Implementation of a Multidisciplinary Team to Improve the Quality of Care for Older Surgical Patients at a Rural Academic Medical Center.

For the first time in history, people age older than 65 years make up >20% of the non-metro population, compared with 16% of the metro population. From 2010 to 2020 the nonmetro population age older than 65 years grew by 22%, while the working-age population declined by 4.9%, and the population aged under 18 years declined by 5.7%.1,2 Multidisciplinary geriatric surgical programs are an increasingly recognized approach to the care of older surgical patients and preliminary data suggest they can reduce length of stay. Although rural areas have the greatest proportion of patients age older than 65 years, implementation of such programs faces special challenges in rural settings with limited resources. Dartmouth-Hitchcock Medical Center is one of the most rural academic centers in the United States. Challenges include a shortage of geriatric-trained providers, long distances to access primary care and subspecialists, and extremely limited postacute care options and skilled nursing facility beds. To address the unique needs of our provider and patient population we began with a development period where we conducted stakeholder interviews. Using these data, we mapped out a workflow and developed pilot projects to address different portions of the workflow, such as preoperative screening for frailty and cognitive impairment, interdisciplinary weekly case conferences, proactive case management, delirium and geriatric surgery postoperative pathway order sets, and a variety of tools for reorientation and delirium management. Herein we describe the process of development and pragmatic clinical implementation of geriatric-focused care for older surgical patients in our rural tertiary center, including some of the main challenges we faced and the strategies we undertook to overcome them, and some of our early patient centered and clinical outcomes. This information may assist other institutions as they design geriatric-focused surgical programs to address the growing population of older adults and the need for compliance with state legislation. The clinical program described is not a research study, and the outcome data we report is for the purpose of description, and should not be interpreted as a rigorous research investigation of the effect of our intervention.

Association of neurocognitive disorders with morbidity and mortality in older adults undergoing major surgery in the USA: a retrospective, population-based, cohort study.

BACKGROUND: Neurocognitive disorders become increasingly common as patients age, and increasing numbers of surgical interventions are done on older patients. The aim of this study was to understand the clinical characteristics and outcomes of surgical patients with neurocognitive disorders in the USA in order to guide future targeted interventions for better care. METHODS: This retrospective cohort study used claims data for US Medicare beneficiaries aged 65 years and older with a record of inpatient admission for a major diagnostic or therapeutic surgical procedure between Jan 1, 2017, and Dec 31, 2018. Data were retrieved through a data use agreement between Dartmouth Hitchcock Medical Center and US Centers for Medicare and Medicaid Services via the Research Data Assistance Center. The exposure of interest was the presence of a pre-existing neurocognitive disorder as defined by diagnostic code within 3 years of index hospital admission. The primary outcome was mortality at 30 days, 90 days, and 365 days from date of surgery among all patients with available data. FINDINGS: Among 5 263 264 Medicare patients who underwent a major surgical procedure, 767 830 (14·59%) had a pre-existing neurocognitive disorder and 4 495 434 (85·41%) had no pre-existing neurocognitive disorder. Adjusting for demographic factors and comorbidities, patients with a neurocognitive disorder had higher 30-day (hazard ratio 1·24 [95% CI 1·23-1·25]; p<0·0001), 90-day (1·25 [1·24-1·26]; p<0·0001), and 365-day mortality (1·25 [1·25-1·26]; p<0·0001) compared with patients without a neurocognitive disorder. INTERPRETATION: Our findings suggest that the presence of a neurocognitive disorder is independently associated with an increased risk of mortality. Identification of a neurocognitive disorder before surgery can help clinicians to better disclose risks and plan for patient care after hospital discharge. FUNDING: Department of Anesthesiology and Perioperative Medicine at Dartmouth Hitchcock Medical Center.

Postoperative rehospitalization in older surgical patients: an age-stratified analysis.

BACKGROUND: Older adults comprise 40% of surgical inpatients and are at increased risk of postoperative rehospitalization. A decade ago, 30-day rehospitalizations for Medicare patients were reported as 15%, and more than 70% was attributed to medical causes. In the interim, there have been several large-scale efforts to establish best practice for older patients through surgical quality programs and national initiatives by Medicare and the National Health Service. To understand the current state of rehospitalization in the USA, we sought to report the incidence and cause of 30-day rehospitalization across surgical types by age. STUDY DESIGN: We performed a retrospective study utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) dataset from 2015 to 2019. Our primary exposure of interest was age. Patients were categorized into four groups: 18-49, 50-64, 65-74, and 75 + years old. Reasons for rehospitalization were evaluated using NSQIP defined causes and reported International Classification of Disease (ICD)-9 and ICD-10 codes. Our primary outcome was the incidence of unplanned 30-day rehospitalization and secondary outcome the cause for rehospitalization. Variables were summarized by age group through relative (%) and absolute (n) frequencies; chi-square tests were used to compare proportions. Since rehospitalization is a time-to-event outcome in which death is a competing event, the cumulative incidence of rehospitalization at 30 days was estimated using the procedure proposed by Gray. The same strategy was used for estimating the cumulative incidence for unplanned rehospitalizations. RESULTS: A total of 2,798,486 patients met inclusion criteria; 198,542 had unplanned rehospitalization (overall 7.09%). Rehospitalization by age category was 6.12, 6.99, 7.50, and 9.50% for ages 18-49, 50-64, 65-74, and 75 + , respectively. Complications related to the digestive system were the single most common cause of rehospitalization across age groups. Surgical site infection was the second most common cause, with the relative frequency decreasing with age as follows: 21.74%, 19.08%, 15.09%, and 9.44% (p < .0001). Medical causes such as circulatory or respiratory complications were more common with increasing age (2.10%, 4.43%, 6.27%, 8.86% and 3.27, 4.51, 6.07, 8.11%, respectively). CONCLUSION: We observed a decrease in overall rehospitalization for older surgical patients compared to studies a decade ago. The oldest (≥ 75) surgical patients had the highest 30-day rehospitalization rates (9.50%). The single most common reason for rehospitalization was the same across age groups and likely attributed to surgery (ileus). However, the aggregate of medical causes of rehospitalization was more common in older patients; surgical and respiratory reasons were twice as common in this group. Rehospitalization increased by age for some surgery types, e.g., lower extremity bypass, more than others, e.g., ventral hernia repair. Future investigations should focus on interventions to reduce medical complications and further decrease postoperative rehospitalization for older surgical patients undergoing high-risk procedures.

Impact of Rurality on Geriatric Emergency General Surgery Patients in New Hampshire.

BACKGROUND: Geriatric patients requiring emergency general surgery (EGS) have significant risk of morbidity and mortality. Rural patients face decreased access to care. We sought to characterize the EGS needs and impact of rurality for geriatric residents of New Hampshire. STUDY DESIGN: A retrospective cohort study of the New Hampshire Uniform Healthcare Facility Discharge Dataset, including patients 65 years and older with urgent/emergent admission who underwent 1 of 7 EGS procedures, grouped by urban or rural county of residence, discharged between 2012-2015. RESULTS: New Hampshire has 26 acute care hospitals: 10 (38.5%) are in urban counties and 16 (61.5%) are in rural counties. Thirteen (50.0%) are critical access hospitals (1 urban and 12 rural). Of 2,445 geriatric patient discharges, 40% of patients were from rural counties and were demographically similar to urban patients. Rural patients were more likely to present as a hospital transfer (15.4% vs 2.5%, p < 0.01), receive care at a critical access hospital (24.1% vs 1.0%, p < 0.01), receive care outside their home county (32.5% vs 12.8%, p < 0.01), and be transferred to another hospital after surgery. Rural and urban patients underwent similar procedures, with similar lengths of stay, cost of index hospitalization, and mortality. CONCLUSIONS: Rural geriatric patients in New Hampshire are more likely to receive care outside of their home county or be transferred to another hospital. Costs of care were similar but are likely underestimated for rural patients. There was no difference in unadjusted mortality. Further investigation is merited to determine the reasons for hospital transfer in the geriatric EGS population to evaluate which patients may benefit most from remaining close to home vs transferring to other facilities.

Complexity of Transferred Geriatric Adults Requiring Emergency General Surgery: A Rural Tertiary Center Experience.

INTRODUCTION: As the American population ages, the number of geriatric adults requiring emergency general surgery (EGS) care is increasing. EGS regionalization could significantly affect the pattern of care for rural older adults. The aim of this study was to determine the current pattern of care for geriatric EGS patients at our rural academic center, with a focus on transfer status. MATERIALS AND METHODS: We performed a retrospective chart review of patients aged ≥65 undergoing EGS procedures within 48 h of admission from 2014 to 2019 at our rural academic medical center. We collected demographic, admission, operative, and outcomes data. The primary outcomes of interest were mortality and nonhome discharge. Univariate and multivariate analyses were performed. RESULTS: Over the 5-y study period, 674 patients underwent EGS procedures, with 407 (60%) transferred to our facility. Transfer patients (TPs) had higher American Society of Anesthesiology (ASA) scores (P < 0.001), higher rates of open abdomen (13% versus 5.6%, P = 0.001), and multiple operations (24 versus 11%, P < 0.001) than direct admit patients. However, after adjustment there was no difference in mortality (OR 1.64; 95% CI, 0.82-3.38) or nonhome discharge (OR 1.49; 95% CI, 0.95-2.36). CONCLUSIONS: At our institution, the majority of rural geriatric EGS patients were transferred from another hospital for care. These patients had higher medical and operative complexity than patients presenting directly to our facility for care. After adjustment, transfer status was not independently associated with in-hospital mortality or nonhome discharge. These patients were appropriately transferred given their level of complexity.

Cognitive impairment and frailty screening in older surgical patients: a rural tertiary care centre experience.

INTRODUCTION: Despite a clear association between cognitive impairment and physical frailty and poor postoperative outcomes in older adults, preoperative rates are rarely assessed. We sought to implement a preoperative cognitive impairment and frailty screening programme to meet the unique needs of our rural academic centre. METHODS: Through stakeholder interviews, we identified five primary drivers underlying screening implementation: staff education, technology infrastructure, workload impact, screening value and patient-provider communication. Based on these findings, we implemented cognitive dysfunction (AD8, Mini-Cog) and frailty (Clinical Frailty Scale) screening in our preoperative care clinic and select surgical clinics. RESULTS: In the preoperative care clinic, many of our patients scored positive for clinical frailty (428 of 1231, 35%) and for cognitive impairment (264 of 1781, 14.8%). In our surgical clinics, 27% (35 of 131) and 9% (12 of 131) scored positive for clinical frailty and cognitive impairment, respectively. Compliance to screening improved from 48% to 86% 1 year later. CONCLUSION: We qualitatively analysed stakeholder feedback to drive the successful implementation of a preoperative cognitive impairment and frailty screening programme in our rural tertiary care centre. Preliminary data suggest that a clinically significant proportion of older adults screen positive for preoperative cognitive impairment and frailty and would benefit from tailored inpatient care.

Surgical Diseases are Common and Complicated for Criminal Justice Involved Populations.

BACKGROUND: At any given time, almost 2 million individuals are in prisons or jails in the United States. Incarceration status has been associated with disproportionate rates of cancer and infectious diseases. However, little is known about the burden emergency general surgery (EGS) in criminal justice involved (CJI) populations. MATERIALS AND METHODS: The California Office of Statewide Health Planning and Development (OSHPD) database was used to evaluate all hospital admissions with common EGS diagnoses in CJI persons from 2012-2014. The population of CJI individuals in California was determined using United States Bureau of Justice Statistics data. Primary outcomes were rates of admission and procedures for five common EGS diagnoses, while the secondary outcome was probability of complex presentation. RESULTS: A total of 4,345 admissions for CJI patients with EGS diagnoses were identified. The largest percentage of EGS admissions were with peptic ulcer disease (41.0%), followed by gallbladder disease (27.5%), small bowel obstruction (14.0%), appendicitis (13.8%), and diverticulitis (10.5%). CJI patients had variable probabilities of receipt of surgery depending on condition, ranging from 6.2% to 90.7%. 5.6% to 21.0% of admissions presented with complicated disease, the highest being with peptic ulcer disease and appendicitis. CONCLUSION: Admissions with EGS diagnoses were common and comparable to previously published rates of disease in general population. CJI individuals had high rates of complicated presentation, but low rates of surgical intervention. More granular evaluation of the burden and management of these common, morbid, and costly surgical diagnoses is essential for ensuring timely and quality care delivery for this vulnerable population.

Inner Deliberations of Surgeons Treating Critically-ill Emergency General Surgery Patients: A Qualitative Analysis.

BACKGROUND: 30% of elderly patients who require emergency general surgery (EGS) die in the year after the operation. Preoperative discussions can determine whether patients receive preference-sensitive care. Theoretically, surgeons frame their conversations after systematically assessing the risks and benefits of management options based on the clinical characteristics of each case. However, little is known about how surgeons actually deliberate about those options. OBJECTIVE: To identify variables that influence surgeons' assessment of management options for critically-ill EGS patients. METHODS: We conducted semi-structured interviews with 40 general surgeons in western Pennsylvania who worked in a variety of hospital settings. Interviews explored perioperative decision-making by asking surgeons to think aloud about selected memorable cases and a standardized case vignette of a frail patient with acute mesenteric ischemia. We used constant comparative methods to analyze interview transcripts and inductively developed a framework for the decision-making process. RESULTS: Surgeons averaged 13 years (standard deviation (SD) 10.4) of experience; 40% specialized in trauma/acute care surgery. Important themes regarding the main topic of "perioperative decision-making" included many considerations beyond the clinical characteristics of cases. Surgeons described the importance of variables ranging from the availability of institutional resources to professional norms. Surgeons often remarked on their desire to achieve individual flow, team efficiency, and concordant expectations of treatment and prognosis with patients. CONCLUSIONS: This is the first study to explore how surgeons decide among management options for critically-ill EGS patients. Surgeons' decision-making reflected a broad array of clinical, personal, and institutional variables. Effective interventions to ensure preference-sensitive care for EGS patients must address all of these variables.

Identifying Naturalistic Coaching Behavior Among Practicing Surgeons in the Operating Room.

OBJECTIVE: The aim of this study was to identify examples of naturalistic coaching behavior among practicing surgeons operating together by analyzing their intraoperative discussion. BACKGROUND: Opportunities to improve surgical performance are limited for practicing surgeons; surgical coaching is one strategy to address this need. To develop peer coaching programs that integrate with surgical culture, a better understanding is needed of how surgeons routinely discuss operative performance. METHODS: As part of a "co-surgery" quality improvement program, 20 faculty surgeons were randomized into 10 dyads who performed an operation together. Discourse analysis was conducted on transcribed intraoperative discussions. Themes were coded using an existing framework of surgical coaching principles (self-identified goals, collaborative analysis, constructive feedback, peer learning support) and surgical coaching content (technical skills, nontechnical skills). Coaching principles were cross-referenced with coaching content; c-coefficient measured the strength of association between pairs of themes. RESULTS: Overall, 44 unique coaching examples were identified in 10 operations. Of the 4 principles of surgical coaching, only self-identified goals and collaborative analysis were identified consistently. Self-identified goals were most associated with discussions regarding technical skills of "tissue exposure," "flow of operation," and "instrument handling" and the nontechnical skill "situation awareness." Collaborative analysis was most associated with discussions regarding technical skills of "respect for tissue" and "flow of operation" and nontechnical skills of "communication and teamwork." CONCLUSIONS: In naturalistic discussions between practicing surgeons in the operating room, numerous examples of unprompted coaching behavior were identified that target intraoperative performance. Prominent coaching gaps-constructive feedback and peer learning support-were also observed. Surgical coach trainings should address these gaps.

Helmet use is associated with higher Injury Severity Scores in alpine skiers and snowboarders evaluated at a Level I trauma center.

BACKGROUND: There is uncertainty regarding the efficacy of ski helmets in preventing traumatic injury. We investigated the relationship between helmet use, injury types, and injury severity among skiers and snowboarders. METHODS: The trauma registry at a Northeast American College of Surgeons Level I trauma center was queried by International Classification of Diseases Codes-9th or 10th Revision for skiing and snowboarding injury between 2010 and 2018. The primary exposure was helmet use and primary outcome was severe injury (Injury Severity Score >15). We performed univariate and multivariable logistic regression to assess for injury types and severity associated with helmet use. RESULTS: Seven hundred twenty-one patients (65% helmeted, 35% unhelmeted) met inclusion criteria. Helmet use doubled during the study period (43% to 81%, p < 0.001), but the rate of any head injury did not significantly change (49% to 43%, p = 0.499). On multivariable regression, helmeted patients were significantly more likely to suffer severe injury (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.30-3.11), intracranial hemorrhage (OR, 1.81; 95% CI, 1.10-2.96), chest injury (OR, 1.66; 95% CI, 1.05-2.61), and/or lumbosacral spine injury (OR, 1.84; 95% CI, 1.04-3.25) than unhelmeted patients. Helmeted patients were half as likely to suffer cervical spine injury (OR, 0.51; 95% CI, 0.30-0.89) and a third as likely to sustain skull fracture and/or scalp laceration (OR, 0.30; 95% CI, 0.14-0.64). More patients who hit a stationary object were helmeted compared with those who fell from standing height onto snow (70% vs. 56% respectively, p < 0.001). After adjustment, hitting a stationary object was the injury mechanism most significantly associated with severe injury (OR, 2.80; 95% CI, 1.79-4.38). CONCLUSION: Helmeted skiers and snowboarders evaluated at a Level I trauma center were more likely to suffer severe injury, including intracranial hemorrhage, as compared with unhelmeted participants. However, they were less likely to sustain skull fractures or cervical spine injuries. Helmeted patients were also more likely to hit a stationary object. Our findings reinforce the importance of safe skiing practices and trauma evaluation after high-impact injury, regardless of helmet use. LEVEL OF EVIDENCE: Prognostic and epidemiological, level IV.

Predisposed to failure? The challenge of rescue in the medical intensive care unit.

BACKGROUND: Medical intensive care unit (MICU) patients develop acute surgical processes that require operative intervention. There are limited data addressing outcomes of emergency general surgery (EGS) in this population. The aim of our study was to characterize the breadth of surgical consults from the MICU and assess mortality after abdominal EGS cases. METHODS: All MICU patients with an EGS consult in an academic medical center between January 2010 and 2016 were identified from an electronic medical record-based registry. Charts were reviewed to determine reason for consult, procedures performed, and to obtain additional clinical data. A multivariate logistic regression was used to determine patient factors associated with patient mortality. RESULTS: Of 911 MICU patients seen by our service, 411(45%) required operative intervention, with 186 patients undergoing an abdominal operation. The postoperative mortality rate after abdominal operations was 37% (69/186), significantly higher than the mortality of 16% (1833/11192) for all patients admitted to the MICU over the same period (p < 0.05). Damage-control procedures were performed in 64 (34%) patients, with 46% mortality in this group. The most common procedures were bowel resections, with mortality of 42% (28/66) and procedures for severe clostridium difficile, mortality of 38% (9/24). Twenty-seven patients met our definition of surgical rescue, requiring intervention for complications of prior procedures, with mortality of 48%. Need for surgical rescue was associated with increased admission mortality (odds ratio, 13.07; 95% confidence interval, 2.86-59.77). Twenty-six patients had pathology amenable to surgical intervention but did not undergo operation, with 100% mortality. In patients with abdominal pathology at the time of operation, in-hospital delay was associated with increased mortality (odds ratio, 5.13; 95% confidence interval, 1.11-23.77). CONCLUSION: Twenty percent of EGS consults from the MICU had an abdominal process requiring an operative intervention. While the MICU population as a whole has a high baseline mortality, patients requiring abdominal surgical intervention are an even higher risk. LEVEL OF EVIDENCE: Prognostic and epidemiological, level III.

Acute kidney injury predicts mortality in emergency general surgery patients.

BACKGROUND: Patients undergoing Emergency General Surgery (EGS) have increased risk of complications and death. The risk of AKI in patients undergoing EGS, along with associated outcomes, is unknown. METHODS: This two-institution observational study included adults admitted to intensive care units between 1997 and 2012. EGS was defined by 7 procedures occurring within 48 hours of ICU admission. The main outcome studied was AKI within 5 days, along with 90-day mortality. RESULTS: In our cohort of 59,604 patients, 1758 (2.9%) underwent EGS. Risk of AKI in EGD patients was significantly increased relative to non-EGS patients, with adjusted odds of 1.7 (95%CI 1.40-1.94; P < 0.001). Risk of renal replacement for EGS patients was also increased, with odds of 1.8 (95%CI 1.37-2.46; P < 0.001). EGS patients were at significantly higher risk of 90-day mortality, with adjusted odds of 3.1 (95%CI 2.16-4.33,p < 0.001) for AKI and 4.5 (95%CI 2.58-7.96,p < 0.001) for AKI requiring renal replacement, relative to the absence of AKI. CONCLUSIONS: EGS is a robust risk factor for AKI in critically ill patients, the development of which is strongly predictive of increased 90-day mortality.

Surgical Rescue in Medical Patients: The Role of Acute Care Surgeons as the Surgical Rapid Response Team.

Failure to rescue is death occurring after a complication. Rapid response teams developed as a prompt intervention for patients with early clinical deterioration, generally from medical conditions or complications. Patients with surgical complications or surgical pathology require prompt evaluation and management by surgeons to avoid deterioration; this is surgical rescue. Patients in the medical intensive care unit may develop intra-abdominal pathology that requires expeditious operative intervention. Acute care surgeons should serve as the surgical rapid response team to help assess and manage these complex patients. Collaboration between intensivists and surgeons is essential to rescue patients from complications and surgical disease.

Tips, Tricks, and Technique for Laparoscopic Colectomy.

In the United States, there are in excess of 300,000 operations for diseases of the colon yearly. Minimally invasive colectomy became a reality early in the 21st century with the advent of laparoscopic colectomy. The goal of minimally invasive colectomy is to improve postoperative pain control, decrease length of hospital stay, decrease recovery time, decrease complications, and thereby decrease the cost of colon resections. There are many facets to laparoscopic colectomy, including completely laparoscopic approach versus hand-assisted approach and the medial versus lateral approach. These decisions are often based on the disease process, surgeon preference and comfort with technique, and patient considerations such as weight and prior operations. This article outlines the pros and cons of each of these factors.

BWH emergency radiology-surgical correlation: intraperitoneal urinary bladder rupture.

We describe the radiological and intraoperative correlation of two cases of intraperitoneal bladder rupture: a 23-year-old man involved in a high-speed motor vehicle collision and a 49-year-old man with hematuria and abdominal pain after a night of heavy alcohol ingestion. Both patients underwent urgent exploratory laparotomies and repair of their bladder injuries. The purpose of this article is to emphasize the importance of understanding the different etiologies of bladder rupture and recognizing the imaging findings on computed tomography (CT) and CT cystography to help guide the surgeons in the patient's management.

Antitumor effects of hyaluronan inhibition in desmoid tumors.

Desmoid tumors (DTs) are rare, mesenchymal tumors that exhibit features of an abundant wound healing process. Previously, we showed that mesenchymal stem cells (MSCs) are constituents of DTs and may contribute to desmoid tumorigenesis via activities associated with wound healing. Hyaluronan (HA) is a long-charged chain of repeating glucuronate and N-acetylglucosamine disaccharides that is synthesized by HA synthases (HAS) and degraded by hyaluronidases (HYAL). HA is secreted into the extracellular matrix by injured stroma and is important for normal tissue repair and neoplastic progression. Here, we investigated the presence of HA in DTs and the antitumor effects of the HA inhibitor, 4-methylumbelliferone (4-MU), on DT-derived mesenchymal cells. By immunohistochemistry and enzyme-linked immunosorbent assay, we found abundant expression of HA in 29/30 DTs as well as >5-fold increased HA levels in DT-derived cell lines relative to controls. Immunohistochemistry also demonstrated high expression of HAS2 in DTs, and quantitative PCR analysis showed increased HAS2 upregulation in frozen DTs and DT-derived cells. 4-MU treatment of DT-derived cells significantly decreased proliferation as well as HA and HAS2 levels. Fluorescent immunohistochemistry showed that MSCs in DTs coexpressed HA, HAS2, HYAL2, as well as the major HA receptor CD44 and HA coreceptor TLR4. Taken together, our results suggest that paracrine regulation of HA signaling in DTs may contribute to MSC recruitment and tumor proliferation. Future studies investigating the role of HA in tumor-stroma crosstalk and inhibition of HA-MSC interactions as a novel therapeutic target in DTs and other solid tumors are warranted.

Lack of anti-tumor activity with the ß-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis.

BACKGROUND: Previously, we showed that short-term inhibition of ß-catenin expression and reversal of aberrant ß-catenin subcellular localization by the selective COX-2 inhibitor celecoxib is associated with adenoma regression in the C57BL/6J Min/+ mouse. Conversly, long-term administration resulted in tumor resistance, leading us to investigate alternative methods for selective ß-catenin chemoprevention. In this study, we hypothesized that disruption of ß-catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based ß-catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. MATERIALS AND METHODS: C57BL/6J Apc(+/+) wild-type (WT) and Min/+ mice were treated with the maximum tolerated dose (MTD) of EZN-3892 (30mg/kg). Drug effect on tumor numbers, ß-catenin protein expression, and nuclear ß-catenin localization were determined. RESULTS: Although the tumor phenotype and ß-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in ß-catenin expression levels in the mature intestinal tissue of treated Min/+ and WT mice, providing proof of principle regarding successful delivery of the LNA-based antisense vehicle. Higher doses of EZN-3892 resulted in fatal outcomes in Min/+ mice, likely due to ß-catenin ablation in the intestinal tissue and loss of function. CONCLUSIONS: Our data support the critical role of Wnt/ß-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent toxicity to normal cellular function.

Estrogen receptor α or ß loss in the colon of Min/+ mice promotes crypt expansion and impairs TGFß and HNF3ß signaling.

Adenomatous polyposis coli (APC)-regulated Wnt and transforming growth factor-ß (TGFß) signaling cooperate in the intestine to maintain normal enterocyte functions. Human clinical trials showed that estrogen [17ß-estradiol (E2)], the ligand of nuclear receptors estrogen receptor α (ERα) and ERß, inhibited colorectal cancer (CRC) in women. Consistent with this finding, we reported that E2, ERα and ERß suppressed intestinal tumorigenesis in the C57BL/6J-Min/+ (Min/+) mouse, a CRC model. Here, we extended our results with further comparisons of colon and small intestine from intact female Apc (+/+) (WT), Min/+ and ER-deficient Min/+ mice. In the colon of ER-deficient Min/+ mice, ER loss reduced TGFß signaling in crypt base cells as evidenced by minimal expression of the effectors Smad 2, 3 and 4 in these strains. We also found reduced expression of Indian hedgehog (Ihh), bone morphogenetic protein 4 and hepatocyte nuclear factor 3ß or FoxA2, factors needed for paracrine signaling between enterocytes and mesenchyme. In proximal colon, ER loss produced a >10-fold increased incidence of crypt fission, a marker for wound healing and tumor promotion. These data, combined with our previous work detailing the specific roles of E2, ERα and ERß in the colon, suggest that ER activity helps to maintain the intestinal stem cell (ISC) microenvironment by modulating epithelial-stromal crosstalk in ways that regulate cytokine, Wnt and Ihh availability in the extracellular matrix (ECM).