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.

Pediatric and adolescent and young adult (AYA) thromboembolism is treated with anticoagulation. While anticoagulation non-adherence in adults has been linked to increased morbidity and mortality, much is unknown concerning medication adherence in pediatric and AYA populations. The aims of this study were to describe barriers to adherence in anticoagulated pediatric and AYA outpatients and to explore the relationship between barriers and self-reported adherence. Nearly 75% of patients and caregivers reported barriers to anticoagulation adherence, and a greater number of reported barriers was associated with lower adherence (rpb = 0.48, p = .01). Limitations, clinical implications, and future directions are discussed.

Objective : Spectrum of hepatic presentation in Langerhans cell histiocytosis (LCH) varies from asymptomatic hepatomegaly to secondary sclerosing cholangitis leading to cirrhosis with or without decompensation. Conventional chemotherapy may be counterproductive in a patient with LCH and hepatic decompensation. We analysed the outcomes of our patients with hepatic presentation of LCH, including their post liver transplant (LT) follow up. Methods: A retrospective analysis was performed on patients with hepatic presentation of LCH referred to our unit. Their clinical profile, chemotherapy protocol, details of LT and survival were analysed. A management algorithm based on the outcomes was proposed. Results: Five of 8 patients were male. Median age of diagnosis was 25(9-48) months. 8(100%) patients had portal hypertension with 4(50%) having decompensated cirrhosis. 6 (75%) patients underwent LT of which 2 had acute decompensation and 4 had sclerosing cholangitis with portal hypertension. Of the two remaining patients, 1 did not tolerate chemotherapy and succumbed, whereas 1 patient after first cycle of chemotherapy was lost to follow up. As their liver disease was worsening during chemotherapy (after 8 & 20 weeks of chemotherapy), two patients underwent urgent LT followed by continuation of chemotherapy. After median follow-up of 30.5 (10.5-50) months, all patients were alive with stable graft function and no disease recurrence. Conclusion: As shown in our series, an algorithmic approach to patient and treatment selection for LCH patients with liver involvement combined with newer chemotherapeutic agents and an optimized immunosuppression can result in excellent outcomes for a hitherto unfamiliar disease.

The New Reality is VirtualWilliam L. Carroll, MD*Perlmutter Cancer Center, NYU-Langone Medical Center, New York, New York*Correspondence to: William L. Carroll, MD Division of Pediatric Hematology-Oncology, Departments of Pediatrics and Pathology, Perlmutter Cancer Center, NYU-Langone Medical Center, 560 East First Avenue, Smilow Room 1211, New York, NY, 10016E-mail: [email protected] COVID-19 pandemic led to a precipitous and severe disruption to healthcare delivery and consumption worldwide. Ongoing analyses (and debate) about the effectiveness of early response measures will continue, but there is no doubt the pandemic brought about dramatic changes to health care, some of which are likely to last.The health care industry is built on a model of in-person visits between patients and providers, which is reinforced by economic incentives. However, tremendous pressure was put on health care systems to pivot quickly from in-person visits given the explosive spread of COVID-19. Non-essential in-person visits and elective procedures were reduced, or paused, allowing hospitals to marshal capacity for a surge in COVID-19 cases and to mitigate risk of infection to patients and staff. Patients deferred care, in many cases with negative results1. Outpatient in-person volume plummeted over 40%2.In any crisis, opportunities emerge and telehealth visits surged providing a safe alternative to in-person visits3. Telehealth or virtual visits are not novel and has been in place since the mid 1990’s especially for rural care but regulation and reimbursement limited its application4. With changes in payer reimbursement, telehealth visits increased dramatically. Early in the pandemic up to a third of office visits were through virtual care. This trend was most pronounced in primary care and mental health/psychiatry but whether it can be applied safely to patients with complex conditions requiring therapy with medications associated with a narrow therapeutic index like cancer is less certain.In this issue of Pediatric Blood and Cancer Rabinowicz et al, raise the question of how essential are in-person visits during maintenance therapy for B acute lymphoblastic leukemia (ALL), the most common childhood cancer5. The authors conducted a retrospective study to determine if an in-person visit was essential to detect an abnormal finding on physical examination especially if it resulted in a change in medical management. They excluded patients during the first three months of maintenance when more frequent laboratory evaluations are needed to titrate medication dosages, when children required intrathecal or intravenous therapy, or when other specialists saw patients. All others could be considered candidates for virtual care delivery. Seventy-five children with 240 routine visits were analyzed. Fourteen were associated with a new abnormal finding and in only six cases was a direct physical examination deemed required for diagnosis. Only three such visits resulted in a change in medical management. Based on these results, the authors argue, justifiably, that there is a large potential for virtual visits during maintenance treatment.The results of this study are not surprising especially as most patients, including the fourteen with new findings on exam in this report, will have symptoms (not analyzed in the study) alerting parents and providers to new medical conditions warranting in-person visits. Most ALL treatment protocols mandate physical examination with routine laboratory monitoring on a monthly basis and it is hard to justify more frequent intervals in the absence of follow up medication adjustments or specific problems. There might a subset of families with particular hardships related to travel where the in-person interval can be extended further. COG protocols now use every 12 week vincristine/decadron pulses with intrathecal methotrexate administration. Home phlebotomy services have been piloted to obtain laboratory blood draws and perform port flushes6. Virtual visits can be used to ascertain any side effects, adjust medications, and emphasize compliance. Another positive aspect of the pandemic is the widespread adaption of at home viral testing and there is no doubt that COVID-19 has changed the future of in-home medical diagnostics.The authors provided a thoughtful, balanced analyses and discussion of the pros, including decreasing the burden of care (e.g. school absences, time off work for parents, and transportation costs) and cons of virtual visits. Two important considerations are warranted when deciding on frequency of virtual vs. in-person visits. First, a “digital divide” is well described where limited access to high-speed internet services, lower socioeconomic status and limited English proficiency are barriers to access. Second, medical monitoring is only one part of a broader strategy in pediatric cancer care to decrease the physical, neuropsychological, educational and financial burden of cancer on children and their families. Thus, children and their families may routinely interact with physicians, nurses, social workers, physical therapists, child life therapists, teachers and psychologists as part of a personalized care model during clinic visits. Such multidisciplinary services may be difficult to replicate through virtual care delivery.It is also time to consider other aspects of digital technology that can enhance the health of our patients and their families7. Mobile health is especially attractive as the overwhelming majority of adults and adolescents have access to a smartphone8. Applications such as MyChart (EPIC) allows patients and parents to view their electronic record in real time and interact with providers. Multiple studies have shown that customized, interactive apps can also be used to augment education about disease and management, manage side effects such as nausea and vomiting, and promote medication adherence9,10. It is time to accelerate the implementation of these tools in every day practice.The article by Rabinowicz and colleagues should motivate us to consider implementing and expanding adaptive strategies developed in response to the COVID-19 pandemic to improve patient care for children and their families with cancer. Virtual visits can never completely replace in-person visits where emotional bonds and trust between providers and patients are required to promote optimal outcomes. However after such relationships are cemented early in treatment virtual visits can reduce the burden of therapy without sacrificing quality.1. Quarello P, Ferrari A, Mascarin M, et al. Diagnostic Delay in Adolescents with Cancer During COVID-19 Pandemic: A New Price for Our Patients to Pay. J Adolesc Young Adult Oncol. 2021.2. Dupraz J, Le Pogam MA, Peytremann-Bridevaux I. Early impact of the COVID-19 pandemic on in-person outpatient care utilisation: a rapid review. BMJ Open. 2022;12(3):e056086.3. Uscher-Pines L, McCullough C, Dworsky MS, et al. Use of Telehealth Across Pediatric Subspecialties Before and During the COVID-19 Pandemic.JAMA Netw Open. 2022;5(3):e224759.4. Werner RM, Glied SA. Covid-Induced Changes in Health Care Delivery - Can They Last? N Engl J Med. 2021;385(10):868-870.5. Rabinowicz R, Maguire B, Hitzler J, Punnett A. How Essential are In-Person Clinic Visits During Maintenance Treatment of Children with Acute Lymphoblastic Leukemia? Pediatric Blood & Cancer. 2022.6. Sisler I, Cohen D, Skinner LA, Aiken C, Laver J. Feasibility of a Pilot Home Phlebotomy Program for Pediatric Hematology/Oncology Patients During the COVID-19 Pandemic. J Pediatr Hematol Oncol.2022;44(1):e185-e187.7. Keesara S, Jonas A, Schulman K. Covid-19 and Health Care’s Digital Revolution. N Engl J Med. 2020;382(23):e82.8. Nievas Soriano BJ, Uribe-Toril J, Ruiz-Real JL, Parron-Carreno T. Pediatric apps: what are they for? A scoping review. Eur J Pediatr. 2022;181(4):1321-1327.9. Heneghan MB, Hussain T, Barrera L, et al. Access to Technology and Preferences for an mHealth Intervention to Promote Medication Adherence in Pediatric Acute Lymphoblastic Leukemia: Approach Leveraging Behavior Change Techniques. J Med Internet Res. 2021;23(2):e24893.10. Semerci R, Akgun Kostak M, Taskin C. The effect of using an interactive mobile application for the management of chemotherapy-induced nausea and vomiting in children: Randomized controlled study. Eur J Oncol Nurs. 2022;58:102121.

For a Life Beyond the CureTissy Lagun Costa11Division of Pedagogical Coordination, Nursery and Pre-kindergarten, Escolinha do Faz-de-Conta, Orlândia, São Paulo, Brasil* Correspondence to:Tissy Lagun Costa, Avenida Dois, 894, Centro, Orlândia, São Paulo, 14620-000, Brasil, Tel.: +55(16)99608-2350, Email: [email protected] word count 1099;Abstract word count: 0;Brief running title: For a life beyond the cureKey words: palliative care, DIPG, brain, tumor, CNS tumorTables: 0Figures: 0I didn’t expect that pregnancy. I really wanted it; but after going through a fertility treatment to have my first son, I couldn’t imagine that the second would come so easily. It was only eighteen months between one birth and the next one. First a boy and then a girl. A girl we called Alice.She was a beautiful baby. Delicate. From the first sight, we knew she would have great hair. She was never bald. When her newborn hair started to fall out, strong thick hair grew immediately covering her cute round head. She had a perfect body. Slender and – believe me! – with a well-defined waist.At three months, the color of her eyes began to change. One eye changed first, followed by the other. Is that normal? I don’t know. But that is how it happened. One eye was already brown, while the other still had shades of light green.She smiled for the first time. She used to grab all the objects surrounding her crib and, several times she watched her own hand moving in awe as if there was magic about it. She sat, crawled and walked all at the proper ages. She spoke her first words and quickly expanded her vocabulary. She admired her chatty brother, and there was no shortage of stimuli.She started to go to school. She was a happy and clever student. Praised by all her teachers. She actively participated in all activities. She rehearsed for presentations and cultural events. My sole contribution was to smile filled with pride – and to sew costumes for her plays and dresses for dancing around.She made bonds. Her friends were dear. They played together all the time. Her gang consisted of two boys, the twin girls, the two other girls who loved to make mischief and her best friend. Alice was the peacemaker of the group; she didn’t like conflict.Her birthdays were celebrated with many guests. When she started to understand what a party was, she made sure to always choose a theme: Little Red Riding Hood, Enchanted Fairies and Doll Tea Party complete with a full set of porcelain tea cups and pots for the stuffed guests.One day, running to get to the door to greet her best friend, she tripped and fell, hitting her mouth on the floor. Her two front teeth blackened. I didn’t worry. They were her baby teeth. After several toothless smiles, new strong teeth would grow. My life was normal, like any other mom.Until in January 2014, when everything changed.“Unfortunately, Alice has a very aggressive tumor called Diffuse Intrinsic Pontine Glioma, a.k.a. DIPG. In ninety-five percent of cases, the child dies after a few months.”; that was her diagnosis.What?! How could a routine medical appointment end up like that? I brought to the doctor a simple question: do we have to do something about her right eye being a bit misaligned? How can a question as simple as that require several appointments, examinations and two MRIs?After a crash course in neuro-oncology, we understood that Alice’s right eye couldn’t move to the right because of the sixth cranial nerve. And that nerve was connected to a time bomb about to explode.Our first reaction was of shock and awe. There must be a mistake. The doctors weren’t considering a second opinion when interpreting the images? Couldn’t it be something else? Maybe some dirt on the lens?When reality finally struck me, I faced a storm. The picture that comes to mind is a dam bursting; my body taking all that chaotic energy to avoid complete devastation. A torrential flow of conflicting emotions compounded each other. It took from me and my family our capacity to breathe, to feel and think – it got into our bones. It made us physically crumble on top of ourselves. But, no matter what, we needed to make the most important decision of our lives, so we didn’t fall apart.And we chose life.It didn’t matter how much time Alice had to live. Her life would be worth it. Each hour, each minute and each second would have meaning.Our first reaction was to avoid medical treatment. To put our plan in motion and to wait for the inevitable outcome. But it is too hard to do nothing. So, we chose the treatment that had the least impact on quality of life. Which until then was perfect. As I said, it was only her eye…What marked that period was the sorrow for the loss of what could be. It was the death of all the dreams we once dreamt for Alice: a long life full of accomplishments. The ending would be a family picture, a big family with grandkids all around and great grandkids on her lap.With our goals reevaluated, our objective was to live intensely in her last months of life. We travel to several places. The kids learned karate. We camped in the forest. We went fishing. We played in the snow. Anything was worthy of celebration. A sunny day. A fun movie. The birth of a puppy at the farm. A shower in the rain. And, against all odds, we celebrated three more birthdays.During those three years, we held our breath and focused on the present. One day, that effort took a toll on us. We were exhausted. After several MRIs that didn’t show any change in the tumor, nobody could tell if it was really dead. But suddenly, the uncertainty became certainty; the tumor started to grow again.Without the same energy we had before, we had to start a new plan. To face the most feared challenges we had avoided until now — the devastating symptoms that would take Alice from us piece by piece.The loss of movement on the right side of her face. The loss of movement of her legs and arms. The loss of her muscular tone. The loss of her ability to swallow. And, in the end… the loss of her heartbeat.Alice left the scene at nine years old.She is deeply missed; it’s painful. It’s a void that establishes itself as a physical being that we learn to live with.Drop by drop, I began to fill this void with memories. Writing helped me to get closer to my daughter. I wrote a book. These memories are dear to me. They are forever etched in paper.And like that, whenever I sit to write, I chat with my daughter Alice.What do we talk about?We talk about the beautiful life she lived.