Purpose: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard-of-care has not been established due to a paucity of data. Methods: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. Results: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n=13; 31.7%), followed by posterior fossa (n=7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, one from pneumonia and one from Moyamoya following radiation-therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types – 62% germinomas, 79% for NGGCTs, and 53% for teratomas. Conclusion: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.

Nonprofit organizations (NPOs) play critical roles as funding sources, research partners, and disseminators of emerging drug developments in pediatric cancer, yet the literature offers limited understanding or guidance of ethical best practices and processes. We conducted a systematic search for peer reviewed articles, commentaries, newsletters, and white papers indexed in the PubMed and Web of Science databases to identify the ethical, legal, and social responsibilities of NPOs to i) patients/families, ii) researchers, iii) sponsors, and iv) donors when funding clinical trials. Fifty-four articles met the inclusion criteria. Minimizing conflicts of interest, ensuring transparent reporting of trial endpoints, and communicating with families about trial opportunities emerged as key themes. We identified critical gaps in the literature related to negotiating research partnerships, setting trial priorities and establishing best ethical practices in the emerging field of venture philanthropy. Results informed points to consider for NPOs when funding pediatric cancer clinical trials going forward.

Background and objectives: To investigate the feasibility and safety of ultrasound-guided totally implantable venous access ports (TIVAPs) via the right brachiocephalic vein (BCV) in pediatric patients. Methods: A single institutional retrospective review was performed on 35 pediatric patients with hematological malignancies who underwent TIVAPs implantation via ultrasound-guided right BCV approach from July 2018 to June 2021. Technical success rate, procedural information and TIVAP related complications were evaluated. Results: All the pediatric TIVAP devices were successfully implanted via right BCV access. Venous access was successful by first attempt in 32 children (91.42%); two cases (5.71%) required a second attempt; one patient (2.86%) required a third attempt. The mean procedural time was 44.63 ± 6.41 mins (range, 34-62 mins). No intraoperative complications occurred. The average TIVAP indwelling time was 563.51 ± 208.47 days (range, 193-1014 days) with a cumulative 19,723 catheter-days. The incidence of postoperative complications was 11.43% (4/35), corresponding to a rate of 0.20 complications per 1000 catheter-days. Two cases of local hematoma and two catheter dysfunctions occurred in three patients. No other complications such as wound dehiscence, delayed incision healing, catheter-related thrombosis (CRT), catheter malposition/fracture, surgical site infection, catheter-related bloodstream infection (CRBSI), pinch-off syndrome and drug extravasation were observed during follow-up. Conclusions: Ultrasound-guided right BCV access for TIVAPs placement in pediatric patients appears to be technically feasible, safe and effective. Further large-sample, prospective studies are warranted.

To the editor: Is it possible to achieve long-term survival in relapsed Intracranial Non-Germinomatous Germ Cell Tumours?

Title: Posterior Reversible Encephalopathy Syndrome and Necrotizing Enterocolitis in a Pediatric Patient with Medulloblastoma Infected with COVID-19

Background: Flow artifact, intrinsic to Magnetic Resonance Angiography (MRA), is dependent on technical parameters and can lead to overinterpretation of stenosis. Degree of cerebrovascular stenosis in pediatric patients with sickle cell anemia (SCA) informs need for chronic transfusion therapy, which may have significant risks. The primary objective of this study was to document any change in stroke prevention therapy that could be attributed to the implementation of a standardized MRA scanning protocol. Procedure: A standardized MRA scanning protocol with an echo time of <5 msec was implemented at Montefiore Medical Center in May 2016. Retrospective chart review identified 29 patients ≤ 21 years with SCA cerebral vasculopathy and an MRA head pre- and post-May 2016. Level of arterial stenosis on MRA, echo time, and treatment plans were documented both pre- and post-implementation. McNemar analysis determined the significance of change in treatment plans before and after implementation of the standardized scanning protocol. Results: Previously seen stenosis was re-classified to a lower degree in 12/29 patients (41%). Notably, 6 patients had a reclassification of vasculopathy leading to discontinuation of chronic transfusion therapy whereas 0 patients required escalation of therapy to chronic transfusions. McNemar analysis showed this difference to be statistically significant (p = 0.042). Conclusion: Minimizing flow artifact with echo time <5msec improves accurate interpretation of true cerebrovascular disease and ensures appropriate treatment plans are in place for stroke prevention. This is especially important when trying to implement “TCD With Transfusions Changing to Hydroxyurea (TWiTCH)” clinical trial results in the real-world setting.

A document by H Shafeeq Ahmed. Click on the document to view its contents.

A document by Bilawal Nadeem. Click on the document to view its contents.

High-dose methotrexate (HD-MTX) with rigorous supportive care is essential to the treatment of pediatric non-Hodgkin lymphomas (NHL). We describe the safety and tolerability of HD-MTX in patients with NHL treated at our center. In our cohort of 46 patients, the majority had at least one course of delayed clearance and/or creatinine elevation. Additionally, more than one-third of patients experienced an episode of grade ≥3 mucositis. Creatinine elevations and delayed clearance were independently associated with subsequent grade ≥3 mucositis. We advocate for greater availability of methotrexate monitoring to allow dose escalation of this essential modality around the world.

Comment on: Standardizing the surgical management of benign ovarian tumors in children and adolescents: A best practice Delphi consensus statement.Matthew J. Murray1,2, Nigel J. Hall3, Sara Stoneham4, Anthony Penn5, Mark Brougham6, James C. Nicholson1,7; on behalf of the Children’s Cancer and Leukaemia Group (CCLG) Germ Cell Tumour (GCT) Special Interest Group (SIG).1 Department of Paediatric Haematology and Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK2 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK3 University Surgery Unit, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK4 Department of Paediatrics and Child Health, University College Hospital London NHS Foundation Trust, London, UK5 Department of Paediatric Oncology, Royal Manchester Children’s Hospital, Oxford Road, Manchester, M13 9WL, UK6 Department of Paediatric Oncology, Royal Hospital for Children & Young People, 50 Little France Crescent, Edinburgh bio Quarter, Edinburgh, EH16 4TJ, UK7 Department of Paediatrics, University of Cambridge, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UKConflict of interest statement : the authors declare no conflicts of interest.We read with interest the article from Braungart and colleagues, discussing management of young females with benign ovarian tumors [1]. This is important and timely, and we agree with the need for clarity in management of this under-investigated group. As the authors note, published evidence to support decisions is limited, so in certain areas, guidance may have to rely on expert opinion. The authors emphasize the importance of multidisciplinary team (MDT) discussion to optimise management and risk-stratification [1]. They highlight the importance and safety of ovarian-sparing-surgery in benign tumors, to preserve fertility and avoid long-term effects including premature ovarian failure [1].However, important aspects of their methodology are unclear. The denominator (number of experts approached to be involved) and response rate is not stated. The standard thresholds for accepting Delphi statements is >70% votes in support from >60% of experts in each voting round [2], as used in Delphi studies undertaken by the authors here [3,4]. Furthermore, there is no indication of level of support for statement(s) not reaching the 70% threshold. Moreover, they list specialties involved without defining numbers in each group, preventing assessment of the work’s objectivity and relative representation. Frequent criticisms of Delphi method work are poor questionnaire/statement design, compounded by inadequate definition/ selection of experts [5]. For example, ‘the inclusion of other clinicians… may be appropriate to provide an alternative clinical view, particularly when the study is expected to have an impact beyond a particular specialist field’ [5]. Of particular note, the study states that a ‘…. Delphi panel was instigated that included… pediatric oncologists representing CCLG Germ Cell Tumour Group’ [1]. Unfortunately, there was no pediatric oncologist involvement from the group in formulating the statements for discussion. Subsequently, only one was invited to participate in the Delphi itself, once the statements had been finalized. Furthermore, there was no patient/parent representation in the Delphi process, crucial to involve for a benign disease, with issues regarding surgical approach, fertility, and the burden of proposed ultrasound follow-up.The surgical guidance is useful; however, a size cut-off for minimally invasive surgery is specified, without supportive evidence [1]. Another incongruity is for tumor marker follow-up (section 2.3, bullet 7) if they were elevated preoperatively; by definition this group should have had normal markers at diagnosis (section 2.1, first paragraph) [1]. In the follow-up section (2.3), bullet-points 3-5 are most contentious as no evidence is presented for dictating time-interval to scan, and a recent systematic review looking at this indication, which concluded, based on available evidence, that ‘routine surveillance… should certainly be considered’ and suggested annual ultrasound [6], was overlooked. In addition, no reference is provided here to existing guidelines [7]. The recommended two-year interval between ultrasounds [1] is therefore neither evidence-based nor considers the patient/parent opinion. Furthermore, there is no justification for gynecologic fertility referral following ovarian-sparing-surgery where subsequent ultrasound shows normal ovarian reserve bilaterally. Consequently, terms relating to specific aspects that ‘should’ include/be undertaken/performed are inappropriate. Suggesting that ‘a reasonable strategy that could be considered might be as follows…’ would be a better approach.In summary, attempts to improve the management of young females with benign ovarian tumors are laudable. Some of the surgical recommendations made should help to streamline care. However, a representative group of key stakeholders were not included in the Delphi method and most of the follow-up recommendations cannot be justified based on use of a limited group of experts with limited supporting evidence. What is required is a wider collaborative approach, including GCT, surgical, gynecologic, radiology, and importantly patient groups, to answer these questions more robustly, preferably with international collaboration. This will also ensure appropriate clinician engagement, minimise inconsistencies in management and optimise outcomes for this patient group.

The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT) consists of a collaboration between the Children’s Oncology Group (COG) Soft Tissue Sarcoma Committee, the European pediatric Soft-Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to provide consensus expert opinions for clinical treatment of pediatric soft tissue sarcoma, we sought to provide updated, evidenced-based consensus guidelines for local treatment of parameningeal rhabdomyosarcoma using both existing literature as well as recommendations from the relevant cooperative group clinical trials. Overall, parameningeal rhabdomyosarcoma represents a distinctly challenging disease to treat given its location near many critical structures in the head and neck, frequently advanced local presentation, and predilection for local failure. Definitive chemoradiation remains the standard treatment approach for parameningeal rhabdomyosarcoma, with surgery often limited to biopsy or salvage therapy for recurrent disease. In this consensus paper, we specifically discuss consensus guidelines and evidence for definitive local management with radiotherapy, with a focus on imaging for radiotherapy planning, dose and timing of radiation, approach for nodal irradiation, various radiation techniques including proton therapy, and the limited role of surgical resection.

A document by Patrick Reeves. Click on the document to view its contents.

A document by Gauthier Toutain. Click on the document to view its contents.

AIMS This study analysed the clinical features of children with intracranial germ cell tumours (IC-GCTs) treated at two European centres. We retrospectively reviewed timelag between symptoms onset, clinic-radiological findings, diagnosis and outcomes. METHODS Symptoms at diagnosis were divided into four groups: 1)raised intracranial pressure (RICP); 2)visual impairment; 3)endocrinopathy; 4)other. Total diagnostic interval (TDI), defined as the interval between symptom onset (including retrospective recall of symptoms) and definitive diagnosis of IC-GCT, was calculated and compared to survival rates. RESULTS Our cohort included 55 children with a median follow-up of 78.9 months (0.5-249.9). The majority (63.6%) had germinomas and 10.9% were metastatic at diagnosis. IC-GCTs were suprasellar (41.8%), pineal (36.4%), bifocal (12.7%) or in atypical sites (9.1%). The most common presenting symptoms were related to RICP (43.6%); however, by the time of tumour diagnosis, 50.9% of the patients had developed endocrine dysfunctions. All pineal GCTs manifested with RICP or visual impairment. All suprasellar GCTs presented with endocrinopathies. TDI ranged between 0.25-58.5 months (median 4 months). Pineal GCTs had the shortest TDI (median TDI 1 month versus 24 months in suprasellar GCTs, p<0.001). TDI >6 months was observed in 47.3% of patients and was significantly associated with endocrine presenting symptoms. No statistically significant difference was found in progression-free survival and overall survival between patients with TDI >6 months and with TDI 6 months. CONCLUSION Approximately half of our patients had TDI >6 months, mostly with endocrine deficiencies as presenting symptoms. TDI >6 months was not associated with increased relapse rate or mortality.

Background Adolescent and young adult (AYA) women with sickle cell disease (SCD) have increased pregnancy-related health risks and are prescribed potentially teratogenic medications, yet little is known about pediatric SCD provider contraceptive practices. We aimed to assess pediatric hematology providers’ beliefs, practices, motivators, and barriers for providing contraceptive care to female AYA with SCD. Methods Guided by the Health Belief Model (HBM), we developed a 25-question, web-based survey to assess providers’ practices. Survey links were distributed nation-wide to pediatric SCD and/or general hematology providers through their publicly available emails and by request to directors of U.S. accredited Pediatric Hematology-Oncology fellowship programs for distribution to their SCD providers. Data analysis included descriptive statistics, chi-square analysis, logistic regression. Results Of 177 respondents, 160 surveys meeting inclusion criteria were analyzed. Most providers reported counseling (77.5%) and referring female AYA patients for contraception (90.8%), but fewer reported prescribing contraception (41.8%). Counseling practices significantly differed in trainees versus established providers (54% vs. 85%, p<0.001) with a similar trend for prescribing (p=0.05). Prescription practices did not differ significantly by provider beliefs regarding potential teratogenicity of hydroxyurea. Key motivators included patient request and disclosure of sexual activity. Key barriers included inadequate provider training, limited visit time, and perceived patient/parent interest. Conclusion Provider contraceptive practices for female AYA with SCD varied, especially by provider status. Health beliefs regarding teratogenic potential of hydroxyurea did not correlate with contraceptive practices. Clinical guidelines, provider training, and patient/parent decision-making tools may be tested to assess whether provider contraceptive practices could be improved.

Survival of Wilms tumor (WT) is >90% in high-resource settings but <30% in low-resource settings. Adapting a standardized surgical approach to WT is challenging in low-resource settings, but a local control strategy is crucial to improving outcomes. Objective: Provide resource-sensitive recommendations for the surgical management of WT. Methods: We performed a systematic review of PubMed and EMBASE through July 7, 2020, and used the GRADE approach to assess evidence and recommendations. Recommendations: Initiation of treatment should be expedited, and surgery should be done in a high-volume setting. Cross-sectional imaging should be done to optimize preoperative planning. For patients with typical clinical features of WT, biopsy should not be done before chemotherapy, and neoadjuvant chemotherapy should precede surgical resection. Also, resection should include a large transperitoneal laparotomy, adequate lymph node sampling, and documentation of staging findings. For WT with tumor thrombus in the inferior vena cava, neoadjuvant chemotherapy should be given before en bloc resection of the tumor and thrombus and evaluation for viable tumor thrombus. For those with bilateral WT, neoadjuvant chemotherapy should be given for 6–12 weeks. Neither routine use of complex hilar control techniques during nephron-sparing surgery, nor nephron-sparing resection for unilateral WT with a normal contralateral kidney is recommended. When indicated, postoperative radiotherapy should be administered within 14 days of surgery. Post-chemotherapy pulmonary oligometastasis should be resected when feasible, if local protocols allow omission of whole-lung irradiation in patients with non-anaplastic histology stage IV WT with pulmonary metastasis without evidence of extrapulmonary metastasis. Conclusion: We provide evidence-based recommendations for the surgical management of WT, considering the benefits/risks associated with limited-resource settings.

GLUTEUS AS A RARE LOCALIZATION OF EXTRAGONADAL TERATOMAAuthorship: Leardini Davide 1, Cerasi Sara1, Cantarini Maria Elena 1, Facchini Elena 1, Prete Arcangelo 1, Masetti Riccardo 11 Pediatric Oncology and Hematology Unit ”Lalla Seràgnoli”, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyCorrespondence: Sara Cerasi; address: via G. Massarenti 11, 40138, Bologna (BO), Italy; phone: +39 051 2144665; e-mail:[email protected] Count for Main Text: 547 wordsAttached to this manuscript there is 1 figureKeywords: extragonadal teratoma, gluteal mass, immature teratomaRunning title: Rare non-midline teratomaTo the Editor,Teratomas represent the most common germ cell tumors in children1. They can be gonadal, more common in adolescents, or extragonadal, primarily in neonates and young children. Teratomas develop from totipotent primordial cells and may originate anywhere along the midline. Common sites for extragonadal teratomas are the sacrococcygeal region, which accounts for 35-60% of all teratomas, the mediastinum, the retroperitoneum, the head and neck and the central nervous system2–4. Other localizations are rare, especially non-midline ones that are very often lateralized expansions of midline teratomas, such as those arising from sacrococcygeal region.We here describe the case of a newborn girl presenting with a gluteal mass, that revealed to be a primary extragonadal teratoma. At birth she presented with a hard-elastic, mobile and painless mass localized within the right gluteus (Fig.1), that had not been noted on prenatal ultrasound. At two days of life, an echography was performed, revealing a subcutaneous irregularly hypoechoic mass with fluid areas inside and small vessels, with aspecific characteristics. The dimension of the mass was 24x15 mm and rapidly increased in size, reaching 40x25mm, and in the number of fluid areas (Fig. 1). Alfafetoprotein serum concentration resulted 4586 ng/mL (refence value at the 2 week-1 month interval at which she was tested 316-6310 ng/mL) and hCG was 0,8 UI/L (normal value <5 UI/L)5. After performing an MRI that excluded other lesions, the mass was removed and a biopsy was performed, revealing an immature teratoma, grade 3 according to Norris’s classification. Since extragonadal teratomas out of the midline are very rare, she has been followed up thoroughly for 3 years with regular periodic blood tests and radiological assessments, but no other primary lesions or recurrencies were found.Teratomas can be malignant (12-14%) or benign, further divided into mature (50-60%) and immature (18-34%). Immature teratomas contain fetal tissue, most often neuroectodermal, the amount of which is scored according to a grading system introduced by Norris. Grade 3 is that with most neuroectodermal tissue, and have an increased incidence of local recurrence and malignant degeneration3,4,6. Complete and prompt surgical resection is the gold standard for definitive therapy in benign teratomas, both mature and immature4,6.Teratomas develop along the midline because they originate from the incomplete differentiation of totipotent primordial cells that arise in the yolk sac and migrate along the mesentery to the gonadal ridge during the 4th-5th week of embryologic development3,4. Indeed, most of the gluteal teratomas reported in literature are lateralized sacrococcygeal teratomas with a connection to the coccyx, since sacrococcygeal teratomas are thought to be derived from totipotent cells of the Hensen’s node (primitive knot), an area at the cranial end of the primitive streak7,6.Other authors reported rare sites for lateralized teratoma development such as kidney, liver and temporozygomatic region8,9. Rare lateralized extragonadal localizations should not mislead the clinical suspicion of teratomas, and a primary localization should always be excluded. Taking also the patient’s age into account, it can sometimes be considered to perform a PET scan. To the best of our knowledge, there is just one case in literature of a gluteal teratoma not in connection with the coccyx, as in our patient, thus confirming the possibility of this very rare localization10. The biological mechanism for germ-cell migration in such anatomical regions is still to be elucidated.ACKNOWLEDGEMENTS: None.CONFLICT OF INTERESTThe authors declare that there is no conflict of interest.ETHICS STATEMENTWritten informed consent has been obtained from the patient to publish this paper.

Background: Sickle cell disease (SCD) is characterized by both acute and chronic complications that affect the daily lives of patients and lower their quality of life. Objective: To describe the health-related quality of life (HRQoL) and the associated factors in children aged 8 to 17 with SCD attending the paediatric haematology clinic at Kamuzu Central Hospital (KCH) in Lilongwe, Malawi. Methods: A mixed methods cross sectional study was conducted at KCH. Patient data was collected with the aid of a standardized case report form. HRQoL was assessed using PedsQL™ Sickle Cell Disease Module by child’s report. Associations between HRQoL scores and independent variables were evaluated by a linear regression model. In-depth interviews were then carried out and the qualitative data was analyzed using content thematic analysis. Results: A hundred and sixty-three children with SCD were enrolled, 52.1% were females. Their median age was 11.2±2.7 years. The mean global HRQoL score of the children was 62±17.3. The highest scores were in the treatment domain (72.5±15.1) while the lowest scores were in the emotions domain (55.2±28.7). The mean pain score was 58.8±16.3. The factors associated with low HRQoL scores were pain (β-coefficient -6.97 CI (-3.07,-15.58); p value 0.034) and low haemoglobin levels (β-coefficient 2.29 CI (0.65-3.91); p value 0.006 ). Conclusion: The HRQoL of this population is low. Pain and low hemoglobin were significantly associated with low HRQoL scores. A biopsychosocial model of heath care delivery and health campaigns are recommended to improve the HRQoL of the children.