RESUMEN
Background: Homozygous or compound heterozygous mutations in JAGN1 cause severe congenital neutropenia. JAGN1-mutant patients present with severe early-onset bacterial infections and most have been described as low-responders to recombinant granulocyte colony-stimulating factor (G-CSF) therapy. In a murine, hematopoietic JAGN1 knockout model, which displays susceptibility to Candida albicans infection in the absence of neutropenia, treatment with granulocyte-macrophage-CSF (GM-CSF) was able to restore the functional defect of neutrophils. Patients: We present two unrelated patients with biallelic JAGN1 mutations, who were both treated with subcutaneous GM-CSF (sargramostim) after treatment failure to G-CSF. The first patient was an 18-year-old pregnant woman who received GM-CSF at 12 weeks of gestation up to a dose of 10 µg/kg/d for 7 days. The second patient was a 5-month-old girl who received GM-CSF for a total of 9 days at a dose of up to 20 µg/kg/d. GM-CSF did not increase neutrophil counts in our patients. Treatment was stopped when neutrophil numbers declined further, no beneficial effect was noticed, and patients presented with infections. No adverse effects were observed in either patient and the fetus. Both patients ultimately underwent successful hematopoietic stem cell transplantation. Discussion: Both patients showed a high recurrence rate of severe infections on G-CSF treatment. GM-CSF therapy did not ameliorate the clinical phenotype, in contrast to the improvement of neutrophil function observed in the JAGN1 mouse model. No major additional extra-hematopoietic manifestations were evident in our patients. Conclusion: In two unrelated patients, GM-CSF did not have any beneficial effect on neutrophil counts. Patients with JAGN1-mutant SCN with reduced G-CSF responsiveness and elevated infection rate should be evaluated early for stem cell transplantation.
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Síndromes Congénitos de Insuficiencia de la Médula Ósea , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Mutación , Neutropenia , Neutrófilos , Proteínas Recombinantes , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Femenino , Neutropenia/congénito , Neutropenia/tratamiento farmacológico , Neutropenia/genética , Neutrófilos/inmunología , Adolescente , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Lactante , Proteínas Recombinantes/uso terapéutico , Fenotipo , Embarazo , Proteínas de la MembranaRESUMEN
BACKGROUND: F-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®). METHODS: This was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated. RESULTS: The mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 - 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim. CONCLUSIONS: A single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04174599, on 22/11/2019.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Factor Estimulante de Colonias de Granulocitos , Neutropenia , Humanos , Femenino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Adulto , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Filgrastim/administración & dosificación , Filgrastim/efectos adversos , Filgrastim/uso terapéutico , Ciclofosfamida/efectos adversos , Ciclofosfamida/administración & dosificación , Epirrubicina/efectos adversos , Epirrubicina/administración & dosificación , Esquema de MedicaciónRESUMEN
PURPOSE: We aimed at identifying prevalence, clinical outcomes and prognostic factors in cancer patients with intravenous chemotherapy-induced severe neutropenia (ICISN). METHODS: In this multicenter retrospective cohort study on the clinical data warehouse of Greater Paris University Hospitals (AP-HP), we included all adult patients with solid cancer hospitalized between 2016 and 2021 with intravenous chemotherapy within 30 days prior to severe neutropenia (D70 or D611 ICD-10 codes AND a neutrophil count < 500/mm3). The primary endpoint was referral to intensive care unit (ICU) or death within 30 days. We collected cancer, patient, and treatment characteristics. RESULTS: Among 141,586 cancer inpatients, 40,660 received chemotherapy among whom 661 (1.6%) had ICISN. Median age was 63 years (interquartile range (IQR), 54-70) and 330 patients (49%) were female. The median Charlson score was 10 (IQR, 8-11). Main primary cancers were lung (n = 204, 31%) and breast (n = 87, 13%). Advanced cancers were found in 551 patients (83%), 331 (50%) were in 1st line of chemotherapy, 284 (42%) in the 1st cycle of the current line and 149 (22%) had primary G-CSF. Documented bacterial (mostly gram-negative bacilli) and fungal infections were observed in 113 (17%) and 19 (3%) patients; 58 (9%) were transferred to ICU and 82 (12%) died within 30 days, 372 (56%) patients received subsequent chemotherapy. Independent prognostic factors were the level of monocyte, lymphocyte counts or albuminemia and a documented bacterial infection, while Charlson index and primary prophylactic G-CSF were not associated with patient clinical outcomes. CONCLUSION: Despite the use of primary G-CSF, ICISN remains a frequent event, which leads to ICU death in one on five cases Some prognostic factors of severity have been highlighted and could help clinicians to prevent severe complications.
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Antineoplásicos , Neoplasias , Neutropenia , Humanos , Estudios Retrospectivos , Persona de Mediana Edad , Femenino , Masculino , Anciano , Neoplasias/tratamiento farmacológico , Prevalencia , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Estudios de Cohortes , Pronóstico , Unidades de Cuidados Intensivos/estadística & datos numéricos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Administración IntravenosaAsunto(s)
Antipsicóticos , Clozapina , Factor Estimulante de Colonias de Granulocitos , Neutropenia , Humanos , Clozapina/efectos adversos , Clozapina/administración & dosificación , Neutropenia/inducido químicamente , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Antipsicóticos/efectos adversos , Antipsicóticos/administración & dosificación , Masculino , Persona de Mediana Edad , FemeninoRESUMEN
BACKGROUND: Trilaciclib, in comparison to placebo plus carboplatin, etoposide, ± atezolizumab (PEA), has shown significant reductions in incidence of severe neutropenia (SN) among patients with extensive-stage small cell lung cancer (ES-SCLC). Despite these findings, real-world utility remains limited. METHODS: A single-center quasi-experimental study compared trilaciclib + PEA (PEAT) versus PEA in ES-SCLC patients. The study period ranged from April 1, 2021 to July 31, 2022, for the PEAT recipients and February 1, 2020, to February 28, 2021, for PEA recipients. The primary endpoint evaluated was incidence of SN after cycle 1 and during the treatment period. Secondary endpoints included measures related to myelopreservation and patient outcomes. RESULTS: Among 34 PEAT and 44 PEA patients, baseline characteristics were similar, except for a higher median age (69 vs 64 years) and more males (64.7% vs 38.6%) in the PEAT cohort. The PEAT cohort exhibited a lower SN rate (3%) versus the PEA cohort (18%), with statistical significance demonstrated on multivariate analysis (p = 0.015). Additionally, the PEAT cohort also demonstrated significant reductions in red blood cell transfusion requirements (3% vs 23%; p = 0.02), grade 3-4 anemia (6% vs 25%; p = 0.03), and grade 3-4 thrombocytopenia (0% vs 11%, p = 0.045). CONCLUSION: Trilaciclib, in combination with PEA, demonstrated an improvement in the safety profile without compromising survival outcomes in ES-SCLC patients. These findings underscore the potential benefits of incorporating trilaciclib in real-world clinical settings for enhanced patient care.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Masculino , Femenino , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Persona de Mediana Edad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Estadificación de Neoplasias , Pirimidinas , PirrolesRESUMEN
Polatuzumab vedotin(Pola)combination therapy is used for diffuse large B-cell lymphoma(DLBCL)treatment. In clinical trials, more than 90% of the patients have received granulocyte-colony stimulating factor(G-CSF)as primary prophylaxis. However, reports investigating the benefit of prophylactic administration are lacking. In this study, we addressed the incidence of febrile neutropenia(FN)with and without primary prophylaxis with G-CSF combined with Pola therapy. We observed that the incidence of FN with Pola-BR therapy was 0% and 9.5% with and without G-CSF, respectively. The incidence of FN with Pola-R-CHP tended to be higher: 0% and 31.2% with and without G-CSF, respectively. The duration of hospitalization significantly decreased in the Pola-BR group with G-CSF(11 days vs. 18 days in the group without G-CSF), suggesting that prophylaxis might contribute to this reduction. Although not statistically significant, prophylactic G-CSF administration tended to reduce the incidence of Grade 3 or higher leukopenia and neutropenia, suggesting that primary prophylactic G-CSF administration in Pola combination therapy could contribute to reduced hematologic toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica , Filgrastim , Polietilenglicoles , Humanos , Filgrastim/administración & dosificación , Filgrastim/uso terapéutico , Polietilenglicoles/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Adulto , Anciano de 80 o más Años , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , InmunoconjugadosRESUMEN
BACKGROUND: Mecapegfilgrastim, a long-acting granulocyte-colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China. OBJECTIVE: We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S-1/capecitabine-based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens. METHOD: Five hundred and sixty-one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians. RESULTS: The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S-1/capecitabine-based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S-1/capecitabine-based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively. CONCLUSION: In a real-world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high-risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles.
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Protocolos de Quimioterapia Combinada Antineoplásica , Fluorouracilo , Neoplasias Gastrointestinales , Neutropenia , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Neoplasias Gastrointestinales/tratamiento farmacológico , Neutropenia/prevención & control , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Adulto , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Leucovorina/efectos adversos , Irinotecán/uso terapéutico , Irinotecán/efectos adversos , Oxaliplatino/efectos adversos , Oxaliplatino/uso terapéutico , China/epidemiologíaRESUMEN
PURPOSE: Haematology patients with high-risk neutropenia are prone to mucosal-barrier injury-associated laboratory-confirmed bloodstream infections (MBI-LCBI). We assessed risk factors for MBI-LCBI including candidaemia in neutropenic haematology patients with fever. METHODS: This prospective observational study was performed in six dedicated haematology units in the Netherlands. Eligible haematology patients had neutropenia < 500/mL for ≥ 7 days and had fever. MBI-LCBIs were classified according to Centers for Disease Control (CDC) definitions and were followed until the end of neutropenia > 500/mL or discharge. RESULTS: We included 416 patients from December 2014 until August 2019. We observed 63 MBI-LCBIs. Neither clinical mucositis scores nor the blood level of citrulline at fever onset was associated with MBI-LCBI. In the multivariable analysis, MASCC-score (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.05 to 1.29 per point decrease), intensive chemotherapy (OR 3·81, 95% CI 2.10 to 6.90) and Pichia kudriavzevii (formerly Candida krusei) colonisation (OR 5.40, 95% CI 1.75 to 16.7) were retained as risk factors for MBI-LCBI, while quinolone use seemed protective (OR 0.42, 95% CI 0.20 to 0.92). Citrulline level (OR 1.57, 95% CI 1.07 to 2.31 per µmol/L decrease), active chronic obstructive pulmonary disease (OR 15.4, 95% CI 1.61 to 14.7) and colonisation with fluconazole-resistant Candida (OR 8.54, 95% CI 1.51 to 48.4) were associated with candidaemia. CONCLUSION: In haematology patients with fever during neutropenia, hypocitrullinaemia at fever onset was associated with candidaemia, but not with bacterial MBI-LCBI. Patients with intensive chemotherapy with a low MASCC-score and colonisation with Pichia kudriavzevii had the highest risk of MBI-LCBI. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02149329) at 19-NOV-2014.
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Fiebre , Mucositis , Neutropenia , Humanos , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Factores de Riesgo , Mucositis/etiología , Neutropenia/etiología , Neutropenia/complicaciones , Anciano , Fiebre/etiología , Adulto , Países Bajos , Índice de Severidad de la Enfermedad , Candidemia/etiología , Candidemia/epidemiología , Neoplasias Hematológicas/complicacionesRESUMEN
Invasive candidiasis is characterized by the systemic dissemination of Candida spp. and colonization of multiple organs. We are reporting a case of invasive candidiasis in a 3.5-year-old female mixed-breed dog with a history of limb injury. After clinical evaluation and complementary examinations a sepsis diagnose was established. The patient remained hospitalized under antibiotic therapy, dying three days later. Necropsy revealed white, nodular (pyogranulomas), and multifocal areas on the liver, button ulcers in the stomach and intestines, and a random lung consolidation. Impression smears were made from the liver and lung surface lesions during necropsy showing yeast and pseudohyphae structures. Fragments of these organs were sent for fungal culture and subsequent molecular etiologic characterization, identifying it as Candida albicans. Histological examination of different organs showed pyogranulomatous inflammation surrounding the necrosis areas, which were full of yeast and pseudohyphae, as evidenced by periodic acid Schiff and immunohistochemistry. Neutropenia, as a consequence of sepsis, associated with the use of antibiotics may have allowed yeast invasion and proliferation in the mucosa of the gastrointestinal tract, reaching the liver and lungs through hematogenous route. Invasive candidiasis is a rare canine disease, and no other cases of neutropenia associated with antibiotic therapy, as a predisposing factors, have been reported.
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Candida albicans , Candidiasis Invasiva , Enfermedades de los Perros , Perros , Animales , Femenino , Candidiasis Invasiva/diagnóstico , Candidiasis Invasiva/microbiología , Candidiasis Invasiva/tratamiento farmacológico , Candidiasis Invasiva/patología , Enfermedades de los Perros/microbiología , Enfermedades de los Perros/patología , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/tratamiento farmacológico , Candida albicans/aislamiento & purificación , Resultado Fatal , Neutropenia/microbiología , Antifúngicos/uso terapéuticoRESUMEN
Severe congenital neutropenia (SCN) comprises a diverse range of rare hematological disorders characterized by recurrent, often life-threatening infections that manifest within the first months of life. Mutations in the ELANE gene are the most prevalent cause of SCN. While over 230 mutations in ELANE have been documented, including substitutions, frameshifts, nonsense mutations, and splice site alterations, the occurrence of deep intronic mutations has not been previously reported. Herein, we present the case of a young girl who exhibited recurrent fever, respiratory infections, skin abscesses, and gingivitis shortly after birth. Laboratory analysis revealed markedly diminished neutrophil levels alongside elevated monocyte and eosinophil counts. Bone marrow examination disclosed a halt in myelopoiesis maturation. ELANE gene full-length sequencing identified a novel de novo deep intron mutation in ELANE (c.598 + 79G > T), subsequently confirmed by Sanger sequencing. cDNA sequencing of the patient demonstrated aberrant gene splicing. Utilizing a mini-gene splicing assay for ELANE intronic variants, we identified a mutant ELANE allele (c.597 + 1_597 + 83ins) leading to the creation of a premature termination codon (p.Gly200ValfsTer40). Confocal microscopy revealed heightened expression of myeloperoxidase and neutrophil elastase in the patient, suggesting a potential role for the unfolded protein response in the pathogenesis of the deep intron ELANE mutation. In summary, our findings illustrate the first reported instance of de novo deep intron ELANE mutations associated with SCN, underscoring the importance of exploring deep intronic regions in SCN patients lacking identifiable disease-causing gene mutations.
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Síndromes Congénitos de Insuficiencia de la Médula Ósea , Intrones , Elastasa de Leucocito , Mutación , Neutropenia , Humanos , Femenino , Neutropenia/genética , Neutropenia/congénito , Neutropenia/diagnóstico , Elastasa de Leucocito/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/diagnóstico , Intrones/genética , Mutación/genética , Predisposición Genética a la Enfermedad , AlelosRESUMEN
The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (â¼95 %) and loading capacity (â¼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (â¼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.
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Antineoplásicos , Docetaxel , Glutatión , Liposomas , Ratones Endogámicos BALB C , Docetaxel/administración & dosificación , Docetaxel/farmacocinética , Docetaxel/farmacología , Docetaxel/química , Animales , Ratones , Glutatión/química , Femenino , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Profármacos/administración & dosificación , Profármacos/química , Profármacos/farmacología , Taxoides/administración & dosificación , Taxoides/farmacología , Taxoides/farmacocinética , Taxoides/química , Polisorbatos/química , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológicoRESUMEN
BACKGROUND: Concern about clozapine-associated neutropenia contributes to clozapine's underutilization and racial disparities in access. People with African ancestry are more likely to have lower normative absolute neutrophil counts (ANC), associated with the Duffy null genetic polymorphism. Recent data on clozapine-associated neutropenia in the US are lacking. METHODS: Patients prescribed clozapine in the Johns Hopkins Medicine electronic medical record (EMR) between 2013 and 2023 were identified. Duffy null Associated Neutrophil Count (DANC) was assigned if there were two ANC's < 2000 cells/µL, >30 days apart, before starting clozapine. Rates of neutropenia, timing of first neutropenia, and demographic differences were explored. RESULTS: 974 received clozapine and had ANC's available, with 63.9 % male, 51.1 % White, and 39 % Black. 287 were presumed to start clozapine during the study period, and were 62.4 % male, 46 % White, and 44.9 % Black. No patients developed severe neutropenia. 59 (6.1 %) developed mild or moderate neutropenia. 19 (6.6 %) new starts had presumed DANC, and none developed neutropenia. 11 of 16 presumed new starts who developed neutropenia did so within eight months. No demographic differences were found between groups for presumed new starts. For non-new starts, where DANC assignment was not possible, Black patients were more likely than White patients to develop neutropenia (OR 3.48, 95 % CI [1.65, 7.73]). DISCUSSION: To our knowledge, this is the first observational study of clozapine-associated neutropenia in the US in the past decade, and it includes a substantial proportion of Black patients. ANC monitoring requirements may be too strict, contributing to clozapine underutilization.
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Antipsicóticos , Clozapina , Neutropenia , Humanos , Clozapina/efectos adversos , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Masculino , Femenino , Adulto , Antipsicóticos/efectos adversos , Persona de Mediana Edad , Estados Unidos , Negro o Afroamericano , Población Blanca , Factores de Tiempo , Recuento de Leucocitos , Esquizofrenia/tratamiento farmacológico , Adulto Joven , Sistema del Grupo Sanguíneo Duffy/genética , AncianoRESUMEN
AIMS: In Tunisia, limited research has focused on characterizing clinical vancomycin-resistant Enterococcus faecium (VREfm). This study aimed to bridge this knowledge gap by molecular characterization of antimicrobial resistance, determining the genetic elements mediating vancomycin-resistance, and whole-genome sequencing of one representative VREfm isolate. METHODS AND RESULTS: Over 6 years (2011-2016), a total of eighty VREfm isolates responsible for infection or colonization were identified from hospitalized patients, with the incidence rate increasing from 2% in 2011 to 27% in 2016. All of these strains harbored the vanA gene. The screening for antimicrobial resistance genes revealed the predominance of ermB, tetM, and aac(6')-Ie-aph(2'')-Ia genes and 81.2% of strains harbored the Tn1545. Pulsed-field gel electrophoresis identified seven clusters, with two major clusters (belonging to ST117 and ST80) persisting throughout the study period. Seven Tn1546 types were detected, with type VI (truncated transposon) being the most prevalent (57.5%). Whole-genome sequencing revealed a 3 028 373 bp chromosome and five plasmids. Mobile genetic elements and a type I CRISPR-cas locus were identified. Notably, the vanA gene was carried by the classic Tn1546 transposon with ISL3 insertion on a rep17pRUM plasmid. CONCLUSION: A concerning trend in the prevalence of VREfm essentially attributed to CC17 persistence and to horizontal transfer of multiple genetic variants of truncated vanA-Tn1546.
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Elementos Transponibles de ADN , Enterococcus faecium , Variación Genética , Infecciones por Bacterias Grampositivas , Neutropenia , Enterococos Resistentes a la Vancomicina , Secuenciación Completa del Genoma , Humanos , Enterococcus faecium/genética , Enterococcus faecium/aislamiento & purificación , Enterococcus faecium/efectos de los fármacos , Túnez , Enterococos Resistentes a la Vancomicina/genética , Enterococos Resistentes a la Vancomicina/aislamiento & purificación , Infecciones por Bacterias Grampositivas/microbiología , Infecciones por Bacterias Grampositivas/epidemiología , Elementos Transponibles de ADN/genética , Neutropenia/microbiología , Neutropenia/complicaciones , Antibacterianos/farmacología , Proteínas Bacterianas/genética , Pruebas de Sensibilidad Microbiana , Electroforesis en Gel de Campo Pulsado , Resistencia a la Vancomicina/genética , Vancomicina/farmacologíaRESUMEN
T-cell large granular lymphocytic (T-LGL) leukaemia is frequently associated with an autoimmune phenomenon; approximately one-third of patients have rheumatoid arthritis (RA). Intriguingly, one-third of patients with rheumatoid arthritis exhibit clonal T-cell patterns. Here, we present a patient with RA undergoing evaluation for neutropenia and splenomegaly who was later diagnosed with T-LGL leukaemia.
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Artritis Reumatoide , Leucemia Linfocítica Granular Grande , Humanos , Artritis Reumatoide/complicaciones , Leucemia Linfocítica Granular Grande/diagnóstico , Leucemia Linfocítica Granular Grande/complicaciones , Esplenomegalia/etiología , Masculino , Neutropenia/etiología , Persona de Mediana Edad , FemeninoRESUMEN
BACKGROUND: Liver transplantation (LT) normalizes fasting tolerance in glycogen storage disease type (GSD) 1b. However, reported outcomes post-LT with respect to correction of neutropenia, infection risk and growth are varied. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been recently shown to improve neutropenia in GSD1b patients. METHODS: In this single-center retrospective study, we reviewed all children who underwent LT for GSD1b. Neutropenia, dose of granulocyte colony-stimulating factor (G-CSF), unplanned hospital attendance, anthropometrics, graft rejection, survival, and the effects of dapagliflozin were analyzed. Data from protocol biopsies obtained at 1, 5, and 10 years post-LT and immunosuppression levels were collected. RESULTS: Eight children (6 female), all on G-CSF pre-transplant, underwent cadaveric LT for GSD1b at median age 3.6 years (IQR 3.3-5.1) with mean follow-up time of 10.3 years (95% CI 7.5-13.1). Neutrophil count and G-CSF requirement did not improve post-LT. Although a reduction in unplanned hospital attendance due to infection (0.98 [95% CI 0.76-1.26] vs. 0.49 [95% CI 0.41 to 0.57] per person-year, p < 0.01) was observed, gastrointestinal complaints and graft dysfunction accounted for a similar hospitalization burden pre- versus post-LT. Body mass index (BMI) reduced post-LT (Z-score 1.47 [95%CI 0.39-2.23] vs. 0.56 [95% CI -0.74 to 1.45], p = 0.02), with no significant change in height. Although all children and grafts have survived, 75% of recipients developed rejection, despite adequate immunosuppression levels, with two children having been found to have developed significant fibrosis on their 5-year protocol biopsy. Although dapagliflozin allowed cessation of G-CSF, no improvement in neutrophil count was observed. Despite this, a reduction in gastrointestinal and infection-related morbidity was noted following dapagliflozin. CONCLUSION: Although LT normalizes fasting tolerance in GSD1b and reduces hospital attendance due to infection, morbidity from infection and gastrointestinal manifestations persist. Children in our cohort experienced high rates of rejection necessitating titration of immunosuppression to balance risk of infection against organ rejection. Future studies should investigate whether early introduction of SGLT2 inhibitors post-LT impact morbidity in this group.
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Enfermedad del Almacenamiento de Glucógeno Tipo I , Trasplante de Hígado , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo I/cirugía , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Femenino , Masculino , Estudios Retrospectivos , Preescolar , Niño , Resultado del Tratamiento , Neutropenia , Estudios de Seguimiento , Rechazo de Injerto , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Supervivencia de Injerto , LactanteAsunto(s)
Acitretina , Ictiosis Lamelar , Queratolíticos , Neutropenia , Humanos , Acitretina/efectos adversos , Acitretina/uso terapéutico , Ictiosis Lamelar/tratamiento farmacológico , Queratolíticos/efectos adversos , Queratolíticos/uso terapéutico , Neutropenia/inducido químicamente , Lactante , Masculino , FemeninoRESUMEN
BACKGROUND: Glutathione S-Transferase (GST) is a family of phase II metabolizing enzymes contribute to detoxification and elimination of variety of endogenous as well as exogenous xenobiotics including chemotherapeutic agents. The comprehensive knowledge on the impact of genetic polymorphisms in GST) enzyme coding gene will help to understand the clinical outcomes in breast cancer patients treated with either Adriamycin or paclitaxel or combination of both. In this study we attempted to assess the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and their association with Adriamycin and Paclitaxel induced toxicity reactions in breast cancer patients. METHODS: Two hundred BC patients receiving Adriamycin and Paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in GSTM1, GSTP1 and GSTT1 gene were studied by PCR and RFLP analysis. RESULTS: After the univariate analysis of the genetic polymorphisms of GSTM1, GSTP1 and GSTT1 showed that GSTT1 null genotype showed significant association with neutropenia (OR=2.84, 95% CI: 1.06-7.56; p=0.036) in breast cancer patients treated with Adriamycin and GSTT1 null genotype in patients with >1 CINV toxicity confirmed significant correlation (OR=3.75, 95% CI: 1.46-9.59; p=0.005). The genetic polymorphisms of GSTP1 (exon 5) A/G heterozygous genotype was significant in grade >1 toxicity reactions of mucositis (OR=3.22, 95% CI: 1.06-9.71; p=0.037) in breast cancer patients administered with Paclitaxel chemotherapy. CONCLUSION: The findings obtained from this study proposed significant involvement of GSTT1-null genotype in hematological neutropenia toxicity in response to Adriamycin and GSTM1-null genotype showed negative association with non-hematological toxicity (bodyache) in response to Paclitaxel.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Doxorrubicina , Gutatión-S-Transferasa pi , Glutatión Transferasa , Paclitaxel , Polimorfismo Genético , Humanos , Glutatión Transferasa/genética , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Gutatión-S-Transferasa pi/genética , Paclitaxel/efectos adversos , Doxorrubicina/efectos adversos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Pronóstico , Genotipo , Anciano , Estudios de Seguimiento , Neutropenia/inducido químicamente , Neutropenia/genéticaRESUMEN
Phaeohyphomycoses are infections caused by dark-walled dematiaceous fungi. Alternaria and Curvularia are two genera of dematiaceous molds known to cause invasive fungal rhinosinusitis, particularly in immunocompromised patients. Co-infection with two dematiaceous fungi is rarely reported in the literature. This report describes a case of biopsy proven invasive fungal rhinosinusitis with Alternaria spp. and Curvularia spp. co-infection in a neutropenic host. The infection characteristics, microbiologic findings, and treatment are described.
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Alternaria , Ascomicetos , Coinfección , Huésped Inmunocomprometido , Neutropenia , Feohifomicosis , Humanos , Feohifomicosis/microbiología , Feohifomicosis/diagnóstico , Feohifomicosis/complicaciones , Feohifomicosis/tratamiento farmacológico , Coinfección/microbiología , Coinfección/diagnóstico , Alternaria/aislamiento & purificación , Neutropenia/complicaciones , Neutropenia/microbiología , Ascomicetos/aislamiento & purificación , Masculino , Alternariosis/microbiología , Alternariosis/complicaciones , Alternariosis/diagnóstico , Antifúngicos/uso terapéutico , Persona de Mediana Edad , Sinusitis/microbiología , Sinusitis/complicaciones , Sinusitis/diagnóstico , Rinitis/microbiología , Rinitis/complicacionesRESUMEN
Neutropenia, a common side effect of chemotherapy for ovarian cancer, was observed in a 47-year-old female patient undergoing a six-cycle chemotherapy regimen. She experienced recurrent neutropenia and leukopenia but refused granulocyte colony-stimulating factor (G-CSF) due to severe bone pain and high costs. Moxibustion combined with guasha therapy (MGT) was administered each time neutropenia occurred. The treatment involved guasha therapy on the bladder meridian (BL) and the governor vessel (GV), followed by moxibustion at Zhongwan (CV 12), Guanyuan (CV 4), and Shenzhu (GV 12) points over 2-3 days. This approach led to the recovery of neutrophil and leukocyte counts, enabling the patient to complete six chemotherapy cycles without G-CSF. These findings suggest that MGT may enhance neutrophil and leukocyte counts in patients with chemotherapy-induced myelosuppression, presenting a potential alternative for those intolerant to G-CSF. However, further high-quality research is needed to confirm its efficacy.
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Moxibustión , Neutropenia , Neoplasias Ováricas , Humanos , Femenino , Persona de Mediana Edad , Neutropenia/terapia , Neutropenia/inducido químicamente , Neoplasias Ováricas/tratamiento farmacológico , Moxibustión/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recuento de Leucocitos , Neutrófilos , Terapia Combinada , RecurrenciaRESUMEN
PURPOSE: Data on short courses of antibiotic therapy for Enterobacterales bacteremia in high-risk neutropenic patients are limited. The aim of the study was to describe and compare the frequency of bacteremia relapse, 30-day overall and infection-related mortality, Clostridiodes difficile infection and length of hospital stay since bacteremia among those who received antibiotic therapy for 7 or 14 days. METHODS: This is a multicenter, prospective, observational cohort study in adult high-risk neutropenic patients with hematologic malignancies or hematopoietic stem cell transplant and monomicrobial Enterobacterales bacteremia. They received appropriate empirical antibiotic therapy, had a clinical response within 7 days, and infection source control. Clinical, epidemiological and outcomes variables were compared based on 7 or 14 days of AT. RESULTS: Two hundred patients were included (100, 7-day antibiotic therapy; 100, 14-day antibiotic therapy). Escherichia coli was the pathogen most frequently isolated (47.5%), followed by Klebsiella sp. (40.5%). Among those patients that received 7-day vs. 14-day antibiotic course, a clinical source of bacteremia was found in 54% vs. 57% (p = 0.66), multidrug-resistant Enterobacterales isolates in 28% vs. 30% (p = 0.75), and 40% vs. 47% (p = 0.31) received combined empirical antibiotic therapy. Overall mortality was 3% vs. 1% (p = 0.62), in no case related to infection; bacteremia relapse was 7% vs. 2% (p = 0.17), and length of hospital stay since bacteremia had a median of 9 days (IQR: 7-15) vs. 14 days (IQR: 13-22) (p = < 0.001). CONCLUSIONS: These data suggest that seven-day antibiotic therapy might be adequate for patients with high-risk neutropenia and Enterobacterales bacteremia, who receive appropriate empirical therapy, with clinical response and infection source control.