Hernandez, Matthew C.

Background The American Association for the Surgery of Trauma (AAST) has developed a grading system for emergency general surgery (EGS) conditions. We sought to validate the AAST EGS grades for patients undergoing urgent/emergent colorectal resection. Methods Patients enrolled in the “Eastern Association for the Surgery of Trauma Multicenter Colorectal Resection in EGS—to anastomose or not to anastomose” study undergoing urgent/emergent surgery for obstruction, ischemia, or diverticulitis were included. Baseline demographics, comorbidity severity as defined by Charlson comorbidity index (CCI), procedure type, and AAST grade were prospectively collected. Outcomes included length of stay (LOS) in-hospital mortality, and surgical complications (superficial/deep/organ-space surgical site infection, anastomotic leak, stoma complication, fascial dehiscence, and need for further intervention). Multivariable logistic regression models were used to describe outcomes and risk factors for surgical complication or mortality. Results There were 367 patients, with a mean (± SD) age of 62 ± 15 years. 39% were women. The median interquartile range (IQR) CCI was 4 (2-6). Overall, the pathologies encompassed the following AAST EGS grades: I (17, 5%), II (54, 15%), III (115, 31%), IV (95, 26%), and V (86, 23%). Management included laparoscopic (24, 7%), open (319, 87%), and laparoscopy converted to laparotomy (24, 6%). Higher AAST grade was associated with laparotomy ( P = .01). The median LOS was 13 days (8-22). At least 1 surgical complication occurred in 33% of patients and the mortality rate was 14%. Development of at least 1 surgical complication, need for unplanned intervention, mortality, and increased LOS were associated with increasing AAST severity grade. On multivariable analysis, factors predictive of in-hospital mortality included AAST organ grade, CCI, and preoperative vasopressor use (odds ratio (OR) 1.9, 1.6, 3.1, respectively). The American Association for the Surgery of Trauma emergency general surgery grade was also associated with the development of at least 1 surgical complication (OR 2.5), while CCI, preoperative vasopressor use, respiratory failure, and pneumoperitoneum were not. Conclusion The American Association for the Surgery of Trauma emergency general surgery grading systems display construct validity for mortality and surgical complications after urgent/emergent colorectal resection. These results support incorporation of AAST EGS grades for quality benchmarking and surgical outcomes research.

Abstract Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion–positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. Significance: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.

AbstractBackgroundComprehensive analysis of trauma care between high‐, middle‐, and low‐income countries (HIC/MIC/LIC) is needed to improve global health. Comparison of HIC and MIC outcomes after damage control laparotomy (DCL) for patients is unknown. We evaluated DCL utilization among patients treated at high‐volume trauma centers in the USA and South Africa, an MIC, hypothesizing similar mortality outcomes despite differences in resources and setting.MethodsPost hoc analysis of prospectively collected trauma databases from participating centers was performed. Injury severity, physiologic, operative data and post‐operative outcomes were abstracted. Univariate and multivariable analyses were performed to assess differences between HIC/MIC for the primary outcome of mortality.ResultsThere were 967 HIC and 602 MIC patients who underwent laparotomy. DCL occurred in 144 MIC patients (25%) and 241 HIC (24%) patients. Most sustained (58%) penetrating trauma with higher rates in the MIC compared to the HIC (71 vs. 32%, p = 0.001). Between groups, no differences were found for admission physiology, coagulopathy, or markers of shock except for increased presence of hypotension among patients in the HIC. Crystalloid infusion volumes were greater among MIC patients, and MIC patients received fewer blood products than those in the HIC. Overall mortality was 30% with similar rates between groups (29 in HIC vs. 33% in MIC, p = 0.4). On regression, base excess and penetrating injury were independent predictors of mortality but not patient residential status.ConclusionUse and survival of DCL for patients with severe abdominal trauma was similar between trauma centers in HIC and MIC settings despite increased penetrating trauma and less transfusion in the MIC center. While the results overall suggest no gap in care for patients requiring DCL in this MIC, it highlights improvements that can be made in damage control resuscitation.

Symptomatic rib nonunions are a rare complication after rib fractures. Methods used to address these nonunions range from pain management, rib resection, and rib fixation with plates and occasional autologous bone grafting. Given potential complications associated with rib resections such as pulmonary hernia, we hypothesized that plate fixation and autologous bone grafting would yield satisfactory long-term outcomes and a high union rate. Patients (aged ≥18 years) at a single institution with a symptomatic rib nonunion who underwent surgical rib stabilization of the nonunion coupled with bone autograft were evaluated (2010–2014). Pertinent clinical, operative, radiologic, and follow-up data were abstracted. Univariate analyses to assess the relationship of clinical outcomes were performed. Six patients underwent nonunion repair with autograft and plating. The mean time from injury to surgical repair of nonunion was 15 (66.1) months. A median of 3 [1–3] ribs were repaired with surgery. Postoperative radiographic union was demonstrated on cross-sectional imaging at three months in four patients (57%) and in all patients at five months postoperatively. No patients developed postoperative pulmonary hernia during follow-up. All patients had a significant reduction in median patient-reported pain at follow-up. Surgical rib fixation and bone autograft can provide acceptable outcomes for patients with rib fracture nonunion. This method provides pain relief and promotes healing of the nonunion gap without pulmonary hernia development. Operative fixation and bone autograft should be considered as a viable technical alternative to resection alone for rib nonunion.

Abstract Background The pediatric resuscitation and trauma outcome (PRESTO) model was developed to aid comparisons of risk‐adjusted mortality after injury in low‐ and middle‐income countries (LMICs). We sought to validate PRESTO using data from a middle‐income country (MIC) trauma registry and compare its performance to the Pediatric Trauma Score (PTS), Revised Trauma Score, and pediatric age‐adjusted shock index (SIPA). Methods We included children (age < 15 years) admitted to a single trauma center in South Africa from December 2012 to January 2019. We excluded patients missing variables necessary for the PRESTO model—age, systolic blood pressure, pulse, oxygen saturation, neurologic status, and airway support. Trauma scores were assigned retrospectively. PRESTO's previously high‐income country (HIC)‐validated optimal threshold was compared to MIC‐validated threshold using area under the receiver operating characteristic curves (AUROC). Prediction of in‐hospital death using trauma scoring systems was compared using ROC analysis. Results Of 1160 injured children, 988 (85%) had complete data for calculation of PRESTO. Median age was 7 (IQR: 4, 11), and 67% were male. Mortality was 2% ( n = 23). Mean predicted mortality was 0.5% (range 0–25.7%, AUROC 0.93). Using the HIC‐validated threshold, PRESTO had a sensitivity of 26.1% and a specificity of 99.7%. The MIC threshold showed a sensitivity of 82.6% and specificity of 89.4%. The MIC threshold yielded superior discrimination (AUROC 0.86 [CI 0.78, 0.94]) compared to the previously established HIC threshold (0.63 [CI 0.54, 0.72], p < 0.0001). PRESTO showed superior prediction of in‐hospital death compared to PTS and SIPA (all p < 0.01). Conclusion PRESTO can be applied in MIC settings and discriminates between children at risk for in‐hospital death following trauma. Further research should clarify optimal decision thresholds for quality improvement and benchmarking in LMIC settings.

AbstractIntroductionWe aimed to expand on the global surgical discussion around splenic trauma in order to understand locally and clinically relevant factors for operative (OP) and non‐operative management (NOM) of splenic trauma in a South African setting.MethodsA retrospective cohort study was performed using 2013–2017 data from the Pietermaritzburg Metropolitan Trauma Service. All adult patients (≥15 years) were included. Those managed with OP or NOM for splenic trauma were identified and analyzed descriptively. Multiple logistic regression analysis identified patients and clinical factors associated with management type.ResultsThere were 127 patients with splenic injury. Median age was 29 [19–35] years with 42 (33%) women and 85 (67%) men. Blunt injuries occurred in the majority (81, 64%). Organ Injury Scale (OIS) grades included I (25, 20%), II (43, 34%), III (36, 28%), IV (15, 11%), and V (8, 6%). Nine patients expired. On univariate analysis, increasing OIS was associated with OP management, need for intensive care unit (ICU) admission, and hospital and ICU duration of stay, but not mortality. In patients with a delayed compared to early presentation, ICU utilization (62% vs. 36%, p = 0.008) and mortality (14% vs. 4%, p = 0.03) were increased. After adjusting for age, sex, presence of shock, and splenic OIS, penetrating trauma (adjusted odds ratio, 5.7; 95%CI, 1.7–9.8) and admission lactate concentration (adjusted odds ratio, 1.4; 95%CI 1.1–1.9) were significantly associated with OP compared to NOM (p = 0.002; area under the curve 0.81).ConclusionsWe have identified injury mechanism and admission lactate as factors predictive of OP in South African patients with splenic trauma. Timely presentation to definitive care affects both ICU duration of stay and mortality outcomes. Future global surgical efforts may focus on expanding non‐operative management protocols and improving pre‐hospital care in patients with splenic trauma.

AbstractBackgroundAdhesive small bowel obstruction (ASBO) severity has been associated with important clinical outcomes. However, the impact of ASBO severity on hospitalization cost is unknown. The American Association for the Surgery of Trauma (AAST) developed an Emergency General Surgery (EGS) disease severity grading system for ASBO. We stratified patients’ ASBO severity and captured hospitalization costs hypothesizing that increased disease severity would correlate with greater costs.MethodsThis was a single‐center study of hospitalized adult patients with SBO during 2015–2017. Clinical data and estimated total cost (direct + indirect) were abstracted. AAST EGS grades (I–IV) stratified disease severity. Costs were normalized to the median grade I cost. Univariate and multivariate analyses evaluated the relationship between normalized cost and AAST EGS grade, length of hospital and ICU stay, operative time, and Charlson comorbidity index.ResultsThere were 214 patients; 119 (56%) were female. AAST EGS grades included: I (62%, n = 132), II (23%, n = 49), III (7%, n = 16), and IV (8%, n = 17). Relative to grade I, median normalized cost increased by 1.4‐fold for grade II, 1.6‐fold for grade III, and 4.3‐fold for grade IV disease. No considerable differences in patient comorbidity between grades were observed. Pair‐wise comparisons demonstrated that grade I disease cost less than higher grades (corrected p < 0.001). Non‐operative management was associated with lower normalized cost compared to operative management (1.1 vs. 4.5, p < 0.0001). In patients who failed non‐operative management, normalized cost was increased 7.2‐fold. Collectively, the AAST EGS grade correlated well with cost (Spearman's p = 0.7, p < 0.0001). After adjustment for covariates, AAST EGS grade maintained a persistent relationship with cost.ConclusionIncreasing ASBO severity is independently associated with greater costs. Efforts to identify and mitigate costs associated with this burdensome disease are warranted.Level of evidenceIII, economic/decision.

AbstractBackgroundSnake envenomation is associated with major morbidity especially in low‐ and middle‐income countries and may require fasciotomy. We determined patient factors associated with the need for fasciotomy after venomous snake bites in children located in KwaZulu‐Natal, South Africa.MethodsSingle institutional review of historical data (2012–2017) for children (<18 years) sustaining snake envenomation was performed. Clinical data, management, and outcomes were abstracted. Syndromes after snake bite were classified according to Blaylock nomenclature: progressive painful swelling (PPS), progressive weakness (PW), or bleeding (B), as it is difficult to reliably identify the species of snake after a bite. Comparative and multivariable analyses to determine factors associated with fasciotomy were performed.ResultsThere were 72 children; mean age was 7 (±3) years, 59% male. Feet were most commonly affected (n = 27, 38%) followed by legs (n = 18, 25%). Syndromes (according to Blaylock) included PPS (n = 63, 88%), PW (n = 5, 7%), and B (n = 4, 5%). Eighteen patients underwent fasciotomy, and one required above knee amputation. Nine patients received anti‐venom. Few patients (15%) received prophylactic beta‐lactam antibiotics. Hemoglobin < 11 mg/dL, leukocytosis, INR >1.2, and age‐adjusted shock index were associated with fasciotomy. On regression, age‐adjusted shock index and hemoglobin concentration < 11 mg/dL, presentation >24 h after snake bite, and INR >1.2 were independently associated with fasciotomy. Model sensitivity was 0.89 and demonstrated good fit.ConclusionsPatient factors were associated with the fasciotomy. These factors, coupled with clinical examination, may identify those who need early operative intervention. Improving time to treatment and the appropriate administration of anti‐venom will minimize the need for surgery.Level of evidenceIII

Perioperative radiation therapy (RT) has been associated with reduced local recurrence in patients with retroperitoneal sarcomas (RPS); however, selection criteria remain unclear. We hypothesized that perioperative RT would improve survival in patients with RPS and would be associated with pathological factors. The National Cancer Database (NCDB) from 2004 to 2012 was reviewed for patients with nonmetastatic RPS undergoing curative intent resection. Tumor size was dichotomized at 15 cm based on 8th edition American Joint Committee on Cancer (AJCC) staging. Patients with the highest comorbidity score were excluded. Unadjusted Kaplan–Meier and adjusted Cox proportional hazards modeling analyzed overall survival (OS). Multivariable logistic regression modeled margin positivity. A total of 2,264 patients were included; 727 patients (32.1%) had perioperative radiation in whom 203 (9.0%) had radiation preoperatively. Median (IQR) RPS size was 17.5 [11.0–27.0] cm. Histopathology was high grade in 1048 patients (43.7%). Multivariable analysis revealed that perioperative radiation was independently associated with decreased mortality (HR 0.72, 95% confidence intervals (CIs) 0.62–0.84,p<0.001), and preoperative RT was associated with reduced margin positivity (HR 0.72, 95% CI 0.53–0.97,p=0.032). Stratified survival analysis showed that radiation was associated with prolonged median OS for RPS that were high-grade (64.3 vs. 43.6 months,p<0.001), less than 15 cm (104.1 vs. 84.2 months,p=0.007), and leiomyosarcomatous (104.8 vs. 61.8 months,p<0.001). Perioperative radiation is independently associated with decreased mortality in patients with high-grade, less than 15 cm, and leiomyosarcomatous tumors. Preoperative radiation is independently associated with margin-negative resection. These data support the selective use of perioperative radiation in the multidisciplinary management of RPS.

Abstract The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2–LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556–67. ©2018 AACR.