There have been concerns among pediatric oncologists that adolescent and minority patients are not getting adequate access to care. This study examines access to cancer care and survival outcomes ...based on age, race, and type of cancer in patients in Georgia.
We performed a retrospective review of 1,751 cancer patients aged 0 to 19 years, diagnosed between 1998 and 2002, in the Georgia Comprehensive Cancer Registry, which identified patients who were treated at one of five Georgia pediatric cancer centers (Children's Oncology Group COG members) at any point in their treatment. Data were further analyzed for age at diagnosis, race, county of residence, and 5-year survival.
Eighty-seven percent of patients aged 0 to 14 years and 36% of those aged 15 to 19 years were treated at a COG institution. Twenty-five percent of all patients were of African descent, with 75.4% of black versus 70.3% of white patients (age 0 to 19 years) treated at a COG institution (P < .01); 97.1% of other minorities were treated at a COG institution (P < .05). The 5-year actuarial survival rates for more pediatric-specific cancers were significantly lower in all leukemias (75.1% v 46.4%; P = .0015), and acute lymphoblastic leukemia specifically (86.3% v 53.3%; P < .05) for patients not treated at a COG institution. Actuarial survival rates were much lower for blacks than whites in all cancers as a whole (70% v 82%; P < .001) and for many specific subtypes.
Adolescent-aged patients are less likely to be referred to a COG institution, potentially exposing them to worse outcomes in some cancer subtypes. Reassuringly, minority populations are receiving adequate access to pediatric cancer care; unfortunately their survival rates are lower.
The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce ...polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.
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► Screen identifies > 200 compounds regulating megakaryocyte polyploidization ► Integrated target identification approach suggests regulatory kinase networks ► Aurora kinase A activity mediates megakaryocyte polyploidization and differentiation ► Induction of polyploidization provides a therapeutic strategy for AMKL
Megakaryocytes undergo a modified form of the cell cycle termed endomitosis, in which cells skip the late stages of mitosis to become polyploid. Using a chemical screening approach, Wen et al. now provide insight into the protein kinase networks that regulate endomitosis and reveal a differentiation therapy strategy for the treatment of acute megakaryocytic leukemia.
We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid ...metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7-36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking beta-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.
There is interest in using ligands of chemosensory binding proteins (CBP) to augment an insect's responsiveness to chemosensory cues. We showed previously that combining a synthetic ligand of a CBP ...with limonene, a common citrus volatile, enhanced the probing response of Asian citrus psyllid (
). Here, we determined whether synthetic compounds, which were ligands of
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olfactory binding protein (OBP) DCSAP4, influenced the settling and aggregation levels of psyllids on young citrus shoots. The test ligands and Cmac scent were dispensed from a droplet of an emulsified wax product (SPLAT) placed on the bottom of each vial. The shoots were presented: (1) alone (shoot + blank SPLAT), (2) with a mixture of citrus volatiles ("Cmac scent") (shoot + SPLAT with Cmac scent), or (3) with different concentrations of test ligands (shoot + SPLAT with test ligand at concentration 1, shoot + SPLAT with test ligand at concentration 2, etc.). Depending on the availability of test ligands, sprigs, and psyllids, each test included from two to four replicates of each treatment (i.e., shoot only, shoot + Cmac scent, shoot + test ligand at concentration 1, shoot + test ligand at concentration 2, etc.); only a single test ligand was presented in each test. For each test, 200
were released in the test area and the numbers of psyllids on each sprig were counted 24 h later. Sprigs with ≥7 psyllids were considered to be an aggregation. A total of seven ligands were tested individually. Four of the ligands (654, 717, 784, and 861) modulated psyllid settling and aggregation response, causing greater settling and aggregation to sprigs presented with the Cmac scent than to those sprigs with blank SPLAT. Presentation of one of the ligands (019) resulted in an opposite effect in which psyllid settling and aggregation levels were lower on sprigs with Cmac scent than on those with blank SPLAT. There were no differences in settling levels in the different treatment vials in the Ligand 905 experiment. In the Ligand 937 experiment, settling levels did not vary significantly between treatment vials although settling levels were relatively high in all treatment vials and there was a significant treatment effect. Increased settling and aggregation levels were largely not observed with in the vials with only the test ligands, and there was little effect of ligand concentration on psyllid response levels. This suggests that the test ligands themselves did not attract the psyllids but rather modulated the psyllid's response to the Cmac scent. The results suggest that synthetic ligands of
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CBPs can be used to increase the effectiveness of citrus scent lures used to attract psyllids to monitoring traps and attract and kill devices.
Children who are treated for myeloid leukemia associated with Down syndrome (DS) experience superior survival compared with children who have myeloid leukemia without DS. To maintain excellent ...outcomes while avoiding toxicity, the Children's Oncology Group (COG) conducted the phase 3 trial COG A2971, the first trial solely designed to provide uniform treatment of myeloid leukemia in North American children with DS. A2971 eliminated 2 induction drugs and 3 months of maintenance therapy from the standard-timing regimen of dexamethasone, cytarabine, 6-thioguanine, etoposide, and rubidomycin/daunomycin (DCTER) used in the previous study (Children's Cancer Group CCG 2891).
COG A2971 was a multi-institutional, nonrandomized, clinical trial that enrolled 132 patients who had DS with either acute myeloid leukemia (n = 91) or myelodysplastic syndrome (n = 41).
The median follow-up was 4.8 years (range, 0.8-8.6 years), the median age at diagnosis was 1.7 years (range, 0.3-13.6 years), and the median white blood cell count was 6200/μL (range, 900-164,900/μL). The remission rate (92.7% ± 6%) was similar to that reported in the CCG 2891 study (91.3% ± 5%; P = .679). The 5-year event free survival (EFS) rate was 79% ± 7% (vs 77% ± 7% in CCG 2891; P = .589), the disease-free survival (DFS) rate was 89% ± 6% (vs 85% ± 6% in CCG 2891; P = .337), and the overall survival rate was 84% ± 6% (vs 79% ± 7% in CCG 2891; P = .302). Induction day-14 bone marrow response trended toward a more favorable outcome (EFS: P = .12). Age >4 years was an adverse risk factor (5-year EFS rate: 33% ± 38% for children aged >4 years median, 8.5 years; n = 6 vs 81% ± 7% for children ages 0-4 years median, 1.7 years; n = 126; P = .001).
The COG A2971 trial reduced the chemotherapy dose and maintained survival to that achieved by the CCG 2891 trial in children who had myeloid leukemia associated with DS.
Infant acute lymphoblastic leukemia (ALL) has a poor therapeutic outcome despite attempts to treat it based on prognostic factor–guided therapy. This is the first cooperative group trial ...characterizing all infants at the molecular level for MLL/11q23 rearrangement. All infants enrolled on Children's Cancer Group (CCG) 1953 were tested for MLL rearrangement by Southern blot and the 11q23 translocation partner was identified (4;11, 9;11, 11;19, or “other”) by reverse-transcriptase polymerase chain reaction (PCR). One hundred fifteen infants were enrolled; overall event-free survival (EFS) was 41.7% (SD = 9.2%) and overall survival (OS) was 44.8% at 5 years. Five-year EFS for MLL-rearranged cases was 33.6% and for MLL-nonrearranged cases was 60.3%. The difference in EFS between the 3 major MLL rearrangements did not reach statistical significance. Multivariate Cox regression analyses showed a rank order of significance for negative impact on prognosis of CD10 negativity, age younger than 6 months, and MLL rearrangement, in that order. Toxicity was the most frequent cause of death. Relapse as a first event in CCG 1953 was later (median, 295 days) compared with CCG 1883 historic control (median, 207 days). MLL/11q23 rearrangement, CD10 expression, and age are important prognostic factors in infant ALL, but molecular 11q23 translocation partners do not predict outcome.
•Low-risk pediatric acute myeloid leukemia (AML) has good outcomes with chemotherapy.•However, high anthracycline-based regimens increase risk of cardiotoxicity.•Aflac-AML regimen reduces ...anthracycline while increasing total cytarabine exposure.•Favorable outcomes were maintained with this regimen while reducing cardiotoxicity.•Aflac LL1901 (NCT04326439) will test this approach prospectively in low-risk AML.
Advances in risk stratification have improved the 3-year disease-free survival (DFS) and overall survival (OS) of low-risk pediatric acute myeloid leukemia (LR-AML) to approximately 70 % and 85 % respectively. LR-AML is defined by favorable cytogenetic/molecular features and/or optimal early response to therapy. However, cumulative anthracycline exposure in contemporary Children’s Oncology Group (COG) regimens approach a doxorubicin equivalent exposure of 540 mg/m2; with rates of non-infection related left ventricular systolic dysfunction (LVSD) approaching 15 %. This is a major cause of toxicity in these patients and precludes the further use of anthracyclines in the relapsed setting; therefore, strategies that reduce cardiotoxicity while maintaining excellent outcomes are needed.
Twenty-seven pediatric patients with LR-AML were treated with an anthracycline-reduced approach (Aflac-AML regimen) between 2011 and 2016. Patients received four courses of therapy including three high-dose cytarabine containing courses and a cumulative doxorubicin equivalent exposure of 390 mg/m2, a 28 % reduction in anthracycline dosing compared to current COG regimens.
The 3-year DFS and OS was 70.0 % and 85.5 % respectively, from end of Induction I (first chemotherapy cycle) with a median follow-up of 3.2 years. These survival outcomes are comparable to current LR-AML regimens. Only two patients developed non-infection related LVSD during therapy and more importantly, none developed LVSD after completion of therapy.
These findings suggest that LR-AML outcomes can be maintained using a reduced anthracycline chemotherapy regimen, resulting in lower cardiac toxicity. This new chemotherapy backbone is now being tested prospectively (NCT04326439) to further validate its use in pediatric LR-AML.
Use of soy-based infant formulas and soy/isoflavone supplements has aroused concern because of potential estrogenic effects of the soy isoflavones genistein and daidzein. Here we show that s.c. ...genistein injections in ovariectomized adult mice produced dose-responsive decreases in thymic weight of up to 80%. Genistein's thymic effects occurred through both estrogen receptor (ER) and non-ER-mediated mechanisms, as the genistein effects on thymus were only partially blocked by the ER antagonist ICI 182,780. Genistein decreased thymocyte numbers up to 86% and doubled apoptosis, indicating that the mechanism of the genistein effect on loss of thymocytes is caused in part by increased apoptosis. Genistein injection caused decreases in relative percentages of thymic CD4+CD8-and double-positive CD4+CD8+thymocytes, providing evidence that genistein may affect early thymocyte maturation and the maturation of the CD4+CD8-helper T cell lineage. Decreases in the relative percentages of CD4+CD8-thymocytes were accompanied by decreases in relative percentages of splenic CD4+CD8-cells and a systemic lymphocytopenia. In addition, genistein produced suppression of humoral immunity. Genistein injected at 8 mg/kg per day produced serum genistein levels comparable to those reported in soy-fed human infants, and this dose caused significant thymic and immune changes in mice. Critically, dietary genistein at concentrations that produced serum genistein levels substantially less than those in soy-fed infants produced marked thymic atrophy. These results raise the possibility that serum genistein concentrations found in soy-fed infants may be capable of producing thymic and immune abnormalities, as suggested by previous reports of immune impairments in soy-fed human infants.
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