Description: Publication date: Available online 24 December 2014 Source: The Lancet Author(s): Ashwin N Ananthakrishnan

Description: Publication date: Available online 23 December 2014 Source: The Lancet Author(s): Dara Mohammadi

Description: Publication date: Available online 24 December 2014 Source: The Lancet Author(s): Peter De Cruz , Michael A Kamm , Amy L Hamilton , Kathryn J Ritchie , Efrosinia O Krejany , Alexandra Gorelik , Danny Liew , Lani Prideaux , Ian C Lawrance , Jane M Andrews , Peter A Bampton , Peter R Gibson , Miles Sparrow , Rupert W Leong , Timothy H Florin , Richard B Gearry , Graham Radford-Smith , Finlay A Macrae , Henry Debinski , Warwick Selby , Ian Kronborg , Michael J Johnston , Rodney Woods , P Ross Elliott , Sally J Bell , Steven J Brown , William R Connell , Paul V Desmond Background Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. Methods In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT00989560 . Findings Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0·03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0·03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2·4, 95% CI 1·2–4·8, p=0·02) and the presence of two or more clinical risk factors including smoking (OR 2·8, 95% CI 1·01–7·7, p=0·05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0·51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0·36), respectively. Interpretation Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. Funding AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.

Description: Publication date: Available online 22 December 2014 Source: The Lancet Author(s): Nayanah Siva

Description: Publication date: Available online 23 December 2014 Source: The Lancet Author(s): Christoph Röllig , Stefan Knop , Martin Bornhäuser Multiple myeloma is a malignant disease characterised by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the serum or urine. Increased understanding of the microenvironmental interactions between malignant plasma cells and the bone marrow niche, and their role in disease progression and acquisition of therapy resistance, has helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Together with autologous stem cell transplantation and advances in supportive care, the use of novel drugs such as proteasome inhibitors and immunomodulatory drugs has increased response rates and survival substantially in the past several years. Present clinical research focuses on the balance between treatment efficacy and quality of life, the optimum sequencing of treatment options, the question of long-term remission and potential cure by multimodal treatment, the pre-emptive treatment of high-risk smouldering myeloma, and the role of maintenance. Upcoming results of ongoing clinical trials, together with a pipeline of promising new treatments, raise the hope for continuous improvements in the prognosis of patients with myeloma in the future.

Description: Publication date: Available online 23 December 2014 Source: The Lancet Author(s): Hannah Kibuuka , Nina M Berkowitz , Monica Millard , Mary E Enama , Allan Tindikahwa , Arthur B Sekiziyivu , Pamela Costner , Sandra Sitar , Deline Glover , Zonghui Hu , Gyan Joshi , Daphne Stanley , Meghan Kunchai , Leigh Anne Eller , Robert T Bailer , Richard A Koup , Gary J Nabel , John R Mascola , Nancy J Sullivan , Barney S Graham , Mario Roederer , Nelson L Michael , Merlin L Robb , Julie E Ledgerwood Background Ebola virus and Marburg virus cause serious disease outbreaks with high case fatality rates. We aimed to assess the safety and immunogenicity of two investigational DNA vaccines, one (EBO vaccine) encoding Ebola virus Zaire and Sudan glycoproteins and one (MAR) encoding Marburg virus glycoprotein. Methods RV 247 was a phase 1b, double-blinded, randomised, placebo-controlled clinical trial in Kampala, Uganda to examine the safety and immunogenicity of the EBO and MAR vaccines given individually and concomitantly. Healthy adult volunteers aged 18–50 years were randomly assigned (5:1) to receive three injections of vaccine or placebo at weeks 0, 4, and 8, with vaccine allocations divided equally between three active vaccine groups: EBO vaccine only, MAR vaccine only, and both vaccines. The primary study objective was to investigate the safety and tolerability of the vaccines, as assessed by local and systemic reactogenicity and adverse events. We also assessed immunogenicity on the basis of antibody responses (ELISA) and T-cell responses (ELISpot and intracellular cytokine staining assays) 4 weeks after the third injection. Participants and investigators were masked to group assignment. Analysis was based on the intention-to-treat principle. This trial is registered at ClinicalTrials.gov , number NCT00997607 . Findings 108 participants were enrolled into the study between Nov 2, 2009, and April 15, 2010. All 108 participants received at least one study injection (including 100 who completed the injection schedule) and were included in safety and tolerability analyses; 107 for whom data were available were included in the immunogenicity analyses. Study injections were well tolerated, with no significant differences in local or systemic reactions between groups. The vaccines elicited antibody and T-cell responses specific to the glycoproteins received and we detected no differences between the separate and concomitant use of the two vaccines. 17 of 30 (57%, 95% CI 37–75) participants in the EBO vaccine group had an antibody response to the Ebola Zaire glycoprotein, as did 14 of 30 (47%, 28–66) in the group that received both vaccines. 15 of 30 (50%, 31–69) participants in the EBO vaccine group had an antibody response to the Ebola Sudan glycoprotein, as did 15 of 30 (50%, 31–69) in the group that received both vaccines. Nine of 29 (31%, 15–51) participants in the MAR vaccine groups had an antibody response to the Marburg glycoprotein, as did seven of 30 (23%, 10–42) in the group that received both vaccines. 19 of 30 (63%, 44–80) participants in the EBO vaccine group had a T-cell response to the Ebola Zaire glycoprotein, as did 10 of 30 (33%, 17–53) in the group that received both vaccines. 13 of 30 (43%, 25–63) participants in the EBO vaccine group had a T-cell response to the Ebola Sudan glycoprotein, as did 10 of 30 (33%, 17–53) in the group that received both vaccines. 15 of 29 (52%, 33–71) participants in the MAR vaccine group had a T-cell response to the Marburg glycoprotein, as did 13 of 30 (43%, 25–63) in the group that received both vaccines. Interpretation This study is the first Ebola or Marburg vaccine trial done in Africa, and the results show that, given separately or together, both vaccines were well tolerated and elicited antigen-specific humoral and cellular immune responses. These findings have contributed to the accelerated development of more potent Ebola virus vaccines that encode the same wild-type glycoprotein antigens as the EBO vaccine, which are being assessed during the 2014 Ebola virus disease outbreak in west Africa. Funding US Department of Defense Infectious Disease Clinical Research Program and US National Institutes of Health Intramural Research Program.

Description: Publication date: Available online 23 December 2014 Source: The Lancet Author(s): Saranya Sridhar

Description: Publication date: Available online 22 December 2014 Source: The Lancet Author(s): Olivier Casasnovas , Bertrand Coiffier

Description: Publication date: Available online 22 December 2014 Source: The Lancet Author(s): Karolin Behringer , Helen Goergen , Felicitas Hitz , Josée M Zijlstra , Richard Greil , Jana Markova , Stephanie Sasse , Michael Fuchs , Max S Topp , Martin Soekler , Stephan Mathas , Julia Meissner , Martin Wilhelm , Peter Koch , Hans-Walter Lindemann , Enrico Schalk , Robert Semrau , Jan Kriz , Tom Vieler , Martin Bentz , Elisabeth Lange , Rolf Mahlberg , Andre Hassler , Martin Vogelhuber , Dennis Hahn , Jörg Mezger , Stefan W Krause , Nicole Skoetz , Boris Böll , Bastian von Tresckow , Volker Diehl , Michael Hallek , Peter Borchmann , Harald Stein , Hans Eich , Andreas Engert Background The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma. Methods In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1·72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366. Findings Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93·1%, 81·4%, 89·2%, and 77·1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of −11·5% (95% CI −18·3 to −4·7; HR 2·06 [1·21 to 3·52]) for ABV and −15·2% (−23·0 to −7·4; HR 2·57 [1·51 to 4·40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference −3·9%, −7·7 to −0·1; HR 1·50, 1·00 to 2·26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin. Interpretation Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT. Funding Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.

Description: Publication date: Available online 19 December 2014 Source: The Lancet Author(s): Anders Heijl