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1.
Nanoscale ; 16(28): 13471-13482, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-38938080

RESUMO

Efficient exciton migration is crucial for optoelectronic organic devices. While the transport of triplet excitons is generally slow compared to singlet excitons, triplet exciton migration in certain molecular semiconductors with endothermic singlet fission appears to be enhanced by a time-delayed regeneration of the more mobile singlet species via triplet fusion. This combined transport mechanism could be exploited for devices, but the interplay between singlet fission and triplet fusion, as well as the role of trap states is not yet well understood. Here, we study the spatiotemporal exciton dynamics in the singlet fission material tetracene by means of time resolved photoluminescence micro-spectroscopy on crystalline samples of different quality. Varying the temperature allows us to modify the dynamic equilibrium between singlet, triplet and trapped excitons. Supported by a kinetic model, we find that thermally activated dissociation of triplet pairs into free triplet excitons can account for an increase of the diffusion length below room temperature. Moreover, we demonstrate that trapping competes efficiently with exciton migration.

2.
JACC Heart Fail ; 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38739124

RESUMO

BACKGROUND: Limited evidence exists regarding efficacy and safety of diuretic regimens in ambulatory, congestion-refractory, chronic heart failure (CHF) patients. OBJECTIVES: The authors sought to compare the potency and safety of commonly used diuretic regimens in CHF patients. METHODS: A prospective, randomized, open-label, crossover study conducted in NYHA functional class II to IV CHF patients, treated in an ambulatory day-care unit. Each patient received 3 different diuretic regimens: intravenous (IV) furosemide 250 mg; IV furosemide 250 mg plus oral metolazone 5 mg; and IV furosemide 250 mg plus IV acetazolamide 500 mg. Treatments were administered once a week, in 1 of 6 randomized sequences. The primary endpoint was total sodium excretion, and the secondary was total urinary volume excreted, both measured for 6 hours post-treatment initiation. RESULTS: A total of 42 patients were recruited. Administration of furosemide plus metolazone resulted in the highest weight of sodium excreted, 4,691 mg (95% CI: 4,153-5,229 mg) compared with furosemide alone, 3,835 mg (95% CI: 3,279-4,392 mg; P = 0.015) and to furosemide plus acetazolamide 3,584 mg (95% CI: 3,020-4,148 mg; P = 0.001). Furosemide plus metolazone resulted in 1.84 L of urine (95% CI: 1.63-2.05 L), compared with 1.58 L (95% CI: 1.37-1.8); P = 0.039 collected following administration of furosemide plus acetazolamide and 1.71 L (95% CI: 1.49-1.93 L) following furosemide alone. The incidence of worsening renal function was significantly higher when adding metolazone (39%) to furosemide compared with furosemide alone (16%) and to furosemide plus acetazolamide (2.6%) (P < 0.001). CONCLUSIONS: In ambulatory CHF patients, furosemide plus metolazone resulted in a significantly higher natriuresis compared with IV furosemide alone or furosemide plus acetazolamide.

3.
Rev Sci Instrum ; 92(3): 034101, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33820004

RESUMO

In this work, we present a single-pole magnetic tweezers (MT) device designed for integration with substrate deformation tracking microscopy and/or traction force microscopy experiments intended to explore extracellular matrix rheology and human epidermal keratinocyte mechanobiology. Assembled from commercially available off-the-shelf electronics hardware and software, the MT device is amenable to replication in the basic biology laboratory. In contrast to conventional solenoid current-controlled MT devices, operation of this instrument is based on real-time feedback control of the magnetic flux density emanating from the blunt end of the needle core using a cascade control scheme and a digital proportional-integral-derivative (PID) controller. Algorithms that compensate for a spatially non-uniform remnant magnetization of the needle core that develops during actuation are implemented into the feedback control scheme. Through optimization of PID gain scheduling, the MT device exhibits magnetization and demagnetization response times of less than 100 ms without overshoot over a wide range of magnetic flux density setpoints. Compared to current-based control, magnetic flux density-based control allows for more accurate and precise magnetic actuation forces by compensating for temperature increases within the needle core due to heat generated by the applied solenoid currents. Near field calibrations validate the ability of the MT device to actuate 4.5 µm-diameter superparamagnetic beads with forces up to 25 nN with maximum relative uncertainties of ±30% for beads positioned between 2.5 and 40 µm from the needle tip.

4.
Br J Haematol ; 192(6): 1015-1019, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32436212

RESUMO

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline ß2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma Difuso de Grandes Células B , Rituximab/administração & dosagem , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Reino Unido/epidemiologia , Vincristina/administração & dosagem
5.
Ann Hematol ; 96(7): 1105-1112, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28526957

RESUMO

The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3-9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fit the entry criteria of the registry, because they were diagnosed uniformly as CMML or AML by the panel members. The agreement by WHO 2001 classification was strong as well (ICC = 0.83). The concordance of the assessment of dysplastic lineages was substantial for megakaryopoiesis and myelopoiesis and moderate for erythropoiesis. Our data show that in general, the inter-observer agreement was high and a very low percentage of misdiagnosed cases had been entered into the EUMDS registry. Further studies including histomorphology are warranted.


Assuntos
Citodiagnóstico/métodos , Síndromes Mielodisplásicas/diagnóstico , Variações Dependentes do Observador , Sistema de Registros/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Exame de Medula Óssea/métodos , Exame de Medula Óssea/normas , Citodiagnóstico/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto Jovem
6.
J Neurosci Methods ; 277: 101-112, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28012852

RESUMO

BACKGROUND: Understanding brain function requires knowledge of how one brain region causally influences another. This information is difficult to obtain directly in the human brain, and is instead typically inferred from resting-state fMRI. NEW METHOD: Here, we demonstrate the safety and scientific promise of a novel and complementary approach: concurrent electrical stimulation and fMRI (es-fMRI) at 3T in awake neurosurgical patients with implanted depth electrodes. RESULTS: We document the results of safety testing, actual experimental setup, and stimulation parameters, that safely and reliably evoke activation in distal structures through stimulation of amygdala, cingulate, or prefrontal cortex. We compare connectivity inferred from the evoked patterns of activation with that estimated from standard resting-state fMRI in the same patients: while connectivity patterns obtained with each approach are correlated, each method produces unique results. Response patterns were stable over the course of 11min of es-fMRI runs. COMPARISON WITH EXISTING METHOD: es-fMRI in awake humans yields unique information about effective connectivity, complementing resting-state fMRI. Although our stimulations were below the level of inducing any apparent behavioral or perceptual effects, a next step would be to use es-fMRI to modulate task performances. This would reveal the acute network-level changes induced by the stimulation that mediate the behavioral and cognitive effects seen with brain stimulation. CONCLUSIONS: es-fMRI provides a novel and safe approach for mapping effective connectivity in the human brain in a clinical setting, and will inform treatments for psychiatric and neurodegenerative disorders that use deep brain stimulation.


Assuntos
Mapeamento Encefálico , Encéfalo , Estimulação Elétrica , Imageamento por Ressonância Magnética , Vias Neurais/fisiologia , Adulto , Biofísica , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Oxigênio/sangue , Adulto Jovem
7.
Br J Haematol ; 178(2): 327-329, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27197509
8.
Br J Haematol ; 175(4): 668-672, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27477167

RESUMO

We performed a subgroup analysis of the phase III UK National Cancer Research Institute R-CHOP-14 versus R-CHOP-21 (two- versus three-weekly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) trial to evaluate the outcomes for 50 patients with World Health Organization 2008 classified primary mediastinal B-cell lymphoma identified from the trial database. At a median follow-up of 7·2 years the 5-year progression-free survival and overall survival was 79·8% and 83·8%, respectively. An exploratory analysis raised the possibility of a better outcome in those who received R-CHOP-14 and time intensification may still, in the rituximab era, merit testing in a randomised trial in this subgroup of patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/mortalidade , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/mortalidade , Pessoa de Meia-Idade , Imagem Multimodal , Estadiamento de Neoplasias , Prednisona/uso terapêutico , Prognóstico , Modelos de Riscos Proporcionais , Rituximab , Resultado do Tratamento , Carga Tumoral , Vincristina/uso terapêutico , Adulto Jovem
9.
J Oral Maxillofac Surg ; 74(6): 1180.e1-7, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26850867

RESUMO

This report describes the case of a 76-year-old woman diagnosed with Epstein-Barr virus-positive diffuse large B-cell non-Hodgkin lymphoma of the elderly. She had an unusual presentation of the disease with widespread skeletal muscle, masticatory muscle, and parotid gland involvement and the development of interesting erythematous lesions in the neck during chemotherapy. One month after completion of chemotherapy, positron-emission tomography (PET) showed features of persistent lymphoma, but a repeat PET scan a month later showed no active disease. This case reiterates 2 important points: first, to consider lymphoma a differential diagnosis in masticatory muscle enlargement and second, to question false positivity when interpreting post-treatment PET scan results, especially in the absence of clinical disease.


Assuntos
Infecções por Vírus Epstein-Barr/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Idoso , Diagnóstico Diferencial , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Infecções por Vírus Epstein-Barr/patologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Músculos da Mastigação/patologia , Músculo Esquelético/patologia , Glândula Parótida/patologia , Tomografia por Emissão de Pósitrons
10.
Haematologica ; 101(2): 235-40, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26611473

RESUMO

Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P<0.001) and overall survival from 37.0 to 44.5 months (P=0.005). This equates to absolute differences of 9.0% and 22.1% for overall and progression-free survival, respectively, at two years. Overall response rates were similar, but complete response rates were significantly higher in the rituximab arm: 52.7% vs. 39.9% (P=0.014). There was no clinically significant additional toxicity observed with the addition of rituximab. Overall, approximately 18% of patients died of non-lymphomatous causes, most commonly infections. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy significantly improves outcomes in patients with mantle cell lymphoma. However, these regimens have significant late toxicity and should be used with caution. This trial has been registered (ISRCTN81133184 and clinicaltrials.gov:00641095) and is supported by the UK National Cancer Research Network.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Segunda Neoplasia Primária/tratamento farmacológico , Infecções Oportunistas/tratamento farmacológico , Rituximab/uso terapêutico , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/patologia , Infecções Oportunistas/mortalidade , Infecções Oportunistas/patologia , Análise de Sobrevida , Vidarabina/uso terapêutico
11.
N Engl J Med ; 372(17): 1598-607, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25901426

RESUMO

BACKGROUND: It is unclear whether patients with early-stage Hodgkin's lymphoma and negative findings on positron-emission tomography (PET) after three cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) require radiotherapy. METHODS: Patients with newly diagnosed stage IA or stage IIA Hodgkin's lymphoma received three cycles of ABVD and then underwent PET scanning. Patients with negative PET findings were randomly assigned to receive involved-field radiotherapy or no further treatment; patients with positive PET findings received a fourth cycle of ABVD and radiotherapy. This trial assessing the noninferiority of no further treatment was designed to exclude a difference in the 3-year progression-free survival rate of 7 or more percentage points from the assumed 95% progression-free survival rate in the radiotherapy group. RESULTS: A total of 602 patients (53.3% male; median age, 34 years) were recruited, and 571 patients underwent PET scanning. The PET findings were negative in 426 of these patients (74.6%), 420 of whom were randomly assigned to a study group (209 to the radiotherapy group and 211 to no further therapy). At a median of 60 months of follow-up, there had been 8 instances of disease progression in the radiotherapy group, and 8 patients had died (3 with disease progression, 1 of whom died from Hodgkin's lymphoma); there had been 20 instances of disease progression in the group with no further therapy, and 4 patients had died (2 with disease progression and none from Hodgkin's lymphoma). In the radiotherapy group, 5 of the deaths occurred in patients who received no radiotherapy. The 3-year progression-free survival rate was 94.6% (95% confidence interval [CI], 91.5 to 97.7) in the radiotherapy group and 90.8% (95% CI, 86.9 to 94.8) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3). CONCLUSIONS: The results of this study did not show the noninferiority of the strategy of no further treatment after chemotherapy with regard to progression-free survival. Nevertheless, patients in this study with early-stage Hodgkin's lymphoma and negative PET findings after three cycles of ABVD had a very good prognosis either with or without consolidation radiotherapy. (Funded by Leukaemia and Lymphoma Research and others; RAPID ClinicalTrials.gov number, NCT00943423.).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Idoso , Bleomicina/uso terapêutico , Terapia Combinada , Dacarbazina/uso terapêutico , Progressão da Doença , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Recidiva , Análise de Sobrevida , Vimblastina/uso terapêutico , Adulto Jovem
12.
Front Plant Sci ; 6: 123, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25806035

RESUMO

Budburst is a key adaptive trait that can help us understand how plants respond to a changing climate from the molecular to landscape scale. Despite this, acquisition of budburst data is constrained by a lack of information at the plant scale on the environmental stimuli associated with the release of bud dormancy. Additionally, to date, little effort has been devoted to phenotyping plants in natural populations due to the challenge of accounting for the effect of environmental variation. Nonetheless, natural selection operates on natural populations, and investigation of adaptive phenotypes in situ is warranted and can validate results from controlled laboratory experiments. To identify genomic effects on individual plant phenotypes in nature, environmental drivers must be concurrently measured, and characterized. Here, we designed and evaluated a sensor to meet these requirements for temperate woody plants. It was designed for use on a tree branch to measure the timing of budburst together with its key environmental drivers; temperature, and photoperiod. Specifically, we evaluated the sensor through independent corroboration with time-lapse photography and a suite of environmental sampling instruments. We also tested whether the presence of the device on a branch influenced the timing of budburst. Our results indicated the following: the temperatures measured by the budburst sensor's digital thermometer closely approximated the temperatures measured using a thermocouple touching plant tissue; the photoperiod detector measured ambient light with the same accuracy as did time lapse photography; the budburst sensor accurately detected the timing of budburst; and the sensor itself did not influence the budburst timing of Populus clones. Among other potential applications, future use of the sensor may provide plant phenotyping at the landscape level for integration with landscape genomics.

13.
Br J Haematol ; 168(1): 55-62, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25146720

RESUMO

The proteasome inhibitor, bortezomib, potentially increases cell sensitivity to chemotherapy. This study was performed to determine the overall response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) compared to CHOP + bortezomib chemotherapy in mantle cell lymphoma (MCL) patients at first relapse. Forty-six patients were randomly assigned to standard dose CHOP ± bortezomib 1·6 mg/m(2) given on a 21-d cycle for up to eight cycles of treatment. Median age was 71 years (CHOP arm) and 69 years (CHOP-bortezomib arm). Median Eastern Cooperative Oncology Group performance status was 1 (CHOP) and 0 (CHOP-bortezomib) with 65% and 52%, respectively, having a disease stage of IV. ORR was 47·8% (CHOP) and 82·6% (CHOP-bortezomib). Complete response rate was 21·7% (CHOP) vs. 34·8% (CHOP-bortezomib); partial response rate was 26·1% (CHOP) vs. 47·8% (CHOP-bortezomib). Median OS was 11·8 months (CHOP) and 35·6 months (CHOP-bortezomib) (P = 0·01, Hazard ratio [HR] 0·37 [95% confidence interval (CI) 0·16-0·83)] and there was a non-significant improvement in PFS: 8·1 months (CHOP) and 16·5 months (CHOP-bortezomib) [P = 0·12, HR 0·60 (95% CI 0·31-1·15)]. Severe (≥grade 3) sensory neuropathy was similar in both arms (4·3% CHOP vs. 6·5% CHOP-bortezomib). We conclude that the addition of bortezomib to CHOP chemotherapy for relapsed MCL significantly improves outcome with a manageable increase in toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Pirazinas/administração & dosagem , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
14.
Lancet ; 381(9880): 1817-26, 2013 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-23615461

RESUMO

BACKGROUND: Dose intensification with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) every 2 weeks improves outcomes in patients older than 60 years with diffuse large B-cell lymphoma compared with CHOP every 3 weeks. We investigated whether this survival benefit from dose intensification persists in the presence of rituximab (R-CHOP) in all age groups. METHODS: Patients (aged ≥18 years) with previously untreated bulky stage IA to stage IV diffuse large B-cell lymphoma in 119 centres in the UK were randomly assigned centrally in a one-to-one ratio, using minimisation, to receive six cycles of R-CHOP every 14 days plus two cycles of rituximab (R-CHOP-14) or eight cycles of R-CHOP every 21 days (R-CHOP-21). R-CHOP-21 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1·4 mg/m(2) (maximum dose 2 mg), and rituximab 375 mg/m(2) on day 1, and oral prednisolone 40 mg/m(2) on days 1-5, administered every 21 days for a total of eight cycles. R-CHOP-14 was intravenous cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 2 mg, rituximab 375 mg/m(2) on day 1, and oral prednisolone 100 mg on days 1-5, administered every 14 days for six cycles, followed by two further infusions of rituximab 375 mg/m(2) on day 1 every 14 days. The trial was not masked. The primary outcome was overall survival (OS). This study is registered, number ISRCTN 16017947. FINDINGS: 1080 patients were assigned to R-CHOP-21 (n=540) and R-CHOP-14 (n=540). With a median follow-up of 46 months (IQR 35-57), 2-year OS was 82·7% (79·5-85·9) in the R-CHOP-14 group and 80·8% (77·5-84·2) in the R-CHOP-21 (standard) group (hazard ratio 0·90, 95% CI 0·70-1·15; p=0·3763). No significant improvement was noted in 2-year progression-free survival (R-CHOP-14 75·4%, 71·8-79·1, and R-CHOP-21 74·8%, 71·0-78·4; 0·94, 0·76-1·17; p=0·5907). High international prognostic index, poor-prognosis molecular characteristics, and cell of origin were not predictive for benefit from either schedule. Grade 3 or 4 neutropenia was higher in the R-CHOP-21 group (318 [60%] of 534 vs 167 [31%] of 534), with no prophylactic use of recombinant human granulocyte-colony stimulating factor mandated in this group, whereas grade 3 or 4 thrombocytopenia was higher with R-CHOP-14 (50 [9%] vs 28 [5%]); other frequent grade 3 or 4 adverse events were febrile neutropenia (58 [11%] vs 28 [5%]) and infection (125 [23%] vs 96 [18%]). Frequencies of non-haematological adverse events were similar in the R-CHOP-21 and R-CHOP-14 groups. INTERPRETATION: R-CHOP-14 is not superior to R-CHOP-21 chemotherapy for previously untreated diffuse large B-cell lymphoma; therefore, R-CHOP-21 remains the standard first-line treatment in patients with this haematological malignancy. No molecular or clinical subgroup benefited from dose intensification in this study. FUNDING: Chugai Pharmaceutical, Cancer Research UK, National Institute for Health Research Biomedical Research Centres scheme at both University College London and the Royal Marsden NHS Foundation Trust, and Institute of Cancer Research.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem
15.
J Clin Oncol ; 30(14): 1647-55, 2012 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-22493413

RESUMO

PURPOSE: In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. PATIENTS AND METHODS: Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. CONCLUSION: Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Deleção de Genes , Genes p53/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Metilprednisolona/administração & dosagem , Academias e Institutos , Adulto , Idoso , Idoso de 80 Anos ou mais , Alemtuzumab , Antibioticoprofilaxia/métodos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Indução de Remissão , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento , Reino Unido
16.
Eur J Heart Fail ; 9(4): 409-14, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17067854

RESUMO

AIMS: To assess prospectively (1) the incidence of early anthracycline-induced cardiotoxicity; (2) the best predictor for identifying individuals at risk of developing functional cardiotoxicity; and (3) the most sensitive standard echocardiographic measure for the detection of anthracycline-induced changes in left ventricular (LV) function. METHODS: Sixty-seven consecutive patients (45 male, mean age 50+/-18 years) requiring doxorubicin-containing chemotherapy were enrolled. Clinical and echocardiographic assessments occurred before they received any anthracycline, after low-dose anthracyclines and 1-3 months after completion of their chemotherapy. RESULTS: Twenty six percent of patients without significant pre-existing cardiac disease developed cardiotoxicity. The parameter that best predicted the development of functional cardiotoxicity was the change in EF between baseline and low dose with an area under the curve of 0.92. The Tei index detected declines in LV function earlier in the course of treatment with anthracyclines and to a greater significance than any other standard echocardiographic measurement but did not predict functional cardiotoxicity. CONCLUSIONS: All patients receiving potential cardiotoxic chemotherapy should be under the care of a cardiologist and have their EF monitored closely.


Assuntos
Antraciclinas/farmacologia , Antineoplásicos/farmacologia , Cardiopatias/induzido quimicamente , Ventrículos do Coração/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias , Estudos Prospectivos , Fatores de Risco , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Ultrassonografia
17.
J Am Soc Echocardiogr ; 19(2): 206-10, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16455426

RESUMO

OBJECTIVE: We sought to study the relative effect on left ventricular (LV) and right ventricular (RV) function of low-dose anthracycline-containing chemotherapy regimes. METHODS: A total of 23 patients (mean age 48 +/- 20 years) underwent echocardiographic examinations before any anthracycline had been administered and then after low-dose anthracycline (doxorubicin 50-125 mg/m2). The Tei index was used to compare the relative effects on RV and LV function. RESULTS: Anthracycline administration was significantly associated with an increase in the LV Tei index (0.38 +/- 0.12 vs 0.46 +/- 0.16, P = .02). There was no significant change in the RV Tei index (0.19 +/- 0.10 vs 0.20 +/- 0.10, P = .72). Comparing the relative effect on global LV and RV function the change in LV Tei was significantly greater than the change in RV Tei (0.07 +/- 0.13 vs 0.01 +/- 0.09, P = .044). CONCLUSIONS: Low-dose anthracycline administration has a significant negative impact on LV function but does not affect RV function.


Assuntos
Antraciclinas/efeitos adversos , Interpretação de Imagem Assistida por Computador/métodos , Índice de Gravidade de Doença , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/diagnóstico por imagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Ultrassonografia
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