Childrens Hospital Mi Hematology/Oncology 3901 Beaubien 2Nd Floor - Carl&Apos;S Building
Detroit MI 48201
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AluY-mediated germline deletion, duplication and somatic stem cell reversion in UBE2T defines a new subtype of Fanconi anemia. - Human molecular genetics
Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.Â© The Author 2015. Published by Oxford University Press.
Controversies in the role of radiotherapy in the treatment of pediatric Hodgkin lymphoma. - Indian journal of pediatrics
Hodgkin lymphoma in children is a highly curable malignancy with current approaches utilizing combined modality therapy and a risk-adapted approach. The combination of anthracyclines, bleomycin, and radiotherapy, as well as other alkylating agents, are significant risk factors for secondary malignancies and cardiopulmonary toxicity. Therefore, current strategies aim to optimize cure rates while minimizing late effects. The role of radiotherapy has been examined in recent pediatric trials, with varying results. However, they provide evidence, as a whole, for the omission of radiotherapy for a subgroup of patients, without compromising outcomes.
Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. - Blood
In pediatric acute myeloid leukemia (AML), cytogenetic abnormalities are strong indicators of prognosis. Some recurrent cytogenetic abnormalities, such as t(8;16)(p11;p13), are so rare that collaborative studies are required to define their prognostic impact. We collected the clinical characteristics, morphology, and immunophenotypes of 62 pediatric AML patients with t(8;16)(p11;p13) from 18 countries participating in the International Berlin-Frankfurt-MÃ¼nster (I-BFM) AML study group. We used the AML-BFM cohort diagnosed from 1995-2005 (n = 543) as a reference cohort. Median age of the pediatric t(8;16)(p11;p13) AML patients was significantly lower (1.2 years). The majority (97%) had M4-M5 French-American-British type, significantly different from the reference cohort. Erythrophagocytosis (70%), leukemia cutis (58%), and disseminated intravascular coagulation (39%) occurred frequently. Strikingly, spontaneous remissions occurred in 7 neonates with t(8;16)(p11;p13), of whom 3 remain in continuous remission. The 5-year overall survival of patients diagnosed after 1993 was 59%, similar to the reference cohort (P = .14). Gene expression profiles of t(8;16)(p11;p13) pediatric AML cases clustered close to, but distinct from, MLL-rearranged AML. Highly expressed genes included HOXA11, HOXA10, RET, PERP, and GGA2. In conclusion, pediatric t(8;16)(p11;p13) AML is a rare entity defined by a unique gene expression signature and distinct clinical features in whom spontaneous remissions occur in a subset of neonatal cases.
Hereditary intrinsic factor deficiency in chaldeans. - JIMD reports
Juvenile vitamin B(12) or cobalamin (Cbl) deficiency is notoriously difficult to explain due to numerous acquired and inherited causes. The consequences of insufficient Cbl are megaloblastic anemia, nutrient malabsorption, and neurological problems. The treatment is straightforward with parenteral Cbl supplementation that resolves most health issues without an urgent need to clarify their cause. Aside from being clinically unsatisfying, failing to elucidate the basis of Cbl deficiency means important information regarding recurrence risk is not available to the individual if the cause is contagious or inherited. Acquired causes have largely disappeared in the Modern World because they were mostly due to parasites or malnutrition. Today, perhaps the most common causes of juvenile Cbl deficiency are Imerslund-GrÃ¤sbeck syndrome and inherited intrinsic factor deficiency (IFD). Three genes are involved and genetic testing is complicated and not widely available. We used self-identified ancestry to accelerate and confirm the genetic diagnosis of IFD in three families of Chaldean origin. A founder mutation limited to Chaldeans from Iraq in the intrinsic factor gene GIF was identified as the cause. World events reshape the genetic structure of populations and inherited diseases in many ways. In this case, all the patients were diagnosed in the USA among recent immigrants from a single region. While IFD itself is not restricted to one kind of people, certain mutations are limited in their range but migrations relocate them along with their host population. As a result, self-identified ancestry as a stratifying characteristic should perhaps be considered in diagnostic strategies for rare genetic disorders.
A randomized placebo-controlled trial of massage therapy on the immune system of preterm infants. - Pediatrics
The aim of this study was to investigate the effects of massage therapy (MT) on the immune system of preterm infants. The primary hypothesis was that MT compared with sham therapy (control) will enhance the immune system of stable premature infants by increasing the proportion of their natural killer (NK) cell numbers.A randomized placebo-controlled trial of MT versus sham therapy (control) was conducted among stable premature infants in the NICU. Study intervention was provided 5 days per week until hospital discharge for a maximum of 4 weeks. Immunologic evaluations (absolute NK cells, T and B cells, T cell subsets, and NK cytotoxicity), weight, number of infections, and length of hospital stay were also evaluated.The study enrolled 120 infants (58 massage; 62 control). At the end of the study, absolute NK cells were not different between the 2 groups; however, NK cytotoxicity was higher in the massage group, particularly among those who received â‰¥5 consecutive days of study intervention compared with control (13.79 vs 10 lytic units, respectively; P = .04). Infants in the massage group were heavier at end of study and had greater daily weight gain compared with those in the control group; other immunologic parameters, number of infections, and length of stay were not different between the 2 groups.In this study, MT administered to stable preterm infants was associated with higher NK cytotoxicity and more daily weight gain. MT may improve the overall outcome of these infants. Larger studies are needed.
Effect of melatonin on the cytotoxicity of chemotherapeutic drugs in human leukemia cells. - In vivo (Athens, Greece)
Limited data are available on the effect of melatonin (MLT) on the cytotoxicity of chemotherapeutic drugs in tumor cells. In this study, we aimed to evaluate the effect of MLT on the cytotoxicity of different chemotherapeutic agents in leukemia cells in vitro.The experiments were carried out using human leukemia cell lines, Jurkat, MOLT-4, Daudi, HL-60, CMK, and K562, and two patient samples. Leukemia cells were incubated with cytarabine, daunorubicin, and etoposide with or without 10(-5) M and 10(-3) M concentrations of MLT. Cytotoxicity was measured by detecting apoptosis using flow cytometry.Overall, co-incubation with melatonin did not alter the cytotoxicity of chemotherapeutic drugs in cell lines and patient samples except one. In a patient sample with acute myeloid leukemia, etoposide treatment in combination either concentrations of MLT resulted in increased elimination of the leukemia cells.Melatonin does not interfere with the cytotoxic effect of cytarabine, daunorubicin and etoposide in leukemia cells.
Selective IgM deficiency in CD30+ cutaneous lymphoproliferative disorder. - Journal of pediatric hematology/oncology
Primary cutaneous anaplastic large cell lymphoma with local lymph node involvement was diagnosed in a 13-year-old boy with an ulcerative facial lesion and a history of skin lesions of lymphomatoid papulosis. The tumor regressed with chemotherapy. He continued to develop recurrent self-limited lesions of lymphomatoid papulosis , with a halo surrounding these lesions during the healing phase. He developed selective immunoglobulin M deficiency with decline in levels even 4 years after the chemotherapy with no recurrent infections noted and adequate IgG response to immunizations. Both peripheral blood IgM+ and memory B cells were low, suggesting a possible cause-effect relationship between selective immunoglobulin M deficiency and chronic CD30+ cutaneous lymphoproliferative disorders.
Malignant fibrous histiocytoma two years after autologous stem cell transplant for Hodgkin lymphoma: evidence for genomic instability. - Pediatric blood & cancer
Secondary malignancies (SMs) in Hodgkin lymphoma (HL) are thought to be related to exposure to alkalating agents, topoisomerase II inhibitors and ionizing radiation, and tend to occur a decade after initial therapy. We report a 14 year old autistic male, who developed malignant fibrous histiocytoma (MFH) two years after autologous stem cell transplantation for advanced stage HL. The MFH and post-surgical reactive tissues exhibited multiple clonal abnormalities. In addition, PHA-stimulated peripheral blood lymphocytes showed increased frequency of non-clonal chromosomal aberrations. The potential role of genomic instability in early onset of SM in our patient is discussed.Copyright Â© 2011 Wiley-Liss, Inc.
Positron emission tomography in subcutaneous panniculitis-like T-cell lymphoma. - Pediatric blood & cancer
Subcutaneous panniculitis-like T-cell lymphoma (SPTCL), an uncommon disorder, was diagnosed in a 17-year-old female when she presented with multiple hard subcutaneous masses that developed over 3 years. She was treated on chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone. Pre- and post-treatment positron emission tomography study demonstrated dramatic resolution of the subcutaneous lesions indicating its usefulness in SPTCL staging and treatment response monitoring.
Increased lymphocyte Fas expression and high incidence of common variable immunodeficiency disorder in childhood Evans' syndrome. - Clinical immunology (Orlando, Fla.)
Evans' syndrome (ES) is characterized by autoimmune hemolytic anemia and thrombocytopenia and has been associated with immune deficiency and lymphoproliferation in some cases. Abnormalities of Fas-mediated apoptosis have been reported in various immune dysregulation disorders associated with autoimmunity and lymphoproliferation. We measured lymphocyte Fas expression and Fas-mediated T lymphocyte apoptosis in 7 children with ES, 7 with acute idiopathic thrombocytopenic purpura (ITP) and 9 with non-immune-mediated disorders. Patients with ES had higher Fas expression on peripheral blood T and B lymphocytes (P<0.001 and P=0.046, respectively) and increased Fas-mediated elimination of activated T lymphocytes compared with the control groups. While two ES patients had panhypogammaglobulinemia at testing, three more developed it later, reaching a frequency of 83%. Some children with ES have increased lymphocyte Fas expression and Fas-mediated T lymphocyte apoptosis and these may be early signs of common variable immunodeficiency disorder in ES.
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Childrens Hospital Mi Hematology/Oncology 3901 Beaubien 2Nd Floor - Carl&Apos;S Building Detroit, MI 48201
4201 St Antione Detroit Medical Center
4646 John R St
4201 St. Antione Uhc 6F University Pediatricians