Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup.

In neuroblastoma, MYCN amplification and 11q-deletion are important, although incomplete, markers of high-risk disease. It is therefore relevant to characterize additional alterations that can function as prognostic and/or predictive markers. Using SNP-microarrays, a group of neuroblastoma patients showing amplification of one or multiple 12q loci was identified. Two loci containing CDK4 and MDM2 were commonly co-amplified, although amplification of either locus in the absence of the other was observed. Pharmacological inhibition of CDK4/6 with ribociclib or abemaciclib decreased proliferation in a broad set of neuroblastoma cell lines, including CDK4/MDM2-amplified, whereas MDM2 inhibition by Nutlin-3a was only effective in p53wild-type cells. Combined CDK4/MDM2 targeting had an additive effect in p53wild-type cell lines, while no or negative additive effect was observed in p53mutated cells. Most 12q-amplified primary tumors were of abdominal origin, including those of intrarenal origin initially suspected of being Wilms' tumor. An atypical metastatic pattern was also observed with low degree of bone marrow involvement, favoring other sites such as the lungs. Here we present detailed biological data of an aggressive neuroblastoma subgroup hallmarked by 12q amplification and atypical clinical presentation for which our in vitro studies indicate that CDK4 and/or MDM2 inhibition also could be beneficial.

Kostmann disease and other forms of severe congenital neutropenia.

Congenital neutropenia with autosomal recessive inheritance was first described by the Swedish paediatrician Rolf Kostmann who coined the term 'infantile genetic agranulocytosis'. The condition is now commonly referred to as Kostmann disease. These patients display a maturation arrest of the myelopoiesis in the bone marrow and reduced neutrophil numbers and suffer from recurrent, often life-threatening infections. The molecular mechanism underlying congenital neutropenia has been intensively investigated, and mutations in genes that impinge on programmed cell death have been identified. The present review provides an overview of these studies.

Characteristics and outcome of pediatric renal cell carcinoma patients registered in the International Society of Pediatric Oncology (SIOP) 93-01, 2001 and UK-IMPORT database: A report of the SIOP-Renal Tumor Study Group.

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93-01, 2001 and UK-IMPORT databases, were included. Event-free survival (EFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT-RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE-cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5-year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE-testing.

Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers.

Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, with somatic inactivation of the second allele occurring through 11p loss of heterozygosity. The time point of this second hit has remained unknown. We analyzed seven Wilms tumors from two patients with constitutional WT1 mutations by whole exome sequencing and genomic array. All tumors exhibited wild type WT1 loss through uniparental isodisomy. Each tumor had a unique genomic breakpoint in 11p, typically accompanied by a private activating mutation of CTNNB1. Hence, convergent evolution rather than field carcinogenesis underlies multifocal tumors in WT1 mutation carriers.

Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer.

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1-5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.

Doxorubicin-provoked increase of mitotic activity and concomitant drain of G0-pool in therapy-resistant BE(2)-C neuroblastoma.

In this study chemotherapy response in neuroblastoma (NB) was assessed for the first time in a transplantation model comprising non-malignant human embryonic microenvironment of pluripotent stem cell teratoma (PSCT) derived from diploid bona fide hESC. Two NB cell lines with known high-risk phenotypes; the multi-resistant BE(2)-C and the drug sensitive IMR-32, were transplanted to the PSCT model and the tumour growth was exposed to single or repeated treatments with doxorubicin, and thereafter evaluated for cell death, apoptosis, and proliferation. Dose dependent cytotoxic effects were observed, this way corroborating the experimental platform for this type of analysis. Notably, analysis of doxorubicin-resilient BE(2)-C growth in the PSCT model revealed an unexpected 1,5-fold increase in Ki67-index (p<0.05), indicating that non-cycling (G0) cells entered the cell cycle following the doxorubicin exposure. Support for this notion was obtained also in vitro. A pharmacologically relevant dose (1µM) resulted in a marked accumulation of Ki67 positive BE(2)-C cells (p<0.0001), as well as a >3-fold increase in active cell cycle (i.e. cells positive staining for PH3 together with incorporation of EdU) (p<0.01). Considering the clinical challenge for treating high-risk NB, the discovery of a therapy-provoked growth-stimulating effect in the multi-resistant and p53-mutated BE(2)-C cell line, but not in the drug-sensitive p53wt IMR-32 cell line, warrants further studies concerning generality and clinical significance of this new observation.

Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. METHODS: For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 µg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. FINDINGS: Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. INTERPRETATION: Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification. FUNDING: See Acknowledgments for funders.

Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.

Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.

Minimally invasive nephrectomy for Wilms tumors in children - data from SIOP 2001.

PURPOSE: To analyse the surgical and oncological outcome of minimally invasive surgery (MIS) for tumor nephrectomy in Wilms tumor (WT) patients. METHODS: WT patients from the SIOP 2001 trial, undergoing MIS for tumor nephrectomy were analyzed with regard to demographic characterization, surgical specifications, complications, and outcome. RESULTS: There were 24 children matching the inclusion criteria. Median age at operation was 40.35 months (14.3-65.4). All patients received preoperative chemotherapy. Median tumor volume was 177.5 ml at diagnosis (46.5-958) and 73.0 ml at surgery (3.8-776). There was one surgical complication (splenic injury), no intraoperative tumor rupture occurred. Abdominal stage was I in 14, II in 7, and III in 3 patients. Adequate lymph node sampling was performed in only 2 patients. One local relapse occurred. Event-free survival was 23/24, overall survival was 24/24, median follow up was 47 months (2-114). CONCLUSIONS: We present the largest series so far of minimally invasive nephrectomies for nephroblastoma based on a multinational trial. Treatment results were comparable to those of open surgery; however, experience of operating surgeons was generally high. Discipline of lymph node sampling was inadequate. Based on this analysis a prospective study on MIS in nephroblastoma is planned by the SIOP Renal Tumor Study Group.

Nephron sparing surgery (NSS) for unilateral wilms tumor (UWT): the SIOP 2001 experience.

BACKGROUND: Total nephrectomy (TN) remains the standard treatment of unilateral Wilms tumors (uWT). The SIOP WT-2001 protocol allowed Nephron Sparing Surgery (NSS) for polar or peripherally non-infiltrating tumors. AIM: Inventory of the current SIOP NSS-experience. PROCEDURES: 2,800 patients with a unilateral, localized or metastatic and an unequivocal surgical technique recorded were included. All had neo-adjuvant chemotherapy and delayed surgery. In 91 (3%) NSS was performed and in 2709 TN. Data was retrieved from the SIOP WT 2001 database. RESULTS: NSS group contained 65% stage I tumours and the TN group 48%. Tumor volume (at diagnosis and surgery) was significantly smaller in the NSS group. Within stage III, after NSS, 7/12 (58%) had positive margins (M +), 5 with tumor negative lymph nodes (LN-). After TN, 355/712 (55%) had M + , 182 were LN-. Treatment of M+ in the NSS group resulted in two conversions to TN (one combined with radiotherapy), three patients had radiotherapy only and in two patients local therapy, if given, was not recorded. After NSS, four recurrences occurred. For localized disease the 5-year overall (OS) and event free survival (EFS) in NSS group was 100 and 94.8 (95% CI:89.9-99.9), respectively, while OS and EFS in the TN group were 94.4 (95% CI: 93.2-95.5, log-rank test P = 0.06) and 86.5 (95% CI:85.0-88.1, log-rank test P = 0.06), respectively. CONCLUSIONS: NSS was only performed in 3% of patients with uWT. Despite excellent survival with few relapses, the gain of nephrons needs to be weighed against the risk to induce stage III with intensified therapy.

Experimental teratoma: at the crossroad of fetal- and onco-development.

Xenografting is the so far only available in vivo model for assessing pluripotency of human stem cells. This review describes known biological features of experimental teratoma from human pluripotent stem cells. We focus on the dual nature mimicking both normal and abnormal development, and propose this model system to be particularly interesting for investigations of the relationship between developmentally controlled differentiation and neoplasia of embryonic origin. In resemblance to the wide range of clinical teratomas, pluripotent stem cell (PSC) induced teratoma (PSCT) typically shows a mixture of developing tissues in randomly distributed compartments. The combined literature suggests that for teratomas derived from human diploid bona fide PSC the embryonic development in the separate tissue-niches can show a controlled differentiation into organoid patterns closely mimicking early development. In the experimental situation such PSCT human homologous in vivo tissue-niches have been shown to provide also matching microenvironment for a micrometastatic colonization and outgrowth of embryonic tumors transplanted directly from patients. Single or small clusters of normal and neoplastic cells can easily be visualized together in microscope-based imaging systems, enabling multi-parameter detection of in the scans of tissue slides/specimens.

Minimally-invasive treatment of early stage breast cancer: a feasibility study using radiofrequency ablation under local anesthesia.

The objective of this study was to assess efficacy and safety of percutaneous ultrasound (US) guided preferential radiofrequency ablation (PRFA) in early breast carcinoma under local anesthesia and to evaluate a new assessment protocol. Eighteen breast cancer patients were enrolled in order to receive PRFA treatment three weeks prior to resection. Pain assessment was performed using the visual analoge scale. Analysis of treatment success was performed using magnetic resonance imaging (MRI) as well as histological assays for hematoxylin & eosin (H&E) and cytokeratine 8 (CK8). In a subset of patients contrast enhanced ultrasound (CEUS) was performed before and after treatment. MRI showed no residual tumor growth in 100% (18/18) of cases. Complete tumor devitalization was indicated in 83% (15/18) of patients as judged by H&E staining and in 89% (16/18) as judged by immunostaining for CK8. In 100% (18/18) at least one histologic method showed devitalization in the entire tumor. Treatment was well tolerated. Pain experienced during the procedure was mild. US-guided PRFA of small breast carcinoma is feasible under local anesthesia. MRI and CK8 have proven valuable additions to the RF breast tumor ablation protocol. CEUS shows potential as a modality for radiological follow-up.

Tropism of the in situ growth from biopsies of childhood neuroectodermal tumors following transplantation into experimental teratoma.

Experimental teratoma induced from human pluripotent stem cells with normal karyotype can be described as a failed embryonic process and includes besides advanced organoid development also large elements of tissue with a prolonged occurrence of immature neural components. Such immature components, although benign, exhibit strong morphological resemblance with tumors of embryonic neuroectodermal origin. Here, we demonstrate that biopsy material from childhood tumors of neural embryonic origin transplanted to mature experimental teratoma can show an exclusive preference for matching tissue. Tumor specimens from five children with; Supratentorial primitive neuroectodermal tumor (sPNET); Pilocytic astrocytoma of the brainstem; Classic medulloblastoma; peripheral primitive neuroectodermal tumor (pPNET) or neuroblastoma (NB), respectively, were transplanted. Analysis of up to 120 sections of each tumor revealed an engraftment for three of the transplanted tumors: pPNET, sPNET, and NB, with a protruding growth from the latter two that were selected for detailed examination. The histology revealed a strict tropism with a non-random integration into what morphologically appeared as matched embryonic microenvironment recuperating the patient tumor histology. The findings suggest specific advantages over xenotransplantation and lead us to propose that transplantation to the human embryonic microenvironment in experimental teratoma can be a well-needed complement for preclinical in vivo studies of childhood neuroectodermal tumors.

Treatment of pulmonary metastases in children with stage IV nephroblastoma with risk-based use of pulmonary radiotherapy.

PURPOSE: The purpose of this study was to determine the outcome of children with nephroblastoma and pulmonary metastases (PM) treated according to International Society of Pediatric Oncology (SIOP) 93-01 recommendations using pulmonary radiotherapy (RT) in selected patients. PATIENTS AND METHODS: Patients (6 months to 18 years) were treated with preoperative chemotherapy consisting of 6 weeks of vincristine, dactinomycin, and epirubicin or doxorubicin. If pulmonary complete remission (CR) was not obtained, metastasectomy was considered. Patients in CR received three-drug postoperative chemotherapy, whereas patients not in CR were switched to a high-risk (HR) regimen with an assessment at week 11. If CR was not obtained, pulmonary RT was mandatory. RESULTS: Two hundred thirty-four of 1,770 patients had PM. Patients with PM were older (P < .001) and had larger tumor volumes compared with nonmetastatic patients (P < .001). Eighty-four percent of patients were in CR postoperatively, with 17% requiring metastasectomy. Thirty-five patients (16%) had multiple inoperable PM and required the HR protocol. Only 14% of patients received pulmonary RT during first-line treatment. For patients with PM, 5-year event-free survival rate was 73% (95% CI, 68% to 79%), and 5-year overall survival (OS) rate was 82% (95% CI, 77% to 88%). Five-year OS was similar for patients with local stage I and II disease (92% and 90%, respectively) but lower for patients with local stage III disease (68%; P < .001). Patients in CR after chemotherapy only and patients in CR after chemotherapy and metastasectomy had a better outcome than patients with multiple unresectable PM (5-year OS, 88%, 92%, and 48%, respectively; P < .001). CONCLUSION: Following the SIOP protocol, pulmonary RT can be omitted for a majority of patients with PM and results in a relatively good outcome.

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.

SIX1 protein expression selectively identifies blastemal elements in Wilms tumor.

BACKGROUND: Wilms tumor (WT) is the most common renal neoplasm in children. Histologically, most WTs consist of three tissue elements: blastema, epithelium, and stroma. Some cases also show diffuse or focal anaplastic features. Previous studies have shown that a predominance of blastemal cells in post-chemotherapy WT specimens is associated with a poor clinical course. However, there is currently no molecular marker for blastemal cells, and risk stratification for post-nephrectomy treatment is therefore often based on clinico-histological parameters alone. PROCEDURE: In the present study, three public gene expression microarray datasets, including 82 WTs and 8 normal fetal kidneys, were used to establish a consensus gene expression profile of WT. By bioinformatic analyses, 17 genes overexpressed in WT compared to fetal kidney were then selected for evaluation of their protein expression in WT cell lines and in the different histological components in paraffin-embedded WT tissue sections by immunofluorescence. RESULTS: Most of the evaluated proteins were expressed in all three common histological components. A prominent exception was SIX1, being expressed predominantly in blastemal elements in 24/25 pediatric cases containing blastema. Anaplastic elements exhibited highly variable SIX1-positivity. The SIX2 protein, known to be co-expressed with SIX1 during nephrogenesis, only exhibited blastemal-predominant expression in half of the SIX2 evaluated cases. CONCLUSIONS: Genes highly expressed in WT compared to fetal kidney are generally overexpressed in all of the three common WT tissue elements. An exception is the predominant expression of SIX1 in blastemal cells, hereby identifying this protein as a candidate marker for blastema.

Early events in xenograft development from the human embryonic stem cell line HS181--resemblance with an initial multiple epiblast formation.

Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at day 5, and characterized by the appearance of multiple sites of engraftment, with structures of single or pseudostratified columnar epithelium surrounding small cavities. The striking histological resemblance to developing embryonic ectoderm, and the formation of epiblast-like structures was supported by the expression of the markers OCT4, NANOG, SSEA-4 and KLF4, but a lack of REX1. The early neural marker NESTIN was uniformly expressed, while markers linked to gastrulation, such as BMP-4, NODAL or BRACHYURY were not detected. Thus, observations on day 5 indicated differentiation comparable to the most early transient cell populations in human post implantation development. Confirming and expanding on previous findings from HS181 xenografts, these early events were followed by an increasingly chaotic development, incorporated in the formation of a benign teratoma with complex embryonic components. In the mature HS181 teratomas not all types of organs/tissues were detected, indicating a restricted differentiation, and a lack of adequate spatial developmental cues during the further teratoma formation. Uniquely, a kinetic alignment of rare complex structures was made to human embryos at diagnosed gestation stages, showing minor kinetic deviations between HS181 teratoma and the human counterpart.

Nephroblastoma: does the decrease in tumor volume under preoperative chemotherapy predict the lymph nodes status at surgery?

BACKGROUND: Partial nephrectomy (NSS) for unilateral nephroblastoma may be beneficial, although in case of regional lymph node (LN) involvement, radiotherapy counteracts the functional benefit of NSS. The aim is to verify whether decrease of tumor volume under preoperative chemotherapy implies clearance of regional LN. PROCEDURE: SIOP 9301 (1993-2001) collected 1,450 localized nephroblastoma patients of whom 1,360 (93%) had sufficiently available data and were retrospectively reviewed. RESULTS: Histologic subtypes were classically distributed. Patients were divided in those with tumor positive LN (76, 5.5%) and those with tumor negative LN (1,284, 94.5%) at surgery. In the LN(+) group, the tumor volume changed from a median of 554 (318-772) to 192 (63-458) ml = 67% (27-88%) during preoperative ChT. In the LN(-) group-377 (200-612) to 130 (44-294) ml = 62% (28-83%) (NS). Increase of tumor volume was observed in 16% of patients with LN(+), and 11% of those with LN(-) (NS); ranges are interquartile. Initial tumor volume was significantly larger in the LN(+) patients (P = 0.00091) but not different (NS) at surgery; patients with initial tumor volume under 318 ml had the regional LN involved significantly less frequently (P = 0.00751). CONCLUSIONS: Change in tumor volume under preoperative chemotherapy is not a predictor for LN status at surgery, although larger initial volume is associated with a higher risk of LN invasion. The decrease of tumor volume is not a good criterion for the safety of NSS. The low rate of LN(+) (5.5%) indicates that this risk is low.

Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group.

BACKGROUND: Survival data of malignant rhabdoid tumour of the kidney (MRTK) registered in SIOP trials, advocating preoperative chemotherapy, are not available. AIM: To evaluate characteristics, response and survival of MRTK patients registered in recent SIOP protocols. METHODS: An evaluation of all MRTK patients treated from 1993 to 2005 (SIOP trials 93-01 and 2001) was performed. Data were obtained from study specific case record forms and entered centrally in a database. RESULTS: Hundred and seven patients were identified (57 male), with a median age at diagnosis of 13 months (interquartile range 6-27 months), and a median follow-up time of 60 months. Left and right kidneys were equally affected. Tumour stage distribution was stage I (6%), stage II (22%), stage III (43%), stage IV (22%) and stage V (3%). Stage IV patients included 17 with pulmonary metastasis (8 lung-only) and 12 with multiple organ metastases (bone, brain and liver). Primary surgery was the upfront treatment approach in 22/107 patients (21%), by which 19 patients reached a complete remission (CR). Median difference in tumour volume before and after preoperative chemotherapy was 69 ml (interquartile range: 4.5-158.0, P < 0.0001), indicating marked chemosensitivity. The 5-year event-free survival (EFS) of the total group was 22% (95% CI: 15-33) and overall survival 26% (95% CI: 18-37). Most events (86%) occurred within the first 2 years after diagnosis. Younger age at diagnosis was an important adverse prognostic factors for survival. In contrast, tumour volume at diagnosis, nor volume reduction was associated with outcome. CONCLUSION: MRTK has a poor outcome especially in young and advanced-stage disease patients. Neither tumour volume at diagnosis, nor pre-operative chemosensitivity are prognostic factors for survival.

Incidence and survival analyses in children with solid tumours diagnosed in Sweden between 1983 and 2007.

AIM: Solid tumours constitute 40% of childhood malignancies. The Swedish Childhood Cancer Registry is population based and includes all children with cancer reported from the six paediatric oncology centres in Sweden. The aim was to investigate incidence and survival. METHODS: We used the new WHO ICCC-3 for reclassification of the patients. Incidence and survival analyses were performed in the study population. RESULTS: Two thousand four hundred and eighty-seven children (<15 years) were diagnosed with solid tumours in Sweden between 1983 and 2007. The distribution of diagnoses was similar to that reported in other studies. The annual incidence was 65.3 per million children. The survival rates at 10 years of follow-up have improved significantly when comparing the two time periods, 1983-1995 and 1995-2007 (76 vs. 82%; p < 0.01). CONCLUSIONS: The mean annual incidence of solid tumours in children was 65.3/million and has been stable during the study period. Survival rates for solid tumours at 5, 10 and 20 years follow-up were 80, 79 and 76%, respectively.