Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at distal regulatory elements to regulate human neural differentiation.

Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression, though mechanisms through which pioneer transcription factors remodel chromatin remain unclear. Here, using single-cell transcriptomics, we show that endogenous expression of neurogenic transcription factor ASCL1, considered a classical pioneer factor, defines a transient population of progenitors in human neural differentiation. Testing ASCL1's pioneer function using a knockout model to define the unbound state, we found that endogenous expression of ASCL1 drives progenitor differentiation by cis-regulation both as a classical pioneer factor and as a nonpioneer remodeler, where ASCL1 binds permissive chromatin to induce chromatin conformation changes. ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor, and we provide evidence for codependent DNA binding and remodeling at a subset of ASCL1 and SWI/SNF cotargets. Our findings provide new insights into ASCL1 function regulating activation of long-range regulatory elements in human neurogenesis and uncover a novel mechanism of its chromatin remodeling function codependent on partner ATPase activity.

Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD.

Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.

Trends and Determinants of Location of Death Due to Colorectal Cancer in the United States : A Nationwide Study.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States (US); however, there are limited data on location of death in patients who die from CRC. We examined the trends in location of death and determinants in patients dying from CRC in the US. METHODS: We utilized the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database to extract nationwide data on underlying cause of death as CRC. A multinomial logistic regression was performed to assess associations between clinico-sociodemographic characteristics and location of death. RESULTS: There were 850,750 deaths due to CRC from 2003 to 2019. There was a gradual decrease in deaths in hospital, nursing home, or outpatient facility/emergency department over time and an increase in deaths at home and in hospice. Relative to White decedents, Black, Asian, and American Indian/Alaska Native decedents were less likely to die at home and in hospice compared with hospitals. Individuals with lower educational status also had a lower risk of dying at home or in hospice compared with in hospitals. CONCLUSIONS: The gradual shift in location of death of patients who die of CRC from institutionalized settings to home and hospice is a promising trend and reflects the prioritization of patient goals for end-of-life care by healthcare providers. However, there are existing sociodemographic disparities in access to deaths at home and in hospice, which emphasizes the need for policy interventions to reduce health inequity in end-of-life care for CRC.

Incidence of Secondary Cancers After Neoadjuvant Therapy for Locally Advanced Rectal Cancer.

INTRODUCTION: Whether neoadjuvant chemoradiation for locally advanced rectal cancer (LARC) induces secondary cancers is controversial. This retrospective cohort study describes the incidence of secondary cancers in LARC patients. METHODS: We compared 364 LARC patients who received conventional (50.4 Gy) or short course neoadjuvant radiation (25 Gy x 5 fractions) followed by resection to 142 patients with surgically resected rectal cancer who did not receive radiation at a single institution from 2004 to 2018. Secondary cancer was defined as any nonmetastatic noncolorectal malignancy diagnosed via biopsy or definitive imaging criteria at least 6 mo after completion of neoadjuvant therapy or after resection in the comparison group. RESULTS: Among the neoadjuvant radiation group (364 patients, 40% female, age 61 ± 13 y), 32 patients developed 34 (9.3%) secondary cancers. Three cases involved a pelvic organ. Among the comparison group (142 patients, 39% female, age 64 ± 15 y), 15 patients (10.6%) developed a secondary cancer. Five cases involved pelvic organs. Secondary cancer incidence did not differ between groups. Latency period to secondary cancer diagnosis was 6.7 ± 4.3 y. Patients who received radiation underwent longer median follow-up (6.8 versus 4.5 y, P < 0.01) and were significantly less likely to develop a pelvic organ cancer (odds ratio 0.18; 95% confidence interval, 0.04-0.83; P = 0.02). No genetic mutations or cancer syndromes were identified among patients with secondary cancers. CONCLUSIONS: Neoadjuvant chemoradiation is not associated with increased secondary cancer risk in LARC patients and may have a local protective effect on pelvic organs, especially prostate. Ongoing follow-up is critical to continue risk assessment.

Outcomes comparison of robotic-assisted versus laparoscopic and open surgery for patients undergoing rectal cancer resection with concurrent stoma creation.

BACKGROUND: Despite widespread adoption of robotic-assisted surgery (RAS) in rectal cancer resection, there remains limited knowledge of its clinical advantage over laparoscopic (Lap) and open (OS) surgery. We aimed to compare clinical outcomes of RAS with Lap and OS for rectal cancer. METHODS: We identified all patients aged ≥ 18 years who had elective rectal cancer resection requiring temporary or permanent stoma formation from 1/2013 to 12/2020 from the PINC AI™ Healthcare Database. We completed multivariable logistic regression analysis accounting for hospital clustering to compare ileostomy formation between surgical approaches. Next, we built inverse probability of treatment-weighted analyses to compare outcomes for ileostomy and permanent colostomy separately. Outcomes included postoperative complications, in-hospital mortality, discharge to home, reoperation, and 30-day readmission. RESULTS: A total of 12,787 patients (OS: 5599 [43.8%]; Lap: 2872 [22.5%]; RAS: 4316 [33.7%]) underwent elective rectal cancer resection. Compared to OS, patients who had Lap (OR 1.29, p < 0.001) or RAS (OR 1.53, p < 0.001) were more likely to have an ileostomy rather than permanent colostomy. In those with ileostomy, RAS was associated with fewer ileus (OR 0.71, p < 0.001) and less bleeding (OR 0.50, p < 0.001) compared to Lap. In addition, RAS was associated with lower anastomotic leak (OR 0.25, p < 0.001), less bleeding (OR 0.51, p < 0.001), and fewer blood transfusions (OR 0.70, p = 0.022) when compared to OS. In those patients who had permanent colostomy formation, RAS was associated with fewer ileus (OR 0.72, p < 0.001), less bleeding (OR 0.78, p = 0.021), lower 30-day reoperation (OR 0.49, p < 0.001), and higher discharge to home (OR 1.26, p = 0.013) than Lap, as well as OS. CONCLUSION: Rectal cancer patients treated with RAS were more likely to have an ileostomy rather than a permanent colostomy and more enhanced recovery compared to Lap and OS.

Oncologic outcomes following transanal total mesorectal excision: the United States experience.

AIM: The benefits and short-term outcomes of transanal total mesorectal excision (taTME) for rectal cancer have been demonstrated previously, but questions remain regarding the oncologic outcomes following this challenging procedure. The purpose of this study was to analyze the oncologic outcomes following taTME at high-volume centers in the USA. METHODS: This was a multicenter, retrospective observational study of 8 tertiary care centers. All consecutive taTME cases for primary rectal cancer performed between 2011 and 2020 were included. Clinical, histopathologic, and oncologic data were analyzed. Primary endpoints were rate of local recurrence, distal recurrence, 3-year disease recurrence, and 3-year overall survival. Secondary endpoints included perioperative complications and TME specimen quality. RESULTS: A total of 391 patients were included in the study. The median age was 57 years (IQR: 49, 66), 68% of patients were male, and the median BMI was 27.4 (IQR: 24.1, 31.0). TME specimen was complete or near complete in 94.5% of cases and the rates of positive circumferential radial margin and distal resection margin were 2.0% and 0.3%, respectively. Median follow-up time was 30.7 months as calculated using reverse-KM estimator (CI 28.1-33.8) and there were 9 cases (2.5%) of local recurrence not accounting for competing risk. The 3-year estimated rate of disease recurrence was 19% (CI 15-25%) and the 3-year estimated overall survival was 90% (CI 87-94%). CONCLUSION: This large multicenter study confirms the oncologic safety and perioperative benefits of taTME for rectal cancer when performed by experienced surgeons at experienced referral centers.

Implementation of a New Surgeon Onboarding Program in an Academic-affiliated Community Hospital.

Best practices in onboarding are well-established, but surgeons frequently receive suboptimal introductions to new practice settings. At the same time, increasing regionalization of surgical programs and strategic alignments between academic and community hospitals have increased the demand for surgeons to practice at multiple sites with variable resources and institutional cultures. In response to this growing problem, we developed and implemented a surgeon onboarding program in an academic-affiliated community hospital. This pilot demonstrated excellent process adherence, user satisfaction, and significant improvements in preparedness to practice. We therefore conclude that robust onboarding is feasible and can be readily implemented by a local team to promote safe transitions in practice settings for surgeons.

Stratification of Stage II Colon Cancer Using Recurrence Prediction Value: A Multi-institutional International Retrospective Study.

OBJECTIVE: To create a recurrence prediction value (RPV) of high-risk factor and identify the patients with high risk of cancer recurrence. SUMMARY BACKGROUND DATA: There are several high-risk factors known to lead to poor outcomes. Weighting each high-risk factor based on their association with increased risk of cancer recurrence can provide a more precise understanding of risk of recurrence. METHODS: We performed a multi-institutional international retrospective analysis of patients with Stage II colon cancer patients who underwent surgery from 2010 to 2020. Patient data from a multi-institutional database were used as the Training data, and data from a completely separate international database from two countries were used as the Validation data. The primary endpoint was recurrence-free survival (RFS). RESULTS: A total of 739 patients were included from Training data. To validate the feasibility of RPV, 467 patients were included from Validation data. Training data patients were divided into RPV low (n = 564) and RPV high (n = 175). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (Hazard ratio (HR) 2.628; 95% confidence interval (CI) 1.887-3.660; P < 0.001). Validation data patients were divided into two groups (RPV low, n = 420) and RPV high (n = 47). Multivariate analysis revealed that risk of recurrence was significantly higher in the RPV high than the RPV low (HR 3.053; 95% CI 1.962-4.750; P < 0.001). CONCLUSIONS: RPV can identify Stage II colon cancer patients with high risk of cancer recurrence world-wide.

Promoting spontaneous analogical transfer by idealizing target representations.

Recent results demonstrate that inducing an abstract representation of target analogs at retrieval time aids access to analogous situations with mismatching surface features (i.e., the late abstraction principle). A limitation of current implementations of this principle is that they either require the external provision of target-specific information or demand very high intellectual effort. Experiment 1 demonstrated that constructing an idealized situation model of a target problem increases the rate of correct solutions compared with constructing either concrete simulations or no simulations. Experiment 2 confirmed that these results were based on an advantage for accessing the base analog, and not merely an advantage of idealized simulations for understanding the target problem in its own terms. This target idealization strategy has broader applicability than prior interventions based on the late abstraction principle because it can be achieved by a greater proportion of participants and without the need to receive target-specific information. We present a computational model, SampComp, that predicts successful retrieval of a stored situation to understand a target based on the overlap of a random, but potentially biased, sample of features from each. SampComp is able to account for the relative benefits of base and target idealization, and their interaction.

Laparoscopic Intracorporeal Anastomosis.

Given the progression of laparoscopic surgery, questions continue to arise as to the ideal technique for a laparoscopic colectomy. The most debated of these questions is whether it is best to complete an intracorporeal (ICA) or extracorporeal (ECA) intestinal anastomosis. Here, we review the literature to date and report the equivalent safety and efficacy of ICA and ECA for laparoscopic right colectomy. However, these studies also indicate that when completed, ICA may prove beneficial with respect to earlier return of bowel function, less postoperative pain, shorter incision length, and reduced risk of wound infections. For this, we present the tips and tricks for completing all forms of laparoscopic ICAs during laparoscopic colectomy.

Racially Conscious Cancer Screening Guidelines: A Path Towards Culturally Competent Science.

OBJECTIVE: To review the racial composition of the study populations that the current USPSTF screening guidelines for lung, breast, and colorectal cancer are based on, and the effects of their application across non-white individuals. SUMMARY OF BACKGROUND DATA: USPSTF guidelines commonly become the basis for establishing standards of care, yet providers are often unaware of the racial composition of the study populations they are based on. METHODS: We accessed the USPSTF screening guidelines for lung, breast, and colorectal cancer via their website, and reviewed all referenced publications for randomized controlled trials (RCTs), focusing on the racial composition of their study populations. We then used PubMed to identify publications addressing the generalizability of such guidelines across non-white individuals. Lastly, we reviewed all guidelines published by non-USPSTF organizations to identify the availability of race-specific recommendations. RESULTS: Most RCTs used as basis for the current USPSTF guidelines either did not report race, or enrolled cohorts that were not representative of the U.S. population. Several studies were identified demonstrating the broad application of such guidelines across non-white individuals can lead to underdiagnosis and higher levels of advanced disease. Nearly all guideline-issuing bodies fail to provide race-specific recommendations, despite often acknowledging increased disease burden among non-whites. CONCLUSION: Concerted efforts to overcome limitations in the generalizability of RCTs are required to provide screening guidelines that are truly applicable to non-white populations. Broader policy changes to improve the pipeline for minority populations into science and medicine are needed to address the ongoing lack of diversity in these fields.

Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts.

BACKGROUND & AIMS: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). We conducted an integrated study of the cancer tissue and associated tumor microenvironment (TME) from patients treated with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab to dissect the cellular and molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy. METHODS: We selected multiple regions per tumor showing variable T-cell infiltration for a total of 738 regions from 29 patients, divided into discovery and validation cohorts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytometry, detection of programmed death-ligand 1 (PDL1) interaction in situ, multiplexed immunofluorescence, and computational spatial analysis of the TME. RESULTS: In hypermutated CRCs, response to anti-PD1 immunotherapy was not associated with TMB but with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1+CD8 T cells interacting with PDL1+ antigen-presenting macrophages. CONCLUSIONS: Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.

Molecular Basis of Extramural Vascular Invasion (EMVI) in Colorectal Carcinoma.

BACKGROUND: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.

An instance-based model account of the benefits of varied practice in visuomotor skill.

Exposing learners to variability during training has been demonstrated to improve performance in subsequent transfer testing. Such variability benefits are often accounted for by assuming that learners are developing some general task schema or structure. However much of this research has neglected to account for differences in similarity between varied and constant training conditions. In a between-groups manipulation, we trained participants on a simple projectile launching task, with either varied or constant conditions. We replicate previous findings showing a transfer advantage of varied over constant training. Furthermore, we show that a standard similarity model is insufficient to account for the benefits of variation, but, if the model is adjusted to assume that varied learners are tuned towards a broader generalization gradient, then a similarity-based model is sufficient to explain the observed benefits of variation. Our results therefore suggest that some variability benefits can be accommodated within instance-based models without positing the learning of some schemata or structure.

Impact of Bundled Payment Care Improvement Initiative on Health Care Expenditure in Major Bowel Procedures.

BACKGROUND: The Bundled Payments for Care Improvement initiative links payments for Medicare beneficiaries during an episode of care (90 days from index surgery). OBJECTIVE: This study aimed to determine whether major bowel participating Bundled Payments for Care Improvement organizations experience greater cost savings for colectomy while maintaining satisfactory quality outcomes compared to nonparticipating organizations. DESIGN: This is an Analysis of all Bundled Payments for Care Improvement participating hospitals for major bowel procedures (major bowel group) and propensity score-matched against Bundled Payments for Care Improvement organizations that do not include major bowel procedures (nonmajor bowel group) and those that do not participate in any Bundled Payments for Care Improvement program (non-Bundled Payments for Care Improvement group). SETTING: Programs accepting Medicare and Medicaid in the United States. PATIENTS: Patients included were major bowel cases in the Medicare Standard Analytic file within Medicare Severity Diagnosis-Related Groups 329-331 at participating facilities between January 1, 2011, and June 30, 2016. MAIN OUTCOME MEASURES: Main outcome measures included average total care expenditure and quality of care (length of stay, morbidity, and mortality) from 3 days preoperatively to 90 days postoperatively. RESULTS: We abstracted 7609 major bowel episodes from 23 major bowel group facilities, 21,872 episodes from nonmajor bowel-matched hospitals, and 19,383 episodes from non-Bundled Payments for Care Improvement-matched hospitals. From the baseline (January 2011 to June 2012) to final period (July 2015 to June 2016), we noted a $2955 average reduction in care expenditures. The largest decrease in average total episode expenditure occurred within the major bowel group (14% reduction) compared to the other groups (6% reduction for nonmajor bowel and 5% reduction for non-Bundled Payments for Care Improvement). Utilizing a generalized estimating equation to adjust for patient demographics, comorbidities, and hospital characteristics, the average total episode expenditure for the major bowel group decreased by $4885 (95% CI $4838-$4932; p < 0.001) compared to $2050 (95% CI $2038-$2061) for the non-Bundled Payments for Care Improvement group. All groups had similar reductions in length of stay, 30-day and 90-day complication rates, and readmission rates. LIMITATIONS: Analyses were limited by the retrospective nature of the study. CONCLUSIONS: Bundled Payments for Care Improvement participation for major bowel procedures resulted in a greater decrease in average total cost per episode of care than in nonparticipating hospitals without compromise in quality of care. See Video Abstract at http://links.lww.com/DCR/B837.IMPACTO DE LA INICIATIVA BUNDLED PAYMENT AGRUPADOS PARA LA MEJORA DE LA ATENCIÓN DEL GASTO SANITARIO EN LOS PROCEDIMIENTOS INTESTINALES MAYORESANTECEDENTES:La iniciativa de Bundled Payment para la mejora de la atención vincula los pagos para los beneficiarios de Medicare durante un episodio de atención (90 días desde la cirugía índice).OBJETIVO:Determinar si las principales organizaciones de Bundled Payment para el mejoramiento de la atención relacionados a los procedimientos intestinales experimentan mayores ahorros en los costos para una colectomía manteniendo resultados satisfactorios de calidad en comparación con las organizaciones no participantes.DISEÑO:Análisis de todos los hospitales participantes del programa Bundled Payment para la mejora de la atención para procedimientos intestinales mayores (grupo que incluyen procedimientos intestinales mayores) y puntaje de propensión comparado con las organizaciones que no incluyen dichos procedimientos (grupo que no incluye procedimientos intestinales mayores) y aquellos que no participan en ningún programa de Bundled Payment para la mejora de la atención (grupo no BPCI).MARCO:Programas que aceptan Medicare y Medicaid en los Estados Unidos.PACIENTES:Casos intestinales mayores en el archivo analítico estándar de Medicare dentro de los grupos relacionados con el diagnóstico 329-331 en los centros participantes entre el 1/1/2011-30/6/2016.PRINCIPALES MEDIDAS DE RESULTADO:Gasto total promedio y calidad de la atención (duración de la estadía, morbilidad, mortalidad) desde los 3 días preoperatorio hasta los 90 días postoperatorio.RESULTADOS:Hemos extraído 7609 episodios intestinales mayores de 23 instalaciones del grupo que incluyen procedimientos intestinales mayores, 21.872 episodios de hospitales del grupo que no incluyen procedimientos intestinales mayores y 19.383 episodios de hospitales del grupo no BPCI. Desde la línea de base (1/2011 - 6/2012) hasta el período final (7/2015 - 6/2016), notamos una reducción promedio de $2955 en los gastos de atención. La mayor disminución en el gasto promedio total por episodios ocurrió dentro del grupo que incluyen intestinales mayores (14% de reducción) en comparación con los otros grupos (6% de reducción para el grupo que no incluyen procedimientos intestinales mayores, 5% de reducción para el no BPCI). Utilizando una ecuación de estimación generalizada para ajustar los datos demográficos del paciente, las comorbilidades y las características del hospital, el gasto total promedio por episodio para el grupo que incluyen procedimientos intestinales mayores disminuyó en $ 4885 (IC del 95%: $4838-4932; p <0,001) en comparación con $2050 (IC del 95%: $2038-2061) para el grupo que no pertenece al programa BPCI. Todos los grupos tuvieron reducciones similares en la duración de la estancia, tasas de complicaciones de 30/90 días y de readmisión.LIMITACIONES:Análisis limitados por la naturaleza retrospectiva del estudio.CONCLUSIONES:La participación de Bundled Payment para la mejora de la atención en aquellos procedimientos intestinales mayores resultó en una disminución mayor en el costo total promedio por episodio de atención que en los hospitales no participantes, sin comprometer la calidad de la atención. Consulte Video Resumen en http://links.lww.com/DCR/B837. (Traducción-Dr Osvaldo Gauto).

Patient Survival With ypT0N+ Following Neoadjuvant Therapy in Rectal Cancer.

BACKGROUND: After neoadjuvant therapy, pathologic analysis of rectal cancer resected specimens may show a complete response in the primary tissue cancer with residual tumor in the lymph nodes (ypT0N+). OBJECTIVES: The aim of this study was to describe the 5-year overall survival and factors associated with survival of ypT0N+ patients with rectal cancer who had neoadjuvant therapy followed by surgery and to compare these patients' survival with patients in other pathologic categories. DESIGN: We conducted a retrospective analysis. SETTINGS: We used the National Cancer Database. PATIENTS: We identified patients with rectal adenocarcinoma who underwent total neoadjuvant therapy or neoadjuvant chemoradiation followed by surgery between 2006 and 2016. Besides ypT0N+, 5 pathologic categories were identified: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, and ypT3-4N+. MAIN OUTCOME MEASURE: The primary outcome measure was 5-year overall survival. RESULTS: We included 30,751 patients with rectal adenocarcinoma. A total of 342 patients developed ypT0N+, of whom 181 (52.9%) received total neoadjuvant therapy. Among patients who received total neoadjuvant therapy, developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, ypT0N+ disease was associated with a higher 5-year overall survival than ypT3-4N+. There were no differences in 5-year overall survival between ypT0N+ and ypT3-4N0 or ypT1-2N+. Similar findings were noticed among patients who received neoadjuvant chemoradiation and adjuvant chemotherapy. For patients with ypT0N+, older age, male gender, and higher number of positive lymph nodes were all associated with a decrease in the overall survival. LIMITATIONS: Limitations include the retrospective nature of this study, lack of variables describing the chemotherapy and radiation regimens used, and paucity of data on disease-specific survival or recurrence. CONCLUSIONS: Developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, it was associated with a higher 5-year overall survival than ypT3-4N+. See Video Abstract at http://links.lww.com/DCR/B863 . SOBREVIDA DE LOS PACIENTES CON YPTN DESPUS DE LA TERAPIA NEOADYUVANTE EN EL CNCER DE RECTO: ANTECEDENTES:Después del tratamiento neoadyuvante en el cáncer de recto bajo, el análisis patológico de la pieza operatoria resecada, puede mostrar una respuesta patológica completa del tumor primario pero con tumor residual en los ganglios linfáticos (ypT0N+).OBJETIVOS:Describir la sobrevida general a 5 años y los factores asociados con la sobrevida de los pacientes ypT0N+ con cáncer de recto, que recibieron terapia neoadyuvante seguida de cirugía y comparar la sobrevida de estos pacientes con la de pacientes con otros estadios patológicos.DISEÑO:Realizamos un análisis retrospectivo.AJUSTES:Utilizamos la base de datos nacional del cáncer.PACIENTES:Identificamos pacientes con adenocarcinoma de recto que se sometieron a terapia neoadyuvante total, seguida de cirugía entre 2006 y 2016. Además de ypT0N +, se identificaron 5 categorías patológicas: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, e ypT3-4N+.PRINCIPAL MEDIDA DE RESULTADO:La medida de resultado principal fue la supervivencia general a 5 años.RESULTADOS:Se incluyeron 30.751 pacientes con adenocarcinoma de recto. Un total de 342 pacientes desarrollaron ypT0N+, de los cuales 181 (52,9%) recibieron terapia neoadyuvante total. Entre los pacientes que recibieron terapia neoadyuvante total, el desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, la enfermedad ypT0N+ se asoció con una supervivencia general a 5 años más alta que ypT3-4N+. No hubo diferencias en la supervivencia global a 5 años entre ypT0N+ y ypT3-4N0 o ypT1-2N+. Se observaron hallazgos similares entre los pacientes que recibieron terapia neoadyuvante y quimioterapia adyuvante. Para los pacientes con ypT0N+, la edad avanzada, el sexo masculino y un mayor número de ganglios linfáticos positivos se asociaron con una disminución en la supervivencia general.LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva del estudio, la falta de variables que describan los regímenes de quimioterapia y radiación utilizados y la escasez de datos sobre la supervivencia o la recurrencia específicas de la enfermedad.CONCLUSIONES:El desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, se asoció con una supervivencia global a 5 años más alta que ypT3-4N+. Consulte Video Resumen en http://links.lww.com/DCR/B863 . (Traducción-Dr. Rodrigo Azolas ).

Tumour genotypes account for survival differences in right- and left-sided colon cancers.

AIM: We sought to identify genetic differences between right- and left-sided colon cancers and using these differences explain lower survival in right-sided cancers. METHOD: A retrospective review of patients diagnosed with colon cancer was performed using The Cancer Genome Atlas, a cancer genetics registry with patient and tumour data from 20 North American institutions. The primary outcome was 5-year overall survival. Predictors for survival were identified using directed acyclic graphs and Cox proportional hazards models. RESULTS: A total of 206 right- and 214 left-sided colon cancer patients with 84 recorded deaths were identified. The frequency of mutated alleles differed significantly in 12 of 25 genes between right- and left-sided tumours. Right-sided tumours had worse survival with a hazard ratio of 1.71 (95% confidence interval 1.10-2.64, P = 0.017). The total effect of the genetic loci on survival showed five genes had a sizeable effect on survival: DNAH5, MUC16, NEB, SMAD4, and USH2A. Lasso-penalized Cox regression selected 13 variables for the highest-performing model, which included cancer stage, positive resection margin, and mutated alleles at nine genes: MUC16, USH2A, SMAD4, SYNE1, FLG, NEB, TTN, OBSCN, and DNAH5. Post-selection inference demonstrated that mutations in MUC16 (P = 0.01) and DNAH5 (P = 0.02) were particularly predictive of 5-year overall survival. CONCLUSIONS: Our study showed that genetic mutations may explain survival differences between tumour sites. Further studies on larger patient populations may identify other genes, which could form the foundation for more precise prognostication and treatment decisions beyond current rudimentary TNM staging.

Healthcare Resource Utilization After Surgical Treatment of Cancer: Value of Minimally Invasive Surgery.

BACKGROUND: As the US healthcare system moves towards value-based care, hospitals have increased efforts to improve quality and reduce unnecessary resource use. Surgery is one of the most resource-intensive areas of healthcare and we aim to compare health resource utilization between open and minimally invasive cancer procedures. METHODS: We retrospectively analyzed cancer patients who underwent colon resection, rectal resection, lobectomy, or radical nephrectomy within the Premier hospital database between 2014 and 2019. Study outcomes included length of stay (LOS), discharge status, reoperation, and 30-day readmission. The open surgical approach was compared to minimally invasive approach (MIS), with subgroup analysis of laparoscopic/video-assisted thoracoscopic surgery (LAP/VATS) and robotic (RS) approaches, using inverse probability of treatment weighting. RESULTS: MIS patients had shorter LOS compared to open approach: - 1.87 days for lobectomy, - 1.34 days for colon resection, - 0.47 days for rectal resection, and - 1.21 days for radical nephrectomy (all p < .001). All MIS procedures except for rectal resection are associated with higher discharge to home rates and lower reoperation and readmission rates. Within MIS, robotic approach was further associated with shorter LOS than LAP/VATS: - 0.13 days for lobectomy, - 0.28 days for colon resection, - 0.67 days for rectal resection, and - 0.33 days for radical nephrectomy (all p < .05) and with equivalent readmission rates. CONCLUSION: Our data demonstrate a significant shorter LOS, higher discharge to home rate, and lower rates of reoperation and readmission for MIS as compared to open procedures in patients with lung, kidney, and colorectal cancer. Patients who underwent robotic procedures had further reductions in LOS compare to laparoscopic/video-assisted thoracoscopic approach, while the reductions in LOS did not lead to increased rates of readmission.

Transfer of virtual reality endoscopy training to live animal colonoscopy: a randomized control trial of proficiency vs. repetition-based training.

BACKGROUND: Low first-time pass rates of the Fundamentals of Endoscopic Surgery (FES) exam stimulated development of virtual reality (VR) simulation curricula for test preparation. This study evaluates the transfer of VR endoscopy training to live porcine endoscopy performance and compares the relative effectiveness of a proficiency-based vs repetition-based VR training curriculum. METHODS: Novice endoscopists completed pretesting including the FES manual skills examination and Global Assessment of GI Endoscopic Skills (GAGES) assessment of porcine upper and lower endoscopy. Participants were randomly assigned one of two curricula: proficiency-based or repetition-based. Following curriculum completion, participants post-tested via repeat FES examination and GAGES porcine endoscopy assessments. The two cohorts pre-to-post-test differences were compared using ANCOVA. RESULTS: Twenty-two residents completed the curricula. There were no differences in demographics or clinical endoscopy experience between the groups. The repetition group spent significantly more time on the simulator (repetition: 242.2 min, SD 48.6) compared to the proficiency group (proficiency: 170.0 min, SD 66.3; p = 0.013). There was a significant improvement in porcine endoscopy (pre: 10.6, SD 2.8, post: 16.6, SD 3.4; p < 0.001) and colonoscopy (pre: 10.4, SD 2.7, post: 16.4, SD 4.2; p < 0.001) GAGES scores as well as FES manual skills performance (pre: 270.9, SD 105.5, post: 477.4, SD 68.9; p < 0.001) for the total cohort. There was no difference in post-test GAGES performance or FES manual skills exam performance between the two groups. Both the proficiency and repetition group had a 100% pass rate on the FES skills exam following VR curriculum completion. CONCLUSION: A VR endoscopy curriculum translates to improved performance in upper and lower endoscopy in a live animal model. VR curricula type did not affect FES manual skills examination or live colonoscopy outcomes; however, a proficiency curriculum is less time-consuming and can provide a structured approach to prepare for both the FES exam and clinical endoscopy.

Generalizability, transferability, and the practice-to-practice gap.

Emphasizing the predictive success and practical utility of psychological science is an admirable goal but it will require a substantive shift in how we design research. Applied research often assumes that findings are transferable to all practices, insensitive to variation between implementations. We describe efforts to quantify and close this practice-to-practice gap in education research.