Publications by authors named "Martine van Grotel"

31 Publications

Clinical and Molecular Characteristics and Outcome of Cystic Partially Differentiated Nephroblastoma and Cystic Nephroma: A Narrative Review of the Literature.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.

In children presenting with a predominantly cystic renal tumor, the most likely diagnoses include cystic partially differentiated nephroblastoma (CPDN) and cystic nephroma (CN). Both entities are rare and limited information on the clinical and molecular characteristics, treatment, and outcome is available since large cohort studies are lacking. We performed an extensive literature review, in which we identified 113 CPDN and 167 CN. The median age at presentation for CPDN and CN was 12 months (range: 3 weeks-4 years) and 16 months (prenatal diagnosis-16 years), respectively. No patients presented with metastatic disease. Bilateral disease occurred in both entities. Surgery was the main treatment for both. Two/113 CPDN patients and 26/167 CN patients had previous, concomitant, or subsequent other tumors. Unlike CPDN, CN was strongly associated with somatic ( = 27/29) and germline ( = 12/12) -mutations. Four CPDN patients and one CN patient relapsed. Death was reported in six/103 patients with CPDN and six/118 CN patients, none directly due to disease. In conclusion, children with CPDN and CN are young, do not present with metastases, and have an excellent outcome. Awareness of concomitant or subsequent tumors and genetic testing is important. International registration of cystic renal tumor cohorts is required to enable a better understanding of clinical and genetic characteristics.
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http://dx.doi.org/10.3390/cancers13050997DOI Listing
February 2021

Outcome of Stage IV Completely Necrotic Wilms Tumour and Local Stage III Treated According to the SIOP 2001 Protocol.

Cancers (Basel) 2021 Feb 26;13(5). Epub 2021 Feb 26.

Department of Paediatric Oncology, La Timone Children's Hospital, Assistance Publique Hôpitaux de Marseille, 13005 Marseille, France.

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 SIOP- Renal Tumour Study Group (SIOP-RTSG) 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 1-151 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 SIOP-RTSG 2016 UMBRELLA protocol.
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http://dx.doi.org/10.3390/cancers13050976DOI Listing
February 2021

The contribution of surgical clips for optimizing highly-conformal image-guided flank irradiation in pediatric renal tumors: A single center experience.

Radiother Oncol 2020 Dec 11;156:62-68. Epub 2020 Dec 11.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background And Aims: Two-opposing photon beams are considered standard of care for flank irradiation in pediatric patients with renal tumors. Nowadays, Image-Guided Radiotherapy (IGRT) techniques allow high-precision dose delivery to complex flank target volumes taking into account postoperative organ shifts and tumor bed motion. This study examines the contribution of a lateral and superior surgical clip on flank target volume delineation intended for IGRT.

Methods: Between 01-2015 and 09-2019, 30/162 newly-diagnosed pediatric patients with renal tumors, lateral/superior surgical clips (n = 30/30) and available 4D-CT-scans (n = 27/30), underwent postoperative flank irradiation. The lateral and superior clip, as respective markers for the lateral tumor extension and intrafraction motion, were analyzed. The positive and negative values depict the lateral/dorsal/cranial or the medial/ventral/caudal direction, respectively. Planning target volumes (PTV) were generated based on lateral clips (PTV), superior clips with 4D-CT technology (PTV), and both clips combined (PTV), and compared to an approach without clips (PTV).

Results: Indicated by clips, the mean lateral tumor bed extension along the posterior wall was 74° (range: 50°-93°), while mean intrafraction motion was +1.2 mm (range: -1.8/+4.8 mm), +0.6 mm (range: +0.6/+4.9 mm), -0.3 mm (range: -3.8/+0.7 mm) in craniocaudal, ventrodorsal, mediolateral direction, respectively. The median PTV (556 mL) was statistically different from the median PTV (454 mL, p = <0.01), median PTV (373 mL, p = <0.01) and median PTV (348 mL p = <0.01).

Conclusion: In pediatric patients with renal tumors, surgical clips at the lateral and superior border of the tumor bed can optimize flank target volume delineation and, consequently, reduce the normal tissue volume receiving high-dose irradiation when IGRT techniques are applied.
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http://dx.doi.org/10.1016/j.radonc.2020.12.010DOI Listing
December 2020

Risk factors associated with tinnitus in 2948 Dutch survivors of childhood cancer: a Dutch LATER questionnaire study.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa122. Epub 2020 Sep 15.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background: Tinnitus is a serious late effect of childhood cancer treatment. The aim of this study was to determine the occurrence and risk factors for tinnitus in a national cohort of childhood cancer survivors (CCS).

Methods: Data were collected within the national Dutch Childhood Oncology Group - Long-Term Effects after Childhood Cancer (DCOG-LATER) cohort by a self-reported health questionnaire among 5327 Dutch CCS treated between 1963 and 2002. Siblings ( = 1663) were invited to complete the same questionnaire. Relevant patient characteristics and treatment factors were obtained from the Dutch LATER database. The occurrence of tinnitus in survivors was compared to siblings. To study the effect of risk factors, multivariate logistic regression models were estimated.

Results: In total, 2948 CCS and 1055 siblings completed the tinnitus item. Tinnitus was reported in 9.5% of survivors and in 3.7% of siblings (odds ratio [OR] 3.0, 95% confidence interval [CI] 2.9-3.1). Risk factors associated with tinnitus in CCS were total cumulative dose cisplatin ≥400 mg/m (OR 2.4, 95% CI 1.4-4.0), age at diagnosis (≥10 years: OR 2.1, 95% CI 1.6-2.8), cranial irradiation/total body irradiation (TBI; OR 1.9, 95% CI 1.5-2.5), and neuro/ear, nose, throat (ENT) surgery (OR 1.8, 95% CI 1.1-2.9). Fifty-one percent of CCS with tinnitus had received treatment with either cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery.

Conclusions: Tinnitus in CCS was present nearly 3 times more often than in siblings. Awareness in CCS previously treated with cisplatin, cranial irradiation/TBI, and/or neuro/ENT surgery is warranted. As only half of affected CCS had a history of these treatments, it seems that other factors might be associated with tinnitus occurrence in this population.
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http://dx.doi.org/10.1093/noajnl/vdaa122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648591PMC
September 2020

The SIOP-Renal Tumour Study Group consensus statement on flank target volume delineation for highly conformal radiotherapy.

Lancet Child Adolesc Health 2020 11;4(11):846-852

Department of Radiation Oncology, Saarland University Hospital, Homburg, Germany.

For decades, radiotherapy with two opposing photon beams has been the standard technique used to cover the flank target volume in paediatric patients with renal tumours. Nowadays, many institutes are implementing advanced radiotherapy techniques that spare healthy tissue. To decrease the radiotherapy dose to healthy structures while preserving oncological efficacy, the conventional approach of flank irradiation has been adapted into a guideline for highly conformal flank target-volume delineation by paediatric radiation oncologists and representatives of the International Society of Paediatric Oncology's Renal Tumour Study Group (SIOP-RTSG) board during four live international consensus meetings. The consensus was refined by delineation exercises and videoconferences by ten collaborating paediatric radiation oncologists. The final guideline includes eight chronological steps to generate the tumour bed and clinical, internal, and planning target volumes, and it describes the optional use of surgical clips to optimise treatment planning. This guideline will be added into the radiotherapy guideline of the UMBRELLA SIOP-RTSG protocol for paediatric renal tumours to improve international consistency of highly conformal flank target-volume delineation.
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http://dx.doi.org/10.1016/S2352-4642(20)30183-8DOI Listing
November 2020

Executive functioning in 6 year old children exposed to chemotherapy in utero.

Early Hum Dev 2020 12 21;151:105198. Epub 2020 Sep 21.

Center for Gynecologic Oncology Amsterdam, Antoni van Leeuwenhoek - Netherlands, Cancer Institute, Amsterdam, the Netherlands; Department of Oncology, KU Leuven, Leuven, Belgium; Department of Obstetrics and Gynecology, Amsterdam UMC, University of Amsterdam, the Netherlands. Electronic address:

Background: Cancer treatment during pregnancy imposes a dilemma. Maternal advantage should be weighed against the potential impact of chemotherapy on child development. Recent studies in cancer survivors have shown that exposure to chemotherapeutic agents can have late adverse effects on cognitive functioning and executive functioning (EF). It is still unclear whether these late adverse effects also arise if a child is exposed to chemotherapy in utero.

Aim: To compare the development of executive functioning in 6 year old children prenatally exposed to chemotherapy (study group) and children born to healthy women after an uncomplicated pregnancy (control group).

Methods And Study Design: In a multicenter cohort study, the outcome on a measure of EF was compared. Study and control children were prospectively examined by means of the Behavior Rating Inventory of Executive Function (BRIEF), a health questionnaire and an intelligence test.

Results: In total 37 study children and 37 matched controls were included. In the study group, 11 children (29.7%) were exposed to chemotherapy alone, 22 children (59.5%) were exposed to chemotherapy and surgery and 4 children (10.8%) were exposed to chemotherapy, surgery and radiotherapy during pregnancy. All outcome scales of the BRIEF were within normal ranges. However, a significant between-group difference in emotional control was found.

Conclusion: Overall outcomes of EF were reassuring. However, children prenatally exposed to chemotherapy have weaker emotion regulation skills compared to their matched controls. The results underscore the need for long-term follow-up of these children.
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http://dx.doi.org/10.1016/j.earlhumdev.2020.105198DOI Listing
December 2020

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

Data Brief 2020 Oct 24;32:106227. Epub 2020 Aug 24.

Institute of Clinical Pharmacology, Immanuel Klinik Rüdersdorf, Brandenburg Medical School Theodor Fontane, Germany.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase () is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes ( and ) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.
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http://dx.doi.org/10.1016/j.dib.2020.106227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477761PMC
October 2020

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

Eur J Cancer 2020 10 6;138:212-224. Epub 2020 Sep 6.

Institute of Clinical Pharmacology, Immanuel Klinik Rüdersdorf, Brandenburg Medical School Theodor Fontane, Germany; Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University Medical Center, Ulm, Germany. Electronic address:

Background: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers.

Methods: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined.

Results: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors.

Conclusions: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.
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http://dx.doi.org/10.1016/j.ejca.2020.07.019DOI Listing
October 2020

Paediatric metanephric tumours: a clinicopathological and molecular characterisation.

Crit Rev Oncol Hematol 2020 Jun 24;150:102970. Epub 2020 Apr 24.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

To characterize metanephric tumours in children, we performed a literature review investigating paediatric metanephric adenomas (MA), metanephric stromal tumours (MST) and metanephric adenofibromas (MAF). Including two patients from our own institution (MA, MAF), 110 individual cases (41 MA, 20 MAF, 49 MST) were identified. Additionally, fifteen composite tumours were identified, with areas of MA/MAF and Wilms tumour (WT) or papillary carcinoma. No distinct clinical or radiological features could be defined. In pure metanephric tumours, histologically proven distant metastases were reported once (MA), relapse was reported once (MST) and one tumour-related death occurred (MST). Somatic BRAF-V600E mutations were tested in 15 cases, and identified in 3/6 MA, 3/3 MAF, and 6/6 MST. In our institution the MA harboured a somatic KRAS-G12R mutation. Overall, paediatric metanephric tumours are difficult to discriminate from other renal tumours at presentation, behave relatively benign, and the occurrence of composite tumours warrants analysis of underlying (genetic) pathways.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102970DOI Listing
June 2020

Clinical Characteristics of Invasive Fungal Infections in Pediatric Oncology Patients With Solid Tumors.

J Pediatr Hematol Oncol 2020 Feb 24. Epub 2020 Feb 24.

Princess Máxima Center for Pediatric Oncology.

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer. Studies on the clinical characteristics of IFI in children with solid tumors are limited. This Dutch retrospective cohort study reviewed the medical records of 61 children with solid tumors to analyze the clinical characteristics during their full treatment period. Seven IFI episodes were reported in 6/61 patients (10%), all diagnosed with intermediate-risk or high-risk Wilms tumor or neuroblastoma. Larger studies are necessary to reveal the determinants of IFI in this group of patients and the value of fungal prophylaxis.
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http://dx.doi.org/10.1097/MPH.0000000000001761DOI Listing
February 2020

Daily life participation in childhood chronic disease: a qualitative study.

Arch Dis Child 2020 05 20;105(5):463-469. Epub 2019 Nov 20.

Paediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: Opportunities to participate in daily life have improved considerably for children with chronic disease. Nevertheless, they still face challenges associated with their ever-present illness affecting every aspect of their lives. To best help these children, we aimed to assess the child's own perspective on participation and the main considerations that affect participation in a stable phase of disease.

Methods: Qualitative study design was applied. Semistructured, indepth interviews were conducted and analysed by a general inductive approach using constant comparison, coding and categorisation. Children 8-18 years old with a chronic disease were recruited from a cohort study involving cystic fibrosis, autoimmune disease and post-treatment paediatric cancer.

Results: 31 of the 56 (55%) invited patients participated. From the perspective of children with chronic disease, participation is considered more than merely engaging in activities; rather, they view having a sense of belonging, the ability to affect social interactions and the capacity to keep up with peers as key elements of full participation. Some children typically placed a higher priority on participation, whereas other children typically placed a higher priority on their current and/or future needs, both weighing the costs and benefits of their choices and using disclosure as a strategy.

Conclusions: Enabling full participation from the child's perspective will help realise patient-centred care, ultimately helping children self-manage their participation. Caregivers can stimulate this participation by evaluating with children how to achieve a sense of belonging, active involvement and a role within a peer group. This requires active collaboration between children, healthcare providers and caregivers.
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http://dx.doi.org/10.1136/archdischild-2019-318062DOI Listing
May 2020

PICU Admission Rates in Pediatric Cancer and Hematopoietic Stem Cell Transplant Patients Receiving High-flow Nasal Cannula Oxygen Therapy on the General Ward.

J Pediatr Hematol Oncol 2020 01;42(1):e1-e6

Department of Pediatric Intensive Care, Wilhelmina Children's Hospital, University Medical Center Utrecht.

The use of high-flow nasal cannula (HFNC) oxygen therapy is growing as an alternative to standard oxygen. However, its use in patients treated for malignancies, including hematopoietic stem cell transplantation (HSCT) patients, is controversial. In this retrospective cohort study, we assessed outcomes of pediatric cancer and HSCT patients (including nonmalignant indications) with acute hypoxemic respiratory failure treated with HFNC on the ward. Among 39 patients included in the study, 53 episodes of HFNC treatment were analyzed. Of these episodes, 18 (34%) failed and patients required subsequently pediatric intensive care unit (PICU) admission. A significant median higher C reactive protein (175 [range, 72 to 308] vs. 80 [13.5 to 187.8] mg/dL; P=0.006) and higher Bedside Pediatric Early Warning Score (PEWS) 1 to 4 hours after initiation of HFNC (10.1±0.8 vs. 7.1±0.4; P=0.001) was found in the failure group compared with the nonfailure group. Among the 18 patients admitted to PICU, 14 (78%) needed intubation. Five (28%) patients died during their PICU admission. In summary, one third of the pediatric cancer and HSCT patients receiving HFNC on the ward eventually required PICU admission of which 78% were intubated. C reactive protein and BedsidePEWS 1 to 4 hours after initiation of HFNC were significantly associated with the need for PICU admission. However, no firm conclusion can be drawn whether HFNC treatment should actually be initiated in the ward in this vulnerable patient population. Larger, prospective studies are needed to evaluate the most appropriate treatment and setting (PICU or general ward) for these patients.
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http://dx.doi.org/10.1097/MPH.0000000000001649DOI Listing
January 2020

Genetic variation of cisplatin-induced ototoxicity in non-cranial-irradiated pediatric patients using a candidate gene approach: The International PanCareLIFE Study.

Pharmacogenomics J 2020 04 31;20(2):294-305. Epub 2019 Oct 31.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Ototoxicity is a common side effect of platinum treatment and manifests as irreversible, high-frequency sensorineural hearing loss. Genetic association studies have suggested a role for SNPs in genes related to the disposition of cisplatin or deafness. In this study, 429 pediatric patients that were treated with cisplatin were genotyped for 10 candidate SNPs. Logistic regression analyses revealed that younger age at treatment (≤5 years vs >15 years: OR: 9.1; 95% CI: 3.8-21.5; P = 5.6 × 10) and higher cumulative dose of cisplatin (>450 vs ≤300 mg/m: OR: 2.4; 95% CI: 1.3-4.6; P = 0.007) confer a significant risk of ototoxicity. Of the SNPs investigated, none of them were significantly associated with an increase of ototoxicity. In the meta-analysis, ACYP2 rs1872328 (OR: 3.94; 95% CI: 1.04-14.03; P = 0.04) and SLC22A2 rs316019 (OR: 1.46; 95% CI: 1.07-2.00; P = 0.02) were associated with ototoxicity. In order to increase the understanding of the association between SNPs and ototoxicity, we propose a polygenic model, which takes into account multiple interacting genes of the cisplatin pathway that together confer an increased risk of ototoxicity.
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http://dx.doi.org/10.1038/s41397-019-0113-1DOI Listing
April 2020

Is radiotherapy required in first-line treatment of stage I diffuse anaplastic Wilms tumor? A report of SIOP-RTSG, AIEOP, JWiTS, and UKCCSG.

Pediatr Blood Cancer 2020 02 18;67(2):e28039. Epub 2019 Oct 18.

Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background: As a significant proportion of relapses occurred in the tumor bed or abdomen on patients with the fifth National Wilms Tumor Study stage I anaplastic Wilms tumor (WT), flank radiotherapy was added for stage I anaplastic WT in the subsequent study of the Children's Oncology Group (AREN0321). Preliminary results revealed reduction of relapse rate and improved survival. In cases treated with preoperative chemotherapy, such as in International Society of Pediatric Oncology (SIOP), the value of radiotherapy has never been studied. The aim of this observational study is to describe the pattern of recurrence and survival of patients with stage I diffuse anaplastic WT (DAWT) after induction chemotherapy.

Methods: Retrospective data analysis of the pattern of relapse and survival of all patients with stage I DAWT were included in recent SIOP, L'Associazone Italiana Ematologica Oncologia Pediatrica (AIEOP), Japan Wilms Tumor Study Group (JWiTS), United Kingdom Children's Cancer Study Group (UKCCSG) renal tumor registries. Postoperative treatment consisted of actinomycin D, vincristine, and doxorubicin for 28 weeks without local irradiation.

Results: One hundred nine cases with stage I DAWT were identified, of which 95 cases received preoperative chemotherapy. Of these, seven patients underwent preoperative true-cut biopsy. Sixteen of the 95 patients relapsed (17%), six locally, four at distant site, and six combined, and all treated according to SIOP 2001 relapse protocol, which resulted in a 5-year overall survival of 93%.

Conclusion: Despite 13% locoregional relapse rate, an excellent rescue rate was achieved after salvage treatment, in patients with stage I DAWT whose first-line treatment comprised three-drug chemotherapy (including doxorubicin), without flank irradiation. Therefore, we continue not to advocate the use of radiotherapy in first-line treatment after preoperative chemotherapy in stage I DAWT in the next SIOP protocol.
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http://dx.doi.org/10.1002/pbc.28039DOI Listing
February 2020

PICU mortality of children with cancer admitted to pediatric intensive care unit a systematic review and meta-analysis.

Crit Rev Oncol Hematol 2019 Oct 3;142:153-163. Epub 2019 Aug 3.

Department of Critical Care & Bioethics, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London, UK.

Background: Outcomes for children diagnosed with cancer have improved dramatically over the past 20 years. However, although 40% of pediatric cancer patients require at least one intensive care admission throughout their disease course, PICU outcomes and resource utilization by this population have not been rigorously studied in this specific group.

Methods: Using a systematic strategy, we searched Medline, Embase, and CINAHL databases for articles describing PICU mortality of pediatric cancer patients admitted to PICU. Two investigators independently applied eligibility criteria, assessed data quality, and extracted data. We pooled PICU mortality estimates using random-effects models and examined mortality trends over time using meta-regression models.

Results: Out of 1218 identified manuscripts, 31 studies were included covering 16,853 PICU admissions with the majority being retrospective in nature. Overall pooled weighted mortality was 27.8% (95% confidence interval (CI), 23.7-31.9%). Mortality decreased slightly over time when post-operative patients were excluded. The use of mechanical ventilation (odds ratio (OR): 18.49 [95% CI 13.79-24.78], p < 0.001), inotropic support (OR: 14.05 [95% CI 9.16-21.57], p < 0.001), or continuous renal replacement therapy (OR: 3.24 [95% CI 1.31-8.04], p = 0.01) was significantly associated with PICU mortality.

Conclusions: PICU mortality rates of pediatric cancer patients are far higher when compared to current mortality rates of the general PICU population. PICU mortality has remained relatively unchanged over the past decades, a slight decrease was only seen when post-operative patients were excluded. This compared infavorably with the improved mortality seen in adults with cancer admitted to ICU, where research-led improvements have led to the paradigm of unlimited, aggressive ICU management without any limitations on resuscitations status, for a time-limited trial.
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http://dx.doi.org/10.1016/j.critrevonc.2019.07.014DOI Listing
October 2019

Frequency and Determinants of Invasive Fungal Infections in Children With Solid and Hematologic Malignancies in a Nonallogeneic Stem Cell Transplantation Setting: A Narrative Review.

J Pediatr Hematol Oncol 2019 07;41(5):345-354

Princess Máxima Center for Pediatric Oncology.

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer. An overview of studies on the frequency and determinants of IFI in pediatric oncology patients in nonallogeneic stem cell transplantation settings is lacking. We performed a literature review in Pubmed and Embase, and included 13 prospective and 23 retrospective studies. The IFI frequency (proven/probable based on EORTC criteria) in nonallogeneic stem cell transplantation pediatric cancer patients ranged between 1.0% and 38.0%, with the highest frequencies reported in hematologic malignancies. The most common fungal species seen in the studied population was Candida, followed by Aspergillus. IFI are not well investigated in solid tumor patients. Significant recurrent determinants from univariate analysis were the diagnosis acute myeloid leukemia, (prolonged) neutropenia and an older age (above 10 years). The only 2 significant determinants based on multivariate analysis were the preceding number of days of broad-spectrum antibiotics (odds ratio, 1.05; 95% confidence interval, 1.02-1.07; P=0.0006) and the number of days of corticosteroids (odds ratio, 1.05; 95% confidence interval, 1.02-1.09; P=0.005), that were both based on a group of acute myeloid leukemia patients only. Future studies are necessary to determine the frequency and determinants of IFI in pediatric oncology including a representative number of solid tumor patients.
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http://dx.doi.org/10.1097/MPH.0000000000001468DOI Listing
July 2019

Tinnitus during and after childhood cancer: A systematic review.

Crit Rev Oncol Hematol 2019 Mar 11;135:1-7. Epub 2019 Jan 11.

Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands; Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.

Background: Tinnitus can occur during and after treatment for childhood cancer. Studies on the occurrence of, and risk factors for tinnitus during and after childhood cancer treatment are scarce. The aim of this study is to get insight into the frequency and risk factors of tinnitus during and after childhood cancer therapy, based on a review of all previously reported literature.

Materials And Methods: Systematic electronic literature searches that combined childhood cancer with different treatments and tinnitus terms were performed in the databases EMBASE, Medline, Cochrane, Web of Science, and Google Scholar. Studies were included based on reporting the frequency of tinnitus during and/or after childhood cancer, with 75% of participants being under the age of 25 at time of diagnosis, diagnosed with any type of childhood malignancy and treated with any type of chemotherapy and/or radiotherapy. A risk of bias assessment per research question was performed.

Results: Tinnitus incidence rates were reported up to 15.9 (95% CI 11.8-21.4) during therapy and up to 5.4 (95% CI 4.3-6.9) more than 5 years after diagnosis. The relative risk of developing tinnitus as compared to siblings during and after childhood cancer therapy were reported up to 17.2 (95% CI 11.8-25.0) during therapy and up to 3.7 (95% CI 2.7-5.1) more than 5 years after diagnosis. Independent risk factors for tinnitus development included high dose cranial radiation and platinum based chemotherapy.

Conclusion: The frequency of and risk to develop tinnitus seems to be higher in childhood cancer patients and survivors as compared to the normal population. Regular tinnitus screening before, during and after therapy with standardized questionnaires for early detection seems therefore reasonable in order to identify high-risk patients and eventually develop successful clinical preventive, supportive and management strategies.
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http://dx.doi.org/10.1016/j.critrevonc.2019.01.004DOI Listing
March 2019

Incidence, severity and outcome of central line related complications in pediatric oncology patients; A single center study.

J Pediatr Surg 2019 Sep 30;54(9):1894-1900. Epub 2018 Oct 30.

Department of Pediatric Surgical Oncology, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584, CS, Utrecht, The Netherlands. Electronic address:

Background: Central venous access device (CVAD)-related complications are associated with high morbidity rates. This study was performed to underline the importance of CVAD-complication prevention and treatment.

Methods: An audit of practice of CVAD-related complications in pediatric oncology patients receiving a CVAD between January 2015 and June 2017 was performed. CVADs included were totally implantable venous access ports (TIVAPs), Hickman-Broviac® (HB), nontunneled, and peripherally inserted CVADs.

Results: A total of 201 children, with 307 CVADs, were analyzed. The incidence rates per 1000 CVAD-days for the most common complications were 1.66 for malfunctions, and 1.51 for central line-associated bloodstream infections (CLABSIs). Of all CVADs inserted, 37.1% were removed owing to complications, of which 45.6% were owing to CLABSIs. In 42% of the CLABSIs, the CLABSI could be successfully cured with systemic antibiotic treatment only. Of all included patients, 5.0% were admitted to the intensive care unit owing to CLABSI. The HB-CVAD compared to the TIVAP was a risk factor for CVAD-related complications, CLABSIs and dislocations in particular.

Conclusions: The incidence of CVAD-related complications is high. Research on the prevention and treatment of CVAD-related complications in pediatric oncology patients should be a high priority for all health care professionals.

Type Of Study: Prognosis study (retrospective).

Level Of Evidence: Level II.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.10.054DOI Listing
September 2019

Evaluation of boost irradiation in patients with intermediate-risk stage III Wilms tumour with positive lymph nodes only: Results from the SIOP-WT-2001 Registry.

Pediatr Blood Cancer 2018 08 25;65(8):e27085. Epub 2018 Apr 25.

Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands.

Objective: To evaluate the value of radiotherapy boost omission in patients with intermediate-risk, stage III Wilms tumours (WT) with positive lymph nodes (LN).

Methods And Materials: All patients with intermediate-risk, stage III (LN positive) WT consecutively registered in the SIOP-WT-2001 study were included in this analysis. Endpoints were 5-year event-free survival (EFS), loco-regional control (LRC) and overall survival (OS).

Results: Between June 2001 and May 2015, 2,569 patients with stage I to III WT after preoperative chemotherapy were registered in the SIOP-WT-2001 study. Five hundred and twenty-three (20%) had stage III disease, of which 113 patients had stage III due to positive LN only. Of those, 101 (89%) received radiotherapy, 36 of which (36%) received, apart from flank irradiation, a boost dose to the LN positive area. Four patients (4%) did not receive any adjuvant radiotherapy. In eight patients information on radiotherapy was not available. With a median follow-up of 71 months, no difference in 5-year EFS (84% vs. 83%, P = 0.77) and LRC (96% vs. 97%, P = 0.91) was observed between patients receiving a radiotherapy boost and those without boost, respectively. Five-year OS, including salvage therapy, was excellent (boost vs. no boost: 97% vs. 95%, P = 0.58).

Conclusions: Outcome data demonstrate that omission of the radiotherapy boost to the loco-regional positive lymph nodes in patients with intermediate-risk, stage III WT who receive preoperative chemotherapy and postoperative flank irradiation (14.4 Gy) can be considered a safe approach for future SIOP protocols.
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http://dx.doi.org/10.1002/pbc.27085DOI Listing
August 2018

Very Long-term Sequelae After Nonradical Surgery Combined With Brachytherapy in an Infant With a Chemotherapy-resistant Rhabdomyosarcoma of the Tongue.

J Pediatr Hematol Oncol 2017 10;39(7):566-569

*Princess Máxima Center for Pediatric Oncology §Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands †Department of Pediatrics, Erasmus MC-Sophia Children's Hospital ‡Department of Radiotherapy, Erasmus MC ∥Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital ¶Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.

In 2003, van Grotel and colleagues reported an infant suffering a chemotherapy-resistant eRMS of the tongue, that was treated with subtotal tumor resection and brachytherapy after major medical ethical discussions. As no long-term sequelae of such a procedure have been described, perspectives were uncertain at that time. Now, after 15 years, we describe hypoplasia of the mandibula, compromised dentation, osteopenia, neuropsychological deficits, and moderate speech impairment as the most prominent late effects. Also, mandibular cysts and basal cell carcinomas in the irradiated area, eventually led to the diagnosis Gorlin syndrome.
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http://dx.doi.org/10.1097/MPH.0000000000000935DOI Listing
October 2017

Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors.

Pediatr Hematol Oncol 2017 Mar 7;34(2):120-129. Epub 2017 Jun 7.

a Department of Pediatric Oncology , Erasmus Medical Center - Sophia Children's Hospital , Rotterdam , the Netherlands.

Cisplatin and carboplatin are effective antineoplastic agents. They are also considered to be potentially highly ototoxic. To date, no long-term follow-up data from well-documented cohorts with substantial numbers of childhood cancer survivors (CCS) with platinum-related hearing loss are available. Therefore, in this study, we studied the reversibility of ototoxicity from discontinuation of treatment onwards in a national cohort of platinum-treated survivors with hearing loss at the end of cancer treatment. Of the 168 CCS with follow-up audiograms, we longitudinally evaluated the course of hearing function in 61 CCS who showed hearing impairment at discontinuation of treatment according to the Münster criteria (>20 dB at ≥4-8 kHz). Survivors were treated with platinum (median total cumulative dose cisplatin: 480 mg/m and median total cumulative dose carboplatin: 2520 mg/m). Median follow-up time was 5.5 years (range: 1.0-28.8 years). The results showed that none of these survivors revealed improvement of hearing function even till 28.8 years after discontinuation of treatment (grade <2b during long-term follow-up). An increase in hearing loss with two or three Münster degrees was observed in five of 61 survivors after 1.6-19.6 years. Overall, this indicates that ototoxicity after platinum treatment may be irreversible and that longitudinal clinical audiological monitoring and care is required in long-term survivors of childhood cancer on a large scale.
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http://dx.doi.org/10.1080/08880018.2017.1323985DOI Listing
March 2017

Demodicosis in Pediatric Cancer.

J Pediatr Hematol Oncol 2017 07;39(5):402-406

*Princess Máxima Center for Pediatric Oncology †Department of Dermatology, University Medical Center-Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Demodicosis is a rare condition that most often occurs in immunocompromised patients. We here describe a boy with T-cell non-Hodgkin lymphoma who developed a facial papulopustular eruption just before finalizing T-cell non-Hodgkin lymphoma treatment. He was treated for several infectious diseases without improvement. Demodicosis was considered and complete resolution was finally reached with topical metronidazole. We conducted a systematic search of all previously described cases of this condition in children with cancer, which showed that almost all demodicosis cases occurred in patients with lymphoreticular malignancies during maintenance chemotherapy. Hence, demodicosis may be seriously considered in antibiotic-resistant facial papulopustular eruptions in this group of patients to prevent delay of adequate treatment.
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http://dx.doi.org/10.1097/MPH.0000000000000836DOI Listing
July 2017

Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: A DCOG late-effects study.

Eur J Cancer 2016 12 4;69:77-85. Epub 2016 Nov 4.

Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Platinum-containing chemotherapeutics are efficacious for a variety of pediatric malignancies, nevertheless these drugs can induce ototoxicity. However, ototoxicity data on large cohorts of childhood cancer survivors (CCSs) who received platinum agents, but not cranial irradiation are scarce. Therefore, we have studied the frequency and determinants of ototoxicity in a cross-sectional multicenter CCS cohort, including the role of co-medication since it has been suggested that these play a role in ototoxicity. We have collected treatment data and audiograms from the medical records of CCS treated in the seven pediatric oncology centres in The Netherlands. Ototoxicity was defined as Münster grade ≥2b (>20 dB at ≥4-8 kHz). Four-hundred-fifty-one CCS who received platinum agents, but not cranial irradiation (median age at diagnosis: 4.9 years, range: 0.01-19 years) were included. The overall frequency of ototoxicity was 42%. Ototoxicity was observed in 45% of the cisplatin-treated CCS, in 17% of the carboplatin-treated CCS and in 75% of the CCS that had received both agents. Multivariate analysis showed that younger age at diagnosis (odds ratio [OR]: 0.6, 95% confidence interval [CI]: 0.5-0.6 per 5 years increase); higher total cumulative dose cisplatin (OR: 1.2, 95% CI: 1.2-1.5 per 100 mg/m increase); and co-treatment with furosemide (OR: 2.3, 95% CI: 1.4-3.9) were associated with ototoxicity. We conclude that treatment with (higher total cumulative dose of) cisplatin, young age and furosemide co-medication independently are associated with an increased risk of ototoxicity in CCS. Future prospective studies are necessary to confirm the additive risk of co-medication on the development of ototoxicity.
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http://dx.doi.org/10.1016/j.ejca.2016.09.023DOI Listing
December 2016

A neonate with a unique non-Down syndrome transient proliferative megakaryoblastic disease.

Pediatr Blood Cancer 2017 03 26;64(3). Epub 2016 Sep 26.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Transient myeloproliferative disorder (TMD) is a leukemia type that occurs typically in newborns. In Down syndrome, TMD is referred to as transient abnormal myelopoiesis (TAM). Recently, transientness has also been reported in acute myeloid leukemia patients with germline trisomy 21 mosaicism, and even in cases with somatic trisomy 21, with or without GATA1 mutations. TMD cases without trisomy 21 are rare, and recurrent genetic aberrations that aid in clinical decision-making are scarcely described. We describe here a TMD patient without trisomy 21 or GATA1 mutation in whom single-nucleotide polymorphism analysis of leukemic blasts revealed a novel combined submicroscopic deletion (5q31.1-5q31.3 and 8q23.2q24).
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http://dx.doi.org/10.1002/pbc.26230DOI Listing
March 2017

Distant metastatic spread of molecularly proven infantile fibrosarcoma of the chest in a 2-month-old girl: case report and review of literature.

J Pediatr Hematol Oncol 2014 Apr;36(3):231-3

Departments of *Pediatric Oncology ‡Pathology, Great Ormond Street Hospital for Children NHS Trust §Unit of Molecular Hematology and Cancer Biology, Institute of Child Health, University College London, London, UK †Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

Infantile fibrosarcoma (IFS) is a malignant neoplasm, arising in children younger than 2 years of age and with a hallmark chromosomal translocation t(12;15)(p13;q26) encoding an ETV6-NTRK3 fusion oncoprotein. A review of the world literature found no reported cases of molecularly proven IFS with distant metastatic spread at presentation. We report the case of a 2-month-old infant girl presenting with a chest wall primary IFS bearing and expressing the ETV6-NTRK3 fusion, who had several pulmonary metastatic deposits at diagnosis. She achieved complete remission with chemotherapy and surgery. To our knowledge, this is the first reported case of molecularly proven IFS with distant metastatic spread.
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http://dx.doi.org/10.1097/MPH.0000000000000055DOI Listing
April 2014

CD34 expression is associated with poor survival in pediatric T-cell acute lymphoblastic leukemia.

Pediatr Blood Cancer 2008 Dec;51(6):737-40

Department of Pediatric Oncology/Hematology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Children with T-lineage acute lymphoblastic leukemia (T-ALL) have an inferior outcome with combination chemotherapy compared to B-lineage ALL, and still about 30% of the patients relapse within the first 2 years following diagnosis. As CD34 has been related with poor outcome in ALL in general, we investigated the prognostic significance of the stem cell marker CD34, as well as the association of CD34 positivity with the expression of several multidrug resistance (MDR) genes.

Procedure: In this retrospective study, we investigated the prognostic significance of the expression of the early T-cell differentiation marker CD34 and the expression of MDR genes in relation to outcome in a cohort of 72 newly diagnosed pediatric T-ALL patients.

Results: CD34 expression was related to a poor 5-year disease-free-survival and a poor 5-year overall survival. Using the Cox proportional hazard model, CD34 expression predicted for increased risk for relapse and death. Expression of CD34 was associated with elevated MDR1 and MRP1 mRNA expression levels. For the entire T-ALL cohort, these expression levels of MDR1 or MRP1 did not independently predict for poor outcome.

Conclusions: We conclude that CD34-positive T-ALL has a relatively poor survival that is not explained by the mRNA expression levels of MDR1, LRP, or MRP1.
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http://dx.doi.org/10.1002/pbc.21707DOI Listing
December 2008

The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia.

Blood 2008 May 25;111(9):4668-80. Epub 2008 Feb 25.

Department of Pediatric Oncology/Hematology, Erasmus Medical Center Sophia Children's Hospital, Rotterdam, The Netherlands.

T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression-based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest.
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http://dx.doi.org/10.1182/blood-2007-09-111872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2343598PMC
May 2008

High relapse rate in children with non-advanced nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL or nodular paragranuloma) treated with chemotherapy only.

Leuk Lymphoma 2006 Aug;47(8):1504-10

Department of Pediatric Oncology/Hematology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare variant of Hodgkin's lymphoma (HL) in children. Since specific immunohistochemical staining has become available, NLPHL can be separated from classical Hodgkin's lymphoma (cHL) more accurately. Scarce information is available about pediatric NLPHL treated with chemotherapy only. Therefore, clinical characteristics, treatment, response and outcome of seven pediatric NLPHL patients, median age 9.2 years (range 7.5 - 14.2 years), diagnosed between 1986 - 2003 among 58 HL patients, uniformly treated in a single center with chemotherapy only, were evaluated. The median follow-up time was 4.2 years (range 2.1 - 10.2 years). NLPHL patients were stage I (n = 5), II (n = 2), whereas cHL, median age 11.4 years (range 3.3 - 15.9 years), were stage I (n = 8), II (n = 17), III (n = 9), IV (n = 1). Upfront treatment of NLPHL patients consisted of six courses of epirubicin, bleomycin, vinblastine and dacarbazine (EBVD) without radiotherapy, whereas cHL patients received six courses of EBVD (n = 14) or 4 - 6 courses of EBVD/MOPP (mitoxin, oncovin, procarbazine, prednison; n = 21). Chemotherapy was used as primary treatment thereby aiming to avoid radiotherapy with potential serious side effects to growing jaws and thyroid. All seven patients reached complete remission (CR). Four patients relapsed, of which three locally. These three were salvaged with second-line chemotherapy without radiation therapy (RT) and are in second CR. One patient relapsing with stage III disease was salvaged by EBVD/MOPP followed by autologous BMT and is also in second CR for 36 months. The event-free survival (EFS) is 43% and overall survival (OS) 100%. This study shows that apart from histology, immunohistochemistry (ICH) is required for diagnosing NLPHL. Moreover, it illustrates that although cure of pediatric NLPHL is feasible with chemotherapy only, high dosages of cytotoxic drugs are necessary as salvage treatment in a relatively high proportion of patients after relapse.
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http://dx.doi.org/10.1080/10428190600573291DOI Listing
August 2006

The outcome of molecular-cytogenetic subgroups in pediatric T-cell acute lymphoblastic leukemia: a retrospective study of patients treated according to DCOG or COALL protocols.

Haematologica 2006 Sep;91(9):1212-21

Department of Pediatric Oncology/Hematology, room Sp2456, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands.

Background And Objectives: Subgroups of T-cell acute lymphoblastic leukemia (T-ALL), defined according to recurrent cytogenetic aberrations, may have different prognoses. The aim of this study was to determine the prognostic relevance of molecular-cytogenetic abnormalities in pediatric patients using quantitative real-time polymerase chain reaction and fluorescence in situ hybridization.

Design And Methods: The patients were assigned to TAL1, HOX11/TLX1, HOX11L2/TLX3, or CALM-AF10 subgroups. The cytogenetic subgroups were characterized in relation to immunophenotype and the expression of aberrantly expressed transcription factors.

Results: In our cohort study, CALM-AF10 was associated with an immature immunophenotype and poor outcome (p=0.005). HOX11L2 was associated with both immunophenotypically immature cases as well as cases committed to the gammadelta-lineage. HOX11L2 was significantly associated with poor outcome (p=0.01), independently of the expression of CD1 or the presence of NOTCH1 mutations. TAL1 abnormalities were associated with alphabeta-lineage commitment, and tended to be associated with a good outcome. Cells in HOX11 cases resembled early CD1-positive cortical thymocytes without expression of Cytbeta and TCR molecules. In relation to the expression of early T-cell transcription factors, high TAL1 levels were found in immunophenotypically-advanced cases, whereas high LYL1 levels were found in immature subgroups.

Interpretation And Conclusions: The reported outcomes for HOX11L2-rearranged T-ALL cases are conflicting; the prognostic impact may depend on the therapy given. In our cohort, this cytogenetic aberration was associated with a poor outcome. Our data on CALM-AF10 rearranged T-ALL, albeit based on only three patients, suggest that this type of leukemia is associated with a poor outcome.
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September 2006

The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia.

Blood 2006 Nov 27;108(10):3520-9. Epub 2006 Jul 27.

Erasmus MC/Sophia Children's Hospital, Department of Pediatric Oncology/Hematology, 3000 CB Rotterdam, The Netherlands.

To identify new cytogenetic abnormalities associated with leukemogenesis or disease outcome, T-cell acute lymphoblastic leukemia (T-ALL) patient samples were analyzed by means of the array-comparative genome hybridization technique (array-CGH). Here, we report the identification of a new recurrent and cryptic deletion on chromosome 11 (del(11)(p12p13)) in about 4% (6/138) of pediatric T-ALL patients. Detailed molecular-cytogenetic analysis revealed that this deletion activates the LMO2 oncogene in 4 of 6 del(11)(p12p13)-positive T-ALL patients, in the same manner as in patients with an LMO2 translocation (9/138). The LMO2 activation mechanism of this deletion is loss of a negative regulatory region upstream of LMO2, causing activation of the proximal LMO2 promoter. LMO2 rearrangements, including this del(11)(p12p13) and t(11;14) (p13;q11) or t(7;11)(q35;p13), were found in the absence of other recurrent cytogenetic abnormalities involving HOX11L2, HOX11, CALM-AF10, TAL1, MLL, or MYC. LMO2 abnormalities represent about 9% (13/138) of pediatric T-ALL cases and are more frequent in pediatric T-ALL than appreciated until now.
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http://dx.doi.org/10.1182/blood-2006-04-019927DOI Listing
November 2006