"Surgery First" vs. "Endoscopy First" for Pediatric Choledocholithiasis Presenting at the End of the Week - A CARES Working Group Study.

BACKGROUND: Choledocholithiasis in children is commonly managed with an "endoscopy-first" (EF) strategy (endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy (LC)). Because ERCP availability is often limited at the end of the week (EoW), we hypothesized that a "surgery-first" (SF) approach (LC with intraoperative cholangiogram (IOC) ± transcystic laparoscopic common bile exploration (LCBDE)) would decrease length of stay (LOS) and time to definitive intervention (TTDI). METHODS: A multicenter, retrospective cohort study was conducted on pediatric patients from 2018 to 2023 with suspected choledocholithiasis. Work week (WW) presentation was defined as admission between Monday to Thursday. TTDI was defined as time to LC or postoperative ERCP (if required). RESULTS: Among seven hospitals, there were 354 pediatric patients; 217 (61%) managed with SF (125 WW, 92 EoW) and 137 (39%) managed with EF (74 WW, 63 EoW). SF groups had a shorter LOS for both WW and EoW presentation (60.2 h and 58.3 h vs 88.5 h and 93.6 h respectively; p < 0.05). TTDI decreased in SF (26.4 h and 28.9 h vs 61.4 h and 72.8 h; p < 0.05). All EF patients underwent at least two anesthetics (preoperative ERCP followed by LC) while the majority (79%) of the SF group had only one procedure (LC + IOC ± LCBDE). CONCLUSION: Children who present with choledocholithiasis at EoW have a longer LOS and TTDI. These findings are amplified when children enter an EF pathway. A surgery-first approach results in fewer procedures, decreased TTDI, and shorter LOS, regardless of the time of presentation. LEVEL OF EVIDENCE: Level III.

Patient Safety and Radiation Exposure in Transcystic Laparoscopic Common Bile Duct Exploration: A CARES Working Group Multicenter Study.

BACKGROUND: Treatment of choledocholithiasis with laparoscopic cholecystectomy (LC) and intraoperative cholangiogram (IOC) ± transcystic laparoscopic common bile duct exploration (LCBDE) is associated with fewer procedures and shorter length of stay (LOS) compared to preoperative endoscopic retrograde cholangiopancreatography (ERCP) followed by LC. Fluoroscopy is required for both LCBDE and ERCP but fluoroscopic time (FT) and radiation dose (RD) in LCBDE has not been studied. METHODS: The Choledocholithiasis Alliance for Research, Education, and Surgery (CARES) Working Group conducted this retrospective study on pediatric patients with suspected choledocholithiasis who received IOC. Demographics, type of LCBDE, FT and RD during IOC ± LCBDE, were analyzed. Statistical analysis was completed using Microsoft Excel and R software. RESULTS: From five centers, 157 patients were identified (79 without LCBDE, 78 with LCBDE). Wire access into the duodenum was successful in 67 patients (86%) and 64 patients (82%) had successful duct clearance. Median FT for all LCBDE cases was 3.3 min [1.6, 6.7] and RD was 59.8 mGy [30.1, 125.0] with no difference between successful and unsuccessful duct clearance (66.7 mGy [29.0, 115.0], 55.8 mGy [35.8, 154.1], respectfully; p = 0.51). CONCLUSION: Although both ERCP and LCBDE approaches result in fluoroscopic radiation exposure, FT, and RD in LCBDE have not previously been studied and are inadequately described in ERCP. Limiting radiation exposure in children is essential and fluoroscopy stewardship is a key component of pediatric safety in LCBDE. LEVEL OF EVIDENCE: Level III.

Reducing MRCP Utilization Through a "Surgery First" Approach for Pediatric Choledocholithiasis: A CARES Working Group Retrospective Study.

BACKGROUND: Choledocholithiasis in children is rising and frequently managed with an endoscopy-first (EF) approach that utilizes endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy (LC). Magnetic resonance cholangiopancreatography (MRCP) is a resource intensive modality that often precedes ERCP to gain further assurance of choledocholithiasis prior to intervention. MRCP can lead to a longer length of stay (LOS) and strain healthcare resources. We hypothesized that the use of MRCP is decreased with a surgery-first (SF) approach. METHODS: The Choledocholithiasis Alliance for Research, Education, and Surgery (CARES) Working Group conducted this retrospective study on pediatric patients with suspected choledocholithiasis. SF patients underwent LC + intraoperative cholangiogram (IOC) ± laparoscopic common bile duct exploration (LCBDE). Imaging studies included ultrasound (US), MRCP, and computed tomography (CT). RESULTS: From seven institutions, 357 pediatric patients were identified. The SF (n = 220) group received fewer imaging studies then EF (n = 137) (1.29 vs. 1.62; p < 0.05). US was more commonly employed and the number of US and CT scans was similar. The SF group had lower MRCP utilization than EF (29% vs. 59%; p < 0.05). EF patients that received an MRCP had the longest LOS (4.0 d [2.4, 6.3]) compared to SF that did not (1.9 d [1.2, 3.2]) (p < 0.05). CONCLUSION: Children with choledocholithiasis managed with an EF approach receive more diagnostic imaging, especially MRCP. While MRCP remains a powerful diagnostic tool, a surgery-first approach can minimize the resource utilization and LOS associated with magnetic resonance imaging. LEVEL OF EVIDENCE: Level III.

Multi-institutional Analysis of Choledocholithiasis in Pediatric vs Adult Patients.

BACKGROUND: In adults, upfront intraoperative cholangiogram with laparoscopic common bile duct exploration (LCBDE) is well accepted for management of choledocholithiasis. Despite recent evidence supporting LCBDE utility in children, there has been hesitation to adopt this surgery first (SF) approach over ERCP first (EF) due to perceived technical challenges. We compared rates of successful stone clearance during LCBDE between adult and pediatric patients to evaluate if pediatric surgeons could anticipate similar rates of successful clearance. METHODS: A multicenter, retrospective review of pediatric (<18 years) and adult patients with choledocholithiasis managed from 2018 to 2024 was performed. Demographic and clinical data were obtained. Rate of successful duct clearance with LCBDE was compared. Surgical and endoscopic complications (infections, bleeding, pancreatitis, bile leak) were also compared. RESULTS: 724 patients, 333 (45.9%) pediatric and 391 (54.0%) adults, were included. The median age of pediatric vs adult patients was 15.2 years [13.1, 16.6] vs 55.5 years [34.1, 70.5], respectively. Of these, 201 (60.4%) pediatric vs 169 (43.2%) adult patients underwent SF, p < 0.001. LCBDE was attempted in 84 (41.7%) pediatric vs 140 (82.8%) adults, p = 0.002. LCBDE success was higher in pediatric vs adult patients (82.1% vs 71.4%, p = 0.004). Complications rates were similar however, pediatric patients who underwent EF had higher endoscopic complications (9.1% vs 3.6%, p = 0.03). CONCLUSION: LCBDE is highly successful in children vs adults with no increased surgical complications. This data, coupled with the limited ERCP access for children, supports that LCBDE is an equally effective tool for managing choledocholithiasis in children as is accepted in adults. LEVEL OF EVIDENCE: Level III.

Venous Thromboembolism Prophylaxis in High-Risk Pediatric Trauma Patients.

Importance: The indications, safety, and efficacy of chemical venous thromboembolism prophylaxis (cVTE) in pediatric trauma patients remain unclear. A set of high-risk criteria to guide cVTE use was recently recommended; however, these criteria have not been evaluated prospectively. Objective: To examine high-risk criteria and cVTE use in a prospective multi-institutional study of pediatric trauma patients. Design, Setting, and Participants: This cohort study was completed between October 2019 and October 2022 in 8 free-standing pediatric hospitals designated as American College of Surgeons level I pediatric trauma centers. Participants were pediatric trauma patients younger than 18 years who met defined high-risk criteria on admission. It was hypothesized that cVTE would be safe and reduce the incidence of VTE. Exposures: Receipt and timing of chemical VTE prophylaxis. Main Outcomes and Measures: The primary outcome was overall VTE rate stratified by receipt and timing of cVTE. The secondary outcome was safety of cVTE as measured by bleeding or other complications from anticoagulation. Results: Among 460 high-risk pediatric trauma patients, the median (IQR) age was 14.5 years (10.4-16.2 years); 313 patients (68%) were male and 147 female (32%). The median (IQR) Injury Severity Score (ISS) was 23 (16-30), and median (IQR) number of high-risk factors was 3 (2-4). A total of 251 (54.5%) patients received cVTE; 62 (13.5%) received cVTE within 24 hours of admission. Patients who received cVTE after 24 hours had more high-risk factors and higher ISS. The most common reason for delayed cVTE was central nervous system bleed (120 patients; 30.2%). There were 28 VTE events among 25 patients (5.4%). VTE occurred in 1 of 62 patients (1.6%) receiving cVTE within 24 hours, 13 of 189 patients (6.9%) receiving cVTE after 24 hours, and 11 of 209 (5.3%) who had no cVTE (P = .31). Increasing time between admission and cVTE initiation was significantly associated with VTE (odds ratio, 1.01; 95% CI, 1.00-1.01; P = .01). No bleeding complications were observed while patients received cVTE. Conclusions and Relevance: In this prospective study, use of cVTE based on a set of high-risk criteria was safe and did not lead to bleeding complications. Delay to initiation of cVTE was significantly associated with development of VTE. Quality improvement in pediatric VTE prevention may center on timing of prophylaxis and barriers to implementation.

Antegrade Continence Enema Alone for the Management of Functional Constipation and Segmental Colonic Dysmotility (ACE-FC): A Pediatric Colorectal and Pelvic Learning Consortium Study.

PURPOSE: The purpose of the study was to determine if antegrade continence enema (ACE) alone is an effective treatment for patients with severe functional constipation and segmental colonic dysmotility. METHODS: A retrospective study of patients with functional constipation and segmental colonic dysmotility who underwent ACE as their initial means of management. Data was collected from six participating sites in the Pediatric Colorectal and Pelvic Learning Consortium. Patients who had a colonic resection at the same time as an ACE or previously were excluded from analysis. Only patients who were 21 years old or younger and had at least 1-year follow-up after ACE were included. All patients had segmental colonic dysmotility documented by colonic manometry. Patient characteristics including preoperative colonic and anorectal manometry were summarized, and associations with colonic resection following ACE were evaluated using Fisher's exact test and Wilcoxon rank-sum test. p-Values of less than 0.05 were considered significant. Statistical analyses and summaries were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, United States). RESULTS: A total of 104 patients from 6 institutions were included in the study with an even gender distribution (males n = 50, 48.1%) and a median age of 9.6 years (interquartile range 7.4, 12.8). At 1-year follow-up, 96 patients (92%) were successfully managed with ACE alone and 8 patients (7%) underwent subsequent colonic resection for persistent symptoms. Behavioral disorder, type of bowel management, and the need for botulinum toxin administered to the anal sphincters was not associated with the need for subsequent colonic resection. On anorectal manometry, lack of pelvic floor dyssynergia was significantly associated with the need for subsequent colonic resection; 3/8, 37.5% without pelvic dyssynergia versus 1/8, 12.5% (p = 0.023) with pelvic dyssynergia underwent subsequent colonic resection. CONCLUSION: In patients with severe functional constipation and documented segmental colonic dysmotility, ACE alone is an effective treatment modality at 1-year follow-up. Patients without pelvic floor dyssynergia on anorectal manometry are more likely to receive colonic resection after ACE. The vast majority of such patients can avoid a colonic resection.

Association between COVID-19 related elective surgery cancellations and pediatric inguinal hernia complications: A nationwide multicenter cohort study.

BACKGROUND: Optimal inguinal hernia repair timing remains controversial. It remains unclear how COVID-19 related elective surgery cancellations impacted timing of inguinal hernia repair and whether any delays led to complications. This study aims to determine whether elective surgery cancellations are safe in pediatric inguinal hernia. METHODS: This multicenter retrospective cohort study at 14 children's hospitals included patients ≤18 years who underwent inguinal hernia repair between September 13, 2019, through September 13, 2020. Patients were categorized by whether their inguinal hernia repair occurred before or after their hospital's COVID-19 elective surgery cancellation date. Incarceration and emergency department encounters were compared between pre and postcancellation. RESULTS: Of 1,404 patients, 604 (43.0%) underwent inguinal hernia repair during the postcancellation period, 92 (6.6%) experienced incarceration, and 213 (15.2%) had an emergency department encounter. The postcancellation period was not associated with incarceration (odds ratio 1.54; 95% confidence interval 0.88-2.71; P = .13) or emergency department encounters (odds ratio 1.53; 95% confidence interval 0.94-2.48; P = .09) despite longer median times to inguinal hernia repair (precancellation 29 days [interquartile range 13-55 days] versus postcancellation 31 days [interquartile range 14-73 days], P = .01). Infants were more likely to have the emergency department be their index presentation in the postcancellation period (odds ratio 1.69; 95% confidence interval 1.24-2.31; P < .01). CONCLUSION: Overall, COVID-19 elective surgery cancellations do not appear to increase the likelihood of incarceration or emergency department encounters despite delays in inguinal hernia repair, suggesting that cancellations are safe in children with inguinal hernia. Assessment of elective surgery cancellation safety has important implications for health policy.

Risk profile of subcutaneous port placement in small children.

BACKGROUND/PURPOSE: Long-term central venous access is a safe and common procedure in children. However, complications with devices are a reality. Smaller children are thought to have a higher rate of complication after port placement, and some surgeons avoid placing ports with an arbitrary weight cutoff out of concern for surgical site morbidity. METHODS: We performed a multi-institutional retrospective review of 500 patients less than 5 years of age undergoing port placement at three large volume children's hospitals from 2014 to 2018. Patients were divided by weight greater than or less than 10 kg at the time of insertion. Statistical analysis was performed to evaluate for differences in outcomes between the two groups. RESULTS: The majority of ports were placed for chemotherapy access (71.8%). Other indications included long-term infusions (18.8%) and difficult chronic IV access (9.4%). Of the 500 charts reviewed, 110 (22%) experienced some documented complication (28.9% <10 kg, 20.6% >10 kg, p = 0.096). There were no differences between the two groups in terms of the type or timing of complications. Overall, 16.3% of ports required removal prior to the end of therapy owing to a complication. Complication rate per day with the port in place was not different between the two groups (<10 kg: 0.68 complications/1000 port-days vs >10 kg 0.44 complications/1000 port-days, p = 0.068). CONCLUSION: Weight less than 10 kg was not associated with a significantly higher incidence of any type of port complication in our cohort. This suggests that concern for complications should not exclude children less than 10 kg from port placement. TYPE OF STUDY: Multi-institutional retrospective review. LEVEL OF EVIDENCE: Level III.

The danger zone: Injuries and conditions associated with immediately fatal motorcycle crashes in the state of Michigan.

BACKGROUND: Immediately fatal motorcycle crashes have not been well characterized. This study catalogues injuries sustained in fatal motorcycle crashes and assesses the impact of crash conditions on injury patterns. METHODS: Autopsy records from the office of the medical examiner of Kent County, MI and publicly available traffic reports were queried for information pertaining to motorcyclists declared dead on-scene between January 1, 2007, and December 31, 2016. RESULTS: A total of 71 autopsies of on-scene motorcycle crash fatalities were identified. The two most prevalent injuries were traumatic brain injury (TBI) (85%) and rib fractures (79%). The majority of fatalities occurred in daylight hours (54.3%) and in a 55 mph speed limit zone (63.8%). CONCLUSIONS: This study provides a catalogue of the injuries sustained in immediately fatal motorcycle crashes and the associated conditions. Advocacy efforts that highlight the risks associated with motorcycle riding and that promote safe riding practices are warranted.

Atomic force microscopy probing of receptor-nanoparticle interactions for riboflavin receptor targeted gold-dendrimer nanocomposites.

Riboflavin receptors are overexpressed in malignant cells from certain human breast and prostate cancers, and they constitute a group of potential surface markers important for cancer targeted delivery of therapeutic agents and imaging molecules. Here we report on the fabrication and atomic force microscopy (AFM) characterization of a core-shell nanocomposite consisting of a gold nanoparticle (AuNP) coated with riboflavin receptor-targeting poly(amido amine) dendrimer. We designed this nanocomposite for potential applications such as a cancer targeted imaging material based on its surface plasmon resonance properties conferred by AuNP. We employed AFM as a technique for probing the binding interaction between the nanocomposite and riboflavin binding protein (RfBP) in solution. AFM enabled precise measurement of the AuNP height distribution before (13.5 nm) and after chemisorption of riboflavin-conjugated dendrimer (AuNP-dendrimer; 20.5 nm). Binding of RfBP to the AuNP-dendrimer caused a height increase to 26.7 nm, which decreased to 22.8 nm when coincubated with riboflavin as a competitive ligand, supporting interaction of AuNP-dendrimer and its target protein. In summary, physical determination of size distribution by AFM imaging can serve as a quantitative approach to monitor and characterize the nanoscale interaction between a dendrimer-covered AuNP and target protein molecules in vitro.

Molecular imaging reveals a role for AKT in resistance to cisplatin for ovarian endometrioid adenocarcinoma.

PURPOSE: Ovarian cancer is the fifth leading cause of cancer-related deaths among American women. Platinum-based chemotherapy, such as cisplatin, represents the standard-of-care for ovarian cancer. However, toxicity and acquired resistance to cisplatin have proven challenging in the treatment of patients with ovarian cancer. EXPERIMENTAL DESIGN: Using a genetically engineered mouse model of ovarian endometrioid adenocarcinoma (OEA) in combination with molecular-imaging technologies, we studied the activation of the AKT serine/threonine kinase in response to long-term cisplatin therapy. RESULTS: Treatment of cells in culture and tumor-bearing animals with cisplatin resulted in activation of AKT, a key mediator of cell survival. On the basis of these results, we investigated the therapeutic use of AKT inhibition in combination with cisplatin, which resulted in enhanced and prolonged induction of apoptosis and in significantly improved tumor control as compared with either agent alone. CONCLUSION: These results provide an impetus for clinical trials using combination therapy. To facilitate these trials, we also show the use of diffusion-weighted MRI as an imaging biomarker for evaluation of therapeutic efficacy in OEA.

Biophysical characterization of a riboflavin-conjugated dendrimer platform for targeted drug delivery.

The present study describes the biophysical characterization of generation-five poly(amidoamine) (PAMAM) dendrimers conjugated with riboflavin (RF) as a cancer-targeting platform. Two new series of dendrimers were designed, each presenting the riboflavin ligand attached at a different site (isoalloxazine at N-3 and d-ribose at N-10) and at varying ligand valency. Isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC) were used to determine the binding activity for riboflavin binding protein (RfBP) in a cell-free solution. The ITC data shows dendrimer conjugates have K(D) values of ≥ 465 nM on a riboflavin basis, an affinity ~93-fold lower than that of free riboflavin. The N-3 series showed greater binding affinity in comparison with the N-10 series. Notably, the affinity is inversely correlated with ligand valency. These findings are also corroborated by DSC, where greater protein-conjugate stability is achieved with the N-3 series and at lower ligand valency.