National implementation of an optimal standardised technique for right-sided colon cancer:protocol of an interventional sequential cohort study (Right study)

Purpose: Minimally invasive right hemicolectomy (MIRH) is the cornerstone of treatment for patients with right-sided colon cancer. This operation has evolved during recent decades, with many innovations and improvements but this has also resulted in high variability of uptake with subsequent substantial variableness. The aim of this ongoing study is to identify current surgical variations, determine the most optimal and standardised MIRH and nationally train and implement that technique to improve short-term clinical and long-term oncological outcomes. Methods: The Right study is a national multicentre prospective interventional sequential cohort study. Firstly, current local practice was evaluated. Subsequently, a standardised surgical technique for right-sided colon cancer was determined using the Delphi consensus method, and this procedure was trained during hands-on courses. The standardised MIRH will be implemented with proctoring (implementation cohort), after which the performance will be monitored (consolidation cohort). Patients who will receive a minimally invasive (extended) right hemicolectomy for cT1-3N0-2M0 colon cancer will be included. The primary outcome is patient safety reflected in the 90-day overall complication rate according to the Clavien–Dindo classification. Secondary outcomes will include intraoperative complications, 90-day mortality rate, number of resected tumour-positive lymph nodes, completeness of mesocolic excision, surgical quality score, locoregional and distant recurrence and 5-year overall survival. A total number of 1095 patients (365 per cohort) will be included. Discussion: The Right study is designed to safely implement the best surgical practice concerning patients with right-sided colon cancer aiming to standardise and improve the surgical quality of MIRH at a national level. Trial registration: ClinicalTrials.gov: NCT04889456, May 2021.</p

Comparison of three-year oncological results after restorative low anterior resection, non-restorative low anterior resection and abdominoperineal resection for rectal cancer

Introduction: Oncological outcome might be influenced by the type of resection in total mesorectal excision (TME) for rectal cancer. The aim was to see if non-restorative LAR would have worse oncological outcome. A comparison was made between non-restorative low anterior resection (NRLAR), restorative low anterior resection (RLAR) and abdominoperineal resection (APR). Materials and methods: This retrospective cohort included data from patients undergoing TME for rectal cancer between 2015 and 2017 in eleven Dutch hospitals. A comparison was made for each different type of procedure (APR, NRLAR or RLAR). Primary outcome was 3-year overall survival (OS). Secondary outcomes included 3-year disease-free survival (DFS) and 3-year local recurrence (LR) rate. Results: Of 998 patients 363 underwent APR, 132 NRLAR and 503 RLAR. Three-year OS was worse after NRLAR (78.2%) compared to APR (86.3%) and RLAR (92.2%, p < 0.001). This was confirmed in a multivariable Cox regression analysis (HR 1.85 (1.07, 3.19), p = 0.03). The 3-year DFS was also worse after NRLAR (60.3%), compared to APR (70.5%) and RLAR (80.1%, p < 0.001), HR 2.05 (1.42, 2.97), p < 0.001. The LR rate was 14.6% after NRLAR, 5.2% after APR and 4.8% after RLAR (p = 0.005), HR 3.22 (1.61, 6.47), p < 0.001. Conclusion: NRLAR might be associated with worse 3-year OS, DFS and LR rate compared to RLAR and APR

Nationwide standardization of minimally invasive right hemicolectomy for colon cancer and development and validation of a video-based competency assessment tool (the Right study)

BACKGROUND: Substantial variation exists when performing a minimally invasive right hemicolectomy (MIRH) due to disparities in training, expertise and differences in implementation of innovations. This study aimed to achieve national consensus on an optimal and standardized MIRH technique for colon cancer and to develop and validate a video-based competency assessment tool (CAT) for MIRH. METHOD: Statements covering all elements of MIRH were formulated. Subsequently, the Delphi technique was used to reach consensus on a standardized MIRH among 76 colorectal surgeons from 43 different centres. A CAT was developed based on the Delphi results. Nine surgeons assessed the same 12 unedited full-length videos using the CAT, allowing evaluation of the intraclass correlation coefficient (ICC). RESULTS: After three Delphi rounds, consensus (≥80% agreement) was achieved on 23 of the 24 statements. Consensus statements included the use of low intra-abdominal pressure, detailed anatomical outline how to perform complete mesocolic excision with central vascular ligation, the creation of an intracorporeal anastomosis, and specimen extraction through a Pfannenstiel incision using a wound protector. The CAT included seven consecutive steps to measure competency of the MIRH and showed high consistency among surgeons with an overall ICC of 0.923. CONCLUSION: Nationwide consensus on a standardized and optimized technique of MIRH was reached. The CAT developed showed excellent interrater reliability. These achievements are crucial steps to an ongoing nationwide quality improvement project (the Right study).</p

Nationwide standardization of minimally invasive right hemicolectomy for colon cancer and development and validation of a video-based competency assessment tool (the Right study)

BACKGROUND: Substantial variation exists when performing a minimally invasive right hemicolectomy (MIRH) due to disparities in training, expertise and differences in implementation of innovations. This study aimed to achieve national consensus on an optimal and standardized MIRH technique for colon cancer and to develop and validate a video-based competency assessment tool (CAT) for MIRH. METHOD: Statements covering all elements of MIRH were formulated. Subsequently, the Delphi technique was used to reach consensus on a standardized MIRH among 76 colorectal surgeons from 43 different centres. A CAT was developed based on the Delphi results. Nine surgeons assessed the same 12 unedited full-length videos using the CAT, allowing evaluation of the intraclass correlation coefficient (ICC). RESULTS: After three Delphi rounds, consensus (≥80% agreement) was achieved on 23 of the 24 statements. Consensus statements included the use of low intra-abdominal pressure, detailed anatomical outline how to perform complete mesocolic excision with central vascular ligation, the creation of an intracorporeal anastomosis, and specimen extraction through a Pfannenstiel incision using a wound protector. The CAT included seven consecutive steps to measure competency of the MIRH and showed high consistency among surgeons with an overall ICC of 0.923. CONCLUSION: Nationwide consensus on a standardized and optimized technique of MIRH was reached. The CAT developed showed excellent interrater reliability. These achievements are crucial steps to an ongoing nationwide quality improvement project (the Right study).</p

Chromosomal copy number heterogeneity predicts survival rates across cancers.

Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types

Serum-based measurements of stromal activation through ADAM12 associate with poor prognosis in colorectal cancer.

BACKGROUND Recently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal activation, A Disintegrin and Metalloprotease 12 (ADAM12) in colorectal cancer (CRC). METHODS Using gene expression databases we investigated ADAM12 expression in CRC and delineated the source of ADAM12 expression. The clinical value of ADAM12 was retrospectively assessed in the CAIRO2 trial in metastatic CRC with 235 patients (31% of total cohort), and an independent rectal cancer cohort (n = 20). RESULTS ADAM12 is expressed by activated CRC associated fibroblasts. In the CAIRO2 trial cohort, ADAM12 serum levels were prognostic (ADAM12 low versus ADAM12 high; median OS 25.3 vs. 17.1 months, HR 1.48 [95% CI 1.11-1.96], P = 0.007). The prognostic potential was specifically high for metastatic rectal cancer (HR 1.78 [95% CI 1.06-3.00], P = 0.030) and mesenchymal subtype tumors (HR 2.12 [95% CI 1.25-3.60], P = 0.004). ADAM12 also showed potential for predicting recurrence in an exploratory analysis of non-metastatic rectal cancers. CONCLUSIONS Here we describe a non-invasive marker for activated stroma in CRC which associates with poor outcome, especially for primary cancers located in the rectum

Oncologic outcomes of screen-detected and non-screen-detected T1 colorectal cancers

Background:The incidence of T1 colorectal cancer (CRC) has increased with the implementation of CRC screening programs. It is unknown whether the outcomes and risk models for T1 CRC based on non-screen-detected patients can be extrapolated to screen-detected T1 CRC. This study aimed to compare the stage distribution and oncologic outcomes of T1 CRC patients within and outside the screening program. Methods: Data from T1 CRC patients diagnosed between 2014 and 2017 were collected from 12 hospitals in the Netherlands. The presence of lymph node metastasis (LNM) at diagnosis was compared between screen-detected and non-screen-detected patients using multivariable logistic regression. Cox proportional hazard regression was used to analyze differences in the time to recurrence (TTR), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival. Additionally, the performance of conventional risk factors for LNM was evaluated across the groups. Results: 1803 patients were included (1114 [62%] screendetected), with median follow-up of 51 months (interquartile range 30). The proportion of LNM did not significantly differ between screen- and non-screen-detected patients (12.6% vs. 8.9%; odds ratio 1.41; 95%CI 0.89-2.23); a prediction model for LNM performed equally in both groups. The 3- and 5-year TTR, MFS, and CSS were similar for patients within and outside the screening program. However, overall survival was significantly longer in screen-detected T1 CRC patients (adjusted hazard ratio 0.51; 95%CI 0.38- 0.68). Conclusions: Screen-detected and non-screen-detected T1 CRCs have similar stage distributions and oncologic outcomes and can therefore be treated equally. However, screen-detected T1 CRC patients exhibit a lower rate of non-CRC-related mortality, resulting in longer overall survival.</p

A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis.

Limited clinical benefits derived from anti-VEGF therapy have driven the identification of new targets involved in tumor angiogenesis. Here, we report an integrative meta-analysis to define the transcriptional program underlying angiogenesis in human cancer. This approach identified ELTD1, an orphan G-protein-coupled receptor whose expression is induced by VEGF/bFGF and repressed by DLL4 signaling. Extensive analysis of multiple cancer types demonstrates significant upregulation of ELTD1 in tumor-associated endothelial cells, with a higher expression correlating with favorable prognosis. Importantly, ELTD1 silencing impairs endothelial sprouting and vessel formation in vitro and in vivo, drastically reducing tumor growth and greatly improving survival. Collectively, these results provide insight into the regulation of tumor angiogenesis and highlight ELTD1 as key player in blood vessel formation

Transanal minimally invasive surgery (TAMIS) versus endoscopic submucosal dissection (ESD) for resection of non-pedunculated rectal lesions (TRIASSIC study):study protocol of a European multicenter randomised controlled trial

BACKGROUND: In the recent years two innovative approaches have become available for minimally invasive en bloc resections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. METHODS: Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. DISCUSSION: This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for the en bloc resection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. TRIAL REGISTRATION: Netherlands Trial Register, NL7083 , 06 July 2018

Comparison of Peptide Array Substrate Phosphorylation of c-Raf and Mitogen Activated Protein Kinase Kinase Kinase 8

Kinases are pivotal regulators of cellular physiology. The human genome contains more than 500 putative kinases, which exert their action via the phosphorylation of specific substrates. The determinants of this specificity are still only partly understood and as a consequence it is difficult to predict kinase substrate preferences from the primary structure, hampering the understanding of kinase function in physiology and prompting the development of technologies that allow easy assessment of kinase substrate consensus sequences. Hence, we decided to explore the usefulness of phosphorylation of peptide arrays comprising of 1176 different peptide substrates with recombinant kinases for determining kinase substrate preferences, based on the contribution of individual amino acids to total array phosphorylation. Employing this technology, we were able to determine the consensus peptide sequences for substrates of both c-Raf and Mitogen Activated Protein Kinase Kinase Kinase 8, two highly homologous kinases with distinct signalling roles in cellular physiology. The results show that although consensus sequences for these two kinases identified through our analysis share important chemical similarities, there is still some sequence specificity that could explain the different biological action of the two enzymes. Thus peptide arrays are a useful instrument for deducing substrate consensus sequences and highly homologous kinases can differ in their requirement for phosphorylation events