Short-course radiation with consolidation chemotherapy does not increase operative morbidity compared to long-course chemoradiation: A retrospective study of the US rectal cancer consortium.

BACKGROUND AND OBJECTIVES: Neoadjuvant short-course radiation and consolidation chemotherapy (SC TNT) remains less widely used for rectal cancer in the United States than long-course chemoradiation (LCRT). SC TNT may improve compliance and downstaging; however, a longer radiation-to-surgery interval may worsen pelvic fibrosis and morbidity with total mesorectal excision (TME). A single, US-center retrospective analysis has shown comparable risk of morbidity after neoadjuvant short-course radiation with consolidation chemotherapy (SC TNT) and long-course chemoradiation (LCRT). Validation by a multi-institutional study is needed. METHODS: The US Rectal Cancer Consortium database (2010-2018) was retrospectively reviewed for patients with nonmetastatic, rectal adenocarcinoma treated with neoadjuvant LCRT or SC TNT before TME. The primary endpoint was severe postoperative morbidity. Cohorts were compared by univariate analysis. Multivariable logistic regression modeled the odds of severe complication. RESULTS: Of 788 included patients, 151 (19%) received SC TNT and 637 (81%) LCRT. The SC TNT group had fewer distal tumors (33.8% vs. 50.2%, p < 0.0001) and more clinical node-positive disease (74.2% vs. 47.6%, p < 0.0001). The intraoperative complication rate was similar (SC TNT 5.3% vs. 4.4%, p = 0.65). There was no difference in overall postoperative morbidity (38.4% vs. 46.3%, p = 0.08). Severe morbidity was similar with low anterior resection (9.1% vs. 15.3%, p = 0.10) and abdominoperineal resection (24.4% vs. 29.7%, p = 0.49). SC TNT did not increase the odds of severe morbidity relative to LCRT on multivariable analysis (OR 0.64, 95% CI 0.37-1.10). CONCLUSIONS: SC TNT does not increase morbidity after TME for rectal cancer relative to LCRT. Concern for surgical complications should not discourage the use of SC TNT when aiming to increase the likelihood of complete clinical response.

Increased expression of phosphodiesterase 4 in activated hepatic stellate cells promotes cytoskeleton remodeling and cell migration.

Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho-specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho-associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFß1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP-degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFß1 levels were highly correlated with PDE4 expression. TGFß1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC-specific agonist decreased TGFß1-mediated cell migration in vitro. In vivo, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis-related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.

Prophylactic defunctioning stomas improve clinical outcomes of anastomotic leak following rectal cancer resections: An analysis of the US Rectal Cancer Consortium.

PURPOSE: Anastomotic leak (AL) is a complication of low anterior resection (LAR) that results in substantial morbidity. There is immense interest in evaluating immediate postoperative and long-term oncologic outcomes in patients who undergo diverting loop ileostomies (DLI). The purpose of this study is to understand the relationship between fecal diversion, AL, and oncologic outcomes. METHODS: This is a retrospective multicenter cohort study using patient data obtained from the US Rectal Cancer Consortium database compiled from six academic institutions. The study population included patients with rectal adenocarcinoma undergoing LAR. The primary outcome was the incidence of AL among patients who did or did not receive DLI during LAR. Secondary outcomes included risk factors for AL, receipt of adjuvant therapy, 3-year overall survival, and 3-year recurrence. RESULTS: Of 815 patients, 38 (4.7%) suffered AL after LAR. Patients with AL were more likely to be male, have unintentional preoperative weight loss, and are less likely to undergo DLI. On multivariable analysis, DLI remained protective against AL (p < 0.001). Diverted patients were less likely to undergo future surgical procedures including additional ostomy creation, completion proctectomy, or pelvic washout for AL. Subgroup analysis of 456 patients with locally advanced disease showed that DLI was correlated with increased receipt of adjuvant therapy for patients with and without AL on univariate analysis (SHR:1.59; [95% CI 1.19-2.14]; p = 0.002), but significance was not met in multivariate models. CONCLUSION: Lack of DLI and preoperative weight loss was associated with anastomotic leak. Fecal diversion may improve the timely initiation of adjuvant oncologic therapy. The long-term outcomes following routine diverting stomas warrant further study.

Management and Outcomes of Pathologic Upstaging of Clinical Stage I Rectal Cancers: An Exploratory Analysis.

BACKGROUND: Preoperative staging of clinical stage I rectal cancer can fail to diagnose T3 or nodal disease. Adjuvant treatment of these upstaged patients remains controversial. OBJECTIVE: The objective was to identify predictors of clinical stage I rectal cancer upstaging and quantify rates of local and systemic recurrence. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted using data from the United States Rectal Cancer Consortium, a registry of 1881 rectal cancer resections performed at 6 academic medical centers. PATIENTS: There were a total of 94 clinical stage I rectal cancer patients who underwent proctectomy without preoperative therapy. MAIN OUTCOME MEASURES: The primary measures were incidence of pathologic upstaging, recurrence (local and systemic), and overall survival. RESULTS: Among 94 clinical stage I patients who underwent proctectomy without preoperative therapy, 23 (24.5%) were upstaged by surgical pathology. There were 6 pT3N0 patients, 8 pT1-2N+ patients, and 9 pT3N+ patients. There were no significant differences in demographic or clinical characteristics between upstaged and nonupstaged patients. Of the 6 patients who were upstaged to T3N0 disease, none received adjuvant therapy and none developed recurrence. Of the 17 patients who were upstaged to N+ disease, 14 (82%) received adjuvant chemotherapy and 6 (35%) received adjuvant chemoradiation. None developed a local recurrence, but 4 (24%) developed systemic recurrence, and 2 (12%) died of disease over a mean of 36 months of follow-up. Among the 9 pT3N+ patients, the systemic recurrence rate was 33%, despite 8 of 9 patients receiving adjuvant fluorouracil, leucovorin, and oxaliplatin. LIMITATIONS: Small sample size hinders the ability to draw significant conclusions. CONCLUSIONS: One in 4 patients with stage I rectal cancer had unrecognized T3 or nodal disease found on operative pathology. Occult nodal disease was associated with worse outcomes, despite receiving adjuvant therapy. Systemic recurrence was more common than local recurrence. See Video Abstract at http://links.lww.com/DCR/B885 . MANEJO Y RESULTADOS DEL AUMENTO DEL ESTADIO PATOLGICO DE LOS CNCERES DE RECTO EN ESTADIO CLNICO I UN ANLISIS EXPLORATORIO: ANTECEDENTES:El estadiaje pre-operatorio del cáncer de recto en fase clínica I puede ser erróneo en el diagnóstico T3 o en la diseminación ganglionar. El tratamiento adyuvante de estos pacientes sobre-estadificados ​​sigue siendo controvertido.OBJETIVO:El identificar los factores predictivos en fase clínica I del cáncer de recto y cuantificar las tasas de recurrencia local y sistémica.DISEÑO:Estudio de cohortes retrospectivo.AJUSTE:El estudio se realizó utilizando los datos del Consorcio del Cáncer de Recto de los Estados Unidos, con un registro de 1.881 resecciones oncológicas rectales realizadas en seis centros médicos académicos.PACIENTES:Un total de 94 pacientes con cáncer de recto en fase clínica I fueron sometidos a proctectomía sin terapia preoperatoria.PRINCIPALES MEDIDAS DE RESULTADO:Las medidas primarias fueron la incidencia del sobre-estadiaje histopatológico, la recurrencia (local y sistémica) y la sobrevida general.RESULTADOS:De 94 pacientes en fase clínica I que se sometieron a una proctectomía sin terapia preoperatoria, 23 (24,5%) fueron sobre-estadiados ​​por la histopatología quirúrgica. Hubieron 6 pacientes pT3N0, 8 pT1-2N + y 9 pT3N +. No hubo diferencias significativas en las características demográficas o clínicas entre los pacientes sobre-estadiados ​​y los no sobre-estadiados. De los 6 pacientes que fueron sobre-estadiados en la enfermedad T3N0, ninguno de ellos recibió terapia adyuvante y ninguno recidivó. De los 17 pacientes que fueron sobre-estadiados a la enfermedad N +, 14 (82%) recibieron quimioterapia adyuvante y 6 (35%) recibieron quimio-radioterapia adyuvante. Ninguno desarrolló recidiva local, pero 4 (24%) desarrollaron recidiva sistémica y 2 (12%) murieron a causa de la enfermedad durante el seguimiento medio de 36 meses. Entre los 9 pacientes con pT3N +, la tasa de recidiva sistémica fue del 33%, a pesar de que 8 de 9 pacientes recibieron fluorouracilo, leucovorina y oxaliplatino como quimio-adyuvantes.LIMITACIONES:El tamaño pequeño de la muestra dificulta la capacidad de obtener conclusiones significativas.CONCLUSIONES:Uno de cada cuatro pacientes con cáncer de recto en estadío I presentaba enfermedad ganglionar o T3 no descrita en la histopatología operatoria. La enfermedad ganglionar oculta se asoció con peores resultados, a pesar de recibir terapia adyuvante. La recidiva sistémica fue más común que la recidiva local. Consulte Video Resumen en http://links.lww.com/DCR/B885 . (Traducción-Dr. Xavier Delgadillo ).

Discharge Prescribing Protocol Decreases Opioids in Circulation and Does Not Increase Refills After Colorectal Surgery.

BACKGROUND: Up to 10% of patients develop new, persistent opioid use after surgery. We aimed to assess our prescribing practices and patient utilization of opioids after colorectal surgery. OBJECTIVE: This study aimed to implement an opioid-prescribing protocol that will minimize the number of postoperative opioids to decrease community circulation and persistent use by patients. DESIGN: This was a single-institution, prospective study based on questionnaires of postoperative patients in 2019 and 2020 to determine opioid prescribing and usage patterns. Based on these preliminary results, a protocol was implemented in which patients were discharged with 5 or 15 oxycodone 5 mg equivalents based on opioid usage in the 24 hours before discharge. Patients were surveyed after protocol implementation. SETTINGS: Our institution is a large referral center for surgical treatment of colorectal disease. PATIENTS: Adults who underwent inpatient abdominal colorectal procedures. MAIN OUTCOME MEASURES: End points included the number of opioids prescribed, number of prescribed opioids taken, and refill rate. Nonparametric testing was used. RESULTS: Of 77 eligible patients, 61 were opioid naive. Preprotocol, opioid-naive patients (n = 29) were prescribed a median of 30 (interquartile range [IQR], 30-45) tablets but took only 10 (IQR, 0-10; p < 0.0001). Eighty-three percent took 20 or fewer tablets. After protocol implementation, opioid-naive patients (n = 32) were prescribed fewer tablets (median 15; IQR, 7-15; p < 0.0001) but took a similar number of tablets as the preprotocol group (median 10; IQR, 0-10; p = 0.21). The refill rate remained similar (13.8% vs 18.8%; p = 0.60). Protocol adherence was 90.6%. LIMITATIONS: This study is limited by sample size, cohort heterogeneity, and generalizability. CONCLUSIONS: Patients took significantly fewer opioids than were prescribed. Our protocol limited overprescribing and resulted in fewer opioids in the community without opportunity costs such as increased refills. Long-term studies are needed to assess the effects of persistent opioid use after surgery. See Video Abstract at http://links.lww.com/DCR/C93 .

ANTECEDENTES: Hasta el 10% de los pacientes desarrollan un nuevo uso persistente de opioides después de la cirugía. Nuestro objetivo fue evaluar nuestras prácticas de prescripción y la utilización de opioides por parte de los pacientes después de la cirugía colorrectal. OBJETIVO: Nuestro objetivo es implementar un protocolo de prescripción de opioides que minimice la cantidad de opioides posoperatorios para disminuir la circulación en la comunidad y el uso persistente por parte de los pacientes. DISEÑO: Estudio prospectivo, de una sola institución, basado en cuestionarios de pacientes postoperatorios en 2019 y 2020 para determinar los patrones de prescripción y uso de opioides. Con base en estos resultados preliminares, se implementó un protocolo en el que los pacientes eran dados de alta con 5 o 15 equivalentes de oxicodona de 5 mg según el uso de opioides en las 24 horas previas al alta. Los pacientes fueron encuestados después de la implementación del protocolo. AJUSTES: Nuestra institución es un gran centro de referencia para el tratamiento quirúrgico de la enfermedad colorrectal. PACIENTES: Adultos que se sometieron a procedimientos colorrectales abdominales con hospitalización. PRINCIPALES MEDIDAS DE RESULTADO: Los criterios de valoración incluyeron el número de opioides recetados, el número de opioides recetados tomados y la tasa de reabastecimiento. Se utilizaron pruebas no paramétricas. RESULTADOS: De 77 pacientes elegibles, 61 no habian recibido opioides. A los pacientes sin tratamiento previo con opioides antes del protocolo (n = 29) se les prescribió una mediana de 30 (rango intercuartilico [RIC] 30­45) comprimidos, pero solo tomaron 10 (RIC 0.10, p < 0,0001). El ochenta y tres por ciento tomo ≤20 comprimidos. Despues de la implementacion del protocolo, a los pacientes sin tratamiento previo con opioides (n = 32) se les prescribieron menos comprimidos (15; RIC 7.15, p < 0,0001), pero tomaron un numero similar antes de la intervención (10; RIC 0­10, p = 0,21). La tasa de reabastecimiento se mantuvo similar (13,8% frente a 18,8%, p = 0,60). La adherencia al protocolo fue del 90,6%. LIMITACIONES: Este estudio está limitado por el tamaño de la muestra, la heterogeneidad de la cohorte y la generalización. CONCLUSIONES: Los pacientes tomaron significativamente menos opioides de los prescritos. Nuestro protocolo limitó la prescripción excesiva y dio como resultados menos opioides en la comunidad sin costos de oportunidad, como el aumento de reabastecimiento. Se necesitan estudios a largo plazo para evaluar los efectos sobre el uso persistente de opioides después de la cirugía. Consulte Video Resumen en http://links.lww.com/DCR/C93 . (Traducción­Dr. Francisco M. Abarca-Rendon).

Perioperative Complications After Proctectomy for Rectal Cancer: Does Neoadjuvant Regimen Matter?

OBJECTIVE: Investigate the association between neoadjuvant treatment strategy and perioperative complications in patients undergoing proctectomy for nonmetastatic rectal cancer. SUMMARY OF BACKGROUND DATA: Neoadjuvant SC-TNT is an alternative to neoadjuvant CRT for rectal cancer. Some have argued that short-course radiation and extended radiation-to-surgery intervals increase operative difficulty and complication risk. However, the association between SC-TNT and surgical complications has not been previously investigated. METHODS: This single-center retrospective cohort study included patients undergoing total mesorectal excision for nonmetastatic rectal cancer after SC-TNT or CRT between 2010 and 2018. Univariate analysis of severe POM and multiple secondary outcomes, including overall POM, intraoperative complications, and resection margins, was performed. Logistic regression of severe POM was also performed. RESULTS: Of 415 included patients, 156 (38%) received SC-TNT and 259 (62%) received CRT. The cohorts were largely similar, though patients with higher tumors (69.9% vs 47.5%, P < 0.0001) or node-positive disease (76.9% vs 62.6%, P = 0.004) were more likely to receive SC-TNT. We found no difference in incidence of severe POM (9.6% SC-TNT vs 12.0% CRT, P = 0.46) or overall POM (39.7% SC-TNT vs 37.5% CRT, P = 0.64) between cohorts. Neoadjuvant regimen was also not associated with a difference in severe POM (odds ratio 0.42, 95% confidence interval 0.04-4.70, P = 0.48) in multivariate analysis. There was no significant association between neoadjuvant regimen and any secondary outcome. CONCLUSION: In rectal cancer patients treated with SC-TNT and proctectomy, we found no significant association with POM compared to patients undergoing CRT. SC-TNT does not significantly increase the risk of POM compared to CRT.

Total Neoadjuvant Therapy With Short-Course Radiation: US Experience of a Neoadjuvant Rectal Cancer Therapy.

BACKGROUND: Short-course radiation followed by chemotherapy as total neoadjuvant therapy has been investigated primarily in Europe and Australia with increasing global acceptance. There are limited data on this regimen's use in the United States, however, potentially delaying implementation. OBJECTIVE: This study aimed to compare clinical performance and oncologic outcomes of 2 rectal cancer neoadjuvant treatment modalities: short-course total neoadjuvant therapy versus standard chemoradiation. DESIGN: This is a retrospective cohort study. SETTING: This study was performed at a National Cancer Institute-designated cancer center. PATIENTS: A total of 413 patients had locally advanced rectal cancers diagnosed from June 2009 to May 2018 and received either short-course total neoadjuvant therapy or standard chemoradiation. INTERVENTIONS: There were 187 patients treated with short-course total neoadjuvant therapy (5 × 5 Gy radiation followed by consolidation oxaliplatin-based chemotherapy) compared with 226 chemoradiation recipients (approximately 50.4 Gy radiation in 28 fractions with concurrent fluorouracil equivalent). MAIN OUTCOME MEASURES: Primary end points were tumor downstaging, measured by complete response and "low" neoadjuvant rectal score rates, and progression-free survival. Secondary analyses included treatment characteristics and completion, sphincter preservation, and recurrence rates. RESULTS: Short-course total neoadjuvant therapy was associated with higher rates of complete response (26.2% vs 17.3%; p = 0.03) and "low" neoadjuvant rectal scores (40.1% vs 25.7%; p < 0.01) despite a higher burden of node-positive disease (78.6% vs 68.9%; p = 0.03). Short-course recipients also completed trimodal treatment more frequently (88.4% vs 50.4%; p < 0.01) and had fewer months with temporary stomas (4.8 vs 7.0; p < 0.01). Both regimens achieved comparable local control (local recurrence: 2.7% short-course total neoadjuvant therapy vs 2.2% chemoradiation, p = 0.76) and 2-year progression-free survival (88.2% short-course total neoadjuvant therapy (95% CI, 82.9-93.5) vs 85.6% chemoradiation (95% CI, 80.5-90.7)). LIMITATIONS: Retrospective design, unbalanced disease severity, and variable dosing of neoadjuvant consolidation chemotherapy were limitations of this study. CONCLUSIONS: Short-course total neoadjuvant therapy was associated with improved downstaging and similar progression-free survival compared with chemoradiation. These results were achieved with shortened radiation courses, improved treatment completion, and less time with diverting ostomies. Short-course total neoadjuvant therapy is an optimal regimen for locally advanced rectal cancer. See Video Abstract at http://links.lww.com/DCR/B724.TERAPIA NEOADYUVANTE TOTAL CON RADIACIÓN DE CORTA DURACIÓN: EXPERIENCIA ESTADOUNIDENSE DE UNA TERAPIA NEOADYUVANTE CONTRA EL CÁNCER DE RECTO. ANTECEDENTES: La radiación de corta duración seguida de quimioterapia como terapia neoadyuvante total se ha investigado principalmente en Europa y Australia con una aceptación mundial cada vez mayor. Sin embargo, datos limitados sobre el uso de este régimen en los Estados Unidos, han potencialmente retrasando su implementación. OBJETIVO: Comparar el desempeño clínico y los resultados oncológicos de dos modalidades de tratamiento neoadyuvante del cáncer de recto: terapia neoadyuvante total de corta duración versus quimioradiación. estándar. DISEO: Cohorte retrospectivo. AJUSTE: Centro oncológico designado por el NCI. PACIENTES: Un total de 413 cánceres rectales localmente avanzados diagnosticados entre junio de 2009 y mayo de 2018 que recibieron cualquiera de los regímenes neoadyuvantes. INTERVENCIONES: Hubo 187 pacientes tratados con terapia neoadyuvante total de ciclo corto (radiación 5 × 5 Gy seguida de quimioterapia de consolidación basada en oxaliplatino) en comparación con 226 pacientes de quimiorradiación (aproximadamente 50,4 Gy de radiación en 28 fracciones con equivalente de fluorouracilo concurrente). PRINCIPALES MEDIDAS DE RESULTADO: Los criterios primarios de valoración fueron la disminución del estadio del tumor, medido por la respuesta completa y las tasas de puntuación rectal neoadyuvante "baja", y la supervivencia libre de progresión. Los análisis secundarios incluyeron las características del tratamiento y las tasas de finalización, conservación del esfínter y recurrencia. RESULTADOS: La terapia neoadyuvante total de corta duración, se asoció con tasas más altas de respuesta completa (26,2% versus 17,3%, p = 0,03) y puntuaciones rectales neoadyuvantes "bajas" (40,1% versus 25,7%, p < 0,01) a pesar de una mayor carga de enfermedad con ganglios positivos (78,6% versus 68,9%, p = 0,03). Los pacientes de ciclo corto también completaron el tratamiento trimodal con mayor frecuencia (88,4% versus 50,4%, p < 0,01) y tuvieron menos meses con estomas temporales (4,8 versus 7,0, p < 0,01). Ambos regímenes lograron un control local comparable (recidiva local: 2,7% de SC-TNT versus 2,2% de TRC, p = 0,76) y supervivencia libre de progresión a 2 años (88,2% de SC-TNT [IC: 82,9 - 93,5] versus 85,6% CRT [CI: 80,5 - 90,7]). LIMITACIONES: Diseño retrospectivo, gravedad de la enfermedad desequilibrada y dosificación variable de quimioterapia neoadyuvante de consolidación. CONCLUSIONES: La terapia neoadyuvante total de ciclo corto se asoció con una mejora en la reducción del estadio y una supervivencia libre de progresión similar en comparación con la quimioradiación. Estos resultados se lograron con ciclos de radiación más cortos, tratamientos mejor finalizados y menos tiempo en ostomías de derivación. La terapia neoadyuvante total de corta duración es un régimen óptimo para el cáncer de recto localmente avanzado. Consulte Video Resumen en http://links.lww.com/DCR/B724. (Traducción- Dr. Fidel Ruiz Healy).

Impact of Postoperative Complications on Oncologic Outcomes After Rectal Cancer Surgery: An Analysis of the US Rectal Cancer Consortium.

BACKGROUND: Postoperative complications (POCs) are associated with worse oncologic outcomes in several cancer types. The implications of complications after rectal cancer surgery are not well studied. METHODS: The United States Rectal Cancer Consortium (2007-2017) was reviewed for primary rectal adenocarcinoma patients who underwent R0/R1 resection. Ninety-day POCs were categorized as major or minor and were grouped into infectious, cardiopulmonary, thromboembolic, renal, or intestinal dysmotility. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). RESULTS: Among 1136 patients, the POC rate was 46% (n = 527), with 63% classified as minor and 32% classified as major. Of all POCs, infectious complications comprised 20%, cardiopulmonary 3%, thromboembolic 5%, renal 9%, and intestinal dysmotility 19%. Compared with minor or no POCs, major POCs were associated with both worse RFS and worse OS (both p < 0.01). Compared with no POCs, a single POC was associated with worse RFS (p < 0.01), while multiple POCs were associated with worse OS (p = 0.02). Regardless of complication grade, infectious POCs were associated with worse RFS (p < 0.01), while cardiopulmonary and thromboembolic POCs were associated with worse OS (both p < 0.01). Renal POCs were associated with both worse RFS (p < 0.001) and worse OS (p = 0.01). After accounting for pathologic stage, neoadjuvant therapy, and final margin status, Multivariable analysis (MVA) demonstrated worse outcomes with cardiopulmonary, thromboembolic, and renal POCs for OS (cardiopulmonary: hazard ratio [HR] 3.6, p = 0.01; thromboembolic: HR 19.4, p < 0.01; renal: HR 2.4, p = 0.01), and renal and infectious POCs for RFS (infectious: HR 2.1, p < 0.01; renal: HR 3.2, p < 0.01). CONCLUSIONS: Major complications after proctectomy for cancer are associated with decreased RFS and OS. Given the association of infectious complications and postoperative renal dysfunction with earlier recurrence of disease, efforts must be directed towards defining best practices and standardizing care.

Travel Time to a High Volume Center Negatively Impacts Timing of Care in Rectal Cancer.

BACKGROUND: Regionalization of rectal cancer surgery may lead to worse disease free survival owing to longer travel time to reach a high volume center yet no study has evaluated this relationship at a single high volume center volume center. MATERIALS AND METHODS: This was a retrospective review of rectal cancer patients undergoing surgery from 2009 to 2019 at a single high volume center. Patients were divided into two groups based on travel time. The primary outcome was disease-free survival (DFS). Additional outcomes included treatment within 60 d of diagnosis, completeness of preoperative staging, and evaluation by a colorectal surgeon prior to initiation of treatment. RESULTS: A lower proportion of patients with long travel time began definitive treatment within 60 d of diagnosis (74.0% versus 84.0%, P= 0.01) or were seen by the treating colorectal surgeon before beginning definitive treatment (74.8% versus 85.4%, P < 0.01). On multivariable logistic regression analysis, patients with long travel time were significantly less likely to begin definitive treatment within 60 d of diagnosis (OR = 0.54; 95% CI = 0.31-0.93) or to be evaluated by a colorectal surgeon prior to initiating treatment (OR = 0.45; 95% CI = 0.25-0.80). There were no significant differences in DFS based on travel time. CONCLUSIONS: Although patients with long travel times may be vulnerable to delayed, lower quality rectal cancer care, there is no difference in DFS when definitive surgery is performed at a high volume canter. Ongoing research is needed to identify explanations for delays in treatment to ensure all patients receive the highest quality care.

Radiological assessment of persistent retroperitoneal and lateral pelvic lymph nodes after neoadjuvant therapy for rectal cancer: An analysis of the United States Rectal Cancer Consortium.

INTRODUCTION: Management of retroperitoneal and lateral pelvic lymph nodes (RLPN) in rectal cancer remains unclear. With total neoadjuvant therapy (TNT), more patients have radiologic complete clinical response (rCR). We sought to evaluate the impact of radiographic persistent RLPN after neoadjuvant therapy on survival. MATERIALS AND METHODS: Patients with rectal adenocarcinoma with isolated RLPN metastasis, who received neoadjuvant therapy before surgery were included from the United States Rectal Cancer Consortium database. Primary outcomes were recurrence-free survival (RFS) and overall survival (OS). RESULTS: Of 77 patients, all received neoadjuvant therapy, with 35 (46%) receiving TNT. Posttreatment, 33 (43%) had rCR while 44 (57%) had radiographic persistent RLPN. Median number of radiographic positive RLPN was 1 (IQR 1-2). Receipt of TNT was associated with radiographic RLPN rCR (OR 4.77, 95% CI 1.81-12.60, p < .01). However, there was no difference in RFS and OS between patients who achieved rCR or with persistent RLPN (all p > .05). CONCLUSIONS: Radiographic persistence of RLPN was not associated with worse survival in well-selected patients and may not be a reliable indicator of pathological response. TNT may be the preferred management strategy to select patients given its association with rCR. Radiographic persistence of RLPN after preoperative therapy should not necessarily preclude surgery.

Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench.

Alcoholic liver disease (ALD) is a major cause of liver-related mortality. There is still no US Food and Drug Administration-approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up-regulation of cAMP-degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol-induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up-regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti-inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin-inducible proinflammatory cytokine production ex vivo in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol-mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in in vivo and in vitro models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol-induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both in vivo and in vitro. Conclusion: Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.

Clinicopathologic determinants of pathologic treatment response in neoadjuvant treated rectal adenocarcinoma.

Neoadjuvant treatment (NAT) followed by total mesorectal excision is currently considered the standard of treatment for rectal adenocarcinoma. The degree of pathologic treatment response (pTR) correlates significantly with the recurrence free survival and overall survival (OS). However, it remains unclear which clinical and pathologic factors are associated with a more robust response to NAT, including showing pathologic complete response (pCR). Chemokine receptor 4 (CXCR4) overexpression has been associated with unfavorable OS in some studies. In this study, we sought to evaluate the clinicopathologic determinants of pTR in neoadjuvant treated rectal adenocarcinoma (NAT-RA). We retrospectively identified 91 patients who underwent pre-treatment diagnostic biopsy, NAT, and surgical resection at our institution. The archival slides were reviewed for pathologic features in the pre-treatment biopsies and for assessment of pTR in the resection specimens according to the current College of American Pathologist (CAP)'s guidelines. pCR was obtained in 16.5% of the cases, whereas 20.9% had near pCR, 30.8% had partial response, and 31.9% had a poor/no response. CXCR4 immunohistochemical analysis was also performed on the pre-treatment biopsies. Lower pre-treatment cT-stage (p = 0.019) and pre-treatment AJCC cTNM stage groups (p = 0.004), longer time interval between completion of NAT and resection (p = 0.022), and presence of tumor-infiltrating lymphocytes in the pre-treatment biopsies (p = 0.019) were significantly associated with a better pTR. CXCR4 nuclear expression was associated with a lower percentage of residual tumor (p = 0.036). Pre-treatment CEA levels, tumor differentiation, CAP treatment response groups and lower percentage of residual tumor were associated with a better OS.

Spatial Distributions of Thrips (Thysanoptera: Thripidae) in Cotton.

A 4-yr study was conducted to determine the degree of aggregation of thrips and injury in cotton, Gossypium hirsutum L., and their spatial association with a multispectral vegetation index (normalized difference vegetation index [NDVI]) and soil apparent electrical conductivity (ECa). Using the Spatial Analysis by Distance IndicEs analyses (SADIE), adult thrips were significantly (P < 0.05) aggregated in 4 out of 24 analyses for adult thrips (17%), 4 out of 24 analyses for immature thrips (17%), and 2 out of 15 analyses for injury (13%). The SADIE association tool showed that NDVI values were associated with adult thrips in 2 out of 20 paired datasets (10%), with immature thrips in 3 out of 20 paired datasets (15%), and with thrips injury in 1 out of 14 paired datasets (7.1%). Soil ECa values were generally more associated with thrips variables than NDVI, with shallow ECa positively associated with adult thrips in 6 out of 21 paired datasets (28.6%), with immature thrips in 8 out of 21 paired datasets (40.0%), and with thrips injury in 8 out of 14 paired datasets (57.1%). The greater frequency of positive associations between thrips variables and soil ECa suggests a greater potential for site-specific management, particularly in the Coastal Plain of the southeastern United States, where soil types are highly variable.

Dementia-like pathology in type-2 diabetes: A novel microRNA mechanism.

Although type-2 diabetes (T2D) has been reported to increase the risk of cognitive dysfunction and dementia, the underlying mechanisms remain unclear. Dementia-like pathology is attributed to the accumulation of cellular prion protein (PrPc) which plays a role in cognitive dysfunction. However, its involvement and regulation in diabetic dementia-like pathology is not well understood. Using T2D db/db (leptin receptor knockout) mice subjected to object recognition and Y-maze behavioral tests, we determined that short-term memory was compromised and that the mice displayed abrupt spontaneous behaviour compared to db/m control mice. MicroRNA analysis using qRT2-PCR array demonstrated a significant reduction in the transcript expression of microRNA-146a (miR-146a) in the brain of T2D db/db mice as compared to db/m controls. The sequence matching tools validated the binding of miR-146a to a conserved domain of the PrPc gene. Administration of mouse brain endothelial cell-derived exosomes (BECDEs) loaded with miR-146a into the brain's ventricle of T2D db/db mice attenuated brain PrPc levels and restored short-term memory function though not significant. Also, we observed hyperphosphorylation of tau through decreased expression of glycogen synthase kinase-3 in T2D db/db brains that regulates microtubule organization and memory function. We conclude that underexpression of miR-146a upregulates PrPc production in T2D db/db mice and the delivery of BECDEs loaded with a miR-146a can down regulate PrPc levels and restore short term memory function up to a certain extent.

Phosphorylation of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) by Akt promotes stability and mitogenic function of S-phase kinase-associated protein-2 (Skp2).

The regulation of the cell cycle by the ubiquitin-proteasome system is dependent on the activity of E3 ligases. Skp2 (S-phase kinase associated protein-2) is the substrate recognition subunit of the E3 ligase that ubiquitylates the cell cycle inhibitors p21(cip1) and p27(kip1) thus promoting cell cycle progression. Increased expression of Skp2 is frequently observed in diseases characterized by excessive cell proliferation, such as cancer and neointima hyperplasia. The stability and cellular localization of Skp2 are regulated by Akt, but the molecular mechanisms underlying these effects remain only partly understood. The scaffolding protein Ezrin-Binding Phosphoprotein of 50 kDa (EBP50) contains two PDZ domains and plays a critical role in the development of neointimal hyperplasia. Here we report that EBP50 directly binds Skp2 via its first PDZ domain. Moreover, EBP50 is phosphorylated by Akt on Thr-156 within the second PDZ domain, an event that allosterically promotes binding to Skp2. The interaction with EBP50 causes cytoplasmic localization of Skp2, increases Skp2 stability and promotes proliferation of primary vascular smooth muscle cells. Collectively, these studies define a novel regulatory mechanism contributing to aberrant cell growth and highlight the importance of scaffolding function of EBP50 in Akt-dependent cell proliferation.

Genetic deletion of toll-like receptor 4 on platelets attenuates experimental pulmonary hypertension.

RATIONALE: Recent studies demonstrate a role for toll-like receptor 4 (TLR4) in the pathogenesis of pulmonary hypertension (PH); however, the cell types involved in mediating the effects of TLR4 remain unknown. OBJECTIVES: The objective of this study was to determine the contribution of TLR4 expressed on nonparenchymal cells to the pathogenesis of PH. METHODS AND RESULTS: TLR4 bone marrow chimeric mice revealed an equal contribution of TLR4 on nonparenchymal and parenchymal cells in the pathogenesis of PH as determined by measuring right ventricular (RV) systolic pressure and RV hypertrophy. However, the deletion of TLR4 from myeloid lineage cells had no effect on the development of PH because we found no difference in RV systolic pressure or RV hypertrophy in wild-type versus LysM-TLR4(-/-) mice. To explore the potential role of platelet TLR4 in the pathogenesis of PH, platelet-specific TLR4(-/-) mice were generated (PF4-TLR4(-/-) mice). TLR4(-/-) platelets from either global TLR4(-/-) or PF4-TLR4(-/-) mice were functional but failed to respond to lipopolysaccharide, demonstrating a lack of TLR4. PF4-TLR4(-/-) mice demonstrated significant protection from hypoxia-induced PH, including attenuated increases in RV systolic pressure and RV hypertrophy, decreased platelet activation, and less pulmonary vascular remodeling. The deletion of TLR4 from platelets attenuated serotonin release after chronic hypoxia, and lipopolysaccharide-stimulated platelets released serotonin and promoted pulmonary artery smooth muscle cell proliferation in a serotonin-dependent manner. CONCLUSIONS: Our data demonstrate that TLR4 on platelets contributes to the pathogenesis of PH and further highlights the role of platelets in PH.

High mobility group Box 1 inhibits human pulmonary artery endothelial cell migration via a Toll-like receptor 4- and interferon response factor 3-dependent mechanism(s).

In pulmonary hypertension the loss of precapillary arterioles results from vascular injury causing endothelial dysfunction. Endothelial cell migration and proliferation are critical for vascular regeneration. This study focused on the effect of high mobility group box 1 protein (HMGB1) on these critical processes. HMGB1 had no effect on human pulmonary artery endothelial cell (HPAEC) proliferation. In contrast, treatment of HPAECs with HMGB1 dose-dependently inhibited VEGF-stimulated HPAEC migration. The effect of HMGB1 on HPAEC migration was TLR4-dependent because it was reversed by TLR4 siRNA or TLR4-neutralizing antibody. Exposure of HPAECs to hypoxia caused translocation and release of HMGB1 and inhibition of HPAEC migration. The effect of hypoxia on HPAEC migration was mediated by HMGB1 because HMGB1-neutralizing antibody but not control IgG restored HPAEC migration. Likewise, TLR4 siRNA but not control siRNA reversed the inhibitory effect of hypoxia in HPAECs. The canonical TLR4 signaling pathway requires the adaptor protein MyD88 and leads to downstream NFκB activation. Interestingly, HMGB1 failed to stimulate NFκB translocation to the nucleus, but instead activated an alternative pathway characterized by activation of interferon response factor 3 (IRF3). This was in contrast to human umbilical vein endothelial cells in which HMGB1 stimulated nuclear translocation of NFκB but not IRF3. IRF3 siRNA, but not MyD88 siRNA, reversed the inhibitory effect of HMGB1 on HPAEC migration. These data demonstrate that HMGB1 inhibits HPAEC migration, a critical process for vascular regeneration, via TLR4- and IRF3-dependent mechanisms.

Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) and nuclear factor-κB (NF-κB): a feed-forward loop for systemic and vascular inflammation.

The interaction between vascular cells and macrophages is critical during vascular remodeling. Here we report that the scaffolding protein, ezrin-binding phosphoprotein 50 (EBP50), is a central regulator of macrophage and vascular smooth muscle cells (VSMC) function. EBP50 is up-regulated in intimal VSMC following endoluminal injury and promotes neointima formation. However, the mechanisms underlying these effects are not fully understood. Because of the fundamental role that inflammation plays in vascular diseases, we hypothesized that EBP50 mediates macrophage activation and the response of vessels to inflammation. Indeed, EBP50 expression increased in primary macrophages and VSMC, and in the aorta of mice, upon treatment with LPS or TNFα. This increase was nuclear factor-κB (NF-κB)-dependent. Conversely, activation of NF-κB was impaired in EBP50-null VSMC and macrophages. We found that inflammatory stimuli promote the formation of an EBP50-PKCζ complex at the cell membrane that induces NF-κB signaling. Macrophage activation and vascular inflammation after acute LPS treatment were reduced in EBP50-null cells and mice as compared with WT. Furthermore, macrophage recruitment to vascular lesions was significantly reduced in EBP50 knock-out mice. Thus, EBP50 and NF-κB participate in a feed-forward loop leading to increased macrophage activation and enhanced response of vascular cells to inflammation.

Impact of epidermal growth factor receptor (EGFR) cell surface expression levels on effector mechanisms of EGFR antibodies.

The epidermal growth factor receptor (EGFR) is a widely expressed Ag that is successfully targeted in tumor patients by mAbs or tyrosine kinase inhibitors. A clinical study in non-small cell lung cancer patients demonstrated a positive correlation between EGFR expression levels and the therapeutic efficacy of the EGFR mAb cetuximab. However, the impact of EGFR expression on the different mechanisms of action (MoAs) triggered by the EGFR mAb has not been defined. In this study, BHK-21 cells were stably transfected to express different EGFR levels, which were quantified by immunofluorescence and immunohistochemistry and compared with EGFR levels of clinical non-small cell lung cancer samples. These cells were used to systematically investigate the impact of target Ag expression levels on Fab- or Fc-mediated MoAs of EGFR mAb. A negative correlation between EGFR levels and potency of Fab-mediated MoA was observed. Interestingly, Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells, monocytes, or polymorphonuclear cells as well as complement-dependent cytotoxicity positively correlated with the number of EGFR molecules. In comparison with ADCC by mononuclear cells, polymorphonuclear cell-mediated ADCC and complement-dependent cytotoxicity required higher EGFR expression levels and higher mAb concentrations to trigger significant tumor cell killing. This correlation between EGFR expression levels and Fc-mediated MoA was confirmed in an independent panel of human tumor cell lines carrying diverse genetic alterations. Furthermore, RNA interference-induced knockdown experiments reinforced the impact of EGFR expression on tumor cell killing by EGFR mAb. In conclusion, these results suggest that EGFR expression levels may determine distinct patterns of MoAs that contribute to the therapeutic efficacy of EGFR mAb.

Hippocampus and medial prefrontal cortex contributions to trace and contextual fear memory expression over time.

Previous work has shown that damage to the dorsal hippocampus (DH) occurring at recent, but not remote, timepoints following acquisition produces a deficit in trace conditioned fear memory expression. The opposite pattern has been observed with lesions to the medial prefrontal cortex (mPFC). The present studies address: (1) whether these lesion effects are observable within 30 d of training; (2) whether lesions of the ventral hippocampus (VH) produce temporally graded retrograde amnesia similar to DH lesions; and (3) whether the lesion-to-test interval critically contributes to these lesion deficits. In Experiment 1, excitotoxic lesions of the DH, VH, or mPFC were made at 1 or 30 d following trace fear conditioning. DH and VH lesioned animals showed a deficit in freezing to the tone at the recent, but not remote, timepoint. Medial PFC lesioned animals showed the opposite pattern. In Experiment 2, lesions to DH, VH, or mPFC were made 1 d following training, while testing occurred 30 d later. There were no deficits in freezing to the tone in any lesion condition compared to controls. These results suggest that systems consolidation of trace fear memory occurs within 30 d of acquisition, but does not depend on hippocampus-mPFC interactions during this period.