Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial.

PURPOSE: Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS: Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS: Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION: This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.     

Adult ovary transfer counteracts the callosal enlargement resulting from prepubertal ovariectomy

The rat corpus callosum (CC) is larger in males than females, and is sensitive to hormone manipulations during development. Previous research found that, in rats, CC sensitivity to testosterone ended by postnatal day 8 (P8). In contrast, more recent findings demonstrated that CC responsivity to ovarian hormones continued at least through P70. The current experiment extends these findings by showing that the female callosum is still sensitive to ovarian hormones as late as P130, well into adulthood.     

Perspectives on colorectal cancer screening: a focus group study

Objective To assess attitudes and acceptability of Ontario consumers and doctors towards colorectal screening with faecal occult blood testing (FOBT) and colonoscopy. Design, setting and participants Focus groups with gender‐specific samples of the population, high‐risk gastroenterology patients and family doctors. Method Semi‐structured interview guides used by facilitator to lead groups through knowledge of risk factors and prevention of colorectal cancer, the screening modalities, requirements for implementing screening programmes, barriers to screening and preferences towards screening. Main findings There were low levels of knowledge about colorectal cancer and its prevention in the general population. FOBT was an acceptable screening modality, but considerable education about its use and benefits would be necessary to implement a screening programme. Colonoscopy was not perceived to be a good choice for a primary screen in the general population. The high‐risk group supported use of FOBT in the general population and emphasized the need for education. The doctors were more reluctant about screening, requesting clear guidelines. They also identified the time and resources that would be required if a screening programme were initiated. Conclusion While colorectal screening is acceptable in this sample, information and decision aids are required to enable consumers and providers to make effective decisions. Implementation of colorectal screening programmes requires substantial educational efforts for both consumers and doctors.     

Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer.

PURPOSE: A randomized three-arm phase II study was undertaken to evaluate the optimum administration schedule of pemetrexed and gemcitabine in chemotherapy-na?ve patients with non-small-cell lung cancer. PATIENTS AND METHODS: Patients were randomly assigned to three schedules of pemetrexed 500 mg/m2 plus gemcitabine 1,250 mg/m2, separated by a 90-minute interval, on a 21-day cycle as follows: schedule A, pemetrexed followed by gemcitabine on day 1 and gemcitabine on day 8; schedule B, gemcitabine followed by pemetrexed on day 1 and gemcitabine on day 8; and schedule C, gemcitabine on day 1 and pemetrexed followed by gemcitabine on day 8. RESULTS: One hundred fifty-two eligible patients (schedule A, n = 59; schedule B, n = 31, and schedule C, n = 62) received a median of five (schedule A), two (schedule B), and four (schedule C) treatment cycles. Overall, 66% of patients experienced grade 3 or 4 neutropenia. Common grade 3 and 4 nonhematologic toxicities were dyspnea (11%), fatigue (16%), and transaminase elevation (9%). Schedule A seemed less toxic compared with schedule C (grade 3 or 4 events: 86% v 94%, respectively; P = .19; grade 4 events: 39% v 48%, respectively; P = .30). Schedule B was closed at interim analysis for inferior efficacy. Schedule A, with a confirmed response rate of 31% (95% CI, 20% to 45%), met the protocol-defined efficacy criteria, whereas schedule C, with a confirmed response rate of 16.1% (95% CI, 11% to 34%), did not. Median survival time and time to progression were 11.4 and 4.4 months, respectively, with no observable difference between the arms. CONCLUSION: Pemetrexed and gemcitabine administered as outlined for schedule A met the protocol-defined efficacy criteria, was less toxic compared with the other treatment schedules, and should be further evaluated.     

Efficacy of phytol-derived diterpenoid immunoadjuvants over alum in shaping the murine host's immune response to Staphylococcus aureus

The ubiquitous gram-positive bacterium Staphylococcus aureus occupies a unique niche in humans for its ability to survive both as a commensal and a life-threatening pathogen. Its complex relationship with the host and its ability to engender a throng of virulence factors, have hindered the development of a successful vaccine against it. The use of immunoadjuvants to enhance host immunity and prevent the shift from commensalism to pathogenicity is a rational approach for containing infection. The objective of this study was to understand the mechanisms by which alum and two phytol-derived immunoadjuvants, phytanol (PHIS-01) ¹ and phytanyl chloride (PCl) ² shape the interaction between S. aureus and its murine host. We studied the effects of the phytol derivatives, relative to alum, on the induction of inflammatory cytokines and chemokines, recruitment of CD11b⁺ cells, generation of specific anti-S. aureus antibodies and in vitro clearance of S. aureus. Our results showed that both PHIS-01 and PCl were stronger inducers of protective cytokines IL-17 and IL-1β than alum, and far exceeded alum in enhancing anti-S. aureus antibody response. However, both alum and the phytol derivatives (particularly PCl) promoted efficient recruitment of CD11b⁺ cells. Furthermore, PHIS-01, alum and to a lesser extent, PCl were able to up-regulate the expression of key inflammation-related genes that were highly down-regulated by S. aureus alone. In vitro killing assays showed that both PHIS-01 and PCl were far more potent than alum in promoting S. aureus clearance; this indicated their efficiency in shaping an effective anti-S. aureus immune microenvironment. In summary, our study provides evidence for the better effectiveness of phytol-derived immunoadjuvants over alum in enhancing anti-S. aureus immunity.     

Longitudinal Commercial Claims–Based Cost Analysis of Diabetic Retinopathy Screening Patterns

Background

Diabetic retinopathy is one of the most common complications of diabetes. The screening of patients with diabetes to detect retinopathy is recommended by several professional guidelines but is an underutilized service.

Objective

To analyze the relationship between the frequency of retinopathy screening and the cost of care in adult patients with diabetes.

Methods

Truven Health MarketScan commercial databases (2000–2013) were used to identify the diabetic population aged 18 to 64 years for the performance of a 2001–2013 annual trend analysis of patients with type 1 and type 2 diabetes and a 10-year longitudinal analysis of patients with newly diagnosed type 2 diabetes. In the trend analysis, the prevalence of diabetes, screening rate, and allowed cost per member per month (PMPM) were calculated. In the longitudinal analysis, data from 4 index years (2001–2004) of patients newly diagnosed with type 2 diabetes were combined, and the costs were adjusted to be comparable to the 2004 index year cohort, using the annual diabetes population cost trends calculated in the trend analysis. The longitudinal population was segmented into the number of years of diabetic retinopathy screening (ie, 0, 1–4, 5–7, and 8–10), and the relationship between the years of screening and the PMPM allowed costs was analyzed. The difference in mean incremental cost between years 1 and 10 in each of the 4 cohorts was compared after adjusting for explanatory variables.

Results

In the trend analysis, between 2001 and 2013, the prevalence of diabetes increased from 3.93% to 5.08%, retinal screening increased from 26.27% to 29.58%, and the average total unadjusted allowed cost of care for each patient with diabetes increased from $822 to $1395 PMPM. In the longitudinal analysis, the difference between the screening cohorts’ mean incremental cost increase was $185 between the 0- and 1–4–year cohorts (P <.003) and $202 between the 0- and 5–7–year cohorts (P <.023). The cost differences between the other cohorts, including $217 between the 0- and 8–10–year cohorts (P <.066), were not statistically significant.

Conclusions

Based on our analysis, the annual retinopathy screening rate for patients with diabetes has remained low since 2001, and has been well below the guideline-recommended screening levels. For patients with type 2 diabetes, the mean increase in healthcare expenditures over a 10-year period after diagnosis is not statistically different among those with various retinopathy screening rates, although the increase in healthcare spending is lower for patients with diabetes who were not screened for retinopathy compared with patients who did get screened.     

The appropriateness of use of percutaneous transluminal coronary angioplasty in Spain

BACKGROUND: The rapid increase in the number of percutaneous transluminal coronary angioplasty (PTCA) procedures performed in Spain in recent years raises questions about how appropriately this procedure is being used. To examine this issue, we studied the appropriateness of use of PTCA in Spanish patients and factors associated with inappropriate use. METHODS: We applied criteria for the appropriate use of PTCA developed by an expert panel of Spanish cardiologists and cardiovascular surgeons to a random sample of 1913 patients undergoing PTCA in Spain in 1997. The patients were selected through a two-step sampling process, stratifying by hospital type (public/private) and volume of procedures (low/medium/high). We examined the association between inappropriate use of PTCA and different clinical and sociodemographic factors. RESULTS: Overall, 46% of the PTCA procedures were appropriate, 31% were uncertain and 22% were inappropriate. Two factors contributing to inappropriate use were patients' receipt of less than optimal medical therapy and their failure to undergo stress testing. Institutional type and volume of procedures were not significantly related with inappropriate use. CONCLUSIONS: One of every five PTCA procedures in Spain is done for inappropriate reasons. Assuring that patients receive optimal medical therapy and undergo stress testing when indicated could contribute to more appropriate use of PTCA.     

The gamma chain of the high-affinity receptor for IgE is a major functional subunit of the T-cell antigen receptor complex in gamma delta T lymphocytes.

T-cell activation is a consequence of the clonotypic T-cell antigen receptor (TCR) binding to an antigen followed by signal transduction via the invariant subunits of the TCR/CD3 complex. gamma delta TCR cells are a small subset of T cells that populate both the epithelial and lymphoid tissues and have unique antigen specificity and function. However, the composition of invariant chains within the gamma delta TCR/CD3 complex has not been well characterized. Here we report that, unlike the majority of alpha beta T cell, gamma delta T cells isolated from spleen and intestinal epithelial tissue express high levels of the gamma chain of the high-affinity receptor for IgE (Fc epsilon RI gamma) as one invariant subunit of their TCR/CD3 complex. Fc epsilon RI gamma exists as both a homodimer and a heterodimer associated with the TCR zeta chain. Moreover, stimulation of the gamma delta TCR results in rapid tyrosine phosphorylation of Fc epsilon RI gamma. Our results suggest that utilization of distinct receptor signaling components may enable the coupling of antigen stimulation to the activation of different signal transduction pathways in alpha beta and gamma delta T cells.