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Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarthe rhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab. [ABSTRACT FROM AUTHOR]

Introduction: Radiotherapy protocols for high-risk neuroblastoma (HR-NBL) vary across international studies. The purpose of this study was to evaluate the locoregional control in a national HR-NBL cohort treated with highly-conformal image-guided radiotherapy (IGRT), using reduced margins, and a boost dose for residual lesions., Materials and Methods: Patients treated with radiotherapy as part of first-line HR-NBL treatment between 2015 and 2022 were eligible. To obtain clinical, internal, and planning target volumes, +0.5 cm, 4DCT-based, and + 0.3/0.5 cm margins, respectively, were added to the edited gross tumour volumes. Prescription dose was 21.6/1.8 Gy, followed by 14.4/1.8 Gy for any residual lesions measuring ≥ 1 cm 3 at the time of radiotherapy planning. Intensity-modulated arc therapy was combined with daily cone beam CT-based online patient position verification. Locoregional failure (LRF) rates were compared for the presence of residual lesions < 1 cm 3 vs. ≥ 1 cm 3 (with/without locoregional activity on nuclear- and MRI[diffusion-weighted imaging]-scans) pre-radiotherapy, age at diagnosis, MYCN-status, [ 131 I]mIBG therapy, response to induction chemotherapy, interval to radiotherapy onset, and metastatic site irradiation., Results: Among the 77 included patients, 34 had residual lesions (median volume: 10.0 cm 3 , IQR 4.8-29.9) with activity visible on 17 nuclear- and 10 MRI-scans. Five-year LRF rate was 7.8 % (95 % confidence interval 1.8-13.8), and not significantly different between those with residual lesions < 1 cm 3 vs. ≥ 1 cm 3 (6.4 % vs. 14.3 %, respectively, p = 0.27), or any of the other variables. All 6 LRFs (2 isolated, 4 combined) occurred < 1.5 years post-radiotherapy., Conclusion: In HR-NBL, IGRT with reduced margins and a boost dose for residual lesions ≥ 1 cm 3 demonstrated excellent locoregional control, comparable to modern literature., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Atia Samim, Annemieke S. Littooij, Max Peters, Bart de Keizer, Alida F.W. van der Steeg, Raquel Dávila Fajardo, Kathelijne C.J.M. Kraal, Miranda P. Dierselhuis, Natasha K.A. van Eijkelenburg, Martine van Grotel, Roel Polak, Cornelis P. van de Ven, Marc H.W.A. Wijnen, Enrica Seravalli, Mirjam E. Willemsen-Bosman, Max M. van Noesel, Godelieve A.M. Tytgat, Geert O. Janssens: No conflict of interest]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The main data available on the safety of radiation during pregnancy originate from animal studies and from studies of survivors of atomic or nuclear disasters. The effect of radiotherapy to treat maternal cancer on fetal development is uncertain. This report presents a unique cohort and aims to determine the long-term neurocognitive, psychosocial and physical outcomes of offspring of mothers treated with radiotherapy during pregnancy., Methods: In this international, multicentre, mixed retrospective-prospective cohort study, we recruited participants between Aug 5, 2006, and Aug 24, 2023, aged between 1·5 and 46 years, at three referral centres in Belgium, the Netherlands, and the USA. Participants were eligible if they were born from mothers treated with radiotherapy during pregnancy. Fetal radiation doses were obtained from medical records and participants were followed up at predefined ages (1·5, 3, 6, 9, 12, 15, and 18 years) and 5-yearly in adulthood, based on age at enrolment, using a neurocognitive test battery (measuring intelligence, attention, and memory), parent-reported executive function and psychosocial questionnaires, and a medical assessment. Results were compared with test-specific normative data. Linear regression models investigated associations between radiotherapy factors (fetal radiation dose, gestational age at the start and end of radiotherapy, and radiotherapy duration) and outcomes., Findings: 68 maternal cases of radiotherapy during pregnancy were registered by the three participating centres, of which 61 resulted in a livebirth and were therefore eligible to participate in the child follow-up study. After excluding those who did not give consent, 43 participants born from 42 mothers treated with radiotherapy during pregnancy were included in the study (median age at first assessment 3 years [IQR 2-11]; median age at last assessment 12 years [9-18]; median number of assessments two [1-4]). 18 (42%) of the included participants were female and 25 (58%) male, and 37 (86%) were of White ethnicity. Mean neurocognitive outcomes of the entire cohort were within normal ranges. No associations were found with fetal radiation dose or timing of radiotherapy during pregnancy. Six (16%) of 38 participants with neurocognitive outcomes scored lower than one SD on at least one neurocognitive outcome, three (7%) reported chronic medical conditions (spasmophilia, spastic diplegia, and IgG deficiency), and three (7%) were diagnosed with attention-deficit hyperactivity disorder (of whom two scored lower on attention). Of ten (23%) participants with lower neurocognitive score(s), a chronic medical condition, or attention-deficit hyperactivity disorder, eight were born preterm. The remaining 33 (77%) participants showed no neurocognitive, psychosocial, or chronic physical problems., Interpretation: We show on average normal neurocognitive, psychosocial, and physical outcomes after prenatal exposure to radiotherapy. Differences in outcomes could not be explained by exposure to radiotherapy during pregnancy. These results suggest that extra-abdomino-pelvic radiotherapy exposure during pregnancy in general does not adversely affect outcomes of liveborn children. Further research with a larger sample is necessary to confirm these findings., Funding: Kom Op Tegen Kanker, KWF Kankerbestrijding, Stichting Tegen Kanker, Research Foundation Flanders., Competing Interests: Declaration of interests FA is on the MiMARK advisory board for early detection of endometrial cancer and is Chair of the International Network on Cancer, Infertility, and Pregnancy of the European Society of Gynecologic Oncology, and of the Advisory Board on Cancer, Infertility and Pregnancy. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Nephrotoxicity can occur as a side effect after treatment for kidney tumor in childhood. The use of radiotherapy (RT) has a potential additional effect., Methods: A systematic electronic literature search that combined childhood kidney cancer with different treatments and nephrotoxicity terms was performed in EMBASE. Studies were included based on the reporting of nephrotoxicity occurrence after treatment for kidney tumor during pediatric age, with 75% of participants being under the age of 25 years at the time of diagnosis, and having been treated with any type of kidney surgery, chemotherapy, and/or RT., Results: A pooled analysis did not show significant difference in estimated glomerular filtration rate between the group of patients who received RT compared with the group treated without RT (SMD -0.11 [95% CI -1.07-0.84] p = .733)., Conclusion: The current literature suggests that the use of RT does not have a significant impact on the decline of kidney function as independent factor., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background and Aims: Solid tumors account for about 30% of all pediatric cancers. The diagnosis is typically based on histological and molecular analysis of a primary tumor biopsy. Liquid biopsies carry several advantages over conventional tissue biopsy. However, their use for genomic analysis and response monitoring of pediatric solid tumors is still in experimental stages and mostly performed retrospectively without direct impact on patient management. In this case series we discuss six clinical cases of children with a solid tumor for whom a liquid biopsy assay was performed and demonstrate the potential of liquid biopsy for future clinical decision making., Methods: We performed quantitative real-time PCR (RT-qPCR), droplet digital PCR (ddPCR) or reduced representation bisulphite sequencing of cell-free DNA (cfRRBS) on liquid biopsies collected from six pediatric patients with a solid tumor treated between 2017 and 2023 at the Princess Máxima Center for Pediatric Oncology in the Netherlands. Results were used to aid in clinical decision making by contribution to establish a diagnosis, by prognostication and response to therapy monitoring., Results: In three patients cfRRBS helped to establish the diagnosis of a rhabdomyosarcoma, an Ewing sarcoma and a neuroblastoma (case 1-3). In two patients, liquid biopsies were used for prognostication, by MYCN ddPCR in a patient with neuroblastoma and by RT-qPCR testing rhabdomyosarcoma-specific mRNA in bone marrow of a patient with a rhabdomyosarcoma (case 4 and 5). In case 6, mRNA testing demonstrated disease progression and assisted clinical decision making., Conclusion: This case series illustrates the value of liquid biopsy. We further demonstrate and recommend the use of liquid biopsies to be used in conjunction with conventional methods for the determination of metastatic status, prognostication and monitoring of treatment response in patients with pediatric solid tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gelineau, van Barneveld, Samim, Van Zogchel, Lak, Tas, Matser, Mavinkurve-Groothuis, van Grotel, Zsiros, van Eijkelenburg, Knops, van Ewijk, Langenberg, Krijger, Hiemcke-Jiwa, Van Paemel, Cornelli, De Preter, De Wilde, Van Der Schoot and Tytgat.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. This multicenter cohort study reports on the long-term effects of prenatal exposure to maternal cancer and its treatment on cognitive and behavioral outcomes in 9-year-old children. In total, 151 children (mean age, 9.3 years; range, 7.8-10.6 years) were assessed using a neurocognitive test battery and parent-report behavioral questionnaires. During pregnancy, 109 children (72.2%) were exposed to chemotherapy (only or in combination with other treatment modalities), 18 (11.9%) to surgery only, 16 (10.6%) to radiotherapy, one to trastuzumab, and 16 (10.6%) were not exposed to oncologic treatment. Mean cognitive and behavioral outcomes were within normal ranges. Gestational age at birth showed a positive association with Full Scale Intelligence Quotient (FSIQ), with the average FSIQ score increasing by 1.6 points for each week increase in gestational age (95% CI, 0.7 to 2.5; P < .001). No difference in FSIQ was found between treatment types (F[4,140] = 0.45, P = .776). In children prenatally exposed to chemotherapy, no associations were found between FSIQ and chemotherapeutic agent, exposure level, or timing during pregnancy. These results indicate a reassuring follow-up during the critical maturational period of late childhood, when complex functions develop and rely on the integrity of early brain development. However, associations were observed with preterm birth, maternal death, and maternal education.

Importance: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on., Objective: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice., Methods: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel., Findings: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources., Conclusions and Relevance: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.

Data on the long-term neurodevelopmental outcomes of children exposed to hematological maternal cancer with or without treatment during pregnancy are lacking. A total of 57 children, of whom 33 males and 24 females, prenatally exposed to hematological malignancies and its treatment, were invited for neuropsychological and physical examinations at 18 months, 36 months, 6, 9, 12, 15 and 18 years of age. Oncological, obstetrical, neonatal and follow-up data of these children were collected. Parents were asked to complete questionnaires on their child's general health, school performances, social situation, behavioral development, executive functioning, and if their child receives supportive care. Non-Hodgkin lymphoma was diagnosed in 35.1%, Hodgkin lymphoma in 28.1%, acute myeloid leukemia in 15.8%, chronic myeloid leukemia in 12.3%, and acute lymphoblastic leukemia in 8.8%. Cognitive development at a median age of 10.7 years was within the normal range. In subgroup analyses of children in early childhood, the gestational age at birth was correlated with the cognitive outcome at a median age of 1.7 years. Scores for language development, intelligence, attention, memory and behavior, as well as clinical neurological and general pediatric examinations were within normal ranges. In subgroup analyses, the need for supportive care in the child was associated with the loss of the mother. Prenatal exposure to hematological maternal malignancies with or without treatment did not affect the neurodevelopment of the child in the long term. Yet, caution is indicated and surveillance of the emotional development of the child is needed, especially when the mother is deceased to cancer.

The importance of viral infections as a leading cause of morbidity and mortality is well documented in severely immunosuppressed patients undergoing allogeneic stem cell transplantation. By contrast, viral infections generally receive less attention in patients with malignant disorders undergoing chemotherapy, where the onset of neutropenic fever is mostly associated with bacterial or fungal infections, and screening for viral infections is not routinely performed. To address the occurrence of invasive viral infections in a clinical setting commonly associated with less pronounced immunosuppression, we have prospectively screened 237 febrile neutropenic episodes in pediatric (n = 77) and adult (n = 69) patients undergoing intensive chemotherapy, primarily for treatment of acute leukemia. Serial peripheral blood specimens were tested by RQ-PCR assays for the presence and quantity of the clinically relevant viruses CMV, EBV, HHV6 and HAdV, commonly reactivated in highly immunocompromised patients. Viremia was documented in 36 (15%) episodes investigated, including the detection of HHV6 (n = 14), EBV (n = 15), CMV (n = 6), or HAdV (n = 1). While low or intermediate levels of viremia (<10 4 virus copies/mL) were commonly associated with bacterial or fungal co-infection, viremia at higher levels (>10 4 copies/mL) was documented in patients without evidence for other infections, raising the possibility that at least in some instances the onset of fever may have been attributable to the virus detected. The observations suggest that viral infections, potentially resulting from reactivation, might also play a clinically relevant role in patients receiving chemotherapy for treatment of malignant neoplasms, and routine screening for viremia in this clinical setting might be warranted., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: For decades, Anterior-Posterior/Posterior-Anterior (AP/PA) photon beams were standard-of-care for flank irradiation in children with renal cancer. Recently, highly conformal flank target volumes were defined correcting for postoperative organ shift and intra-fraction motion.By radiotherapy treatment plan comparison, this study aims to estimate the clinical benefits and potential risks of combining highly conformal target volumes with Volumetric-Modulated Arc Therapy (VMAT) versus conventional target volumes with AP/PA beams for flank irradiation., Materials and Methods: Twenty consecutive renal tumor cases (left/right-sided:10/10; median age:3.2 years) were selected. Highly conformal flank target volumes were generated for VMAT, while conventional target volumes were used for AP/PA. For each case, the dose to the organs at risk (OARs) and Total Body Volume (TBV) was calculated to compare VMAT with AP/PA treatment plans for a prescribed dose (PD) of 14.4/1.8 Gy. Dose constraint violation of the tail of the pancreas and spleen (D mean  < 10 Gy), heart (D 50  < 5 Gy) or mammary buds (D mean  < 10 Gy) were prioritized as potentially beneficial for clinics., Results: Highly conformal Planning Target Volumes (PTV) were smaller than conventional volumes (mean ΔPTV AP/PA -PTV VMAT : 555 mL, Δ60%, p=<0.01). A mean dose reduction favoring VMAT was observed for almost all OARs. Dose constraints to the tail of the pancreas, spleen, heart and mammary buds were fulfilled in 8/20, 12/20, 16/20 and 19/20 cases with AP/PA, versus 14/20, 17/20, 20/20 and 20/20 cases with VMAT, respectively. In 12/20 cases, VMAT prevented the dose constraint violation of one or more OARs otherwise exceeded by AP/PA. VMAT increased the TBV receiving 10% of the PD, but reduced the amount of irradiated TBV for all higher doses., Conclusion: Compared to 14.4 Gy flank irradiation using conventional AP/PA photon beams, an estimated clinical benefit by dose reduction to the OARs can be expected in 60% of the pediatric renal tumor cases using highly conformal flank target volumes combined with VMAT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Objective: Growing up with a chronic disease comes with challenges, such as coping with fatigue. Many adolescents are severely fatigued, though its associated factors exhibit considerable interpersonal and longitudinal variation. We assessed whether PROfeel, a combination of a smartphone-based ecological momentary assessment (EMA) method using the internet, followed by a face-to-face dialogue and personalized advice for improvement of symptoms or tailor treatment based on a dynamic network analysis report, was feasible and useful., Study Design: Feasibility study in fatigued outpatient adolescents 12-18 years of age with cystic fibrosis, autoimmune disease, post-cancer treatment, or with medically unexplained fatigue. Participants were assessed at baseline to personalize EMA questions. EMA was conducted via smartphone notifications five times per day for approximately six weeks. Hereby, data was collected via the internet. The EMA results were translated into a personalized report, discussed with the participant, and subsequently translated into a personalized advice. Afterwards, semi-structured interviews on feasibility and usefulness were held., Results: Fifty-seven adolescents were assessed (mean age 16.2 y ± 1.6, 16% male). Adolescents deemed the smartphone-based EMA feasible, with the app being used for an average of 49 days. Forty-two percent of the notifications were answered and 85% of the participants would recommend the app to other adolescents. The personalized report was deemed useful and comprehensible and 95% recognized themselves in the personalized report, with 64% rating improved insight in their symptoms and subsequent steps towards an approach to reduce one's fatigue as good or very good., Conclusions: PROfeel was found to be highly feasible and useful for fatigued adolescents with a chronic condition. This innovative method has clinical relevance through bringing a patient's daily life into the clinical conversation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Background and Purpose: Recently, the SIOP-RTSG developed a highly-conformal flank target volume definition for children with renal tumors. The aims of this study were to evaluate the inter-clinician delineation variation of this new target volume definition in an international multicenter setting and to explore the necessity of quality assurance., Materials and Methods: Six pediatric renal cancer cases were transferred to ten radiation oncologists from seven European countries ('participants'). These participants delineated the pre- and postoperative Gross Tumor Volume (GTV pre/post ), and Clinical Target Volume (CTV) during two test phases (case 1-2 and 3-4), followed by guideline refinement and a quality assurance phase (case 5-6). Reference target volumes (TV ref ) were established by three experienced radiation oncologists. The Dice Similarity Coefficient between the reference and participants (DSC ref/part ) was calculated per case. Delineations of case 5-6 were graded by four independent reviewers as 'per protocol' (0-4 mm), 'minor deviation' (5-9 mm) or 'major deviation' (≥10 mm) from the delineation guideline using 18 standardized criteria. Also, a major deviation resulting in underestimation of the CTV ref was regarded as an unacceptable variation., Results: A total of 57/60 delineation sets were completed. The median DSC ref/part for the CTV was 0.55 without improvement after sequential cases (case 3-4 vs. case 5-6: p = 0.15). For case 5-6, a major deviation was found for 5/18, 12/17, 18/18 and 4/9 collected delineations of the GTV pre , GTV post , CTV-T and CTV-N, respectively. An unacceptable variation from the CTV ref was found for 7/9 participants for case 5 and 6/9 participants for case 6., Conclusion: This international multicenter delineation exercise demonstrates that the new consensus for highly-conformal postoperative flank target volume delineation leads to geometrical variation among participants. Moreover, standardized review showed an unacceptable delineation variation in the majority of the participants. These findings strongly suggest the need for additional training and centralized pre-treatment review when this target volume delineation approach is implemented on a larger scale., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

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., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (© 2019 Wiley Periodicals, Inc.)

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.

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 2 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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.