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PURPOSE: Metabolic dysfunction-associated steatotic liver disease (MASLD) may have distinctive pathophysiological features in type 1 diabetes (T1D). We evaluated the independent role of blood glucose control on MASLD in T1D. METHODS: In a cross-sectional study on 659 T1D adult patients, MASLD was assessed by the Fatty Liver Index (FLI) and the Hepatic Steatosis Index (HSI). Anthropometric, biochemical, and clinical parameters were retrieved from electronic records. Blood glucose control status was evaluated by dividing participants into subgroups according to the median value of HbA1c [7.6% (60 mmol/mol)], and this analysis was repeated excluding overweight/obese patients. RESULTS: Patients with HbA1c above 7.6% (60 mmol/mol) showed significantly higher MASLD indices (HSI 38 ± 6 vs. 36 ± 5, p < 0.001; FLI 26 ± 26 vs.19 ± 19, p < 0.001), and higher proportions of MASLD identified by HSI (57 vs. 44%, p < 0.001) and FLI (14 vs. 7%, p < 0.001) than patients with HbA1c below 7.6% (60 mmol/mol). Similar results were obtained for HSI after the exclusion of overweight/obese patients. Stepwise linear regression analysis confirmed that HbA1c was independently associated with HSI (r = 0.496, p = 0.009) and FLI (r = 0.722, p = 0.007); waist circumference with HSI (r = 0.492, p < 0.001); and waist circumference (r = 0.700, p < 0.001), HDL cholesterol (r = 0.719, p < 0.001), and LDL cholesterol (r = 0.712, p < 0.001) with FLI. CONCLUSIONS: Blood glucose control is a main factor associated with MASLD in adults with T1D, also independently of overweight and obesity. Appropriate therapeutic strategies focused on tight blood glucose control may also be needed for the prevention and treatment of MASLD in T1D.
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BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Células Mieloides/efectos de los fármacos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/secundario , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Método Doble Ciego , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Pronóstico , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Carcinoma Pulmonar de Células Pequeñas/enzimología , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , Distribución TisularRESUMEN
Health-care personnel handling antineoplastic drugs could be at risk for adverse health effects. We aimed to evaluate genotoxic and cytotoxic effects of antineoplastic drug exposure of personnel preparing and administering such drugs in three Oncology Hospitals in Italy enrolling 42 exposed subjects and 53 controls. Furthermore, we aimed to study the possible influence of XRCC1 and hOGG1 DNA repair genes polymorphisms on genotoxicity induced on buccal cells. We performed workplace and personal monitoring of some drugs and used exposure diary informations to characterize the exposure. Urinary 5-FU metabolite (α-fluoro-ß-alanine) was measured. Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate DNA damage and other cellular anomalies. GEM and 5-FU contamination was found in 68% and 42% of wipe/swab samples respectively. GEM deposition was found on workers' pads while no α-fluoro-ß-alanine was found. BMCyt-assay showed higher genotoxicity and cytotoxicity on nurses administering antineoplastics than on preparators and controls. Among micronucleus (MN) positive (with MN frequency higher than 1.5) exposed subjects, the percentage of those carrying XRCC1 mut/het genotype was higher than in MN positive-controls. Using the sensitive BMCyt assay, we demonstrated that handling antineoplastics still represents a potential occupational health risk for workers that should be better trained/informed regarding such risks.
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Antineoplásicos/efectos adversos , Desoxicitidina/análogos & derivados , Monitoreo del Ambiente/métodos , Fluorouracilo/efectos adversos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Pruebas de Micronúcleos , Mucosa Bucal/efectos de los fármacos , Personal de Enfermería en Hospital , Exposición Profesional/efectos adversos , Salud Laboral , Enfermería Oncológica , Adulto , Antineoplásicos/orina , Biomarcadores/orina , Estudios de Casos y Controles , ADN Glicosilasas/genética , Desoxicitidina/efectos adversos , Desoxicitidina/orina , Femenino , Fluorouracilo/orina , Humanos , Italia , Masculino , Persona de Mediana Edad , Mucosa Bucal/metabolismo , Exposición Profesional/prevención & control , Polimorfismo Genético , Medición de Riesgo , Factores de Riesgo , Urinálisis , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , GemcitabinaRESUMEN
In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m(2) on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m(2)), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progression-free survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; ⩾grade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (⩾grade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at http://www.clinicaltrials.gov (#NCT01365559).
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Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Oligopéptidos/efectos de los fármacos , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/uso terapéutico , Bortezomib , Sustitución de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Estadificación de Neoplasias , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Pirazinas/administración & dosificación , Pirazinas/uso terapéutico , Resultado del TratamientoRESUMEN
Darbepoetin alfa is a novel erythropoiesis stimulating protein (NESP), which stimulates erythropoiesis by the same mechanism as recombinant human erythropoietin (rHuEPO). NESP has been shown to be safe and efficacious in patients with chronic renal failure. NESP is biochemically distinct from rHuEPO, due to its increased sialic acid content. NESP has an approximately 3-fold greater half-life. rHuEPO has been shown to be safe and effective for the treatment of chemotherapy-induced anaemia. This study assessed the safety and efficacy of NESP administered once per week, under the supervision of a physician, to patients with solid tumours who were receiving multicycle chemotherapy for up to 12 weeks. Three dose cohorts are presented in this sequential, unblinded and dose-escalating study. Thirteen to 59 patients received NESP (0.5, 1.5 or 2.25 mcg kg(-1)wk(-1)) in each cohort. Patients were monitored for adverse events, including antibody formation to NESP and for effects on haemoglobin. NESP appeared to be well tolerated. Adverse events were similar across all cohorts and were consistent with the population being studied. No antibody formation was detected over the 16-week study period and follow-up. A dose-response relationship was evident for NESP and multiple measures of efficacy, including proportion of patients responding to NESP and the mean change in haemoglobin by week 4 and end of treatment for NESP 0.5, 1.5 and 2.25 mcg kg(-1)wk(-1)cohorts (mean change in haemoglobin at end of treatment was 1.24, 1.73 and 2.15 g dl(-1)respectively). Controlled studies of this agent at higher doses and less frequent schedules of administration are ongoing.
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Anemia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Eritropoyetina/administración & dosificación , Neoplasias/complicaciones , Adulto , Anciano , Anemia/etiología , Anemia/terapia , Transfusión Sanguínea/estadística & datos numéricos , Estudios de Cohortes , Terapia Combinada , Darbepoetina alfa , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Transfusión de Eritrocitos/estadística & datos numéricos , Eritropoyesis/efectos de los fármacos , Eritropoyetina/efectos adversos , Eritropoyetina/análogos & derivados , Eritropoyetina/química , Eritropoyetina/inmunología , Eritropoyetina/uso terapéutico , Femenino , Semivida , Hemoglobinas/análisis , Humanos , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Ácido N-Acetilneuramínico/química , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/química , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Seguridad , Resultado del TratamientoRESUMEN
The synthesis and antimicrobial activity of some Mannich bases of diarylpyrroles are reported. The obtained data show that activity is closely connected to molecular basicity. Results are discussed on the basis of structure activity relationships.
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Antiinfecciosos/síntesis química , Antifúngicos/síntesis química , Pirroles/síntesis química , Antibacterianos , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Pirroles/química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
Hodgkin's disease and mycosis fungoides have been rarely reported in the same patient. This coexistence has been debated in the medical literature. We studied such a patient and report, to our knowledge, the first immunophenotypic evidence for such a coexistence. Reed-Sternberg cells and their variants stained with anti-Leu-M1, Hefi-1, anti-Tac, anti-HLA-DR, and OKT9, but were negative for T cell markers 3A1, Leu-1, Leu-2a, and Leu-3a, a phenotype typical of Hodgkin's disease; infiltrating small lymphocytes were predominantly T cells and were phenotypically normal. In the skin lesions, cells with the phenotype of Hodgkin's disease were not present; the infiltrate was composed of helper T lymphocytes that were 3A1-negative, a phenotype characteristic of the malignant cells of mycosis fungoides. Unexpectedly, a dermatopathic lymph node from the same patient showed the presence of the Leu-M1 antigen on the majority of normal-appearing interdigitating reticulum cells; this was not the case with control dermatopathic lymph nodes from patients without a malignancy. The significance, implications, and possible interrelationships of the findings are discussed.
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Enfermedad de Hodgkin/complicaciones , Micosis Fungoide/complicaciones , Adulto , Anticuerpos Monoclonales , Antígenos de Diferenciación de Linfocitos T , Antígenos de Neoplasias/análisis , Antígenos de Superficie/análisis , Enfermedad de Hodgkin/patología , Humanos , Técnicas para Inmunoenzimas , Ganglios Linfáticos/patología , Masculino , Micosis Fungoide/patologíaRESUMEN
Acute tumor lysis syndrome (ATLS) is an entity consisting of combinations of hyperuricemia, lactic acidosis, hyperkalemia, hyperphosphatemia, and hypocalcemia and occurring generally in aggressive, rapidly proliferating lymphoproliferative disorders with high tumor burdens. A patient is described with a diffuse intermediately differentiated lymphocytic lymphoma, considered by most an indolent B-cell non-Hodgkin's lymphoma, in whom developed multiple recurrences of ATLS after treatment when tumor regrowth occurred between cycles of therapy. The mitotic rate of this lymphoma was relatively high (30-80 mitoses/ten high-power fields). Lymph proliferative disorders with a high mitotic rate, and large tumor burden, regardless of histologic features, should be treated prophylactically against tumor lysis if regrowth between cycles occurs.
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Linfoma no Hodgkin/tratamiento farmacológico , Enfermedad Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Nitrógeno de la Urea Sanguínea , Femenino , Humanos , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/patología , Persona de Mediana Edad , Fosfatos/sangre , Recurrencia , Síndrome , Ácido Úrico/sangreAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Enteritis/etiología , Infecciones por Salmonella/etiología , Sepsis/etiología , Adulto , Enteritis/microbiología , Heces/microbiología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Infecciones por Salmonella/microbiología , Salmonella typhimurium/aislamiento & purificación , Sarcoma de Kaposi/etiología , Sepsis/microbiologíaRESUMEN
46 adults with previously untreated acute myelogenous leukaemia who achieved complete remission with 6-thioguanine, cytarabine, and daunorubicin (TAD) received two courses of intensive consolidation chemotherapy. The first cycle consisted of 5-azacytidine and doxorubicin followed by a second consolidation cycle with TAD. Maintenance chemotherapy was not administered. Median remission duration was 14 months and 26% (95% confidence interval, 11%-41%) remained in continuous remission at 5 years. Actuarial 5 year survival was 31% (+/- 15%). Results were most favourable in patients who achieved complete remission within 60 days of chemotherapy being initiated. These data indicate that prolonged disease-free survival can be achieved in patients treated with intensive induction and consolidation treatment alone without maintenance chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/mortalidad , Adolescente , Adulto , Anciano , Azacitidina/administración & dosificación , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Recurrencia , Tioguanina/administración & dosificación , Factores de TiempoRESUMEN
27 patients with resistant acute myelogenous leukemia (AML) were treated with AMSA. Three achieved a complete remission, and two a partial remission. Median survival for all patients was 12 weeks and was 16 weeks for responders.