NCCN Guideline Concordance Improves Survival in Pediatric and Young Adult Rectal Cancer.

BACKGROUND: Although management guidelines in adult rectal cancer are widely studied, no consensus guidelines exist for the management of pediatric and young adult rectal cancer. METHODS: The National Cancer Database (2004-2018) was queried for pediatric (age 0-21) and young adult (age 22-40) patients with rectal cancer. Patients were analyzed for receipt of National Comprehensive Cancer Network (NCCN) guideline-concordant therapy. Impact on survival was evaluated using Cox regression and Kaplan-Meier analysis. RESULTS: 6655 patients (108 pediatric and 6547 young adult patients) with rectal cancer were included. Similar to previously published NCCN quality measures with overall guideline concordance approaching 90 % in adults, 89.6 % of pediatric and 84.6 % of young adult patients were classified as receiving pre-operative guideline-concordant therapy. However, pediatric patients were significantly less likely to receive post-operative guideline-concordant therapy than young adult patients (65.3 % verse 76.7 %, respectively, p = 0.008). Risk of death was significantly lower for pediatric patients who received post-operative guideline-concordant therapy (HR, 0.313; CI, 0.168-0.581; p < 0.001). In young adult patients, risk of death was significantly lower for those who received pre-operative guideline-concordant therapy (HR, 0.376, CI 0.338-0.417, p < 0.001), and post-operative guideline-concordant therapy (HR, 0.456; CI 0.413-0.505; p < 0.001). DISCUSSION: NCCN-based guidelines may reasonably guide peri-operative management decisions and improve survival in pediatric and young adult rectal cancer. Given the rarity of this cancer in young patients, employment of an experienced surgical and oncologic multidisciplinary team, along with discussion and involvement of the patient and family, are keys for balancing risks and benefits to offering the best therapeutic strategy. TYPE OF STUDY: Retrospective. LEVEL OF EVIDENCE: Level III.

Extracellular CIRP induces acute kidney injury via endothelial TREM-1.

Introduction: Acute kidney injury is associated with elevated serum levels of extracellular cold-inducible RNA-binding protein (eCIRP), a damage-associated molecular pattern released during ischemia/reperfusion injury, hemorrhagic shock, and sepsis. It is unknown if circulating eCIRP and eCIRP-induced activation of receptor triggering receptor expressed on myeloid cells-1 (TREM-1), expressed on endothelial cells, play an important role in the pathogenesis of AKI. Methods: Male B6 wild-type (WT) and TREM-1-/- mice were subjected to intravenous injection of recombinant murine (rm) CIRP. Serum, urine, and renal tissue were collected 6 h later for analysis. Additionally, primary human renal glomerular endothelial cells (HRGEC) were stimulated in vitro with rmCIRP after pretreatment with M3, a novel inhibitory peptide of TREM-1, or vehicle. Supernatants and cells were collected 20 h after stimulation. Results: After injection with rmCIRP, WT mice had a significant increase in serum levels of BUN, creatinine, and NGAL compared to control. Additionally, NGAL was significantly increased in the urine of rmCIRP-injected mice, suggesting that circulating eCIRP can directly induce AKI. The levels of TREM-1 mRNA in the kidneys, as well as soluble (s) TREM-1 released into the serum and urine, were significantly increased in rmCIRP-injected mice. TREM-1-/- mice injected with rmCIRP had attenuated AKI, indicated by significantly decreased serum BUN, creatinine, and NGAL, and renal mRNA expression of NGAL and KIM-1 compared to WT mice. TREM-1-/- mice also had attenuated endothelial activation, with decreased mRNA and protein expression of ICAM-1 in renal tissue. HRGEC stimulated with rmCIRP in vitro had significant increases in cytokine production and sTREM-1 release, which was attenuated in cells treated with M3. Conclusion: Activation of renal TREM-1 with circulating eCIRP is sufficient to cause AKI. Elevated levels of eCIRP may be critical for the development of AKI under conditions such as ischemia/reperfusion injury, hemorrhagic shock, and sepsis. Mice deficient in the TREM-1 receptor have attenuated AKI and reduced endothelial cell activation after injection of rmCIRP. TREM-1 inhibition with M3 attenuates HRGEC activation after eCIRP stimulation. Targeting eCIRP activation of TREM-1 may provide a novel and effective treatment for AKI.

TREM-1 Modulation Strategies for Sepsis.

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor, which can be upregulated in inflammatory diseases as an amplifier of immune responses. Once activated, TREM-1 induces the production and release of pro-inflammatory cytokines and chemokines, in addition to increasing its own expression and circulating levels of the cleaved soluble extracellular portion of TREM-1 (sTREM-1). This amplification of the inflammatory response by TREM-1 has now been considered as a critical contributor to the dysregulated immune responses in sepsis. Studies have shown that in septic patients there is an elevated expression of TREM-1 on immune cells and increased circulating levels of sTREM-1, associated with increased mortality. As a result, a considerable effort has been made towards identifying endogenous ligands of TREM-1 and developing TREM-1 inhibitory peptides to attenuate the exacerbated inflammatory response in sepsis. TREM-1 modulation has proven a promising strategy for the development of therapeutic agents to treat sepsis. Therefore, this review encompasses the ligands investigated as activators of TREM-1 thus far and highlights the development and efficacy of novel inhibitors for the treatment of sepsis and septic shock.

A novel eCIRP/TREM-1 pathway inhibitor attenuates acute kidney injury.

BACKGROUND: Extracellular cold-inducible RNA-binding protein aggravates acute kidney injury after renal ischemia/reperfusion. Although extracellular cold-inducible RNA-binding protein activates triggering receptor expressed on myeloid cells-1, how this receptor and its antagonism with a novel peptide M3 affects acute kidney injury is poorly understood. We, therefore, hypothesize that inhibiting the extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway with M3 attenuates acute kidney injury. METHODS: Wild-type and triggering receptor expressed on myeloid cells-1-/- mice were subjected to bilateral 30-minute renal hilum clamping followed by reperfusion or sham. After 4 hours, wild-type mice received M3 (10 mg/kg BW) or normal saline intraperitoneally. After 24 hours, renal tissue and serum were collected for analysis. Additionally, wild-type mice were subjected to bilateral renal ischemia for 34 minutes and treated with M3 at 10 mg/kg BW or vehicle at the time of reperfusion. Survival was monitored for 10 days. RESULTS: After renal ischemia/reperfusion, triggering receptor expressed on myeloid cells-1 messenger ribonucleic acid expression increased by 9-fold in wild-type mice compared to sham mice. Wild-type mice also demonstrated significant increases in serum blood urea nitrogen, creatinine, and interleukin-6 and renal tissue levels of interleukin-6 and neutrophil gelatinase-associated lipocalin after renal ischemia/reperfusion compared to sham mice. Triggering receptor expressed on myeloid cells-1-/- mice demonstrated significant reductions in serum blood urea nitrogen, creatinine, and interleukin-6 compared to wild-type mice after renal ischemia/reperfusion. Levels of renal interleukin-6 and neutrophil gelatinase-associated lipocalin were also significantly decreased in the kidneys of triggering receptor expressed on myeloid cells-1-/- mice. Furthermore, treatment with M3 in wild-type mice significantly decreased serum and renal levels of interleukin-6 after renal ischemia/reperfusion. M3 treatment demonstrated significant reductions in renal messenger ribonucleic acid and protein levels of neutrophil gelatinase-associated lipocalin, serum blood urea nitrogen and creatinine, and histologic structural damage as well as apoptosis. Treatment with M3 also increased survival from 35% to 65% in mice with acute kidney injury. CONCLUSION: Triggering receptor expressed on myeloid cells-1 mediates the deleterious effects of extracellular cold-inducible RNA-binding protein in acute kidney injury after renal ischemia/reperfusion. The novel extracellular cold-inducible RNA-binding protein/triggering receptor expressed on myeloid cells-1 pathway antagonist, M3, attenuates acute kidney injury and has the potential to be developed as a therapeutic agent for acute kidney injury.

Do It to Them, Not to Me: Doctors' and Nurses' Personal Preferences Versus Recommendations for End-of-Life Care.

BACKGROUND: The emotional toll and financial cost of end-of-life care can be high. Existing literature suggests that medical providers often choose to forego many aggressive interventions and life-prolonging therapies for themselves. To further investigate this phenomenon, we compared how providers make medical decisions for themselves versus for relatives and unrelated patients. METHODS: Between 2016 and 2019, anonymous surveys were emailed to physicians (attendings, fellows, and residents), nurse practitioners, physician assistances, and nurses at two multifacility tertiary medical centers. Participants were asked to decide how likely they would offer a tracheostomy and feeding gastrostomy to a hypothetical patient with a devastating neurological injury and an uncertain prognosis. Participants were then asked to reconsider their decision if the patient was their own family member or if they themselves were the patient. The Kruskal-Wallis H, Mann-Whitney U, and Tukey tests were used to compare quantitative data. Statistical significance was set at P < 0.05. RESULTS: Seven hundred seventy-three surveys were completed with a 10% response rate at both institutions. Regardless of professional identity, age, or gender, providers were significantly more likely to recommend a tracheostomy and feeding gastrostomy to an unrelated patient than for themselves. Professional identity and age of the respondent did influence recommendations made to a family member. CONCLUSIONS: We demonstrate that medical practitioners make different end-of-life care decisions for themselves compared with others. It is worth investigating further why there is such a discrepancy between what medical providers choose for themselves compared with what they recommend for others.

Cleaning Up the MESS: Can Machine Learning Be Used to Predict Lower Extremity Amputation after Trauma-Associated Arterial Injury?

BACKGROUND: Thirty years after the Mangled Extremity Severity Score was developed, advances in vascular, trauma, and orthopaedic surgery have rendered the sensitivity of this score obsolete. A significant number of patients receive amputation during subsequent admissions, which are often missed in the analysis of amputation at the index admission. We aimed to identify risk factors for and predict amputation on initial admission or within 30 days of discharge (peritraumatic amputation [PTA]). STUDY DESIGN: The Nationwide Readmission Database for 2016 and 2017 was used in our analysis. Factors associated with PTA were identified. We used XGBoost, random forest, and logistic regression methods to develop a framework for machine learning-based prediction models for PTA. RESULTS: We identified 1,098 adult patients with traumatic lower extremity fracture and arterial injuries; 206 underwent amputation. One hundred and seventy-six patients (85.4%) underwent amputation during the index admission and 30 (14.6%) underwent amputation within a 30-day readmission period. After identifying factors associated with PTA, we constructed machine learning models based on random forest, XGBoost, and logistic regression to predict PTA. We discovered that logistic regression had the most robust predictive ability, with an accuracy of 0.88, sensitivity of 0.47, and specificity of 0.98. We then built on the logistic regression by the NearMiss algorithm, increasing sensitivity to 0.71, but decreasing accuracy to 0.74 and specificity to 0.75. CONCLUSIONS: Machine learning-based prediction models combined with sampling algorithms (such as the NearMiss algorithm in this study), can help identify patients with traumatic arterial injuries at high risk for amputation and guide targeted intervention in the modern age of vascular surgery.