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1.
Gastroenterology ; 2020 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-31926173

RESUMEN

BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 y was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P<.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 y (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P=.001 and P=.003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P=.015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P=.002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

2.
Z Gastroenterol ; 57(11): 1309-1320, 2019 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-31739377

RESUMEN

INTRODUCTION: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. METHODS: The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. RESULTS: A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. CONCLUSION: LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN , Endoscopía del Sistema Digestivo/métodos , Guías de Práctica Clínica como Asunto , Conducta de Reducción del Riesgo , Neoplasias Colorrectales , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Alemania , Humanos , Vigilancia de la Población , Factores de Tiempo
3.
Artículo en Inglés | MEDLINE | ID: mdl-31636762

RESUMEN

Background: We previously reported that in pathogenic mismatch repair (path_MMR) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated. Methods: The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. Results: Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1, 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5-3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively (p < 0.001). Ten-year crude survival when the last colonoscopy had been < 1.5, 1.5-2.5, 2.5-3.5 or > 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively (p = 0.91). Conclusions: In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.

4.
Genet Med ; 21(10): 2390-2400, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30918358

RESUMEN

PURPOSE: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients. METHODS: Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice. RESULTS: Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer. CONCLUSION: This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.

5.
Artículo en Inglés | MEDLINE | ID: mdl-30858900

RESUMEN

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

6.
Gastroenterology ; 155(5): 1400-1409.e2, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30063918

RESUMEN

BACKGROUND & AIMS: Patients with Lynch syndrome are at high risk for developing colorectal cancer (CRC). Regular colonoscopic surveillance is recommended, but there is no international consensus on the appropriate interval. We investigated whether shorter intervals are associated with lower CRC incidence and detection at earlier stages by comparing the surveillance policies in Germany, which evaluates patients by colonoscopy annually, in the Netherlands (patients evaluated at 1-2-year intervals), and Finland (patients evaluated at 2-3-year intervals). METHODS: We collected data from 16,327 colonoscopic examinations (conducted from 1984 through 2015) of 2747 patients with Lynch syndrome (pathogenic variants in the MLH1, MSH2, or MSH6 genes) from the German HNPCC Consortium, the Dutch Lynch Syndrome Registry, and the Finnish Lynch Syndrome Registry. Our analysis included 23,309 person-years of cumulative observation time. Time from the index colonoscopy to incident CRC or adenoma was analyzed using the Kaplan-Meier method; groups were compared using the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk (diagnosis of CRC before the index colonoscopy, sex, mutation, age, and presence of adenoma at the index colonoscopy). RESULTS: The 10-year cumulative CRC incidence ranged from 4.1% to 18.4% in patients with low- and high-risk profiles, respectively, and varied with age, sex, mutation, and prior detection of CRC or adenoma. Observed colonoscopy intervals were largely in accordance with the country-specific recommendations. We found no significant differences in cumulative CRC incidence or CRC stage at detection among countries. There was no significant association between CRC stage and time since last colonoscopy. CONCLUSIONS: We did not find a significant reduction in CRC incidence or stage of detection in Germany (annual colonoscopic surveillance) than in countries with longer surveillance intervals (the Netherlands, with 1-2-year intervals, and Finland, with 2-3-year intervals). Overall, we did not find a significant association of the interval with CRC risk, although age, sex, mutation, and prior neoplasia were used to individually modify colonoscopy intervals. Studies are needed to develop and validate risk-adapted surveillance strategies and to identify patients who benefit from shorter surveillance intervals.


Asunto(s)
Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales/diagnóstico , Adulto , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales
7.
Dtsch Arztebl Int ; 115(11): 182-187, 2018 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-29607805

RESUMEN

BACKGROUND: About 100 000 ostomy carriers are estimated to live in Germany today. The creation of an ostomy represents a major life event that can be associated with impaired quality of life. Optimal ostomy creation and proper ostomy care are crucially important determinants of the success of treatment and of the patients' quality of life. METHODS: This article is based on pertinent publications retrieved by a selective search in PubMed, GoogleScholar, and Scopus, and on the authors' experience. RESULTS: Intestinal stomata can be created using either the small or the large bowel. More than 75% of all stomata are placed as part of the treatment of colorectal cancer. The incidence of stoma-related complications is reported to be 10-70%. Skin irritation, erosion, and ulceration are the most common early complications, with a combined incidence of 25-34%, while stoma prolapse is the most common late complication, with an incidence of 8-75%. Most early complications can be managed conservatively, while most late complications require surgical revision. In 19% of cases, an ostomy that was initially planned to be temporary becomes permanent. Inappropriate stoma location and inadequate ostomy care are the most common causes of early complications. Both surgical and patient-related factors influence late complications. CONCLUSION: Every step from the planning of a stoma to its postoperative care should be discussed with the patient in detail. Preoperative marking is essential for an optimal stoma site. Optimal patient management with the involvement of an ostomy nurse increases ostomy acceptance, reduces ostomy-related complications, and improves the quality of life of ostomy carriers.


Asunto(s)
Estomía/estadística & datos numéricos , Adulto , Anciano , Femenino , Alemania , Humanos , Neoplasias Intestinales/complicaciones , Neoplasias Intestinales/cirugía , Masculino , Persona de Mediana Edad , Estomía/métodos , Calidad de Vida/psicología , Factores de Riesgo , Automanejo/métodos , Automanejo/psicología , Estomas Quirúrgicos
8.
World J Surg ; 42(6): 1867-1871, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29147895

RESUMEN

BACKGROUND: Anastomotic leakage (AL) is the most feared complication in colorectal surgery. A diverting ileostomy is routinely used to prevent or reduce morbidity and mortality following AL. However, a diverting ileostomy cannot prevent AL. Besides, diverting ileostomy might be associated with relevant complications. Herein, we introduce the virtual ileostomy as an alternative to diverting ileostomy in patients undergoing restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for familial adenomatous polyposis (FAP). MATERIALS AND METHODS: The results of eight patients, five females and three males with a median age of 19.5 ± 6.0 years (range 16.0-31.0 years), undergoing restorative proctocolectomy with IPAA and virtual ileostomy for FAP are presented. RESULTS: All cases were laparoscopically managed. The virtual ileostomy was released between postoperative day 7 and 9. No AL was registered. Postoperative recovery was uneventful in all cases. CONCLUSION: A diverting ileostomy was prevented via the use of virtual ileostomy in all cases. Thus, virtual ileostomy is a good alternative to diverting ileostomy in patients undergoing restorative proctocolectomy with IPAA for FAP.


Asunto(s)
Poliposis Adenomatosa del Colon/cirugía , Ileostomía/métodos , Proctocolectomía Restauradora/métodos , Adolescente , Adulto , Fuga Anastomótica/cirugía , Femenino , Humanos , Masculino
9.
Artículo en Inglés | MEDLINE | ID: mdl-29046738

RESUMEN

BACKGROUND: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. METHODS: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. RESULTS: Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). CONCLUSIONS: The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.

10.
Gut ; 66(3): 464-472, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-26657901

RESUMEN

OBJECTIVE: Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. DESIGN: We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. RESULTS: 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. CONCLUSIONS: The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Endometriales/epidemiología , Neoplasias Ováricas/epidemiología , Vigilancia de la Población , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico por imagen , Neoplasias Colorrectales Hereditarias sin Poliposis/mortalidad , Proteínas de Unión al ADN/genética , Bases de Datos Factuales , Neoplasias Endometriales/mortalidad , Femenino , Expresión Génica , Heterocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Neoplasias Ováricas/mortalidad , Estudios Prospectivos , Tasa de Supervivencia , Adulto Joven
11.
Gut ; 66(9): 1657-1664, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-27261338

RESUMEN

OBJECTIVE: Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers? DESIGN: Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants. RESULTS: 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%). CONCLUSIONS: Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales Hereditarias sin Poliposis , Proteínas de Unión al ADN/genética , Homólogo 1 de la Proteína MutL/genética , Proteína 2 Homóloga a MutS/genética , Adulto , Anciano , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN/genética , Progresión de la Enfermedad , Europa (Continente)/epidemiología , Femenino , Variación Genética , Mutación de Línea Germinal , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Análisis de Supervivencia
12.
Am J Hum Genet ; 99(2): 337-51, 2016 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-27476653

RESUMEN

In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Alelos , Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Exoma/genética , Genes Recesivos/genética , Mutación de Línea Germinal/genética , Adolescente , Adulto , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Proteína 3 Homóloga de MutS , Linaje
13.
Chirurg ; 87(8): 709-22, 2016 Aug.
Artículo en Alemán | MEDLINE | ID: mdl-27339646

RESUMEN

Due to the advances in molecular genetic diagnostics of adenomatous polyposis variants, identification of patients with a genetic predisposition and their at risk relatives is becoming increasingly important in clinical practice. Precise knowledge of the specific risk profile is gaining significance especially for surgeons and requires a clinically differentiated approach in order to correctly identify the indications for prophylactic surgery. In this article reference will be made to the technical details of the pouch operation rather than the decision-making process per se, since this has become common knowledge for specialized colorectal surgeons. Besides the more commonly known polyposis syndromes, such as familial adenomatous polyposis (FAP), surgeons should nowadays at least be able to clinically distinguish between attenuated and classical variants of FAP, be aware of MUTYH-associated polyposis (MAP) and also the new polyposis syndrome polymerase proofreading-associated polyposis (PPAP). Surgeons should be familiar with the specific indications and extent of surgery for prophylactic organ removal in the lower gastrointestinal tract in order to be able to competently advise patients.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/cirugía , Poliposis Adenomatosa del Colon/clasificación , ADN Glicosilasas/genética , Análisis Mutacional de ADN , ADN Polimerasa I/genética , ADN Polimerasa II/genética , Humanos , Síndrome de Peutz-Jeghers/clasificación , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/cirugía
14.
Fam Cancer ; 15(3): 457-66, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27194409

RESUMEN

The ileoanal pouch has become the standard restorative procedure of choice for patients with the classical phenotype in FAP (familial adenomatous polyposis) and also for ulcerative colitis (UC). Whilst we tend to encounter descriptive analyses comparing functional outcome, fertility and quality of life (QOL) between series in literature, there may be an urgent need to discuss the subtle technical modifications that may be pivotal for improving long-term QOL in FAP patients. Our aim is to review the current literature and discuss the aspects of ileal pouch-anal anastomosis that may require specific reevaluation for FAP. Surgical strategies aimed at minimizing post-interventional desmoid growth is one of the most important aspects. For this study, the following topics of interest were selected: Timing of surgery, IRA or ileoanal pouch for classical FAP, laparoscopic or conventional surgery, TME or mesenteric dissection, preservation of the ileocolic vessels, handsewn or double-staple anastomosis, shape and size of pouch, protective ileostomy, Last and definitely not least: how to manage desmoid plaques or desmoids at the time of prophylactic surgery. For the depicted technicalities of the procedure, a review of recent literature was performed and evaluated. For the topics selected, only sparse reference in literature was identified that was focused on the specific condition situation of FAP. Almost all pouch literature focusses on the procedural aspects, and FAP patients are always a very minor number. Therefore it becomes obvious that the specific entity is not adequately taken into account. This is a serious bias for identification of important steps in the procedure that may be beneficial for patients with either of the diseases. The results of this study demonstrate that several technical differences for construction of ileoanal pouches in FAP patients deserve more attention and prospective evaluation-perhaps even randomized trials. The role, importance and potential benefit or deterioration of outcome in most of the discussed technicalities remains unclear to date. Significant differences between the underlying diseases (UC and FAP) have not been taken into consideration, such as specifically the management of precursor desmoid lesions at the time of prophylactic surgery as well as prevention of desmoid tumors. Several of the aspects discussed in this paper should be prospectively evaluated in larger and exclusive series of FAP patients.


Asunto(s)
Poliposis Adenomatosa del Colon/cirugía , Anastomosis Quirúrgica/métodos , Colitis Ulcerosa/cirugía , Reservorios Cólicos , Fibromatosis Agresiva/prevención & control , Proctocolectomía Restauradora/métodos , Procedimientos Quirúrgicos Profilácticos/métodos , Femenino , Fertilidad , Fibromatosis Agresiva/cirugía , Humanos , Laparoscopía/métodos , Complicaciones Posoperatorias , Calidad de Vida , Tiempo de Tratamiento , Resultado del Tratamiento
15.
Fam Cancer ; 15(1): 31-40, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26275868

RESUMEN

Aim of this study is to evaluate the outcome of long-term conservative treatment with sulindac and high-dose selective estrogen receptor modulators (SERMs) for sporadic and FAP-associated desmoid tumors. Desmoids are very rare tumors in the general population but occur frequently in FAP patients, being encountered in 23-38 %. Treatment of desmoids is still most controversial since response cannot be predicted and they are prone to develop recurrence. This study included all desmoid patients that were treated and followed at our institution and had completed at least 1 year of treatment. Response was defined as stable size or regression of desmoid size between two CT or MRI scans. A total of 134 patients were included. 64 (47.8 %) patients had a confirmed diagnosis of FAP, 69 (51.5 %) patients were sporadic. Overall 114 (85.1 %) patients showed regressive or stable desmoid size. Patients with previous history of multiple desmoid-related surgeries showed less-favorable response. The mean time to reach at least stable size was 14.9 (±9.1) months. After regression or stabilization, medication was tapered in 69 (60.5 %) of the treated patients with only one long-term recurrence after >10 years. The results of this study fortify the role of sulindac and high-dose SERMs as an effective and safe treatment for both, sporadic and FAP-associated desmoid tumors. While invasive treatment frequently results in high recurrence rates, high morbidity and high mortality, this conservative treatment is successful in most patients. The recurrence rate is negligible with no desmoid-related mortality in this large series. Therefore surgical resection, especially for mesenteric desmoids, should be deferred favoring this convincingly effective, well tolerated regimen.


Asunto(s)
Neoplasias Abdominales/tratamiento farmacológico , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fibromatosis Agresiva/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Sulindac/uso terapéutico , Resultado del Tratamiento
16.
Int J Colorectal Dis ; 30(8): 1109-15, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25935449

RESUMEN

PURPOSE: Prophylactic proctocolectomy with an ileoanal neo-reservoir is the established procedure in non-attenuated familial adenomatous polyposis (FAP). Traditionally, the ileal J-pouch is created by doubling 15 cm of the terminal ileum. Pouch inlet problems are not infrequently encountered in longer pouches. On this rationale, this series reports on the functional outcome and quality of life (QoL) following standardized construction of a shorter J-pouch with a limb of 8-9 cm length. METHODS: All patients of a single-surgeon series with FAP who underwent hand-assisted laparoscopic proctocolectomy and small ileal pouch-anal anastomosis as the primary procedure between 10/2005 and 04/2010 and responded to the questionnaire were included and retrospectively analyzed. RESULTS: A total of 46 patients (78 %) out of the consecutive series who underwent operation in this period were included in the study. After a mean follow-up of 38 months, 40/46 patients (87 %) did not report any incontinence and 3 patients (6.5 %) complained about occasional nocturnal incontinence (3 failed to answer this question). The mean stool frequency per 24 h was 6.25. No significant difference was encountered between the QoL outcome of our patients versus the German normative population. Comparable results were achieved in a study analyzing the long-term results in FAP patients with a 15-cm pouch. CONCLUSIONS: Smaller, 8-9 cm J-pouches show excellent functional results both in short- and in long-term results. The hand-assisted procedure was safe and no conversions were required. QoL is equal to a normative population, as it is in a series of patients with larger J-pouches.


Asunto(s)
Poliposis Adenomatosa del Colon/cirugía , Reservorios Cólicos , Proctocolectomía Restauradora/métodos , Adulto , Femenino , Alemania , Mano , Humanos , Masculino , Encuestas y Cuestionarios , Factores de Tiempo
17.
Viszeralmedizin ; 30(2): 82-8, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26288582

RESUMEN

BACKGROUND: The most frequent hereditary colorectal cancer (CRC) syndromes are Lynch syndrome and familial adenomatous polyposis (FAP), accounting for approximately 5% of the CRC burden. Both are characterized by an autosomal dominant mode of transmission and require an individualized approach of intensified screening and prophylactic surgery. METHODS: In this review, we provide an overview of the literature regarding gene- and gender-specific aspects of Lynch syndrome and FAP. Based upon available data, a personalized approach when treating patients and families with these predisposition syndromes is increasingly warranted. RESULTS: In Lynch syndrome patients, men have a significantly higher lifetime risk and earlier age of manifestation for CRC - especially in MSH6 mutation carriers. Moreover, incidence of gastric, bladder, and urothelial cancers is much higher in males. Females with an MSH6 mutation have to be aware of a very high risk especially for endometrial, but also for ovarian cancer. In FAP families, females are more prone to papillary thyroid cancers and also to desmoid tumors. CONCLUSION: It is timely to suggest gene- and gender-based adapted screening and surgical recommendations for Lynch syndrome patients. In FAP patients, females should follow intensified screening recommendations for early detection of precursors or papillary cancer of the thyroid. Moreover, desmoid patients should primarily not be subjected to surgical resection but rather to a gender-specific conservative medical treatment.

19.
Gut ; 62(6): 812-23, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23408351

RESUMEN

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families.


Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/terapia , Adulto , Anciano , Colonoscopía/normas , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Neoplasias/etiología , Neoplasias/genética , Neoplasias/terapia , Vigilancia en Salud Pública , Factores de Riesgo , Adulto Joven
20.
Langenbecks Arch Surg ; 397(4): 513-25, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22362054

RESUMEN

INTRODUCTION: Lynch syndrome as the most common hereditary colorectal cancer syndrome and the most common cause of hereditary endometrial cancer is characterized by an autosomal dominant inheritance with a penetrance of 85-90%. The molecular genetic underlying mechanism is a mutation in one of the mismatch repair genes. METHODS: In order to identify patients with Lynch syndrome, a nuclear family history should be ascertained and matched with the Amsterdam criteria. A different approach for identification is the adherence to Bethesda criteria and subsequent testing for microsatellite instability. In patients with unstable tumors as an indicator for mismatch repair deficiency, genetic counseling and mutation analysis are warranted. For families fulfilling the Amsterdam criteria, intensified screening is recommended, even if a pathogenic mutation is not identified. RESULTS: Individuals from families with a proven pathogenic mutation that are tested negative are at normal population risk for cancers and may be dismissed from intensified surveillance. Prophylactic surgery in high-risk individuals without neoplasia is not generally recommended. At the time of a colon primary, however, extended surgery should be discussed in the light of a high rate of metachronous cancers. The worries of impairing functional results have now been evaluated in the light of quality of life in a large international cohort. Interestingly, extended (prophylactic) surgery does not lead to inferior quality of life with equal perioperative risks. CONCLUSIONS: Therefore, taking the risk reduction into account, extended surgery at the time of the first colon primary should at least be discussed, if not recommended. Also, prophylactic hysterectomy and bilateral oophorectomy at the time of a colorectal primary should be recommended if family planning has been completed.


Asunto(s)
Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Adulto , Anciano , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/prevención & control , Neoplasias Colorrectales Hereditarias sin Poliposis/cirugía , Reparación de la Incompatibilidad de ADN/genética , Análisis Mutacional de ADN , Femenino , Tamización de Portadores Genéticos , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Adhesión a Directriz , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Linaje , Calidad de Vida/psicología
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