Management of undifferentiated embryonal sarcoma of the liver: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare tumor for which there are few evidence-based guidelines. The aim of this study was to define current management strategies and outcomes for these patients using a multi-institutional dataset curated by the Pediatric Surgical Oncology Research Collaborative. METHODS: Data were collected retrospectively for patients with UESL treated across 17 children's hospitals in North America from 1989 to 2019. Factors analyzed included patient and tumor characteristics, PRETEXT group, operative details, and neoadjuvant/adjuvant regimens. Event-free and overall survival (EFS, OS) were the primary and secondary outcomes, respectively. RESULTS: Seventy-eight patients were identified with a median age of 9.9 years [interquartile range [IQR): 7-12]. Twenty-seven patients underwent resection at diagnosis, and 47 patients underwent delayed resection, including eight liver transplants. Neoadjuvant chemotherapy led to a median change in maximum tumor diameter of 1.6 cm [IQR: 0.0-4.4] and greater than 90% tumor necrosis in 79% of the patients undergoing delayed resection. R0 resections were accomplished in 63 patients (81%). Univariate analysis found that metastatic disease impacted OS, and completeness of resection impacted both EFS and OS, while multivariate analysis revealed that R0 resection was associated with decreased expected hazards of experiencing an event [hazard ratio (HR): 0.14, 95% confidence interval (CI): 0.04-0.6]. At a median follow-up of 4 years [IQR: 2-8], the EFS was 70.0% [95% CI: 60%-82%] and OS was 83% [95% CI: 75%-93%]. CONCLUSION: Complete resection is associated with improved survival for patients with UESL. Neoadjuvant chemotherapy causes minimal radiographic response, but significant tumor necrosis.

Outcomes of Central Hepatectomy for Pediatric Liver Tumors.

BACKGROUND: Central hepatectomy (CH) is an uncommon surgical technique that is an option for resection of centrally located tumors, with the advantage of sparing normal hepatic parenchyma. Few studies have described outcomes in children undergoing CH. MATERIALS AND METHODS: An IRB-approved, retrospective chart review of patients who underwent CH at Children's Hospital Los Angeles between 2005 and 2016 was performed. Data included patient demographics, peri-operative factors, and post-operative outcomes. The IRB approved waiver of consent. RESULTS: Eight patients (4F:4M) with median age of 1.9 Y underwent CH: 7 patients for HB and 1 patient for focal nodular hyperplasia. Two of the seven HB patients had metastatic disease at diagnosis. Six of the seven HB patients received a median of 4 rounds (3-7 rounds) of pre-operative chemotherapy. The median operative time was 197.5 Min (143-394 Min) with median blood loss of 175 mL (100-1200 mL). Complications included a bile fluid collection requiring aspiration. Seven patients had negative margins on pathology. One patient with a positive margin successfully completed therapy, without recurrent disease. All patients survived to follow-up, with a median follow-up duration of 1.1 Y (0.1-12.1 Y). Two patients developed recurrent disease requiring formal hepatic lobectomy and orthotopic liver transplantation. These patients had negative pathologic margins, with tumor within 1 mm of resection margins. CONCLUSION: CH is an effective alternative to extended hepatectomy for patients with centrally located liver tumors and is associated with good clinical and pathologic outcomes.

The Effect of Gross Total Resection on Patients with Pleuropulmonary Blastoma.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common primary lung cancer in children. While rare, these tumors are highly aggressive. Tumor recurrence and overall survival are dependent on histologic grade and extent of surgical resection. We sought to examine our institutional experience with PPB to determine the effect of gross total resection (GTR) on recurrence and patient outcomes. MATERIALS AND METHODS: After IRB approval, a retrospective chart review from 1998 to 2018 was performed. Cases were confirmed by histology and Dehner Grade (I to III). Data collection included demographics, treatment, extent of surgical resection, and patient outcomes. RESULTS: Eight patients with nine procedures were identified. Histologically, three cases were type 1, 2 type 2, and four poor prognosis type 3. Three patients received neoadjuvant chemotherapy to facilitate surgical resection. The operative goal was to achieve GTR (>95%), and to this end, three partial lobectomies, five lobectomies, and one pneumonectomy were performed. All nine cases achieved GTR, of which eight had negative microscopic margins. Two patients with type III disease recurred (one locally, one distant) and died. One type 3 patient had a positive microscopic hilar margin not amenable to further resection. The patient recurred (distant) but is in remission. With respect to patient outcomes, the event-free survival was 2.3 y with an overall survival of 3.3 y. CONCLUSIONS: From our experience, GTR of PPB is associated with minimal surgical morbidity and good overall survival. Multi-institutional studies are needed to determine if positive surgical margins affect outcomes given the morbidity of mediastinal dissection.

Gabapentin is Associated With Decreased Postoperative Opioid Use and Length of Stay After Appendectomy in Children With Perforated Appendicitis: A Propensity Score-Matched Analysis.

BACKGROUND: Gabapentin is increasingly used as an off-label, opioid-sparing pain medication in children. We investigated perioperative gabapentin administration and postoperative opioid use in children who underwent appendectomy for perforated appendicitis. METHODS: A retrospective cohort study of healthy children ages 2-18 years undergoing appendectomy for perforated appendicitis from 2014 to 2019 was performed using the Pediatric Health Information System®. Propensity score matched (PSM) analysis was conducted with 1:1 matching based on patient and hospital characteristics. Multivariable linear regression analysis was used to evaluate an association between gabapentin, postoperative opioid use, and postoperative length of stay. RESULTS: Of 29,467 children with perforated appendicitis who underwent appendectomy, 236 (0.8%) received gabapentin. In 2014, <10 children received gabapentin, but by 2019, 110 children received gabapentin. On univariate analysis of the PSM cohort, children receiving gabapentin had decreased total postoperative opiate use (2.3 SD ± 2.3 versus 3.0 SD ± 2.5 days, p < 0.001). On adjusted analysis, children receiving gabapentin had 0.65 fewer days of postoperative total opioid use (95% CI: -1.09, -0.21) and spent 0.69 fewer days in the hospital after surgery (95% CI: -1.30, -0.08). CONCLUSION: While overall use is infrequent, gabapentin is increasingly administered to children with perforated appendicitis who undergo an appendectomy and is associated with decreased postoperative opioid use and reduced postoperative length of stay. Multimodal pain management strategies incorporating gabapentin may reduce postoperative opioid consumption, but further studies of drug safety are needed for this off-label use in children undergoing surgery. LEVEL OF EVIDENCE: III.

Opioid and Methadone Use for Infants With Surgically Treated Necrotizing Enterocolitis.

Importance: Necrotizing enterocolitis (NEC) requiring surgical intervention is the most common reason for surgical procedures in preterm neonates. Opioids are used to manage postoperative pain, with some infants requiring methadone to treat physiologic opioid dependence or wean from nonmethadone opioid treatment during recovery. Objective: To describe postoperative opioid use and methadone treatment for infants with surgically treated NEC and evaluate postoperative outcomes. Design, Setting, and Participants: A cohort study of infants with surgically treated NEC admitted from January 1, 2013, to December 31, 2022, to 48 Children's Hospital Association hospitals contributing data to the Pediatric Health Information System (PHIS) was performed. Infants who received methadone preoperatively, were aged 14 days or less at the time of the operation, had a congenital heart disease-related operation, or died within 90 days of the operation were excluded. Mixed-effects multivariable logistic regression was used to evaluate thresholds for duration of opioid use after the operation associated with methadone treatment and clinical outcomes associated with methadone use were enumerated. Exposure: Postoperative administration of nonmethadone opioids. Main Outcomes and Measures: Methadone use and postoperative length of stay, ventilator days, and total parenteral nutrition (TPN) days. Results: Of the 2037 infants with surgically treated NEC identified, the median birth weight was 920 (IQR, 700.0-1479.5) g; 1204 were male (59.1%), 911 were White (44.7%), and 343 were Hispanic (16.8%). Infants received nonmethadone opioids for a median of 15 (IQR, 6-30) days after the operation and 231 received methadone (11.3%). The median first day of methadone use was postoperative day 18 (IQR, days 9-64) and continued for 28 days (IQR, 14-73). Compared with infants who received nonmethadone opioids for 1 to 5 days, infants receiving 16 to 21 days of opioids were most likely to receive methadone treatment (odds ratio, 11.45; 95% CI, 6.31-20.77). Methadone use was associated with 21.41 (95% CI, 10.81-32.02) more days of postoperative length of stay, 10.80 (95% CI, 3.63-17.98) more ventilator days, and 16.21 (95% CI, 6.34-26.10) more TPN days. Conclusions and Relevance: In this cohort study of infants with surgically treated NEC, prolonged use of nonmethadone opioids after the operation was associated with an increased likelihood of methadone treatment and increased postoperative length of stay, ventilation, and TPN use. Optimizing postoperative pain management for infants requiring an operation may decrease the need for methadone treatment and improve health care use.

A multidisciplinary approach to management of abdominal lymphatic malformations.

BACKGROUND/PURPOSE: Abdominal lymphatic malformations (LM) are a rare subset of vascular anomaly caused by abnormal development of the lymphatic system. They are classified as macrocystic, microcystic or combination macrocystic and microcystic. Surgical resection, percutaneous sclerotherapy, and medical therapy are all employed to treat these complex and often symptomatic lesions. No standardized treatment algorithm exists currently. The purpose of this study was to establish a multidisciplinary treatment approach to abdominal LMs. METHODS: A retrospective observational study was conducted from 2013 to 2019 on patients with abdominal LMs at a single tertiary children's hospital vascular anomalies center. Demographics, imaging, and treatment modality were recorded. Clinical and/or radiographic response to the primary treatment modality as well as complications was the outcomes measured. RESULTS: Nineteen patients (12 macrocystic, 5 microcystic and 2 combined) were identified, with a median age at diagnosis of 2.2 years (range 0.1-20.8 years). Sclerotherapy was the most common primary treatment, followed by surgical resection and sirolimus. No difference in clinical response (p = 0.58) or complications (p = 0.31) was observed based on primary treatment or subtypes. CONCLUSIONS: Based on our institutional experience, we propose an LM subtype-based treatment algorithm for abdominal LMs. It employs a multidisciplinary approach, and results in satisfactory patient outcomes with minimal complications. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Fewer postoperative opioids are associated with decreased duration of stay for children with perforated appendicitis.

BACKGROUND: The impact of postoperative opioid use on outcomes for children with perforated appendicitis is unknown. METHODS: A retrospective cohort study was performed using the Pediatric Health Information System database from 2005 to 2015. Children 2 to 18 years with perforated appendicitis who underwent an appendectomy were identified. Postoperative day analgesic use was categorized as nonopioid analgesia alone, opioids (with or without nonopioid analgesia), or no analgesics. The impact of postoperative opioid use on postoperative duration of stay and 30-day readmission was evaluated using multivariable mixed-effects regression analysis. RESULTS: Overall, 47,726 children with perforated appendicitis were identified. On postoperative day 1, 17.7% received nonopioid analgesia alone, 77.6% received opioids, and 4.7% received no analgesics. On adjusted analysis, postoperative day 1 opioid use was associated with a 0.75-day (95% confidence interval: 0.54-0.96) increased postoperative duration of stay. Starting opioids after postoperative day 1 was associated with 2.21 days (95% confidence interval: 1.90-2.51) longer postoperative duration of stay. Among children who received opioids on postoperative day 1, continued use of opioids after postoperative day 1 was associated with a 1.88 day (95% confidence interval: 1.77-1.98) longer postoperative duration of stay. Postoperative day 1 opioid use did not significantly affect 30-day readmission. CONCLUSION: Early and continued postoperative opioid use is associated with prolonged postoperative duration of stay in children undergoing appendectomy for perforated appendicitis. Minimizing opioid use, even on postoperative day 2, may result in a decreased postoperative duration of stay.

Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice.

BACKGROUND: Immunotherapy with anti-disialoganglioside dinutuximab has improved survival for children with high-risk neuroblastoma (NB) when given after induction chemotherapy and surgery. However, disease recurrence and resistance persist. Dinutuximab efficacy has not been evaluated when initiated before primary tumor removal. Using a surgical mouse model of human NB, we examined if initiating dinutuximab plus ex vivo-activated natural killer (aNK) cells before resection of the primary tumor improves survival. METHODS: In vitro, human NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc) were treated with dinutuximab and/or aNK cells and cytotoxicity was measured. In vivo, NB cells (SMS-KCNR-Fluc, CHLA-255-Fluc, or COG-N-415x PDX) were injected into the kidney of NOD-scid gamma mice. Mice received eight intravenous infusions of aNK cells plus dinutuximab beginning either 12 days before or 2 days after resection of primary tumors. Tumors in control mice were treated by resection alone or with immunotherapy alone. Disease was quantified by bioluminescent imaging and survival was monitored. aNK cell infiltration into primary tumors was quantified by flow cytometry and immunohistochemistry at varying timepoints. RESULTS: In vitro, aNK cells and dinutuximab were more cytotoxic than either treatment alone. In vivo, treatment with aNK cells plus dinutuximab prior to resection of the primary tumor was most effective in limiting metastatic disease and prolonging survival. aNK cell infiltration into xenograft tumors was observed after 1 day and peaked at 5 days following injection. CONCLUSION: Dinutuximab plus aNK cell immunotherapy initiated before resection of primary tumors decreases disease burden and prolongs survival in an experimental mouse model of NB. These findings support the clinical investigation of this treatment strategy during induction therapy in patients with high-risk NB.

Modulation of remifentanil-induced postinfusion hyperalgesia by the ß-blocker propranolol in humans.

Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the ß(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the ß-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. ß-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.

The endogenous opioid system is not involved in modulation of opioid-induced hyperalgesia.

UNLABELLED: Some recent studies suggested a role of the endogenous opioid system in modulating opioid-induced hyperalgesia (OIH). In order to test this hypothesis, we conducted a prospective randomized, placebo-controlled, 2-way crossover study in healthy human volunteers. We utilized a well-established model of inducing OIH after a brief exposure to the µ-opioid agonist remifentanil using intradermal electrical stimulation. Patients were exposed to a randomized 90-minute infusion of remifentanil or saline placebo during 2 separate occasions. Development of OIH was quantified using changes in the average radius of the area of secondary hyperalgesia generated by electrical pain stimulation. A 23.6% (20.2) increase in area of secondary hyperalgesia over baseline was observed in the postinfusion period of the remifentanil session, demonstrating development of OIH (P = .03). In order to test endogenous opioid system modulation of OIH, patients were given a 1-time bolus of naloxone, which had no effect on the size of the hyperalgesic lesion in either the remifentinal or placebo session. These results suggested that the endogenous opioid system did not appear to modulate OIH. PERSPECTIVE: Experimental evidence suggested that the endogenous opioid system did not significantly affect opioid-induced hyperalgesia. Consequently, this study suggested that alternative mechanisms such as pronociceptive stimulation and neuroplastic changes might be responsible for expression of OIH.