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.

Identification of irritable bowel syndrome in the Swedish National Patient Register: a validation study.

BACKGROUND AND OBJECTIVE: National patient registers are valuable in epidemiological studies. To ensure high-quality data for studies of irritable bowel syndrome (IBS), this study aimed to validate the ICD-10 code for IBS in the Swedish National Patient Register. METHODS: The positive predictive values (PPV) for IBS defined by the Rome criteria were calculated based on a review of medical records of randomly selected individuals with a first-ever diagnostic listing of IBS in the Swedish National Patient register in the year 2005 (Rome II criteria) or 2010 (Rome III criteria). KEY RESULTS: 340 medical records were reviewed (172 from 2005 and 168 from 2010). The majority of patients were females (74%), and the mean age was 42 years. IBS used in any type of department had a PPV of 76% (95% confidence interval 71-80%), which increased to 80% (76-84%) when we included individuals likely to have IBS but where information about some aspects of the Rome criteria was lacking in the medical record. Two highly specialized gastroenterological departments had the best PPV, 96%, while departments of internal medicine in general had a PPV of 82% (80-95%). The PPV for the IBS subtype was 62% (55-67%). The PPVs were not significantly different comparing the two time periods investigated. CONCLUSION AND INFERENCES: The validity of a register-based definition of IBS in the Swedish National Patient register is high and can be used to identify patients with IBS in observational research. The data source, i.e., type of hospital and department, influences reliability.

Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk.

OBJECTIVE: Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes, such as the PMS2 gene, and is characterised by a familial accumulation of colorectal cancer. The penetrance of cancer in PMS2 carriers is still not fully elucidated as a colorectal cancer risk has been shown to vary between PMS2 carriers, suggesting the presence of risk modifiers. METHODS: Whole exome sequencing was performed in a Swedish family carrying a PMS2 missense mutation [c.2113G>A, p.(Glu705Lys)]. Thirteen genetic sequence variants were further selected and analysed in a case-control study (724 cases and 711 controls). RESULTS: The most interesting variant was an 18 bp deletion in gene BAG1. BAG1 has been linked to colorectal tumour progression with poor prognosis and is thought to promote colorectal tumour cell survival through increased NF-κB activity. CONCLUSIONS: We conclude the genetic architecture behind the incomplete penetrance of PMS2 is complicated and must be assessed in a genome wide manner using large families and multifactorial analysis.

[Updated Swedish guidelines for endoscopic surveillance after colorectal polypectomy]. / Nya riktlinjer: endoskopisk kontroll efter kolorektal polypektomi.

These new guidelines are based on the recommendations published by European Society of Gastrointestinal Endoscopy (ESGE) in 2020. Low risk patients, i.e. after removal of 1-4 <10 mm adenomas with low grade dysplasia (irrespective of villous components), or any serrated lesion (hyperplastic polyp, sessile serrated lesion, or traditional serrated adenoma) <10 mm without dysplasia, are not recommended a surveillance colonoscopy. High-risk patients, i.e. after removal of at least one adenoma ≥10 mm or with high grade dysplasia or any serrated lesion ≥10 mm or with dysplasia, should undergo a surveillance colonoscopy after 3 years. If high-risk lesions are detected at surveillance colonoscopy, a 3-year repetition of the next endoscopic examination is recommended. If a high-risk patient has no high-risk lesions at surveillance colonoscopy, a 5-year period is recommended until the next surveillance colonoscopy. In general, follow-up should be terminated at 80 years of age.

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.

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.

Pre- and perinatal stress and irritable bowel syndrome in young adults - A nationwide register-based cohort study.

BACKGROUND: The etiology of irritable bowel syndrome (IBS) is poorly understood. Animal and human data suggest that early life stress may induce long-term changes in the nociceptive circuitry, but conclusive studies are lacking. METHODS: We identified all Swedish children born between 1973 and 1992 in the Swedish Medical Birth Register. We had access to all diagnostic codes for specialized (nonprimary care) outpatient visits 2001-2009 (the National Patient Register) and identified individuals who were diagnosed with IBS (ICD-10 code: K58) after 18 years of age. We compared incidence of IBS in individuals with and without pre- and perinatal stress using multivariable logistic regression. KEY RESULTS: 2 056 430 children were included in the study. After turning 18 years, 14 382 of them were diagnosed with IBS in specialized outpatient care. Neither high, nor low birth weight was a risk factor for IBS in young adults. Preterm birth was associated with lower occurrence of IBS (adjusted OR 0.82 [0.75-0.90]) and vaginal instrumental delivery and Cesarean delivery were associated with slightly increased odds of IBS (adjusted OR 1.14 [1.06-1.24] and 1.09 [1.03-1.16] respectively). Neonatal distress and respiratory distress were not associated with future IBS. Female gender was by far the strongest risk factor for IBS in young adults (adjusted OR 3.48 [3.34-3.63]). CONCLUSIONS & INFERENCES: In this large population-based study, we found that mode of delivery was associated with an increased risk for IBS in young adulthood, while other proxies for pre- and perinatal stress were not. Female gender remains the most important risk factor for IBS.

[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.

Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort.

Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patient's germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

Use of healthcare information and advice among non-urgent patients visiting emergency department or primary care.

BACKGROUND: Healthcare information provided by telephone service and internet sources is growing but has not been shown to reduce inappropriate emergency department (ED) visits. OBJECTIVE: To describe the use of advice or healthcare information among patients with non-urgent illnesses seeking care before attendance at an ED, or primary care (PC) centres in an urban region in Sweden. DESIGN: Patients with non-urgent illnesses seeking care at an ED or patients attending the PC were followed up with a combination of patient interviews, a questionnaire to the treating physician and a prospective follow-up of healthcare use through a population-based registry. RESULTS: Half of the non-urgent patients attending the ED had used healthcare information or advice before the visit, mainly from a healthcare professional source. In PC, men were more likely to have used information or advice compared with women (OR 2.5 95% CI 1.3 to 5.0), whereas the situation was reversed among ED patients (OR=0.4 95% CI 0.2 to 0.9). Men with no previous healthcare experience attending the ED had the lowest use of healthcare information (p<0.01). Very few in both groups had utilised healthcare information on the internet in a case of perceived emergency. CONCLUSION: ED patients rated as non-urgent by the triage nurse used more advice and healthcare information than PC patients, irrespective of the physician-rated urgency of the symptoms. The problem seems not to be lack of information about appropriate ED use, but to find ways to direct the information to the right target group.

Health care utilization following a non-urgent visit in emergency department and primary care.

Unscheduled visits to an emergency department (ED) or to primary care (PC) are often followed by further healthcare contacts. Present knowledge about predisposing factors and differences between healthcare levels is sparse. The objectives of this study were to describe and to analyze factors influencing subsequent healthcare contacts within 30 days following a non-urgent ED visit or an unscheduled visit in PC. In this prospective cohort study, subjects were identified and interviewed at the time of a non-urgent ED visit or unscheduled visits to PC. Data of all healthcare contacts during 1 month were collected. The probability of reattendance was analyzed regarding socio-demographic factors, previous and present health care utilization, the physicians' perceptions of the urgency of the visit, and appropriateness of its level of care. More than half of the patients in both settings had at least one contact with healthcare the following month. In 16% of the ED patients and 9% of PC patients, these contacts were to an ED. In the multivariate analysis, patients with regular monitoring of chronic disease were associated with an increased probability of having one or more physician visit the following month (OR 1.97 CI 95% 1.15-3.36). In conclusion, previous health care utilization was associated with an increased probability of one or more further physician visits the following month, regardless of the setting for the index visit or other patients characteristics. Physicians' perception of urgency did not influence the probability of further contacts.

Physician assessment of appropriate healthcare level among nonurgent patients.

OBJECTIVES: To analyze the appropriateness of healthcare level chosen by nonurgent patients in an emergency department (ED) compared with unscheduled primary care (PC) patients and the factors influencing physician consideration of appropriate care level. STUDY DESIGN: Cross-sectional study. METHODS: This study used structured face-to-face interviews with nonurgent patients at an urban ED and with unscheduled PC patients from a defined catchment area, concomitant with a questionnaire to the treating physician. RESULTS: General practitioners considered to a higher extent than their ED colleagues that patients chose an appropriate level of care. General practitioners were older and had longer clinical experience than physicians at the ED. Patients considered at an appropriate care level were distinguished by their symptom presentation, shorter duration of symptoms, and more regular previous healthcare use. Men with little regular previous healthcare use were more likely to present with symptoms assessed as inappropriate for the ED (P <.001). CONCLUSIONS: Patients with disorders that ED physicians considered inappropriate for the setting had little regular previous healthcare use but were also managed by less experienced physicians compared with patients in PC. General practitioners agreed with the choice of healthcare level among their patients to a large extent. It is important to meet patient demands and concerns in a professional way and to develop organizational ways to manage patient needs that are suitable for the setting.

Characteristics of non-urgent patients. Cross-sectional study of emergency department and primary care patients.

OBJECTIVE: To describe characteristics of patients seeking medical attention for non-urgent conditions at an emergency department (ED) and patients who use non-scheduled services in primary healthcare. DESIGN: Descriptive cross-sectional study. SETTING: Primary healthcare centres and an ED with the same catchment area in Stockholm, Sweden. PATIENTS: Non-scheduled primary care patients and non-referred non-urgent ED patients within a defined catchment area investigated by structured face-to-face interviews in office hours during a nine-week period. MAIN OUTCOME MEASURES: Sociodemographic characteristics, chief complaints, previous healthcare use, perception of symptoms, and duration of symptoms before seeking care. RESULTS: Of 924 eligible patients, 736 (80%) agreed to participate, 194 at the ED and 542 at nine corresponding primary care centres. The two groups shared demographic characteristics except gender. A majority (47%) of the patients at the primary care centres had respiratory symptoms, whereas most ED patients (52%) had digestive, musculoskeletal, or traumatic symptoms. Compared with primary care patients, a higher proportion (35%) of the ED patients had been hospitalized previously. ED patients were also more anxious about and disturbed by their symptoms and had had a shorter duration of symptoms. Both groups had previously used healthcare frequently. CONCLUSIONS: Symptoms, previous hospitalization and current perception of symptoms seemed to be the main factors discriminating between patients studied at the different sites. There were no substantial sociodemographic differences between the primary care centre patients and the ED patients.