Hot off the presses! Dec 17 LANCET

The Dec 17 issue of the LANCET is now up on Pubget (About LANCET): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• The UK Public Health White Paper: "just words"
  - LANCET 376(9757):1959 (2010)
  
• Child wellbeing in Africa: the true wealth of nations
  - LANCET 376(9757):1960 (2010)
  
• New palliative care funding system needed
  - LANCET 376(9757):1960 (2010)
  
• Cholera's western front
  - LANCET 376(9757):1961-1965 (2010)
  
• Zoledronic acid in myeloma: MRC Myeloma IX
  - LANCET 376(9757):1965-1966 (2010)
  
• Treatment of older patients with acute myeloid leukaemia
  - LANCET 376(9757):1967-1968 (2010)
  
• Mitoxantrone in first-relapse paediatric ALL: the ALL R3 trial
  - LANCET 376(9757):1968-1970 (2010)
  
• Resuscitation of newborn infants: from oxygen to room air
  - LANCET 376(9757):1970-1971 (2010)
  
• Offline: If I were a rich man
  - LANCET 376(9757):1972 (2010)
  
• Canada accused of hypocrisy over asbestos exports
  - LANCET 376(9757):1973-1974 (2010)
  
• US reviews human trial participant protections
  - LANCET 376(9757):1975-1976 (2010)
  
• Barks and quacks: London's alcoholic remedies
  - LANCET 376(9757):1977 (2010)
  
• Surgeons on the high seas
  - LANCET 376(9757):1978 (2010)
  
• Regina Obeng—dedicated to improving newborn health in Ghana
  - LANCET 376(9757):1979 (2010)
  
• Music for healing: from magic to medicine
  - LANCET 376(9757):1980-1981 (2010)
  
• John Conrad Waterlow
  - LANCET 376(9757):1982 (2010)
  
• Health inequalities in the UK
  - LANCET 376(9757):1983 (2010)
  
• Termination of the CRESCENDO trial
  - LANCET 376(9757):1983-1984 (2010)
  
• Termination of the CRESCENDO trial
  - LANCET 376(9757):1984 (2010)
  
• Termination of the CRESCENDO trial – Authors' reply
  - LANCET 376(9757):1984-1985 (2010)
  
• Inhaled nitric oxide for premature babies
  - LANCET 376(9757):1985 (2010)
  
• Inhaled nitric oxide for premature babies – Authors' reply
  - LANCET 376(9757):1985-1986 (2010)
  
• Calcium reduces risk of pre-eclampsia
  - LANCET 376(9757):1986 (2010)
  
• Calcium reduces risk of pre-eclampsia – Authors' reply
  - LANCET 376(9757):1986-1987 (2010)
  
• Ciprofloxacin-resistant campylobacteriosis in the UK
  - LANCET 376(9757):1987 (2010)
  
• Here is diabetes in The Lancet's tuberculosis Series!
  - LANCET 376(9757):1987-1988 (2010)
  
• Providing paediatric palliative care in Kenya
  - LANCET 376(9757):1988 (2010)
  
• Department of Error
  - LANCET 376(9757):1988 (2010)
  
• Department of Error
  - LANCET 376(9757):1988 (2010)
  
• First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial
  - LANCET 376(9757):1989-1999 (2010)
  Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma. Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111. Findings 1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137–632) before disease progression, with a median of 3·7 years' follow-up (IQR 2·9–4·7). Zoledronic acid reduced mortality by 16% (95% CI 4–26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74–0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2–20) versus clodronic acid (HR 0·88, 95% CI 0·80–0·98; p=0·0179), and increased medi! an progression-free survival by 2·0 months (19·5 months, IQR 9·0–38·0 vs 17·5 months, IQR 8·5–34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]). Interpretation Consistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits. Funding Medical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.
• Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes
  - LANCET 376(9757):2000-2008 (2010)
  Background About 50% of patients (age ≥60 years) who have acute myeloid leukaemia and are otherwise medically healthy (ie, able to undergo intensive chemotherapy) achieve a complete remission (CR) after intensive chemotherapy, but with a substantially increased risk of early death (ED) compared with younger patients. We verified the association of standard clinical and laboratory variables with CR and ED and developed a web-based application for risk assessment of intensive chemotherapy in these patients. Methods Multivariate regression analysis was used to develop risk scores with or without knowledge of the cytogenetic and molecular risk profiles for a cohort of 1406 patients (aged ≥60 years) with acute myeloid leukaemia, but otherwise medically healthy, who were treated with two courses of intensive induction chemotherapy (tioguanine, standard-dose cytarabine, and daunorubicin followed by high-dose cytarabine and mitoxantrone; or with high-dose cytarabine and mitoxantrone in the first and second induction courses) in the German Acute Myeloid Leukaemia Cooperative Group 1999 study. Risk prediction was validated in an independent cohort of 801 patients (aged >60 years) with acute myeloid leukaemia who were given two courses of cytarabine and daunorubicin in the Acute Myeloid Leukaemia 1996 study. Findings Body temperature, age, de-novo leukaemia versus leukaemia secondary to cytotoxic treatment or an antecedent haematological disease, haemoglobin, platelet count, fibrinogen, and serum concentration of lactate dehydrogenase were significantly associated with CR or ED. The probability of CR with knowledge of cytogenetic and molecular risk (score 1) was from 12% to 91%, and without knowledge (score 2) from 21% to 80%. The predicted risk of ED was from 6% to 69% for score 1 and from 7% to 63% for score 2. The predictive power of the risk scores was confirmed in the independent patient cohort (CR score 1, from 10% to 91%; CR score 2, from 16% to 80%; ED score 1, from 6% to 69%; and ED score 2, from 7% to 61%). Interpretation The scores for acute myeloid leukaemia can be used to predict the probability of CR and the risk of ED in older patients with acute myeloid leukaemia, but otherwise medically healthy, for whom intensive induction chemotherapy is planned. This information can help physicians with difficult decisions for treatment of these patients. Funding Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft.
• Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial
  - LANCET 376(9757):2009-2017 (2010)
  Background Although survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens. Methods This open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1–18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10−4 cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease (<10−4 cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-! to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312. Findings Of 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9–45·9) in the idarubicin group versus 64·6% (54·2–73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5–55·3) versus 69·0% (58·5–77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34–0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24–1·11, p=0·11). Interpretation As compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation. Funding Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.
• Sickle-cell disease
  - LANCET 376(9757):2018-2031 (2010)
  Sickle-cell disease is one of the most common severe monogenic disorders in the world. Haemoglobin polymerisation, leading to erythrocyte rigidity and vaso-occlusion, is central to the pathophysiology of this disease, although the importance of chronic anaemia, haemolysis, and vasculopathy has been established. Clinical management is basic and few treatments have a robust evidence base. One of the main problems of sickle-cell disease in children is the development of cerebrovascular disease and cognitive impairment, and the role of blood transfusion and hydroxycarbamide for prevention of these complications is starting to be understood. Recurrent episodes of vaso-occlusion and inflammation result in progressive damage to most organs, including the brain, kidneys, lungs, bones, and cardiovascular system, which becomes apparent with increasing age. Most people with sickle-cell disease live in Africa, where little is known about this disease; however, we do know that the ! disorder follows a more severe clinical course in Africa than for the rest of the world and that infectious diseases have a role in causing this increased severity of sickle-cell disease. More work is needed to develop effective treatments that specifically target pathophysiological changes and clinical complications of sickle-cell disease.
• Risk assessment for recurrent venous thrombosis
  - LANCET 376(9757):2032-2039 (2010)
  Venous thrombosis is a common disease that frequently recurs. Recurrence can be prevented by anticoagulants, albeit at the cost of bleeding. Thus, assessment of the risk of recurrence is important to balance the risks and benefits of anticoagulation treatment. Many clinical and laboratory risk factors for recurrent venous thrombosis have been established. Nevertheless, prediction of recurrence in an individual patient remains a challenge. Detection of some laboratory markers is associated with only a moderate risk of recurrence, and the relevance of others is not known. Many patients have several risk factors and the effect of combined defects is obscure. Routine screening for these laboratory markers should therefore be abandoned. Risk assessment can be improved by measurement of global markers that encompass the effects of clotting and fibrinolytic disorders. Analysis of preliminary data suggests that risk assessment can also be refined through integration of prothro! mbotic coagulation changes and clinical risk factors.
• Danger lurks in the Mediterranean
  - LANCET 376(9757):2040 (2010)