Search

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.

Background We examined incidence and survival in relation to age, gender, socioeconomic deprivation, rurality and trends over time. We also examined the association between volume of patients treated by hospitals and survival. Methods Incident cases (2001–12) were identified using comprehensive National Health Service admissions data for England, with follow-up to March 2013. Socioeconomic deprivation was based on census area of residence. Volume was assessed in a three-year subset of the data with consistent hospital provider codes. Results There were 2921 adults aged 18 or more years diagnosed with acute lymphoblastic leukaemia (ALL) in the 12-year time span, giving a crude annual incidence of 0.61/100,000 population. Five-year survival was 32% (1870 deaths). Compared with patients living in least deprived areas, survival was worse for patients living in intermediate and most deprived areas, with mortality hazard ratios 21% (95% CI 8–35%) and 16% (95% CI 3–30%) higher respectively. Hospitals treating low volumes of adults with ALL were associated with poorer survival. The adjusted mortality hazard ratio in this subset of 465 patients was 33% (95% CI 3–73%) higher in low volume hospitals. There was no evidence of association between socioeconomic deprivation and incidence. Rurality did not appear to be associated with incidence or survival. Incidence was higher in men but there was no evidence of a gender difference in survival. Survival improved over time. Conclusion The associations between socioeconomic deprivation and survival and between volume and outcome for adults with ALL, if confirmed, are likely to have significant implications for the organisation of services for adults with ALL.

In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukaemia (CLL) patients. The UK CLL Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year (Discontinuation Free Survival; DFS) and 1 year overall survival (OS). With a median 16 months follow-up, data on 315 patients demonstrated 1 year DFS of 73.7% and 1 year OS of 83.8%. Patients with better pre-treatment performance status (PS 0/1 vs 2+) had superior DFS (77.5% vs 61.3%;p14 days and had OS of 89.7%, while 26% of patients had dose reductions and 13% had temporary treatment breaks >14 days. We could not demonstrate a detrimental effect of dose reductions alone (1 year OS: 91.7%), but patients who had first year treatment breaks > 14 days, particularly permanent cessation of ibrutinib had both reduced 1 year OS (68.5%) and also a statistically significant excess mortality rate beyond one year. Although outcomes appear inferior to the RESONATE trial (1 year OS;90%: PFS;84%), this may partly reflect the inclusion of PS 2+ patients and that 17.5% of patients permanently discontinued ibrutinib due to an event other than disease progression.

Why does Thucydides currently occupy such an important position as one of the (very few) great classical thinkers about international politics? He has not always enjoyed this prominence. Indeed, during some periods in the history of the academic study of international relations, one could even say that Thucydides was actually neglected in favor of other voices from the past. This chapter argues that one of the stimuli for the modern turn to Thucydides was the experience of total war: Thucydides’ History has always been seen as one of the great books for understanding what it is to live in a time of terrible conflict. The chapter goes on to suggest that a key moment in this process was Arnold Toynbee's experience of the contemporaneity of Thucydides during World War I. Toynbee wove his reading of Thucydides’ History into his theories about the lifecycles of civilizations and the dynamics of power politics. After World War II, this exercised a profound influence on some of the makers of early Cold War US foreign policy, such as Louis J. Halle, and on realist theorists such as Robert Gilpin, Kenneth Thompson, Kenneth Waltz, and Martin Wight.

Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma.The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090.Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted.In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile.Janssen ResearchDevelopment.

Remote sensing and inverse modelling studies indicate that the tropics emit more CH4 and N2O than predicted by bottom-up emissions inventories, suggesting that terrestrial sources are stronger or more numerous than previously thought. Tropical uplands are a potentially large and important source of CH4 and N2O often overlooked by past empirical and modelling studies. To address this knowledge gap, we investigated spatial, temporal and environmental trends in soil CH4 and N2O fluxes across a long elevation gradient (600–3700 m a.s.l.) in the Kosñipata Valley, in the southern Peruvian Andes, that experiences seasonal fluctuations in rainfall. The aim of this work was to produce preliminary estimates of soil CH4 and N2O fluxes from representative habitats within this region, and to identify the proximate controls on soil CH4 and N2O dynamics. Area-weighted flux calculations indicated that ecosystems across this altitudinal gradient were both atmospheric sources and sinks of CH4 on an annual basis. Montane grasslands (3200–3700 m a.s.l.) were strong atmospheric sources, emitting 56.94 ± 7.81 kg CH4-C ha−1 yr−1. Upper montane forest (2200–3200 m a.s.l.) and lower montane forest (1200–2200 m a.s.l.) were net atmospheric sinks (−2.99 ± 0.29 and −2.34 ± 0.29 kg CH4-C ha−1 yr−1, respectively); while premontane forests (600–1200 m a.s.l.) fluctuated between source or sink depending on the season (wet season: 1.86 ± 1.50 kg CH4-C ha−1 yr−1; dry season: −1.17 ± 0.40 kg CH4-C ha−1 yr−1). Analysis of spatial, temporal and environmental trends in soil CH4 flux across the study site suggest that soil redox was a dominant control on net soil CH4 flux. Soil CH4 emissions were greatest from habitats, landforms and during times of year when soils were suboxic, and soil CH4 efflux was inversely correlated with soil O2 concentration (Spearman's ρ = −0.45, P < 0.0001) and positively correlated with water-filled pore space (Spearman's ρ = 0.63, P