Attenuated Dengue virus PV001-DV induces oncolytic tumor cell death and potent immune responses.

BACKGROUND: Viral therapies developed for cancer treatment have classically prioritized direct oncolytic effects over their immune activating properties. However, recent clinical insights have challenged this longstanding prioritization and have shifted the focus to more immune-based mechanisms. Through the potential utilization of novel, inherently immune-stimulating, oncotropic viruses there is a therapeutic opportunity to improve anti-tumor outcomes through virus-mediated immune activation. PV001-DV is an attenuated strain of Dengue virus (DEN-1 #45AZ5) with a favorable clinical safety profile that also maintains the potent immune stimulatory properties characterstic of Dengue virus infection. METHODS: In this study, we utilized in vitro tumor killing and immune multiplex assays to examine the anti-tumor effects of PV001-DV as a potential novel cancer immunotherapy. RESULTS: In vitro assays demonstrated that PV001-DV possesses the ability to directly kill human melanoma cells lines as well as patient melanoma tissue ex vivo. Importantly, further work demonstrated that, when patient peripheral blood mononuclear cells (PBMCs) were exposed to PV001-DV, a substantial induction in the production of apoptotic factors and immunostimulatory cytokines was detected. When tumor cells were cultured with the resulting soluble mediators from these PBMCs, rapid cell death of melanoma and breast cancer cell lines was observed. These soluble mediators also increased dengue virus binding ligands and immune checkpoint receptor, PD-L1 expression. CONCLUSIONS: The direct in vitro tumor-killing and immune-mediated tumor cytotoxicity facilitated by PV001-DV contributes support of its upcoming clinical evaluation in patients with advanced melanoma who have failed prior therapy.

Mediating Factors Between Race and Time to Treatment in Colorectal Cancer.

BACKGROUND: Previous disparities research has demonstrated that underrepresented racial minority patients have worse colorectal cancer outcomes and that they experience unnecessary delays in time to treatment. These delays may explain worse colorectal cancer outcomes for minority patients and serve as a marker of inequalities in our healthcare system. OBJECTIVE: This study aims to quantify the mechanisms that contribute to this disparity in treatment delay. DESIGN: This is a retrospective analysis of colorectal cancer patients who underwent elective resection from 2004 to 2017. A causal inference mediation analysis using the counterfactual framework was utilized to estimate the extent to which racial disparities among patient factors explain the racial disparities in time to treatment. Mediators included income, education, comorbidities, insurance, and hospital type. SETTINGS: This study was conducted at hospitals participating in the National Cancer Database. PATIENTS: Stage I-III colorectal cancer patients, ≥18 years old, who underwent elective resection from 2004 through 2017 were included. MAIN OUTCOMES MEASURES: The primary measures were indirect effects of mediators between race and delayed time to treatment. RESULTS: Of the 504,405 patients (370,051 colon and 134,354 rectal), 10%, 5%, and 4% were black, Hispanic, and other. In multivariable models, compared to white patients, these patients had 25%, 27%, and 17% greater odds of delayed treatment. Mediation analyses suggested that 43%, 20%, and 31% of the treatment delay among them could be removed if an intervention equalized income, education, comorbidities, insurance, and hospital type to that of white patients. Treatment at an academic hospital explained 15% to 32% of the racial disparity and was the most potent mediator. LIMITATIONS: This study was limited by its retrospective design and failure to capture all meaningful mediators. CONCLUSIONS: Black, Hispanic, and other colorectal cancer patients experience treatment delays when compared to white patients. Equalization of the mediators used in this study could reduce treatment delays by 20% to 43% depending on the racial/ethnic group. Future research should identify other causes of racial disparities in treatment delay and intervene accordingly. See Video Abstract at http://links.lww.com/DCR/B871 . FACTORES MEDIADORES ENTRE LA RAZA Y EL TIEMPO HASTA EL TRATAMIENTO EN EL CNCER COLORECTAL: ANTECEDENTES:Investigaciones anteriores sobre disparidades han demostrado que los pacientes de minorías raciales subrepresentados tienen peores resultados de cáncer colorrectal y que experimentan retrasos innecesarios en el tiempo de tratamiento. Estos retrasos pueden explicar los peores resultados del cáncer colorrectal para los pacientes de minorías y servir como un marcador de desigualdades en nuestro sistema de salud.OBJETIVO:Este estudio tiene como objetivo cuantificar los mecanismos que contribuyen a esta disparidad en el retraso del tratamiento.DISEÑO:Este es un análisis retrospectivo de pacientes con cáncer colorrectal que se sometieron a resección electiva entre 2004 y 2017. Se utilizó un análisis de mediación de inferencia causal utilizando el marco contra factual para estimar hasta qué punto las disparidades raciales entre los factores del paciente explican las disparidades raciales en el tiempo hasta el tratamiento. Los mediadores incluyeron ingresos económicos, educación, comorbilidades, seguro médico y tipo de hospital.AJUSTES:Este estudio se realizó en hospitales que participan en la Base de datos nacional del cáncer.PACIENTES:Se incluyeron pacientes con cáncer colorrectal en estadio I-III, ≥18 años, que se sometieron a resección electiva entre 2004 y 2017.PRINCIPALES RESULTADOS MEDIDAS:Las principales mediciones fueron el efecto indirecto de los mediadores entre la raza y el retraso en el tratamiento.RESULTADOS:De los 504,405 pacientes (370,051 de colon, 134,354 rectal), 10%, 5%, 4% eran negros, hispanos, y otros, respectivamente. En modelos multivariables, en comparación con los pacientes blancos, estos pacientes tenían un 25%, 27%, y 17% más de probabilidades de retrasar el tratamiento. Los análisis de medición sugirieron que el 43%, 20%, 31% del retraso del tratamiento entre, respectivamente, podría eliminarse si una intervención igualara los ingresos económicos, la educación, las comorbilidades, el seguro médico y el tipo de hospital a los de los pacientes blancos. El tratamiento en un hospital académico demostró entre el 15% y el 32% de la disparidad racial y fue el mediador más potente.LIMITACIONES:Este estudio estuvo limitado por su diseño retrospectivo; falla en capturar a todos los mediadores significativos.CONCLUSIONES:Los pacientes negros, hispanos y otros con cáncer colorrectal experimentan retrasos en el tratamiento en comparación con los pacientes blancos. La igualación de los mediadores utilizados en este estudio podría reducir los retrasos en el tratamiento en un 20-43%, según el grupo racial / étnico. Las investigaciones futuras deberían identificar otras causas de disparidades raciales en el retraso del tratamiento e intervenir sobre ellas. Consulte Video Resumen en http://links.lww.com/DCR/B871 . (Traducción-Dr. Yolanda Colorado ).

Associations of Race, Ethnicity, and Social Determinants of Health With Colorectal Cancer Screening.

BACKGROUND: Racial and ethnic disparities in receipt of recommended colorectal cancer screening exist; however, the impact of social determinants of health on such disparities has not been recently studied in a national cohort. OBJECTIVE: This study aimed to determine whether social determinants of health attenuate racial disparities in receipt of colorectal cancer screening. DESIGN: This was a cross-sectional telephone survey of self-reported race and ethnicity and up-to-date colorectal cancer screening. Associations between race/ethnicity and colorectal cancer screening were tested before and after adjustment for demographics, behavioral factors, and social determinants of health. SETTING: This was a nationally representative telephone survey of US residents in 2018. PATIENTS: The patients included were US residents aged 50 to 75 years. MAIN OUTCOME MEASURES: The primary outcome was up-to-date colorectal cancer screening status, according to 2008 US Preventive Services Task Force recommendations. RESULTS: This study included 226,106 respondents aged 50 to 75 years. Before adjustment, all minority racial and ethnic groups demonstrated a significantly lower odds of screening than those of non-Hispanic white respondents. After adjustment for demographics, behavioral factors, and social determinants of health, compared to non-Hispanic white respondents, odds of screening were found to be increased among non-Hispanic black respondents (OR, 1.10; p = 0.02); lower but attenuated among Hispanic respondents (OR, 0.73; p < 0.001), non-Hispanic American Indian/Alaskan Native respondents (OR, 0.85; p = 0.048), and non-Hispanic respondents of other races (OR, 0.82; p = 0.01); and lower but not attenuated among non-Hispanic Asian respondents (OR, 0.68; p < 0.001). LIMITATIONS: Recall bias, participant bias, and residual confounding. CONCLUSIONS: Adjustment for social determinants of health reduced racial and ethnic disparities in colorectal cancer screening among all minority racial and ethnic groups except non-Hispanic Asian individuals; however, other unmeasured confounders likely exist. See Video Abstract at http://links.lww.com/DCR/B977 . ASOCIACIN DE RAZA, ETNICIDAD Y DETERMINANTES SOCIALES DE LA SALUD CON LA DETECCIN DEL CNCER COLORRECTAL: ANTECEDENTES: Existen disparidades raciales y étnicas en la recepción de las pruebas recomendadas de detección de cáncer colorrectal; sin embargo, el impacto de los determinantes sociales de la salud en dichas disparidades no se ha estudiado recientemente en una cohorte nacional.OBJETIVO: El objetivo de este estudio fue determinar si los determinantes sociales de la salud atenúan las disparidades raciales en la recepción de pruebas de detección del cáncer colorrectal.DISEÑO: Encuesta telefónica transversal de raza y etnia autoinformada y detección actualizada de cáncer colorrectal. Las asociaciones entre la raza/etnicidad y la detección del cáncer colorrectal se probaron antes y después del ajuste por demografía, factores conductuales y determinantes sociales de la salud.ESCENARIO: Esta fue una encuesta telefónica representativa a nivel nacional de los residentes de EE. UU. en 2018.PACIENTES: Los pacientes eran residentes de EE. UU. de 50 a 75 años.PRINCIPALES MEDIDAS DE RESULTADO: Estado actualizado de detección de cáncer colorrectal, según las recomendaciones del Grupo de Trabajo de Servicios Preventivos de EE. UU. de 2008.RESULTADOS: Este estudio incluyó a 226.106 encuestados de 50 a 75 años. Antes del ajuste, todos los grupos étnicos y raciales minoritarios demostraron probabilidades significativamente más bajas de detección en comparación con los encuestados blancos no hispanos. Después del ajuste por demografía, factores conductuales y determinantes sociales de la salud, en comparación con los encuestados blancos no hispanos, las probabilidades de detección aumentaron entre los encuestados negros no hispanos (OR 1,10, p = 0,02); más bajo pero atenuado entre los encuestados hispanos (OR 0,73, p < 0,001), los encuestados indios americanos/nativos de Alaska no hispanos (OR 0,85, p = 0,048) y los encuestados no hispanos de otras razas (OR 0,82, p = 0,01); y menor pero no atenuado entre los encuestados asiáticos no hispanos (OR 0,68, p < 0,001).LIMITACIONES: Sesgo de recuerdo y sesgo de participante, así como confusión residual.CONCLUSIONES: El ajuste para los determinantes sociales de la salud redujo las disparidades raciales y étnicas en la detección del cáncer colorrectal entre todos los grupos étnicos y raciales minoritarios, excepto las personas asiáticas no hispanas; sin embargo, es probable que existan otros factores de confusión no medidos. Consulte Video Resumen en http://links.lww.com/DCR/B977 . (Traducción-Dr. Felipe Bellolio ).

Laser Ablation of Pilonidal Sinus Disease: A Pilot Study.

BACKGROUND: Pilonidal disease is classically treated with wide local excision, although a number of minimally invasive approaches are currently under investigation. We aimed to determine the safety and feasibility of laser ablation of pilonidal sinus disease. IMPACT OF INNOVATION: Laser ablation provides a minimally invasive means of obliterating pilonidal sinus tracts without a need for excessive tract dilation. Laser ablation can be performed more than once on the same patient if necessary. TECHNOLOGY MATERIALS AND METHODS: This technique uses the NeoV V1470 Diode Laser (neoLaser Ltd, Caesarea, Israel) with a 2-mm probe. We performed laser ablation in adults and pediatric patients. PRELIMINARY RESULTS: We performed 27 laser ablation procedures in 25 patients, with a median operative time of 30 minutes. Eighty percent of patients reported either no pain or mild pain at the 2-week postoperative visit. The median time to return to work or school was 3 days. Eighty-eight percent of patients reported being satisfied or very satisfied with the procedure at their most recent follow-up (median, 6 mo). Eighty-two percent of patients were healed at 6 months. CONCLUSIONS AND FUTURE DIRECTIONS: Laser ablation of pilonidal disease is safe and feasible. Patients experienced short recovery time and reported low levels of pain and high levels of satisfaction.

Prophylactic antireflux procedures are not necessary in neurologically impaired children undergoing gastrostomy placement.

PURPOSE: Fundoplication is frequently used in children with neurologic impairment even in the absence of reflux due to concerns for future gastric feeding intolerance, but supporting data are lacking. We aimed to determine the incidence of secondary antireflux procedures (fundoplication or gastrojejunostomy (GJ)) post gastrostomy tube (GT) placement in children with and without neurologic impairment. METHODS: Children under 18 undergoing a GT placement without fundoplication between 2010 and 2020 were identified utilizing the PearlDiver Mariner national patient claims database. Children with a diagnosis of cerebral palsy or a degenerative neurologic disease were identified and compared to children without these diagnoses. The incidence of delayed fundoplication or conversion to GJ were compared utilizing Kaplan-Meier and Cox proportional hazards regression analyses. RESULTS: A total of 14,965 children underwent GT placement, of which 3712 (24.8%) had a diagnosis of neurologic impairment. The rate of concomitant fundoplication was significantly higher among children with a diagnosis of neurologic impairment as compared to those without (9.3% vs 6.4%, p < 0.001). While children with neurologic impairment had a significantly higher rate of fundoplication or GJ conversion at 5 years compared to children without (12.6% [95% confidence interval (CI): 11.4%-13.8%] vs 8.6% [95% CI 8.0%-9.2%], p < 0.001), the overall incidence remained low. CONCLUSION: Although children with neurologic impairment have a higher rate of requiring an antireflux procedure or GJ conversion than other children, the overall rate remains less than 15%. Fundoplication should not be utilized in children without clinical reflux on the basis of neurologic impairment alone.

Outcomes of Laparoscopic Versus Open Resection of Meckel's Diverticulum.

BACKGROUND: Meckel's Diverticulum (MD) is a common congenital anomaly accounting for half of pediatric gastrointestinal bleeds. No large-scale studies exist comparing open and laparoscopic surgery and conversion rates remain high. We sought to compare postoperative outcomes associated with each approach and to determine risk factors for conversion. MATERIALS AND METHODS: NSQIP-Pediatric was used to identify patients who underwent a MD resection from 2012 to 2018. Outcomes between patients treated with a laparoscopic versus open versus laparoscopic converted to open (LCO) surgery were compared. Chi-square tests and adjusted logistic regression analysis were used to determine significance and factors associated with conversion. RESULTS: Six hundred eighty-one patients were identified, 295 (43.3%) underwent open, 267 (39.2%) laparoscopic, and 119 (17.5%) LCO resection. Patients undergoing laparoscopic compared to open procedures had shorter length of stay (LOS; 3 versus 4, P= 0.009), and similar morbidities (10.5% versus 16.6%, P= 0.164) and operative times (71.6 versus 76.6 mins, P= 0.449) on adjusted analysis. Patients with LCO compared to open procedures had similar LOS (4 versus 4, P= 0.334) and morbidities (14.3% versus 16.6%, P= 0.358), but longer operative times (90.1 versus 76.6 mins, P= 0.002) on adjusted analysis. Patients with laparoscopic and LCO procedures had fewer unplanned intubations compared to open procedures (0.0% versus 0.0% versus 2.4%, P= 0.011) and lower mortality (0.0% versus 0.0% versus 1.7%, P= 0.046) on univariate analysis. CONCLUSIONS: Laparoscopic MD resection has shorter LOS and similar complications and operative time compared to an open approach while LCO resection increases operative time but not LOS or morbidities.

Enhancing Medical Students' Interprofessional Teamwork Through Simulated Room of Errors Experience.

BACKGROUND: Fostering medical students' appreciation for team members particularly those from other disciplines with varying levels of experience promotes a promising beginning to a health care career. METHODS: During surgical clerkship orientation, third-year medical students completed 30-item TeamSTEPPS Teamwork Attitudes Questionnaire preintervention and postintervention, spent 7 min identifying errors in a simulated operating room, followed by recorded physician-led 30-min discussions. RESULTS: Postintervention (67) compared with preintervention (141) mean TeamSTEPPS Teamwork Attitudes Questionnaire domain scores were statistically significantly higher for team structure (4.59, 4.70; P = 0.03) and higher but not significant for leadership (4.74, 4.75; P = 0.86), situation monitoring (4.62, 4.68; P = 0.32), communication (4.40, 4.50; P = 0.14), and decreased for mutual support (4.43, 4.36; P = 0.43). Medical students identified 2%-93% of 33 staged errors and 291 additional errors, which were placed into 14 categories. Soiled gloves in the operative field and urinary bag on the floor were the most frequently identified staged errors. Experienced nurses compared with medical students identified significantly more errors (mean, 17.7 versus 11.7, respectively; P < 0.001). Recognizing errors when lacking familiarity with the operative environment and appreciating teammates' perspectives were themes that emerged from discussions. CONCLUSIONS: This well-received teamwork exercise enabled medical students to appreciate team members' contributions and other disciplines' perspectives, in addition to the synergy that occurs with multidisciplinary teams.

Fewer thromboembolic events after implementation of a venous thromboembolism risk stratification tool.

BACKGROUND: Deep venous thrombosis and pulmonary embolus are leading preventable causes of death after surgery. Venous thromboembolism (VTE) prophylaxis management guidelines, with evidenced-based recommendations, are available in the literature. However, over 40% of "at-risk" surgical patients fail to receive appropriate VTE prophylaxis. Decision support-based interventions to reduce venous thromboembolic events were explored. METHODS: A venous thromboembolic risk stratification tool embedded in the electronic medical record, Epic, linking risk category to venous thromboembolic prophylaxis order sets was created, implemented, and analyzed for general surgery patients. Logistic regression analysis was used to compare rates of venous thromboembolic events before and after the intervention, controlling for age, gender, race, body mass index, inpatient status, transfer status, elective/emergent case status, American Society of Anesthesiologists classification, and wound classification. RESULTS: Venous thromboembolic events in the preintervention and postintervention periods were 55 (1.25%) and 12 (0.64%), respectively (P = 0.033). All-cause mortality events decreased after intervention from 49 (1.12%) to 14 (0.75%; P = 0.187). Multivariable analyses show that the risk of a venous thromboembolic event after intervention was half (odds ratio = 0.532; 95% confidence interval, 0.284-0.997; P = 0.049) as likely compared to that in the preintervention period. From 2012 to 2015, our institution moved from the ninth decile (poor) to the first decile (best) for the incidence of venous thromboembolic events among 760 National Surgical Quality Improvement Program hospitals across the nation. CONCLUSIONS: Postoperative thromboembolic events decreased after implementation of a VTE risk stratification tool, linking risk category to venous thromboembolic prophylaxis order sets, embedded in the electronic medical record, Epic.

Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma.

Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to the lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti-tumour efficacy of chemotherapy. Gemcitabine and all-trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSCs) respectively, in 3D organotypic culture models and genetically engineered mice (LSL-Kras(G12D) (/+) ;LSL-Trp53(R172H) (/+) ;Pdx-1-Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extracellular matrix proteins such as collagen and fibronectin) and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid, and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial-mesenchymal transition, cellular polarity, and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co-targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour-stroma cross-talk, rather than ablating stroma or targeting a single pathway. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Fecal Metabolome in Hmga1 Transgenic Mice with Polyposis: Evidence for Potential Screen for Early Detection of Precursor Lesions in Colorectal Cancer.

Because colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, more accessible screening tests are urgently needed to identify early stage lesions. We hypothesized that highly sensitive, metabolic profile analysis of stool samples will identify metabolites associated with early stage lesions and could serve as a noninvasive screening test. We therefore applied traveling wave ion mobility mass spectrometry (TWIMMS) coupled with ultraperformance liquid chromatography (UPLC) to investigate metabolic aberrations in stool samples in a transgenic model of premalignant polyposis aberrantly expressing the gene encoding the high mobility group A (Hmga1) chromatin remodeling protein. Here, we report for the first time that the fecal metabolome of Hmga1 mice is distinct from that of control mice and includes metabolites previously identified in human CRC. Significant alterations were observed in fatty acid metabolites and metabolites associated with bile acids (hypoxanthine xanthine, taurine) in Hmga1 mice compared to controls. Surprisingly, a marked increase in the levels of distinctive short, arginine-enriched, tetra-peptide fragments was observed in the transgenic mice. Together these findings suggest that specific metabolites are associated with Hmga1-induced polyposis and abnormal proliferation in intestinal epithelium. Although further studies are needed, these data provide a compelling rationale to develop fecal metabolomic analysis as a noninvasive screening tool to detect early precursor lesions to CRC in humans.

The prehospital and hospital costs of emergency care for frequent ED patients.

INTRODUCTION: Frequent emergency department (ED) use has been identified as a cause of ED overcrowding and increasing health care costs. Studies have examined the expense of frequent patients (FPs) to hospitals but have not added the cost Emergency Medical Services (EMS) to estimate the total cost of this pattern of care. METHODS: Data on 2012 ED visits to a rural Level I Trauma Center and public safety net hospital were collected through a deidentified patient database. Transport data and 2012 Medicare Reimbursement Schedules were used to estimate the cost of EMS transport. Health information, outcomes, and costs were compared to find differences between the FP and non-FP group. RESULTS: This study identified 1242 FPs who visited the ED 5 or more times in 2012. Frequent patients comprised 3.25% of ED patients but accounted for 17% of ED visits and 13.7% of hospital costs. Frequent patients had higher rates of chronic disease, severity scores, and mortality. Frequent patients arrived more often via ambulance and accounted for 32% of total transports at an estimated cost of $2.5-$3.2 million. Hospital costs attributable to FPs were $29.1 million, bringing the total cost of emergency care to $31.6-$32.3 million, approximately $25,000 per patient. CONCLUSIONS: This study demonstrates that the inclusion of a prehospital cost estimate adds approximately 10% to the cost of care for the FP population. In addition to improving care for a sick population of patients, programs that reduce frequent EMS and ED use have the potential to produce a favorable cost benefit to communities and health systems.

HMGA1 drives metabolic reprogramming of intestinal epithelium during hyperproliferation, polyposis, and colorectal carcinogenesis.

Although significant progress has been made in the diagnosis and treatment of colorectal cancer (CRC), it remains a leading cause of cancer death worldwide. Early identification and removal of polyps that may progress to overt CRC is the cornerstone of CRC prevention. Expression of the High Mobility Group A1 (HMGA1) gene is significantly elevated in CRCs as compared with adjacent, nonmalignant tissues. We investigated metabolic aberrations induced by HMGA1 overexpression in small intestinal and colonic epithelium using traveling wave ion mobility mass spectrometry (TWIMMS) in a transgenic model in which murine Hmga1 was misexpressed in colonic epithelium. To determine if these Hmga1-induced metabolic alterations in mice were relevant to human colorectal carcinogenesis, we also investigated tumors from patients with CRC and matched, adjacent, nonmalignant tissues. Multivariate statistical methods and manual comparisons were used to identify metabolites specific to Hmga1 and CRC. Statistical modeling of data revealed distinct metabolic patterns in Hmga1 transgenics and human CRC samples as compared with the control tissues. We discovered that 13 metabolites were specific for Hmga1 in murine intestinal epithelium and also found in human CRC. Several of these metabolites function in fatty acid metabolism and membrane composition. Although further validation is needed, our results suggest that high levels of HMGA1 protein drive metabolic alterations that contribute to CRC pathogenesis through fatty acid synthesis. These metabolites could serve as potential biomarkers or therapeutic targets.

Characterizing metabolic changes in human colorectal cancer.

Colorectal cancer (CRC) remains a leading cause of cancer death worldwide, despite the fact that it is a curable disease when diagnosed early. The development of new screening methods to aid in early diagnosis or identify precursor lesions at risk for progressing to CRC will be vital to improving the survival rate of individuals predisposed to CRC. Metabolomics is an advancing area that has recently seen numerous applications to the field of cancer research. Altered metabolism has been studied for many years as a means to understand and characterize cancer. However, further work is required to establish standard procedures and improve our ability to identify distinct metabolomic profiles that can be used to diagnose CRC or predict disease progression. The present study demonstrates the use of direct infusion traveling wave ion mobility mass spectrometry to distinguish metabolic profiles from CRC samples and matched non-neoplastic epithelium as well as metastatic and primary tumors at different stages of disease (T1-T4). By directly infusing our samples, the analysis time was reduced significantly, thus increasing the speed and efficiency of this method compared to traditional metabolomics platforms. Partial least squares discriminant analysis was used to visualize differences between the metabolic profiles of sample types and to identify the specific m/z features that led to this differentiation. Identification of the distinct m/z features was made using the human metabolome database. We discovered alterations in fatty acid biosynthesis and oxidative, glycolytic, and polyamine pathways that distinguish tumors from non-malignant colonic epithelium as well as various stages of CRC. Although further studies are needed, our results indicate that colonic epithelial cells undergo metabolic reprogramming during their evolution to CRC, and the distinct metabolites could serve as diagnostic tools or potential targets in therapy or primary prevention. Graphical Abstract Colon tissue biopsy samples were collected from patients after which metabolites were extracted via sonication. Two-dimensional data were collected via IMS in tandem with MS (IMMS). Data were then interpreted statistically via PLS-DA. Scores plots provided a visualization of statistical separation and groupings of sample types. Loading plots allowed identification of influential ion features. Lists of these features were exported and analyzed for specific differences. Direct comparisons of the ion features led to the identification and comparative analyses of candidate biomarkers. These differences were then expressed visually in charts and tables.

VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children.

Although genetic and environmental factors explain approximately half of the interindividual variability in warfarin dose requirement in adults, there is limited information available in children. In a cross-sectional study of anticoagulated children from 5 tertiary care centers, 120 children with a stable warfarin dose were genotyped for VKORC1 (-1639G > A; rs9923231), CYP2C9 (*2 and *3 alleles; rs1799853 and rs1057910), and CYP4F2 (V433M; rs2108622) polymorphisms. Clinical and demographic features were recorded. Multiple regression analysis of the data showed that, although CYP4F2 made no contribution to the dose model, 72.4% of the variability in warfarin dose requirement is attributed to by patient height, genetic polymorphisms in VKORC1 and CYP2C9, and indication for warfarin. The recently published International Warfarin Pharmacogenetics Consortium pharmacogenetic-based warfarin dosing algorithm (based on data derived from anticoagulated adults) consistently overestimated warfarin dose for our cohort of children. A similar proportion of the interindividual variability in warfarin dose is explained by genetic factors in children compared with adult patients, although height is a greater predictor in children. A pharmacogenomic approach to warfarin dosing has the potential to improve the efficacy and safety of warfarin therapy in children. However, algorithms should be derived from data in children if their potential benefit is to be realized.

Extended sacropelvic resection for locally recurrent rectal cancer: can it be done safely and with good oncologic outcomes?

BACKGROUND: A multimodality approach to patients with locally recurrent rectal cancer that includes surgery is associated with a significant survival advantage when tumor-free margins are achieved. Patients with advanced tumors will require extended sacropelvic resection to optimize oncologic outcomes. OBJECTIVE: The aim of this study was to assess the safety, feasibility, and oncologic outcomes of extended sacropelvic resection for locally recurrent rectal cancer at our institution. DESIGN: A retrospective review identified 406 patients who had surgery for locally recurrent rectal cancer between 1997 and 2007. From this group, all patients who underwent a curative-intent sacropelvic resection were analyzed. SETTINGS: This investigation was conducted at an academic tertiary referral center. PATIENTS: Thirty patients (24 male) were identified. Median age was 59 years (range, 25-84). Operations were performed for a first local recurrence (n = 24), a second recurrence (n = 5) and for a third recurrence (n = 1). INTERVENTIONS: Twenty-six patients underwent neoadjuvant radiation, and 20 received intraoperative radiation therapy. All patients underwent extended sacropelvic resection. MAIN OUTCOME MEASURES: The primary outcomes measured were early (<30 days) and late (>30 days) surgical complications. Overall and disease-free survivals were estimated by using the Kaplan-Meier technique. RESULTS: Margin-negative resection was achieved in 93%. The most proximal level of spinal transection was the fourth lumbar space, and 4 patients underwent lower extremity amputation. There was no mortality, and early morbidity was seen in 76%. Median follow-up was 2.7 years (range, 2 months to 10.8 years). Overall survival at 2 and 5 years was 86% and 46%. Disease-free survival at 2 and 5 years was 79% and 43%. LIMITATIONS: This study was limited by its retrospective nature and the limited number of patients. CONCLUSIONS: We found extended sacropelvic resection for locally recurrent rectal cancer to be feasible and safe with overall and disease-free survival rates in comparison with survival rates seen in patients undergoing nonsacropelvic resections for locally recurrent rectal cancer.

Evaluation of telemedicine for screening of diabetic retinopathy in the Veterans Health Administration.

OBJECTIVE: To explore the cost-effectiveness of telemedicine for the screening of diabetic retinopathy (DR) and identify changes within the demographics of a patient population after telemedicine implementation. DESIGN: A retrospective medical chart review (cohort study) was conducted. PARTICIPANTS: A total of 900 type 1 and type 2 diabetic patients enrolled in a medical system with a telemedicine screening program for DR. METHODS: The cost-effectiveness of the DR telemedicine program was determined by using a finite-horizon, discrete time, discounted Markov decision process model populated by parameters and testing frequency obtained from patient records. The model estimated the progression of DR and determined average quality-adjusted life years (QALYs) saved and average additional cost incurred by the telemedicine screening program. MAIN OUTCOME MEASURES: Diabetic retinopathy, macular edema, blindness, and associated QALYs. RESULTS: The results indicate that telemedicine screening is cost-effective for DR under most conditions. On average, it is cost-effective for patient populations of >3500, patients aged <80 years, and all racial groups. Observable trends were identified in the screening population since the implementation of telemedicine screening: the number of known DR cases has increased, the overall age of patients receiving screenings has decreased, the percentage of nonwhites receiving screenings has increased, the average number of miles traveled by a patient to receive a screening has decreased, and the teleretinal screening participation is increasing. CONCLUSIONS: The current teleretinal screening program is effective in terms of being cost-effective and increasing population reach. Future screening policies should give consideration to the age of patients receiving screenings and the system's patient pool size because our results indicate it is not cost-effective to screen patients aged older than 80 years or in populations with <3500 patients.

Metabolomics of colorectal cancer: past and current analytical platforms.

Metabolomics is coming of age as an important area of investigation which may help reveal answers to questions left unanswered or only partially understood from proteomic or genomic approaches. Increased knowledge of the relationship of genes and proteins to smaller biomolecules (metabolites) will advance our ability to diagnose, treat, and perhaps prevent cancer and other diseases that have eluded scientists for generations. Colorectal tumors are the second leading cause of cancer mortality in the USA, and the incidence is rising. Many patients present late, after the onset of symptoms, when the tumor has spread from the primary site. Once metastases have occurred, the prognosis is significantly worse. Understanding alterations in metabolic profiles that occur with tumor onset and progression could lead to better diagnostic tests as well as uncover new approaches to treat or even prevent colorectal cancer (CRC). In this review, we explore the various analytical technologies that have been applied in CRC metabolomics research and summarize all metabolites measured in CRC and integrate them into metabolic pathways. Early studies with nuclear magnetic resonance and gas-chromatographic mass spectrometry suggest that tumor cells are characterized by aerobic glycolysis, increased purine metabolism for DNA synthesis, and protein synthesis. Liquid chromatography, capillary electrophoresis, and ion mobility, each coupled with mass spectrometry, promise to advance the field and provide new insight into metabolic pathways used by cancer cells. Studies with improved technology are needed to identify better biomarkers and targets for treatment or prevention of CRC.

Accuracy of Surgeon and Patient Estimated Cost and Reimbursement for Common General Surgical Operations and Benefit of Centers for Medicare and Medicaid Services Price Transparency Rules.

BACKGROUND: On January 1, 2021, the Centers for Medicare and Medicaid Services implemented a hospital price transparency rule. Consumerism as a means of reducing healthcare expenditure is predicated on informed consumers making discrete choices. STUDY DESIGN: For 10 months, immediately after a preoperative clinic visit at an academic medical center, patients and their surgeons were surveyed regarding their estimation of hospital cost and hospital reimbursement for the upcoming operation. Responses were compared to average institutional cost (fiscal year 2019) for Medicare patients undergoing a laparoscopic approach for each operation. We calculated the difference between actual reimbursement and cost with patients' estimates and actual reimbursement and cost with surgeons' estimates. RESULTS: Sixty-six questionnaires were collected from patients who underwent laparoscopic operations, that included cholecystectomy (n = 20), inguinal hernia (n = 17), umbilical hernia repair (n = 6), ventral hernia repair (n = 6), incisional hernia (n = 6), hiatal hernia repair (n = 1), and lipoma or cyst excision (n = 10). Patients' estimates of hospital cost exceeded actual hospital cost by a median of $4,502 and were less than hospital reimbursement by a median of $1,834. Surgeon estimates for direct cost were $825 less than hospital direct cost and $1,659 less than hospital reimbursement. CONCLUSIONS: Patients as well as their surgeons do not estimate healthcare cost or remuneration accurately and therefore will be ineffective change agents in reducing surgical spending based on price transparency without further education of both parties. Patients consistently overestimated surgical cost while surgeons consistently underestimated surgical cost and reimbursement. It is likely that better-informed surgeons and patients are necessary prerequisites for Centers for Medicare and Medicaid Services price transparency rules to be effective in reducing Medicare expenditures in surgery.