Codon-Optimized and de novo-Synthesized E-Selectin/AAV2 Dose-Response Study for Vascular Regeneration Gene Therapy.

OBJECTIVE: This study focuses on dose-response investigation using a codon-optimized and de novo-synthesized E-Selectin/AAV2 (E-Sel/AAV2) vector in preparation for Investigational New Drug enabling of subsequent clinical studies. BACKGROUND: Gene therapy is a potential solution for patients suffering from chronic limb-threatening ischemia. Understanding the dose for effective gene delivery is crucial for future Investigational New Drug-enabling studies. METHODS: Expression of the codon-optimized E-Selectin gene was assessed by flow cytometry following in vitro cell transfection assay and RT-qPCR for murine limbs injected in vivo with AAV-m-E-Selectin (E-Sel/AAV2). Dose-response studies involved 3 cohorts of FVB/NJ mice (n=6/group) with escalating log doses of E-Selectin/AAV2 injected intramuscularly in divided aliquots, ranging from 2 × 10 9 VG to 2 × 10 11 VG, into ischemic limbs created by left femoral artery/vein ligation/excision and administration of nitric oxide synthase inhibitor, L-NAME. Limb perfusion, extent of gangrene free limb, functional limb recovery, and therapeutic angiogenesis were assessed. RESULTS: Codon-optimized E-Sel/AAV2 gene therapy exhibits a superior expression level than WT E-Sel/AAV2 gene therapy both in vitro and in vivo. Mice treated with a high dose (2 × 10 11 VG) of E-Sel/AAV2 showed significantly improved perfusion indices, lower Faber scores, increased running stamina, and neovascularization compared with lower doses tested with control groups, indicating a distinct dose-dependent response. No toxicity was detected in any of the animal groups studied. CONCLUSIONS: E-Sel/AAV2 Vascular Regeneration Gene Therapy holds promise for enhancing the recovery of ischemic hindlimb perfusion and function, with the effective dose identified in this study as 2 × 10 11 VG aliquots injected intramuscularly.

Outcomes After Pectus Excavatum Repair: A Nationwide Comparison of Nuss Versus Ravitch Operations.

INTRODUCTION: Pectus excavatum is the most prevalent chest wall deformity. Repair may be offered via Nuss or Ravitch technique. This study aims to investigate the outcomes of these repairs using a national cohort. METHODS: The Nationwide Readmission Database was queried from 2016 to 2020 for patients aged 12-21 y old with pectus excavatum. Demographics, hospital characteristics, and outcomes were analyzed using standard statistical tests. The results were weighted for national estimates. RESULTS: A total of 10,053 patients with pectus excavatum underwent repair (86% Nuss, n = 8673 and 14% Ravitch, n = 1380). Baseline characteristics were similar between cohorts. Nuss repair patients traveled more frequently out of state for repair (10.5% versus 8.7%) and were in the highest income quartiles (61.1% versus 57.3%), both P < 0.05. Of reporting hospitals, 60% performed only the Nuss procedure. The Ravitch cohort experienced higher rates of complications during index admission, including chest tube placement (5.1% versus 2.2%), bleeding (2.4% versus 0.6%), air leak (0.9% versus 0.3%), and respiratory failure (1.0% versus 0.3%), as well as longer median length of stay (4 versus 3 d), all with a P value < 0.05. While both cohorts had similar overall readmission rates, Ravitch repairs had higher rates of readmissions for bleeding (18.3% versus 4.5%), pain (32.9% versus 13.5%), and psychiatric complications (31.7% versus 21.2%), all with a P value < 0.05. Ravitch repairs also incurred higher total hospital costs ($18,670 versus 17,462, P < 0.001). CONCLUSIONS: Nuss repairs were associated with fewer index complications with no increase in readmissions compared to Ravitch procedures. However, disparities may exist in access to Nuss repair.

Timing of Pediatric Incarcerated Inguinal Hernia Repair: A Review of Nationwide Readmissions Data.

INTRODUCTION: In pediatric patients, incarcerated inguinal hernias are often repaired on presentation. We hypothesize that in appropriate patients, repair may be safely deferred. METHODS: The Nationwide Readmissions Database was used to identify pediatric patients (aged < 18 y) with incarcerated inguinal hernia from 2010 to 2014. Patients were stratified by management approach (Early Repair versus Deferral). Overall frequencies of these operative strategies were calculated. Propensity score matching was then performed to control for patient age, comorbidities, perinatal conditions, and congenital anomalies. Outcomes including complications, surgical procedures, and readmissions were compared. Outpatient surgeries were not assessed. RESULTS: Among 6148 total patients with incarcerated inguinal hernia, the most common strategy was to perform Early Repair (88% versus 12% Deferral). Following propensity score matching, the cohort included 1288 patients (86% male, average age 1.7 ± 4.1 years). Deferral was associated with equivalent rates of readmission within one year (13% versus 15%, P = 0.143), but higher readmissions within the first 30 days (7% versus 3%, P = 0.002) than Early Repair. Deferral patients had lower rates of orchiectomy (2% versus 5%, P = 0.001), wound infections (< 2% versus 2%, P = 0.020), and other infections (7% versus 15%, P < 0.001). The frequency of other complications including bowel resection, oophorectomy, testicular atrophy, sepsis, and pneumonia were equivalent between groups. Three percent of Deferrals had a diagnosis of incarceration on readmission. CONCLUSIONS: Deferral of incarcerated inguinal hernia repair at index admission is associated with higher rates of hospital readmissions within the first 30 days but equivalent readmission within the entire calendar year. These patients are at risk of repeat incarceration but have significantly lower rates of orchiectomy than their counterparts who undergo inguinal hernia repair at the index admission. We propose that prospective studies be performed to identify good candidates for Elective Deferral following manual reduction and overnight observation. Such studies must capture outpatient surgical outcomes.

Fibroblasts in Diabetic Foot Ulcers.

Fibroblasts are stromal cells ubiquitously distributed in the body of nearly every organ tissue. These cells were previously considered to be "passive cells", solely responsible for ensuring the turnover of the extracellular matrix (ECM). However, their versatility, including their ability to switch phenotypes in response to tissue injury and dynamic activity in the maintenance of tissue specific homeostasis and integrity have been recently revealed by the innovation of technological tools such as genetically modified mouse models and single cell analysis. These highly plastic and heterogeneous cells equipped with multifaceted functions including the regulation of angiogenesis, inflammation as well as their innate stemness characteristics, play a central role in the delicately regulated process of wound healing. Fibroblast dysregulation underlies many chronic conditions, including cardiovascular diseases, cancer, inflammatory diseases, and diabetes mellitus (DM), which represent the current major causes of morbidity and mortality worldwide. Diabetic foot ulcer (DFU), one of the most severe complications of DM affects 40 to 60 million people. Chronic non-healing DFU wounds expose patients to substantial sequelae including infections, gangrene, amputation, and death. A complete understanding of the pathophysiology of DFU and targeting pathways involved in the dysregulation of fibroblasts are required for the development of innovative new therapeutic treatments, critically needed for these patients.

Augmented Safety Profile of Ultrasound-Guided Gluteal Fat Transfer: Retrospective Study With 1815 Patients.

BACKGROUND: Gluteal augmentation with autologous fat transfer is one of the fastest growing aesthetic surgical procedures worldwide over the past decade. However, this procedure can be associated with high mortality from fatal pulmonary fat embolism events caused by intramuscular injection of fat. Ultrasound-guided fat grafting allows visualization of the transfer in the subcutaneous space, avoiding intramuscular injection. OBJECTIVES: The aim of this study was to assess the safety and efficacy of gluteal fat grafting performed with ultrasound-guided cannulation. METHODS: A retrospective chart review of all patients undergoing ultrasound-guided gluteal fat grafting at the authors' center between 2019 and 2022 was performed. All cases were performed by board-certified and board-eligible plastic surgeons under general anesthesia in ASA Class I or II patients. Fat was only transferred to the subcutaneous plane when over the gluteal muscle. Patients underwent postoperative follow-up from a minimum of 3 months up to 2 years. Results were analyzed with standard statistical tests. RESULTS: The study encompassed 1815 female patients with a median age of 34 years. Controlled medical comorbidities were present in 14%, with the most frequent being hypothyroidism (0.7%), polycystic ovarian syndrome (0.7%), anxiety (0.6%), and asthma (0.6%). Postoperative complications occurred in 4% of the total cohort, with the most common being seroma (1.2%), local skin ischemia (1.2%), and surgical site infection (0.8%). There were no macroscopic fat emboli complications or mortalities. CONCLUSIONS: These data suggest that direct visualization of anatomic plane injection through ultrasound guidance is associated with a low rate of complications. Ultrasound guidance is an efficacious adjunct to gluteal fat grafting and is associated with an improved safety profile that should be considered by every surgeon performing this procedure.

Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs.

OBJECTIVE: Here, we report a new method to increase the therapeutic potential of mesenchymal stem/stromal cells (MSCs) for ischemic wound healing. We tested biological effects of MSCs modified with E-selectin, a cell adhesion molecule capable of inducing postnatal neovascularization, on a translational murine model. BACKGROUND: Tissue loss significantly worsens the risk of extremity amputation for patients with chronic limb-threatening ischemia. MSC-based therapeutics hold major promise for wound healing and therapeutic angiogenesis, but unmodified MSCs demonstrate only modest benefits. METHODS: Bone marrow cells harvested from FVB/ROSA26Sor mTmG donor mice were transduced with E-selectin-green fluorescent protein (GFP)/AAV-DJ or GFP/AAV-DJ (control). Ischemic wounds were created via a 4 mm punch biopsy in the ipsilateral limb after femoral artery ligation in recipient FVB mice and subsequently injected with phosphate-buffered saline or 1×10 6 donor MSC GFP or MSC E-selectin-GFP . Wound closure was monitored daily for 7 postoperative days, and tissues were harvested for molecular and histologic analysis and immunofluorescence. Whole-body DiI perfusion and confocal microscopy were utilized to evaluate wound angiogenesis. RESULTS: Unmodified MSCs do not express E-selectin, and MSC E-selectin-GFP gain stronger MSC phenotype yet maintain trilineage differentiation and colony-forming capability. MSC E-selectin-GFP therapy accelerates wound healing compared with MSC GFP and phosphate-buffered saline treatment. Engrafted MSC E-selectin-GFP manifest stronger survival and viability in wounds at postoperative day 7. Ischemic wounds treated with MSC E-selectin-GFP exhibit more abundant collagen deposition and enhanced angiogenic response. CONCLUSIONS: We establish a novel method to potentiate regenerative and proangiogenic capability of MSCs by modification with E-selectin/adeno-associated virus. This innovative therapy carries the potential as a platform worthy of future clinical studies.

Outcomes of Incidental Appendectomy During Ovarian Operations in a National Pediatric Cohort.

INTRODUCTION: The utility of incidental appendectomy (IA) during many ovarian operations has not been evaluated in the pediatric population. This study sought to compare outcomes after ovarian surgery with IA in the pediatric population. METHODS: Females (≤20 y old) undergoing ovarian surgeries (oophorectomy, detorsion and/or drainage) were identified from the Nationwide Readmissions Database (2016-2018). Those with appendicitis were excluded. A propensity score-matched analysis (PSMA) with 46 covariates (demographics, comorbidities, hospitalization factors, etc.) was performed between those receiving ovarian surgery with or without IA. RESULTS: There were 13,202 females (median age 17 [IQR 14-20] y old) who underwent oophorectomy (90%), detorsion (26%), and/or ovarian drainage (13%). There were more episodes of torsion in the PSMA cohort receiving ovarian surgery alone (17% versus 10% IA; P = 0.016), while other indications (ovarian mass, cyst) were similar. Open (66% versus 34% laparoscopic) IAs were more frequent. Length of stay (LOS) was longer for those undergoing IA (3 [2-4] versus 2 [2-4] days ovarian surgery alone; P < 0.001). There was a higher rate of postoperative GI complications in the IA cohort. Subgroup analysis of those undergoing laparoscopic operations demonstrated no difference in LOS or postoperative complications between patients undergoing IA or not. CONCLUSIONS: These data indicate that IA in pediatric ovarian operations is associated with longer LOS and higher GI postoperative complications. However, laparoscopic IA was not associated with higher cost, complications, LOS, or readmissions. This suggests that IA performed during ovarian surgeries in select patients may be cost-effective and worthy of future study.

Higher Complication Rates for Total versus Partial Thyroidectomy in the Pediatric Population.

INTRODUCTION: This study aims to analyze the relative risks for total thyroidectomies by comparing complication rates for total versus partial thyroidectomy in the pediatric population. METHODS: We queried the Kids' Inpatient Database (KID) 1997-2012 for all cases of total (n = 3253) or partial (n = 2380) thyroidectomy. We then designed a propensity score matching model and compared total versus partial thyroidectomy based on surgical complications and outcomes. RESULTS: In our cohort, the median age was 16 years and 79% were females. Those treated at a specialty pediatric hospital or pediatric unit in a general hospital comprised 73% of all patients. The most common indications for surgery were malignancy (46%) and goiter (42%). The most common complications were hypocalcemia and nerve injury with an unweighted incidence of 9% (n = 174) and 3% (n = 57) respectively. When compared to partial thyroidectomy, total thyroidectomy was associated with increased rates of postoperative complications. Additionally, the median length of stay was significantly higher for total thyroidectomy patients. CONCLUSIONS: This is the largest analysis to date comparing outcomes for total versus partial thyroidectomy in the pediatric population. Surgeons should consider the increased rates of hypocalcemia and nerve injury complications when selecting total compared to partial thyroidectomy in children.

Outcomes of Abdominal Firearm Injury and Damage Control Laparotomy in the Pediatric Population.

INTRODUCTION: Firearm injuries (GSW) in the pediatric population is a public health crisis. Little is known about the outcomes of damage control laparotomy (DCL) following abdominal GSW. This study aims to evaluate outcomes from abdominal GSWs in the pediatric population. METHODS: The trauma registry from an urban Level 1 trauma was queried for pediatric (0-18 y) GSW was queried from September 2013 to June 2020. Demographics, clinical variables, outcomes, readmissions, and recidivism were analyzed. RESULTS: Abdominal GSW were identified in 83 patients (17% of all GSW). The median age was 16 [15-17], 84% were male and 86% Black. Violent intent accounted for 90% of GSW. The injury severity score was 16 [9-26] and 80% went directly from the resuscitation bay to the operating room. Laparotomy was required in 87% of patients, and surgery was not required in any patient initially managed nonoperatively. The most common complications were intraabdominal infection (20%), other infections (13%), and small bowel obstruction (8%). DCL with temporary abdominal closure was performed in 16% of laparotomies and was associated with a longer length of stay, more infections, but similar rates of readmission and mortality. Overall mortality was 13%, with all but one patient expiring in the resuscitation bay or the operating room. All patients who underwent DCL survived to discharge. CONCLUSIONS: Abdominal firearm injuries have high morbidity and mortality in the pediatric population. Damage control operations for abdominal GSWs are a valuable surgical option with similar outcomes to primary abdominal closure after initial injury survival.

Radical Resection of Pediatric Fibrosarcoma Is Not Associated With Survival Benefit: A Nationwide Database Analysis.

INTRODUCTION: Fibrosarcoma is one of the most common nonrhabdomyosarcoma soft tissue sarcomas in the pediatric population. Surgical resection is the cornerstone of treatment; however, optimal factors regarding the extent of fibrosarcoma resection in localized versus regional disease is poorly understood. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients who are 19 y old or younger with a diagnosis of fibrosarcoma from 1975 to 2016. Kaplan-Meier analyses were performed for disease-specific survival on clinical and pathologic variables. Multivariate analysis was performed based on significant predictors of disease-specific survival. RESULTS: There were 1290 patients (median age 13 [7-17] y) identified with fibrosarcoma. The overall survival rate at 20 y was 93%. Radical resection was performed on 22%, 40%, and 52% of patients with localized, regional, and distant Surveillance, Epidemiology, and End Results disease stage, respectively. Chemotherapy (P < 0.001), radiation (P < 0.001), histology (P < 0.001), and stage (P = 0.004) were significant predictors of increased mortality using univariate Kaplan-Meier analysis. Most patients (86%) with localized or regional stage who underwent radiation had fibrosarcomas of nondermatofibrosarcoma histology (P < 0.001). Dermatofibrosarcoma subtype comprised most radical resections (41%). Excluding distant stage, nondermatofibroma histology (hazard ratio 16.94, 95% confidence interval 3.77-76.01) and regional stage (hazard ratio 8.15, 95% confidence interval 2.93-22.69) were independent prognostic factors of mortality (both P < 0.001). Radical resection was not a significant independent prognostic indicator of survival. CONCLUSIONS: Nondermatofibrosarcoma subtype is independently associated with increased mortality. Although surgery remains the mainstay of treatment, the extent of resection is not a predictor of survival for patients with the localized and regional stage of disease.

Outcomes of Gastrostomy Tubes in Newborns With Congenital Heart Disease and Comparison of Techniques.

INTRODUCTION: Gastrostomy tube (GT) placement for enteral access is one of the most common procedures for infants with numerous conditions such as congenital heart disease (CHD). Discrepancies in the literature exist regarding outcomes of newborns with CHD undergoing GT placement. This study sought to characterize postoperative outcomes and readmission complications in this patient population. METHODS: The Nationwide Readmission Database was queried from 2010 to 2014 for all newborns who underwent GT placement during their index hospitalization. Newborns with or without CHD other than an isolated atrial or ventricular septal defect were compared using standard statistical tests. A propensity score-matched analysis was performed among newborns with or without CHD using > 100 covariates. RESULTS: Seven thousand seven hundred thirty six patients underwent GT placement. Newborns with CHD (27%) more frequently underwent open GT (59% versus 55%) and less frequently underwent laparoscopic (17% versus 19%) or percutaneous (24% versus 26%) GT placement compared to those without CHD, P = 0.043. GT-related complications on index admission were similar between groups (7% versus 7%, P = 0.770). Newborns with CHD had higher overall readmission rates (39% versus 31%), more GT-related readmission complications (7% versus 3%), and higher readmission costs ($35,787 versus $20,073) compared to newborns without CHD, all P < 0.001. Laparoscopic GT was associated with the lowest rate of GT-related complications (0%) and overall readmission rates (27%) compared to open or percutaneous endoscopic gastrostomy (all P < 0.001). CONCLUSIONS: Compared to newborns without CHD, newborns with CHD had higher rates of overall readmissions, readmission costs, and GT-related complications on readmission. The laparoscopic GT approach was underused despite fewer complications and readmissions.

National burden of pediatric abusive injuries: patterns vary by age.

PURPOSE: Child abuse is often unrecognized by healthcare practitioners. This study sought to characterize pediatric abuse injury patterns and associated mortality rates in a nationwide cohort. METHODS: The Kids' Inpatient Database (1997-2012) was queried for patients < 18 years old with a diagnosis of child abuse (utilizing ICD-9 codes for abusive head trauma [AHT], neglect, physical, emotional, sexual, and other abuse). Demographic factors, mortality, and injury patterns were compared with demographic factors using standard statistical tests. RESULTS: > 39,000 children were hospitalized for abuse from 1997 to 2012. The majority were Caucasian (36%), male (51%) and < 4 years old (70%). Most sustained physical abuse (53%), followed by AHT (14%), sexual (9%) and emotional abuse (2%). Multiple injuries were sustained by 44% of patients. Mortality was 4% (n = 1476). Burns (2%) and intrathoracic (2%) injuries had the highest mortality compared to other injuries (21% and 19%, respectively; both P < 0.001). Emotional abuse (5%) and neglect (1%) were highest in those ≥ 13 years old (both P  = 0.001). CONCLUSION: Physical injuries are less common in adolescents (13-18 years) hospitalized for abuse. However, they are more likely to report emotional abuse and neglect, which has not been compared in previous studies. Intrathoracic injuries and AHT are associated with significant mortality.

Risk factors associated with recent opioid-related hospitalizations in children: a nationwide analysis.

PURPOSE: Identifying at-risk children can provide a crucial opportunity for preventative measures to avoid opioid addiction. This study sought to determine at-risk pediatric patients that were previously hospitalized due to other causes prior to their opioid-related admission. METHODS: The Nationwide Readmissions Database (2010-2014) was queried for children 1-18 years old with an opioid-related hospitalization. Previous admissions (up to 1 year prior) and associated diagnoses were compared. Results were weighted for national estimates. RESULTS: 51,349 opioid-related hospitalizations were identified with an overall in-hospital mortality of 0.8%. Seventeen percent had a previous admission during the same calendar year of which 44% had > 1 and 11% had ≥ 5 prior admissions. Only 4% of prior admissions occurred at a different hospital. Males and females were equally represented, and 82% were ≥ 13 years old. Only 16% of previously admitted patients underwent a major surgical procedure during a previous hospitalization. The most common concomitant diagnoses for patients with prior hospitalizations were drug abuse (37%), chronic pulmonary disease (18%), and depression (10%). CONCLUSION: Opioid-related hospitalizations often occur among children with multiple recent admissions, usually to the same hospital. Most patients do not have a history of cancer or recent surgery to account for their opioid use.

Nationwide outcomes of incidental appendectomy during cholecystectomy versus cholecystectomy alone in children: a propensity score-matched analysis.

BACKGROUND: The utility of incidental appendectomy, appendectomy during another index surgery in the absence of appendicitis, has not been evaluated in the pediatric population during cholecystectomy. This study sought to compare nationwide outcomes after cholecystectomy with incidental appendectomy in children. METHODS: Patients ≤ 18 years old who underwent cholecystectomy from 2010-2014 were identified from the Nationwide Readmissions Database. A propensity score-matched analysis (PSMA) with > 40 covariates including demographics, comorbidities, and hospitalization factors was performed between those receiving cholecystectomy alone versus incidental appendectomy at the time of cholecystectomy. RESULTS: 34,390 patients underwent cholecystectomy (median age 15 [13-17] years). Laparoscopic (92%) approach was utilized most frequently, with 2% requiring conversion to open cholecystectomy. PSMA demonstrated a higher frequency of perforation or laceration of adjacent organs occurring in those receiving cholecystectomy alone during index admission. No significant differences in readmissions within 30 days or the calendar year were detected. Those undergoing cholecystectomy alone had higher overall readmission costs ($11,783 [$4942-$39,836] vs. $6,100 [$2358-$19,719] cholecystectomy with appendectomy; p = 0.010). CONCLUSION: This nationwide PSMA indicates that incidental appendectomy in pediatric cholecystectomies is not associated with higher postoperative complications, cost, or readmissions. This suggests that incidental appendectomy during cholecystectomy is safe, cost-effective, and worthy of future study. LEVEL OF EVIDENCE: Level III.

Neoadjuvant Therapy in Stage II/III Rectal Cancer: A Retrospective Study in a Disparate Population and the Effect on Survival.

BACKGROUND: Kentucky has one of the highest rectal cancer incidences in the United States. High poverty rates have led to poor insurance coverage and inadequate access to care. The treatment of locally advanced rectal cancer utilizes a multimodal regimen requiring regular access to expert care. The rate of receipt of neoadjuvant therapy in Kentucky is unknown. OBJECTIVE: This study aimed to evaluate the rate and factors associated with the receipt of neoadjuvant therapy for localized advanced rectal cancer in Kentucky and the effect on overall survival. DESIGN: This is a retrospective database review. SETTINGS: This study was conducted by utilizing the Kentucky Cancer Registry at an academic center. PATIENTS: All patients diagnosed with stage II/III rectal adenocarcinoma from 2005 to 2015 in the Commonwealth of Kentucky were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the factors associated with nonreceipt of neoadjuvant therapy and overall survival. RESULTS: Of 1896 patients, only 46.8% received neoadjuvant therapy. Factors associated with not receiving neoadjuvant therapy included older age, female sex, low education level, high poverty level, and treatment at nonacademic centers. Survival analysis demonstrated significantly improved survival in patients receiving neoadjuvant therapy compared with other treatment regimens. LIMITATIONS: This study was limited by the retrospective nature of the review and by unmeasured confounders. CONCLUSIONS: Our study was the first to evaluate the factors behind the low rates of neoadjuvant therapy for locally advanced rectal cancer in Kentucky. Neoadjuvant therapy in this population is beneficial for survival; efforts should be made in policy and education with focus on older patients, female patients, and treatment at nonacademic centers. Centralization of rectal cancer care improves outcomes, but we must be aware of the effect it may have on disparate populations with poor access. See Video Abstract at http://links.lww.com/DCR/B596. TERAPIA NEOADYUVANTE EN EL MANEJO DEL CNCER DE RECTO EN ESTADIO II / III UN ESTUDIO RETROSPECTIVO EN UNA POBLACIN DISPAR Y EL EFECTO EN LA SUPERVIVENCIA: ANTECEDENTES:El estado de Kentucky tiene una de las mayores incidencias de cáncer de recto en los EE. UU. Debido a una alta tasa de pobreza, el porcentaje de la población que cuenta con seguro de salud, es muy limitado, y por lo tanto el acceso a una atención de alto nivel es muy bajo. El tratamiento del cáncer de recto localmente avanzado, es multidisciplinario, lo que exige acceso y disponibilidad a un grupo experto. Se desconoce la tasa de pacientes que reciben terapia neoadyuvante en Kentucky.OBJETIVO:Establecer la tasa y los factores asociados con el uso de terapia neoadyuvante en el tratamiento del cáncer de recto localmente avanzado en Kentucky, y su efecto en la supervivencia global.DISEÑO:Revisión retrospectiva de una base de datos.ESCENARIO:Este estudio se llevó a cabo utilizando el Registro de Cáncer de Kentucky en un centro académico.PACIENTES:Se incluyen todos los pacientes diagnosticados con adenocarcinoma de recto, de la Mancomunidad (Commonwealth) de Kentucky, en estadio II / III entre 2005 y 2015.PRINCIPALES MEDIDAS DE RESULTADO:Establecer los factores asociados con el hecho de no recibir terapia neoadyuvante; y establecer la supervivencia global.RESULTADOS:De 1896 pacientes evaluados, solo el 46,8% recibió terapia neoadyuvante. Los factores asociados, para no haber recibido terapia neoadyuvante fueron: la edad avanzada, sexo femenino, bajo nivel educativo, alto nivel de pobreza y tratamiento en centros no académicos. El análisis de la supervivencia mostró una supervivencia significativamente mejor en los pacientes que recibieron terapia neoadyuvante en comparación con otros esquemas de tratamiento.LIMITACIONES:Revisión retrospectiva, factores de confusión no medidos.CONCLUSIONES:Nuestro estudio ha sido el primero en evaluar los factores determinantes de las bajas tasas de terapia neoadyuvante para el tratamiento del cáncer de recto localmente avanzado en Kentucky. La terapia neoadyuvante mejora y favorece la supervivencia en esta población, por lo tanto se deben hacer esfuerzos en las políticas de salud, así como en educación, enfocados a los pacientes mayores, pacientes femeninas y tratamiento en centros no académicos. El centralizar la atención del cáncer de recto, mejora los resultados, pero debemos ser conscientes del efecto que puede tener en poblaciones desiguales económicamente, con acceso deficiente a la posibilidad de recibir atención de alto nivel. Consulte Video Resumen en http://links.lww.com/DCR/B596.

Direct Retrograde Bypass is Preferable to Antegrade Bypass for Open Mesenteric Revascularization.

BACKGROUND: Mesenteric bypass grafts can be constructed either antegrade or retrograde. There is debate regarding which is the optimal approach. We have modified the technique for retrograde mesenteric revascularization using a direct open retrograde revascularization (DORR) technique. This report is a retrospective single-institution study that describes the DORR technique and compares it with antegrade mesenteric bypass. METHODS: The medical records of patients undergoing open mesenteric bypass between January 2001 and December 2017 for mesenteric ischemia were reviewed. Patients who underwent mesenteric thromboembolectomy, retrograde stenting, or bypass for aneurysmal disease were excluded. Patient demographics, operative details, and follow-up data were recorded. Antegrade bypasses were constructed using a polyester, collagen-coated, knitted, (Maquet, Getinge Group)- bifurcated graft. The supraceliac aorta was exposed, and the Dacron graft limbs were tunneled to the celiac and/or superior mesenteric artery (SMA). The DORR was constructed by anastomosing a vein graft to an iliac artery. The vein was tunneled through the base of the small bowel mesentery to create a direct course to the SMA. When revascularization to both the SMA and celiac vessels was indicated, the vein was anastomosed to the SMA in a side-to-side fashion with the distal vein tunneled through the mesocolon and anastomosed in a end-to-side fashion to the hepatic artery. Statistical analysis was done using Student's t-test, Mann-Whitney U test, Fisher's exact test, and log-rank test with a P ≤ 0.05 considered significant. RESULTS: Forty-one patients underwent open mesenteric bypass: 16 antegrade and 25 retrograde. Patient age, gender, and body mass index were similar. Indication for operation was acute ischemia in a greater portion of patients undergoing retrograde bypass (P = 0.025). For antegrade bypasses, Dacron was used in 15 and saphenous vein in 1. The DORR bypass originated from an iliac artery (21), limb of an aortofemoral graft (2), or infrarenal aorta (2). All DORR were constructed using veins (19 femoral veins and 6 greater saphenous veins). In DORR configurations, the bypass was created to only the SMA in 23 cases (92%). By comparison, in antegrade bypasses, the bypass was constructed to both the SMA and celiac arteries in all but 1 case (P < 0.00001). Median operative time was significantly shorter for DORR compared with antegrade bypass (282 vs. 375 min; P < 0.05). Blood loss, need for second-look laparotomy, morbidity, mortality, length of stay, and discharge disposition were similar between groups. There was a shift in favor of the DORR technique in the second half of the study (4 of 15 [27%] DORR from 2001 to 2009 vs. 21 of 26 [81%] DORR from 2010 to 2017). In survivors, 57% of the antegrade cohort and 74% of the DORR cohort had documented follow-up (average, 47.5 ± 59.9 and 28.8 ± 31.3 months, respectively). No difference was noted in survival between groups. All grafts in both cohorts were patented at follow-up. CONCLUSIONS: Direct tunneling of the graft under the mesentery with the DORR technique avoids concern for kinking and has shorter operative time despite the need for vein harvest. No differences were noted in long-term survival between patient groups. The use of a venous conduit makes DORR adaptable for both chronic and acute mesenteric ischemia. These factors have resulted in the DORR technique to be our preferred method for open mesenteric revascularization.

Identification of a candidate therapeutic autophagy-inducing peptide.

The lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. Accordingly, agents that induce autophagy may have broad therapeutic applications. One approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. Here we show that a peptide, Tat-beclin 1-derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (HIV)-1 Nef-is a potent inducer of autophagy, and interacts with a newly identified negative regulator of autophagy, GAPR-1 (also called GLIPR2). Tat-beclin 1 decreases the accumulation of polyglutamine expansion protein aggregates and the replication of several pathogens (including HIV-1) in vitro, and reduces mortality in mice infected with chikungunya or West Nile virus. Thus, through the characterization of a domain of beclin 1 that interacts with HIV-1 Nef, we have developed an autophagy-inducing peptide that has potential efficacy in the treatment of human diseases.

Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding.

BACKGROUND: Semi-synthetic oleanane triterpenoid antioxidant inflammation modulators (tpAIMs) are small molecules that interact with KEAP1 cysteine residue 151 (C151) and activate NRF2. Exploration of the structure-activity relationship between the tpAIMs and KEAP1 is limited by the predominantly hydrocarbon nature of the oleanane triterpenoid pentacyclic ring structure. Therefore, we used novel, chemically-tractable, synthetic antioxidant inflammation modulators (sAIMs) to probe the stereoselectivity of the ligand-protein interaction. METHODS: We measured several parameters of NRF2 activation to assess the potency of sAIM enantiomers with natural (tpAIM-like) 4(S),5(S),10(R) or unnatural 4(R),5(R),10(S) configurations. Additionally, we determined the crystal structure of the KEAP1 BTB domain in complex with two different sAIMs. RESULTS: We found that the potencies of sAIM enantiomers in the natural configuration were similar to those of the tpAIM, RTA 405. Strikingly, sAIM enantiomers in the unnatural configuration were 10- to 40-fold less potent than their natural counterparts. Crystallographic studies of sAIMs in complex with the KEAP1 BTB domain demonstrated that these ligands form a covalent bond with C151 and revealed the presence of additional hydrogen bonds, Van der Waals interactions, and pi-stacking interactions. CONCLUSIONS: Although KEAP1 C151 is required for NRF2 activation by tpAIMs and sAIMs, interactions with other KEAP1 residues are critical for the stereospecific recognition and potency of these ligands. GENERAL SIGNIFICANCE: This work demonstrates that reversible cyanoenone Michael acceptors, such as the tpAIMs and sAIMs, can be specifically tuned to regulate redox sensitive cysteine residues on key signaling molecules, an approach with significant promise for innovative drug development.