate segmentation tools can be more accurate. Minimizing the errors in obtaining the LSF can lead to more effective 90 Y SIRT treatment planning for hepatic tumors while ensuring the lung dose will not exceed the standard acceptable safety thresholds