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.

A Novel MECOM Variant Associated with Congenital Amegakaryocytic Thrombocytopenia and Radioulnar Synostosis Hanan Al-Abboh1, Akmal Zahra1 and Adekunle Adekile1,2Pediatric Hematology Unit, Mubarak Hospital1 and Department of Pediatrics, Faculty of Medicine, Kuwait University2, Kuwait Address Correspondence to: Professor Adekunle Adekile Department of Pediatrics Faculty of Medicine Kuwait University PO Box 24923 Safat 13110 Kuwait Email: [email protected] Tel: +96525319486To the EditorCongenital radioulnar synostosis (RUS) is a rare developmental anomaly of proximal fusion of the radius and ulna, resulting in limited pronation and supination of the forearm. It may accompany other abnormalities in the skeleton, kidney, heart and aneuploidy syndromes1,2. A subset of patients with RUS present with bone marrow failure (BMF) syndromes, characterized by amegakaryocytic thrombocytopenia (RUSAT), progressing to myelodysplasia and pancytopenia2,3. The hematological manifestations are quite variable, with some presenting with severe BMF in childhood, while others are mild and may not present until adulthood.Heterozygous germline variants in the homeobox A11 (HOXA11) gene were the first to be associated with RUS and designated RUSAT14, but lately, several families have been described with variants in the MDS1 and EVI1 complex (MECOM) locus, and referred to as RUSAT22,5,6. Many of these variants appear de novo , while others follow an autosomal dominant inheritance. We, hereby, report the case of a Kuwaiti patient who presented with congenital amegakaryocytic thrombocytopenia (CAMT) in the neonatal period and later noticed to have RUS. Whole exome sequencing revealed a novel MECOM variant.A.A. is a male Kuwaiti, the first child of consanguineous parents and was first seen at the age of 36 days, following antenatal ultrasound diagnosis of bilateral hydronephrosis and right renal cyst. He was a product of induced vaginal delivery with a birth weight of 2.3 kg. After delivery, he was kept under observation in the neonatal intensive care unit. His CBC showed isolated thrombocytopenia (Plt 34 x109/L). He received several platelet transfusions, as well as IVIG twice. Postnatal abdominal ultrasound showed multicystic right kidney, in addition to bilateral hydronephrosis. The mother had no history of thrombocytopenia during pregnancy and there was no other pertinent family history.Physical examination at presentation showed 2 café-au-lait spots, one on the back, measuring 1x2 cm and another over the left leg, that was less than 0.6 cm. There were no obvious dysmorphic features and other systems were unremarkable. CBC showed WBC 11.2 x109/L Hb 10.4 g/dL, MCV 83fl, Plt 49 x109/L, ANC 1.8 x109/L. Renal function tests were normal. Blood film showed no abnormal cells; there was true thrombocytopenia with giant forms. Antiplatelet antibody was negative. Abdominal ultrasound at age 1 month showed complete replacement of the right kidney by cystic changes with left moderate hydronephrosis. Skeletal survey was reportedly normal.Bone marrow biopsy showed normal distribution of granulocytic and erythroid precursors, with severe suppression of megakaryocytosis, consistent with a bone marrow failure syndrome. Chromosomal breakage study was normal. The patient was diagnosed with right undescended testis, as well as right inguinal hernia that were operated at age 1 year and 10 months. At the age 2 and a half years, A.A. was noticed to have limited bilateral arm movement supination and pronation. The mother volunteered that she has a similar defect. X-rays confirmed that the child had bilateral radioulnar synostosis. Whole exome sequencing showed that the patient is heterozygous for a previously-unreported MECOM gene, c.2282A>G mutation. Unfortunately, the parents have not been screened for these mutations.The patient has been under follow up for 4 years, his platelet count has been stable, ranging between 40-50 x109/L, with no bleeding tendency. In spite of his limited arm rotation, he currently functions normally in his daily activities, however, his hand writing skills and ability to engage in sports are yet to be observed since he is still pre-school age. Platelet transfusion is reserved only for severe bleeding, which he has not had. Bone marrow transplant may be considered in future if his bone marrow failure worsens and/or his marrow shows dysplastic changes.Dokal et al3 were the first to report an association between RUS and late-onset BMF, while Thompson et al described its association with CAMT and linked it to the c.872delA ,p.Asn291Thrfs3 variant of the HOXA11gene4,7. More recently, several germline mutations in the MECOM locus have been reported and appear to be the more common cause of RUSAT. Indeed, no other cases of HOXA11 mutations linked to RUSAT have been described since the initial report. Niihori et al8 reported the first 3 heterozygous MECOMmutations in 3 sporadic patients. These variants and those subsequently reported by Walne et al2 are in a highly conserved cluster within 10 amino acids (aa750-760) and impact on either the highly conserved Cys2His2 zinc finger motif (zinc finger 8, aa733-755) or the adjacent linker motif (aa756-760). It has been shown that removal of the 8th zinc finger causes granulopoiesis arrest while mutations and deletions in other parts of the complex, outside the 8th and 9th fingers, are associated with hematological disorders without RUS9.MECOM codes for a zinc finger transcription factor with important roles in normal development and oncogenesis and is involved in the regulation of embryonic development and hematopoietic stem-cell renewal. Hence the phenotype in individuals with these mutations is very variable ranging from BMF to different skeletal, cardiac, renal malformations, B cell deficiency and sensorineural deafness.Our patient showed a previously unreported variant in the region of the 8th zinc finger of the MECOM locus. This c.2282A>G missense variant results in the tyrosine to cysteine substitution at codon 761 (p.Tyr761Cys). The amino acid is in the Zinc finger, C2H2 and Zinc finger, C2H2-like protein domains and is highly evolutionarily conserved. Unfortunately, the parents were not screened for the mutation, however, the mother shows RUS, with normal blood counts. This is consistent with the marked variability in the clinical phenotype. The father is also physically and hematologically normal.Apart from thrombocytopenia, our patient also had renal abnormalities – hydronephrosis and multicystic kidney disease. The natural history of his condition is that he may develop pancytopenia and/or myelodysplasia in the future. He is under close follow up and will be considered for bone marrow transplantation if his condition worsens. In the meantime, he remains hypomegakaryocytic with a platelet count at 30 – 50 x 109/l while other blood cellular elements are normal. His renal function and hearing are being monitored, but still remain normal.AcknowledgementsWe thank the patient’s family for allowing us to report this case. The whole exome sequencing was done at the Laboratory of Genetics and Genomics, Cincinnati Children’s Hospital, Cincinnati, Ohio.References1. Rizzo R, Pavone V, Corsello G, Sorge G, Neri G, Opitz JM. Autosomal dominant and sporadic radio-ulnar synostosis. Am J Med Genet.1997;68(2):127-134.2. Walne A, Tummala H, Ellison A, et al. Expanding the phenotypic and genetic spectrum of radioulnar synostosis associated hematological disease. Haematologica. 2018;103(7):e284-e287.3. Dokal I, Ganly P, Riebero I, et al. Late onset bone marrow failure associated with proximal fusion of radius and ulna: a new syndrome.Br J Haematol. 1989;71(2):277-280.4. Thompson AA, Nguyen LT. Amegakaryocytic thrombocytopenia and radio-ulnar synostosis are associated with HOXA11 mutation. Nat Genet. 2000;26(4):397-398.5. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586-596.6. Ripperger T, Hofmann W, Koch JC, et al. MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies. Haematologica. 2018;103(2):e55-e58.7. Thompson AA, Woodruff K, Feig SA, Nguyen LT, Schanen NC. Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.Br J Haematol. 2001;113(4):866-870.8. Niihori T, Ouchi-Uchiyama M, Sasahara Y, et al. Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. Am J Hum Genet.2015;97(6):848-854.9. Nielsen M, Vermont CL, Aten E, et al. Deletion of the 3q26 region including the EVI1 and MDS1 genes in a neonate with congenital thrombocytopenia and subsequent aplastic anaemia. J Med Genet.2012;49(9):598-600.

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni Syndrome (LFS), resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) have been associated with a high rate of germline TP53 PVs. This study provides an updated estimate of the prevalence of TP53 germline PVs from a large cohort of patients (n=239) enrolled in five Children’s Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in anRMS patients in this series is much lower than previously reported, this prevalence remains significantly elevated. Germline genetic evaluation for TP53 PVs should be strongly considered in patients with anRMS.

Social determinants of health (SDoH) are associated with stark disparities in cancer outcomes, but systematic SDoH data collection is currently absent from oncology clinical trials. Trial-based SDoH data are essential to ensure representation of marginalized populations, contextualize outcomes, and identify health-equity intervention opportunities. We report the feasibility of the first pediatric oncology multicenter trial-embedded SDoH investigation. Among 448 trial participants, 392 (87.5%) opted-in to the embedded SDoH study; 375 (95.7%) completed baseline surveys, with high longitudinal response rates (87.2-92.8%) over 24-months of therapy. Trial-embedded SDoH data collection is feasible and acceptable, and must be consistently included within future oncology trials.

Erythroid sarcoma is very rare form of pure erythroid leukemia with undetermined biological features. Here, we present an infant with a multifocal erythroid sarcoma, diagnosed because the tumor cells were positive for glycophorin A. After acute myeloid leukemia-oriented chemotherapy and surgical resection followed by cord blood transplantation, he has successfully maintained complete remission without any late effects. Total transcriptome analysis of the tumor identified a novel fusion gene, RCC1-LCK, and high LCK expression levels, suggesting that LCK overexpression was involved in leukemogenesis in this case.