Assessing the benefit–risk of new treatments using generalised pairwise comparisons: the case of erlotinib in pancreatic cancer

Background:

Efficacy and safety are the two considerations when characterising the effects of a new therapy. We sought to apply an innovative method of assessing the benefit–risk balance using data from a completed randomised controlled trial that compared erlotinib vs placebo added to gemcitabine in patients with advanced pancreatic cancer (NCIC CTG PA.3).

Methods:

We applied generalised pairwise comparisons with several prioritised outcome measures (e.g., one or more benefit outcomes and one or more risk outcomes). Here, the first priority outcome was overall survival (OS) time. Differences in OS that exceeded 2 months were considered clinically meaningful. The second priority outcome was toxicity. The overall treatment effect was quantified using the proportion in favour of erlotinib, which can be interpreted as the net proportion of patients who have a better overall outcome with erlotinib as compared with placebo. Sensitivity analyses were performed.

Results:

In this trial 569 patients were randomly assigned in a 1 : 1 ratio to receive gemcitabine plus either erlotinib or a matched placebo. Overall, the method indicated no statistically significant overall treatment effect in favour of erlotinib; if anything, the point estimate of the net proportion leaned in favour of the placebo group (overall proportion in favour of erlotinib=−3.6%, 95% CI, −14.2– 7.1% P=0.51). The net proportion was never in favour of the erlotinib group throughout all sensitivity analyses.

Conclusions:

Generalised pairwise comparisons make it possible to assess the benefit–risk balance of new treatments using a single statistical test for any number of prioritised outcomes. The benefit–risk assessment was not in favour of adding erlotinib to gemcitabine for the treatment of patients with advanced pancreatic cancer.     

Synaptopodin-2 induces assembly of peripheral actin bundles and immature focal adhesions to promote lamellipodia formation and prostate cancer cell migration

Synaptopodin-2 (Synpo2), an actin-binding protein and invasive cancer biomarker, induces formation of complex stress fiber networks in the cell body and promotes PC3 prostate cancer cell migration in response to serum stimulation. The role of these actin networks in enhanced cancer cell migration is unknown. Using time-course analysis and live cell imaging of mock- and Synpo2-transduced PC3 cells, we now show that Synpo2 induces assembly of actin fibers near the cell periphery and Arp2/3-dependent lamellipodia formation. Lamellipodia formed in a non-directional manner or repeatedly changed direction, explaining the enhanced chemokinetic activity of PC3 cells in response to serum stimulation. Myosin contraction promotes retrograde flow of the Synpo2-associated actin filaments at the leading edge and their merger with actin networks in the cell body. Enhanced PC3 cell migration correlates with Synpo2-induced formation of lamellipodia and immature focal adhesions (FAs), but is not dependent on myosin contraction or FA maturation. The previously reported correlation between Synpo2-induced stress fiber assembly and enhanced PC3 cell migration therefore reflects the role of Synpo2 as a newly identified regulator of actin bundle formation and nascent FA assembly near the leading cell edge.     

Intracranial granulocytic sarcoma in postpolycythemia myeloid metaplasia

A 57-year-old man with a ten-year history of polycythemia vera had myeloid metaplasia, extramedullary hematopoiesis, and terminally, possible leukemic transformation with intracranial granulocytic sarcoma. Radiation therapy produced a partial and temporary beneficial response. Intracranial granulocytic sarcoma is typically associated with acute or chronic myelogenous leukemia and has not been previously associated with postpolycythemia myeloid metaplasia.     

Influenza A pneumonia with rhabdomyolysis

Influenza A pneumonia accounts for a significant number of the community-acquired pneumonias in the United States. While myalgia is a common complaint in influenza A infection, few cases of rhabdomyolysis associated with this virus have been described. Although it has been recently recognized that rhabdomyolysis complicating certain bacterial pneumonias has important prognostic implications, rhabdomyolysis in the setting of influenza A pneumonia does not appear to carry the same prognostic significance.     

Nonverbal imitation skills in children with specific language delay

Research in children with language problems has focussed on verbal deficits, and we have less understanding of children's deficits with nonverbal sociocognitive skills which have been proposed to be important for language acquisition. This study was designed to investigate elicited nonverbal imitation in children with specific language delay (SLD). It is argued that difficulties in nonverbal imitation, which do not involve the processing of structural aspects of language, may be indicative of sociocognitive deficits. Participants were German-speaking typically developing children (n = 60) and children with SLD (n = 45) aged 2–3½ years. A novel battery of tasks measured their ability to imitate a range of nonverbal target acts that to a greater or lesser extent involve sociocognitive skills (body movements, instrumental acts on objects, pretend acts). Significant group differences were found for all body movement and pretend act tasks, but not for the instrumental act tasks. The poorer imitative performance of the SLD sample was not explained by motor or nonverbal cognitive skills. Thus, it appeared that the nature of the task affected children's imitation performance. It is argued that the ability to establish a sense of connectedness with the demonstrator was at the core of children's imitation difficulty in the SLD sample.     

Making errorless learning more active: Self-generation in an error free learning context is superior to standard errorless learning of face–name associations in people with Alzheimer's disease

Errorless learning (EL) principles have been shown to enable people with memory impairments to acquire various types of information (Grandmaison & Simard, 2003; Wilson, 2005). However, the effects of EL, based on simple repetition only, tend to be limited with regards to their size and longevity. The present study investigated whether EL could be improved by actively engaging people with Alzheimer's disease in the learning process. Patients learned the names of famous faces over 10 training sessions, treated either with a non-learning control, a simple repetition EL procedure, or an EL condition in which responses had to be self-generated. Cued recall rates after the final training session were significantly greater for the names treated with the self-generated EL technique compared to the control and the repetition EL conditions. In addition, there was evidence that patients with less severe general cognitive impairment benefit more from active generation than more severely impaired patients. The implications of this research for individualised memory rehabilitation programmes are discussed.     

Exercise in a Cold Climate

Dr. Shephard reviews practical advice required by the winter sportsman in relation to more fundamental aspects of the bodily response to cold. Heat loss occurs by radiation, convection, conduction, and evaporation of sweat; this loss must be made good by metabolism if the body is not to be chilled. Convection is the main source of heat loss in the sportsman, and must be minimized by appropriate clothing. Chilling below a body temperature of 95°F is undesirable; temperatures below 90°F are rapidly fatal. Heat is restored to the body by warming, by the “waste” energy of physical activity, and by shivering.