Search

The distribution of carcinoembryonic antigen (CEA) in colorectal cancer (CRC) differs from that in normal colorectal tissue, being found on all borders of the cell membrane and hence enabling access to intravenous antibody, making CEA a good target for antibody-based therapy. The distinctive anti-CEA antibody, PR1A3, binds only membrane-bound CEA. Humanised PR1A3 (hPR1A3) was assessed both in vitro cytotoxicity and binding assays with colorectal cancer cell lines expressing varying levels of CEA. Human peripheral blood mononuclear cells (PBMCs) and purified natural killer (NK) cells were used as effectors. The in vitro assays demonstrated hPR1A3 CEA-specific binding and antibody-dependent and CEA-specific killing of human colorectal cancer cell lines by human PBMCs. The effect increased with increasing concentration of antibody and surface CEA, and was lost by using the parent murine IgG1 PR1A3. Killing was also blocked by antibody to the Fc-gammaIIIA receptor. Purified human NK cells were effective at much lower effector:target ratios than unfractionated PBMCs, indicating that NK cells were the main mediators of hPR1A3-based CEA-specific killing. The results support the development of hPR1A3 for therapy of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Circular staplers perform a critical function for creation of anastomoses in colorectal surgeries. Powered stapling systems allow for reduced force required by surgeons to fire the device and may provide advantages for creating a secure anastomosis. The objective of this study was to evaluate the clinical performance of a novel circular powered stapler in a post-market setting, during left-sided colectomy procedures., Materials and Methods: Consecutive subjects underwent left-sided colorectal resections that included anastomosis performed with the ECHELON CIRCULAR™ Powered Stapler (ECP). The primary endpoint was the frequency in which a stapler performance issue was observed. Secondary endpoints included evaluation of ease of use of the device via a surgeon satisfaction questionnaire, and monitoring/recording of procedure-related adverse events (AEs)., Results: A total of 168 anastomoses were performed with the ECP. Surgical approaches included robotic-assisted (n = 74, 44.0%), laparoscopic (n = 71, 42.3%), open (n = 20, 11.9%), and hand-assisted minimally invasive (n = 3, 1.8%) procedures. There were 22 occurrences of device performance issues in 20 (11.9%) subjects during surgery. No positive intraoperative leak tests were observed, and only 1 issue was related to a procedure-related AE or surgical complication, which was an instance of incomplete surgical donut necessitating re-anastomosis. Postoperative anastomotic leaks were experienced in 4 (2.4%) subjects. Clavien-Dindo classification of all AEs indicated that 92.0% were Grades I or II. Participating surgeons rated the ECP as easier to use compared to previously used manual circular staplers in 85.7% of procedures., Conclusion: The circular powered stapler exhibited few clinically relevant performance issues, an overall favorable safety profile, and ease of use for creation of left-sided colon anastomoses., (Copyright © 2020 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Aim: Transanal endoscopic microsurgery (TEM) enables organ preservation after rectal tumour surgery. Its application is being expanded using adjuvant and neoadjuvant treatments. Our objective was to evaluate the changes over time in anorectal function, urinary symptoms and quality of life (QoL) in patients who had TEM surgery for a rectal tumour., Method: Between September 2009 and October 2012, a consecutive series of 102 patients underwent TEM at a single institution. Patients were asked to fill out standardized questionnaires at baseline and then at 6, 12, 26 and 52 weeks after surgery. The QoL among these patients was assessed using one generic (EQ-5D) and two disease-specific [European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29] questionnaires. Anorectal and urinary symptoms were studied using the COlo-REctal Functional Outcome (COREFO) and the International Prostate Symptom Score (I-PSS) questionnaires, respectively., Results: The response rate was 90% (92/102 patients). Postoperative complications occurred in 14% (13/92) of patients. The general QoL (as assessed using the EQ-5D) was lower 6 and 12 weeks after TEM compared with baseline QoL (P < 0.05) but returned towards baseline after 26 weeks. Anorectal function (determined using the COREFO) was worse 6 weeks postoperatively (P < 0.01) but had normalized by 12 weeks. Urinary function (determined using the I-PSS) was not affected at any time point after surgery. The total COREFO score and the American Society of Anesthesiologists (ASA) score were correlated with the deterioration in QoL., Conclusion: The study demonstrates that TEM has a temporary and reversible impact on QoL and anorectal function. Intensive interrogation of QoL and function using appropriate questionnaires will help to define the role of organ-preserving surgery for rectal cancer before and after chemoradiotherapy., (Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.)

Drugs that inhibit insulin-like growth factor 1 (IGFI) receptor IGFIR were encouraging in early trials, but predictive biomarkers were lacking and the drugs provided insufficient benefit in unselected patients. In this study, we used genetic screening and downstream validation to identify the WNT pathway element DVL3 as a mediator of resistance to IGFIR inhibition. Sensitivity to IGFIR inhibition was enhanced specifically in vitro and in vivo by genetic or pharmacologic blockade of DVL3. In breast and prostate cancer cells, sensitization tracked with enhanced MEK-ERK activation and relied upon MEK activity and DVL3 expression. Mechanistic investigations showed that DVL3 is present in an adaptor complex that links IGFIR to RAS, which includes Shc, growth factor receptor-bound-2 (Grb2), son-of-sevenless (SOS), and the tumor suppressor DAB2. Dual DVL and DAB2 blockade synergized in activating ERKs and sensitizing cells to IGFIR inhibition, suggesting a nonredundant role for DVL3 in the Shc-Grb2-SOS complex. Clinically, tumors that responded to IGFIR inhibition contained relatively lower levels of DVL3 protein than resistant tumors, and DVL3 levels in tumors correlated inversely with progression-free survival in patients treated with IGFIR antibodies. Because IGFIR does not contain activating mutations analogous to EGFR variants associated with response to EGFR inhibitors, we suggest that IGF signaling achieves an equivalent integration at the postreceptor level through adaptor protein complexes, influencing cellular dependence on the IGF axis and identifying a patient population with potential to benefit from IGFIR inhibition., (©2014 American Association for Cancer Research.)

Aim: Our aim was to determine the frequency and economic impact of anastomotic leakage (AL) at local and national levels in England., Method: All patients who underwent AR in Oxford between 2007 and 2009 were evaluated for AL. Hospital Episode Statistics (HES) data were used to determine reoperation rates after elective AR (n = 23 388) in England between 2000 and 2008. Hospital episode remuneration costs were calculated by the local commissioning department and compared with Department of Health (DH) reference index costs., Results: The frequency of AL following anterior resection was 10.9% (31 out of 285) in Oxford. Laparotomy for leakage was performed in 5.6% of cases. The 30-day hospital mortality rate for all ARs was 2.1%, compared with 3.2% after AL. The national relaparotomy rate (within 28 days) and 30-day hospital mortality in English National Health Service (NHS) trusts following AR were 5.9% and 2.9%, respectively. Institutional remunerated tariffs (£6233 (SD ± 965)) were similar to DH reference costs (£6319 (SD ± 1830)) after uncomplicated AR. However, there was a significant (P = 0.008) discrepancy between the remunerated tariff for AL (£9605 (SD ± 6908)) and the actual cost (£17 220 (SD ± 9642)). AL resulted in an additional annual cost of approximately £1.1 million to £3.5 million when extrapolated nationally., Conclusion: The estimated economic burden of anastomotic leakage following AR is approximately double that of the remunerated tariff., (© 2013 The Authors. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.)

A significant proportion of colorectal cancer (CRC) patients are resistant to anti-ERBB1 [avian erythroblastic leukemia viral (v-erb-b) oncogene homolog, receptor for EGF] monoclonal antibodies (Mabs). We evaluated both immune and nonimmune effects of cetuximab (anti-ERBB1 Mab), trastuzumab (anti-ERBB2 Mab), pertuzumab (anti-ERBB2 Mab), and lapatinib (dual ERBB1 and ERBB2 tyrosine kinase inhibitor) in a large well-characterized panel of 64 CRC cell lines to find response predictive tumor characteristics. There was a significant correlation between the direct effects of cetuximab and lapatinib. Both agents were associated (P = 0.0004) with "triple' wild-type status in KRAS, BRAF, and PIK3CA exon 20. Most cell lines were resistant to the direct effects of anti-ERBB2 Mabs, suggesting that the effects of lapatinib might mainly be through ERBB1. Microarray mRNA expression profiles of sensitive and resistant cell lines showed that although ERBB1 receptor or ligand levels did not associate with cetuximab sensitivity, high levels of ERBB2 (P = 0.036) and amphiregulin (P = 0.026) predicted sensitivity to lapatinib. However, higher ERBB1 expression predicted susceptibility to cetuximab-induced antibody-dependent cellular cytotoxicity and occurred independently of KRAS/BRAF/PIK3CA mutations (P = 0.69). Lapatinib may be an effective alternative therapy to cetuximab in triple wild-type tumors. Microarray analysis provides suggestive biomarkers for resistance. ERBB1 levels, independent of mutation status, predict immune killing. Therefore, anti-ERBB1 antibodies may be considered in CRC tumors with higher ERBB1 expression and favorable FcγR polymorphisms.

Introduction: Effective post-operative pain management can positively influence patient outcome. Multimodal analgesic regimes are often limited by side-effects. Epidural analgesia may be resource-consuming, restrict mobility and have negative cardiovascular and gastrointestinal consequences. Consequently, there is a need for regional anaesthetic techniques to minimise opioid use, and provide alternatives to epidurals, especially within the context of minimally invasive abdominal surgery and enhanced recovery programmes. This review aims to evaluate the evidence base underlying Transversus abdominis plane (TAP) blockade., Methods: A literature search was performed using the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) using the parameters 'transversus abdominis plane' and 'TAP'. The references within were then searched for applicable studies. Case reports and correspondence were excluded., Findings: Thirteen studies assessed technique and mechanisms of action. Fourteen clinical studies involved a total of 1250 patients. Seven studies (6 Randomised Controlled Trials, RCTs) demonstrated reductions in post-operative morphine requirements (33.3%-73.1%). Five RCTs demonstrated concomitant improvements in pain scores. Five RCTs demonstrated reduced opioid side effects. The one study assessing functional outcome (a Prospective Controlled Trial, PCT) demonstrated earlier return of gastrointestinal function and hospital discharge., Conclusion: The limited evidence to date suggests that TAP blockade is an effective adjunct to multimodal post-operative analgesia following a range of abdominal surgical procedures. Whether TAP blocks are a viable alternative to epidural analgesia remains to be determined. However, it is likely that as this technique grows in popularity its role, particularly that in enhanced recovery programmes, will be better delineated and refined., (Copyright © 2012 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Background: The effect of glycoengineering a membrane specific anti-carcinoembryonic antigen (CEA) (this paper uses the original term CEA for the formally designated CEACAM5) antibody (PR1A3) on its ability to enhance killing of colorectal cancer (CRC) cell lines by human immune effector cells was assessed. In vivo efficacy of the antibody was also tested., Methods: The antibody was modified using EBNA cells cotransfected with beta-1,4-N-acetylglucosaminyltransferase III and the humanised hPR1A3 antibody genes., Results: The resulting alteration of the Fc segment glycosylation pattern enhances the antibody's binding affinity to the FcgammaRIIIa receptor on human immune effector cells but does not alter the antibody's binding capacity. Antibody-dependent cellular cytotoxicity (ADCC) is inhibited in the presence of anti-FcgammaRIII blocking antibodies. This glycovariant of hPR1A3 enhances ADCC 10-fold relative to the parent unmodified antibody using either unfractionated peripheral blood mononuclear or natural killer (NK) cells and CEA-positive CRC cells as targets. NK cells are far more potent in eliciting ADCC than either freshly isolated monocytes or granulocytes. Flow cytometry and automated fluorescent microscopy have been used to show that both versions of hPR1A3 can induce antibody-dependent cellular phagocytosis (ADCP) by monocyte-derived macrophages. However, the glycovariant antibody did not mediate enhanced ADCP. This may be explained by the relatively low expression of FcgammaRIIIa on cultured macrophages. In vivo studies show the efficacy of glycoengineered humanised IgG1 PR1A3 in significantly improving survival in a CRC metastatic murine model., Conclusion: The greatly enhanced in vitro ADCC activity of the glycoengineered version of hPR1A3 is likely to be clinically beneficial.

We have developed an automated, highly sensitive and specific method for identifying and enumerating circulating tumour cells (CTCs) in the blood. Blood samples from 10 prostate, 25 colorectal and 4 ovarian cancer patients were analysed. Eleven healthy donors and seven men with elevated serum prostate-specific antigen (PSA) levels but no evidence of malignancy served as controls. Spiking experiments with cancer cell lines were performed to estimate recovery yield. Isolation was performed either by density gradient centrifugation or by filtration, and the CTCs were labelled with monoclonal antibodies against cytokeratins 7/8 and either AUA1 (against EpCam) or anti-PSA. The slides were analysed with the Ikoniscope robotic fluorescence microscope imaging system. Spiking experiments showed that less than one epithelial cell per millilitre of blood could be detected, and that fluorescence in situ hybridisation (FISH) could identify chromosomal abnormalities in these cells. No positive cells were detected in the 11 healthy control samples. Circulating tumour cells were detected in 23 out of 25 colorectal, 10 out of 10 prostate and 4 out of 4 ovarian cancer patients. Five samples (three colorectal and two ovarian) were analysed by FISH for chromosomes 7 and 8 combined and all had significantly more than four dots per cell. We have demonstrated an Ikoniscope based relatively simple and rapid procedure for the clear-cut identification of CTCs. The method has considerable promise for screening, early detection of recurrence and evaluation of treatment response for a wide variety of carcinomas.