Endoscopic surveillance of Lynch syndrome at a highly specialized center in Sweden: An observational study of interval colorectal cancer and individual risk factors.

Introduction: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC). In order to detect CRCs amongst LS patients, regular colonoscopies are recommended. However, an international agreement on an optimal surveillance interval has not yet been reached. In addition, few studies have investigated factors that could potentially increase the CRC risk amongst LS patients. Aims: The primary aim was to describe the frequency of CRCs detected during endoscopic surveillance and to estimate the interval from a clean colonoscopy to CRC detection amongst LS patients. The secondary aim was to investigate individual risk factors, including sex, LS genotype, smoking, aspirin use and body mass index (BMI), on CRC risk amongst patients that develop CRC before and during surveillance. Material and methods: Clinical data and colonoscopy findings from 366 LS patients' 1437 surveillance colonoscopies were collected from medical records and patient protocols. Logistic regression and Fisher's exact test were used to investigate associations between individual risk factors and CRC development. Mann-Whitney U test was used to compare the distribution of TNM stages of CRC detected before surveillance and after index. Results: CRC was detected in 80 patients before surveillance and in 28 patients during surveillance (10 at index and 18 after index). During the surveillance programme, CRC was detected within 24 months in 65% of the patients, and after 24 months within 35% of the patients. CRC was more common amongst men, previous and current smokers, and the odds of developing CRC also increased with an increasing BMI. CRCs were more often detected amongst MLH1 and MSH2 carriers during surveillance, compared to the other genotypes. Conclusions: We found that 35% of the CRC cases detected during surveillance were found after 24 months. MLH1 and MSH2 carriers were at higher risk of developing CRC during surveillance. Additionally, men, current or previous smokers, and patients with a higher BMI were at higher risk of developing CRC. Currently, LS patients are recommended a "one-size-fits-all" surveillance program. The results support the development of a risk-score whereby individual risk factors should be taken into consideration when deciding on an optimal surveillance interval.

Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer.

BACKGROUND: Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today's clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance. METHODS: This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994-September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation. RESULTS: A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time. CONCLUSION: A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.

Older age is a risk factor for inadequate energy intake during acute, severe IBD and is associated with shorter time to relapse.

BACKGROUND: Effects of nutritional intake on inflammatory bowel disease (IBD) flare resolution are unknown. We hypothesised that nutritional factors during hospitalisation for acute severe IBD are associated with risk of subsequent relapse. We also studied risk factors for inadequate energy intake. METHODS: Patients admitted to the Karolinska Hospital Gastroenterology ward with IBD flare during 2015-2016 were retrospectively identified. In total, 91 patients were included. Data on nutrition, disease factors, inflammatory markers, and daily energy requirement were extracted. Requirement of new systemic steroid prescription, intensification of biological therapy, readmission, surgery, and calprotectin level were individually used as proxies for disease relapse. Follow-up was one year after discharge. Adjustments for age and sex were made where appropriate. RESULTS: Overall, 19%, 31%, and 45% of patients had days with energy intake <30, <50, and <70% of calculated requirement. Older age was associated with a higher number of days with energy intake <30, <50, and <70% of calculated requirement (regression coefficient 0.03, 0.04, 0.06 respectively, p = .012, .017, .008). The number of days with energy intake <30 and <70% of the calculated requirement and the length of the hospitalisation were associated with shorter time to new steroid prescription (hazard ratio 1.3, 1.1, 1.04 respectively, p = .016, .034, .011). CRP and calprotectin were not associated with relapse. CONCLUSION: Older age is a predictor of inadequate energy intake during hospitalisation for acute severe IBD. Inadequate energy intake adjusted for age and sex during IBD flare was better predictor of time to the next steroid-requiring relapse than inflammatory markers.

The use of ICD codes to identify IBD subtypes and phenotypes of the Montreal classification in the Swedish National Patient Register.

Introduction: Whether data on International Classification of Diseases (ICD)-codes from the Swedish National Patient Register (NPR) correctly correspond to subtypes of inflammatory bowel disease (IBD) and phenotypes of the Montreal classification scheme among patients with prevalent disease is unknown.Materials and methods: We obtained information on IBD subtypes and phenotypes from the medical records of 1403 patients with known IBD who underwent biological treatment at ten Swedish hospitals and retrieved information on their IBD-associated diagnostic codes from the NPR. We used previously described algorithms to define IBD subtypes and phenotypes. Finally, we compared these register-generated subtypes and phenotypes with the corresponding information from the medical records and calculated positive predictive values (PPV) with 95% confidence intervals.Results: Among patients with clinically confirmed disease and diagnostic listings of IBD in the NPR (N = 1401), the PPV was 97 (96-99)% for Crohn's disease, 98 (97-100)% for ulcerative colitis, and 8 (4-11)% for IBD-unclassified. The overall accuracy for age at diagnosis was 95% (when defined as A1, A2, or A3). Examining the validity of codes representing disease phenotype, the PPV was 36 (32-40)% for colonic Crohn's disease (L2), 61 (56-65)% for non-stricturing/non-penetrating Crohn's disease behaviour (B1) and 83 (78-87)% for perianal disease. Correspondingly, the PPV was 80 (71-89)% for proctitis (E1)/left-sided colitis (E2) in ulcerative colitis.Conclusions: Among people with known IBD, the NPR is a reliable source of data to classify most subtypes of prevalent IBD, even though misclassification commonly occurred in Crohn's disease location and behaviour and also among IBD-unclassified patients.

Fracture Risk in Patients With Inflammatory Bowel Disease: A Nationwide Population-Based Cohort Study From 1964 to 2014.

INTRODUCTION: Most studies on fractures in inflammatory bowel disease (IBD) are based on patients from tertiary centers or patients followed up before the introduction of immunomodulators or biologics. In addition, the role of corticosteroids in fracture risk has rarely been examined. METHODS: We conducted a nationwide population-based cohort study of 83,435 patients with incident IBD (ulcerative colitis [UC]: n = 50,162, Crohn's disease [CD]: n = 26,763, and IBD unclassified: 6,510) and 825,817 reference individuals from 1964 to 2014. Using multivariable Cox regression, we estimated hazard ratios (HRs) for hip fracture and any fracture and the association with cumulative corticosteroid exposure. RESULTS: During 1,225,415 person-years of follow-up in patients with IBD, there were 2,491 first-time hip fractures (203/100,000 person-years) compared with 20,583 hip fractures during 12,405,642 person-years in reference individuals (159/100,000 person-years). This corresponded to an HR of 1.42 (95% confidence interval [CI] = 1.36-1.48). The risk for hip fracture was higher in CD compared with UC (P < 0.001). Inflammatory bowel disease was also associated with any fracture (IBD: HR = 1.18; 95% CI = 1.15-1.20). Hazard ratios for hip fracture had not changed since the introduction of immunomodulators or biologics. Increasing exposure to corticosteroids was associated with hip fracture in both IBD and non-IBD individuals (P < 0.001), but only in elderly (>60 years) patients with IBD. The association between IBD and hip fracture was nonsignificant among individuals without corticosteroids (HR = 1.11; 95% CI = 0.86-1.44). CONCLUSIONS: Inflammatory bowel disease (CD and UC) is associated with an increased risk of hip fracture and any fracture, but not in individuals without a history of corticosteroid treatment. The association between corticosteroids and hip fracture was restricted to elderly patients with IBD.

Clinical effectiveness of golimumab in Crohn's disease: an observational study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).

OBJECTIVE: The effectiveness of golimumab in Crohn's disease (CD) is largely unknown as it is not approved for the treatment of the disease. We aimed to identify the population of CD patients treated with golimumab in Sweden, to assess the effectiveness of golimumab (defined as the drug retention rate), and to identify predictors of drug discontinuation. METHODS: Patients with CD who received at least one injection of golimumab were identified through the Swedish National Quality Registry for Inflammatory Bowel Disease, which includes prospectively collected clinical information. Cox regression models were used to identify predictors of golimumab discontinuation. RESULTS: The study cohort involved 94 patients of whom the majority (96.8%) had previously discontinued at least one anti-tumour necrosis factor (anti-TNF) agent. The drug retention rate at 12 weeks was 85.1%. Predictors of golimumab discontinuation at 12 weeks were previous surgery (adjusted HR = 7.52, 95% CI: 1.12-50.36), concomitant corticosteroid use at baseline (adjusted HR = 5.70, 95% CI: 1.13-28.68) and female sex (adjusted HR = 6.59; 95% CI: 1.04-41.62). The median duration of follow-up was 89 (IQR: 32-158) weeks. The drug retention at the most recent follow-up was 35.1%. Predictors of golimumab discontinuation at the most recent follow-up were corticosteroid use at baseline (adjusted HR = 2.60, 95% CI: 1.17-5.79) and female sex (adjusted HR = 2.24; 95% CI: 1.19-4.23). CONCLUSION: Patients with CD treated with golimumab were a treatment-refractory group. Despite this, more than one-third of the patients appeared to have had clinical benefit after a median follow-up of more than 1.5 years.

[Lynch syndrome is a major cause of monogenetic familial colorectal cancer]. / Många fall av Lynchs syndrom upptäcks först vid cancerdiagnos - Ökad medvetenhet om ärftlig cancer och regelbunden kontroll av anlagsbärare kan minska mortalitet och morbiditet.

Individuals with a history of colorectal or endometrial cancer younger than 50 years of age or with relatives younger than 50 years of age with a history of any of these malignances should be referred to clinical genetics for further diagnostic examinations and genetic counseling. Lynch syndrome is caused by mutations in mismatch repair genes and implicates an increased risk for colorectal cancer as well as endometrial cancer. Routine surveillance for this group of individuals regarding colorectal cancer by means of colonoscopy and endometrial cancer by means of transvaginal ultrasound as well as endometrial biopsies is recommended annually or biennially. Several preventive measures are under development, such as chemoprevention and vaccination. During 2015 we investigated reasons for diagnosis among those registered at Karolinska University Hospital. We found that a substantial part of this group of individuals was diagnosed in conjunction with their diagnosis of cancer; a prerequisite in order to offer at-risk individuals preventive measures is to improve identification of these individuals and offer them presymptomatic genetic testing in order to identify predisposing mutations.

Sclerosing mesenteritis and mesenteric panniculitis - clinical experience and radiological features.

BACKGROUND: Sclerosing mesenteritis (SM) is sometimes used as an umbrella-term for idiopathic inflammatory conditions in the mesentery. Mesenteric panniculitis (MP) is a radiological finding and its relation to clinical SM is not fully understood. The aims of this study were to determine whether any correlation could be found between the radiological findings and the clinical disease course. METHODS: Patients observed due to idiopathic inflammation of the mesentery were identified. If SM could be verified histologically or MP radiologically, the patients were included in this descriptive retro perspective study. RESULTS: Typical radiological changes were observed in 27 patients. A majority (23/27) of these patients had mild to moderate symptoms. This group with typical radiology was labelled MP. Four patients were included due to histologically verified disease but had uncharacteristic radiology involving multiple compartments of the abdomen. All four had marked systemic inflammation, fever and fluctuating radiologic findings. Three had severe disease with multiple hospitalisations and complications but responded promptly to corticosteroids. This group was denoted SM. CONCLUSIONS: We have identified two subgroups of patients; firstly, MP with stable and characteristic radiologic changes and secondly SM with atypical radiology and a more aggressive clinical course. We propose that the term SM should be reserved for this latter condition.

[Endoscopic surveillance after colorectal polypectomy]. / Riktlinjer för endoskopisk kontroll efter kolorektal polypektomi.

Endoscopic surveillance after colorectal polypectomy These guidelines for endoscopic surveillance after colorectal polypectomy are based on the recommendations published by European Society of Gastrointestinal Endoscopy (ESGE) in 2013. A precondition for the guidelines is that patients have undergone a high-quality colonoscopy, including complete removal and histopathological evaluation of all detected neoplastic lesions. Current research has made it possible to stratify patients into a low-risk and a high-risk group in terms of metachronous cancer. Low-risk group patients (1-2 tubular adenomas <10 mm in size) are recommended a surveillance colonoscopy 10 years after the index colonoscopy if the patient is less than 50 years old, otherwise not. High-risk group patients (adenomas with villous histology or high grade dysplasia or ≥10 mm in size, or ≥ 3 adenomas), should undergo a repetition colonoscopy 3 years after the index colonoscopy. If high-risk adenomas are detected at first or subsequent surveillance colonoscopy, a 3-year repetition of the next endoscopic examination is recommended. If a high-risk patient has no high-risk adenomas at the first surveillance colonoscopy, a 5-year period is recommended until the second surveillance colonoscopy. ESGE recommends termination of the follow-up at 80 years of age although individualised recommendations should consider general health and co-morbidity of the patients as well as findings at previous colonoscopies.

Long-term effectiveness of vedolizumab in inflammatory bowel disease: a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG).

OBJECTIVES: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. MATERIALS AND METHODS: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn's disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). RESULTS: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14-20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96-16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10-4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16-6.48). CONCLUSION: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.

OBJECTIVE: Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role. DESIGN: Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin. RESULTS: Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10-10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10-11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis). CONCLUSIONS: HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.

Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing.

Hereditary syndromes causing colorectal cancer include both polyposis and non-polyposis syndromes. Overlapping phenotypes between the syndromes have been recognized and this make targeted molecular testing for single genes less favorable, instead there is a gaining interest for multi-gene panel-based approaches detecting both SNVs, indels and CNVs in the same assay. We applied a panel including 19 CRC susceptibility genes to 91 individuals of six phenotypic subgroups. Targeted NGS-based sequencing of the whole gene regions including introns of the 19 genes was used. The individuals had a family history of CRC or had a phenotype consistent with a known CRC syndrome. The purpose of the study was to demonstrate the diagnostic difficulties linked to genotype-phenotype diversity and the benefits of using a gene panel. Pathogenicity classification was carried out on 46 detected variants. In total we detected sixteen pathogenic or likely pathogenic variants and 30 variants of unknown clinical significance. Four of the pathogenic or likely pathogenic variants were found in BMPR1A in patients with unexplained familial adenomatous polyposis or atypical adenomatous polyposis, which extends the genotype-phenotype spectrum for this gene. Nine patients had more than one variant remaining after the filtration, including three with truncating mutations in BMPR1A, PMS2 and AXIN2. CNVs were found in three patients, in upstream regions of SMAD4, MSH3 and CTNNB1, and one additional individual harbored a 24.2 kb duplication in CDH1 intron1.

Cronkhite-Canada syndrome - A Case report.

BACKGROUND/AIM: Cronkhite-Canada syndrome (CCS) is a non-inherited, sporadic disorder characterized by generalized gastrointestinal polyps (hamartomas), cutaneous pigmentation, alopecia and onychodystrophy. More than 500 CCS patients have been reported, mostly from Asian countries. Patients with CCS have a propensity to develop colonic traditional serrated adenomas (TSA). Some authors found increased frequency of colonic carcinomas in CCS patients. In the present communication, we report a patient with CCS in whom a colonoscopic examination failed to disclose a coexistent TSA. CASE REPORT: A 73-year-old female had a history of alopecia and nail atrophy. Because of iron deficiency anemia and occult gastrointestinal bleeding, she underwent a colonoscopic examination. RESULTS: Colonoscopy revealed multiple broad-based polyps. Due to continuous bleedings, a coloproctectomy was performed four months after colonoscopy. Pathology disclosed 50 hamartomas and, unexpectedly, a TSA with high-grade dysplasia in the cecum. CONCLUSION: The TSA was either overlooked at colonoscopy or not interpreted as different from the other colonic polyps by the endoscopist. CCS cases are very rare in Western countries. Given this circumstance, it is suggested that, when confronting the next CCS case, endoscopists should perform a comprehensive colonoscopic examination, including chromoscopy and directed biopsies from irregular polyps, to rule out a TSA, an adenoma prone to evolve into invasive carcinoma.

GREM1 and POLE variants in hereditary colorectal cancer syndromes.

Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy-number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease-causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease-causing mutations in hereditary CRC syndromes.

The role of illness perceptions in adherence to surveillance in patients with familial adenomatous polyposis (FAP).

OBJECTIVE: The aim of the study was to examine patients' beliefs about having familial adenomatous polyposis (FAP), a hereditary colorectal cancer syndrome, and how these beliefs are associated with adherence to endoscopic surveillance. METHODS: Adult patients diagnosed with FAP on the national Swedish polyposis register who had undergone prophylactic colorectal surgery (n 209, response rate 76%) completed the Illness Perception Questionnaire (IPQ). Logistic regression analysis was used to investigate the relationships between illness perceptions and adherence, when controlling for demographic and clinical factors. RESULTS: FAP was less distressing in men and those with fewer symptoms, reporting less serious consequences and more coherent understanding of FAP. Non-adherence (14%) to surveillance was associated with being older, having undergone surgery less recently and no history of malignancy. Patients' beliefs about their FAP were able to explain unique variance in non-adherence, in particular those who believed FAP was less distressing. CONCLUSIONS: Patients who were non-adherent to endoscopic surveillance had more positive perceptions about their FAP and, in particular, were less emotionally affected compared to those who adhered. As non-adherence implies a greater risk of future malignancies, special efforts are required to effectively prevent cancer in all patients with FAP. Those who have lived with the condition for a long time, and are not troubled by gastrointestinal symptoms or worried about their FAP, may be in need of specific information and support. Further prospective research is required to examine emotional predictors and consequences of non-adherence. Copyright © 2015 John Wiley & Sons, Ltd.