Assunta Tornesello

Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia

Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3–independent growth in Ba/F3 cells and/or IL-9–independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.

Relationship between maternal parity, basal prolactin levels and neonatal breast milk intake

Basal serum levels of prolactin (PRL) in 21 nursing mothers were measured by radioimmunoassay on the 2nd, 3rd and 4th days of the puerperium. The quantity of breast milk suckled during the 4th day of life was also evaluated by calculating the difference in the babys weight before and after each feeding. During the first postpartum days, mean basal levels of PRL did not change. However these levels were noted to be significantly lower in the multiparas (p less than 0.05) than in the primiparas. In addition, the milk intake in neonates of multiparous mothers was significantly greater (p less than 0.05) than that in neonates of primiparous mothers. The authors hypothesis, based on the results of animal experimentation described in the literature, is that initiation of breast-feeding is facilitated in multiparas by the increased number of occupied PRL receptors in the mammary glands reflected by the lowered serum levels of the hormone.

Constitutional trisomy 8 and myelodysplasia: Report of a case and review of the literature

A diagnosis of myelodysplastic syndrome was made in an 18-year-old patient with Warkany syndrome due to constitutional trisomy 8 mosaicism. The possible causal role of this particular chromosome constitution with respect to myelodysplasia and embryonal childhood tumors is discussed.

Metastatic Group 3 Medulloblastoma in a Patient With Tuberous Sclerosis Complex: Case Description and Molecular Characterization of the Tumor

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment‐induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; H&E, haematoxilin and eosin; Gd, gadolinium.

Deep neck infection complicating lymphadenitis caused by Streptococcus intermedius in an immunocompetent child

BackgroundStreptococcus intermedius belongs to the Streptococcus anginosus group. It is part of the normal flora of the human mouth, but it can be etiologically associated with deep-site infections.Case presentationWe present a case of deep neck infection complicating Streptococcus intermedius lymphadenitis, which developed in an immunocompetent 14-year-old boy with a history of recent dental work. The infection was ultimately eradicated by a combined medical and surgical approach.ConclusionOur report suggests that combined medical and surgical therapy is essential for the complete resolution of deep infections caused by Streptococcus intermedius. Molecular biological techniques can be useful in guiding the diagnostic investigation and providing insight into the possibility of occult abscesses, which are particularly common with Streptococcus intermedius infections.

Position paper: Role of131I-metaiodobenzylguanidine in the treatment of neuroblastoma

BACKGROUND Standard chemo-radiotherapy methods for the treatment of children with advanced neuroblastoma (NBL) including bone marrow transplant approaches have been disappointing. These poor results can be ascribed to the evolution of residual drug-resistant cell populations. Curative attempts should therefore be directed to their elimination during induction treatment. This can best be accomplished through the use of multiple, non-cross-resistant agents early in therapy. 131I-Metaiodobenzylguanidine (131I-MIBG) provides a mechanism for the delivery of high doses of radiation to NBL lesions. Experience reported from several institutions indicates an approximate 50% response rate in previously treated children with advanced NBL. CONCLUSIONS A better strategy is to employ 131I-MIBG together with intensive chemotherapy at the time of diagnosis. A pilot study adopting these principles and supported by laboratory data has been designed and is underway.

Use of allogenic umbilical cord blood for red cells transfusion in premature infants:utopia or reality?

Extremely low birth weight (ELBW) infants almost always receive blood transfusions early in life. Newborn infants are currently transfused with leukocyte-depleted, irradiated red blood cells (RBCs) obtained from adult donor, which contains adult hemoglobin. Adult hemoglobin affinity for oxygen is lower than fetal, therefore red cell transfusion could be responsible for increased oxygen delivery to tissues increasing the risk of the “oxygen radicals disease of the newborn”. Though clinical studies have demonstrated that autologous cord blood transfusions in newborns is feasible, the clinical use of umbilical cord blood (UCB) for RBC transfusion purposes is still limited, expecially because of the small volumes achieved after processing of the UCB unit. The preliminary results of the first clinical study assessing the feasibility and the effectiveness of a transfusional program in preterm infants with packed RBSs obtained from allogenic UCB are shown.

MRI features as a helpful tool to predict the molecular subgroups of medulloblastoma: state of the art

Medulloblastoma is the most common malignant pediatric brain tumor. Medulloblastoma should not be viewed as a single disease, but as a heterogeneous mixture of various subgroups with distinct characteristics. Based on genomic profiles, four distinct molecular subgroups are identified: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4. Each of these subgroups are associated with specific genetic aberrations, typical age of onset as well as survival prognosis. Magnetic resonance imaging (MRI) is performed for all patients with brain tumors, and has a key role in the diagnosis, surgical guidance and follow up of patients with medulloblastoma. Several studies indicate MRI as a promising tool for early detection of medulloblastoma subgroups. The early identification of the subgroup can influence the extent of surgical resection, radiotherapy and chemotherapy targeted treatments. In this article, we review the state of the art in MRI-facilitated medulloblastoma subgrouping, with a summary of the main MRI features in medulloblastoma and a brief discussion on molecular characterization of medulloblastoma subgroups. The main focus of the article is MRI features that correlate with medulloblastoma subtypes, as well as features suggestive of molecular subgroups. Finally, we briefly discuss the latest trends in MRI studies and latest developments in molecular characterization.

A human neuroblastoma xenograft model for 125-I-metaiodobenzylguanidine biodistribution studies.

We developed an animal model to evaluate the 125-I-metaiodobenzylguanidine (125-I-mIBG) biodistribution in tumor bearing mice. Six weeks old nude-atimic mice were subcutaneously injected with 30 × 106 cells of the human neuroblastoma (NB) cell line SH-SY5Y. TE-671, a rhabdomyosarcoma cell line, was used as a control tumor without a specific mIBG uptake mechanism. In order to prevent possible tumor rejection mediated by NK activity the anti asialo GM1 antiserum was administered intraperitoneally once a week for 4 weeks. The maximum anti asialo mediated effect was obtained by administering the first dose the same day as the cell implant. In this group of animals by 9 weeks 98% of mice had a measurable tumor. We have utilized this model to evaluate the biodistribution of 125-I-mIBG given as two different formulations: standard preparation with a specific activity of 84 mCi/mg and the no carrier added (n.c.a.) formulation with a specific activity of approximatelly 8,000 mCi/mg. Our preliminary results indicate that the biodistribution of the two different formulations in the various organs are similar.Therefore it appears that n.c.a. mIBG should not cause an increased toxicity in possible normal target organs such as heart or adrenals. Additional experiments will be performed in this model to ascertain if there is a potential advantage of the clinical use of n.c.a. mIBG over the standard preparation.

Failure of Immunoglobulins to Prevent Neonatal Thrombocytopenia in Mothers with Immunothrombocytopenic Purpura

We report the case of a full-term (gestational age: 39 weeks) female newborn of a mother affected by immunothrombocytopenic purpura, treated with a high total dose (2 g/kg) of intravenous IgG, administered over a 3-day period starting 3 days before delivery. Infant platelet count at birth was 20,000/mm3 and she showed a great number of petechiae on the first day of life. After a random donor platelet transfusion and treatment with intravenous high-dose IgG (400 mg/kg for 5 days), platelet count began to increase. We conclude that exogenous IgG, even at high concentrations, apparently does not significantly cross the placenta, despite adequate maternal blood levels.