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

Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the 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

Burkitt lymphoma in a child with Joubert syndrome

Joubert syndrome is a rare disorder, characterized by hypoplasia, or aplasia of the cerebellar vermis, hypotonia, ataxia, and psychomotor retardation. The molecular basis underlying the disease is still unknown. There are various syndromes, which are associated with malignancies. Previously known associations between Joubert syndrome and tumors, are benign soft tissue tumors of the tongue and laryngeal lymphangioma. This report describes a 17-year-old boy known with Joubert syndrome, who was diagnosed with Burkitt lymphoma. The boy received chemotherapy, which successfully induced complete remission. (C) 2004 Wiley-Liss, In

Stromal and Epithelial Predominant Wilms Tumours Have an Excellent Outcome: The SIOP 93 01 Experience

Background. Wilms tumour (WT) has various subtypes that are correlated with prognosis and require distinct therapy. Stromal predominant (SpWT) and epithelial WT (EpWT) have previously been associated with a good outcome. The current analysis describes the outcome and (tumour) characteristics of all patients with SpWT, EpWT, including highly differentiated epithelial type (HDET), treated according to the International Society of Pediatric Oncology (SIOP) 93-01 study. Procedure. All children older than 6 months and below 18 years of age with localized or metastatic WT and intermediate risk (IR) histology or HDET treated with pre-operative chemotherapy were included in the present analysis. Results. A total of 1,389 eligible patients had IR or HDET histology: 1% HDET, 4% EpWT, 10% SpWT, and 85% other IR. For EpWT/HDET, 93% had stage I/IIN-, 5-year EFS was 90.2% and overall survival of (OS) 98.4%, as compared to 84.0% and 92.5% in other IR histology (NS). Stage I EpWT/HDET had a significant better outcome than stage I of other IR. In SpWT 82% of cases had stage I/IIN-; 5-year EFS was 94.3% and OS 99.2%, significantly better compared to other IR histology. All patients with stage I are alive (2/149 relapses); 3/52 stage IIN-, 2/21 stage IIN+/III, and 6/12 stage IV patients relapsed (1 deceased per stage group). Conclusions. The good outcome for EpWT and SpWT generally is very good which may be related to low age and low stage in most cases. A reduction of treatment intensity and/or duration may be justified especially for low stage SpWT that has an EFS close to 100%. Pediatr Blood Cancer 2010;55:233-238. (C) 2010 Wiley-Liss, In

Cyclopentenyl cytosine increases the phosphorylation and incorporation into DNA of 1-beta-D-arabinofuranosyl cytosine in a human T-lymphoblastic cell line

The cytotoxic effect of I-P-D-arabinofuranosyl cytosine (araC) depends on the intracellular phosphorylation into its active compound araCTP, on the degree of degradation of araCTP and on the incorporation of araCTP into DNA. Deoxycytidine triphosphate (dCTP) inhibits the phosphorylation of araC (by feedback inhibition of the enzyme deoxycyticline kinase) and the incorporation of araCTP into DNA (by competition for DNA polymerase). In a T-lymphoblastic cell line, we studied whether the cytotoxicity of araC (2 nM-50 muM) could be enhanced by decreasing the concentration of dCTP, using the nucleoside-analogue cyclopentenyl cytosine (CPEC), an inhibitor of the enzyme CTP synthetase. Preincubation of the cells with CPEC (100-1,600 nM) for 2 hr increased the concentrations of araCMP 1.6-9.5-fold, which was significant for each concentration of CPEC used. The concentration of araCDP remained low, whereas the concentration of araCTP changed depending on the concentration of araC used. With 2-15 muM of araC and a preincubation with 400 nM of CPEC, the araCTP concentration increased by 4 -15% (not significant), and the total amount of araC nucleotides increased significantly by 21-45%. When using a concentration of araC of 2 nM after a preincubation with CPEC of 100 nM, the concentration of araCMP increased by 60% (p = 0.015), whereas that of araCTP decreased by 10% (p = 0.008). This was compensated by an increase of 41% (p = 0.005) of araCTP incorporation into DNA, which represented 43% of all araC metabolites. Moreover, by performing pulse/chase experiments with 400 nM of CPEC and 2muM of araC, the retention of cytosolic araCTP and the incorporated amount of araCTP into DNA were increased by CPEC. The modulation by CPEC of araC metabolism was accompanied by a synergistic increase of araC-induced apoptosis and by an additive effect on the araC-induced growth inhibition. (C) 2002 Wiley-Liss, In

Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age

PURPOSE: To determine the response to radionuclide targeted therapy with I-131-metaiodobenzylguanidine ((131)I-MIBG) as induction therapy in high-risk neuroblastoma patients. PATIENTS AND METHODS: The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months. RESULTS: Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%. CONCLUSION: First line (131)I-MIBG-targeted therapy is a valuable tool in the treatment of MIBG-positive high-risk neuroblastoma patient

Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors:An Innovative Therapy for Children with Cancer Study

Purpose: This phase Ib study defined the safety, MTD, and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. Patients and Methods: Patients aged 6 months to &lt;18 years with relapsed/refractory solid malignancies [≥50% with rhabdomyosarcoma (RMS)] received regorafenib (starting dose 72 mg/m 2/day) concomitantly or sequentially with vincristine 1.5 mg/m 2 on days 1 and 8, and irinotecan 50 mg/m 2 on days 1–5 (21-day cycle). Adverse events (AE) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. Results: We enrolled 21 patients [median age, 10 years; 12, RMS; 5, Ewing sarcoma (EWS)]. The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m 2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2 of 2 patients treated. Most common grade 3/4 (&gt;30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate [complete response (CR)/partial response/stable disease/non-CR/non-progressive disease] was 86%. Median progression-free survival was 7.0 months [95% confidence interval (CI), 2.9–14.8] and median overall survival was 8.7 months (95% CI, 5.5–16.3). When combined with VI, regorafenib PK was similar to single-agent PK in children and adults (treated with regorafenib 160 mg/day). Conclusions: Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS.</p

Characteristics and outcome of children with renal cell carcinoma: A narrative review

Pediatric renal cell carcinoma (RCC) is a rare type of kidney cancer, most commonly occurring in teenagers and young adolescents. Few relatively large series of pediatric RCC have been reported. Knowledge of clinical characteristics, outcome and treatment strategies are often based on the more frequently occurring adult types of RCC. However, published pediatric data suggest that clinical, molecular and histological characteristics of pediatric RCC differ from adult RCC. This paper summarizes reported series consisting of ≥10 RCC pediatric patients in order to create an up-to-date overview of the clinical and histopathological characteristics, treatment and outcome of pediatric RCC patients

Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology—Renal Tumor Study Group (SIOP‐RTSG)‐related retrospective descriptive study

Abstract Introduction Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology–Renal Tumor Study Group (SIOP‐RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. Methods This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti‐programmed cell death 1 (PD‐(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced‐stage and relapsed pediatric RCC. Results Of the 31 identified patients (0–18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT‐RCC) (21/31) and the remaining patients mainly presented with papillary or clear‐cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono‐ or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. Conclusion This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies

Outcome of patients with stage IV high-risk Wilms tumour treated according to the SIOP2001 protocol: A report of the SIOP Renal Tumour Study Group

Introduction: High-risk (HR) metastatic (stage IV) Wilms tumours (WTs) have a particular poor outcome. Methods: Here, we report the results of HR (diffuse anaplastic [DA] or blastemal type [BT]) stage IV WT treated patients according to the HR arm in the SIOP2001 prospective study. Results: From January 2002 to August 2014, 3559 patients with WT were included in the SIOP2001 trial. Among the 525 patients (15%) with metastatic WT, 74 (14%) had stage IV HR-WT. The median age at diagnosis was 5.5 years (range: 1.4–18.3). Thirty-four patients (47%) had BT-WT and 40 (53%) had DA-WT. Five-year event-free survival rates were 44 ± 17% and 28 ± 15% for BT-WT and DA-WT, respectively (p = 0.09). Five-year overall survival rates were 53 ± 17% and 29 ± 16% for BT-WT and DA-WT, respectively (p = 0.03). Metastatic complete response after preoperative treatment was significantly associated with outcome in univariate and multivariate analyses (hazards ratio = 0.3; p = 0.01). Postoperative radiotherapy of metastatic sites might also be beneficial. Forty-three of 74 patients experienced a relapse or progression predominantly in the lungs (80%). The median time to relapse/progression after diagnosis was 7.3 months (range: 1.6–33.3) and 4.9 months (range: 0.7–28.4) for BT-WT and DA-WT, respectively (p = 0.67). This is the first prospective evidence of inferior survival of stage IV BT-WT as compared with historical intermediate-risk WT. Survival of patients with stage IV DA-WT has not improved compared to the previous SIOP93-01 study. Conclusion: These results call for new treatment approaches for patients with HR stage IV WT