A Novel Standard for Systematic Reporting of Neuroblastoma Surgery: The International Neuroblastoma Surgical Report Form (INSRF): A Joint Initiative by the Pediatric Oncological Cooperative Groups SIOPEN∗, COG∗∗, and GPOH∗∗∗.

OBJECTIVE: To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes. SUMMARY OF BACKGROUND DATA: NBL, the most common extracranial solid malignant tumor in children, covers a wide spectrum of tumors with significant differences in anatomical localization, organ or vessel involvement, and tumor biology. Complete surgical resection of the primary tumor is an important part of NBL treatment, but maybe hazardous, prone to complications and its role in high-risk disease remains debated. Various surgical guidelines exist within the protocols of the different cooperative groups, although there is no standardized operative report form to document the surgical treatment of NBL. METHODS: After analyzing the treatment protocols of the SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology pediatric cooperative groups, important variables were defined to completely describe surgical biopsy and resection of NBL and their outcomes. All variables were discussed within the Surgical Committees of SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology. Thereafter, joint meetings were organized to obtain intercontinental consensus. RESULTS: The "International Neuroblastoma Surgical Report Form" provides a structured reporting tool for all NBL surgery, in every anatomical region, documenting all Image Defined Risk Factors and structures involved, with obligatory reporting of intraoperative and 30 day-postoperative complications. CONCLUSION: The International Neuroblastoma Surgical Report Form is the first universal form for the structured and uniform reporting of NBL-related surgical procedures and their outcomes, aiming to facilitate the postoperative communication, treatment planning and analysis of surgical treatment of NBL.

Intra- and inter-fraction uncertainties during IGRT for Wilms' tumor.

BACKGROUND AND PURPOSE: To assess intra- and inter-fraction motion uncertainties, due to displacements of the tumor bed (TB) and organs at risk (OAR), as well as intra- and inter-fraction patient set-up uncertainties, due to positioning variations, during image-guided radiation therapy (IGRT) in children with Wilms' tumor. MATERIAL AND METHODS: Four-dimensional computed tomography (4D-CT) and daily pre- and post-treatment cone-beam CT (CBCT)-scans of 15 patients (average 4, range 1-8 years) undergoing flank irradiation after nephrectomy were analyzed. TB (marked by four surgical clips) and OAR motion uncertainties were quantified by displacements of the center of mass in all orthogonal directions. Translational and rotational bone off-sets were recorded for patient set-up uncertainties assessment in all orthogonal directions. The average results, systematic and random errors were computed. RESULTS: Average intra- and inter-fraction motion uncertainties were ≤1.1 mm (range: [-6.9;7.9] mm) for the TB and ≤3.2 mm (range: [-9.1;9.6] mm) for the OAR. Average intra- and inter-fraction patient set-up uncertainties were ≤0.1 mm (range: [-3.3;4.8] mm) and ≤0.9° (range: [0.0;2.8°]). Both motion and patient set-up uncertainties were larger for the cranio-caudal direction. Calculated systematic and random errors were ≤2.4 mm for the motion uncertainties and ≤0.8 mm/0.7° for the patient set-up uncertainties. CONCLUSIONS: Average motion and patient set-up uncertainties during radiotherapy treatment were found to be limited. However, uncertainties were larger for the cranio-caudal direction and outliers were found in all orthogonal directions. When having available 4D-CT and CBCT information, the use of patient-specific and anisotropic safety margin expansions is advised for both target volume and OAR.

Apparent diffusion coefficient as it relates to histopathology findings in post-chemotherapy nephroblastoma: a feasibility study.

BACKGROUND: Nephroblastomas represent a group of heterogeneous tumours with variable proportions of distinct histopathological components. OBJECTIVE: The purpose of this study was to investigate whether direct comparison of apparent diffusion coefficient (ADC) measurements with post-resection histopathology subtypes is feasible and whether ADC metrics are related to histopathological components. MATERIALS AND METHODS: Twenty-three children were eligible for inclusion in this retrospective study. All children had MRI including diffusion-weighted imaging (DWI) after preoperative chemotherapy, just before tumour resection. A pathologist and radiologist identified corresponding slices at MRI and postoperative specimens using tumour morphology, the upper/lower calyx and hilar vessels as reference points. An experienced reader performed ADC measurements, excluding non-enhancing areas. A pathologist reviewed the corresponding postoperative slides according to the international standard guidelines. We tested potential associations with the Spearman rank test. RESULTS: Side-by-side comparison of MRI-DWI with corresponding histopathology slides was feasible in 15 transverse slices in 9 lesions in 8 patients. Most exclusions were related to extensive areas of necrosis/haemorrhage. In one lesion correlation was not possible because of the different orientation of sectioning of the specimen and MRI slices. The 25% ADC showed a strong relationship with percentage of blastema (Spearman rho=-0.71, P=0.003), whereas median ADC was strongly related to the percentage stroma (Spearman rho=0.74, P=0.002) at histopathology. CONCLUSION: Side-by-side comparison of MRI-DWI and histopathology is feasible in the majority of patients who do not have massive necrosis and hemorrhage. Blastemal and stromal components have a strong linear relationship with ADC markers.

Early conversion to below-elbow cast for non-reduced diaphyseal both-bone forearm fractures in children is safe: preliminary results of a multicentre randomised controlled trial.

INTRODUCTION: This multicentre randomised controlled trial was designed to explore whether 6 weeks above-elbow cast (AEC) or 3 weeks AEC followed by 3 weeks below-elbow cast (BEC) cause similar limitation of pronation and supination in non-reduced diaphyseal both-bone forearm fractures in children. MATERIALS AND METHODS: Children were randomly allocated to 6 weeks AEC or to 3 weeks AEC followed by 3 weeks BEC. The primary outcome was limitation of pronation and supination after 6 months. The secondary outcomes were re-displacement of the fracture, complication rate, limitation of flexion and extension of wrist and elbow, cast comfort, cosmetics, complaints in daily life and assessment of radiographs. RESULTS: A group of 23 children was treated with 6 weeks AEC and 24 children with 3 weeks AEC and 3 weeks BEC. The follow-up rate was 98 % with a mean follow-up of 7.0 months. The mean limitation of pronation and supination was 23.3 ± 22.0 for children treated with AEC and 18.0 ± 16.9 for children treated with AEC and BEC. The other study outcomes were similar in both groups. CONCLUSIONS: Early conversion to BEC is safe in the treatment of non-reduced diaphyseal both-bone forearm fractures in children. LEVEL OF EVIDENCE: Multicentre randomised controlled trial, Level II.

Conversion to below-elbow cast after 3 weeks is safe for diaphyseal both-bone forearm fractures in children.

BACKGROUND: It is unclear whether it is safe to convert above-elbow cast (AEC) to below-elbow cast (BEC) in a child who has sustained a displaced diaphyseal both-bone forearm fracture that is stable after reduction. In this multicenter study, we wanted to answer the question: does early conversion to BEC cause similar forearm rotation to that after treatment with AEC alone? CHILDREN AND METHODS: Children were randomly allocated to 6 weeks of AEC, or 3 weeks of AEC followed by 3 weeks of BEC. The primary outcome was limitation of pronation/supination after 6 months. The secondary outcomes were re-displacement of the fracture, limitation of flexion/extension of the wrist and elbow, complication rate, cast comfort, complaints in daily life, and cosmetics of the fractured arm. RESULTS: 62 children were treated with 6 weeks of AEC, and 65 children were treated with 3 weeks of AEC plus 3 weeks of BEC. The follow-up rate was 60/62 and 64/65, respectively with a mean time of 6.9 (4.7-13) months. The limitation of pronation/supination was similar in both groups (18 degrees for the AEC group and 11 degrees for the AEC/BEC group). The secondary outcomes were similar in both groups, with the exception of cast comfort, which was in favor of the AEC/BEC group. INTERPRETATION: Early conversion to BEC cast is safe and results in greater cast comfort.

Characteristics and outcome of children with renal tumors in the Netherlands: The first five-year's experience of national centralization.

Around 6% of all childhood malignancies represent renal tumors, of which a majority includes Wilms tumor (WT). Although survival rates have improved over the last decades, specific patients are still at risk for adverse outcome. In the Netherlands, since 2015, pediatric oncology care for renal tumors has been centralized in the Princess Máxima Center for Pediatric Oncology. Here, we describe experiences of the first 5 years of centralized care and explore whether this influences the epidemiological landscape by comparing data with the Netherlands Cancer Registry (NCR). We identified all patients <19 years with a renal mass diagnosed between 01-01-2015 and 31-12-2019 in the Princess Máxima Center. Epidemiology, characteristics and management were analyzed. We identified 164 patients (including 1 patient who refused consent for registration), in our center with a suspicion of a renal tumor. The remaining 163 cases included WT (n = 118)/cystic partially differentiated nephroblastoma (n = 2)/nephrogenic rests only (n = 6) and non-WT (n = 37). In this period, the NCR included 138 children, 1 17-year-old patient was not referred to the Princess Máxima Center. Central radiology review (before starting treatment) was performed in 121/163 patients, and central pathology review in 148/152 patients that underwent surgery. Treatment stratification, according to SIOP/EpSSG protocols was pursued based on multidisciplinary consensus. Preoperative chemotherapy was administered in 133 patients, whereas 19 patients underwent upfront surgery. Surgery was performed in 152 patients, and from 133 biomaterial was stored. Centralization of care for children with renal tumors led to referral of all but 1 new renal tumor cases in the Netherlands, and leads to referral of very rare subtypes not registered in the NCR, that benefit from high quality diagnostics and multidisciplinary decision making. National centralization of care led to enhanced development of molecular diagnostics and other innovation-based treatments for the future.

Imatinib mesylate for children with dermatofibrosarcoma protuberans (DFSP).

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant soft tissue tumor in children. DFSP is characterized by a specific fusion of the platelet-derived growth factor beta (PDGFbeta) with the collagen type 1alpha1 (COL1alpha1) gene which renders these tumors responsive to targeted therapy with tyrosine kinase inhibitors, such as imatinib mesylate, as is reported in adults. In the current report, we describe the first small pediatric DFSP series, in which response to imatinib mesylate contributed to successful treatment outcome.

Rectal Omeprazole in Infants With Gastroesophageal Reflux Disease: A Randomized Pilot Trial.

BACKGROUND AND OBJECTIVE: Omeprazole is a proton pump inhibitor that is used in acid suppression therapy in infants. Infants cannot swallow the oral tablets or capsules. Since, infants require a non-standard dose of omeprazole, the granules or tablets are often crushed or suspended in water or sodium bicarbonate, which may destroy the enteric coating. In this study we explore the efficacy and pharmacokinetics of rectally administered omeprazole in infants with gastroesophageal reflux disease (GERD) due to esophageal atresia (EA) or congenital diaphragmatic hernia (CDH) and compare these with orally administered omeprazole. METHODS: Infants (6-12 weeks postnatal and bodyweight > 3 kg) with EA or CDH and GERD were randomized to receive a single dose of 1 mg/kg omeprazole rectally or orally. The primary outcome was the percentage of infants for whom omeprazole was effective according to predefined criteria for 24-h intraesophageal pH. Secondary outcomes were the percentages of time that gastric pH was < 3 or < 4, as well as the pharmacokinetic parameters. RESULTS: Seventeen infants, 4 with EA and 13 with CDH, were included. The proportion of infants for whom omeprazole was effective was 56% (5 of 9 infants) after rectal administration and 50% (4 of 8 infants) after oral administration. The total reflux time in minutes and percentages and the number of reflux episodes of pH < 4 decreased statistically significantly after both rectal and oral omeprazole administration. Rectal and oral administration of omeprazole resulted in similar serum exposure. CONCLUSIONS: A single rectal omeprazole dose (1 mg/kg) results in consistent increases in intraesophageal and gastric pH in infants with EA- or CDH-related GERD, similar to an oral dose. Considering the challenges with existing oral formulations, rectal omeprazole presents as an innovative, promising alternative for infants with pathological GERD. CLINICAL TRIAL REGISTER: ClinicalTrials.gov Identifier: NCT00226044.

Which factors affect limitation of pronation/supination after forearm fractures in children? A prospective multicentre study.

INTRODUCTION: Both-bone forearm fractures in children frequently result in a limitation of pronation/supination, which hinders daily activities. The purpose of this prospective multicentre study was to investigate which clinical factors are related to the limitation of pronation/supination in children with a both-bone forearm fracture. METHODS: In four Dutch hospitals, consecutive children (<16 years) who sustained a both-bone forearm fracture were included. Children were followed up for 6-9 months and data from questionnaires, physical examination and X-rays were collected. Univariate and multivariate logistic regression analyses were used to assess the relationship between limitation of pronation/supination (≥20°) and several clinical factors. RESULTS: A group of 410 children with both-bone forearm fractures were included, of which 10 children missed the final examination (follow-up rate of 97.6%). We found that a re-fracture (odds ratio (OR) 11.7, 95% confidence interval (CI) 1.2; 118.5), a fracture in the diaphysis (OR 3.3, 95% CI 1.4; 7.9) and less physiotherapy during follow-up (OR 0.90, 95% CI 0.82; 0.98) were independently associated with a limitation of pronation/supination of 20° or more. CONCLUSIONS: These findings imply that a re-fracture and a diaphyseal located fracture were associated independently of each other with a limitation of pronation/supination in children with a both-bone forearm fracture. Furthermore, in children with severe limitation extensive physiotherapy is associated with better functional outcome.

Re-displacement of stable distal both-bone forearm fractures in children: a randomised controlled multicentre trial.

INTRODUCTION: Displaced metaphyseal both-bone fractures of the distal forearm are generally reduced and stabilised by an above-elbow cast (AEC) with or without additional pinning. The purpose of this study was to find out if re-displacement of a reduced stable metaphyseal both-bone fracture of the distal forearm in a child could be prevented by stabilisation with Kirschner wires. METHODS: Consecutive children aged <16 years with a displaced metaphyseal both-bone fracture of the distal forearm (n = 128) that was stable after reduction were randomised to AEC with or without percutaneous fixation with Kirschner wires. The primary outcome was re-displacement of the fracture. RESULTS: A total of 67 children were allocated to fracture reduction and AEC and 61 to reduction of the fracture, fixation with Kirschner wires and AEC. The follow-up rate was 96% with a mean follow-up of 7.1 months. Fractures treated with additional pinning showed less re-displacement (8% vs. 45%), less limitation of pronation and supination (mean limitation 6.9 (± 9.4)° vs. 14.3 (± 13.6)°) but more complications (14 vs. 1). CONCLUSIONS: Pinning of apparent stable both-bone fractures of the distal forearm in children might reduce fracture re-displacement. The frequently seen complications of pinning might be reduced by a proper surgical technique.

Below-elbow cast for metaphyseal both-bone fractures of the distal forearm in children: a randomised multicentre study.

INTRODUCTION: Minimally displaced metaphyseal both-bone fractures of the distal forearm in children are often treated with an above-elbow cast (AEC). Treatment with a below-elbow cast (BEC) could give more comfort, but might lead to fracture displacement reducing pronation and supination. Because this has not been systematically investigated, we set up a randomised multicentre study. The purpose of this study was to find out whether BEC causes equal limitation of pronation and supination but with higher comfort level, compared with AEC. PATIENTS AND METHODS: In four hospitals, consecutive children aged<16 (mean 7.1) years with a minimally displaced metaphyseal both-bone fracture of the distal forearm were randomised to 4 weeks BEC (n=35) or 4 weeks AEC (n=31). Primary outcome was limitation of pronation and supination 6 months after initial trauma. The secondary outcomes were cast comfort, limitation of flexion/extension of wrist/elbow, complications, cosmetics, complaints, and radiological assessment. RESULTS: A group of 35 children received BEC and 31 children received AEC. All children attended for the final examination at a mean follow-up of 7.0 months (range 5.0-11.6 months). Limitation of pronation and supination 6 months after initial trauma showed no significant difference between the two groups [4.4° (± 5.8) for BEC and 5.8° (± 9.8) for AEC]. Children treated with BEC had significantly higher cast comfort on a visual analogue scale [5.6 (± 2.7) vs. 8.4 (± 1.4)] and needed significantly less help with dressing (8.2 days vs. 15.1 days). Six complications occurred in the BEC group and 14 in the AEC group. Other secondary outcomes were similar between the two groups. CONCLUSIONS: Children with minimally displaced metaphyseal both-bone fractures of the distal forearm should be treated with a below-elbow cast.

Identification of Familial Adenomatous Polyposis carriers among children with desmoid tumours.

OBJECTIVE: Desmoid tumours are rare mesenchymal tumours with unpredictable progression and high recurrence risk. They can occur sporadically or in association with Familial Adenomatous Polyposis (FAP), which is caused by germline APC mutations. The Wnt/ß-catenin pathway has a central role in the pathogenesis of desmoid tumours. These tumours can occur due to either a somatic CTNNB1 or APC mutation but can also be the first manifestation of FAP. Because germline APC analysis is not routinely performed in children with desmoid tumours, the diagnosis FAP may escape detection. The aim of this study is to form guidelines for the identification of possible APC germline mutation carriers among children with desmoid tumours, based on CTNNB1 mutation analysis and immunohistochemical analysis (IHC) for ß-catenin. PATIENTS AND METHODS: We performed IHC of ß-catenin and mutation analysis of CTNNB1 and APC in 18 paediatric desmoid tumours, diagnosed between 1990 and 2009 in the Erasmus MC, Rotterdam. RESULTS: In 11 tumours, IHC showed an abnormal nuclear ß-catenin accumulation. In this group a CTNNB1 mutation was detected in seven tumours. In two tumours with an abnormal nuclear ß-catenin accumulation and no CTNNB1 mutation, an APC mutation was identified, which appeared to be a germline mutation. CONCLUSIONS: Aberrant staining of ß-catenin in paediatric desmoids helps to identify children at risk for FAP. We recommend to screen paediatric desmoid tumours for nuclear localisation of ß-catenin and consequently for CTNNB1 mutations. For patients with nuclear ß-catenin expression and no CTNNB1 mutations, APC mutation analysis should be offered after genetic counselling.

Pediatric aggressive fibromatosis: a retrospective analysis of 13 patients and review of literature.

BACKGROUND: Aggressive fibromatosis (AF) is a soft tissue tumor and is rare in childhood, with high potential for local invasiveness and recurrence. General recommendations for the clinical management of pediatric patients with AF remain undetermined. METHODS: The authors retrospectively analyzed 13 children with AF who were diagnosed from 1987 until 2004 in the Erasmus MC-Sophia Children's Hospital, and a review of the pediatric literature was conducted. RESULTS: Two patients received preoperative chemotherapy with combined vincristine, actinomycin-D, and cyclophosphamide (VAC). All 13 patients underwent surgery. Three of six patients who underwent incomplete resection received adjuvant treatment, two patients received radiotherapy, and one patient received chemotherapy (VAC). The median follow-up was 3.9 years (range, 0.6-14.0 years). Three patients developed recurrent AF, including two recurrences after patients underwent incomplete resection without adjuvant treatment. Secondary resection was performed, which was incomplete in one patient who subsequently received chemotherapy (VAC). At the time of the current report, all 13 patients were in complete remission. Ten pediatric AF studies, including the current study, with a total of 187 patients were reviewed. Incomplete resection was the most important determinant for disease recurrence; in the authors' opinion, the role of adjuvant therapy needs to be studied further. CONCLUSIONS: Primary surgery with negative surgical margins was found to be the most successful primary treatment modality for children with AF. Positive margins after surgery indicated a high risk for disease recurrence. Multicenter, prospective (randomized) trials will be necessary to clarify the role of adjuvant treatment for patients with pediatric AF.

Strategy for management of newborns with cervical teratoma.

BACKGROUND: Cervical teratomas are extremely rare tumors with high perinatal mortality and morbidity rates. OBJECTIVE: To compare our experience and outcome in newborns with cervical teratoma with similar reports from the literature, in order to propose a structured approach. METHODS: A retrospective review of seven patients treated between 1986 and 2000 was performed. The results of these seven patients were compared with and added to a series of 44 well-documented patients retrieved from the literature. RESULTS: In four of the seven patients, the diagnosis was not suspected antenatally. Three of the patients survived, one died. In the other three, the diagnosis was made antenatally. Two were born using the ex-utero intrapartum treatment (EXIT) procedure, one by planned cesarean section. Only one of these three survived. Mortality in the total series of 51 patients was 33% overall, and 46% in the group in which the diagnosis had been made antenatally. Peri- and post-operative complications were reported in 27%. Although larger tumors caused polyhydramnios more frequently than smaller tumors, and were associated with more severe respiratory distress, the relationship between tumor volume at birth and final outcome could not be established. This makes difficult the identification of fetuses with a disastrous prognosis. CONCLUSION: Although mostly benign, cervical teratomas are still associated with high mortality rates. Timely antenatal diagnosis is indispensable in reducing morbidity and mortality caused by upper airway obstruction. A structured approach to the management of cervical teratoma is proposed.