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.
•A common core angiogenesis metasignature exists for different types of cancer•ELTD1 is upregulated in tumor endothelial cells and is a good prognostic marker•VEGF/DLL4 regulate ELTD1, which is important for tip cell function and angiogenesis•ELTD1 inhibition blocks tumor angiogenesis and substantially inhibits tumor growth
OBJECTIVE:The aim of this study was to evaluate oncological outcome for patients with and without anastomotic leakage after colon or rectal cancer surgery.
SUMMARY OF BACKGROUND DATA:The role of ...anastomotic leakage in oncological outcome after colorectal cancer surgery is still topic of debate and impact on follow-up and consideration for further treatment remains unclear.
METHODS:Patients included in the international, multicenter, non-inferior, open label, randomized, controlled trials COLOR and COLOR II, comparing laparoscopic surgery for curable colon (COLOR) and rectal (COLOR II) cancer with open surgery, were analyzed. Patients operated by abdominoperineal excision were excluded. Both univariate and multivariate analyses were performed to investigate the impact of leakage on overall survival, disease-free survival, local and distant recurrences, adjusted for possible confounders. Primary endpoints in the COLOR and COLOR II trial were disease-free survival and local recurrence at 3-year follow-up, respectively, and secondary endpoints included anastomotic leakage rate.
RESULTS:For colon cancer, anastomotic leakage was not associated with increased percentage of local recurrence or decreased disease-free-survival. For rectal cancer, an increase of local recurrences (13.3% vs 4.6%; hazard ratio 2.96; 95% confidence interval 1.38–6.34; P = 0.005) and a decrease of disease-free survival (53.6% vs 70.9%; hazard ratio 1.67; 95% confidence interval 1.16–2.41; P = 0.006) at 5-year follow-up were found in patients with anastomotic leakage.
CONCLUSION:Short-term morbidity, mortality, and long-term oncological outcomes are negatively influenced by the occurrence of anastomotic leakage after rectal cancer surgery. For colon cancer, no significant effect was observed; however, due to low power, no conclusions on the influence of anastomotic leakage on outcomes after colon surgery could be reached. Clinical awareness of increased risk of local recurrence after anastomotic leakage throughout the follow-up is mandatory.Trial RegistrationRegistered with ClinicalTrials.gov, number NCT00387842 and NCT00297791.
Background
Transanal total mesorectal excision (TaTME) for mid and low rectal cancer has been shown to improve short-term outcomes, mostly due to lower conversion rates and with improved quality of ...the specimen. However, robust long-term oncological data supporting the encouraging clinical and pathological outcomes are lacking.
Methods
All consecutive patients undergoing TaTME with curative intent for mid or low rectal cancer in two referral centers in The Netherlands between January 2012 and April 2016 with a complete and minimum follow-up of 36 months were included. The primary outcome was local recurrence rate. Secondary outcomes were disease-free survival, overall survival and development of metastasis.
Results
There were 159 consecutive patients. Their mean age was 66.9 (10.2) years and 66.7% of all patients were men. Pathological analysis showed a complete mesorectum in 139 patients (87.4%), nearly complete in 16 (10.1%) and an incomplete mesorectum in 4 (2.5%). There was involvement of the CRM (< 1 mm) in one patient (0.6%) and no patients had involvement of the distal margin (< 5 mm). Final postoperative staging after neoadjuvant therapy was stage 0 in 11 patients (6.9%), stage I in 73 (45.9%), stage II in 31 (19.5%), stage III in 37 (23.3%) and stage IV in 7 (4.4%). The 3-year local recurrence rate was 2.0% and the 5-year local recurrence rate was 4.0%. Median time to local recurrence was 19.2 months. Distant metastases were found in 22 (13.8%) patients and were diagnosed after a median of 6.9 months (range 1.1–50.4) months. Disease-free survival was 92% at 3 years and 81% at 5 years. Overall survival was 83.6% at 3 years and 77.3% at 5 years.
Conclusions
The long-term follow-up of the current cohort confirms the oncological safety and feasibility of TaTME in two high volume referral centers for rectal carcinoma. However, further robust and audited data must confirm current findings before widespread implementation of TaTME.
Background
Transanal total mesorectal excision (TaTME) is a safe alternative to laparoscopic TME for mid and low rectal cancer. TaTME allows improved visualization of the surgical planes and margins, ...and may potentially improve oncological outcomes. However, functional results after total mesorectal excision (TME) are variable and there are currently only a few published studies that include functional data related to the outcomes of TaTME.
Methods
Fifty-four consecutive patients were included in this study: one group included 27 patients who underwent laparoscopic low anterior and the other included 27 patients who underwent TaTME. All patients were asked to complete five questionnaires related to quality of life (QOL) and function EQ-5D-3L, EORTC-QLQ C30, EORTC-QLQ C29, Low Anterior Resection Syndrome score (LARS), and International Prostate Symptom Score IPSS. All TaTME patients were operated on at The Gelderse Vallei Hospital by a single surgeon and had a follow-up of at least 6.6 months.
Results
The EORTC-QLQ C30 and EQ-5D-3L questionnaires showed comparable outcomes in terms of QOL between the two groups. Almost all items evaluated by the EORTC-QLQ C29, including sexual outcomes, were similar between the two groups. One item concerning fecal incontinence, however, was scored worse for TaTME. There were no significant differences between the groups in terms of LARS symptoms or urinary function.
Conclusions
Patients undergoing laparoscopic or transanal TME showed comparable functional and QOL outcomes. Although the TaTME technique is still evolving, this study indicates that this technique is a safe alternative to laparoscopic surgery in terms of functional outcomes for mid and low rectal cancers.
Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted ...agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy.
Despite the presence of mutations in APC or beta-catenin, which are believed to activate the Wnt signalling cascade constitutively, most colorectal cancers show cellular heterogeneity when ...beta-catenin localization is analysed, indicating a more complex regulation of Wnt signalling. We explored this heterogeneity with a Wnt reporter construct and observed that high Wnt activity functionally designates the colon cancer stem cell (CSC) population. In adenocarcinomas, high activity of the Wnt pathway is observed preferentially in tumour cells located close to stromal myofibroblasts, indicating that Wnt activity and cancer stemness may be regulated by extrinsic cues. In agreement with this notion, myofibroblast-secreted factors, specifically hepatocyte growth factor, activate beta-catenin-dependent transcription and subsequently CSC clonogenicity. More significantly, myofibroblast-secreted factors also restore the CSC phenotype in more differentiated tumour cells both in vitro and in vivo. We therefore propose that stemness of colon cancer cells is in part orchestrated by the microenvironment and is a much more dynamic quality than previously expected that can be defined by high Wnt activity.
Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for colorectal CSCs defined by high Wnt signaling activity, ...which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures. We discovered that several Wnt target genes, including
ASCL2 and
LGR5, become silenced by CpG island methylation during progression of tumorigenesis, and that their re-expression was associated with reduced tumor growth. Taken together, our data show that promoter methylation of Wnt target genes is a strong predictor for recurrence of colorectal cancer, and suggest that CSC gene signatures, rather than reflecting CSC numbers, may reflect differentiation status of the malignant tissue.
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► Wnt target genes, including stem cell markers, inversely correlate with prognosis ► Progression of CRC is associated with methylation of Wnt target genes ► Adherence to CSC signatures reflects an immature clonal trait, not CSC numbers ► Wnt target methylation is a strong prognostic marker
Introduction
Total mesorectal excision (TME) is an essential component of surgical management of rectal cancer. Both open and laparoscopic TME have been proven to be oncologically safe. However, it ...remains a challenge to achieve complete TME with clear circumferential resections margin (CRM) with the conventional transabdominal approach, particularly in mid and low rectal tumours. Transanal TME (TaTME) was developed to improve oncological and functional outcomes of patients with mid and low rectal cancer.
Methods
An international, multicentre, superiority, randomised trial was designed to compare TaTME and conventional laparoscopic TME as the surgical treatment of mid and low rectal carcinomas. The primary endpoint is involved CRM. Secondary endpoints include completeness of mesorectum, residual mesorectum, morbidity and mortality, local recurrence, disease-free and overall survival, percentage of sphincter-saving procedures, functional outcome and quality of life. A Quality Assurance Protocol including centralised MRI review, histopathology re-evaluation, standardisation of surgical techniques, and monitoring and assessment of surgical quality will be conducted.
Discussion
The difference in involvement of CRM between the two treatment strategies is thought to be in favour of the TaTME. TaTME is therefore expected to be superior to laparoscopic TME in terms of oncological outcomes in case of mid and low rectal carcinomas.
Abstract Background This study evaluates the incidence of delirium and risk factors associated with delirium in elderly patients admitted to a general surgical ward. Methods Patients aged over ...60 years who were admitted with an acute or elective general surgical diagnosis were eligible for this prospective cohort study. Risk factors associated with delirium were analyzed using univariate and multivariate analysis to identify those independently associated with delirium. Results A total of 209 patients were included in the study. The incidence of delirium was 16.9% (23.2% for acute admission, P < .001). Variables associated with delirium were dementia, presence of an urinary catheter, cognitive decline at admission measured with the mini-mental state examination, white blood cell count >10.0 × 109 /L, and urea >7.5 mmol/L. Median length of hospital stay was 13 days (range 3–85) for patients with delirium versus 7 (range 1–54) for patients without ( P = .002). Conclusions The incidence of delirium is high in elderly patients, especially after an acute admission, leading to an increase in length of hospital stay. To minimize delirium, associated risk factors must be identified and, if possible, treated.
Abstract
A significant proportion of colorectal cancer (CRC) patients develop peritoneal metastases (PM) in the course of their disease. PMs are associated with a poor quality of life, significant ...morbidity and dismal disease outcome. To improve care for this patient group, a better understanding of the molecular characteristics of CRC-PM is required. Here we present a comprehensive molecular characterization of a cohort of 52 patients. This reveals that CRC-PM represent a distinct CRC molecular subtype, CMS4, but can be further divided in three separate categories, each presenting with unique features. We uncover that the CMS4-associated structural protein Moesin plays a key role in peritoneal dissemination. Finally, we define specific evolutionary features of CRC-PM which indicate that polyclonal metastatic seeding underlies these lesions. Together our results suggest that CRC-PM should be perceived as a distinct disease entity.
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