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.

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 ).

Assessment of auditory and vestibular damage in a mouse model after single and triple blast exposures.

The use of explosive devices in war and terrorism has increased exposure to concussive blasts among both military personnel and civilians, which can cause permanent hearing and balance deficits that adversely affect survivors' quality of life. Significant knowledge gaps on the underlying etiology of blast-induced hearing loss and balance disorders remain, especially with regard to the effect of blast exposure on the vestibular system, the impact of multiple blast exposures, and long-term recovery. To address this, we investigated the effects of blast exposure on the inner ear using a mouse model in conjunction with a high-fidelity blast simulator. Anesthetized animals were subjected to single or triple blast exposures, and physiological measurements and tissue were collected over the course of recovery for up to 180 days. Auditory brainstem responses (ABRs) indicated significantly elevated thresholds across multiple frequencies. Limited recovery was observed at low frequencies in single-blasted mice. Distortion Product Otoacoustic Emissions (DPOAEs) were initially absent in all blast-exposed mice, but low-amplitude DPOAEs could be detected at low frequencies in some single-blast mice by 30 days post-blast, and in some triple-blast mice at 180 days post-blast. All blast-exposed mice showed signs of Tympanic Membrane (TM) rupture immediately following exposure and loss of outer hair cells (OHCs) in the basal cochlear turn. In contrast, the number of Inner Hair Cells (IHCs) and spiral ganglion neurons was unchanged following blast-exposure. A significant reduction in IHC pre-synaptic puncta was observed in the upper turns of blast-exposed cochleae. Finally, we found no significant loss of utricular hair cells or changes in vestibular function as assessed by vestibular evoked potentials. Our results suggest that (1) blast exposure can cause severe, long-term hearing loss which may be partially due to slow TM healing or altered mechanical properties of healed TMs, (2) traumatic levels of sound can still reach the inner ear and cause basal OHC loss despite middle ear dysfunction caused by TM rupture, (3) blast exposure may result in synaptopathy in humans, and (4) balance deficits after blast exposure may be primarily due to traumatic brain injury, rather than damage to the peripheral vestibular system.

Patient-Reported Outcome Measures in Colon and Rectal Surgery: A Systematic Review and Quality Assessment.

BACKGROUND: There is growing interest in using patient-reported outcome measures to support value-based care in colorectal surgery. To draw valid conclusions regarding patient-reported outcomes data, measures with robust measurement properties are required. OBJECTIVE: The purpose of this study was to assess the use and quality of patient-reported outcome measures in colorectal surgery. DATA SOURCES: Three major databases were searched for studies using patient-reported outcome measures in the context of colorectal surgery. STUDY SELECTION: Articles that used patient-reported outcome measures as outcome for colorectal surgical intervention in a comparative effectiveness analysis were included. Exclusion criteria included articles older than 11 years, non-English language, age <18 years, fewer than 40 patients, case reports, review articles, and studies without comparison. MAIN OUTCOME MEASURES: This was a quality assessment using a previously reported checklist of psychometric properties. RESULTS: From 2007 to 2018, 368 studies were deemed to meet inclusion criteria. These studies used 165 distinct patient-reported outcome measures. Thirty were used 5 or more times and were selected for quality assessment. Overall, the measures were generally high quality, with 21 (70%) scoring ≥14 on an 18-point scale. Notable weaknesses included management of missing data (14%) and description of literacy level (0%). LIMITATIONS: The study was limited by its use of original articles for quality assessment. Measures were selected for quality analysis based on frequency of use rather than other factors, such as impact of the article or number of patients in the study. CONCLUSIONS: Patient-reported outcome measures are widely used in colorectal research. There was a wide range of measures available, and many were used only once. The most frequently used measures are generally high quality, but a majority lack details on how to deal with missing data and information on literacy levels. As the use of patient-reported outcome measures to assess colorectal surgical intervention increases, researchers and practitioners need to become more knowledgeable about the measures available and their quality.

Short-term NAD+ supplementation prevents hearing loss in mouse models of Cockayne syndrome.

Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS (CSA -/- and CSB m/m ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD+, a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD+ levels are reduced in the cochlea of CSB m/m mice and that short-term treatment (10 days) with the NAD+ precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in CSB m/m mice. Similar, but more modest effects were observed in CSA -/- mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both CSA -/- and CSB m/m mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD(H) binding pocket which regulates its activity. Intriguingly, NAD+ supplementation rescues reduced synaptic ribbon formation in both CSA -/- and CSB m/m mutant cochleae. These findings provide valuable insight into the mechanism of CS- and ARHL-associated hearing loss, and suggest a possible intervention.