RESUMO
BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Instabilidade de Microssatélites , Neoplasias Encefálicas , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Humanos , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Mutação , Síndromes Neoplásicas HereditáriasRESUMO
BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and pan-chromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.
Assuntos
Adenoma , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/epidemiologia , Colonoscopia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Detecção Precoce de Câncer , Humanos , Incidência , Fatores de RiscoRESUMO
BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤â5âmm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81â%), the optical diagnostic confidence was high and showed an NPV of 96.0â% (95â% confidence interval [CI] 88.9â%-98.6â%) and accuracy of 89.3â% (95â%CI 81.9â%-93.9â%). By following the diagnose-and-leave-in policy, we would have avoided 59â% (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.
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Pólipos do Colo , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/cirurgia , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Humanos , Imagem de Banda EstreitaRESUMO
BACKGROUND & AIMS: There is a lack of clinical studies to establish indications and methodology for tattooing, therefore technique and practice of tattooing is very variable. We aimed to establish a consensus on the indications and appropriate techniques for colonic tattoo through a modified Delphi process. METHODS: The baseline questionnaire was classified into 3 areas: where tattooing should not be used (1 domain, 6 questions), where tattooing should be used (4 domains, 20 questions), and how to perform tattooing (1 domain 20 questions). A total of 29 experts participated in the 3 rounds of the Delphi process. RESULTS: A total of 15 statements were approved. The statements that achieved the highest agreement were as follows: tattooing should always be used after endoscopic resection of a lesion with suspicion of submucosal invasion (agreement score, 4.59; degree of consensus, 97%). For a colorectal lesion that is left in situ but considered suitable for endoscopic resection, tattooing may be used if the lesion is considered difficult to detect at a subsequent endoscopy (agreement score, 4.62; degree of consensus, 100%). A tattoo should never be injected directly into or underneath a lesion that might be removed endoscopically at a later point in time (agreement score, 4.79; degree of consensus, 97%). Details of the tattoo injection should be stated clearly in the endoscopy report (agreement score, 4.76; degree of consensus, 100%). CONCLUSIONS: This expert consensus has developed different statements about where tattooing should not be used, when it should be used, and how that should be done.
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Tatuagem , Colo , Endoscopia , HumanosRESUMO
BACKGROUND & AIMS: Dye-based pancolonic chromoendoscopy is recommended for colorectal cancer surveillance in patients with Lynch syndrome. However, there is scarce evidence to support its superiority to high-definition white-light endoscopy. We performed a prospective study assess whether in the hands of high detecting colonoscopists, high-definition, white-light endoscopy is noninferior to pancolonic chromoendoscopy for detection of adenomas in patients with Lynch syndrome. METHODS: We conducted a parallel controlled study, from July 2016 through January 2018 at 14 centers in Spain of adults with pathogenic germline variants in mismatch repair genes (60% women; mean age, 47 ± 14 years) under surveillance. Patients were randomly assigned to groups that underwent high-definition white-light endoscopy (n = 128) or pancolonic chromoendoscopy (n = 128) evaluations by 24 colonoscopists who specialized in detection of colorectal lesions in high-risk patients for colorectal cancer. Adenoma detection rates (defined as the proportion of patients with at least 1 adenoma) were compared between groups, with a noninferiority margin (relative difference) of 15%. RESULTS: We found an important overlap of confidence intervals (CIs) and no significant difference in adenoma detection rates by pancolonic chromoendoscopy (34.4%; 95% CI 26.4%-43.3%) vs white-light endoscopy (28.1%; 95% CI 21.1%-36.4%; P = .28). However, pancolonic chromoendoscopy detected serrated lesions in a significantly higher proportion of patients (37.5%; 95% CI 29.5-46.1) than white-light endoscopy (23.4%; 95% CI 16.9-31.4; P = .01). However, there were no significant differences between groups in proportions of patients found to have serrated lesions of 5 mm or larger (9.4% vs 7.0%; P = .49), of proximal location (11.7% vs 10.2%; P = .68), or sessile serrated lesions (3.9% vs 5.5%; P = .55), respectively. Total procedure and withdrawal times with pancolonic chromoendoscopy (30.7 ± 12.8 minutes and 18.3 ± 7.6 minutes, respectively) were significantly longer than with white-light endoscopy (22.4 ± 8.7 minutes and 13.5 ± 5.6 minutes; P < .001). CONCLUSIONS: In a randomized parallel trial, we found that for Lynch syndrome surveillance, high-definition white-light endoscopy is not inferior to pancolonic chromoendoscopy if performed by experienced and dedicated endoscopists. ClinicalTrials.gov no: NCT02951390.
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Adenoma/diagnóstico , Colonoscopia/métodos , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer/métodos , Vigilância da População/métodos , Adenoma/congênito , Adulto , Neoplasias Colorretais/congênito , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
INTRODUCTION: obscure gastrointestinal bleeding is defined as bleeding from a source that cannot be identified on upper or lower gastrointestinal endoscopy and capsule endoscopy is the next step in these patients. Some patients may be unsuitable for conventional endoscopy and performing a capsule panendoscopic test as a first line procedure might potentially reduce the number of endoscopies and their subsequent risk. AIM: to analyze our experience with capsule endoscopy in the bleeding setting. METHODS: the first 100 panendoscopic capsule procedures performed in our center from August 2011 until December 2016 were retrospectively reviewed. RESULTS: positive findings were observed in 61.2 % of patients; 46.26 % had a previous negative gastroscopy and the capsule detected small bowel lesions in 67.7 % and colonic findings in 80.64 %. Taking into consideration that our population were high-risk patients (mainly because of comorbidities) and that we used up to 45 ml of sodium phosphate, sodium, potassium and creatinine changes were analyzed before and after procedure. The mean "before" values were 140.68, 4.04 and 1.36, respectively. The mean "after" values were 140.28, 3.9 and 1.35 (p = n.s.). According to our findings, no other endoscopic studies would be needed in 64.5 % of patients with negative gastroscopy. According to capsule results, conventional endoscopy could have been avoided in 68.6 % of cases. CONCLUSION: panendoscopy with a capsule may be useful and safe in bleeding high-risk patients, by selecting those who need therapeutic endoscopy, avoiding up to 68.6 % of diagnostic endoscopies in our series.
Assuntos
Endoscopia por Cápsula , Hemorragia Gastrointestinal/diagnóstico , Gastroscopia , Humanos , Intestino Delgado , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: Most fulfillment and benchmarking information for colonoscopy quality indicators has been obtained from studies of primary screening colonoscopies. We analyzed differences in the fulfillment of colonoscopy quality indicators based on the indication for endoscopy. METHODS: We performed an observational, multicenter, cross-sectional study of 14,867 patients who underwent endoscopy procedures for gastrointestinal symptoms (40.3%), a positive result from a fecal immunochemical test (36.0%), postpolypectomy surveillance (15.3%), or primary screening (8.4%), from February 2016 through December 2017 at 14 centers in Spain. We evaluated rates of adequate colon cleansing, cecal intubation, adenoma detection, and colorectal cancer detection, among others. We used findings from primary screening colonoscopies as the reference standard. RESULTS: Fewer than 90% of patients had adequate bowel preparation; 83.1% of patients with gastrointestinal symptoms had adequate bowel preparation (odds ratio [OR] compared with patients with primary screening colonoscopies, 0.62; 95% CI, 0.49-0.78) and 85.3% of patients receiving postpolypectomy surveillance had adequate bowel preparation (OR, 0.71; 95% CI, 0.55-0.91). The cecal intubation rate was also lower in patients with gastrointestinal symptoms (93.1%) (OR, 0.34; 95% CI, 0.22-0.52). The adenoma detection rate was higher in patients with a positive result from a fecal immunochemical test (46.4%) (OR, 2.01; 95% CI, 1.71-2.35) and in patients undergoing postpolypectomy surveillance (48.2%) (OR, 1.41; 95% CI, 1.20-1.67). The highest proportion of patients with colorectal cancer was in the gastrointestinal symptom group (5.1%) (OR, 5.24; 95% CI, 2.30-11.93) and the lowest was in patients undergoing surveillance (0.8%) (OR, 0.83; 95% CI, 0.32-2.14). CONCLUSIONS: Fulfillment of colonoscopy performance measures varies substantially by indication. Policies addressing performance measures beyond colonoscopy screening procedures should be developed. Benchmarking recommendations could be adjusted according to colonoscopy indication.
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Adenoma , Neoplasias Colorretais , Adenoma/diagnóstico , Adenoma/cirurgia , Ceco , Colonoscopia , Neoplasias Colorretais/diagnóstico , Estudos Transversais , Detecção Precoce de Câncer , HumanosRESUMO
BACKGROUND & AIMS: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. METHODS: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. RESULTS: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. CONCLUSIONS: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Síndromes Neoplásicas Hereditárias , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutLRESUMO
There is limited scientific evidence available to stratify the risk of developing metachronous colorectal cancer after resection of colonic polyps and to determine surveillance intervals and is mostly based on observational studies. However, while awaiting further evidence, the criteria of endoscopic follow-up needs to be unified in our setting. Therefore, the Spanish Association of Gastroenterology, the Spanish Society of Family and Community Medicine, the Spanish Society of Digestive Endoscopy, and the Colorectal Cancer Screening Group of the Spanish Society of Epidemiology, have written this consensus document, which is included in chapter 10 of the "Clinical Practice Guideline for Diagnosis and Prevention of Colorectal Cancer. 2018 Update". Important developments will also be presented as regards the previous edition published in 2009. First of all, situations that require and do not require endoscopic surveillance are established, and the need of endoscopic surveillance of individuals who do not present a special risk of metachronous colon cancer is eliminated. Secondly, endoscopic surveillance recommendations are established in individuals with serrated polyps. Finally, unlike the previous edition, endoscopic surveillance recommendations are given in patients operated on for colorectal cancer. At the same time, it represents an advance on the European guideline for quality assurance in colorectal cancer screening, since it eliminates the division between intermediate risk group and high risk group, which means the elimination of a considerable proportion of colonoscopies of early surveillance. Finally, clear recommendations are given on the absence of need for follow-up in the low risk group, for which the European guidelines maintained some ambiguity.
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Neoplasias do Colo/diagnóstico , Pólipos do Colo/cirurgia , Colonoscopia/normas , Neoplasias Colorretais/cirurgia , Vigilância da População , Guias de Prática Clínica como Assunto , Algoritmos , Pólipos do Colo/patologia , Progressão da Doença , Humanos , RiscoRESUMO
BACKGROUND & AIMS: We investigated whether patients with multiple serrated polyps, but not meeting the World Health Organization criteria for serrated polyposis syndrome, and their relatives have similar risks for colorectal cancer (CRC) as those diagnosed with serrated polyposis. METHODS: We collected data from patients with more than 10 colonic polyps, recruited in 2008-2009 from 24 hospitals in Spain for a study of causes of multiple colonic polyps. We analyzed data from 53 patients who met the criteria for serrated polyposis and 145 patients who did not meet these criteria, but who had more than 10 polyps throughout the colon, of which more than 50% were serrated. We calculated age- and sex-adjusted standardized incidence ratios (SIRs) for CRC in both groups, as well as in their first-degree relatives. RESULTS: The prevalence of CRC was similar between patients with confirmed serrated polyposis and multiple serrated polyps (odds ratio, 1.35; 95% confidence interval [CI], 0.64-2.82; P = .40). The SIR for CRC in patients with serrated polyposis (0.51; 95% CI, 0.01-2.82) did not differ significantly from the SIR for CRC in patients with multiple serrated polyps (0.74; 95% CI, 0.20-1.90; P = .70). The SIR for CRC also did not differ significantly between first-degree relatives of these groups (serrated polyposis: 3.28, 95% CI, 2.16-4.77; multiple serrated polyps: 2.79, 95% CI, 2.10-3.63; P = .50). Kaplan-Meier analysis showed no differences in the incidence of CRC between groups during the follow-up period (log-rank, 0.6). CONCLUSIONS: The risk of CRC in patients with multiple serrated polyps who do not meet the criteria for serrated polyposis, and in their first-degree relatives, is similar to that of patients diagnosed with serrated polyposis.
Assuntos
Adenoma/diagnóstico , Pólipos do Colo/genética , Pólipos do Colo/patologia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Vigilância da População , Adenoma/patologia , Adulto , Idoso , Pólipos do Colo/diagnóstico , Colonoscopia , Neoplasias Colorretais/patologia , DNA Glicosilases/genética , Análise Mutacional de DNA , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Prevalência , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Risco , Síndrome , Carga TumoralRESUMO
BACKGROUND: Type I gastric neuroendocrine tumors (gNETs) classically arise because of hypergastrinemia and involve destruction of parietal cells, which are responsible for gastric acid secretion through the ATP4A proton pump and for intrinsic factor production. METHODS: By whole exome sequencing, we studied a family with three members with gNETs plus hypothyroidism and rheumatoid arthritis to uncover their genetic origin. RESULTS: A heterozygous missense mutation in the ATP4A gene was identified. Carriers of this variant had low ferritin and vitamin B12 levels but did not develop gNETs. A second heterozygous mutation was also uncovered (PTH1R p.E546K). Carriers exhibited hypothyroidism and one of them had rheumatoid arthritis. Gastrin activates parathyroid hormone like hormone/parathyroid hormone 1 receptor (PTH1R) signaling, which is involved in gastric cell homeostasis. Activation of parathyroid hormone/PTH1R, which is upregulated by thyrotropin in the thyroid, is also involved in RANKL expression, which regulates bone homeostasis. Thyrotropin and RANKL expression were deregulated in PTH1R mutation carriers, suggesting a link between the PTH1R gene, hypothyroidism, rheumatoid arthritis, and gastric disease. Only patients with both mutations developed gNETs plus hypothyroidism and rheumatoid arthritis. CONCLUSION: Both mutations suggest that a collaborative mechanism is operative in this family, in which mutations in these genes affect the function and viability of parietal cells and lead to the achlorhydria that drives hypergastrinemia and the formation of gNETs.
Assuntos
ATPase Trocadora de Hidrogênio-Potássio/genética , Tumores Neuroendócrinos/genética , Receptor Tipo 1 de Hormônio Paratireóideo/genética , Neoplasias Gástricas/genética , Adulto , Artrite Reumatoide/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Hipotireoidismo/genética , Masculino , Pessoa de Meia-Idade , Mutação , LinhagemRESUMO
BACKGROUND AND STUDY AIMS: Endoscopic surveillance in patients with multiple colorectal polyps aims to reduce colorectal cancer (CRC) incidence and mortality, as well as the need for colorectal surgery. The aim of this study was to determine the risk of developing CRC or the need for surgery during endoscopic surveillance in a cohort of patients with multiple (10â-â100) colorectal polyps. PATIENTS AND METHODS: This was a multicentrer, longitudinal, observational study in 15 CRC high risk clinics in Spain, carried out between January 2009 and December 2010.âPatients who were included in the EPIPOLIP trial and had at least 1 year of follow-up were included in the study. The primary outcome of interest was the incidence of CRC at least 1 year following the initial colonoscopy. The secondary outcome was the need for colorectal surgery. RESULTS: A total of 265 patients were followed for a median of 3.8 years. Patients underwent a median of 5 colonoscopies, and 17 patients (6.4â%) were diagnosed with CRC. A total of 32 patients (12.1â%) underwent surgery, including 15 (5.7â%) for prophylaxis without a diagnosis of CRC. The corresponding incidence density rates for CRC and colorectal surgery were 1.4 (95â% confidence interval [CI] 0.7 to 2.1) and 2.7 (95â%CI 1.7 to 3.6) per 100 patient-years, respectively. Only the presence of symptoms at first colonoscopy was independently associated with CRC diagnosis (hazard ratio [HR] 7.7, 95â%CI 1.1 to 59.3) and colorectal surgery (HR 4.6, 95â%CI 1.02 to 20.6). CONCLUSIONS: Patients with more than 10 neoplastic polyps required frequent colonoscopies within a short follow-up period. More than 10â% of patients required colorectal surgery within 4 years, more than half for incident CRC.
Assuntos
Pólipos Adenomatosos/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer , Pólipos Intestinais/patologia , Lesões Pré-Cancerosas/patologia , Adolescente , Adulto , Idoso , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Espanha , Adulto JovemRESUMO
Age-related neurodegenerative diseases involving amyloid aggregation remain one of the biggest challenges of modern medicine. Alterations in the gastrointestinal microbiome play an active role in the aetiology of neurological disorders. Here, we dissect the amyloidogenic properties of biofilm-associated proteins (BAPs) of the gut microbiota and their implications for synucleinopathies. We demonstrate that BAPs are naturally assembled as amyloid-like fibrils in insoluble fractions isolated from the human gut microbiota. We show that BAP genes are part of the accessory genomes, revealing microbiome variability. Remarkably, the abundance of certain BAP genes in the gut microbiome is correlated with Parkinson's disease (PD) incidence. Using cultured dopaminergic neurons and Caenorhabditis elegans models, we report that BAP-derived amyloids induce α-synuclein aggregation. Our results show that the chaperone-mediated autophagy is compromised by BAP amyloids. Indeed, inoculation of BAP fibrils into the brains of wild-type mice promote key pathological features of PD. Therefore, our findings establish the use of BAP amyloids as potential targets and biomarkers of α-synucleinopathies.
Assuntos
Amiloide , Biofilmes , Caenorhabditis elegans , Neurônios Dopaminérgicos , Microbioma Gastrointestinal , Doença de Parkinson , alfa-Sinucleína , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/microbiologia , Humanos , Biofilmes/crescimento & desenvolvimento , Amiloide/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/microbiologia , Doença de Parkinson/patologia , Camundongos , Neurônios Dopaminérgicos/metabolismo , Autofagia , Doenças Neurodegenerativas/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Encéfalo/metabolismo , Encéfalo/patologia , Sinucleinopatias/metabolismo , Sinucleinopatias/patologiaRESUMO
BACKGROUND: Computer-aided detection (CADe) systems for colonoscopy have been shown to increase small polyp detection during colonoscopy in the general population. People with Lynch syndrome represent an ideal target population for CADe-assisted colonoscopy because adenomas, the primary cancer precursor lesions, are characterised by their small size and higher likelihood of showing advanced histology. We aimed to evaluate the performance of CADe-assisted colonoscopy in detecting adenomas in individuals with Lynch syndrome. METHODS: TIMELY was an international, multicentre, parallel, randomised controlled trial done in 11 academic centres and six community centres in Belgium, Germany, Italy, and Spain. We enrolled individuals aged 18 years or older with pathogenic or likely pathogenic MLH1, MSH2, MSH6, or EPCAM variants. Participants were consecutively randomly assigned (1:1) to either CADe (GI Genius) assisted white light endoscopy (WLE) or WLE alone. A centre-stratified randomisation sequence was generated through a computer-generated system with a separate randomisation list for each centre according to block-permuted randomisation (block size 26 patients per centre). Allocation was automatically provided by the online AEG-REDCap database. Participants were masked to the random assignment but endoscopists were not. The primary outcome was the mean number of adenomas per colonoscopy, calculated by dividing the total number of adenomas detected by the total number of colonoscopies and assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04909671. FINDINGS: Between Sept 13, 2021, and April 6, 2023, 456 participants were screened for eligibility, 430 of whom were randomly assigned to receive CADe-assisted colonoscopy (n=214) or WLE (n=216). 256 (60%) participants were female and 174 (40%) were male. In the intention-to-treat analysis, the mean number of adenomas per colonoscopy was 0·64 (SD 1·57) in the CADe group and 0·64 (1·17) in the WLE group (adjusted rate ratio 1·03 [95% CI 0·72-1·47); p=0·87). No adverse events were reported during the trial. INTERPRETATION: In this multicentre international trial, CADe did not improve the detection of adenomas in individuals with Lynch syndrome. High-quality procedures and thorough inspection and exposure of the colonic mucosa remain the cornerstone in surveillance of Lynch syndrome. FUNDING: Spanish Gastroenterology Association, Spanish Society of Digestive Endoscopy, European Society of Gastrointestinal Endoscopy, Societat Catalana de Digestologia, Instituto Carlos III, Beca de la Marato de TV3 2020. Co-funded by the European Union.
Assuntos
Adenoma , Inteligência Artificial , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Masculino , Feminino , Colonoscopia/métodos , Pessoa de Meia-Idade , Adenoma/diagnóstico , Adenoma/patologia , Adulto , Detecção Precoce de Câncer/métodos , Idoso , Diagnóstico por Computador/métodosRESUMO
BACKGROUND & AIMS: We investigated clinical and molecular differences between the different phenotypes of serrated polyposis syndrome (SPS) and the frequency of mutations in BRAF or KRAS in polyps from patients with SPS. METHODS: We collected data on clinical and demographic characteristics of 50 patients who fulfilled the criteria for SPS. Polymerase chain reaction and sequence analysis were used to identify BRAF and KRAS mutations in 432 polyps collected from 37 patients; we analyzed CpG island methylator phenotypes in 272 of these polyps. RESULTS: Fifteen patients (30%) had type 1 SPS and 35 had type 2 SPS. There were no significant differences in age at diagnosis, sex, smoking frequency, body mass index, or colorectal cancer predisposition between groups of patients, or in the pathologic or molecular characteristics of their polyps. A familial history of colorectal cancer or colonic polyps was reported more frequently by patients with type 2 SPS. BRAF mutations were found in 63% of polyps and KRAS mutations were found in 9.9%; 43.4% of polyps had the CpG island methylator phenotype-high phenotype. A per-patient analysis revealed that all patients had a BRAF or KRAS mutation in more than 25% of their polyps; 84.8% of patients had a mutation in BRAF or KRAS in more than 50% of their polyps. CONCLUSIONS: Except for a greater likelihood of familial history of colorectal cancer or colonic polyps in patients with type 2 SPS, we found no significant demographic, pathologic, or molecular differences between types 1 and 2 SPS. All patients had a BRAF or KRAS mutation in at least 25% of their polyps.
Assuntos
Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Polimorfismo Genético , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Idoso , Ilhas de CpG , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas p21(ras) , Análise de Sequência de DNARESUMO
Colonoscopy is an essential diagnostic and therapeutic tool for many gastrointestinal diseases and is also a key element in the prevention and early diagnosis of colon cancer. Despite numerous technical advances, colonoscopy continues to be uncomfortable for patients, both during and after the procedure. To a large extent, the discomfort of colonoscopy depends on the need to distend the colon, which usually produces abdominal pain. Although ambient air is usually employed to expand and inflate the colon, in the last few years devices that allow carbon dioxide (CO(2)) insufflation in colonoscopy have been developed. This gas is a highly attractive option for pain-free colonoscopy.
Assuntos
Dióxido de Carbono , Colonoscopia/métodos , Insuflação , HumanosRESUMO
The main goal at a High-Risk Gastrointestinal Cancer Clinic is to identify individuals at increased risk of developing tumors for diagnosis them in presymptomatic stages, when they are potentially curable. We report an asymptomatic patient belonging to a family with hereditary diffuse gastric cancer syndrome with a novel pathogenic mutation in the E-cadherin gene. In the absence of any proven diagnostic tool in surveillance tumor of this syndrome, the recommendation accepted today for an asymptomatic individual with known mutation is to perform prophylactic surgery. This patient underwent total laparoscopic gastrectomy. A microscopic focus of tumor was detected in the surgical specimen. Strategies to reduce the tumor risk in the hereditary diffuse gastric cancer syndrome are limited, but it is necessary to recognize them in order to treat these patients accordingly to the available evidence.
Assuntos
Adenocarcinoma/prevenção & controle , Caderinas/genética , Gastrectomia , Neoplasias Gástricas/prevenção & controle , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Antígenos CD , Códon sem Sentido , Feminino , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genéticaRESUMO
BACKGROUND AND OBJECTIVE: Different factors may influence colonoscopy performance measures. We aimed to analyze procedure- and endoscopist-related factors associated with detection of colorectal lesions and whether these factors have a similar influence in the context of different colonoscopy indications: positive fecal immunochemical test (+FIT) and post-polypectomy surveillance colonoscopies. METHODS: This multicenter cross-sectional study included adults aged 40-80 years. Endoscopists (N = 96) who had performed ≥50 examinations were assessed for physician-related factors. Adenoma detection rate (ADR), adenomas per colonoscopy rate (APCR), advanced ADR, serrated polyp detection (SDR), and serrated polyps per colonoscopy rate (SPPCR) were calculated. RESULTS: We included 12,932 procedures, with 4810 carried out after a positive FIT and 1967 for surveillance. Of the 96 endoscopists evaluated, 43.8% were women, and the mean age was 41.9 years. The ADR, advanced ADR, and SDR were 39.7%, 17.7%, and 12.8%, respectively. Adenoma detection rate was higher in colonoscopies after a +FIT (50.3%) with a more than doubled advanced ADR compared to non-FIT procedures (27.6% vs. 13.0%) and similar results in serrated lesions (14.7% vs. 13.5%). Among all the detection indicators analyzed, withdrawal time was the only factor independently related to improvement (p < 0.001). Regarding FIT-positive and surveillance procedures, for both indications, withdrawal time was also the only factor associated with a higher detection of adenomas and serrated polyps (p < 0.001). Endoscopist-related factors (i.e., weekly hours dedicated to endoscopy, annual colonoscopy volume and lifetime number of colonoscopies performed) had also impact on lesion detection (APCR, advanced ADR and SPPCR). CONCLUSIONS: Withdrawal time was the factor most commonly associated with improved detection of colonic lesions globally and in endoscopies for + FIT and post-polypectomy surveillance. Physician-related factors may help to address strategies to support training and service provision. Our results can be used for establishing future benchmarking and quality improvement in different colonoscopy indications.
Assuntos
Adenoma , Feminino , Humanos , Adulto , Masculino , Estudos Transversais , Adenoma/diagnósticoRESUMO
BACKGROUND AND OBJECTIVES: Familial adenomatous polyposis is an inherited disorder characterized by the presence of multiple colorectal adenomas (more than 100 in the classic form and between 10 and 100 in the attenuated one), with a high risk of colorectal cancer development. To improve the diagnostic and therapeutic management of these patients, the Spanish Registry of Familial Adenomatous Polyposis was created in 2007.We aimed to evaluate the clinicopathological characteristics of patients with familial adenomatous polyposis in Spain. PATIENTS AND METHODS: All patients included in the Registry during one year were evaluated with respect to their demographic, clinical, pathological, and genetic characteristics. RESULTS: 243 patients of 156 unrelated families from 15 Spanish centers were included. One hundred thirty patients were male, and the mean age at diagnosis was 40 years. According to the clinical presentation, 127 corresponded to the classic form and 116 to the attenuated one. Colorectal adenoma with high-grade dysplasia was identified in 67 (28%) patients, and colorectal cancer in 42 (17%). Extracolonic manifestations were: duodenal involvement (n=46), gastric involvement (n=44), desmoid tumors (n=24), thyroid cancer (n=8), osteomas (n=6) and brain tumor (n=1). APC and/or MYH gene testing was performed in 140 (90%) families, detecting the causative mutation in 75 (54%) of them (70 in the APC gene and 5 in the MYH gene). CONCLUSIONS: During its first year of operability, a large number of patients and families were included in the Registry. The reduced prevalence of colorectal cancer as well as the large proportion of families submitted to gene testing demonstrated a high-quality clinical practice in Spain.
Assuntos
Polipose Adenomatosa do Colo , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Espanha , Adulto JovemRESUMO
Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56-2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67-4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44-2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26-5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.