Importance of Adequate Surgical Local Control in Fusion-Negative Para-Testicular Rhabdomyosarcoma: Data From the Cooperative Weichteilsarkom Studiengruppe Trials (CWS-96 and CWS-2002P) and the European Soft Tissue Sarcoma Registry (SoTiSaR).

BACKGROUND: This study aimed to assess the impact that the quality of primary and subsequent surgeries has on the survival of patients with para-testicular rhabdomyosarcoma (PTRMS). METHODS: Patients with localized (IRS I-III) and metastatic (IRS IV) PTRMS were enrolled in the two Cooperative Weichteilsarkom Studiengruppe (CWS) trials (CWS-96, CWS-2002P) and the Soft Tissue Sarcoma Registry (SoTiSaR). RESULTS: Among 196 patients (median age, 8.4 years), 106 (54.1%) had primary complete resection. Image-defined lymph node (LN) disease was detected in 21 (11.5%) patients in the localized cohort and 12 (92.3%) patients in the metastatic cohort. The 5-year event-free survival (EFS) and overall survival (OS) were respectively 87.3% and 94.0% for the patients with localized PTRMS and 46.2% and 42.2% for the patients with metastatic PTRMS. Protocol violations during the primary surgery (PV-PS) were observed in 70 (42%) of the IRS I-III patients. This resulted in higher rates of R1/R2 resections (n = 53 [76%] vs n = 20 [21%]; p < 0.001) with a need for pretreatment re-excision (PRE) (n = 50 [83%] vs n = 10 [17%]; p < 0.001) compared with the patients undergoing correct primary surgery. Protocol violations during PRE occurred for 13 (20%) patients. Although PV-PS did not influence the 5-year EFS or OS in the localized PTRMS cohort, the unadjusted log-rank test showed that R status after PRE is a prognostic factor for 5-year OS (R1 vs R0 [81.8% vs 97.6%]; p = 0.02). CONCLUSIONS: The quality of surgical local control in PTRMS is unsatisfactory. Emphasis should be placed on evaluating the resection status after PRE in further clinical trials.

Centromere sequence-independent but biased loading of subgenome-specific CENH3 variants in allopolyploid Arabidopsis suecica.

Centromeric nucleosomes are determined by the replacement of the canonical histone H3 with the centromere-specific histone H3 (CENH3) variant. Little is known about the centromere organization in allopolyploid species where different subgenome-specific CENH3s and subgenome-specific centromeric sequences coexist. Here, we analyzed the transcription and centromeric localization of subgenome-specific CENH3 variants in the allopolyploid species Arabidopsis suecica. Synthetic A. thaliana x A. arenosa hybrids were generated and analyzed to mimic the early evolution of A. suecica. Our expression analyses indicated that CENH3 has generally higher expression levels in A. arenosa compared to A. thaliana, and this pattern persists in the hybrids. We also demonstrated that despite a different centromere DNA composition, the centromeres of both subgenomes incorporate CENH3 encoded by both subgenomes, but with a positive bias towards the A. arenosa-type CENH3. The intermingled arrangement of both CENH3 variants demonstrates centromere plasticity and may be an evolutionary adaption to handle more than one CENH3 variant in the process of allopolyploidization.

Can Lymph Node Involvement in Unilateral Wilms Tumor be Predicted by Preoperatively known Data in Combination with Intraoperative Findings?

OBJECTIVE: This study aimed to identify parameters that allow the estimation of tumor-infiltrated lymph nodes (LN) after pretreatment for unilateral Wilms tumor (WT). SUMMARY BACKGROUND DATA: Complete tumor resection with removal of regional LN is always necessary. Positive LNs require local irradiation influencing benefits in case of NSS in long-term follow-up. Clinical and tumor-related data available at the time of surgery in combination with intraoperative findings (IAF) were used to estimate the LN status during surgery. METHODS: Altogether, 2115 patients with unilateral WT were prospectively enrolled in SIOP-93-01 / GPOH and SIOP-2001 / GPOH over a period of 30 years (1993-2023). LN infiltration by tumor was calculated for age, sex, metastases at diagnosis, tumor volume (TV), TV shrinkage, and intraoperative findings (IAF) using logistic regression models. RESULTS: Age ≥48 months (P<0.001, OR 2.17, CI 1.57 - 3.00), TV at diagnosis ≥300 (P<0.001, OR 3.72, CI 2.37 - 5.85), metastasis at diagnosis (P<0.001, OR 6.21, CI 4.47 - 8.62) and IAF (>1: P<0.001, OR 3.54, CI 2.13 - 5.88) correlated with positive LNs. TV shrinkage was not predictive of positive LN. Three flow charts were developed based on age, TV at diagnosis, metastasis, and IAF. These flowcharts defined risks between 0% and 41.5% for LN infiltration by tumor. CONCLUSIONS: The combination of age, TV at diagnosis, and metastasis with IAF allows the estimation of the frequency of positive LNs, which may help surgeons deciding about NSS.

Treatment of unstable forearm fractures at the metaphyseal-diaphyseal junction in children: antegrade ESIN vs. transepiphyseal intramedullary K-wire fixation.

BACKGROUND: Treatment of unstable forearm fractures in the metaphyseal-diaphyseal junction (MDJ) zone is still a matter of debate. Major drawbacks of all types of fixations include either invasiveness, technical impracticality, or lack of acceptance by patients. This study reports results after antegrade ESIN (a-ESIN) compared to transepiphyseal intramedullary K-wire (TIK) for unstable MDJ forearm fractures. METHODS: The MDJ of the forearm was defined as the square over the joints of both forearm bones subtracted with the square over the metaphysis of the radius alone. The data of 40 consecutive patients < 16 years of age who were treated either by a-ESIN (later treatment period) or TIK (early treatment period) for an unstable MDJ forearm fracture at a single high-volume pediatric trauma center were retrospectively analyzed. RESULTS: The average age was slightly lower in the first group (TIK = 7.42 years; a-ESIN = 10.5 years). An additional ulna fracture was found in 50% of cases and was treated with a classic antegrade ESIN in 10/20 (TIK) and 6/20 cases (a-ESIN). Additional plaster cast immobilization was performed in all cases with TIK and in three cases with a-ESIN. After TIK, no complication, malalignment, or functional limitation occurred. After a-ESIN, 19/20 patients had an event-free course with stable retention and healing without axial malalignment. In one case, a temporary sensor dysfunction occurred. The same patient suffered a refracture two months after the original trauma, which required a closed reduction. Metal removal was performed after 84 days (TIK) and 150 days (a-ESIN). The outcome in all patients was good. CONCLUSION: Both a-ESIN and TIK are minimally invasive procedures that are technically easy to perform. Both methods are safe and lead to a complete restoration of the forearm's range of motion. The decisive advantage of a-ESIN is the possibility of postoperative immobilization-free rehabilitation.

How to improve initial diagnostic accuracy of kidney tumours in childhood?-A non-invasive approach.

Non-invasive differentiation of paediatric kidney tumours is particularly important in the SIOP-RTSG protocols, which recommend pre-operative chemotherapy without histological confirmation. The identification of clinical and tumour-related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93-01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI-characteristics, including diffusion-weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis-based neoadjuvant treatment.

Trap-Door Thoracotomy and Clamshell Thoracotomy as Surgical Approaches for Neuroblastoma and Other Thoracic Tumors in Children.

Solid tumors of the cervicothoracic junction, the posterior mediastinum, or bilateral dorsal thoracic tumors represent a challenge in pediatric surgical oncology. The aim of this study was to evaluate trap-door thoracotomy and clamshell thoracotomy as surgical approaches. A single-center retrospective study of children with solid tumors in these specific localizations was performed. From 2015 to 2023, 26 children (17 girls; 9 boys) were treated at a median age of 54 months (range 8-229). Tumor resection was performed for neuroblastoma (n = 11); metastatic disease (n = 7); malignant rhabdoid tumor (n = 4); Ewing sarcoma (n = 1); inflammatory myofibroblastic tumor (n = 1); rhabdomyosarcoma (n = 1); and neurofibroma (n = 1). The surgical goal of macroscopic complete excision was achieved in all of the 14 children who underwent trap-door thoracotomy and in 11 of the 12 children who underwent clamshell thoracotomy. There were no major complications. At a median follow-up of 8 months (range 0-60), the disease was under local control or in complete remission in 66.7% of the children. In conclusion, surgical resection of solid tumors of the cervicothoracic junction in children can be performed safely and successfully with trap-door thoracotomy and with clamshell thoracotomy for posterior mediastinal or bilateral dorsal thoracic tumors.

The effect of intraoperative cerebral oxygen desaturations on postoperative cerebral oxygen metabolism in neonates and infants a pilot study.

INTRODUCTION: Cerebral oxygen desaturation during pediatric surgery has been associated with adverse perioperative outcomes. The aim of this pilot study was to analyze the frequency and severity of intraoperative cerebral oxygen desaturations and their impact on postoperative cerebral oxygen metabolism in neonates and infants undergoing pediatric surgery. METHODS: In a prospective pilot study, intra- and postoperative regional cerebral oxygen saturation and blood flow were measured noninvasively using a device combining laser Doppler flowmetry and white-light-spectrometry. Thirty-seven consecutive neonates and infants undergoing noncardiac surgery under general anesthesia for more than 30 min and necessity for invasive arterial blood pressure monitoring were included. Patients with pre-known congenital structural heart disease or cerebral disease were excluded. Continuously brain monitor recording was started in sedated patients before induction of anesthesia (preoperative baseline) and was completed 1 h postoperatively in the PICU in sedated, intubated, and mechanically ventilated states at the PICU (postoperative state). Baseline and postoperative state for cerebral fractional tissue oxygen extraction and approximated cerebral metabolic rate of oxygen were calculated. RESULTS: Seventeen (46%) of the 37 studied neonates and infants suffered from intraoperative periods of regional cerebral oxygen desaturation below 20% of the baseline (event group). Severity of cerebral desaturations was median 4.0%min/h [range 0.1-58.7; interquartile range [IQR] 0.99-21.29]. In the event group, the duration of surgery was significantly longer (median 135 min [range 11-260; IQR 113.5-167.0] vs median 46.5 min [range 11-180; IQR 30.5-159.3]; difference of -62.94; 95% confidence interval [CI] -105.17 to -20.71; p = .021). In the event group, cerebral fractional tissue oxygen extraction (median 0.41 [range 0.20-0.55; IQR 0.26-0.44] vs. median 0.27 [range 0.11-0.41; IQR 0.20-0.31]; difference of -0.11; 95% CI -0.17 to -0.05; p = .001) and approximated cerebral metabolic rate of oxygen (median 6.15 arbitrary unit [range 2.69-12.07; IQR 5.12-7.21] vs. median 4.14 arbitrary unit [range 1.78-7.86; IQR 3.82-6.31]; difference of -1.76; 95% CI -3.03 to -0.49; p = .009) were significantly higher and the cerebral regional oxygen saturation (median 58.99% [range 44.87-79.1; IQR 54.26-72.61] vs median 70.94% [range 57.9-86.13; IQR 67.07-76.59]; difference of 10.01; 95% CI 4.13-15.90; p = .002) significantly lower after surgery compared to the nonevent group. DISCUSSION: The increase of approximated cerebral metabolic rate of oxygen could indicate an elevated oxidative energy metabolism in the "stressed" brain, due to repair processes. The increased cerebral fractional tissue oxygen extraction fits with the decreased NIRS cerebral oxygenation. Our data suggest that an increase in cerebral oxygen metabolism was the cause. CONCLUSION: Cerebral oxygen desaturation during major surgery in neonates and infants is associated with early postoperative increased cerebral oxygen extraction and possibly increased cerebral oxygen metabolism.

Redo nephron-sparing surgery in stage V pediatric renal tumors - A report from the SIOP/GPOH study group for renal tumors.

PURPOSE: Nephron-sparing Surgery (NSS) is the surgical treatment of choice in children with bilateral renal tumors or in syndromatic patients. With an increasing role of this surgical approach, there is also an increased number of tumor relapses after NSS. Aim of this study was to evaluate a second ("Redo-") NSS in children with relapsed renal tumors. MATERIALS AND METHODS: We retrospectively analysed patients undergoing Redo-NSS for relapsed kidney tumors between 2009 and 2021 at our institution, which represents a national reference center of the SIOP/GPOH renal tumor study group. RESULTS: Nine patients (5 girls, 4 boys) underwent Redo-NSS with resection of 15 lesions. Mean age at surgery was 58 months (12-137), mean operative time for Redo-NSS was 195 min (137-260). R0 resection status was achieved in all children. Two patients had second relapses, one of them was resected via NSS, the other child underwent tumor nephrectomy. Two patients with anaplastic relapses died from combined second relapses. Thus, 7/9 patients are alive without evidence of disease, an impaired renal function was observed in one child. Mean follow-up after Redo-NSS was 35 months (6-49). CONCLUSIONS: In renal tumor relapses, Redo-NSS can be performed with satisfactory oncological and functional results. Occurrence of diffuse anaplasia should possibly refrain from this approach. Further evaluation in international multicenter analyses are necessary for a definitive determination of Redo-NSS.

TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants.

Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite-motif-containing-28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93-01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case - either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc-binding clusters of the RING, B-box-2, and PHD domains or the central coiled-coil region. TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Local MRI before and after Tumor Resection in Neuroblastoma: Impact of Residual Disease on Event Free Survival.

(1) Background: The study aimed to investigate the influence of MRI-defined residual disease on local tumor control after resection of neuroblastic tumors in patients without routine adjuvant radiotherapy. (2) Methods: Patients, who underwent tumor resection between 2009 and 2019 and received a pre- and postoperative MRI, were included in this retrospective single-center study. Measurement of residual disease (RD) was performed using standardized criteria. Primary endpoint was the local or combined (local and metastatic) event free survival (EFS). (3) Results: Forty-one patients (20 female) with median age of 39 months were analyzed. Risk group analysis showed eleven low-, eight intermediate-, and twenty-two high-risk patients (LR, IR, HR). RD was found in 16 cases by MRI. A local or combined relapse or progression was found in nine patients of whom eight patients had RD (p = 0.0004). From the six patients with local or combined relapse in the HR group, five had RD (p = 0.005). Only one of 25 patients without RD had a local event. Mean EFS (month) was significantly higher if MRI showed no residual tumor (81 ± 5 vs. 43 ± 9; p = 0.0014) for the total cohort and the HR subgroup (62 ± 7 vs. 31 ± 11; p = 0.016). (4) Conclusions: In our series, evidence of residual tumor, detectable by MRI, was associated with insufficient local control, resulting in relapses or local progression in 50% of patients. Only one of the patients without residual tumor had a local relapse.

Locally Advanced Adrenocortical Carcinoma in Children and Adolescents-Enigmatic and Challenging Cases.

BACKGROUND: Locally advanced tumors account for approximately 50% of children and adolescents with adrenocortical carcinoma (ACC), and of these, up to 50% relapse. We explored the five-item microscopic score and the pS-GRAS score for guiding management. METHODS: Data from children and adolescents with COG stage II and III ACC registered in the MET studies were included. The five-item and pS-GRAS score were retrospectively calculated. RESULTS: By December 2021, 55 patients with stage II and III (stage II n = 18, stage III n = 37) had been reported. Median age was 4.3 years [0.1-17.8], median duration of follow-up 6.0 years [0-16.7]. 3-year event-free survival (EFS) rate was 76.5% and 49.8% (p = 0.088), respectively. In stage II tumors, neither the five-item score (p = 0.872) nor pS-GRAS grouping (p = 0.218) had any effect as prognostic factors. In stage III patients, EFS was impaired in tumors with unfavorable histology according to the five-item score (100% vs. 30.8%, p = 0.018). No difference was observed for pS-GRAS groups (p = 0.798). CONCLUSIONS: In patients with COG stage III, but not stage II, the five-item score affected EFS. Further studies are needed to identify patients at risk in COG stage II.

Solid pseudopapillary neoplasms of the pancreas in childhood and adolescence-an analysis of the German Registry for Rare Pediatric Tumors (STEP).

Solid pseudopapillary neoplasms (SPNs) are the most common entity among pediatric pancreatic tumors. Still, these are rare tumors with an annual incidence of 0.1-0.2/1,000,000, and little is known about their optimal treatment. This analysis aimed to increase knowledge about the occurrence and treatment strategies of SPN in childhood. Data regarding diagnostics, treatment, and outcome of children aged 0-18 years with SPN recorded in the German Registry for Rare Pediatric Tumors (STEP) were analyzed. Thirty-eight patients were identified with a median age of 14.5 years at diagnosis (range: 8-18) and a female preponderance (81.6%). The most frequent location of the tumor was the pancreatic tail. In histopathological and immunohistochemical examination, pseudopapillary, solid, and cystic lesions as well as expression of beta-catenin, progesterone receptors, and cyclin D1 were the most common findings. All patients underwent surgical resection. Most patients underwent open resection, predominantly tail resection for tumors in the tail region and pylorus-preserving pancreaticoduodenectomy for tumors in the head region. The main postoperative sequela was exogenous pancreatic insufficiency (23.7%), especially with SPN in the pancreatic head. No recurrence occurred during follow-up, although two patients underwent resection with microscopic residue. CONCLUSION: SPN of the pancreas in childhood are low-grade malignancies with usually favorable treatment outcomes. However, therapy can lead to relevant long-term sequelae. To prevent recurrence, complete surgical resection is recommended, sparing as much healthy pancreatic tissue as possible. Interdisciplinary collaboration between specialists is essential to optimize treatment. Molecular genetic analysis of these tumors could improve understanding of their genesis. WHAT IS KNOWN: • Solid pseudopapillary neoplasms (SPNs) of the pancreas are very rare tumors in childhood. • Little is known about tumorigenesis, and there are no specific guidelines for treatment and follow-up in pediatric patients. WHAT IS NEW: • Characteristics, treatment, and outcome were comprehensively assessed in a large cohort of pediatric patients with SPN. • We propose recommendations for diagnosis, treatment, and follow-up of children with SPN, based on our analysis and considering published experience.

Image-defined risk factors in localized thoracic neuroblastoma and ganglioneuroma.

BACKGROUND: The pretreatment International Neuroblastoma Risk Group Staging System (INRGSS) discriminates localized tumors L1/L2 depending on the absence/presence of image-defined risk factors (IDRFs) at diagnosis. Referring to this new staging system, we assessed initial imaging of localized thoracic neuroblastoma (NB) and ganglioneuroma (GN) and the extent of initial tumor resection. METHODS: Patients with localized thoracic NB/GN from the German clinical trials NB97 and NB2004 were included. Imaging at diagnosis and operative reports were reviewed retrospectively. IDRFs were assessed centrally and correlated to International Neuroblastoma Staging System (INSS) stage and extent of tumor resection. Additionally, we analyzed data on surgery-related complications. RESULTS: Imaging series of 88 patients were available for central review. In 18 children, no IDRF was present, 28 exhibited one IDRF, 42 two or more IDRFs, resulting in 70 patients with L2 disease. The most frequently observed IDRF was encasement of any vessel (n = 38). Initial surgical resection was aimed for in 45 patients (L1: n = 11; L2: n = 34). Complete and gross total resection rates were higher children with L2 NB (n = 8/25 L1, n = 17/25 L2 vs. n = 2/15 L1, n = 13/15 L2, respectively). The proportion of surgical complications was very similar between INRGSS L1 and L2 (n = 4/11 vs. n = 17/34). All complications were manageable, and no surgery-related deaths were observed. CONCLUSION: In this retrospective cohort, the extent of resection and the rate of surgical complications did not differ substantially between patients classified as L1/L2, indicating that INRGSS L2 does not equate unresectability. It appeared that individual IDRFs differ in value. Larger studies are needed to assess the significance and therapeutic/prognostic impact of such findings.

The role of surgery in the treatment of neuroblastoma metastases at rare sites.

PURPOSE: Treatment of neuroblastoma metastases usually consists of chemotherapy and irradiation. However, in selected cases, surgical treatment is also indicated. In this study, we present three cases of patients with neuroblastoma metastases at rare sites that underwent surgery. MATERIALS AND METHODS: We retrospectively analyzed data of patients who underwent surgery for neuroblastoma at our department of Pediatric Surgery and Pediatric Urology at the University Children's Hospital in Tuebingen and selected those patients who had surgery explicitly for a metastasis. RESULTS: Between 2002 and 2020, 277 children underwent surgical treatment for neuroblastoma. Three cases with metastases at exceptional sites are presented here after therapy according to protocols. One patient had a penile metastasis and received surgery including a plastic reconstruction. The patient showed no signs of erectile or urinary dysfunction at follow-up. Another patient had a metastasis in the proximal ulna, which remained vital even after exhausted treatment after two relapses. Afterward there was no restriction of movement of the extremity. The third patient had, amongst others, metastases to the pancreatic body and to the liver. Both were surgically removed during primary tumor resection. This patient died after local tumor relapse. The other two patients showed no evidence of tumor relapse after a follow-up of 18 and 17 months, respectively. CONCLUSION: Although children with neuroblastoma often present with metastases, there is no recommendation for surgical treatment other than diagnostic biopsies. In case of persistence of metastasis or after exhaustion of high-risk therapy, surgical resection must be considered.

Increasing Patient Safety and Treatment Quality by Using Intraoperative MRI for Organ-Preserving Tumor Resection and High-Dose Rate Brachytherapy in Children with Bladder/Prostate and Perianal Rhabdomyosarcoma.

In children with bladder/prostate (BP) and perianal rhabdomyosarcoma (RMS), we use a hybrid treatment concept for those suitable, combining organ-preserving tumor resection and high-dose rate brachytherapy (HDR-BT). This treatment concept has been shown to improve outcomes. However, it is associated with specific challenges for the clinicians. The exact position of the tubes for BT is a prerequisite for precise radiotherapy. It can finally be determined only with an MRI or CT scan. We evaluated the use of an intraoperative MRI (iMRI) to control the position of the BT tubes and for radiotherapy planning in all patients with BP and perianal RMS who received the above-mentioned combination therapy in our department since January 2021. iMRI was used in 12 children. All tubes were clearly localized. No adverse events occurred. In all 12 children, radiotherapy could be started on time. In a historical cohort without iMRI, this was not possible in 3 out of 20 children. The use of iMRI in children with BP and perianal RMS improved patient safety and treatment quality. This technology has proven to be successful for the patient population we have defined and has become a standard procedure in our institution.

Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN.

Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis.

Characterisation of a Spontaneous Mutant of Lemna gibba G3 (Lemnaceae).

A spontaneous mutant of the duckweed Lemna gibba clone no. 7796 (known as strain G3, WT) was discovered. In this mutant clone, L. gibba clone no. 9602 (mt), the morphological parameters (frond length, frond width, root length, root diameter) indicated an enlarged size. A change in the frond shape was indicated by the decreased frond length/width ratio, which could have taxonomic consequences. Several different cell types in both the frond and the root were also enlarged. Flow cytometric measurements disclosed the genome size of the WT as 557 Mbp/1C and that of the mt strain as 1153 Mbp/1C. This represents the results of polyploidisation of a diploid clone to a tetraploid one. The mutant clone flowered under the influence of long day-treatment in half-strength Hutner's medium in striking contrast to the diploid WT. Low concentration of salicylic acid (<1 µM) induced flowering in the tetraploid mutant but not in the diploid plants. The transcript levels of nuclear-encoded genes of the photosynthetic apparatus (CAB, RBCS) showed higher abundance in light and less dramatic decline in darkness in the mt than in WT, while this was not the case with plastid-encoded genes (RBCL, PSAA, PSBA, PSBC).

Second-line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR).

BACKGROUND: Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance. METHODS: Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009-2018) were retrospectively analyzed. RESULTS: Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively. CONCLUSION: Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.

Successful on-ECLS Repair of CDH and Omphalocele in a Newborn.

Both congenital diaphragmatic hernias (CDHs) and omphaloceles show relevant overall mortality rates as individual findings. The combination of the two has been described only sparsely in the literature and almost always with a fatal course. Here, we describe a term neonate with a rare high-risk constellation of left-sided CDH and a large omphalocele who was successfully treated on extracorporeal life support (ECLS). Prenatally, the patient was diagnosed with a large omphalocele and a left CDH with a lung volume of ∼27% and an observed to expected lung-to-head ratio of 30%. Due to respiratory insufficiency, an ECLS device was implanted. As weaning from ECLS was not foreseeable, the female infant underwent successful surgery on ECLS on the ninth day of life. Perioperative high-frequency oscillatory ventilation and circulatory and coagulation management under point-of-care monitoring were the main anesthesiological challenges. Over the following 3 days, ECLS weaning was successful, and the patient was extubated after another 43 days. Surgical treatment on ECLS can expand the spectrum of therapy in high-risk constellations if potential risks are minimized and there is close interdisciplinary cooperation.