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ABSTRACT: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.
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Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Nucleofosmina , Sulfonamidas , Humanos , Prognóstico , Mutação , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Citarabina , Neoplasia Residual/genéticaRESUMO
Favourable outcomes with CPX-351 versus conventional 7 + 3 were demonstrated in the pivotal phase III trial in adults aged 60-75 years with newly diagnosed, highrisk/secondary acute myeloid leukaemia (AML). As a complement to the clinical trial and to address important data gaps, the CPX-351 Real-World Effectiveness and SafeTy (CREST-UK; NCT05169307) study evaluated the use of CPX-351 in routine clinical practice in the UK, in 147 patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Best response of complete remission or complete remission with incomplete platelet or neutrophil recovery was achieved by 53% of evaluable patients. Kaplan-Meier median overall survival (OS) was 12.8 months (95% confidence interval 9.2-15.3). Fifty (34%) patients proceeded to haematopoietic cell transplantation (HCT); median OS landmarked from the HCT date was not reached. There were no new safety concerns with CPX-351 identified in CREST-UK. Patients treated with CPX-351 in the outpatient setting spent an average of 24.4, 16.7, 28.2, and 27.7 fewer days on the ward compared with inpatients during first induction, second induction, first consolidation, and second consolidation, respectively. The results from CREST-UK provide valuable insights into the effectiveness, safety, and outpatient delivery of CPX-351 in routine clinical practice in the UK.
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Limited data exist on COVID-19 vaccination efficacy in patients with acute myeloid leukemia and myelodysplasia with excess blasts (AML/MDS-EB2). We report results from a prospective study, PACE (Patients with AML and COVID-19 Epidemiology). 93 patients provided samples post-vaccine 2 or 3 (PV2, PV3). Antibodies against SARS-COV-2 spike antigen were detectable in all samples. Neutralization of the omicron variant was poorer than ancestral variants but improved PV3. In contrast, adequate T-cell reactivity to SARS-COV-2 spike protein was seen in only 16/47 (34%) patients PV2 and 23/52 (44%) PV3. Using regression models, disease response (not in CR/Cri), and increasing age predicted poor T cell response.
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COVID-19 , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Vacinas contra COVID-19 , Estudos Prospectivos , Linfócitos T , COVID-19/prevenção & controle , SARS-CoV-2 , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Vacinação , Anticorpos AntiviraisRESUMO
Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).
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Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Nucleofosmina , Recidiva , Adulto JovemRESUMO
OBJECTIVES: The objective of this study was to describe the nosocomial spread of carbapenemase-producing enterobacteria and characterize a plasmid involved in KPC dissemination. METHODS: Two Klebsiella pneumoniae, one Escherichia coli and one Citrobacter freundii isolated from two patients were studied. Susceptibility profiles were obtained using Etest. Carbapenemase activity was detected using the Carba NP test. ß-Lactamase gene content was screened by PCR and sequencing. K. pneumoniae isolates were genotyped by MLST and PFGE. KPC plasmid sizes were estimated by S1-DNA digestion and PFGE-Southern blot. Plasmids were sequenced using Illumina's technology and Sanger sequencing. RESULTS: Two patients sharing a room on a surgical unit were positive for carbapenemase-producing K. pneumoniae. One patient was also colonized with carbapenemase-producing C. freundii and E. coli. Neither patient had known risk factors for carbapenemase acquisition, although one patient had recent surgery at another Toronto hospital; the other patient's husband had surgery in New York City 3 years prior to her presentation. An extensive investigation was conducted at both hospitals, but no additional cases were identified. blaKPC-3 was detected in all clinical isolates. Variable carbapenem resistance levels were observed. Both K. pneumoniae belonged to the same clone by PFGE and MLST (ST277). pKPC-SMH (â¼ 53 kb) was identified in all the clinical isolates, showing identity only with structurally similar IncN plasmids. CONCLUSIONS: We describe intra- and inter-patient dissemination of blaKPC. The involvement of a clone related to the successful K. pneumoniae ST258 and the blaKPC-3 gene detected in an active Tn4401 transposon carried on a conjugative broad-host-range plasmid increased the potential for this horizontal transmission.
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Citrobacter freundii/enzimologia , Infecções por Enterobacteriaceae/microbiologia , Escherichia coli/enzimologia , Klebsiella pneumoniae/enzimologia , Plasmídeos/análise , Resistência beta-Lactâmica , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Southern Blotting , Citrobacter freundii/genética , Citrobacter freundii/isolamento & purificação , Conjugação Genética , Infecção Hospitalar/microbiologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Eletroforese em Gel de Campo Pulsado , Escherichia coli/genética , Escherichia coli/isolamento & purificação , Feminino , Transferência Genética Horizontal , Genótipo , Humanos , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Pessoa de Meia-Idade , Tipagem de Sequências Multilocus , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , beta-Lactamases/genéticaRESUMO
BACKGROUND: Cognitive and motor abilities in multiple sclerosis (MS) are typically quantified using reliable, consensus standard tests validated in the MS population. While these performance measures are associated with vocational disability in parametric analyses, translation of raw scores into anchors reflecting clinically relevant, functional impairment requires further research. OBJECTIVE: To examine performance-based motor and cognitive outcomes among definitive anchors that designate varying degrees of functional impairment, thereby establishing benchmarks for score interpretation. METHODS: We evaluated MS patients and healthy controls, all undergoing a brief test battery. Outcomes were derived from the MS Functional Composite (MSFC) and the Brief International Cognitive Assessment for MS (BICAMS). Functional impairment anchors were (1) disability benefits, (2) employed with negative work events, and (3) employed without problems. RESULTS: All measures yielded statistically significant differences across all levels of work status, after accounting for the effects of age and education. Benchmark values distinguished the functional impairment groups. When evaluated in combination, the Timed 25-Foot Walk and the Symbol Digit Modalities Test were the most robust predictors of functional decline. CONCLUSION: We have established benchmark scores for popular motor and cognitive tests that are associated with specific degrees of impairment in work status.
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Benchmarking/métodos , Disfunção Cognitiva/diagnóstico , Emprego/estatística & dados numéricos , Teste de Esforço/métodos , Esclerose Múltipla/diagnóstico , Testes Neuropsicológicos , Índice de Gravidade de Doença , Adulto , Disfunção Cognitiva/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicaçõesRESUMO
We investigated whether positron emission tomography combined with computed tomography (PET-CT) identifies clinically important bone marrow involvement by diffuse large B-cell lymphoma (DLBCL) with sufficient accuracy to replace routine staging bone marrow biopsy. All patients from a single centre diagnosed as DLBCL since 2005 had data extracted from staging PET-CT, marrow biopsy, and treatment records. Of 130 patients, 35 (27%) were judged to have marrow involvement; 33 were identified by PET-CT compared with 14 by marrow histology. PET identified all clinically important marrow lymphoma, while biopsy did not upstage any patient. Sensitivity and specificity were 94% and 100% for PET-CT and 40% and 100% for marrow biopsy. As a secondary aim, we compared the prognosis of marrow involvement, as detected by PET-CT or biopsy. Cases with marrow deposits identified by PET-CT but not biopsy had progression-free survival (PFS) and overall survival similar to stage IV disease without involved marrow. Positive biopsy conferred significantly inferior PFS (P = .003); these cases frequently had other markers of poor-risk disease. These data confirm that in experienced hands PET-CT has a high level of accuracy for identifying marrow disease in DLBCL, and provide new insight into the nature and clinical significance of marrow involvement.
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Medula Óssea/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Medula Óssea/patologia , Feminino , Humanos , Ílio/patologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Heart failure is a multifactorial disease associated with staggeringly high morbidity and motility. Recently, alterations of multiple metabolites have been implicated in heart failure; however, the lack of an effective technology platform to assess these metabolites has limited our understanding on how they contribute to this disease phenotype. We have successfully developed a new workflow combining specific sample preparation with tandem mass spectrometry that enables us to extract most of the targeted metabolites. 19 metabolites were chosen ascribing to their biological relevance to heart failure, including extracellular matrix remodeling, inflammation, insulin resistance, renal dysfunction, and cardioprotection against ischemic injury. RESULTS: In this report, we systematically engineered, optimized and refined a protocol applicable to human plasma samples; this study contributes to the methodology development with respect to deproteinization, incubation, reconstitution, and detection with mass spectrometry. The deproteinization step was optimized with 20% methanol/ethanol at a plasma:solvent ratio of 1:3. Subsequently, an incubation step was implemented which remarkably enhanced the metabolite signals and the number of metabolite peaks detected by mass spectrometry in both positive and negative modes. With respect to the step of reconstitution, 0.1% formic acid was designated as the reconstitution solvent vs. 6.5 mM ammonium bicarbonate, based on the comparable number of metabolite peaks detected in both solvents, and yet the signal detected in the former was higher. By adapting this finalized protocol, we were able to retrieve 13 out of 19 targeted metabolites from human plasma. CONCLUSIONS: We have successfully devised a simple albeit effective workflow for the targeted plasma metabolites relevant to human heart failure. This will be employed in tandem with high throughput liquid chromatography mass spectrometry platform to validate and characterize these potential metabolic biomarkers for diagnostic and therapeutic development of heart failure patients.
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Introduction: COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. Methods: This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. Results: The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. Discussion: Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.
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COVID-19 , Doenças Transmissíveis , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Pessoa de Meia-Idade , Medula Óssea , Transplante Homólogo , COVID-19/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doenças Transmissíveis/complicações , Infecções por Citomegalovirus/complicações , Sistema de RegistrosRESUMO
Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.
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Leucemia Mieloide Aguda , Terapia de Salvação , Humanos , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Recidiva Local de Neoplasia , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
INTRODUCTION: We report an internal validation of the Medication Quantification Scale (MQS III) using a chronic pain population. The MQS was designed as a methodology of quantifying different drug regimens in 1992, updated in 1998 (MQS II), and again updated in 2003 (MQS III) using "detriment" weights determined by surveying physician members of the American Pain Society. The MQS has been used as a unitary clinical and research outcome. METHODS: A retrospective chart review was collected from 400 patients in an interdisciplinary outpatient chronic pain clinic. A linear regression equation was developed using the patients' composite MQS III score, and those values were used in a Pearson correlation analysis. RESULTS: The correlation between the subjects' computed regression detriment weights and the corresponding MQS III detriment weights yielded a significant result (r = 0.962, P < 0.01; two-tailed). DISCUSSION: Our chronic pain sample-derived detriment weights did differ in some drug classes from that of the physician consensus, most notably the selective serotonin reuptake inhibitor, Opioid Schedule II, and NSAID class detriment. It is necessary to periodically resurvey large groups of physicians in order to control and modify the detriment weights of our categories in light of new information about detrimental effects (eg, COX-2 inhibitors), or to accommodate medical or political changes in prescribing habits (eg, more liberal opioid prescribing in the later years). This work suggests it may also be important to assess patients' perspective on detriment, as well as statistical and empiric use patterns.
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Analgésicos/efeitos adversos , Medição da Dor/normas , Dor/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/classificação , Analgésicos/uso terapêutico , Chicago , Criança , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/psicologia , Clínicas de Dor/estatística & dados numéricos , Pacientes/psicologia , Médicos/psicologia , Estudos RetrospectivosRESUMO
OBJECTIVE: To test the hypothesis that distal residual limbs (DRLs) have significant vasomotor abnormalities. DESIGN: Comparative surface temperature studies of DRLs using paired samples (DRL vs. similar site on intact contralateral limb). SUBJECTS/PATIENTS: Thirty-six volunteer subjects with unilateral, upper or lower limb amputations were recruited and evaluated at a pain research center in an urban academic rehabilitation facility. METHODS: Our main outcomes were subjects' residual limb temperature as measured by quantitative infrared telethermography (qIRT), temperature strips, and examiner's palpation, compared with the contralateral limb. RESULTS: The qIRT showed that the DRLs were significantly cooler than the corresponding area of the contralateral intact limbs (P < 0.01). The difference using temperature strips supported this finding (P < 0.05); while on physical examination, 39% of the residual limbs were perceived by the examiner as cooler than the corresponding unaffected limbs. CONCLUSIONS: DRLs as measured by qIRT were significantly cooler than the corresponding area of the contralateral intact limbs. A better understanding of these findings may be important in elucidating the pathophysiology of relevant clinical features such as a potential sympathetic component of postamputation pain.
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Cotos de Amputação/fisiopatologia , Temperatura Corporal/fisiologia , Extremidades/fisiopatologia , Membro Fantasma/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Adulto , Idoso , Cotos de Amputação/irrigação sanguínea , Cotos de Amputação/inervação , Amputados/reabilitação , Vasos Sanguíneos/inervação , Vasos Sanguíneos/fisiopatologia , Regulação da Temperatura Corporal/fisiologia , Extremidades/irrigação sanguínea , Extremidades/inervação , Feminino , Lateralidade Funcional/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Medição da Dor/métodos , Limiar da Dor/fisiologia , Temperatura Cutânea/fisiologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
The purpose of this cross-sectional study is to examine the relationship between surgical treatments for sleep-disordered breathing (SDB) and composite measure of surgical complications in a nationally representative sample of hospital discharges among U.S. adults. We performed secondary analyses of 33,679 hospital discharges from the 2002-2012 Nationwide Inpatient Sample that corresponded to U.S. adults (≥18 years) who were free of head-and-neck neoplasms, were diagnosed with SDB and had undergone at least one of seven procedures. Multivariate logistic regression models were constructed to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI), controlling for age, sex, race/ethnicity, obstructive sleep apnea (OSA) and obesity diagnoses. Positive associations were found between composite measure of surgical complications and specific procedures: palatal procedure (aOR = 12.69, 95% CI: 11.91,13.53), nasal surgery (aOR = 6.47, 95% CI: 5.99,6.99), transoral robotic assist (aOR = 5.06, 95% CI: 4.34-5.88), tongue base/hypopharynx (aOR = 4.24, 95% CI: 3.88,4.62), maxillomandibular advancement (MMA) (aOR = 3.24, 95% CI: 2.74,3.84), supraglottoplasty (aOR = 2.75, 95% CI: 1.81,4.19). By contrast, a negative association was found between composite measures of surgical complications and tracheostomy (aOR = 0.033, 95% CI: 0.031,0.035). In conclusion, most procedures for SDB, except tracheostomy, were positively associated with complications, whereby palatal procedures exhibited the strongest and supraglottoplasty exhibited the weakest association.
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Complicações Pós-Operatórias/etiologia , Síndromes da Apneia do Sono/cirurgia , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Hospitalização , Humanos , Modelos Logísticos , Masculino , Avanço Mandibular/efeitos adversos , Pessoa de Meia-Idade , Nariz/cirurgia , Obesidade/complicações , Razão de Chances , Palato/cirurgia , Complicações Pós-Operatórias/epidemiologia , Fatores de Risco , Apneia Obstrutiva do Sono/cirurgia , Língua/cirurgia , Traqueostomia/efeitos adversos , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: Cognitive impairment can be seen in patients of all ages with multiple sclerosis (MS). However, there is limited research on neurocognitive disorder in older adults with MS and how to detect Alzheimer's disease (AD) or its prodromal stage, amnestic mild cognitive impairment (aMCI). Thus, the MS clinician is challenged to discriminate between signs of MS-related cognitive decline versus a secondary neurodegenerative process. OBJECTIVE: Compare cognition in older MS patients to patients with AD and aMCI. METHODS: We evaluated cognitively impaired and unimpaired MS patients, AD patients, aMCI patients, and healthy controls (HCs), all elderly (nâ¯=â¯20 per group). AD and aMCI diagnoses were derived by consensus conference independent of the MS research project. Neuropsychological measures assessed domains commonly affected in AD, including verbal memory and expressive language. RESULTS: Cognitively impaired and unimpaired MS groups did not differ on any measures sensitive to AD. Unimpaired MS patients were comparable to HCs. Impaired MS patients showed decreased semantic fluency, similar to aMCI patients. Lastly, while both AD and aMCI groups had deficient memory retention, there was no evidence of a retention deficit in either MS group. CONCLUSION: Our findings suggest that the cognitive profiles of MS and AD are distinct. In contrast to AD, MS is not associated with impairment of memory consolidation. However, there may be overlap between cognitive deficits related to MS and aMCI. Thus, evidence of poor memory retention, in an older MS patient may merit comprehensive dementia evaluation. The study is preliminary and includes no AD biomarkers (e.g., amyloid imaging) to confirm or rule out AD pathology.
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Doença de Alzheimer/psicologia , Cognição , Disfunção Cognitiva/psicologia , Esclerose Múltipla/psicologia , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Comorbidade , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/epidemiologia , Testes NeuropsicológicosRESUMO
A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that redirecting T cells to specialized niches in the BM that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration toward vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis, and a heightened capacity to generate polyfunctional cytokine-producing effector cells. Following transfer to lymphoma-bearing mice, TCXCR4 showed a greater capacity for effector expansion and better tumor protection, the latter being independent of changes in trafficking to the tumor bed or local out-competition of regulatory T cells. Thus, redirected homing of T cells to the BM confers increased memory differentiation and antitumor immunity, suggesting an innovative solution to increase the persistence and functions of therapeutic T cells.
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Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Memória Imunológica , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Medula Óssea/patologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Quimiocina CXCL12/genética , Quimiocina CXCL12/imunologia , Humanos , Interleucina-15/genética , Interleucina-15/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Linfócitos T Reguladores/patologiaRESUMO
OBJECTIVE: We endeavored to clarify how distinct co-occurring symptoms relate to the presence of negative work events in employed multiple sclerosis (MS) patients. Latent profile analysis (LPA) was utilized to elucidate common disability patterns by isolating patient subpopulations. METHOD: Samples of 272 employed MS patients and 209 healthy controls (HC) were administered neuroperformance tests of ambulation, hand dexterity, processing speed, and memory. Regression-based norms were created from the HC sample. LPA identified latent profiles using the regression-based z-scores. Finally, multinomial logistic regression tested for negative work event differences among the latent profiles. RESULTS: Four profiles were identified via LPA: a common profile (55%) characterized by slightly below average performance in all domains, a broadly low-performing profile (18%), a poor motor abilities profile with average cognition (17%), and a generally high-functioning profile (9%). Multinomial regression analysis revealed that the uniformly low-performing profile demonstrated a higher likelihood of reported negative work events. CONCLUSIONS: Employed MS patients with co-occurring motor, memory and processing speed impairments were most likely to report a negative work event, classifying them as uniquely at risk for job loss.