Subcutaneous checkpoint inhibition is equivalent to systemic delivery when combined with nelitolimod delivered via pressure-enabled drug delivery for depletion of intrahepatic myeloid-derived suppressor cells and control of liver metastases.

BACKGROUND: Toll-like receptor 9 (TLR9) agonists induce inflammatory responses that promote the killing of infectious micro-organisms, cancer cells and develop adaptive immune responses. Their ability as immunomodulators to enhance the activity of checkpoint inhibitors (CPI) in treating liver tumors is limited in part by the distinctive biology of intrahepatic myeloid-derived suppressor cells (MDSC) and challenges with tumor-specific therapeutic delivery. We have shown that the regional delivery of type C TLR9 agonist via pressure-enabled drug delivery (PEDD) system improves delivery to the tumor, enhances depletion of MDSCs and overall, stimulates the immune system in combination with or without CPI. Currently, CPIs are delivered intravenously, although there is a growing interest in its subcutaneous (SQ) administration. We compared nelitolimod formerly known as SD-101 administered using PEDD in combination with systemic (Sys) or SQ CPI in murine liver metastases (LM). METHODS: The LM model was developed by injecting MC38-Luc cells via the spleen of 8-12 week old male C57/BL6 mice followed by splenectomy. After a week, fluorescently labeled nelitolimod (10 µg/mouse) was delivered via PEDD and co-administered anti-programmed cell death-1 (α-PD-1) either via Sys or SQ. Tumor burden was monitored by in vivo imaging system. Serum cytokine levels were analyzed by Luminex. Tissues were harvested on Day 3 (D3) or Day 10 (D10) post-PEDD to enrich CD45+ cells and were analyzed via NanoString targeted transcriptomics (D3) or flow cytometry (FC, D10) to interrogate immune cell populations (D10). For NanoString analysis, the innate immune panels were selected, and for FC, MDSCs (CD11b+Gr1+), B cells (B220+), dendritic cells (DC, CD11c+), T (CD3+) cells, and M1-like macrophages (F4/80+CD38+Egr2-) were quantified. RESULTS: Nelitolimod delivered via PEDD resulted in changes in innate and adaptive immune cells within LM, including depletion of liver MDSC and increased M1-like macrophages in the liver, which are supportive of antitumor immunity. While CPI monotherapy failed to control tumor progression, nelitolimod and CPI combination improved LM control, survival and antitumor immunity beyond the nelitolimod monotherapy effect, irrespective of CPI delivery route. CONCLUSION: The SQ route of CPI delivery was equivalent to Sys in combination with nelitolimod, suggesting SQ-CPI may be a rational choice in combination with PEDD of nelitolimod for liver tumor treatment.

Association between Surgery, Anesthesia, and Obstetric Workforce and Emergent Surgical and Obstetric Mortality among United States Hospital Referral Regions.

OBJECTIVE: To determine the association between SAO workforce and mortality from emergent surgical and obstetric conditions within US HR Rs. BACKGROUND: SAO workforce per capita has been identified as a core metric of surgical capacity by the Lancet Commission on Global Surgery, but its utility has not been assessed at the subnational level for a high-income country. METHODS: The number of practicing surgeons, anesthesiologists, and obstetricians per capita was estimated for all HRRs using the US Health Resources & Services Administration Area Health Resource File Database. Deaths due to emergent general surgical and obstetric conditions were determined from the Center for Disease Control and Prevention WONDER database. We utilized B-spline quantile regression to model the relationship between SAO workforce and emergent surgical mortality at different quantiles of mortality and calculated the expected change in mortality associated with increases in SAO workforce. RESULTS: The median SAO workforce across all HRRs was 74.2 per 100,000 population (interquartile range 33.3-241.0). All HRRs met the Lancet Commission on Global Surgery lower target of 20 SAO per 100,000, and 97.7% met the upper target of 40 per 100,000. Nearly 2.8 million Americans lived in HRRs with fewer than 40 SAO per 100,000. Increases in SAO workforce were associated with decreases in surgical mortality in HRRs with high mortality, with minimal additional decreases in mortality above 60 to 80 SAO per 100,000. CONCLUSIONS: Increasing SAO workforce capacity may reduce emergent surgical and obstetric mortality in regions with high surgical mortality but diminishing returns may be seen above 60 to 80 SAO per 100,000. Trial Registration: N/A.

Associations of cephalad drainage in neonatal veno-venous ECMO - A mixed-effects, propensity score adjusted retrospective analysis of 20 years of ELSO data.

BACKGROUND: Neurologic complications can occur during neonatal Veno-Venous (VV) ECMO. The addition of a cephalad drainage cannula (i.e., VVDL+V) to dual lumen cannulation (i.e., VVDL) has been advocated to reduce such complications, but previous studies have presented mixed results. METHODS: Data from the ECMO Registry of the Extracorporeal Life Support Organization was used to extract all neonates (≤28 days old) who underwent VV ECMO for respiratory support between 2000 and 2019. Primary outcomes were mortality, conversion to Veno-Arterial (VA) ECMO, pump flows, and complications. A mixed-effects, propensity score adjusted analysis was performed. RESULTS: 4,275 neonates underwent VV ECMO, 581 (13.6%) via VVDL+V cannulation, and 3,694 (86.4%) via VVDL. On unadjusted analyses, VVDL+V patients had higher rates of mortality (25.5% vs 19.0%, p<0.001), conversion to VA ECMO (14.5% vs 4.1%, p<0.001), and higher pump flows at 4 h from ECMO initiation (112.7 vs 105.5 mL/Kg/min, p<0.001), but lower at 24 h (100.3 vs 104.0 mL/Kg/min, p = 0.004), and a higher proportion of them experienced hemorrhagic (29.3% vs 18.3%, p<0.001), cardiovascular (60.8% vs 45.8%, p<0.001), and mechanical (42.5% vs 32.6%, p<0.001) complications compared to VVDL patients. After adjusting for propensity scores and the multi-level nature of ELSO data, there were no differences in neurologic outcomes, pump flows, or mortality. Rather, VVDL+V cannulation was associated with higher rates of conversion to VA ECMO (adjusted odds ratio [AOR] 43.3, 95% CI 24.3 - 77.4, p<0.001), and increased mechanical (AOR 2.2, 95% CI 1.6 - 3.0, p<0.001) and hemorrhagic (AOR 2.0, 95% CI 1.4 - 3.0, p<0.001) complications. CONCLUSIONS: In this analysis, VVDL+V cannulation was not associated with any improvement in neurologic outcomes, pump flows, or mortality, but was rather associated with higher rates of conversion to Veno-Arterial ECMO, mechanical, and hemorrhagic complications.

Sistrunk vs modified Sistrunk procedures: Does procedure type matter?

BACKGROUND: Thyroglossal Duct Cyst (TDC) is the most common congenital neck mass in children and is surgically managed with a Sistrunk procedure. Some surgeons perform a modified Sistrunk (mSis), involving the dissection of the fistula beyond the hyoid bone without coring out the foramen cecum at the base of the tongue. We aim to evaluate surgical outcomes of children undergoing Sistrunk (Sis) or modified Sistrunk (mSis) procedures for TDC at an academic pediatric institution. MATERIALS AND METHODS: We conducted a retrospective chart review of the Children's National Medical Center database from 2004 to 2014. Basic demographic information, preoperative characteristics, postoperative complications, and recurrence were extracted for children diagnosed with TDC. We estimated descriptive statistics using Kruskal-Wallis tests and Pearson's chi-square for continuous and categorical values. RESULTS: 157 patients that underwent TDC excision were identified. Sistrunk (Sis) was performed in 52 cases (33%) and modified Sistrunk (mSis) performed in 105 (67%) cases. 84 (54%) were female and the mean age at surgery was 5.4 years (SD=4.5). Overall recurrence was detected in 8 cases (5.1%) and did not differ significantly by procedure type [2 (4%) in Sis and 6 (6%) in mSis, p = 0.616]. Post-operative complications did not differ significantly between Sis and mSis procedure: swelling [6 (12%) and 18 (17%), p = 0.481]; seroma [5 (10%) and 10 (10%), p = 1.00]; surgical site infection [3 (6%) and 8 (8%), p = 0.752]; or post-excision incision and drainage [3 (6%) and 9 (9%), p = 0.752] (respectively). CONCLUSIONS: Our findings reveal no statistical difference in recurrence rates between Sis and mSis with no risk factors for recurrence identified. Furthermore, there was no difference in post-operative complications between the groups. Both surgical procedures were associated with few complications and low recurrence.