Of Guinea pigs and gratitude: the difficult discourse of clinical trials from the cancer patient perspective.

In an ongoing longitudinal qualitative cohort study of cancer patients' needs and preferences across the cancer journey, we harvested a subset of accounts pertaining to conversations between patients and their clinicians around clinical trials. Recognising these conversations as a departure from the more routine discourses of clinical care, in that they enter into new dimensions of investment and motivation on the part of clinicians, we engaged in both secondary analysis of banked data and focussed interviewing of cancer patients to better understand how cancer patients describe communications in relation to decisions pertaining to clinical trials participation. Using constant comparative techniques informed by the interpretive description approach to applied qualitative methodology to guide a systematic analysis of this set of data, we documented patterns and themes across patient accounts. The resulting thematic depiction of clinical trials discourses from a patient perspective contrasts with assumptions apparent in the professional literature relating to the clinical advantage of trials participation, and illuminates aspects of patient-clinician interaction that are particularly amenable to disruption within this delicate and nuanced discourse. Findings from this study have implications for our understanding of the complexities of cancer communication at the delicate intersection of patient care and knowledge generation.

Clinical, quality of life, and economic value of acromegaly disease control.

Although acromegaly is a rare disease, the clinical, economic and health-related quality of life (HRQoL) burden is considerable due to the broad spectrum of comorbidities as well as the need for lifelong management. We performed a comprehensive literature review of the past 12 years (1998-2010) to determine the benefit of disease control (defined as a growth hormone [GH] concentration <2.5 µg/l and insulin-like growth factor [IGF]-1 normal for age) on clinical, HRQoL, and economic outcomes. Increased GH and IGF-1 levels and low frequency of somatostatin analogue use directly predicted increased mortality risk. Clinical outcome measures that may improve with disease control include joint articular cartilage thickness, vertebral fractures, left ventricular function, exercise capacity and endurance, lipid profile, and obstructive apnea events. Some evidence suggests an association between controlled disease and improved HRQoL. Total direct treatment costs were higher for patients with uncontrolled compared to controlled disease. Costs incurred for management of comorbidities, and indirect cost could further add to treatment costs. Optimizing disease control in patients with acromegaly appears to improve outcomes. Future studies need to evaluate clinical outcomes, as well as HRQoL and comprehensive economic outcomes achieved with controlled disease.

Expression and compartmentalization of caveolin in adipose cells: coordinate regulation with and structural segregation from GLUT4.

Native rat adipocytes and the mouse adipocyte cell line, 3T3-L1, possess transport vesicles of apparently uniform composition and size which translocate the tissue-specific glucose transporter isoform, GLUT4, from an intracellular pool to the cell surface in an insulin-sensitive fashion. Caveolin, the presumed structural protein of caveolae, has also been proposed to function in vesicular transport. Thus, we studied the expression and subcellular distribution of caveolin in adipocytes. We found that rat fat cells express the highest level of caveolin protein of any tissue studied, and caveolin is also expressed at high levels in cardiac muscle, another tissue possessing insulin responsive GLUT4 translocation. Both proteins are absent from 3T3-L1 fibroblasts and undergo a dramatic coordinate increase in expression upon differentiation of these cells into adipocytes. However, unlike GLUT4 in rat adipocytes not exposed to insulin, the majority of caveolin is present in the plasma membrane. In native rat adipocytes, intracellular GLUT4 and caveolin reside in vesicles practically indistinguishable by their size and buoyant density in sucrose gradients, and both proteins show insulin-dependent translocation to the cell surface. However, by immunoadsorption of GLUT4-containing vesicles with anti-GLUT4 antibody, we show that these vesicles have no detectable caveolin, and therefore, this protein is present in a distinct vesicle population. Thus, caveolin has no direct structural relation to the organization of the intracellular glucose transporting machinery in fat cells.

Ferromagnetic imprinting of nuclear spins in semiconductors.

We examine how a ferromagnetic layer affects the coherent electron spin dynamics in a neighboring gallium arsenide semiconductor. Ultrafast optical pump-probe measurements reveal that the spin dynamics are unexpectedly dominated by hyperpolarized nuclear spins that align along the ferromagnet's magnetization. We find evidence that photoexcited carriers acquire spin-polarization from the ferromagnet, and dynamically polarize these nuclear spins. The resulting hyperfine fields are as high as 9000 gauss in small external fields (less than 1000 gauss), enabling ferromagnetic control of local electron spin coherence.

Economic burden of haematological adverse effects in cancer patients: a systematic review.

OBJECTIVE: Patients receiving cancer treatments commonly experience haematological adverse effects (AEs) related to chemotherapy or molecularly targeted therapies, which may be associated with high healthcare costs. The objective of this review was to summarise the published literature on the economic burden of neutropenia, thrombocytopenia and anaemia as AEs of cancer treatment. METHODS: A systematic search of the medical literature published between 1990 and 2006 was conducted using PubMed/MEDLINE, EMBASE, BIOSIS, related article links and supplemental searches. References selected for inclusion were prospective or retrospective studies specifically designed to examine the burden of illness, direct medical costs, indirect costs and/or cost drivers associated with neutropenia, thrombocytopenia and anaemia in adult cancer patients. All costs are reported as originally published and adjusted to 2006 US dollars. RESULTS: In the US, the cost of neutropenia ranged from $US 1893 (2006 value $US 2632) per outpatient episode to $US 38,583 ($US 49,917) per febrile neutropenia hospitalisation. For countries outside the US, the cost of neutropenia appeared to be lower. The cost of thrombocytopenia ranged from $US 1035 ($US 1395) to $US 5328 ($US 7635) per cycle or episode in the US. Costs attributable to anaemia ranged from $US 18,418 ($US 22,775) to $US 69,478 ($US 93,454) per year in the US. The costs of AEs for patients with haematological malignancies appeared to be up to 2-3 times higher than those for patients with solid tumours. Economic studies of the cost of haematological AEs specific to new molecularly targeted treatments for haematological malignancy have not been published. CONCLUSIONS: Chemotherapy-related haematological AEs result in a substantial economic burden on patients, payers, caregivers and society in general. Because of their burden, the frequency and severity of these toxicities should be one of the key factors in the selection of optimal treatments for patients with cancer, especially those with haematological malignancies. Future research is needed to assess the economic burden of AEs associated with new molecularly targeted treatments for haematological malignancies.

Regulation of signal transducers and activators of transcription (STATs) by effectors of adipogenesis: coordinate regulation of STATs 1, 5A, and 5B with peroxisome proliferator-activated receptor-gamma and C/AAAT enhancer binding protein-alpha.

We have recently demonstrated that three signal transducers and activators of transcription (STAT) family members are induced during adipocyte differentiation (Stephens et al., J. Biol. Chem. 271 (1996) 10441-10444). Since STATs 1, 5A, and 5B are induced during adipocyte differentiation, we have examined the ability of these proteins to be regulated by components of the differentiation cocktail. In addition, we have examined the effects of potent effectors of differentiation on STAT protein expression during adipogenesis. A negative effector, tumor necrosis factor-alpha (TNFalpha), and a positive effector, a thiazolidinedione, were used in these experiments. Our results demonstrate that the expression of STATs 1, 5A, and 5B is not dramatically influenced by individual components of the differentiation cocktail. However, the expression of these three STAT family members tightly correlates with lipid accumulation. Moreover, the expression of STATs 1, 5A, and 5B, but not STATs 3 and 6, are regulated in an identical fashion to both C/AAAT enhancer binding proteins alpha and peroxisome proliferator-activated receptor-gamma by TNFalpha and a thiazolidinedione. Furthermore, the expression of adipocyte-expressed JAK kinases are unaffected by effectors of differentiation. These findings suggest that three STAT family members may play a role in the regulation of adipocyte gene expression.

Expression of c-fos, c-jun and jun B in peripheral blood lymphocytes from young and elderly adults.

The expression of c-fos, c-jun and jun B proto-oncogenes was studied in phytohemagglutinin (PHA) activated peripheral blood lymphocytes (PBL) from young and aged humans. Specific mRNAs for c-fos and c-jun were detectable within 30 min after cell activation and reached maximal levels within 2 h. Both c-fos and jun B mRNAs decreased to pre-activation levels within 6 h, while c-jun mRNA remained elevated. In PHA-activated PBL, no age-related differences were observed in c-fos or jun B mRNA expression. However, c-jun mRNA levels decreased significantly (1.73 +/- 0.08 vs. 1.16 +/- 0.09 arbitrary units, P < 0.01, young vs. old) in PBL from elderly individuals activated with PHA. Because previous work has demonstrated that T cells from elderly individuals may display normal proliferative responses when activated via the anti-CD2 pathway, c-jun and jun B mRNA expression was also studied in anti-CD2-activated purified T cells. No age-related differences were found in the expression of either of these two proto-oncogenes by anti-CD2 activated T cells. These results suggest that the decreased IL-2 production and proliferative response displayed by PHA-activated PBL from elderly adults may be related to age-related changes in c-jun mRNA expression and in the ratio of c-fos to c-jun mRNA.

Regulation of transcription factor mRNA accumulation during 3T3-L1 preadipocyte differentiation by tumour necrosis factor-alpha.

3T3-L1 preadipocytes differentiate into cells having the biochemical properties of adipocytes; tumour necrosis factor-alpha (TNF) attenuates this process. Inhibition of differentiation by this cytokine, thought to be mediated at the level of transcription, has been investigated by examining the accumulation of mRNA for six transcription factors and three diversely regulated genes during the first 24 h of the differentiation process. Upon induction of differentiation, a rapid and major accumulation of c-fos and jun-B mRNA, which returned to near basal levels within 4-6 h, was observed. In contrast, c-jun mRNA, although rapidly expressed at the induction of differentiation, remained at relatively constant levels throughout the time-course. Exposure of the cells to 5 nM TNF potentiated the accumulation of all three mRNAs but most significantly that of c-jun (12-fold), which remained elevated for at least 24 h after treatment. In control differentiating cells, krox-20 and fos-B were expressed transiently from 30 min to 2 h, while fra-1 mRNA accumulated over an extended period of 1 to 8 h. Again, TNF enhanced the accumulation of these mRNAs. Accumulation of mRNA for C/EBP, a transcription factor proposed to control the expression of genes involved in the terminally differentiated state, was attenuated after exposure of the cells to TNF. Interleukin-6 (IL-6) mRNA was expressed briefly (30 min to 2 h) and again transiently (at 8 h after induction of differentiation). TNF treatment markedly enhanced accumulation of IL-6 message. We propose that an increased cellular content of one or more transcription factors or the suppression of C/EBP may be responsible for the attenuation of differentiation induced by exposure of the cells to TNF.

Acrylamide induces immediate-early gene expression in rat brain.

Northern blot analysis was used to study the effects of acrylamide, a potent neurotoxin, on the induction of c-fos and c-jun mRNA in rat brain. Male Sprague-Dawley rats (10-12 weeks old) treated with acrylamide as a single dose (100 mg/kg, i.p.) or via drinking water (0.03% w/v) for 4 weeks, were used to study acute and chronic effects on immediate-early gene expression, respectively. Acute administration of acrylamide caused a statistically significant increase in the expression of c-fos (approx. 37%) and c-jun (approx. 17%) mRNA in rat brain. By contrast, the level of c-fos mRNA in chronic acrylamide treatment was not altered significantly, but the expression of c-jun mRNA was increased almost 100% as compared to control. These data show that the neurotoxin acrylamide induces immediate-early gene expression in the brain. The effects appear to be related to the route of administration, dose and duration of acrylamide treatment.

A short-term cost-of-treatment model for type 2 diabetes: comparison of glipizide gastrointestinal therapeutic system, metformin, and acarbose.

OBJECTIVE: To compare, from a managed care perspective, the 3-year costs of 3 first-line monotherapy strategies in type 2 diabetes patients: glipizide gastrointestinal therapeutic system (GITS), metformin, and acarbose. STUDY DESIGN: A Markov model, with a Monte Carlo simulation, was developed to compare the costs to achieve full glycemic control (hemoglobin A1c of < or = 7%) with each first-line strategy. PATIENTS AND METHODS: The patient population for the model was assumed to be all newly diagnosed type 2 diabetes patients eligible for monotherapy with an oral agent. Each monotherapy could be succeeded by add-on treatments. The model included the costs of routine medical care and supplies, medication, adverse events, and treatment failures. RESULTS: Using a Monte Carlo simulation, the mean 3-year cumulative costs per patient were $4971, $5273, and $5311 for glipizide GITS, metformin, and acarbose first-line strategies, respectively. The main cost drivers were drug prices. Mean 3-year cost savings for first-line glipizide GITS were $301 over metformin and $340 over acarbose. Between 83% and 85% of all simulations showed cost savings with glipizide GITS compared with the other agents. CONCLUSIONS: The model suggests first-line monotherapy with glipizide GITS should result in desirable short-term economic benefits for managed care. Because the model incorporates recommended glycemic goals and performed well in sensitivity analyses, it should be applicable to a variety of clinical practices and useful for economic assessments of new therapies. Results of this model should be verified prospectively in typical care settings.

Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections.

The objective of this study was to document pan-European real-world treatment patterns and healthcare resource use and estimate opportunities for early switch (ES) from intravenous (IV) to oral antibiotics and early discharge (ED) in hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infections (cSSTIs). This retrospective observational medical chart review study enrolled 342 physicians across 12 European countries who collected data from 1542 patients with documented MRSA cSSTI who were hospitalized (July 2010 to June 2011) and discharged alive (by July 2011). Data included clinical characteristics and outcomes, hospital length of stay (LOS), MRSA-targeted IV and oral antibiotic use, and ES and ED eligibility according to literature-based and expert-validated criteria. The most frequent initial MRSA-active antibiotics were vancomycin (50.2%), linezolid (15.1%), clindamycin (10.8%), and teicoplanin (10.4%). Patients discharged with MRSA-active antibiotics (n = 480) were most frequently prescribed linezolid (42.1%) and clindamycin (19.8%). IV treatment duration (9.3 ± 6.5 vs. 14.6 ± 9.9 days; p <0.001) and hospital LOS (19.1 ± 12.9 vs. 21.0 ± 18.2 days; p 0.162) tended to be shorter for patients switched from IV to oral treatment than for patients who received IV treatment only. Of the patients, 33.6% met ES criteria and could have discontinued IV treatment 6.0 ± 5.5 days earlier, and 37.9% met ED criteria and could have been discharged 6.2 ± 8.2 days earlier. More than one-third of European patients hospitalized for MRSA cSSTI could be eligible for ES and ED, resulting in substantial reductions in IV days and bed-days, with potential savings of €2000 per ED-eligible patient.

Association between drug tolerability and medical resource use in prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplant.

OBJECTIVES: To conduct a retrospective analysis of the association between drug tolerability and potential economic impact measured by medical resource utilization (MRU) for prophylaxis of invasive antifungal infections (IFI) after allogeneic hematopoietic stem cell transplantation (alloHCT). METHODS: An open-label, multi-center study (IMPROVIT) included patients (≥12-years old) who were randomized to receive oral voriconazole (VOR) or oral itraconazole (ITR) from the alloHCT day for at least 100 days and up to 180 days. Trial data on discontinuation and MRU for the first 100 days were analyzed. RESULTS: Two hundred and twenty-four patients were in VOR and 241 in ITR, with similar demographic distributions (average age of 43 years, 58% male, 92% Caucasian). All-cause and study drug intolerance discontinuations were less frequent with VOR than ITR (50% vs 63%, p = 0.0137; 7% vs 22%, p < 0.0001). VOR patients had longer study drug exposure (median = 96 vs 68 days, p < 0.0001; mean = 68 vs 60 days, p = 0.0044). ITR patients were 2-times more likely (p = 0.0110) to use other antifungals vs VOR patients. Controlling for treatment and key baseline variables, longer IFI prophylaxis was associated with fewer hospital days (p < 0.0001) and less other antifungal use (p < 0.0001). Patients who discontinued prophylaxis during the first 100 days incurred 10 more hospital days (p < 0.0001) and 17 more other antifungal days (p < 0.0001) compared to their counterparts. Eight more prophylaxis days were associated with ∼1 less hospital day and 3.6 less other antifungal days (p < 0.0001). Key limitation: MRU data collection was limited to the first 100 days post-transplant, which may not fully capture the real-world utilization and outcomes. CONCLUSIONS: Patients' ability to tolerate and continue their antifungal prophylaxis after alloHCT is associated with less use of MRU such as other antifungals and hospital days. In the current resource-constrained healthcare environment, it is important to consider the potential economic impact of the tolerability of antifungal prophylaxis.

Cost-effectiveness of zoledronic acid in the prevention of skeletal-related events in patients with bone metastases secondary to advanced renal cell carcinoma: application to France, Germany, and the United Kingdom.

BACKGROUND: The use of zoledronic acid (ZOL) has recently been shown to significantly reduce the risk of new skeletal-related events (SREs) in renal cell carcinoma (RCC) patients with bone metastases. The present exploratory study assessed the cost-effectiveness of ZOL in this population, adopting a French, German, and United Kingdom (UK) government payer perspective. MATERIALS AND METHODS: This cost-effectiveness model was based on a post hoc retrospective analysis of a subset of patients with RCC who were included in a larger randomized clinical trial of patients with bone metastases secondary to a variety of cancers. In the trial, patients were randomized to receive ZOL (n = 27) or placebo (n = 19) with concomitant antineoplastic therapy every 3 weeks for 9 months (core study) plus 12 months during a study extension. Since the trial did not collect costs or data on the quality-adjusted life years (QALYs) of the patients, these outcomes had to be assumed via modeling exercises. The costs of SREs were estimated using hospital DRG tariffs. These estimates were supplemented with literature-based costs where possible. Drug, administration, and supply costs were obtained from published and internet sources. Consistent with similar economic analyses, patients were assumed to experience quality of life decrements lasting 1 month for each SRE. Uncertainty surrounding outcomes was addressed via multivariate sensitivity analyses. RESULTS: Patients receiving ZOL experienced 1.07 fewer SREs than patients on placebo. Patients on ZOL experienced a gain in discounted QALYs of approximately 0.1563 in France and Germany and 0.1575 in the UK. Discounted SRE-related costs were substantially lower among ZOL than placebo patients (-€ 4,196 in France, - € 3,880 in Germany, and -€ 3,355 in the UK). After taking into consideration the drug therapy costs, ZOL saved € 1,358, € 1,223, and € 719 in France, Germany, and the UK, respectively. In the multivariate sensitivity analyses, therapy with ZOL saved costs in 67-77% of simulations, depending on the country. The cost per QALY gained for ZOL versus placebo was below € 30,000 per QALY gained threshold in approximately 93-94% of multivariate sensitivity analyses simulations. CONCLUSIONS: The present analysis suggests that ZOL saves costs and increases QALYs compared to placebo in French, German, and UK RCC patients with bone metastases. Additional prospective research may be needed to confirm these results in a larger sample of patients.

Inversion of ferromagnetic proximity polarization by MgO interlayers.

We investigate the spin-dependent reflection properties in Fe/MgO/GaAs heterostructures by optical pump-probe measurement of the ferromagnetic proximity polarization (FPP). As a function of MgO thickness, the FPP is initially enhanced (<2.0 A) and then exhibits an unexpected sign reversal at approximately 5.0 A. The identification of two competing thresholds in the intensity dependence of FPP and the observation of FPP sign reversal in Fe/Mg/GaAs suggest that the inversion of FPP is related to an interfacial bonding effect.

A systematic literature review of the clinical and epidemiological burden of acute lymphoblastic leukaemia (ALL).

Our goal was to identify and summarize the published literature pertaining to the incidence, prevalence, mortality, aetiology, clinical diagnosis, and management of acute lymphoblastic leukaemia (ALL). Acute lymphoblastic leukaemia represents 12% of all leukaemia cases, with a worldwide incidence projected to be 1-4.75 per 100,000 people. Italy, the United States (US), Switzerland, and Costa Rica are the countries with the highest incidence of ALL. Hereditary link, genetic defects, and possibly radiation or chemical exposures are listed amongst the most significant risk factors. Acute lymphoblastic leukaemia is predominantly a disease of childhood, but it affects adults as well. It accounts for 80% of all leukaemia cases in children. The incidence is slightly higher in men than in women and greater in white people than in black people. In 2003 in the US, there were an estimated 5800 deaths from ALL. Presenting signs and symptoms of ALL are fairly non-specific and include fever, anaemia, petechiae, and bone and joint pain. Staging of the disease and patient risk profile are routinely performed to define ALL subtypes and guide management. Chemotherapy, cranial radiation in patients with high-risk disease, and stem cell transplantation for selected patients are the prevalent therapies. Complete remission rates are high, especially amongst children (even 100%); however, long-term survival at 10 years (event-free survival) is in the range of 63% for children and 25-35% for adults. This implies that there is still a strong need for new therapies to maintain remission and prolong survival. Future treatment strategies may be driven by the patient's minimal residual disease status, a measure that more precisely defines remission, prognosis, responsiveness to therapy, and expected long-term survival.

Transcriptional repression of the C/EBP-alpha and GLUT4 genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. Regulations is coordinate and independent of protein synthesis.

We have previously demonstrated the ability of tumor necrosis factor-alpha (TNF) to down-regulate the expression of GLUT4 (insulin-responsive glucose transporter) and C/EBP-alpha (CCAAT/enhancer-binding protein) (Stephens J. M., and Pekala, P. H. (1991) J. Biol. Chem. 266, 21839-21845). As C/EBP-alpha has been suggested to control GLUT4 expression, we have examined the time course for attenuation of transcription of these genes. Run-on transcription assays indicate a coordinate transcriptional repression of both GLUT4 and C/EBP-alpha genes (as well as the 422/aP2 gene, the adipocyte lipid-binding protein, whose expression has also been proposed to be controlled by C/EBP-alpha). Inhibition of transcription was observed within 1 h of TNF addition, with maximal suppression observed after 4 h. The inhibition was not blocked by cycloheximide. Okadaic acid treatment (1 h, 0.5 microM) also resulted in the coordinate transcriptional repression of the C/EBP-alpha, GLUT4, and 422/aP2 genes, consistent with involvement of a kinase-phosphatase system in the regulation of these genes. The decrease in C/EBP-alpha protein content was detectable 4 h after TNF addition and declined to 25% of controls within 24 h. A minor decrease in the protein content of GLUT4 was observed during the first 24 h of exposure to TNF; however, after 72 h of exposure GLUT4 protein was not detectable. The rapid coordinate transcriptional regulation of C/EBP-alpha, GLUT4, and 422/aP2 by TNF in the presence of cycloheximide suggests that the TNF-induced loss of GLUT4 protein may be mediated by a post-translational modification of an existing transcription factor. However, the rapid loss of C/EBP-alpha protein may be a contributing factor to further transcriptional suppression of the GLUT4 gene at the later time points. In addition to the transcriptional effect, we report that TNF-induced destabilization of these mRNAs contributes to decreased expression of all three genes.

Agouti regulates adipocyte transcription factors.

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agouti expression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-gamma protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-gamma.