RESUMO
An increased number of autochthonous visceral leishmaniasis (VL) cases has recently been reported in Bologna Province in northern Italy. Over six months from November 2012 to May 2013, 14 cases occurred, whereas the average number of cases per year was 2.6 (range: 0-8) in 2008 to 2012. VL was diagnosed in a median of 40 days (range: 15-120) from disease onset. This delay in diagnosis shows the need for heightened awareness of clinicians for autochthonous VL in Europe.
Assuntos
Surtos de Doenças , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/transmissão , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Itália/epidemiologia , Leishmania infantum/isolamento & purificação , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Distribuição por Sexo , Topografia Médica , Adulto JovemRESUMO
We report the case of a female child with Down's syndrome affected by idiopathic pulmonary haemosiderosis (IPH), who was successfully treated with hydroxychloroquine. First-line conventional treatment of IPH is traditionally based on systemic corticosteroids; however, many steroid-sparing agents are being increasingly used as adjuncts to corticosteroids in children with recurrent or refractory bleeding. The use of these drugs is particularly promising for maintenance treatment, because it tends to avoid the adverse effects of long-term corticosteroids.
Assuntos
Síndrome de Down/complicações , Hemossiderose/complicações , Pneumopatias/complicações , Pré-Escolar , Feminino , Hemossiderose/diagnóstico , Hemossiderose/tratamento farmacológico , Humanos , Hidroxicloroquina/uso terapêutico , Pneumopatias/diagnóstico , Pneumopatias/tratamento farmacológico , Valor Preditivo dos Testes , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Hemossiderose PulmonarRESUMO
Acetaminophen is considered as a safe analgesic and antipyretic drug in paediatric age. The main problem in the use of acetaminophen is acute liver failure after an overdose or an acute intoxication. We report a case of fulminant liver failure and spontaneous recovery in a patient treated with a prolonged course of acetaminophen at recommended dosages.
Assuntos
Acetaminofen/efeitos adversos , Falência Hepática Aguda/induzido quimicamente , Acetaminofen/administração & dosagem , Fatores Etários , Feminino , Seguimentos , Humanos , Lactente , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/terapia , Nefrectomia , Cuidados Pós-Operatórios , Fatores de Tempo , Resultado do Tratamento , Tumor de Wilms/cirurgiaRESUMO
Since 1993 pediatric patients affected by high-risk Ewing sarcoma for the presence at onset of a large pelvic mass and/or metastatic disease, were enrolled in a national pilot study comprehensive, finally, of a high-dose chemotherapy (HDCT) procedure with hemopoietic stem cell support. The HDCT procedure considered as consolidation of the disease status obtained after the first-line therapy was followed by the reinfusion of granulokine colony-stimulating factor-primed (G-CSF) peripheral blood progenitor cell (PBPCT). Here we present the results in terms of treatment-related toxicity, hospitalization and rescue of the bone marrow function, in 17 pediatric patients enrolled in such a pilot protocol and submitted to HDCT and PBPCT at the end of first-line therapy.
Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Sarcoma de Ewing/terapia , Adolescente , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Neutrófilos/citologia , Projetos Piloto , Contagem de Plaquetas , Recidiva , Fatores de Risco , Sarcoma de Ewing/tratamento farmacológico , Sarcoma de Ewing/mortalidade , Taxa de SobrevidaRESUMO
Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G2/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose- and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.
Assuntos
Aminopiridinas/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Animais , Western Blotting , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Constitutively active casein kinase 2 (CK2) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). CK2 phosphorylates PTEN (phosphatase and tensin homolog) tumor suppressor, resulting in PTEN stabilization and functional inactivation. Downregulation of PTEN activity has an impact on PI3K/Akt/mTOR signaling, which is of fundamental importance for T-ALL cell survival. These observations lend compelling weight to the application of CK2 inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of CX-4945-a novel, highly specific, orally available, ATP-competitive inhibitor of CK2α. We show that CX-4945 treatment induced apoptosis in T-ALL cell lines and patient T lymphoblasts. CX-4945 downregulated PI3K/Akt/mTOR signaling in leukemic cells. Notably, CX-4945 affected the unfolded protein response (UPR), as demonstrated by a significant decrease in the levels of the main UPR regulator GRP78/BIP, and led to apoptosis via upregulation of the ER stress/UPR cell death mediators IRE1α and CHOP. In vivo administration of CX-4945 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth. Our findings indicate that modulation of the ER stress/UPR signaling through CK2 inhibition could be exploited for inducing apoptosis in T-ALL cells and that CX-4945 may be an efficient treatment for those T-ALLs displaying upregulation of CK2α/PI3K/Akt/mTOR signaling.
Assuntos
Antineoplásicos/uso terapêutico , Caseína Quinase II/antagonistas & inibidores , Naftiridinas/uso terapêutico , Proteínas de Neoplasias/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Transdução de Sinais , Resposta a Proteínas não Dobradas , Animais , Divisão Celular , Chaperona BiP do Retículo Endoplasmático , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/química , Fenazinas , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologiaRESUMO
BACKGROUND: Germ cell tumors in females are uncommon, and bilateral metachronous ovarian teratoma is even exceptional, with sporadic cases described in the literature. CASE: We report on a girl in whom a metachronous ovarian teratoma occurred 6 years after the first. The simultaneous onset of germ-line anomalies in other members of the family supports the existence of genetic or environmental factors conferring susceptibility to germ cell lesions. SUMMARY AND CONCLUSION: The case here illustrated reminds the issue of the appropriate follow-up of these patients and of their families.
Assuntos
Segunda Neoplasia Primária/cirurgia , Neoplasias Ovarianas/cirurgia , Teratoma/cirurgia , Criança , Feminino , Preservação da Fertilidade , Humanos , Segunda Neoplasia Primária/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Teratoma/diagnóstico , Teratoma/genéticaRESUMO
The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be downmodulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(-)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL.
Assuntos
Adenilato Quinase/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas/metabolismo , Transdução de Sinais , Apoptose , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA , Citometria de Fluxo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Metformina/farmacologia , Complexos Multiproteicos , Fosforilação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Biossíntese de Proteínas/efeitos dos fármacos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Serina-Treonina Quinases TORRESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising from T-cell progenitors. T-ALL accounts for 15% of newly diagnosed ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of polychemotherapy schemes, the outcome of relapsed/chemoresistant T-ALL cases is still poor. A signaling pathway that is frequently upregulated in T-ALL, is the phosphatidylinositol 3-kinase/Akt/mTOR network. To explore whether Akt could represent a target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of human T-ALL cell lines and primary cells from T-ALL patients. MK-2206 decreased T-ALL cell line viability by blocking leukemic cells in the G(0)/G(1) phase of the cell cycle and inducing apoptosis. MK-2206 also induced autophagy, as demonstrated by an increase in the 14-kDa form of LC3A/B. Western blotting analysis documented a concentration-dependent dephosphorylation of Akt and its downstream targets, GSK-3α/ß and FOXO3A, in response to MK-2206. MK-2206 was cytotoxic to primary T-ALL cells and induced apoptosis in a T-ALL patient cell subset (CD34(+)/CD4(-)/CD7(-)), which is enriched in leukemia-initiating cells. Taken together, our findings indicate that Akt inhibition may represent a potential therapeutic strategy in T-ALL.
Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Humanos , Fosforilação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia , Transdução de SinaisRESUMO
The mammalian Target Of Rapamycin (mTOR) serine/threonine kinase belongs to two multi-protein complexes, referred to as mTORC1 and mTORC2. mTOR-generated signals have critical roles in leukemic cell biology by controlling mRNA translation of genes that promote proliferation and survival. However, allosteric inhibition of mTORC1 by rapamycin has only modest effects in T-cell acute lymphoblastic leukemia (T-ALL). Recently, ATP-competitive inhibitors specific for the mTOR kinase active site have been developed. In this study, we have explored the therapeutic potential of active-site mTOR inhibitors against both T-ALL cell lines and primary samples from T-ALL patients displaying activation of mTORC1 and mTORC2. The inhibitors affected T-ALL cell viability by inducing cell-cycle arrest in G(0)/G(1) phase, apoptosis and autophagy. Western blot analysis demonstrated a Ser 473 Akt dephosphorylation (indicative of mTORC2 inhibition) and a dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cell lines treated with active-site mTOR inhibitors. The inhibitors strongly synergized with both vincristine and the Bcl-2 inhibitor, ABT-263. Remarkably, the drugs targeted a putative leukemia-initiating cell sub-population (CD34(+)/CD7(-)/CD4(-)) in patient samples. In conclusion, the inhibitors displayed remarkable anti-leukemic activity, which emphasizes their future development as clinical candidates for therapy in T-ALL.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Western Blotting , Domínio Catalítico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Humanos , Imunossupressores/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Complexos Multiproteicos , Fosforilação/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sirolimo/farmacologia , Serina-Treonina Quinases TOR , Fatores de Transcrição/metabolismoAssuntos
Antineoplásicos/farmacologia , Neurofibromina 1/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Quinolonas/farmacologia , Criança , Feminino , Humanos , Técnicas In Vitro , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Deleção de SequênciaRESUMO
BACKGROUND: The aim of this phase I study was to define the maximum tolerated dose (MTD) of thiotepa (TT), administered with busulfan (BU) 480 mg/m(2) and etoposide 2,400 mg/m(2), followed by autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (APBSCT) support in children with solid tumors either disseminated at diagnosis or after relapse. PROCEDURE: Nineteen patients, between 2 and 16 years of age, received a high-dose chemotherapy regimen including escalating doses of TT starting from 150 mg/m(2). Subsequent dose escalation was determined by a modified Fibonacci scheme. Whenever one patient at one dosage level showed a grade III or grade IV reversible toxicity, additional patients were admitted (one by one) up to a maximum number of 6. Upon observing grade III or IV reversible toxicity in two or more systems, in 3 of the 6 patients, no further escalation was performed, and the corresponding dosage was taken as the MTD. WHO criteria were adopted to assess grade of toxicity. RESULTS: All patients had hematological recovery; and neutrophils and platelet engraftment were observed after median times of 12 and 29 days from stem cell infusion, respectively. The MTD of TT was determined to be 750 mg/ m(2). At this level, 3 of 6 patients experienced grade III mucositis and/or grade III gastrointestinal toxicity. No patient died of treatment-related toxicity. CONCLUSIONS: A dose of 750 mg/m(2) TT is the MTD when it is associated with BU 480 mg/m(2) and etoposide 2, 400 mg/m(2). This ablative regimen represents a feasible and tolerable combination for high-dose chemotherapy followed by hematopoietic stem cell rescue (HSCR). Phase II studies in children with poor-prognosis solid tumors are required to evaluate the effectiveness of this treatment.