11 research outputs found
Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients
Wilms tumour (WT) is the most common renal tumour in children. Most WT
patients respond to chemotherapy, but subsets of tumours develop resistance to
chemotherapeutic agents, which is a major obstacle in their successful treatment.
Multidrug resistance transporters play a crucial role in the development of resistance
in cancer due to the efflux of anticancer agents out of cells. The aim of this study was
to explore several human multidrug resistance transporters in 46 WT and 40 nonneoplastic
control tissues (normal kidney) from patients selected after chemotherapy
treatment SIOP 93â01, SIOP 2001. Our data showed that the majority of the studied
multidrug resistance transporters were downregulated or unchanged between
tumours and control tissues. However, BCRP1, MDR3 and MRP1 were upregulated in
tumours versus control tissues. MDR3 and MRP1 overexpression correlated with highrisk
tumours (SIOP classification) (p = 0.0022 and p < 0.0001, respectively) and the
time of disease-free survival was significantly shorter in patients with high transcript
levels of MDR3 (p = 0.0359). MDR3 and MRP1 play a role in drug resistance in WT
treatment, probably by alteration of an unspecific drug excretion system. Besides,
within the blastemal subtype, we observed patients with low MDR3 expression
were significantly associated with a better outcome than patients with high MDR3
expression. We could define two types of blastemal WT associated with different
disease outcomes, enabling the stratification of blastemal WT patients based on the
expression levels of the multidrug resistance transporter MDR3.Ministerio de EconomĂa y Competitividad PI1401466, RD06/0020/0059, PI1100018, CD06/00001Red Tematica de Investigacion Cooperativa en Cancer RD12/0036/0017UniĂłn Europea FP7-HEALTH- 2011-two-stage, Project ID 278742 EUROSARCInstituto de Salud Carlos III FIS PI13/0228
Outcome of Stage IV Completely Necrotic Wilms Tumour and Local Stage III Treated According to the SIOP 2001 Protocol
Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the
SIOP 2001 protocol, the SIOPâ Renal Tumour Study Group (SIOPâRTSG) has omitted radiotherapy
for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However,
for metastatic patients with local stage III, completely necrotic WT, the recommendations led to
ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with
metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or
not. Methods and materials: all metastatic patients with local stage III, completely necrotic WT after
6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included
in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year
event-free survival (EFS) and overall survival (OS) was analysed. Results: seven hundred and three
metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial
embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal
irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy.
Median follow-up was 6.6 years (range 1â151 months). Two of the 47 patients (4%) developed disease
recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease.
Both patients had received abdominal radiotherapy, one of them combined with lung irradiation.
Five-year EFS and OS were 95% and 95%, respectively. Conclusions: the outcome of patients with
stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that
abdominal irradiation in this patient category may not be of added value in first-line treatment,
consistent with the current recommendation in the SIOPâRTSG 2016 UMBRELLA protocol
Rationale for the treatment of children with CCSK in the UMBRELLA SIOP-RTSG 2016 protocol
The International Society of Paediatric Oncology-Renal Tumour Study Group (SIOP-RTSG) has developed a new protocol for the diagnosis, treatment, and follow-up monitoring of childhood renal tumours-the UMBRELLA SIOP-RTSG 2016 protocol (the UMBRELLA protocol). This protocol has been designed to continue international collaboration in the treatment of childhood renal tumours and will be implemented in over 50 different countries. Clear cell sarcoma of the kidney, which is a rare paediatric renal tumour that most commonly occurs in childre
HMGA2 overexpression predicts relapse susceptibility of blastemal Wilms tumor patients
Wilms tumor (WT) is an embryonal malignant neoplasm of the kidney that accounts for 6â7% of all childhood cancers. WT seems to derive from multipotent embryonic renal stem cells that have failed to differentiate properly. Since mechanisms underlying WT tumorigenesis remain largely unknown, the aim of this study was to explore the expression of embryonic stem cell (ESC) markers in samples of WT patients after chemotherapy treatment SIOP protocol, as the gene expression patterns of ESC are like those of most cancer cells. We found that expression of ESC markers is heterogeneous, and depends on histological WT components. Interestingly, among ESC markers, HMGA2 was expressed significantly stronger in the blastemal component than in the stromal and the normal kidney. Moreover, two subsets of patients of WT blastemal type were identified, depending on the expression levels of HMGA2. High HMGA2 expression levels were significantly associated with a higher proliferation rate (p=0.0345) and worse patient prognosis (p=0.0289). The expression of HMGA2 was a stage-independent factor of clinical outcome in blastemal WT patients. Our multivariate analyses demonstrated the association between LIN28BâLET7AâHMGA2 expression, and the positive correlation between HMGA2 and SLUG expression (p=0.0358) in blastemal WT components. In addition, patients with a poor prognosis and high HMGA2 expression presented high levels of MDR3 (multidrug resistance transporter). Our findings suggest that HMGA2 plays a prominent role in the pathogenesis of a subset of blastemal WT, strongly associated with relapse and resistance to chemotherapy.LHP and DJGD are supported by Red TemĂĄtica de InvestigaciĂłn Cooperativa en CĂĄncer (RD12/0036/0017). CS is supported by a contract from NicolĂĄs Monardes Program, ConsejerĂa de Salud, Junta de AndalucĂa. Research in Enrique de Alavaâs lab is supported by the Ministry of Economy and Competitiveness of Spain-FEDER (CIBERONC, PI1700464, RD06/0020/0059, FMGE) and the European Commission (FP7-HEALTH-2011-two-stage, Project ID 278742 EUROSARC). DJGD is a PhD researcher funded by the ConsejerĂa de Salud, Junta de AndalucĂa (PI-0197-2016). Research in Carmen SĂĄezâs lab is also supported by research grants from the Instituto de Salud Carlos III, FIS PI13/02282.Peer reviewe
Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients
Wilms tumour (WT) is the most common renal tumour in children. Most WT patients respond to chemotherapy, but subsets of tumours develop resistance to chemotherapeutic agents, which is a major obstacle in their successful treatment. Multidrug resistance transporters play a crucial role in the development of resistance in cancer due to the efflux of anticancer agents out of cells. The aim of this study was to explore several human multidrug resistance transporters in 46 WT and 40 non-neoplastic control tissues (normal kidney) from patients selected after chemotherapy treatment SIOP 93â01, SIOP 2001. Our data showed that the majority of the studied multidrug resistance transporters were downregulated or unchanged between tumours and control tissues. However, BCRP1, MDR3 and MRP1 were upregulated in tumours versus control tissues. MDR3 and MRP1 overexpression correlated with high-risk tumours (SIOP classification) (p = 0.0022 and p < 0.0001, respectively) and the time of disease-free survival was significantly shorter in patients with high transcript levels of MDR3 (p = 0.0359). MDR3 and MRP1 play a role in drug resistance in WT treatment, probably by alteration of an unspecific drug excretion system. Besides, within the blastemal subtype, we observed patients with low MDR3 expression were significantly associated with a better outcome than patients with high MDR3 expression. We could define two types of blastemal WT associated with different disease outcomes, enabling the stratification of blastemal WT patients based on the expression levels of the multidrug resistance transporter MDR3.LHP and DJGD are supported by Red TemĂĄtica de InvestigaciĂłn Cooperativa en CĂĄncer (RD12/0036/0017). CS was supported by a contract from NicolĂĄs Monardes Program, ConsejerĂa de Salud, Junta de AndalucĂa. Research in Enrique de Alavaâs lab is also supported by the Ministry of Economy and Competitiveness of Spain-FEDER (PI1401466, RD06/0020/0059, PI1100018, ISCIII postdoc grant CD06/00001), MarĂa GarcĂa-Estrada Foundation and the European Commission (FP7-HEALTH-2011-two-stage, Project ID 278742 EUROSARC). Research in Carmen SĂĄez lab is also supported by research grants from the Instituto de Salud Carlos III, FIS PI13/02282.Peer reviewe
Diagnostic MRI characteristics of pediatric clear cell sarcoma of the kidney and rhabdoid tumor of the kidney: A retrospective multi-center SIOP-RTSG Radiology panel study
Introduction: Clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK) are rare malignant pediatric renal tumors, both accounting for 1â5% of diagnoses. Within the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) protocols diagnostic invasive procedures to determine histology are discouraged. MRI has become the preferred imaging modality, however, non-invasive discrimination of CCSK and RTK remains challenging. Therefore, this study aims to identify diagnostic MRI-characteristics of CCSK and RTK, in the largest series of patients to date. Material and methods: Five SIOP-RTSG national review radiologists identified national diagnostic MRIs of histologically proven CCSKs and RTKs. Scan-protocols were based on MRI-guidelines following SIOP-RTSG protocols. Radiologists assessed their national cases using a validated case report form (CRF). Results: Retrospectively, 59 patients were identified (n = 38 CCSK, n = 21 RTK). CCSKs showed a high median volume (576 cm3, range 54â4414), which was lower for RTKs (290 cm3, range 20â761) (p = 0.006 *10-3). Fifty-two percent (11/21) of RTK-patients showed disease at other locations, predominantly the lungs and brain, compared to 8% of CCSK-patients (3/38). RTKs showed ill-defined margins (12/21, 57%) and infiltrative growth pattern (13/21, 62%). CCSKs appeared hyper-intense on T2-weighted imaging (27/38, 71%) with a characteristics band-like enhancement (13/38, 34%), whereas RTK cases often showed T2-weighted hypo-intensity (11/21, 52%). The overall mean ADC-value for CCSK was 1.11 * 10-3 mm2/s (range 0.57â2.07 *10-3 mm2/s), and 0.72 * 10-3 mm2/s (range 0.53â0.90 *10-3 mm2/s) for RTK. Conclusions: This retrospective study suggests a small size, T2-weighted hypo-intensity and an aggressive growth pattern may be characteristic for RTK. CCSK often showed a typical band-like enhancement pattern with relatively high ADC-values. Identified MRI-characteristics may be used in future studies focusing on validation and discrimination from especially WT, aiming for an early non-invasive diagnosis
Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric OncologyâRenal Tumor Study Group (SIOPâRTSG)ârelated retrospective descriptive study
Abstract Introduction Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric OncologyâRenal Tumor Study Group (SIOPâRTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. Methods This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), antiâprogrammed cell death 1 (PDâ(L)1) monoclonal antibodies, and immunotherapeutic regimens in advancedâstage and relapsed pediatric RCC. Results Of the 31 identified patients (0â18âyears) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiTâRCC) (21/31) and the remaining patients mainly presented with papillary or clearâcell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included monoâ or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. Conclusion This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies
Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30âyear SIOPâRTSG experience
BACKGROUND: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. METHODS: Clinical characteristics, treatments, and outcomes were analyzed for patients
with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study
Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death.
RESULTS: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44
months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease.
Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12
mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after
prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients
with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2%
(95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up
to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). CONCLUSIONS:
Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according
to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. Cancer 2021;127:628-
638. © 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society This is an open access article
under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
LAY SUMMARY:
âą WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with
an increased risk of developing Wilms tumor.
âą In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified
through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the
SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur.
âą Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols.
However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised
Outcome of SIOP patients with low- or intermediate-risk Wilms tumour relapsing after initial vincristine and actinomycin-D therapy only - the SIOP 93-01 and 2001 protocols.
Society of International Pediatric Oncology - Renal Tumor Study Group (SIOP-RTSG) treatment recommendations for relapsed Wilms tumour (WT) are stratified by the intensity of first-line treatment. To explore the evidence for the treatment of patients relapsing after vincristine and actinomycin-D (VA) treatment for primary WT, we retrospectively evaluated rescue treatment and survival of this patient group. We included 109 patients with relapse after VA therapy (no radiotherapy) for stage I-II primary low- or intermediate-risk WT from the SIOP 93-01 and SIOP 2001 studies. Univariate Cox regression analysis was performed to study the effect of relapse treatment intensity on event-free survival (EFS) and overall survival (OS). Relapse treatment intensity was classified into vincristine, actinomycin-D, and either doxorubicin or epirubicin (VAD), and more intensive therapies (ifosfamide/carboplatin/etoposide [ICE]/℠4 drugs/high-dose chemotherapy with haematopoietic stem cell transplantation [HD HSCT]). Relapse treatment regimens included either VAD, or cyclophosphamide/carboplatin/etoposide/doxorubicin (CyCED), or ICE backbones. Radiotherapy was administered in 62 patients and HD HSCT in 15 patients. Overall, 5-year EFS and OS after relapse were 72.3% (95% confidence interval [CI]: 64.0-81.6%) and 79.3% (95% CI: 71.5-88.0%), respectively. Patients treated with VAD did not fare worse when compared with patients treated with more intensive therapies (hazard ratio EFS: 0.611 [95% CI: 0.228-1.638] [p-value = 0.327] and hazard ratio OS: 0.438 [95% CI: 0.126-1.700] [p-value = 0.193]). Patients with relapsed WT after initial VA-only treatment showed no inferior EFS and OS when treated with VAD regimens compared with more intensive rescue regimens. A subset of patients relapsing after VA may benefit from less intensive rescue treatment than ICE/CyCED-based regimens and deserve to be pinpointed by identifying additional (molecular) prognostic factors in future 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 5yâOS of the total group was 70.5% (95% CI = 61.7%-80.6%) and 84.5% (95% CI = 77.5%-92.2%), respectively. Estimated 5yâOS 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