RESUMO
BACKGROUND: The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation. METHODS: We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months. RESULTS: Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor ß chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report. CONCLUSIONS: Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).
Assuntos
Terapia Genética , Imunodeficiência Combinada Severa , Humanos , Lactente , Bussulfano/uso terapêutico , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Imunoglobulina M , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/genética , Antígenos CD34/administração & dosagem , Antígenos CD34/imunologia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Lentivirus , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Vetores Genéticos/uso terapêutico , Linfócitos T/imunologia , Linfócitos B/imunologiaRESUMO
BACKGROUND: It is unclear whether adjuvant or early salvage radiotherapy following radical prostatectomy is more appropriate for men who present with localised or locally advanced prostate cancer. We aimed to prospectively plan a systematic review of randomised controlled trials (RCTs) comparing these radiotherapy approaches. METHODS: We used a prospective framework for adaptive meta-analysis (FAME), starting the review process while eligible trials were ongoing. RCTs were eligible if they aimed to compare immediate adjuvant radiotherapy versus early salvage radiotherapy, following radical prostatectomy in men (age ≥18 years) with intermediate-risk or high-risk, localised or locally advanced prostate cancer. We searched trial registers and conference proceedings until July 8, 2020, to identify eligible RCTs. By establishing the ARTISTIC collaboration with relevant trialists, we were able to anticipate when eligible trial results would emerge, and we developed and registered a protocol with PROSPERO before knowledge of the trial results (CRD42019132669). We used a harmonised definition of event-free survival, as the time from randomisation until the first evidence of either biochemical progression (prostate-specific antigen [PSA] ≥0·4 ng/mL and rising after completion of any postoperative radiotherapy), clinical or radiological progression, initiation of a non-trial treatment, death from prostate cancer, or a PSA level of at least 2·0 ng/mL at any time after randomisation. We predicted when we would have sufficient power to assess whether adjuvant radiotherapy was superior to early salvage radiotherapy. Investigators supplied results for event-free survival, both overall and within predefined patient subgroups. Hazard ratios (HRs) for the effects of radiotherapy timing on event-free survival and subgroup interactions were combined using fixed-effect meta-analysis. FINDINGS: We identified three eligible trials and were able to obtain updated results for event-free survival for 2153 patients recruited between November, 2007, and December, 2016. Median follow-up ranged from 60 months to 78 months, with a maximum follow-up of 132 months. 1075 patients were randomly assigned to receive adjuvant radiotherapy and 1078 to a policy of early salvage radiotherapy, of whom 421 (39·1%) had commenced treatment at the time of analysis. Patient characteristics were balanced within trials and overall. Median age was similar between trials at 64 or 65 years (with IQRs ranging from 59 to 68 years) across the three trials and most patients (1671 [77·6%]) had a Gleason score of 7. All trials were assessed as having low risk of bias. Based on 270 events, the meta-analysis showed no evidence that event-free survival was improved with adjuvant radiotherapy compared with early salvage radiotherapy (HR 0·95, 95% CI 0·75-1·21; p=0·70), with only a 1 percentage point (95% CI -2 to 3) change in 5-year event-free survival (89% vs 88%). Results were consistent across trials (heterogeneity p=0·18; I2=42%). INTERPRETATION: This collaborative and prospectively designed systematic review and meta-analysis suggests that adjuvant radiotherapy does not improve event-free survival in men with localised or locally advanced prostate cancer. Until data on long-term outcomes are available, early salvage treatment would seem the preferable treatment policy as it offers the opportunity to spare many men radiotherapy and its associated side-effects. FUNDING: UK Medical Research Council.
Assuntos
Prostatectomia , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Biomarcadores Tumorais/sangue , Intervalo Livre de Doença , Humanos , Masculino , Gradação de Tumores , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia de SalvaçãoRESUMO
BACKGROUND: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. METHODS: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. FINDINGS: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). INTERPRETATION: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. FUNDING: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.
Assuntos
Adenocarcinoma/radioterapia , Prostatectomia , Neoplasias da Próstata/radioterapia , Terapia de Salvação , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Austrália , Progressão da Doença , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Humanos , Masculino , Doenças Urogenitais Masculinas/epidemiologia , Doenças Urogenitais Masculinas/etiologia , Pessoa de Meia-Idade , Nova Zelândia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Radioterapia Adjuvante/efeitos adversos , Terapia de Salvação/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: To test the hypothesis that observation with early salvage radiotherapy (SRT) is not inferior to 'standard' treatment with adjuvant RT (ART) with respect to biochemical failure in patients with pT3 disease and/or positive surgical margins (SMs) after radical prostatectomy (RP). To compare the following secondary endpoints between the two arms: patient-reported outcomes, adverse events, biochemical failure-free survival, overall survival, disease-specific survival, time to distant failure, time to local failure, cost utility analysis, quality adjusted life years and time to androgen deprivation. PATIENTS AND METHODS: The Radiotherapy - Adjuvant Versus Early Salvage (RAVES) trial is a phase III multicentre randomised controlled trial led by the Trans Tasman Radiation Oncology Group (TROG), in collaboration with the Urological Society of Australia and New Zealand (USANZ), and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). In all, 470 patients are planned to be randomised 1:1 to either ART commenced at ≤4 months of RP (standard of care) or close observation with early SRT triggered by a PSA level of >0.20 ng/mL (experimental arm). Eligible patients have had a RP for adenocarcinoma of the prostate with at least one of the following risk factors: positive SMs ± extraprostatic extension ± seminal vesicle involvement. The postoperative PSA level must be ≤0.10 ng/mL. Rigorous investigator credentialing and a quality assurance programme are designed to promote consistent RT delivery among patients. RESULTS: Trial is currently underway, with 258 patients randomised as of 31 October 2013. International collaborations have developed, including a planned meta-analysis to be undertaken with the UK Medical Research Council/National Cancer Institute of Canada Clinical Trials Group RADICALS (Radiotherapy and Androgen Deprivation In Combination with Local Surgery) trial and an innovative psycho-oncology sub-study to investigate a patient decision aid resource. CONCLUSION: On the current evidence available, it remains unclear if ART is equivalent or superior to observation with early SRT.
Assuntos
Adenocarcinoma/radioterapia , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Prostatectomia , Neoplasias da Próstata/radioterapia , Radioterapia Adjuvante , Terapia de Salvação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Austrália , Intervalo Livre de Doença , Humanos , Masculino , Invasividade Neoplásica , Nova Zelândia , Antígeno Prostático Específico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Medição de Risco , Terapia de Salvação/métodos , Fatores de Tempo , Resultado do TratamentoRESUMO
The Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, and other (LGBTQI+) community continues to experience health inequity and unmet needs. This manuscript examines the application of the Four Tenets of Osteopathic Medicine (FTOM) during a patient's self-disclosure of their sexual orientation and/or gender identity to the provider, also known as coming out. Tenet One discusses the interplay between intersectionality and coming out. Tenet Two elucidates how coming out moves toward a balance of homeostasis and self-healing. Tenet Three examines how structure and function can be understood on a personal level and how society influences coming out. Tenet Four explains the resources available to facilitate the previously forementioned changes. By applying the Four Tenets, the provider may more readily understand what "coming out" means on personal and social levels and what implications they may have on their patients' health.
Assuntos
Enquadramento Interseccional , Medicina Osteopática , Revelação , Feminino , Identidade de Gênero , Desigualdades de Saúde , Humanos , Masculino , Comportamento SexualRESUMO
Transcription factor GATA-1 reprograms immature myeloid cells to three different hematopoietic lineages-erythroid cells, megakaryocytes, and eosinophils. GATA-1 is essential for maturation of erythroid and megakaryocytic precursors, as revealed by gene targeting in mice. Here we demonstrate that deletion of a high-affinity GATA-binding site in the GATA-1 promoter, an element presumed to mediate positive autoregulation of GATA-1 expression, leads to selective loss of the eosinophil lineage. These findings suggest that GATA-1 is required for specification of this lineage during hematopoietic development. Mice lacking the ability to produce eosinophils should prove useful in ascertaining the role of eosinophils in a variety of inflammatory or allergic disorders.
Assuntos
Linhagem da Célula , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Eosinófilos/citologia , Regiões Promotoras Genéticas/genética , Elementos de Resposta/genética , Deleção de Sequência , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Diferenciação Celular , Eosinófilos/metabolismo , Fatores de Ligação de DNA Eritroide Específicos , Eritropoese/genética , Fator de Transcrição GATA1 , Regulação da Expressão Gênica , Interleucina-5/genética , Interleucina-5/metabolismo , Leucopoese/genética , Masculino , Mastócitos/citologia , Mastócitos/metabolismo , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
In vitro differentiation of human embryonic stem cells (hESCs) into pure human cardiomyocytes (hESCMs) would present a powerful tool to further the creation of cell models designed to advance preclinical drug development. Here, we report a novel differentiation method to substantially increase hESCM yield. Upon early and transient treatment of hESCs with Wnt3a, embryoid body and mesendoderm formation is enhanced, leading to greater differentiation toward cardiomyocytes. Moreover, the generated beating clusters are highly enriched with cardiomyocytes (50%) and express genes characteristic of cardiac cells, providing evidence that these hESCMs are competent to develop in vitro into functional and physiologically relevant cardiomyocytes. In summary, this protocol not only has the potential to guarantee a renewable supply of enriched cardiomyocyte populations for developing novel and more predictive cell models, but it also should provide valuable insights into pathways critical for cardiac regeneration.
Assuntos
Células-Tronco Embrionárias/citologia , Miócitos Cardíacos/citologia , Engenharia Tecidual/métodos , Proteínas Wnt/farmacologia , Animais , Comunicação Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Humanos , Insulina/farmacologia , Mesoderma/citologia , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas Recombinantes/farmacologia , Proteína Wnt3 , Proteína Wnt3ARESUMO
INTRODUCTION: Variation in target volume delineation from clinical trial protocols has been shown to contribute to poorer patient outcomes. A clinical trial quality assurance framework can support compliance with trial protocol. Results of the TROG 08.03 RAVES benchmarking exercise considering variation from protocol, inter-observer variability and impact on dosimetry are reported in this paper. METHODS: Clinicians were required to contour and plan a benchmarking case according to trial protocol. Geometric pjmirometers including volume, Hausdorff Distance, Mean Distance to Agreement and DICE similarity coefficient were analysed for targets and organs at risk. Submitted volumes were compared to a STAPLE and consensus 'reference' volume for each structure. Dosimetric analysis was performed using dose volume histogram data. RESULTS: Benchmarking exercise submissions were received from 96 clinicians. In total 205 protocol variations were identified. The most common variation was inadequate contouring of the CTV in 84/205 (41%). The CTV volume ranged from 65.3 to 193.1 cm3 with a median of 113.2 cm3 . The most common dosimetric protocol variation related to rectal dosimetry. The mean submitted rectal volume receiving 40 Gy and 60 Gy, respectively, was 56.14% ± 5.55% and 30.25% ± 6.15%. When corrected to the protocol defined length the mean rectal volume receiving 40 Gy was 60.8% ± 7.92%, while the volume receiving 60 Gy was 33.86% ± 8.21%. CONCLUSION: Variations from protocol were found in the RAVES benchmarking exercise, most notably in CTV and rectum delineation. Inter-observer variability was evident. Incorrect delineation of the rectum impacted on dosimetric compliance with protocol.
Assuntos
Erros Médicos/prevenção & controle , Planejamento de Assistência ao Paciente/normas , Neoplasias da Próstata/radioterapia , Garantia da Qualidade dos Cuidados de Saúde , Planejamento da Radioterapia Assistida por Computador/normas , Austrália , Benchmarking , Fidelidade a Diretrizes , Humanos , Masculino , Nova Zelândia , Variações Dependentes do Observador , Órgãos em Risco , Prostatectomia , Neoplasias da Próstata/cirurgia , Dosagem Radioterapêutica , Radioterapia Adjuvante , Terapia de Salvação , Tomografia Computadorizada por Raios X , Carga TumoralRESUMO
PURPOSE: To explore site- and clinician-level factors associated with protocol violations requiring real-time-review (RTR) resubmission in a multicenter clinical trial to help tailor future quality assurance (QA) protocols. METHODS AND MATERIALS: RAVES (Radiation Therapy-Adjuvant vs Early Salvage) (Trans-Tasman Radiation Oncology Group 08.03) is a randomized trial comparing adjuvant with early salvage radiation therapy in men with positive surgical margins or pT3 disease after prostatectomy. Quality assurance in RAVES required each clinician and site to submit a credentialing dummy run (DR) and for each patient's radiation therapy plan to undergo external RTR before treatment. Prospectively defined major violations from trial protocol required remedy and resubmission. Site and clinician factors associated with RTR resubmission were examined using hierarchical modeling. RESULTS: Data were collected from 171 consecutive patients, treated by 46 clinicians at 32 hospitals. There were 47 RTR resubmissions (27%) due to 65 major violations. The relative rate of resubmission decreased by 29% per year as the study progressed (odds ratio OR. 0.71, P=.02). The majority of resubmissions were due to contouring violations (39 of 65) and dosimetric violations (22 of 65). For each additional patient accrued, significant decreases in RTR resubmission were seen at both clinician level (OR 0.75, P=.02) and site level (OR 0.72, P=.01). The rate of resubmission due to dosimetric violations was only 1.6% after the first 5 patients. Use of IMRT was associated with lower rates of resubmission compared with 3-dimensional conformal radiation therapy (OR 0.38, P=.05). CONCLUSION: Several low- and high-risk factors that may assist with tailoring future clinical trial QA were identified. Because the real-time resubmission rate was largely independent of the credentialing exercise, some form of RTR QA is recommended. The greatest benefit from QA was derived early in trial activation and clinician experience.
Assuntos
Protocolos Clínicos/normas , Neoplasias da Próstata/radioterapia , Garantia da Qualidade dos Cuidados de Saúde , Erros de Configuração em Radioterapia/estatística & dados numéricos , Radioterapia Conformacional/estatística & dados numéricos , Terapia de Salvação/métodos , Benchmarking , Estudos de Viabilidade , Humanos , Masculino , Seleção de Pacientes , Prostatectomia/métodos , Neoplasias da Próstata/diagnóstico por imagem , Garantia da Qualidade dos Cuidados de Saúde/estatística & dados numéricos , Radiografia , Dosagem Radioterapêutica , Radioterapia Adjuvante/métodos , Radioterapia Adjuvante/normas , Radioterapia Adjuvante/estatística & dados numéricos , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/métodos , Radioterapia de Intensidade Modulada/estatística & dados numéricos , Terapia de Salvação/normas , Terapia de Salvação/estatística & dados numéricosRESUMO
PURPOSE: To assess the impact of domicile-based humidification on symptom burden during radiation therapy (RT) for head-and-neck (H&N) cancer. METHODS AND MATERIALS: From June 2007 through June 2011, 210 patients with H&N cancer receiving RT were randomized to either a control arm or to receive humidification using the Fisher & Paykel Healthcare MR880 humidifier. Humidification commenced on day 1 of RT and continued until Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, clinical mucositis (CMuc) grade ≤1 occurred. Forty-three patients (42%) met a defined benchmark for humidification compliance and contributed to per protocol (PP) analysis. Acute toxicities, hospitalizations, and feeding tube events were recorded prospectively. The McMaster University Head and Neck Radiotherapy Questionnaire (HNRQ) was used for patient-reported outcomes. The primary endpoint was area under the curve (AUC) for CMuc grade ≥2. RESULTS: There were no significant differences in AUC for CMuc ≥2 between the 2 arms. Humidification patients had significantly fewer days in hospital (P=.017). In compliant PP patients, the AUC for CTCAE functional mucositis score (FMuc) ≥2 was significantly reduced (P=.009), and the proportion who never required a feeding tube was significantly greater (P=.04). HNRQ PP analysis estimates also in the direction favoring humidification with less symptom severity, although differences at most time points did not reach significance. CONCLUSIONS: TROG 07.03 has provided efficacy signals consistent with a role for humidification in reducing symptom burden from mucositis, but the influence of humidification compliance on the results moderates recommendations regarding its practical utility.