Rhoikos Furtwängler

Population-based study of renal cell carcinoma in children in Germany, 1980-2005: more frequently localized tumors and underlying disorders compared with adult counterparts.

Childhood renal cell carcinomas (RCCs) differ histologically and biologically from their adult counterparts. The characteristics of RCC‐affected children and their tumors, the influence of treatment, and outcome have so far not been studied in a nonselected, population‐based cohort.

Characteristics and outcome of stage II and III non-anaplastic Wilms’ tumour treated according to the SIOP trial and study 93-01

PURPOSE To determine the prognosis of children with stage II and III of low or intermediate risk histology (SIOP classification) in unilateral localised Wilms tumour (WT) after neoadjuvant chemotherapy according to the trial and study of the International Society of Paediatric Oncology, SIOP 93-01. PATIENTS AND METHODS Patients with unilateral localised WT and stage II or III with low (LR) or intermediate risk (IR) histology between 6 months and 18 years of age, were selected from the total sample of patients registered in the SIOP 93-01 study between June 1993 and December 2001. All patients received 4 weeks of actinomycin-D/vincristine before surgery. Postoperative chemotherapy consisted of actinomycin-D, vincristine and epirubicin/doxorubicin for 27 weeks. Flank or whole abdomen irradiation was given for stage III. Event-free survival (EFS) and overall survival (OS) were analysed for various subgroups. RESULTS Of 1476 registered patients 594 (40%) met the inclusion criteria for this analysis. Four hundred and two (67%) had stage II disease and 563 (95%) had intermediate risk histology. Median tumour volume was 439 ml at diagnosis and 163 ml after preoperative chemotherapy. With a median follow-up of 8 years, 5-year EFS was 90% (95% confidence interval [95% CI]: 87-92%) and OS 95% (95% CI: 93-97%). Patients with stage III, blastemal type histology and a large volume at surgery had a worse outcome. CONCLUSION Treatment for stage II and III LR or IR WT is successful in a neoadjuvant setting as advised by the SIOP. Stage, tumour volume and blastemal type histology are the most important prognostic factors.

New prognostic markers revealed by evaluation of genes correlated with clinical parameters in Wilms tumors

Current treatment protocols for Wilms tumor achieve 90% cure rates, but relapse risk and side effects from therapy remain challenging. Over the last decade, numerous markers have been proposed for classification and/or prediction of outcome. However, cohort sizes were quite variable and often small. We now provide a large‐scale reassessment by real‐time RT‐PCR of 40 markers in 102 Wilms tumors followed by validation of potentially relevant markers in an independent set of 74 tumors. In the first data set, individual comparison with clinical data combined with adjustment for multiple testing and multivariate analysis revealed potentially relevant alteration of CA9, DKK1, EGR1, HEY2, MYC, MYCN, TERT, TOP2A, TRIM22, and VEGF expression in association with CTNNB1 mutation status, histological risk, response to chemotherapy, metastasis, relapse, or mortality. To further validate these data, potentially relevant genes for specific outcomes were reanalyzed in a second, independent tumor set. Here, univariate analysis confirmed the association of HEY2 with high‐risk tumors and of TRIM22 with mortality. Even where significance levels could not be reached, the direction and extent of differential expression were generally reproducible. Multivariate analysis verified a weak correlation of TOP2A expression with metastasis and of TRIM22 with fatal outcome. Although we could corroborate only some of the previously reported associations of expression changes with clinical parameters, our results indicate that real‐time RT‐PCR analysis can facilitate further classification of Wilms tumor and prediction of outcome to adjust treatment accordingly. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045‐2257/suppmat.

Clear cell sarcoma of the kidney: a review.

Clear cell sarcoma of the kidney (CCSK) is a rare renal tumour that is observed most often in children under 3years of age. Only a few large series of CCSK have been reported and patients with CCSK are often included among patients with other types of childhood renal tumours. The purpose of this paper is to review the published series and case reports of CCSK and to create an up-to-date overview of clinical and histological features, genetics, treatment, and outcome.

Clear cell sarcomas of the kidney registered on International Society of Pediatric Oncology (SIOP) 93-01 and SIOP 2001 protocols: a report of the SIOP Renal Tumour Study Group.

PURPOSE Clear Cell Sarcoma of the Kidney (CCSK) is a rare childhood renal tumour. Only a few homogeneously treated CCSK cohorts have been reported. This study aims to describe clinical characteristics and survival of CCSK patients treated according to recent International Society of Pediatric Oncology (SIOP) protocols. PATIENTS AND METHODS We analysed the prospectively collected data of patients with a histologically verified CCSK, entered onto SIOP 93-01/2001 trials. RESULTS A total of 191 CCSK patients (64% male) were analysed, with a median age at diagnosis of 2.6 years. Stage distribution for stages I, II, III and IV was 42%, 23%, 28% and 7%, respectively. Pre-operative chemotherapy was administered to 169/191 patients. All patients underwent total nephrectomy and 189/191 patients received post-operative chemotherapy. Radiotherapy was applied in 2/80 stage I, 33/44 stage II, 44/54 stage III and 6/13 stage IV patients. Five year event-free survival (EFS) and overall survival (OS) were 79% (95% confidence interval (CI): 73-85%) and 86% (95% CI: 80-92%) respectively. Stage IV disease and young age were significant adverse prognostic factors for event-free survival. Factors such as gender, tumour volume and type of initial treatment were not found to be prognostic for EFS and OS. CONCLUSION In this largest SIOP cohort described so far, overall outcome of CCSK is reasonable, although treatment of young and advanced-stage disease patients is challenging. As further intensification of treatment is hampered by direct and late toxicity, future directions should include the development of targeted therapy based on specific molecular aberrations of CCSK.

Surgical aspects in the treatment of patients with unilateral wilms tumor: a report from the SIOP 93-01/German Society of Pediatric Oncology and Hematology.

Objective:To assess surgical aspects in the treatment of children with unilateral Wilms tumor based on data from the Cooperative Tumor Study SIOP 93-01 of the German Society of Pediatric Hematology and Oncology. Summary Background Data:Although multiple international study trials exist for the treatment of nephroblastoma, the impact of surgical details and the outcome of the patients have not yet been described comparing different approaches of the trials. Methods:Treatment results of SIOP 93-01 of the German Society of Pediatric Hematology and Oncology were analyzed regarding frequencies of operations by surgeons and hospitals, surgical approaches, and operating subspecialties. Special attention was given to surgical complications, postoperative tumor stages and event-free survival. Results:Data sets from 757 of 1020 registered patients were received for evaluation. A unilateral Wilms tumor was observed in 512 of 757 children. Median follow-up was 4.8 years (1.2–10.7). Event-free survival rates were comparable for frequencies of operation by surgeons and hospitals, surgical approaches, and surgical specialties. Intraoperative tumor rupture rates were 12% in primarily operated patients (protocol violations) versus 3.2% in patients after preoperative chemotherapy. There were 7% intraoperative ruptures for hospitals and surgeons performing 1 operation per year, and 3% when more than 4 operations per year were carried out. Sampling of hilar lymph nodes was often incomplete for all surgical subspecialties. Conclusion:While the event-free survival for all groups is equal, there may be some long-term complications as a result of the more intensified therapy required for patients who suffer intraoperative ruptures. This will be defined only with longer term studies of late effects of the more intensified therapy. There is, however an increased rate of complications and ruptures associated with the use of midline laparotomy rather than a transverse or thoracoabdominal incision.

Development of Hypertension is Less Frequent after Bilateral Nephron Sparing Surgery for Bilateral Wilms Tumor in a Long-Term Survey

PURPOSE The option of nephron sparing surgery for unilateral Wilms tumor has been debated in the recent literature. This procedure is being used increasingly to preserve kidney tissue and function. However, nephron sparing surgery is feasible only for selected cases, and a higher local relapse rate has been observed. Moreover, a significant reduction of nephrons is associated with development of renal hypertension and progressive renal failure. We analyzed outcomes after bilateral partial nephrectomy and unilateral partial plus contralateral total nephrectomy in patients with bilateral Wilms tumor. MATERIALS AND METHODS We analyzed data from the Society of Pediatric Oncology and Hematology database on 22 patients with bilateral Wilms tumor. Kidney size was measured using volumetric analysis of magnetic resonance imaging. Patients were matched with children who had undergone magnetic resonance imaging of the abdomen for other malignancies. RESULTS Mean kidney volumes after unilateral partial plus total contralateral nephrectomy (66.9 cm(3)) were significantly greater than the reference kidneys (p = 0.028), whereas controls were equal to the bilateral partial nephrectomy group (49.7 cm(3), p = 0.959). Total kidney volume was significantly larger after bilateral partial nephrectomy (102.1 cm(3)) vs unilateral partial plus total contralateral nephrectomy (66.9 cm(3), p = 0.0338). Eight patients (66.7%) had renal hypertension after unilateral partial plus total contralateral nephrectomy but only 2 (20%) after bilateral partial nephrectomy (p = 0.043). Overall survival and relapse rates were equal between the groups and did not correlate with unfavorable histology. CONCLUSIONS Our findings suggest that patients with bilateral Wilms tumor benefit from bilateral nephron sparing surgery. Hypertension is less common after bilateral partial nephrectomy, and rates of local relapse or disease associated death are distributed equally between the groups.

Mutually exclusive BCOR internal tandem duplications and YWHAE‐NUTM2 fusions in clear cell sarcoma of kidney: not the full story

Internal tandem duplication within the BCOR gene sequence that encodes the PUFD domain, important in the formation of the non‐canonical or variant polycomb repressor complex 1 (v‐PRC1), was very recently described in 100% of 20 clear cell sarcomas of kidney (CCSKs). None of those 20 cases bore the YWHAE–NUTM2 transcript, previously described by us in CCSK, and which constitutes the only other recurrent genetic aberration observed in CCSK, prompting consideration that these mutations might be mutually exclusive in CCSK. We analysed a cohort of 159 CCSKs and can now not only confirm that there is indeed mutual exclusivity of these BCOR and YWHAE mutations, but also show that a substantial proportion (in this series 11.8%) of CCSKs bear neither mutation when tested by these assays, raising the possibility of distinct aetiologies for subsets of CCSK. Clinical differences observed between the subsets support this notion. As CCSK may show poor chemo‐responsiveness, and current treatment protocols mandate the use of doxorubicin with its associated side‐effects, advances in understanding the disease biology with a view to more targeted and personalized treatment is a pressing need. Copyright

Update on Relapses in Unilateral Nephroblastoma Registered in 3 Consecutive SIOP/GPOH Studies – A Report from the GPOH-Nephroblastoma Study Group

INTRODUCTION Treatment and stratification of progressive/relapsed unilateral nephroblastoma (PD) has significantly evolved over the last 20 years. Early PD (≤ 6 months), initial high risk histology, local stage III, multiple site PD and stage IV have been implemented as high risk classification factors and novel drugs have been introduced. PATIENTS AND METHODS We analysed all 251 patients having had a unilateral nephroblastoma (Stage I-IV) and progressive disease who had been treated according to SIOP9/GPO (n = 77), SIOP93-1/GPOH (n = 93) and SIOP2001/GPOH (n = 81) initially. RESULTS 3y-overall survival (OS) increased from 43% to 61% and 59% respectively (both p<0.01). 3y-OS for localized stage I-III rose from 43% to 65% and 68% respectively while only little improvement can be seen for initial stage IV patients with 43%, 53% and 44% respectively. Multivariate analysis confirmed high risk histology, local stage III, shorter time to PD, combined relapse as independent risk factors. 26 patients had received high-dose chemotherapy showing 64% 3y-OS compared to 54% for all non-transplanted (p=0.11). CONCLUSION Structuring the treatment of progressive nephroblastoma as well as introducing new drugs have improved the outcome significantly. However improvement is depending on the specific risk profile. Very high risk tumours are often resistant to conventional treatment, hence an international uniform treatment concept is needed to achieve conclusive results in this small group.

Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study

Background:Clear cell sarcoma of the kidney (CCSK) is an uncommon paediatric renal tumour. Relapses occur in about 15% of the patients. Since detailed clinical information on relapsed CCSK is scarce, the current study aims to describe outcome of patients with relapsed CCSK treated according to recent European protocols.Patients and methods:We analysed prospectively collected data of all CCSK patients who developed a relapse after complete remission at the end of primary treatment, entered onto SIOP and AIEOP trials between 1992 and 2012.Results:Thirty-seven of 237 CCSK patients (16%) treated according to SIOP and AIEOP protocols developed a relapse. Median time from initial diagnosis to relapse was 17 months (range, 5.5 months - 6.6 years). Thirt-five out of thirty-seven relapses (95%) were metastatic; the most common sites of relapse were the brain (n=13), lungs (n=7) and bone (n=5). Relapse treatment consisted of chemotherapy (n=30), surgery (n=19) and/or radiotherapy (n=18), followed by high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in 14 patients. Twenty-two out of thirty-seven patients (59%) achieved a second complete remission (CR); 15 of whom (68%) developed a second relapse. Five-year event-free survival (EFS) after relapse was 18% (95% CI: 4%–32%), and 5-year overall survival (OS) was 26% (95% CI: 10%–42%).Conclusions:In this largest series of relapsed CCSK patients ever described, overall outcome is poor. Most relapses are metastatic and brain relapses are more common than previously recognised. Intensive treatment aiming for local control, followed by high dose chemotherapy and ABMT, seems to be of benefit to enhance survival. Novel development of targeted therapy is urgently required.