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 TAMmediated 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.
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.
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.
A 14-year-old male presented to the hospital after syn cope 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 Â 10 9 /L, hemoglobin of 14.8 g/L, platelet count of 395Â10 9 /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 B 9 ) orcobalamin (vitamin B 12 ) 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 impro...
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 5×109/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 150×109/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.
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.
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 3 10 3 /mm 3 white blood cells, 10.7 g/dL of hemoglobin, hematocrit 31.5%, and 42 3 10 3 /mm 3 platelets. Peripheral blood smear revealed 85% monoblasts and promonocytes (blast equivalents) as well as cytoplasmic leukemic cell fragments (arrows) mimicking platelets (arrowheads) (panel A and inset). The blasts and "pseudoplatelets" (arrow) stained for nonspecific esterase, confirming their monocytic leukemic origin, whereas platelets (arrowheads) were negative (panel B). The pseudoplatelets accounted for 20% of the platelets counted by the automated counter. Flow cytometry confirmed the diagnosis of acute monocytic leukemia.A spuriously elevated platelet count resulting from leukemic cell fragmentation can be seen in almost all subtypes of acute myeloid leukemia (AML) as well as acute lymphoblastic leukemia, but it is particularly associated with AML with maturation and with acute monoblastic and monocytic leukemias. Therefore, platelet counts obtained by an automated counter may overestimate the true platelet count. Clinicians and pathologists should evaluate the peripheral blood smear visually at diagnosis and before invasive diagnostic and therapeutic interventions to minimize bleeding risk.For additional images, visit the ASH IMAGE BANK, a reference and teaching tool that is continually updated with new atlas and case study images. For more information visit http://imagebank.hematology.org.
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