Systematic review of the published guidelines on Barrett's esophagus: should we stress the consensus or the differences?

Multiple guidelines on Barrett's esophagus (BE) have being published in order to standardize and improve clinical practice. However, studies have shown poor adherence to them. Our aim was to synthetize, compare, and assess the quality of recommendations from recently published guidelines, stressing similarities and differences. We conducted a search in Pubmed and Scopus. When different guidelines from the same society were identified, the most recent one was considered. We used the GRADE system to assess the quality of evidence. We included 24 guidelines and position/consensus statements from the European Society of Gastrointestinal Endoscopy, British Society of Gastroenterology, American Society for Gastrointestinal Endoscopy, American Gastroenterological Association, American College of Gastroenterology, Australian guidelines, and Asia-Pacific consensus. All guidelines defend that BE should be diagnosed when there is an extension of columnar epithelium into the distal esophagus. However, there is still some controversy regarding length and histology criteria for BE diagnosis. All guidelines recommend expert pathologist review for dysplasia diagnosis. All guidelines recommend surveillance for non-dysplastic BE, and some recommend surveillance for indefinite dysplasia. While the majority of guidelines recommend ablation therapy for low-grade dysplasia without visible lesion, others recommend ablation therapy or endoscopic surveillance. However, controversy exists regarding surveillance intervals and biopsy protocols. All guidelines recommend endoscopic resection followed by ablation therapy for neoplastic visible lesion. Several guidelines use the GRADE system, but the majority of recommendations are based on low and moderate quality of evidence. Although there is considerable consensus among guidelines, there are some discrepancies resulting from low-quality evidence. The lack of high-quality evidence for the majority of recommendations highlights the importance of continued well-conducted research in this field.

The nonsense mutation MSH2 c.2152C>T shows a founder effect in Portuguese Lynch syndrome families.

The mutational spectrum of the MMR genes is highly heterogeneous, but specific mutations are observed at high frequencies in well-defined populations or ethnic groups, due to founder effects. The MSH2 mutation c.2152C>T, p.(Gln718*), has occasionally been described in Lynch families worldwide, including in Portuguese Lynch syndrome families. During genetic testing for Lynch syndrome at the Portuguese Oncology Institutes of Porto and Lisbon, this mutation was identified in 28 seemingly unrelated families. In order to evaluate if this alteration is a founder mutation, haplotype analysis using microsatellite and SNP markers flanking the MSH2 gene was performed in the 28 probands and 87 family members. Additionally, the geographic origin of these families was evaluated and the age of the mutation estimated. Twelve different haplotypes were phased for 13 out of the 28 families and shared a conserved region of ∼3.6 Mb. Based on the mutation and recombination events observed in the microsatellite haplotypes and assuming a generation time of 25 years, the age estimate for the MSH2 mutation was 273 ± 64 years. The geographic origins of these families were mostly from the Northern region of Portugal. Concluding, these results suggest that the MSH2 c.2152C>T alteration is a founder mutation in Portugal with a relatively recent origin. Furthermore, its high proportion indicates that screening for this mutation as a first step, together with the previously reported Portuguese founder mutations, may be cost-effective in genetic testing of Lynch syndrome suspects of Portuguese ancestry.

Colorectal malignant polyps: a modern approach.

Colorectal malignant polyps (MP) are polyps with invasive cancer into the submucosa harboring a variable risk of lymph node involvement, which can be estimated through evaluation of morphological, endoscopic, and histologic features. The recent advances in imaging endoscopic techniques have led to the possibility of performing an optical diagnosis of T1 colorectal cancer, allowing the selection of the best therapeutic modality to optimize outcomes for the patient. When MP are diagnosed after endoscopic removal, their management can be challenging. Differentiating low- and high-risk histologic features that influence the possibility of residual tumor, the risk of recurrence and the risk of lymph node metastasis, is crucial to further optimize treatment and surveillance plans. While the presence of high-risk features indicates a need for surgery in the majority of cases, location, comorbidities and the patient's preference should be taken in account when making the final decision. This is a particularly important issue in the management of low rectal MP presenting with high-risk features, where chemoradiotherapy followed by a watch-and-wait strategy has demonstrated promising results. In this review we discuss the important prognostic features of MP and the most modern approaches regarding their management.

Colon Adenocarcinoma Stage IIA-Can We Predict Relapse?

PURPOSE: To determine prognostic factors for stage IIA colon cancer (CC) recurrence in patients undergoing curative intent surgery without adjuvant treatment. METHODS: Single-centre cohort study. All patients with stage IIA CC discussed in a multidisciplinary colorectal cancer clinic from January 2010 to December 2012 were evaluated. Clinical data, laboratory data and tumour features, including expression of DNA repair proteins (EDRP), were analysed. Assessment of overall and disease free survival, recurrence, recurrence site and recurrence's method of diagnosis was performed. The associations between variables were tested through the Fisher's exact test (SPSS 23). RESULTS: Fifty-five patients were included (55% male gender; mean age at diagnosis was 70.3 years (42-88)). CC was in the left colon in 62%, high grade in 7% and had lymphovascular invasion in 7% of the cases. Only one patient was submitted to emergent surgery for obstructive symptoms. In 55% of cases ≥ 12 lymph nodes were collected. There was EDRP loss in nine patients (MLH1/PMS2: six; MSH2/MSH6: three)-only two fulfilled revised Bethesda criteria. Recurrence occurred in five patients (8.9%), and it was diagnosed through surveillance in all of them. No variable showed a statistically significant association with recurrence; however, there were no recurrences in patients with EPRD loss (p = 0.209). Mean follow-up time was 43 months (2-70). In those with recurrence, mean disease-free survival was 23.4 months. CONCLUSIONS: The overall good prognosis and absence of recurrence predictive factors were confirmed, validating the decision of not to submit stage IIA CC patients to chemotherapy risks.

Clinical score predicting a successful endoscopic approach of esophageal anastomotic leaks: external validation.

BACKGROUND: Recently, a clinical prediction rule has been proposed to predict the chance of successful endoscopic stenting in benign esophageal anastomotic leakage, perforation and fistula. We aimed to validate this score in a cohort of patients with anastomotic leaks managed with self-expanding metal esophageal stents, by assessing technical and clinical success rates and comparing the agreement between the predicted and the actual clinical success. METHODS: A multicenter retrospective cohort study including patients submitted to endoscopic stenting due to anastomotic leak was conducted. Variables of the score (leak size, location and C-reactive protein) were collected and the chance of success (≤50, 50-70 and ≥70%) and its accuracy was assessed. RESULTS: Fifty-three patients, submitted to esophageal stenting after cancer (n = 47) and bariatric surgery were included. Clinical success was achieved in 62% of patients. The area under the ROC curve to differentiate between successful and failed therapies showed a good discriminative power of the score (AUC 0.705; P < 0.01). For a predicted chance of success >50%, the positive predictive value was 72.5%; for a chance of success ≤50%, the negative predictive value was 69.2%. CONCLUSIONS: The application of this predictive model in patients with anastomotic leaks proved to be valid in a different cohort from that in which it was derived. Its usefulness in clinical practice may be anticipated, favoring stenting in patients with a chance of success >50%. However, we must be cautious in patients with a lower probability of success and a case-by-case decision should be made.

Low rectal cancer treatment strategies: a cohort study assessing watch and wait.

PURPOSE: Treatment strategies for low rectal cancer have been evolving toward achieving less treatment morbidity with the same oncological success-we aimed to assess the results of the new watch and wait (W&W) strategy in our cohort. METHODS: A tertiary care cohort study was conducted. New patients with rectal adenocarcinoma up to 6 cm from the anal margin, cM0, locally staged higher than cT1N0, evaluated between November 2014 and October 2018, were included. All 93 patients received neoadjuvant radiotherapy ± chemotherapy. Re-evaluation was planned 8-12 weeks after the end of treatment. Patients showing clinical complete response (cCR) were given the choice of either to proceed to surgery or to enter W&W. RESULTS: Of the 93 patients, 82.8% were re-evaluated and 20.8% had cCR. Patients in clinical stages II/III were significantly less likely to achieve cCR than those in stage I (p = 0.017). After a mean follow-up of 17.44 months, there were 4 regrowths in the 16 patients under W&W, all submitted to R0 surgery, ypN0; there were no deaths or local recurrences; one patient with regrowth had distant recurrence. Sixty patients underwent direct surgery after a mean follow-up of 16.23 months; 3 patients had local and distant recurrences; 7 others had only distant recurrences; there were 8 deaths. There were no statistically significant differences between patients under W&W and patients who underwent direct surgery regarding local or distant recurrences, or death (p > 0.9; p = 0.44; p = 0.19, respectively). CONCLUSION: The W&W strategy for low rectal cancer achieved the same oncological outcomes as the traditional strategy while sparing some patients from surgery.

Buried Barrett's Esophagus with High-Grade Dysplasia after Radiofrequency Ablation.

Radiofrequency ablation therapy is an effective endoscopic option for the eradication of Barrett's esophagus that appears to reduce the risk of esophageal cancer. A concern associated with this technique is the development of subsquamous/buried intestinal metaplasia, whose clinical relevance and malignant potential have not yet been fully elucidated. Fewer than 20 cases of subsquamous neoplasia after the successful radiofrequency ablation of Barrett's esophagus have been reported to date. Here, we describe a new case of subsquamous neoplasia (high-grade dysplasia) following radiofrequency ablation that was managed with endoscopic resection. Our experience suggests that a meticulous endoscopic inspection prior to and after radiofrequency ablation is fundamental to reduce the risk of buried neoplasia development.

Intensive Follow-Up After Curative Surgery for Colorectal Cancer.

INTRODUCTION: The purpose of postoperative surveillance programs after curative treatment for colorectal cancer is to detect asymptomatic recurrences with the premise that an important rate will be eligible for curative resection, improving overall survival. We have implemented a surveillance program for patients with colorectal cancer, stages II-III, with periodic clinical, carcinoembryonic antigen and cancer antigen-19-9 assessment, computed tomography and colonoscopy. The aim of this study was to assess the rate of curative treatment of recurrence, colorectal cancer mortality and clinical characteristics associated with non-resectable recurrence. MATERIAL AND METHODS: Open cohort study, single center. All patients on the intensive surveillance program between March 2008 and January 2015 were included. STATISTICS: chi-square, Wilcoxon rank sum test, logistic regression, Kaplan-Meier log-rank test (SPSS20®). RESULTS: We had a total 404 patients evaluated; 59.6% male; mean age of 65 ± 10 years; 50.7% rectal tumor; 56.2% stage III. The average time of follow-up was 37 months and the recurrence rate was 12.9% (n = 52), mostly detected in the first three years (88.4%). The pattern of recurrence was associated with the site of the primary tumor (p < 0.001). Twenty-one patients underwent curative resection. Factors associated with non-resectable recurrence were aged ≥ 70 years (p = 0.022), disease location in the colon (p = 0.033) and cancer antigen-19-9-9 elevation (p = 0.024). The overall rate of cancer-specific mortality was 2.2% (n = 9). DISCUSSION: The association between colon cancer and non-resectable recurrence is explained by the higher rate of disseminated disease in these patients. Cancer antigen-19-9 added no benefit to the surveillance program. CONCLUSION: This intensive real-world postoperative surveillance program allowed performing curative surgery to 40.3% of patients with recurrence.

Introdução: A vigilância intensiva pós-operatória do carcinoma colo-retal permite a deteção da recorrência em fase assintomática, aumentando o número de doentes que podem beneficiar de nova cirurgia. Implementámos um programa de vigilância de doentes com carcinoma colo-retal estádios II-III, operados com intenção curativa, com avaliação clínica, tomografia computorizada e colonoscopia. O presente estudo teve como objectivos avaliar a taxa de cirurgia de intenção curativa, a taxa de mortalidade por cancro e identificar características clínicas associadas à irresecabilidade da recidiva. Material e Métodos: Estudo de coorte, unicêntrico. Foram incluídos todos os doentes com carcinoma colo-retal integrados em programa de vigilância entre março de 2008 e janeiro de 2015. Análise estatística: qui-quadrado, Wilcoxon, regressão logística, Kaplan-Meier (SPSS20®). Resultados: Avaliámos 404 doentes; idade média: 65 ± 10 anos, 59,6% sexo masculino, 50,7% reto, 56,2% estádio III. O tempo médio de vigilância foi 37 meses e a taxa de recidiva foi 12,9% (n = 52), a maioria detetada nos primeiros três anos (88,4%). O padrão de recidiva associou-se à localização do tumor primário (p < 0,001). Vinte e um doentes foram submetidos a cirurgia curativa. Os fatores associados a recidiva irressecável foram: idade ≥ 70 anos (p = 0,022), carcinoma colo-retal localizado no cólon (p = 0,033) e elevação de antigénio carboidrato 19-9 (p = 0,024). A taxa global de mortalidade específica por cancro foi 2,2% (n = 9). Discussão: A associação entre neoplasia do cólon e recidiva irressecável deve-se à taxa mais elevada de doença disseminada nestes doentes. O antigénio carboidrato 19-9 não trouxe benefício acrescido ao programa de vigilância. Conclusão: Este estudo confirma o interesse clínico da vigilância intensiva na deteção de recidiva assintomática, permitindo alcançar cirurgia curativa em 40,3% dos doentes com recidiva.

Low risk of adenocarcinoma and high-grade dysplasia in patients with non-dysplastic Barrett's esophagus: Results from a cohort from a country with low esophageal adenocarcinoma incidence.

BACKGROUND: The risk of esophageal adenocarcinoma (EAC) in non-dysplastic Barrett's esophagus (NDBE) is considered to be approximately 0.3% per year or even lower, according to population-based studies. Data from countries with low EAC incidence are scarce. Our principal aim was to determine the incidence of high-grade dysplasia (HGD) and EAC in NDBE. Our secondary aims were to identify the predictors of progression and to calculate the incidence of HGD/EAC, by using the calculation method for surveillance time in population-based studies. MATERIALS AND METHODS: A cohort of NDBE patients was prospectively followed up. Cases of HGD and EAC (study end points) diagnosed during the first year of follow-up were considered as prevalent. Only cases with an endoscopic surveillance time > 1 year were included in our analysis. RESULTS: We enrolled 331 patients (251 men) in the surveillance program. Their median age was 59 years (interquartile range (IQR): 47-67 years). Their median NDBE length was 3 cm (IQR: 2-4 cm). Of these patients, 80 died during the follow-up (one from EAC) and two were lost to follow-up. After 2284 patient-years of endoscopic follow-up (median surveillance time, 5 years (IQR: 2-10 years)), we found that five cases of HGD and two cases of EAC were diagnosed. The incidence of HGD/EAC was 3.1 cases per 1000 patient-years (95% CI: 1.3-6.0) and that of EAC was 0.9 (95% CI: 0.2-2.9). The incidence of HGD/EAC in short segments (≤ 3 cm) was 0.7 cases per 1000 patient-years (95% CI: 0.3-3.4). The sole variable that we found associated with progression was NDBE length. If the total surveillance time was considered (3537 patient-years), the incidence of HGD and EAC was only slight lower. CONCLUSIONS: The incidence of HGD and EAC was very low in NDBE. Therefore, current surveillance guidelines must be reassessed, at least for short-segment BE.

Health-related quality of life and utilities in gastric premalignant conditions and malignant lesions: a multicentre study in a high prevalence country.

BACKGROUND AND AIMS: A recent review of economic studies relating to gastric cancer revealed that authors use different tests to estimate utilities in patients with and without gastric cancer. Our aim was to determine the utilities of gastric premalignant conditions and adenocarcinoma with a single standardized health measure instrument. METHODS: Cross-sectional nationwide study of patients undergoing upper endoscopy (n=1,434) using the EQ-5D-5L quality of life (QoL) questionnaire. RESULTS: According to EQ-5D-5L, utilities in individuals without gastric lesions were 0.78 (95% confidence interval: 0.76-0.80), with gastric premalignant conditions 0.79 (0.77-0.81), previously treated for gastric cancer 0.77 (0.73-0.81) and with present cancer 0.68 (0.55-0.81). Self-reported QoL according to the visual analogue scale (VAS) for the same groups were 0.67 (0.66-0.69), 0.67 (0.66-0.69), 0.62 (0.59-0.65) and 0.62 (0.54-0.70) respectively. Utilities were consistently lower in women versus men (no lesions 0.71 vs. 0.78; premalignant conditions 0.70 vs. 0.82; treated for cancer 0.72 vs. 0.78 and present cancer 0.66 vs. 0.70). CONCLUSION: The health-related QoL utilities of patients with premalignant conditions are similar to those without gastric diseases whereas patients with present cancer show decreased utilities. Moreover, women had consistently lower utilities than men. These results confirm that the use of a single standardized instrument such as the EQ-5D-5L for all stages of the gastric carcinogenesis cascade is feasible and that it captures differences between conditions and gender dissimilarities, being relevant information for authors pretending to conduct further cost-utility analysis.

Familial adenomatous polyposis and Crohn's disease in one patient: dilemmas and concerns.

Familial adenomatous polyposis (FAP) and Crohn's disease (CD) are two entities with no known etiologic or physiopathogenic relation. The rarity of the former makes the coincidence of both diagnoses in one patient very unlikely. Nevertheless, management in such cases can be puzzling as surgical options must be considered, and immunosuppression/immunomodulation is set in a territory of accelerated carcinogenesis. We report the case of a 29-year-old male with a diagnosis of FAP since adolescence, already submitted to prophylactic proctocolectomy, presenting with anemia and bloody diarrhea, revealing small bowel CD. This case allows for a rich discussion of the clinical dilemmas presenting when FAP and CD are diagnosed in the same patient and for a deep analysis of the concerns inherent to the available therapeutic options.

Bone marrow-derived CD11b+Jagged2+ cells promote epithelial-to-mesenchymal transition and metastasization in colorectal cancer.

Timely detection of colorectal cancer metastases may permit improvements in their clinical management. Here, we investigated a putative role for bone marrow-derived cells in the induction of epithelial-to-mesenchymal transition (EMT) as a marker for onset of metastasis. In ectopic and orthotopic mouse models of colorectal cancer, bone marrow-derived CD11b(Itgam)(+)Jagged2 (Jag2)(+) cells infiltrated primary tumors and surrounded tumor cells that exhibited diminished expression of E-cadherin and increased expression of vimentin, 2 hallmarks of EMT. In vitro coculture experiments showed that the bone marrow-derived CD11b(+)Jag2(+) cells induced EMT through a Notch-dependent pathway. Using neutralizing antibodies, we imposed a blockade on CD11b(+) cells' recruitment to tumors, which decreased the tumor-infiltrating CD11b(+)Jag2(+) cell population of interest, decreasing tumor growth, restoring E-cadherin expression, and delaying EMT. In support of these results, we found that peripheral blood levels of CD11b(+)Jag2(+) cells in mouse models of colorectal cancer and in a cohort of untreated patients with colorectal cancer were indicative of metastatic disease. In patients with colorectal cancer, the presence of circulating CD11b(+)Jag2(+) cells was accompanied by loss of E-cadherin in the corresponding patient tumors. Taken together, our results show that bone marrow-derived CD11b(+)Jag2(+) cells, which infiltrate primary colorectal tumors, are sufficient to induce EMT in tumor cells, thereby triggering onset of metastasis. Furthermore, they argue that quantifying circulating CD11b(+)Jag2(+) cells in patients may offer an indicator of colorectal cancer progression to metastatic levels of the disease.

Bethesda criteria for microsatellite instability testing: impact on the detection of new cases of Lynch syndrome.

In 1997 Bethesda Guidelines (BG) were established and in 2004 those criteria were revised (RBG), with the main goal of selecting colorectal cancers (CRC) that should be subjected to microsatellite instability (MSI) testing. High microsatellite instability (MSI-H) is an intermediate marker for mutational analysis of the mismatch repair (MMR) genes involved in the genesis of Lynch Syndrome (LS). We aimed to evaluate and compare BG/RBG in the detection of MSI-H and subsequent identification of pathogenic MMR genes mutations. We included 174 patients with CRC and indication for MSI analysis according to BG or RBG. MSI testing was performed with the Bethesda markers and mutational analysis of MLH1, MSH2 and MSH6 genes undertaken with DGGE, MLPA and direct sequencing. One hundred fourteen of 174 patients (65.5 %) fulfilled BG and all of them RBG. With the BG, MSI-H was detected in 37/114 (32.5 %) CRCs and mutational analysis was positive in 14/37 (37.8 %) patients. The RBG led to detection of MSI-H in 49/174 (28.2 %) of the CRCs, having the mutational analysis been positive in 16/49 (32.7 %) patients. We could identify 14/114 (12.3 %) new cases of LS, through BG and 16/174 (9.2 %) via RBG. BG presented a similar overall percentage for the detection of MSI-H and mutations when compared with RBG. RBG implicated the analysis of more patients, though they gave rise to detection of two additional LS cases. This difference has a significant impact on the establishment of preventive measures, mainly for CRC, in all the mutation-carriers belonging to these families.

Familial colorectal cancer type X syndrome: two distinct molecular entities?

In a fraction of families fulfilling the Amsterdam criteria for hereditary non-polyposis colorectal cancer, colorectal cancers are microsatellite stable and DNA mismatch repair gene (MMR) mutations are not found. These families were designated as familial colorectal cancer type X (FCCTX). We aimed to characterise a group of FCCTX families defined by the Amsterdam criteria and MSS tumours at clinical and molecular level. Twenty-four tumours from 15 FCCTX families were analysed for loss of known tumour suppressor gene (TSG) loci (APC, TP53, SMAD4 and DCC), MGMT and MMR genes promoter methylation, and also APC and KRAS somatic mutations. FCCTX families presented specific clinical features: absence of endometrial tumours, high adenoma/carcinoma ratio (1.91) and prevalence of rectal cancers (13/27, 48%). New molecular features were found: the majority of FCCTX tumours (13/18; 72%) presented TSG loss. TSG loss positive tumours presented frequent APC and KRAS somatic mutations and MGMT methylation [10/13 (77%), 7/13 (54%) and 6/11 (54%), respectively]. In TSG loss negative tumours (5/18; 28%), the same molecular events were found in 2/5 (40%), 2/5 (40%) and 1/3 (33%) tumours, respectively. Transition mutations in KRAS were more frequent among MGMT methylated tumours than in unmethylated [5/8 (63%) vs. 1/10 (10%), P = 0.03]. Although sharing similar clinical features, at least two different molecular entities should exist among FCCTX families, one whose tumours present frequent TSG loss, APC and KRAS somatic mutations, and MGMT promoter methylation, and a second, lesser predominant, with no evidence of TSG loss and rarely presenting promoter methylation.

Risk factors for metabolic bone disease in Crohn's disease patients.

BACKGROUND: The aim was to evaluate the presence of metabolic bone disease (MBD) in patients with Crohn's disease (CD) and to identify potential etiologic factors. METHODS: The case-control study included 99 patients with CD and 56 controls with a similar age and gender distribution. Both groups had dual-energy x-ray absorptionmetry and a nutritional evaluation. Single nucleotide polymorphisms at the IL1, TNF-α, LTα, and IL-6 genes were analyzed in patients only. Statistical analysis was performed using SPSS software. RESULTS: The prevalence of MBD was significantly higher in patients (P = 0.006). CD patients with osteoporosis were older (P < 0.005), small bowel involvement and surgical resections were more frequent (P < 0.005), they more often exhibited a penetrating or stricturing phenotype (P < 0.05), duration of disease over 15 years (P < 0.005), and body mass index (BMI) under 18.5 kg/m(2) (P < 0.01) were more often found. No association was found with steroid use. Patients with a Z-score < -2.0 more frequently had chronic active disease (P < 0.05). With regard to diet, low vitamin K intake was more frequent (P = 0.03) and intake of total, monounsaturated, and polyunsaturated fat was higher in patients with Z-score < -2.0 (P < 0.05). With respect to genetics, carriage of the polymorphic allele for LTα252 A/G was associated with a higher risk of osteoporosis (P = 0.02). Regression analysis showed that age over 40 years, chronic active disease, and previous colonic resections were independently associated with the risk of developing MBD. CONCLUSIONS: The prevalence of MBD was significantly higher in CD patients. Besides the usual risk factors, we observed that factors related to chronic active and long-lasting disease increased the risk of MBD.