Intercostal spinal nerve cryoablation for analgesia following pectus excavatum repair.

Pectus excavatum is a common chest wall deformity, most often treated during adolescence, that presents a significant postoperative pain control challenge for pediatric surgeons following surgical correction. The purpose of this article is to review the technique and outcomes of intercostal spinal nerve cryoablation for postoperative analgesia following surgical correction of pectus excavatum. Contemporary and historic literature were reviewed. Findings are summarized to provide a concise synopsis of the benefits of intercostal spinal nerve cryoablation relative to alternative analgesic modalities, as well as advocate for more widespread inclusion of this technique into multimodal pain regimens.

Higher Complication Rates for Total versus Partial Thyroidectomy in the Pediatric Population.

INTRODUCTION: This study aims to analyze the relative risks for total thyroidectomies by comparing complication rates for total versus partial thyroidectomy in the pediatric population. METHODS: We queried the Kids' Inpatient Database (KID) 1997-2012 for all cases of total (n = 3253) or partial (n = 2380) thyroidectomy. We then designed a propensity score matching model and compared total versus partial thyroidectomy based on surgical complications and outcomes. RESULTS: In our cohort, the median age was 16 years and 79% were females. Those treated at a specialty pediatric hospital or pediatric unit in a general hospital comprised 73% of all patients. The most common indications for surgery were malignancy (46%) and goiter (42%). The most common complications were hypocalcemia and nerve injury with an unweighted incidence of 9% (n = 174) and 3% (n = 57) respectively. When compared to partial thyroidectomy, total thyroidectomy was associated with increased rates of postoperative complications. Additionally, the median length of stay was significantly higher for total thyroidectomy patients. CONCLUSIONS: This is the largest analysis to date comparing outcomes for total versus partial thyroidectomy in the pediatric population. Surgeons should consider the increased rates of hypocalcemia and nerve injury complications when selecting total compared to partial thyroidectomy in children.

Identification of novel early pancreatic cancer biomarkers KIF5B and SFRP2 from "first contact" interactions in the tumor microenvironment.

BACKGROUND: Pancreatic cancer is one of the most difficult cancers to detect early and most patients die from complications arising due to distant organ metastases. The lack of bona fide early biomarkers is one of the primary reasons for late diagnosis of pancreatic cancer. It is a multifactorial disease and warrants a novel approach to identify early biomarkers. METHODS: In order to characterize the proteome, Extracellular vesicles (EVs) isolated from different in vitro conditions mimicking tumor-microenvironment interactions between pancreatic cancer epithelial and stromal cells were analyzed using high throughput mass spectrometry. The biological activity of the secreted EVome was analyzed by investigating changes in distant organ metastases and associated early changes in the microbiome. Candidate biomarkers (KIF5B, SFRP2, LOXL2, and MMP3) were selected and validated on a mouse-human hybrid Tissue Microarray (TMA) that was specifically generated for this study. Additionally, a human TMA was used to analyze the expression of KIF5B and SFRP2 in progressive stages of pancreatic cancer. RESULTS: The EVome of co-cultured epithelial and stromal cells is different from individual cells with distinct protein compositions. EVs secreted from stromal and cancer cells cultures could not induce significant changes in Pre-Metastatic Niche (PMN) modulation, which was assessed by changes in the distant organ metastases. However, they did induce significant changes in the early microbiome, as indicated by differences in α and ß-diversities. KIF5B and SFRP2 show promise for early detection and investigation in progressive pancreatic cancer. These markers are expressed in all stages of pancreatic cancer such as low grade PanINs, advanced cancer, and in liver and soft tissue metastases. CONCLUSIONS: Proteomic characterization of EVs derived from mimicking conditions of epithelial and stromal cells in the tumor-microenvironment resulted in the identification of several proteins, some for the first time in EVs. These secreted EVs cannot induce changes in distant organ metastases in in vivo models of EV education, but modulate changes in the early murine microbiome. Among all the proteins that were analyzed (MMP3, KIF5B, SFRP2, and LOXL2), KIF5B and SFRP2 show promise as bona fide early pancreatic cancer biomarkers expressed in progressive stages of pancreatic cancer.

Risk factors associated with recent opioid-related hospitalizations in children: a nationwide analysis.

PURPOSE: Identifying at-risk children can provide a crucial opportunity for preventative measures to avoid opioid addiction. This study sought to determine at-risk pediatric patients that were previously hospitalized due to other causes prior to their opioid-related admission. METHODS: The Nationwide Readmissions Database (2010-2014) was queried for children 1-18 years old with an opioid-related hospitalization. Previous admissions (up to 1 year prior) and associated diagnoses were compared. Results were weighted for national estimates. RESULTS: 51,349 opioid-related hospitalizations were identified with an overall in-hospital mortality of 0.8%. Seventeen percent had a previous admission during the same calendar year of which 44% had > 1 and 11% had ≥ 5 prior admissions. Only 4% of prior admissions occurred at a different hospital. Males and females were equally represented, and 82% were ≥ 13 years old. Only 16% of previously admitted patients underwent a major surgical procedure during a previous hospitalization. The most common concomitant diagnoses for patients with prior hospitalizations were drug abuse (37%), chronic pulmonary disease (18%), and depression (10%). CONCLUSION: Opioid-related hospitalizations often occur among children with multiple recent admissions, usually to the same hospital. Most patients do not have a history of cancer or recent surgery to account for their opioid use.

Pirfenidone increases IL-10 and improves acute pancreatitis in multiple clinically relevant murine models.

Despite decades of research, there is no specific therapy for acute pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an antiinflammatory and antifibrotic agent that is approved by the FDA for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (e.g., after initiation of injury), even when administered at the peak of injury, reduces severity of local and systemic injury and inflammation in multiple models of AP. In vitro evaluation suggests that pirfenidone decreases cytokine release from acini and macrophages and disrupts acinar-macrophage crosstalk. Therapeutic pirfenidone treatment increases IL-10 secretion from macrophages preceding changes in histology and modulates the immune phenotype of inflammatory cells with decreased levels of inflammatory cytokines. Antibody-mediated IL-10 depletion, use of IL-10-KO mice, and macrophage depletion experiments confirmed the role of IL-10 and macrophages in its mechanism of action, as pirfenidone was unable to reduce severity of AP in these scenarios. Since pirfenidone is FDA approved for IPF, a trial evaluating the efficacy of pirfenidone in patients with moderate to severe AP can be initiated expeditiously.

Hsp70 modulates immune response in pancreatic cancer through dendritic cells.

Heat shock protein 70 (Hsp70), a protein chaperone, is known to promote cell survival and tumor progression. However, its role in the tumor microenvironment (TME) is largely unknown. We specifically evaluated Hsp70 in the TME by implanting tumors in wild-type (WT) controls or Hsp70-/- animals, thus creating a TME with or without Hsp70. Loss of Hsp70 led to significantly smaller tumors; there were no differences in stromal markers, but interestingly, depletion of CD8 + T-cells abrogated this tumor suppressive effect, indicating that loss of Hsp70 in the TME affects tumor growth through the immune cells. Compared to WT, adoptive transfer of Hsp70-/- splenocytes exhibited greater antitumor activity in immunodeficient NSG and Rag 1-/- mice. Hsp70-/- dendritic cells showed increased expression of MHCII and TNF-α both in vitro and in vivo. These results suggest that the absence of Hsp70 in the TME inhibits tumors through increased dendritic cell activation. Hsp70 inhibition in DCs may emerge as a novel therapeutic strategy against pancreatic cancer.

Prophylactic colectomy for children with familial adenomatous polyposis: resource utilization and outcomes for open and laparoscopic surgery.

BACKGROUND: Laparoscopic approach for the surgical management of familial adenomatous polyposis (FAP) has become increasingly common for pediatric patients. The purpose of this study was to compare short-term outcomes and resource utilization between open and laparoscopic surgery for prophylactic colectomy in children with FAP. METHODS: The Kids' Inpatient Database (2009 and 2012) was analyzed for children (age ≤20 years) with FAP that underwent prophylactic total colectomy or proctocolectomy. Patient demographics, treating hospital characteristics, hospital charges, and short-term outcomes were compared according to the surgical technique utilized (open versus laparoscopic). RESULTS: Overall, we identified 216 patients with FAP that underwent elective total colectomy, of which 95 cases were performed by open surgery and 121 were done laparoscopically. The majority of patients were treated at large, not-for-profit, urban teaching hospitals, and the median age was equal (16 years) in both groups. Complications that were more common for open procedures included accidental perforation or hemorrhage (4% vs. 0%, P=0.023), reopening of surgical site (3% vs. 0%, P=0.049), and pneumonia (3% vs. 0%, P=0.049). Simultaneous proctectomy was performed more commonly in the open cohort (91% vs. 71%, P<0.001) as well as ileostomy creation (74% vs. 49%, P<0.001). The median length of stay was similar in the open and laparoscopic groups (7 vs. 6 days, P=0.712). Median total hospital charges were also similar ($67,334 vs. $68,717, P=0.080). CONCLUSIONS: A laparoscopic approach for prophylactic colectomy can be safely performed in children with FAP, and total hospital charges are equivalent compared to open surgery. However, simultaneous proctectomy was performed less often with laparoscopic surgery.

A retrospective comparison of outcomes for open vs. laparoscopic surgical techniques in pediatric ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is an aggressive disease in the pediatric population and a cause of significant, lifelong morbidity. The aim of this study is to compare surgical complications in pediatric patients undergoing laparoscopic vs. open surgical treatment for UC. METHODS: We queried the Kids' Inpatient Database (KID) for all cases of UC undergoing surgical treatment in 2009 and 2012. We identified patients who received total colectomy without proctectomy (n=413) or total proctocolectomy (n=196) and performed univariate and multivariate analyses comparing laparoscopic vs. open procedures. RESULTS: In pediatric UC patients undergoing total colectomy without proctectomy, open procedures were associated with more complications than laparoscopic, including fluid and electrolyte disorders (40% vs. 28%), surgical wound dehiscence (6% vs. 2%), septicemia (18% vs. 2%), and gastrointestinal disorders (16% vs. 7%) among others, all P<0.05. Likewise, in patients with UC undergoing total proctocolectomy, there were more complications in open vs. laparoscopic technique, including increased transfusion requirements (25% vs. 7%, P=0.001) and significantly more gastrointestinal upset, including nausea, vomiting, and diarrhea (11% vs. 1%, P=0.003). In multivariate analysis, patients who underwent total colectomy with or without proctectomy had an increased risk of experiencing any complication when their procedure was performed in an open or non-elective fashion (all odds ratio >2.4; all P<0.001). CONCLUSIONS: The laparoscopic approach was associated with significantly lower rates of surgical complications in pediatric patients undergoing total colectomy with or without proctectomy for UC. These findings demonstrate that laparoscopic technique compares favorably, and may be preferable, to the open approach in selected pediatric patients with UC.

Complications while awaiting elective inguinal hernia repair in infants: Not as common as you thought.

BACKGROUND: The dogma of early inguinal hernia repair in infants, especially those born prematurely, has dominated clinical practice owing to reports of a high frequency of incarceration and significant complications associated with untreated inguinal hernias. We aim to evaluate the frequency of complications after discharge with delayed surgery for inguinal hernia repair. METHODS: The Nationwide Readmissions Database (2010-2014) was queried to identify infants diagnosed with inguinal hernia. We compared the frequency and characteristics of inguinal hernia repair performed during the index admission, discharge from the index admission without hernia repair, and unplanned readmissions. RESULTS: We identified 33,530 infants (16,624 preterm and 16,906 full-term) diagnosed with an inguinal hernia during an index admission. For those infants diagnosed with an inguinal hernia at birth, inguinal hernia repair was performed during the birth admission for only a minority of both preterm (35%) and full-term infants (18%; P < .001). Of the infants discharged without hernia repair, 15% required nonelective readmission up to 1 year later, but only 2% of preterm and 1% of full-term infants actually underwent inguinal hernia repair during these unplanned readmissions. None of the readmitted infants underwent additional procedures suggestive of a strangulated hernia. CONCLUSION: Complications among infants awaiting inguinal hernia repair may be substantially less common than previously reported, and the occurrence of significant associated morbidity is quite rare.

An Immunocompetent Model of Pancreatic Cancer Resection and Recurrence.

BACKGROUND: Even after surgical resection, most patients with localized pancreatic ductal adenocarcinoma (PDAC) succumb to disease recurrence. Current animal models do not recapitulate this pattern of disease recurrence. Our goal was to develop a clinically relevant, immunocompetent model of PDAC resection to study recurrence and evaluate therapy. METHODS: Pancreatic cancer cells derived from tumors arising in KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) mice were co-injected with stromal cells (pancreatic stellate cells) into the pancreas of immunocompetent mice to simulate the stroma-rich tumors seen in human PDAC. After allowing tumors to form, we resected these localized tumors and followed the mice for tumor recurrence. Circulating tumor cells (CTCs) were isolated, and systemic chemotherapy or immunotherapy was administered following tumor resection. RESULTS: Tumors formed by co-injection of KPC cells and stromal cells demonstrated a dense desmoplastic reaction similar to that seen in human disease. Resection at days 15 and 21 after implantation revealed uniform tumor volumes of 92 ± 19 mm3 on day 15 and 444 ± 54 mm3 on day 21. Histology of resected tumors showed negative margins. Resembling human PDAC, mice that underwent resection showed improved median survival (58 vs 47 days) but most animals developed intra-abdominal recurrence on follow-up. Adjuvant chemotherapy (median survival 69 vs 58 days), but not immunotherapy (median survival 69 vs 65 days) tended towards improved survival as seen in human disease. Circulating tumor cells were reliably identified from mice with and without resection, suggesting utility of this model in studying tumor metastases and recurrence. CONCLUSION: We describe an immunocompetent animal model that recapitulates human disease in morphology and recurrence patterns. We show that it can be used to evaluate therapy in clinical scenarios associated with surgical resection and may help characterize factors responsible for disease recurrence.

Utility of routine intraoperative cholangiogram during cholecystectomy in children: A nationwide analysis of outcomes and readmissions.

PURPOSE: This study aims to determine postoperative outcomes and readmissions in pediatric cholecystectomy with routine intraoperative cholangiogram (IOC) utilization. METHODS: The Nationwide Readmissions Database 2010-2014 was queried for all pediatric cholecystectomies. A propensity score-matched analysis (PSMA) with over 30 covariates was performed between cholecystectomy alone (CCY) versus those with routine IOC (CCY + IOC, no biliary obstruction, dilatation, or pancreatitis). χ2 analysis or Mann-Whitney U were used for statistical analysis with p < 0.05 set as significant. RESULTS: 34,390 cholecystectomies were performed: 92% were laparoscopic, most were teenage females (75%, 15 years [13-17]) and did not undergo IOC (75%). Postoperative mortality rate was 0.1%. The PSMA cohort comprised of 1412 CCY and 1453 CCY + IOC. Patients with CCY alone had higher rates of 30-day (7% vs 5%), 1-year readmissions (13% vs 11%) and had higher rates of overall complications (22% vs 12%) compared with CCY + IOC, all p < 0.05. Although uncommon, bile duct injuries were more prevalent in CCY (2% vs 0%, p < 0.001), while there was no difference in readmissions for retained stones. Resource utilization was increased in CCY patients, likely due to increased complication rates. CONCLUSION: This nationwide PSMA suggests pediatric CCY with routine IOC is associated with decreased readmissions, overall resource utilization, complications, and bile duct injuries. TYPE OF STUDY: Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III.

Can we increase detection? A nationwide analysis of age-related fractures in child abuse.

PURPOSE: The purpose of this study was to stratify fractures associated with child abuse in relation to the child's age. METHODS: The Kids' Inpatient Database (1997-2012) was queried for all patients (<18 years old) with a diagnosis of fracture and child abuse. The primary outcome was age-related determinants of fracture distribution. Chi-squared analysis was used for statistical analysis where appropriate, with significance set at p < 0.05. RESULTS: More than 39,000 children were admitted for child abuse, and 26% sustained fractures. Most were infants (median age 0 year [IQR 0-1]). 28% sustained multiple fractures, and 27% had skull fractures. By age, infants had the highest rate of multiple fractures (33% vs 16% 1-4 years), and the highest rate of closed skull fractures (33% vs 21% ages 1-4), while adolescents had more facial fractures (43% vs 11% ages 9-12), all p < 0.001. Multiple rib fractures were more commonly seen in infants (28% vs 8% ages 1-4), while children 5-8 years had the highest rates of clavicular fractures (7% vs 3% in infants), all p < 0.001. CONCLUSION: Age-related fracture patterns exist and may be due to changing mechanism of abuse as a child grows. These age-related fracture patterns can help aid in healthcare detection of child abuse in hopes to thwart further abuse. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III.

Vaccination against Nonmutated Neoantigens Induced in Recurrent and Future Tumors.

Vaccination of patients against neoantigens expressed in concurrent tumors, recurrent tumors, or tumors developing in individuals at risk of cancer is posing major challenges in terms of which antigens to target and is limited to patients expressing neoantigens in their tumors. Here, we describe a vaccination strategy against antigens that were induced in tumor cells by downregulation of the peptide transporter associated with antigen processing (TAP). Vaccination against TAP downregulation-induced antigens was more effective than vaccination against mutation-derived neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease. Human CD8+ T cells stimulated with TAPlow dendritic cells elicited a polyclonal T-cell response that recognized tumor cells with experimentally reduced TAP expression. Vaccination against TAP downregulation-induced antigens overcomes the main limitations of vaccinating against mostly unique tumor-resident neoantigens and could represent a simpler vaccination strategy that will be applicable to most patients with cancer.

Incidence of recurrent intussusception in young children: A nationwide readmissions analysis.

BACKGROUND/PURPOSE: Recurrent intussusception following successful nonoperative reduction has previously been reported with a frequency of 8%-12% based on data from individual institutions. Meanwhile, the timing of discharge after successful reduction continues to be debated. Here, we evaluate readmissions for recurrent intussusception in young children using a large-scale national database. METHODS: The National Readmissions Database (2010-2014) was queried to identify young children (age < 5 years) diagnosed with intussusception. We compared procedures performed during the index admission and frequency of readmissions for recurrent intussusception. Results were weighted for national estimates. RESULTS: We identified 8289 children diagnosed with intussusception during an index admission. These patients received definitive treatment with nonoperative reduction alone (43%), surgical reduction (42%), or bowel resection (15%). Readmission for recurrent intussusception was required for 3.7% of patients managed with nonoperative reduction alone, 2.3% of patients that underwent surgical reduction, and 0% of those that underwent bowel resection. Median time to readmission was 4 days after nonoperative reduction, and only 1.5% of these patients experienced recurrence within 48 h of discharge. CONCLUSIONS: Recurrent intussusception may be substantially less common than previously reported. Our findings support the practice of discharge shortly after successful nonoperative reduction. TYPE OF STUDY: Retrospective, prognosis study. LEVEL OF EVIDENCE: III.

Open Versus Laparoscopic Right Hemicolectomies in Pediatric Patients with Crohn's Disease.

Introduction: Surgery remains an important treatment modality for the management of pediatric Crohn's disease (CD). The objective of this study was to perform a comparative analysis of open right hemicolectomy (ORH) and laparoscopic right hemicolectomy (LRH) for the management of pediatric CD. Materials and Methods: The Kids' Inpatient Database (KID) was queried (2009-2012) for ICD-9 procedure codes for ORH (45.73) and LRH (17.33) in patients with CD (ICD-9 codes: 555.0, 555.1, 555.2, 555.9). Open and laparoscopic procedures were compared using propensity score (PS)-matched analysis (PSMA) of 41 variables. Results: Overall 889 patients were identified and after PS matching, there were 380 ORHs and 380 LRHs. There were zero in-hospital deaths (0/821). ORH patients were more likely to have septicemia, respiratory compromise, pneumonia, perforation and/or laceration, complications, and require blood transfusions (all, P < .05). Although LRH patients were more likely to develop postoperative nausea/vomiting/diarrhea (P < .0001), they had a shorter hospital length of stay (P < .0001) and lower overall hospital charges and cost (P < .001). Conclusion: ORH and LRH in KID have similar low in-hospital mortality in pediatric CD. However, ORH was associated with higher morbidity including an increased risk for respiratory complications, surgical complications, need for blood transfusions, and increased resource utilization than patients who had laparoscopic procedures. In select patients, LRH is safe, feasible, and potentially superior to ORH.

Pull-through procedure in children with Hirschsprung disease: A nationwide analysis on postoperative outcomes.

PURPOSE: No nationwide studies on hospital readmissions exist for children who have undergone pull-through operations for Hirschsprung disease. The study aim is to identify determinants of postoperative discharge outcomes and hospital readmissions in children with Hirschsprung disease. METHODS: The Nationwide Readmissions Database for 2010-2014 was queried for children (<18yo) with Hirschsprung disease and whom had undergone pull-through procedure, utilizing ICD-9 codes 751.3 and 48.40-69, respectively. Outcomes included complications and readmissions at 30-day and 1-year. Results were weighted for national estimates. RESULTS: The cohort consisted of 3635 patients, 75% male and 79% < 1 year of age. Readmission rates at 30 days and 1-year were 20% and 36%, respectively. Overall, the most common diagnoses for readmission were gastrointestinal disorders (46%) and infections (39%). All age groups had a ≥ 10% readmission rate for gastrointestinal disorders. Infants were more likely to be admitted for enterocolitis and infections (16% and 15%), while children (1-6 years old) were most commonly readmitted for electrolyte disturbances (12%). Total hospitalization cost was over $162 million with $24 million from readmissions. CONCLUSION: Pull-through procedure for Hirschsprung disease is associated with high readmissions and associated economic burden. Age specific interventions to prevent unnecessary readmissions could improve outcomes and curtail healthcare spending. TYPE OF STUDY: Retrospective Comparative Analysis. LEVEL OF EVIDENCE: Level III.

Nationwide analysis of mortality and hospital readmissions in esophageal atresia.

PURPOSE: The purpose of this study is to identify determinants of mortality and hospital readmission in infants born with esophageal atresia ± tracheoesophageal fistula. METHODS: The Nationwide Readmissions Database (2010-2014) was queried for newborns with a diagnosis of esophageal atresia. Outcomes included mortality and readmissions at 30-day and 1-year. RESULTS: 3157 patients were identified, of which 54% were male. 81% had an additional congenital anomaly, and 35% had VACTERL association. Overall mortality at index hospitalization was 11% (n = 360) and was significantly higher with additional congenital anomalies (13%), VACTERL (19%), and Spitz classification II/III (18%) vs. isolated esophageal atresia/tracheoesophageal fistula (4%), all p < 0.001. After esophageal atresia repair (n = 2179), 10% (n = 212) were readmitted within 30 days and 26% (n = 563) within 1 year, with 17% admitted to different hospitals. Common diagnoses during readmission were GERD (54%), infections (42%), failure to thrive (17%), tracheomalacia (14%), and esophageal stricture (10%). Unplanned readmissions accounted for 85% of readmissions. A large number underwent operative procedures, most commonly esophageal dilation (17%) and fundoplication/gastrostomy (12%). CONCLUSION: Our study has uncovered a high likelihood of complications and unplanned readmission within the first year of life for newborns with esophageal atresia. Coordinated multidisciplinary care may help to decrease unnecessary readmissions and improve outcomes in this vulnerable population. TYPE OF STUDY: Retrospective comparative analysis. LEVEL OF EVIDENCE: Level III.

Treatment patterns and outcomes for pancreatic tumors in children: an analysis of the National Cancer Database.

PURPOSE: Pancreatic tumors are rare in children and limited data are available regarding incidence, treatment, and outcomes. We aim to describe patient and tumor characteristics and to report on survival of these diseases. METHODS: Children with pancreatic tumors were queried from the National Cancer Database (2004-2014). The association between treatment and hazard of death was assessed using Kaplan-Meier method and Cox regression model. RESULTS: We identified 109 children with pancreatic tumors; 52% were male and median age at diagnosis was 14 years. Tumors were distributed as follows: pseudopapillary neoplasm (30%), endocrine tumors (27%), pancreatoblastoma (16%), pancreatic adenocarcinoma (16%), sarcoma (6%) and neuroblastoma (5%). Seventy-nine patients underwent surgery, of which 76% achieved R0 resection. Most patients (85%) had lymph nodes examined, of which 22% had positive nodes. Five-year overall survival by tumor histology was 95% (pseudopapillary neoplasm), 75% (neuroblastoma), 70% (pancreatoblastoma), 51% (endocrine tumors), 43% (sarcoma), and 34% (adenocarcinoma). On multivariable analysis, surgical resection was the strongest predictor of survival (HR 0.26, 95% CI 0.10-0.68, p < 0.01). CONCLUSION: Overall survival of children with pancreatic tumors is grim, with varying survival rates among different tumors. Surgical resection is associated with improved long-term survival.

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy.

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.