RESUMEN
BACKGROUND/AIM: Hydration and hydroxyurea (HU) can modify sickle cell disease (SCD) severity. Optimal nutrition and L-glutamine (Gln) may provide further amelioration. PATIENTS AND METHODS: Reviews of medical records and nutrition surveys were used to investigate severity of pediatric patients with SCD in relation to nutrition, growth, hematologic parameters, and diseasemodifying agents. RESULTS: Among 25 females and 25 males (9.1±7 years), beta-globin genotypes were: HbSS/Sß°, 60%; HbSC, 32%; HbSß+, 8%. The mean number of annual pain crises (APC) was 0.97±1.1. APCs increased ≥2-fold as HbF dropped to <10% with age. Proper hydration and nutrition correlated with younger ages and fewer APCs. Height and weight Z-scores were ≤-1SD in 20% of 35 surveyed patients (12±7.8 years), who had more APCs (2.5±2.5 vs. 1±1.3, p=0.03). Prealbumin levels were overall low. Twenty-two of 28 patients on HU reported ≥90% adherence - with higher mean corpuscular volume (92±9.6 vs. 74±10 f/l, p<0.01). Seventy percent of Gln prescriptions were filled. Compliance over 23 months was ≥70% in 12 patients, including 2 on chronic transfusion. Of 10 evaluable patients, 6 (8.8±2.2 years) had fewer APCs with Gln (mean 0.2 vs. 0.9, p=0.016), with increasing prealbumin levels (14.1 to 15.8 mg/dl, p=0.1). CONCLUSION: Younger, and well-nourished, well-hydrated patients have a milder clinic course. Disease severity was the worse in undernourished teenagers with suboptimal compliance. L-Glutamine with prealbumin monitoring should be considered for further evaluation in pediatric SCD.
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Anemia de Células Falciformes , Antidrepanocíticos , Glutamina , Estado Nutricional , Cooperación del Paciente , Adolescente , Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Niño , Femenino , Glutamina/uso terapéutico , Hospitales Públicos , Humanos , Hidroxiurea/uso terapéutico , Masculino , PrealbúminaRESUMEN
BACKGROUND/AIM: In the age of ever-increasing developments in targeted cancer treatments, new immune-based approaches for brain tumor therapy represent an attractive avenue. Despite encouraging pre-clinical data, results in patients have been sub-optimal, likely due to tumor-induced immune suppression and intrinsic resistance to immune attack. Chemotherapy and biologic agents may be able to disrupt these mechanisms and restore tumor sensitivity to immune attack. In this study, we explore whether a combination of gemcitabine and rapamycin can sensitize medulloblastoma cells to immunotherapy in vitro and in vivo. MATERIALS AND METHODS: With the commercial medulloblastoma cell line, Daoy, we explored the concentrations of combinations of Gemcitabine with rapamycin needed to induce cytotoxicity. Next, we used flow cytometry to assess the cytotoxicity of chemotherapy-treated Daoy cells with the addition of anti-tumor T-cells, generated from naive T-cells stimulated in the presence of Daoy lysate-pulsed dendritic cells. Then, we examined the efficacy of chemotherapy alone versus chemotherapy plus immunotherapy in tumor growth inhibition of subcutaneous medulloblastoma xenografts. RESULTS: Rapamycin alone at <1,000 nM had moderate activity against Daoy cells in vitro and IC50 was >1,000 nM. Gemcitabine had a 3-day IC50 alone of 10 nM but in combination with 100 nM rapamycin, it decreased to 1 nM, suggesting increased cytotoxicity with combined therapy. Stimulated T-cells mediated in-vitro cytotoxicity, although background cytotoxicity of unstimulated "naïve" T-cells was also significant. Finally, established subcutaneous Daoy cell xenografts in SCID mice were treated with chemotherapy alone or chemotherapy plus adoptive immunotherapy (stimulated and non-stimulated). Gemcitabine and rapamycin alone significantly slowed tumor growth, but the addition of immunotherapy further augmented inhibition. CONCLUSION: Combining immunotherapy and chemo-biologic therapy inhibit medulloblastoma cell and xenograft growth, and may offer an effective treatment for patients with medulloblastoma.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Cerebelosas/tratamiento farmacológico , Humanos , Inmunoterapia Adoptiva , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/metabolismo , Ratones , Ratones SCIDRESUMEN
Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.
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Anemia de Células Falciformes/tratamiento farmacológico , Dolor/tratamiento farmacológico , Poloxámero/uso terapéutico , Vasodilatadores/uso terapéutico , Adolescente , Adulto , Analgésicos Opioides/uso terapéutico , Anemia de Células Falciformes/complicaciones , Niño , Método Doble Ciego , Femenino , Humanos , Masculino , Dolor/etiología , Placebos/efectos adversos , Placebos/uso terapéutico , Poloxámero/efectos adversos , Vasodilatadores/efectos adversos , Adulto JovenRESUMEN
Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder, characterized by the pathologic clonal proliferation and accumulation of immature Langerhans cells within organs. Multiple organ systems can be affected, resulting in a spectrum of clinical manifestations. Isolated gastrointestinal involvement in LCH is rare and usually presents in childhood as a multisystem disease and usually has poor outcomes. We describe a 20-year-old Hispanic female with multifocal, single-system gastrointestinal LCH. Initially diagnosed from a CD1a, S100, and CD207 (Langerin) positive appendix tissue after an appendectomy and confirmed multifocal with an endoscopy. She had a full clinical and endoscopic resolution of disease with cytarabine therapy.
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Enfermedades Gastrointestinales/patología , Histiocitosis de Células de Langerhans/patología , Adulto , Antimetabolitos Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Femenino , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/tratamiento farmacológico , Histiocitosis de Células de Langerhans/complicaciones , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Humanos , Pronóstico , Adulto JovenRESUMEN
Subfertility is a major concern of long-term cancer survivors at the reproductive age. We have previously demonstrated that a potent humanin analogue, HNG, protected chemotherapy-induced apoptosis in germ cells but not cancer cells in a metastatic melanoma allograft model. In this study, we utilized severe combined immuno-deficiency (SCID) mice bearing human medulloblastoma to study the effect of HNG in Temozolomide (TMZ) induced male germ cell apoptosis and white blood cell (WBC) suppression. Human medulloblastoma DAOY cells were injected subcutaneously into the right flank of male SCID mice. Three weeks later, groups of tumor-bearing mice received one of the following treatments: vehicle, HNG, TMZ, or TMZâ¯+â¯HNG. 24â¯h after last injection, the tumors weights, complete blood counts, liver and spleen weights, male germ cell apoptosis was assessed. HNG did not affect TMZ's significant anti-tumor action. HNG significantly prevented TMZ-induced germ cell apoptosis and attenuated the suppressed total WBC and granulocyte counts in SCID mice with or without TMZ treatment. HNG also attenuated TMZ-induced body weight loss and decrease of spleen and liver weights. In conclusion, HNG ameliorated TMZ-induced germ cell apoptosis; WBC and granulocytes loss; and decreased body/organ weights without compromising the TMZ's anti-cancer action on medulloblastoma xenografts in SCID mice.
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Apoptosis/efectos de los fármacos , Neoplasias Cerebelosas/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/farmacología , Meduloblastoma/tratamiento farmacológico , Espermatozoides/efectos de los fármacos , Temozolomida/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Antineoplásicos Alquilantes/farmacología , Línea Celular Tumoral , Neoplasias Cerebelosas/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Meduloblastoma/patología , Ratones SCID , Tamaño de los Órganos/efectos de los fármacos , Espermatozoides/citología , Bazo/efectos de los fármacos , Bazo/patología , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical-grade l-glutamine (USAN, glutamine) has been shown to increase the proportion of the reduced form of nicotinamide adenine dinucleotides in sickle cell erythrocytes, which probably reduces oxidative stress and could result in fewer episodes of sickle cell-related pain. METHODS: In a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial, we tested the efficacy of pharmaceutical-grade l-glutamine (0.3 g per kilogram of body weight per dose) administered twice daily by mouth, as compared with placebo, in reducing the incidence of pain crises among patients with sickle cell anemia or sickle ß0-thalassemia and a history of two or more pain crises during the previous year. Patients who were receiving hydroxyurea at a dose that had been stable for at least 3 months before screening continued that therapy through the 48-week treatment period. RESULTS: A total of 230 patients (age range, 5 to 58 years; 53.9% female) were randomly assigned, in a 2:1 ratio, to receive l-glutamine (152 patients) or placebo (78 patients). The patients in the l-glutamine group had significantly fewer pain crises than those in the placebo group (P=0.005), with a median of 3.0 in the l-glutamine group and 4.0 in the placebo group. Fewer hospitalizations occurred in the l-glutamine group than in the placebo group (P=0.005), with a median of 2.0 in the l-glutamine group and 3.0 in the placebo group. Two thirds of the patients in both trial groups received concomitant hydroxyurea. Low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain occurred more frequently in the l-glutamine group than in the placebo group. CONCLUSIONS: Among children and adults with sickle cell anemia, the median number of pain crises over 48 weeks was lower among those who received oral therapy with l-glutamine, administered alone or with hydroxyurea, than among those who received placebo, with or without hydroxyurea. (Funded by Emmaus Medical; ClinicalTrials.gov number, NCT01179217 .).
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Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Glutamina/uso terapéutico , Hidroxiurea/uso terapéutico , Manejo del Dolor , Administración Oral , Adolescente , Adulto , Anemia de Células Falciformes/complicaciones , Niño , Preescolar , Método Doble Ciego , Quimioterapia Combinada , Femenino , Glutamina/efectos adversos , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Dolor/etiología , Dolor/prevención & control , Adulto Joven , Talasemia beta/tratamiento farmacológicoRESUMEN
BACKGROUND: Anti-metabolites are less-myelosuppressive than DNA-damaging anticancer drugs and may be useful against brain tumors. MATERIALS AND METHODS: We evaluated the asparagine/glutamine-deaminating agent Erwinaze with/without temozolomide against brain tumor cells and mouse medulloblastomas. RESULTS: Erwinaze treatment of cell lines and neurospheres led to dose-dependent reductions of cells (reversible by L-glutamine), with half maximal inhibitory concentrations (IC50s) of 0.12->10 IU/ml. Erwinaze at <1 IU/ml reduced temozolomide IC50s by 3.6- to 13-fold (300-1,200 µM to 40-330 µM). Seven-week-old SMO/SMO mice treated with Erwinaze (regardless of temozolomide treatment) had better survival 11 weeks post-therapy, compared to those not treated with Erwinaze (81.25% vs. 46.15, p=0.08). Temozolomide-treated mice developed 10% weight loss, impairing survival. All 16 mice treated with temozolomide (regardless of Erwinaze treatment) succumbed by 40-weeks of age, whereas 5/8 animals treated with Erwinaze alone and 2/6 controls survived (p=0.035). CONCLUSION: Erwinaze enhances cytotoxicity of temozolomide in vitro, and improves survival in SMO/SMO mice, likely by reducing cerebrospinal fluid glutamine. Temozolomide-associated toxicity prevented demonstration of any potential combinatorial advantage with Erwinaze in vivo.
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Antineoplásicos/uso terapéutico , Asparaginasa/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Cerebelosas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Meduloblastoma/tratamiento farmacológico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/administración & dosificación , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Medio de Cultivo Libre de Suero , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Dickeya chrysanthemi/enzimología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Glioblastoma/patología , Glioma/tratamiento farmacológico , Glioma/patología , Glutamina/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Tolerancia a Radiación , Esferoides Celulares/efectos de los fármacos , Temozolomida , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM). Literature reviews and GBM database ( http://r2.amc.nl ) analyses were carried out to screen for such targets among 95 AA related enzymes. METHODS: First, we identified the genes that were differentially expressed in GBMs (3 datasets) compared to non-GBM brain tissues (5 datasets), or were associated with survival differences. Further, protein expression for these enzymes was also analyzed in high grade gliomas (HGGs) (proteinatlas.org). Finally, AA enzyme and gene expression were compared among the 4 TCGA (The Cancer Genome Atlas) subtypes of GBMs. RESULTS: We detected differences in enzymes involved in glutamate and urea cycle metabolism in GBM. For example, expression levels of BCAT1 (branched chain amino acid transferase 1) and ASL (argininosuccinate lyase) were high, but ASS1 (argininosuccinate synthase 1) was low in GBM. Proneural and neural TCGA subtypes had low expression of all three. High expression of all three correlated with worse outcome. ASL and ASS1 protein levels were mostly undetected in high grade gliomas, whereas BCAT1 was high. GSS (glutathione synthetase) was not differentially expressed, but higher levels were linked to poor progression free survival. ASPA (aspartoacylase) and GOT1 (glutamic-oxaloacetic transaminase 1) had lower expression in GBM (associated with poor outcomes). All three GABA related genes -- glutamate decarboxylase 1 (GAD1) and 2 (GAD2) and 4-aminobutyrate aminotransferase (ABAT) -- were lower in mesenchymal tumors, which in contrast showed higher IDO1 (indoleamine 2, 3-dioxygenase 1) and TDO2 (tryptophan 2, 3-diaxygenase). Expression of PRODH (proline dehydrogenase), a putative tumor suppressor, was lower in GBM. Higher levels predicted poor survival. CONCLUSIONS: Several AA-metabolizing enzymes that are higher in GBM, are also linked to poor outcome (such as BCAT1), which makes them potential targets for therapeutic inhibition. Moreover, existing drugs that deplete asparagine and arginine may be effective against brain tumors, and should be studied in conjunction with chemotherapy. Last, AA metabolism is heterogeneous in TCGA subtypes of GBM (as well as medulloblastomas and other pediatric tumors), which may translate to variable responses to AA targeted therapies.
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Aminoácidos/metabolismo , Neoplasias Encefálicas/genética , Perfilación de la Expresión Génica/métodos , Glioblastoma/genética , Neoplasias Encefálicas/metabolismo , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Glioblastoma/metabolismo , Ácido Glutámico/metabolismo , Humanos , Redes y Vías Metabólicas , Pronóstico , Análisis de Supervivencia , Urea/metabolismoRESUMEN
Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development.
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Aminoácidos/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Aminoácidos/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica/fisiopatología , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Resultado del TratamientoRESUMEN
Von Willebrand disease (VWD), the most common inherited bleeding disorder, is caused by deficiency or dysfunction in von Willebrand factor. Assessment of hemorrhagic symptoms is essential for early diagnosis, although bleeding histories are taken in a nonstandardized manner. Validated bleeding assessment tools provide objectivity in evaluating bleeding patterns of females at menarche and may improve provider confidence in screening for VWD. Utilizing a pretest/posttest design, in this project we implemented and evaluated the use of a pediatric bleeding questionnaire in eight pediatric primary care clinics for 3 months. Results indicate improved provider knowledge, confidence, and skills after implementation. The importance and quality of the tool were rated highly by the providers, while the ease of use was rated low. Providers were satisfied with the practice change and believed that it improved their clinical abilities. The use of this tool can improve VWD screening in this practice setting.
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Hemorragia/etiología , Tamizaje Masivo/métodos , Menarquia , Atención Primaria de Salud , Encuestas y Cuestionarios , Enfermedades de von Willebrand/diagnóstico , Adolescente , Edad de Inicio , Niño , Femenino , Humanos , Estados Unidos/epidemiología , Enfermedades de von Willebrand/epidemiología , Factor de von WillebrandRESUMEN
OBJECTIVES: To present a clinicocytopathologic correlation of an atypical case of cat scratch disease (CSD) involving retroperitoneal lymph nodes, with emphasis on communication between service teams for managing lymphadenopathy of unknown origin. We consider clinical and cytologic differential diagnoses and review the literature on atypical cases of CSD, with emphasis on abdominal presentation and cytologic findings. METHODS: Clinical services met with the cytology service to review clinical and pathologic features. Literature was reviewed via PubMed search (Harbor-UCLA subscriptions). Immunohistochemistry and Steiner silver stains were performed by Harbor-UCLA Department of Pathology. Enzyme-linked immunosorbent assay IgG and IgM Bartonella henselae titers were carried out by Quest Nichols Institute. RESULTS: Fine-needle aspirate Diff-Quik and Papanicolaou smears and H&E-stained cell block showed abundant histiocytes, monocytoid B cells, and numerous neutrophils associated with necrosis corresponding to a late stage of CSD infection. Silver stain was positive for clumps of pleomorphic organisms. IgM and IgG antibody titers were elevated. CONCLUSIONS: The cytologic findings of CSD in an atypical abdominal presentation are similar to those of a classic presentation. Laboratory workup for atypical CSD should include at least two other modalities aside from cytomorphologic features. Close clinical and cytologic correlation avoided potentially unnecessary and harmful surgery and enabled timely treatment.
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Antibacterianos/uso terapéutico , Bartonella henselae/aislamiento & purificación , Enfermedad por Rasguño de Gato/diagnóstico , Enfermedades Linfáticas/diagnóstico , Anticuerpos Antibacterianos/sangre , Azitromicina/uso terapéutico , Bartonella henselae/inmunología , Enfermedad por Rasguño de Gato/tratamiento farmacológico , Enfermedad por Rasguño de Gato/patología , Diagnóstico Diferencial , Gentamicinas/uso terapéutico , Humanos , Inmunohistoquímica , Ganglios Linfáticos/patología , Enfermedades Linfáticas/tratamiento farmacológico , Enfermedades Linfáticas/microbiología , Enfermedades Linfáticas/patología , Masculino , Resultado del Tratamiento , Adulto JovenRESUMEN
UNLABELLED: Targeting amino acid metabolism has therapeutic implications for aggressive brain tumors. Asparagine is an amino acid that is synthesized by normal cells. However, some cancer cells lack asparagine synthetase (ASNS), the key enzyme for asparagine synthesis. Asparaginase (ASNase) contributes to eradication of acute leukemia by decreasing asparagine levels in serum and cerebrospinal fluid. However, leukemic cells may become ASNase-resistant by upregulating ASNS. High expression of ASNS has also been associated with biologic aggressiveness of other cancers, including gliomas. Here, the impact of enzymatic depletion of asparagine on proliferation of brain tumor cells was determined. ASNase was used as monotherapy or in combination with conventional chemotherapeutic agents. Viability assays for ASNase-treated cells demonstrated significant growth reduction in multiple cell lines. This effect was reversed by glutamine in a dose-dependent manner--as expected, because glutamine is the main amino group donor for asparagine synthesis. ASNase treatment also reduced sphere formation by medulloblastoma and primary glioblastoma cells. ASNase-resistant glioblastoma cells exhibited elevated levels of ASNS mRNA. ASNase cotreatment significantly enhanced gemcitabine or etoposide cytotoxicity against glioblastoma cells. Xenograft tumors in vivo showed no significant response to ASNase monotherapy and little response to temozolomide alone. However, combinatorial therapy with ASNase and temozolomide resulted in significant growth suppression for an extended duration of time. Taken together, these findings indicate that amino acid depletion warrants further investigation as adjunctive therapy for brain tumors. IMPLICATIONS: Findings have potential impact for providing adjuvant means to enhance brain tumor chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Asparaginasa/farmacología , Asparagina/deficiencia , Neoplasias Encefálicas/tratamiento farmacológico , Dacarbazina/análogos & derivados , Animales , Asparaginasa/administración & dosificación , Asparaginasa/metabolismo , Asparagina/metabolismo , Aspartatoamoníaco Ligasa/metabolismo , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Daño del ADN , Dacarbazina/administración & dosificación , Dacarbazina/farmacología , Sinergismo Farmacológico , Glioblastoma/tratamiento farmacológico , Glioblastoma/enzimología , Glioblastoma/metabolismo , Glioblastoma/patología , Glutamina/farmacología , Humanos , Masculino , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/enzimología , Meduloblastoma/metabolismo , Meduloblastoma/patología , Ratones , Ratones Desnudos , Temozolomida , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1 × 10(6) cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required.
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Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , Glioma/terapia , Inmunoterapia , Recurrencia Local de Neoplasia/terapia , Adolescente , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/inmunología , Vacunas contra el Cáncer/inmunología , Niño , Preescolar , Citocinas/metabolismo , Células Dendríticas/trasplante , Estudios de Factibilidad , Femenino , Glioma/diagnóstico , Glioma/inmunología , Humanos , Técnicas para Inmunoenzimas , Lactante , Leucaféresis , Masculino , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/inmunología , Proyectos PilotoRESUMEN
Background. Dose-dependent response makes certain pediatric brain tumors appropriate targets for high-dose chemotherapy with autologous hematopoietic stem-cell rescue (HDCT-AHSCR). Methods. The clinical outcomes and toxicities were analyzed retrospectively for 18 consecutive patients ≤19 y/o treated with HDCT-AHSCR at UCLA (1999-2009). Results. Patients' median age was 2.3 years. Fourteen had primary and 4 recurrent tumors: 12 neural/embryonal (7 medulloblastomas, 4 primitive neuroectodermal tumors, and a pineoblastoma), 3 glial/mixed, and 3 germ cell tumors. Eight patients had initial gross-total and seven subtotal resections. HDCT mostly consisted of carboplatin and/or thiotepa ± etoposide (n = 16). Nine patients underwent a single AHSCR and nine ≥3 tandems. Three-year progression-free and overall survival probabilities were 60.5% ± 16 and 69.3% ± 11.5. Ten patients with pre-AHSCR complete remissions were alive/disease-free, whereas 5 of 8 with measurable disease were deceased (median followup: 2.3 yrs). Nine of 13 survivors avoided radiation. Single AHSCR regimens had greater toxicity than ≥3 AHSCR (P < .01). Conclusion. HDCT-AHSCR has a definitive, though limited role for selected pediatric brain tumors with poor prognosis and pretransplant complete/partial remissions.
RESUMEN
We report the case of an 8-year-old boy who presented with a 2-month history of headaches and mild visual impairment and was found to have a medulloblastoma with primary leptomeningeal involvement. No mass lesion was found on imaging studies, during subsequent intraoperative surgical inspection or at autopsy. The pathologic findings were first documented on cerebrospinal fluid cytologic examination and biopsy of the cerebellum and were later confirmed at necropsy. To our knowledge, this is the third reported case of medulloblastoma identified with primary leptomeningeal involvement without a cerebellar mass and the first such case with documented autopsy findings.
Asunto(s)
Neoplasias Cerebelosas/patología , Meduloblastoma/patología , Neoplasias Meníngeas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cerebelosas/terapia , Niño , Terapia Combinada , Resultado Fatal , Humanos , Masculino , Meduloblastoma/terapia , Neoplasias Meníngeas/terapia , Procedimientos NeuroquirúrgicosRESUMEN
Central nervous system (CNS) tumors remain the leading cause of death among pediatric neoplasms. Although standard therapies cure many pediatric CNS tumors, the long-term cognitive and physical consequences of these therapies are devastating. Furthermore, recurrent disease carries a dismal prognosis. Although recent studies have focused on molecular mechanisms that underlie the initiation and progression of adult glioblastoma multiforme (GBM), these tumors differ phenotypically and at a molecular level from pediatric brain tumors. Recent investigations have identified a stem cell population, termed "brain tumor stem cells" (BTSC) within the heterogeneous cell populations that comprise malignant brain tumors which may be partly responsible for the resistance to current therapies. These have been identified in several pediatric tumors including medulloblastoma, ependymomas, and malignant gliomas. By exploiting molecular differences present within these heterogeneous populations of brain tumor cells, we may be able to achieve specific eradication of BTSC and long-lasting remissions, while causing less toxicity to normal tissues. In this review, we describe the issues surrounding the identification and characterization of BTSC, the molecular biology of BTSC for different pediatric brain tumors, and suggest future avenues for the development of treatments for this devastating disease.
Asunto(s)
Neoplasias Encefálicas/patología , Ependimoma/patología , Meduloblastoma/patología , Células Madre Neoplásicas/patología , Glioma del Nervio Óptico/patología , Células Madre Adultas/patología , Biomarcadores/metabolismo , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/terapia , Diferenciación Celular , Quimioterapia Adyuvante , Niño , Ependimoma/fisiopatología , Ependimoma/terapia , Humanos , Meduloblastoma/fisiopatología , Meduloblastoma/terapia , Células Madre Neoplásicas/metabolismo , Glioma del Nervio Óptico/fisiopatología , Glioma del Nervio Óptico/terapia , Procedimientos Quirúrgicos OperativosRESUMEN
Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-Kit(mid)CD3(+)Lin(-) compartment, where unphosphorylated beta-catenin is significantly increased. Conditional ablation of one allele of the beta-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the beta-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit(mid)CD3(+)Lin(-) LSCs and CD3(+) leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation.
Asunto(s)
Leucemia-Linfoma de Células T del Adulto/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Animales , Complejo CD3/metabolismo , Proliferación Celular , Cromosomas de los Mamíferos/genética , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/patología , Hibridación Fluorescente in Situ , Masculino , Ratones , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Translocación Genética , beta Catenina/metabolismoRESUMEN
Congenital brain tumors are rare and make up only 2% of all pediatric central nervous system tumors. We present 12 cases of congenital brain tumors of various histopathologies. Most of these tumors were of astrocytic lineage. One patient was diagnosed before birth with prenatal ultrasound, but the rest were diagnosed after birth owing to increased head circumference. Four patients received adjuvant chemotherapy after surgery. None received radiation therapy. Seven out of 12 (58%) are long-term survivors. Four of these survivors (57%) have significant neurocognitive or psychomotor impairment. Although rare, congenital brain tumors are one of the more common tumors presenting in the perinatal period and generally carry a poor prognosis. Novel therapies are needed to improve efficacy and decrease the devastating side effects of treatment in this age group.
Asunto(s)
Neoplasias Encefálicas/congénito , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Diagnóstico Prenatal , Resultado del TratamientoRESUMEN
Ocular neuromyotonia is an uncommon disorder resulting from episodic involuntary discharge of ocular motor nerves producing sustained contraction of their respective ocular muscles. Ocular neuromyotonia manifests in brief spells of diplopia occurring spontaneously or after eccentric gaze holding. In most cases, ocular neuromyotonia follows months or years after radiotherapy to the sellar and parasellar region and involves the oculomotor nerve. We report two unusual cases of abducens nerve ocular neuromyotonia that followed radiation therapy of tumors in areas other than the sellar or parasellar region.