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Tumor cells can migrate from a primary cancer and form metastases by localizing to niches within other organs including the bone marrow, where tumor cells may exploit the hematopoietic stem cell niche. The precise composition of the premetastatic and the hematopoietic niches and the degree of overlap between them remain elusive. Because the extracellular matrix protein fibronectin is expressed in the pre-metastatic lung microenvironment, we evaluated the implications of its loss, as well as those of loss of its primary receptor subunit, β1 integrin, in various bone marrow cell types both in breast cancer bone metastasis and hematopoiesis. Using eight transgenic mouse models, we established that fibronectin production by osterix-expressing marrow cells, or β1 integrin expression (on vav, mx, or leptin receptor expressing cells), affects MDA-MB-231 breast cancer cell numbers in the bone marrow. Additionally, we identified stromal subpopulations that modulate transmigration through blood vessel walls. Not the number of tumor cells, but rather the changes in the microenvironment dictated whether the tumor progresses. Furthermore, hematopoiesis, particularly myelopoiesis, was affected in some of the models showing changes in tumor homing. In conclusion, there is partial overlap between the pre-metastatic and the hematopoietic niches in the bone marrow. Moreover, we have delineated a cascade starting with fibronectin secreted by pre-osteoblastic cells, which potentially acts on β1 integrin in specific stromal cell subsets, thereby inhibiting the formation of new breast cancer lesions in the bone marrow. This work therefore sheds light on the role of various stromal cell subpopulations that influence tumor behavior and affect hematopoiesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction:  The treatment of newborns with congenital diaphragmatic hernia (CDH) is associated with a significant complication rate. Information on major thrombotic complications and their incidence in newborns with CDH is lacking. The aims of our analysis were to evaluate the frequency of vena cava thrombosis and to determine its predictors within a consecutive series of patients with CDH., Materials and Methods:  We retrospectively analyzed charts of all neonates of our department that underwent CDH repair from 2007 to 2021, focusing on vena cava thrombosis. Vena cava thrombosis was diagnosed sonographically and classified as complete or partial venous occlusion. Complete occlusion was confirmed by cavography. Variables evaluated were CDH side, liver position, central vein line, surgical approach, and extracorporeal membrane oxygenation (ECMO). Univariate and multivariate tests were utilized., Results:  Among 57 neonates who underwent CDH repair, vena cava thrombosis was diagnosed in 14 (24.6%), seven of whom had complete occlusion of the vena cava. Factors associated with vena cava thrombosis were femoral or saphenous venous catheter ( p  = 0.044), right sided CDH ( p  = 0.027) and chylothorax ( p  < 0.0001). ECMO was not associated with vena cava thrombosis. Seven patients (50%) with vena cava thrombosis were treated interventionally with angioplasty and seven (50%) conservatively with anticoagulation only. Mortality was not higher in patients with compared with patients without vena cava thrombosis., Conclusion:  The incidence of vena cava thrombosis in newborns with CDH in our series is high. Routine postoperative abdominal sonography focusing on vena cava thrombosis is mandatory in all patients with CDH. Patients who developed vena cava thrombosis were more likely to develop chylothorax after CDH repair. Considering the good outcome of medical therapy of partial vena cava thrombosis, it may be discussed whether low dose anticoagulation may be provided to all newborns with CDH., Competing Interests: None declared, (Thieme. All rights reserved.)

Introduction:  Despite its wide acceptance, the superiority of laparoscopic versus open pediatric surgery has remained controversial. There is still a call for well-founded evidence. We reviewed the literature on studies published in the last three decades and dealing with advantages and disadvantages of laparoscopy compared to open surgery., Materials and Methods:  Studies comparing laparoscopic versus open abdominal procedures in children were searched in PubMed/MEDLINE. Reports on upper and lower gastrointestinal as hepatobiliary surgery and on surgery of pancreas and spleen were included. Advantages and disadvantages of laparoscopic surgery were analyzed for different types of procedures. Complications were categorized using the Clavien-Dindo classification., Results:  A total of 239 studies dealing with 19 types of procedures and outcomes in 929,157 patients were analyzed. We identified 26 randomized controlled trials (10.8%) and 213 comparative studies (89.2%). The most frequently reported advantage of laparoscopy was shorter hospital stay in 60.4% of studies. Longer operative time was the most frequently reported disadvantage of laparoscopy in 52.7% of studies. Clavien-Dindo grade I to III complications (mild-moderate) were less frequently identified in laparoscopic compared to open procedures (80.3% of studies). Grade-IV complications (severe) were less frequently reported after laparoscopic versus open appendectomy for perforated appendicitis and more frequently after laparoscopic Kasai's portoenterostomy. We identified a decreased frequency of reporting on advantages after laparoscopy and increased reporting on disadvantages for all surgery types over the decades., Conclusion:  Laparoscopic compared with open pediatric surgery seems to be beneficial in most types of procedures. The number of randomized controlled trials (RCTs) remains limited. However, the number of reports on disadvantages increased during the past decades., Competing Interests: None declared., (Thieme. All rights reserved.)

Osteoblasts are not only responsible for bone formation. They also support hematopoiesis. This requires responding to cues originating from several signaling pathways, a task performed by Rho GTPases. We therefore examined several transgenic mouse models and used inhibitors of Cdc42 in vitro. Deletion of Cdc42 in vivo using the Osterix promoter suppressed osteoblast function, while its deletion in differentiating osteoblasts using the Collagen-α1(I) promoter decreased osteoblast numbers. In both cases, bone mineral density diminished confirming the importance of Cdc42. Evaluation of hematopoiesis revealed that deletion of Cdc42 using the Osterix, but not the Collagen-α1(I) promoter increased the common myeloid progenitors (CMPs) in the bone marrow as well as the erythrocytes and the thrombocytes/platelets in peripheral blood. Causality between Cdc42 loss in early osteoblasts and increased myelopoiesis was confirmed in vitro. Work in vitro supported the conclusion that interleukin-4 mediated the increase in myelopoiesis. Thus, Cdc42 is required for healthy bone through regulation of bone formation in Osterix-expressing osteoblasts and the number of osteoblasts in differentiating osteoblasts. In addition, its expression in early osteoblasts/stromal cells modulates myelopoiesis. This highlights the importance of osteoblasts in regulating hematopoiesis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Postoperative adverse events may be associated with substantial morbidity and mortality. Numerous severity grading systems for these events have been introduced and validated but have not yet been systematically applied in paediatric surgery. This study aimed to analyse the advantages and disadvantages of these classifications in a paediatric cohort., Methods: Unexpected events associated with interventional or organizational problems in the department of paediatric surgery during 2017-2020 were prospectively documented daily for all children. Events were classified according to the Clavien-Dindo grading system during monthly morbidity and mortality conferences. All events were also classified according to five additional grading systems: T92, contracted Accordion, expanded Accordion, Memorial Sloan Kettering Cancer Center, and Comprehensive Complication Index (CCI)®., Results: Of 6296 patients, 673 (10.7 per cent) developed adverse events and 240 (35.7 per cent) had multiple events. Overall, 1253 adverse events were identified; of these, 574 (45.2 per cent) were associated with surgical or medical interventions and 679 (54.8 per cent) included organizational problems. The grading systems demonstrated high overall correlation (rpears = 0.9), with minor differences in sentinel events. The Clavien-Dindo classification offered the most detailed assessment. However, these details had only limited additional value. The CCI® scores were correlated with other grading systems (rpears = 0.9) and were useful in analysing multiple events within individual patients., Conclusion: Grading systems demonstrated similar scoring patterns for minor and sentinel events, with none being superior for unexpected events in children. However, the CCI® can be a major improvement in assessing morbidity in patients with multiple events. Its use is therefore recommended in prospective studies on paediatric surgery., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Purpose: Besides surgical complications, a variety of adverse events may affect patients' comfort and outcome. The purpose of this prospective study was to identify the incidence and impact of all unexpected events in pediatric surgical patients., Methods: All unexpected events that occurred in our department during the period of February 2017-July 2018 were prospectively assessed. Complications associated with surgery, non-surgical treatment, errors and organizational problems were included. Events were classified using a modified version of Clavien-Dindo. Sentinel events were defined as death, serious injury, or the risk thereof (grade IV-V). Organizational events were analyzed separately. All events were discussed during morbidity and mortality-conferences, and the results and measures were documented., Results: Unexpected events occurred in 297 of 1605 patients (18.5%), of whom 1124 (70%) had undergone surgery. More than half of all events were not associated with an operation (n=237; 54%). The severity of all events was mostly minor (grade I-IIIb; n=410; 94%). Twenty-eight sentinel events (IV-V) occurred (6% of all events). Twenty-two (2%) patients died; however, none of these deaths were related to surgery. The top 5 events included organizational problems in 78 instants (18%), wound healing disorders in 44 (10%), recurrence of initial problems in 36 (8%), dislocation of indwelling catheters in 26 (6%) and bleeding in 16 (4%). Errors were identified in 15 patients (3%). We derived 10 changes of concepts of management or treatment., Conclusion: The incidence of unexpected events in pediatric surgical patients is high when complications associated with surgical and non-surgical treatment and organizational alterations are documented prospectively. In our study, most events were minor and did not substantially affect patients' outcomes. Prospective assessment helped to identify organizational shortcomings and develop preventive strategies., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction:  The pros and cons of video-assisted thoracoscopic versus conventional thoracic surgery in infants and children are still under debate. We assessed reported advantages and disadvantages of video-assisted thoracoscopy in pediatric surgical procedures, as well as the evidence level of the available data., Materials and Methods:  A systematic literature search was performed to identify manuscripts comparing video-assisted thoracoscopic and the respective conventional thoracic approach in classic operative indications of pediatric surgery. Outcome parameters were analyzed and graded for level of evidence (according to the Oxford Centre of Evidence-Based Medicine)., Results:  A total of 48 comparative studies reporting on 12,709 patients, 11 meta-analyses, and one pilot randomized controlled trial including 20 patients were identified. More than 15 different types of advantages for video-assisted thoracoscopic surgery were described, mostly with a level of evidence 3b or 3a. Most frequently video-assisted thoracoscopic surgery was associated with shorter hospital stay, shorter postoperative ventilation, and shorter time to chest drain removal. Mortality rate and severe complications did not differ between thoracoscopic and conventional thoracic pediatric surgery, except for congenital diaphragmatic hernia repair with a lower mortality and higher recurrence rate after thoracoscopic repair. The most frequently reported disadvantage for video-assisted thoracoscopic surgery was longer operative time., Conclusion:  The available data point toward improved recovery in pediatric video-assisted thoracoscopic surgery despite longer operative times. Further randomized controlled trials are needed to justify the widespread use of video assisted thoracoscopy in pediatric surgery., Competing Interests: None declared., (Thieme. All rights reserved.)

To study the molecular interplay between TLRs and complement representing ancient danger-sensing mechanisms, we examined the regulation of the C3a/anaphylatoxin C3a receptor (C3aR) axis in normal human epidermal keratinocytes (NHEKs) by treatment with different TLR ligands. Protein staining followed by flow cytometry revealed highly constitutive intracellular expression levels of the C3aR in NHEKs. Stimulation with Poly I:C up-regulated C3aR mRNA and intra- and extracellular expression in NHEKs which showed functional relevance by up-regulating CXCL10 and down-regulating C3 expression in response to C3a. mRNA and protein levels of C3 and protease cathepsin L (CTSL) that can cleave C3 were up-regulated by the TLR3 ligand Poly I:C. Enhanced intracellular expression levels of the biologically active C3 fragment (C3a), in response to TLR3 stimulation were also detectable in NHEKs. Cathelicidin antimicrobial peptide LL-37 potentiated Poly I:C-induced C3aR, C3, and CTSL up-regulation. In conclusion, we point to a role of TLR3 to promote up-regulation of C3aR, C3, and CTSL expression levels and generation of C3a. Our data provide evidence that local generation and activation of complement components as described for T cells or myeloid cells represent a scenario which may take place in a similar way in NHEKs., (The Author(s). Published by S. Karger AG, Basel.)

The regulation of the differentiation of the bone-forming cells, the osteoblasts, is complex. Many signaling pathways converge on the master regulator of osteoblast differentiation Runx2. The role of molecules that integrate several signaling pathways such as the Rho GTPases need to be better understood. We, therefore, asked at which stage Rac1, one of the Rho GTPase, is needed for osteoblast differentiation and whether it is involved in two pathways, the anabolic response to parathyroid hormone and the stimulatory effect of fibronectin isoforms on integrins. Genetic deletion of Rac1 in preosteoblasts using the osterix promoter diminished osteoblast differentiation in vitro. This effect was however similar to the presence of the promoter by itself. We, therefore, applied a Rac1 inhibitor and confirmed a decrease in differentiation. In vivo , Rac1 deletion using the osterix promoter decreased bone mineral density as well as histomorphometric measures of osteoblast function. In contrast, deleting Rac1 in differentiating osteoblasts using the collagen α1(I) promoter had no effects. We then evaluated whether intermittent parathyroid hormone (PTH) was able to affect bone mineral density in the absence of Rac1 in preosteoblasts. The increase in bone mineral density was similar in control animals and in mice in which Rac1 was deleted using the osterix promoter. Furthermore, stimulation of integrin by integrin isoforms was able to enhance osteoblast differentiation, despite the deletion of Rac1. In summary, Rac1 in preosteoblasts is required for normal osteoblast function and bone density, but it is neither needed for PTH-mediated anabolic effects nor for integrin-mediated enhancement of differentiation.

Introduction:  Negative pressure wound therapy (NPWT) is a novel tool to reduce surgical site infections (SSIs). Although SSIs are a common source of morbidity in infants undergoing laparotomy, the cost of the available NPWT devices has restricted its use to adult high-risk patients. We developed a low-cost method of NPWT in infants and analyzed its impact on the incidence of SSIs in infant patients., Materials and Methods:  A consecutive series of infants (age ≤ 12 months) who underwent a clean-contaminated, contaminated, or dirty abdominal procedure via laparotomy from 08/2015 to 12/2016 were included. The choice of the applied dressing, either NPWT or standard surgical dressing (SSD), was made at the surgeon's discretion. SSIs were documented prospectively. The Horan definition and the Clavien-Dindo classification were used. The cost of material was calculated for both groups., Results:  Ninety-three consecutive patients were included (65 SSD and 28 NPWT). SSI occurred in 10 patients in the SSD group, Grade I in 7 and Grade II in 3 (Clavien-Dindo classification). No SSI occurred in patients with NPWT ( p  < 0.05). The cost of an SSD was less than 1 €, and the cost of a NPWT was less than 10 €., Conclusion:  The routine use of this modified vacuum wound dressing may be an efficient and affordable technique to decrease SSIs in infants who underwent contaminated abdominal operations., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Systemic treatment is necessary for one third of patients with renal cell carcinoma. No valid biomarker is currently available to tailor personalized therapy. In this study we established a representative panel of patient derived xenograft (PDX) mouse models from patients with renal cell carcinomas and determined serum levels of high mobility group B1 (HMGB1) protein under treatment with sunitinib, pazopanib, sorafenib, axitinib, temsirolimus and bevacizumab. Serum HMGB1 levels were significantly higher in a subset of the PDX collection, which exhibited slower tumor growth during subsequent passages than tumors with low HMGB1 serum levels. Pre-treatment PDX serum HMGB1 levels also correlated with response to systemic treatment: PDX models with high HMGB1 levels predicted response to bevacizumab. Taken together, we provide for the first time evidence that the damage associated molecular pattern biomarker HMGB1 can predict response to systemic treatment with bevacizumab. Our data support the future evaluation of HMGB1 as a predictive biomarker for bevacizumab sensitivity in patients with renal cell carcinoma., Competing Interests: CONFLICTS OF INTEREST JS, KK, AM, ML and ALP are salaried employees of Charles River Discovery, Freiburg, Germany. This employment does not alter our adherence to all the journal policies on sharing data and materials. All experiments were approved by the local ethics committee with written informed consent. The authors declare no competing financial interest.

Video-assisted thoracoscopic surgery (VATS) has gained broad acceptance among pediatric surgeons. Today, VATS can be regarded as a routine approach for various conditions in neonates and infants. However, there is a lack of information concerning the complications of thoracoscopic pulmonary surgery in neonates and infants. We aimed to review the available data. A systematic review of the literature was performed using PubMed. All publications reporting on VATS for pulmonary procedures in neonates and infants up to the age of 1 year were included. Articles were reviewed in detail for occurrence of perioperative complications and their treatment. Nine case series were eligible for analysis. Entities treated included lung sequestration, congenital pulmonary airway malformation, congenital lobar emphysema, and bronchogenic cyst. Case series reported on a total number of 135 patients. Complications occurred in 14 patients (10.4%). The major complication was an accidental transection of the middle lobar bronchus that concluded in a later resection of a prior unaffected lung lobe. Other relevant complications reported were bleeding in four patients (3.0%) and persistent air leak in four cases (3.0%). Infectious complications were reported in four patients (3.0%). Additionally, iatrogenic phrenic nerve paralysis occurred in one patient. There were no deaths related to the VATS technique. In 11 cases (8.1%), conversion to thoracotomy had been necessary. General recommendations on the treatment of complications could not be derived due to small patient numbers and lack of details of the complications reported. Reports on major complications of pulmonary VATS in neonates and infants below 1 year of age are scarce. As severe complications such as accidental bronchus transection have been described, feasibility of neonatal/infant VATS cannot be unequivocally confirmed. No literature-based recommendation can be given on the treatment of complications., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Introduction The presentation of health institutions in the internet is highly variable concerning marketing features and medical information. We aimed to investigate the structure and the kind of information provided on the Web sites of all departments of pediatric surgery in Germany. Furthermore, we aimed to identify the degree to which these Web sites comply with internet marketing recommendations for generating business. Method The Web sites of all pediatric surgery units referred to as departments on the official Web site of the German Society of Pediatric Surgery (GSPS) were assessed. The search engine Google was used by entering the terms "pediatric surgery" and the name of the city. Besides general data eight content characteristics focusing on ranking, accessibility, use of social media, multilingual sites, navigation options, selected images, contact details, and medical information were evaluated according to published recommendations. Results A total of 85 departments of pediatric surgery were included. On Google search results 44 (52%) ranked number one and 34 (40%) of the department's homepages were accessible directly through the homepage link of the GSPS. A link to own digital and/or social media was offered on 11 (13%) homepages. Nine sites were multilingual. The most common navigation bar item was clinical services on 74 (87%) homepages. Overall, 76 (89%) departments presented their doctors and 17 (20%) presented other staff members with images of doctors on 53 (62%) and contact data access from the homepage on 68 (80%) Web sites. On 25 (29%) Web sites information on the medical conditions treated were presented, on 17 (20%) details of treating concepts, and on 4 (5%) numbers of patients with specific conditions treated in the own department per year. Conclusion We conclude that numerous of the investigated online presentations do not comply with recommended criteria for offering professional information for patients and for promoting services. Only less than one-third of the departments of pediatric surgery in Germany offer information about the medical conditions they treat. Features, which may influence the decision of patients and parents such as ranking, accessibility, use of social media, multilingual sites, navigation options, selected images, and contact information were differently lacking on many Web sites., (Georg Thieme Verlag KG Stuttgart · New York.)

Traditionally, pediatric surgical education consisted of exposure to patients, textbooks, lectures, team-based education, congresses, and workshops. Over the last decades, however, new information technology (IT) and the internet revolutionized the sharing of information and communication. IT has become relevant in particular for the younger generation of pediatric surgeons. Today, gaps in children's health and the quality of pediatric surgical education persist between countries and regions. Advances in health care are not shared equitably. The use of IT for resource libraries, teleconferences, virtual symposiums, and telementoring has great potential in closing this gap and meeting the global needs for pediatric surgical education. This article focuses on the potential role of IT in this respect., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: We compared our experience with intra- and extracorporeal stenting in laparoscopic transabdominal pyeloplasty in children and adolescents. As the placement of transanastomotic stents during laparoscopy can be difficult, we developed a technique for laparoscopic transrenal stent placement., Subjects and Methods: Eighty-six consecutive patients who underwent laparoscopic transabdominal pyeloplasty in our institution from December 2003 to November 2012 were retrospectively analyzed. Initially we antegradely placed the double J catheter (n=48), whereas in later patients transrenal/transcutaneous stents were inserted (n=38), either via a cannula from the flank (n=33) or from the inside-out by transrenal puncture using a specially constructed spear (n=5). End points of the analysis were stent-related technical problems and complications and the need for reoperation., Results: Sixty-two boys and 24 girls with a mean age of 5.6 years (range, 78 days-17.3 years) and mean weight of 22.1 kg (range, 5.5-71 kg) underwent laparoscopic transabdominal pyeloplasty. The most common technical problem in the double J group was inability to place the double J catheter in 9 of the 48 patients. In combination with other complications such as dislocations, urinary tract infections, or catheter occlusions, this led to an overall complication rate of 35% in the group that underwent double J catheter insertion versus 13% in the group with transrenal stenting (P<.05). In the whole series, 4 patients required a redo pyeloplasty, all of them in the double J group., Conclusions: We recommend transrenal stents to facilitate stent removal without general anesthesia and to minimize complications such as stent dislocation. The initial experience with our simple device for transrenal puncture and stent placement is promising.