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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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  • Orthorexia nervosa is the term used to describe a growing serious 'health food eating disorder'
  • The number of people suffering from the condition is believed to be millions and increasing
  • Orthorexia often begins by cutting out certain food groups and only eating 'clean' foods in an attempt to become healthier
  • Sufferers become obsessed with ‘clean’ food, often feel superior to people with different eating habits, and indulge in excessive fitness routines
  • Experts warn that orthorexia can lead to malnutrition, social isolation and depression.  
     
Orthorexia: when eating healthily becomes unhealthy

Have you encountered someone who genuinely wants to live a healthier life by eating well, but then becomes so obsessed with “healthy” food that they become unwell and socially isolated?
 
If you have, then the person is likely to be suffering from orthorexia nervosa, an emerging dietary disorder in which an individual restricts intake to include only “healthy” foods, such as vegetables or organic foods, but in doing so develops an obsession with eating food believed to support “clean living”. Clean living is being mindful of the food's pathway between its origin and your plate, and eating food that is un- or minimally processed, refined, and handled, making them as close to their natural form as possible.
 
Having said this, it is important to mention that some restrictive diets can be healthy, and even necessary, for medical, ethical or religious reasons. Also, being mindful about what you consume is a positive way to live a healthy life: there is nothing wrong with eating healthily. However, orthorexia is different: becoming fixated on “clean” food can result in serious health problems.
 
Orthorexia is not anorexia

Unlike anorexics, orthorexics are preoccupied with the quality of food they consume rather than its quantity. The condition usually starts in a quest to be wholesome, when a person cuts out a food group, such as sugar, pulses, dairy products and processed food, but over time ends up with a diet so restrictive, that it contains only a limited number of ‘safe foods’, that the person becomes malnourished.
 

Orthorexia nervosa
 
Orthorexia nervosa describes a pathological obsession with “clean” nutrition, which is characterized by a restrictive diet, ritualized patterns of eating, rigid avoidance of foods believed to be unhealthy or impure, and excessive exercise. Although prompted by a desire to be healthy, orthorexia may lead to nutritional deficiencies, medical complications, and a poor quality of life.
 
Social isolation

Typically, orthorexics spend significant amounts of their time scrutinizing the source of food, and how it is processed and packaged to ensure that it is “clean”. The self-esteem of people with orthrexia becomes associated with their ability to stick to their diet of “clean food”, and they often feel guilty and angry with themselves if they stray from their strict list of acceptable foods.  Orthorexics may develop feelings of social superiority to others, and judge those who indulge in “unclean” foods. Their obsession with specific foods often stops them socializing with family and friends, as social events frequently involve drinking and eating “unhealthily”.  Also, excessive exercising plays an important role in relation to orthorexia. 
 
Because orthorexics are “addicted” to thinking they are doing the right thing, they tend not to question whether their diet and lifestyle might have a negative impact on their health. Sufferers often take their eating habits to dangerous levels, cutting out food groups and combining their strict diet with too much exercise. In the video below, Dr Seth Rankin, founder and CEO of the London Doctors Clinic suggests that, “denial is the hallmark of an obsession”, and that you cannot treat someone with an obsession unless they recognize that they have a problem.
 
 
 
First diagnosed sufferer

Steven Bratman, a physician who coined the term orthorexia nervosa in 1997, diagnosed himself with the condition after he became obsessive about clean eating. According to Bratman, “Eventually orthorexia reaches a point at which the orthorexic devotes much of his life to planning, purchasing, preparing and eating meals.” Bratman developed 10 questions based on his experience to show how people with the condition could be identified: see below. Bratman’s work has not been validated as indicative of a syndrome; and therefore the diagnostic criteria for orthorexia are still uncertain.
 

Bratman’s 10-point test for orthorexia

Do you spend more than 3 hours a day thinking about your diet?
Do you plan your meals several days ahead?
Is the nutritional value of your meal more important than the pleasure of eating it?
Has the quality of your life decreased as the quality of your diet has increased?
Have you become stricter with yourself lately?
Does your self-esteem get a boost from eating healthily?
Have you given up foods you used to enjoy in order to eat the 'right' foods?
Does your diet make it difficult for you to eat out, distancing you from family and friends?
Do you feel guilty when you stray from your diet?
Do you feel at peace with yourself and in total control when you eat healthily?
RESULTS
Yes to 4 or 5 of the above questions means it is time to relax more about food.
Yes to all of them means a full-blown obsession with eating healthy food.

 
Orthorexia is not officially recognized
 
One of the reasons you might not have heard of orthorexia is because it is not officially recognized as an eating disorder. It is not mentioned as a diagnosis 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. Its lack of recognition leads primary care doctors to refer sufferers to nutritionists, which is a mistake because orthorexics require therapy that de-emphasizes food.
 
Prevalence difficult to determine

Without being officially recognized as a disease there has been no epidemiological studies on the condition. Notwithstanding, orthorexia is believed to affect millions and be on the increase. Some psychiatrists are beginning to study the condition and offer treatment to patients. In a recent survey of healthcare professionals, 66% reported having observed patients presenting with clinically significant orthorexia; and 66% suggested that the syndrome deserves more scientific attention.
 
The American National Association of Anorexia Nervosa and Associated Disorders suggests there are some 30m people in the US suffering from eating disorders. Instagram has 26m posts with the #eatclean hashtag. According to the UK’s National Osteoporosis Society, 20% of people under 25 are cutting out or reducing dairy from their diets. A 2016 National Diet and Nutrition Study undertaken by Public Health England found that the calcium intake of 1 in 6 women under 24 was “worryingly low”.
 
The ORTO-15 test and research beginnings

Orthorexia’s lack of formal status also means that there is a dearth of research on the condition, although published literature and research data have increased in the past few years. In 2005 a group of Italian scientists modified Bratman’s criteria for detecting orthorexia, and developed the ORTO-15 questionnaire, which identifies how far such criteria can be used for psychometric and specific diagnosis. Researchers enrolled 525 participants; 404 were used in the construction of the ORTO-15 test, which comprised 15 multiple-choice questions; and 121 people participated in the ORTO-test’s validation. A score below 40 implies the presence of an obsessive pathological behavior characterized by a strong preoccupation with “clean” eating. Findings from this validation study reported that the ORTO-15 test has an efficacy of 73.8%, a sensitivity of 55.6%, and a specificity of 75.8%.
 
At least four studies have used the ORTO-15 test to evaluate the prevalence of a preoccupation with “clean” food. A 2010 Turkish study published in the journal of Comprehensive Psychiatry found that 43.6% of medical students showed a preoccupation with healthy food. A large Hungarian study published in 2014 in the journal BMC Psychiatry used the ORTO-15 test on 810 predominantly female (89.4%) university students, and found that over 70% had orthorexia tendencies. American studies have reported a prevalence of orthorexic behaviours ranging from 69% to 82.8% among undergraduate students.
 
The first study to examine the prevalence of orthorexia nervosa in athletes was completed in 2012 and showed a high frequency of orthorexia across both male (30%) and female (28%) athletes who were largely professional athletes involved in a range of sports. In 2013 a meta study published in Eating and Weight Disorders reviewed 11 studies of orthorexia. Findings suggest that the average prevalence rate for orthorexia was 6.9% for the general population, 35% to 57.8% for high-risk groups such as dieticians, other healthcare professionals, and artists. Risk factors were suggested to be obsessive-compulsive features, eating-related disturbances, and higher socioeconomic status.
  
Takeaways
 
Orthorexia appears to be on the increase at a time when the vast and escalating healthy lifestyle-information industry is complemented by the rapid exchange of ideas via social media. This means that individuals are regularly bombarded with dietary and healthcare advice, which they can share instantly. Orthorexia seems yet another serious condition of affluent societies, which is growing in significance.
 
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  • 3m men in the US and 330,000 men in the UK are living with prostate cancer
  • The standard test used to diagnose prostate cancer is inaccurate
  • This inaccuracy causes anxiety in men and leads to unnecessary treatments
  • Standard therapies for prostate cancer can result in incontinence and impotence
  • Two new studies describe procedures that promise significant improvements in diagnosis and treatment
 
New developments in the management of prostate cancer
 
A vicious circle

There is general agreement on two issues concerning the management of prostate cancer: one, over-diagnosis and overtreatment rates are high; and two, there is a need to refine the standard prostate-specific antigen (PSA) diagnostic test.
 
The test does not provide information to allow doctors to determine which early-stage prostate tumors pose a risk of being aggressive and need treatment, and which should be left alone. Therefore, efforts to reduce the prevalence of prostate cancer by early detection using the PSA test can lead to over-diagnosis, which in turn can result in overtreatment, which in the case of prostate cancer, can result in incontinence and impotence.
 
Current official advice to UK GPs says: “The PSA test is available free to any well man aged 50 and over who requests it.” But, “GPs should not proactively raise the issue of PSA testing with asymptomatic men”. And, “GPs should use their clinical judgment to manage symptomatic men and those aged under 50 who are considered to have higher risk for prostate cancer”. In 2014 the National Institute for Health and Care Excellence (NICE) updated its guidelines and suggested that prostate cancer patients should avoid immediate treatment and keep their disease under “surveillance”.
 
A killer disease on the increase
 
Prostate cancer is increasing in significance worldwide. In many industrialized countries such as the US and the UK, it is one of the most common cancers and among the leading causes of cancer deaths. In developing countries it may be less common, but its incidence and mortality rates have been on the rise. In the US there are some 3m men living with the disease.  It is expected that in 2017, 161,000 new cases of prostate cancer will be diagnosed in the US, and 27,000 men will die from it. In the UK, there are some 330,000 men living with prostate cancer; each year around 47,000 men are diagnosed with the disease, and each year some 11,000 die from it, which equates to one every hour. Worldwide, there are an estimated 1.6m new cases of prostate cancer, and 366,000 prostate cancer deaths annually, making it the most commonly diagnosed cancer in men and the seventh leading cause of male cancer death.
 
The prostate and prostate cancer

The prostate is a small gland in men, which is located below the bladder and above the rectum. The urethra, which is the tube that carries urine and semen out of the body through the penis, goes through the centre of the prostate. In younger men the prostate is about the size of a walnut, but in older men it can be much larger. Symptoms of prostate cancer include persistent burning, difficult, frequent, uncontrolled or bloody urination in the absence of any infection. The average age of onset is 65 to 69. It is particularly prevalent in African-Caribbean men: affecting I in 4, and killing I in 12, which is double the rate for that of Caucasian men. The main risk factor is age: 80% of all men diagnosed with prostate cancer are over 65. Between 5% and 9% of cases occur in men with a family history of prostate, breast or ovarian cancer. Environmental factors are unclear, but rates of prostate cancer are lower in less urbanised societies, and rates rise when people move to a more westernised diet and lifestyle.
 
The prostate-specific antigen (PSA) test

In the 1980s a simple and cheap blood test was introduced to detect prostate cancer in its earliest, most curable, stage. In the video below Professor Karol Sikora, a cancer expert, describes the PSA test. Although used to detect prostate cancer, it is not a test for prostate cancer, and as a consequence, it has unresolved challenges. The most significant arises because the test is not accurate enough to either rule out or confirm the presence of cancer. Indeed, it is possible for PSA levels to be elevated when cancer is not present, and not to be elevated when it is present. More than 65% of men with elevated PSA levels do not have cancer. Excessive reliance on the test may lead to unnecessary interventions, while insufficient reliance may cause cancers to be missed.
 
 
Biopsies
 
A biopsy will often be recommended if a PSA test is high. It may also be recommended if a digital rectal examination (DRE) reveals a lump or some other abnormality in the prostate. The most commonly used biopsy for diagnosing prostate cancer is the trans-rectal ultrasound-guided prostate biopsy (TRUS-biopsy). This is a surgical procedure, in which tissue is removed from the prostate for microscopic examination. Each year, over 100,000 prostate biopsies are carried out in the UK and 1m in Europe.
 
75 to 80% of men who have TRUS-biopsies have no cancerous cells, and therefore did not need the biopsy. 20 to 25% do have cancerous cells, but a large percentage of these do not need any treatment because the cancers are slow growing.  A 2014 paper by the Harvard School of Public Health estimates that only 3% of men suspected of prostate cancer have an aggressive tumor requiring immediate intervention.
 
Further, doctors cannot tell from a biopsy whether cancerous cells are aggressive and need treatment, or whether they are developing slowly and do not require treatment. This creates confusion and anxiety among men, which prompts a percentage to opt for treatment even though the overwhelming majority do not need it. 25% of older men who elect to have treatment will become incontinent or impotent as a result, despite the fact that they did not need the treatment.
 
Active surveillance
 
In a significant proportion of men, prostate cancer cells grow slowly and never pose a serious risk to health and longevity. Evidence suggests that early treatment with either surgery or radiation does not reduce mortality rates, but leaves a significant percentage of men with urinary or erectile problems and other adverse effects. As a result, more men are willing to manage their condition by active surveillance, in which doctors monitor low-risk cancers closely and consider treatment only when the condition appears to make threatening moves toward growing and spreading. These men choose to live with prostate cancer until it advances, sometimes avoiding potentially life-altering side effects for several years. Active surveillance is a powerful solution to the problem of over-diagnosis and overtreatment.
 
New studies promise significantly improved management

Prostate cancer lags behind other cancers in diagnosis, treatment and research funding. But this is beginning to change. Over the past year, findings of two clinical studies promise significant improvements in the management of the condition.

The first, published in 2017 in the Lancet, describes a process, which uses MRI-guided biopsies to improve the accuracy of prostate cancer diagnosis, and spares those who do not have aggressive cancers from undergoing an unnecessary biopsy, so reducing the confusion and anxiety which prostate patients often experience.

The second, published in 2016 in the Lancet Oncology, describes findings of a laser-activated drug derived from bacteria found at the bottom of the sea that attacks and kills prostate cancer cells without either removing or destroying the prostate gland. This is significant because it avoids the potential adverse effects of surgery and radiotherapy, which can render patients incontinent and/or impotent. 

 
The multi-parametric MRI

The 2017 Lancet study used an advanced type of MRI scan, known as a multi-parametric MRI (MP-MRI), which in addition to recording the shape and size of the prostate, also assesses the blood flow through the gland. Led by Dr Hashim Ahmed of University College London, the study was comprised of more than 500 British men with suspected prostate cancer. Results suggest that using the MP-MRI to triage men would safely reduce the number needing a primary biopsy by about 27%, and substantially improve the detection of clinically significant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancers might be detected compared with the standard pathway of TRUS-biopsy for all.
 
A paradigm shift in prostate cancer treatment

The second study compared the safety and effectiveness of a new therapy called vascular-targeted photodynamic therapy (VTP, also known as TOOKAD), with active surveillance in men with low-risk prostate cancer. It funded by STEBA Biotech, which holds the commercial licence for the therapy. Photodynamic therapy (PDT) is not new, and has been used to treat skin and other cancers where light can easily penetrate.  VTP therapy, however, is viewed as a paradigm shift in prostate cancer care. It involves injecting a light-sensitive drug (padeliporfin or WST11) into the bloodstream, and then activating it with a laser to destroy cancerous tissue.  The benefit of this approach is damage to healthy prostate tissue is minimised, reducing the risk of side effects.
 
Findings

The study was comprised of 413 men at low risk of prostate cancer, and carried out across 47 treatment sites in 10 European countries, most of which were performing VTP therapy for the first time. Only men classified with low-risk cancer were included in this study. Participants were randomly assigned either to VTP therapy or active surveillance. At the end of two years, of the 196 men who received the VTP treatment, about half showed no signs of the disease, compared with 13.5% of those given standard care. Only 6% of the VTP group later needed radical treatment, compared with 30% of active surveillance patients. VTP treatment also doubled the average time of cancer progression from 14 to 28 months. Findings suggest that 49% of patients treated with VTP therapy went into complete remission compared with 13.5% in the control group.

A third of the VTP group experienced side effects compared to only 10 of the active surveillance group. Notwithstanding, the study concluded that, “VTP therapy is a safe, effective treatment for low-risk, localised prostate cancer, which might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy”. Patient monitoring will continue in order to ascertain whether the cancer stays away. Further studies should help to understand better which cancers VTP  treatment is most appropriate for so that men can make more informed treatment decisions.

Study enhanced by MRI scanning
 
The study was conducted with people at low risk of prostate cancer. Those at very low risk are better off with no treatment and no adverse-effects. Professor Mark Emberton of University College London, the lead author of the study, believes the therapy will be most useful in patients in the “grey zone”, between low and high risk. “The fact that the treatment was performed so successfully by non-specialist centres in various health systems is really remarkable”, says Emberton because the lack of complication suggests that the treatment protocol is safe, and relatively easy to scale.

At the beginning of the study MRI scans were not universally available, and Emberton believes MRI scanning as suggested by the Ahmed 2017 study will have a significant positive effect on prostate cancer treatment in the future. When carrying out biopsies without guidance from MRI scans researchers had to guess where in the prostate the cancer was; so biopsies were sub-optimal. “If they were to do the study now, with the help of MRI scans, they could hit the cancerous parts of the prostate rather than going in blind and the results would be much better,” says Emberton.

 
Takeaways
 
These two recent studies are potential “game changers”. They promise to significantly enhance the management of prostate cancer and substantially reduce the uncertainty and anxiety, as well as the risks of the life altering side effects of treatment, experienced by millions of men living with the disease.
 
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  • Each year cancer kills 8m people worldwide and cost billions
  • 40% of cancer deaths could be prevented by early detection
  • Nearly half of all cancer sufferers are diagnosed late when the tumors have already spread
  • Victims and doctors often miss early warning signs of cancer
  • Traditional tissue biopsies used to diagnose cancer are invasive, slow, costly, and often yield insufficient tissue
  • New blood tests are being devised that simultaneously detect cancer early and inform where the cancer is in the body
  • Such tests - liquid biopsies - are positioned to end the late diagnosis of cancer
  • But before liquid biopsies become common practice they need to overcome a number of significant challenges
  
World’s first blood tests that detect and locate cancer
 
Just as there is a global race among immunotherapists to enhance cancer treatment, so there is a parallel race among bioengineers to speed up and improve the detection of cancer. Such races are important because nearly half of all cancer sufferers are diagnosed late, when their tumors have already metastasized: 30% to 40% of cancer deaths could be prevented by early detection and treatment.
 
Here we describe advances in blood tests - “liquid biopsies” - which can simultaneously detect cancer early, and identify its tissue of origin. We also, describe the growing commercialization of the technology, and some significant hurdles it still has to be overcome.
 
A costly killer disease

Each year cancer kills more than 8m people worldwide, 0.6m in the US and nearly 0.17m in the UK. Survival rates for pancreatic, liver, lung, ovarian, stomach, uterine and oesophageal cancers are particularly low. A large proportion of people do not know they have cancer, and many primary care doctors fail to detect its early warning signs. According to The Journal of Clinical Oncology, a staggering 44% of some types of cancers are misdiagnosed. A significant proportion of people discover that they have cancer only after presenting a different condition at A&E. Each year, the total cost of cancer to the UK’s exchequer is nearly £20bn. In the US, national spending on cancer is expected to reach US$156bn by 2020. And as populations age so some cancer prevalence rates increase, despite substantial endeavours to reduce the burden of the disease.
  
The UK: a stereotypical case

The UK is indicative of what is happening elsewhere in the developed world with regard to cancer diagnosis and treatment. Epidemiological trends suggest that although progress is being made to fight the disease, much work is still required. Death rates for a number of individual cancer types have declined, but rates for a few cancers have increased.

Recently, the UK’s Department of Health invested £450m to improve diagnosis, including giving primary care doctors better access to tests such as CT and MRI scans. But each year there are still some 0.17m cancer deaths in the UK, and 1 in 4 British cancer patients are unlikely to live longer than 6 months after diagnosis because they and their doctors have missed early signs of the disease. For example, in the UK only 23% of lung cancer cases are diagnosed early, as are 32% of cases of non-Hodgkin lymphoma, and 44% of ovarian cancer.

Not only does late detection increase morbidity and mortality, it significantly increases treatment costs. According to the UK’s NHS National Intelligence Network, a case of ovarian cancer detected early costs an average of £5,000 to treat, whereas one detected late at stage three or four costs £15,000. Similarly, a colon cancer patient detected early typically costs £3,000, while one not identified until a later stage would cost some £13,000.

 
Traditional tissue biopsies

Currently, oncologists look to pathologists for assistance in tumor diagnosis. Indeed, oncologists cannot proceed with therapy without a tissue diagnosis, nor are they able to discuss prognosis with the patient. After detecting a tumor through a physical examination or imaging, doctors use traditional tissue biopsies to gather information on the attributes of a patient’s cancer.
 
These pinpoint a cancer’s mutations and malignancy, but solid tissue biopsies are not always straightforward. While some cancers are easily accessed, others are hidden deep inside the body or buried in critical organs. Beyond the physical challenge, sampling from such tumors can be dangerous to patients, and once achieved, they do not always inform on current tumor dynamics. Further, traditional solid tissue biopsies are costly and time consuming to perform; they can yield insufficient tissue to obtain a good understanding of the tumor, and they can be hampered by a patient’s comorbidities, and lack of compliance.

 
Two significant studies
 
Although solid tumor tissue is still the gold standard source for clinical molecular analyses, cancer-derived material circulating in the bloodstream has become an appealing alternative showing potential to overcome some of the challenges of solid tissue biopsies.

Findings of two significant studies of liquid biopsies published in 2017 promise a more effective and patient-friendly method for diagnosing cancer: one in the journal Genome Biology, and the other in the journal Nature Genetics. Both studies are on the cusp of developing the world’s first simple blood test, which can both detect early stage cancer, and identify where in the body the cancer is located.

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The Genome Biology study
 
​The study, reported in Genome Biology, describes findings of a blood test, referred to as the CancerLocator, which has been developed by Jasmine Zhou, Professor of Biological and Computer Sciences and her team at the University of California, Los Angeles (UCLA). The  Locator detected early stage cancer in 80% of breast, lung and liver cases.
 
Zhou and her colleagues devised a computer program that uses genetic data to detect circulating tumor DNA (ctDNA) in blood samples. Once identified, the ctDNA is compared to a database of genetic information from hundreds of people to identify where the tumor is located.  Zhou’s team discovered that tumors, which arise in different parts of the body, have different signatures, which a computer can spot. “The technology is in its infancy and requires further validation, but the potential benefits to patients are huge  . . . . . Non-invasive diagnosis of cancer is important, as it allows the early detection of cancer, and the earlier the cancer is caught, the higher chance a patient has of beating the disease,” says Zhou.
 
The Nature Genetics study

Researchers led by Kun Zhang, Professor of Bioengineering at the University of California, San Diego (UCSD), are responsible for the study published in the journal Nature Genetics. Zhang developed a test that examined ctDNA in blood from cancer patients and, like Zhou, discovered that not only could it detect cancer early, but could also locate where the tumor is growing in the body. When a tumor starts to take over a part of the body, it competes with normal cells for nutrients and space, killing them off in the process. As normal cells die, they release their DNA into the bloodstream; and that DNA can identify the affected tissue.
 
There are many technical differences on how each approach works . . . The work by the UCLA group is a computer program that uses data published previously by other groups, and has reduced the cancer detection error from roughly 60% to 26.5%. In contrast, we developed a new theoretical framework, generated our own data from over 100 patients and healthy people, and our accuracy of locating cancer in an organ is around 90%,” says Zhang, but he adds, “Major medical challenges don’t get solved by one team working alone”.
 
Confluence and advances in computing and biology

The research endeavors of Professors Zhou and Zhang have been made possible by the confluence and advances in computing and molecular biology. Over the past 20 years, there has been a paradigm shift in biology, a substantial increase in computing power, huge advances in artificial intelligence (AI), and the costs of data storage have plummeted. It took 13 years, US$3bn, and help from 7 governments to produce the first map of the human genome, which was completed in 2003. Soon it will be possible to sequence an entire genome in less than an hour for US$100.
 
The end of traditional in vitro diagnostics

Liquid biopsies are a sequencing-based technology used to detect microscopic fragments of DNA in just a few drops of blood, and hold out the potential to diagnose cancers before the onset of symptoms. Roger Kornberg, Professor of Structural Biology at Stanford University, and 2006 Nobel Laureate for Chemistry for his work in understanding how DNA is converted into RNA, “which gives a voice to genetic information that, on its own, is silent,” describes how advances in molecular science are fueling the replacement of traditional in vitro diagnostics with virtually instantaneous, point-of-care diagnostics without resort to complex processes or elaborate and expensive infrastructure. Liquid biopsies, such as those developed by Zhou and Zhang, have the potential to provide clinicians with a rapid and cheap means to detect cancer early, thereby enabling immediate treatment closely tailored to each patient’s disease state.

 
 
FDA approval of liquid biopsy
 
In 2016, the US Food and Drug Administration (FDA) granted Swiss pharmaceutical and biotech firm Roche approval for a liquid biopsy, which can detect gene mutations in the most common type of lung cancer, and thereby predict whether certain types of drugs can help treat it. 

The clinical implementations of such a test are not widespread, and there has been no regulatory approval of liquid biopsies for diagnosing cancer generally. Notwithstanding, ctDNA is now being extensively studied, as it is a non-invasive “real-time” biomarker that can provide diagnostic and prognostic information before and during treatment; and at progression.
 

cfDNA and ctDNA

Cell-free DNA (cfDNA) is a broad term that describes DNA, which is freely circulating in the bloodstream, but does not necessarily originate from a tumor. Circulating tumor DNA (ctDNA) is fragmented DNA, which is derived directly from a tumor or from circulating tumor cells (CTCs).
 
Commercialization of the liquid biopsy race
 
Bill Gates, Jeff Bezos and leading venture capitalists have poured hundreds of millions into the goal of developing liquid biopsies. The US market alone is projected at US$29bn, according to a 2015 report from investment bank Piper Jaffray. Currently, there are about 40 companies in the US analyzing blood for fragments of DNA shed by dying cancer cells. Notwithstanding, only a few companies have successfully marketed liquid biopsies, and these are limited to identifying the best treatments for certain cancers, and to update treatments as the cancer mutates. So far, no one has been successful in diagnosing incipient cancer from a vial of blood drawn from a patient who looks and feels perfectly healthy.
 
Some US companies in the liquid biopsy race

At the 2016 meeting of the American Society of Clinical Oncology (ASCO), a Silicon Valley start-up, Guardant Health, which has raised some US$200m, presented findings from a large study involving over 15,000 participants, which demonstrated the accuracy of its liquid biopsy test, Guardant360, for patients with advanced solid tumors. The study found the same patterns of genomic changes in cfDNA reported by the Guardant360 test as those found in 398 patients with matching tissue samples between 94% and 100% of the time.

The 70-gene test is the first comprehensive, non-invasive genomic cancer-sequencing test to market, and according to the company, about 2,000 physicians worldwide have used it. Guardant expects to continue to develop its technology, and maintain a commercial lead in the cfDNA liquid biopsy space. The next step for Guardant is to go beyond sequencing, which matches patients to targeted oncology drugs to the early detection of cancer itself. 
 
Also in 2016 Gates and Bezos teamed up with San Diego's Illumina, which makes most of the DNA sequencing machines that pick appropriate treatments for cancer patients, to launch another liquid biopsy start-up called Grail. In 2017, Grail raised US$900m to help it develop blood-based diagnostics to enable routine, early detection of cancer. The company aims to refine and validate its liquid biopsy technology by running a number of large-scale clinical studies where it expects to sequence hundreds of thousands of patients. Another Californian-based biotech start-up, Freemome,  raised US$65m to validate its liquid biopsy technology for the early detection of cancer.
 
Takeaways

Despite findings of the two 2017 studies reported in the journals Genome Biology and Nature genetics, FDA approval of Roche’s liquid biopsy, massive increase in investment, and significant commercial biotech activity, there is a gap between reality and aspirations for liquid biopsies. To provide doctors with a reliable, point-of-care means to detect cancer early, liquid biopsies will have to overcome several significant challenges. The major one is assay sensitivity and specificity for analysis of ctDNA and cfDNA. To compete with the gold standard solid tissue biopsy, and to ensure that patients receive early diagnosis and appropriate treatment, a successful liquid biopsy assay will have to demonstrate a high positive predictive value. Concomitantly, good sensitivity and excellent specificity will be required to yield acceptable rates of false positives and false negatives. Notwithstanding, the race among bioengineers to develop a non-invasive “real-time” liquid biopsy to detect cancer early is gaining momentum.
 

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  • Competition is intensifying among scientists to develop and use gene editing and immunotherapy to defeat intractable diseases
  • Chinese scientists were the first to inject people with cells modified by the CRISPR–Cas9 gene-editing technique
  • Several studies have extracted a patient’s own immune cells, modified them using gene-editing techniques, and re-infused them into the patient to seek and destroy cancer cells
  • A new prêt à l'emploi gene editing treatment disables the gene that causes donor immune cells to attack their host
  • The technique harvests immune cells from a donor, modifies and multiplies them so that they may be used quickly, easily and cheaply on different patients
  • Commercial, technical, regulatory and ethical barriers to gene editing differ in different geographies 

Gene editing battles

Gene editing and immunotherapy are developing at a pace. They have been innovative and effective in the fight against melanoma, lung cancer, lymphomas and some leukaemias, and promise much more. Somatic gene therapy changes, fixes and replaces genes at the tissue or cellular levels to treat a patient, and the changes are not passed on to the patient’s offspring. Germ line gene therapy inserts genes into reproductive cells and embryos to correct genetic defects that could be passed on to future generations.  Although there are still many unanswered clinical, commercial and ethical questions surrounding gene therapy, its future is assured and will be shaped by unexpected new market entrants and competition between Chinese and Western scientists, which is gaining momentum.
  
14 February 2017

On the 14th February 2017 an influential US science advisory group formed by the National Academy of Sciences and the National Academy of Medicine gave support to the modification of human embryos to prevent “serious diseases and disabilities” in cases where there are no other “reasonable alternatives”. This is one step closer to making the once unthinkable heritable changes in the human genome. The Report, however, insisted that before humanity intervenes in its own evolution, there should be a wide-ranging public debate, since the technology is associated with a number of unresolved ethical challenges. The French oppose gene editing, the Dutch and the Swedes support it, and a recent Nature editorial suggested that the EU is, “habitually paralysed whenever genetic modification is discussed”. In the meantime, clinical studies, which involve gene-editing are advancing at a pace in China, while the rest of the world appears to be embroiled in intellectual property and ethical debates, and playing catch-up.
 
15 February 2017

On the 15th February 2017, after a long, high-profile, heated and costly intellectual property action, judges at the US Patent and Trademark Office ruled in favor of Professor Feng Zhang and the Broad Institute of MIT and Harvard, over patents issued to them associated with the ownership of the gene-editing technology CRISPR-Cas9: a cheap and easy-to-use, all-purpose gene-editing tool, with huge therapeutic and commercial potential.
 
The proceedings were brought by University College Berkeley who claimed that the CRISPR technology had been invented by Professor Jennifer Doudna of the University, and Professor Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology in Berlin, and described in a paper they published in the journal Science in 2012. Berkeley argued that after the 2012 publication, an “obvious” development of the technology was to edit eukaryotic cells, which Berkeley claimed is all that Zhang did, and therefore his patents are without merit.

The Broad Institute countered, suggesting that Zhang made a significant inventive leap in applying CRISPR knowledge to edit complex organisms such as human cells, that there was no overlap with the University of California’s research outcomes, and that the patents were therefore deserved. The judges agreed, and ruled that the 10 CRISPR-Cas9 patents awarded to Zhang and the Broad Institute are sufficiently different from patents applied for by Berkeley, so that they can stand. 
 
The scientific community

Interestingly, before the 15th February 2017 ruling, the scientific community had appeared to side with Berkeley. In 2015 Doudna, and Charpentier were awarded US$3m and US$0.5m respectively for the prestigious Breakthrough Prize in life sciences and the Gruber Genetics Prize. In 2017 they were awarded the Japan Prize of US$0.45m for, “extending the boundaries of life sciences”. Doudna and Charpentier have each founded companies to commercially exploit their discovery: respectively Intellia Therapeutic, and CRISPR Therapeutics.
 
16 February 2017

A day after the patent ruling, Doudna said: “The Broad Institute is happy that their patent didn’t get thrown out, but we are pleased that our patent based on earlier work can now proceed to be issued”. According to Doudna, her patents are applicable to all cells, whereas Zhang’s patents are much more narrowly indicated. “They (Zhang and the Broad Institute) will have patents on green tennis balls. We will get patents on all tennis balls,” says Doudna.
 
Gene biology

Gene therapy has evolved from the science of genetics, which is an understanding of how heredity works. According to scientists life begins in a cell that is the basic building block of all multicellular organisms, which are made up of trillions of cells, each performing a specific function. Pairs of chromosomes comprising a single molecule of DNA reside in a cell’s nucleus. These contain the blueprint of life: genes, which determine inherited characteristics. Each gene has millions of sequences organised into segments of the chromosome and DNA. These contain hereditary information, which determine an organism’s growth and characteristics, and genes produce proteins that are responsible for most of the body’s chemical functions and biological reactions.

Roger Kornberg, an American structural biologist who won the 2006 Nobel Prize in Chemistry "for his studies of the molecular basis of eukaryotic transcription", describes the Impact of human genome determination on pharmaceuticals:
 
 
China’s first
 
While American scientists were fighting over intellectual property associated with CRISPR-Cas9, and American national scientific and medical academies were making lukewarm pronouncements about gene editing, Chinese scientists  had edited the genomes of human embryos in an attempt to modify the gene responsible for β-thalassemia and HIV, and are planning further clinical studies. In October 2016, Nature reported that a team of scientists, led by oncologist Lu You, at Ghengdu’s Sichuan University in China established a world first by using CRISPR-Cas9 technology to genetically modify a human patient’s immune cells, and re-infused them into the patient with aggressive lung cancer, with the expectation that the edited cells would seek, attack and destroy the cancer. Lu is recruiting more lung cancer patients to treat in this way, and he is planning further clinical studies that use similar ex vivo CRISPR-Cas9 approaches to treat bladder, kidney and prostate cancers
 
The Parker Institute for Cancer Immunotherapy
 
Conscious of the Chinese scientists’ achievements, Carl June, Professor of Pathology and Laboratory Medicine at the University of Pennsylvania and director of the new Parker Institute for Cancer Immunotherapy, believes America has the scientific infrastructure and support to accelerate gene editing and immunotherapies. Gene editing was first used therapeutically in humans at the University of Pennsylvania in 2014, when scientists modified the CCR5 gene (a co-receptor for HIV entry) on T-cells, which were injected in patients with AIDS to tackle HIV replication. Twelve patients with chronic HIV infection received autologous cells carrying a modified CCR5 gene, and HIV DNA levels were decreased in most patients.
 
Medical science and the music industry

The Parker Institute was founded in 2016 with a US$250m donation from Sean Parker, founder of Napster, an online music site, and former chairman of Facebook. This represents the largest single contribution ever made to the field of immunotherapy. The Institute unites 6 American medical schools and cancer centres with the aim of accelerating cures for cancer through immunotherapy approaches. 

Parker, who is 37, believes that medical research could learn from the music industry, which has been transformed by music sharing services such as Spotify. According to Parker, more scientists sharing intellectual property might transform immunotherapy research. He also suggests that T-cells, which have had significant success as a treatment for leukaemia, are similar to computers because they can be re-programed to become more effective at fighting certain cancers. The studies proposed by June and colleagues focus on removing T-cells, from a patient’s blood, modifying them in a laboratory to express chemeric antigen receptors that will attack cancer cells, and then re-infusing them into the patient to destroy cancer. This approach, however, is expensive, and in very young children it is not always possible to extract enough immune cells for the technique to work.

 
Prêt à l'emploi therapy

Waseem Qasim, Professor of Cell & Gene Therapy at University College London and Consultant in Paediatric immunology at Great Ormond Street Hospital, has overcome some of the challenges raised by June and his research. In 2015 Qasim and his team successfully used a prêt à l'emploi gene editing technique on a very young leukaemia patient. The technique, developed by the Paris-based pharmaceutical company Cellectis, disables the gene that causes donor-immune cells to attack their host. This was a world-first to treat leukaemia with genetically engineered immune cells from another person. Today, the young leukaemia patient is in remission. A second child, treated similarly by Qasim in December 2015, also shows no signs of the leukaemia returning. The cases were reported in 2017 in the journal Science Translational Medicine.
 
Universal cells to treat anyone cost effectively

The principal attraction of the prêt à l'emploi gene editing technique is that it can be used to create batches of cells to treat anyone. Blood is collected from a donor, and then turned into “hundreds” of doses that can then be stored frozen. At a later point in time the modified cells can be taken out of storage, and easily re-infused into different patients to become exemplars of a new generation of “living drugs” that seek and destroy specific cancer cells. The cost to manufacture a batch of prêt à l'emploi cells is estimated to be about US$4,000 compared to some US$50,000 using the more conventional method of altering a patient’s cells and returning them to the same patient. Qasim’s clinical successes raise the possibility of relatively cheap cellular therapy using supplies of universal cells that could be dripped into patients' veins on a moment’s notice.
 
Takeaways
 
CRISPR-Cas9 provides a relatively cheap and easy-to-use means to get an all-purpose gene-editing technology into clinics throughout the world. Clinical studies using the technology have shown a lot of promise especially in blood cancers. These studies are accelerating, and prêt à l'emploi gene editing techniques as an immunotherapy suggest a new and efficacious therapeutic pathway. Notwithstanding the clinical successes, there remain significant clinical, commercial and ethical challenges, but expect these to be approached differently in different parts of the world. And expect these differences to impact on the outcome of the scientific race, which is gaining momentum.
 
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