Cancer Research UK.

No abstract

Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

Background The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival.Methods New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m² administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m² administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m² repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m² administered intravenously over 2 h and oral capecitabine 1000 mg/m² twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m² intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m² every 2 weeks with regimen one and three or a loading dose of 400 mg/m² followed by a weekly infusion of 250 mg/m² with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-totreat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367.

No abstract

To the Editor: I have several concerns about the metaanalysis by Dr Gould and colleagues 1 about positron emission tomography (PET) imaging for diagnosis of pulmonary nodules. First, the prevalence of malignancy in the articles that they included was extremely high (55%-100%; mean, 72%), suggesting that the types of lesions that have been evaluated thus far with PET imaging are those with a very high likelihood of malignancy. The accuracy of PET imaging may be far lower in a population in whom the risk of malignancy is lower. The sensitivity might be lower because of a milder spectrum of disease in patients with a lower risk of malignancy, and the specificity might be lower because of more overlapping PET findings in small lesions of varying etiologies. 2 Thus, the results of their review are only applicable to a population of patients with a very high prevalence of cancer. Until additional studies provide evidence that PET imaging is accurate in a population with a low prevalence of cancer, it is premature to suggest application of PET imaging in this group, as the authors have done.Second, Gould et al did not sufficiently address the issue of heterogeneity of the different studies in their meta-analysis. The data appear fairly consistent with respect to sensitivity but appear extremely variable with respect to specificity, and it is not appropriate to average the specificity estimates when the results are so inconsistent. While I believe that specificity is less important if patients would otherwise proceed to surgery in the absence of PET imaging, if PET imaging were applied to a low-risk population as the authors suggest, the false-positive rate would become quite important.Finally, the authors apply receiver operating characteristic (ROC) curve methods to the data, but it does not appear that the different accuracy reported by the different studies has much to do with threshold differences. Was there truly a significant correlation between the sensitivity and the false-positive rate? I would guess that sorting the studies in Figure 1 by sensitivity would not show an inverse relationship between sensitivity and specificity but rather would confirm that there is simply a lot of heterogeneity with respect to specificity. ROC curve methodology is complex and difficult to understand, and I think it is best used to compare the results of more than 1 test. In this case, the ROC curve does not provide accurate information for the clinician who would like to know what performance they can hope to obtain from this test. It seems clear that the sensitivity of PET imaging (in a high-risk population) is high but that the specificity is more difficult to estimate.

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin – integrin α3/α6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness — a hallmark of pancreatic cancer — was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo . This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro .