Wounds Inhibit Tumor Growth In Vivo.

OBJECTIVE: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo. SUMMARY OF BACKGROUND DATA: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo. METHODS: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells. RESULTS: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds. CONCLUSION: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.

Virtual Interviews in the Era of COVID-19: A Primer for Applicants.

PROBLEM: The COVID-19 pandemic is an evolving crisis with widespread impact upon our medical system, including senior trainee travel for fellowship interviews. Numerous institutions have conscientiously deferred in-person interviews or virtual formats. Given the competitive nature of fellowship interviews, candidates may express concern that they are at a disadvantage in engaging in online meetings versus live, on-site interviews, and similarly may feel ill prepared to perform optimally during online interviews. APPROACH: We draw upon our experience with online interview platforms in this guide for fellowship candidates who are rapidly adapting to new technology and styles associated with videoconference interviews so that they can best promote themselves for competitive positions.

More Is Less: The Advantages of Performing Concurrent Laparoscopic Cholecystectomy and Endoscopic Retrograde Cholangiopancreatography for Pediatric Choledocholithiasis.

Introduction: Endoscopic retrograde cholangiopancreatography (ERCP) and laparoscopic cholecystectomy (LC) are standard of care for pediatric choledocholithiasis. Patients typically undergo separate procedures during hospitalization. Collaboration between surgical and gastroenterology services led to performance of both procedures concurrently during one anesthetic. We hypothesized that concurrent procedures would reduce costs without increasing complications as compared with separate procedures. Materials and Methods: We evaluated patients admitted to our institution from 2013 to 2018 with choledocholithiasis who underwent both ERCP and LC during the same admission. Fourteen patients underwent both procedures during concurrent anesthetic. Forty-two patients who underwent LC and ERCP under separate anesthetics were randomly selected to perform a 3:1 matched case-control study. Demographic and clinical data were collected, including imaging and laboratory findings, outcomes, and costs. Comparative analysis was completed with Fisher's exact and Mann-Whitney U tests. Results: On presentation, there was no difference in common bile duct size, total bilirubin, or white blood cell count between the concurrent and separate procedure cohorts. Significantly, there was no difference in total length of anesthesia (117.9 ± 40 minutes versus 119.6 ± 52 minutes, P = .747). There were also no differences in complications, emergency department visits, or readmissions. Patients who underwent concurrent procedures had significantly lower total cost of stay ($45,597 ± 11,513 versus $61,008 ± 17,960, P = .006). Conclusions: In pediatric patients with choledocholithiasis, performing LC and ERCP may be performed concurrently during one anesthetic, which decreases costs without increasing in anesthesia time or complications.

An investigation of social determinants of health and outcomes in pediatric nonaccidental trauma.

OBJECTIVES: Nonaccidental trauma (NAT) is a leading cause of pediatric mortality and disability. We examined our institution's experience with NAT to determine if socioeconomic status is correlated with patient outcomes. METHODS: NAT cases were reviewed retrospectively. Socioeconomic determinants included insurance status and race; outcomes included mortality, discharge disability and disposition. Correlations were identified using t test, Fisher's exact test, and logistic regression. RESULTS: The cohort comprised of 337 patients, with an overall uninsured rate of 5.6%. This rate was achieved by insuring 64.7% of the cohort after admission. Non-survivors were more likely to have no insurance coverage (14.8% versus 4.8%, p = 0.041). Regression revealed that uninsured had 8 times (95% CI 1.7-38.7, p = 0.008) higher in-hospital mortality than those with insurance when controlling for injury severity. Additionally, injury severity score ≥ 15, transfer from outside hospital, need for ICU or operative treatment were predictive of mortality. Adjusted risk factors for severe disability at discharge did not include insurance status or race, while ISS ≥ 15 and ICU stay were predictive. CONCLUSIONS: There are significant associations of insurance status with pediatric NAT outcomes, highlighting that determinants other than disease severity may influence mortality and morbidity. High-risk patients should be identified to develop strategies to improve outcomes.

Clinical and Imaging Correlates of Pediatric Mucosal Appendicitis.

BACKGROUND: Mucosal appendicitis is a controversial entity that is histologically distinct from transmural appendicitis. There is mixed opinion regarding mucosal inflammation as a spectrum of appendicitis versus a negative appendectomy. The ability to distinguish these diagnoses preoperatively is of importance to prevent unnecessary surgery. We hypothesize that patients with mucosal appendicitis can be discriminated from those with transmural disease based on specific preoperative clinical and imaging findings. MATERIALS AND METHODS: After IRB approval, all patients who underwent laparoscopic appendectomy at our institution during 2015 were reviewed in the electronic medical record. Patients with mucosal appendicitis were identified and matched 2:1 to a random cohort of nonperforated transmural appendicitis cases. Demographic and clinical data were collected, including history, examination, laboratory, and imaging findings. Preoperative factors associated with mucosal appendicitis were modeled using binomial logistic regression analysis. RESULTS: Of 1153 appendectomies performed during 2015, 103 patients had pathologic diagnosis of mucosal appendicitis. When compared with patients with mucosal infection, leukocytosis >10,000 per microliter led to 5.9 times higher likelihood of transmural pathology (P = 0.000). Noncompressibility on ultrasound was associated with 7.3 times higher likelihood of transmural disease (P = 0.015). Echogenic changes were predictive of transmural appendicitis, conferring 3.9 times the risk (P = 0.007). Presence of free fluid led to 2.3 times the rate of transmural pathology (P = 0.007). Finally, for every millimeter decrease in appendiceal diameter, patients were half as likely to exhibit transmural disease (P = 0.000). Together, these variables can successfully predict presence of mucosal appendicitis on final pathology report at a rate of 82.1%, and explain 60% of the variance in diagnosis of mucosal versus transmural appendicitis (P = 0.000). CONCLUSIONS: Mucosal appendicitis remains a controversial pathologic entity, but is not associated with greater complications compared with transmural appendicitis when treated with laparoscopic appendectomy. Transmural disease can be predicted by leukocytosis, noncompressible appendix, presence of free fluid, larger appendiceal diameter and echogenicity.

Diagnostic Utilization and Accuracy of Pediatric Appendicitis Imaging at Adult and Pediatric Centers.

BACKGROUND: Diagnostic imaging in pediatric appendicitis may decrease rates of negative appendectomy and identify alternate pathologies. We compared imaging practices for children transferred from nonpediatric facilities versus directly admitted to our tertiary children's hospital for laparoscopic appendectomy, and assessed the diagnostic accuracy in each population based on final pathologic diagnosis. MATERIALS AND METHODS: After institutional review board approval, all cases of laparoscopic appendectomy at our children's hospital during 2015 were reviewed. Demographic and clinical data were collected, including age, transfer status, imaging studies, and pathologic diagnosis. Imaging practices in patients transferred from adult centers were compared with those directly admitted. RESULTS: There were 1153 included patients who underwent laparoscopic appendectomy for acute appendicitis during the study period, with 242 (20.9%) presenting as transfers from nonpediatric facilities. Of these, 73.5% underwent preoperative computed tomography (CT), compared with 26.4% of nontransfer patients (P < 0.000). All remaining patients received ultrasound (US). Despite variation in imaging strategies, rates of negative appendectomy were similar in transfer and nontransfer groups (1.7% versus 2.0%, respectively, P = 0.744). There were marginal differences in sensitivity of US and CT to detect appendix features between the transferring and referral centers. CONCLUSIONS: Our results show that nonpediatric facilities use CT more frequently to diagnose pediatric appendicitis. Rates of nontherapeutic surgery were equivalent between transferred and directly admitted patients, which is likely related to high performance of both imaging strategies. Transferring centers should strive to rely more heavily on US, which may require education and development of improved pediatric US capacity.

Wound healing and fibrosis: current stem cell therapies.

Scarring is a result of the wound healing response and causes tissue dysfunction after injury. This process is readily evident in the skin, but also occurs internally across organ systems in the form of fibrosis. Stem cells are crucial to the innate tissue healing response and, as such, present a possible modality to therapeutically promote regenerative healing while minimizing scaring. In this review, the cellular basis of scaring and fibrosis is examined. Current stem cell therapies under exploration for skin wound healing and internal organ fibrosis are discussed. While most therapeutic approaches rely on the direct application of progenitor-type cells to injured tissue to promote healing, novel strategies to manipulate the scarring response are also presented. As our understanding of developmental and stem cell biology continues to increase, therapies to encourage regeneration of healthy functional tissue after damage secondary to injury or disease will continue to expand.

Author Correction: Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes.

In the original version of this Article, the authors inadvertently omitted Elizabeth A. Brett, who contributed to the generation of the histology figures, from the author list.This has now been corrected in both the PDF and HTML versions of the Article.

Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration.

During both embryonic development and adult tissue regeneration, changes in chromatin structure driven by master transcription factors lead to stimulus-responsive transcriptional programs. A thorough understanding of how stem cells in the skeleton interpret mechanical stimuli and enact regeneration would shed light on how forces are transduced to the nucleus in regenerative processes. Here we develop a genetically dissectible mouse model of mandibular distraction osteogenesis-which is a process that is used in humans to correct an undersized lower jaw that involves surgically separating the jaw bone, which elicits new bone growth in the gap. We use this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, we show that these stem-cell populations gain activity within the focal adhesion kinase (FAK) signalling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene-regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem-cell-based regeneration of adult skeletal tissue.

Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes.

Targeted genetic dissection of tissues to identify precise cell populations has vast biological and therapeutic applications. Here we develop an approach, through the packaging and delivery of 4-hydroxytamoxifen liposomes (LiTMX), that enables localized induction of CreERT2 recombinase in mice. Our method permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control. This technology is effective using mice with both specific and ubiquitous Cre drivers in a variety of tissue types, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. This methodology is directly and immediately applicable to the developmental biology, stem cell biology and regenerative medicine, and cancer biology fields.

Correlation of payor status and pediatric transfer for acute appendicitis.

BACKGROUND: Tertiary referral centers provide specialty and critical care for patients presenting to hospitals that lack these resources. There is a notion among tertiary centers that outside hospitals are more likely to transfer uninsured or underinsured patients. We examined funding status of patients transferred to our tertiary pediatric hospital for surgical management of appendicitis, hypothesizing that transferred patients were more likely to have unfavorable coverage. MATERIALS AND METHODS: The electronic medical record was queried for all cases of laparoscopic appendectomy at our hospital between 2011 and 2015. Insurance was grouped into three categories: commercial, Medicaid/Children's Health Insurance Plan, or none. Transferred patients were compared to patients who presented directly. RESULTS: A total of 5758 patients underwent laparoscopic appendectomy during the study period, of which 1683 (29.2%) were transfer patients. Transfer patients were more likely to be older, with a median age of 10.5 y versus 9.8 y in nontransferred patients (P ≤ 0.0001), and were more likely to be identified as non-Hispanic (50.0% versus 36.5%; P ≤ 0.0001). Insurance coverage was similar between groups. However, subgroup analysis of the hospitals that most frequently used our transfer services revealed a trend to transfer a higher proportion of Medicaid/Children's Health Insurance Plan patients. CONCLUSIONS: Overall, pediatric patients transferred for laparoscopic appendectomy had similar insurance coverage to patients admitted directly, but subgroup analysis shows that not all centers follow this trend. Transfer patients were more frequently older and non-Hispanic. This builds upon the existing literature regarding the correlation of funding and transfer practices and highlights the need for additional research in this area.

Renal artery aneurysm associated with Leber hereditary optic neuropathy.

Leber hereditary optic neuropathy is an inherited, rare, mitochondrial metabolic disease that leads to progressive vision loss due to the accumulation of reactive oxygen species. The disorder has been associated with microangiopathy and macroangiopathy. We present a novel case of saccular left renal artery aneurysm in a 27-year-old man with known Leber hereditary optic neuropathy. The lesion was asymptomatic and grew from 1.8 to 2.0 cm during the course of 1 year. We successfully performed an endovascular left renal artery aneurysm repair.

Peritoneal Dialysis Is Feasible as a Bridge to Combined Liver-Kidney Transplant.

Patients with combined liver and kidney failure may remain on dialysis for years while awaiting simultaneous liver-kidney transplantation (SLKT). The role of peritoneal dialysis (PD) in patients with advanced liver and kidney failure awaiting SLKT remains to be defined. We present our single-institution experience with PD in cirrhotics, 3 of whom went on to receive successful SLKT. Patients initiated in our PD program between 2006 and 2016 who had both liver and kidney failure were identified. Medical and dialysis records were reviewed retrospectively. Outcomes included mortality, transplantation status, hospitalizations, need for large-volume paracentesis (LVP), peritonitis rates, PD treatment longevity, and albumin level. Twelve patients with combined liver and kidney failure were treated in our PD program. No patients died and 3 patients received SLKT. Four patients remain listed for transplantation. There was no need for LVP after initiating dialysis. The rate of peritonitis was 0.2 events per patient per year, most commonly due to coagulase-negative Staphylococcus Our data illustrate that PD is a viable bridging therapy for patients with liver and kidney failure who await SLKT.