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Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort. Supplementary Information The online version contains supplementary material available at 10.1007/s10689-021-00237-1.

Background: The prognosis of childhood acute lymphoblastic leukemia (ALL) in Indonesia, a lower-middle-income country (LMIC), is lower than in high income countries (HICs). The Indonesian ALL2013 protocol resulted in too many toxic deaths (21%) and abandonments (11%). Therefore, we drafted an adapted protocol, ALL2016. Main changes: no anthracyclines in standard risk (SR), prednisone replaced dexamethasone at induction in high risk (HR), and anthracyclines and cyclophosphamide were rescheduled in HR. Procedure: Patients (aged: 1–18 years) were stratified into SR and HR. HR was defined as age over 10 years, leucocyte count over 50 × 109/L, central nervous system (CNS) involvement, mediastinal mass, T-cell phenotype, testicular involvement, or poor prednisone response. Results: ALL2013 included 174 patients (106 SR and 68 HR) and ALL2016 188 (91 SR and 97 HR). Although the number of HR patients was significantly higher in ALL2016 (51.6% vs. 39.1%; p =.017), the outcome of ALL2016 improved over ALL2013 (4-year-probable overall survival (pOS) 60.1% vs. 50.0%; p =.042 and 4-year-probable event-free survival (pEFS) 49.5% vs. 36.8%; p =.018). ALL2016 showed a nonsignificant advantage for SR patients (4-year-pEFS 56.0% vs. 47.2%; p =.220 and 4-year-pOS 70.3% vs. 61.3%; p =.166), but less toxic deaths (7% vs. 20%; p =.011). In HR group, the outcomes were significantly better in ALL2016 (4-year-pEFS 43.3% vs. 20.6%; p =.004; 4-year-pOS 50.5% vs. 32.4%; p =.014) especially due to less relapses (31% vs. 62%; p =.001). Isolated CNS relapses went down from 18 to 8% in HR (p =.010) and 11 to 5% in SR (p =.474). Both SR and HR showed lower numbers of abandonment in ALL2016 (6% vs. 14%; p =.039). Conclusions: Overall ALL2016 results improved over ALL2013. Modest changes in protocol resulted in less initial toxicity and abandonments.

Background: Although survival rates for retinoblastoma (RB) are over 95% in high-income countries, its high mortality rate in low and middle-income countries remains a great concern. Few studies investigated treatment outcome and factors contributing to RB survival in these latter settings. Aims of this study are to determine treatment outcome of Indonesian children diagnosed with RB and to explore factors predictive of treatment outcome. Methods: This study was a retrospective medical records review combined with an illustrative case report. Children newly diagnosed with RB between January 2011 and December 2016 at a tertiary care referral hospital in Indonesia were included. A home visit was conducted to perform an in-depth interview with a mother of two children affected by RB. Results: Of all 61 children with RB, 39% abandoned treatment, 21% died, 20% had progressive or relapsed disease and 20% event-free survival. Progressive or relapsed disease was more common in older (≥ 2 years at diagnosis, 29%) than young (

Topic To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms. Clinical relevance Approximately 45% of patients with retinoblastoma—those with a germline RB1 pathogenic variant—are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued. Methods We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus. Results One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9–29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively. Conclusions Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low.

PURPOSE: To determine the risk of patients with an early diagnosis of heritable retinoblastoma being diagnosed with TRb (or pineoblastoma) asynchronously in a later stage and its effect on screening.METHODS: We updated the search (PubMed and Embase) for published literature as performed by our research group in 2014 and 2019. Trilateral retinoblastoma (TRb) patients were eligible for inclusion if identifiable as unique and the age at which TRb was diagnosed was available. The search yielded 97 new studies. Three new studies and eight new patients were included. Combined with 189 patients from the previous meta-analysis, the database included 197 patients. The main outcome was the percentage of asynchronous TRb in patients diagnosed before and after preset age thresholds of 6 and 12 months of age at retinoblastoma diagnosis.RESULTS: Seventy-nine per cent of patients with pineoblastoma are diagnosed with retinoblastoma before the age of 12 months. However, baseline MRI screening at time of retinoblastoma diagnosis fails to detect the later diagnosed pineal TRb in 89% of patients. We modelled that an additional MRI performed at the age of 29 months picks up 53% of pineoblastomas in an asymptomatic phase. The detection rate increased to 72%, 87% and 92%, respectively, with 2, 3 and 4 additional MRIs.CONCLUSIONS: An MRI of the brain in heritable retinoblastoma before the age of 12 months misses most pineoblastomas, while retinoblastomas are diagnosed most often before the age of 12 months. Optimally timed additional MRI scans of the brain can increase the asymptomatic detection rate of pineoblastoma.

OBJECTIVE: Generate recommendations for long-term follow-up for adult survivors of heritable retinoblastoma.DESIGN: We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence.SUBJECTS: Retinoblastoma is a rare childhood cancer of the retina. Approximately forty percent of retinoblastoma cases are heritable, due to a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. Survivors of heritable retinoblastoma, however, have significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. In spite of these risks, no surveillance recommendations for this population are currently in place and surveillance practices vary widely by center.METHODS: Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 papers; after abstract and full text review, 37 papers underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations.MAIN OUTCOME MEASURES: Diagnosis and mortality from subsequent neoplasm.RESULTS: While evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent.CONCLUSIONS: This review of the literature confirmed some of the common second cancers in retinoblastoma survivors, but found little evidence for a benefit to currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

Purpose The current study aimed to evaluate the feasibility of RetinoQuest in clinical practice, from survivors and healthcare professionals’ (HCPs) point of view. Methods RetinoQuest is a touch screen computer program to monitor health-related quality of life (HRQoL) of retinoblastoma survivors via patient-reported outcome measures (PROMs) targeting children (4–10 years) as evaluated by their parents (proxy measures), adolescents (11–18 years), and adults. Feasibility was evaluated by the actual time taken to complete the PROMs, acceptability of the time as perceived by the users, the content of PROMs in RetinoQuest, and overall satisfaction with RetinoQuest. Results Ninety-six survivors participated: 41 parents of children, 38 adolescents, and 17 adults. Mean time to complete the evaluation form was 7.8 min (median 6.7, range 2.4–24.5), and 90% of the users stated that the time needed to complete PROMs in RetinoQuest was acceptable. The majority of users reported that it was important to answer the questions (88% of the parents, 66% of the adolescents, and 76% of the adult survivors) and that all important issues were covered, e.g., no missing questions (78, 84, and 76%, respectively). Satisfaction rate was high, 7.8 according to parents, 8.1 according to adolescents, and 7.7 for adults. Conclusions RetinoQuest is a feasible e-health application to monitor HRQoL in retinoblastoma survivors in clinical practice. Implications for cancer survivors This tool allows for open and structured communication which can lead to early detection of psychosocial impacts on quality of life and referral of the retinoblastoma survivors. Electronic supplementary material The online version of this article (10.1007/s11764-017-0642-z) contains supplementary material, which is available to authorized users.

BACKGROUND: Children treated for retinoblastoma with carboplatin have an increased risk for ototoxicity. Impaired hearing may have major consequences for these children, because they often suffer from reduced vision. Previous studies have shown limited information on the incidence and severity of carboplatin-induced ototoxicity and the used audiologic methods. The frequency of audiological testing is often limited and the audiologic follow-up time is relatively short.OBJECTIVE: The aim of this study was to determine the long-term effects of carboplatin ototoxicity in children with retinoblastoma.MATERIALS AND METHODS: In this retrospective non-randomized single center cohort study, we reviewed audiologic results of 25 patients. Experienced audiologists analyzed the pure-tone audiograms.RESULTS: All patients had normal hearing prior to therapy and had a mean age of 11 months at first carboplatin administration. The mean audiologic follow-up was 12.0 years with a median of 11.6 (IQR 4.8) years. Three patients were excluded: two passed away and one could not participate in the audiologic tests. One of the 22 included patients developed sustained low-grade bilateral high-frequency hearing loss between 2 and 7 years after the last carboplatin dose. In one patient it was not possible to make a reliable conclusion due to a conductive hearing loss component. Twenty patients had normal hearing.CONCLUSIONS: We observed no clear effect between carboplatin administration in young children and clinical significant ototoxicity in the long term. One child showed low-grade bilateral high-frequency hearing loss.

Both hereditary and nonhereditary retinoblastoma (Rb) are commonly initiated by loss of both copies of the retinoblastoma tumor suppressor gene (RB1), while additional genomic changes are required for tumor initiation and progression. Our aim was to determine whether there is genomic heterogeneity between different clinical Rb subtypes. Therefore, 21 Rb tumors from 11 hereditary patients and 10 nonhereditary Rb patients were analyzed using high-resolution single nucleotide polymorphism (SNP) arrays and gene losses and gains were validated with Multiplex Ligation-dependent Probe Amplification. In these tumors only a few focal aberrations were detected. The most frequent was a focal gain on chromosome 2p24.3, the minimal region of gain encompassing the oncogene MYCN. The genes BAZ1A, OTX2, FUT8, and AKT1 were detected in four focal regions on chromosome 14 in one nonhereditary Rb. There was a large difference in number of copy number aberrations between tumors. A subset of nonhereditary Rbs turned out to be the most genomic unstable, while especially very young patients with hereditary Rb display stable genomes. Established Rb copy number aberrations, including gain of chromosome arm 1q and loss of chromosome arm 16q, turned out to be preferentially associated with the nonhereditary Rbs with later age of diagnosis. In contrast, copy number neutral loss of heterozygosity was detected mainly on chromosome 13, where RB1 resides, irrespective of hereditary status or age. Focal amplifications and deletions and copy number neutral loss of heterozygosity besides chromosome 13 appear to be rare events in retinoblastoma.

Patients with hereditary retinoblastoma (Rb) have an increased risk of developing pineoblastoma.1 Unfortunately, most patients with concurrent pineoblastoma do not survive; Kivelä2 has shown that only patients who were diagnosed by screening and had a tumor smaller than 15 mm had a chance of survival. However, not all pineal lesions found with screening at the time of retinoblastoma diagnosis are pineoblastomas. Pineal cysts are a relatively common finding in the general population. In children up to 5 years of age the prevalence of pineal cysts diagnosed with magnetic resonance imaging (MRI) is 2.0%.3 Potentially, about 50% of pineoblastomas can be found at baseline screening and another 25% during the first year after Rb diagnosis.2 Therefore, baseline screening of the brain in newly diagnosed retinoblastoma is currently advised in imaging guidelines.4 In a recent study Rodjan and colleagues5 showed that the majority of pineoblastomas in Rb patients had a cystic appearance. Consequently baseline brain imaging with extended follow-up of pineal cysts might help early detection of pineoblastoma. We present a rare case of unilateral familial retinoblastoma and a suspicious cystic pineal gland on brain MR imaging that progressed into a pineoblastoma.

About 5% of children with retinoblastoma from germline mutation of the RB1 gene are at risk of developing trilateral retinoblastoma--intraocular retinoblastoma combined with a histologically similar brain tumour, most commonly in the pineal gland. We aimed to provide a systematic overview of published data for trilateral retinoblastoma, and to analyse how survival has changed.We searched Medline and Embase for scientific literature published between Jan 1, 1966, and April 14, 2014, that assessed trilateral retinoblastoma cases. We undertook a meta-analysis of survival with the Kaplan-Meier method and Cox proportional hazards regression, stratified on the basis of the original study, to account for between-study heterogeneity.We included 90 studies, with 174 patients with trilateral retinoblastoma. 5-year survival after pineal trilateral retinoblastoma increased from 6% (95% CI 2-15) in patients diagnosed before 1995, to 44% (26-61; p0·0001) in those diagnosed from 1995 onwards. Before 1995, no patients with non-pineal trilateral retinoblastoma survived, but from 1995 onwards, 5-year survival was 57% (30-77; p=0·035). Hazard ratios (HR) adjusted for the presence of leptomeningeal metastases and trilateral retinoblastoma location, suggested that both conventional (HR 0·059, 95% CI 0·016-0·226; p0·0001) and high-dose chemotherapy with stem-cell rescue (0·013, 0·002-0·064; p0·0001) most strongly contributed to this improvement. Absence of leptomeningeal metastases (HR 2·13, 95% CI 0·98-4·60; p=0·055) were associated with improved survival. Non-pineal trilateral retinoblastomas were larger than pineal tumours (median 30 mm [range 6-100] vs 22 mm [7-60]; p=0·012), but both had similar outcomes since 1995.Our results suggest that improvements in overall survival are attributable to improved chemotherapy regimens and early detection of pineal trilateral retinoblastoma. As such, successful treatment of trilateral retinoblastoma should include screening at least at the time of retinoblastoma diagnosis and chemotherapy, which would preferably be a high-dose regimen with autologous stem-cell rescue.None.

Serum cystatin C, β2-microglobulin, and β-trace protein are endogenous markers of glomerular filtration rate (GFR). Cystatin C, in particular, is a promising alternative to creatinine for the detection of incipient renal failure. However, corticosteroids affect the extrarenal metabolism of cystatin C, which limits the use of cystatin C as a marker of GFR in a variety of clinical settings. Low-molecular–weight (LMW) β-trace protein might be a useful alternative in this respect. The present study set out to compare the effect of corticosteroid therapy on the serum concentrations of cystatin C, β2-microglobulin, and β-trace protein. We studied a group of 108 children being treated or followed for malignancy (n = 41) or renal disease (n = 67). In the former group 14 patients (34%) were treated with glucocorticoids, in the latter 18 (27%). We compared single-injection inulin clearance studies in 76 patients not receiving steroids with 32 in patients receiving corticosteroid treatment (median dose 33.0 mg prednisone-equivalent per m2 body surface area per day, range 1.2–70.4). Mean (SD) age was 9.7 (5.8) years, mean (SD) GFR 92.8 (34.6) mL · min−1 · (1.73 m2)−1. Patients included in the …

Both hereditary and nonhereditary retinoblastoma (Rb) are commonly initiated by loss of both copies of the retinoblastoma tumor suppressor gene (RB1), while additional genomic changes are required for tumor initiation and progression. Our aim was to determine whether there is genomic heterogeneity between different clinical Rb subtypes. Therefore, 21 Rb tumors from 11 hereditary patients and 10 nonhereditary Rb patients were analyzed using high-resolution single nucleotide polymorphism (SNP) arrays and gene losses and gains were validated with Multiplex Ligation-dependent Probe Amplification. In these tumors only a few focal aberrations were detected. The most frequent was a focal gain on chromosome 2p24.3, the minimal region of gain encompassing the oncogene MYCN. The genes BAZ1A, OTX2, FUT8, and AKT1 were detected in four focal regions on chromosome 14 in one nonhereditary Rb. There was a large difference in number of copy number aberrations between tumors. A subset of nonhereditary Rbs turned out to be the most genomic unstable, while especially very young patients with hereditary Rb display stable genomes. Established Rb copy number aberrations, including gain of chromosome arm 1q and loss of chromosome arm 16q, turned out to be preferentially associated with the nonhereditary Rbs with later age of diagnosis. In contrast, copy number neutral loss of heterozygosity was detected mainly on chromosome 13, where RB1 resides, irrespective of hereditary status or age. Focal amplifications and deletions and copy number neutral loss of heterozygosity besides chromosome 13 appear to be rare events in retinoblastoma.

Purpose To estimate the incidence of trilateral retinoblastoma in patients with retinoblastoma. Design Systematic review and meta-analysis. Methods We searched Medline and Embase for scientific literature published between January 1966 and July 2015 that assessed trilateral retinoblastoma incidence. We used a random-effects model for the statistical analyses. Results We included 23 retinoblastoma cohorts from 26 studies. For patients with bilateral retinoblastoma the unadjusted chance of developing trilateral retinoblastoma across all cohorts was 5.3% (95% confidence interval [CI]: 3.3%–7.7%); the chance of pineal trilateral retinoblastoma was 4.2% (95% CI: 2.6%–6.2%) and the chance of nonpineal trilateral retinoblastoma was 0.8% (95% CI: 0.4%–1.3%). In patients with hereditary retinoblastoma (all bilateral cases, and the unilateral cases with a family history or germline RB1 mutation) we found a trilateral retinoblastoma incidence of 4.1% (95% CI: 1.9%–7.1%) and a pineal trilateral retinoblastoma incidence of 3.7% (95% CI: 1.8%–6.2%). To reduce the risk of overestimation bias we restricted analysis to retinoblastoma cohorts with a minimum size of 100 patients, resulting in adjusted incidences of 3.8% (95% CI: 2.4%–5.4%), 2.9% (95% CI: 1.9%–4.2%), and 0.7% (95% CI: 0.3%–1.2%) for any, pineal, and nonpineal trilateral retinoblastoma, respectively, among patients with bilateral retinoblastoma. Among hereditary retinoblastoma we found an adjusted trilateral retinoblastoma incidence of 3.5% (95% CI: 1.2%–6.7%) and a pineal trilateral retinoblastoma incidence of 3.2% (95% CI: 1.4%–5.6%). Conclusion The estimated incidence of trilateral retinoblastoma is lower than what is reported in previous literature, especially after exclusion of small cohorts that were subject to overestimation bias in this context.

Objectives Comparison of the effect of corticosteroid therapy on the diagnostic performance of cystatin C (Cys) and β-trace protein (bTP), two endogenous markers of GFR. Design and methods Out of a total of 193 pediatric inulin clearance studies, a random sample of 85 steroid-free studies served to establish GFR prediction equations (eGFR), which were used to compare the remaining 76 steroid-free and 32 steroid-positive studies (median prednisone dose 33.0 mg m− 2 day− 1). Results We found a positive relationship between prednisone dose and eGFRβTP (b = 0.414, p = 0.0002) and a negative relationship with eGFRcys (b = −0.208, p = 0.0091). Only Cys independently predicted GFR below 90 mL min− 1 1.73 m− 2, both in steroid-positives (b = 6.260, p = 0.010) and steroid-negatives (b = 6.845, p = 0.012). Glucocorticoid therapy did not affect the accuracy in estimating GFR within 30% of measured GFR for Cys, while accuracy was lower with bTP (65.6% vs. 81.6%, p = 0.08). Conclusion Glucocorticoids have less impact on the diagnostic accuracy of Cys than bTP.