Recent Rapid Responses

We read with great interest the paper by J Green et al[1] on oral bisphosphonates and the risk of cancer of the oesophagus.

As a practicing GP, rather than an epidemiologist, EW became interested in this area after observing some cases of oesophageal cancer in patients without the usual risk factors but who had been on bisphosphonates. We have independently analyzed a very similar data set also drawn from the General Practice Research Database (GPRD), and have come to a similar conclusion - an increased proportion of cases of upper GI cancer had been prescribed bisphosphonates compared to controls.

We carried out a case control study comparing bisphosphonate prescribing in cases of upper GI cancer with that in controls from 1995 (date alendronate first licensed) to 2007. The study population included all cases of upper GI malignancy diagnosed in each year from 1995 to 2007 in the GPRD with up-to-standard data. Each case was matched to four controls on age and gender only.

The odds of being a case are increased 1.17 times for those on bisphosphonates during the study period (Odds ratio 1.17, 95% Confidence Interval 1.04 to 1.31). The effect was greater in women alone: (OR 1.29, CI 1.12 to 1.47) and there appeared to be no effect in men (OR 0.95, CI 0.77 to 1.17).

Smoking was an independent effect on GI cancer and did not appear to influence the effect of bisphosphonates.

In our study, the difference between the two groups was much smaller, although highly significant, and this is presumably because we combined oesophageal and gastric cancers together in one group. We did this a) to maximize the number of cases and b) on the observation that most of the increase in oesophageal cancer is adenocarcinoma rather than squamous and the hypothesis that these lower oesophageal tumours and gastric tumours occurring at the cardia may be a discrete group with similar aetiology.

The results in Green et al's paper do seem to support this in that they found the adjusted relative risks for one or more bisphosphonate prescriptions versus no prescription were 2.02 (CI 1.02 to 4.01) among 437 cases of adenocarcinoma and 2183 matched controls and 0.83 (CI 0.36 to 1.93) among 156 cases of squamous cell carcinoma and 776 matched controls (heterogeneity test: P=0.1).

On re-running our analysis looking at oesophageal cancer cases v controls only we found the odds of being a case increased to 1.24 (CI 1.08 to 1.44). Again there was a greater effect in women alone (OR 1.40, CI 1.18 to 1.67) and no effect in men (OR 0.97, CI 0.74 to 1.26). This last result is in contrast to Green's finding of no interaction with gender, and may be in part due to women being exposed to bisphosphonates for a greater period.

If the association is true then from our initial analysis 85 out of 4442 female cases of upper GI cancer annually in the UK could be linked to bisphosphonate use. This may be outweighed by the benefits of fracture prevention but given the high morbidity and mortality of oesophageal cancer individual patients may take a different view.

There is another analysis by Cardwell [2] investigating the same question, again using the GPRD, but the authors followed a cohort design and did not include enough cases to detect the small effects found by ourselves and Green. These three research teams worked in ignorance of each other prior to publication. We wonder if other users of electronic databases have had similar experiences?

Ellen Wright, Paul Seed, Peter Schofield and Roger Jones.

References:

[1] Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010;341:c4444 doi:10.1136/bmj.c4444

[2] Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA, August 11, 2010--Vol 304, No. 6

Competing interests: None declared

The clinical review on the management of gastro-oesophageal reflux (GOR) in infants underline that there is poor evidence in the use of different class of drugs, most frequently prescribed as off-label in children (1). However, in order to provide clear management guidelines, we believe that the first step is to differentiate GOR (i.e., physiological) from gastro- oesophageal reflux disease (GORD) (i.e., pathological). Many symptoms usually attributed to GORD (crying, regurgitation, feeding refusal, wheezing) may more appropriately be attributed to a "misalignment" between culture of the mother and of paediatrician and the biological events (2). The improper diagnosis of GORD and the consequent unjustified and ineffective prescription of anti-reflux therapy, as well as elimination diets, may confuse the family and lead to food refusal in the baby or other side effects (i.e., lower respiratory tract infections) (4). The largely inappropriate prescription of proton pump inhibitors (PPIs) in children with physiological GOR has already been reported and is confirmed by the more than sevenfold increase of prescriptions in infants documented from 1999 through 2004 (3). On the other hand, when GORD is true and proven (i.e. in children with cerebral palsy or oesophageal atresia) and its management with PPIs necessary, it seems unreasonable - as reported in the Clinical Review (1) - that in Europe omeprazole only has a paediatric indication, while all other PPIs are still off-label. At present, the appropriateness of the use of PPI in children may be based on a large body of clinical evidence (5) and in the USA esomeprazole and lansoprazole beside omeprazole are currently authorized for children (although with exclusion of infant and neonate age groups). Therefore regulatory agencies should translate clinical evidence into clinical practice providing formal paediatric indication, and ethical committees should cope with this issue to avoid unnecessary trial replication.

References

(1) Drug and Therapeutics Bulletin. Managing gastro-oesophageal reflux in infant. BMJ 2010; 341:c4420.

(2) Tornese G, Maschio M, Marchetti F, Ventura A. To GERD or not to GERD, this is the question. J Pediatr 2009;155:601.

(3) Barron JJ, Hiangkiat T, Spalding J, Bakst AW, Singer J. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr 2007;45:421.

(4) Ventura A, Marchetti F, Cannioto Z, Barbi E, Martelossi S. Feeding difficulties in infants: how much a iatrogenic condition? [eLetter] Arch Dis Child 2008. Available at: http://adc.bmj.com/cgi/eletters/adc.2006.108829v1

(5) Tafuri G, Trotta F, Leufkens HGM, Martini N, Sagliocca L, Traversa G. Off-label use of medicines in children: can available evidence avoid useless paediatric trials? The case of proton pump inhibitors for the treatment of gastroesophageal reflux disease. Eur J Clin Pharmalcol 2009;65:209-216.

Federico Marchetti, Gianluca Tornese, Alessandro Ventura

Department of Paediatrics, Institute of Child Health, IRCCS Burlo Garofolo, University of Trieste Via dell'Istria 65/1, 34100 Trieste, Italy

Corresponding author: Federico Marchetti, MD phone +39 040 378454; fax +39 040 3785362 e-mail: marchetti@burlo.trieste.it

Competing interests: None declared

Despite recent advances in medical care and management, WHO predicts India the second largest country in the world with 1.1 billion crore population may have population of affected by diabetes during 2025 with 195% diabetic patients mainly due to life style! herbs plays a powerful role in treating Diabetes along with diet as mentioned by Mr.Jim Mann, Dagfinn Aune. Despite the attention and interest paid by scholars, there are the few data of research on the actual prevalence of Complementary and alternative systems like Ayurveda, Yoga, Pranayama ,Meditation etc. use in people with diabetes. It is plays vital role in remote places which get physicians services, In India people have coping Diabetes Mellitus by own way like concoction of herbs as well as plants. nature has gifted us the power to cure any disease by its own way. So even modern pharmaceuticals turn their eye towards that make up most of the medicines that forms the contemporary one medicine. The role of daily regimen are equally or even more important in to controls well as to prevent blood sugar level and its complications .The most common vegetables used in rural India to coping with Diabetes are as follows Bittergourd (Momordica charantia) studies show that it reduces blood sugar level to maximum control or helps the maintain the same. An plant insulin-like chemical constituent i.e. polypeptide bittergourd plays vital role here. Use of a oral intake of 50-60 ml of bitter melon juice shows good results in maintaining sugar level, Additional to these Jamun seeds and Fenugreek (Trigonella foenum-graecum) seeds raw or cooked1 or juice or powdered form ,And the most common herbal combination of Indian medical system , the Triphala is an herbal formulation consisting of the dried and powdered fruits of three plants such as Terminalia chebula, Emblica officinalis and Terminalia bellerica in equal proportions shown good result in maintaining good health in DM. One more Prevention can be done by practicing Yoga(Science of posture) an ancient science with the history of 8000 years .Phase one studies prove the role of Yoga shown positive result2.One more measure we can use is relaxation technique i .e meditation. A simple meditation may balance our hormone cycle and help to control stress as it is also one among the causative factor for DM3.One more practice is Hatha Yoga modality of yoga helps to face oxidative stress as well as lipid profile most common in those encounter discrimination in the workplace, shift work, harassments as well as employment and income generation is also is important 4.Pranayama the yogic breathing exercise also have its own role here for instance the energy loss on the body in case of treadmill-walking was 3.59 kilocalories per minute, in comparison to 2.23 K Cal/minute for Pranayama.

01. Kochhar A, Nagi M. Effect of supplementation of traditional medicinal plants on blood glucose in non-insulin-dependent diabetics: a pilot study. J Med Food. 2005 Winter;8(4):545-9. 02.Robin Monro et.al Yoga therapy for NIDDM; A controlled trial. J of Complement Med res 1992.6(2):66-68 03.Udupa K.N.-Disorders of stress management with Yoga Special monograph 1978. 04.Godaon A et.al ,Effect of exercise therapy on lipid profile and oxidative stress indicators in patient with type 2 diabetes ,BMC Complement Altern Med .2008 May 13;8:21.

Competing interests: None declared

It is interesting that there is such a difference in attitudes towards end of life care between hospital speciality and palliative care doctors. We agree with Professor Seale that it is 'plausible that doctors in different specialities have different approaches to the care of people who are dying'.

Perhaps the 'increased willingness of many hospital doctors to consider measures to hasten death' can be explained by a desire to alleviate the symptoms they fear may accompany a prolonged end of life phase. They may be less aware than palliative care doctors that symptom control can often bring comfort to patients as they are dying.

A 2006 study in Amsterdam showed that, where palliative care options were available and accepted by patients who requested euthanasia, 46% withdrew their request.1

The difference in attitudes between hospital speciality and palliative care doctors may reflect a need for further palliative care education in all medical training.

Miss Charlotte Talbot,
Medical Student, University of Leeds,
on elective at Willow Wood Hospice, Ashton-under-Lyne, Lancashire, OL6 6SL
char1ie_talbot@hotmail.com

Dr Michael Tapley,
m.tapley@willowwood.info

References:

1. Jansen-van der Weide MC, Onwuteaka-Philipsen BD, van der Wal G. Requests for euthanasia and physician-assisted suicide and the availability and application of palliative options. Palliat Support Care 2006;4(4):399-406

Competing interests: None declared

Surely the issue about this case is not so much about the legislation, but the professional use of powers of persuasion with competent patients. Just because a patient is competent and not detainable under the Mental Health Act does not absolve professionals of the responsibility to try to change an "imprudent" decision that may have contributed to her death.

Competing interests: None declared