A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer

Our purpose was to determine the response rate and median and overall survival of gemcitabine as monotherapy versus gemcitabine plus irinotecan in advanced or metastatic pancreatic cancer. Patients with histologically or cytologically confirmed adenocarcinoma who were chemotherapy and radiotherapy naive were enrolled. Patients were centrally randomised at a one-to-one ratio to receive either gemcitabine monotherapy (900 mg m−2 on days 1, 8 and 15 every 4 weeks (arm G), or gemcitabine (days 1 and 8) plus irinotecan (300 mg m−2 on day 8) (arm IG), repeated every 3 weeks. The total number of cycles administered was 255 in the IG arm and 245 in the G arm; the median number of cycles was 3. In all, 145 patients (71 in arm IG and 74 in arm G) were enrolled; 60 and 70 patients from arms IG and G, respectively, were evaluable. A complete clinical response was achieved in three (4.3%) arm G patients; nine (15%) patients in arm IG and four (5.7%) in arm G achieved a partial response. The overall response rate was: arm IG 15% and arm G 10% (95% CI 5.96–24.04 and 95% CI 2.97–17.03, respectively; P=0.387). The median time to tumour progression was 2.8 months and 2.9 months and median survival time was 6.4 and 6.5 months for the IG and G arms, respectively. One-year survival was 24.3% for the IG arm and 21.8% for the G arm. No statistically significant difference was observed comparing gemcitabine monotherapy versus gemcitabine plus irinotecan in the treatment of advanced pancreatic cancer, with respect to overall and 1-year survival

Mapping anhedonia onto reinforcement learning: A behavioural meta-analysis

BACKGROUND: Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. METHODS: Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. RESULTS: MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. CONCLUSION: Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior

Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease

Background Vedolizumab specifically recognizes the 47 integrin and selectively blocks gut lymphocyte trafficking: potentially, it offers gut-specific immunosuppression. Aims To review the safety of vedolizumab and summarise post-marketing data to assess if any safety concerns that differ from registration trials have emerged. Method A systematic bibliographic search identified six registration trials and nine cohort studies. Results Integrated data from registration trials included 2830 vedolizumab-exposed patients (4811 person-years exposure (PYs)) and 513 placebo patients. This reported lower exposure-adjusted incidence rates of infection (63.5/100 PYs; 95% CI 59.6 to 67.3) and serious adverse events (20.0/100 PYs; 95% CI 18.5 to 21.5) compared to placebo (82.9/100 PYs; 95% CI 68.3 to 97.5) and (28.3/100 PYs 95% CI 20.6 to 35.9) respectively. Higher, but statistically insignificant rates of enteric infections occurred in vedolizumab-exposed patients (7.4/100 PYs; 95% CI 6.6 to 8.3) compared to placebo (6.7 PYs; 95% CI 3.2 to 10.1). Six post-marketing cohort studies (1049 patients, 403 PYs) demonstrated rates of infection of 8% (82/1049); enteric infection of 2% (21/1049) and adverse events of 16% (166/1049). Multivariate analysis in one cohort study suggested increased risk of surgical site infection with perioperative VDZ. Human experience in pregnancy is limited. Conclusions Post-marketing data confirm the excellent safety of vedolizumab observed in registration trials. The signal of post-operative complications should be interpreted with caution, but warrants further study. Although comparative studies are needed, Vedolizumab may be a safe alternative in patients who best avoid systematic immunosuppression, including those predisposed to infection, malignancy, or the elderly.</p

Separate neural pathways process different decision costs

Behavioral ecologists and economists emphasize that potential costs, as well as rewards, influence decision making. Although neuroscientists assume that frontal areas are central to decision making, the evidence is contradictory and the critical region remains unclear. Here it is shown that frontal lobe contributions to cost-benefit decision making can be understood by positing the existence of two independent systems that make decisions about delay and effort costs. Anterior cingulate cortex lesions affected how much effort rats decided to invest for rewards. Orbitofrontal cortical lesions affected how long rats decided to wait for rewards. The pattern of disruption suggested the deficit could be related to impaired associative learning. Impairments of the two systems may underlie apathetic and impulsive choice patterns in neurological and psychiatric illnesses. Although the existence of two systems is not predicted by economic accounts of decision making, our results suggest that delay and effort may exert distinct influences on decision making. © 2006 Nature Publishing Group