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Throughout the cancer trajectory, parents of childhood cancer survivors (CCSs) may experience mental and social challenges requiring continual adaptation to cancer-induced stress. Using Lazarus and Folkman’s Transactional Model of Stress and Coping framework, this qualitative study aimed to describe Hispanic parents’ psychological health and explore their coping strategies. Purposive sampling was used to recruit 15 Hispanic caregivers from a safety-net hospital in Los Angeles County. To be eligible, participants had to be: the primary caregiver of a CCS who had completed active treatment, the primary caregiver or child self-identified as Hispanic, and proficient in English or Spanish. The interviews lasted approximately 60 min, were audio-recorded (in English and Spanish), and professionally transcribed. Data were analyzed following a thematic content analysis with deductive and inductive approaches on Dedoose. Participants described high levels of stress and fear when their child was diagnosed with cancer. They also shared experiencing symptoms of social anxiety, post-traumatic stress disorder, and depression. Participants’ coping strategies were encompassed by three major themes: problem-focused, emotion-focused, and avoidant coping strategies. Problem-focused coping strategies included self-efficacy, behavioral change, and social support. Emotion-focused coping strategies included religious practices and positive reframing. Avoidant coping strategies included denial and self-distraction. Despite the evident disparities in psychological health for Hispanic parents of CCSs, gaps remain in designing a culturally tailored program to help alleviate the caregiver burden. This study provides insights regarding coping strategies that Hispanic caregivers use to deal with the psychological impact of their child’s cancer diagnosis. Our findings also delve into the contextual and cultural factors that impact psychological adjustment.

Purpose While limited, dyadic research demonstrates the interdependent relationship between the health and adjustment after treatment between cancer survivors and caregivers. We examined interrelationships between coping resources and mental health among childhood cancer survivors (CCS)–parent dyads. Methods One hundred sixty CCS-parent dyads from the Project Forward pilot study completed validated questions assessing social support, religiosity, spirituality, depressive symptoms, and perceived stress. Bidirectional associations were identified with path analysis utilizing the actor-partner interdependence model (APIM). We used a multigroup approach to test for the moderating effects by Hispanic ethnicity on these relationships. Results Mean age of CCS was 20 years old, 51% female, 30% diagnosed with leukemia, and mean of 7 years from diagnosis. The mean age of parents was 49 years old and 89% were mothers. For both CCS and parents, perceived social support was inversely associated with their depressive symptoms and perceived stress (e.g., actor effects). Parents’ social support was not significantly associated with CCS’s depressive symptoms and stress. However, higher perceived social support by the CCS was inversely associated with parents’ depressive symptoms (β = − 0.202, p β = − 0.164, p Conclusion Partner effects of social support among CCS-parent dyads may influence psychological distress. Implication for Cancer Survivors Our findings on parent–child associations between social support and psychosocial well-being imply that survivorship care can be enhanced when the social support needs of both survivors and their parents are addressed together.

AIM The purpose of this study was to assess for an association between higher body mass index and disease severity, morbidity and mortality in children admitted for an acute respiratory distress and failure. METHODS A single-institution retrospective cross-sectional study performed in the United States evaluating paediatric patients, 2-20 years of age, admitted for diagnoses related to acute respiratory distress and acute respiratory failure. Main outcomes include disease severity as assessed using the respiratory component of the Paediatric Early Warning Score (PEWS) with adjustment for altered mental status (Resp-PEWS + AMS), hospital or intensive care length of stay (LOS) and death. RESULTS Children with obesity made up 42/334 (13%) of the cohort. There was no significant difference in Resp-PEWS + AMS between obese and non-obese cohorts (mean of 0.93, {standard deviation 1.11} vs. 1.13 {1.35}, range 0-6, rank sum p = 0.46). There was no significant difference in overall hospital LOS or intensive care LOS. Multivariate analysis including diagnosis as a control variable did not change the results. CONCLUSION We found that body habitus was not an independent factor for illness severity or clinical outcomes.

Development of post-chemotherapy histiocyte-rich pseudotumor (PHP) is an underrecognized event following therapy in lymphoma patients and may mimic residual tumor using current therapy monitoring protocols. We report a series of 5 patients with PHP along with a review of the literature. In our series, we describe 3 patients with persistent hypermetabolic masses by positron emission tomography-computed tomography, one with persistent terminal ileal nodules on endoscopy, and one with bone marrow involvement, a site not associated with mass-like disease. Twenty-three patients with long-term follow-up were identified from our series and review of the literature. Forty-four percent of patients received additional therapy, and only 4% of patients died of lymphoma. This study illustrates that PHPs are not identified using current lymphoma therapy monitoring algorithms and may result in overtreatment with risk for additional therapy-related complications. The need for confirmatory tissue biopsy in this setting is recommended.

The 2020 American Diabetes Association’s Standards of Care underscore the importance of psychosocial screening in all persons with type 1 diabetes as an important step in optimized type 1 diabetes management. Youth with type 1 diabetes from low socioeconomic backgrounds and from minority racial groups have increased psychosocial burden but often do not meet psychosocial screening guidelines. We present findings from psychosocial measures in a predominately Latino and low socioeconomic cohort. Our findings demonstrate:(1) higher global health scores were strongly associated with both lower HbA1c and more frequent self-monitoring blood glucose(2) given that the study population was predominately young adults, these are important considerations in the transition of care(3) successful psychosocial screening in a resource limited urban hospital(4) associations between HbA1c and SMBG and psychosocial measures support increasing attention to assessing and optimizing positive psychological states as a means to improve diabetes outcomesOur motivation for this study is to demonstrate that psychosocial screening is both clinically meaningful and feasible, particularly in this age of transition. Therefore, diabetes clinics should strive to meet national and international guidelines by screening all persons with type 1 diabetes for psychosocial stressors as a means of improved type 1 diabetes care.Consistent with the aim of Diabetes Spectrum, this manuscript aims to reach health care providers to promote better management of persons with type 1 diabetes, including those from the most vulnerable subgroups. We look forward to hearing from your editorial office regarding this manuscript. Thank you for your consideration.

PURPOSE:The triad of communication between young adult childhood cancer survivors (YACCSs), their parents, and their medical providers is an important process in managing health care engagement. This study sought to identify communication patterns among this triad, factors associated with communication, and engagement of survivorship care.METHODS:We analyzed data from Project Forward, a population-based study that surveyed YACCSs and their parents. YACCSs were on average age 20 years, 7 years from diagnosis, 50% female, and 57% identified as Hispanic/Latino (N = 160 dyads). Latent class analysis of nine communication indicators from parent and YACCS surveys identified distinct classes of communication between YACCSs, parents, and medical providers. Associations between resulting classes and YACCS/parent characteristics were examined using multinomial logistic regression. Logistic regression was used to examine the association between communication classes and cancer-related follow-up care.RESULTS:Latent class analysis identified three classes of triad communication: (1) high health care–focused communication (37.5%), (2) high comprehensive communication (15.6%), and (3) overall low communication (46.9%). After adjusting for covariates, greater time since diagnosis was associated with reduced odds of membership in class 2 while dyads with Spanish-speaking Hispanic parents were more likely to be in class 2 ( v class 3). Additionally, YACCSs who were in either of the high communication groups were more likely to have received recent follow-up care.CONCLUSION:Examining language preference provides an important contextual understanding as we found Spanish-speaking Hispanic parents engaged in high communication, which was associated with cancer-related follow-up care. Yet, our results also support the need to enhance communication between this triad to improve outcomes.

Background Severe immune thrombocytopenia complicating pregnancy may require treatment beyond first-line medications (intravenous immunoglobulins or corticosteroids), but there is a paucity of literature on the use of such second-line agents in pregnancy. Case The patient is a 29-year-old woman with early-onset severe immune thrombocytopenia at 13 weeks of gestation. Maternal platelet counts reached a nadir of less than 5×10/L. The thrombocytopenia persisted despite first-line medications. Romiplostim, rituximab, and azathioprine were added to the therapeutic regimen. Platelet counts eventually stabilized at greater than 150×10/L before delivery. After delivery at term, the neonate had transient B-cell suppression, which was presumed to be secondary to rituximab, but was otherwise doing well and meeting all milestones at 7 months of age. Conclusion The addition of second-line agents was associated with sustained elevation in maternal platelet counts and may have obviated the need for splenectomy.

We investigated social and logistic factors eg, distance from the medical center, language barriers, other children to care for, number of caregivers, etc.) for families to delay seeking immediate emergency care for neutropenic fever in a retrospective cohort study of all pediatric hematology-oncology patients who presented for fever in the setting of neutropenia to our emergency department or clinic from 2015 to 2020. Patients with a history of at least 2 prior admissions for neutropenic fever waited more often for a second fever before presenting versus those without such history (odds ratio 5.00, 95% CI 1.26 to 19.84, P=0.04). No other significant associations were found.

This qualitative study aimed to explore Hispanic parents of childhood cancer survivors (CCS) perceptions of facilitators and barriers to their caregiving experience.We conducted semi-structured phone interviews with 15 Hispanic/Latino parents (English and Spanish). Parents were recruited using a purposive sampling method in a safety-net hospital in Los Angeles County from July-September 2020. Interviews were audio-recorded, professionally transcribed, and analyzed in the language they were conducted. Two coders independently coded interviews following reflexive thematic analysis and elements of grounded theory methodology.Most caregivers were mothers caring for leukemia CCS who had finished treatment more than 2 years prior. Caregivers expressed gratitude to social workers for introducing and aiding with the application process for safety-net programs that enabled caregivers to focus on their child's care and well-being. Caregivers revealed the importance of supportive communication with the medical team, particularly after their child's treatment was considered complete. All caregivers found caring for a child with cancer overwhelming, and many described deteriorations in their health and well-being. Financial instability, transportation difficulties, and work disruptions were identified as barriers, resulting in caregiver distress. Caregivers also shared the challenges they experienced navigating the healthcare system, seeking care despite lack of legal residency, and staying afloat despite limited employment opportunities.Improving navigation to resources and improving relationships with the medical team may reduce the perceived caregiving burden among Hispanic/Latino caregivers throughout their family's cancer journey.

BACKGROUND: Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), the de-facto standard-of-care in adult-onset Hodgkin lymphoma (HL), has not been directly compared to doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC), a pediatric-aimed regimen designed to reduce late-effects. We aimed to describe the single institution experience of using both regimens in patients with pediatric HL. METHODS: This retrospective cohort study evaluated a total of 224 patients diagnosed with HL between 1999 and 2018 at Children’s Hospital Los Angeles (CHLA), of which 93 patients were eligible having received ABVD (n=46) or ABVE-PC (n=47) chemotherapy as their initial treatment. Descriptive analyses were performed using the Student’s t-test or Fisher’s exact test. Survival analysis used the Kaplan-Meier method. Events included death, relapse and secondary malignancy. We also describe the use of radiation therapy, pulmonary toxicity and cardiomyopathy determined by shortening fraction

Background: Parents are the primary caregivers throughout their child's cancer journey. As a result, they may experience a shift in their self and social identity both immediately and in the long term after their child is diagnosed with cancer. Insights into Hispanic/Latino parents of childhood cancer survivors' social support is limited, however. This qualitative study aimed to address the existing gap by describing the social support experiences of Hispanic/Latino parents while caregiving. Methods: Caregivers were recruited from a safety-net hospital in Los Angeles County between July to September 2020. Qualitative semi-structured interviews were conducted with 15 Hispanic/Latino caregivers of childhood cancer survivors (in English and Spanish). The interviews were audio-recorded, professionally transcribed, and analyzed following a reflexive thematic analysis approach. Two coders independently reviewed and coded transcripts and used grounded theory methodology elements (e.g., gerund coding and memo-writing) on Dedoose. Results: Two related themes were identified: the positive influence of social support when available and the challenges associated with lack of social support. All caregivers spoke about the positive influence of social support throughout their caregiving experience (both during and after treatment). Participants' descriptions of the influence of social support included (1) information sharing enhanced knowledge, (2) receiving comfort and encouragement, (3) receiving tangible assistance reducing the caregiving burden, and (4) enhancing caregiving empowerment/self-efficacy. The most common form of social support among these caregivers was tangible assistance, which included financial support for groceries, bills, rent, and essential services such as transportation, work hour flexibility, childcare for other children, and help with household maintenance. Sub-themes regarding the lack of social support included (1) being a single parent and (2) family and friends withdrawing after the child's cancer diagnosis. Single parents described juggling multiple roles, including caring for the patient, maintaining financial support for the entire family, and caring for other children while managing their child's illness. One caregiver expressed that "if there were two of us [during treatment], it would have been easier." Conclusion: When a child is diagnosed with cancer, parents are the primary caregivers and the presence or absence of social support may impact their caregiving experience, particularly for Latino/Hispanic caregivers who are medically underserved. The findings of this study indicate that Hispanic/Latino parents strongly value social support as it enables them to have essential resources that support caregiving for their child and themselves. Efforts should ensure that caregivers are routinely screened to identify their supportive needs. In an effort to optimize support services for caregivers, it needs to be tailored as those with a lack of social support may experience excessive caregiver burden. Citation Format: Carol Ochoa, Randall Y. Chan, Lissette Cervantes, Kimberly A. Miller. A qualitative study on caregiving social support among Hispanic/Latino parents of childhood cancer survivors in a safety-net hospital [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B115.

Immune checkpoint therapy has resulted in minimal clinical response in many pediatric cancers. We sought to understand the influence of immune checkpoint inhibition using anti-PD-1 and anti-CTLA-4 antibodies individually, in combination, and after chemotherapy on immune responses in minimal and established murine neuroblastoma models. We also sought to understand the role of the tumor microenvironment (TME) and PD-L1 expression and their alteration post-chemotherapy in our models and human tissues. PD-L1 expression was enriched in human tumor-associated macrophages and up-regulated after chemotherapy. In a murine minimal disease model, single and dual immune checkpoint blockade promoted tumor rejection, improved survival, and established immune memory with long-term anti-tumor immunity against re-challenge. In an established tumor model, only dual immune checkpoint blockade showed efficacy. Interestingly, dual immune checkpoint therapy distinctly influenced adaptive and innate immune responses, with significant increase in CD8+CD28+PD-1+ T cells and inflammatory macrophages (CD11bhiCD11c−F4/80+Ly6Chi) in tumor-draining lymph nodes. Adding chemotherapy before immunotherapy provided significant survival benefit for mice with established tumors receiving anti-PD-1 or dual immune checkpoint blockade. Our findings demonstrate anti-PD-1 and anti-CTLA-4 therapy induces a novel subset of effector T cells, and support administration of induction chemotherapy immediately prior to immune checkpoint blockade in children with high-risk neuroblastoma.

Introduction: The triad of communication between childhood cancer survivors (CCS), their parents, and their medical providers may motivate CCS healthcare engagement but has not been examined. This may be particularly important for Hispanic/Latino populations, who are more likely to trust and receive health information from hospital providers and are less likely to remain engaged in survivorship care compared to non-Hispanic white persons. Methods: We analyzed data from the Project Forward pilot study, a population-based study that evaluated follow-up care among 160 CCS-parent dyads (CCS mean age=20 years, 7 years from diagnosis, and 29% of parents identified as Spanish-speaking Hispanic). Nine indicators representing multiple dimensions of communication were used in latent class analysis to identify distinct classes of communication. These indicators were selected from the parent and CCS survey and asked about communication between CCS, parents, and medical providers. The association between resulting classes and various covariates (e.g., parent ethnicity/language, CCS demographic, clinical characteristics) was examined using multinomial logistic regression. Results: Three classes of the triad of communication were identified: (1) high healthcare-focused communication (37.5%); (2) high comprehensive communication (15.6%); and (3) overall low communication (46.9%). The high healthcare-focused communication class was characterized by patterns of high probability for communication about future health care needs among CCS, parents, and medical providers. The high comprehensive communication class was characterized by a high probability of communication about future healthcare needs and a high probability for parent-CCS communication about different cancer facets. The overall low communication class was characterized by a low probability of endorsing any communication items. Greater time since diagnosis was marginally significantly associated with reduced odds of the dyad's membership in class 2 [OR=0.798, 95% CI=0.635, 1.002, p-value=0.0520], compared to class 3 (low communication). Additionally, dyads with English-speaking non-Hispanic parents were less likely to be in class 2 [OR=0.361, 95% CI=0.130, 1.005, p-value=0.0511], compared to class 3. After adjusting for all covariates simultaneously, greater time since diagnosis was associated with reduced odds of membership in class 2 (vs class 3). Dyads with Spanish-speaking Hispanic parents were more likely to be in classes 1 and 2 (vs. class 3). Discussion: Our results support the need to enhance communication among CCS, parents, and medical providers generally to improve knowledge and understanding about the long-term effects of cancer, treatment, and outcomes. Our study suggests that dyads, where parents were Spanish-speaking Hispanics tended to engage in high communication. Examining language preference provides an important contextual understanding as it supports the notion that Hispanic/Latino cultural values may play a favorable role in high levels of communication. Citation Format: Carol Y. Ochoa, Junhan Cho, Kimberly A. Miller, Lourdes Baezconde-Garbanati, Randall Y. Chan, Albert J. Farias, Joel E. Milam. A latent class analysis of communication patterns between Hispanic and non-Hispanic childhood cancer survivors, parents, and medical providers [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-016.

// Michael D. Hadjidaniel 1, * , Sakunthala Muthugounder 1, * , Long T. Hung 1, * , Michael A. Sheard 1 , Soheila Shirinbak 1 , Randall Y. Chan 1, 3 , Rie Nakata 1 , Lucia Borriello 1 , Jemily Malvar 1 , Rebekah J. Kennedy 1 , Hiroshi Iwakura 2 , Takashi Akamizu 2 , Richard Sposto 1, 3 , Hiroyuki Shimada 1, 3 , Yves A. DeClerck 1, 3 and Shahab Asgharzadeh 1, 3 1 Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA 2 The First Department of Medicine, Wakayama Medical University, Wakayama, Japan 3 Keck School of Medicine, University of Southern California, Los Angeles, CA, USA * These authors have contributed equally to this work Correspondence to: Shahab Asgharzadeh, email: sasgharzadeh@chla.usc.edu Keywords: neuroblastoma, tumor-associated macrophages, tumor microenvironment, STAT3, MYC Received: March 17, 2017 Accepted: July 19, 2017 Published: September 16, 2017 ABSTRACT Tumor-associated macrophages (TAMs) are strongly associated with poor survival in neuroblastomas that lack MYCN amplification. To study TAM action in neuroblastomas, we used a novel murine model of spontaneous neuroblastoma lacking MYCN amplification, and observed recruitment and polarization of TAMs, which in turn enhanced neuroblastoma proliferation and growth. In both murine and human neuroblastoma cells, we found that TAMs increased STAT3 activation in neuroblastoma cells and transcriptionally up-regulated the MYC oncogene. Analysis of human neuroblastoma tumor specimens revealed that MYC up-regulation correlates with markers of TAM infiltration. In an IL6 ko neuroblastoma model, the absence of IL-6 protein had no effect on tumor development and prevented neither STAT3 activation nor MYC up-regulation. In contrast, inhibition of JAK-STAT activation using AZD1480 or the clinically admissible inhibitor ruxolitinib significantly reduced TAM-mediated growth of neuroblastomas implanted subcutaneously in NOD scid gamma mice. Our results point to a unique mechanism in which TAMs promote tumor cells that lack amplification of an oncogene common to the malignancy by up-regulating transcriptional expression of a distinct oncogene from the same gene family, and underscore the role of IL-6-independent activation of STAT3 in this mechanism. Amplification of MYCN or constitutive up-regulation of MYC protein is observed in approximately half of high-risk tumors; our findings indicate a novel role of TAMs as inducers of MYC expression in neuroblastomas lacking independent oncogene activation.

We present the case of a 16-year-old boy who presented with fatigue, polyuria, and polydipsia while on chemotherapy for his relapsed acute lymphoblastic leukemia (ALL). Blood gas examination confirmed the diagnosis of hyperosmolar hyperglycemic state. The etiology for his hyperglycemia was most likely a result of oral glucocorticoid therapy combined with asparaginase therapy-both are a cornerstone of induction chemotherapy for ALL. The patient was aggressively rehydrated with saline, and medications were administered to correct his hyperkalemia. He was then slowly brought to euglycemia with a continuous infusion of insulin. Although hyperosmolar hyperglycemic state is rare during the treatment of ALL, frontline providers should be aware of this diagnosis because of the significant risk of hypovolemic shock and death if correction of hyperglycemia occurs prior to complete fluid resuscitation.

[Figure][1] A 57-year-old man presented with 2 months of weakness, fatigue, gingival bleeding, and cachexia. Examination revealed right mydriasis, bilateral retinal hemorrhages, diffuse lung crackles, a tense abdomen, and normal lymph nodes. Increased blood viscosity prevented laboratory

Background: Psychosocial determinants of health are thought to play a significant role in type 1 diabetes (T1D) management. Higher rates of stress have also been shown to result in poorer health outcomes. The role that self-perceived well-being, stress, and barriers to diabetes care have in T1D outcomes is less well known. Methods: At routine clinic visits, patients with known T1D completed a self-reported survey packet consisting of Perceived Stress Scale-4 (PSS), Diabetes Distress Scale-2 (DDS), and Global Well-Being Scale (GWB), as well as a novel barriers-to-care survey we developed. Inclusion criteria included all T1D patients older than 13 years of age (n=49); the instrument was administered to all participants recruited. Multivariate linear regression analysis assessed correlations between objective data (HgA1c and blood glucose checks per day) and the four self-reported measures. Results: GWB scale was inversely correlated with HgA1C (R2=0.111; p=0.04) and positively correlated with glucose checks per day (R2=0.211; p=0.001). PSS scale was positively correlated with HgA1C (R2=0.109; p=0.04) and DDS was inversely correlated with glucose checks per day (R2=0.103; p=0.01). Increasing numbers of barriers trended toward positive correlation with HgA1C and inverse correlation with glucose checks per day but did not reach statistical significance. Conclusion: Patient-reported markers of well-being and stress were predictive of home glucose monitoring frequency and glycemic control. The associations between HgA1C as well as glucose monitoring with well-being suggest that attention to assessing and optimizing positive psychological states may be valuable in achieving improved diabetes outcomes in adolescents with T1D. Disclosure A. Addala: None. R. Chan: None. M. Weigensberg: None.

Introduction Hemophagocytic Lymphohistiocytosis (HLH) is a rare syndrome of immune system derangement leading to over-activation of macrophages, cytokine storm, and tissue destruction with multiple organ involvement. Its survival rate is approximately 2 months without treatment. We discuss a well-appearing 13 month old with HLH discovered in the setting of hospitalization for fever of unknown origin (FUO). Case Presentation A 13-month-old male presented with a 10-day history of persistent fever, mild cough, and 3 days of mucoid diarrhea. Initial physical exam …

[Figure][1] A 19-year-old man presented with fever and gum pain for 2 weeks. Physical examination revealed pallor, gingival hyperplasia, and cervical and axillary lymphadenopathy. Automated blood count demonstrated 115 × 103/mm3 white blood cells, 10.7 g/dL of hemoglobin, hematocrit 31.5%

Both hepatoblastoma and hypoplastic kidneys are rare in children. A review of all patients with hepatoblastoma treated at our institution between 1993 and 2011 revealed three cases of hepatoblastoma occurring in children with hypoplastic kidneys and significantly impaired renal function. Two patients were treated with doxorubicin-based therapy without cisplatin. One was treated with carboplatin. The former two are long-term survivors while the third patient died of sepsis following chemotherapy. This association is unlikely due to chance alone and chemotherapy regimens without cisplatin may be effective in treating these children.

Childhood malignant tumors and their treatment are not well described in the natural history of methylmalonic aciduria (MMA). Here we present a case of hepatoblastoma occurring in the native liver of a 19-month-old male with MMA. His tumor was unresectable at diagnosis and he received neoadjuvant chemotherapy with cisplatin, 5-fluorouracil and vincristine. He developed metabolic acidosis and hyperglycemia during chemotherapy. In addition, he developed anemia, thrombocytopenia and febrile neutropenia. He underwent a combined liver-kidney transplant for local control of his tumor and to treat MMA. He remains in remission more than five years after his transplant. In addition, his transplant has cured his MMA and he is able to tolerate a regular diet without developing metabolic crises.

Background: The tumor microenvironment (TME) plays an important role in neuroblastoma (NBL) biology. Infiltrations of tumor-associated macrophages with alterations in patterns of pro-inflammatory genes are associated with poor prognosis in NBL. However, the role of regulatory T-cells in NBL remains unknown. As several genes in MAPK pathway are among recurrent mutations in neuroblastomas, and the production of pro-inflammatory mediators in immune cells is MAPK-dependent, we hypothesized targeted kinase inhibitor in combination with check-point blockade could exert synergistic effects on the TME's response to tumor cells. Therefore, we assessed the efficacy of combined therapy using a transgenic MYCN non-amplified neuroblastoma murine model driven by SV40 large T antigen (NB-Tag). Methods: Three human neuroblastoma cell lines and two NB-Tag derived mouse cell-lines were used for in vitro cell proliferation assay. For in vivo tumor growth models, combinations of cyclophosphamide, topotecan, trametinib, anti-CTLA4, and anti-PD1 therapies were studied in NB-Tag transgenic and transplantable subcutaneous (NB-SQ) murine models. Results: In vitro studies demonstrated trametinib had the highest anti-proliferative activity compared to other kinase inhibitors, and it effectively blocked cell cycle arrest in G1 phase. These anti-proliferative effects could not be rescued by co-culturing tumor cells with murine or human macrophages. In NB-Tag mice, which develop neuroblastoma spontaneously at 12 weeks, daily oral administration of trametinib (0.6mg/Kg) at pre-tumoral age (10 wk) significantly impaired tumor growth by 17 weeks (1424 mm3 in controls vs. 43 mm3 in treated mice). Treatment of 15 week-old NB-Tag mice (visible tumor by MRI) with trametinib after chemotherapy administration (5-days of Cyclophosphamide + Topotecan) also significantly impaired tumor regrowth (volume four weeks post-chemo, 491 vs. 42 mm3, p = 0.037), and more importantly, treatment increased the survival of NB-Tag mice compared to control (median survival: control = 24.5 wk, treated = 35 wk, p Conclusions: Our results provide strong evidence that MEK inhibition combined with checkpoint blockade significantly inhibited tumor formation in a syngeneic subcutaneous model. These findings indicate opportunities to enhance antitumor immunity with the potential to produce durable clinical responses in children with neuroblastomas. Citation Format: Sakunthala Muthugounder, Long Hung, Randall Chan, Jin Kim, Soheila Shirinbak, Hiroyuki Shimada, Shahab Asgharzadeh. MEK inhibition enhances immune checkpoint blockade treatment of murine models of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 400. doi:10.1158/1538-7445.AM2015-400

A 14-year-old male presented to the hospital after syncope during football practice on a hot summer day. On examination, temperature was 40.41C (104.71F) and heart rate was 180 beats per minute. He was unresponsive, intubated, and cooled in the pediatric intensive care unit. Laboratory values revealed acute kidney injury and ischemic hepatitis. Complete blood count showed a white blood cell count of 17!10/L, hemoglobin of 14.8 g/L, platelet count of 395!10/L, and mean corpuscular volume of 83.8 fL (normal, 81.4 to 91.9 fL). Peripheral blood smear showed hypersegmented neutrophils with “botryoid” nuclei (Supplemental Fig. 1 Supplemental Digital Content 1, http://links.lww.com/JPHO/A98). Hypersegmented neutrophils are classically seen with folate (vitamin B9) orcobalamin (vitamin B12) deficiency. These morphologic changes of the neutrophil nucleus occur due to impaired DNA synthesis from inadequate substrate or impaired replication from a toxin or medication effect. Arrest of nuclear maturation, impaired cell division, and unbalanced cell growth results in characteristic large cells with immature nuclei with relative cytoplasmic maturity. Red blood cell macrocytosis often accompanies hypersegmented neutrophils and can be seen in hypothyroidism, alcohol abuse, uremia, and myelodysplastic syndromes. Hypersegmented neutrophils without red blood cell macrocytosis, as in our patient, has been described in patients with hyperthermia, uremia, and concurrent megaloblastic and microcytic anemia from combined folate and/ or cobalamin deficiency along with iron deficiency or thalassemia. As the finding of hypersegmented neutrophils preceeds macrocytosis, neutrophil hypersegmentation without macrocytosismay represent early cobalamin and folate deficiency.1 The term “botryoid” refers to nuclei that appear like a cluster of grapes around a stem.2 Botryoid nuclei have been described in patients with hyperthermia due to cocaine and methamphetamine use,3 malignant hyperthermia, neuroleptic malignant syndrome,4 and autoimmune disorders such as rheumatoid arthritis, psoriatic arthritis, and systemic sclerosis.5 In comparison, the multilobed nuclei in cobalamin and folate deficiency appear disorganized. The pathogenesis of botryoid nuclei in hyperthermia has not been clearly elucidated. Hyperthermia may activate the intrinsic signaling pathway that initiates apoptosis since pyknosis, nuclear condensation in the setting of irreversible cell death, is seen in neutrophils in response to hyperthermia.6 In addition, microtubular decomposition may play a role.7 In vitro experiments have shown that radially segmented neutrophils are induced by applying heat.8 Botryoid changes in >50% of neutrophils on a peripheral blood smear may be sufficient to diagnose heatstroke.2 Fewer than 50% botryoid neutrophils is suggestive of heatstroke. Clinicians should be aware that hyperthermia can cause hypersegmented neutrophils so as to avoid unnecessary evaluations for other etiologies. Our patient’s mental status and renal function improved with cooling and intravenous fluids. He was extubated on the first day of hospitalization. Subsequent peripheral blood smears showed resolution of hypersegmented neutrophils by the second hospital day. He was discharged home after 3 days without any complications.

Background: The tumor microenvironment is important in the prognosis of Neuroblastoma (NBL), a common childhood cancer of the sympathetic nervous system. However little is know about the role of T regulatory-cells (Treg cells) in NBL. We hypothesize that Treg cells may play an important role in NBL development and immunotherapy targeted to Treg cells may modify the natural course of murine model of neuroblastoma driven by SV40's large T-antigen (NBL-Tag). Methods: Treg cells (positive for CD25/FOXP3/CD4/CD3ϵ) along with other common leukocytes were identified by flow cytometry in single-cell suspensions of adrenal tumors, lymph nodes, spleens, bone marrow and blood of NBL-Tag mice at 14-22 weeks of age. Age dependent pattern of T-cell infiltration and expression of 45 inflammation-relate genes (including CD4) were assessed by CD4 immunohistochemical staining (IHC), and RT-PCR (TaqMan-Low-Density-Array:TLDA), respectively. A luciferase-expressing NBL-Tag cell line (NBTH-Luc) was used to establish a subcutaneous neuroblastoma models in C57Bl/6 mice and tumors were profiled using similar flow cytometry strategies as above. Animals with subcutaneous tumors or transgenic animals were subjected to immunotherapy using anti-CTLA-4, anti-PD-1, or combination of the two (with appropriate isotype controls) in low and high tumor burden scenarios. Results: IHC showed presence and increasing number of CD4+ cells in tumors of NBL-Tag mice over time. In comparison, no CD4+ cells were identified in wild-type adrenal glands. TLDA analysis also showed on average a 4-fold increased expression of CD4 cells in tumors compared to wild-type adrenal glands. Flow cytometry data demonstrated that the CD4+CD25+FOXP3+ Treg cells infiltrate NBL-Tag tumors at all ages (mean=2.9% of all CD45+ cells, n=17 mice). Subcutaneous syngeneic tumors were also infiltrated with CD4+CD25+FOXP3+ Treg cells (mean=8.6% of all CD45+ cells, n=7 mice). Combination of anti-CTLA-4 or anti-PD-1 was not effective in well-established tumors in either NBL-Tag transgenic model or subcutaneous model (p=NS). However, combination immunotherapy prevented formation of subcutaneous tumors (minimal residual disease model) compared to control group (p Conclusion and Future Directions: Our results demonstrate presence of Treg cells in NBL-Tag tumors. Treatment with anti-CTLA-4 and anti-PD-1 prevented formation of neuroblastoma tumors in a syngeneic subcutaneous model. Our data provides pre-clinical evidence that Ipilimumab and Nivolumab, recently approved melanoma drugs, may be useful in treating neuroblastoma children with minimal residual disease. Citation Format: Randall Chan, Soheila Shirinbak, Sakunthala Muthugounder, Long Hung, Janahan Gnanachandran, Michael Hajidaniel, Shahab Asgharzadeh. Regulatory T-cells and effects of anti-CTLA4 and anti-PD1 therapy in a transgenic murine model of neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5021. doi:10.1158/1538-7445.AM2014-5021