Deprivation and Rurality Mediate Income Inequality's Association with Colorectal Cancer Outcomes.

INTRODUCTION: Income inequality is associated with poor health outcomes, but its association with colorectal cancer is not well-studied. The authors aimed to determine the association between income inequality and colorectal cancer incidence/mortality in U.S. counties, and hypothesized that this association was mediated by deprivation. METHODS: The authors performed a cross-sectional study of U.S. counties from 2015-2019 using statewide cancer registries and the Centers for Disease Control and Prevention WONDER database. Generalized linear negative binomial regression was performed in 2024 to estimate the association between Gini coefficient (income inequality) and colorectal cancer incidence/mortality using incidence rate ratios (IRRs) for the entire cohort and stratified by rurality. RESULTS: A total of 697,981 colorectal cancer cases were diagnosed in the 5-year study period. On adjusted regression, for every 0.1 higher Gini coefficient, there was an 11% higher risk of both colorectal cancer incidence and mortality (IRR 1.11, 95%CI 1.03,1.19 and IRR 1.11, 95%CI 1.05, 1.18 respectively). The association between income inequality and incidence/mortality peaked in more rural counties, however there was not an overall dose-dependent relationship between rurality and these associations. Deprivation mediated the association between income inequality and colorectal cancer incidence (indirect effect B coefficient 0.088, p<0.001) and mortality (B coefficient 0.088, p<0.001). The magnitude and direction of the direct, indirect, and total effects differed in each rurality strata. CONCLUSIONS: Much of income inequality's association with colorectal cancer outcomes operates through deprivation. Rural counties have a stronger association between higher income inequality and higher mortality, which works in tandem with deprivation.

Predictors of recurrence and long-term patient reported outcomes following surgical repair of anal fistula, a retrospective analysis.

PURPOSE: Surgery for anal fistulas can result in devastating complications, including reoperations and fecal incontinence. There is limited contemporary evidence comparing outcomes since the adoption of the ligation of intersphincteric fistula tract procedure into mainstream practice. The purpose of this study is to compare recurrence rates and long-term outcomes of anal fistula following repair. METHODS: Data was collected from the electronic medical records or patient reported outcomes from patients aged 18 or older with a primary or recurrent cryptoglandular anal fistula. Primary outcome was recurrence defined as the identification of at least one fistula os or a high clinical suspicion of anal fistula. Secondary outcomes included fecal incontinence and postoperative quality of life. RESULTS: A total of 171 patients underwent definitive surgical repairs for their anal fistula. So 66.5% had a simple fistula, and 33.5% had a complex fistula. Of the 171 patients, 12.5% had a recurrence. The recurrence rates were 5.9% for simple fistula and 25.4% for complex fistula. Predictors of recurrence included diabetes mellitus, history of anorectal abscess, complex fistula, and sphincter sparing surgery. LIFT or plug/biologic procedures were both associated with a 50% or greater recurrence rate. No significant differences were found in fecal incontinence or associated quality of life between sphincter sparing or non-sphincter sparing surgical resections. CONCLUSION: The study provides insights into the long-term outcomes of surgical repair for anal fistula. We demonstrate that sphincter sparing operations are associated with increased recurrence, meanwhile, non-sphincter sparing surgeries did not increase the risk of fecal incontinence or worsen quality of life.

Drainage of anorectal abscesses in the operating room is associated with a decreased risk of abscess recurrence and fistula formation.

BACKGROUND: Timely incision and drainage (I&D) is first line management for anorectal abscesses. We aimed to define current practices in anorectal abscess management and identify factors associated with abscess recurrence and fistula formation. METHODS: Index episodes of anorectal abscesses treated with I&D in 2014-2018 at a multi-hospital healthcare system were included. Association with one-year abscess recurrence or fistula formation was evaluated using Cox proportional hazard regression. Fistulae were captured only among patients without fistulae at the index operation. RESULTS: A total of 458 patients met study criteria. One-year rate of abscess recurrence or fistula formation was 20.3%. When compared to bedside procedures, drainage in the operating room was associated with a reduced risk of either recurrence or fistula formation (aHR 0.20 [95%CI 0.114-0.367]). CONCLUSIONS: Improved exposure and patient comfort in the operating room may allow more complete drainage contributing to decreased rates of abscess recurrence or fistula formation.

DNA Mismatch Repair-deficient Rectal Cancer Is Frequently Associated With Lynch Syndrome and With Poor Response to Neoadjuvant Therapy.

We evaluated 368 consecutively resected rectal cancers with neoadjuvant therapy for DNA mismatch repair (MMR) protein status, tumor response to neoadjuvant therapy, histopathologic features, and patient survival. Nine (2.4%) rectal cancers were mismatch repair-deficient (MMRD): 8 (89%) Lynch syndrome-associated tumors and 1 (11%) sporadic MLH1-deficient tumor. Of the 9 MMRD rectal cancers, 89% (8/9) had a tumor regression score 3 (poor response) compared with 23% (81/359) of MMR proficient rectal cancers ( P <0.001). Patients with MMRD rectal cancer less often had downstaging after neoadjuvant therapy compared with patients with MMR proficient rectal cancer (11% vs. 57%, P =0.007). In the multivariable logistic regression analysis, MMRD in rectal cancer was associated with a 25.11-fold increased risk of poor response to neoadjuvant therapy (tumor regression score 3) (95% confidence interval [CI]: 3.08-44.63, P =0.003). In the multivariable Cox regression analysis, the only variables significantly associated with disease-free survival were pathologic stage III disease (hazard ratio [HR]=2.46, 95% CI: 1.54-3.93, P <0.001), College of American Pathologists (CAP) tumor regression score 2 to 3 (HR=3.44, 95% CI: 1.76-6.73, P <0.001), and positive margins (HR=2.86, 95% CI: 1.56-5.25, P =0.001). In conclusion, we demonstrated that MMRD in rectal cancer is an independent predictor of poor response to neoadjuvant therapy and infrequently results in pathologic downstaging following neoadjuvant therapy. We also confirmed that MMRD in rectal cancer is strongly associated with a diagnosis of Lynch syndrome. Our results suggest that MMR status may help to provide a more patient-centered approach when selecting neoadjuvant treatment regimens and may help predict tumor response to neoadjuvant therapy.

Developing Opioid Prescription Guidelines After Anorectal Surgery: Do Patient-Reported Outcomes and Risk Factors Influence Consumption?

BACKGROUND: Opioids prescribed to address postoperative pain drive opioid-related deaths in the United States. Prescribing guidelines have been developed for many general surgical procedures, which have decreased opioid prescription and consumption. The literature on opioids after anorectal surgery is lacking. OBJECTIVE: We analyzed our data on opioid prescription and consumption to create opioid-prescribing guidelines for anorectal procedures. DESIGN: We designed a prospectively collected postoperative survey given to consecutive patients undergoing anorectal surgery by colorectal surgeons. SETTINGS: Patients had surgery at 2 academic, university-affiliated hospitals. PATIENTS: Patients undergoing anorectal surgery from May 3, 2018, to December 18, 2019, were included in the study. Patients were excluded if they were <18 years of age, had a concurrent abdominopelvic surgery, consumed opioids in the week before their operation, or were without follow-up at 3 months postoperatively. MAIN OUTCOME MEASURES: The primary outcome of this study was the number of opioid pills needed to fulfill consumption of 80% of patients. Secondary outcome measures were patient, operative, and postoperative factors associated with increasing pill consumption. RESULTS: Eighteen 5-mg oxycodone tablets were needed to fulfill the needs of 80% of patients. An overall median of 8 pills was consumed. Pill prescription was independently predictive of increased consumption. The only patient factor associated with increased consumption was race; no other patient or operative factors were predictive of consumption. LIMITATIONS: Limitations of this study include its partially retrospective nature, use of self-reported data, and lack of racial diversity among our cohort. CONCLUSIONS: Without any clinical factors predictive of increased consumption, prescription guidelines can be standardized to ≤18 5-mg oxycodone tablets across anorectal surgery patients. As prescription is correlated with consumption, further work is needed to determine whether lesser quantities of opioids prescribed offer similar postoperative pain relief for patients undergoing anorectal surgery. See Video Abstract at http://links.lww.com/DCR/B821 .DESARROLLO DE PAUTAS PARA LA PRESCRIPCIÓN DE OPIOIDES DESPUÉS DE CIRUGÍA ANORRECTAL: ¿INFLUYEN EN EL CONSUMO LOS RESULTADOS INFORMADOS POR EL PACIENTE Y LOS FACTORES DE RIESGO? ANTECEDENTES: Los opioides recetados para tratar el dolor posoperatorio provocan muertes relacionadas con los opioides en los Estados Unidos. Se han desarrollado pautas de prescripción para muchos procedimientos quirúrgicos generales y estas han conducido a una disminución de la prescripción y el consumo de opioides. Hay una carencia de literatura sobre el uso de opioides después de cirugía anorrectal. OBJETIVO: Analizamos nuestros datos sobre prescripción y consumo de opioides para crear pautas de prescripción de opioides para procedimientos anorrectales. DISEO: Diseñamos una encuesta postoperatoria recopilada prospectivamente que se administró a pacientes consecutivos sometidos a cirugía anorrectal por cirujanos colorrectales. AJUSTES: Los pacientes fueron operados en dos hospitales académicos afiliados a la universidad. PACIENTES: Se incluyeron en el estudio pacientes sometidos a cirugía anorrectal desde el 3/05/2018 hasta el 18/12/2019. Se excluyó a los pacientes que tenían menos de 18 años, a los que se sometieron a cirugía abdominopélvica concurrente, a los que consumieron opioides en la semana anterior a la operación, o si no tenían seguimiento a los 3 meses del postoperatorio. PRINCIPALES MEDIDAS DE DESENLACE: El desenlace principal de este estudio fue el número de píldoras de opioides necesarias para satisfacer el consumo del 80% de los pacientes. Las medidas de desenlace secundarias fueron los factores del paciente, operatorios y posoperatorios asociados con el aumento del consumo de píldoras. RESULTADOS: Fueron necesarios dieciocho comprimidos de oxicodona de 5 mg para cubrir las necesidades del 80% de los pacientes. Se consumió una mediana general de 8 píldoras. La prescripción de la píldora fue un predictor independiente de un mayor consumo. El único factor del paciente asociado con un mayor consumo fue la raza; ningún otro paciente o factores operativos fueron predictivos del consumo. LIMITACIONES: Las limitaciones de este estudio incluyen su naturaleza parcialmente retrospectiva, el uso de datos autoinformados y la falta de diversidad racial entre nuestra cohorte. CONCLUSIONES: Sin ningún factor clínico que prediga un aumento del consumo, las pautas de prescripción se pueden estandarizar a dieciocho o menos comprimidos de oxicodona de 5 mg en pacientes sometidos a cirugía anorrectal. Como la prescripción se correlaciona con el consumo, se necesita más trabajo para determinar si cantidades menores de opioides prescritos ofrecen un alivio del dolor posoperatorio similar para los pacientes sometidos a cirugía anorrectal. Consulte Video Resumen en http://links.lww.com/DCR/B821 . (Traducción-Juan Carlos Reyes ).

Transanal excision with adjuvant therapy for pT1N0 rectal tumors with high-risk features offers equivalent survival to radical resection: A National Cancer Database analysis.

BACKGROUND: Current guidelines favor transabdominal radical resection (RR) over transanal local excision (TAX) followed by adjuvant therapy (TAXa) for pT1N0 rectal tumors with high-risk features. Comparison of oncologic outcomes between these approaches is limited, although the former is associated with increased postoperative morbidity. We hypothesize that such treatment strategies result in equivalent long-term survival. METHODS: A retrospective cohort study was conducted using the National Cancer Database (2010-2016) to identify patients with pT1N0 rectal adenocarcinoma with high-risk features who underwent TAX or RR for curative intent. The primary outcome was 5-year overall survival (OS), evaluated with log-rank and Cox-proportional hazards testing. RESULTS: A total of 1159 patients (age 67.4 ± 12.9 years; 56.6% male; 83.3% White) met study criteria, of which 1009 (87.1%) underwent RR and 150 (12.9%) underwent TAXa. Patients undergoing TAXa had shorter lengths of stay (RR = 6.5 days, TAXa = 2.7 days, p < 0.001). The 5-year OS was equivalent between groups. TAX without adjuvant therapy was associated with an increased risk of mortality (hazard ratio 1.81, 95% confidence interval 1.17-2.78, p = 0.01). CONCLUSIONS: This is the largest study to demonstrate equivalent 5-year OS between TAXa and RR for T1N0 rectal cancer with high-risk features. These findings may guide the development of prospective, randomized trials and influence changes in practice recommendations for early-stage rectal cancer.

Nix-Mediated Mitophagy Modulates Mitochondrial Damage During Intestinal Inflammation.

Aims: Mitochondrial stress and dysfunction within the intestinal epithelium are known to contribute to the pathogenesis of inflammatory bowel disease (IBD). However, the importance of mitophagy during intestinal inflammation remains poorly understood. The primary aim of this study was to investigate how the mitophagy protein BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L/NIX) mitigates mitochondrial damage during intestinal inflammation in the hopes that these data will allow us to target mitochondrial health in the intestinal epithelium as an adjunct to immune-based treatment strategies. Results: In the intestinal epithelium of patients with ulcerative colitis, we found that NIX was upregulated and targeted to the mitochondria. We obtained similar findings in wild-type mice undergoing experimental colitis. An increase in NIX expression was found to depend on stabilization of hypoxia-inducible factor-1 alpha (HIF1α), which binds to the Nix promoter region. Using the reactive oxygen species (ROS) scavenger MitoTEMPO, we were able to attenuate disease and inhibit both HIF1α stabilization and subsequent NIX expression, suggesting that mitochondrially derived ROS are crucial to initiating the mitophagic response during intestinal inflammation. We subjected a global Nix-/- mouse to dextran sodium sulfate colitis and found that these mice developed worse disease. In addition, Nix-/- mice were found to exhibit increased mitochondrial mass, likely due to the inability to clear damaged or dysfunctional mitochondria. Innovation: These results demonstrate the importance of mitophagy within the intestinal epithelium during IBD pathogenesis. Conclusion: NIX-mediated mitophagy is required to maintain intestinal homeostasis during inflammation, highlighting the impact of mitochondrial damage on IBD progression.

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation.

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide. IBD is known to be multifactorial, but inflammatory signaling within the intestinal epithelium and a subsequent failure of the intestinal epithelial barrier have been shown to play essential roles in disease pathogenesis. CaMKIV is a multifunctional protein kinase associated with inflammation and cell cycle regulation. CaMKIV has been extensively studied in autoimmune diseases, but a role in idiopathic intestinal inflammation has not been described. In this study, active CaMKIV was highly expressed within the intestinal epithelium of humans with ulcerative colitis and wild-type (WT) mice with experimental induced colitis. Clinical disease severity directly correlates with CaMKIV activation, as does expression of proinflammatory cytokines and histologic features of colitis. In WT mice, CaMKIV activation is associated with increases in expression of 2 cell cycle proarrest signals: p53 and p21. Cell cycle arrest inhibits proliferation of the intestinal epithelium and ultimately results in compromised intestinal epithelial barrier integrity, further perpetuating intestinal inflammation during experimental colitis. Using a CaMKIV null mutant mouse, we demonstrate that a loss of CaMKIV protects against murine DSS colitis. Small molecules targeting CaMKIV activation may provide therapeutic benefit for patients with IBD.-Cunningham, K. E., Novak, E. A., Vincent, G., Siow, V. S., Griffith, B. D., Ranganathan, S., Rosengart, M. R., Piganelli, J. D., Mollen, K. P. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation.

Red blood cell transfusion in premature infants leads to worse necrotizing enterocolitis outcomes.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe intestinal disease of premature infants with high mortality. Studies suggest a causative relationship between red blood cell (RBC) transfusion and NEC; however, whether RBC transfusion leads to worse outcomes in NEC is unknown. We sought to determine whether RBC transfusion was associated with an increased risk of surgical NEC and mortality. METHODS: In this retrospective study, 115 patients were enrolled with NEC Bell's stage 2A or greater from 2010-2015. Patients were classified based on the timing of RBC transfusion before NEC: ≤72 h, >72 h, and no transfusion. Variables including gestational age (GA), birth weight (BW), feedings, and hematocrit levels were analyzed. Outcomes were surgical intervention for NEC following RBC transfusion and mortality. RESULTS: Twenty-three (20%) infants developed NEC ≤ 72 h after RBC transfusion, 16 (69.6%) required surgery with a mortality rate of 21.7% (n = 5). Seventeen (15%) infants developed NEC > 72 h after RBC transfusion, 12 (70.6%) required surgery with a mortality rate of 23.5% (n = 4). 75 (65%) patients developed NEC without RBC transfusion, 17 (22.7%) required surgery with a mortality rate of 4% (n = 3). Lower GA and BW were significantly associated with RBC transfusion and the need for surgical intervention. RBC transfusion ≤72 h before NEC was associated with surgical NEC (pairwise adjusted P < 0.001) and mortality (pairwise adjusted P = 0.048). However, multivariable logistic regression analysis revealed RBC transfusion is not an independent risk factor for surgical NEC. CONCLUSIONS: Infants of lower GA and BW were more likely to receive an RBC transfusion before NEC, which was significantly associated with surgical intervention and an increasing risk of mortality. Judicious use of transfusions in premature infants may improve NEC outcomes.

A policy of omitting an intensive care unit stay after robotic pancreaticoduodenectomy is safe and cost-effective.

BACKGROUND: Immediate postoperative admission to the intensive care unit (ICU) after pancreaticoduodenectomy (PD) is still a standard practice at many institutions. Our aim was to examine whether omission of an immediate postoperative ICU admission would be safe and result in improved outcomes and cost after robotic pancreaticoduodenectomy (RPD). METHODS: In December 2014, a non-ICU admission policy was implemented for patients undergoing RPD. Before this date, all RPDs were routinely admitted to the ICU on post operative day = 0. Using a prospective database, outcomes of the patients in the no-ICU cohort were compared with those of the patients routinely admitted to the ICU before implementation of this policy. RESULTS: The ICU (n = 49) and no-ICU cohorts (n = 47) were comparable in age, gender, body mass index, Charlson comorbidity index and American Society of Anesthesiologists scores, receipt of neoadjuvant therapy, operative time, estimated blood loss, tumor size, and pathologic diagnosis (all P values = NS). Clavien complications, pancreatic leak, reoperation, readmission, and mortality were similar between both the groups (all P values = NS). Hospital length of stay (LOS) was shorter for the no-ICU group (median 6.8 versus 7.7 d, P = 0.01). This reduced LOS and omission of routine postoperative ICU admission translated into a cost reduction from $23,933 (interquartile range $19,833-$28,991) in the ICU group to $19,516 (interquartile range $17,046-$23,893) in the no-ICU group, P = 0.004. The reduction in LOS and cost remained significant after adjusting for all related demographics and perioperative characteristics. CONCLUSIONS: A standard policy of omitting a postoperative ICU admission on post operative day 0 after RPD is safe and can result in reduced LOS and overall savings in total hospital cost.

Peroxisome Proliferator-activated Receptor-γ Coactivator 1-α (PGC1α) Protects against Experimental Murine Colitis.

Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is the primary regulator of mitochondrial biogenesis and was recently found to be highly expressed within the intestinal epithelium. PGC1α is decreased in the intestinal epithelium of patients with inflammatory bowel disease, but its role in pathogenesis is uncertain. We now hypothesize that PGC1α protects against the development of colitis and helps to maintain the integrity of the intestinal barrier. We selectively deleted PGC1α from the intestinal epithelium of mice by breeding a PGC1α(loxP/loxP) mouse with a villin-cre mouse. Their progeny (PGC1α(ΔIEC) mice) were subjected to 2% dextran sodium sulfate (DSS) colitis for 7 days. The SIRT1 agonist SRT1720 was used to enhance PGC1α activation in wild-type mice during DSS exposure. Mice lacking PGC1α within the intestinal epithelium were more susceptible to DSS colitis than their wild-type littermates. Pharmacologic activation of PGC1α successfully ameliorated disease and restored mitochondrial integrity. These findings suggest that a depletion of PGC1α in the intestinal epithelium contributes to inflammatory changes through a failure of mitochondrial structure and function as well as a breakdown of the intestinal barrier, which leads to increased bacterial translocation. PGC1α induction helps to maintain mitochondrial integrity, enhance intestinal barrier function, and decrease inflammation.

Functional insights from structural genomics.

Structural genomics efforts have produced structural information, either directly or by modeling, for thousands of proteins over the past few years. While many of these proteins have known functions, a large percentage of them have not been characterized at the functional level. The structural information has provided valuable functional insights on some of these proteins, through careful structural analyses, serendipity, and structure-guided functional screening. Some of the success stories based on structures solved at the Northeast Structural Genomics Consortium (NESG) are reported here. These include a novel methyl salicylate esterase with important role in plant innate immunity, a novel RNA methyltransferase (H. influenzae yggJ (HI0303)), a novel spermidine/spermine N-acetyltransferase (B. subtilis PaiA), a novel methyltransferase or AdoMet binding protein (A. fulgidus AF_0241), an ATP:cob(I)alamin adenosyltransferase (B. subtilis YvqK), a novel carboxysome pore (E. coli EutN), a proline racemase homolog with a disrupted active site (B. melitensis BME11586), an FMN-dependent enzyme (S. pneumoniae SP_1951), and a 12-stranded beta-barrel with a novel fold (V. parahaemolyticus VPA1032).