Antibody Kinetics after Three Doses of SARS-CoV-2 mRNA Vaccination in Patients with Inflammatory Bowel Disease.

Background: The emergence of new SARS-CoV-2 variants calls for more data on SARS-CoV-2 mRNA vaccine response. Aims: We aimed to assess the response to a third mRNA vaccine dose against SARS-CoV-2 in inflammatory bowel disease (IBD) patients. Methods: This was a single-center, observational prospective study of IBD patients who received a third mRNA vaccine dose against SARS-CoV-2. Antibody titers were taken post-third-dose at one and three months using the Roche Elecsys anti-SARS-CoV-2-S enzyme immunoassay. Titers less than 0.8 units/mL were considered negative according to the manufactures. Titers between 0.8 units/mL and 250 units/mL were considered non-neutralizing. Titers greater than 250 units/mL were considered neutralizing. Results: Eighty-three patients were included, all of whom had detectable antibodies at 3 months post-third dose. A total of 89% showed neutralizing and 11% non-neutralizing titers. Participants with non-neutralizing titers were more likely to be on systemic corticosteroids (p = 0.04). Two participants seroconverted from negative to positive, whereas 86% with non-neutralizing titers boosted to neutralizing levels. Only one participant with neutralizing titers after a third dose had a decrease to a non-neutralizing level within 3 months. Conclusions: Our findings support the ongoing recommendations for additional doses in immunocompromised individuals. However, longitudinal studies with a greater-sized patient population are needed.

Risk Factors for Infection and Health Impacts of the Coronavirus Disease 2019 (COVID-19) Pandemic in People With Autoimmune Diseases.

BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

Antibody Response 3 Months After 2-Dose SARS-CoV-2 mRNA Vaccination in Patients With Inflammatory Bowel Disease.

INTRODUCTION: The response to SARS-CoV-2 vaccination of patients with inflammatory bowel disease (IBD) on immune-modifying therapies requires further investigation because previous studies indicate that patients on immune therapy might have decreased antibody concentrations. METHODS: We present the antireceptor binding domain antibody response over a period of 3 months in 217 patients with IBD who completed standard 2-dose SARS-CoV-2 mRNA vaccine series. RESULTS: Almost all (98.6%) IBD vaccine recipients had a positive antireceptor binding domain antibody response at least 3 months after vaccination. Decreased antibody titers at 3 months were seen in a subset of patients on antitumor necrosis factor-alpha. Approximately 10% of the participants with high-titer antibodies at 1 month had a decrease to low-positive titers at 3 months, which was mostly observed in those on combination therapy and antitumor necrosis factor-alpha monotherapy. DISCUSSION: Larger longitudinal studies are required to define the response in IBD population and its clinical impact.

The impact of inflammatory bowel disease on women's lives.

PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) affects women differently than men. This review outlines the current thinking on the impact of IBD, Crohn's disease and ulcerative colitis, on women's health. RECENT FINDINGS: IBD symptoms worsen during the menstrual cycle without corelating to disease activity. Endometriosis is more frequent in women with than those without IBD. Low fertility rate is rather because of voluntary childlessness than severe disease, perianal involvement, and ileal pouch anal anastomosis (IPAA) surgery. For women with ulcerative colitis, in-vitro fertilization successfully overcomes the post-IPAA infertility. The use of biologics and thiopurines throughout pregnancy is well tolerated for both the mother and the child but the use of small molecule therapy still needs more data. These medications increase the risk of cervical cancer, anal cancer, and aggressive vulvar cancer. More screening efforts are required to keep patients healthy. Women with Crohn's disease report worse psychological well being less resilience than men but they develop more escape and avoidance strategies to cope with the disease. Depression impairs the quality of sexual life but sexual dysfunction is rarely discussed with the provider. SUMMARY: Understanding the effects of sex on IBD allows personalized care and improves women's quality of life.

Outcomes for Ulcerative Colitis With Delayed Emergency Colectomy Are Worse When Controlling for Preoperative Risk Factors.

BACKGROUND: Increasing evidence supports immediate colectomy in acute fulminant ulcerative colitis in comparison with ongoing medical management. Prior studies have been limited to inpatient-only administrative data sets or single-institution experiences. OBJECTIVE: The purpose of this study was to compare outcomes of early versus delayed emergency colectomy in patients admitted with ulcerative colitis flares while controlling for known preoperative risks and acuity. DESIGN: This is a cohort study of patients undergoing emergent total abdominal colectomies for ulcerative colitis compared by the timing of surgery. SETTING: Adult patients undergoing an emergent total abdominal colectomy for ulcerative colitis, 2005 to 2015, were identified in the American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS: Patients undergoing total abdominal colectomy with an operative indication of ulcerative colitis admitted on a nonelective basis were selected. MAIN OUTCOME MEASURE: The primary outcomes measured were 30-day National Surgical Quality Improvement Program-reported mortality and postoperative complications, and early operation within 2 days of admission. RESULTS: We identified 573 total abdominal colectomies after propensity score matching. Median time to surgery was 1 hospital day in the early group versus 6 hospital days in the delayed group (p < 0.001). Early operation was associated with a lower mortality rate (4.9% versus 20.3% in matched groups, p < 0.001) and lower complication rate (64.5% versus 72.0%, p = 0.052). Multivariable logistic regression with propensity weighting of mortality on preoperative risk factors demonstrated that early surgery is associated with an 82% decrease in the odds of death compared with delayed surgery (p < 0.001). Regression of morbidity on preoperative risk factors demonstrated that early surgery is associated with a 35% decrease in the odds of a complication with delayed surgery (p = 0.034). LIMITATIONS: Quality improvement data were used for clinical research questions. CONCLUSIONS: Patients undergoing immediate surgical intervention for acute ulcerative colitis have decreased postoperative complications and mortality rates. Rapid and early transitioning from medical to surgical management may benefit those expected to require surgery on the same admission. See Video Abstract at http://links.lww.com/DCR/A800.

Routine Pouchoscopy Prior to Ileostomy Takedown May Not Be Necessary in Patients with Chronic Ulcerative Colitis.

BACKGROUND: Creation of a J pouch is the gold standard surgical intervention in the treatment of chronic ulcerative colitis (UC). Pouchoscopy prior to ileostomy takedown is commonly performed. We describe the frequency, indication, and findings on pouchoscopy, and determine if pouchoscopy affects rates of complications after takedown. METHODS: All UC or indeterminate inflammatory bowel disease patients with a J pouch were retrospectively evaluated from January 1994 to December 2014. Cases were defined as having routine (asymptomatic) pouchoscopy after pouch creation but before ileostomy takedown. Controls were defined as having no pouchoscopy or pouchoscopy on the same day as that of takedown. RESULTS: The study included 178 patients (81.5% cases, 18.5% controls). Fifty two percent of pouchoscopies were reported as normal. Common abnormal endoscopy findings included stricture (35%), pouchitis (7%), and cuffitis (0.7%). Length of stay during takedown hospitalization was shorter for cases than controls (3 vs. 5 days; p = 0.001), but neither short- nor long-term complications were statistically different between cases and controls. Abnormalities on pouchoscopy were not predictive for short-term complications (p = 0.73) or long-term complications (p = 0.55). Routine pouchoscopy did not delay takedown surgery in any of the included patients. CONCLUSIONS: Routine pouchoscopy may not be necessary prior to ileostomy takedown; its greatest utility is in patients with suspected pouch complications.

Smoking and Inflammatory Bowel Disease: A Comparison of China, India, and the USA.

BACKGROUND: Cigarette smoking is thought to increase the risk of Crohn's disease (CD) and exacerbate the disease course, with opposite roles in ulcerative colitis (UC). However, these findings are from Western populations, and the association between smoking and inflammatory bowel disease (IBD) has not been well studied in Asia. AIMS: We aimed to compare the prevalence of smoking at diagnosis between IBD cases and controls recruited in China, India, and the USA, and to investigate the impact of smoking on disease outcomes. METHODS: We recruited IBD cases and controls between 2014 and 2018. All participants completed a questionnaire about demographic characteristics, environmental risk factors and IBD history. RESULTS: We recruited 337 participants from China, 194 from India, and 645 from the USA. In China, CD cases were less likely than controls to be current smokers (adjusted odds ratio [95% CI] 0.4 [0.2-0.9]). There was no association between current or former smoking and CD in the USA. In China and the USA, UC cases were more likely to be former smokers than controls (China 14.6 [3.3-64.8]; USA 1.8 [1.0-3.3]). In India, both CD and UC had similar current smoking status to controls at diagnosis. Current smoking at diagnosis was significantly associated with greater use of immunosuppressants (4.4 [1.1-18.1]) in CD cases in China. CONCLUSIONS: We found heterogeneity in the associations of smoking and IBD risk and outcomes between China, India, and the USA. Further study with more adequate sample size and more uniform definition of smoking status is warranted.

Nearly a Third of High-Grade Dysplasia and Colorectal Cancer Is Undetected in Patients with Inflammatory Bowel Disease.

BACKGROUND: It is unclear whether intensive surveillance protocols have resulted in a decreased incidence of colorectal cancer (CRC) in inflammatory bowel disease (IBD). AIMS: To determine the prevalence and characteristics of IBD associated high-grade dysplasia (HGD) or CRC that was undetected on prior colonoscopy. METHODS: This is a single-center, retrospective study from 1994 to 2013. All participants had a confirmed IBD diagnosis and underwent a colectomy with either HGD or CRC found in the colectomy specimen.The undetected group had no HGD or CRC on prior colonoscopies. The detected group had HGD or CRC identified on previous biopsies. RESULTS: Of 70 participants, with ulcerative colitis (UC) (n = 47), Crohn's disease (CD) (n = 21), and indeterminate colitis (n = 2), 29% (n = 20) had undetected HGD/CRC at colectomy (15 HGD and 5 CRC). In the undetected group, 75% had prior LGD, 15% had indefinite dysplasia, and 10% had no dysplasia (HGD was found in colonic strictures). Patients in the undetected group were more likely to have pancolitis (55 vs. 20%) and multifocal dysplasia (35 vs. 8%). The undetected group was less likely to have CRC at colectomy (25 vs. 62%). There was a trend toward right-sided HGD/CRC at colectomy (40 vs. 20%; p = 0.08). In addition, 84% of the lesions found in the rectum at colectomy were not seen on prior colonoscopy in the undetected group. CONCLUSIONS: The prevalence of previously undetected HGD/CRC in IBD found at colectomy was 29%. The high proportion of undetected rectal and right-sided HGD/CRC suggests that these areas may need greater attention during surveillance.

Serologic markers associated with development of Crohn's disease after ileal pouch anal anastomosis for ulcerative colitis.

BACKGROUND AND AIMS: One of the causes of pouch failure after ileal pouch anal anastomosis (IPAA) for ulcerative colitis (UC) is the development of de novo Crohn's disease (CD). Our aim was to clearly define factors associated with post-IPAA CD. METHODS: We conducted a cross-sectional study to compare demographic, clinical, and serological characteristics of patients with and without post-IPAA CD. All subjects underwent testing for anti-neutrophil cytoplasm antibodies, anti-Saccaromyces cerevisiae antibodies, anti-outer membrane porin C antibodies, and anti-CBir1 flagellin (anti-CBir1). A multivariable model assessed factors associated with post-IPAA CD. RESULTS: Thirty-nine subjects were enrolled in the study: 20 cases and 19 controls. Patients who developed post-IPAA CD were significantly younger (median 22 ± 9.9 vs. 30 ± 11.3, p = .027) at the time of UC diagnosis and exhibited more extraintestinal manifestations compared to controls (p = .023). No significant difference between the groups was found with respect to family history, smoking, duration of illness prior to colectomy, time to the onset of pouchitis, preoperative treatment, and indication for surgery. However, the post-operative serologic profile differed significantly with far more cases having elevated anti-CBir1 titers (p = .016, OR 8.81), the latter being the only independent predictor in the combined model. CONCLUSIONS: Patients with Crohn's disease of the pouch were more likely to have elevated CBir1 antibodies titers than those with simple pouchitis and healthy pouches. The stability of the CBir1 antibodies (pre- and post-colectomy) must be further assessed to establish its value as an independent predictor for development of post-IPAA CD.

Inflammatory Bowel Diseases Before and After 1990.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is caused by interaction of genetic and environmental risk factors. We evaluated potential determinants of the post-1990 increased incidence in North America. METHODS: Using fitted generalized linear models, we assessed clinical features, smoking and genetic risk scores (GRS) for Crohn's disease (CD) and ulcerative colitis (UC) in the National Institutes of Diabetes, Digestion and Kidney Diseases IBD Genetics Consortium database, before and post 1990. RESULTS: Among 2744 patients (55% CD, 42.2% UC), smoking status and GRS were the main determinants of diagnosis age. After 1990, smoking at diagnosis declined significantly in both UC and CD (34.1% vs 20.8%, P < .001, and 14.7% vs 8.7%, P = .06, respectively). In UC, ex-smoking increased (9% vs 15%, P < .001), and nonsmoking rates remained unchanged, whereas in CD, ex-smoking remained unchanged. CD-GRS and IBD-GRS were significantly associated with young diagnosis age, Jewish ethnicity, IBD family history, and surgery. CD-GRS showed a borderline significant decrease (P = .058) in multivariate analysis post 1990 but only when excluding surgery in the model; surgery significantly decreased post 1990 in both CD and UC. CD-GRS inversely correlated with smoking at diagnosis (P < .001) suggesting that, in the presence of smoking, CD may only require a low genetic risk to develop. CONCLUSION: Significantly increase in ex-smoking correlates with UC incidence post 1990. Conversely, smoking risk decreased significantly post 1990 despite rising CD incidence. CD-GRS likewise trended to decrease post 1990 only when not accounting for a significant decrease in CD surgery. We therefore deduce that unaccounted risk factors (eg, dietary, obesity, antibiotic use, improved hygiene, etc.) or greater detection or presence of mild CD may underlie post-1990 increased CD incidence.

Therapeutic drug monitoring in inflammatory bowel disease: At the right time in the right place.

Therapeutic drug monitoring (TDM) was one of most sought-after objective tools to determine therapeutic efficiency of different biologics and its role in the management of patients with inflammatory bowel disease (IBD) was regarded with great anticipation. But implementation of the TDM in clinical practice was challenged by several factors including uncertainty of the optimal cut-off values, assay variable sensitivity in detecting drug levels and antibodies and, most importantly, individual pharmacokinetics. While reactive TDM was embraced in clinical practice as a useful tool in assessing lack of response to therapy, the utility of proactive TDM in managing IBD therapy is still challenged by the lack of consistency between evidence. Described here, there are four groups of IBD patients for whom proactive TDM has the potential to greatly impact their therapeutic outcomes: Patients with perianal Crohn's disease, patients with severe ulcerative colitis, pregnant women with IBD and children. As the future of IBD management moves towards personalizing treatment, TDM will be an important decision node in a machine learning based algorithm predicting the best strategy to maximize treatment results while minimizing the loss of response to therapy.

RISK FACTORS FOR INFECTION AND HEALTH IMPACTS OF THE COVID-19 PANDEMIC IN PEOPLE WITH AUTOIMMUNE DISEASES.

Background: People with autoimmune or inflammatory conditions who take immunomodulatory/suppressive medications may have a higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. Objective: Assess whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterize pandemic-associated changes to care. Design: Longitudinal registry study. Participants: 4666 individuals with autoimmune or inflammatory conditions followed by specialists in neurology, rheumatology, cardiology, pulmonology or gastroenterology at Johns Hopkins. Measurements: Periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. Results: A total of 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medication exposure) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in multivariable models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and chronic kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were each associated with higher odds of COVID-19. Pandemic-related disruption to care was common. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions. Individuals experiencing changes to employment or income were at highest odds of care disruption. Limitations: Results may not be generalizable to all patients with autoimmune or inflammatory conditions. Information was self-reported. Conclusions: Exposure to glucocorticoids may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

Role of telomere shortening in anticipation of inflammatory bowel disease.

BACKGROUND: The existence of genetic anticipation has been long disputed in inflammatory bowel disease (IBD) in the absence of the explanatory mechanism. AIM: To determine whether it was predictive of genetic anticipation, we evaluated telomere length in IBD. We hypothesized that multiplex IBD families exhibit a genetic defect impacting telomere maintenance mechanisms. METHODS: We studied three IBD families with multiple affected members in three successive generations. We determined telomere length (TL) in lymphocytes and granulocytes from peripheral blood of the affected members using flow cytometry and fluorescence in-situ hybridization (flow FISH). We also performed whole exome sequencing in the blood of all available family members and used PhenoDB to identify potential candidate gene variants with recessive or dominant modes of inheritance. RESULTS: Out of twenty-four patients of European descent selected to participate in the study, eleven patients, eight parent-child pairs affected by IBD, were included in the genetic anticipation analysis. Median difference in age at diagnosis between two successive generations was 16.5 years, with earlier age at onset in the younger generations. In most of the affected members, the disease harbored similar gastrointestinal and extraintestinal involvement but was more aggressive among the younger generations. TL was not associated with earlier age at onset or more severe disease in members of successive generations affected by IBD. NOD2 gene mutations were present in the Crohn's disease patients of one family. However, no gene variants were identified as potential candidates for inheritance. CONCLUSION: Telomere shortening appears unlikely to be involved in mechanisms of possible genetic anticipation in IBD. Further studies using a larger sample size are required to confirm or refute our findings.

Early Discontinuation of Infliximab in Pregnant Women With Inflammatory Bowel Disease.

OBJECTIVES: Early discontinuation of infliximab (IFX) in pregnant women with inflammatory bowel disease (IBD) decreases the intrauterine fetal exposure to the drug but may increase the risk of disease flaring leading to poor pregnancy outcomes. In this study, we assessed the impact of early IFX discontinuation on mother's disease activity and on their at-risk babies. METHODS: In a retrospective study of the Truven Health Analytics MarketScan database from 2011 to 2015, we compared IBD patients who discontinued IFX more than 90 days ("early IFX") with those who discontinue IFX 90 days or less ("late IFX) before delivery. We evaluated the risk of flaring, defined by new steroid prescriptions, visits to emergency room and/or hospital admissions, the pregnancy outcomes, and the at-risk babies. RESULTS: After IFX discontinuation, the early IFX group (68 deliveries) required significantly more steroid prescriptions than the late IFX group (318 deliveries) to control disease activity (P < 001). There were more preterm babies in the early IFX group (P < 049), but no difference within the 2 groups was noticed in the rate of intrauterine growth retardation, small for gestation, and stillborn babies. Similarly, there was no increase in acute respiratory infections, development delays, and congenital malformations in babies of the mothers from the late IFX vs early IFX groups. CONCLUSIONS: Steroid-free remission IBD mothers are at risk for disease flares and preterm babies when IFX is discontinued early in pregnancy. Continuation of IFX seems to be safe at least for the first year of life.

Tumor histology helps to identify Lynch syndrome among colorectal cancer patients.

OBJECTIVE: To determine the value of histology in identifying Lynch syndrome among those patients with early onset of colorectal cancer (CRC). METHODS: Demographic, clinical and cancer history data from patients diagnosed with CRC before 60 years of age, and treated at our institution between 1997 and 2005, were collected from medical records and direct interview. Their tumors were assessed to identify histological features suggestive of high frequency microsatellite instability (MSI-H): tumor infiltrating lymphocytes, Crohn's like inflammatory reaction, mucinous, signet ring cells, medullary growth pattern and then, tested for microsatellite instability (MSI) and MLH1/ MSH2 protein expression. RESULTS: Sixty-five patients were included in the study. The mean age at diagnosis was 48 +/- 9.9 years. Overall, 28 (43%) patients, including 13 of 35 diagnosed between ages 50 and 60, had tumor demonstrating one or more histological features suggestive of MSI-H. These patients were younger (45 vs. 50 years, P = 0.02) and more commonly had family history of Lynch syndrome-related cancers (36 vs. 19%), though the latter feature did not reach statistical significance (P = 0.07). Eleven of 25 tumors with MSI-H histology, but only 1 of 29 tumors without special histological features were found to be MSI-H (P < 0.0001). Histology had a positive predictive value of 44% and a negative predictive value of 97% for identifying MSI-H tumors. CONCLUSIONS: Limiting MSI analysis only to those tumors with suggestive histology would have reduced the need for testing by nearly 60% of all tumors from patients that met the revised Bethesda guidelines.

Low Incidence of Dysplasia and Colorectal Cancer Observed among Inflammatory Bowel Disease Patients with Prolonged Colonic Diversion.

Background: In inflammatory bowel disease (IBD), many scenarios call for fecal diversion, leaving behind defunctionalized bowel. The theoretical risk of colorectal cancer (CRC) in this segment is frequently cited as a reason for resection. To date, no studies have characterized the incidence of neoplasia in the diverted colorectal segments of IBD patients. Methods: A retrospective cohort analysis was conducted for IBD patients identified through a tertiary care center pathology database. Patients that had undergone colorectal diversion and were diverted for ≥ 1 year were included. Incidence of diverted dysplasia/CRC was calculated for Crohn's disease (CD) and ulcerative colitis (UC) with respect to diverted patient-years (dpy) and patient-years of disease (pyd). Results: In total, 154 patients comprising 754 dpy and 1984 pyd were analyzed. Only 2 cases of diverted colorectal dysplasia (CD 1, UC 1) and 1 case of diverted CRC (UC) were observed. In the UC cohort (n = 75), the rate of diversion-associated CRC was 4.5 cases/1000 dpy (95% CI 0.11-25/1000) or 1.5 cases/1000 pyd (95% CI 0.04-8.2/1000). In the CD cohort (n = 79), no patients developed CRC, although a dysplasia rate of 1.9 cases/1000 dpy (95% CI 0.05-11/1000) or 0.77 cases/1000 pyd (95% CI 0.02-4.3/1000) was observed. All patients developing neoplasia had disease duration > 10 years and microscopic inflammation. Conclusions: Diverted dysplasia occurred infrequently with rates overlapping those reported in registries for IBD-based rectal cancers. Neoplasia was undetected in patients with < 10 pyd, regardless of diversion duration, suggesting low yield for endoscopic surveillance before this time.

A rare case of Crohn's ileitis in a patient with constitutional mismatch repair deficiency.

Constitutional mismatch repair deficiency (CMMRD), a variant of Lynch syndrome, is a rare disease characterized by café-au-lait spots, oligopolyposis, glioblastoma and lymphoma. A 24-year-old male, under surveillance for CMMRD, developed Crohn's ileitis after total colectomy with end ileostomy for colorectal cancer and failed to respond to oral corticosteroids. The patient underwent induction and maintenance of remission with vedolizumab infusions. We report the first patient with CMMRD developing Crohn's disease. The choice of immunosuppressive therapy in these patients is challenging and needs to be made according to their risk for malignancy.

Early Surgical Intervention for Acute Ulcerative Colitis Is Associated with Improved Postoperative Outcomes.

BACKGROUND: Timing of surgical intervention for acute ulcerative colitis has not been fully examined during the modern immunotherapy era. Although early surgical intervention is recommended, historical consensus for "early" ranges widely. The purpose of this study was to evaluate outcomes according to timing of urgent surgery for acute ulcerative colitis. METHODS: All non-elective total colectomies in ulcerative colitis patients were identified in the National Inpatient Sample from 2002 to 2014. Procedures, comorbidities, diagnoses, and in-hospital outcomes were collected using International Classification of Disease, 9th Revision codes. An operation was defined as early if within 24 hours of admission. Results were compared between the early versus delayed surgery groups. RESULTS: We found 69,936 patients that were admitted with ulcerative colitis, and 2650 patients that underwent non-elective total colectomy (3.8%). Early intervention was performed in 20.4% of patients who went to surgery. More early operations were performed laparoscopically (28.1% versus 23.3%, p = 0.021) and on more comorbid patients (Charlson Index, p = 0.008). Median total hospitalization costs were $20,948 with an early operation versus $33,666 with a delayed operation (p < 0.001). Delayed operation was an independent risk for a complication (OR = 1.46, p = 0.001). Increased hospitalization costs in the delayed surgery group were statistically significantly higher with a reported complication (OR = 3.00, p < 0.001) and lengths of stay (OR = 1.26, p < 0.001). CONCLUSION: Delayed operations for acute ulcerative colitis are associated with increased postoperative complications, increased lengths of stay, and increased hospital costs. Further prospective studies could demonstrate that this association leads to improved outcomes with immediate surgical intervention for medically refractory ulcerative colitis.

A comparison of the phenotype and genotype in adenomatous polyposis patients with and without a family history.

OBJECTIVES: Adenomatous polyposis of the colon is often secondary to an inherited mutation in adenomatous polyposis coli (APC) gene, however, approximately one third of patients have no family history of the disease. We studied the phenotype and genotype of adenomatous polyposis in patients without a family history. METHODS: A cohort of 57 unrelated adenomatous polyposis patients were evaluated. Seventeen patients with no family history were compared with 40 patients who had a positive family history of the disease. Family history and medical records were collected and analyzed. Germline APC and Mut Y homologue (MYH) testing was undertaken. RESULTS: Patients without a family history were diagnosed with polyposis at an older age (41 years vs. 32 years) and presenting more frequently with symptoms (76 vs 20, P < 0.05). The number of colonic polyps and frequency of extracolonic manifestation associated with adenomatous polyposis did not differ between the two groups. APC mutations were detected less frequently among patients without a family history of the disease (4 out of 17 vs 25 out of 40, P=0.007), even among those with greater than 100 colorectal adenomas (4 out of 12 versus 21 out of 29, P=0.03). One homozygous MYH mutation carrier (G382D) was detected among the six patients without a family history and without a germline APC mutation who were tested. CONCLUSIONS: Adenomatous polyposis patients without a family history are usually diagnosed with symptoms, and at a later age. Phenotypically, they are similar to those with a family history. However, germline APC mutations are detected far less frequently in patients without a family history. A small percentage of these cases may be secondary to biallelic germline MYH mutations.

BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer.

PURPOSE: The BRAF gene encodes a serine/threonine kinase and plays an important role in the mitogen-activated protein kinase signaling pathway. BRAF mutations in sporadic colorectal cancer with microsatellite instability (MSI) are more frequently detected than those in microsatellite stable cancer. In this study, we sought to compare the frequencies of BRAF mutations in sporadic colorectal cancer with MSI with those in hereditary nonpolyposis colorectal cancer (HNPCC). EXPERIMENTAL DESIGN: We analyzed BRAF mutations in 26 colorectal cancer cell lines, 80 sporadic colorectal cancers, and 20 tumors from HNPCC patients by DNA sequencing and sequence-specific PCR. The methylation status of the hMLH1 gene was measured by either sequencing or restriction enzyme digestion after NaHSO(3) treatment. RESULTS: We observed a strong correlation of BRAF mutation with hMLH1 promoter methylation. BRAF mutations were present in 13 of 15 (87%) of the colorectal cell lines and cancers with methylated hMLH1, whereas only 4 of 91 (4%) of the cell lines and cancers with unmethylated hMLH1 carried the mutations (P < 0.00001). Sixteen of 17 mutations were at residue 599 (V599E). A BRAF mutation was also identified at residue 463 (G463V) in one cell line. In addition, BRAF mutations were not found in any cancers or cell lines with K-ras mutations. In 20 MSI+ cancers from HNPCC patients, however, BRAF mutations were not detectable, including a subset of 9 tumors with negative hMLH1 immunostaining and methylated hMLH1. CONCLUSIONS: BRAF mutations are frequently present in sporadic colorectal cancer with methylated hMLH1, but not in HNPCC-related cancers. This discrepancy of BRAF mutations between sporadic MSI+ cancer and HNPCC might be used in a strategy for the detection of HNPCC families.