A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer

Background:

We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) and report the first prospective extended RAS analysis in a phase 3 trial.

Methods:

Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg⁻¹ Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint.

Results:

Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57–0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53–0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49–2.00). No new safety signals were observed.

Conclusions:

Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.     

Plaque formation and gingivitis after supervised mouthrinsing with 0.2% delmopinol hydrochloride, 0.2% chlorhexidine digluconate and placebo for 6 months

OBJECTIVES AND METHODS: A double-blind, randomized, 6-month clinical trial with parallel group design in 162 patients with gingivitis divided into three rinsing groups was conducted in order to study the efficacy and safety of a flavoured solution of delmopinol hydrochloride 2 mg ml“‘ (0.2% w/v, Decapinol Mouthwash”^®) used for supervised mouthrinsing in one rinsing group, in comparison with chlorhexidine digluconate 2 mg ml^-1 (0.2% w/v, Hibitane Dental’^{a, b}) in a second rinsing group, and placebo in the third group. The criteria of the Plaque Index (PI) were used to assess plaque formation. Bleeding on probing (BOP) to the bottom of the pocket with a standard pressure was used as the primary gingivitis assessment. The occurrence of supragingival dental calculus and extrinsic tooth staining were also assessed. In addition, patients were asked to report adverse events at each visit. RESULTS: Delmopinol and chlorhexidine exhibited lower scores of the mean PI and the BOP percentage than placebo, both at the 3-month and 6-month examinations. Furthermore, both active solutions showed a higher extent of staining of the teeth than placebo during these two observation periods. Rinsing with chlorhexidine resulted in more dental calculus than placebo after 6 months. Chlorhexidine showed lower scores for plaque formation and gingivitis development but higher scores of supragingival dental calculus (after 6 months) and tooth staining than did delmopinol. Both active solutions were reported by the patients–approximately to the same extent but more frequently than placebo–to induce taste alterations and a transient anaesthetic sensation of the oral mucosa. However, subjective staining of the teeth and tongue was reported by 16% of the delmopinol patients, but by 86% of the patients rinsing with chlorhexidine for 6 months. Furthermore, 24% of the patients in the chlorhexidine group, 9% in the delmopinol group and 4% in the placebo group wished to withdraw from treatment. CONCLUSIONS: The results from this clinical trial indicate that supervised rinsing with 0.2% delmopinol hydrochloride or with 0.2% chlorhexidine digluconate twice daily for 60 s as a supplement to normal mechanical oral hygiene procedures resulted in less plaque formation and gingivitis than rinsing with placebo. Although chlorhexidine was more effective than delmopinol regarding plaque formation and gingivitis, it was considered by the patients as less tolerable.     

A method to assess the clinical outcome of ridge augmentation procedures

BACKGROUND: Alveolar ridge augmentation procedures are often needed prior to implant placement or prosthetic rehabilitation. The purpose of this study was to develop a quantitative method to assess the clinical outcome of such procedures. METHODS: Two volumetric methods, based on the volume difference between the pre- and postoperative ridge, were developed. Either a transparent vacuum stent material (method A) or a silicone impression material in a custom acrylic tray (method B) was used to make an impression of the postoperative stone cast. This impression was then filled with polyvinylsiloxane bite registration material (PBRM) and placed on the preoperative cast. The volume of PBRM at the site of the augmented ridge (corresponding to the achieved ridge volume increase, in ml) was measured gravimetrically. Two independent examiners used both methods, in random order, to assess the outcome of 6 diverse clinical cases. Triplicate measurements were made (method precision). Method accuracy was assessed by fabrication of metal castings (known volumes) applied on a preoperative cast to simulate an augmentation procedure. RESULTS: Intra- and inter-examiner reproducibility was high (intraclass correlation coefficients > or =0.84) for both methods. The volumetric measurements obtained by method B showed excellent correlation with the predetermined augmentation volumes (r2 = 0.99; y = 0.94x + 0.12), in contrast to the measurements obtained by method A (r2 = 0.46; y = 0.43x + 1.37). CONCLUSIONS: The developed volumetric method (method B) is both precise and accurate in assessing the outcome of ridge augmentation. This simple, cost-effective, and easy to implement method should be helpful in clinical studies of ridge augmentation procedures.     

Long horizon input parameterisations to enlarge the region of attraction of MPC

In this paper, the efficacy of structured and unstructured parameterisations of the degree of freedom within a predictive control algorithm is investigated. While several earlier papers investigated the enlargement of the region of attraction using structured prediction dynamics, little consideration has been given to the potential of unstructured parameterisations to handle the trade‐off between the region of attraction, performance and computational burden. This paper demonstrates how unstructured dynamics can be both selected and used effectively and furthermore gives a comparison with structured methods. Copyright © 2014 John Wiley & Sons, Ltd.     

High-confidence prediction of global interactomes based on genome-wide coevolutionary networks

Interacting or functionally related protein families tend to have similar phylogenetic trees. Based on this observation, techniques have been developed to predict interaction partners. The observed degree of similarity between the phylogenetic trees of two proteins is the result of many different factors besides the actual interaction or functional relationship between them. Such factors influence the performance of interaction predictions. One aspect that can influence this similarity is related to the fact that a given protein interacts with many others, and hence it must adapt to all of them. Accordingly, the interaction or coadaptation signal within its tree is a composite of the influence of all of the interactors. Here, we introduce a new estimator of coevolution to overcome this and other problems. Instead of relying on the individual value of tree similarity between two proteins, we use the whole network of similarities between all of the pairs of proteins within a genome to reassess the similarity of that pair, thereby taking into account its coevolutionary context. We show that this approach offers a substantial improvement in interaction prediction performance, providing a degree of accuracy/coverage comparable with, or in some cases better than, that of experimental techniques. Moreover, important information on the structure, function, and evolution of macromolecular complexes can be inferred with this methodology.     

Mean arterial pressure at 11(+0) to 13(+6) weeks in the prediction of preeclampsia

This study aimed to determine the performance of screening for preeclampsia (PE) by maternal medical history and mean arterial pressure (MAP) at 11(+0) to 13(+6) weeks. In 5590 women with singleton pregnancies attending for routine care at 11(+0) to 13(+6) week's gestation we recorded maternal variables and measured the MAP. We excluded 397 because they had missing outcome data or the pregnancies resulted in miscarriage or termination. In 104 patients there was subsequent development of PE, 97 developed gestational hypertension, 574 delivered small-for-gestational-age newborns, and 4418 were unaffected by PE, gestational hypertension, or small for gestational age. A multivariate Gaussian model was fitted to the distribution of log multiple of the median MAP in the PE and unaffected groups. Likelihood ratios for log multiple of the median MAP were computed and used together with maternal variables to produce patient-specific risks for each case. Detection rates and false-positive rates were calculated by taking the proportions with risks above a given risk threshold. In the unaffected group, log MAP was influenced by maternal age, ethnic origin, smoking, family and personal history of PE, and fetal crown-rump length. In the prediction of PE, significant contributions were provided by log multiple of the median MAP, ethnic origin, body mass index, and personal history of PE. The detection rate of PE by log multiple of the median MAP and maternal variables was 62.5% for a false-positive rate of 10%. Maternal variables, together with MAP, at 11(+0) to 13(+6) weeks identify a group at high risk for development of PE.     

Intubation routes for enteroclysis

The transnasal and peroral intubation routes for enteroclysis examination are described. A survey of 22 patients who underwent enteroclysis by both approaches revealed an overwhelming preference for the transnasal route. Transnasal intubation for enteroclysis is rapidly performed with adequate catheter control and in most patients is associated with less discomfort compared with the peroral route.