Association of Age and Overall Survival in Surgically Resected Colorectal Cancer Patients.

INTRODUCTION: Incidence of colorectal cancer (CRC) among young patients has increased in the last 20 y often with more aggressive tumor biology. It is unclear if age < 50 y is an independent factor for shorter overall survival in CRC patients. Our objective was to determine if younger age at diagnosis was associated with worse overall survival. METHODS: This study used the National Cancer Data Base (2004-2016), retrospectively reviewing patients who underwent surgical resection for CRC. Patients were limited to only those without comorbidities and primary outcome was overall survival for all patients. RESULTS: Older patients have worse overall survival as compared to younger patients at a lower stage of disease (I and II) after adjusting for tumor location, gender, histology, stage, and systemic chemotherapy (< 36 y old versus 36-55 y old hazard ratio [HR] 1.16, confidence interval [CI] 1.03-1.29). This survival benefit is eliminated at a higher stage of disease, stage III in 36-55 y old versus < 36 y old (HR 0.96 [CI 0.90-1.03.99]) and stage IV (HR 0.94 [CI 0.89-0.99]). CONCLUSIONS: Older patients (aged > 36 y) have worse overall survival at a lower stage of disease, but the survival among all age groups was similar for stage III or IV disease in CRC.

Retrospective Cohort Analysis of the Effect of Age on Lymph Node Harvest, Positivity, and Ratio in Colorectal Cancer.

Introduction: Colon cancer among young patients has increased in incidence and mortality over the past decade. Our objective was to determine if age-related differences exist for total positive nodes (TPN), total lymph node harvest (TLH), and lymph node ratio (LNR). Material and Methods: A retrospective review of stage III surgically resected colorectal cancer patient data in the National Cancer Database (2004−2016) was performed, reviewing TPN, TLH, and LNR (TPN/TLH). Results: Unadjusted analyses suggested significantly higher levels of TLH and TPN (p < 0.0001) in younger patients, while LNR did not differ by age group. On adjusted analysis, TLH remained higher in younger patients (<35 years 1.56 (CI 95 1.54, 1.59)). The age-related effect was less pronounced for LNR (<35 years 1.16 (CI 95 1.13, 1.2)). Conclusion: Younger patients have increased TLH, even after adjusting for known confounders, while age does not have a strong independent impact on LNR.

Traumatic Pediatric Fatalities: Are They Preventable?

INTRODUCTION: Trauma related injury remains the leading cause of mortality in pediatric patients, many of which are preventable. The goal of our study was to identify the mechanism of injury (MOI) in pediatric trauma-related fatalities and determine if these injuries were preventable to direct future injury prevention efforts within trauma programs. METHODS: After IRB approval, a retrospective, single-institution review of pediatric (age ≤18) trauma fatalities from 2010 to 2019 was performed. MOI, use of protective devices, demographics, and whether the injury was preventable were collected. Patients were divided into five age cohorts, and frequencies and proportions were used to summarize data. Bivariate testing was done using Fisher's exact and Monte Carlo estimates for the exact test. RESULTS: MOI was found to vary by age with non-accidental trauma found to be the most common cause of trauma related deaths in children <1 (88.5%) and 1-4 (33.3%). MVC was the most common MOI in children >5 y, with 68.4% in the 5-9, 34.4% in the 10-14, and 45.8% in the 15-18 age group. The majority of fatalities resulted from a preventable injury (P < 0.0001) in the younger children with a negative association as age increased: 92.3% <1, 53.3% in 1-4, 36.8% in 5-9, 46.9% in 10-14 and 48.6% in 15-18. Of the preventable injuries, non-accidental trauma was the most common MOI in children <5, while GSW was the most common MOI in children >10. CONCLUSIONS: This study demonstrates many pediatric fatalities are the result of a preventable traumatic injury. This data can guide focused traumatic injury prevention efforts.

Retrospective review of intervention for traumatic blunt spleen injuries in adolescents by trauma center type.

BACKGROUND: Management guidelines for pediatric blunt spleen injuries (BSI) include adolescent patients but few studies have compared current management of adolescents with respect to other age groups by center type. METHODS: A retrospective review of 2017-2018 National Trauma Quality Improvement (TQIP) data of children (6-12), adolescents (13-17) and young adults (18-24) with BSI presenting to an adult, pediatric only, or adult/pediatric trauma center, comparing the rate of splenic intervention for adolescents by trauma center was performed. RESULTS: Children had lower odds of spleen intervention than adolescents at both adult (OR 0.61 95%CI 0.39, 0.95) and adult/pediatric (OR 0.55 95%CI 0.35, 0.87) centers but did not differ at pediatric centers (OR 0.94 95%CI 0.39, 2.2) (n = 10,494). Adolescents adjusted odds of intervention was equal to adults at adult trauma centers (OR 1.2 95%CI 0.95, 1.4). CONCLUSION: Adolescents are more likely to undergo interventions for BSI as compared to children at both adult and adult/pediatric trauma centers.

Correlation of Supervised Independence and Performance with Procedure Difficulty amongst Surgical Residents Stratified by Post Graduate Year.

PURPOSE: This study investigates the role of procedure difficulty on attending ratings of supervised levels of independence and procedural performance amongst general surgery residents, while accounting for case complexity. METHODS: Attending ratings for residents were obtained from System for Improving and Measuring Procedural Learning (SIMPL) database. Current procedural terminology (CPT) codes were used to match procedures to a corresponding work relative value unit (wRVU) as a surrogate for procedure difficulty. Three categories of wRVU (<13.07, 13.07-22, >22) were identified using recursive partitioning. Procedures were also divided into 'Core' or 'Advanced' as defined by the American Board of Surgery Surgical Council on Resident Education (SCORE). Temporal advancement in resident skill was accounted for through academic quarterly analysis. A generalized estimating equations (GEE) approach was used to form separate multivariable logistic regression models for meaningful autonomy (MA) and satisfactory performance (SP) adjusted for potential clustering by program, subject, and rater. Models were further adjusted for core/advanced procedures, attending rated complexity, and academic quarter. RESULTS: A total of 33,281 ratings were analyzed. Overall, 51.6% were rated as MA and 44.4% as SP. For core procedures, surgical residents rated as MA (53.5%) and SP (45.7%), which was twice as high as those for advance procedures (MA-29.2%, SP-29.0%). MA and SP both decreased with increasing wRVU (Figure 2 &3). Using a wRVU<13.07 as a reference, the adjusted odds ratios of MA and SP were significantly lower with increasing procedure difficulty, 0.44 for wRVU 13.07-22.0 and 0.24 for wRVU >22.00 (Table 3). Post graduate year (PGY) 5 residents in the final quarter of training obtain MA in 95.5% and SP 92.9% for core procedures with wRVU <13.07 (Table 4). CONCLUSION: Increasing procedural difficulty is independently associated with decreases in meaningful autonomy and satisfactory performance. As residents approach graduation the level of meaningful autonomy and satisfactory performance both reach high levels for common core procedures but decrease as procedural difficulty increases.

Infant Essential Fatty Acid Status Is Not Associated With Postoperative Wound Complication Severity.

BACKGROUND: Neonates are susceptible to postoperative wound complications (POWCs), as prematurity, hypoxia, steroid use, immunosuppression, and malnutrition are all common comorbidities. Critically ill infants, dependent on parenteral nutrition, are at even further risk of developing essential fatty acid deficiency (EFAD). We hypothesized that POWC severity and EFAD were associated because of increased susceptibility to infections and impaired wound healing seen with EFAD. METHODS: Institutional review board-approved (OUHSC10554), retrospective review from our academic Level IV Neonatal Intensive Care Unit. Infants aged <1 y who underwent a fascial-compromising gastrointestinal surgery from June 1, 2015, to March 15, 2019, and who had essential fatty acids (EFAs) measured ±2 wk from surgery were included. Three blinded investigators independently categorized POWC using the World Union of Wound Healing Society Surgical Wound Grading System. Infants were categorized into three groups: no POWC, POWC Grades 1 and 2 (superficial tissue nonintegrity), and POWC Grades 3 and 4 (deep tissue nonintegrity and complete dehiscence). EFA status and other possible POWC-associated factors were analyzed to determine any association with wound severity. RESULTS: Fifty infants met the inclusion criteria. Half (25/50) had no POWC, 30% (15/50) had Grade 1 or 2, and 20% (10/50) had Grade 3 or 4. We found no association between EFAD and POWC severity. CONCLUSIONS: In our cohort, EFA status did not predict POWC severity. At this time, we cannot suggest delaying elective surgical procedures to correct EFAD as an approach to preventing POWC.

Context-specific function of the LIM homeobox 1 transcription factor in head formation of the mouse embryo.

Lhx1 encodes a LIM homeobox transcription factor that is expressed in the primitive streak, mesoderm and anterior mesendoderm of the mouse embryo. Using a conditional Lhx1 flox mutation and three different Cre deleters, we demonstrated that LHX1 is required in the anterior mesendoderm, but not in the mesoderm, for formation of the head. LHX1 enables the morphogenetic movement of cells that accompanies the formation of the anterior mesendoderm, in part through regulation of Pcdh7 expression. LHX1 also regulates, in the anterior mesendoderm, the transcription of genes encoding negative regulators of WNT signalling, such as Dkk1, Hesx1, Cer1 and Gsc. Embryos carrying mutations in Pcdh7, generated using CRISPR-Cas9 technology, and embryos without Lhx1 function specifically in the anterior mesendoderm displayed head defects that partially phenocopied the truncation defects of Lhx1-null mutants. Therefore, disruption of Lhx1-dependent movement of the anterior mesendoderm cells and failure to modulate WNT signalling both resulted in the truncation of head structures. Compound mutants of Lhx1, Dkk1 and Ctnnb1 show an enhanced head truncation phenotype, pointing to a functional link between LHX1 transcriptional activity and the regulation of WNT signalling. Collectively, these results provide comprehensive insight into the context-specific function of LHX1 in head formation: LHX1 enables the formation of the anterior mesendoderm that is instrumental for mediating the inductive interaction with the anterior neuroectoderm and LHX1 also regulates the expression of factors in the signalling cascade that modulate the level of WNT activity.

Dkk1 and Wnt3 interact to control head morphogenesis in the mouse.

Loss of Dkk1 results in ectopic WNT/beta-catenin signalling activity in the anterior germ layer tissues and impairs cell movement in the endoderm of the mouse gastrula. The juxtaposition of the expression domains of Dkk1 and Wnt3 is suggestive of an antagonist-agonist interaction. The downregulation of Dkk1 when Wnt3 activity is reduced reveals a feedback mechanism for regulating WNT signalling. Compound Dkk1;Wnt3 heterozygous mutant embryos display head truncation and trunk malformation, which are not found in either Dkk1(+/-) or Wnt3(+/-) embryos. Reducing the dose of Wnt3 gene in Dkk1(-/-) embryos partially rescues the truncated head phenotype. These findings highlight that head development is sensitive to the level of WNT3 signalling and that DKK1 is the key antagonist that modulates WNT3 activity during anterior morphogenesis.

Sequential allocation and global pattern of movement of the definitive endoderm in the mouse embryo during gastrulation.

During mouse gastrulation, endoderm cells of the dorsal foregut are recruited ahead of the ventral foregut and move to the anterior region of the embryo via different routes. Precursors of the anterior-most part of the foregut and those of the mid- and hind-gut are allocated to the endoderm of the mid-streak-stage embryo, whereas the precursors of the rest of the foregut are recruited at later stages of gastrulation. Loss of Mixl1 function results in reduced recruitment of the definitive endoderm, and causes cells in the endoderm to remain stationary during gastrulation. The observation that the endoderm cells are inherently unable to move despite the expansion of the mesoderm in the Mixl1-null mutant suggests that the movement of the endoderm and the mesoderm is driven independently of one another.

Genetic interaction of Gsc and Dkk1 in head morphogenesis of the mouse.

Mouse embryos lacking Gsc and Dkk1 function display severe deficiencies in craniofacial structures which are not found in either Dkk1 homozygous null or Gsc homozygous null mutant embryos. Loss of Gsc has a dosage-related effect on the severity of head truncation phenotype in Dkk1 heterozygous embryos. The synergistic effect of these mutations in enhancing head truncation provides direct evidence of a genetic interaction between Gsc and Dkk1, which display overlapping expression in the prechordal mesoderm. In the absence of Gsc activity, the expression of Dkk1, WNT genes and a transgenic reporter for WNT signalling are altered. Our results show that Gsc and Dkk1 functions are non-redundant in the anterior mesendoderm for normal anterior development and Gsc may influence Wnt signalling as a negative regulator.

Definitive endoderm of the mouse embryo: formation, cell fates, and morphogenetic function.

The endoderm is one of the primary germ layers but, in comparison to ectoderm and mesoderm, has received less attention. The definitive endoderm forms during gastrulation and replaces the extraembryonic visceral endoderm. It participates in the complex morphogenesis of the gut tube and contributes to the associated visceral organs. This review highlights the role of the definitive endoderm as a source of patterning cues for the morphogenesis of other germ-layer tissues, such as the anterior neurectoderm and the pharyngeal region, and also emphasizes the intricate patterning that the endoderm itself undergoes enabling the acquisition of regionalized cell fates.

New developments in developmental biology.

A report on the 15th International Society of Developmental Biologists Congress, Sydney, Australia, 3-7 September 2005.

Isolation and embryonic expression of avian ADAM 12 and ADAM 19.

Members of the ADAM gene family encode large multi-domain proteins containing A Disintegrin And Metalloprotease domain. We have cloned quail orthologs of ADAM 12 and 19 using PCR-based screening and describe their expression patterns over the period E2.5 (Hamilton and Hamburger stage 14) to E5.0 (HH 25) using in situ hybridisation. Quail ADAM 12 is expressed in mesenchyme, cranially, in the tail and in the limb buds, and also in visceral mesenchyme. In the nervous system it is expressed in dorsal root ganglia and ventral roots. Quail ADAM 19 is expressed in cranial and dorsal root ganglia, sympathetic ganglia, ventral mixed nerves and in the allantois. Avian ADAM 12 and 19 genes exhibit similarities and differences in expression pattern compared to their murine orthologs, for example, expression of ADAM 12 in the nervous system, limb and tail bud in quail but not mouse. Interestingly, in mouse ADAM 19 is expressed in these locations. We have generated a sheep antibody to quail ADAM 19 and, in embryonic cells in vitro, found the protein at cell-cell junctions in many cell types. Some of these did have detectable ADAM 19 by in situ hybridisation but RT-PCR analysis confirmed the presence of low level ADAM 19 transcripts not detectable by in situ hybridisation.