An organoid biobank for childhood kidney cancers that captures disease and tissue heterogeneity.

Kidney tumours are among the most common solid tumours in children, comprising distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. Paediatric kidney tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug sensitivities. Using single cell RNA-sequencing and high resolution 3D imaging, we further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like cells. Our organoid biobank captures the heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterised models for basic cancer research, drug-screening and personalised medicine.

Dramatic bone remodeling following larotrectinib administration for bone metastasis in a patient with TRK fusion congenital mesoblastic nephroma.

Mesoblastic nephroma is the most frequent renal tumor in newborns and young infants, and the cellular type is characterized by an ETV6-NTRK fusion, which constitutively activates the tropomyosin-related kinase (TRK) signaling pathway. Larotrectinib is a highly selective TRK inhibitor with activity in adult and pediatric patients who have TRK fusions. We present a rare case of a patient with mesoblastic nephroma metastatic to bone who had a dramatic response to larotrectinib.

Congenital mesoblastic nephroma rich from mitosis after in vitro fertilization: a case report.

Recently, various childhood tumors such as leukemia, neuroblastoma, hepatoblastoma, retinoblastoma, and central nervous system tumors in patients born after assisted conception have been reported. Although involvement of in vitro fertilization in the tumor pathogenesis was not established, the likely effect of assisted reproductive technology has been increasingly considered in these tumors in the last decade. Congenital mesoblastic nephroma is the most common renal tumor of infancy younger than 6 months associated with an overall good prognosis. The cellular variant of congenital mesoblastic nephroma, which occurs primarily in infants older than 3 months, confers a less favorable prognosis. We present a case of an atypical congenital mesoblastic nephroma with cellular elements in a 2-month-old infant who was born after in vitro fertilization. To our knowledge, this is the second congenital mesoblastic nephroma case and the first one with cellular variant reported to date in the English literature after a pregnancy induced by an assisted reproductive technology.

Results of the SIOP 93-01/GPOH trial and study for the treatment of patients with unilateral nonmetastatic Wilms Tumor.

BACKGROUND: The treatment of Wilms Tumor is integrated into clinical trials since the 1970's. In contrast to the National Wilms Tumor Study Group (NWTSG) the SIOP trials and studies largely focus on the issue of preoperative therapy to facilitate surgery of a shrunken tumor and to treat metastasis as early as possible. PATIENTS AND METHODS: In the SIOP 93-01/GPOH trial and study 1 020 patients with a newly diagnosed renal tumor were registered. 847 of them had a histological proven Wilms Tumor, of whom 637 were unilateral localized, and 173 tumors had an other histology [40 congenital mesoblastic nephroma (CMN), 51 clear cell sarcoma (CCSK), 24 rhabdoid tumor (RTK) and 58 other tumors]. Preoperative chemotherapy in benign tumors was given to 1.3 % of the patients. The main objective of the trial was the randomized question, if the postoperative two drug chemotherapy for stage I in intermediate risk or anaplasia can be reduced from conventional 3 courses to an experimental 1 course without loss of efficacy. RESULTS: 519 patients with unilateral nonmetastatic Wilms did receive preoperative chemotherapy. The histology in this group of patients was of intermediate risk in 469 (90 %) patients, 14 (3 %) tumors were low risk and 36 (7 %) high risk. The stage distribution of the tumors was stage I in 315 (61 %), stage II N- in 126 (24 %), stage II N+ in 25 (5 %) and stage III in 36 (7 %) patients. In 17 (3 %) patients the tumor stage remained unclear. Tumor volume was measured in 487 patients before and in 402 after preoperative chemotherapy. The median tumor volume did shrink from 353 to 126 ml. The amount of volume reduction depends on the histological subtype. The event free survival (EFS) after 5 years was 91 % for all patients with unilateral Wilms tumor without distant metastasis. Randomisation was done in 43.7 % for stage I patients and there was no difference in EFS for both treatment arms (90 versus 91 %). The EFS is identical for patients with stage I and II N- (0.92), as well as for stage II N+ and III (0.82). The tumor volume after chemotherapy is a prognostic factor for intermediate risk tumors with the exception of epithelial and stromal predominant tumors. These two subtypes often present as large tumors, they do not shrink during preoperative chemotherapy but they still have an excellent prognosis. On the other hand the prognosis of patients with blastemal predominant subtype after preoperative chemotherapy is worse than in any other patient group of intermediate risk tumors. There are less blastemal predominant tumors compared to primary surgery, but they are chemotherapeutic resistant selected by the preoperative chemotherapy. CONCLUSION: Patients with unilateral Wilms tumor without metastasis have an excellent prognosis. The post-operative chemotherapy in stage I can be reduced to 4 weeks without worsening treatment outcome. The reduction of the tumor volume could be identified as a helpful marker for stratification of post-operative treatment. Post-chemotherapy blastemal predominant subtype of Wilms tumor has to be classified as high risk tumor. Focal anaplasia has a better prognosis than diffuse anaplasia and will be classified as intermediate risk tumor.

Use of sarcoma-based chemotherapy in a case of congenital mesoblastic nephroma with liver metastases.

Congenital mesoblastic nephroma was originally considered to be a benign neoplasm. A more aggressive cellular form, however, that has a close relationship to congenital fibrosarcoma, is widely described. Previous reported sites of metastases are the lungs, heart, brain, and bone. We describe a patient with isolated metastasis to liver and review the management, together with evidence that it may be more appropriate to use a vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) regimen rather than Wilm's tumor-based regimens in those cases for which chemotherapy is indicated.

Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy.

BACKGROUND: Recently, the ETV6-NTRK3 gene fusion has been identified in both infantile fibrosarcoma and cellular mesoblastic nephroma. For both these tumors standard curative treatment has been primarily surgical with wide local excision. This has frequently involved radical and even mutilating surgery. PROCEDURE: This report discusses three infants with congenital tumors, two congenital fibrosarcomas, and one atypical congenital mesoblastic nephroma, not easily amenable to surgical intervention. RESULTS: All three were treated with pre-operative chemotherapy with excellent responses negating the need for amputation in two patients. In each patient, the ETV6-NTRK3 gene fusion was identified by reverse transcriptase-polymerase chain reaction (RT-PCR) in the tumor specimens. CONCLUSIONS: Our findings suggest that the ETV6-NTRK3 gene fusion may underlie the distinctive biological properties of these tumors and may also indicate tumor chemosensitivity. In this group of patients pre-operative chemotherapy may abrogate the need for morbid surgical procedures.

Complete response of recurrent cellular congenital mesoblastic nephroma to chemotherapy.

Congenital mesoblastic nephroma (CMN) is usually cured by surgery. The sensitivity of this tumor to chemotherapy is unknown. The recent description of a t(12;15)(p13;q25) chromosomal translocation in both cellular CMN and congenital infantile fibrosarcoma suggests that these entities have a common pathogenesis, and that cellular CMN might respond to chemotherapy like congenital infantile fibrosarcoma does. The authors describe three patients with recurrent cellular CMN who showed a complete response to chemotherapy. Based on these patients and a review of the literature, the authors suggest that chemotherapy be considered as a part of the therapy for recurrent or unresectable cellular CMN.

SIOP treatment guidelines for renal tumours in small infants: fact or fantasy?

AIMS: Since as far back as 1980, SIOP (Société Internationale d>>Oncologie Pédiatrique) have advocated primary nephrectomy (PN) only for unilateral renal tumours in patients > tumour (WT). Fourteen of the 25 patients (56%) were treated with PN, including four patients with CMN. In group B there was one patient (2%) with CMN and 40 patients with WT. Thirteen of the patients (31%) were treated with PN. A total of 15 patients were treated before 1980 and 26 after 1980. Eight of 15 (53%) patients were treated with PN before 1980 and 21/26 (81%) were pre-treated after 1980, according to the protocol. CONCLUSION: Despite the SIOP recommendations, only 56% of patients

Preoperative chemotherapy for mesoblastic nephroma.

A neonate with extensive stage III mesoblastic nephroma was confirmed at operation to have a tumor that was too infiltrative and too advanced for primary excision. The abdomen was closed after multiple biopsies. Vincristine (1.1 mg/m2) was given intravenously once a week for a total of eight doses. Repeat CT scan confirmed shrinkage of the tumor and a nephrectomy could be performed safely and the tumor removed at the second laparotomy. CT scan repeated 1 year later showed no recurrence. This case illustrates the effective use of a single drug pre-excision chemotherapy which allowed a nephrectomy for extensive stage III mesoblastic nephroma to be carried out safely.

[Successful therapy of local recurrence of congenital mesoblastic nephroma]. / Erfolgreiche Therapie eines lokalen Rezidivs bei Congenitalem Mesoblastischem Nephrom (CMN).

A 3 1/2 month old girl was found to have a large abdominal tumor originating in the upper pole of the right kidney. At laparotomy the tumor had infiltrated the perirenal fat, the right lobe of the liver and the diaphragm. Partial nephrectomy was performed and the tumor was completely resected. However, an adequate safety margin could not be achieved. Histology showed a congenital mesoblastic nephroma of the cellular subtype. Postoperatively no chemotherapy was considered necessary. 11 months after diagnosis the patient had an extensive local recurrence with infiltration of the perirenal fat, mesenterium and colon. Complete resection could not be achieved and the tumor was classified as stage III. There was a striking morphological change from spindle cells in the initial tumor to malignant round cells in the relapse specimen. The patient was treated with Vincristine, Actinomycin-D and Adriblastin. Radiotherapy was not given. 38 months after relapse the patient is free of disease and developing normally. Our patient obviously had an aggressive variant of CMN. The significance of the potentially aggressive variant of CMN, atypical mesoblastic nephroma, is discussed and possibilities are suggested for management.