Local therapies replaced systemic chemotherapy for ocular preservation in retinoblastoma. In middle income countries, these techniques pose specific challenges mostly related to more advanced disease at diagnosis. The Grupo de America Latina de Oncologia Pediatrica (GALOP developed a consensus document for the management of conservative therapy for retinoblastoma. Intra-arterial chemotherapy (OAC) is the preferred therapy, except those with less advanced disease or age younger than 6 months. OAC allowed for the elimination of the use of external beam radiotherapy in our setting. Intravitreal chemotherapy is the preferred treatment for vitreous seeding. Enucleation is the treatment of choice for advanced eyes.

Background: Irinotecan and temozolmide achieve objective responses in patients with Ewing sarcoma which recurrences after initial therapy. Optional dose schedules have not been defined. Procedure: We reviewed published series of patients treated with irinotecan and temozolomide for Ewing sarcoma which recurred after initial therapy. We compared objective response rates for patients who received 5 day irinotecan treatment schedules to response rates for patients who achieved 10 day irinotecan treatment schedules. Results: Among 94 patients treated with a 10 day irinotecan schedule there were 48 objective responses (51%). Among 218 patients treated with a 5 day irinotecan schedule there were 65 responses (30%). Conclusion: When we use irinotecan to treat Ewing sarcoma we should administer 10 days of treatment.

Background and Objective: Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Anti-glycoprotein autoantibodies play a key role in the pathophysiology of ITP, but the relationship between platelet-specific antibodies and bleeding severity is unclear. This study aimed to analyze the relationship between anti-glycoprotein autoantibodies and bleeding severity in children with newly diagnosed ITP and platelet count <10×109/L. Method: This was a single-center prospective observational study that analyzed children with newly diagnosed ITP and platelet count <10×109/L between June 2018 and September 2021 at our hospital. The children were classified into the mild and severe groups based on the bleeding scores. The type and titer of anti-glycoprotein autoantibodies were detected using an ELISA kit (PAKAUTO). We analyzed the relationship between bleeding severity and anti-glycoprotein autoantibodies. Results: A total of 86 cases were enrolled, including 42 in the mild group and 44 in the severe group. Patients with anti-GPIIb/IIIa or anti-GPIb/IX antibodies suffered more severe bleeding than patients without them (c2=7.303, p=0.007; c2=3.875, p=0.049), but there was no significant difference between patients with or without anti-GPIa/IIa antibody (c2=0.745, p=0.388). When antibodies were analyzed together, patients with three antibodies suffered more severe bleeding than those without three antibodies (c2=5.053, p=0.025). Patients with higher antibody titer in the eluent, but not in the plasma, suffered more severe bleeding in all three antibodies (Z=-2.389, p=0.017; Z=-2.108, p=0.035; Z=-2.557, p=0.011). Conclusion: Anti-glycoprotein autoantibodies led to more severe bleeding in children under 18 years of age without drug treatment with newly diagnosed ITP and platelet count <10×109/L.

A document by Seema Biswas. Click on the document to view its contents.

Relapsed or refractive pediatric B-Acute Lymphoblastic Leukemia (B-ALL) patients have high rates of toxicities and relapse, and novel therapy is needed. We present a case of a 5-year-old male with high-risk B-ALL that was refractive to several re-induction regimens. He was put into MRD-negative remission after re-induction with chemotherapy plus overlapping rituximab, inotuzumab ozogamicin and blinatumomab, termed Mini-Hyper-CVD plus CRIB. This was well tolerated, and he received his transplant and engrafted with no significant infections, toxicities, or sinusoidal obstruction syndrome. This is the first reported use in pediatrics of a condensed sequential immunotherapy/chemotherapy regimen in a pediatric leukemia patient.

Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. High-risk and metastatic disease continues to be associated with very poor prognosis. RMS model systems that faithfully recapitulate the human disease and provide rapid, cost-efficient estimates of anti-tumor efficacy of candidate drugs are needed to facilitate drug development and personalized medicine approaches. Here, we present a new zebrafish-based xenotransplant model allowing for rapid and easily accessible drug screening using low numbers of viable tumor cells and relatively small amounts of water-soluble chemicals. Under optimized temperature conditions, embryonal RMS-xenografts were established in zebrafish embryos at 3 hours post fertilization (hpf). In proof-of-principle experiments, chemotherapy drugs with established clinical anti-RMS efficacy (vincristine, dactinomycin) and the MEK inhibitor trametinib were shown to significantly reduce the cross-sectional area of the tumors by 120 hpf. RMS xenograft models in zebrafish embryos henceforth could serve as a valuable addition to cell culture and mammalian models of RMS and represent a rapid and cost-effective solution for pre-clinical candidate drug testing.

Juxtaglomerular cell tumor with pulmonary metastases: A case report and review of the literatureHideki Sakiyama1, Satoru Hamada1,2, Tokiko Oshiro1,2, Nobuyuki Hyakuna1,2 Masaaki Kuda3, Tomoro Hishiki4, Hajime Aoyama5, Naoto Kuroda6, Kenji Yorita7, Naoki Wada8, Takako Yoshioka9, Yuhki Koga10, Koichi Nakanishi1,21) Department of Pediatrics, University of the Ryukyus Hospital, Uehara, Nishihara, Okinawa, Japan2) Department of Child Health and Welfare, Graduate School of Medicine, University of the Ryukyus, Uehara, Nishihara, Okinawa, Japan3) Department of Digestive and General Surgery Graduate School of Medicine, University of the Ryukyus, Uehara, Nishihara, Okinawa, Japan4) Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan5) Department of Pathology, Heartlife Hospital, Okinawa, Japan6) Department of Internal Medicine, Kinro Hospital, Kochi, Japan7) Department of Diagnostic Pathology, Japanese Red Cross Kochi Hospital, Kochi, Japan8) Department of Pathology and Oncology, Graduate School of Medicine, University of Ryukyus, Uehara, Nishihara, Okinawa, Japan9) Department of Pathology, National Center for Child Health and Development, Tokyo, Japan10) Department of Pediatrics, Graduate School of Medical Science, Kyusyu University, Fukuoka, JapanCorrespondence: Satoru Hamada,Department of Pediatrics, Faculty of Medicine, University of Ryukyus, 207 Uehara, Nishihara-cho, Okinawa 903-0125, [email protected] the Editor: Juxtaglomerular cell tumor (JGT) is a relatively rare, benign renin-producing tumor that causes hypertension, hyperaldosteronism, and hypokalemia due to excessive renin secretion. Here, we report a case of malignant JGT with pulmonary metastases. A 7-year-old male patient was referred to the hospital for proteinuria found during a school medical checkup. An ultrasound examination revealed a tumor on the right kidney. His blood pressure was 170/120 mmHg, and plasma renin activity was high at 30 ng/mL/hr. Computed tomography (CT) revealed a mass of 3.4 cm diameter on the right kidney with multiple pulmonary metastases, which was suggestive of nephroblastoma. He underwent right nephrectomy, resulting in a return of blood pressure and plasma renin activity to normal levels (reference range, 0.2–2.3 ng/mL/hr). Gross examination of the tumor revealed a 3.2 × 3.2 × 10-cm yellowish-white mass with necrosis in the mid pole of the kidney. Most of the tumor was covered with a fibrous membrane that partially extended into the normal tissue. Histology revealed a mesenchymal neoplasm with a blastemal component that was suggestive of nephroblastoma. No vascular invasion was observed within the analyzed area (Supplemental Figures S1, S2). Subsequently, he received chemotherapy according to the DD-4A regimen of the National Wilms Tumor Study Group. The immunophenotype demonstrated renin and CD34 positivity (Supplemental Figures S3, S4). This led to a definitive diagnosis of JGT, which was consistent with the clinical feature of hypertension. Chemotherapy was stopped at week 6, at which point CT revealed unchanged metastatic lung lesions. He then underwent a two-stage surgical resection for bilateral lung metastases, and total resection was achieved. Pathologically, the metastatic lung lesions were consistent with the resected renal tumor. Because no reports of effective chemotherapy for malignant JGT were found, we followed-up this patient without administering adjuvant chemotherapy. He showed no evidence of disease after a 2-year follow-up. Targeted DNA sequencing using FoundationOne® CDx detected six genetic mutations:NOTCH3 T272M, BRAF D22N, MAP3K1 L78P, CDKN2BA56D, DAXX E451del, and ERBB4 P3L in the primary tumor.JGT is a rare benign tumor that is more common in relatively young adults. JGT causes various clinical symptoms, such as headache, nausea, dizziness, weakness, hypertension, and proteinuria.1,2JGT is generally curable by surgical resection, and tumor removal results in the improvement of hyperreninemia and clinical symptoms.1 Immunohistochemically, the diagnosis is confirmed by renin positivity in the cytoplasm. In addition, CD34, CD117, vimentin, and ACTA2 are often positive.2,3Although JGT is generally considered benign, eight malignant or pathologically atypical cases have been reported in the literature (Table).3–10 Six were adult cases, and one was a pediatric case. In all cases, the tumor diameter was relatively large (>5 cm). Pathologically, seven of eight showed either vascular invasion or mitotic figures, and among these cases, four had distant metastasis: case 1 demonstrated bilateral lung metastases 6 years after nephrectomy,4 case 4 demonstrated bilateral lung metastases at initial diagnosis,9 case 6 demonstrated multicentric synchronous disease in the liver and spleen,7 case 8 succumbed to hepatic and bone metastases 10 months after nephrectomy.3 In our case, complete metastasectomy of the bilateral pulmonary nodules was achieved after nephrectomy. Thus, he was in remission at 2 years without adjuvant chemotherapy.Ours is the first reported case of pediatric malignant JGT with multiple pulmonary metastases. Although most patients with malignant JGT present with a large tumor that is pathologically characterized by vascular invasion, our case had a relatively small-sized tumor with no vascular invasion or nuclear atypia. Few reports have described genetic abnormalities in JGT. Targeted DNA sequences in our case revealed six gene mutations although the significance of these mutations in the pathogenesis of malignant JGT is unclear. A previous study reported that the NOTCH3 receptor is highly expressed in reninoma in mice.11 Dysregulation of NOTCH3 signaling plays a role in soft tissue tumor pathogenesis.12 Therefore, the NOTCH3 mutation in our case might have been involved in this malignant transformation. In addition, NOTCH3 signaling has shown to contributed to chemoresistance to doxorubicin13, which was consistence with the clinical feature of an ineffective for metastatic lung lesions after chemotherapy including doxorubicin. JGT is generally considered to be a benign tumor, but malignant cases have recently been reported. Our patient was successfully treated with complete pulmonary metastasectomy after primary tumor resection without adjuvant chemotherapy. Pulmonary metastasectomy represents an effective approach in the treatment of JGT-related lung metastases alone. However, no established reports on the prognosis and treatment of malignant JGT exist; thus, additional case reports are needed.Conflict of Interest StatementThe authors declare that there is no conflict of interest.1. McVicar M, Carman C, Chandra M, Abbi RJ, Teichberg S, Kahn E. Hypertension secondary to renin-secreting juxtaglomerular cell tumor: case report and review of 38 cases. Pediatr Nephrol 1993;7:404-412.2. Kuroda N, Gotoda H, Ohe C, et al. Review of juxtaglomerular cell tumor with focus on pathobiological aspect. Diagn Pathol 2011;6:80.3. Zhou J, Zheng S, Zhang Y, et al. Juxtaglomerular cell tumor: clinicopathologic evaluation in a large series emphasizing its broad histologic spectrum. Pathol Int 2020;70:844-856.4. Duan X, Bruneval P, Hammadeh R, et al. Metastatic juxtaglomerular cell tumor in a 52-year-old man. Am J Surg Pathol 2004;28:1098-1102.5. Beaudoin J, Périgny M, Têtu B, Lebel M. A patient with a juxtaglomerular cell tumor with histological vascular invasion. Nat Clin Pract Nephrol 2008;4:458-462.6. Shera AH, Baba AA, Bakshi IH, Lone IA. Recurrent malignant juxtaglomerular cell tumor: a rare cause of malignant hypertension in a child. J Indian Assoc Pediatr Surg 2011;16:152-154.7. Cucchiari D, Bertuzzi A, Colombo P, et al. Juxtaglomerular cell tumor: multicentric synchronous disease associated with paraneoplastic syndrome. J Clin Oncol 2013;31:e240-e242.8. Munakata S, Tomiyama E, Takayama H. Case report of atypical juxtaglomerular cell tumor. Case Rep Pathol 2018;2018:6407360.9. Huang PW, Lin YC, Wu KF, Sheng TW, Su PJ. Juxtaglomerular cell tumor with lung metastases in a young male patient. J Cancer Surviv . 2019;6(3):128.10. Hagiya A, Zhou M, Hung A, Aron M. Juxtaglomerular cell tumor with atypical pathological features: report of a case and review of literature. Int J Surg Pathol 2020;28:87-91.11. Martini AG, Xa LK, Lacombe M-J, et al. Transcriptome analysis of human reninomas as an approach to understanding juxtaglomerular cell biology. Hypertension 2017;69:1145-1155.12. Raimondi L, Ciarapica R, De Salvo M. Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21(Cip1) expression and hampers tumour cell growth in vitro and in vivo. Cell Death Differ 2012;19:871-881.13. Xiu M, Wang Y, Li B, et al. The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies. Front Mol Biosci. 2021;14:694141.Figure legendsFigure S1. Neoplastic cells with an ovoid shape proliferate in a solid sheet growth pattern, 40×.Figure S2. Neoplastic cells display rare mitotic activity and mild nuclear atypia, 200×.Figure S3. Neoplastic cells show CD34 labeling, 200×.Figure S4. Renin is diffusely distributed in the tumor cytoplasm, 200×.

Time for a Reboot:

In this study, we reported a patient who presents with multicentric reticulohistiocytosis (MRH)-like clinical feature, but the histology is not compatible with it. Like our patient, a couple of patients described previously also had the dilemma that they could not be classified appropriately into any current histiocytosis entity. Considering the clinical and pathological features together, all these patients had a similar clinical profile: xanthomatous rash, erosive arthritis and histopathological findings showing xanthomized histiocytes. Therefore, we propose a new disease entity - xanthomatous erosive arthritis (XEA), to accommodate these patients that cannot be classified appropriately into the current system.

Background The prognosis of children with acute lymphoblastic leukemia (ALL) has improved considerably over the past decades. However, to achieve cure in patients with refractory disease or relapse new treatment options are mandatory. Methods In the multicenter-trial CoALL-08-09, an additional treatment element consisting of the rarely used chemotherapeutic agent amsacrine combined with etoposide and methylprednisolone (AEP) (amsacrine 2 x 100 mg/m2, etoposide 2 x 500 mg/m2 and methylprednisolone 4 x 1000 mg/m2) was implemented into the first-line treatment of pediatric patients with a poor treatment response at the end of induction (EOI) measured by minimal residual disease (MRD). These patients were stratified into a high-risk intensified arm (HR-I) including an AEP element at the end of consolidation. Patients with induction failure (IF), i.e. lack of cytomorphological remission EOI, were eligible for hematopoietic stem cell transplantation (HSCT) after remission had been reached later on. These patients received AEP as a part of their MRD-guided bridging-to-transplant treatment. Results A significant improvement in probality of overall survival (pOS) for the CoALL-08-09 HR-I patients was noted compared to MRD-matched patients from the preceding CoALL-07-03 trial in the absence of severe or persistent treatment-related toxicities. Relapse rate and probability of event-free survival (pEFS) did not differ significantly between trials. In patients with IF a stable or improved MRD response after AEP was observed without severe or persistent treatment-related toxicities. Conclusion In conclusion, AEP is well-tolerated as a component of the HR treatment and useful in bridging-to-transplant settings.

Background: Cancer diagnosis and its treatment may impair the long-term body image of childhood cancer survivors. This may be particularly relevant in adolescence, a critical period of psycho-social development. We compared the body image between adolescent cancer survivors and their siblings, and determined whether survivors’ body image is associated with socio-demographic characteristics, clinical characteristics, and health conditions. Procedure: As part of the nationwide Swiss Childhood Cancer Survivor Study, we sent questionnaires to adolescents (aged 16-19 years), who survived >5 years after having been diagnosed with childhood cancer between 1976-2010. Siblings received the same questionnaire. We assessed the level of agreement with three body image statements referring to body satisfaction and preferences for changes. Chronic health conditions were classified into cardiovascular, pulmonary, endocrine, musculoskeletal, renal/ digestive, neurological, and hearing or vision impairment. We used ordered logistic regression models to identify determinants of a more negative body image. Results: Our study included 504 survivors (48% female) with a median age at study of 17.7 years (IQR 16.8-18.6) and 136 siblings. Survivors and siblings reported overall comparable levels of the three body image statements (all p>0.05). Female survivors (all ORs ≥ 1.7), survivors treated with haematopoietic stem cell transplantation (all ORs ≥ 2.2), and survivors with ≥ 2 chronic health conditions (all ORs ≥ 1.4) reported a more negative body image. This was particularly pronounced for survivors suffering from musculoskeletal or endocrine conditions. Conclusion: Clinicians should address body image concerns in adolescent survivors with chronic conditions and offer psycho-social support if necessary.

Social determinants of health (SDoH) may impact outcomes in sickle cell disease (SCD). We conducted a comprehensive literature review of five electronic databases to elucidate the relationship between SDoH and SCD and identify gaps in the literature. Our search yielded 59 articles which we organized into five SDoH areas: Neighborhood and Built Environment, Health and Healthcare, Social and Community Context, Education, and Economic Stability. We found that social determinants, such as access to healthcare, were inconsistently evaluated. Improved recognition and understanding of SDoH should enhance the development of programs that directly address its detrimental effects on patients with SCD.

The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

Precursor B-cell Acute Lymphoblastic Leukemia in a pediatric patient with Bainbridge-Ropers Syndrome

While Wilms tumors are the most frequently detected renal cancer type in children, extrarenal Wilms tumors (ERWTs) remain rare. This report is the first to describe hypertension and dilated cardiomyopathy in a patient with an ERWT. A six-month-old male infant presented with an abdominal mass and paroxysmal hypertension, echocardiography revealed dilated cardiomyopathy with an ejection fraction of 34%, as well as substantially increased plasma renin activity. Pathology yielded a definitive diagnosis of ERWT. Cardiac function and blood pressure gradually returned to normal after tumorectomy. The early diagnosis of such a tumor together with efficient oncologic treatment are vital to optimal patient outcomes.

Background Childhood cancer survivors face late health problems; despite advances in research, details on risk remain unclear. We describe the methodological aspects of the Dutch Childhood Cancer Survivor Study (DCCSS) cross-sectional clinical study (LATER 2 study). Procedure From the multi-center DCCSS LATER cohort of 6,165 five-year survivors diagnosed 1963-2001, we invited 4,735 eligible in 2016, as well as siblings and parents of survivors. Gaps in evidence identified during development of surveillance guidelines were translated into clinical research questions for 16 outcome-specific sub-projects. The regular care visit to the LATER outpatient clinic forms the backbone of outcome assessment complemented with research-defined measurements (physical examination, diagnostic tests, questionnaires). Furthermore, blood/saliva samples were taken for DNA extraction. Results In total, 2519 (53.2%) survivors participated in the LATER 2 study. Of those participating survivors, 49.3% was female. Median time since childhood cancer diagnosis was 26.9 years (range 14.8 to 54.7 years) and median attained age was 34.4 years (range 15.4 to 66.6 years). Conclusions The high-quality data generated in the LATER 2 study will provide valuable insights into risks of and risk factors for clinical and (psychosocial) health outcomes and factors for early recognition of (psychosocial) health outcomes in long-term childhood cancer survivors. This will contribute to fill in important gaps in knowledge and improve the quality of life and care for childhood cancer survivors.

ABSTRACT Objective: Recent increased awareness and research studies reflect possible associations between opioid exposure and cancer outcomes. Children with neuroblastoma (NB) often require opioid treatment for pain. However, associations between tumor response to chemotherapy and opioid exposure have not been investigated in clinical settings. Methods: This is a single institution retrospective review of patients with NB treated between 2013 and 2016. We evaluated opioid consumption quantified in morphine equivalent doses (mg/kg) based on nurse- or patient-controlled analgesia during antibody infusions. We also analyzed their associations with change in tumor volume and extra-adrenal tumor burden. Results: Of 42 patients given opioids for pain related to anti-GD2 mAb, data completion was achieved for 36 and details of statistical analyses were entered. Median total weight-based morphine equivalent (over 8 days) was 4.71 mg/kg (interquartile range 3.49-7.96). We found a statistically insignificant weak negative relationship between total weight-based morphine equivalents and tumor volume ratio (correlation coefficient -0.0103, p-value 0.9525) and a statistically insignificant weak positive relationship between total weight-based morphine equivalent and Curie score (correlation coefficient 0.1096, p-value 0.5247). Conclusion: Our study found no statistically significant correlation between opioid consumption and NK cell-mediated killing of NB cells as measured by effects on tumor volume/tumor load.

BACKGROUND: Rhabdomyosarcoma (RMS) is an aggressive malignancy, and 20% of children present with metastases at diagnosis. Patients presenting with disseminated disease very occasionally have no clear evidence of a primary tumor mass. Since these patients have rarely been investigated, we report on a series of patients with RMS and unknown primary tumor site registered in the MTS 2008 protocol (October 2008 - December 2016) coordinated by the European pediatric Soft tissue sarcoma Study Group. METHODS: Patients were administered 9 cycles of induction chemotherapy, and 48 weeks of maintenance chemotherapy. Surgery and/or radiotherapy was planned after the first assessment of tumor response, and implemented after six cycles of chemotherapy. If feasible, radiotherapy to all sites of metastasis was recommended. RESULTS: We identified 10 patients with RMS and unknown primary site, most of them adolescents (median age 15.8 years, range 4.6-20.4). Nine had fusion-positive alveolar RMS. Multiple organ involvement was identified in 7 patients, 2 only had bone marrow disease, and 1 only had leptomeningeal dissemination. All patients were given chemotherapy, 4 were irradiated, and none had surgery. Three patients underwent allogeneic bone marrow transplantation. At the time of this analysis, only 2 patients are alive in complete remission: 1 had received radiotherapy; and 1 had a bone marrow transplant. CONCLUSIONS: RMS with unknown primary tumor occurs mainly in adolescents and is typically fusion-positive alveolar. Radiotherapy may be important, but survival is poor and patients should be offered enrollment in investigational trials.