Individuals with familial adenomatous polyposis (FAP) have an almost 20% lifetime risk of duodenal adenocarcinoma, currently the leading cause of death in FAP. The Spigelman staging system provides ...guidance on the surveillance intervals and timing of prophylactic surgery. Still, its accuracy in predicting duodenal and papillary cancer development has not been systematically evaluated. We investigated the sensitivity and cancer risk of the Spigelman stages.
We performed a systematic review on PubMed, MEDLINE, EMBASE, and Cochrane and used a random-effects model to pool effect sizes.
After removing duplicate entries, we screened 1,170 records and included 27 studies for quantitative analysis. Once duodenal polyposis reaches Spigelman stage IV, the risk of duodenal and papillary cancers increased to 25% (95% confidence interval CI 12%-45%). However, the sensitivity of Spigelman stage IV for these cancers was low (51%, 95% CI 42%-60%), especially for papillary adenocarcinoma (39%, 95% CI 16%-68%). We investigated the reasons behind these low values and observed that duodenal cancer risk factors included polyps >10 mm, polyp count >20, and polyps with high-grade dysplasia. Risk factors associated with papillary cancer included a papilla with high-grade dysplasia or >10 mm. The evidence on other risk factors was inconclusive.
The current Spigelman staging system had a low sensitivity for duodenal and papillary adenocarcinomas. Two Spigelman variables (duodenal villous histology and polyp count) and the lack of papilla-specific variables likely contributed to the low sensitivity values for duodenal and papillary cancers, respectively. While clinicians may be familiar with its current form, there is an urgent need to update it.
The incidence of early-onset colorectal cancer, defined as colorectal cancer occurring in young adults under the age of 50, is increasing globally. Knowledge of the etiological factors in young ...adults is far from complete. Questionable eoCRCs’ exogenous factors are represented by processed meat, sugary drinks, alcohol, Western dietary pattern, overweight and obesity, physical inactivity, and smoking, though with heterogeneous results. Therefore, we performed a systematic review to summarize the current evidence on the role of diet and lifestyle as eoCRC risk factors. We systematically searched PubMed, Scopus, and EMBASE up to July 2021, for original studies evaluating diet, alcohol, physical activity, BMI, and smoking in eoCRC and included twenty-six studies. Indeed, the exogenous factors could represent modifiable key factors, whose recognition could establish areas of future interventions through public health strategies for eoCRC primary prevention. Additionally, we discussed the role of additional non-modifiable risk factors, and of epigenetic regulation and microbiota as mediators of the eoCRC triggered by diet and lifestyle.
Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts (AGE). ...Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP).
Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples.
In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: p = 0.07, logistic regression: p = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087).
Common GLO1 variants do not increase chronic pancreatitis risk.
Aims
A higher
SGLT1
and
GLUT2
gene expression was shown in the intestine of subjects with type 2 diabetes, while no data have been reported in type 1 diabetes (T1D). The purpose of our study was to ...evaluate the expression of glucose transporters in duodenal mucosa of subjects with T1D, compared to healthy controls (CTRL) and to patients with celiac disease (CD), as gut inflammatory disease control group.
Materials and methods
Gene expression of
GLUT1
,
GLUT2
,
SGLT1
and
SGLT2
was quantified on duodenal mucosa biopsies of subjects with T1D (
n
= 19), CD (
n
= 16), T1D and CD (
n
= 6) and CTRL (
n
= 12), recruited at San Raffaele Hospital (Milan, Italy), between 2009 and 2018.
SGLT2
expression was further evaluated by immunohistochemical and immunofluorescence staining.
Results
The expression of all four glucose transporters was detected in duodenal mucosa of all groups. A reduced
GLUT2
,
SGLT1
and
SGLT2
expression was observed in CD in comparison with T1D and CTRL, as expected;
GLUT1
was significantly more expressed in T1D compared to CTRL.
SGLT2
expression was quantified at much lower levels than other transporters, with no differences between groups.
SGLT2
expression was confirmed by immunohistochemistry in a restricted number of enterocytes lining in the mucosa of intestinal villi, also shown on immunofluorescence.
Conclusions
Our results show that glucose transporters expression in duodenal mucosa of subjects with T1D, except an increased
GLUT1
, is not different from that observed in healthy controls. The expression of
SGLT2
in human duodenal mucosa, although at low intensity, represents a novel finding.
Abstract
Background and study aims
Few reports exist about long-term outcomes of transoral incisionless fundoplication (TIF) for treating refractory gastro-esophageal reflux disease (GERD).
Methods
...A literature search of four major scientific databases was performed up to May 2020 for studies reporting on more than 3-year outcomes of TIF. Data on atient satisfaction, proton pump inhibitor (PPI) daily consumption, PPI use reduction, GERD health-related quality-of-life (GERD-HRQL) score, and normalization of heartburn and regurgitation scores were pooled and summarized with forest plots. Publication bias and heterogeneity were explored.
Results
Overall, eight studies (418 patients, 232 men; 55.5 %) with a mean follow-up of 5.3 years (range: 3–10 years) were included. The pooled proportion of patient-reported satisfaction before and after TIF was 12.3 % (95 % CI:12.3–35.1 %, I
2
= 87.4 %) and 70.6 % (95 % CI:51.2–84.6, I
2
= 80 %), respectively, corresponding to an odds ratio of 21.4 (95 % CI:3.27–140.5). Pooled rates of patients completely off PPIs and on occasional PPIs were 53.8 % (95 %CI: 42.0 %-65.1 %) and 75.8 % (95 %CI: 67.6–82.6), respectively. The pooled estimated mean GERD-HRQL scores off PPI before and after TIF werey 26.1 (95 %CI: 21.5–30.7; range: 20.0–35.5) and 5.9, respectively (95 %CI:0.35.1–11.4; range: 5.3–9.8;
P
< 0.001). The overall pooled rates of heartburn and regurgitation scores normalization were 73.0 % (95 %CI: 0.62–0.82) and 86 %, respectively (95 %CI: 75.0–91.0 %).
Conclusion
Our study shows that TIF appears to offer a long-term safe therapeutic option for selected patients with GERD who refuse life-long medical therapy or surgery, are intolerant to PPIs, or are at increased surgical risk.
Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased ...probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes.
We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms.
Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers.
Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.
Acute, acute recurrent, and chronic pancreatitis are inflammatory diseases with multifactorial pathogenic mechanisms. Genetic mutations and polymorphisms have been correlated with pancreatitis. The ...aim of this study was to investigate the association of cystic fibrosis transmembrane conductance regulator (CFTR) and serine protease inhibitor Kazal type 1 (SPINK-1) gene mutations and monocyte chemoattractant protein 1 (MCP-1) -2518A/G polymorphism with acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic pancreatitis (CP), and to associate genetic backgrounds with clinical phenotype in these three conditions.
One hundred eighteen AP, 64 ARP, 142 CP patients, and 88 normal controls were enrolled consecutively. We analyzed MCP-1 serum levels using enzyme-linked immunosorbent assay. Polymorphism -2518 of MCP-1 and SPINK-1 N34S gene mutations were determined by PCR-restriction-fragment length polymorphism. Sequence analysis was performed when necessary. Thirty-three CFTR mutations were analyzed in CP and ARP patients using multiplex DNA testing.
Serum MCP-1 levels were significantly higher in all patients affected by pancreatic inflammatory diseases. Moreover, we found a significant over-representation of the MCP-1G allele in ARP patients. We found a statistically significant association of CFTR gene mutations with ARP, but not with CP. We did not find a statistically significant association of ARP or CP with the N34S SPINK-1 gene mutation. Interestingly, 39 of 64 ARP patients (61%) carried at least one genetic mutation and/or polymorphism. Five of 64 ARP patients had pancreas divisum and four of these five also carried the G allele.
Analysis of a comprehensive range of potential susceptibility variants is needed to support modeling of the effects of genes and environment in pancreatitis. As such, beyond gene mutations, the context within which those mutations exist must be considered. In pancreatitis the context includes the inflammatory response, clinical features, and exogenous factors.
AIM:To assess the rate of relapses of acute pancreatitis(AP),recurrent AP(RAP)and the evolution of endosonographic signs of chronic pancreatitis(CP)in patients with pancreas divisum(PDiv)and ...RAP.METHODS:Over a five-year period,patients with PDiv and RAP prospectively enrolled were divided into two groups:(1)those with relapses of AP in the year before enrollment were assigned to have endoscopic therapy(recent RAP group);and(2)those free of recurrences were conservatively managed,unless they relapsed during follow-up(previous RAP group).All patients in both groups entered a follow-up protocol that includedclinical and biochemical evaluation,pancreatic endoscopic ultrasonography(EUS)every year and after every recurrence of AP,at the same time as endoscopic retrograde cholangiopancreatography(ERCP).RESULTS:Twenty-two were treated by ERCP and 14were conservatively managed during a mean follow-up of 4.5±1.2 years.In the recent RAP group in whom dorsal duct drainage was achieved,AP still recurred in11(57.9%)after the first ERCP,in 6 after the second ERCP(31.6%)and in 5 after the third ERCP(26.3%).Overall,endotherapy was successful 73.7%.There were no cases of recurrences in the previous RAP group.EUS signs of CP developed in 57.9%of treated and 64.3%of untreated patients.EUS signs of CP occurred in 42.8%of patients whose ERCPs were successful and in all those in whom it was unsuccessful(P=0.04).There were no significant differences in the rate of AP recurrences after endotherapy and in the prevalence of EUS signs suggesting CP when comparing patients with dilated and non-dilated dorsal pancreatic ducts within each group.CONCLUSION:Patients with PDiv and recent episodes of AP can benefit from endoscopic therapy.Effective endotherapy may reduce the risk of developing EUS signs of CP at a rate similar to that seen in patients of previous RAP group,managed conservatively.However,in a subset of patients,endotherapy,although successful,did not prevent the evolution of endosonographic signs of CP.
The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with ...microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.
Oral and Fecal Microbiota in Lynch Syndrome Ferrarese, Roberto; Zuppardo, Raffaella Alessia; Puzzono, Marta ...
Journal of clinical medicine,
08/2020, Letnik:
9, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Background: The role of microbiota in Lynch syndrome (LS) is still under debate. We compared oral and fecal microbiota of LS saliva and stool samples with normal healthy controls (NHC). Methods: ...Total DNA was purified from feces and saliva to amplify the V3–V4 region of the 16s rRNA gene. Sequences with a high-quality score and length >250 bp were used for taxonomic analysis with QIIME software. Results: Compared to NHC, LS fecal samples demonstrated a statistically significant increase of Bacteroidetes and Proteobacteria and a significant decrease of Firmicutes at the phylum level and of Ruminococcaceae at the family level. Moreover, LS oral samples exhibited a statistically significant increase of Veillonellaceae and Leptotrichiaceae and a statistically significant decrease of Pasteurellaceae. A beta-diversity index allowed differentiation of the two groups. Conclusions: A peculiar microbial signature is associated with LS, similar to that of sporadic colorectal cancer and Crohn’s disease. These data suggest a possible role of proinflammatory bacteria in tumor development in a condition of genetic predisposition, such as LS.
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