Publications by authors named "Jörg Fuchs"

221 Publications

Anticancer bioactivity of zerumbone on pediatric rhabdomyosarcoma cells.

J Cancer Res Clin Oncol 2022 Aug 5. Epub 2022 Aug 5.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.

Purpose: Natural products are generally regarded as safe and have been shown to mediate anticancer activities against a variety of cell types. Zerumbone is a natural cyclic sesquiterpene derived from the rhizome of Zingiber zerumbet, which has attracted extensive attention in the recent decade for anticancer activities. The present study investigates the in vitro effect of zerumbone on rhabdomyosarcoma cells.

Methods: Two rhabdomyosarcoma cell lines (RD and RH30) were used as the model system. The growth inhibition of zerumbone was measured by MTT-assay, apoptosis via flow cytometry, gene expression by real-time PCR, the migration by transwell assay, and intracellular signaling by Western blotting.

Results: Zerumbone shows anticancer effects on RD and RH30 cells in a dose-dependent manner via cell growth inhibition and induction of apoptosis. Exposure of RD and RH30 cells on zerumbone also resulted in a decrease of migration and downregulation of the hedgehog pathway.

Conclusions: Taken together, our study provided the first evidence that zerumbone imparted strong inhibitory and apoptotic effects on pediatric rhabdomyosarcoma cell lines and merit further investigation as a promising candidate for the anticancer therapy.
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http://dx.doi.org/10.1007/s00432-022-04237-1DOI Listing
August 2022

Epitope detection in monocytes (EDIM) for liquid biopsy including identification of GD2 in childhood neuroblastoma-a pilot study.

Br J Cancer 2022 Jul 21. Epub 2022 Jul 21.

Department of Pediatric Surgery & Pediatric Urology, Children's Hospital, Eberhard-Karls-University Tuebingen, Tuebingen, Germany.

Background: Neuroblastoma (NB) is the most common paediatric extracranial solid malignancy. We analysed the role of the epitope detection in monocytes (EDIM) technique for liquid biopsy in NB patients.

Methods: Tumour epitopes transketolase-like 1 (TKTL1), Apo10 (DNaseX) and GD2 were assessed: expression levels in seven NB tumour samples and five NB cell lines were analysed using RT-PCR and flow cytometry. LAN-1 cells were co-cultured with blood and assessed using EDIM. Peripheral blood macrophages of patients with neuroblastoma (n = 38) and healthy individuals (control group, n = 37) were labelled (CD14/CD16) and assessed for TKTL1, Apo10 and GD2 using the EDIM technology.

Results: mRNA expression of TKTL1 and DNaseX/Apo10 was elevated in 6/7 NB samples. Spike experiments showed upregulation of TKTL1, Apo10 and GD2 in LAN-1 cells following co-culturing with blood. TKTL1 and Apo10 were present in macrophages of 36/38 patients, and GD2 in 15/19 patients. The 37 control samples were all negative. EDIM expression scores of the three epitopes allowed differentiation between NB patients and healthy individuals.

Conclusions: The EDIM test might serve as a non-invasive tool for liquid biopsy in children suffering from NB. Future studies are necessary for assessing risk stratification, tumour biology, treatment monitoring, and early detection of tumour relapses.
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http://dx.doi.org/10.1038/s41416-022-01855-xDOI Listing
July 2022

Club-mosses (Diphasiastrum, Lycopodiaceae) from the Far East - Introgression and possible cryptic speciation.

Mol Phylogenet Evol 2022 Oct 10;175:107587. Epub 2022 Jul 10.

Institute of Botany and Landscape Ecology, University of Greifswald, Soldmannstraße 15, D-17487 Greifswald, Germany.

Hybridization occurs often in the genus Diphasiastrum (Lycopodiaceae), which corroborates reports for the two other recognized lycophyte families, Isoëtaceae and Selaginellaceae. Here we investigate the case of D. alpinum and D. sitchense from the Russian Far East (Kamchatka). Their hybrid, D. × takedae, was morphologically recognizable in 16 out of 22 accessions showing molecular signatures of hybridization; the remaining accessions displayed the morphology of either D. alpinum (3) or D. sitchense (3). We sequenced markers for chloroplast microsatellites (cp, 175 accessions from Kamchatka) and for the two nuclear markers RPB and LFY (175 and 152 accessions). A selection of 42 accessions, including all hybrid accessions, was analysed via genotyping by sequencing (GBS). We found multiple, but apparently uniparental hybridization, clearly characterized by a deviating group of haplotypes for D. sitchense and all hybrids. All accessions showing molecular signatures of hybridization in nuclear markers revealed the parental haplotype of D. sitchense, however only the LFY marker differentiated between the parent species. GBS, including 69,819 quality-filtered single nucleotid polymorphisms, unambiguously identified the hybrids and revealed introgression to occur. Most of the hybrids were F, but three turned out to be backcrosses with D. alpinum (one) and with D. sitchense (two). These observations are in contrast to prior findings on three European species and their intermediates where all three hybrids turned out to be independent F crosses without evidence of recent backcrossing. In this study, backcrossing was detected, which indicates a limited fertility of the hybrid taxon D. × takedae. A comparison of accessions of Kamchatkian D. alpinum with plants from Europe indicated possible cryptic speciation. Accessions from the Far East had (i) a lower DNA content (7.0 vs. 7.5 pg/2C), (ii) different prevailing cp haplotypes, and (iii) RPB genotypes, and (iv) a clearly different SNP pattern in GBS. Diphasiastrum sitchense and the similar D. nikoënse, for the latter additional accessions from Japan were investigated, appeared as forms of one diverse species, sharing genotypes in both nuclear markers, although chloroplast haplotypes and DNA content show slight variations.
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http://dx.doi.org/10.1016/j.ympev.2022.107587DOI Listing
October 2022

Variation in the Number and Position of rDNA Loci Contributes to the Diversification and Speciation in (Ranunculaceae).

Front Plant Sci 2022 9;13:917310. Epub 2022 Jun 9.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.

is a small genus belonging to the Ranunculaceae family which is presumably originated and distributed in Aegean and the adjacent Western-Irano-Turanian region. Comparative repeat analysis of , and was performed using low-pass Illumina genomic reads followed by karyotyping and FISH mapping of seven species using the identified repeats and ribosomal DNA (rDNA) probes. High- and moderate-copy repeat sequences occupy 57.52, 59.01, and 64.73% of , and genomes, respectively. Roughly, half of the genomes are retrotransposons (class I transposons), while DNA transposons (class II transposons) contributed to only about 2% of the genomes. The analyzed species possess large genomes of about 7.4 to 12.4 Gbp/1C. Only two satellite repeats in , one in and four in were identified, which were mostly (peri)centromeric and represented about 1% of each genome. A high variation in number and position of 45S rDNA loci were found among species. Interestingly, in , each chromosome revealed at least one 45S rDNA site and one of them occurs in hemizygous condition. Based on the chromosome numbers, genome size and (peri)centromeric satellites, three karyotype groups were observed: Two with 2 = 2 = 12 and a karyotype formula of 10m + 2t (including , , as the first group and and as the second group) and a more distant group with 2 = 2 = 14 and a karyotype formula of 8m + 2st + 4t (including and ). These karyotype groups agreed with the phylogenetic analysis using ITS and L sequences. We conclude that variation in (peri)centromeric sequences, number and localization of rDNA sites as well as chromosome number (dysploidy) are involved in the diversification of the genus .
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http://dx.doi.org/10.3389/fpls.2022.917310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261981PMC
June 2022

Combination therapy of doxorubicin and Sildenafil inhibits the growth of pediatric rhabdomyosarcoma.

J Cancer Res Clin Oncol 2022 Jun 28. Epub 2022 Jun 28.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Background: Overexpression of phosphodiesterase type 5 (PDE5) has been detected in many types of malignant tumors. Sildenafil, a potent and selective inhibitor of a cGMP-specific PDE5, has been found to enhance the cytotoxic activity of different chemotherapeutic agents including doxorubicin. The combined therapy of doxorubicin with Sildenafil might reduce the possible side effects of chemotherapy while maintaining synergistic anticancer activity. The present study explored for the first time the effects of Sildenafil, alone and in combination with doxorubicin, on pediatric RMS cells.

Methods: Human RMS cells lines RH30 and RD were used. Western blotting and RT-PCR were performed to analyze PDE5 expression in RMS cells. Cell viability was determined using MTT assay. Cell migration was analyzed via transwell chambers, clonal growth and mitotic cell death were analyzed using the clonogenic assay. FACS analysis was performed to evaluate reactive oxygen species (ROS) and apoptosis.

Results: Sildenafil significantly decreased cell viability and migration of RD and RH30 cells. The exposure of RMS cells to doxorubicin resulted in a dose-dependent decrease in their viability. Simultaneous administration of Sildenafil enhanced this effect. The incubation of the RMS cells with Sildenafil in the presence of doxorubicin significantly increased the proportion of apoptotic cells and ROS production compared to the treatment with Sildenafil alone.

Conclusions: The results of our study indicate a link between PDE5 inhibition by Sildenafil and decreased calcium signalling leading to significantly impaired viability, migration, and colony forming of RMS cells. Increased ROS production and apoptosis are mechanisms relevantly contributing to this observation.
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http://dx.doi.org/10.1007/s00432-022-04092-0DOI Listing
June 2022

Pre-operative radiotherapy is associated with superior local relapse-free survival in advanced synovial sarcoma.

J Cancer Res Clin Oncol 2022 Jun 10. Epub 2022 Jun 10.

Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart, Olgahospital, Stuttgart, Germany.

Purpose: Optimization of local therapies in synovial sarcoma (SS) considered unresectable at diagnosis is needed. We evaluated the effects of neoadjuvant versus adjuvant radiation versus surgery only on long-term outcomes.

Methods: Patients with macroscopic SS tumors before chemotherapy (IRS-group-III) in the trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P and SoTiSaR-registry were analyzed. Local therapies were scheduled after 3 neoadjuvant chemotherapy cycles.

Results: Median age of 145 patients was 14.5 years. 106 survivors had median follow-up of 7.0 years. Tumor site was 96 extremities, 19 head-neck, 16 shoulder/hip, 14 trunk. Tumors were < 3 cm in 16, 3-5 cm in 28, 5-10 cm in 55, > 10 cm in 34 patients. In a secondary resection during chemotherapy, R0-status was accomplished in 82, R1 in 30, R2 in 21 (12 missing). Radiotherapy was administered to 115 (R0 61, R1 29, R2 20, missing 5), thereof 57 before and 52 after tumor resection. 23 were treated with surgery only. For all patients, 5 year event-free (EFS) and overall survival (OS) was 68.9% ± 7.6 (95%CI) and 79.1% ± 6.9. To establish independent significance, tumor site, size, surgical results and sequencing of local therapies were analyzed in a Cox regression analysis. Variables associated with EFS and OS are site, size and sequencing of local therapies. Variables associated with local recurrence are site, surgical results and sequencing of local therapies. The only variable associated with suffering metastatic recurrence is tumor size.

Conclusion: Differences in sequencing of local therapy procedures are independently associated with outcomes. Best local control is achieved when tumors are irradiated pre-operatively and undergo R0 or R1 resection thereafter.
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http://dx.doi.org/10.1007/s00432-022-04051-9DOI Listing
June 2022

Results after skin traction for femur shaft fractures in children below the age of four years.

Eur J Trauma Emerg Surg 2022 May 31. Epub 2022 May 31.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Tübingen, Germany.

Purpose: Nonsurgical management has been identified as the treatment of choice for femoral shaft fractures in children below four years of age. For various reasons, the surgical approach has become increasingly popular in recent years. The aim of this study is to report results after vertical skin traction and analyze the benefits of this technique as well as to point out advantages compared with surgery in this age group.

Methods: The authors performed a retrospective data analysis, including all patients with femoral shaft fractures below the age of four who were treated with vertical skin traction at our institution between January 2006 and December 2016.

Results: Skin traction for a femoral shaft fracture was performed for 36 patients (mean age 1.6 years; 1 day-3.5 years). The mean duration of traction was 18.5 days (14-30). Complications included soft tissue affections (n = 5), which all healed spontaneously. Consolidation was observed in all fractures. Initial axial deviations and shortening did not change during traction until consolidation (p > 0.05), and no relevant torsion deformity occurred (p = 0.01). Patients gained full weight-bearing within 12.3 days (7-40) following end of traction. At the final follow-up, after a mean of 29.3 months (12-192), leg-length discrepancy (mean 7.1 mm; 5-20) was found on radiograms in nine cases, and axial deviations (mean 7.7°; 5-25) were documented in seven cases. None of the patients had limitations in daily activities or sports.

Conclusion: Skin traction is a technically easy, safe, and non-invasive treatment modality for femoral shaft fractures in children below the age of four years. Strong results are obtained benefited from a high potential of growth-related correction, and in principle no anesthesia is needed. A prolonged hospitalization and socio-economic factors maintain the ongoing debate in comparison with the surgical approach.

Level Of Evidence: Level III, retrospective.
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http://dx.doi.org/10.1007/s00068-022-01996-xDOI Listing
May 2022

Two-cavities approach for resection of pediatric abdominal neuroblastic tumors: experience of a national reference pediatric onco-surgical center.

J Cancer Res Clin Oncol 2022 May 6. Epub 2022 May 6.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Purpose: Surgery of complex neuroblastic tumors often requires additional procedures, especially in the situation of tumor extension within thorax and impossibility of securing the aorta above the tumor. These situations prompt the opening of the thoracic cavity. The concern regarding increased operative trauma and morbidity associated with this approach make surgeons reluctant regarding this technique. The aim of this study was to evaluate the efficacy of two-cavities approach based on our experience in a reference pediatric onco-surgical center.

Methods: Between 2003 and 2021, we operated on 232 neuroblastic tumors. 31/232 patients with complex, advanced-stage neuroblastic tumors underwent tumor resection through a two-cavities approach. A retrospective review of patient's records was performed.

Results: The median age at operation was 48 months (5-180). 23/31 patients presented image-defined risk factors (IDRF). The approach most commonly used was the transverse laparotomy with incision of the diaphragm (n = 14), followed by the thoraco-abdominal incision (n = 10). Gross total resection (GTR) was achieved in 24 patients, a near-GTR in 4 cases, and an incomplete resection in 3 cases. Median duration of surgery was 288 min (99-900) and median duration of mechanical ventilation was 22 h (0-336). Postoperative complications occurred in 10 patients, 6/10 required surgical reintervention. The 5-year overall survival (OS) was 90% and the 5-year event-free survival (EFS) was 50%.

Conclusions: The two-cavities approach for resection of abdominal neuroblastoma in children is a safe technique with no added morbidity.
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http://dx.doi.org/10.1007/s00432-022-04027-9DOI Listing
May 2022

International Society of Paediatric Surgical Oncology (IPSO) Surgical Practice Guidelines.

Ecancermedicalscience 2022 17;16:1356. Epub 2022 Feb 17.

Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

Most children with tumors will require one or more surgical interventions as part of the care and treatment, including making a diagnosis, obtaining adequate venous access, performing a surgical resection for solid tumors (with staging and reconstruction), performing procedures for cancer prevention and its late effects, and managing complications of treatment; all with the goal of improving survival and quality of life. It is important for surgeons to adhere to sound pediatric surgical oncology principles, as they are closely associated with improved local control and survival. Unfortunately, there is a significant disparity in survival rates in low and middle income countries, when compared to those from high income countries. The International Society of Paediatric Surgical Oncology (IPSO) is the leading organization that deals with pediatric surgical oncology worldwide. This organization allows experts in the field from around the globe to gather and address the surgical needs of children with cancer. IPSO has been invited to contribute surgical guidance as part of the World Health Organization Initiative for Childhood Cancer. One of our goals is to provide surgical guidance for different scenarios, including those experienced in High- (HICs) and Low- and Middle-Income Countries (LMICs). With this in mind, the following guidelines have been developed by authors from both HICs and LMICs. These have been further validated by experts with the aim of providing evidence-based information for surgeons who care for children with cancer. We hope that this initiative will benefit children worldwide in the best way possible. Simone Abib, IPSO President Justin T Gerstle, IPSO Education Committee Chair Chan Hon Chui, IPSO Secretary.
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http://dx.doi.org/10.3332/ecancer.2022.1356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023308PMC
February 2022

Spectrum of Interventional Procedures During Hybrid Central Line Placement in Pediatric Intestinal Rehabilitation Patients With End-Stage Vascular Access.

Front Nutr 2022 28;9:863063. Epub 2022 Mar 28.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, University of Tübingen, Tübingen, Germany.

Background: Loss of available central vein access sites for parenteral nutrition delivery represents one of the main indications for intestinal transplantation in children with intestinal failure. Placement of central venous catheters can be challenging in advanced loss of patent venous pathways. We recently described the hybrid technique (interventional plus surgical approach) of central line placement in children. The aim of this study was to describe and analyze the interventions used during the hybrid procedures regarding feasibility, safety and outcome.

Methods: We retrospectively analyzed the course of all children in our intestinal rehabilitation program undergoing hybrid central line placement. We evaluated patients' conditions, interventional techniques and surgical peculiarities as well as outcome.

Results: 203 children were treated in our intestinal rehabilitation program between 2010 and 2021. Due to loss of venous access, hybrid technique was performed in 53 children during 76 interventions. In 40 cases the same vessel was reused Seldinger technique. Among the 30 ultrasound-guided new vessel punctures, 12 were performed by puncture of collateral vessels. Extended interventions due to thoracic central venous obstruction and/or thrombosis requiring additional access a femoral vein for rehabilitation of the vascular system was performed during 29 procedures including catheter extraction (1), angioplasties (18), stent placement (1), revascularization (5) and thrombectomy (4). Placement of a central line was not possible in 6 children which eventually underwent extended thoracic/vascular surgery: in three children the previously placed catheter could not be removed, in one child, placement of a thrombectomy-catheter was not possible because of inferior vena cava occlusion, and in two children, revascularization failed. Intestinal transplantation was considered in one patient because of impending loss of vascular access. Two self-limiting minor extravasations and one intervention-associated pericardial effusion occurred.

Conclusions: Hybrid interventions for central venous catheter placement and vascular rehabilitation enable a high success rate in children with intestinal failure and end-stage vascular access, circumventing the need for intestinal transplantation or advanced surgery. The relevant procedures are complex and require a foresighted and individualized approach with a wide range of interventional techniques. If performed with expertise, this combined interventional/surgical approach is feasible and safe.
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http://dx.doi.org/10.3389/fnut.2022.863063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995563PMC
March 2022

B-A Chromosome Translocations Possessing an A Centromere Partly Overcome the Root-Restricted Process of Chromosome Elimination in .

Front Cell Dev Biol 2022 28;10:875523. Epub 2022 Mar 28.

Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.

Some eukaryotes exhibit dramatic genome size differences between cells of different organs, resulting from the programmed elimination of chromosomes. is an annual diploid species from the Poaceae family, with a maximum number of eight B chromosomes (Bs) in addition to its inherent seven pairs of standard A chromosomes (As). The Bs of this species undergo precise elimination in roots early in embryo development. In areal parts of the plant, the number of Bs is stable. To affect the root restricted process of B chromosome elimination, we employed X-ray mutagenesis, and different types of restructured Bs were identified. Standard Bs were observed in all analyzed shoots of mutagenized plants, while B-A translocations were only observed in 35.7% of F plants. In total 40 different B variants inconsistently escaped the elimination process in roots. As a result, mosaicism of B chromosome variants was found in roots. Only a small B chromosome fragment fused to an A chromosome was stably maintained in roots and shoots across F to F generations. The absence of B-A translocation chromosomes possessing a derived B centromere in root cells implies that the centromere of the B is a key component of the chromosome elimination process.
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http://dx.doi.org/10.3389/fcell.2022.875523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995527PMC
March 2022

The Ribosomal DNA Loci of the Ancient Monocot L. (Araceae) Contain Different Variants of the 35S and 5S Ribosomal RNA Gene Units.

Front Plant Sci 2022 3;13:819750. Epub 2022 Mar 3.

Jiangsu Key Laboratory for Eco-Agricultural Biotechnology Around Hongze Lake and Jiangsu Collaborative Innovation Centre of Regional Modern Agriculture and Environmental Protection, School of Life Sciences, Huaiyin Normal University, Huai'an, China.

The freshwater plant water lettuce ( L.) grows in warm climatic zones and is used for phytoremediation and biomass production. belongs to the Araceae, an ecologically and structurally diverse early monocot family, but the phylogenetic relationships among Araceae members are poorly understood. Ribosomal DNAs (rDNAs), including the 35S and 5S rDNA, encode the RNA components of ribosomes and are widely used in phylogenetic and evolutionary studies of various plant taxa. Here, we comprehensively characterized the chromosomal locations and molecular organization of 35S and 5S rDNA genes in water lettuce using karyological and molecular methods. Fluorescence hybridization revealed a single location for the 35S and 5S rDNA loci, each on a different pair of the species' 28 chromosomes. Molecular cloning and nucleotide sequencing of 35S rDNA of , the first representative Araceae in which such a study was performed, displayed typical structural characteristics. The full-length repeat showed high sequence conservation of the regions producing the 18S, 5.8S, and 25S rRNAs and divergence of the internal transcribed spacers ITS1 and ITS2 as well as the large intergenic spacer (IGS). Alignments of the deduced sequence of 18S rDNA with the sequences available for other Araceae and representatives of other clades were used for phylogenetic analysis. Examination of 11 IGS sequences revealed significant intra-genomic length variability due to variation in subrepeat number, with four types of units detected within the 35S rDNA locus of the genome (estimated size 407 Mb/1C). Similarly, the 5S rDNA locus harbors gene units comprising a conserved 119-bp sequence encoding 5S rRNA and two types of non-transcribed spacer (NTS) sequences. Type I was classified into four subtypes, which apparently originated via progressive loss of subrepeats within the duplicated NTS region containing the 3' part of the 5S rRNA gene. The minor Type II NTS is shorter than Type I and differs in nucleotide composition. Some DNA clones containing two or three consecutive 5S rDNA repeats harbored 5S rDNA genes with different types of NTSs, confirming the mosaic composition of the 5S rDNA locus.
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http://dx.doi.org/10.3389/fpls.2022.819750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8928438PMC
March 2022

Targeted Analysis of Cell-free Circulating Tumor DNA is Suitable for Early Relapse and Actionable Target Detection in Patients with Neuroblastoma.

Clin Cancer Res 2022 05;28(9):1809-1820

Department of Pediatric Hematology and Oncology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Purpose: Treating refractory or relapsed neuroblastoma remains challenging. Monitoring body fluids for tumor-derived molecular information indicating minimal residual disease supports more frequent diagnostic surveillance and may have the power to detect resistant subclones before they give rise to relapses. If actionable targets are identified from liquid biopsies, targeted treatment options can be considered earlier.

Experimental Design: Droplet digital PCR assays assessing MYCN and ALK copy numbers and allelic frequencies of ALK p.F1174L and ALK p.R1275Q mutations were applied to longitudinally collected liquid biopsies and matched tumor tissue samples from 31 patients with high-risk neuroblastoma. Total cell-free DNA (cfDNA) levels and marker detection were compared with data from routine clinical diagnostics.

Results: Total cfDNA concentrations in blood plasma from patients with high-risk neuroblastoma were higher than in healthy controls and consistently correlated with neuron-specific enolase levels and lactate dehydrogenase activity but not with 123I-meta-iodobenzylguanidine scores at relapse diagnosis. Targeted cfDNA diagnostics proved superior for early relapse detection to all current diagnostics in 2 patients. Marker analysis in cfDNA indicated intratumor heterogeneity for cell clones harboring MYCN amplifications and druggable ALK alterations that were not detectable in matched tumor tissue samples in 17 patients from our cohort. Proof of concept is provided for molecular target detection in cerebrospinal fluid from patients with isolated central nervous system relapses.

Conclusions: Tumor-specific alterations can be identified and monitored during disease course in liquid biopsies from pediatric patients with high-risk neuroblastoma. This approach to cfDNA surveillance warrants further prospective validation and exploitation for diagnostic purposes and to guide therapeutic decisions.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-3716DOI Listing
May 2022

Gastric Transposition for Repair of Long-Gap Esophageal Atresia: Indications, Complications, and Outcome of Minimally Invasive and Open Surgery.

Neonatology 2022 2;119(2):238-245. Epub 2022 Mar 2.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Tübingen, Germany.

Background: Gastric transposition (GT) is a possible option for esophageal replacement in long-gap esophageal atresia (LGEA). The present study aims to report and compare indications and outcome of laparoscopic-assisted GT (LAGT) versus open (OGT) GT for LGEA repair.

Methods: Retrospective single-center analysis of all LGEA patients undergoing GT between 2002 and 2021.

Results: Thirty-one children with LGEA underwent GT. Of these, 19 underwent LAGT (mean weight at surgery 5.6 kg; mean age 167 days) and 12 underwent OGT (6.1 kg; 233 days). Indications for OGT were previous surgery (n = 7), associated severe cardiac malformations (n = 4), and a simultaneous resection of a choledochal cyst (n = 1). The conversion rate was 1. The two procedures (LAGT/OGT) differed in anesthetic time (308/350 min), duration of ventilation (5.1/5.3 days), hospital stay (34/32 days), and complications (22/15). None of the differences reached statistical significance. Outcome was also comparable: completely oral nutrition uptake in 66%/73%, slow weight gain in the low centiles in both groups, no patient developed dumping syndrome, symptomatic reflux was seen in 1 patient after OGT.

Conclusion: In our cohort, LAGT for repair of LGEA provided similar outcomes as open surgery. The minimally invasive approach preserves thoracal structures, prevents additional thoracotomy or laparotomy, and is faster. To realize LAGT, a postpartal treatment concept including gastrostomy placement via a microincision to minimize adhesions is essential. The open surgical approach should be considered in cases of previous extensive surgical attempts of EA correction causing severe adhesions as well as associated anomalies or genetic syndromes causing hemodynamic instability.
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http://dx.doi.org/10.1159/000522288DOI Listing
April 2022

Long-Term Clinical Outcome and Prognostic Factors of Children and Adolescents with Localized Rhabdomyosarcoma Treated on the CWS-2002P Protocol.

Cancers (Basel) 2022 Feb 11;14(4). Epub 2022 Feb 11.

Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, 60590 Frankfurt, Germany.

We report here the results of the prospective, non-randomized, historically controlled CWS-2002P study in patients ≤ 21 years with localized RMS developed with the aim to improve the long-term outcome by adapting the burden of therapy to risk profile and to investigate the feasibility and relation to the outcome of maintenance therapy (MT) in the high-risk groups. Patients were allocated into low-risk (LR), standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. Chemotherapy consisted of vincristine (VCR) and dactinomycin (ACTO-D) for all patients with the addition of ifosfamide (IFO) in the SR, HR, and VHR and doxorubicin (DOX) in the HR and VHR groups. Low-dose cyclophosphamide and vinblastine maintenance therapy (MT) over 6 months was recommended in the HR and VHR groups. A total of 444 patients have been included in this analysis. With a median follow-up of 9·6 years (IQR 7·6-10·9) for patients alive, the 5-year EFS and OS for the whole group was 73% (95% CI 69-77) and 80% (95% CI 76-84), respectively. The 5-year EFS by risk group was 100% in the LR, 79% (95% CI 72-84) in the SR, 69% (95% CI 63-75) in the HR, and 42% (95% CI 23-61) in the VHR (log-rank = 0.000). The 5-year EFS was 77% (95% CI 70-84) for 155 patients in the HR group who received MT as compared to 63% (95% CI 50-76) for 49 patients who did not (log-rank = 0.015). Neither the reduction in the IFO dose in the SR nor the increased dose intensity of DOX in HR groups influenced the outcome when compared to the previous CWS and other European studies. MT was feasible, seemed to have an impact on prognosis, and should be studied in a well-controlled prospective trial in this patient population. The weighting of risk factors used for therapy stratification needs to be reevaluated.
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http://dx.doi.org/10.3390/cancers14040899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870315PMC
February 2022

D,L-Methadone enhances the cytotoxic activity of standard chemotherapeutic agents on pediatric rhabdomyosarcoma.

J Cancer Res Clin Oncol 2022 Jun 19;148(6):1337-1350. Epub 2022 Feb 19.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tuebingen, Germany.

Purpose: In advanced tumor stages, pediatric rhabdomyosarcoma (RMS) shows an intrinsic resistance to standard chemotherapy, which is associated with a dismal prognosis. Alternative therapeutic approaches and optimization of already existent treatment protocols are urgently needed in these conditions. The µ-opioid receptor (OPRM1) agonist, D,L-methadone is frequently used for analgesia in oncological patients. Recent evidence has shown that D,L-methadone in combination with chemotherapeutic agents may enhance their cytotoxic effect against cancer cells. There are no related data in pediatric rhabdomyosarcoma (RMS).

Methods: Antitumor effects of combined D,L-methadone and doxorubicin, carboplatin, and vincristine on RMS cell lines RD and RH30 were analyzed using following outcome data: expression of the OPRM1 receptor (Western blot), cell growth inhibition (MTT assay), cell migration (wound-healing assay), apoptosis induction (caspase-3/7 assay), and reactive oxygen species (ROS) production (flow cytometry).

Results: In both cell lines, OPRM1 expression was significantly increased after combined treatment of D,L-methadone with all three cytotoxic drugs tested, which resulted in suppression of tumor cell growth and increase of apoptosis rates. These effects were mediated by increased ROS production and up-regulation of caspase-3/7 activity. Doxorubicin combined with D,L-methadone significantly reduced cell migration in both cell lines. Carboplatin or vincristine in combination with D,L-methadone had only an impact on cell migration in RH30 cells.

Conclusions: This new therapeutic approach in RMS provides strong antitumor effects in vitro. The combination of standard chemotherapy and D,L-methadone requires further investigation. Especially advanced tumors with a limited effectiveness of conventional treatment regimens seem a potential target of this approach.
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http://dx.doi.org/10.1007/s00432-022-03945-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114081PMC
June 2022

Operative Volume of Newborn Surgery in German University Hospitals: High Volume Versus Low Volume Centers.

Eur J Pediatr Surg 2022 Jan 13. Epub 2022 Jan 13.

Department of Paediatric Surgery and Paediatric Urology, University Hospital Frankfurt, Frankfurt/M., Germany.

Introduction:  Adequate patient volume is essential for the maintenance of quality, meaningful research, and training of the next generation of pediatric surgeons. The role of university hospitals is to fulfill these tasks at the highest possible level. Due to decentralization of pediatric surgical care during the last decades, there is a trend toward reduction of operative caseloads. The aim of this study was to assess the operative volume of the most relevant congenital malformations at German academic pediatric surgical institutions over the past years.

Methods:  Nineteen chairpersons representing university-chairs in pediatric surgery in Germany submitted data on 10 index procedures regarding congenital malformations or neonatal abdominal emergencies over a 3-year period (2015 through 2017). All institutions were categorized according to the total number of respective cases into "high," "medium," and "low" volume centers by terciles. Some operative numbers were verified using data from health insurance companies, when available. Finally, the ratio of cumulative case load versus prevalence of the particular malformation was calculated for the study period.

Results:  From 2015 through 2017, a total 2,162 newborns underwent surgery for congenital malformations and neonatal abdominal emergencies at German academic medical centers, representing 51% of all expected newborn cases nationwide. The median of cases per center within the study period was 101 (range 18-258). Four institutions (21%) were classified as "high volume" centers, four (21%) as "medium volume" centers, and 11 (58%) as "low volume" centers. The proportion of patients operated on in high-volume centers varied per disease category: esophageal atresia/tracheoesophageal fistula: 40%, duodenal atresia: 40%, small and large bowel atresia: 39%, anorectal malformations: 40%, congenital diaphragmatic hernia: 56%, gastroschisis: 39%, omphalocele: 41%, Hirschsprung disease: 45%, posterior urethral valves: 39%, and necrotizing enterocolitis (NEC)/focal intestinal perforation (FIP)/gastric perforation (GP): 45%.

Conclusion:  This study provides a national benchmark for neonatal surgery performed in German university hospitals. The rarity of these cases highlights the difficulties for individual pediatric surgeons to gain adequate clinical and surgical experience and research capabilities. Therefore, a discussion on the centralization of care for these rare entities is necessary.
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http://dx.doi.org/10.1055/s-0041-1740479DOI Listing
January 2022

The Evolutionary Dynamics of Repetitive DNA and Its Impact on the Genome Diversification in the Genus .

Front Plant Sci 2021 12;12:729734. Epub 2021 Aug 12.

Department of Agronomy, National Taiwan University, Taipei, Taiwan.

Polyploidization is an evolutionary event leading to structural changes of the genome(s), particularly allopolyploidization, which combines different genomes of distinct species. The tetraploid species, , is assumed an allopolyploid species formed by hybridization between diploid and . The repeat profiles of , , and their relatives were compared to elucidate the repeats' role in shaping their genomes. The repeat frequencies and profiles of the three diploid accessions (, ssp. , and var. ) and two tetraploid accessions () are similar. However, the polymorphic distribution of the subtelomeric satellites preferentially enriched in the tetraploid indicates drastic genome rearrangements after the allopolyploidization event. Verified by CENH3 chromatin immunoprecipitation (ChIP)-sequencing and fluorescence hybridization (FISH) analysis the centromeres of are mainly composed of the abundant satellite SorSat137 (CEN38) and diverse CRMs, Athila of Ty3_gypsy and Ty1_copia-SIRE long terminal repeat (LTR) retroelements. A similar centromere composition was found in . The potential contribution of in the formation of tetraploid is discussed.
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http://dx.doi.org/10.3389/fpls.2021.729734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8407070PMC
August 2021

Neuroblastoma Risk Assessment and Treatment Stratification with Hybrid Capture-Based Panel Sequencing.

J Pers Med 2021 Jul 22;11(8). Epub 2021 Jul 22.

Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.

For many years, the risk-based therapy stratification of children with neuroblastoma has relied on clinical and molecular covariates. In recent years, genome analysis has revealed further alterations defining risk, tumor biology, and therapeutic targets. The implementation of a robust and scalable method for analyzing traditional and new molecular markers in routine diagnostics is an urgent clinical need. Here, we investigated targeted panel sequencing as a diagnostic approach to analyze all relevant genomic neuroblastoma risk markers in one assay. Our "neuroblastoma hybrid capture sequencing panel" (NB-HCSP) assay employs a technology for the high-coverage sequencing (>1000×) of 55 selected genes and neuroblastoma-relevant genomic regions, which allows for the detection of single nucleotide changes, structural rearrangements, and copy number alterations. We validated our assay by analyzing 15 neuroblastoma cell lines and a cohort of 20 neuroblastomas, for which reference routine diagnostic data and genome sequencing data were available. We observed a high concordance for risk markers identified by the NB-HSCP assay, clinical routine diagnostics, and genome sequencing. Subsequently, we demonstrated clinical applicability of the NB-HCSP assay by analyzing routine clinical samples. We conclude that the NB-HCSP assay may be implemented into routine diagnostics as a single assay that covers all essential covariates for initial neuroblastoma classification, extended risk stratification, and targeted therapy selection.
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http://dx.doi.org/10.3390/jpm11080691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398598PMC
July 2021

Implant removal associated complications after ESIN osteosynthesis in pediatric fractures.

Eur J Trauma Emerg Surg 2021 Aug 2. Epub 2021 Aug 2.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Tübingen, Germany.

Purpose: ESIN (elastic stable intramedullary nailing) is considered the gold standard for various pediatric fractures. The aim of this study was to analyze the incidence and type of complications during or after TEN (titanium elastic nail) removal.

Methods: A retrospective data analysis was performed. Metal removal associated complications and preoperative extraosseous length/outlet angle of TENs as possible causes of complications were assessed.

Results: The complication rate in 384 TEN removals was 3.1% (n = 12). One major complication (rupture of M. extensor pollicis brevis) was documented. One refracture at the forearm occurred, however, remodeling prior TEN removal was completed. Ten minor complications were temporary or without irreversible restrictions (3 infections, 5 scaring/granuloma, 2 temporary paraesthesia). In 38 cases (16 forearms, 10 femora, 9 humeri, 3 lower legs), intra-operative fluoroscopy had to be used to locate the implants. In patients with forearm fractures, extraosseous implant length was relatively shorter than in cases without fluoroscopy (p = 0.01), but outlet angle of TENs was not significantly different in these two groups (28.5° vs 25.6°). In patients with femur fractures, extraosseous implant length and outlet angle were tendentially shorter, respectively, lower, but this did not reach statistical significance.

Conclusion: Removal of TENs after ESIN is a safe procedure with a low complication rate. Technically inaccurate TEN implantation makes removal more difficult and complicated. To prevent an untimely removal and patient discomfort, nail ends must be exactly positioned and cut. Intraoperative complications may be minimized with removal of TENs before signs of overgrowth.

Evidence: Level III, retrospective.
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http://dx.doi.org/10.1007/s00068-021-01763-4DOI Listing
August 2021

The Relevance of Preoperative Identification of the Adamkiewicz Artery in Posterior Mediastinal Pediatric Tumors.

Ann Surg Oncol 2022 Jan 31;29(1):493-499. Epub 2021 Jul 31.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Tübingen, Germany.

Background: Injury to the artery of Adamkiewicz (AKA) during surgery may lead to spinal cord ischemia and severe neurologic complications. Posterior mediastinal tumors may be adjacent to AKA, but data on preoperative visualization of AKA in children are rare. This study analyzed the importance of identifying the AKA preoperatively by spinal digital subtraction angiography (DSA) in children with posterior mediastinal tumors for therapeutic procedure.

Methods: Between 2002 and 2021, 36 children with posterior mediastinal tumors were evaluated for surgery at the authors' clinic. In 10 children with left-sided or bilateral tumor located at vertebral levels T8 to L1, spinal DSA was performed during preoperative workup to assess AKA. The patient and tumor characteristics as well as the diagnostic and therapeutic procedures were analyzed.

Results: The median age of the 10 children at examination was 69 months (range, 16-217 months). Three of the children were younger than 2 years. The tumor entities were neuroblastoma, ganglioneuroblastoma, ganglioneuroma, local relapse of a hepatocellular carcinoma, and neurofibroma. The AKA was identified in all cases, and proximity to the tumor was detected in four patients, three of whom had their planned surgery changed to irradiation. No complications occurred during spinal DSA or surgery.

Conclusions: In posterior mediastinal pediatric tumors, spinal DSA is a safe and reliable method for preoperative visualization of the AKA. It can show proximity to the tumor and guide the local therapy, thereby avoiding critical intra- and postoperative situations.
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http://dx.doi.org/10.1245/s10434-021-10381-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677641PMC
January 2022

The effect of adjuvant therapies on long-term outcome for primary resected synovial sarcoma in a series of mainly children and adolescents.

J Cancer Res Clin Oncol 2021 Dec 17;147(12):3735-3747. Epub 2021 Jul 17.

Hospital for Children and Adolescents, Goethe-University Frankfurt (Main), Frankfurt, Germany.

Background: The benefit of adjuvant therapy in synovial sarcoma (SS) treatment is under debate. Long-term follow-up data are missing.

Methods: SS patients treated in the consecutive trials CWS-81, CWS-86, CWS-91, CWS-96, CWS-2002-P, and the SoTiSaR-registry till 2013 were analyzed.

Results: Median age of 185 patients was 13.9 years (0.1-56)-with median follow-up of 7.4 years for 163 survivors. Most tumors (76%) were located in extremities. Size was < 3 cm in 58 (31%), 3-5 cm in 59 (32%), 5-10 cm in 42 (23%), and > 10 cm in 13 (7%) (13 missing). In 84 (45%) tumors, first excision was complete (R0 corresponding to IRS-I-group) and in 101 (55%) marginal (R1 corresponding to IRS-II-group). In a subsequent surgical intervention during chemotherapy, R0-status was accomplished in 23 additional IRS-II-group patients with secondary surgery. Radiotherapy was administered to 135 (73%), thereof 62 with R0-status and 67 R1-status (6 missing information). Adjuvant chemotherapy was administered to all but six patients. 5-year event-free (EFS) and overall survival (OS) was 82.9% ± 5.7 (95%CI) and 92.5% ± 3.9. Local and metastatic relapse-free survival was 91.3% ± 4.3 and 92.3% ± 4.1 at 5 years, respectively. In the multivariate analysis, tumor size and no chemotherapy were independently associated with EFS. Size and site were associated with OS. In a detailed analysis of local and metastatic events, tumor size was associated with an independent risk for developing metastases. No independent factor for suffering local recurrence could be identified.

Discussion: Omission of chemotherapy in a non-stratified way seems not justified. Size governs survival due to high linear association with risk of suffering metastatic recurrence in a granular classification.
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http://dx.doi.org/10.1007/s00432-021-03614-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557198PMC
December 2021

Hepatoblastoma: glutamine depletion hinders cell viability in the embryonal subtype but high GLUL expression is associated with better overall survival.

J Cancer Res Clin Oncol 2021 Nov 7;147(11):3169-3181. Epub 2021 Jul 7.

Department of Paediatric Surgery and Paediatric Urology, University Children's Hospital, Eberhard Karls University Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany.

Purpose: Glutamine plays an important role in cell viability and growth of various tumors. For the fetal subtype of hepatoblastoma, growth inhibition through glutamine depletion was shown. We studied glutamine depletion in embryonal cell lines of hepatoblastoma carrying different mutations. Since asparagine synthetase was identified as a prognostic factor and potential therapeutic target in adult hepatocellular carcinoma, we investigated the expression of its gene ASNS and of the gene GLUL, encoding for glutamine synthetase, in hepatoblastoma specimens and cell lines and investigated the correlation with overall survival.

Methods: We correlated GLUL and ASNS expression with overall survival using publicly available microarray and clinical data. We examined GLUL and ASNS expression by RT-qPCR and by Western blot analysis in the embryonal cell lines Huh-6 and HepT1, and in five hepatoblastoma specimens. In the same cell lines, we investigated the effects of glutamine depletion. Hepatoblastoma biopsies were examined for histology and CTNNB1 mutations.

Results: High GLUL expression was associated with a higher median survival time. Independent of mutations and histology, hepatoblastoma samples showed strong GLUL expression and glutamine synthesis. Glutamine depletion resulted in the inhibition of proliferation and of cell viability in both embryonal hepatoblastoma cell lines. ASNS expression did not correlate with overall survival.

Conclusion: Growth inhibition resulting from glutamine depletion, as described for the hepatoblastoma fetal subtype, is also detected in established embryonal hepatoblastoma cell lines carrying different mutations. At variance with adult hepatocellular carcinoma, in hepatoblastoma asparagine synthetase has no prognostic significance.
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http://dx.doi.org/10.1007/s00432-021-03713-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484192PMC
November 2021

Changes in the management of pediatric medial humeral epicondyle fractures with and without associated elbow dislocation.

Injury 2021 Aug 30;52(8):2257-2264. Epub 2021 May 30.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72070 Tuebingen, Germany.

Purpose The optimal management of medial humeral epicondyle fractures continues to be debated since decades. This single center study analyzes changes and optimizations of treatment over an observation period of 16 years and reports the results. Materials and Methods Retrospective analysis of all patients treated with a medial humeral epicondyle fracture between 2005 and 2020 at our institution. Results Ninety-six patients (mean 9.3 years, range 1 - 15) were included in the study. In 25 cases (26 %), the fracture was associated with an elbow dislocation. Most patients received surgical treatment (83.3 %), whereas 17.7 % were treated nonoperatively. Surgical treatment consisted of open reduction and fixation with compression screw (n = 44 steel, n = 2 absorbable), K-wire (n = 30), a combination of screw/K-wire (n = 2), or a PDS suture (n = 1). Compression screws have been used significantly more often in the latter half of the study period (p = 0.006). Patients were immobilized in a long arm cast for 29 days (range 11 - 50). Eleven surgically treated patients were early mobilized in an elbow orthosis. After a mean follow up of 7.6 months [2 - 61), Mayo elbow performance index (MEPI) outcome was excellent in all 96 patients. Loss of elbow movement (LOM) was found to be mild in 30 and moderate in 15 patients. LOM was found to be associated with surgical treatment (p = 0.001), and with concomitant elbow dislocations (p = 0.29). One pseudarthrosis occurred after conservative treatment. A persistence of ulnar nerve palsy or recurrent joint instability has not been described. Conclusion Most children with medial humeral epicondyle fractures nowadays undergo surgery. Screw osteosynthesis represents the increasingly preferred method in order to prevent joint instability or non-union, and to allow shorter immobilization duration. Overall results after medial epicondyle fractures are good.
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http://dx.doi.org/10.1016/j.injury.2021.05.041DOI Listing
August 2021

Stakeholder engagement to ensure the sustainability of biobanks: a survey of potential users of biobank services.

Eur J Hum Genet 2021 May 24. Epub 2021 May 24.

German Biobank Node, Charité Universitätsmedizin Berlin, Berlin, Germany.

Biobanks are important infrastructures facilitating biomedical research. After a decade of rolling out such infrastructures, a shift in attention to the sustainability of biobanks could be observed in recent years. In this regard, an increase in the as yet relatively low utilisation rates of biobanks has been formulated as a goal. Higher utilisation rates can only be achieved if the perspectives of potential users of biobanks-particularly researchers not yet collaborating with biobanks-are adequately considered. To better understand their perspectives, a survey was conducted at ten different research institutions in Germany hosting a centralised biobank. The survey targeted potential users of biobank services, i.e. researchers working with biosamples. It addressed the general demand for biosamples, strategies for biosample acquisition/storage and reasons for/against collaborating with biobanks. In total, 354 researchers filled out the survey. Most interestingly, only a minority of researchers (12%) acquired their biosamples via biobanks. Of the respondents not collaborating with biobanks on sample acquisition, around half were not aware of the (services of the) respective local biobank. Those who actively decided against acquiring biosamples via a biobank provided different reasons. Most commonly, respondents stated that the biosamples required were not available, the costs were too high and information about the available biosamples was not readily accessible. Biobanks can draw many lessons from the results of the survey. Particularly, external communication and outreach should be improved. Additionally, biobanks might have to reassess whether their particular collection strategies are adequately aligned with local researchers' needs.
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http://dx.doi.org/10.1038/s41431-021-00905-xDOI Listing
May 2021

Fractures of the proximal radius in children: management and results of 100 consecutive cases.

Arch Orthop Trauma Surg 2022 Aug 11;142(8):1903-1910. Epub 2021 May 11.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.

Introduction: Pediatric radial neck and head fractures are rare, accounting for only 1% of all fractures in children. The aim of this study is to describe the management and results of the respective fracture types and different injury characteristics.

Materials And Methods: This study performs a retrospective data analysis of 100 consecutive patients with a fracture of the proximal radius treated in a single high-volume pediatric trauma center.

Results: One hundred patients [mean age 7.5 years (1-15)] were documented with a fracture of the proximal radius between 3/2011 and 12/2019. The gender distribution was 62 girls and 38 boys. Twenty-seven patients had concomitant injuries. Conservative treatment was performed in 63 patients (Judet I = 27; II = 30; III = 6; Mason I = 2) using an above-the-elbow cast for 21 days (6-35). Surgical treatment was performed in 37 patients (Judet II = 3; III = 22; IV = 5; V = 7) using elastic stable intramedullary nailing (ESIN). Open reduction was necessary in five cases, and additional immobilization was performed in 32 cases. Six complications occurred: loss of implant stability (n = 2), healing in malalignment, pseudarthrosis, radioulnar synostosis, and a persisting hypoesthesia at the thumb. As a result, two ESIN osteosynthesis were revised, and one radial head resection was performed. Loss of movement was seen in 11% of cases, overall Mayo elbow performance index (MEPI) was 99.8 (90-100), and none of the patients experienced negative impacts on activities of daily life.

Conclusions: Proximal radial fractures occur predominately without dislocation. Good results are obtained with conservative treatment throughout. In cases with displacement exceeding growth-related correction, ESIN is the undisputed treatment of choice. Open surgery and long immobilization periods should be avoided whenever possible.
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http://dx.doi.org/10.1007/s00402-021-03917-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296417PMC
August 2022

Academic pediatric surgery - The German perspective.

Semin Pediatr Surg 2021 Feb 30;30(1):151025. Epub 2021 Jan 30.

Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany.

Today Pediatric surgery has become well established as fix point in the operative care of infants and children in Germany. The academic platform has traditionally been a strong driver for this development. However, as in other places around the world, academic pediatric surgery in Germany is currently facing relevant challenges. These challenges include internal aspects of the field (for example the broad spectrum with a rapidly ongoing development towards sub-specialization) but also external aspects (for example political specifications in form of the working hours act). Out of over 230 pediatric surgical institutions in Germany, only 33 are University-based. Sixteen of those 33 institutions are completely independent, whereas the other 18 are based within adult surgical University departments. In this article the authors give an overview over the current status of academic Pediatric surgery in Germany with its challenges and perspectives.
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http://dx.doi.org/10.1016/j.sempedsurg.2021.151025DOI Listing
February 2021

Proton Beam Therapy for Children With Neuroblastoma: Experiences From the Prospective KiProReg Registry.

Front Oncol 2020 20;10:617506. Epub 2021 Jan 20.

Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), Essen, Germany.

Objective: Radiotherapy (RT) is an integral part of the interdisciplinary treatment of patients with high-risk neuroblastoma (NB). With the continuous improvements of outcome, the interest in local treatment strategies that reduce treatment-related side effects while achieving optimal oncological results is growing. Proton beam therapy (PBT) represents a promising alternative to conventional photon irradiation with regard to the reduction of treatment burden.

Method: Retrospective analysis of children with high or intermediate risk NB receiving PBT of the primary tumor site during first-line therapy between 2015 and 2020 was performed. Data from the prospective in-house registry Standard Protonentherapie WPE - Kinder- (KiProReg) with respect to tumor control and treatment toxicity were analyzed. Adverse events were classified according to CTCAE Version 4 (V4.0) before, during, and after PBT.

Results: In total, 44 patients (24 male, 20 female) with high (n = 39) or intermediate risk NB (n = 5) were included in the analysis. Median age was 3.4 years (range, 1.4-9.9 years). PBT doses ranged from 21.0 to 39.6 Gray (Gy) (median 36.0 Gy). Five patients received PBT to the MIBG-avid residual at the primary tumor site at time of PBT according to the NB-2004 protocol. In 39 patients radiation was given to the pre-operative tumor bed with or without an additional boost in case of residual tumor. After a median follow-up (FU) of 27.6 months, eight patients developed progression, either local recurrence (n = 1) or distant metastases (n = 7). Four patients died due to tumor progression. At three years, the estimated local control, distant metastatic free survival, progression free survival, and overall survival was 97.7, 84.1, 81.8, and 90.9%, respectively. During radiation, seven patients experienced higher-grade (CTCAE ≥ °3) hematologic toxicity. No other higher grade acute toxicity occurred. After PBT, one patient developed transient myelitis while receiving immunotherapy. No higher grade long-term toxicity was observed up to date.

Conclusion: PBT was a well tolerated and effective local treatment in children with high and intermediate risk NB. The role of RT in an intensive multidisciplinary treatment regimen remains to be studied in the future in order to better define timing, doses, target volumes, and general need for RT in a particularly sensitive cohort of patients.
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http://dx.doi.org/10.3389/fonc.2020.617506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855697PMC
January 2021

Surgical management of paratesticular rhabdomyosarcoma: A consensus opinion from the Children's Oncology Group, European paediatric Soft tissue sarcoma Study Group, and the Cooperative Weichteilsarkom Studiengruppe.

Pediatr Blood Cancer 2021 04 1;68(4):e28938. Epub 2021 Feb 1.

Division Pediatric Surgery, East Carolina University, Greenville, North Carolina, USA.

The treatment of paratesticular rhabdomyosarcoma (PT-RMS) has varied over time and by cooperative group. The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) is a collaboration of the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, European pediatric Soft tissue sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). The INSTRuCT surgical committee has been given charge of the development of internationally applicable consensus guidelines for the surgical treatment of rhabdomyosarcoma. This clinical consensus opinion document addresses accepted principles and areas of controversy, such as scrotal violation and retroperitoneal nodal evaluation, providing an evidence-based guideline for the surgical treatment for PT-RMS.
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http://dx.doi.org/10.1002/pbc.28938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9019908PMC
April 2021
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