The future is now: Model-based clinical trial design for Alzheimer's disease

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease.1 CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA)

Salvage chemotherapy with high-dose leucovorin (LV) and 48-hour continuous infusion (CI) of 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) in patients with metastatic breast cancer (MBC) pretreated with anthracycline and taxanes

The purpose of this study was to evaluate the activity and tolerance of high-dose leucovorin (LV) and infusional 5-fluorouracil (5-FU) in combination with conventional doses of cyclophosphamide (CPM) as salvage chemotherapy in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. 41 patients (median age 59 years) with MBC refractory or resistant to anthracyclines and taxanes were enrolled. The patients' performance status (WHO) was 0 in 10 patients (24%), 1 in 22 (54%), and 2 in 9 (22%). 30 (73%) patients had received 2 or more prior chemotherapy regimens. Cyclophosphamide (600 mg m−2) was given i.v. bolus on day 1 and LV (500 mg m−2 d−1) as a 2-h infusion followed by 5-FU (1.5 g m−2 d−1) over a 22 h c.i. for 2 consecutive days. Cyclophosphamide was administered every 28 days while 5-FU/LV every 14 days. In an intention-to-treat analysis, complete response (CR) was achieved in 2 (4.9%) patients and partial response (PR) in 9 (22%) (overall response rate 26.9%; 95% CI: 13.27–40.39%). Stable disease (SD) and progressive disease (PD) were observed in 9 (22%) and 21 (51%) patients, respectively. The overall response rate was 6% and 40% in patients with primary and secondary resistance to anthracyclines/taxanes, respectively (P = 0.047). The median duration of response and the median time to disease progression was 8 and 9.5 months, respectively. The median overall survival was 13 months and the probability for 1-year survival 51%. Grade 3/4 neutropenia occurred in 9 (22%) patients and 4 (9%) patients developed grade 3/4 thrombocytopenia. Non-haematological toxicity was mild. There were no cases of febrile neutropenia, toxic deaths or treatment-related hospital admissions due to toxicity. The combination of high-dose 5-FU/LV with conventional doses of cyclophosphamide is a well tolerated and effective salvage regimen in patients with MBC heavily pretreated with both anthracyclines and taxanes. © 2001 Cancer Research Campaignhttp://www.bjcancer.comhttp://www.bjcancer.co

Universal WBC reduction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75583/1/j.1537-2995.2000.40060751.x.pd

How does study quality affect the results of a diagnostic meta-analysis?

Background: The use of systematic literature review to inform evidence based practice in diagnostics is rapidly expanding. Although the primary diagnostic literature is extensive, studies are often of low methodological quality or poorly reported. There has been no rigorously evaluated, evidence based tool to assess the methodological quality of diagnostic studies. The primary objective of this study was to determine the extent to which variations in the quality of primary studies impact the results of a diagnostic meta-analysis and whether this differs with diagnostic test type. A secondary objective was to contribute to the evaluation of QUADAS, an evidence-based tool for the assessment of quality in diagnostic accuracy studies. Methods: This study was conducted as part of large systematic review of tests used in the diagnosis and further investigation of urinary tract infection (UTI) in children. All studies included in this review were assessed using QUADAS, an evidence-based tool for the assessment of quality in systematic reviews of diagnostic accuracy studies. The impact of individual components of QUADAS on a summary measure of diagnostic accuracy was investigated using regression analysis. The review divided the diagnosis and further investigation of UTI into the following three clinical stages: diagnosis of UTI, localisation of infection, and further investigation of the UTI. Each stage used different types of diagnostic test, which were considered to involve different quality concerns. Results: Many of the studies included in our review were poorly reported. The proportion of QUADAS items fulfilled was similar for studies in different sections of the review. However, as might be expected, the individual items fulfilled differed between the three clinical stages. Regression analysis found that different items showed a strong association with test performance for the different tests evaluated. These differences were observed both within and between the three clinical stages assessed by the review. The results of regression analyses were also affected by whether or not a weighting (by sample size) was applied. Our analysis was severely limited by the completeness of reporting and the differences between the index tests evaluated and the reference standards used to confirm diagnoses in the primary studies. Few tests were evaluated by sufficient studies to allow meaningful use of meta-analytic pooling and investigation of heterogeneity. This meant that further analysis to investigate heterogeneity could only be undertaken using a subset of studies, and that the findings are open to various interpretations. Conclusion: Further work is needed to investigate the influence of methodological quality on the results of diagnostic meta-analyses. Large data sets of well-reported primary studies are needed to address this question. Without significant improvements in the completeness of reporting of primary studies, progress in this area will be limited

Analysis of blood transfusion predictors in patients undergoing elective oesophagectomy for cancer

<p>Abstract</p> <p>Background</p> <p>Oesophagectomy for cancers is a major operation with significant blood loss and usage. Concerns exist about the side effects of blood transfusion, cost and availability of donated blood. We are not aware of any previous study that has evaluated predictive factors for perioperative blood transfusion in patients undergoing elective oesophagectomy for cancer.</p> <p>This study aimed to audit the pattern of blood crossmatch and to evaluate factors predictive of transfusion requirements in oesophagectomy patients.</p> <p>Methods</p> <p>Data was collected from the database of all patients who underwent oesophagectomy for cancer over a 2-year period. Clinico-pathological data collected included patients demographics, clinical factors, tumour histopathological data, preoperative and discharge haemoglobin levels, total blood loss, number of units of blood crossmatched pre-, intra- and postoperatively, number of blood units transfused, crossmatched units reused for another patient and number of blood units wasted.</p> <p>Clinico-pathological variables were evaluated and logistic regression analysis was performed to determine which factors were predictive of blood transfusion.</p> <p>Results</p> <p>A total of 145 patients with a male to female ratio of 2.5:1 and median age of 68 (40–85) years were audited. The mean preoperative haemoglobin (Hb) was 13.0 g/dl. 37% of males (Hb < 13.0 g/dl) and 29% of females (Hb < 11.5 g/dl) were anaemic preoperatively. A total of 1241 blood units were crossmatched and 316 units were transfused to 71 patients. Seventy four patients (51%) did not require blood transfusion during their hospital episode. 846 blood units not used for oesophagectomy patients were reused for other patients and 79 units were wasted. The overall crossmatch to transfusion ratio was 4:1 and reuse and wastage rates were 65.2% and 6.3% respectively. The independent predictors of blood transfusion include age >70 years, Hb level <11.0 g/dl, T-stage, presence of postoperative complications and anastomotic leak.</p> <p>Conclusion</p> <p>The cohort of patients audited was over-crossmatched. The identified independent predictors of blood transfusion should be considered in preoperative blood ordering for oesophagectomy patients. This study has directly led to a reduction in the maximum surgical blood-ordering schedule for oesophagectomy to 2 units and a reaudit is underway.</p

Seroprevalence of HHV-8, CMV, and EBV among the general population in Ghana, West Africa

<p>Abstract</p> <p>Background</p> <p>Human herpesvirus 8 (HHV-8), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are prevalent in Africa, but less common elsewhere and the modes of transmission are still subject to debate. Generally, they rarely cause disease in the immunocompetent host but are highly oncogenic when associated with immunosuppression. Although the high prevalence of HHV-8, CMV and EBV has been well documented in Africa, such data are sparse from Ghana.</p> <p>Methods</p> <p>Serum samples from 3275 HIV-seronegative healthy blood donors and 250 HIV-AIDS patients were tested for antibodies specific for HHV-8, CMV and EBV by IgG ELISA assays. Differences in seropositivity rates by gender and age were evaluated using the Chi-square test with Yates correction.</p> <p>Results</p> <p>Of the 3275 HIV-seronegative healthy blood donors tested, 2573 (78.6%) were males and 702 (21.4%) were females, with ages ranging from 18 to 65 years (median 32.6; mean 31.2; mode 30). Of the 250 HIV-AIDS patients tested, 140 (56%) were males and 110 (44%) were females, with ages ranging from 17 to 64 years (median 30.8; mean 30.3; mode 28). Among the HIV-seronegative healthy blood donors, overall seroprevalence of HHV-8, CMV and EBV was 23.7%, 77.6% and 20.0%, respectively. Among the HIV-AIDS patients, overall seroprevalence of HHV-8, CMV and EBV was 65.6%, 59.2% and 87.2%, respectively. The seroprevalence of HHV-8 (p < 0.005) and EBV (p < 0.001) was statistically significantly higher in HIV-AIDS patients compared to HIV-seronegative healthy blood donors. There was no statistically significant difference (p = 0.24) between CMV seroprevalence in HIV-AIDS patients and HIV-seronegative healthy blood donors. Age and gender were not independent determinants (p > 0.05) for all three infections among HIV-seronegative healthy blood donors and HIV-AIDS patients in Ghana.</p> <p>Conclusion</p> <p>The results presented herein indicate that HHV-8, CMV and EBV infections are hyperendemic in both HIV-seronegative and HIV-seropositive Ghanaians, and suggest primarily a horizontal route of transmission of these three viral infections in Ghana.</p

Perioperative blood transfusion is associated with a gene transcription profile characteristic of immunosuppression: a prospective cohort study

INTRODUCTION Blood transfusion in the perioperative period has frequently been associated with an excess of nosocomial infections. Whilst transfused whole blood induces specific host immune alteration that may predispose to nosocomial infections, the immunomodulating properties associated with leukodepleted blood remain incompletely understood. In this study, we explore the hypothesis that the transfusion of leukodepleted allogeneic blood during or following major gastrointestinal surgery is associated with an immunosuppressed phenotype, which may in turn predispose to postoperative infectious complications. METHODS Patients aged over 45 years undergoing scheduled inpatient major gastrointestinal surgery were recruited. Gene expression profiles of specific inflammatory genes were assayed from blood collected preoperatively, at 24 and at 48 hours after surgery. Genes were selected based on their ability to represent specific immune pathways. Gene expression was quantified using quantitative real-time polymerase chain reaction (qRT-PCR) to measure messenger RNA (mRNA) levels. Postoperative infections were documented using predefined criteria. RESULTS One hundred and nineteen patients were recruited. Fifteen (13%) patients required blood transfusion within 24 hours of surgery, 44 (37%) patients developed infections and 3 (2%) patients died prior to discharge. Patients receiving a blood transfusion were more likely to develop postoperative infections (P =0.02) and to have lower tumour necrosis factor alpha (TNFα), interleukin (IL)-12, IL-23 and RAR-related orphan receptor gamma T (RORγt) gene expression in the postoperative period (P <0.05). The TNFα/IL-10 mRNA ratio at 24 hours (P =0.0006) and at 48 hours (P =0.01) was lower in patients receiving a blood transfusion over this period. Multivariable analysis confirmed that these observations were independent of the severity of the surgical insult. CONCLUSIONS An association between an immunosuppressive pattern of gene expression and blood transfusion following major elective gastrointestinal surgery is described. This gene expression profile includes a reduction in the activity of innate immunity and T helper cell type 1 (Th1) and T helper cell type 17 (Th17) pathways in those patients receiving a blood transfusion. Blood transfusion was also associated with an excess of infectious complications in this cohort. A mechanistic link is suggested but not proven

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and gemcitabine in patients with advanced solid tumours

To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of pegylated liposomal doxorubicin (PLD), paclitaxel (PCX) and gemcitabine (GEM) combination administered biweekly in patients with advanced solid tumours. Twenty-two patients with advanced-stage solid tumours were treated with escalated doses of PLD on day 1 and PCX plus GEM on day 2 (starting doses: 10, 100 and 800 mg m−2, respectively) every 2 weeks. DLTs and pharmacokinetic (PK) parameters of all drugs were determined during the first cycle of treatment. All but six (73%) patients had previously received at least one chemotherapy regimen. The DLT dose level was reached at PLD 12 mg m−2, PCX 110 mg m−2 and GEM 1000 mg m−2 with neutropaenia being the dose-limiting event. Of the 86 chemotherapy cycles delivered, grade 3 and 4 neutropaenia occurred in 20% with no cases of febrile neutropaenia. Non-haematological toxicities were mild. The recommended MTDs are PLD 12 mg m−2, PCX 100 mg m−2 and GEM 1000 mg m−2 administered every 2 weeks. The PK data revealed no obvious drug interactions. Biweekly administration of PLD, PCX and GEM is a well-tolerated chemotherapy regimen, which merits further evaluation in various types of solid tumours