Showing papers by "Francesc Balaguer published in 2022"

Motorized Spiral Enteroscopy Is Effective in Patients with Prior Abdominal Surgery

Abstract: Motorized Spiral Enteroscopy (MSE) reduces procedure time and increases insertion depth into the small bowel; however, there is scarce evidence on factors affecting MSE efficacy.To evaluate diagnostic yield and adverse events of MSE including patients with prior major abdominal surgery.A prospective observational study was conducted on patients undergoing MSE from June 2019 to December 2021. Demographic characteristics, procedure time, depth of maximum insertion (DMI), technical success, diagnostic yield, and adverse events were collected.Seventy-four anterograde (54.4%) and 62 retrograde (45.6%) enteroscopies were performed in 117 patients (64 males, median age 67 years). Fifty patients (42.7%) had prior major abdominal surgery. Technical success was 91.9% for anterograde and 90.3% for retrograde route. Diagnostic yield was 71.6% and 61.3%, respectively. The median DMI was 415 cm (264-585) for anterograde and 120 cm (37-225) for retrograde enteroscopy. In patients with prior major abdominal surgery, MSE showed significantly longer small bowel insertion time (38 vs 29 min, p = 0.004), with similar diagnostic yield (61 vs 71.4%, p = 0.201) and DMI (315 vs 204 cm, p = 0.226). The overall adverse event rate was 10.3% (SAE 1.5%), with no differences related to prior abdominal surgery (p = 0.598). Patients with prior surgeries directly involving the gastrointestinal tract showed lower DMI (189 vs 374 cm, p = 0.019) with equal exploration time (37.5 vs 38 min, p = 0.642) compared to those with other abdominal surgeries.MSE is effective and safe in patients with major abdominal surgery, although longer procedure times were observed. A lower depth of insertion was detected in patients with gastrointestinal surgery.

miRNome Profiling and Functional Analysis Reveal Involvement of hsa-miR-1246 in Colon Adenoma-Carcinoma Transition by Targeting AXIN2 and CFTR

Abstract: Regulatory changes occurring early in colorectal cancer development remain poorly investigated. Since the majority of cases develop from polyps in the adenoma-carcinoma transition, a search of early molecular features, such as aberrations in miRNA expression occurring prior to cancer development, would enable identification of potentially causal, rather than consequential, candidates in the progression of polyp to cancer. In the current study, by employing small RNA-seq profiling of colon biopsy samples, we described differentially expressed miRNAs and their isoforms in the adenoma-carcinoma transition. Analysis of healthy-adenoma-carcinoma sequence in an independent validation group enabled us to identify early deregulated miRNAs including hsa-miR-1246 and hsa-miR-215-5p, the expressions of which are, respectively, gradually increasing and decreasing. Loss-of-function experiments revealed that inhibition of hsa-miR-1246 lead to reduced cell viability, colony formation, and migration rate, thereby indicating an oncogenic effect of this miRNA in vitro. Subsequent western blot and luciferase reporter assay provided evidence of hsa-miR-1246 being involved in the regulation of target AXIN2 and CFTR genes’ expression. To conclude, the present study revealed possible involvement of hsa-miR-1246 in early colorectal cancer development and regulation of tumor suppressors AXIN2 and CFTR.

Differentially deregulated microRNAs as novel biomarkers for neoplastic progression in ulcerative colitis.

Abstract: BACKGROUND Colorectal cancer (CRC) is a potentially life-threatening complication of long-standing ulcerative colitis (UC). MicroRNAs are epigenetic regulators that have been involved in the development of UC associated CRC. However, their role as potential mucosal biomarkers of neoplastic progression has not been adequately studied. METHODS In this study, we analyzed the expression of 96 pre-selected microRNAs in human formalin-fixed and paraffin embedded tissue of 52 case biopsies (20 normal mucosa, 20 dysplasia and 12 UC associated CRCs) and 50 control biopsies (10 normal mucosa, 21 sporadic adenomas and 19 sporadic CRCs) by using Custom TaqMan Array Cards. For validation of deregulated miRNAs, we performed individual qRT-PCR in an independent cohort of 50 cases (13 normal mucosa, 25 dysplasia, and 12 UC associated CRCs) and 46 controls (7 normal mucosa, 19 sporadic adenomas, and 20 sporadic CRCs). RESULTS Sixty-four microRNAs were found to be differentially deregulated in the UC associated CRC sequence. Eight of these microRNAs were chosen for further validation. We confirmed miR-31, -106a and -135b to be significantly deregulated between normal mucosa and dysplasia, as well as across the UC associated CRC sequence (all P<0.01). Notably, these microRNAs also confirmed to have a significant differential expression compared to sporadic CRC (all P<0.05). CONCLUSIONS UC associated and sporadic CRCs have distinct microRNA expression patterns and some microRNAs indicate early neoplastic progression. TRANSLATIONAL IMPACT The microRNAs identified in this study can guide further large-scale clinical validation studies to improve the early detection of UC associated preneoplastic lesions and cancer.

Serrated polyposis syndrome; epidemiology and management.

Abstract: Serrated colorectal polyps, long considered innocent, are currently recognized as the precursors to one-third of all colorectal cancers (CRC). Serrated polyposis syndrome (SPS), characterized by accumulation of multiple and/or large serrated polyps, symbolizes the highest expression of serrated pathway of carcinogenesis, leading to a high risk of CRC when it is not detected or treated on time. Although previously considered uncommon, SPS is now acknowledged as the most prevalent colorectal polyposis. This syndrome has attracted increasing interest over the past decade and has become a hot topic in the field of gastrointestinal oncology. Besides a small proportion of cases caused by germline mutations in RNF43, no clear genetic cause has been identified. Both epigenetic and environmental factors, especially smoking, have been related to this syndrome, but the etiology of SPS remains uncertain and diagnosis is based on endoscopic criteria. Recent studies on SPS have focused on identifying the underlying risk-factors for CRC, defining the best endoscopic techniques for surveillance and establishing optimal preventive strategies aimed at reducing CRC-incidence without exposing patients to unnecessary procedures. The purpose of this chapter is to review, from a practical perspective, current knowledge and future directions in the diagnosis and management of serrated polyposis syndrome.

Familial component of early-onset colorectal cancer: opportunity for prevention.

Abstract: BACKGROUND Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. METHODS This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. RESULTS Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). CONCLUSION ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.

Real-time diagnostic accuracy of blue light imaging, linked color imaging and white-light endoscopy for colorectal polyp characterization

Abstract: Background and study aims Fujifilm has developed a novel ELUXEO 7000 endoscope system that employs light-emitting diodes (LEDs) at four different wavelengths as light sources that enable blue light imaging (BLI), linked color imaging (LCI), and high-definition white-light endoscopy (HD-WLE). The aim of this study was to address the diagnostic accuracy of real-time polyp characterization using BLI, LCI and HD-WLE (ELUXEO 7000 endoscopy system). Patients methods This is a prespecified post-hoc analysis of a prospective study in which 22 experienced endoscopists (> 2,000 colonoscopies) from eight international centers participated. Using a combination of BLI, LCI, and HD-WLE, lesions were endoscopically characterized including a high- or low-confidence statement. Per protocol, digital images were created from all three imaging modalities. Histopathology was the reference standard. Endoscopists were familiar with polyp characterization, but did not take dedicated training for purposes of this study. Results Overall, 341 lesions were detected in 332 patients. Of the lesions, 269 histologically confirmed polyps with an optical diagnosis were included for analysis (165 adenomas, 27 sessile serrated lesions, and 77 hyperplastic polyps). Overall, polyp characterization was performed with high confidence in 82.9 %. The overall accuracy for polyp characterization was 75.1 % (95 % confidence interval [CI] 69.5–80.1 %), compared with an accuracy of 78.0 % (95 % CI 72.0–83.2 %) for high confidence assignments. The accuracy for endoscopic characterization for diminutive polyps was 74.7 % (95 %CI 68.4–80.3 %), compared with an accuracy of 78.2 % (95 % CI 71.4–84.0 %) for high-confidence assignments. Conclusions The diagnostic accuracy of BLI, LCI, and HD-WLE by experienced endoscopist for real-time polyp characterization seems limited (NCT03344289).

Germline mutations in WNK2 could be associated with serrated polyposis syndrome

Abstract: Background Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. Methods After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. Results We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. Conclusion After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.

Serum DNA methylome of the colorectal cancer serrated pathway

Abstract: Objective: The clinical relevance of the serrated pathway of colorectal carcinogenesis is evident but the screening of serrated lesions remains challenging. We aimed to characterize the serum methylome of the serrated pathway, and to evaluate circulating cell-free DNA (cfDNA) methylation as a source of biomarkers for the non-invasive screening and diagnosis of serrated lesions. Design: We collected serum samples from individuals with serrated adenocarcinoma (SAC), traditional serrated adenomas, sessile serrated lesions, hyperplastic polyps and with no colorectal findings. First, epigenome-wide methylation was quantified in cfDNA pooled samples with the MethylationEPIC array. Then, methylation profiles were compared to tissue and serum cfDNA datasets. Finally, biomarker utility of serum cfDNA methylation was evaluated. Results: We identified a differential methylation profile that can distinguish high-risk serrated lesions from the absence of serrated neoplasia, showing concordance with tissue methylation from SAC and sessile serrated lesions (external datasets). We report that the methylation profiles in serum cfDNA are pathway-specific, clearly separating serrated lesions from conventional adenomas. Among the differentially methylated regions (DMR) we report, the combination of two DMRs within the genes NINJ2 and ERICH1 discriminated high-risk serrated lesions and SAC with 91.4% sensitivity and 64.4% specificity, while methylation from a DMR within ZNF718 reported 100% sensitivity for the detection of SAC at 96% specificity. Conclusion: This is the only study available to date exploring the serum methylome of serrated lesions. We have identified a differential methylation profile in serum specific to the serrated pathway. The serum methylome may serve as a source of non-invasive biomarkers for screening and detection of high-risk serrated lesions.

Personalized endoscopic surveillance and intervention protocols for patients with familial adenomatous polyposis: the European FAP Consortium strategy

Abstract: Abstract Background and study aims Patients with familial adenomatous polyposis (FAP) undergo colectomy and lifelong endoscopic surveillance to prevent colorectal, duodenal and gastric cancer. Endoscopy has advanced significantly in recent years, including both detection technology as well as treatment options. For the lower gastrointestinal tract, current guidelines do not provide clear recommendations for surveillance intervals. Furthermore, the Spigelman staging system for duodenal polyposis has its limitations. We present a newly developed personalized endoscopic surveillance strategy for the lower and upper gastrointestinal tract, aiming to improve the care for patients with FAP. We aim to inform centers caring for FAP patients and encourage the discussion on optimizing endoscopic surveillance and treatment in this high-risk population. Methods The European FAP Consortium, consisting of endoscopists with expertise in FAP, collaboratively developed new surveillance protocols. The proposed strategy was consensus-based and a result of several consortium meetings, discussing current evidence and limitations of existing systems. This strategy provides clear indications for endoscopic polypectomy in the rectum, pouch, duodenum and stomach and defines new criteria for surveillance intervals. This strategy will be evaluated in a 5-year prospective study in nine FAP expert centers in Europe. Results We present a newly developed personalized endoscopic surveillance and endoscopic treatment strategy for patients with FAP aiming to prevent cancer, optimize endoscopic resources and limit the number of surgical interventions. Following this new strategy, prospectively collected data in a large cohort of patients will inform us on the efficacy and safety of the proposed approaches.

Cytology Smears: An Enhanced Alternative Method for Colorectal Cancer pN Stage—A Multicentre Study

Abstract: Simple Summary Recurrence of stage II (pT3-T4 pN0) colorectal cancer (CRC) occurs in about 15% of patients and it is often due to undetected lymph node (LN) metastases with conventional pathology haematoxylin and eosin (H&E) LN analysis. Despite more sensitive molecular methods of LN staging having proved to have prognostic value in stage II CRC, we aimed at determining whether the pN stage could be better assessed with LN cytology smears. We analysed 3936 LNs from 217 CRC surgical resections, using three methods, H&E, cytology smears, and the One Step Nucleic Acid Amplification (OSNA) molecular assay. We compared the pN stages obtained from both H&E and cytology, as well as with the OSNA results. We concluded that LN analysis with cytology smears not only enables performing the pN stage, but detects more LN metastases than H&E, with a similar detection rate to molecular methods. Cytology LN analysis would allow a better patient therapeutic management. Abstract Stage II colorectal cancer (CRC) recurrence remains a clinical problem. Some of these patients are true stage III CRC with a pN0 pathology stage. This large prospective multicentre cohort study aimed at evaluating the diagnostic ability of lymph node (LN) cytology smears to perform the pN stage and compare it with the conventional haematoxylin and eosin (H&E) pathology pN stage. Additionally, we used the One-Step Nucleic Acid Amplification (OSNA), a high-sensitive molecular method of LN staging. A total of 3936 fresh LNs from 217 CRC surgical specimens were examined by three methods, H&E, LN cytology smears, and OSNA. H&E detected 29% of patients with positive LNs, cytology smears 35%, and OSNA 33.2% (p < 0.0001). H&E and cytology concordantly classified 92.2% of tumours, and 88.5% between OSNA and H&E. Cytology had 96.8% sensitivity and 90.3% specificity to discriminate positive/negative patients compared to H&E (p = 0.004), and 87.3% sensitivity and 89% specificity when compared to OSNA (p = 0.56). Patients with positive LNs detected by any of the three methods had significantly worse disease-free and overall survival. We conclude that pN stage accuracy for detecting positive LNs is superior with LN cytological smears than with conventional H&E, which would enable a better pN stage and management of early-stage CRC patients.