Additional value of EGFR downstream signaling phosphoprotein expression to KRAS status for response to anti‐EGFR antibodies in colorectal cancer

KRAS mutations are a strong predictive marker of resistance to anti‐epidermal growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC) but only a subset of wild‐type (WT) KRAS patients are responders, suggesting the existence of additional markers of resistance to this treatment. The activation of EGFR downstream signaling pathways may be one of these ones. In a series of 42 patients with advanced CRC treated with cetuximab/panitumumab, for whom KRAS status was previously determined, we retrospectively analyzed the intratumor expression of EGFR downstream signaling phosphoproteins of the RAS/MAPK and PI3K/AKT pathways (pERK1/2, pMEK1, pAKT, pP70S6K and pGSK3β) using Bio‐Plex® phosphoprotein array. Association with tumor response, progression‐free survival (PFS) and overall survival (OS) was assessed. The expression of all the phosphoproteins was higher in KRAS mutated tumors than in WT tumors. The expression of pP70S6K was lower in responders than in nonresponder patients. In univariate analysis, patients with high pMEK1 or pP70S6K expression had a shorter PFS than those with low expression. Patients with high pP70S6K expression also had a shorter OS. In multivariate analysis, PFS was shorter for patients with high pMEK1 or pP70S6K expression, independently of KRAS status, as OS for patients with high pP70S6K expression. Therefore, WT KRAS patients with high pP70S6K expression had a shorter survival than those with low expression. Our results suggest the importance of EGFR downstream signaling phosphoproteins expression in addition to KRAS status to define the subgroup of patients who will not benefit from anti‐EGFR therapy.     

Loss of NF2/Merlin expression in advanced sporadic colorectal cancer

Purpose

NF2/Merlin was first identified through its association with neurofibromatosis type 2 (NF2). However, accumulating evidence suggests a more general involvement in tumorigenesis and, in particular, a broader role in tumor suppression. The aim of this study was to examine NF2/Merlin involvement in sporadic colorectal cancer.

Methods

This study is the first to examine the role of NF2/Merlin in sporadic colorectal cancer through LOH analysis at the NF2 locus and mRNA expression analysis via quantitative RT-PCR of total NF2, NF2 isoform I and II. In addition, Merlin protein expression was assessed by immunohistochemistry and Western blotting.

Results

NF2 LOH was detected in 20.0 % of heterozygous cases and was found to be more frequent in tumors larger than 5 cm in diameter (p?=?0.041) and in tumors with a less differentiated phenotype (p?=?0.027). No differences were observed in total NF2 and NF2 isoform I/isoform II mRNA expression between the tumors and their corresponding normal mucous tissues. NF2 isoform II was the most predominant isoform in all samples analyzed. mRNA expression levels of total NF2 and isoforms I and II were significantly lower in poorly differentiated tumors (p?=?0.033, p?=?0.036 and p?=?0.044, respectively). Weak Merlin immunostaining was more frequent in poorly differentiated tumors (p?=?0.034) and tumors classified as Dukes’ C (p?=?0.023). A distinct pattern of Merin phosphorylation was observed in tumors compared to normal mucous tissues.

Conclusion

Our data indicate that NF2/Merlin may serve as a potential target in the management of colorectal cancer.     

Morbidly Obese are Ghrelin and Leptin Hyporesponders with Lesser Intragastric Balloon Treatment Efficiency

Background

Ghrelin and leptin recently emerged as the most influential neuroendocrine factors in the pathophysiology of obesity. The said peptides act in reciprocity and are responsible for regulation of appetite and energy metabolism. Intragastric balloons acquired worldwide popularity for obesity treatment. However, the roles of ghrelin and leptin in intragastric balloon treatment were still not systematically studied.

Methods

A prospective single-center study included 43 Caucasians treated with BioEnterics intragastric balloon, with age range of 18?C60, and divided to non-morbid (body mass index cutoff 40 kg/m²) or morbid type of obesity, with 12 months follow-up. Serum hormonal samples were taken from fasting patients and kept frozen until analyses.

Results

Significant differences were observed in anthropometrics and there were no differences between genders or comorbidities. The baseline weight for non-morbid vs. morbid was 104 kg (90?C135) vs. 128.5 kg (104?C197). Weight loss was statistically different between the studied groups during the study course with a median control weight at 6 months of 92 kg (72?C121) vs. 107 kg (84?C163), p?<?0.001. Treatment was successful for 18 (94.7%) vs. 16 (66.7%) patients, p?=?0.026. Ghrelin varied from 333.3 to 3,416.8 pg/ml and leptin from 1.7 to 61.2 ng/ml, with a statistically significant time-dependent relationship. A significant difference (p?=?0.04) with emphasized ghrelin peak was found in the 3rd month of treatment for non-morbidly obese subjects.

Conclusions

The importance of ghrelin and leptin in treatment-induced changes was reaffirmed. Ghrelin hyper-response in non-morbidly obese subjects characterized greater short-term treatment efficiency and landmarked an inclination to weight regain. The results suggest a potential pattern of individualization between obese patients according to body mass index towards intragastric balloon or bariatric surgery. Further studies are needed in order to get better insights in the pathophysiologic mechanisms of obesity.     

The neural network for tool-related cognition: An activation likelihood estimation meta-analysis of 70 neuroimaging contrasts

ABSTRACT

The ability to recognize and use a variety of tools is an intriguing human cognitive function. Multiple neuroimaging studies have investigated neural activations with various types of tool-related tasks. In the present paper, we reviewed tool-related neural activations reported in 70 contrasts from 56 neuroimaging studies and performed a series of activation likelihood estimation (ALE) meta-analyses to identify tool-related cortical circuits dedicated either to general tool knowledge or to task-specific processes. The results indicate the following: (a) Common, task-general processing regions for tools are located in the left inferior parietal lobule (IPL) and ventral premotor cortex; and (b) task-specific regions are located in superior parietal lobule (SPL) and dorsal premotor area for imagining/executing actions with tools and in bilateral occipito-temporal cortex for recognizing/naming tools. The roles of these regions in task-general and task-specific activities are discussed with reference to evidence from neuropsychology, experimental psychology and other neuroimaging studies.