Using CT-Based Pelvimetry and Visceral Obesity Measurements to Predict Total Mesorectal Excision Quality for Patients Undergoing Rectal Cancer Surgery.

BACKGROUND: A complete total mesorectal excision is the criterion standard in curative rectal cancer surgery. Ensuring quality is challenging in a narrow pelvis, and obesity amplifies technical difficulties. Pelvimetry is the measurement of pelvic dimensions, but its role in gauging preoperatively the difficulty of proctectomy is largely unexplored. OBJECTIVE: To determine pelvic structural factors associated with incomplete total mesorectal excision after curative proctectomy and build a predictive model for total mesorectal excision quality. DESIGN: Retrospective cohort study. SETTING: A quaternary referral center database of patients diagnosed with rectal adenocarcinoma (2009-2017). PATIENTS: Curative-intent proctectomy for rectal adenocarcinoma. INTERVENTIONS: All radiological measurements were obtained from preoperative CT images using validated imaging processing software tools. Completeness of total mesorectal excision was obtained from histology reports. MAIN OUTCOME MEASURES: Ability of radiological pelvimetry and obesity measurements to predict total mesorectal excision quality. RESULTS: Of the 410 cases meeting inclusion criteria, 362 underwent a complete total mesorectal excision (88%). Multivariable regression identified a deeper sacral curve (per 100 mm 2 [OR: 1.14; 95% CI, 1.06-1.23; p < 0.001]) and a greater transverse distance of the pelvic outlet (per 10 mm [OR:1.41, 95% CI, 1.08-1.84; p = 0.012]) to be independently associated with incomplete total mesorectal excision. An increased area of the pelvic inlet (per 10 cm 2 [OR: 0.85; 95% CI, 0.75-0.97; p = 0.02) was associated with a higher rate of complete mesorectal excision. No difference in visceral obesity ratio and visceral obesity (ratio >0.4 vs <0.4) between BMI (<30 vs ≥30) and sex was identified. A model was built to predict mesorectal quality using the following variables: depth of sacral curve, area of pelvic inlet, and transverse distance of the pelvic outlet. LIMITATIONS: Retrospective analysis is not controlled for the choice of surgical approach. CONCLUSIONS: Pelvimetry predicts total mesorectal excision quality in rectal cancer surgery and can alert surgeons preoperatively to cases of unusual difficulty. This predictive model may contribute to treatment strategy and aid in the comparison of outcomes between traditional and novel techniques of total mesorectal excision. See Video Abstract . USO DE MEDICIONES DE PELVIMETRA Y OBESIDAD VISCERAL BASADAS EN TC PARA PREDECIR LA CALIDAD DE TME EN PACIENTES SOMETIDOS A CIRUGA DE CNCER DE RECTO: ANTECEDENTES:Una escisión mesorrectal total y completa es el estándar de oro en la cirugía curativa del cáncer de recto. Garantizar la calidad es un desafío en una pelvis estrecha y la obesidad amplifica las dificultades técnicas. La pelvimetría es la medición de las dimensiones pélvicas, pero su papel para medir la dificultad preoperatoria de la proctectomía está en gran medida inexplorado.OBJETIVO:Determinar los factores estructurales pélvicos asociados con la escisión mesorrectal total incompleta después de una proctectomía curativa y construir un modelo predictivo para la calidad de la escisión mesorrectal total.DISEÑO:Estudio de cohorte retrospectivo.ÁMBITO:Base de datos de un centro de referencia cuaternario de pacientes diagnosticados con adenocarcinoma de recto (2009-2017).PACIENTES:Proctectomía con intención curativa para adenocarcinoma de recto.INTERVENCIONES:Todas las mediciones radiológicas se obtuvieron a partir de imágenes de TC preoperatorias utilizando herramientas de software de procesamiento de imágenes validadas. La integridad de la escisión mesorrectal total se obtuvo a partir de informes histológicos.PRINCIPALES MEDIDAS DE VALORACIÓN:Capacidad de la pelvimetría radiológica y las mediciones de obesidad para predecir la calidad total de la escisión mesorrectal.RESULTADOS:De los 410 casos que cumplieron los criterios de inclusión, 362 tuvieron una escisión mesorrectal total completa (88%). Una regresión multivariable identificó una curva sacra más profunda (por 100 mm2); OR:1,14,[IC95%:1,06-1,23,p<0,001], y mayor distancia transversal de salida pélvica (por 10mm); OR:1,41, [IC 95%:1,08-1,84,p=0,012] como asociación independiente con escisión mesorrectal total incompleta. Un área aumentada de entrada pélvica (por 10 cm2); OR:0,85, [IC95%:0,75-0,97,p=0,02] se asoció con una mayor tasa de escisión mesorrectal completa. No se identificaron diferencias en la proporción de obesidad visceral y la obesidad visceral (proporción>0,4 vs.<0,4) entre el índice de masa corporal (<30 vs.>=30) o el sexo. Se construyó un modelo para predecir la calidad mesorrectal utilizando variables: profundidad de la curva sacra, área de la entrada pélvica y distancia transversal de la salida pélvica.LIMITACIONES:Análisis retrospectivo no controlado por la elección del abordaje quirúrgico.CONCLUSIONES:La pelvimetría predice la calidad de la escisión mesorrectal total en la cirugía del cáncer de recto y puede alertar a los cirujanos preoperatoriamente sobre casos de dificultad inusual. Este modelo predictivo puede contribuir a la estrategia de tratamiento y ayudar en la comparación de resultados entre técnicas tradicionales y novedosas de escisión mesorrectal total. (Traducción- Dr. Ingrid Melo).

Comparison of perioperative and histopathologic outcomes among neoadjuvant treatment strategies for locoregional gastric cancer.

BACKGROUND AND OBJECTIVES: Neoadjuvant chemotherapy (NAC) and chemoradiation (NCRT) have demonstrated improved survival for gastric cancer. However, the optimal neoadjuvant treatment remains unclear. We sought to evaluate perioperative and histopathologic outcomes among neoadjuvant treatments for locoregional gastric cancer. METHODS: The National Cancer Database queried patients who received NAC or NCRT followed by resection for T2-T4 and/or node-positive gastric cancer (2006-2018). Logistic and Poisson regression assessed perioperative (30-day readmission, 30- and 90-day mortality, length of stay [LOS]) and histopathologic outcomes (pathologic complete response [PCR], margin status, and negative pathologic lymph nodes [ypN0]). Kaplan-Meier methods and Cox regression assessed overall survival (OS). RESULTS: Of 9831 patients, 4221 (42.9%) received NAC and 5610 (57.1%) NCRT. There were no differences in perioperative outcomes, apart from patients treated with NCRT exhibiting increased LOS (incidence rate ratio 1.09, 95% confidence interval [CI] 1.03-1.16). Patients who received NCRT were more likely to achieve PCR, margin-negative resection, and ypN0 (all p < 0.05). Median OS was 36.8 months for NAC and 33.6 months for NCRT (p < 0.001). NCRT independently predicted worse OS (vs. NAC, hazard ratio 1.10, 95% CI 1.03-1.18). CONCLUSION: NCRT was associated with better histologic tumor response although NAC was associated with improved OS. Better understanding prognostication through histologic assessment following neoadjuvant therapy is needed.

Utilization and survival outcomes of neoadjuvant chemotherapy for early-stage gastric cancer.

BACKGROUND AND OBJECTIVES: Given increased utilization of neoadjuvant therapy (NAT) for gastric adenocarcinoma, practice patterns deviating from standard of care (upfront resection) remain unknown. We sought to identify factors associated with NAT use and survival outcomes among early-stage gastric cancers. METHODS: The National Cancer Database identified patients with early-stage (T1N0M0) gastric cancer (2010-2020). Multivariable logistic regression assessed characteristics associated with NAT utilization compared to upfront surgery. After 1:1 propensity score matching, Kaplan-Meier methods and Cox regression assessed overall survival (OS). RESULTS: Of 6452 patients with early-stage gastric cancer, 626 (9.7%) received NAT. Patients who received NAT were more likely treated at community hospitals, had moderate to poorly differentiated disease, and tumors located in the cardia (all p < 0.05). After propensity score matching, 1,248 patients remained. Median OS for NAT was 37.1 months (IQR 20.2-64.0) versus 45.6 months (IQR 22.5-72.8) for resection (p < 0.001). Treatment with NAT remained independently predictive of worse OS on Cox regression (hazard ratio 1.19; 95% confidence interval 1.05-1.34). CONCLUSIONS: Although patients who received NAT had more aggressive prognostic features, NAT was associated with worse OS despite accounting for this selection bias. These results highlight the importance of adhering to guidelines, regardless of differing disease characteristics, which has significant implications on outcomes.

Establishing the clinical relevance of grade A post-hepatectomy liver failure.

INTRODUCTION: The International Study Group of Liver Surgery's criteria stratifies post-hepatectomy liver failure (PHLF) into grades A, B, and C. The clinical significance of these grades has not been fully established. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) hepatectomy-targeted database was analyzed. Outcomes between patients without PHLF, with grade A PHLF, and grade B or C PHLF were compared. Univariate and multivariable logistic regression were performed. RESULTS: Six thousand two hundred seventy-four adults undergoing elective major hepatectomy were included in the analysis. The incidence of grade A PHLF was 4.3% and grade B or C was 5.3%. Mortality was similar between patients without PHLF (1.2%) and with grade A PHLF (1.1%), but higher in those with grades B or C PHLF (25.4%). Overall morbidities rates were 19.3%, 41.7%, and 72.8% in patients without PHLF, with grade A PHLF, and with grade B or C PHLF, respectively (p < 0.001). Grade A PHLF was associated with increased morbidity (grade A: odds ratios [OR] 2.7 [95% CI: 2.0-3.5]), unplanned reoperation (grade A: OR 3.4 [95% CI: 2.2-5.1]), nonoperative intervention (grade A: OR 2.6 [95% CI: 1.9-3.6]), length of stay (grade A: OR 3.1 [95% CI: 2.3-4.1]), and readmission (grade A: OR 1.8 [95% CI: 1.3-2.5]) compared to patients without PHLF. CONCLUSIONS: Although mortality was similar between patients without PHLF and with grade A PHLF, other postoperative outcomes were notably inferior. Grade A PHLF is a clinically distinct entity with relevant associated postoperative morbidity.

A review of response in neoadjuvant therapy for exocrine pancreatic cancer.

Despite overall advances in cancer therapy, patients with pancreatic ductal adenocarcinoma continue to have a poor prognosis. While adjuvant therapy is still considered standard, there is mounting evidence that neoadjuvant therapy confers similar benefits in patients with locally advanced disease. The primary measures of response are radiographic, biochemical, margin status, and pathologic. Given overall low response rates and the need for new treatment strategies, standard metrics remain important to the investigation of new systemic agents.

Gender as a risk factor for adverse intraoperative and postoperative outcomes of elective pancreatectomy.

BACKGROUND AND OBJECTIVES: Patient selection remains paramount when developing and adopting quality-based assessment and reimbursement models, and enhanced recovery protocols. Gender is a patient characteristic known before surgery which can inform risk stratification. Our aim was to evaluate the effect of gender on intraoperative blood transfusions, operative time, length of hospital stay, estimated blood loss (EBL) as well as postoperative surgical site infections (SSIs), and mortality. METHODS: Patients undergoing elective pancreatectomy from 2005 to 2013 were identified in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) and Northwestern institutional databases. Multivariable analyses were conducted to identify the association between gender and these outcomes. RESULTS: Analyses demonstrated that male gender was independently associated with blood transfusion (OR 1.23), operative time >6 hr (OR 1.76), length of stay greater than 11 days (OR 1.17), and all-type SSIs (OR 1.17), especially superficial SSIs (OR 1.15) and organ space SSIs (OR 1.18). Analysis of the institutional cohort found that male gender was independently associated with increased odds of EBL > 1 L for Whipple procedures (OR 2.85). CONCLUSIONS: Male gender is a significant predictor of increased operative time, length of stay, transfusions, EBL > 1L, as well as postoperative organ space surgical site infections in these patients. J. Surg. Oncol. 2017;115:131-136. © 2016 Wiley Periodicals, Inc.

Utilization of Neoadjuvant Therapy for Localized Gastric Gastrointestinal Stromal Tumors and the Association with Survival.

BACKGROUND: For gastric GISTs, neoadjuvant imatinib is most often reserved for tumors near the gastroesophageal junction, multi-visceral involvement, or limited metastatic disease. Whether localized gastric GISTs benefit from neoadjuvant therapy (NAT) remains unknown. We sought to examine factors associated with NAT utilization for localized gastric GISTs and evaluate implications on survival. METHODS: The National Cancer Database identified patients with localized gastric GISTs treated with NAT (2010-2020), excluding tumors extending beyond the gastric wall, located in the cardia, or with metastatic disease. Multivariable logistic regression assessed characteristics of NAT use. After 1:1 propensity score matching, Kaplan-Meier methods and multivariable Cox regression assessed overall survival (OS). RESULTS: Of 7,203 patients, 762 (10.6%) received NAT followed by resection. On multivariable analysis, increasing tumor size was associated with NAT use (<2.0cm vs 2.0-5.0cm OR:2.03, 95%CI 1.19-3.47, p=0.010; vs >5cm OR:16.87, 95%CI 10.02-28.40, p<0.001). After propensity score matching, 1,506 patients remained. Median OS for NAT was 46.0 months vs 43.0 months for resection (p=0.059) which was independently predictive of improved survival (HR:0.89; 95%CI 0.80-0.99, p=0.041). Subgroup analysis by tumor size showed no survival differences for tumors <2.0cm or 2.0-5.0cm. Median OS was higher for tumors >5.0cm treated with NAT (NAT:45.4 months [IQR 29.5-65.9]. vs upfront resection:42.3 months [26.9-62.8]) and associated with improved survival on multivariable analysis (HR:0.88; 95%CI 0.78-0.99, p=0.040). CONCLUSION: Although patients who received NAT had improved survival, this was primarily due to tumors >5.0cm. Expanding NAT selection criteria to include localized gastric GISTs >5.0cm may improve outcomes and warrants investigation through clinical trials.

Venous Thromboembolism Chemoprophylaxis Adherence Rates After Major Cancer Surgery.

Importance: Venous thromboembolism (VTE) represents a major source of preventable morbidity and mortality and is a leading cause of death in the US after cancer surgery. Previous research demonstrated variability in VTE chemoprophylaxis prescribing, although it is unknown how these rates compare with performance in the Veterans Health Administration (VHA). Objective: To determine VTE rates after cancer surgery, as well as rates of inpatient and outpatient (posthospital discharge) chemoprophylaxis adherence within the VHA. Design, Setting, and Participants: This retrospective cohort study within 101 hospitals of the VHA health system included patients aged 41 years or older without preexisting bleeding disorders or anticoagulation usage who underwent surgical treatment for cancer with general surgery, thoracic surgery, or urology between January 1, 2015, and December 31, 2022. The VHA Corporate Data Warehouse, Pharmacy Benefits Management database, and the Veterans Affairs Surgical Quality Improvement Program database were used to identify eligible patients. Data analysis was conducted between January 2022 and July 2023. Exposures: Inpatient surgery for cancer with general surgery, thoracic surgery, or urology. Main Outcomes and Measures: Rates of postoperative VTE events within 30 days of surgery and VTE chemoprophylaxis adherence were determined. Multivariable Poisson regression was used to determine incidence-rate ratios of inpatient and postdischarge chemoprophylaxis adherence by surgical specialty. Results: Overall, 30 039 veterans (median [IQR] age, 67 [62-71] years; 29 386 men [97.8%]; 7771 African American or Black patients [25.9%]) who underwent surgery for cancer and were at highest risk for VTE were included. The overall postoperative VTE rate was 1.3% (385 patients) with 199 patients (0.7%) receiving a diagnosis during inpatient hospitalization and 186 patients (0.6%) receiving a diagnosis postdischarge. Inpatient chemoprophylaxis was ordered for 24 139 patients (80.4%). Inpatient chemoprophylaxis ordering rates were highest for patients who underwent procedures with general surgery (10 102 of 10 301 patients [98.1%]) and lowest for patients who underwent procedures with urology (11 471 of 17 089 patients [67.1%]). Overall, 3142 patients (10.5%) received postdischarge chemoprophylaxis, with notable variation by specialty. Conclusions and Relevance: These findings indicate the overall VTE rate after cancer surgery within the VHA is low, VHA inpatient chemoprophylaxis rates are high, and postdischarge VTE chemoprophylaxis prescribing is similar to that of non-VHA health systems. Specialty and procedure variation exists for chemoprophylaxis and may be justified given the low risks of overall and postdischarge VTE.

Can Enteric Fistulae in Patients with Crohn's Disease Occur in Isolation: Findings from 500 Consecutive Operative Cases.

BACKGROUND OR PURPOSE: Enteric Crohn's disease (CD) is characterized by transmural inflammation resulting in inflammatory, stricturing, or penetrating phenotypes. However, data regarding the relationship between stricturing and penetrating behavior is lacking. The incidence of penetrating CD in the absence of a stricture is unclear. The aim of this study is to assess if enteric fistulae in adult patients undergoing abdominal surgery for symptomatic CD occur in isolation. METHODS: Resection or repair of enteric CD fistulae performed in a quaternary care referral center (2009-2017) was analyzed. Fistulae associated with pelvic or continent pouch, rectal stump, or ano-vagina were excluded. Fistulae were stratified based on origin, tract, target, and relationship to stricture. Strictures were stratified as inflammatory or fibrostenotic. RESULTS: Five hundred consecutive operative reports were reviewed. A total of 490 fistulae were evaluated. Two hundred ninety-nine fistulae were in patients undergoing index surgery. Incidence of CD fistulae not associated with stricture was 14.9% in total, but only 8% in the index surgery cohort. The majority of fistulae originated from the ileum (95%). CD fistulae originating from the stomach or duodenum were not identified in the index cohort. Fistulae within an inflammatory stricture were likely to include an intra-abdominal abscess (p < 0.001). Fistulae associated with a fibrostenotic stricture were more likely to originate proximal to the stricture (p < 0.001). The incidence of fistula-associated adenocarcinoma was 0.6%. CONCLUSIONS: Symptomatic CD fistulae in the absence of stricture are uncommon. Caution should be exercised when making a diagnosis of CD in the presence of enteric fistulae, but an absence of stricture, particularly in patients with prior abdominal surgery.

An up-to-date predictive model for rectal cancer survivorship reflecting tumor biology and clinical factors.

INTRODUCTION: Our aim was to develop a nomogram taking into account factors such as tumor biology to predict overall and disease-free survival for patients with primary rectal adenocarcinoma undergoing curative intent surgical resection. METHODS: Patients undergoing resection for primary rectal adenocarcinoma (2007-2017) were included. Factors reflecting tumor biology and important clinical prognosticators were included in nomogram development. Prognostic factors were assessed with multivariable analysis using Cox regression. The impact of each was assessed using Kaplan Meier survival curves. RESULTS: Overall, 1688 patients (male, 61%) with a mean age of 59.8 years (±13.5) and a median follow-up of 34.8 months (range, 12-132) were included. The only significant factors affecting the overall and disease-free survival were age at diagnosis, pathological staging, regression grade, resection margin, and tumor deposits. CONCLUSION: The current model incorporates histopathological and clinical factors. It emphasizes the importance of tumor biological factors like tumor deposits in predicting overall and disease-free survival in rectal cancer. SUMMARY: Rectal cancer outcomes are associated with certain clinical and pathological factors that can be evaluated. Tumor deposits are one such factor that can affect overall and disease-free survival.

Curative intent resection for loco-regionally recurrent colon cancer: Cleveland clinic experience.

BACKGROUND: Locoregional colon cancer recurrence occurs in around 10% of patients following initial curative intent primary resection. We hypothesized oncological results can vary based on the recurrence site. Our aim was to determine outcomes for patients undergoing resection with curative intent for locally recurrent colon cancer. METHODS: Patients with locoregional recurrence after curative intent resection for colon cancer were identified (1999-2017). Demographics, operative details and outcome data were recorded. Kaplan-Meier method was used to compare survival differences. RESULTS: Fifty-two patients (mean age, 62) were included. The most common recurrence site was primary anastomosis (48%). R0 resection was obtained in 68%. Major morbidity occurred in 37%. Patients with anastomotic recurrence had a statistically significant overall survival compared to other sites (71.6 vs. 40.8 months respectively with a P value of 0.05). CONCLUSIONS: Excellent outcomes are possible for curative intent recurrent colon cancer surgery. The site of loco-regional recurrence plays a significant role in outcomes. Table of Contents Summary: Colon cancer recurrence can be treated surgically with optimal outcomes. Anastomotic recurrence is associated with improved survival.

Loss of TGFß signaling promotes colon cancer progression and tumor-associated inflammation.

TGFß has both tumor suppressive and tumor promoting effects in colon cancer. Also, TGFß can affect the extent and composition of inflammatory cells present in tumors, contextually promoting and inhibiting inflammation. While colon tumors display intratumoral inflammation, the contributions of TGFß to this process are poorly understood. In human patients, we found that epithelial loss of TGFß signaling was associated with increased inflammatory burden; yet overexpression of TGFß was also associated with increased inflammation. These findings were recapitulated in mutant APC models of murine tumorigenesis, where epithelial truncation of TGFBR2 led to lethal inflammatory disease and invasive colon cancer, mediated by IL8 and TGFß1. Interestingly, mutant APC mice with global suppression of TGFß signals displayed an intermediate phenotype, presenting with an overall increase in IL8-mediated inflammation and accelerated tumor formation, yet with a longer latency to the onset of disease observed in mice with epithelial TGFBR-deficiency. These results suggest that the loss of TGFß signaling, particularly in colon epithelial cells, elicits a strong inflammatory response and promotes tumor progression. This implies that treating colon cancer patients with TGFß inhibitors may result in a worse outcome by enhancing inflammatory responses.

Bariatric Surgery Among Obese Veterans: a Retrospective Review of Complications and Intermediate Term Results from a Single Institution.

BACKGROUND: The purpose of this study was to compare the results and complications among obese veterans undergoing sleeve gastrectomy and gastric bypass at a low-volume center. MATERIALS AND METHODS: This is a retrospective review of bariatric procedures performed by a single surgeon from 2009-2013. Outcomes of interest were mortality, complications, and length of stay. Weight loss and comorbidity resolution were compared between sleeve gastrectomy (SG) and Roux-y gastric bypass (RYGB). Length of stay and distance traveled to receive services were analyzed. Distributed groups were compared with Student's t test. Welch's correction was used where variances were unequal via ANOVA. Complications were compared using Fisher's exact test. RESULTS: Eighty-five patients (SG = 51, RYGB = 34) were analyzed. Postoperatively, patients were seen in clinic, contacted by phone or email, and their electronic health care records were reviewed. Average length of follow-up was 114.3 weeks. Mortality was 0 %. Complication rates were comparable between groups. The percent total weight loss was 22.6 % for the SG and 27.5 % for the RYGB (p = 0.02). The percent excess weight loss was 49 % for SG and 55 % for RYGB (p = 0.149). Percent excess body mass index (BMI) loss was 54 and 61 % (p = 0.197) for SG and RYGB, respectively. Comorbidity resolution was similar between groups except for diabetes which was superior for RYGB (p = 0.03). Veterans lived an average of 141.3 miles from our VA, and all 85 patients were able to be contacted for follow-up. CONCLUSIONS: Despite long travel distances for high-risk veterans, bariatric surgery can be performed safely even at a low-volume VA hospital with acceptable morbidity and mortality and excellent follow-up. There was no difference in morbidity or mortality between patients undergoing SG vs RYGB.

Blood Density Is Nearly Equal to Water Density: A Validation Study of the Gravimetric Method of Measuring Intraoperative Blood Loss.

Purpose. The gravimetric method of weighing surgical sponges is used to quantify intraoperative blood loss. The dry mass minus the wet mass of the gauze equals the volume of blood lost. This method assumes that the density of blood is equivalent to water (1 gm/mL). This study's purpose was to validate the assumption that the density of blood is equivalent to water and to correlate density with hematocrit. Methods. 50 µL of whole blood was weighed from eighteen rats. A distilled water control was weighed for each blood sample. The averages of the blood and water were compared utilizing a Student's unpaired, one-tailed t-test. The masses of the blood samples and the hematocrits were compared using a linear regression. Results. The average mass of the eighteen blood samples was 0.0489 g and that of the distilled water controls was 0.0492 g. The t-test showed P = 0.2269 and R (2) = 0.03154. The hematocrit values ranged from 24% to 48%. The linear regression R (2) value was 0.1767. Conclusions. The R (2) value comparing the blood and distilled water masses suggests high correlation between the two populations. Linear regression showed the hematocrit was not proportional to the mass of the blood. The study confirmed that the measured density of blood is similar to water.

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion.

Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.

Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.

PURPOSE: Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. EXPERIMENTAL DESIGN: In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. RESULTS: Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. CONCLUSIONS: This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.