Society: AGA

Background
Colonoscopy withdrawal time (CWT) of at least 6-9 minutes is the minimum time needed for adequate adenoma detection in the general population. The ideal CWT in patients with inflammatory bowel disease (IBD) has not been determined. We aimed to identify the optimal CWT associated with the detection of polypoid dysplasia in patients with IBD.

Methods
This is a single center, retrospective study from 1/1/2017-9/1/2022 of adult patients 18 years of age with IBD in endoscopic healing (absence of erosions/ulcers in Crohn’s disease; Mayo ulcerative colitis (UC) endoscopic sub-score of 0 or 1) undergoing surveillance via high-definition white light colonoscopy. We excluded incomplete colonoscopies, dye-chromoendoscopy exams and patients with previous colonic surgeries. CWT was defined as the time from cecal intubation to withdrawal from the anal canal rounded to the nearest minute. The primary outcome was the association of CWT with the presence of polypoid dysplasia (adenomas and sessile serrated polyps (SSP)) evaluated as a composite outcome. The secondary outcome was to identify an optimal CWT cutoff associated with polypoid dysplasia detection.

Results
A total of 259 patients (mean age 56 ± 14.8 years; 51.3% female, 68% with UC; 8.9% with primary sclerosing cholangitis) underwent 330 colonoscopies. A total of 12 patients (4.6%) had a personal history of invisible dysplasia while 24.7% (n=64) had a history of polypoid dysplasia and 10% had a family history of colorectal cancer. Colonoscopies were performed by IBD specialists in 40.9% (n=135), gastroenterology fellows in 9.7% (n=32) and non-targeted biopsies were obtained in 97.3% (n=321) of colonoscopies performed. The median CWT in the whole cohort was 22 minutes (interquartile range 15-29).

Invisible dysplasia was noted in 2.1% (n=7) while polypoid dysplasia was detected in 17.3% (n=57; 43 adenomas and 16 SSP) of procedures. Baseline characteristics comparing the groups with and without polypoid dysplasia are shown in Table 1. The mean CWT was significantly higher in the polypoid dysplasia group at 32.6 ± 22.3 minutes vs. 22.7 ± 11.1 minutes in procedures without polypoid dysplasia (p=0.002) (Table 1). On multivariable analysis, advanced age (p < 0.001), personal history of adenoma/SSP (p=0.01) and CWT (p <0.001) were independently associated with polypoid dysplasia (Table 2).

A CWT of 15 minutes (odds ratio (OR) 2.71, 95% CI: 1.11-6.6; p=0.02) and not ≥ 9 minutes (OR 2.57, 95% CI: 0.33-20.2; p=0.35) is significantly associated with detection of polypoid dysplasia.

Conclusion
In our cohort of patients with IBD undergoing surveillance via high-definition white light colonoscopy, the mean CWT was independently associated with the detection of polypoid dysplasia. A CWT of at least 15 minutes and not 9 minutes was significantly associated with the detection of polypoid dysplasia.

Background and aims: Colorectal cancer (CRC) incidence rates are increasing among younger adults in the U.S., but little is known about the unique survivorship needs of this population after diagnosis. We estimated risk of second cancers among survivors of early-onset CRC and identified factors associated with risk.
Methods: We identified young adults (age 18-49 years) with stage 0-III CRC diagnosed between 1992-1999 using population-based data from National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. We estimated cumulative incidence of a second cancer of any type, as well as a second CRC, using the Fine and Gray method to account for the competing risk of death. To illustrate findings, we plotted cumulative incidence curves on both a calendar time and age scale. We also identified patient-, tumor- and treatment-level factors associated with risk of second cancers using hazard regression models, similarly accounting for the competing risk of death. All analyses were stratified by sex.
Results: Among 7,041 persons diagnosed with early-onset CRC, 52.4% were men, 60.5% were non-Hispanic White and 72.6% were 40-49 years old. Of all, 16.2% developed a second cancer, including 337 second CRCs. Accounting for death as a competing event, 25-year cumulative incidence of a second cancer of any type was 18.5% (95% CI 17, 20) for men and 16.8% (95% CI 15, 18) for women (Figure); 25-year cumulative incidence of a second CRC was 6.4% (95% CI 5, 7) for men and 4.4% (95% CI 4, 5) for women. Similarly, by age 70 years, cumulative incidence of a second cancer of any type was 19.7% (95% CI 18, 21) for men and 18.4% (95% CI 17, 20) for women; cumulative incidence of a second CRC was 6.6% (95% CI 6, 8) for men and 4.5% (95% CI 4, 5) for women at age 70 years.
For men, lower county-level median household income (<70K vs. >70K: HR=1.3, 95% CI 1.0, 1.5), higher tumor grade (4 vs. 1: HR=3.9, 95% CI 1.8, 8.4), and histology (mucinous adenocarcinoma vs. non-adenocarcinoma: HR=4.6, 95% CI 1.6, 12.9) were associated with increased risk of second cancer of any type. Among women, higher stage (II vs. 0-I: HR 0.75, 95% CI 0.59, 0.97; III vs. 0-I: HR 0.51, 95% CI 0.39, 0.66) and tumor location (distal vs. proximal colon: HR 0.75, 95% CI 0.60, 0.95; rectum vs. proximal colon: HR 0.5, 95% CI 0.38, 0.65) was associated with reduced risk of second cancer of any type.
Conclusion: One in six persons diagnosed with stage 0-III early-onset CRC will be diagnosed with a second cancer, and most of these second cancers are not CRC. Given these risks, additional studies to inform evidence-based screening and surveillance recommendations in this population are needed.

Cumulative incidence of a second cancer of any type among persons diagnosed with stage 0-III early-onset colorectal cancer

Cumulative incidence of a second cancer of any type among persons diagnosed with stage 0-III early-onset colorectal cancer

Background. DNA mismatch repair allows for repair of frameshift mutations that causes microsatellite instability (MSI) associated with a subset of colorectal cancers (CRCs). Elevated microsatellite alterations at select tetranucleotide repeats (EMAST) is a form of MSI that associates with alterations in MSH3 function causing dinucleotide or longer MSI. Germline biallelic loss-of-function MSH3 variants result in a familial polyposis syndrome. A 27 base-pair deletion (△27bp) polymorphism has been described in the polyalanine tract (PAT) within MSH3 exon 1 proximate to its nuclear localization signal (NLS), enhancing MSH3 nuclear-to-cytoplasmic accumulation under conditions of inflammation. △27bpMSH3 attenuates MSH3 nuclear function during oxidative stress, permissive for EMAST. This polymorphism has been shown to be prevalent in a small cohort of patients with ulcerative colitis (UC); prior studies have not examined the variability of MSH3’s PAT across multiple disease states.
Methods. We obtained genomic DNA from subjects in the Michigan Genomics Initiative for genotyping of MSH3 PAT using gel electrophoresis and sequencing. We genotyped 182 healthy controls, 197 UC patients, 199 early onset CRC patients (eoCRC; diagnosed <50 years) and 194 later onset CRC patients (loCRC; diagnosed >50 years). Clinicopathologic data were analyzed for associations with PAT variants. We transfected MSH3-FLAG containing various PAT variants into MSH3-null cells to assess intracellular localization.
Results. Prior genome-wide sequencing data across multiple databases have not shown significant prevalence of △27bp or any other PAT variants of MSH3. Here we identified that in healthy controls, MSH3 PAT variants are abundant, with 37% of subjects having homozygous WTMSH3, 48% having heterozygous WTMSH3 and 15% having no WTMSH3. Interestingly, 18% of UC, 17% of eoCRC and 14% of loCRC patients had no WTMSH3 (p>0.05 vs controls). Advanced CRC patients (stage 3/4) trended higher with no WTMSH3 (17.8% eoCRC, 10.5% loCRC, 15.3% CRC) compared to stage 2 patients (15.4% eoCRC, 5% loCRC, 9.1% CRC; p>0.05). Transfected cells containing the MSH3 △PA and △A12 PAT variants accumulated MSH3 into the cytosol over WTMSH3 (P<0.009).
Conclusions. We discovered that 15% of healthy individuals lack an allele for WTMSH3; that percentage appears to be similar amongst UC and CRC patients. MSH3 PAT variants occur in exon 1 proximate to its NLS compromising its function and attenuating inflammation induced cytosolic MSH3 returning to the nucleus, allowing DNA to potentially accumulate mutations. It is unclear if this has consequences for disease progression as we only observed a trend for advanced staged CRC patients over early staged patients. MSH3 polymorphisms warrant further study to determine the risk of these variants in the development of inflammatory bowel disease and colorectal neoplasia.

Background:
Rectal neuroendocrine tumors (RNET) are rare neoplasms with an incidence rate of 0.17% during screening colonoscopies. Previous data showed an increasing incidence of RNET with greater rates in older adults. However, there are limited data on recent age and sex-specific incidence rates. Therefore, the aim of this study was to conduct a time-trend analysis of RNET incidence rates using a nationwide US database, the United States Cancer Statistics (USCS) database.

Methods:
Incidence data between 2001-2018 were collected from the USCS database, a comprehensive source of cancer data covering nearly 100% of US population. Tumor location was specified as “Rectum and Rectosigmoid Junction” and histopathological type was identified using ICD-O-3 codes. RNET incidence rates were calculated and age-adjusted to the 2000 standard US population using SEER*Stat software (v.8.4.0.1, NCI), and categorized by sex and age into older adults, aged ≥55 years, and younger adults, aged 15-54 (<55 years). Time-trends were reported as annual percentage change (APC) and average APC (AAPC) using Joinpoint Regression Software (v.4.9.0.1, NCI) and Monte Carlo permutation analysis which generates the simplest trend. Pairwise comparison was conducted between the age-specific trends using the tests of parallelism and coincidence and the absolute AAPC difference was evaluated. A two-sided P-value cut-off at 0.05 was utilized for statistical significance.

Results:
Between 2001-2018, there were 53,188 patients diagnosed with RNET in the US. Overall, RNET incidence rates have been significantly increasing in younger adults but not in older adults (AAPC= 4.52 vs 1.35; AAPC difference=3.17, P=0.004). Age-specific trends were not identical (P<0.001) nor parallel (P<0.001) suggesting that RNET incidence rates are different and increasing at a greater rate compared to older adults. Similar results were seen in men (26,438 patients) with an absolute AAPC difference between younger and older adults of 3.03 (P=0.02). However, in women (26,738 patients), while similar results were seen, a greater AAPC difference between younger and older adults of 4.21 (<0.001) was noted suggesting that the greatest disparity between RNET incidence trends between age-specific groups arises from women.

Discussion:
Nationwide USCS data, covering 100% of US population, suggest that RENT incidence trends have been increasing in younger adults while stable in older adults over the last two decades. The greatest difference between older and younger adults seemed to be arising from younger women. While this increase can be due to increased detection of RNET in younger adults due to improvements in screening modalities, it can also represent a true increase in incidence. Future studies are warranted to investigate risk factors associated with the increasing incidence in younger adults, especially younger women.

<b>Table:</b> Age-Specific Trends for Rectal Neuroendocrine Tumors (RNET) Incidence Rates Among Men and Women.<br /> <sup>a</sup> Data are presented as count numbers followed by percentages of the count numbers from the total cases of RNET cancer in the database. <br /> <sup>b</sup> Time-trends were computed using Joinpoint Regression Program (v4.9.0.1, NCI) with 3 maximum joinpoints allowed (4-line segments). <br /> <sup>c</sup> A positive value indicates a greater AAPC in younger adults compared to older adults. <br /> <sup>d</sup> Tests whether age-specific trends were identical. A significant P-value indicates that the trends were not identical (i.e., they had different incidence rates and coincidence was rejected). <br /> <sup>e</sup> Tests whether age-specific trends were parallel. A significant P-value indicates that the trends were not parallel (i.e., parallelism was rejected).

Table: Age-Specific Trends for Rectal Neuroendocrine Tumors (RNET) Incidence Rates Among Men and Women.
^a Data are presented as count numbers followed by percentages of the count numbers from the total cases of RNET cancer in the database.
^b Time-trends were computed using Joinpoint Regression Program (v4.9.0.1, NCI) with 3 maximum joinpoints allowed (4-line segments).
^c A positive value indicates a greater AAPC in younger adults compared to older adults.
^d Tests whether age-specific trends were identical. A significant P-value indicates that the trends were not identical (i.e., they had different incidence rates and coincidence was rejected).
^e Tests whether age-specific trends were parallel. A significant P-value indicates that the trends were not parallel (i.e., parallelism was rejected).

<b>Figure:</b> Age-specific Trends and Incidence Rates Per 100,000 Population for Rectal Neuroendocrine Tumors (RNET) Among Men and Women.<br /> A: The average annual percentage change (AAPC) is increasing in younger adults at a greater rate compared to the stable trend in older adults with a significant difference (4.52 vs 1.35, P=0.004).<br /> B: The average annual percentage change (AAPC) is increasing in younger men at a greater rate compared to the stable trend in older men with a significant difference (4.78 vs 1.75, P=0.02).<br /> C: The average annual percentage change (AAPC) is increasing in younger women at a greater rate compared to the stable trend in older women with a significant difference (4.52 vs 0.30, P<0.001).

Figure: Age-specific Trends and Incidence Rates Per 100,000 Population for Rectal Neuroendocrine Tumors (RNET) Among Men and Women.
A: The average annual percentage change (AAPC) is increasing in younger adults at a greater rate compared to the stable trend in older adults with a significant difference (4.52 vs 1.35, P=0.004).
B: The average annual percentage change (AAPC) is increasing in younger men at a greater rate compared to the stable trend in older men with a significant difference (4.78 vs 1.75, P=0.02).
C: The average annual percentage change (AAPC) is increasing in younger women at a greater rate compared to the stable trend in older women with a significant difference (4.52 vs 0.30, P<0.001).

Introduction: Short term use of Hormone replacement therapy (HRT) is indicated for the treatment of menopausal symptoms. However, women in the United States (US) use HRTs for far longer than the intended duration. Harzadous effect of HRT Is seen amngst long term and ever user groups. Comprehensive studies have shown that the risk of breast cancer and endometrial cancer is established to be associated with increasing duration of use and risk remained elevated even 5 years after discontinuation. Though we have studies highlighting effects of HRT and reproductive malignancies, the impacts of history/long-term use of HRT and development of gastrointestinal (GI) malignant neoplasms is lacking. Therefore, we decided to carry out a study highlighting the prevalence of upper GI tumors in postmenopausal women who have used HRT.

Methods: A validated multicenter and research platform database (Explorys Inc.) of more than 360 hospitals from 26 different healthcare systems across the United States from 1999 to September 2022 was utilized to construct this study. Females aged 65 years and above were included in the study. Patients with autoimmune diseases were excluded. Three separate multivariate regression analyses, assessing the risk of developing esophageal, stomach, and pancreatic cancer, were performed by controlling for potential cofounders. A two-sided P value <0.05 was considered as statistically significant, and all statistical analyses were performed using R version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria, 2008).

Results: 79,368,988 individuals were screened in the database and 11,177,050 were selected in the final analysis after accounting for inclusion and exclusion criteria. The baseline characteristics of patients with esophageal, stomach, and pancreatic cancer is seen in Table 1. Three separate multivariate regression analyses were performed to assess the risk of developing esophageal, stomach, and pancreatic cancer (Table 2). The risk of for developing pancreatic cancer In HRT users was (OR: 1.40; 95% CI 1.26-1.56), Gastric cancer (OR: 1.74; 96% CI 1.51-1.99), and Esophageal cancer (OR: 0.93; 95% CI 0.79-1.08)

Conclusion: In our study, post-menopausal women on HRT have increased prevalence and odds of having gastric cancer and pancreatic cancers. The odds remained significant when controlled for common risk factors. We believe the impact of reproductive hormones on a cellular level span across the reproductive system to also involve the GI system. The US Preventive Services Task Force (USPSTF) agrees that evidence is lacking to guide recommendations for or against the use of HRT. We push that clinicians be familiar with these associations so that the decision to initiate drug should solely be based on the patient's willingness, complete understanding of benefits and potential risk factors.

<b>Table 1:</b> Baseline characteristics of patients with esophageal, stomach, and pancreatic and control (patients without cancer)<br /> <b>Abbreviations:</b> HRT, hormone replacement therapy

Table 1: Baseline characteristics of patients with esophageal, stomach, and pancreatic and control (patients without cancer)
Abbreviations: HRT, hormone replacement therapy

<b>Table 2:</b> Multivariate regression analysis assessing the risk of developing esophageal, stomach, and pancreatic cancer compared to control<br /> <b>Abbreviations:</b> CI, confidence interval; GERD, gastroesophageal reflux disease; HRT, hormone replacement therapy; OR, odd ratio, PPI, proton-pump inhibitor; T2DM, type 2 diabetes mellitus; X, variable not included in multivariate regression analysis

Table 2: Multivariate regression analysis assessing the risk of developing esophageal, stomach, and pancreatic cancer compared to control
Abbreviations: CI, confidence interval; GERD, gastroesophageal reflux disease; HRT, hormone replacement therapy; OR, odd ratio, PPI, proton-pump inhibitor; T2DM, type 2 diabetes mellitus; X, variable not included in multivariate regression analysis

Imad Asaad

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