RESUMEN
ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.
Asunto(s)
Transfusión de Plaquetas , Humanos , Transfusión de Plaquetas/efectos adversos , Femenino , Persona de Mediana Edad , Masculino , Anciano , Lesión Pulmonar Aguda/etiología , Plaquetas , Estudios Prospectivos , Adulto , Trombocitopenia/etiología , Enfermedades Hematológicas/terapiaRESUMEN
BACKGROUND: Platelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion. STUDY DESIGN: An open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality. RESULTS: By modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio = 0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p = .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p = .151; odds ratio = 0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p = .256); and allergic TR were significantly less with PRPC (p = .006). PC and RBC use were not increased with PRPC. DISCUSSION: PRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.
Asunto(s)
Síndrome de Dificultad Respiratoria , Reacción a la Transfusión , Plaquetas , Transfusión Sanguínea , Estudios de Cohortes , Humanos , Fármacos Fotosensibilizantes , Transfusión de Plaquetas/efectos adversos , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/terapia , Reacción a la Transfusión/epidemiología , Reacción a la Transfusión/etiologíaAsunto(s)
Algoritmos , Atención Ambulatoria/métodos , Antineoplásicos/efectos adversos , COVID-19 , Neoplasias/tratamiento farmacológico , Neutropenia/diagnóstico , Asignación de Recursos/métodos , Antineoplásicos/uso terapéutico , Biomarcadores/sangre , COVID-19/epidemiología , COVID-19/terapia , Humanos , Neutropenia/inducido químicamente , Neutropenia/metabolismo , Neutrófilos/metabolismo , Ciudad de Nueva York/epidemiología , Pandemias , Estudios RetrospectivosRESUMEN
The gut microbiota influences development1-3 and homeostasis4-7 of the mammalian immune system, and is associated with human inflammatory8 and immune diseases9,10 as well as responses to immunotherapy11-14. Nevertheless, our understanding of how gut bacteria modulate the immune system remains limited, particularly in humans, where the difficulty of direct experimentation makes inference challenging. Here we study hundreds of hospitalized-and closely monitored-patients with cancer receiving haematopoietic cell transplantation as they recover from chemotherapy and stem-cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, enabling the relationships between the two to be studied simultaneously. Analysis of observed daily changes in circulating neutrophil, lymphocyte and monocyte counts and more than 10,000 longitudinal microbiota samples revealed consistent associations between gut bacteria and immune cell dynamics. High-resolution clinical metadata and Bayesian inference allowed us to compare the effects of bacterial genera in relation to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota-together and over time-on systemic immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.
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Microbioma Gastrointestinal/inmunología , Leucocitos/citología , Leucocitos/inmunología , Factores de Edad , Teorema de Bayes , Trasplante de Microbiota Fecal , Femenino , Humanos , Recuento de Leucocitos , Linfocitos/citología , Linfocitos/inmunología , Monocitos/citología , Monocitos/inmunología , Neutrófilos/citología , Neutrófilos/inmunología , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Lumbar puncture (LP) is a frequently performed diagnostic and therapeutic procedure in oncology patients. Transfusing to a minimum preprocedural platelet threshold of 50 × 109 /L is widely upheld without good quality evidence. The objective was to compare the outcomes of LPs performed with platelets above and below this threshold. An increased risk of adverse events in patients with lower platelet counts was not expected. As a corollary, transfusion reaction rates incurred by transfusing to this recommended threshold are also reported. METHODS: A total of 2259 LPs performed on 1137 oncology patients (adult, n = 871, and pediatric, n = 266) were retrospectively analyzed between February 2011 and December 2017. The incidence of LP-related complications for groups above and below the minimum platelet threshold was compared. Traumatic tap was defined as 500 or more red blood cells per high-power field in the cerebral spinal fluid. Groups were compared using the 2-Proportion Z-test and Fisher exact test. RESULTS: At time of LP, the total number of events with platelets less than 50 × 109 /L and 50 × 109 /L or greater were 110 and 2149, respectively. There were no significant differences in LP-associated complications between patients with platelet counts above or below 50 × 109 /L (P = .29). Patients with a pre-LP platelet count of less than 50 × 109 /L had a higher proportion of traumatic taps (P < .001). Three patients developed transfusion-related adverse events. CONCLUSION: Patients with platelet counts less than 50 × 109 /L did not have a higher incidence of clinically significant post-lumbar puncture complications (P = .29).
Asunto(s)
Neoplasias , Transfusión de Plaquetas/efectos adversos , Punción Espinal/efectos adversos , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/terapia , Recuento de Plaquetas , Estudios RetrospectivosRESUMEN
OBJECTIVES: To evaluate the use of a pretest probability score (4Ts score) in cancer patients to guide ordering of laboratory screening tests for heparin-induced thrombocytopenia (HIT). METHODS: A retrospective chart review was conducted for patients (n = 140) in whom laboratory testing for HIT was requested. 4Ts scores were calculated and correlated with heparin-endogenous platelet factor 4 antibody enzyme-linked immunosorbent assay (ELISA) test results. RESULTS: All patients with a high pretest probability of HIT (4Ts score = 6-7) had positive ELISA results, compared to 26.1% of patients with intermediate (4Ts score = 4-5) and 4.3% of patients with low (4Ts score ≤3) pretest probability. No patients with 4Ts scores of 2 or less had positive ELISA results. CONCLUSIONS: HIT can be ruled out in cancer patients (negative predictive value and sensitivity = 100%) with low pretest probability, defined by 4Ts scores of 2 or less, significantly reducing the need for laboratory testing in this patient population.
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Neoplasias , Trombocitopenia/inducido químicamente , Trombocitopenia/diagnóstico , Adulto , Anciano , Anticoagulantes/efectos adversos , Ensayo de Inmunoadsorción Enzimática , Femenino , Heparina/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de RiesgoRESUMEN
CD99(MIC2) is a widely expressed cell surface glycoprotein and functions as a tumor suppressor involved in downregulation of SRC family of tyrosine kinase. CD99 expression is tightly regulated through B-cell development. The principal aims of this study were to investigate the clinical utility of CD99 expression (i) in distinguishing normal plasma cells from primary plasma cell neoplasms; (ii) in detection of minimal residual disease in primary plasma cell neoplasms; and (iii) in distinguishing plasma cell component of B-cell lymphomas from primary plasma cell neoplasms. We analyzed expression of CD99 by flow cytometry and immunohistochemistry in lymph nodes, peripheral blood, and bone marrow samples. CD99 showed stage-specific expression with highest expression seen in precursor B and plasma cells. In contrast to the uniform bright expression on normal plasma cells, CD99 expression on neoplastic plasma cells was lost in 39 out of 56 (69.6%) cases. Furthermore, 8 out of 56 samples (14%) showed visibly (>10-fold) reduced CD99 expression. Overall, CD99 expression was informative (absent or visibly dimmer than normal) in 84% of primary plasma cell neoplasm. In the context of minimal residual disease detection, CD99 showed superior utility in separating normal and abnormal plasma cells over currently established antigens CD117, CD81, and CD27 by principal component analysis. Preservation of CD99 expression was strongly associated with cyclin D1 translocation in myeloma (p < 0.05). B-cell lymphomas with plasma cell component could be distinguished from myeloma by CD99 expression. In summary, we established that tumor suppressor CD99 is markedly downregulated in multiple myeloma. The loss is highly specific for identification of abnormal cells in primary plasma cell neoplasms, and can be exploited for diagnostic purposes. The role of CD99 in myeloma pathogenesis requires further investigation.
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Antígeno 12E7/metabolismo , Linfocitos B/metabolismo , Ciclina D1/metabolismo , Regulación hacia Abajo , Linfoma de Células B/metabolismo , Neoplasias de Células Plasmáticas/metabolismo , Células Plasmáticas/metabolismo , Antígeno 12E7/genética , Linfocitos B/patología , Ciclina D1/genética , Diagnóstico Diferencial , Humanos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Neoplasias de Células Plasmáticas/diagnóstico , Neoplasias de Células Plasmáticas/genética , Células Plasmáticas/patología , Transporte de ProteínasRESUMEN
BACKGROUND: At a high-volume center, it became necessary to provide benchmarks for the accuracy and risk of malignancy per urine cytology diagnostic category. The additive sensitivity for the determination of the residual risk of disease was calculated with the goal of determining the performance of cytology and optimal triage, including the number of urine samples, before the detection of malignancy in surveillance patients. METHODS: A 2-year laboratory information system-based search was conducted, and it yielded 587 subjects (695 biopsy and cytology pairs) with histological follow-up. The sensitivity and specificity of cytology for urothelial malignancy, the risk of malignancy per diagnostic category, the additive sensitivity, and the time for conversion from a negative initial cytology result to a positive cytology result were examined. RESULTS: The overall average sensitivity and specificity of cytology were 48.9% and 83.0%, respectively. The additive sensitivity increased with each subsequent cytology and peaked with the third cytology. A median conversion time of 22.2 months from a negative initial cytology result to a positive cytology result and a decline in predictive positive cytology after the fourth cytology were noted. Subcategorization of the atypical category failed to show statistical significance in predicting outcomes of biopsy. Surveillance subjects, as compared to primary subjects, showed a higher sensitivity for the detection of high and low grade cancers. CONCLUSIONS: The findings suggest that atypia favoring malignancy is being appropriately flagged. However, further definition of the atypical category is needed to increase specificity with a better qualitative or quantitative morphological algorithm. This study provides a risk of malignancy for each category for benchmarking and clinical triage. The data suggest that follow-up should include at least 4 consecutive urine specimens over a period of 22.2 months.
Asunto(s)
Neoplasias de la Vejiga Urinaria/diagnóstico , Orina/citología , Área Bajo la Curva , Benchmarking , Citodiagnóstico , Humanos , Modelos Logísticos , Riesgo , Sensibilidad y EspecificidadRESUMEN
GOALS: We have developed the anti-cancer peptide, PNC-27, which is a membrane-active peptide that binds to the HDM-2 protein expressed in the cancer cell membranes of solid tissue tumor cells and induces transmembrane pore formation in cancer, but not in normal cells, resulting in tumor cell necrosis that is independent of p53 activity in these cells. We now extend our study to non-solid tissue tumor cells, in this case, a primitive, possible stem cell human leukemia cell line (K562) that is also p53-homozygously deleted. Our purpose was twofold: to investigate if these cells likewise express HDM-2 in their plasma membranes and to determine if our anti-cancer peptide induces tumor cell necrosis in these non-solid tissue tumor cells in a manner that depends on the interaction between the peptide and membrane-bound HDM-2. PROCEDURES: The anti-cancer activity and mechanism of PNC-27, which carries a p53 aa12-26-leader sequence connected on its carboxyl terminal end to a trans-membrane-penetrating sequence or membrane residency peptide (MRP), was studied against p53-null K562 leukemia cells. Murine leukocytes were used as a non-cancer cell control. Necrosis was determined by measuring the lactate dehydrogenase (LDH) release and apoptosis was determined by the detection of Caspases 3 and 7. Membrane colocalization of PNC-27 with HDM-2 was analyzed microscopically using fluorescently labeled antibodies against HDM-2 and PNC-27 peptides. RESULTS: We found that K562 cells strongly express HDM-2 protein in their membranes and that PNC-27 co-localizes with this protein in the membranes of these cells. PNC-27, but not the negative control peptide PNC-29, is selectively cytotoxic to K562 cells, inducing nearly 100 percent cell killing with LDH release. In contrast, this peptide had no effect on the lymphocyte control cells. CONCLUSIONS: The results suggest that HDM-2 is expressed in the membranes of non-solid tissue tumor cells in addition to the membranes of solid tissue tumor cells. Since K-562 cells appear to be in the stem cell family, the results suggest that early developing tumor cells also express HDM-2 protein in their membranes. Since PNC-27 induces necrosis of K-562 leukemia cells and co-localizes with HDM-2 in the tumor cell membrane as an early event, we conclude that the association of PNC-27 with HDM-2 in the cancer cell membrane results in trans-membrane pore formation which results in cancer cell death, as previously discovered in a number of different solid tissue tumor cells. Since K562 cells lack p53 expression, these effects of PNC-27 on this leukemia cell line occur by a p53-independent pathway.
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Membrana Celular/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Diferenciación Celular , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Células K562 , Ratones , Microscopía Confocal , Unión Proteica/efectos de los fármacosRESUMEN
We have employed computer-based molecular modeling approaches to design peptides from the ras-p21 and p53 proteins that either induce tumor cell reversion to the untransformed phenotype or induce tumor cell necrosis without affecting normal cells. For rasp21, we have computed and superimposed the average low energy structures for the wild-type protein and oncogenic forms of this protein and found that specific domains change conformation in the oncogenic proteins. We have synthesized peptides corresponding to these and found that ras peptides, 35-47 (PNC-7) and 96-110 (PNC-2), block oncogenic ras-p21-induced oocyte maturation but have no effect on insulin-induced oocyte maturation that requires activation of endogenous wild-type ras-p21. These results show signal transduction pathway differences between oncogenic and activated wild-type ras-p21. Both peptides, attached to a membrane-penetrating peptide (membrane residency peptide or MRP), either induce phenotypic reversion to the untransformed phenotype or tumor cell necrosis of several ras-transformed cell lines, but have no effect on the growth of normal cells. Using other computational methods, we have designed two peptides, PNC-27 and 28, containing HDM-2-protein-binding domain sequences from p53 linked on their C-termini to the MRP that induce pore formation in the membranes of a wide range of cancer cells but not any normal cells tested. This is due to the expression of HDM-2 in the cancer cell membrane that does not occur in normal cells. These peptides eradicate a highly malignant tumor in nude mice with no apparent side effects. Both ras and p53 peptides show promise as anti-tumor agents in humans.