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  • A 2017 research project found that only 6 out of 18 FDA-approved blood glucose monitoring (BGM) systems tested were accurate
  • Each day BGM systems are used by millions of people with diabetes to help them self-manage their condition, and avoid devastating and costly complications
  • Thousands of similar smart devices support the prevention and self management of other chronic lifetime conditions, whose prevalence levels are high
  • The increasing demand for healthcare, its escalating costs, and rapidly evolving technologies are driving the growth of such remote self-managed devices
  • The most valuable aspect of such devices is the data they produce
  • These data tend to be under valued and under utilized by healthcare providers
  • This has created an opportunity for giant technology companies to enter the healthcare market with a plethora of smart devices and start utilizing the data they collect to enhance patient outcomes and lower costs
  • Giant technology companies could dis-intermediate GPs and re-engineer primary care
 

Digital blood glucose monitors and the disruptive impact of giant tech companies on healthcare


A 2017 research project, which tested 18 FDA-approved digital blood glucose monitoring (BGM) systems, which are used daily by millions of people with diabetes to check the concentration of glucose in their blood, found that only 6 were accurate. The research, led by David Klonoff of the Diabetes Research Institute at San Mateo, California, was funded by Abbott Laboratories.
 
This Commentary describes both traditional and next-generation BGM systems, and Klonoff’s research. The Commentary suggests that BGM systems are just one part of a vast, global, rapidly growing market for consumer healthcare devices, and argues that the most valuable aspect of these devices is the data they collect. With some notable exceptions, healthcare professionals do not optimally utilize these data to enhance care and reduce costs. This has created for an opportunity for technology companies to enter the healthcare market and re-engineer primary care. The one thing, which might slow the march of giant technology companies into mainstream healthcare, is the privacy issue.
 

Traditional and next-generation BGM systems
 
Traditional BGM systems
Regularly, each day, BGM systems are used by millions of people with diabetes to help them manage their condition. Managing diabetes varies from individual to individual, and peoples with diabetes usually self-monitor their blood glucose concentration from a small drop of capillary blood taken from a finger prick. They then apply the blood to a chemically active disposable 'test-strip'. Different manufacturers use different technology, but most systems measure an electrical characteristic, and use this to determine the glucose level in the blood. Such monitoring is the most common way for a person with diabetes to understand how different foods, medications, and activities affect their condition. The challenge for individuals with diabetes is that blood glucose levels have to be tested up to 12 times a day. People obliged to do this find finger pricking painful, inconvenient and intrusive, and, as a consequence, many people with diabetes do not check their glucose levels as frequently as they should, and this can have significant health implications. If your levels drop too low, you face the threat of hypoglycemia, which can cause confusion or disorientation, and in its most severe forms, loss of consciousness, coma or even death. Conversely, if your blood glucose levels are too high over a long period, you risk heart disease, blindness, renal failure and lower limb amputation.
 

Next generation BGM system
Abbott Laboratories Inc. markets a BGM system, which eliminates the need for routine finger pricks that are necessary when using traditional glucose monitors. Instead of finger pricks and strips, the BGM system, which measures interstitial fluid glucose levels, comprises a small sensor and a reader. An optional companion app for Android mobile devices is also available. The sensor is a few centimetres in diameter and is designed to stay in place for 10 days. It is applied to the skin, usually on the upper arm. A thin (0.4 mm), flexible and sterile fibre within the sensor is inserted in the skin to a depth of 5 mm. The fibre draws interstitial fluid from the muscle into the sensor, where glucose levels are automatically measured every minute and stored at 15-minute intervals for 8 hours. Glucose levels can be seen at any time by scanning the reader over the sensor. When scanned the sensor provides an answer immediately. It also shows an 8-hour history of your blood glucose levels, and a trend arrow showing the direction your glucose is heading. The device avoids the pain, and inconvenience caused by finger-prick sampling, which can deter people with diabetes from taking regular measurements. In the UK the system costs £58 for the reader, plus £58 for a disposable sensor, which must be replaced every 10 days and from November 2017 have been available on the NHSAbbott Laboratories is a global NASDAQ traded US MedTech Company, with a market cap of US$86bn; annual revenues of US$21bn, and a diabetes care division, which produces annual revenues of some US$600m.
 
Klonoff’s research on BGM systems

BGM systems used by Klonoff and his team for their research were acquired over-the-counter and independent of their manufacturers. All were tested according to a protocol developed by a panel of experts in BGM surveillance testing.
 
Klonoff’s research specified that for a BGM system to be compliant, a blood glucose value must be within 15% of a reference plasma value for a blood glucose >100 mg/dl, and within 15 mg/dl of a reference plasma value for a blood glucose approved” a BGM system had to pass all 3 trials.  Only 6 out of 18 passed by achieving an overall compliance rate of 95% or higher. 

 

The FDA
Klonoff’s findings add credibility to patients’ concerns about the accuracy of BGM systems, which triggered responses from both manufactures and the US Food and Drug Administration  (FDA). Manufacturers suggest that increasing the accuracy of BGM systems would raise their costs, and reduce their availability, which patients do not want. The FDA tightened approvals for BGM systems, and in 2016 issued 2 sets of guidelines, one for clinical settings, and another for personal home-use. The guidelines only apply to new products, and do not impact BGM systems already on the market. So while the FDA’s tighter accuracy requirements are a positive change, there are a significant number of less-accurate BGM systems still on the market. 
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The convergence of MedTech and pharma and the role of biosensors

 

Next-generation BGM systems
Next generation BGM systems use ‘sensing’ technology, and have the capacity to automatically track and send blood glucose readings to the user’s smartphone, then onto their healthcare provider through the cloud where they can be amalgamated with other data. Analytics can then track an individual’s data, and compare them to larger aggregated data sets to detect trends, and provide personalized care.

Large rapidly growing remote self-managed device market

Although BGM systems address a vast global market, they represent just one part of a much larger, rapidly growing, remote monitoring market to help prevent and self-manage all chronic lifetime conditions, while improving healthcare utilization, and reducing costs. In 2015 some 165,000 healthcare apps were downloaded more than 3bn times. Of these, 44% were medical apps, and 12% were apps for managing chronic lifetime conditions. Today, mobile devices enable people to use their smartphones to inspect their eardrums, detect sleep apnoea, test haemoglobin, vital signs such as blood pressure, and oxygen concentration in the blood. This is a significant advance from the early precursor of activity tracker and step counting.

Chronic lifetime conditions
21st century healthcare in developed countries is predominantly about managing chronic lifetime illnesses such as diabetes, cancer, heart disease and respiratory conditions. These 4 diseases have high prevalence levels, relatively poor outcomes, and account for the overwhelming proportion of healthcare costs. For instance, in the US alone, almost 50% of adults (117m) suffer from a chronic lifetime condition, and 25% have multiple chronic conditions. 86% of America’s $2.7 trillion annual health care expenditures are for people with chronic health conditions. This chronic disease pattern is replicated throughout the developed world, and has significant healthcare utilization and cost implications for public and private payers, individuals, and families.
 
Healthcare providers tend not to optimally utilize data

Although personal remote devices are increasingly important in the management of chronic conditions, the data these devices create are underutilized, despite their potential for improving outcomes and reducing costs. This is partly because doctors and health providers neither have the capacity nor the resources to exploit the full potential of these data; partly because doctors tend to resist technology to improve doctor-patient interactions, and partly because remote healthcare devices have not been validated for clinical use. 

Validation
Although health professionals tend to prefer to use more expensive medical grade devices, which ensure data validity, but often drive up costs, research validating the data collected by remote self-managed devices for clinical use is beginning to emerge. In 2016 Analog Devices, a US multinational semiconductor company specializing in data conversion and signal processing technology, and LifeQa private US company with advanced bio-mathematical capabilities, announced a joint venture to establish whether data from wearable’s are accurate enough for clinical use.
 
A study published in 2017 in the journal Nature Biotechnologyprovides some validation for data derived from apps to be used clinically. Using ResearchKit, an open source framework introduced by Apple in 2015 that allows researchers and developers to create powerful apps for medical research, the 6-month study enrolled 7,600 smartphone users who completed surveys on how they used an app to manage their asthma. Researchers then compared these patient-reported data with similar data from traditional asthma research, and found that there were no significant differences. Although there still remains some methodological challenges, the findings gave scientists confidence that data derived from an app could be reliable enough for clinical research. If data from self-managed remote monitoring devices are validated, then such devices could be used to unobtrusively and cost effectively enter the daily lives of patients to collect meaningful healthcare patient data, which could be used to enhance outcomes. Early research adopters of ResearchKit include the University of Oxford, Stanford Medicine, and the Dana-Farber Cancer Institute.

 
Giant technology companies entering healthcare market
 
The increasing validation of data generated by mobile devices and the continued underutilization of such data by health providers has created an opportunity for giant global technology companies to enter the healthcare market by: (i) developing and marketing self-monitoring devices directly to consumers, (ii) collecting, integrating, storing and analysing data generated by these remote devices, and (iii) supporting research initiatives to validate data from remote devices for clinical use.
 

Apple Inc.
Just one example of giant technology companies entering the healthcare market is Apple Inc., which has a market cap of about US$1tn and 700m users worldwide. In 2017, Apple announced that it has been testing a BGM system, which pairs with the company’s existing Watch wearable. In August 2017, the US Patent and Trademark Office officially published a series of 50 newly granted patents to Apple. One covers an invention relating to health data, and more specifically to a smartphone that computes health data. 
 
The technology involves emitting light onto a user’s body part and measuring the amount of light reflected back. This data can then help to determine body fat, breathing and even emotional health. This, and other patents issued to Apple fuel rumors that the company is preparing to turn its flagship smartphone into a predominantly healthcare-focused device.

 
Takeaway
 
Given the size and momentum of technology giants entering the healthcare market, and given the powerful demographic, technological, social and economic drivers of this market, it seems reasonable to assume that in the medium term, giant technology companies are well positioned to dis-intermediate primary care doctors, and re-engineer primary care. One thing that could slow this march, is the question of privacy. Health records are as private as private gets - from alcohol or drug abuse to sexually transmitted diseases or details of abortions: things we may never want to reveal to employers, friends or even family members. Significantly, these data are permanent, and privacy at this point is non-negotiable.
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  • 'Drunkorexia' is a growing and dangerous trend among young people to eat less, purge or exercise excessively before binge drinking
  • Purging prior to drinking includes vomiting, laxatives or self-starvation
  • The intention is to save calories for binge-drinking
  • 41% of 18 to 24 year olds in a 2016 survey of 3,000 say they are not concerned about their overall health
  • Health providers are wasting millions on traditional healthcare education
  • Experts say we need to rethink how to encourage people to assume greater personal responsibility and accountability for their health
  • Healthcare providers have failed to leverage ubiquitous technologies and people’s changed lifestyles to engage and educate patients
  • To reduce the burden of drunkorexia healthcare providers will need to gain a better understanding of patients’ behaviors and ubiquitous 21st century technologies

Drunkorexia: a devastating and costly growing condition
 
Drunkorexia is using extreme weight control methods as a means to compensate for planned binge drinking. The French refer to it as alcoolorexie: l'ivresse sans les kilos. Manger moins pour être ivre plus vite et ne pas trop grossir. Drunkorexia is a term coined by the media to describe the combination of disordered eating and heavy alcohol consumption. The condition is gaining recognition in the fields of co-occurring disorders (people who have both substance use and mental health disorders), psychiatry, and addictionology. The term attempts to reconcile 2 conflicting cultures: binge drinking and a desire to be thin. The former involves ingesting significant amounts of unwanted extra calories, so people starve themselves in preparation for a night out drinking. Drunkorexia results in significant human costs from hypoglycaemia, depression, memory loss, and liver disease, and substantial and unnecessary costs to healthcare providers.
 
Experts argue that traditional methods to lower the burden of drunkorexia cost millions and are failing, and suggest there is an urgent need to, “rethink how we try and engage with people and try and encourage them to assume greater personal responsibility and accountability for their health.” This Commentary describes drunkorexia, reports some research findings on the condition, and suggests health providers would lower the large and growing burden of drunkorexia by leveraging ubiquitous technologies such as the Internet and smartphones.
 
Not an officially medical diagnosis

Drunkorexia is not an officially recognized medical condition. There is no mention of it in Mediline Plus, the US National Institutes of Health's online medical information service produced by the National Library of Medicine. It is not mentioned in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), which is published by the American Psychiatric Association, and popularly known as  “The Psychiatrist’s Bible”. Neither is the condition included in the World Health Organization's International Classification of Disease; nor in WebMD, the UK’s NHS online, NHS Choices, and the UK’s General Medical Council’s (GMC) website.
Signs and symptoms
 
Signs and symptoms include calorie counting to ensure no weight is gained when binge drinking, missing meals to conserve calories so that they can be spent on the consumption of alcohol, over-exercising to counterbalance calorie intake, and binge drinking to vomit previously digested food.

A dangerous condition

Despite evidence to suggest that more people are turning away from alcohol and becoming teetotallers, the prevalence of drunkorexia is increasing.

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Orthorexia: when eating healthily becomes unhealthy

It is a dangerous trend, especially among young people, which can lead to an array of physical and psychological consequences. For example, drinking in a state of malnutrition can predispose you to a higher rate of blackouts, alcohol poisoning, alcohol-related injury, violence, or illness. Drinking on an empty stomach allows ethanol to reach the blood system more rapidly, and raises your blood alcohol content often with dangerous speed. This can render you more vulnerable to alcohol-related brain damage. In addition, alcohol abuse can have a detrimental impact on hydration and your body's retention of minerals and nutrients, further exacerbating the consequences of malnutrition, and damaging your cognitive faculties. This can lead to short and long-term cognitive problems, including difficulty concentrating and making decisions, which ultimately can have a negative impact on academic and work-related performance. Drunkorexia also increases the risk of developing more serious eating disorders and alcohol abuse problems. As binge drinking is involved there is also a greater risk of violence, of risky sexual behavior, alcohol poisoning, substance abuse and chronic disease later in life.
 
Research

Although much of the research on drunkorexia is focused on university students, the condition is believed to be more widely spread. A challenge for researchers is the attitudes of university administrators and parents who are reluctant to admit that there is a problem either in their institutions or homes. The condition is often dismissed as a rite-of-passage. Notwithstanding, there have been a number of research studies, which suggest that drunkorexia is significant, growing fast and dangerous.
 
University of Missouri study

A 2011 University of Missouri study of the relationship between alcohol misuse and disordered eating, including calorie restriction and purging, suggests that drunkorexia is predominately a young women’s condition, which could affect their long-term health. The study found that 16% of respondents reported restricting calories to "save them" for drinking. 67% of students who restrict calories prior to binge drinking did so to prevent weight gain, while 21% did so to facilitate alcohol intoxication. 3 times as many women reported engaging in the behavior than men, and their stated motivations included “preventing weight gain”, “getting intoxicated faster” and “saving money”, which could be either spent on food or to buy alcohol. According to Victoria Osborne, Professor of Social Work and Public Health at the university, and lead author of the study, drunkorexia can have dangerous cognitive, behavioural and physical consequences. It also puts people at risk for developing more serious eating disorders or addiction problems.
 
Australian study

In an Australian context, a 2013 study surveyed 139 female university students, aged between 18 and 29 to examine compensatory eating and behaviors in response to alcohol consumption to test for drunkorexia symptomatology. 79% of respondents engaged in characterized drunkorexia behavior. The study also found that social norms of drinking, and the social norms associated with body image and thinness, impacted significantly upon the motivation for these behaviors.
 
University of Houston study

Findings of a University of Houston study on drunkorexia presented at the 2016 annual meeting of the Research Society on Alcoholism in New Orleans, found that 80% of the 1,200 students surveyed had at least one heavy night of drinking in the previous month, and engaged in drunkorexic behavior. The methods of purging prior to drinking include vomiting, use of laxatives or missing meals. The study also reported that the condition is not limited to the US, and is present in both men and women.
 
Benenden’s National Health study
 
Healthcare group Benenden’s 2016 National Health Report suggests that drunkorexia is gaining ground among young people in the UK, and creating concerns among healthcare professionals. According to the study, young people in the UK prefer to eat less in order to “save” calories for alcohol consumption. Of the 3,000 people surveyed, 2 out of 5 (41%), between the ages of 18 and 24 said they eat healthily only to look good, but are not concerned about their overall health. According to the report, “Pressure to be slim, an awareness of exercising calorie control, and peer pressure to drink large amounts of alcohol are all factors in this phenomenon”, adding that a growing number of men are following this trend.

Survey participants were also asked general questions about healthy lifestyles. “By and large, the findings highlight that the public is in denial about how much they think they know about healthy eating, they claim to be near-experts, but when drilling down to real-life examples, the vast majority of respondents failed to choose the right answer to simple diet-related questions, or the healthier option when offered the choice between everyday food and drinks,” the report found.
 
There also seems to be a woeful lack of awareness about basic dietary advice, despite legislation and attempts by the food production and manufacturing industry. It isn't clear whether this is down to poor education or a lack of interest, but I think we need to rethink how we try and engage with people and try and encourage them to assume greater personal responsibility and accountability for their health," says Dr John Giles, Benenden’s medical director.

Traditional healthcare providers failing

Traditional healthcare providers continue to waste billions on failing traditional methods of engaging and educating patients. Increasing self-management of your health is relevant, especially as primary care resources are shrinking as the prevalence of drunkorexia is rapidly increasing. However, achieving effective education and self-management requires a fundamental transformation of the way healthcare is delivered. The majority of people living with drunkorexia regularly use their smartphones for 24-hour banking, education, entertainment, shopping, and dating. Health providers have failed to effectively leverage this vast and rapidly growing free infrastructure and people’s changed lifestyles to introduce effective educational support systems to enhance the quality of drunkorexia care, increase efficiency, and improve patient outcomes. Today, mobile technology is part of everyday life and people expect to be connected with their relevant healthcare providers 24-7, 365 days of the year from anywhere. 

Takeaways

A necessary pre-requisite for effective healthcare education to reduce the burden of drunkorexia is the actual engagement of people with the condition. Once patients are engaged, education should inform and empower people, and provide them with access to continuous self-management support. This is substantially different to the way traditional healthcare education is delivered as it transforms the patient–educator relationship into a continuous, rich, collaborative partnership. 
 

 

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  • Many people still view China as a ‘copycat’ economy, but this is rapidly changing
  • China is:
    • Pursuing a multi-billion dollar-15 year strategy to become a world leader in genomic engineering and personalized medicine
    • Systematically upgrading and incentivizing its large and growing pool of scientists who are making important breakthroughs in the life sciences
    • Empowering and encouraging state owned and private life science companies to own and control the capacity to transform genomic, clinical and personal data into personalized medicines
  • The difference in national approaches to individualism and privacy confers an added competitive advantage to China and its life science ambitions
  • China’s approach to individualism and privacy issues could have implications for society


The global competition to translate genomic data into personal medical therapies

 

PART 2
 
China is no longer a low cost ‘copycat’ economy. Indeed, it has bold plans to become a preeminent global force in genomic engineering to prevent and manage devastating and costly diseases. Here we briefly describe aspects of China’s multibillion-dollar, government-backed initiative, to own and control significant capacity to transform genomic data into precision medicines. This is not only a ‘numbers’ game. China’s drive to achieve its life science ambitions is also advantaged by a different approach to ‘individualism’ and privacy compared to that of the US; and this could have far-reaching implications for future civilizations.

Uneven playing field
Genomic engineering and precision medicine have the potential to revolutionize how we prevent and treat intractable diseases. Who owns the intellectual property associated with genomic engineering, and who first exploits it, will reap significant commercial benefits in the future. However, genomic technologies are not like any other. This is because genetically modifying human genomes could trigger genetic changes across future generations. Misuse of such technologies therefore could result in serious harm for individuals and their families. On the other hand, over regulation of genomic engineering could slow or even derail the prevention and treatment of devastating and costly diseases. Establishing a balance, which supports measures to mitigate misuse of genomic technologies while allowing the advancement of precision medicine is critical. However, this has proven difficult to establish internationally.

Chinese scientists have crossed an ethical line
Chinese culture interprets individualism and privacy differently to American culture, and therefore China responds differently to certain ethical standards compared to the US and some other Western nations. Indeed, national differences were ignited in 2012 when Chinese researchers published their findings of the world’s first endeavors to modify the genomes of human embryos to confer genetic resistance to certain diseases. Because such modifications are heritable critics argued that the Chinese scientists crossed a significant ethical line, and this was the start of a “slippery slope”, which could eventually lead to the creation of a two-tiered society, with elite citizens genetically engineered to be smarter, healthier and to live longer, and an underclass of biologically run-of-the-mill human beings.

International code of conduct called for but not adhered to
2 prominent scientific journals, Nature and Science, rejected the Chinese research papers reporting world-first scientific breakthroughs on ethical grounds. Subsequently, Nature published a note calling for a global moratorium on the genetic modification of human embryos, suggesting that there are “grave concerns” about the ethics and safety of the technology. 40 countries have banned genetically modifying human embryos. In 2016, a report from the UK’s Nuffield Council on Bioethics stressed the importance of an internationally agreed ethical code of conduct before genomic engineering develops further.
 
In 2017 an influential US science advisory group formed by the National Academy of Sciences and the National Academy of Medicine gave ‘lukewarm’ support to the modification of human embryos to prevent, “serious diseases and disabilities” in cases only where there are no other “reasonable alternatives”. The French oppose genomic modification, the Dutch and the Swedes support it, and a recent Nature editorial suggested that the EU is, “habitually paralyzed whenever genetic modification is discussed”. In the meantime, clinical studies, which involve genomic engineering, are advancing at a pace in China.

With regard to genome testing, western human rights activists have warned that China is targeting vulnerable groups and minorities to help build vast genomic databases without appropriate protection for individuals. Those include migrant workers, political dissidents and ethnic or religious minorities such as the Muslim Uighurs in China's far western Xinjiang region. Xinjiang authorities are reported to have invested some US$10bn in advanced sequencing equipment to enhance the collection and indexing of these data.


Different national interpretations of ‘individualism’
Individualism’, which is at the core of ethical considerations of genomic engineering, is challenging to define because of its different cultural, political and social interpretations. For example, following the French Revolution, individualisme was used pejoratively in France to signify the sources of social dissolution and anarchy, and the elevation of individual interests above those of the collective. The contemporary Chinese interpretation of individualism is similar to the early 19th century French interpretation. It does not stress a person’s uniqueness and separation from the State, but emphasizes an individual’s social; contract and harmony with the State. By contrast, American individualism is perceived as an inalienable natural right of all citizens, and independent of the State.

Further, American individuals are actively encouraged to challenge and influence the government and its regulatory bodies, whereas in China citizens are expected to unquestionably support the State. China is a one party state, where individuals generally accept that their government and its leaders represent their higher interests, and most citizens therefore accept the fact that they are not expected to challenge and influence policies determined by the State and its leaders. This difference provides China with a significant competitive advantage in its endeavors to become a world leader in the life sciences,

 
Human capital

By 2025, some 2bn human genomes could be sequenced. This not only presents ethical challenges, but also significant human capital challenges. The development of personalized medicines is predicated upon the ability to aggregate and process vast amounts of individual genomic, physiological, health, environmental and lifestyle data. This requires next generation sequencing technologies, smart AI systems, and advanced data managers of which there is a global shortage. Thus, the cultivation and recruitment of appropriate human capital is central to competing within the rapidly evolving international genomic engineering marketplace. The fact that China has a more efficacious strategy to achieve this than the US and other Western democracies provides it with another significant competitive advantage.

STEM graduates
Since the turn of the century, China has been engaged in a silent revolution to substantially increase its pool of graduates in science, technology, engineering and mathematics (STEM), while the pool of such graduates in the US and other Western democracies has been shrinking. In 2016, China was building the equivalent of almost one university a week, which has resulted in a significant shift in the world's population of STEM graduates. According to the World Economic Forumin 2016, the number of people graduating in China and India were respectively 4.7m and 2.6m, while in the US only 568,000 graduated. In 2013, 40% of all Chinese graduates finished a degree in STEM, over twice the share of that in US universities. In 2016, India had the most graduates of any country worldwide with 78m, China followed closely with 77.7m, and the US came third with 67m graduates.

University education thriving in China and struggling in the West
In addition to China being ahead of both the US and Europe in producing STEM graduates; the gap behind the top 2 countries and the US is widening. Projections suggest that by 2030 the number of 25 to 34-year-old graduates in China will increase by a further 300%, compared with an expected rise of around 30% in the US and Europe. In the US students have been struggling to afford university fees, and most European countries have put a brake on expanding their universities by either not making public investments or restricting universities to raise money themselves.
 

The increasing impact of Chinese life sciences
China's rapid expansion in STEM graduates suggests that the future might be different to the past. Today, China has more graduate researchers than any other country, and it is rapidly catching up with the US in the number of scientific papers published. The first published papers to describe genetic modifications of human embryos came from Chinese scientists

Further, according to the World Intellectual Property Organization, domestic patent applications inside China have soared from zero at the start of the 21st century to some 928,000 in 2014: 40% more than the US’s 579,000, and almost 3 times that of Japan’s 326,000.
 

China’s strategy to reverse the brain drain
Complementing China’s prioritization of domestic STEM education is its “Qianren Jihua” (Thousand Talents) strategy. This, established in the wake of the 2008 global financial crisis to reverse China’s brain drain, trawls the world to seek and attract highly skilled human capital to China by offering them incentives. Qianren Jihua’s objective is to encourage STEM qualified Chinese ex patriots to return to China, and encourage those who already reside in China to stay, and together help create an internationally competitive university sector by increasing the production of world-class research to support China’s plans to dominate precision medicine and life sciences.
 
Government commitment

In 2016, China announced plans for a multi-billion dollar project to enhance its competitiveness by becoming a global leader in molecular science and genomics. China is committed to supporting at least three principal institutions, including the Beijing Genomics Institute (BGI), to sequence the genomes of many millions.
 
In addition to investments at home, China also is investing in centers similar to that of BGI abroad. Over the past 2 years China has invested more than US$110bn on technology M&A deals, which it justifies by suggesting that emerging technologies are, “the main battlefields of the economy”. Early in 2017 BGI announced the launch of a US Innovation Center, co-located in Seattle and San Jose. The Seattle organization is focused on precision medicine and includes collaborations with the University of Washington, the Allen Institute for Brain Science, and the Bill and Melinda Gates Foundation. The San Jose facility, where BGI already has a laboratory employing over 100, supports its ambitions to develop next-generation sequencing technologies, which until now have been dominated by the US sequencing company Illumina.


Changing structure of China’s economy
Some suggest that China’s rise on the world life sciences stage will be short lived because the nation is in the midst of a challenging transition to a slower-growing, consumption-driven economy, and therefore will not be able to sustain such levels of investment; and this will dent its ambition to become a global player in genomic science. An alternative argument suggests slower growth forces China to act smarter, and this is what drives its precision medicine ambitions.

Between 1985 and 2015, China’s annual GDP rose, on average, by 9.4%. Fuelling this growth was a steady supply of workers entering the labour force and massive government led infrastructure investments. Now, because of China’s ageing population, its labour capacity has peaked and started to decline. Without labour force expansion, and investment constrained by debt, China is obliged to rely more heavily on innovation to improve its productivity. And this drives, rather than slows, China’s strategy to become a world leader in genomic technologies and personalized medicine.
 

China’s economic growth is slowing, but its production of scientific research is growing
Although China’s economy is slowing, it is still comparatively large. In 2000, China spent as much on R&D as France; now it invests more in genomics than the EU, when adjusted for the purchasing power of its currency. Today, China produces more research articles than any other nation, apart from the US, and its authors’ feature on around 20% of the world’s most-cited peer reviewed papers. Top Chinese scientific institutions are breaking into lists of the world’s best, and the nation has created some unparalleled research facilities. Even now, every 16 weeks China produces a Greece-size economy, and doubles the entire size of its economy every 7 years. Today, China has an economy similar in size to that of the US, and most projections suggest that, over the next 2 decades, China’s economy will dwarf that of the US.
 
Takeaways

China is cloning its successful strategy to own and control significant mineral and mining rights to the life sciences. Over the past 20 years China has actively pursued mining deals in different global geographies, and now controls significant mining rights and mineral assets in Africa and a few other countries. This allows China to affect the aggregate supply and world market prices of certain natural resources. Now, China is cloning this commercially successful strategy to the life sciences, and has empowered and encouraged a number of state owned and private companies to own and control genomic engineering and precision medicine. China’s single-minded determination to become a world leader in life sciences, and its interpretation of individualism and privacy issues could have far reaching implications for the future of humanity.
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  • In 2003 the US first discovered the genome and became the preeminent nation in genomics
  • This could change
  • World power and influence have moved East
  • China has invested heavily in genomic technologies and established itself as a significant competitive force in precision medicine
  • Ownership of intellectual property and knowhow is key to driving national wealth 
 

The global competition to translate genomic data into personal medical therapies

 

PART 1

Professor Dame Sally Davies, England’s Chief Medical Officer, is right. (Genomics) “has the potential to change medicine forever. . . . The age of precision medicine is now, and the NHS must act fast to keep its place at the forefront of global science.”
 
It is doubtful whether the UK will be able to maintain its place as a global frontrunner in genomics and personalized medicine. It is even doubtful whether the US, the first nation to discover the genome, and which became preeminent in genomic research, will be able to maintain its position. China, with its well-funded strategy to become the world’s leader in genomics and targeted therapies, is likely to usurp the UK and the US in the next decade.
 
This Commentary is in 2 parts. Part 1 provides a brief description of the global scientific competition between nation states to turn genomic data into medical benefits. China’s rise, which is described, could have significant implications for the future ownership of medical innovations, data protection, and bio-security. Part 2, which follows in 2 weeks, describes some of the ethical, privacy, human capital and economic challenges associated with transforming genomic data into effective personal therapies.
  
Turning genomic data into medical benefits
 
Turning genomic data into medical benefits is very demanding. It requires a committed government willing and able to spend billions, a deep understanding of the relationship between genes and physiological traits, next generation sequencing technologies, artificial intelligence (AI) systems to identify patterns in petabytes (1 petabyte is equivalent to 1m gigabytes) of complex data, world-class bio-informaticians, who are in short supply; comprehensive and sophisticated bio depositories, a living bio bank, a secure data center, digitization synthesis and editing platforms, and petabytes of both genomic, clinical, and personal data. Before describing how the UK, US and China are endeavoring to transform genomic data into personal medicine, let us refresh our understanding of genomics.

  
Genomics, the Human Genomic Project and epigenetics
 
It is widely understood that your genes are responsible for passing specific features or diseases from one generation to the next via DNA, and genetics is the study of the way this is done. However, it is less widely known that your genes are influenced by environmental and other factors. Scientists have demonstrated that inherited genes are not static, and lifestyles and environmental factors can precipitate a chemical reaction within your body that could permanently alter the way your genes react. This environmentally triggered gene expression, or epigenetic imprint, can be bad, such as a disease; or good, such as a tolerant predisposition. Epigenetics is still developing as an area of research, but it has demonstrated that preventing and managing disease is as much to do with lifestyles and the environment, as it is to do with inherited genes and drugs. If environmental exposure can trigger a chemical change in your genes that results in the onset of disease, then scientists might be able to pharmacologically manipulate the same mechanisms in order to reverse the disease.
 
DNA is constantly subject to mutations, which can lead to missing or malformed proteins, and that can lead to disease. You all start your lives with some mutations, which are inherited from your parents, and are called germ-line mutations. However, you can also acquire mutations during your lifetime. Some happen during cell division, when DNA gets duplicated, other mutations are caused when environmental factors including, UV radiation, chemicals, and viruses damage DNA.

You have a complete set of genes in almost every healthy cell in your body. One set of all these genes, (plus the DNA between them), is called a genome. The genome is the collection of 20,000 genes, including 3.2bn letters of DNA, which make up an individual. We all share about 99.8% of the genome. The secrets of your individuality, and also of the diseases you are prone to, lie in the other 0.2%, which is about 3 or 4m letters of DNA. The genome is known as ‘the blueprint’ of life’, and genomics is the study of the whole genome, and how it works. Whole genome sequencing (WGS) is the process of determining the complete DNA sequence of an organism's genome at a point in time.
 
‘The Human Genome Project’ officially began in 1990 as an international research effort to determine a complete and accurate sequence of the 3bn DNA base pairs, which make up the human genome, and to find all of the estimated 20 to 25,000 human genes. The project was completed in April 2003. This first sequencing of the human genome took 13 years and cost some US$3bn. Today, it takes a couple of days to sequence a genome, and costs range from US$260 for targeted sequencing to some US$4,000 for WGS. Despite the rapidly improving capacity to read, sequence and edit the information contained in the human genome, we still do not understand most of the genome’s functions and how they impact our physiology and health.

 
Roger Kornberg explains the importance of genomics
 
Roger Kornberg, Professor of Structural Biology at Stanford University, and 2006 Nobel Laureate for Chemistry, explains the significance of sequencing the human genome, “The determination of the human genome sequence and the associated activity called genomics; and the purposes for which they may be put for medical uses, takes several forms. The knowledge of the sequence enables us to identify every component of the body responsible for all of the processes of life. In particular, to identify any component that is either defective or whose activity we may adjust to address a problem or a condition. So the human genome sequence makes available to us the entire array of potential targets for drug development. . . . . The second way in which the sequence and the associated science of genomics play an important role is in regard to individual variations. Not every human genome sequence is the same. There is a wide variation, which in the first instance is manifest in our different appearances and capabilities. But it goes far deeper because it is also reflected in our different responses to invasion by microorganisms, to the development of cancer and to our susceptibility to disease in general. It will ultimately be possible, by analyzing individual genome sequences to construct a profile of such susceptibilities for every individual, a profile of the response to pharmaceuticals for every individual, and thus to tailor medicines to the needs of individuals.” See video below.
 
 
UK’s endeavors to transform genomic data into personal therapies

In 2013 the UK government set up Genomics England, a company charged with sequencing 100,000 whole genomes by 2017. In 2014, the government announced a £78m deal with Illumina, a US sequencing company, to provide Genomics England with next generation whole genome sequencing services. At the same time the Wellcome Trust invested £27m in a state-of-the-art sequencing hub to enable Genomics England to become part of the Wellcome Trust’s Genome Campus in Hinxton, near Cambridge, England. In 2015, the UK government pledged £215m to Genomics England.
 
DNA testing and cancer
DNA sequencing is simply the process of reading the code that is in any organism . . . It’s essentially a technology that allows us to extract DNA from a cell, or many cells, pass it through a sophisticated machine and read out the sequence for that organism or individual,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia; see video below. “DNA testing has becomeincreasingly widespread because advances in technology have made the opportunity to sequence the DNA of individuals affordable and rapid  . . . DNA testing in the context of cancer can be useful to identify a genetic risk of cancer, and to help clinicians make therapeutic decisions for someone who has cancer,” says Bowtell, see video below.
 

What is DNA sequencing?


What are the advanteges of a person having a DNA test?

Need for National Genome Board
Despite significant investments by the UK government, Professor Davies, England’s Chief Medical Officer, complained in her 2017 Annual Report that genomic testing in the UK is like a “cottage industry” and recommended setting up a new National Genome Board tasked with making whole genome sequencing (WGS) standard practice in the NHS across cancer care, as well as some other areas of medicine, within the next 5 years.
 
USA’s endeavors to transform genomic data into personal therapies

In early 2015 President Obama announced plans to launch a $215m public-private precision medicine initiative, which involved the health records and DNA of 1m people, to leverage advances in genomics with the intention of accelerating biomedical discoveries in the hope of yielding more personalized medical treatments for patients. A White House spokesperson described this as “a game changer that holds the potential to revolutionize how we approach health in the US and around the world.
 

Data management challenges
The American plan did not seek to create a single bio-bank, but instead chose a distributive approach that combines data from over 200 large on-going health studies, which together involves some 2m people. The ability of computer systems or software to exchange and make use of information stored in such diverse medical records, and numerous gene databases presents a significant challenge for the US plan. According to Bowtell, “Data sharing is widespread in an ethically appropriate way between research institutions and clinical groups. The main obstacles to more effective sharing of information are the very substantial informatics challenges. Often health systems have their own particular ways of coding information, which are not cross compatible between different jurisdictions. Hospitals are limited in their ability to capture information because it takes time and effort. Often information that could be useful to researchers, and ultimately to patients, is lost, just because the data are not being systematically collected.” See video below.
 
 
 
China’s endeavors to transform genomic data into personal therapies

In 2016, the Chinese government launched a US$9bn-15-year endeavor aimed at turning China into a global scientific leader by harnessing computing and AI technologies for interpreting genomic and health data.  This positions China to eclipse similar UK and US initiatives.
 

Virtuous circle
Transforming genomic data to medical therapies is more than a numbers race. Chinese scientists are gaining access to ever growing amounts of human genomic data, and developing the machine-learning capabilities required to transform these data into sophisticated diagnostics and therapeutics, which are expected to drive the economy of the future.  The more genomic data a nation has the better its potential clinical outcomes. The better a nation’s clinical outcomes the more data a nation can collect. The more data a nation collects the more talent a nation attracts. The more talent a nation attracts the better its clinical outcomes.
 

The Beijing Genomics Institute
In 2010 China became the global leader in DNA sequencing because of one company: the Beijing Genomics Institute (BGI), which was created in 1999 as a non-governmental independent research institute, then affiliated to the Chinese Academy of Sciences, in order to participate in the Human Genome Project as China's representative. In 2010, BGI received US$1.5bn from the China Development Bank, and established branches in the US and Europe. In 2011 BGI employed 4,000 scientists and technicians. While BGI has had a chequered history, today it is one of the world’s most comprehensive and sophisticated bio depositories.

The China National GeneBank
In 2016 BGI-Shenzhen established the China National GeneBank (CNGB) on a 47,500sq.m site. This is the first national gene bank to integrate a large-scale bio-repository and a genomic database, with a goal of enabling breakthroughs in human health research. The gene-bank is supported by BGI’s high-throughput sequencing and bio-informatics capacity, and will not only provide a repository for biological collection, but more importantly, it is expected to develop a novel platform to further understand genomic mechanisms of life. During the first phase of its development the CNGB will have saved more than 10m bio-samples, and have storage capacity for 20 petabytes (20m gigabytes) of data, which are expected to increase to 500 petabytes in the second phase of its development. The CNGB represents the new generation of a genetic resource repository, bioinformatics database, knowledge database and a tool library, “to systematically store, read, understand, write, and apply genetic data,” says Mei Yonghong, its Director.

Whole-genome sequencing for $100
The CNGB could also help to bring down the cost of genomic sequencing. It is currently possible to sequence an individual's entire genome for under US$1,000, but the CNGB aims to reduce the price to US$152. Meanwhile, researchers at Complete Genomicsa US company acquired by BGI in 2013, which has developed and commercialized a DNA sequencing platform for human genome sequencing and analysis, are pushing the technology further to enable whole-genome sequencing for US$100 per sample. China's share of the world's sequencing-capacity is estimated to be between 20% and 30%, which is lower than when BGI was in its heyday, but expected to increase fast. “Sequencing capacity is rising rapidly everywhere, but it's rising more rapidly in China than anywhere else,” says Richard Daly, CEO, DNAnexus, a US company, which supplies cloud platforms for large-scale genomics data.

The intersection of genomics and AI
Making sense of 1m human genomes is a major challenge, says Professor Jian Wang, former BGI President and co-founder, who has started another company called iCarbonX. Also based in Shenzhen, the company is at the intersection of genomics and AI. iCarbonX has raised more than US$600m, and plans to collect genomic data from more than 1m people, and complement these data with other biological information including changes in levels of proteins and metabolites. This is expected to allow iCarbonX to develop a new digital ecosystem, comprised of billions of connections between huge amounts of individuals’ biological, medical, behavioural and psychological data in order to understand how their genes interact and mutate, how diseases and aging manifest themselves in cells over time, how everyday lifestyle choices affect morbidity, and how these personal susceptibilities play a role in a wide range of treatments.

iCarbonX is expected to gather data from brain imaging, biosensors, and smart toilets, which will allow real-time monitoring of urine and faeces. The Company’s goal is to be able to study the evolution of our genome as we age and design personalized health predictions such as susceptibilities to diseases and tailored treatment options. iCarbonX’s endeavours are expected to dwarf efforts by other US Internet giants at the intersection of genomics and AI.

 
Ethical challenges

China’s single-minded objective to turn its knowhow and experience of genome sequencing into personal targeted medical therapies has made it a significant global competitive force in life sciences. However, precision medicine’s potential to revolutionize advances in how we treat diseases confers on it moral and ethical obligations. For personal therapies to be effective, it is important that genomic data are complemented with clinical and other personal data. This combination of data is as personal as personal information gets. There could be potential harm to the tested individual and family if genomic information from testing is misused. Reconciling therapy and privacy is important, because privacy issues concerning patients' genomic data can slow or derail the progression of novel personal therapies to prevent and manage intractable diseases. The stakes are high in terms of biosecurity, as genomic research is both therapeutic and a strategic element of national security. While it is crucial to leverage genomic data for future health, economic and biodefense capital, these data will also have to be appropriately managed and protected. Part 2 of this Commentary dives into these challenges a little deeper, and describes some of China’s competitive advantages in the race to become the world’s preeminent nation in genomics and precision medicine. 
 
Takeaways

Despite the endeavours of the UK and US to remain at the forefront of the international competition to transform genomic data into personalized medical therapies for some of the worlds most common and intractable diseases, it seems reasonable to assume that China is on the cusp of becoming the most dominant nation in novel personalized treatments. Notwithstanding, China’s determination to assume the global frontrunner position in genomic science might have blunted its concerns for some of the ethical issues, which surround the life sciences. To the extent that this might be the case the future of humanity might well differ significantly from the generally accepted western vision. 
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  • A number of new studies on ovarian cancer show “promising” results for patients who develop chemo-resistance
  • A Dutch study uses conventional chemotherapeutics more intensively
  • Another study uses a new class of drug discovered by the UK’s Institute of Cancer Research
  • Genetic testing is playing an increasing role in the reduction of chemo-resistance
  • Since 2014 the Royal Marsden NHS Trust Hospital in London has employed genetic profiling of ovarian cancer patients
  • The UK’s Chief Medical Officer suggests that whole genome sequencing should become standard practice on the NHS across cancer care
  • A new class of chemotherapeutic agent is directed at targeting cancers with defective DNA-damage repair
  • Improvements in cancer care have been both scientific and organizational
  • Utilizing and sequencing the treatment options for ovarian cancer may have a significant impact on the overall survival rates of patients
  • Multidisciplinary teams are transforming ovarian cancer care 
 
Improving ovarian cancer treatment 

Part II

Part-1 described ovarian cancer, the difficulties of diagnosing the disease early, and the challenges of developing effective screening mechanisms for it in pre-symptomatic women. Here, in part-2, we report new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.
 
1

Established chemotherapy agents combined and used intensively

The first study we describe is Dutch, published in 2017 in the British Journal of Cancer. It reports findings of a pioneering type of intensive chemotherapy, which was effective in 80% of patients with advanced ovarian cancer and whose first line of chemotherapy had failed. Currently, such patients have few options because more than 50% do not respond to follow-up chemotherapy.
 
Intensive combinations
The study, led by Dr. Ronald de Wit, of the Rotterdam Cancer Institute, involved 98 patients who first responded to chemotherapy only later to relapse. Patients in the study were divided into three groups according to the severity of their condition, and treated with a combination of two well established chemotherapy agents:  cisplatin and etopside, but the new treatment used the drugs much more intensively than usual.
 
Usually, chemotherapy is delivered as a course of a number of 21-day sessions (cycles) over several months. Between cycles patients are given time to recover from the toxic side effects, including neurotoxicity, nephrotoxicity, ototoxicity, and chemotherapy-induced nausea and vomiting (CINV). In de Wit’s study the combined chemotherapy drugs were given intensively, on a weekly basis, along with drugs to prevent adverse side effects.
 
Findings
Among the group of women in de Wit’s study who were most seriously ill, 46% responded to the new treatment, compared with less than 15% for current therapies. The response rates of the two groups of women who were least ill to the new treatment were 92% and 91%. This compares to responses of 50% and 20 to 30% with standard therapies. Overall, 80% of the women's tumours shrank, and 43% showed a complete response, with all signs of their cancers disappearing.
 
Immediate benefit
"We were delighted by the success of the study. The new drug combination was highly effective at keeping women alive for longer, giving real hope to those who would otherwise have had very little . . . . We were worried the women would be too ill to cope with the treatment, but in fact, they suffered relatively few side effects. And since these drugs are readily available, there's no reason why women shouldn't start to benefit from them right away," says de Wit.
 
2
 
ONX-0801 study

The second study we report was presented at the 2017 American Society of Clinical Oncology (ASCO) meeting in Chicago. It describes findings of an experimental new treatment that was found to dramatically shrink advanced ovarian cancer tumors, which researchers suggest is, “much more than anything that has been achieved in the last 10 years”.
 
“Very promising” findings
Dr. Udai Banerji, the leader of the study, is the Deputy Director of Drug Development at the UK’s Institute of Cancer Research (ICR). Banerji and his team were testing a drug, known as ONX-0801, for safety, but found that tumors, in half of the 15 women studied, shrank during the trial. A response Banerji called, “highly unusual”, and “very promising”. The drug, which is, “a completely new mechanism of action,” could add, “upward of six months to the lives of patients with minimal side effects”. If further clinical studies prove the drug’s effectiveness, it could potentially be used in early-stage ovarian cancer where, “the impact on survival may be better,” says Banerji.
 
New class of drug
ONX-0801 is the first in a new class of drug discovered by the ICR, and tested with the Royal Marsden NHS Foundation Trust. It attacks ovarian cancer by mimicking folic acid in order to enter the cancer cells. The drug then kills these cells by blocking a molecule called thymidylate synthase. ONX-0801 could be effective in treating the large group of chemo-resistant sufferers for whom there are currently limited options. Additionally, because the new therapy targets cancer cells and does not affect surrounding healthy cells, there are fewer side effects. Further, experts have developed tests to detect the cells that respond positively to this new treatment, which means oncologists can identify those women who are likely to benefit from the therapy the most.
 
Cautious note
Although the study is said to be “very promising”, Michel Coleman, Professor of Epidemiology at the London School of Hygiene & Tropical Medicine, suggests caution in interpreting its findings as it is such a small study and while, “shrinkage of tumors is important . . . it is not the same as producing the hoped-for extension of survival for women with ovarian cancer.”
 
3
 
Genetic testing

Resistance to chemotherapy can be reduced by DNA testing to obtain an increased knowledge of the molecular mechanisms of ovarian cancer pathogenesis, which facilitate personalized therapies that target certain subtypes of the disease. “Some people choose to have DNA testing because either they have developed cancer or family members have,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia. “In the context of cancer, personalized medicine is the concept that we look into the cancer cell and understand for that person what specific genetic changes have occurred in their cancer. Based on those specific changes, for that person we then decide on a type of therapy, which is most appropriate for the genetic changes that have occurred in that cancer . . . . . Typically this involves taking a sample of the cancer, running it through DNA sequencing machines, and using bioinformatics to interpret the information. Then, the results, which include gene mutations need to be interpreted by a multidisciplinary team, in order to decide the best possible treatment options for that particular patient,” says Bowtell: see videos below.
.
 
How do genetic mutations translate into personalised medicine?


How is personalised medicine implemented?
 
Mainstreaming cancer genetics
Since 2014 the Royal Marsden NHS Trust Hospital in London has employed genetic profiling of ovarian cancer patients, and have used laboratories with enhanced genetic testing capabilities to streamline and speed up processing time, lower costs, and help meet the large and growing demand for rapid, accurate and affordable genetic testing. The program called, Mainstreaming Cancer Genetics, helps women cancer patients make critical decisions about their treatment options. Currently, fewer than 33% of patients are tested, but this study spearheaded the beginning of a significant change. In her 2017 Annual Report, Professor Dame Sally Davies, England’s Chief Medical Office suggested that within the next 5 years all cancer patients should be routinely offered DNA tests on the NHS to help them select the best personalized treatments.
 

Bringing genetic testing to patients
According to Nazneen Rahman, Professor and Head of the Division of Genetics and Epidemiology at the ICR, and Head of the Cancer Genetics Unit at the Royal Marsden Hospital, London, “There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex . . . . We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital.” 
 

More people benefiting from affordable rapid advanced genetic testing
Treatment strategies that improve the selectivity of current chemotherapy have the potential to make a dramatic impact on ovarian cancer patient outcomes. The Marsden is now offering genetic tests to three times more cancer patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.” If the UK government acts on the recommendations of Davies, there could be a national center for genetic testing within the next 5 years.
 
4

PARP Inhibitors and personalized therapy
 
Since 2 seminal 2005 publications in Nature,  (Bryant et al, 2005; and Farmer et al, 2005) which reported the extremely high sensitivity of BRCA mutant cell lines to the enzyme poly (ADP-ribose) polymerase (PARP) inhibition, there has been a scientific race to exploit a new class of cancer drug called PARP inhibitors. The family of PARP inhibitors represents a widely researched and promising alternative for the targeted therapy of ovarian malignancies. Over the past few years, PARP inhibitors have successfully moved into clinical practice, and are now used to help improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer.

 
Recent (PARP) approvals
In 2014, olaparib was the first PARP inhibitor to obtain EU approval as a treatment for ovarian cancer patients who had become resistant to platinum-based chemotherapy. In 2017, the FDA granted the drug ‘priority review’ as a maintenance therapy in relapsed patients with platinum-sensitive ovarian cancer while confirmatory studies are completed. In December 2016, the FDA granted ‘accelerated approval’ for rucaparib, another (PARP) inhibitor for the treatment of women with advanced ovarian cancers who have been treated with two or more chemotherapies, and whose tumors have specific BRCA gene mutations. 
 
Early in 2017, the drug niraparib was the first PARP inhibitor to be approved by the FDA for the maintenance treatment of adult patients with recurrent gynaecological cancers who are resistant to platinum-based chemotherapy.  The approval was based upon data from an international randomized, prospectively designed phase III clinical study, which enrolled 553 patients, and showed a clinically meaningful increase in progression-free survival (PFS) in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status. In conjunction with the accelerated 2017 FDA approval for rucaparib, the FDA also approved a BRCA diagnostic test, which identifies patients with advanced ovarian cancer eligible for treatment with rucaparib.
 

New class of chemotherapies
PARP inhibitors may represent a potentially significant new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. Currently, these drugs have a palliative indication for a relatively small cohort of patients. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clearer understanding of the mechanism of action, and a better understanding of their toxicity profile will be required. Once this is achieved PARP inhibitors could to be employed in the curative, rather than the palliative setting.
 
5
 
The future of cancer care and multidisciplinary teams
 
According to Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit, we now have “many options” for treating ovarian cancer. However, “how we utilize and sequence these options may have a significant impact on the overall survival of a patient. Better understanding of the disease through science is constantly turning up new options. For the first time in the last 5 years we are developing options in real time for patients. Patients almost are able to benefit from these options as they are relapsing from their disease. Keeping patients alive for longer allows them to access new treatments . . . It’s truly remarkable to see this in real time as a doctor,” says Gabra: see video.
 

A significant number of mostly private patients diagnosed with ovarian cancer draw comfort from the belief that they, “have the best oncologist”.  This view fails to grasp the challenges facing individual clinicians acting on their own to treat a devilishly complex disease such as ovarian cancer. “The main improvements in cancer care have been organizational and scientific.” says Gabra. “It is not enough to create new science and new treatments. It is also important to rigorously implement these. The most effective way to do this is via a ‘tumor board’ or a ‘multidisciplinary clinic or team’, where various specialists such as surgeons, radiotherapists, medical oncologists, pathologists, clinical nurse specialists, etc come together and discuss each individual patient. Such multidisciplinary discussion results in the best utilizations of currently available treatment options in the right sequence. It’s difficult to do this for a doctor acting on his or her own and making isolated decisions . . . Multidisciplinary decision-making has transformed cancer care,” says Gabra: see video.
 
 
Takeaways

This Commentary provides a flavor of some of the recent advances in ovarian cancer research and care, and suggests that treatment options have improved in the 4 years since Maurice Saatchi described ovarian cancer care as, “degrading, medieval and ineffective” leading “only to death”. However, it is worth stressing that care is both organizational and scientific, and multidisciplinary teams can transform care and prolong life.
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  • Ovarian cancer is a deadly disease that is challenging to diagnose and manage
  • Although it only accounts for 3% of cancers in women, it is the 5th leading cause of cancer death among women
  • If diagnosed and treated early before it spreads the 5-year survival rate is 92%
  • But only 15% of women with ovarian cancer are diagnosed early
  • The disease is hard to diagnose because it is rare, the symptoms are relatively benign, and there is no effective screening
  • Ovarian cancer is not one disease, but a collection of subtypes each demanding specific treatment pathways
  • Gold standard treatment is surgery followed by chemotherapy
  • A large proportion of patients develop resistance to chemotherapy
 
Improving ovarian cancer treatment

Part I
 
Are things beginning to improve for people living with ovarian cancer? When the British advertising magnate Lord Maurice Saatchi’s wife died of ovarian cancer in 2012 he described her treatment as, “degrading, medieval and ineffective” leading “only to death”. Ovarian cancer patients have long had limited treatment options, which have not changed much in the past two decades, but recently things have begun to change.

 
In this Commentary
 
This is the first of a 2-part Commentary on ovarian cancer, which briefly describes the condition, explains the difficulties of diagnosing it early, and discusses some of the challenges of developing effective screening mechanisms for the cancer in pre-symptomatic women. Part 2, which will follow separately next week, reports new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. It also suggests that improvements in ovarian cancer care are both organizational and scientific. Experts believe that they now have a number of treatment options available to them. Utilising and sequencing these appropriately can have a significant impact on the overall survival rates of patients. Multidisciplinary teams, which are not universally available to all ovarian cancer patients, bring together all specialisms involved in the therapeutic pathway to consider and suggest optimal treatment steps for individual patients, and make a significant contribution to improved ovarian cancer care. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.
 
Ovarian cancer: a complex and deadly disease
 
The ovaries are a pair of small organs located low in the stomach that are connected to the womb and store a woman’s supply of eggs. Ovarian cancer is driven by multicellular pathways, and is better understood as a collection of subtypes with changing origins and clinical behaviors, rather than as a single disease. The tumors often have heterogeneous cell populations, which form unique microcellular environments. The prevalence of ovarian cancer among gynecological malignancies is rising, and is one the most deadly and hard to treat malignancies. While the disease only accounts for about 3% of cancers in women, it is one of the most common types of cancer in women, the 5th leading cause of cancer-related death among women, and the deadliest of gynecologic cancers. The risk of ovarian cancer increases with age. It is rare in women younger than 40, most ovarian cancers develop after menopause. 50% of all ovarian cancers are found in women 63 or older. According to the American Cancer Society the five-year survival rate for all ovarian cancers is 45%. Most women are diagnosed with late-stage ovarian disease and, the 5-year survival rates for these patients are roughly 30%. Age adjusted survival rates of ovarian cancer are improving in most developed countries. For instance, between 1970 and 2010, the 10-year survival rates for ovarian cancer in England increased by 16%, and the 5-year survival rates have almost doubled. This is because of the favorable trends in the use of oral contraceptives, which were introduced early in developed countries. Declines in menopausal hormone use may also have had a favorable effect in older women as well as improved diagnosis, management and therapies. According to Public Health England, over the past 20 years the incidence of ovarian cancer in England has remained fairly stable, although it has decreased slightly in the last few years. Between 2008 and 2010 in England, 36% of some 14,000 women diagnosed with ovarian cancer died in the first year, and more than 1,600 died in the first month. There were 7,378 new cases of ovarian cancer in the UK in 2014 and more than 4,000 women died from the disease.
 
Benign symptoms difficult to diagnose

If ovarian cancer is diagnosed and treated early before it spreads from the ovaries to the abdomen, the 5-year relative survival rate is 92%. However, only 15% of all ovarian cancers are found at this early stage.  This is because it is hard to diagnose since the disease is so rare, the symptoms are relatively benign, and there is no effective screening. As a result, the illness tends not to be detected until the latter stages in around 60% of women, when the prognosis is poor. In about 20% of cases the disease is not diagnosed until it is incurable. Feeling bloated most days for three weeks or more is a significant sign of ovarian cancer. Other symptoms include: feeling full quickly, loss of appetite, pelvic or stomach pain, needing to urinate more frequently than normal, changes in bowel habit, feeling very tired, and unexplained weight loss.
 
“Tumors go from the earliest stage 1 directly to stage 3”
In the video below Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit says, “Ovarian cancer is often diagnosed late because in many cases the disease disseminates into the peritoneal cavity almost simultaneously with the primary declaring itself. Unlike other cancers, the notion that ovarian cancer progresses from stage 1 to stage 2, to stage 3 is possibly mythological. The reality is, these cancer cells often commence in the fallopian tube with a very small primary tumor, which disseminates directly into the peritoneal cavity. In other words, the tumors go from the earliest of stage 1 directly to stage 3."
 
 
Ovarian cancer screening and CA-125

For years scientists have been searching for an effective screening test for ovarian cancer in pre-symptomtic women. The 2 most common are transvaginal ultrasound (TVUS) and the CA-125 blood test. The former uses sound waves to examine the uterus, fallopian tubes, and ovaries by putting an ultrasound wand into the vagina. It can help find a tumor in the ovary, but cannot tell if the tumor is cancerous or benign. Most tumors identified by TVUS are not cancerous. So far, the most promising screening method is CA-125, which measures a protein antigen produced by the tumor.
 
CA-125 studies
To-date, 2 large ovarian cancer screening studies have been completed: one in the US, and another in the UK. Both looked at using the CA-125 blood test along with TVUS to detect ovarian cancer. In these studies, more cancers were found in the women who were screened, and some were at an early stage. But the outcomes of the women who were screened were no better than the women who were not screened: the screened women did not live longer and were not less likely to die from ovarian cancer.

Another study published in 2017 in the Journal of Clinical Oncology screened 4,346 women over 3 years at 42 centers across the UK, undertook follow-up studies 5 years later, and came to similar conclusions as the 2 previous studies. Further, “there are a number of non-ovarian diseases, which can cause elevated CA-125’s. Breast cancer, endometriosis, and irritation of the peritoneal cavity can all cause elevated CA-125,” says Michael Birrer, Director of Medical Gynecologic Oncology at the Massachusetts General Hospital and Professor of Medicine at Harvard University.


Controversial findings
Findings from screening tests using CA-125 can give false positives for ovarian cancer, and this puts pressure on patients to have further, often unnecessary interventions, which sometimes include surgery. Also, the limitations of the CA-125 test mean that many women with early stage ovarian cancer will receive a false negative from testing, and not get further treatment for their condition. Thus, the potential role of CA-125 for the early detection of ovarian cancer is controversial, and therefore it has not been adopted for widespread screening in asymptomatic women.
 
In the video below Birrer explains that, “pre-operatively and during therapy physicians will usually check CA-125 as a measure of the effectiveness of the therapy. At the completion of therapy one would anticipate that the CA-125 would be normal. After that, it is somewhat controversial as to whether follow-up with CA-125 to test for recurring disease is clinically relevant,” says Birrer. Since the discovery of CA-125 in 1981, there has been intense research focus on novel biomarkers for cancer, and significant scientific advances in genomics, proteomic, and epigenomics etc., which have been extensively used in scientific discovery, but as yet no new major cancer biomarkers have been introduced to practicing oncologists. 

 
Limited treatment options

As most ovarian cancer patients are diagnosed late when the disease has already spread, treatment options are limited. The first line treatment is surgery called debulking, (also known as cytoreduction or cytoreductive surgery), which is the reduction of as much of the volume (bulk) of a tumor as possible. 
 
Be prepared for extensive surgery
Whether a patient is a candidate for surgery depends on a number of factors including the type, size, location, grade and stage of the tumor, pre-existing medical conditions, and in the case of a recurrence, when the last cancer treatment was performed, as well as general health factors such as age, physical fitness and other medical comorbidities. People diagnosed with ovarian cancer, “need to be prepared to have extensive surgery because the real extent of the tumor dissemination cannot be detected by conventional imagining pre-operatively,” says Professor Christina Fotopoulou, consultant gynaecological oncologist at Queen Charlotte's & Chelsea Hospital, London: see video below. 
 
 
Platinum resistance

Surgery is usually followed by chemotherapy. There are more than 100 chemotherapy agents used to treat cancer either alone or in combination. Chemotherapy drugs target cells at different phases of the process of forming new cells, called the cell cycle. Understanding how these drugs work helps oncologists predict, which drugs are likely to work well together. Clinicians can also plan how often doses of each drug should be given based on the timing of the cell phases. Chemotherapy drugs can be grouped by their chemical composition, their relationship with other drugs, their utility in treating specific forms of cancer, and their side effects.  
 
You can reduce chemotherapy resistance by using a combination of drugs that target different processes in the cancer so that the probability that the cancer will simultaneously become resistant to both drugs is much lower than if you use one drug at a time, ” says David Bowtell,  Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia: see video:
 
 
Improving the chemotherapy agent cisplatin
The standard chemotherapy treatment for ovarian cancer is a combination of a platinum compound, such as cisplatin or carboplatin, and a taxane, which represents a class of drug originally identified from plants. Since cisplatin’s discovery in 1965 and its FDA approval in 1978, it has been used continuously in treatments for several types of cancer, and is best known as a cure for testicular cancer. Scientists have searched for ways to improve the anti-tumor efficacy of platinum based drugs, reducing their toxicity, strengthening them against resistance by expanding the class to include several new analogues of cisplatin, and putting these through clinical studies to broaden the different types of cancers against which they can be safely used.
 
Slow progress transitioning research into clinical practice
Despite these endeavors, platinum resistance remains a significant clinical challenge. Between 55 and 75% of women with ovarian cancer develop resistance to platinum based chemotherapy treatments. Significant research efforts have been dedicated to understanding this, but there has been relatively slow progress transitioning the research into effective clinical applications. According to Birrer, “the mechanism of platinum resistance from a molecular standpoint has not been well defined. It is likely to be heterogeneous, which means that each patient’s tumor may be slightly different. The hope is for targeted therapies and personalised medicine to have a chance of overcoming this, in that we could characterize the mechanism of the platinum resistance and apply and target therapy.”
 
2 theories of platinum resistance
In the video below, Birrer posits 2 theories to explain platinum resistance. “One suggests that under the influence of platinum the tumor changes and becomes resistant. Another suggests that there are 2 groups of cells to begin with. The vast majority of the tumor is sensitive, but there are small clusters of resistant cells. Once you kill the sensitive cells you have only the resistant cells left. Although these 2 theories have been around for about 25 years, there are no definitive data to suggest which theory is right. I have a personal scientific bias to think that the resistant cells are present at the time that we start the therapy. Being able to identify and characterize these cells upfront would be a radical breakthrough because then we would be able to target them at a time when they are only a small portion of the tumor,” says Birrer.
 
 
Takeaways

Saatchi is right; for decades ovarian cancer treatment has been wanting, but studies we describe in part-2 of this Commentary suggest that the tide might be turning for people living with ovarian cancer. So don't miss part-2 next week!
 
 
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  • Over the next decade the combination of big data, analytics and the Internet of Things (IoT) will radically change healthcare
  • The social media revolution has raised peoples’ awareness of lifestyles and healthcare
  • The rise of smart watches and fitness sensors combined with IOT and Artificial Intelligence (AI) paves the way for preventative medicine becoming a key driver in the management of straining healthcare services and spending
  • Big data, analytics and the IoT is positioned to accelerate change away from output-orientated healthcare systems to value-based outcome-orientated systems
  • Patients and payers are increasingly aware of the opportunities and demanding change
  • The slowness for MedTech companies to change creates opportunities for newcomers to penetrate and grab share of healthcare markets
  • Regulation and requirements to undergo significant clinical studies to become standard of care will slow consumer and patient access to services
  
The IoT and healthcare
 
The Internet of Things (IoT) is positioned to radically transform healthcare. There are powerful social, demographic, technological, and economic drivers of this change. We describe some of these, and suggest that, within the next 10 years, there will be hundreds of millions of networked medical devices sharing data and knowhow, and this will drive a significant shift away from traditional healthcare systems focused on outputs to value-based systems dedicated to prevention and improving outcomes while lowering costs.
 

The IoT and its potential impact on healthcare
 
The IoT, which Cisco refers to as “the Internet of Everything” and GE as the “Industrial Internet” is also referred to as “machine-to-machine” (M2M) technologies, and as “smart sensors”. Whatever term is used, the IoT is an ever-expanding universe of devices embedded with microchips, sensors, and wireless communications capabilities, which enable them to collect, store, send and receive data. These smart devices and the data they collect are interconnected via the Internet, which significantly expands their potential uses and value. The IoT enables connectivity from anywhere to anywhere at any time, and facilitates the accumulation of big data and artificial intelligence (AI) to either complement or replace the human decision-maker. Over the next decade, anything that can be connected to the Internet probably will be. The Internet provides an almost ubiquitous, high-speed network, and cloud-based analytics, which, in nanoseconds, can read, analyse and act upon terabytes of aggregated medical data. Smart distributed services are positioned to become a powerful tool for health providers by optimizing medical results, preventing mistakes, relieving overburdened health professionals, improving patient outcomes, and lowering costs.
 
Two approaches to a common healthcare challenge

Let us illustrate the shift in healthcare referred to above by considering two different approaches to a shared healthcare challenge: that of providing people with personalized advice about maintaining and improving their wellbeing in order to ward-off lifestyle related illnesses, such as type 2 diabetes (T2DM). This is important because T2DM is a devastating lifestyle induced condition, which affects millions, costs billions, and in most cases can be prevented by lifestyle changes.
 
Approach 1

One approach is the world’s first nationwide diabetes prevention program, Healthier You, which was launched by NHS England, Public Health England and Diabetes UK in 2016. It is aimed at the 11m people in England thought to have pre-diabetes, which is where blood sugar levels are higher than normal, but not high enough for a diagnosis of T2DM. About 5-10% of people with pre-diabetes progress to "full-blown" T2DM in any given year. Healthier You is expected to be fully operational by 2020. Each year thereafter the program is expected to recruit 100,000 people at risk of T2DM. Personal lifestyle coaches will periodically monitor the blood sugar levels of these, and make recommendations about their diets and lifestyles. This is expected to prevent or slow the people with pre-diabetes progressing to full-blown T2DM.
 
Approach 2

The second approach is GymKit and Chatbox. The former is a new feature Apple is expected to add to its watch in late 2017, and the latter is a mobile app developed by Equinox, a New York-based health club chain, for its members.

Gymkit will enable the Apple watch to have seamless connectivity to the overwhelming majority of different kinds of cardiovascular equipment used in most fitness centres. Currently, there are a variety of smartphone apps, which allow gym users to connect to cardiovascular machines, but these are at best patchy. Gymkit is different, and will automatically adjust a user’s personalized needs to any cardiovascular machine without the user having to press a button. Itwill then wirelessly collect a range of data - if on a treadmill: speed, duration, incline, etc., - and combine these data with the user’s heart rate, age, gender, weight and body type to make health-related calculations and recommendations, and wirelessly transmit these to the user.

Chatbox does something similar. Ituses artificial intelligence (AI) to simulate the human voice, which talks to new health club members, encourages them to set personal goals, and sends them messages when they fall short. Further, Chatbox has sensors, which track users while they are in the gym, and suggests ways of improving and extending their personalized workouts. A survey, undertaken by Equinox of its members across 88 of its facilities reported that Chatbox users visited the fitness centres 40% more often than those without the app. This is significant because people who fail to form a habit of physical exercise tend to drop lifestyle goals.

The 2 approaches compared

Healthier You is unlikely to have more than a modest impact on the UK’s diabetes burden because the format it has adopted is like filling a swimming pool with a teaspoon. It would take over 100 years to recruit and counsel the 11m people with pre-diabetes, especially while the prevalence levels of pre-diabetes and T2DM in the UK are increasing.  Successfully changing the diets and lifestyles of large numbers of people requires an understanding of 21st century technologies. Ubiquitous healthcare technologies such as smartphone apps and wearable’s that support lifestyles abound, and have leveraged people's enhanced awareness of themselves and their health. Hence peoples’ large and rapidly growing demands for such devices to track their weight, blood pressure, daily exercise, diet etc. From apps to wearables, healthcare technology lets people feel in control of their health, while potentially providing health professionals with more patient data than ever before.  

The IoT and consumers

There are more than 165,000 healthcare apps currently on the market, there is a rapid growth in wearables, and smartphone penetration in the US and UK has surpassed 80% and 75% respectively. According to a 2017 US survey by Anthem Blue Cross, 70m people in the US use wearable health monitoring devices, 52% of smartphone users gather health information using mobile apps, and 93% of doctors believe mobile apps can improve health. 86% of doctors say wearables increase patient engagement with their own health, and 88% of doctors want patients to monitor their health. 51% of doctors use electronic access to clinical information from other doctors, and 91% of hospitals in the US have moved to electronic patient records (EPR).
 
Notwithstanding, these apps and wearables are rarely configured to aggregate, export and share the data they collect in order to improve outcomes and lower costs. This reduces their utility and value. However, the large and rapid growth of this market on the back of the social media revolution, and the impact it is having on shaping the attitudes and expectations of millions of consumers of healthcare, positions it well as a potential driver of significant change.

 A “minuscule fraction” of what is ultimately possible

According to Roger Kornberg, Professor of Structural Biology at Stanford University, the current capabilities of smart sensors like those used in Apple’sGymKit and Equinox’s Chatbox, “is only a minuscule fraction of what is ultimately possible . . . A sensor attached to a smartphone will enable it to answer any question that we may have about ourselves, and our environment,” says Kornberg. Smart sensors can provide you with a doctor in your pocket, which can be connected to a plethora of other devices that could collect, store, analyze and feedback terabytes of medical information in real time. Kornberg, who won the 2006 Nobel Prize for Chemistry, is excited about the disruptive effect, which smart sensors are having on traditional healthcare systems. This is because they can be connected to almost any medical device and human organ to, “monitor specimens . . . record in real time the health status of individuals,  . . . transmitelectronic signals wirelessly,  . . .  (and) provide responses to any treatment,” says Kornberg. 

Kornberg is engaged in developing sensors with the ability to detect and measure biological signals and data from humans, which can be wirelessly linked to smartphones to transmit the information for analysis, storage and further communication. Kornberg is convinced that, in the near term, we will be able to create a simple and affordable networked device that will, “detectan impending heart attack, in a precise and quantitative manner, before any symptoms”.
 


Potential of sensor technology



The excitement in the development of biosensors

 
Drivers of the IoT and market trends

Partly driving the IoT in healthcare and other industries are the: (i) general availability of affordable broadband Internet, (ii) almost ubiquitous smartphone penetration, (iii) increases in computer processing power, (iv) enhanced networking capabilities, (v) miniaturization, especially of computer chips and cameras, (vi) the digitalization of data, (vii) growth of big data repositories, and (viii) advances in AI and data mining.
 
Market trends suggest substantial growth in the total number of networked smart devices in use. By 2020, when the world’s population is expected to reach 7.6bn, it is projected that there will be between 19 and 50bn IoT-connected devices worldwide, more than 8bn broadband access points, more than 4m IoT jobs, and the number of installed IoT technologies will exceed that of personal computers by a factor of 10.
 
Crisis in primary care is a significant driver of change
 
In addition to these technological drivers, the simultaneous population aging and the shrinking pool of doctors also drives the IoT in healthcare. Increasing numbers of older people presenting with complex comorbidities significantly increases the large and rapidly growing demands on an over-stretched, shrinking population of doctors. This results in a crisis of care.
 
A 2015 Report from the Association of American Medical Colleges (AAMC) suggests that there is an 11 to 17% growth in total healthcare demand, of which a growing and aging population is a significant component. Further, the Report suggests that the US could lose 100,000 doctors by 2025, and that primary care physicians will account for 33% of that shortage.

There is a similar crisis in the UK, where trainee GPs are dwindling, young GPs are moving abroad, and experienced GPs are retiring early. According to data from the UK’s General Medical Council (GMC), between 2008 and 2014 an average of nearly 3,000 certificates were issued annually to enable British doctors to work abroad. Currently, there are hundreds of vacancies for GP trainees. Findings from a 2015 British Medical Association (BMA) poll of over 15,000 GPs, found that 34% of respondents plan to retire by 2020 because of high stress levels, unmanageable workloads, and too little time with patients.
 
Interestingly, Brexit is expected to compound the crisis of care in the UK. According to a 2017 General Medical Council survey of more than 2,000 doctors from the EU working in the UK, 60% said they were considering leaving the UK, and, of those, 91% said the UK’s decision to leave the EU was a factor in their considerations. 

 
Changing healthcare ecosystems

These trends help healthcare payers to employ IoT strategies in an attempt to replace traditional healthcare systems, which act when illnesses occur and report services rendered, with value-based healthcare systems focused on outcomes. US payers are leading this transformation. Some payers in the US have employed IoT strategies to convert a number of devices used in various therapeutic pathways into smart devices that collect, aggregate and process terabytes of healthcare data gathered from thousands of healthcare providers, and electronic patient records (EPRs) describing millions of treatments doctors have prescribed to people presenting similar symptoms and disease states. Cognitive computing systems analyse these data and instantaneously identify patterns that doctors cannot. Such systems, although proprietary, are positioned to help reduce the ongoing challenges of inaccurate, late, and delayed diagnoses, which each year cost the US economy some US$750bn and lead to between 40,000 and 80,000 patient deaths.
 
IBM Watson
 
IBM’s supercomputer, Watson is a well-known proprietary system that uses IoT strategies that include a network of smart sensors and databases to assist doctors in various aspects of diagnoses and treatment plans tailored to patients’ individual symptoms, genetics, and medical histories. Watson draws from 600,000 medical evidence reports, 1.5m EPRs, millions of clinical trials, and 2m pages of text from medical journals. A variant, IBM Watson for Oncology, has been designed specifically to help oncologists, and is currently in use at the Memorial Sloan-Kettering Cancer Center in New York. Also, it is being used in India where there is a shortage of oncologists. The Manipal Hospital Group, India’s third largest healthcare group, which manages about 5,000 beds, and provides comprehensive care to around 2m patients every year, is using Watson for Oncology to support diagnosis and treatment for more than 200,000 cancer patients each year across 16 of its hospitals.
 
In 2016 IBM, made a US$3bn investment designed to increase the alignment of its Watson super cognitive computing with the IoT, and allocated more than US$200m to its global Watson IoT headquarters in Munich. IBM will have over 1,000 Munich-based researchers, engineers, developers and business experts working closely with specific industries, including healthcare, to draw insights from billions of sensors embedded in medical devices, hospital beds, health clinics, wearables and apps in endeavors to develop IoT healthcare solutions.
 
Babylon
 
Using a similar IoT network of smart sensors and databases, Babylon, a UK-based subscription health service start-up, has launched a digital healthcare AI-based app, which offers patients video and text-based consultations with doctors, and is designed to improve medical diagnoses and treatments. Early in 2017, NHS England started a 6-month study to test the app’s efficacy by making it available to 1.2m London residents. The Babylon app is expected to be able to analyse, “hundreds of millions of combinations of symptoms” in real time, while taking into account individualized information of a patient’s genetics, environment, behavior, and biology. Current regulations do not allow the Babylon app to make formal diagnoses, so it is employed to assist doctors by recommending diagnoses and treatment options. Notwithstanding, Ali Parsa, Babylon’s founder and CEO says, "Our scientists have little doubt that our AI will soon diagnose and predict personal health better than doctors”.
 
Market forecasts

Market studies stress the vast and growing economic impact of the IoT on healthcare. Business Insider Intelligence (BII) suggested that the IoT has created nearly US$100bn additional revenue in medical devices alone. It forecasts that cost savings and productivity gains generated through the IoT and subsequent changes will create between US$1.1 and US$2.5trillion in value in the healthcare sector by 2025. In 2016, Grand View Research Inc. projected that the global IoT healthcare market will reach nearly US$410bn by 2022. A 2013 Report from the McKinsey Global Institute on Disruptive Technologies, suggests that the potential total economic impact of IoT will be between US$3 and US$6trillion per year by 2025, the largest of which will be felt in healthcare and manufacturing sectors. Although forecasts differ, there is general agreement that, over the next decade, the IoT is projected to provide substantial economic and healthcare benefits in the way of cost savings, improved outcomes, and efficiency improvements.
  
IoT and MedTech companies

We have briefly described the impact of the IoT on patients, healthcare payers and providers. But what about MedTech companies? They have the capabilities and knowhow to develop and integrate the IoT into their next generation devices. However, MedTech innovations tend to be small improvements to existing product offerings. Data, accumulated from numerous smart medical devices, are enhanced in value once they are merged, aggregated, analyzed and communicated. And herein lies the challenge of data security. Arguably the greater the connectivity between medical devices, the greater the security threat. In 2013 the FDA issued a safety communication regarding cyber security for medical devices and health providers, and recommended that MedTech companies determine appropriate safeguards to reduce the risk of device failure due to cyber-attacks. The cautious modus vivendi of most MedTech companies suggests that, in the near term, a significant proportion will not develop IoT strategies, and this creates a gap in the market.
 
The IoT and new and rising healthcare players

Taking advantage of this market gap is a relatively small group of data-orientated companies, which have started to employ IoT technologies to gain access to healthcare markets by developing specific product offerings, increasing collaborative R&D, and acquiring new data oriented start-ups. For instance, in addition to IBM and Apple mentioned above, Amazon is expected to enter the global pharmaceutical market, which is anticipated to reach over US$1 trillion by 2022. Microsoft has used IoT strategies to build its Microsoft Azure cloud platform to facilitate cloud-based delivery of multiple healthcare services. Google Genomics is using IoT strategies to assist the life science community organise the world’s genomic data and make it accessible by applying the same technologies that power Google Search to securely store petabytes of genomic information, which can be analysed, and shared by life science researchers throughout the world.

Takeaways
 
The powerful social, demographic, technological and economic drivers of healthcare change over the next decade suggest an increasing influence of IoT technologies in a sector not known for radical or innovative change. Research suggests that hundreds of millions of networked medical devices will proliferate globally within the next decade. The potential healthcare benefits to be derived from these are expected to be significant, especially through enhancing preventative and outcome-oriented healthcare while reducing costs. This has to be achieved in a highly regulated environment where concerns of data security are paramount. To reap the potential benefits of the IoT in healthcare, policymakers will have to reconcile the need for IoT regulation with the significant projected benefits of the IoT. Smart technologies require smart management and smart regulation.
 
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  • The clandestine status of cannabis and its attendant risks are beginning to erode
  • The idea of cannabis as an evil drug is a relatively recent phenomenon
  • Plants have been the historical source of medicine for most of human history, and cannabis is no exception
  • There is a large and growing pharmacological and clinical interest in cannabis as medicine
  • Two distinct legal markets for cannabis are emerging: the tightly regulated pharmaceutical market and the less regulated market of herbal preparations
  • The FDA has approved cannabis-related drugs, which are used for a number of indications
  • There may be a recognizable pathway leading to more cannabis compounds becoming medicine
  • To become accepted as a medicine that doctors prescribe, pharmacists supply and healthcare providers support, cannabis compounds need to demonstrate their biochemical uniformity, stability, safety and efficacy
 
Medical cannabis and modern healthcare

Today, cannabis medicine for most people involves the black market with its attendant risks and lack of quality control. But this is changing to a more desirable alternative. As legal opinion changes, and clinical studies increase; the clandestine nature of cannabis and its attendant risks are beginning to erode, and two distinct legal markets for medical cannabis are emerging. One is the tightly regulated pharmaceutical market where medical cannabis provides safe and effective pharmaceutical solutions, which doctors prescribe, pharmacists’ supply, and healthcare providers support, and the other is the less regulated market of herbal preparations. A report by ArcView Market Research reported that 2016 annual sales of legal cannabis in the US grew by 25%, to US$6.7bn, and projects sales will reach US$21.8bn by 2020. This Commentary focuses on the pharmaceutical market, which relies on randomized clinical studies to demonstrate biochemical consistency, safety and efficacy.
 
The cannabis plant and its main properties

Cannabis is a genus of an annual herbaceous flowering plant, which includes 2 familiar sub-species or chemovars: ‘C sativa’, and ‘C indica’. Modern molecular techniques applied to the taxonomic classification of cannabis have resulted in many more classifications, which, in time, will become increasingly relevant as the plant’s medicinal qualities are increasingly identified. Cannabis is an indigenous plant of central Asia and India, but can be grown in almost any climate in any part of the world, and is increasingly being cultivated by means of indoor hydroponic technology. The cannabis plant contains more than 100 cannabinoids, which are chemical compounds secreted by cannabis flowers. About 60 of these have been identified as pharmacologically active, with the primary active cannabinoids being delta-9-tetrohydro-cannabinol, commonly known as THC, and cannabidiol, which is commonly known as CBD. THC provides the principal mind-altering ingredient, while CBD does not affect the mind or behavior.
 
Cannabis as medicine

Medical cannabis refers to using extracts from the cannabis plant - cannabinoids - to treat a range of conditions or their symptoms. Cannabinoids can be administered orally, sublingually, or topically; they can be smoked, inhaled, mixed with food, or made into tea. When cannabis is consumed, cannabinoids bind to receptor sites throughout the brain and body. Different cannabinoids have different effects depending on which receptors they bind to. For example, THC binds with receptors in the brain called CB-1, while CBD has a strong affinity for CB-2 receptors located throughout the body. By aiming the right cannabinoid at the right receptors, different types of relief are achievable. THC is the most active cannabinoid; it has dominated research into medical cannabis and resulted in FDA-approved drugs. Although CBD is one of the least active cannabinoids, it has come to dominate more recent research into medical cannabis as it is considered to have a relatively wide scope of potential medical applications with fewer side effects than THC.
 
Pot-ted history

Plants have been the historical source of medicine for most of human history, and continue to account for the base material of about 25% of modern pharmaceuticals. Approved medicines of botanical origin are relatively common, but require evidence-based randomized clinical studies to demonstrate their biochemical uniformity, stability, safety and efficacy. Medical cannabis is no exception, and the FDA has approved drugs derived from cannabinoids and synthetic cannabinoids. However, regulators have not approved the entire cannabis plant as medicine because there are insufficient clinical studies to demonstrate its benefits against its potential risks to patients it is meant to treat.

For centuries the cannabis plant has been used throughout the world for medicinal purposes. Only in recent history has it acquired the status of a dangerous drug and banned. Its first recorded use is 4000 BC when an extract from the cannabis plant was used in China as an anesthetic during surgery. The Chinese went on to use cannabis compounds extensively for a range of conditions including malaria, constipation, rheumatic pains, "absentmindedness" and "female disorders."
 
From China, cannabis travelled throughout Asia into the Middle East, Africa, Europe, and eventually to the US. Galen, a prominent Greek doctor and scientist in the Roman Empire, noted cannabis as a remedy. In India it was used to lower fevers, quicken the mind, induce sleep, cure dysentery, stimulate appetite, improve digestion, relieve headaches, and cure venereal disease. The Vikings and medieval Germans used cannabis for toothache, and for relieving pain during childbirth. In Africa it was used for a variety of fevers including malaria. Despite its extensive medicinal use in early history, there were warnings against the over-use of cannabis as it was said to result in “seeing demons”.

 
Opinion changing

The idea of cannabis as an evil drug is a relatively recent phenomenon. Despite its contemporary clandestine status, there is a large and growing pharmacological and clinical interest in cannabis as medicine, and a recognizable pathway leading to its return to mainstream medicine. As early as 1985 the FDA approved cannabinoids as medicine. As of June 2016, 25 American states and Washington DC, have legalized cannabis for medical use. Germany is now expected to follow suit. In the UK, more than half of its national parliamentarians, including the former deputy Prime Minister, want to see the legalisation of medical cannabis. In March 2017, Oxford University announced that it is to launch a £10m global centre of excellence in cannabinoid research. The program, which is a partnership between the University and Kingsley Capital Partners, a private equity business based in London, will examine the role of cannabis medicines in treating pain, cancer and inflammatory diseases.
  
FDA approved

The FDA has approved two cannabis-related drugs: dronabinol and nabilone. The former contains the psychoactive compound THC extracted from the resin of C-sativa. The latter contains a synthetic cannabinoid, which mimics THC; the primary psychoactive compound found naturally occurring in cannabis. Both treat chemotherapy-induced nausea and vomiting (CINV), and extreme weight loss caused by HIV/AIDS, among a number of other indications.

Nabiximols, a CBD extract of cannabis, has been approved in 27 countries as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Although it has not yet undergone clinical studies, scientists have recently developed Epidiolex, a CBD-based liquid drug to treat certain forms of childhood epilepsy.

 
Chemotherapy-induced nausea and vomiting
 
Chemotherapy-induced nausea and vomiting (CINV), is one of the most common and feared adverse events that can be experienced by cancer patients. Its occurrence depends on the dose and the type of chemotherapy agent used, but it tends to be more prevalent in anxious woman under 50 who do not drink alcohol, and who have a history of sickness during pregnancy. Despite advances in the prevention and treatment of emesis, of the 70% to 80% of cancer patients who experience CINV, many delay or refuse future chemotherapy treatments, and contemplate stopping all treatments because of fear of further nausea and vomiting. 
 
There are several drug classes for the prevention and management of CINV. In 1985 the FDA approved a cannabinoid, dronabinol, for the treatment of CINV in patients who have failed to respond adequately to conventional antiemetic treatment. The number of people taking cannabinoids for therapeutic purposes is increasing, but very few medicines based on cannabis have yet been developed on rigorous scientific principles. Ahmed Ahmed, professor of gynaecological oncology at Oxford says, “This field holds great promise for developing novel therapeutic opportunities for cancer patients.
 
The endogenous cannabinoid system is a significant pathway involved in the emetic response. Cannabinoids can reduce or prevent chemotherapy-induced emesis by acting at central CB-1 receptors by preventing the pro-emetic effects of endogenous compounds, such as dopamine and serotonin. In addition, by acting as an agonist to CB-1, cannabinoids used as a treatment result in an antiemetic effect. Notwithstanding, few studies have evaluated medical cannabis alone or in combination to treat CINV. The published studies that have been conducted have mixed results. THC has to be dosed relatively highly, so that resultant adverse effects may occur comparatively frequently. Some investigations suggest that THC in low doses improves the efficacy of other antiemetic drugs if given together.

 
Some additional indications

In addition to its ability to reduce nausea, THC is effective as an appetite stimulant in both healthy and sick individuals, and is used to boost appetite in patients with cancer, HIV-associated wasting syndrome, and patients with anorexia.

Another common use of medical cannabis is as an analgesic. Studies suggest that THC activates pathways in the central nervous system, which work to block pain signals from being sent to the brain. THC has been shown to have some effect against neuropathic, cancer and menstrual pain, headache, and chronic bowel inflammation.

The high, which users get from cannabis THC is also associated with temporary loss of memory. For most people this would be concerning, but for people with post-traumatic stress disorder (PTSD), memory loss can be positive. PTSD is a chronic, disabling mental health condition triggered by a significant event, and results in traumatic flashbacks, nightmares, and emotional instability. A 2013 study published in the journal Molecular Psychiatry reported a correlation between the quantity of cannabinoid CB-1 receptors in the human brain and PTSD, and concluded that oral doses of THC could help relieve PTSD-related symptoms.

Review of clinical studies

In 2015 a systematic review of the pros and cons of cannabinoids was published in the Journal of the American Medical Association. The paper analyzed 79 clinical studies of cannabinoids, involving 6,462 participants, for a number of indications including: CINV, chronic pain, appetite stimulation in HIV/AIDS, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, and Tourette syndrome.

Most studies in the review showed improvement in symptoms that were correlated with cannabinoids, compared with a placebo. However, symptoms positively correlated with cannabinoids did not reach statistical significance in all studies. The review reported that there was an increased risk of short-term adverse effects associated with cannabinoids, some of which were severe. Common among these were dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

The review concluded that, “There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were correlated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were also correlated with an increased risk of short-term adverse effects.”

 
Clinical studies design challenges

Although cannabis compounds are currently used to treat disease or alleviate symptoms for a number of conditions, their efficacy for some specific indications is not altogether clear. This reflects the relative dearth of clinical studies that have been carried out on cannabinoids. Further, there are several design challenges associated with clinical studies that involve THC. One is whether cannabis components beyond THC contribute to its medicinal effects. Another is connected with the ability of studies to provide adequate blinding for psychoactive compounds such as THC. Clinical studies generally are known to show a degree of subjective improvement associated with the additional attention participants in a study are given, and this is compounded when a clinical study outcome measures subjective responses, such as pain and mood, as in the case of THC.
 
Gold standard
 
To be accepted by doctors, supplied by pharmacists and supported by healthcare providers, a medical cannabis product must be standardized and consistent, and display a quality equal to any recognized pharmacological compound. It must have a secure supply chain, possess an appropriate low-risk delivery system, and have minimal adverse effects. Although there are entities working to bring this about, the fact remains that the overwhelming majority of cannabis available today is unregulated, and this provides significant challenges, which include the biochemical variability of one chemovar to another, the possibility of the presence of bacteria and pesticides, and the variation in potency.
 
Nabiximols
 
A significant success of medical cannabis is nabiximols, an oromucosal spray produced from whole cannabis extracts, which is used to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Currently nabiximols is available in 27 countries, is biochemically uniform and provides an easy-to-use, reliable delivery system with immediate onset, allowing a therapeutic window for control of symptoms without intoxication. This suggests a gold standard benchmark, which other cannabis-based medicines will be required to follow.

 
Takeaways
 
There seems to be a clear pathway for medical cannabis to increase in importance in modern pharmacology. Modern technology, which facilitates advanced cultivation and extraction processes appear to be well positioned to facilitate the creation and development of cannabis products to target specific medical needs for maximum relief of a number of chronic conditions.
 
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  • Each year about 1.7m women are diagnosed with breast cancer worldwide and over 0.5m die from the condition
  • Between 5% and 10% of these breast cancers result from harmful gene mutations
  • BRCA1 and BRCA2 gene mutations are the most common cause of hereditary breast cancer
  • 45% to 85% of women with a BRCA mutation will develop breast cancer in their lifetime compared to 12% of women in the general population
  • Most women do not know if they have a harmful BRCA mutation
  • Testing for the BRCA gene is now affordable, fast and accessible
  • Surgical interventions of women with BRCA mutations can significantly reduce their risk of developing breast cancer and substantially increase cancer survival
  • Genetic test results for breast cancer are fraught with uncertainty because testing reveals the likelihood of developing cancer rather than a certain fate
  • Research suggests that BRCA test results are not being clearly communicated to women
  • Best practice demands that expert counselors discuss genetic testing and help interpret results
 
Breast cancer and harmful BRCA gene mutations


Few things frighten women more than discovering a lump in one of her breasts The standard treatment: surgery, followed by radio- and chemotherapy, can be disfiguring, painful, sometimes unsuccessful, and the impact of the disease is felt by far more individuals than just those who have the diagnosis.The good news is that over the past 30 years breast cancer survival rates in most developed countries have been improving, largely due to screening, earlier diagnosis and improved treatments. The bad new is that in most developed countries it is twice as likely for a woman to be diagnosed with breast cancer than 60 years ago.
 
Harmful BRCA genes mutations

5 to 10% of breast cancers are thought to be due to gene mutations, and harmful BRCA mutations account for 20 to 25% of these. Women who inherit the BRCA1 mutations have a 60 to 90% risk of developing breast cancer in their lifetime, and those who inherit BRCA2 mutations increase their risk of breast cancer by 45 to 85%, compared to 12% of women in the general population. Most women do not know if they carry the harmful BRCA mutation, but if they discover they do, many elect to have a bilateral mastectomy. This is a significant procedure with potential risks and side effects, but can reduce your mortality risk by about 50%.
 
The gold standard screening for breast cancer is an x-ray picture of the breast (mammography), but increasingly women are turning to genetic testing as their awareness of the harmful BRCA mutations increase, and genetic testing becomes more accessible and affordable. However, results from these tests are not straightforward, and often not communicated well. This can increase the anxiety in women with suspected breast cancer, and make them elect to have unnecessary interventions and procedures.
 
This Commentary describes how advanced genetic testing together with expert counselling help women improve their management of breast cancer.
 

Breast Cancer
 
Cancer is a group of diseases that cause cells in your body to change and grow out of control: they mutate. Most types of cancer cells eventually form a lump or mass called a tumor, and are named after the part of the body where the tumor originates, e.g. “breast cancer”, although this convention is changing with the development of targeted personalized medicine. The exact cause of breast cancer is unknown, but the overwhelming majority result from some combination of environment, lifestyle, and genes. Breast cancer affects about 1 in 8 women at some point during their life, usually after the menopause, and is the most common cancer in women.  The majority of breast cancers begin in the parts of the breast tissue that are made up of glands for milk production, called lobules, and ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective, and lymphatic tissue. Most invasive breast cancers (those that have spread from where they started) are found in women 55 and older. Women with a family history of the disease have an increased risk of getting breast cancer. Each year about 1.7m women are diagnosed with breast cancer worldwide, and over 0.5m die from the condition. However in developed economies more and more women survive the disease. In the US, for instance, the average 5-year survival rate for people with breast cancer is 89%. The 10-year rate is 83%, and the 15-year rate is 78%. Other developed countries have similar success rates. What makes breast cancer fatal is if it spreads to the bones, lungs, liver and other organs. Early detection in order to improve breast cancer outcomes remains the cornerstone of the condition’s management. Although breast cancer is thought to be a disease of the developed world, it is increasing rapidly in emerging countries where the majority of cases present later and die earlier than women in developed countries: almost 50% of breast cancer cases and 58% of deaths occur in emerging economies. This is because women generally have relatively poor knowledge of the risk factors, symptoms and methods for early detection. Also, they experience cancer fatalism, believe in alternative medicine, and lack of autonomy in decision making, which often results in delays in seeking or avoidance of evidence-based medicine.
 
Mammography
 
Mammography, which has long been the mainstay of breast cancer detection, is a specific type of breast imaging that uses low-dose x-rays to detect small changes in the breast before there are any other signs or symptoms of the disease when it is most treatable. Mammography is noninvasive, relatively inexpensive, and has reasonable sensitivity (72–88%), which increases with age. It can also be used to detect and diagnose breast disease in women experiencing symptoms such as a lump, pain, or nipple discharge. If breast cancer is found at an early stage, there is an increased chance for breast-conserving surgery and a better prognosis for long-term survival. Most developed countries operate breast-screening programs, which regularly provides mammography for women between certain ages.
 
Advances in mammography

In recent years, mammography has undergone increased scrutiny for false positives and excessive biopsies, which increase radiation dosage, cost and patient anxiety. In response to these challenges, new forms of mammography screening have been developed, including; low dose mammography, digital mammography, computer-aided detection, tomosynthesis, which is also called 3-D mammography, automated whole breast ultrasound, molecular imaging and MRI. Notwithstanding, there is increasing awareness of subpopulations of women for whom mammography has reduced sensitivity. More recently, women have turned to genetic testing to gain a better understanding of their risk of inherited breast cancer.
 
Genes

Every cell in your body contains genes. These contain the genetic code for your body, which not only determines the color of your eyes and hair etc., but also provides information that affects how the cells in your body behave: for example, how they grow, divide and die. Information in your genes is inherited from both parents, and you pass on this information to your children. A change in your genetic code that affects the function of a gene is called a mutation. Many inherited gene mutations do not have any effect on your health, but some do; the BRCA1 and BRCA2 mutations account for 20 to 25% of all inheritable female breast cancers and 15% of ovarian cancers.
  
BRCA genes

In normal cells, BRCA genes are tumor suppressor genes that assist in preventing cancer developing by making proteins that help to keep cells from growing abnormally. Mutated versions of BRCA genes cannot stop abnormal growth, and this can lead to cancer. Mutated BRCA genes have a higher prevalence in certain ethnic groups, such as those of Ashkenazi Jewish descent.

In the video below Professor Robert Leonard, a medical oncologist and an authority on breast cancer, describes how BRCA genes are influential in breast and ovarian cancer risk. BRCA1 runs in families and may also increase a woman’s risk of developing fallopian tube and peritoneal cancers. BRCA2 also runs in families, and is more breast cancer-specific, but a less commonly inherited abnormality. Both or either of these genes may not be detectably abnormal even in a family with a strong inherited pattern of breast cancer, but there is a significant possibility that you will find them in people with a family history of breast and ovarian cancer. Breast and ovarian cancers associated with BRCA mutations tend to develop at younger ages than their non-hereditary counterparts.

 
 
Enhanced risk when family members have cancer
 
In December 2013, the US Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a familial history that is associated with an increased risk of a harmful mutation in one of the BRCA genes. Compared to women without a family history of cancer, risk of breast cancer is about 2 times higher for women with a close female relative who has been diagnosed with cancer; nearly 3 times higher for women with two relatives, and nearly 4 times higher for women with three or more relatives. Risk is further increased when the affected relative was diagnosed at a young age. Notwithstanding, the Preventive Services Task Force recommends against BRCA testing for women with no family history of cancer.
  
The Angelina Jolie effect

The Hollywood actress and filmmaker Angelina Jolie lost her grandmother and aunt to breast cancer and her mother to ovarian cancer. After discovering that she carried a maternally inherited pathogenic BRCA1 mutation, and being told that she had an 87% chance of developing breast cancer, and a 50% chance of ovarian cancer, Jolie elected to have her breasts, ovaries and fallopian tubes removed. After surgery her risk of developing breast cancer in later life fell to 5%.
 
In May 2013, Jolie described her decision in a New York Times (NYT) article,  “I am writing about it now because I hope that other women can benefit from my experience . . . . . Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.”
 
Over testing of by low-risk women
 
Findings published in December 2016 in the British Medical Journal suggest that tests for the BRCA genes shot up by 64% following Jolie’s article. Researchers analysed data on US health insurance claims from more than 9m women between 18 and 64, and suggested that in just 2 weeks following Jolie’s NYT disclosure, 4,500 additional BRCA tests were carried out, which cost the US healthcare system some US$13.5m. Interestingly, increased testing rates were not accompanied by a corresponding increase in mastectomy rates, which suggests that additional testing did not identify new BRCA mutations. Thus, the Angela Jolie effect might have encouraged over-testing among low-risk women.
 
Mindful of her influence on women’s decisions, in 2015 Jolie wrote another NYT article in which she attempted to correct her earlier support for radical risk reduction surgery for women carriers of BRCA mutations. She said that because surgery worked for her, it is not necessarily the optimal therapeutic pathway for all women, and stressed that non-surgical treatments could be more appropriate.
 
Traditional genetic testing for breast cancer risk was slow and expensive

Genetic testing to detect BRCA mutations has been available since 1996, but for many years it was under-used because of its scarcity, high cost, and the length of time it took to produce a result. The rapid development and plummeting costs of genetic testing, and a 2013 US Supreme Court ruling, which invalidated the patents held by Myriad Genetics Inc., which restricted BRCA testing, have resulted in the growth and accessibility of genetic testing.
 
BRCA testing is not straightforward

There are hundreds of mutations in the BRCA1 and BRCA2 genes that can cause cancer. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member), and tests that check for all possible mutations in both genes. Commercial laboratories usually charge between US$450 and US$5,000 to carry out BRCA testing, depending on whether you are being tested for only a specific area(s) of a gene known to be abnormal or if hundreds of areas are being examined within multiple genes. Tests that use traditional technology take several months to report findings. This means that even if a woman is tested at the time of diagnosis, she might not know the results before she has to decide on treatment.
 
Importance of regulated testing laboratories

Testing for the BRCA genes usually involves a blood sample taken in a doctor’s clinic and sent to a commercial laboratory. In 1988, the US Congress passed the Clinical Laboratory Improvement Amendments (CLIA) to ensure quality standards, and the accuracy and reliability of results across all testing laboratories. Since then, all legitimate genetic testing in the US is undertaken in CLIA-approved facilities. During testing for BRCA mutations, the genes are separated from the rest of the DNA, and then scanned for abnormalities. Unlike other clinical screening such as HIV tests and colonoscopies, which provide a simple positive or negative result; genetic testing is fraught with uncertainty because it reveals the likelihood of developing cancer rather than a certain fate.
 
BRCA1 and BRCA2 genetic test results
 
A positive BRCA test result indicates that you have inherited a known harmful mutation in the BRCA1 or BRCA2 gene. This means that you have an increased risk of developing breast and ovarian cancers, but it does not mean that you will actually develop cancer. Some women who inherit a harmful BRCA mutation will never develop cancer. A positive test result may create anxiety and compel clinicians to perform further tests and women to undergo premature and unnecessary clinical interventions, other women in a similar situation will opt for regular screening.
 
The potential benefits of a true negative result include a sense of relief regarding your future risk of cancer, learning that your children are not at risk of inheriting the family's cancer susceptibility, and that a range of interventions may not be required. However, a negative result sometimes can be difficult to interpret because its meaning partly depends on your family’s history of cancer, and whether a BRCA mutation has been identified in a blood relative. Further, scientists continue to discover new BRCA1 and BRCA2 mutations, and have not yet identified all potentially harmful ones. Therefore, it is possible that although you have a “negative” test result you might have a harmful BRCA1 or BRCA2 mutation, which has not been identified.
 
Counselling
 
Because of these uncertainties and the agonising choices women with suspected breast cancer face, health providers in most developed countries recommend counselling as part of breast cancer treatment pathways. In the video below Dr John Green, a medical oncologist knowledgeable about the influence of inherited BRCA gene mutations on treatment options underlines the importance of expert genetic counselling to help women navigate their therapeutic pathways. Counselling is performed by a health professional experienced in cancer genetics, and usually includes the psychological risks and benefits of genetic tests, a hereditary cancer risk assessment based on a person’s personal and family medical history; a description of the tests, their technical accuracy and appropriateness, medical implications of a positive or a negative test result, the possibility of uncertain or ambiguous test results, cancer risk-reducing treatment options, and the risk of passing on a mutation to children. Because people are more aware of the genetic mutations linked to breast cancer, the demand for genetic testing and counselling have increased, and in some instances it is challenging for genetic counsellors to keep pace with demand.
 
 
The context in which genetic tests are carried out

A 2017 study published in the Journal of Clinical Oncology suggests that genetic test results for breast cancer are not being clearly communicated to women, and this could cause them to opt for treatments that are more aggressive than they actually need. To reduce this possibility the Royal Marsden NHS Trust Hospital in London has introduced the Mainstreaming Cancer Genetics programme. Since 2014 the Marsden has employed genetic counseling and used laboratories with enhanced genetic testing capabilities. This reduces processing time and costs, helps to meet the increased demand for rapid, accurate and affordable BRCA testing, and helps women make critical decisions about their treatment options.
 
There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex,” says Nazneen Rahman, Professor and Head of Cancer Genetics at the UK’s Institute for Cancer Research in London. “We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital,” says Rahman.

The Marsden is now offering tests to three times more patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.”

 
Takeaways

The history of cancer is punctuated with overzealous interventions, many of which have had to be modified once it has been demonstrated that they could cause more harm than good.

As advanced genetic testing becomes affordable and more accessible it is important that their results are interpreted with the help of genetic counsellors in a broader familial context in order to help women make painfully difficult decisions about their treatment.
 
Migration to next generation genetic testing technologies has many benefits, but it also introduces challenges, which arise from, the choice of platform and software, and the need for enhanced bio-informatics analysts, which are in scarce supply. An efficient, cost-effective accurate mutation detection strategy and a standardized, systematic approach to the reporting of BRCA test results are central for diagnostic laboratories wishing to provide a service during a time of increasing demand and downward pressure on costs.
 
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  • A recent study suggests that a drug combined with dietary and lifestyle changes can prevent those with pre-diabetes from progressing to full blown type-2 diabetes (T2DM)
  • T2DM kills millions and cost billions
  • 35% of adults in the UK, and 50% in the US now have prediabetes
  • The UK has launched the world’s first nationwide diabetes prevention program called Healthier You based on personal education and training
  • Prevalence rates of T2DM are still rising 
  • Research on the gut-brain axis suggests that drugs have a role to play in preventing T2DM
  • An optimum strategy might consist of appropriate drug therapy combined with appropriate education, which leverages ubiquitous 21st century communications infrastructures
  
A new therapeutic approach to pre-diabetes
 
Findings of an international clinical study published in The Lancet in 2017 suggest that 3.0mg of the drug liraglutide, may reduce diabetes risk by 80% in individuals with pre-diabetes and obesity, and thereby significantly contribute to the prevention of type-2 diabetes (T2DM). The study investigated whether 3.0mg of liraglutide would delay the onset of T2DM safely in people with pre-diabetes.
 
Liraglutide is the active solution in a drug marketed as Victoza, which obtained FDA approval in 2010.  Victoza is available in 6 mg/ml pre‑filled pens, and is used as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. Victoza is used also as an add-on to other diabetes medicines, when these, together with exercise and diet, are not providing adequate control of blood glucose.
  

Pre-diabetes

Pre-diabetes is a condition that develops when your blood sugar levels are at the very high end of the normal range, but not quite high enough for a diagnosis of T2DM.  Risk factors include age, weight and ethnicity. People of South Asian origin are up to six times more likely to develop pre-diabetes as a genetic susceptibility means they start to develop insulin resistance at a much lower Body Mass Index (BMI). With pre-diabetes your body begins to have trouble using the hormone insulin, which is necessary to transport glucose, which your body uses for energy, into your cells via the bloodstream. Pre-diabetes means that your body either does not make enough insulin or it does not use it well (insulin resistance). If you do not have enough insulin or if you are insulin resistant, you can build up too much glucose in your blood, leading to higher-than-normal blood glucose level and perhaps pre-diabetes. Blood glucose is measured using a test called HbA1c, which provides a picture of your blood sugar levels over the past two to three months. It counts the number of glucose molecules stuck to the red blood cells, which reveals how much sugar you have carried in your blood over the two to three month lifespan of the red blood cell. If your blood sugar is between 5.7 to 6.4%, this is called pre-diabetes (6.5 is officially diabetes). Dr Roni Sharvanu Saha, a consultant in acute medicine, diabetes and endocrinology at St George's Hospital, London describes pre-diabetes:
 


Prevalence and cost 
 
It is estimated that 35% of adults in the UK, and 50% in the US now have pre-diabetes. Around 5-10% of these will progress to "full-blown" T2DM in any given year. Because there are no obvious symptoms for pre-diabetes the overwhelming majority of people with the condition do not know they have it, and are not aware of the long-term risks to their health, which include T2DM and its complications: heart attack, stroke, kidney failure, blindness and lower limb amputation. Over the past decade, the prevalence of T2DM has increased by almost two-thirds, and is now one of the world’s most common long-term health conditions.
 
An estimated £14bn is spent each year on treating diabetes and its complications in the UK. Treating obesity-linked illnesses costs £10bn a year. The annual medical cost of treating diabetes in the US is about US$176bn, and the cost of diabetes in reduced productivity is some US$69bn each year.
 
The gut-brain axis

The study published in The Lancet was led by John Wilding, Professor of Medicine, University of Liverpool, and is a continuation of work he started in 1996 when part of a team at Hammersmith Hospital in London, which first showed that the hormone GLP-1, on which liraglutide is based, was involved in the control of food intake.
 
Over the past two decades scientists have increased their understanding of the two-way communications between the gut and the brain, not only through nerve connections between the organs, but also through biochemical signals, such as hormones that circulate in the body. Dr Sufyan Hussain, Specialist Registrar and Honorary Clinical Lecturer in Diabetes, Endocrinology and Metabolism at Imperial College London, describes the gut-brain axis.
 
 
Targeting gut-brain pathways

An increasing number of different gut microbial species are now postulated to regulate brain function in health and disease. The westernized diet, which is high in saturated fats, red meats, and carbohydrates, and low in fresh fruits and vegetables, whole grains, seafood, and poultry, is hypothesized to be the cause of high obesity levels in many countries. For example, 63% and 69% of adults in the UK and US respectively are either overweight or obese, and therefore at risk of T2DM. Experimental and epidemiological evidence suggest that the gut microbiota is responsible for significant immunologic, neuronal, and endocrine changes that lead to obesity. The gut–brain axis influences obesity, and researchers such as Wilding have targeted communication pathways between the nervous system and the digestive system in an attempt to treat metabolic disorders. 
 
Bariatric surgery and diabetes

A previous HealthPad Commentary describes how bariatric surgery is associated with gut-brain signals, which promote the remission of diabetes in patients. Many of the mechanisms that underlie how bariatric surgery produces metabolic benefits remain unclear, but researchers do know that such surgical procedures elevate levels of the hormones peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) that help to reduce appetite and have effects on the central nervous system.
 
Liraglutide

Liraglutide is a GLP-1 receptor agonist, which interacts with the part of the brain that controls appetite and energy intake. The drug slows food leaving the stomach, helps prevent your liver from making too much sugar, and helps the pancreas to produce more insulin when your blood sugar levels are high. The most common side effects with liraglutide are nausea and diarrhoea.
 
The clinical study

The three-year study followed 2,254 adults with pre-diabetes at 191 research sites in 27 countries worldwide. Participants were randomly allocated to either liraglutide or a placebo delivered by injection under the skin once daily for 160 weeks. Participants in the study were also placed on a reduced calorie diet and advised to increase their physical activity. The study showed that three years of continuous treatment with once-daily 3.0mg of liraglutide, in combination with diet and increased physical activity, reduces the risk of developing T2DM by 80% and results in greater sustained weight loss compared to the placebo.

"On the basis of our findings, liraglutide 3.0mg can provide us with a new therapeutic approach for patients with obesity and pre-diabetes to substantially reduce their risk of developing type 2 diabetes and its related complications . . . . It is very exciting to see a laboratory observation translated into a medicine that has the potential to help so many people, even though it has taken over 20 years,” says Wilding.
 
World’s first nationwide diabetes prevention program

NHS England, Public Health England and Diabetes UK launched the world’s first nationwide diabetes prevention strategy, Healthier You, in 2016. It provides personal coaches to educate people at risk of T2DM in healthy eating and lifestyle, and personal trainers to provide bespoke physical exercise programs that are expected to help people lose weight. By 2020 Healthier You expects to be rolled out to the whole country with 100,000 referrals available each year after that.
 
Extrapolating from previous studies

International clinical studies have shown evidence that lifestyle interventions such as those used in Healthier You can prevent or delay the onset of T2DM. However, the validity of generalizing the results of previous prevention studies is uncertain. Interventions that work in some societies may not work in others, because social, economic, and cultural forces influence diet and exercise. The UK’s Public Accounts Committee has expressed doubts about the way Healthier You is setting about its task, and has warned that, "By itself, it will not be enough to stem the rising number of people with diabetes".
 
Failure of the diabetes establishment and the Public Accounts Committee

Healthier You is a slow, labor-intensive and expensive program, which is unlikely to have more than a relatively small impact.Let us explain. Assume that after 2020 Healthier You obtains its projected annual 100,000 referrals, and that they all successfully reduce their blood glucose levels with diet and exercise. Also assume that the prevalence of pre-diabetes in the UK does not increase, (which is not the case) then Healthier You will take more than 110 years to counsel the estimated 11.5m people in the UK with pre-diabetes: which is long after most people with pre-diabetes would have died from natural causes.
 
21st century communications

Successfully changing the diets and lifestyles of the 11.5m people in the UK believed to have pre-diabetes, and slowing their progression to T2DM will require 21st century technologies. Inexpensive and ubiquitous healthcare technologies used to educate and support diets and lifestyles abound. Increasingly people are demanding devices that track weight, blood pressure, daily exercise and diet. From apps to wearable’s, healthcare technology lets people feel in control of their health, while also providing health professionals with more patient data than ever before. With more than 100,000 healthcare apps, rapid growth in wearables, and 75% of the UK population now owning a smartphone, digital technology is well positioned to significantly improve healthcare education and management.
 
Takeaways

Has Healthier You missed the elephant in the room? Wilding’s study suggests that an exercise and diet program needs to be complemented with a sustained program of appropriate drugs if we are to reduce those with pre-diabetes from progressing to full blown T2DM. Further, simple arithmetic suggests that the education element of such a strategy about diet and lifestyle should leverage ubiquitous 21st century communications infrastructures if they are to be efficacious.
 
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