Medicine Digest
Hippisley-Cox J, Coupland C. Identifying women with suspected ovarian cancer in primary care: deri- vation and validation of algorithm. BMJ 2012; 344 (Jan 28): 17 (d 8009); Hamilton W. Computer assist- ed diagnosis of ovarian cancer in primary care. Ibid: 9 (d7628) (editorial).
Vemurafenib for advanced melanoma
About half of melanomas carry an ac- tivating mutation in the gene encoding the serine-threonine protein kinase B- RAF (BRAF), the BRAF V600 mutation. This causes activation of the mitogen-ac- tivated protein kinase (MAPK) pathway, enhancing cell proliferation and inhibit- ing apoptosis. Vemurafenib is a potent kinase inhibitor acting preferentially on cancer cells with the BRAF V600 muta- tion. Initial studies have suggested that vemurafenib might be active against such melanomas. A multicentre, phase II trial has provided confirmation. A total of 132 patients were treated at
ten US centres and three centres in Aus- tralia. All had previously treated meta- static melanoma with the BRAF V600 mutation (184 of 328 patients (56%) had tested positive for the mutation). Median follow-up was 12.9 months. The overall confirmed response rate was 53% with 6% having a complete response. Re- sponses lasted 6.7 months on average and the median progression-free survival was 6.8 months. Only 14% had primary progression. Some patients responded only after 6 months or more of treat- ment. Median overall survival was 15.9 months. The most common adverse ef- fects were arthralgia, rash, photosensitiv- ity, fatigue, and alopecia. A quarter of the patients (26%) developed squamous cell skin cancers. Among patients with metastatic mela-
noma with a BRAF V600 mutation ve- murafenil produced a clinical response in 53% and an overall median survival of 16 months.
Sosman JA et al. Survival in BRAF V600-mutant ad- vanced melanoma treated with vemurafenib. NEJM 2012; 366: 707–14.
PSA testing and prostate cancer mortality
In 2008, a US task force recommend- ed that prostate-specific antigen (PSA) screening for prostate cancer should not be offered to asymptomatic men. Now follow-up in the European Randomised Study of Screening for Prostate Cancer has been extended to 11 years. The study included 182160 men aged 50–74 years (162388 aged 55–69
July 2012
years) in eight European countries. Ran- domisation was to PSA screening or no PSA screening. After an average follow- up of 11 years in the 55–69 age group there was a significant 21% relative re- duction in prostate cancer deaths in the screening group compared with con- trols (a 29% reduction after allowing for noncompliance). Screening saved 1.07 deaths per 1000 men randomised. To prevent one death from prostate cancer over the 11-year period it would be nec- essary to invite 1055 men for screening and to detect 37 cancers. There was no significant difference between screening and control group in all-cause mortality. PSA screening reduced prostate-can-
cer mortality but not all-cause mortality. These researchers call for more informa- tion before general recommendations about screening can be made. An edito-
rialist tends towards a negative approach. Schröder FH et al. Prostate-cancer mortality at 11years of follow-up. NEJM 2012; 366: 981–90; Miller AB. New data on prostate-cancer mortality af- ter PSA screening. Ibid: 1047–8 (editorial).
in systolic and diastolic blood pressure, serum cholesterol levels, and blood glu- cose control. It did not affect liver en- zyme levels and was not associated with hypoglycaemia. Side-effects included nausea, vomiting, and diarrhoea. Treatment with a GLP-1 receptor ago- nist is associated with weight loss as well as other benefits. A BMJ editorialist cau- tions against using these drugs for weight loss in people without diabetes at pres- ent. They might be used as an addition to metformin for control of type 2 diabetes but there are concerns about safety that need to be addressed in further trials. Pancreatitis, pancreatic metaplasia, and thyroid C cell tumours have occurred in
animal studies. Vilsbøll T et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analysis of randomised controlled trials. BMJ 2012; 344 (January 28): 14 (2011; 343: d7771); Padwal R. Glucagon-like peptide-1 agonists. Ibid: 7 (2011; 343: d7282) (editorial).
GAD65 antigen therapy for new diabetes: negative trial
Diabetes
Glucagon-like peptide-1 receptor agonists and weight loss Glucagon-like-peptide-1 (GLP-1) is se- creted in the lower gastrointestinal tract after meals and stimulates insulin secre- tion depending on blood glucose lev- els. It inhibits glucagon release, delays gastric emptying, and reduces appetite. GLP-1 is not satisfactory for clinical use because it is rapidly degraded but two GLP-1 receptor agonists (exenatide and liraglutide) are currently approved. A systematic review and meta-analysis has concentrated on the weight loss as- sociated with GLP-1 receptor agonist therapy. The meta-analysis included 21 ran- domised controlled trials (6411 over- weight or obese patients) with ran- domisation to a GLP-1 receptor agonist (exenatide or liraglutide) or control (pla- cebo, oral antidiabetic drugs, or insulin). In eighteen trials the patients had type 2 diabetes and in three they did not. Over- all the GLP-1 receptor agonist groups lost, on average, 2.9kg more than con- trols. Average weight loss with a GLP-1 receptor agonist was 3.2kg greater than in controls for patients without diabetes and 2.8kg greater for patients with dia- betes. GLP-1 receptor agonist treatment was also associated with improvements
Type 1 diabetes follows the immuno- logical destruction of pancreatic beta cells. Various attempts have been made to moderate this immune response in patients with new type 1 diabetes with mixed results. Glutamic acid decarbox- ylase (GAD) is an important antigen in the pathogenesis of type 1 diabetes and induction of immune tolerance with the 65-kD isoform (GAD65) gave promising initial results. Now a trial at 63 centres in nine European countries has shown no benefit from this treatment. A total of 334 patients aged 10–20
years with type 1 diabetes, serum anti- bodies against GAD65, and fasting C- peptide levels >0.1nmol per litre (0.3ng per ml) were randomised within 3 months of diagnosis to three groups: s.c. GAD65 with alum (GAD-alum) on days 1, 30, 90, and 270, GAD-alum on days 1 and 30 and placebo on days 90 and 270, or placebo on days 1, 30, 90, and 270. Levels of stimulated C-peptide de- creased similarly in all three groups and the change in stimulated C-peptide level between baseline and 15 months did not differ significantly between the groups. Levels of glycated haemoglobin, insu- lin dosage, and rates of hypoglycaemia were similar in the three groups. There were few adverse events. GAD-alum did not alter the course of early type 1 diabetes.
Ludvigsson J et al. Gad65 antigen therapy in recently diagnosed type 1 diabetes mellitus. NEJM 2012; 366: 433–42.
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