Tamra Slone

Subclinical cardiotoxicity in childhood cancer survivors exposed to very low dose anthracycline therapy

Subclinical cardiotoxicity occurs in childhood cancer survivors following moderate and high anthracycline doses. However, less is known about the subclinical changes in left ventricular (LV) structure that occur after very low anthracycline doses of ≤100 mg/m2. This study was designed to assess LV function and key structural parameters following very low doses of anthracycline.

Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation.

New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.

Infantile mixed phenotype acute leukemia (bilineal and biphenotypic) with t(10;11)(p12;q23);MLL-MLLT10

We report a case of a 6-month-old boy with a mixed phenotype acute leukemia (MPAL), bilineal and biphenotypic immunophenotype (B-lymphoid lineage and combined B-lymphoid and monocytic lineage) with t(10;11)(p12;q23);MLL-MLLT10. He was treated with acute myeloid leukemia protocol and in complete remission at 7-month follow-up. To the best of our knowledge, this is the first reported MLL-MLLT10 rearranged case presenting as MPAL in an infant. From a clinical practice standpoint, this case illustrates the importance of detection of MLL rearrangement due to its prognostic implication and the effectiveness of flow cytometry immunophenotyping in diagnosing MPAL and monitoring minimal residual disease.

Risk factors for readmission after initial diagnosis in children with acute lymphoblastic leukemia.

Specific hospital discharge criteria following the initial diagnosis of children with acute lymphoblastic leukemia (ALL) have not been reported. This retrospective cohort study was designed to identify risk factors for readmission during induction therapy, to assist with development of discharge guidelines.

Distinct DICER1 Hotspot Mutations Identify Bilateral Tumors as Separate Events

DICER1 syndrome1 predisposes to a variety of cancers, including pleuropulmonary blastoma (PPB),2 ovarian Sertoli-Leydig cell tumor (SLCT),3 embryonal rhabdomyosarcoma,4 and kidney tumors.5–8 In DICER1 syndrome, most patients bear a germline null mutation in DICER1, and the tumors uniformly bear a second-hit missense substitution at one of five hotspot positions (1705E, 1709D, 1809G, 1810D, and 1813E). A wide range of clinical phenotypes can be seen in DICER1 syndrome5,9; some patients are asymptomatic, whereas others develop multiple tumors. In the classic cases, patients with a germ-line null mutation develop different somatic hotspot mutations in each tumor.7,10–16 However, in some patients, multiple tumors arise from germline mosaicism of the hotspot mutation, with subsequent somatic loss of the wild-type allele.17–19 Here we report a patient with DICER1 syndrome who developed four tumor types at six anatomic sites over the course of 12 years. These tumors harbor four distinct hotspot mutations, which is one of the highest numbers of distinct somatic DICER1 mutations reported in a single patient. By identifying these mutations, we show that the patient’s bilateral renal tumors and bilateral ovarian SLCTs each constituted a new primary tumor. Because we found no other mutations to explain her particularly severe clinical course, we speculate that her subsequent tumors were a product of the intense chemotherapy and radiation regimens she received.

Novel r(2)(p25q31) cytogenetic abnormality in a pediatric patient with acute leukemia of ambiguous lineage

We describe a case of acute leukemia of ambiguous lineage with a novel cytogenetic abnormality. A 1-year-old boy presented with abnormal complete blood count findings, and was found to have blasts and mild dysgranulopoiesis. The blasts showed immunophenotypic evidence of myeloid and T-lineage differentiation. Subsequent cytogenetic analysis showed r(2)(p25q31) as the sole stem line cytogenetic defect with clonal evolution. While cytogenetic abnormalities can have a critical role in the classification and prognostication of acute lymphoblastic and acute myeloid leukemia, the significance of cytogenetic abnormalities in acute leukemia of ambiguous lineage remains unclear. This finding has not been reported previously to the best of our knowledge.