[The acute abdomen in children]. / Akutes Abdomen im Kindesalter.

BACKGROUND: Because 8-10% of children in the emergency room present with acute abdominal pain, a systematic work-up is essential to rule out acute abdomen. OBJECTIVES: This article highlights the etiology, symptoms, diagnostic workup, and treatment of acute abdomen in children. MATERIALS AND METHODS: Review of the current literature. RESULTS: Abdominal inflammation, ischemia, bowel and ureteral obstruction, or abdominal bleeding are causes of acute abdomen. Extra-abdominal diseases such as otitis media in toddlers or testicular torsion in adolescent boys can also lead to symptoms of acute abdomen. Abdominal pain, (bilious) vomiting, abdominal guarding, constipation, blood-tinged stools, abdominal bruise marks, and poor condition of the patient with symptoms such as tachycardia, tachypnea, and hypotonia up to shock are leading symptoms of acute abdomen. In some cases, emergent abdominal surgery is needed to treat the cause of the acute abdomen. However, in patients with pediatric inflammatory multisystem syndrome temporarily associated with SARS-CoV­2 infection (PIMS-TS), a new disease causing an acute abdomen, surgical treatment is rarely needed. CONCLUSIONS: Acute abdomen can lead to nonreversible loss of an abdominal organ, such as bowel or ovary, or develop into acute deterioration of the patient's condition up to the state of shock. Therefore, a complete history and thorough physical examination are needed to timely diagnose acute abdomen and initiate specific therapy.

MUC-FIRE: Study protocol for a randomized multicenter open-label controlled trial to show that MUCous FIstula REfeeding reduces the time from enterostomy closure to full enteral feeds.

Background: After enterostomy creation, the distal bowel to the ostomy is excluded from the physiologic passage of stool, nutrient uptake, and growth of this intestinal section. Those infants frequently require long-term parenteral nutrition, continued after enterostomy reversal due to the notable diameter discrepancy of the proximal and distal bowel. Previous studies have shown that mucous fistula refeeding (MFR) results in faster weight gain in infants. The aim of the randomized multicenter open-label controlled MUCous FIstula REfeeding ("MUC-FIRE") trial is to demonstrate that MFR between enterostomy creation and reversal reduces the time to full enteral feeds after enterostomy closure compared to controls, resulting in shorter hospital stay and less adverse effects of parenteral nutrition. Methods/Design: A total of 120 infants will be included in the MUC-FIRE trial. Following enterostomy creation, infants will be randomized to either an intervention or a non-intervention group.In the intervention group, perioperative MFR between enterostomy creation and reversal will be performed. The control group receives standard care without MFR.The primary efficacy endpoint of the study is the time to full enteral feeds. Secondary endpoints include first postoperative bowel movement after stoma reversal, postoperative weight gain, and days of postoperative parenteral nutrition. In addition adverse events will be analyzed. Discussion: The MUC-FIRE trial will be the first prospective randomized trial to investigate the benefits and disadvantages of MFR in infants. The results of the trial are expected to provide an evidence-based foundation for guidelines in pediatric surgical centers worldwide. Trial registration: The trial has been registered at clinicaltrials.gov (number: NCT03469609, date of registration: March 19, 2018; last update: January 20, 2023, https://clinicaltrials.gov/ct2/show/NCT03469609?term=NCT03469609&draw=2&rank=1).

Multidisciplinary Treatment Strategies for Wilms Tumor: Recent Advances, Technical Innovations and Future Directions.

Significant progress has been made in the management of Wilms tumor (WT) in recent years, mostly as a result of collaborative efforts and the implementation of protocol-driven, multimodal therapy. This article offers a comprehensive overview of current multidisciplinary treatment strategies for WT, whilst also addressing recent technical innovations including nephron-sparing surgery (NSS) and minimally invasive approaches. In addition, surgical concepts for the treatment of metastatic disease, advances in tumor imaging technology and potentially prognostic biomarkers will be discussed. Current evidence suggests that, in experienced hands and selected cases, laparoscopic radical nephrectomy and laparoscopic-assisted partial nephrectomy for WT may offer the same outcome as the traditional open approach. While NSS is the standard procedure for bilateral WT, NSS has evolved as an alternative technique in patients with smaller unilateral WT and in cases with imminent renal failure. Metastatic disease of the lung or liver that is associated with WT is preferably treated with a three-drug chemotherapy and local radiation therapy. However, surgical sampling of lung nodules may be advisable in persistent nodules before whole lung irradiation is commenced. Several tumor markers such as loss of heterozygosity of chromosomes 1p/16q, 11p15 and gain of function at 1q are associated with an increased risk of recurrence or a decreased risk of overall survival in patients with WT. In summary, complete resection with tumor-free margins remains the primary surgical aim in WT, while NSS and minimally invasive approaches are only suitable in a subset of patients with smaller WT and low-risk disease. In the future, advances in tumor imaging technology may assist the surgeon in defining surgical resection margins and additional biomarkers may emerge as targets for development of new diagnostic tests and potential therapies.

Prenatal Detection of Congenital Duodenal Obstruction-Impact on Postnatal Care.

BACKGROUND: Duodenal obstruction is a rare cause of congenital bowel obstruction. Prenatal ultrasound could be suggestive of duodenal atresia if polyhydramnios and the double bubble sign are visible. Prenatal diagnosis should prompt respective prenatal care, including surgery. The aim of this study was to investigate the rate and importance of prenatally diagnosed duodenal obstruction, comparing incomplete and complete duodenal obstruction. METHODS: A retrospective, single-center study was performed using data from patients operated on for duodenal obstruction between 2004 and 2019. Prenatal ultrasound findings were obtained from maternal logbooks and directly from the investigating obstetricians. Postnatal data were obtained from electronic charts, including imaging, operative notes and follow-up. RESULTS: A total of 33/64 parents of respective patients agreed to provide information on prenatal diagnostics. In total, 11/15 patients with complete duodenal obstruction and 0/18 patients with incomplete duodenal obstruction showed typical prenatal features. Prenatal diagnosis prompted immediate surgical treatment after birth. CONCLUSION: Prenatal diagnosis of congenital duodenal obstruction is only achievable in cases of complete congenital duodenal obstruction by sonographic detection of the pathognomonic double bubble sign. Patients with incomplete duodenal obstruction showed no sign of duodenal obstruction on prenatal scans and thus were diagnosed and treated later.

Outcome of esophageal atresia: inborn versus outborn patients.

Esophageal atresia (EA) is a rare congenital disease which is usually not of the detected prenatally. Due to the lack of prenatal diagnosis, some newborns with EA are born outside of specialized centers. Nevertheless, centralized care of EA has been proposed, even if a clear volume-outcome association in EA management remains unconfirmed. Furthermore, whether outcomes differ between outborn and inborn patients with EA has not been systematically investigated. Therefore, this single-center, retrospective study aimed to investigate EA management and outcomes with a special focus on inborn versus outborn patients. The following data were extracted from the medical records of infants with EA from 2009 to 2019: EA type, associated anomalies, complications, and long-term outcome. Patients were allocated into inborn and outborn groups. Altogether, 57 patients were included. Five patients were excluded (referral before surgery, loss of data, death before surgery [n = 1], and incorrect diagnosis [diverticulum, n = 1]). Among all patients, the overall survival rate was 96%, with no mortalities among outborn patients. The overall hospitalization period was shorter for outborn patients. The median follow-up durations were 3.8 years and 3.2 years for inborn and outborn patients, respectively. Overall, 15% of patients underwent delayed primary anastomosis (long-gap atresia [n = 4] and other reasons [n = 4]). Early complications included three anastomotic leakages and one post-operative fistula; 28% of patients developed strictures, which required dilatation, and 38% of patients showed relevant gastroesophageal reflux, which required fundoplication, without any differences between the groups. The two groups had comparable low mortality and expected high morbidity with no significant differences in outcome. The outborn group showed nonsignificant trends toward lower morbidity and shorter hospitalization periods, which might be explained by the overall better clinical status.

Incidence of penalty corner injuries in international field hockey.

Field hockey penalty corners (PCs) put players at potential risk for injuries. This study evaluated the incidence of PC-related injuries with special regards to head injuries. Video sequences provided by the Fédération Internationale de Hockey (FIH) of 295 matches in 11 elite field hockey tournaments (2015-2016) were analysed for overall injuries and PC-related injuries in detail. In total, 13.9% of all match injuries (49/352 injuries) occurred in relation to a PC, accounting for 7.1 PC-related injuries per 1000 player match hours (95% CI 4.4-9.9). There were 11 head injuries afflicting six defenders and five attackers. One head injury was related to a direct hit by a ball (drag flick). This study provides the first data on PC-related injuries in elite field hockey. The recorded numbers and mechanisms of PC-related injuries should be used as a baseline for further studies and potential rule adaptations.

Comparison of perioperative outcomes between laparoscopic and open partial splenectomy in children and adolescents.

BACKGROUND: In order to avoid consequences of total splenectomy, partial splenectomy (PS) is increasingly reported. The purpose of this study was to compare perioperative outcomes of laparoscopic PS (LPS) and open PS (OPS) in children and adolescents. AIM: To compare perioperative outcomes of patients with LPS and OPS. METHODS: After institutional review board approval, a total of 26 patients that underwent LPS or OPS between January 2008 and July 2018 were identified from the database of our tertiary referral center. In total, 10 patients had LPS, and 16 patients underwent OPS. Blood loss was calculated by Mercuriali's formula. Pain scores, analgesic requirements and complications were assessed. The Wilcoxon rank sum test was used for comparison. To compare categorical variables, Fisher's exact test was applied. RESULTS: LPS was performed in 10 patients; 16 patients had OPS. Demographics (except for body mass index and duration of follow-up), indicating primary disease, preoperative spleen size and postoperative spleen volume, perioperative hematological parameters, postoperative pain scores, analgesic requirements, adverse events according to the Clavien-Dindo classification and the comprehensive complication index, median time from operation to initiation of feeds, median time from operation to full feeds, median time from operation to mobilization and median length of hospital stay did not differ between LPS and OPS. Median (range) operative time (min) was longer in LPS compared to the OPS group [185 (135-298) vs 144 (112-270), respectively; P = 0.048]. Calculated perioperative blood loss (mL of red blood cell count) was higher in the LPS group compared to OPS [87 (-45-777) vs -37 (-114-553), respectively; P = 0.039]. CONCLUSION: This is the first study that compared outcomes of LPS and OPS. Both operative approaches had comparable perioperative outcomes. LPS appears to be a viable alternative to OPS.

Epidemiology and One-Year Follow-Up of Neonates with CDH-Data from Health Insurance Claims in Germany.

Congenital diaphragmatic hernia (CDH) is a major congenital malformation with high mortality. Outcome data on larger unselected patient groups in Germany are unavailable as there is no registry for CDH. Therefore, routine data from the largest German health insurance fund were analyzed for the years 2009-2013. Main outcome measures were incidence, survival and length of hospital stay. Follow-up was 12 months. 285 patients were included. The incidence of CDH was 2.73 per 10,000 live births. Overall mortality was 30.2%. A total of 72.1% of the fatalities occurred before surgery. Highest mortality (64%) was noted in patients who were admitted to specialized care later as the first day of life. Patients receiving surgical repair had a better prognosis (mortality: 10.8%). A total of 67 patients (23.5%) were treated with ECMO with a mortality of 41.8%. The median cumulative hospital stay among one-year survivors was 40 days and differed between ECMO- and non-ECMO-treated patients (91 vs. 32.5 days, p < 0.001). This is the largest German cohort study of CDH patients with a one-year follow-up. The ECMO subgroup showed a higher mortality. Another important finding is that delayed treatment in specialized care increases mortality. Prospective clinical registries are needed to elucidate the treatment outcomes in detail.

Ovarian lesions and tumors in infants and older children.

Objectives: Ovarian lesions are rare but frequent in children. Patients could present with abdominal pain, but ovarian lesions could also be incidentally found on ultrasound. Awareness is required in cases with acute, severe lower abdominal pain, as ovarian torsion could be the cause. Other lesions can be cysts or benign or malignant ovarian tumors. Thus, the aim of this paper is to review typical ovarian lesions according to age, imaging and laboratory findings, and surgical management. Methods: We retrospectively analysed the patient charts of 39 patients aged 10.4 ± 6.1 years (from 3 months to 18 years) with ovarian lesions treated in our institution between 01/2009 and 08/2020. All clinical and pathological findings of infants and children operated on for ovarian lesions were included. Results: Ovarian lesions in children younger than 2 years of age were typically ovarian cysts, and ovarian tumors were not observed in this age group. In older children over 10 years of age, tumors were more common - with mostly teratoma or other germ cell tumors, followed by epithelial tumors. Moreover, acute or chronic ovarian torsion was observed in all age groups. In general, ovarian tumors were much larger in size than ovarian cysts or twisted ovaries and eventually showed tumor marker expression of AFP or ß-HCG. Simple ovarian cysts or twisted ovaries were smaller in size. Surgery for all ovarian lesions should aim to preserve healthy ovarian tissue by performing partial ovariectomy. Conclusions: In adolescent girls with acute abdominal pain, immediate laparoscopy should be performed to rule out ovarian torsion. Careful imaging evaluation and the assessment of tumor markers should be performed in painless ovarian lesions to indicate an adequate surgical ovarian-sparing approach.

Video Analysis of Acute Injuries in Elite Field Hockey.

OBJECTIVE: With this study, we aim to determine the value of video assessment of acute injuries in field hockey. DESIGN: Retrospective video analysis for acute injuries. SETTING: Professional field hockey. PARTICIPANTS: Seven women and men's field hockey tournaments (World League, Champions Trophy) in 2015. INTERVENTIONS: Not applicable. OUTCOME MEASURES: An injury was defined as any new musculoskeletal complaint leading to time stoppage and medical attention. The outcome measures were time at play, location on the pitch, type of injury, injured body part, and injury mechanism. RESULTS: A total of 190 injuries occurred in 179 matches (55/73 female and 135/106 male matches). There were 0.75 injuries per match for women [confidence interval (CI, 0.31-1.13)] and 1.27 injuries per match for men (CI, 0.88-1.61). The number of injuries per 1000 player match hours was 34.20 for women (CI, 14.04-51.29) and 57.89 for men (CI, 29.78-73.12). The highest injury frequency occurred within the third quarter and within the circle. Contusion was the most common injury type (90.9% in women and 96.3% in men). The leading causes of injuries were hits by the ball or stick and collisions with another player. The head/face was the most affected body part in both sex groups (32.7% in women and 29.6% in men). CONCLUSIONS: Video analysis revealed data on injury incidence within the same range of previous reports in elite field hockey. Its advantages, such as slow motion and repetitive play of injury scenes, could contribute valuable information if incorporated into the injury recording process.

Injury surveillance in elite field hockey: a pilot study of three different recording techniques.

OBJECTIVE: In field hockey, injuries are assessed by various recording techniques leading to a heterogenic collection of poorly comparable injury data. METHODS: Injury data were prospectively collected at the 2016 Men's Hockey Junior World Cup using the match injury reports (MIRs), video injury clips provided by the Fédération Internationale de Hockey, and daily medical reports (DMRs). A pilot study comparing injury type, mechanism, location on the field, injured body part and overall injury incidence among the different injury recording techniques was performed. RESULTS: MIRs and video injury clips were completely available for analysis. DMRs were returned from 11 out of 16 teams (69%). In total, MIRs yielded 28, video analysis 36, and DMRs 56 injuries. Overall injury rate varied between 24.8 and 57.9 injuries per 1000 player match hours. The majority of injuries affected the lower limbs by all three methods (41.7-61.2%) and were mainly caused by having been hit by the ball (20.4-50%) or stick (11.1-28.6%). Reports of concussions during competition were incoherent between MIR (2 cases) and DMR (no cases). The DMR was the only method to record overuse injuries (16.1%), injuries in training (12.5%), and time-loss injuries of one or two days (12.5%) or of three or more days (14.3%). CONCLUSION: Injury data vary substantially between the MIR, DMR and injury video recording technique. Each recording technique revealed specific strengths and limitations. To further advance injury research in field hockey, the strengths of each recording technique should be brought together for a synergistic injury assessment model.

Comparison of outcomes between complete and incomplete congenital duodenal obstruction.

BACKGROUND: Congenital duodenal obstruction (CDO) can be complete (CCDO) or incomplete (ICDO). To date there is no outcome analysis available that compares both subtypes. AIM: To quantify and compare the association between CCDO and ICDO with outcome parameters. METHODS: We retrospectively reviewed all patients who underwent operative repair of CCDO or ICDO in our tertiary care institution between January 2004 and January 2017. The demographics, clinical presentation, preoperative diagnostics and postoperative outcomes of 50 patients were compared between CCDO (n = 27; atresia type 1-3, annular pancreas) and ICDO (n = 23; annular pancreas, web, Ladd´s bands). RESULTS: In total, 50 patients who underwent CDO repair were enrolled and followed for a median of 5.2 and 3.9 years (CCDO and ICDO, resp.). CCDO was associated with a significantly higher prenatal ultrasonographic detection rate (88% versus 4%; CCDO vs ICDO, P < 0.01), lower gestational age at birth, lower age and weight at operation, higher rate of associated congenital heart disease (CHD), more extensive preoperative radiologic diagnostics, higher morbidity according to Clavien-Dindo classification and comprehensive complication index (all P ≤ 0.01). The subgroup analysis of patients without CHD and prematurity showed a longer time from operation to the initiation of enteral feeds in the CCDO group (P < 0.01). CONCLUSION: CCDO and ICDO differ with regard to prenatal detection rate, gestational age, age and weight at operation, rate of associated CHD, preoperative diagnostics and morbidity. The degree of CDO in mature patients without CHD influences the postoperative initiation of enteral feeding.

Laparoscopic versus open surgery for the repair of congenital duodenal obstructions in infants and children.

BACKGROUND: Laparoscopic repair of congenital duodenal obstruction (LCDO) was described more than 15 years ago. However, studies comparing outcomes of LCDO with open repair (OCDO) are rare. Standardized assessments of complications using the Clavien-Dindo classification (CDC) and the comprehensive complication index (CCI) are not available. METHODS: All patients undergoing OCDO or LCDO between 2004 and 2017 were identified from the institutional database by retrospective analysis. Postoperative outcomes were assessed, including all complications using the CDC and the CCI. RESULTS: Forty-seven consecutive patients were identified; 27 patients underwent LCDO and 20 patients had OCDO. Both groups did not differ regarding demographics, associated congenital anomalies, intraoperative pathologic findings, and operative procedures. LCDO was associated with a longer operative time [mean (SD), 202 (89) vs. 112 (41) min, P < 0.0001], shorter time to initiation of feeds [median (range), 1 (0-4) vs. 3 (1-12) days, P = 0.0027], and shorter time to full feeds [mean (SD), 8.2 (4.1) vs. 12.2 (6.4) days, P = 0.0243] compared to OCDO. Shorter length of postoperative hospital stay in LCDO group was achieved for patients without cardiac anomalies [mean (SD), 9.4 (3.1) days in LCDO group vs. 17.2 (9.4) days in OCDO, P = 0.0396] and patients without other anomalies [median (range), 12 (3-38) days in LCDO group vs. 21 (7-31) days in OCDO, P = 0.0460]. LCDO was associated with a lower CCI [median (range) 0 (0-39.7) vs. 4.3 (0-100), P = 0.0270]. CONCLUSIONS: Despite a longer operative time for LCDO, a number of advantages of LCDO over OCDO were recognized comparing both approaches in the repair of congenital duodenal obstruction. Such advantages include a lower morbidity, reduced time to initiation and completion of full enteral feeds, and shorter length of postoperative hospitalization for patients without concomitant cardiac anomalies and for patients without other anomalies when operated laparoscopic. In view of the present results, LCDO, performed in selected patients, appears to represent a viable alternative to OCDO.

Radical Surgery Improves Survival in Patients with Stage 4 Neuroblastoma.

BACKGROUND: Neuroblastoma (NBL) is the most common extracranial solid tumor in children. Despite a good overall prognosis in NBL patients, the outcome of children with stage 4 disease, even with multimodal intensive therapy, remains poor. The role of extended surgical resection of the primary tumor is in numerous studies controversial. The aim of this study was to retrospectively analyze the impact of radical surgical resection on the overall- and event-free survival of stage 4 NBL patients. METHODS: We retrospectively analyzed patient charts of 40 patients with stage 4 NBL treated in our institution between January 1990 and May 2012. All clinical and pathological findings of stage 4 NBL patients were included. Extent of surgery was assessed from the operation records and was classified as non-radical (tumor biopsy, partial 50-90% resection) or radical (near-complete >90% resection, complete resection). Overall- (OS) and event-free (EFS) survival was assessed using the Kaplan-Meier analysis and log-rank test. A multivariate Cox regression analysis was used to demonstrate independency. RESULTS: In total, 29/40 patients were operated radically (>90% resection), whereas 11 patients received subtotal resection or biopsy only. OS and EFS were significantly increased in patients with radical operation compared with non-radical resection (p = 0.0003 for OS, p = 0.004 for EFS; log-rank test). A multivariate Cox regression analysis revealed radical operation as a significant and independent parameter for OS and EFS. CONCLUSIONS: Our data indicate that radical (over 90% resection) surgery improves OS and EFS in stage 4 NBL patients.

Crizotinib in ALK+ inflammatory myofibroblastic tumors-Current experience and future perspectives.

Inflammatory myofibroblastic tumor (IMT) and its subtype epithelioid inflammatory myofibroblastic sarcoma (EIMS) are rare soft-tissue tumors. As about 50% of IMT and 100% of EIMS contain activating rearrangements of the anaplastic lymphoma kinase (ALK) gene, targeted kinase inhibition of ALK by compounds such as crizotinib is a potential treatment option. We performed a literature review and analyzed a total of 30 patients with IMT/EIMS treated with crizotinib. A total of 12 patients achieved complete or partial remission. As preliminary data are promising, a prospective study evaluating crizotinib treatment in patients with unresectable/multifocal ALK+ IMT/EIMS is warranted.

Identification of intestinal ganglioneuromatosis leads to early diagnosis of MEN2B: role of rectal biopsy.

BACKGROUND/PURPOSE: Gastrointestinal symptoms are very common in patients with multiple endocrine neoplasia type 2B (MEN2B) syndrome. Herein, we present a case of intestinal ganglioneuromatosis (IGN) in MEN2B syndrome and a systematic literature review with a special focus on gastrointestinal symptoms prior to the diagnosis of MEN2B. METHODS: Literature search was performed (years 1966-2015) using the "Pubmed" and "Scopus" databases. Search terms used were gastrointestinal, intestinal and MEN2B. RESULTS: Literature search revealed 188 publications on MEN2B patients with gastrointestinal symptoms, providing a total of 55 patients including our own case. The far most common gastrointestinal symptom was constipation (72.7%). The onset of gastrointestinal symptoms occurred in 29 out of 55 cases (52.3%) below the age of 1year. However, MEN2B diagnosis was established at a median age of 13.0years (range 0-46years). The histological finding of IGN led to the diagnosis of MEN2B In 15 of 55 patients (27.3%) at a median age of 3years (range 0-31years). CONCLUSION: Paying close attention to gastrointestinal problems in early childhood and taking a rectal biopsy that precisely screens for IGN offers the chance of diagnosing MEN2B syndrome early in infancy.

Injury data of major international field hockey tournaments.

BACKGROUND: Detailed injury data are not available for international tournaments in field hockey. We investigated the epidemiology of field hockey injuries during major International Hockey Federation (Fédération Internationale de Hockey, FIH) tournaments in 2013. MATERIALS AND METHODS: FIH injury reports were used for data collection. All major FIH tournaments for women (n=5) and men (n=11) in 2013 were included. The main focus of this study was to assess the pattern, time, site on the pitch, body site and mechanism of each of the injuries. We calculated the average number of injuries per match and the number of injuries per 1000 player match hours. RESULTS: The average number of injuries was 0.7 (95% CI 0.5 to 1.0) per match in women's tournaments and 1.2 (95% CI 0.8 to 1.7) per match in men's tournaments. The number of injuries per 1000 player match hours ranged from 23.4 to 44.2 (average 29.1; 95% CI 18.6 to 39.7) in women and 20.8 to 90.9 (average 48.3; 95% CI 30.9 to 65.8) in men. Most injuries occurred in the circle (n=25, 50%, in women, n=95, 51%, in men). The rate of injuries increased after the first quarter. Injuries to the head and face (n=20, 40%) were most common in women. The head/face (n=51, 27%) and the thigh/knee (n=52, 28%) were equally affected in men. The ball caused the most injuries, followed by the stick, collisions and tripping/falling. There were no deaths or injuries that required hospital treatment in the entire cohort. SUMMARY: Field hockey has a low incidence of acute injuries during competition.

Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver.

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor ß secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

Aging-dependent reduction in glyoxalase 1 delays wound healing.

Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (≤12 weeks) and old (≥52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 ± 2.2 vs. 55.4 ± 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 ± 1.6 vs. 77.2 ± 3.1%; p < 0.05) and 64% (40.4 ± 7.9 vs. 66.4 ± 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice.