Definitions and statistical properties of master protocols for personalized medicine in oncology

ABSTRACT

Within the field of cancer research, discovery of biomarkers and genetic mutations that are potentially predictive of treatment benefit is motivating a paradigm shift in how cancer clinical trials are conducted. In this review, we provide an overview of the class of trials known as “master protocols,” including basket trials, umbrella trials, and platform trials. For each, we describe standardized terminology, provide a motivating example with modeling details and decision rules, and discuss statistical advantages and limitations. We conclude with a discussion of general statistical considerations and challenges encountered across these types of trials.     

Comparison of a Transplant Multiplex Viral Panel on the ICEPlex System with Real-Time PCR for Detection of Cytomegalovirus,Epstein-Barr Virus,and BK Virus in Clinical Specimens

We compared a multiplex viral transplant panel on the ICEPlex system to real-time PCR for the detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK virus (BKV). The sensitivities of the ICEPlex were 83.3%, 95.5%, and 65.5% for the detection of CMV, EBV, and BKV, respectively. Interestingly, the multiplex assay detected dual infections in 16/280 (5.7%) samples tested.     

Species of Propionibacterium and Propionibacterium acnes phylotypes associated with orthopedic implants

Propionibacterium sp. is commonly isolated in association with orthopedic implants, either as a pathogen or a colonizer. Microbial characteristics that indicate whether the isolated species is a likely cause of orthopedic implant infection versus a colonizing agent would be clinically useful. We performed a prospective trial to determine the species of Propionibacterium and the phylotype (IA, IB, II, III) of Propionibacterium acnes isolated from the surface of removed orthopedic implants, and we correlated these findings with the presence or absence of infection. P. acnes represented 61 of 62 isolates. P. acnes type I was more commonly isolated than was type II (62% versus 38%, respectively), whether associated with infection or not. P. acnes type III was not detected. There was no clear association between types I and II P. acnes and infection or colonization of failed orthopedic implants (P = 0.75), however type IB strains were more frequently isolated than type IA from infected prosthese.     

Idiotype‐pulsed antigen presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival

Vaccines are attractive as consolidation therapy after autologous stem cell transplantation (ASCT) for multiple myeloma (MM). We report the results of a phase II trial of the immunotherapeutic, APC8020 (Mylovenge?), given after ASCT for MM. We compared the results with that of other patients with MM who underwent ASCT at Mayo Clinic during the same time period. Twenty‐seven patients were enrolled on the trial between July, 1998 and June, 2001, and the outcomes were compared to that of 124 consecutive patients transplanted during the same period, but not enrolled on the trial. The median (range) follow‐up for patients still alive from the vaccine trial is 6.5 (2.9–8 years), and 7.1 (6–8 years) in the control group. The median age was 57.4 range (36.1–71.3) in the DB group and 56.4 (range, 30–69) in the trial group. Known prognostic factors including PCLI, B2M, and CRP were comparable between the groups. The median overall survival for the trial patients was 5.3 years (95% CI: 4.0 years—N/A) compared to 3.4 years (95% CI: 2.7–4.6 years) for the DB group (P = 0.02). The median time to progression and progression‐free survival for the trial group was similar to the DB group. Although not a controlled trial, the vaccines given after ASCT appear to be associated with improved overall survival compared to historical controls. This approach warrants further investigation to confirm this and define the role of vaccine therapy in myeloma. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

Additive inhibition of dendritic cell allostimulatory capacity by alcohol and hepatitis C is not restored by DC maturation and involves abnormal IL-10 and IL-2 induction

Background: Excessive alcohol use results in impaired immunity, and it is associated with increased incidence and progression of chronic hepatitis C virus (HCV) infection. Here we investigated the effects of HCV infection and alcohol on myeloid dendritic cells (DC) that are critical in antiviral immunity. Methods: Immature and mature DCs were generated from monocytes of chronic HCV infected patients (HCV‐DC) and controls (N‐DC) with IL‐4 plus granulocyte‐macrophage colony stimulating factor (GM‐CSF) in the presence or absence of alcohol (25 mM). DC allostimulatory capacity was tested in mixed lymphocyte reaction (MLR) and cytokine production by ELISA. Results: Allostimulatory capacity of HCV‐DCs was reduced compared to N‐DCs and it was further inhibited by alcohol treatment (p < 0.01). MLR was also decreased with alcohol‐treated N‐DCs. DC phenotypic markers and apoptosis were comparable between HCV‐DCs and N‐DCs irrespective of alcohol treatment. However, HCV‐DCs and alcohol‐treated N‐DCs exhibited elevated IL‐10 and reduced IL‐12 production. Reduced MLR with HCV‐DCs and its further inhibition by alcohol coexisted with decreasing IL‐2 levels (p < 0.017). DC maturation partially improved but failed to fully restore the reduced allostimulatory function of either alcohol‐treated or alcohol‐naïve HCV‐DCs (p < 0.018). Conclusions: Alcohol and HCV independently and together inhibit DC allostimulatory capacity, increase IL‐10, reduce IL‐12 and IL‐2 production that cannot be normalized by DC maturation. HCV and alcohol interact to modulate innate and adaptive immune responses via dendritic cells.     

Statistical modelling of the differences between successive R-R intervals

Understanding the behaviour of R-R interval data and its successive differences is critical to the dynamics of cardiac control. Several time domain measures that quantify R-R interval variability have important clinical significance in terms of risk stratification and evaluating the effectiveness of treatment procedures. The present approach at examining the distributions of successive beat-to-beat differences of R-R interval data from different populations and under different conditions (baseline and reaction times) provides a valuable insight into their previously unexplored distributional properties. In particular, our analysis reveals that the successive differences have non-normal statistical distributions (a contradiction to the commonly used assumption of normality), and the absolute successive R-R interval differences approximately follows a Weibull distribution. As an illustration of the utility of this approach, we explore the statistical properties of the time domain measure: root mean square successive difference, study the association between the Weibull scale parameter estimate and respiratory sinus arrhythmia, and propose improvements in artifact detection algorithms.     

Temporal trends in infective endocarditis: a population-based study in Olmsted County, Minnesota

Context  Limited data exist regarding population-based epidemiologic changes in incidence of infective endocarditis (IE). Objective  To evaluate temporal trends in the incidence and clinical characteristics of IE. Design, Setting, and Patients  Population-based survey using the resources of the Rochester Epidemiology Project of Olmsted County, Minnesota. One hundred seven IE episodes occurred in 102 Olmsted County residents between 1970 and 2000. The modified Duke criteria were used to validate the diagnosis of definite or possible IE. Main Outcome Measures  Incidence of IE, proportion of patients with underlying heart disease, and causative microorganisms and clinical characteristics. Results  Age- and sex-adjusted incidence of IE ranged from 5.0 to 7.0 cases per 100 000 person-years during the study period and did not change significantly over time (P = .42 for trend). Infective endocarditis caused by viridans group streptococci was the most common organism-specific subgroup, with an annual adjusted incidence of 1.7 to 3.5 cases per 100 000; in comparison, IE due to Staphylococcus aureus had an annual adjusted incidence of 1.0 to 2.2 cases per 100 000. No time trend was detected for either pathogen group (P = .63 and P = .66, respectively). An increasing temporal trend was observed in the proportions of prosthetic valve IE cases (P = .09). Among people with underlying heart disease, there was an increasing temporal trend in mitral valve prolapse (P = .04) and a decreasing trend in rheumatic heart disease (P = .08). However, the absolute numbers were small. There was no time trend in rates of valve surgery or 6-month mortality during the study period (P = .97 and P = .59, respectively). Conclusions  In this community-based temporal trend study, we found no substantial change in the incidence of IE over the past 3 decades. Viridans group streptococci continue to outnumber S aureus as the most common causative organisms of IE in this population.      

RSA 2004: combined basic research satellite symposium - session four: hepatitis virus and alcohol interactions in immunity and liver disease

This article summarizes the proceedings of the RSA 2004 Combined Basic Research Satellite Meeting convened at the Westin Bayshore Resort and Marina, Vancouver, CA. The session "Hepatitis virus and alcohol interactions in immunity and liver disease" featured four speakers and was chaired by Drs. Diane Lucas and Samuel French. The presentations were 1) Mitochondrial effects of HCV proteins and alcohol by Steve Weinman, 2) Chronic alcohol consumption accelerates viral hepatitis and T-cell hepatitis via dysregulation of cytokine signaling by Bin Gao 3) Interactions between alcohol, hepatitis C virus and innate defense pathways by Steve Polyak and 4) Scavenger Receptor-mediated modulation of the innate and adaptive immune responses following chronic ethanol consumption by Geoffrey Thiele.