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Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite-motif-containing-28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93-01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case - either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc-binding clusters of the RING, B-box-2, and PHD domains or the central coiled-coil region. TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Neoplasias Renais/patologia , Bancos de Espécimes Biológicos , Tumor de Wilms/metabolismo , Rim/patologia , Mutação em Linhagem Germinativa , Suscetibilidade a Doenças/patologia , Proteína 28 com Motivo Tripartido/genéticaRESUMO
Non-invasive differentiation of paediatric kidney tumours is particularly important in the SIOP-RTSG protocols, which recommend pre-operative chemotherapy without histological confirmation. The identification of clinical and tumour-related parameters may enhance diagnostic accuracy. Age, metastases, and tumour volume (TV) were retrospectively analysed in 3306 patients enrolled in SIOP/GPOH 9, 93-01, and 2001 including Wilms tumour (WT), congenital mesoblastic nephroma (CMN), clear cell sarcoma (CCSK), malignant rhabdoid tumour of the kidney (MRTK), and renal cell carcinoma (RCC). WT was diagnosed in 2927 (88.5%) patients followed by CMN 138 (4.2%), CCSK 126 (3.8%), MRTK 58 (1.8%) and RCC 57 (1.7%). CMN, the most common localized tumour (71.6%) in patients younger than 3 months of age, was diagnosed earliest and RCC the latest (median age [months]: 0 and 154, respectively) both associated with significantly smaller TV (median TV [mL]: 67.2 and 45.0, respectively). RCC occurred in >14% of patients older than 120 months or older than 84 months with TV <100 mL. Receiver operating characteristic analyses discriminated WT from CMN, RCC and MRTK regarding age (AUC = 0.976, 0.929 and 0.791) and TV (AUC = 0.768, 0.813 and 0.622). MRTK had the highest risk of metastasis (37.9%) despite young age, whereas the risk of metastasis increased significantly with age in WT. Age and TV at diagnosis can differentiate WT from CMN and RCC. MRTK must be considered for metastatic tumours at young age. Identification of CCSK without histology remains challenging. Combined with MRI-characteristics, including diffusion-weighted imaging, and radiomics and liquid biopsies in the future, our approach allows optimization of biopsy recommendations and prevention of misdiagnosis-based neoadjuvant treatment.
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Carcinoma de Células Renais , Neoplasias Renais , Nefroma Mesoblástico , Tumor Rabdoide , Tumor de Wilms , Humanos , Criança , Lactente , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Estudos Retrospectivos , Neoplasias Renais/patologia , Tumor de Wilms/diagnóstico , Tumor de Wilms/patologia , Nefroma Mesoblástico/congênito , Nefroma Mesoblástico/patologia , Nefroma Mesoblástico/cirurgia , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/patologiaRESUMO
BACKGROUND: Among patients with nephroblastoma, those with bilateral disease are a unique population where maximising tumour control must be balanced with preserving renal parenchyma. METHODS: The SIOP 2001 protocol recommended surgery after neoadjuvant cycle(s) of Dactinomycin and Vincristine (AV) with response-adapted intensification, if needed. Adjuvant treatment was given based on the lesion with the worst histology. RESULTS: Three hundred and twenty seven patients with stage V disease were evaluable: 174 had bilateral Wilms tumour (BWT), 101 unilateral WT and contralateral nephroblastomatosis (NB) and 52 bilateral nephroblastomatosis. In these three groups, the estimated 5y-EFS was 76.1%, 84.6%, and 74.9%, respectively. AV chemotherapy alone was the successful chemotherapy for 58.7% of all the patients and 65.6% of the non-metastatic patients. Among the 174 patients with BWT, 149 (88.2%) had at least one nephron-sparing surgery. Twenty of 61 bilateral stage I patients were treated with four-week AV postoperatively achieving 94.4% 5y-EFS. At last follow-up, 87% of patients had normal renal function. CONCLUSIONS: This study demonstrates that AV without anthracyclines is sufficient to achieve NSS and good survival in the majority of patients. For patients with bilateral stage I WT and intermediate risk histology, only four weeks adjuvant AV seems to be sufficient. CLINICAL TRIAL REGISTRATION: NCT00047138.
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OBJECTIVE: This study aimed to identify parameters that allow the estimation of tumor-infiltrated lymph nodes (LN) after pretreatment for unilateral Wilms tumor (WT). SUMMARY BACKGROUND DATA: Complete tumor resection with removal of regional LN is always necessary. Positive LNs require local irradiation influencing benefits in case of NSS in long-term follow-up. Clinical and tumor-related data available at the time of surgery in combination with intraoperative findings (IAF) were used to estimate the LN status during surgery. METHODS: Altogether, 2115 patients with unilateral WT were prospectively enrolled in SIOP-93-01 / GPOH and SIOP-2001 / GPOH over a period of 30 years (1993-2023). LN infiltration by tumor was calculated for age, sex, metastases at diagnosis, tumor volume (TV), TV shrinkage, and intraoperative findings (IAF) using logistic regression models. RESULTS: Age ≥48 months (P<0.001, OR 2.17, CI 1.57 - 3.00), TV at diagnosis ≥300 (P<0.001, OR 3.72, CI 2.37 - 5.85), metastasis at diagnosis (P<0.001, OR 6.21, CI 4.47 - 8.62) and IAF (>1: P<0.001, OR 3.54, CI 2.13 - 5.88) correlated with positive LNs. TV shrinkage was not predictive of positive LN. Three flow charts were developed based on age, TV at diagnosis, metastasis, and IAF. These flowcharts defined risks between 0% and 41.5% for LN infiltration by tumor. CONCLUSIONS: The combination of age, TV at diagnosis, and metastasis with IAF allows the estimation of the frequency of positive LNs, which may help surgeons deciding about NSS.
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BACKGROUND: Completely necrotic Wilms tumor (CN-WT) following preoperative chemotherapy has been regarded as low-risk WT since the International Society of Paediatric Oncology (SIOP) 93-01 study, and patients have been treated with reduced postoperative therapy. The aim of the study was to evaluate whether the omission of adjuvant chemotherapy in patients with localized CN-WT stage I and radiotherapy in stage III was safe. PATIENTS AND METHODS: The retrospective observational study of outcomes of patients diagnosed with localized CN-WT on central pathology review and treated according to the SIOP 93-01 and SIOP-WT-2001 protocols (1993-2022). RESULTS: There were 125 patients with localized CN-WT: 90 with stage I, 10 with stage II, and 25 with stage III. Sixty-two of 125 (49.6%) patients had a discrepant diagnosis and/or staging between the institutional pathologist and central pathology review. In the group of 90 patients with stage I, postoperative chemotherapy was not given to 41 (46%) patients, whereas 49 patients received postoperative chemotherapy-in the latter group, two patients relapsed, and one of them died. One stage I and one stage II patient developed chemotherapy-induced toxicity and died. Nineteen of 25 patients with stage III received no flank radiotherapy. No stage III patient relapsed or died. The overall 5-year event-free survival (EFS) estimate for the entire cohort (stages I-III) was 96.8% [95% confidence interval, CI: 93.6%-99.6%] and the overall survival (OS) was 97.6% [95% CI: 95.0-100%]. The EFS and OS were 97% and 98%, respectively, for stage I, and 100% for stage III. CONCLUSION: Omission of postoperative chemotherapy for patients with CN-WT stage I, and radiotherapy for stage III is safe. Rapid central pathology review is required to assign appropriate treatment and avoid treatment-related side effects.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Lactente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Estadiamento de Neoplasias , Resultado do Tratamento , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/radioterapia , Estudos RetrospectivosRESUMO
BACKGROUND: This study analyzes the RSV season 2021/2022 in a referral children's hospital, compares the epidemiology and illness severity with RSV-infected inpatients from 2016 to 2020 and audits the adherence to our internal therapy standard for RSV bronchiolitis. MATERIAL AND METHODS: Inpatients with rtPCR-confirmed RSV infection (Jan. 2016 to Jan. 2022). RESULTS: The audit comprises 306 RSV inpatients, on average 50 hospitalizations per year; in 03/2020, a rapid RSV Season-Offset was observed. In the winter season 2020/2021, no patient with RSV was hospitalized. Beginning in July, we noticed a rapid increase of RSV-admissions (most cases in Sept./Oct, duration until Dec. 2021; n=53). In 2021-2022, a significant larger share needed PICU admission (9.4% vs 3.2%, p=0.040). Adherence to the internal guidance was low; only 11.8% (n=36) of all patients received supportive treatment without inhalative or systemic medications, 37% of all patients received antibiotics. CONCLUSIONS: This audit confirms the strong impact of public preventive measures directed against SARS-CoV-2 transmission on RSV epidemiology. Few weeks after easing public COVID-19 restrictions (summer 2021), RSV inpatient cases rapidly increased, lasting until Dec. 2021. The audit of bronchiolitis management revealed surprisingly low adherence to the internal guidance, despite a face-to-face educational session with the attending pediatricians in Oct. 2021. Low adherence resulted in an unnecessary exposure of RSV patients to systemic medications of questionable benefit including antibiotics.
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Stage III Wilms' tumour (WT) represents a heterogeneous group which includes different criteria, but all stage III patients are treated according to the same study regiment. The aim of the study was to retrospectively analyse outcomes in patients with stage III due to positive resection margins (RM) only, sub-grouped in RM with viable (RM-v) and nonviable (RM-nv) tumour. Patients were treated pre- and postoperatively according to the SIOP-WT-2001 protocol in the UK-CCLG and GPOH WT trials and studies (2001-2020). There were 197 patients, including 134 with localised, abdominal stage III and 63 with overall stage IV, but abdominal stage III. Stage III due to RM-v had 126 patients, and due to RM-nv 71 patients. The overall 5-year local-relapse-free survival (RFS), event-free (EFS) and overall survival (OS) estimates for all patients with abdominal stage III RM were 95.7% (±SE1.5%), 85.1 (±SE2.6%) and 90.3% (±SE2.2%), respectively. Patients with stage III RM-nv had significantly better RFS and EFS than patients with RM-v (P = .027 and P = .003, respectively). A multivariate analysis showed that RM-v remained a significant factor for EFS when adjusted for age, presence of metastasis at diagnosis, histological risk group and overall stage in Cox regression analysis (P = .006). Patients with stage III due to RM-nv only exhibited no local recurrence and have a significantly better RFS and EFS than patients with RM-v. The results suggest that exclusion of RM-nv as a stage III criterion in the UMBRELLA staging system and consequent treatment reduction is warranted.
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Neoplasias Renais , Tumor de Wilms , Humanos , Lactente , Neoplasias Renais/patologia , Estudos Retrospectivos , Margens de Excisão , Recidiva Local de Neoplasia/patologia , Tumor de Wilms/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Reino Unido/epidemiologia , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Patients treated with preoperative chemotherapy with stage I intermediate-risk Wilms tumor (IR-WT) represent the largest group of patients with Wilms tumor (WT), and they have excellent outcomes. METHODS: The authors performed a retrospective analysis of patients with stage I epithelial (ET-WT) or stromal type WT (ST-WT) treated pre- and postoperatively according to the International Society of Paediatric Oncology-WT-2001 protocol in the UK Children's Cancer and Leukaemia Group and Gesellschaft für Pädiatrische Onkologie und Hämatologie groups' participation in the relevant WT trials and studies (2001-2020). RESULTS: There were 880 patients with stage I IR-WT, including 124 with ET-WT, 156 with ST-WT, and 600 with other IR-WT (oIR-WT). Patients with stage I ET-WT or ST-WT were significantly younger than patients with oIR-WT, represented a large proportion of stage I WTs in their groups, and tumors showed poor histologic response to preoperative chemotherapy. The 5-year event-free survival (EFS) estimates for patients with stage I ET-WT (96.8% ± 1.8 SE) or ST-WT (96.8% ± 1.6 SE) were significantly better than for patients with oIR-WT (90.3% ± 1.3 SE) (p = .014 and p = .009, respectively). A multivariate analysis showed that histologic type (ET-WT or ST-WT) remained a significant factor for EFS when adjusted for age and gender (p = .032 and p = .022, respectively). In both groups, relapses occurred in 3.2% of patients, and the overall survival was 99.2%. CONCLUSIONS: The results suggest that stage I ET-WT or ST-WT could be regarded as low-risk WT, for which omission of postoperative chemotherapy should be considered. PLAIN LANGUAGE SUMMARY: Patients with pretreated intermediate-risk Wilms tumor (WT) represent the largest group of patients with WT. This study reports the outcomes of patients with stage I epithelial type (ET-WT) or stromal type WT (ST-WT). These patients were significantly younger and had a larger proportion of stage I cases than patients with other intermediate-risk WT (oIR-WT). The event-free survival for patients with stage I ET-WT and ST-WT was significantly better than for patients with oIR-WT. Rare relapses were curable resulting in 99.2% overall survival.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Lactente , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Estudos Retrospectivos , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: This study aims to identify factors associated with the occurrence of local relapse (LR) after treatment for unilateral nephroblastoma. BACKGROUND: Despite the fact that LR is rare (~5%) its adverse impact on the need for relapse treatment and outcome (40%-80% overall survival) cannot be neglected. Identifying the causative factors may improve initial treatment to achieve better local control. METHODS: Altogether 2386 patients with unilateral nephroblastoma prospectively enrolled over a period of 32 years (1989-2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH) were retrospectively analyzed. Hazard ratios (HR) of LR were calculated for sex, age, size, local staging, histology, type of removal, rupture, lymph node (LN) removal using univariate and multivariate Cox models. RESULTS: Age >48 months, tumor volume >500 mL, histology and LN extent of removal were identified as significant risk factors for LR [HR: 1.68, P =0.018, confidence interval (CI): 1.09-2.58; HR: 1.84, P =0.015, CI: 1.13-3.00; HR: 3.19, P <0.001, CI: 2.03-5.00; HR: 2.26, P =0.002, CI: 1.36-3.576]. LR occur significantly more often in Stage I and II, even if no LN are removed. The risk of metastases is significantly increased after local recurrence (HR: 11.5, P <0.001, CI: 7.11-18.60). LR is associated with a subsequent 18.79-fold increased risk of death (HR: 18.79, P <0.001, CI: 2.07-5.28). CONCLUSIONS: Several factors are responsible for the occurrence of LR. Surgical ones, like LN sampling allow further reduction of LR and consequently a better outcome of patients with unilateral nephroblastoma.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Pré-Escolar , Neoplasias Renais/cirurgia , Neoplasias Renais/patologia , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/epidemiologia , Tumor de Wilms/cirurgia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Recidiva , Resultado do TratamentoRESUMO
In the SIOP Wilms' tumor (WT) studies, preoperative chemotherapy is used as primary treatment, and tumors are classified thereafter by pathologists. Completely necrotic WTs (CN-WTs) are classified as low-risk tumors. The aim of the study was to evaluate whether a subset of regressive type WTs (RT-WTs) (67%-99% chemotherapy-induced changes [CIC]) showing an exceptionally good response to preoperative chemotherapy had comparably excellent survivals as CN-WTs, and to establish a cut-off point of CIC that could define this subset. The study included 2117 patients with unilateral, nonanaplastic WTs from the UK-CCLG and GPOH-WT studies (2001-2020) treated according to the SIOP-WT-2001 protocol. There were 126 patients with CN-WTs and 773 with RT-WTs, stages I-IV. RT-WTs were subdivided into subtotally necrotic WTs (>95% CIC) (STN-WT96-99) (124 patients) and the remaining of RT-WT (RR-WT67-95) (649 patients). The 5-year event-free survival (EFS) and overall survival (OS) for CN-WTs were 95.3% (±2.1% SE) and 97.3% (±1.5% SE), and for RT-WTs 85.7% (±1.14% SE, P < .01) and 95.2% (±0.01% SE, P = .59), respectively. CN-WT and STN-WT96-99 groups showed significantly better EFS than RR-WT67-95 (P = .003 and P = .02, respectively), which remained significantly superior when adjusted for age, local stage and metastasis at diagnosis, in multivariate analysis, whereas OS were superimposable (97.3 ± 1.5% SE for CN-WT; 97.8 ± 1.5% SE for STN-WT96-99; 94.7 ± 1.0% SE for RR-WT67-95). Patients with STN-WT96-99 share the same excellent EFS and OS as patients with CN-WTs, and although this was achieved by more treatment for patients with STN-WT96-99 than for patients with CN-WT, reduction in postoperative treatment of these patients may be justified.
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Tratamento Farmacológico/métodos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Análise Multivariada , Estadiamento de Neoplasias , Período Pré-Operatório , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Reino UnidoRESUMO
BACKGROUND: Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis in different childhood tumors including WT. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized. METHODS: We screened a large cohort of unselected WTs for MYCN and MAX alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes. RESULTS: Mutation screening revealed mutation frequencies of 3% for MYCN P44L and 0.9% for MAX R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g. PEG10, YEATS2, FOXK1, CBLL1 and MCRS1, whose expression is correlated with MYCN in WT samples and several of these are known for their own oncogenic potential. CONCLUSIONS: The strongly elevated risk of relapse associated with mutant MYCN and MAX or elevated MYCN expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.
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INTRODUCTION: Clear cell sarcoma of the kidney (CCSK) is a rare malignant childhood renal tumour. Recently, the central nervous system (CNS) was found to be the most frequent site of relapse associated with a poor outcome. Optimal treatment strategies are scarce. PATIENTS AND METHODS: Retrospective data analysis of all Austrian children with CCSK. They were enrolled in the Austrian-Hungarian Wilms Tumour Study (AHWTS) 1989, the SIOP93-01 or the SIOP2001 study between 1990 and 2019. Demographic, diagnostic, treatment-related variables and survival data were analysed. RESULTS: We identified 12 children with CCSK (M = 7, F = 5; median age 1.6 years). All had localised disease (stage I: 2; stage II: 2; stage III: 8) at diagnosis, and a first complete remission (CR1) was achieved in 12/12. Six patients are in an ongoing CR1 (median follow-up 10 years). Six other patients had a relapse (local 1; brain 5) a median time of 2.4 years from diagnosis. Two patients died of the disease 4 months and 2.8 years after first relapse. Four of five patients with CNS relapse are in CR2 with a median follow-up time of 9.3 years after relapse diagnosis. Relapse treatment included a combination of chemotherapy, radiation and surgery. Two children received high-dose chemotherapy followed by autologous stem cell rescue, and one child received intrathecal mafosphamide. Long-term side effects after treatment were impaired tubular renal function (n = 4), cardiomyopathy (n = 1) and growth disorders (n = 1). CONCLUSIONS: In this series, the brain was the most common site of relapse. Long-term survival after recurrence was achievable with intensive multimodal therapy.
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Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Sarcoma de Células Claras/mortalidade , Sarcoma de Células Claras/patologia , Áustria/epidemiologia , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/secundário , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Estudos RetrospectivosRESUMO
BACKGROUND: Many pediatric cancer centers still use Gentamicin as first line combination treatment in patients with fever and neutropenia. Since 2011, our center has implemented a dosing regimen with 250 mg/m2 BSA (max. 10 mg/kg, max. 400 mg) as a single daily infusion according to the German guideline. PATIENTS AND METHODS: In this prospective audit (February 2011 to December 2019), 105 Gentamicin treatment cycles were analyzed in 66 pediatric cancer patients, focusing on adherence to the dosing regimen and the drug monitoring results. RESULTS: Adherence to the dosing regimen was high (89%). In 64% of all cycles, the Cmax (drawn 1 h after the 2nd dose) reached the target of 10-20 µg/ml. Cmax significantly correlated with dosing in mg/m2 BSA (p=0,007), but not with dosing in mg/kg (p=0,366). Age below 6 years did not influence these results. The Gentamicin Ctrough (drawn 8-10 h after the second dose) was < 2 µg/ml in 93% of all cycles without any dose correlation. None of the patients experienced Gentamicin-associated nephrotoxicity. DISCUSSION AND CONCLUSION: This prospective audit of single daily infusion Gentamicin in pediatric cancer patients without impaired renal function elicits the feasibility and safety of the dosing regimen in mg/m2 BSA according to the German guideline. Since indications for first-line gentamicin are limited, a multicenter prospective study would be advantageous to confirm these observations.
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Monitoramento de Medicamentos , Gentamicinas , Antibacterianos/efeitos adversos , Criança , Esquema de Medicação , Gentamicinas/efeitos adversos , Humanos , Estudos ProspectivosRESUMO
BACKGROUND: In patients with neurosurgical interventions requiring dura reconstruction, the use of bovine graft material may be required. PATIENTS AND METHODS: Case report. RESULTS: We present a 12-year-old girl with a profound graft reaction with severe neurologic symptoms mimicking post-neurosurgical bacterial meningitis after resection of an infra-tentorial brain tumour. CONCLUSION: It is important to take into consideration this rare clinical entity in children and adults after dura reconstruction using allogenic graft (bovine) material in order to avoid the unnecessary use of antibiotics and antiviral drugs.
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Neoplasias Encefálicas , Meningite Asséptica , Meningites Bacterianas , Adulto , Animais , Bovinos , Criança , Feminino , HumanosRESUMO
BACKGROUND: Wilms' tumour is the most common renal cancer in childhood and about 15% of patients will relapse. There is scarce evidence about optimal surveillance schedules and methods for detection of tumour relapse after therapy. METHODS: The Renal Tumour Study Group-International Society of Paediatric Oncology (RTSG-SIOP) Wilms' tumour 2001 trial and study is an international, multicentre, prospective registration, biological study with an embedded randomised clinical trial for children with renal tumours aged between 6 months and 18 years. The study covers 243 different centres in 27 countries grouped into five consortia. The current protocol of SIOP surveillance for Wilms' tumour recommends that abdominal ultrasound and chest x-ray should be done every 3 months for the first 2 years after treatment and be repeated every 4-6 months in the third and fourth year and annually in the fifth year. In this retrospective cohort study of the protocol database, we analysed data from participating institutions on timing, anatomical site, and mode of detection of all first relapses of Wilms' tumour. The primary outcomes were how relapse of Wilms' tumour was detected (ie, at or between scheduled surveillance and with or without clinical symptoms, scan modality, and physical examination) and to estimate the number of scans needed to capture one subclinical relapse. The RTSG-SIOP study is registered with Eudra-CT, number 2007-004591-39. FINDINGS: Between June 26, 2001, and May 8, 2015, of 4271 eligible patients in the 2001 RTSG-SIOP Wilms' tumour database, 538 (13%) relapsed. Median follow-up from surgery was 62 months (IQR 32-93). The method used to detect relapse was registered for 410 (76%) of 538 relapses. Planned surveillance imaging captured 289 (70%) of these 410 relapses. The primary imaging modality used to detect relapse was reported for 251 patients, among which relapse was identified by abdominal ultrasound (80 [32%] patients), chest x-ray (78 [31%]), CT scan of the chest (64 [25%]) or abdomen (20 [8%]), and abdominal MRI (nine [4%]). 279 (68%) of 410 relapses were not detectable by physical examination and 261 (64%) patients did not have clinical symptoms at relapse. The estimated number of scans needed to detect one subclinical relapse during the first 2 years after nephrectomy was 112 (95% CI 106-119) and, for 2-5 years after nephrectomy, 500 (416-588). INTERPRETATION: Planned surveillance imaging captured more than two-thirds of predominantly asymptomatic relapses of Wilms' tumours, with most detected by abdominal ultrasound, chest x-ray, or chest CT scan. Beyond 2 years post-nephrectomy, a substantial number of surveillance scans are needed to capture one relapse, which places a burden on families and health-care systems. FUNDING: Great Ormond Street Hospital Children's Charity, the European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment, The Danish Childhood Cancer Foundation, Cancer Research UK, the UK National Cancer Research Network and Children's Cancer and Leukaemia Group, Société Française des Cancers de l'Enfant and Association Leon Berard Enfant Cancéreux and Enfant et Santé, Gesellschaft für Pädiatrische Onkologie und Hämatologie and Deutsche Krebshilfe, Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediátrica, the Spanish Society of Pediatric Haematology and Oncology and the Spanish Association Against Cancer, and SIOP-Netherlands.
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Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Metástase Neoplásica/diagnóstico , Tumor de Wilms/diagnóstico , Tumor de Wilms/secundário , Adolescente , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
BACKGROUND: Congenital mesoblastic nephroma (MN) is a rare pediatric renal tumor representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically: classical, cellular, and mixed. A frequent genetic alteration is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular MN. The aim of this study was to determine translocation status of a large cohort of MN with respect to tumor subtype and outcome. PROCEDURE: In total, clinical data from 111 patients were available. Sixty-seven tumors were classical MN (51%), 29 cellular MN (31%), and 15 were mixed MN (18%). From these 111 cases, 79 were analyzed by FISH and RT-PCR. RESULTS: All classical and mixed MN were translocation negative. Seventeen out of 29 (58%) cellular MN harbored the ETV6-NTRK3 translocation. Five-year relapse-free survival (RFS) and overall survival (OS) were 93.2% and 96.8% for the complete cohort. All seven relapses occurred in translocation negative tumors. Five-year RFS was significantly inferior for cellular and mixed MN compared to classic MN (89%, 80%, and 98%), whereas 5-year OS was similar (93%, 96%, and 98%). Within the group of cellular MN, patients having translocation-positive tumors had a significantly superior RFS (5-year RFS: 100% vs. 73%). CONCLUSION: The majority of cellular MNs harbor the ETV6-NTKR3 gene fusion, whereas all classic- and mixed-type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS.
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Cromossomos Humanos Par 12 , Cromossomos Humanos Par 15 , Nefroma Mesoblástico , Proteínas de Fusão Oncogênica , Translocação Genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 12/metabolismo , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Nefroma Mesoblástico/genética , Nefroma Mesoblástico/metabolismo , Nefroma Mesoblástico/mortalidade , Nefroma Mesoblástico/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de SobrevidaRESUMO
BACKGROUND: Congenital rhabdoid tumors are rare and highly aggressive malignancies. In general, patients are considered to be incurable and are often treated using an exclusive, primarily palliative approach. METHODS: A prospective and retrospective collection of 42 patients from the European Rhabdoid Registry (EU-RHAB), France and Moscow (2006-2016) diagnosed within the first 28 days of life was evaluated. Genetic and clinical reference evaluation included SMARCB1 and/or SMARCA4 (fluorescence-in-situ-hybridization, multiplex ligation-dependent probe amplification, and sequencing) mutation analysis and immunohistochemistry. Forty-eight percent (20/42) of patients were treated according to the EU-RHAB therapy, 7% (3/42) according to the pilot approach Rhabdoid 2007, 33% (14/42) with individual schedules, and 12% (5/42) received no chemotherapy at all. RESULTS: Forty point five percent (17/42) of patients presented with extracranial rhabdoid tumors, 33.5% (14/42) with rhabdoid tumors of the central nervous system (atypical teratoid/rhabdoid tumor), and the remainder 26% (11/42) demonstrated synchronous tumors. Metastases at diagnosis were present in 52% (22/42) of patients. A germline mutation was detected in 66% (25/38) and was associated with a poor prognosis (4.2 ± 4.1% vs. 48 ± 16.4%, P < 0.00005). A gross total resection (GTR) was realized in 17%. A GTR (42.9 ± 18.7% vs. 4.9 ± 4.3%, P = 0.04), therapy according to a standardized approach (20.9 ± 8.7% vs. 7.1 ± 6.9 %, P = 0.0018), and a complete remission (CR) (23.6 ± 9.8% vs. 1.3 ± 3.6%, P = 0.04) were significant prognostic factors. CONCLUSIONS: The management of patients with congenital rhabdoid tumors requires a major multidisciplinary effort. In many instances, cure is not possible and a palliative approach is warranted. Our data indicate a positive impact of standardized therapeutic approaches on survival, making a tailored approach toward affected patients and their families mandatory.
Assuntos
Tumor Rabdoide/congênito , Tumor Rabdoide/terapia , Terapia Combinada , Europa (Continente) , Feminino , Seguimentos , Humanos , Recém-Nascido , Masculino , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Tumor Rabdoide/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Malignant rhabdoid tumor of the kidney (MRTK) is the most aggressive childhood renal tumor with overall survival (OS) rates ranging from 22% to 42%. Whether high-dose chemotherapy with autologous stem-cell transplantation (HDSCT) in an intensive first-line treatment offers additional benefit is an ongoing discussion. METHODS: A retrospective analysis of all 58 patients with MRTK from Austria, Switzerland, and Germany treated in the framework of consecutive, prospective renal/rhabdoid tumor studies SIOP9/GPO, SIOP93-01/GPOH (where SIOP is International Society of Pediatric Oncology and GPOH is German Society of Pediatric Oncology and Hematology), SIOP2001/GPOH, and European Rhabdoid Tumor Registry from 1991 to 2014. RESULTS: Median age at diagnosis was 11 months. Fifty percent of patients had metastases or multifocal disease at diagnosis (Stage IV). Local stage distribution was as follows: not done/I/II/III-1/6/11/40. Fifteen (26%) patients underwent upfront surgery. Thirty-seven (64%) patients achieved a complete remission, 17 (29%) relapsed, 34 (59%) died of disease progression, and two (3%) died of treatment-related complication. Mean time to the first event was 3.5 months. Two-year EFS/OS (where EFS is event-free survival) for the whole group was 37 ± 6%/38 ± 6%. Metastases/multifocal disease, younger age, and local stage III were associated with significantly inferior survival. Eleven (19%) patients underwent HDSCT (carboplatin + thiotepa, n = 6; carboplatin + etoposide + melphalan, n = 4; others, n = 1); 2-year OS in this group was 60 ± 15% compared to 34 ± 8% in the non-HDSCT group (P = 0.064). However, the time needed from radiologic to histologic diagnosis, stem-cell harvest, and HDSCT must also be taken into account to avoid selection bias by excluding the highest risk group with early progression (<90 days). Thus, 2-year EFS only for patients without progression until day 90 was 60 ± 16% consolidated by HDSCT compared to 62 ± 11% without (P = 0.8). CONCLUSION: Our retrospective analysis suggests comparable outcomes for patients with and without HDSCT, if adjusted for early disease progression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Sistema de Registros , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/mortalidade , Adolescente , Fatores Etários , Criança , Pré-Escolar , Dactinomicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Taxa de Sobrevida , Vincristina/administração & dosagemRESUMO
Although the fate of nephrogenic rests varies, they are known to be precursors of Wilms tumour. Thus, nephrogenic rests require adequate treatment to prevent malignant transformation. We added 13-cis retinoic acid to the standard chemotherapy with vincristine and actinomycin-D in two patients with bilateral nephrogenic rests/nephroblastomatosis. Patient 1 also had a history of Wilms tumour. 46 (patient 1) and 81 (patient 2) months after end of treatment, both patients show stable conditions with no signs of relapse or progressive disease. Our observation supports further investigation of retinoic acid in patients with nephrogenic rests and nephroblastomatosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Isotretinoína/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico , Pré-Escolar , Dactinomicina/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Lactente , Neoplasias Renais/patologia , Prognóstico , Vincristina/administração & dosagem , Tumor de Wilms/patologiaRESUMO
Internal tandem duplication within the BCOR gene sequence that encodes the PUFD domain, important in the formation of the non-canonical or variant polycomb repressor complex 1 (v-PRC1), was very recently described in 100% of 20 clear cell sarcomas of kidney (CCSKs). None of those 20 cases bore the YWHAE-NUTM2 transcript, previously described by us in CCSK, and which constitutes the only other recurrent genetic aberration observed in CCSK, prompting consideration that these mutations might be mutually exclusive in CCSK. We analysed a cohort of 159 CCSKs and can now not only confirm that there is indeed mutual exclusivity of these BCOR and YWHAE mutations, but also show that a substantial proportion (in this series 11.8%) of CCSKs bear neither mutation when tested by these assays, raising the possibility of distinct aetiologies for subsets of CCSK. Clinical differences observed between the subsets support this notion. As CCSK may show poor chemo-responsiveness, and current treatment protocols mandate the use of doxorubicin with its associated side-effects, advances in understanding the disease biology with a view to more targeted and personalized treatment is a pressing need.