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Background: Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell malignancies. This phase 2 study (CITADEL-203; NCT03126019, EudraCT 2017-001624-22) assessed efficacy and safety of parsaclisib monotherapy in patients with R/R follicular lymphoma (FL). Methods: Patients ≥18 years of age with histologically confirmed R/R FL (grade 1-3a) and prior treatment with ≥2 systemic therapies received parsaclisib 20 mg once daily (QD) for 8 weeks then parsaclisib 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg QD for 8 weeks then parsaclisib 2.5 mg QD (daily dosing group [DG]); DG was selected for further assessment. Primary endpoint was objective response rate (ORR). Findings: At data cut-off (January 15, 2021), 126 patients had been treated (WG: n = 23; DG: n = 103). ORR (95% confidence interval [CI]) was 77.7% (68.4-85.3) with a complete response rate (95% CI) of 19.4% (12.3-28.4) in DG; median (95% CI) duration of response was 14.7 months (10.4-not estimable [NE]), median progression-free survival was 15.8 months (11.0-NE), and median overall survival was not reached. The most common any-grade treatment-emergent adverse events (TEAEs) among all treated patients included diarrhoea (n = 48, 38.1%), nausea (n = 31, 24.6%), and cough (n = 28, 22.2%); the most common grade ≥3 TEAEs were diarrhoea (n = 15, 11.9%), neutropenia (n = 13, 10.3%), and colitis (n = 7, 5.6%). Dose interruption, reduction, and discontinuation from TEAEs occurred in 46.8% (n = 59), 17.5% (n = 22), and 23.8% (n = 30) of patients, respectively. Interpretation: Treatment with parsaclisib demonstrated rapid and durable responses, and a manageable safety profile in patients with R/R FL. Funding: Incyte Corporation.
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BACKGROUND: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival. METHODS: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m2 on day 1 of cycle 1 and at 500 mg/m2 on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m2 per day orally on day 1-5, cyclophosphamide 150 mg/m2 per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete. FINDINGS: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32-0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group. INTERPRETATION: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder. FUNDING: Cancer Research UK and Janssen.
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Leucemia Linfocítica Crônica de Células B , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Rituximab , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Medicina Estatal , Ciclofosfamida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Polymer-borne leachables such as formaldehyde, acetaldehyde, and N-3-(Dimethylamino)propyl)methacrylamide (DMAPMA) may interact with therapeutic proteins. In this study, the leachables were spiked into human derived coagulation factor IX (FIX) at concentrations of 1, 10, 50, 100, and 500 µg/mL, corresponding to a leachable - FIX ratio of 0.5, 5, 25, 50 and 250 %, respectively. The spiked samples were visually inspected, and pH was measured. No visual effects were observed, and pH was within the drug product's specified range. Recovery experiments were performed and no loss of leachables was identified. Protein structure analysis revealed that formaldehyde reacted with lysine contained in two different positions of FIX, in a concentration-dependent manner starting at 10 µg/mL (5 %). The clotting activity of FIX was measured. The activity of the samples spiked with 500 µg/mL (250 %) of formaldehyde dropped by more than half. The activity of the samples spiked with acetaldehyde began to drop at 50 µg/mL (25 %) and continued to decline in concentration-dependent manner. DMAPMA did not impair the activity of FIX. The findings conclude that depending on the concentration, some leachables may react with or modify therapeutic proteins, potentially causing an undesired pharmacological effect however, this is specific to each protein.
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Acetaldeído , Fator IX , Humanos , Proteínas , FormaldeídoRESUMO
This open-label, multicenter, single-arm, phase 2 study assessed the safety and efficacy of blinatumomab consolidation therapy in adult patients with newly diagnosed, high-risk diffuse large B-cell lymphoma (DLBCL; International Prognostic Index 3-5 and/or double-/triple-hit or double MYC/BCL-2 expressors) who achieved complete response (CR), partial response (PR), or stable disease (SD) following run-in with 6 cycles of R-chemotherapy (NCT03023878). Of the 47 patients enrolled, 28 received blinatumomab. Five patients (17.9%) experienced grade 4 treatment-emergent adverse events of interest (neutropenia, n = 4; infection, n = 1). Two deaths reported at the end of the study were unrelated to treatment with blinatumomab (disease progression, n = 1; infection, n = 1). 3/4 patients with PR and 4/4 patients with SD after R-chemotherapy achieved CR following blinatumomab. Consolidation with blinatumomab in patients with newly diagnosed, high-risk DLBCL who did not progress under R-chemotherapy was better tolerated than in previous studies where blinatumomab was used for treatment of patients with lymphoma.
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Anticorpos Biespecíficos , Linfoma Difuso de Grandes Células B , Adulto , Anticorpos Biespecíficos/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2 , Indução de RemissãoRESUMO
BACKGROUND: The outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population. METHODS: This was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25-65 years (BCR-ABL1-negative) or 18-65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA; intravenous fludarabine 30 mg/m2 on days -6 to -2, melphalan 140 mg/m2 on day -2, and alemtuzumab 30 mg on day -1 [sibling donor] and days -2 and -1 [unrelated donor]) before allogeneic HSCT (aged ≥41 years patient pathway). Donor lymphocyte infusions were given from 6 months for mixed chimerism or MRD. The primary endpoint was event-free survival and secondary and transplantation-specific endpoints included overall survival, relapse incidence, TRM, and acute and chronic graft-versus-host disease (GVHD). This study is registered with ClinicalTrials.gov, NCT01085617. FINDINGS: From Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36-70), 4-year event-free survival was 46·8% (95% CI 40·1-53·2) and 4-year overall survival was 54·8% (48·0-61·2). 4-year cumulative incidence of relapse was 33·6% (27·9-40·2) and 4-year TRM was 19·6% (15·1-25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2-4 occurred in 29 (12%) of 247 patients and grade 3-4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 [22%] had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 [95% CI 1·46-3·93]) and time-to-relapse (HR 2·41 [1·29-4·48]). INTERPRETATION: FMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes. FUNDING: Cancer Research UK.
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Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Herpesvirus Humano 4 , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Prospectivos , Linfócitos T , Doadores não RelacionadosRESUMO
A 30-year-old man was admitted to Intensive Therapy Unit (ITU) with status epilepticus secondary to severe hypoglycaemia on a background of type 1 diabetes. CT of the brain showed generalised cerebral oedema. He was successfully stepped down to a medical ward after 2 weeks. He was noted to have persistently high calcium, which required multiple doses of pamidronate. Parathyroid hormone level was appropriately low. CT of the thorax, abdomen and pelvis showed mild hepatosplenomegaly with small pathological lymph nodes throughout the abdomen. Bone marrow biopsy was unremarkable. Lymph node biopsy was difficult to achieve, and therefore a positron emission tomography scan was arranged. This showed an enlarged and hypermetabolic spleen. Differential diagnoses at this point included lymphoma and sarcoidosis. He underwent diagnostic splenectomy, and the diagnosis of sarcoidosis was confirmed histologically. Calcium level remained normal 17 months after splenectomy.
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Diabetes Mellitus Tipo 1 , Hipercalcemia , Sarcoidose , Esplenopatias , Adulto , Diabetes Mellitus Tipo 1/complicações , Humanos , Hipercalcemia/etiologia , Masculino , Pamidronato , Sarcoidose/complicações , Sarcoidose/diagnóstico , Esplenopatias/complicações , Esplenopatias/diagnóstico por imagemRESUMO
Current international guidelines recommend routinely vaccinating haematopoetic stem cell transplant (HSCT) recipients. Despite significant infection-related mortality following autologous HSCT, routine vaccination programmes (RVP) completion is poor. For recovered HSCT recipients, it is uncertain whether catch-up vaccination remains worthwhile years later. To determine potential susceptibility to vaccine preventable infections, we measured antibody titres in 56 patients, a median of 7â¯years (range 0-29) following autologous HSCT, who had not completed RVP. We found that almost all participants had inadequate titres against diphtheria (98.2%) and pneumococcal infection (100%), and a significant proportion had inadequate titres against measles (34.5%). Of those subsequently vaccinated according to available guidelines, many mounted adequate serological responses. These data suggest a pragmatic catch-up approach for autologous HSCT recipients who have not completed RVP is advisable, with universal vaccination against some pathogens (e.g. Streptococcus pneumoniae and diphtheria) and serologically-guided approaches for others (e.g. measles and varicella zoster virus).
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Transplante de Células-Tronco Hematopoéticas , Doenças Preveníveis por Vacina , Humanos , Imunidade Humoral , Vacina contra Sarampo-Caxumba-Rubéola , Sobreviventes , VacinaçãoRESUMO
The phase 2 portion of this open-label phase 2/3 study assessed the efficacy and safety of blinatumomab as second salvage for aggressive relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) following platinum-based first salvage chemotherapy. Forty-one patients with aggressive disease (32% relapsed; 68% refractory) enrolled and received stepwise blinatumomab (9-28-112 µg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46%) completed cycle 1 and 3 (7%) completed cycle 2. The overall response rate after 12 weeks was 37%, including 9 (22%) complete metabolic responses. Eight (20%) patients (all responders) subsequently received stem cell transplants. Grade ≥3 adverse events were reported in 29 (71%) patients. Grade 3 cytokine release syndrome occurred in one patient. Grade 3 neurologic events occurred in 10 (24%) patients; all resolved. Blinatumomab monotherapy appears effective as second salvage therapy in patients with r/r aggressive B-NHL. Trial registration: NCT02910063.
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Linfoma não Hodgkin , Terapia de Salvação , Adulto , Anticorpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Linfócitos B , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Recidiva Local de NeoplasiaRESUMO
INTRODUCTION: The major aim of this study was to test whether abstinence from e-cigarettes causes withdrawal symptoms in former smokers. METHODS: We conducted an unblinded, within-participants, pre-post clinical trial in which 109 former smokers who were current daily electronic cigarette (e-cigarette) users used their own e-cigarette for 7 days followed by 6 days of biologically confirmed abstinence engendered via an escalating contingency payment system. Participants monitored symptoms of nicotine withdrawal daily via an Interactive Voice Response system. They also attended three laboratory visits per week for carbon monoxide and cotinine testing to verify abstinence. RESULTS: Half of participants completely abstained for a week. All the Diagnostic and Statistical Manual, Fifth Edition (DSM-5) tobacco withdrawal symptoms, craving for e-cigarettes, craving for tobacco cigarettes, and the four possible new withdrawal symptoms (anhedonia, impulsivity, mood swings, and positive affect) increased during abstinence. Weight increased and heart rate decreased with abstinence. Symptoms showed the prototypical inverted U time pattern of a withdrawal state. The magnitude of withdrawal appeared to be somewhat less than that in a prior study of abstinent daily tobacco cigarette smokers. More severe withdrawal on the first 2 days of abstinence did not predict abstinence on the last day of the study. CONCLUSIONS: Former smokers who are daily e-cigarette users transfer physical dependence on tobacco cigarettes to dependence on e-cigarettes. The severity of withdrawal from e-cigarettes appears to be only somewhat less than that from daily tobacco cigarette use. Replication tests that include placebo controls, testing for pharmacological specificity, and including never-smokers, non-daily e-cigarette users and dual users are indicated. IMPLICATIONS: Our results indicate e-cigarettes can maintain physical dependence. This adverse effect should be included in any risk vs. benefit calculation. Also, potential and current e-cigarette users should be informed that abrupt cessation of e-cigarettes can cause withdrawal symptoms. TRIAL REGISTRATION: NCT02825459.
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Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Comportamentos Relacionados com a Saúde , Fumantes/psicologia , Abandono do Hábito de Fumar/métodos , Síndrome de Abstinência a Substâncias/epidemiologia , Vaping/epidemiologia , Adolescente , Adulto , Idoso , Monóxido de Carbono/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/prevenção & controle , Estados Unidos/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Use of e-cigarettes among never-smokers has substantially increased; yet there are few descriptions of the consequences of such use. We assessed whether adult never-smokers can have withdrawal from cessation of e-cigarettes. METHODS: In an un-blinded pre-post clinical trial, 30 never-smoker daily e-cigarette users used their own nicotine-containing e-cigarette for 7 days followed by 6 days of biologically confirmed abstinence. Participants monitored symptoms of nicotine withdrawal nightly via an Interactive Voice Response system. They attended three lab visits/week to provide expired carbon monoxide and urine samples to determine compliance. FINDINGS: Abstinence increased all the DSM5 symptoms of tobacco withdrawal and this occurred in the majority of participants. The increase in severity of withdrawal was small and rarely impaired functioning. CONCLUSIONS: Our finding suggests that withdrawal symptoms can occur in never-smokers who stop e-cigarettes abruptly. However, the severity of withdrawal appears to be small and may not be of clinical or regulatory significance. Although our sample size was small and thus replication tests of our results are indicated, it may be prudent to warn never-smokers that withdrawal symptoms may occur. IMPLICATIONS: This study indicates that withdrawal symptoms can occur in never-smokers who are daily e-cigarette users. However, the severity of withdrawal from e-cigarette abstinence in never-smokers appears to be small and may not be of clinical or regulatory significance. Given our small sample size, replication of our results is warranted. Nevertheless, it might be prudent to warn never-smokers of addiction to e-cigarettes.Clinical Trial Registration = NCT02825459.
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Comportamento Aditivo , Sistemas Eletrônicos de Liberação de Nicotina/estatística & dados numéricos , Comportamentos Relacionados com a Saúde , Fumantes/psicologia , Abandono do Hábito de Fumar/métodos , Síndrome de Abstinência a Substâncias/epidemiologia , Adulto , Monóxido de Carbono/análise , Feminino , Humanos , Masculino , Projetos Piloto , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Primary lymphoproliferative disorders of the uterus are rare, with the majority being B-cell diseases or aggressive T-cell disease. We present the case of a 31-yr old in whom an Indolent T-cell lymphoproliferative disorder (iTCLPD) was identified in resection chippings for a suspected fibroid, following presentation with menorrhagia. Laboratory investigations revealed an oligoclonal T-cell infiltrate with the immunophenotype of nonactivated cytotoxic T cells, and a proliferative fraction of 10% to 15%. There was no clinical or radiologic evidence of systemic disease, and the patient remained well with no indication of relapse 1 yr from resection and diagnosis. iTCLPD of the uterine corpus has features in common with the recently described iTCLPD of the gastrointestinal tract and primary cutaneous acral CD8 T-cell lymphoma. Recognition of these parallels is important as few other cases of iTCLPD have been described, and it suggests local resection rather than systemic treatment as the best therapeutic strategy.
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Transtornos Linfoproliferativos/diagnóstico , Adulto , Feminino , Humanos , Imunofenotipagem , Transtornos Linfoproliferativos/patologia , Linfócitos T/patologia , Útero/patologiaRESUMO
BACKGROUND AND AIMS: The United States Food and Drug Administration has proposed regulation to require that cigarettes contain very low nicotine content (VLNC). In contrast, reducing the number of cigarettes per day (CPD) is the most common current method to reduce nicotine. This trial aims to explore whether gradually transitioning to VLNC cigarettes plus nicotine patch or reducing CPD plus nicotine patch is more effective at decreasing nicotine dependence. DESIGN: A two-arm, individually randomized open-label trial. SETTING: Community setting, Vermont, USA. PARTICIPANTS: Sixty-eight adult daily smokers (40% female) of ≥ 10 cigarettes/day who were not planning to quit in the next 30 days. INTERVENTIONS: All participants smoked study cigarettes with a nicotine yield similar to most commercial cigarettes ad libitum for 1 week (baseline). Participants then gradually reduced to 70, 35, 15 and 3% of baseline nicotine over 4 weeks by either (a) transitioning to lower nicotine content cigarettes (n = 36) or (b) reducing the number of full nicotine cigarettes (n = 32). All participants received nicotine patches. MEASUREMENTS: The primary outcome was change in nicotine dependence assessed at baseline and weekly during the intervention with the Nicotine Dependence Syndrome Scale. FINDINGS: Dependence declined over time for both VLNC and CPD participants, but declined more for VLNC (mean decrease in Z-score of 1.0) than CPD (mean decrease in Z-score of 0.5) participants over time (interaction P = 0.018). CONCLUSIONS: Transitioning to very low nicotine content cigarettes reduced nicotine dependence over a 4-week period to a greater extent than reducing cigarettes per day when both conditions were aided by nicotine patch.
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Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Redução do Consumo de Tabaco/métodos , Produtos do Tabaco , Dispositivos para o Abandono do Uso de Tabaco , Tabagismo/terapia , Adulto , Fumar Cigarros , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Abandono do Hábito de FumarRESUMO
BACKGROUND: Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. METHODS: We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0-3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic γδ T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1-5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1-5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of-treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). FINDINGS: Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27·4 months (IQR 16·6-38·4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0·52, 95% CI 0·21-1·31; p=0·164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. INTERPRETATION: The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. FUNDING: Bloodwise and the UK National Institute of Health Research.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Linfoma de Células T Periférico/tratamento farmacológico , Metilprednisolona/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Células T Periférico/diagnóstico por imagem , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Vincristina/efeitos adversos , Vincristina/uso terapêutico , GencitabinaAssuntos
Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Software , Nódulo Pulmonar Solitário/diagnóstico por imagem , Nódulo Pulmonar Solitário/fisiopatologia , Humanos , Invenções , Masculino , Pessoa de Meia-IdadeRESUMO
The increase in atmospheric nitrous oxide (N2O), a potent greenhouse and ozone depleting gas, is of serious global concern. Soils are large contributors to this increase through microbial processes that are enhanced in agricultural land due to nitrogenous fertilizer applications. Denitrification, a respiratory process using nitrogen oxides as electron acceptors in the absence of oxygen, is the main source of N2O. The end product of denitrification is benign dinitrogen (N2) and understanding what regulates the shift in ratio of N2O and N2 emission is crucial for mitigation strategies. The role of organic carbon in controlling N2O reduction is poorly understood, and mostly based on application of glucose. Here we investigated how a range of carbon compounds (succinate, butyrate, malic acid, acetate, glucose, sucrose and cysteine) affect denitrifier N2/N2O production stoichiometry under laboratory conditions. The results show that a soil's capability in efficiently reducing N2O to N2 is C substrate dependent and most compounds tested were different in regards to this efficiency compared to glucose. We challenge the concept of using glucose as a model soil C compound in furthering our understanding of denitrification and specifically the efficiency in the N2O reductase enzyme. Organic acids, commonly exuded by roots, increased N2/N2O ratios compared to glucose, and therefore mitigated net N2O release and we suggest provides better insights into soil regulatory aspects of N2O reduction. The widespread use of glucose in soil laboratory studies could lead to misleading knowledge on the functioning of denitrification in soils with regards to N2O reduction.
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Desnitrificação , Nitrogênio/análise , Óxido Nitroso/análise , Solo/químicaRESUMO
In this chapter, we review different imaging modalities, including radiography, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and nuclear medicine scintigraphy, and their application to musculoskeletal neoplasm. Advantages and limitations of each modality are reviewed, and suggestions for imaging approach are provided.
Assuntos
Neoplasias Musculares/diagnóstico , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Cistos Ósseos/diagnóstico , Condrossarcoma/diagnóstico , Diagnóstico por Imagem/métodos , Fibroma/diagnóstico , Displasia Fibrosa Óssea/diagnóstico , Humanos , Linfoma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Neoplasias Musculares/diagnóstico por imagem , Neoplasias Musculares/patologia , Osteoma/diagnóstico , Osteossarcoma/diagnóstico , Radiografia/métodos , Cintilografia/métodos , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal TotalRESUMO
Enteric duplication cysts are rare congenital anomalies that may occur anywhere along the gastrointestinal tract, most commonly involving the small bowel. The distal ileum, jejunum, and duodenum are affected in descending order of frequency. We describe a case of biliary dilatation and duodenal intussusception caused by an enteric duplication cyst in an adult patient. To our knowledge, there are no other reported cases of this entity in an adult in the English literature. Multidetector computed tomography (MDCT) findings are emphasized, and the value of multiplanar reformation (MPR) in forming a correct preoperative differential diagnosis is discussed.