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Background: The optimal timing of surgery in relation to chemoradiation is still controversial. Retrospective analysis has demonstrated in the recent decades that the regression of adenocarcinoma can be slow and not complete until after several months. More recently, increasing pathologic Complete Response rates have been demonstrated to be correlated with longer time interval. The purpose of the trial is to demonstrate if delayed timing of surgery after neoadjuvant chemoradiotherapy actually affects pathologic Complete Response and reflects on disease-free survival and overall survival rather than standard timing., Methods: The trial is a multicenter, prospective, randomized controlled, unblinded, parallel-group trial comparing standard and delayed surgery after neoadjuvant chemoradiotherapy for the curative treatment of rectal cancer. Three-hundred and forty patients will be randomized on an equal basis to either robotic-assisted/standard laparoscopic rectal cancer surgery after 8 weeks or robotic-assisted/standard laparoscopic rectal cancer surgery after 12 weeks., Discussion: To date, it is well-know that pathologic Complete Response is associated with excellent prognosis and an overall survival of 90%. In the Lyon trial the rate of pCR or near pathologic Complete Response increased from 10.3 to 26% and in retrospective studies the increase rate was about 23-30%. These results may be explained on the relationship between radiation therapy and tumor regression: DNA damage occurs during irradiation, but cellular lysis occurs within the next weeks. Study results, whether confirmed that performing surgery after 12 weeks from neoadjuvant treatment is advantageous from a technical and oncological point of view, may change the current pathway of the treatment in those patient suffering from rectal cancer., Trial Registration: ClinicalTrials.gov NCT3465982.

MiR-182 expression was evaluated by qRT-PCR and in situ hybridization in 20 tubular adenomas, 50 colorectal carcinoma (CRC), and 40 CRC liver metastases. Control samples obtained from patients with irritable bowel syndrome, or tumor-matched normal colon mucosa were analyzed (n=50). MiR-182 expression increased progressively and significantly along with the colorectal carcinogenesis cascade, and in CRC liver metastases. The inverse relation between miR-182 and the expression of its target gene ENTPD5 was investigated by immunohistochemical analysis. We observed that normal colocytes featured a strong ENTPD5 cytoplasmic expression whereas a significantly and progressively lower expression was present along with dedifferentiation of the histologic phenotype. Plasma samples from 51 CRC patients and controls were tested for miR-182 expression. Plasma miR-182 concentrations were significantly higher in CRC patients than in healthy controls or patients with colon polyps at endoscopy. Moreover, miR-182 plasma levels were significantly reduced in post-operative samples after radical hepatic metastasectomy compared to preoperative samples. Our results strengthen the hypothesis of a central role of miR-182 dysregulation in colon mucosa transformation, demonstrate the concomitant progressive down-regulation of ENTPD5 levels during colon carcinogenesis, and indicate the potential of circulating miR-182 as blood based biomarker for screening and monitoring CRC during the follow-up.

Background: An understanding of the activated protein signaling architecture in non-small-cell lung cancer (NSCLC) is of critical importance to the development of new therapeutic approaches and identification of predictive and prognostic biomarkers for patient stratification., Methods: We used reverse-phase protein microarrays to map the activated protein signaling networks of 47 NSCLC tumors, 28 of which were node negative, which were subjected to tumor cellular enrichment using laser capture microdissection. The phosphorylation/cleavage levels of 111 key signaling proteins and total levels of 17 proteins were measured for broadscale signaling analysis., Results: Pathway activation mapping of NSCLC revealed distinct subgroups composed of epidermal growth factor receptor (ERBB1), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3), v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ERBB4), v-akt murine thymoma viral oncogene homolog 1- mammalian target of rapamycin (AKT-mTOR), protein kinase, AMP-activated, alpha 2 catalytic subunit (AMPK), and autophagy-related signaling, along with transforming growth factor-beta-signaling protein 1 (SMAD), insulin-line growth factor receptor (IGFR), rearranged during transfection proto-oncogene (RET), and activated CDC42-associated kinase (ACK) activation. Investigation of epidermal growth factor receptor (EGFR)-driven signaling identified a unique cohort of tumors with low EGFR protein expression yet high relative levels of phosphorylated EGFR and high EGFR total protein with low relative levels of phosphorylation. Last, mapping analysis of patients with NSCLC with N0 disease revealed a pilot pathway activation signature composed of linked epidermal growth factor receptor family (HER)-AMPK-AKT-mTOR signaling network along with focal adhesion kinase- LIM domain kinase-1 (FAK-LIMK) and janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways that correlated with short-term survival and aggressive disease., Conclusions: Functional protein pathway activation mapping of NSCLC reveals distinct activation subgroups that are underpinned by important therapeutic targets and that patients with early-stage node negative disease and poor prognosis may be identified by activation of defined, biochemically linked protein signaling events. Such findings, if confirmed in larger study sets, could help select and stratify patients for personalized targeted therapies.

Objectives: p53 Gene variants BstUI RFLP at codon 72 in exon 4, 16bp tandem repeat in intron 3 and MspI RFLP in intron 6, which code for two functionally different protein isoforms, have been shown to modulate susceptibility to different types of human neoplasms., Methods: p53 genotype was assessed in 90 CRC patients, 321 age-matched controls and 322 centenarians., Results: The p53 codon 72 arginine, the p53 16bp deletion, and the MspI RFLP were significantly more frequent in CRC patients in comparison to the controls and to the centenarians (odd ratio 1.44 and 1.93). In the CRC group, the BstUI RFLP polymorphism was the more frequent combination (62.2%), and it was significantly associated with highly infiltrating (p<0.01), poorly differentiated (p<0.01), and metastatic (p<0.05) tumours. Our findings indicate that the p53 codon 72 polymorphisms are associated with a higher risk of CRC and are associated with more advanced and undifferentiated tumours.

Background: Since specific epidermal growth factor receptor (EGFR) somatic mutations have been demonstrated to influence the response to anti-EGFR therapy in non-small cell lung cancer, EGFR gene mutational analysis of different types of neoplasm is under investigation., Patients and Methods: EGFR protein expression and gene mutations in exons 18, 19 and 21 were investigated in 49 gastric adenocarcinomas., Results: no specific EGFR gene mutations were detected, while EGFR positive staining was detected in 6% of the cases., Conclusion: Our findings indicate that in gastric adenocarcinoma, specific EGFR gene mutations are very rare or absent and the rate of EGFR protein expression is low.

Aims: To investigate the survival benefit of extended lymphadenectomy (D2) in EGC patients in one European Institution., Methods: A review was made of our prospective gastric database from January 1980 to December 2001. Of 527 patients with primary gastric adenocarcinoma, 119 with EGC underwent potentially curative resection (R0) with D2 lymphadenectomy., Results: There were two post-operative deaths. Of the 117 evaluable cases, 96 were classified as N0 and 21 as N+, with metastases in the perigastric lymph nodes (level 1) in 13, and beyond this site (level 2) in eight. Five-year survival was 85.9 and 83.0% in N0 and N+ patients, respectively. During a median follow-up of 90 months, five of the eight patients with level 2 metastases died of recurrent disease and three were alive. The estimated survival benefit for 119 patients with EGC was 2.5% (3/119 cases)., Conclusions: In patients with EGC, metastases to level 2 are rare. Our results indicate that D2 lymphadenectomy has a limited survival benefit and that in these cases a less extensive lymphadenectomy (D1) could be performed.

Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potential in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5-year follow-up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser-microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (alpha-1,3-)-glycoprotein beta-1,4-N-acetyl-glucosaminyl-transferase (GnT-IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT-IV upregulation was confirmed by RT-PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications., (Copyright 2005 Wiley-Liss, Inc)

Background and Objectives: Low tumor expression of the p27(Kip1) protein, which is involved in cell cycle control and apoptosis, is considered a negative prognostic factor in different types of cancer. The aim of this study was to evaluate the clinical and pathological significance of low p27(Kip1) protein expression in patients who had undergone resection for gastric adenocarcinoma., Methods: p27(Kip1) protein was studied by immunohistochemistry in formalin-fixed tumor sections from 95 patients who underwent resection for gastric adenocarcinoma between 1991 and 1996. Based on the median value of protein expression, p27(Kip1) protein expression was classified as low or high., Results: Low p27(Kip1) protein expression was significantly associated with tumor de-differentiation, increased penetration through the gastric wall, lymph node metastasis, and advanced tumor stage. In the group of 84 patients who underwent curative surgery, 5-year survival was 74% in cases with high p27(Kip1) protein expression and 38% in those with low p27(Kip1) protein expression (P < 0.001). At multivariate analysis, low p27(Kip1) protein expression was an independent negative prognostic factor for survival (RR = 3.671; P = 0.004)., Conclusions: In gastric adenocarcinoma, low p27(Kip1) protein expression is associated with poorly differentiated and advanced tumors and is a negative prognostic factor of potential clinical value., (Copyright 2002 Wiley-Liss. Inc.)