Granuloma Presence at Initial Surgery Predicts Need for Repeat Surgery Independent of Rutgeerts Score in Crohn's Disease.

BACKGROUND: Approximately half of Crohn's disease (CD) patients experience recurrence and need for repeat resections, highlighting need for prognostic biomarkers. Presence of epithelioid granuloma on surgical tissue and high Rutgeerts endoscopic score are associated with postoperative CD clinical recurrence. We sought to evaluate presence of epithelioid granuloma at first surgery and Rutgeerts score as a combined risk assessment for CD surgical recurrence. METHODS: Our study included consented CD patients who underwent initial ileocecal resection and were prospectively followed postoperatively. From 2009 to 2019, 418 CD patients underwent initial ileocecal resection with >4 years of follow-up, including postoperative endoscopic assessment (Rutgeerts score). RESULTS: Postoperative CD patients were grouped based on granuloma presence (30.6%; n = 128) or absence (69.4%; n = 290). Endoscopic recurrence (defined as Rutgeerts score ≥i2) was similar between the granuloma (26%) and no granuloma (25%) groups, respectively (P = .82). Patients with granuloma and CD endoscopic recurrence at first postoperative endoscopy had higher number of bowel surgeries compared with all other groups (no granuloma or CD endoscopic recurrence, P = .007; no granuloma but CD endoscopic recurrence present, P = .04; granuloma present and no CD endoscopic recurrence, P = .04). Epithelioid granuloma presence was associated with 1.65 times higher risk of subsequent surgery independently from first postoperative endoscopic recurrence Rutgeerts score. CONCLUSIONS: Granuloma presence on initial surgical histology is immediately available and identifies high-risk CD patients who may benefit from early postoperative treatment, and these precision intervention trials are warranted.

This study shows the presence of epithelioid granuloma as a risk factor for repeat Crohn's disease­related surgery, which is independent of first postoperative Rugteerts score. These 11-year observational data provide a risk factor that is immediately available after surgery and identifies high-risk CD patients who may benefit from early postoperative treatment.

Prospective Evaluation of Coronavirus Disease 2019 (COVID-19) Vaccine Responses Across a Broad Spectrum of Immunocompromising Conditions: the COVID-19 Vaccination in the Immunocompromised Study (COVICS).

BACKGROUND: We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency. METHODS: Prospective study of fully vaccinated immunocompromised adults (solid organ transplant [SOT], hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus [HIV]) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity. RESULTS: A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW. CONCLUSIONS: Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.

High Rate of Inappropriate Fecal Immunochemical Testing at a Large Veterans Affairs Health Care System.

INTRODUCTION: Colonoscopies and fecal immunochemical tests (FITs) are the preferred modalities for colorectal cancer (CRC) screening. In addition to proper patient selection, appropriate fecal immunochemical testing requires that negative tests be repeated annually, positive tests lead to a diagnostic colonoscopy, and FIT not be performed within 5 years of a colonoscopy with adequate bowel preparation. We sought to study the frequency of inappropriate FITs at the Veterans Affairs Pittsburgh Health Care System in Pennsylvania. METHODS: A retrospective quality assurance study was undertaken of veterans undergoing FIT in a 3-year period (2015-2017). We calculated the rate of a negative initial FIT in 2015/2016 followed by a second FIT in 2016/2017 in a random selection of veterans (3% SE, 95% CI). Demographics were compared in an equal random number of veterans that did and did not have a follow-up FIT (5% SE, 95% CI of all negative FIT). We also calculated the rate of completing colonoscopy following a positive FIT in a random selection of veterans (3% SE, 95% CI). Finally, we investigated use of FIT following a colonoscopy for all veterans in the study period. RESULTS: A total of 6,766 FITs were performed; 4,391 unique veterans had at least 1 negative FIT, and 709 unique veterans had a positive FIT. Of 1,742 veterans with at least 1 negative FIT, 870 were eligible for repeat testing during the study period, and only 543 (62.4%) underwent at least 2 FITs. There was no significant demographic difference in veterans that had only 1 or at least 2 FITs. Of 410 veterans with a positive FIT, 113 (27.5%) did not undergo a subsequent colonoscopy within 1 year due to patient refusal, or failure to schedule or keep a colonoscopy appointment. Of 832 veterans who had both a FIT and colonoscopy in the interval, 108 veterans underwent colonoscopy with a subsequent FIT (1.6% of total FITs performed). Of these, 95 (88%) were judged to be inappropriate. Thirteen instances of FIT following colonoscopy were appropriate based on patient preference to undergo fecal immunochemical testing for CRC screening modality after undergoing colonoscopy with an inadequate bowel preparation. CONCLUSIONS: Veterans underwent inappropriate testing due to failure to undergo serial FIT after a negative result (37.6%), failure to complete colonoscopy following a positive FIT (27.5%), and undergoing inappropriate FIT following a recent colonoscopy (88%). Efforts are still required to improve both patient and provider education and adherence to appropriate fecal immunochemical testing and CRC screening guidelines.

Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia.

Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.

KRAS amplification in metastatic colon cancer is associated with a history of inflammatory bowel disease and may confer resistance to anti-EGFR therapy.

Mutations in RAS occur in 30-50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS, NRAS, HRAS, BRAF, and PIK3CA. Molecular testing was performed on 1286 consecutive mCRC from 1271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS, NRAS, and HRAS for 15, 5, and 2 cases, respectively (6-21 gene copies). Patients with a KRAS-amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology, and MMR proficiency (p ≤ 0.017). Four patients with a KRAS-amplified mCRC and no concomitant RAS/BRAF/PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS-amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS-amplified mCRCs is limited, our data suggest the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.

Performance of the Veterans Choice Program for Improving Access to Colonoscopy at a Tertiary VA Facility.

INTRODUCTION: The Veterans Choice Program (VCP) was designed to provide a pathway for veterans to access health care in the community if wait times at the US Department of Veterans Affairs (VA) were > 30 days. However, the performance of this program, in terms of timeliness, quality assurance, and overall utilization by veterans for colonoscopy is not well studied. METHODS: We reviewed records of veterans at VA Pittsburgh Healthcare System (VAPHS) who underwent VCP colonoscopy from June 2015 through March 2017. We compared the number of days from the scheduling encounter to the first available colonoscopy at VAPHS to the actual colonoscopy through the VCP. Additionally, we examined the availability of procedure and pathology results, documentation of quality metrics, and if clear follow-up recommendations were present in community care records. We then separately examined VCP utilization in a representative sample (5% margin of error, 95% CI) of all colonoscopy referrals through the VCP. RESULTS: During the study period 3,855 veterans were eligible for colonoscopy via the VCP, and 190 colonoscopies were performed through VCP. Records were absent for 29 exams (15.3%). There was no statistically significant difference for the number of days from a veteran's initially scheduled first-available colonoscopy at VAPHS when compared with the actual VCP colonoscopy (median 2 days earlier, P = .62). Pathology results were absent in 14 of 118 (11.9%) patient records, and follow-up recommendations were absent in 29 of 161 (18%) cases. Documentation of colonoscopy quality metrics were deficient in 27% to 70% of procedure reports. In a utilization sample of 350 veterans, only 26 (7.4%) veterans referred for colonoscopy had documented VCP colonoscopies, and 231 (66%) had a VAPHS colonoscopy. The median actual wait time for colonoscopy was 61 days for VAPHS and 66 days through VCP (P = .15). CONCLUSIONS: Colonoscopies referred through the VCP were not performed sooner in aggregate compared with the first available colonoscopy at VAPHS, although there was wide variability in wait times. We recommend additional mechanisms be put into place when outsourcing to community care: Ensure seamless and require prompt transfer of records back to the VA, require reporting of quality metrics standard at the VA for community care colonoscopies, and establish clinically meaningful wait-time thresholds for referral into the community, rather than static ones.

Alcoholic hepatitis masquerading as tumor infiltration: Reversibility after abstinence.

A subset of patients with alcoholic hepatitis present with atypical imaging resembling hepatic tumor infiltration. Our case involves a patient who was initially thought to have multiple large hepatic metastases, ultimately found to have alcoholic hepatitis. It is essential to ask about alcohol use when clinical suspicion is high.

A Resident-Led Initiative to Increase Documentation of Surrogate Decision Makers for Hospitalized Patients.

BACKGROUND: Identification of surrogate decision makers (SDMs) is an important part of advance care planning for hospitalized patients. Despite its importance, the best methods for engaging residents to sustainably improve SDM documentation have not been identified. OBJECTIVE: We implemented a hospital-wide quality improvement initiative to increase identification and documentation of SDMs in the electronic health record (EHR) for hospitalized patients, utilizing a Housestaff Quality and Safety Council (HQSC). METHODS: EHR documentation of SDMs for all adult patients admitted to a tertiary academic hospital, excluding psychiatry, were tracked and grouped by specialty in a weekly run chart during the intervention period (July 2015 through April 2016). This also continued postintervention. Interventions included educational outreach for residents, monthly plan-do-study-act cycles based on performance feedback, and a financial incentive of a one-time payment of 0.75% of a resident's salary put into the retirement account of each resident, contingent on meeting an SDM documentation target. Comparisons were made using statistical process control and chi-square tests. RESULTS: At baseline, SDMs were documented for 11.1% of hospitalized adults. The intervention period included 9146 eligible admissions. Hospital-wide SDM documentation increased significantly and peaked near the financial incentive deadline at 48% (196 of 407 admissions, P < 001). Postintervention, hospital-wide SDM documentation declined to 30% (134 of 446 admissions, P < .001), but remained stable. CONCLUSIONS: This resident-led intervention sustainably increased documentation of SDMs, despite a decline from peak rates after the financial incentive period and notable differences in performance patterns by specialty admitting service.

Risk of bacterial exposure to the endoscopist's face during endoscopy.

BACKGROUND AND AIMS: Nonuniversal use of facial protection during endoscopy may place endoscopists at risk of exposure to blood and body fluids; however, the frequency of exposure is unknown. METHODS: A prospective 6-month study of 4 gastroenterologists using a face shield during endoscopy was undertaken. The face shield was swabbed in a standardized fashion before and at the end of the session. Controls included pre- and post-swabs of face shields placed on the (1) endoscopy suite wall, (2) remote patient intake bay wall, and (3) after deliberate contamination with a colonoscope immediately after colonoscopy. The swabs were cultured for 48 hours, and growth was reported as no growth or by number of colony-forming units (CFUs). The groups were compared for +CFU rate and CFU number. RESULTS: A total of 1100 procedures were performed in 239 endoscopy sessions. The +CFU rate in the pre-endoscopy groups (2%-4.8%, not significant) was significantly lower than the postendoscopist face shield (45.8%, P < .001) and endoscopy suite wall groups (21.4%, P < .001), respectively. Using a cut-off of >15 CFUs as an indicator of definite exposure, the occurrence rate was 5.6 per 100 half days of endoscopy to the endoscopist's face and 3.4 per 100 half days of endoscopy 6 feet away. CONCLUSIONS: This is the first study to quantify the rate of unrecognized exposure to the endoscopist's face to potentially infectious biologic samples during endoscopy (5.6/100 days of endoscopy). This exposure may result in transmission of infectious diseases. As such, we recommend the use of universal facial protection during GI endoscopy.

Teaching and Assessing the Responsible Conduct of Research: A Delphi Consensus Panel Report.

In an effort to foster research integrity, the National Institutes of Health and the National Science Foundation mandate education of all trainees in the responsible conduct of research (RCR). Nevertheless, recent studies suggest that rates of questionable research practices and scientific misconduct are both high and considerably underreported. In part, this may be due to the fact that some ethical norms (e.g., authorship assignment) are far from clear and researchers are unsure how to respond to perceived misconduct. With funding from the U.S. Office of Research Integrity (ORI), we convened four panels of experts to develop a consensus on the overarching goals and teaching content of RCR instruction. Our panelists recommended nine overarching objectives for RCR instruction that require us to rethink common modes of instruction, and they identified issues and standards that should be covered within controversial areas such as authorship assignment and whistle-blowing. Additionally, our experts recommended two new core areas for RCR instruction: The social responsibilities of scientists and current topics in RCR.

Patient and tumor characteristics associated with primary tumor resection in women with Stage IV breast cancer: analysis of 1988-2003 SEER data.

Surgery is the cornerstone of treatment for women with nonmetastatic breast cancer. In contrast, standard treatment for patients with Stage IV disease includes chemotherapy and radiation, with surgery usually reserved for local tumor-related complications. Little is known about the predictive factors associated with primary tumor resection for Stage IV breast cancer. We conducted a retrospective, population-based, case-control study using the 1988-2003 Surveillance Epidemiology and End Results (SEER) data. Using multiple logistic regression, we identified patient and tumor characteristics from among SEER region, age at diagnosis, year of diagnosis, marital status, race, Hispanic ethnicity, tumor grade, and size that were associated with surgical resection of the primary breast tumor (compared with no surgical resection) among women with stage IV breast cancer. Adjusted odds ratios and 95% confidence intervals are reported. Of 10,017 patients, 4,836 (48%) underwent surgical resection of the primary breast tumor. Patients in the Northeast and Midwest and patients presenting with two or more primary breast tumors were more likely to have surgical resection. Patients who were older, diagnosed after 1992, unmarried, black, and whose tumors were >5 cm, inflammatory, of unknown size, indeterminate grade, or unknown progesterone status were less likely to have had surgical resection of the primary tumor. Several patient and tumor characteristics were significantly associated with surgical resection of the primary breast tumor in Stage IV disease. Further study of the surgery decision-making process is recommended.

The development and assessment of an NIH-funded research ethics training program.

In an effort to increase the number of researchers with skills "in identifying and addressing the ethical, legal, and social implications of their research," the National Institutes of Health (NIH) solicited training grant proposals from 1999 to 2004 and subsequently funded approved programs. The authors describe the content, format, and outcomes of one such training program that ran from 2002 to 2006 and share key lessons learned about program formats and assessment methods. Jointly developed by the Saint Louis University Center for Health Care Ethics and the Missouri Institute of Mental Health Continuing Education department, the training program focused on mental health research and adopted a train-the-trainer model. It was offered in on-site and distance-learning formats. Key outcomes of the program included educational products (such as 70 case studies posted on the course Web site, a textbook, and an instructional DVD) and program completion by 40 trainees. Assessment involved pre- and posttesting focused on knowledge of research ethics, ethical problem-solving skills, and levels of confidence in addressing ethical issues in mental health research. The program succeeded in increasing participants' knowledge of ethical issues and their beliefs that they could identify issues, identify problem-solving resources, and solve ethical problems. However, scores on the case-based problem-solving assessment dropped in posttesting, apparently because of diminished confidence about the right course of action in the specific dilemma presented; the implications of this finding for ethics assessment are discussed. Overall satisfaction was high, and dropout rates were low but three times higher for distance-learners than for on-site participants.