Direct correlation of MR-DWI and histopathology of Wilms' tumours through a patient-specific 3D-printed cutting guide.

OBJECTIVES: The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) discourages invasive procedures to determine the histology of paediatric renal neoplasms at diagnosis. Therefore, the histological subtype of Wilms' tumours (WT) is unknown at the start of neoadjuvant chemotherapy. MR-DWI shows potential value as a non-invasive biomarker through apparent diffusion coefficients (ADCs). This study aimed to describe MR characteristics and ADC values of paediatric renal tumours to differentiate subtypes. MATERIALS AND METHODS: Children with a renal tumour undergoing surgery within the SIOP-RTSG 2016-UMBRELLA protocol were prospectively included between May 2021 and 2023. In the case of a total nephrectomy, a patient-specific cutting guide based on the neoadjuvant MR was 3D-printed, allowing a correlation between imaging and histopathology. Whole-tumour volumes and ADC values were statistically compared with the Mann-Whitney U-test. Direct correlation on the microscopic slide level was analysed through mixed model analysis. RESULTS: Fifty-nine lesions of 54 patients (58% male, median age 3.0 years (range 0-17.7 years)) were included. Forty-four lesions involved a WT. Stromal type WT showed the lowest median decrease in volume after neoadjuvant chemotherapy (48.1 cm3, range 561.5-(+)332.7 cm3, p = 0.035). On a microscopic slide level (n = 240 slides) after direct correlation through the cutting guide, stromal areas showed a significantly higher median ADC value compared to epithelial and blastemal foci (p < 0.001). With a cut-off value of 1.195 * 10-3 mm2/s, sensitivity, and specificity were 95.2% (95% confidence interval 87.6-98.4%) and 90.5% (95% confidence interval 68.2-98.3%), respectively. CONCLUSION: Correlation between histopathology and MR-DWI through a patient-specific 3D-printed cutting guide resulted in significant discrimination of stromal type WT from epithelial and blastemal subtypes. CLINICAL RELEVANCE STATEMENT: Stromal Wilms' tumours could be discriminated from epithelial- and blastemal lesions based on high apparent diffusion coefficient values and limited decrease in volume after neoadjuvant chemotherapy. This may aid in future decision-making, especially concerning discrimination between low- and high-risk neoplasms. KEY POINTS: MR-DWI shows potential value as a non-invasive biomarker in paediatric renal tumours. The patient-specific cutting guide leads to a correlation between apparent diffusion coefficient values and Wilms' tumour subtype. Stromal areas could be discriminated from epithelial and blastemal foci in Wilms' tumours based on apparent diffusion coefficient values.

Diagnostic magnetic resonance imaging characteristics of congenital mesoblastic nephroma: a retrospective multi-center International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) radiology panel study.

BACKGROUND: Congenital mesoblastic nephroma is the most common solid renal tumor in neonates. Therefore, patients <3 months of age are advised to undergo upfront nephrectomy, whereas invasive procedures at diagnosis in patients ≥3 months of age are discouraged by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Nevertheless, discriminating congenital mesoblastic nephroma, especially from the more common Wilms tumor, solely based on imaging remains difficult. Recently, magnetic resonance imaging (MRI) has become the preferred modality. Studies focusing on MRI characteristics of congenital mesoblastic nephroma are limited. OBJECTIVE: This study aims to identify diagnostic MRI characteristics of congenital mesoblastic nephroma in the largest series of patients to date. MATERIALS AND METHODS: In this retrospective multicenter study, five SIOP-RTSG national review radiologists identified 52 diagnostic MRIs of histologically proven congenital mesoblastic nephromas. MRI was performed following SIOP-RTSG protocols, while radiologists assessed their national cases using a validated case report form. RESULTS: Patients (24/52 classic, 11/52 cellular, and 15/52 mixed type congenital mesoblastic nephroma, 2/52 unknown) had a median age of 1 month (range 1 day-3 months). Classic type congenital mesoblastic nephroma appeared homogeneous with a lack of hemorrhage, necrosis and/or cysts, showing a concentric ring sign in 14 (58.3%) patients. Cellular and mixed type congenital mesoblastic nephroma appeared more heterogeneous and were larger (311.6 and 174.2 cm3, respectively, versus 41.0 cm3 for the classic type (P<0.001)). All cases were predominantly T2-weighted isointense and T1-weighted hypointense, and mean overall apparent diffusion coefficient values ranged from 1.05-1.10×10-3 mm2/s. CONCLUSION: This retrospective international collaborative study showed classic type congenital mesoblastic nephroma predominantly presented as a homogeneous T2-weighted isointense mass with a typical concentric ring sign, whereas the cellular type appeared more heterogeneous. Future studies may use identified MRI characteristic of congenital mesoblastic nephroma for validation and for exploring the discriminative non-invasive value of MRI, especially from Wilms tumor.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy.

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. Since novel and improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 24 tumors (10 pre- and 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated by natural killer (NK), T and B cells, and immunosuppressive myeloid populations. NK cells show reduced cytotoxicity and T cells have a dysfunctional profile. Interaction analysis reveals a vast immunoregulatory network and identifies NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduces neuroblastoma growth, with complete responses (CR) in vivo. Moreover, addition of TIGIT+PD-L1 blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative analysis provides promising targets and a rationale for immunotherapeutic combination strategies.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Primary extrarenal rhabdoid tumour of the liver: a case report and literature review.

Background: Extrarenal rhabdoid tumours (ERT) are highly aggressive tumours that are poorly responsive to standard cytotoxic chemotherapy and are associated with a grim prognosis. Primary ERT of the liver are most commonly observed in early childhood and exceptionally rare later in life. Case presentation: We report the case of a 16-year-old male patient, presenting with flu-like symptoms after his second COVIDvaccination. During the work-up, a large solid liver lesion was incidentally discovered upon abdominal ultrasound examination. Pathological examination rendered the diagnosis of primary ERT of the liver, characterized by the loss of expression of INI-1 protein, encoded by the SMARCB1 gene. We summarized and discuss the existing literature by reviewing 53 pediatric and 6 adult cases, including the histological features treatment and outcomes of primary hepatic ERT. Conclusion: Primary ERT of the liver are usually not associated with specific signs or symptoms, making the diagnosis very challenging. As ERT are associated with a high metastatic rate, delayed diagnoses lead to increased mortality, as complete resection is not possible in advanced-stage cases. Therefore, early diagnoses, enabling complete resection of the tumour are crucial to improve patient outcomes. Of interest, primary ERT of the liver, is associated with biallelic loss of the SMARCB1 (SWI/ SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1) gene, a potential target for cancer therapeutics. This is, to our knowledge, the first case of a hepatic rhabdoid tumour treated with liver transplantation.