"Botox may have cancer fighting role," BBC News reports after research involving mice found using Botox to block nerve signals to the stomach may help slow the growth of stomach cancers. Botox, short for botulinum toxin, is a powerful neurotoxin that can block nerve signals.
The researchers studied genetically modified mice designed to develop stomach cancer as they grew older.
They found that mice treated with Botox injections had improved survival rates, because the cancer spread at a reduced rate or was prevented from developing in the first place.
Cutting the nerve supply to the stomach during an operation called a vagotomy had a similar effect.
In mice that had already developed stomach cancer, Botox injections reduced cancer growth and improved survival rates when combined with chemotherapy.
Further studies of human stomach cancer samples confirmed the finding that nerves play a role in tumour growth.
An early-phase human trial is now underway in Norway to determine the safety of such a procedure and to work out how many people would need to be treated in trials, to see whether the treatment is effective.
Where did the story come from?
The study was carried out by researchers from the Norwegian University of Science and Technology in Trondheim, Columbia University College of Physicians and Surgeons in New York, and universities and institutes of technology in Boston, Germany and Japan.
It was funded by the Research Council of Norway, the Norwegian University of Science and Technology, St Olav's University Hospital, the Central Norway Regional Health Authority, the US National Institutes of Health, the Clyde Wu Family Foundation, the Mitsukoshi Health and Welfare Foundation, the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad, the Uehara Memorial Foundation, the European Union Seventh Framework Programme, the Max Eder Program of the Deutsche Krebshilfe and the German Research Foundation.
The study was published in the peer-reviewed medical journal Science Translational Medicine.
The study was reported accurately by the UK media, making it clear that this potential treatment is not yet available and will take years to assess its potential.
What kind of research was this?
This research was a collection of experiments on mice and studies of human tissue samples. Previous research had shown that cutting the main nerve to the stomach (vagus) in a procedure called a vagotomy reduces the thickness of the stomach wall and decreases cell division.
Another research study found people who had a vagotomy had a 50% reduced risk of developing stomach cancer 10 to 20 years later. The researchers wanted to see if targeting the nerve would reduce stomach cancer growth.
What did the research involve?
Genetically modified mice designed to develop stomach cancer by 12 months of age were studied to see if there was a link between the density of nerves and stomach cancer.
One of four different types of operation was then performed on the vagus nerve of 107 genetically modified mice at the age of six months to see if this made a difference in the development of stomach cancer. This was either:
The researchers then performed a Botox procedure on another set of mice by injecting the anterior vagus nerve (front section) when they were six months old to see if this reduced the development of stomach cancer.
To see if cutting or injecting the nerve had any effect after stomach cancer had developed, the researchers performed UVT on mice aged 8, 10 or 12 months and compared their survival rate with mice who had not had the intervention.
They then injected Botox into the stomach cancer of mice aged 12 months and looked at the subsequent cancer growth. They also compared survival rates for chemotherapy with saline injection, chemotherapy with Botox and chemotherapy with UVT.
The researchers then examined human stomach samples from 137 people who had undergone an operation for stomach cancer, to look at how active the nerves were in the sections of cancer compared with normal tissue.
They also compared tissue samples of 37 people who had already had an operation for stomach cancer, but then developed stomach cancer in the base portion of the stomach. The vagus nerve had been cut in 13 of these people.
What were the basic results?
The genetically modified mice mostly developed stomach cancer in the section of the stomach that had the highest density of nerves.
Cutting the vagus nerve supply reduced the incidence of tumours developing. The percentage of mice that had tumours six months after the operation was:
Six months after the Botox injection into the anterior vagus nerve, the mice still developed stomach cancer. However, the size of the tumour and number of dividing cancer cells in the front section of the stomach was less than half that of the back section.
In mice that had already developed stomach cancer, the normal survival rate was 53% by 18 months, but this was increased by the UVT to:
Botox injection into the stomach tumours of mice reduced the growth by roughly half. Botox and chemotherapy improved mouse survival compared with chemotherapy on its own, as did UVT and chemotherapy.
In the human samples, there was evidence of increased nerve activity in the cancer sections of tissue compared with the normal tissues. This was higher in more advanced tumours.
All 24 people who had not had the vagus nerve cut developed stomach cancer in the base, as well as the remaining front and back sections of the stomach. Only one of the 13 people who had had the vagus nerve cut developed cancer in the front or back section of the stomach, suggesting that the nerve needed to be intact for cancer to develop.
How did the researchers interpret the results?
The researchers say that their "finding that nerves play an important role in cancer initiation and progression highlights a component of the tumour microenvironment contributing to the cancer stem cell niche.
"The data strongly supports the notion that denervation and cholinergic antagonism, in combination with other therapies, could represent a viable approach for the treatment of gastric cancer and possibly other solid malignancies."
These laboratory experiments show that nerves have a role in the development and advancement of stomach cancer. The early experiments in mice found that stopping the nervous supply by either cutting the vagus nerve or injecting it with Botox improved survival rates and reduced cancer growth.
The Botox injections were not performed on any humans in this study. However, an early-phase clinical trial in humans with inoperable stomach cancer began in Norway in January 2013, with the results expected in 2016.
This will determine the safety of such a procedure and work out the number of people who would need to be treated in a larger controlled trial to see whether the treatment is effective.
You can reduce your risk of stomach cancer by quitting smoking if you smoke and moderating your consumption of salt and smoked meats, such as pastrami.
Stomach cancer has also been linked to a chronic infection by H. pylori bacteria, a common cause of stomach ulcers.
If you find yourself having persistent bouts of indigestion or stomach pain, you should contact your GP for advice. The symptoms could be caused by a H. pylori infection, which is relatively straightforward to treat.
Links To The Headlines
Botox may have cancer fighting role. BBC News, August 21 2014
Botox 'could be used to treat stomach cancer'. Daily Mirror, August 21 2014
Botox could halt stomach cancer. The Daily Telegraph, August 21 2014
Links To Science
Zhao C, Hayakawa Y, Kodama Y, et al. Denervation suppresses gastric tumorigenesis. Science Translational Medicine. Published online August 20 2014
“People as young as 30 who are obese may be at greater risk [of dementia],” The Independent reports.
This UK study examined a set 14-year period (1998 to 2011) and looked at whether NHS hospital records documenting obesity in adults above the age of 30 were associated with subsequent hospital or mortality records documenting dementia in the remaining years of the study.
Overall there was actually no significant association between obesity and dementia in later life.
When the researchers broke down the data into 10-year age bands (30s, 40s, 50s and 60s) they found that people in these age groups had increased risk of dementia. However, it must be remembered that the researchers were not looking at lifetime dementia diagnoses, but only looking at diagnoses in the remaining years of the study. Very few people in the younger age groups would have developed dementia over the following few years.
For example, the study found more than a trebled risk of dementia for people with obesity in their 30s, but this was based on only 19 people who developed dementia during the remaining years of the study. Calculations based on small numbers may be less reliable and should be given less "weight".
As expected the greatest number of subsequent dementia diagnoses occurred in people who were 70 or above when obesity was assessed, and obesity did not increase dementia risk in these people.
Aside from any dementia link or not, overweight and obesity are well established to be associated with a variety of chronic diseases and a healthy weight should be the aim.
Where did the story come from?
The study was carried out by two researchers from the University of Oxford and was funded by the English National Institute for Health Research.
The study was published in the peer-reviewed Postgraduate Medical Journal.
The UK media failed to report the various limitations of this research. This includes the lack of a significant association with dementia overall for the total cohort.
And while significant associations for people between the ages of 30 and 60 were found, these are based on only very small numbers who developed dementia during the study so may be less reliable.
As said, the links between vascular dementia specifically and obesity do seem to be more apparent, but this is to be expected.
It is also not clear in the study where the 50% increased risk for people in middle age comes from.
What kind of research was this?
This was a retrospective cohort study that aimed to examine how obesity in middle age may be associated with the risk of subsequent dementia.
The researchers say the worldwide prevalence of dementia in 2010 was around 35.6 million cases, which was estimated to double to 65.7 million by 2030.
Meanwhile we are in the midst of an obesity epidemic, with the World Health Organization reporting that in 2008 just over a third of all adults were overweight (BMI over 25kg/m²) while 10% of men and 14% of women were obese (BMI over 30kg/m²).
As the researchers say, with the rapidly increasing burden of dementia, it is important to identify which modifiable risk factors are associated. The researchers say there is growing evidence that mid-life obesity is associated with “dementia” overall.
Dementia is just the general term for problems with memory and thinking, which has different causes. Alzheimer’s disease is the most common cause of dementia, which is associated with characteristic symptoms and changes in the brain (the formation of protein plaques and tangles). The causes of Alzheimer’s are not fully understood, with increasing age and genetic factors being the most well established. Overweight and obesity are not currently established as risk factors for Alzheimer’s disease.
Meanwhile, vascular dementia – the second most common cause – has the same risk factors as cardiovascular disease, so there would be a plausible link between obesity and this type of dementia.
This study simply examined a set 14 year period (1998 to 2011) and looked at whether hospital re-ords documenting obesity in adults of different ages, was associated with subsequent documentation of dementia in the remaining years of the study.
What did the research involve?
This study used Hospital Episode Statistics (HES) data, which includes data for all hospital admissions including day cases in NHS hospitals in England between April 1998 and December 2011. They also linked with the Office for National Statistics (ONS) to identify deaths up to December 2011.
The researchers identified a cohort of people with obesity by looking for the first admission or day care visit where obesity was recorded as a diagnosis (according to the International Classification of Diseases [ICD] codes). They identified a comparison control cohort without obesity who had received day care or hospital admission for various medical, surgical conditions or injuries. They only included adults in the obesity and comparison groups who were aged 30 or older and did not have an admission for dementia at the same time as, or before, the date of admission when obesity was recorded.
For the obesity and comparison groups they searched the HES and ONS databases for all subsequent hospital care or deaths from dementia (according to ICD codes). The researchers say they subdivided admissions into those specifically documented to be due to Alzheimer’s disease or vascular dementia, and separately examined men and women.
They grouped obesity and comparison groups into 10-year age bands at the time obesity was first recorded, then compared their risk of dementia in the subsequent years. Adjustment was made for sex, time period of the study, region of residence and deprivation score.
What were the basic results?
There were 451,232 adults in the obesity cohort, 43% of whom were male (number in the comparison cohort not specifically reported).
Overall compared to controls, for the total cohort of all adults aged 30 or above, there was no statistically significant association between a hospital record of obesity and subsequent record of dementia in the remaining years of the study (relative risk [RR]0.98, 95% confidence interval [CI] 0.95 to 1.01).
However, when they were then split into 10-year age brackets, there was increased risk of subsequent dementia for people with obesity recorded in the age brackets:
There was no significant association between obesity and dementia for people with obesity between the ages 70 and 79, and an apparent decrease in risk of dementia for people above the age of 80 with obesity.
When they looked by specific type of dementia, there was no clear link between obesity and Alzheimer’s disease. For the full cohort of adults aged 30 or over, obesity actually seemed to decrease the risk of subsequently developing Alzheimer’s disease (RR 0.63, 95% CI 0.59 to 0.67). Then by age group there was an apparent increased risk for those with obesity in the ages 30 to 39 (RR 5.37, 95% CI 1.65 to 13.7); no association for those between the ages 40 and 59; then decreased risk of Alzheimer’s for those with obesity above the age of 60.
Obesity seemed to have a clearer link with risk of vascular dementia. The full cohort of adults aged 30 or over recorded to have obesity had a 14% increased risk of vascular dementia in the subsequent years of the study (RR 1.14, 95% CI 1.08 to 1.19). There were also significantly increased risks for all age groups up to the age of 69. For the 70 to 79 year age group there was no association, and for obese adults over the age of 80, obesity again seemed to decrease the risk.
How did the researchers interpret the results?
The researchers conclude that: “Obesity is associated with a risk of dementia in a way that appears to vary with age. Investigation of the mechanisms mediating this association might give insights into the biology of both conditions.”
As the researchers say: “The dataset spans 14 years and is therefore just a snapshot of people's lifetime experience of obesity.” The study is just looking at a set 14-year period (1998 to 2011) and looking at whether hospital records documenting obesity in adults of different ages, were associated with subsequent documentation of dementia in the remaining years of the study.
Therefore not only is the study looking at a snapshot of obesity in a 14-year period, is also looking at just a snapshot of time in which people could develop dementia in the remaining years of the study. For those in the cohort who were in their 70s or 80s when their obesity was recorded, you may expect that the study could have a better chance of capturing whether those people were ever going to develop dementia in their lifetime. However, for most of the people in the cohort who were between the ages of 30 and 60, their likelihood of developing dementia in the remaining few years of the study is low.
Therefore, this study cannot reliably show whether or not obesity in mid-life is associated with developing dementia, as the follow-up timeframe will not have been long enough for most people.
The main result of this study was that for all adults in the cohort there was no association between a hospital record of obesity and risk of any type of dementia in the subsequent years of the study.
Though the research did then find increased risks for 10-year age bands in the 30s, 40s, 50s and 60s, many of these analyses are based on only small numbers of people who developed dementia in the remaining years of the study.
For example, the highest more than trebled risk of dementia for people with obesity in their 30s was based on only 19 people who developed dementia during the remaining years of the study. An analysis based on such a small number of people has a much higher chance of error.
The 39% increased risk for people with obesity in their 60s was more reliable as this included 1,037 people from this age band who subsequently developed dementia.
But then the pattern is less clear, as for people with obesity in their 70s, of whom the largest number developed dementia (2,215), there was no association between obesity and dementia.
Meanwhile people who were obese in their 80s seemed to have decreased risk of then developing dementia.
Overall this makes a confusing picture from which to obtain any clear understanding of how obesity is associated with dementia. And it seems possible that various confounding hereditary, health and lifestyle factors may be having an influence.
Looking at Alzheimer’s specifically there was no clear link between adult obesity and Alzheimer’s. Therefore the study doesn’t provide evidence of obesity as a modifiable risk factor for the most common type of dementia. The only increased risk was for people with obesity in their 30s, but considering only five people developed Alzheimer’s in the remaining study years, this makes this risk association far from reliable. In fact for people over the age of 60, obesity apparently seems to be protective against Alzheimer’s for some reason. Though again it is highly possible this could be due to confounding from other factors.
As said, vascular dementia – the second most common type – has the same risk factors as cardiovascular disease, so there would be a plausible link between obesity and this type of dementia. And this study does support this, finding for the overall cohort of all adults above the age of 30, obesity was associated with a 14% increased risk of vascular dementia. Therefore, the study generally supports the link between obesity and this vascular condition.
Another point to bear in mind for this study is that, though it benefits from using a large reliable dataset of HES and ONS data which has recorded obesity and dementia based on valid diagnostic codes, it is of course only looking at hospital presentations of both obesity and dementia.
It is therefore unable to capture the large number of people with both of these conditions who may not have accessed hospital care.
Overall, this study contributes to the literature examining how the obesity epidemic may be associated with the growing prevalence of dementia worldwide, however it provides little in the way of conclusive answers.
Links To The Headlines
Further evidence that obesity in middle age increases dementia risk. The Independent, August 21 2014
Slim to reduce the risk of dementia, middle-aged told. The Times, August 21 2014
Dementia risk TRIPLES if you get fat in your thirties. Daily Express, August 21 2014
Links To Science
Wotton CJ, Goldacre MJ. Age at obesity and association with subsequent dementia: record linkage study. Postgraduate Medical Journal. Published online August 20 2014