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  • The burden of breast cancer throughout the world is significant and increasing
  • Research has shown that a cheap pill (anastrozole) halves postmenopausal women’s risk of breast cancer and continues to be effective seven years after women stop taking the drug
  • Anastrozole has less side-effects and is more effective than comparable treatments
  • Government watchdogs both in the UK and US recommend anastrozole
  • But the uptake of the drug in the UK is relatively low
  • Doctors are not prescribing anastrozole and women are not availing themselves of the drug
  • The UK’s NHS should employ new behavioural techniques to influence and change doctors’ and patients’ decisions and increase the uptake of anastrozole to reduce the burden of breast cancer

Will behavioural techniques improve breast cancer outcomes?
 
Being a woman and growing older are two unavoidable risk factors for breast cancer. Indeed, most breast cancers are found in women who are 50 years or older. Despite significant advances in diagnoses and treatments, breast cancer is one of the rapidly increasing cancers among women and a significant cause of cancer-related morbidity and mortality worldwide.  Breast cancer alone accounts for 30% of all new cancer diagnoses among females and has become a major 21st century health challenge.
 
Study shows long term benefits of a cheap breast cancer pill

Research findings reported in the December 2019 edition of The Lancet and also presented at the  December 2019 San Antonio Breast Cancer Symposium in Texas, show that a cheap pill, anastrozole,  if taken once a day for 5 years, not only halves postmenopausal women’s risk of breast cancer, but continues to be effective seven years after stopping treatment, which for the first time, suggests a long-term benefit.
 
Relatively low uptake
 
The UK’s NHS watchdog, the National Institute for Health and Care Excellence (NICE), suggests that hundreds of thousands of healthy older women should take anastrozole to cut their risk of breast cancer and recommends that the drug is offered to postmenopausal women at moderate to high risk of breast cancer unless they have severe osteoporosis. However, evidence suggests that some doctors in the UK are not prescribing anastrozole and some women are not availing themselves of the drug despite its demonstrated clinical benefits and the fact that anastrozole is supported by NICE.
 
Jack Cuzick, the lead author of The Lancet 2019 paper, who is Professor of Epidemiology and the Director of the Wolfson Institute of Preventive Medicine at Queen Mary UniversityLondon, is concerned because although anastrozole is, “An agent that looks really effective with minimal side-effects and is available on the NHS in the UK; its uptake has been quite low with only a tenth of eligible women receiving it”. Cuzick’s concerns are echoed by Delyth Jane Morgan, Chief Executive of the charity Breast Cancer Now, who said: "It is worrying to hear that anastrozole may not be being offered to all that could benefit. We need to understand the extent of this potential issue. It's essential that we raise awareness of this option among doctors and patients".
 
 In this Commentary
 
Part 1 of this Commentary explores some of the reasons for the relatively low uptake of anastrozole. Part 2 describes new behavioural techniques, which could be cheaply and easily employed by health systems to increase the uptake of anastrozole and dent the burden of breast cancer. Also the Commentary: (i) describes breast cancer, (ii) provides some epidemiological facts of the disease, (iii) estimates the cost to treat breast cancer in the UK, (iv) describes hormone receptor positive breast cancer, (v) explains how anastrozole works and (vi) reports the findings of The Lancet 2019 study.

 
Part 1
 
 
Breast cancer
 
Cancer is a group of diseases that cause cells in your body to change and spread out of control. Most types of cancer cells eventually form a lump or mass called a tumour and are named after the part of your body where the tumour originates.

 

Breast cancer is characterized by the presence of cancer cells in the tissue or ducts of your breast. Most breast cancers begin either in the breast tissue made up of glands for milk production, called lobules, or in the ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective and lymphatic tissues. Advanced breast cancer refers to cancer that has spread outside of your breast to lymph nodes and/or distant locations in your body, often invading your vital organs.
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Epidemiology of breast cancer
 
Breast cancer is a common malignancy. Although more and more women are surviving the disease, each year in the UK there are over 55,000 new breast cancer cases: which equates to over 1,000 diagnosed each week. In the US, there are some 250,000 new breast cancer cases diagnosed each year: nearly 5,000 a week. Between 1993 and 2016 the incidence of breast cancer in the UK increased by 24%. Over a similar period, breast cancer incidence in the US declined, but an increasing trend of some 1.1% was observed among American Asians. In China, between 2000 to 2013, breast cancer increased at an annual rate of around 3.5%. Breast cancer rates in China are higher in urban areas than in rural areas: the higher the population density, the higher the rate. It is not altogether clear why breast cancer incidence is increasing. Experts suggest that breast cancer is a complicated disease with a variety of causes. Most cases of the disease are not linked to a family history. Around 5% of people diagnosed with breast cancer have inherited a faulty BRCA1 or BRCA2 gene. However, if you have a faulty gene, it does not mean that you will automatically develop breast cancer, but you are at higher risk. Out of every 100 women with a faulty gene, between 40 and 85 will develop breast cancer in their lifetime. Optimal therapy for breast cancer often requires several different treatment modalities including surgery, radiation, chemotherapy and hormone therapy (see below).
 
Cost of breast cancer treatment in the UK
 
The cost of treating breast cancer in the UK is significant and rising. Findings of research on the treatment costs of breast cancer published in the August 1999 edition of The Breast estimated that the average cost per case of breast cancer in the UK to be £7,247 (US$9,418).  Although the estimate is dated, it provides a guide. With 55,000 new cases of breast cancer diagnosed each year, the annual cost of treating the newly diagnosed alone, would be about £0.4bn (US$0.52bn). According to the UK charity Breast Cancer Now, an estimated 840,000  women  living in the UK have been diagnosed with breast cancer and the charity predicts that this figure will increase to 1.2m over the next decade. Thus, ceteris paribus, we can assume that the current annual cost  of treating breast cancer in the UK is significantly higher than £0.4bn and this figure is expected to increase substantially by 2030.
 
 
Hormones and hormone therapy
 
Hormones are chemical messengers secreted directly into your bloodstream, which carry them to organs and tissues of your body to exercise their functions.  Oestrogen and progesterone are steroid hormones produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women. These hormones play a critical role in regulating reproduction. Oestrogen promotes the development and maintenance of female sex characteristics and the growth of long bones. Progesterone plays a role in the menstrual cycle and pregnancy.
 
Similar hormones are produced artificially either for use in oral contraceptives or to treat menopausal and menstrual disorders. Oestrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive (or hormone-dependent) breast cancers. Hormone-sensitive breast cancer cells contain proteins called hormone receptors, which become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes that can stimulate cell growth.
 
Anastrozole is a hormone therapy (also called hormonal therapy and endocrine therapy), which slows or stops the growth of hormone-sensitive tumours by either blocking the body’s ability to produce hormones or by interfering with the effects of hormones on breast cancer cells. Anastrozole blocks a process called aromatisation, which changes sex hormones called androgens into oestrogen. This happens mainly in the fatty tissues, muscle and the skin and needs a particular enzyme called aromatase.
 
 Prescribing anastrozole
 
Anastrozole belongs to a group of drugs called aromatase inhibitors, which are specifically designed to treat postmenopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer.  It is most often prescribed as an adjuvant therapy (after surgery) to decrease the risk of your cancer returning but can also be used in the neoadjuvant setting (prior to surgery) to decrease the size of your cancer in the breast. Hormone blocking therapy is also used to treat breast cancer that has recurred or spread. Most hormone blocking therapy drugs such as anastrozole are taken daily in pill form.
 
Anastrozole also may be given to reduce the risk of breast cancer in women who have not had breast cancer but have an increased risk of developing it because of their family history. Most experts suggest that your breast cancer risk should be higher than average for you to consider taking anastrozole as a preventative strategy. If your cancer is hormone receptor negative, then anastrozole will not be of any benefit, because these cancers do not need oestrogen to grow and usually such cancer cells do not stop growing when treated with hormones that block oestrogen from binding.
 
Reasons for the relatively low uptake of anastrozole
 
There are at least three probably reasons for the relatively low uptake of anastrozole. These include: (i) doctors becoming so used to prescribing the gold standard tamoxifen as an adjuvant hormone therapy, (ii) doctors wanting to be convinced about anastrozole’s long term benefits, and (iii) doctors wanting assurance about anastrozole’s minimal side effects.
  
Tamoxifen
 
Tamoxifen is the oldest and most-prescribed aromatase inhibitor and for the past three decades has become the standard of care as the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. The drug reduces the risk of breast cancer returning by 40% to 50% in postmenopausal women and by 30% to 50% in premenopausal women. Notwithstanding, over the past two decades a new generation of aromatase inhibitors have been developed, and anastrozole is one of these. How does anastrozole compare with the gold standard tamoxifen?

Tamoxifen and anastrozole compared
 
Findings of two long-term comparative clinical studies undertaken in North America and Europe involving over 1,000 women with oestrogen receptor positive advanced breast cancer, showed that anastrozole is better than tamoxifen for: (i) increasing the time before the cancer returns in those who experience recurrence, (ii) reducing the risk of the cancer spreading to other parts of the body and (iii) reducing the risk of a new cancer developing in the other breast.

Significantly, studies have shown that anastrozole avoids two of tamoxifen's more serious side-effects: an increased risk of developing a blood-clotting disease and an increased risk of developing womb cancer.  Anastrozole can make bones weaker and so it is not recommended for women with osteoporosis and also it can cause stiff joints, hot flushes and vaginal dryness, which clinicians need to recognize and manage. But overall, the benefits of anastrozole over tamoxifen were maintained without a detrimental impact on quality of life. However, anastrozole is not a therapy for  premenopausal women because it blocks the hormone oestrogen and in effect creates a drug-induced menopause.


Part 2

Increasing the uptake of anastrozole
 
For healthcare systems to function effectively and efficiently we expect doctors and patients to behave rationally and make effective and efficient decisions. Traditionally, the rational choice model, which is predicated upon the belief that all human beings (including doctors and patients) act rationally in their own self-interest, has been used to influence people to behave in desirable ways. However, evidence suggests that, despite the well-founded theory and sound evidence to support it, the rational choice approach does not appear to work that well in practice.



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Behavioral scientists not doctors will prevent CVD

 A newer theory to explain peoples’ choices and behaviours
 
A newer approach to influencing behaviour, which builds on decades of research by Nobel prize-winning psychologist Daniel Kahneman, and described in a book published in 2008 entitled Nudge, by Nobel Prize winning economist Richard Thaler and Harvard Law School professor Cass Sunstein, suggests that no choice is ever presented in a neutral way and people - including doctors and patients - are susceptible to biases that can lead them to make suboptimal decisions. The authors suggest that many decisions and consequent behaviours are made automatically rather than after a considered rational decision. And this applies to decisions about your health.
Policymakers have been quick to latch onto the possibilities of these new behavioural techniques. Following the publication of Thaler and Sunstein’s book in 2008, President Obama set up a “Nudge Unit” in the White House and the UK Government, under Prime Minister David Cameron, set up the Behavioural Insights Team, popularly known as the Nudge Unit, in 10 Downing Street, and other governments around the world have since followed suit.

Nudges
 
Nudges are particular types of interventions, which are used to change peoples’ behaviour and improve outcomes at lower cost than traditional tools across a range of policy areas. Nudge techniques have been used in healthcare to influence behaviour and decision making to improve patient outcomes. For instance, the behavioural analysis of the decision-making that leads to a patient taking one drug instead of another. A research paper published in 2015 by the UK’s Health Foundation entitled “Behavioural insights in healthcare” suggests that health messages are often inconsistent and confusing to patients and framing them using social comparison via descriptive social norms (pointing out what is commonly done) or using injunctive norms (pointing out what is approved of) has been demonstrated to change patients’ behaviour and thereby have the potential to improve patient outcomes.
 
Information design
 
Behavioural techniques suggest that more attention should be given to the design of health information because the design and the way information is presented can influence and change doctors' and patients’ behaviour. Clinical guidelines, patients’ checklists and decision aids can all be improved in terms of text and language (e.g. the use of “plain English” and behaviourally specific, concrete statements and presentation of risk) and appearance (e.g. colour, visual stimuli, images etc).
 
HealthPad advocates that health information can have significantly more influence on the choices that doctors and patients make and on their  behaviour simply by presenting critical information in a video format. Over the past few decades people have moved away from consuming information in written and audio formats to consuming information predominantly in a visual format.  
 
Shift to consuming information in video format
 
Consider the following as being indicative of this shift. 82% of Twitter’s 330m average monthly users consume information in video format. The video channel You Tube has over a billion users and more than 500m hours of video are watched on the channel each day. 72 hours of video are uploaded to You Tube every 60 seconds, and more video content is uploaded onto the channel in 30 days than the major US television networks have created in 30 years. To further put things into perspective, in 2017, 56 exabytes (equivalent to 1bn gigabytes) of internet video content was consumed on a monthly basis, and this figure is expected to more than quadruple to 240 exabytes per month by 2022.

Today, almost all industries,  with the exception of healthcare, use video formats to communicate and the overwhelming majority of people who have consumed information in video format say it has influenced their choices and changed their behaviour. With video becoming the most significant influence on consumer decisions, it seems reasonable to suggest that more health information needs to be communicated in a video format if it is to influence and change doctors’ and patients’ behaviours in order to improve medical outcomes, increase the quality of care and slow and prevent chronic lifetime diseases.
 
Prompts cues reminders and audits
 
Prompts, cues and reminders have been demonstrated to be generally effective “nudges” that can successfully change the behaviour of healthcare providers and consumers, as well as being relatively inexpensive and easy to administer. Audit and feedback “nudges” are also effective. A set of best practices derived from systematic review evidence suggests that various nudge-type interventions (notably information design and presentation) may offer new ways to enhance choices and change behaviour.
  
Takeaways
 
The burden of breast cancer is huge and increasing globally. Research has demonstrated that a cheap pill, anastrozole, halves postmenopausal women’s risk of the disease and continues to be effective seven years after women stop taking the drug. We suggest that healthcare systems should consider using new behavioural techniques to influence and change doctors' and patients’ decisions to increase the uptake of anastrozole to help reduce the burden of breast cancer. Evidence suggests that nudge-type interventions, if suitably applied, can influence and change the behaviour of doctors and patients and thereby contribute to the reduction of the burden of breast cancer. However, given the newness of these techniques the quality of evidence available about their impact is relatively thin and patchy. Notwithstanding, this suggests a need for more quality evaluation and synthesised evidence of nudge-type interventions, their behaviour change potential and their impact on reducing the burden of breast cancer and other chronic lifetime diseases.
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  • Bioengineers throughout the world are competing to achieve the Holy Grail: an affordable, point-of-care blood test - liquid biopsy - that detects cancer before any symptoms present
  • Success in achieving this will save millions of lives, substantially reduce healthcare costs and make investors, researchers and organisations billions
  • Despite significant advances no one has yet achieved the Holy Grail and there remains a substantial gap between researchers’ aspirations and reality
  • How close are we?

 
 

Finding the Holy Grail: early detection tests for cancer
 

 

“It’s too soon to even claim that the research is promising," commented Paul Pharoah, a professor at Cambridge University’s Centre for Cancer Genetic Epidemiology, on the research findings of  Daniyah Alfattani, a PhD student in the Centre of Excellence for Autoimmunity in Cancer (CEAC) at Nottingham University’s School of Medicine in the UK.
 
Alfattani was presenting research findings of a small study at the National Cancer Research Institute’s (NCRI) conference in Glasgow, Scotland, in November 2019, which is an international forum for showcasing cancer advances.
 
A September 2019 HealthPad Commentary described another early detection test for breast cancer called CanRisk, which has been developed by researchers from Cambridge University’s Centre for Cancer Genetic Epidemiology and  has the potential to identify women with different levels of risk of breast cancer.
 
Alfattani and bioengineers from the universities of Nottingham and Cambridge are players in a vast and rapidly evolving international army of researchers engaged in an intensely competitive global race to develop an affordable, point-of-care, early detection test (EDT) for cancer based upon a liquid biopsy and next generation sequencing technologies. The Holy Grail is for such a test to detect cancer cells in an asymptomatic patient, locate the tissue of origin and give that person an early diagnosis when treatment is more likely to be successful; and to do all this with 100% accuracy. 

Although Alfattani’s research study is modest, her findings are potentially clinically relevant because they are on the Holy Grail therapeutic pathway, and her preliminary findings suggest that a simple, cheap and easy-to-use blood test - liquid biopsy - could detect breast cancer five years before any symptoms present. If demonstrated to be exquisitely accurate, safe and efficient by a larger study, which already is underway at Nottingham University’s CEAC, Alfattani’s research could be a key to saving thousands of lives and substantial amounts of money.

 


Gold standard breast cancer screening
 
Currently, mammography screening is the gold standard for preventing and controlling breast cancer, which is costly to administer and only has a sensitivity between 72% and 87%.  For every death from breast cancer that is prevented by mammography screening, it is estimated there are three false-positive cases detected and treated unnecessarily. Further, nearly half of all cancer sufferers are diagnosed late, when their tumours have already metastasized. It is estimated that 30% to 40% of cancer deaths could be prevented by early detection and treatment.
 
In this Commentary
 
This Commentary provides a partial update of some bioengineering initiatives described in a 2016 HealthPad Commentary, to speed up and improve liquid biopsies, which can simultaneously detect cancer early and identify its tissue of origin. Although there have been significant developments, the challenge for liquid biopsy assays still remains the level of their positive predictive values. This Commentary provides a brief and partial epidemiology of breast cancer, describes Alfattani’s research and its findings and briefly mentions some similar research that is underway. We describe categories of biomarkers employed by researchers and indicate some advances in EDTs made by some giant biopharma companies as well as briefly describing another innovative university-based development. We conclude by suggesting that: (i) despite significant and well supported research endeavours over the past decade to develop EDTs, there still remains a gap between scientific aspirations and reality; and (ii) there appears to be a gap opening between commercially available personalised cancer therapies, which are by-products of EDT research and standard oncological therapies.
 
Partial epidemiology of breast cancer
 
Despite significant advances in the awareness, diagnosis and treatment of breast cancer, it still remains the most common cancer in women worldwide, contributing 25.4% of the total number of new cases of cancer diagnosed in 2018. Each year, more than 0.5m women throughout the world die from the condition.  In the US each year, over 268,000 new cases of invasive breast cancer are diagnosed in women, and over 41,000 women die from breast cancer. Between 1989 and 2016, death rates from female breast cancer in the US dropped by 40%. Over the past decade, death rates from breast cancer in older women in the US continued to decrease but remained steady in women under 50. Such decreases are attributed to increased awareness of the condition, earlier detection through screening and improved treatments. In the UK, there are over 55,000 new breast cancer cases diagnosed each year. In contrast to the US, since the early 1990s, breast cancer incidence rates in the UK have increased by around 19%, but death rates have fallen because of greater awareness, earlier detection and enhanced therapies. Notwithstanding, each year more than 11,000 women in the UK die from breast cancer. Furthermore, each year in the US, there are over 1.7m new diagnoses of all cancers, while in the UK there are over 360,000 new cases. Although recent advances in EDTs have the potential to decrease cancer deaths, as yet there is not a simple and cheap liquid biopsy, which can be used routinely  in clinics to diagnose a range of cancers early. .
 
Alfattani’s research
 
The research pursued by Alfattani and her Nottingham colleagues is predicated upon the fact that cancer cells produce proteins called antigens, which trigger the body to make antibodies against them. These are called “autoantibodies”. Researchers discovered that these tumour-associated antigens (TAAs) are good indicators (biomarkers) of cancer. Alfattani and her colleagues developed panels of TAAs, which are known to be linked with breast cancer as a technique to detect whether or not there are autoantibodies against them in blood samples taken from patients.

The Nottingham researchers took blood samples from 90 breast cancer patients at the time they were diagnosed with the disease and matched them with samples taken from 90 patients without breast cancer (the control group). Researchers employed technology (protein microarray), which allowed them to screen the blood samples for the presence of autoantibodies against 40 TAAs associated with breast cancer and also 27 TAAs not known to be linked with the disease. The accuracy of the test improved in the panels that contained more TAAs.

Findings

A panel of five TAAs correctly detected breast cancer in 29% of the samples from the cancer patients and correctly identified 84% of the control group as being cancer-free. A panel of seven TAAs was able to detect disease in 35% of cases with breast cancer and rule out 79% of patients in the control group. The most successful technique was a panel of nine antigens, which correctly identified the disease in 37% of cancer samples and no cancer in 79% of the controls. “The results of our study showed that breast cancer does induce autoantibodies against panels of specific tumour-associated antigens. . . . . The results are encouraging and indicate that it is possible to detect a signal for early breast cancer. Once we have improved the accuracy of the test, then it opens the possibility of using a simple blood test to improve early detection of the disease”, said Alfattani.

David Crosby, head of early detection at the Cancer Research UK charitysaid, “Diagnosing cancer at the earliest stages before it grows or spreads gives patients the best chance that their treatment will be successful. So, the potential to detect markers in the blood before other signs appear is promising”.
 
Similar studies
 
Nottingham University’s CEAC is also working on similar tests to that used by Alfattani for pancreatic, colorectal and liver cancers. Solid tumours like these, as well as lung and breast cancer, represent around 70% of all cancers. Further, a similar test for lung cancer is currently being tested in a randomised controlled clinical study in Scotland, which is believed to be the largest trial of its kind in the world, involving 12,000 people at high risk of developing lung cancer because they smoke.
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Participants in the study have been randomly assigned to two groups: one is given an autoantibody blood test and the other (the control group ) is not. Participants who test positive for the autoantibodies are then followed up with a CT scan every two years in order to detect lung cancer in its early stages when it is easier to treat. Findings suggest that the test detects lung cancer four years or more before standard clinical diagnosis. In the UK about 85% of lung cancer patients are left undiagnosed until the disease has spread to other parts of the body.

 


Liquid biopsies

 
Liquid biopsies require biomarkers, which are substances, structures, or processes in your body that can be analysed in order to explain the pathogenesis of cancer and other disease states, and thereby inform diagnosis, predict onset and suggest appropriate therapies. Notwithstanding, the multiple types of biomarkers have varying degrees of reliability. Initially, the principal focus of research into EDTs was largely focussed on circulating tumour cells (CTC) and DNA. More recently however, additional biomarkers have become an important focus for such research. Antibodies are just one type of molecular biomarker. Because antibodies function by binding specific antigens, attempts to identify antibody biomarkers have involved using antigens to capture antibodies that are overproduced in cancer. Identifying relevant antigens is critical for discovering antibody biomarkers. Array-based approaches employed by Alfattani and her colleagues depend on exposing serum samples from patients to an ordered array of putative antigens, capturing those antibodies that bind antigens on the arrays and measuring their levels. Antibodies that are present at significantly higher levels in the serum of patients with breast cancer, (compared to control serums from healthy patients) are candidate biomarkers. 
 
Because of the unreliability of such biomarkers, new liquid biopsy tests tend to be predicated upon the levels of cell-free DNA (cfDNA), circulating tumour DNA (ctDNA) and exosomes. These also pose challenges because of the varying physiological levels of the different biomarker fragments in your bloodstream.
cfDNA refers to DNA molecules that circulate in your blood after cell death. The amount of cfDNA varies significantly depending on the location, type and stage of your cancer. Concentrations of cfDNA can range from 1 to 100,000 fragments per ml of blood.

ctDNA refers to DNA that comes from cancerous cells and is present in your bloodstream. As a tumour grows, your cells die and are replaced by new cells. Your dead cells decompose and their contents, including DNA, are released into your bloodstream. So, ctDNA are small fragments of DNA, the quantity of which varies between individuals and the location, type and stage of your cancerous tumour. Detection of single mutations in ctDNA requires a large volume of blood. The principal challenge of research predicated upon ctDNA is their relatively low abundance in your bloodstream. As a consequence, scientists cannot rely solely on ctDNA, and are forced to search for other genetic and epigenetic mutations in your blood.
Exosomes is another class of biomarker. Cancer related exosomes are nano-size membrane vesicles that play important roles in tumour microenvironment. A 2007 paper in Nature Cell Biology 
suggested that exosomes can load unique cargoes, including proteins and nucleic acids that reflect the condition of a tumour. Since the 2007 Nature paper, research into exosomes has increased and they are now being used as diagnostic and prognostic biomarkers for various cancers. 

 
CancerSEEK

 
An innovative liquid biopsy called CancerSEEK, which has been developed by researchers from the Johns Hopkins Kimmel Cancer Center, in Baltimore, USA, is expected to make early cancer detection a part of routine medical care. Significantly, the test screens for eight common cancers, which account for more than 60% of all cancer deaths in the US. Currently, five of the cancers covered by the test have no screening test. CancerSEEK combines cutting-edge liquid biopsy technology with a machine learning engine, which is expected to improve the test’s accuracy with every person it screens. Findings of a retrospective study of multiple cancer types published in the February 2018 edition of the journal Science suggested that CancerSEEK has a sensitivity between 69% and 98% for ovarian, liver, stomach, pancreatic and oesophageal cancers, a specificity of 99%. Further, the study suggested that the test  has a false-positive rate of less than 1%. In 2019, CancerSEEK received Breakthrough Device designation from the US Food and Drug Administration (FDA) for the detection of genetic mutations and proteins associated with pancreatic and ovarian cancers, and also raised US$110m to launch a start-up company to develop the technology further.
 
FDA approval for a liquid biopsy developed by Roche
 
In June 2016, Roche, a global biopharma, became the first company to receive FDA approval of a liquid biopsy test to detect mutations associated with non-small cell lung cancers (NSCLC). Notwithstanding, the biopsy is not a universal test to detect the presence of NSCLC, but rather a test, which is being used in people with lung cancer to enhance personalised targeted therapies, and to monitor progression of the cancer. Some patients may benefit from the test's accompanying drug erlotinib (Tarceva), which treats NSCLC.
 
In September 2019, Genentech, a member of the Roche Group, announced positive results from the first prospective phase II/III clinical study to use a liquid biopsy and next generation sequencing to select treatment for people with NSCLC, without the need for a tissue biopsy. Next-generation sequencing facilitates the analysis of minute quantities of cfDNA circulating in the blood. In addition, Genentech is using machine learning algorithms on large data sets to characterize the molecular signatures of various cancer types.
 
Guardant and GRAIL
 
Previous HealthPad Commentaries have described research endeavours by Guardant Health  and GRAILwhich are “betting-on” liquid biopsies. Here briefly we update the developments of these two giant biopharma companies.

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In 2014 Guardant launched a next generation sequencing cfDNA assay called Guardant360 for treatment selection in a number of solid tumour cancers. In December 2018, the company launched an assay referred to as LUNAR to detect a range of early stage and recurrent cancers. LUNAR is based on data that Guardant collected from 80,000 advanced cancer patients using its 360 technology. In October 2019, the company launched ECLIPSE, a 10,000-patient clinical study to evaluate the performance of a second generation LUNAR blood test to detect colorectal cancer (CRC) in average-risk adults. The study is intended to improve CRC screening rates by offering a simpler liquid biopsy that overcomes challenges associated with current testing methods described above.
GRAIL has developed a prototype cfDNA sequencing assay to detect a range of cancers, many of which are not screened today and often present at late stages. Significantly, GRAIL has developed a prospective, observational, longitudinal clinical study called the Circulating Cell-free Genome Atlas (CCGA). The study has 15,000 participants across 142 sites in the US and Canada and has been designed to characterize the landscape of genomic cancer biomarkers of people with and without cancer. The company’s STRIVE study is fully enrolled with approximately 115,000 women and another study called SUMMIT also is fully enrolled with approximately 50,000 men and women aged 50 and older who do not have a cancer diagnosis at the time of enrolment.
 
Despite advancing technologies, FDA approvals, ongoing clinical studies and large and increasing investments in the development of liquid biopsies, (see a paper published in the June 2019 edition of Clinical and Translational Science entitled, “The Labyrinth of Product Development and Regulatory Approvals in Liquid Biopsy Diagnostics”) there remains a substantial gap between scientific aspirations and reality. Liquid biopsies still do not provide physicians with a reliable, point-of-care means to detect cancer early and become a reliable substitute for the more invasive and more expensive gold standard tissue biopsy.
 
Takeaways
 
Liquid biopsies represent a large and rapidly evolving area of bioengineering. There are hundreds of research papers published in peer reviewed medical journals, which describe findings of the latest research in this area. Oncologists involved in EDT research are familiar with genomics, the molecular properties of cancer tumours and commercially available innovative therapies, which are by-products of EDT research, but many oncologists are not. This difference of knowhow seems to be creating another gap  between certain personalised cancer therapies advocated by research oncologists and standard cancer management provided in many clinics. Closing these gaps is partly contingent upon continued and open EDT research and more effective education.
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  • Prime editing devised by researchers at the Broad Institute led by David Liu is a significant advance of the original CRISPR gene editing tool discovered in 2012
  • CRISPR can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of incurable diseases and has revolutionized biomedicine
  • The original CRISPR is fraught with inaccuracies referred to as off target effects
  • Prime editing substantially reduces CRISPR’s off target effects and has the potential to correct up to 89% of known disease-causing genetic variations
  • CRISPR also has the capacity to edit genes in an embryo in such a way that the change is heritable
  • In 2018 Chinese researcher He Jiankui “created” the world’s first CRISPR babies
  • This triggered international criticism from scientists and bioethicists
  • A principal concern is that CRISPR is easy-to-use, cheap, regularly used in thousands of laboratories throughout the world and there is no internationally agreed and enforceable regulatory framework for its use
 
For better or worse we all now live in CRISPR’s world
 
In 2012 the world of biomedicine changed when a revolutionary gene editing technology known as CRISPR-Cas9 (an acronym for Clustered Regularly Interspaced Short Palindromic Repeats) was discovered. The technology harnesses your body’s naturally occurring immune system that bacteria use to fight-off viruses and has the potential to forever change the fundamental nature of humanity. Since its discovery CRISPR has been developing at lightning speed primarily because it is simple and affordable and today is used in thousands of laboratories throughout the world.
 
In this Commentary
 
In this Commentary we describe prime editing, which is the latest advance of the CRISPR's tool box, devised bya team of researchers, led by Andrew Anzalone, a Jane Coffin Childs postdoctoral fellow from the Broad Institute of MIT and Harvard and published in the October 2019 edition of Nature. Prime editing is significant because it provides a means to eliminate the unintentional consequences of CRISPR and therefore bring the technique closer for use in clinics. But this is still a long way off.
 
We also review a case where an ambitious scientist “created” the first CRISPR babies. This immediately triggered international criticism and a call for tighter regulatory control of the technology. Scientists and bioethicists are concerned that CRISPR can easily be used to create heritable DNA changes, which ultimately could lead to ‘designer babies’.
 
These two accounts of CRISPR might seem “opposites” and not sit well together in a single Commentary. Notwithstanding, what prompted putting them together was John Travis, the News Managing Editor of the well-known scientific journal Science, who soon after CRISPR’s discovery in 2012  said, “For better or worse we all now live in CRISPR’s world”
 
CRISPR and your DNA

CRISPR is different to traditional gene therapy, which uses viruses to insert new genes into cells to try and treat diseases and has caused some safety challenges. CRISPR, which avoids the use of viruses, was conceived in 2007 when a yogurt company identified an unexpected defence mechanism that its bacteria used to fight off viruses. Subsequent research made a surprising observation that bacteria could remember viruses. CRISPR has been likened to a pair of microscopic scissors that can cut and edit your DNA to correct defects inside your body’s cells to prevent and heal a range of intractable diseases. The standard picture of DNA is a double helix, which looks similar to a ladder that has been twisted. The steps in this twisted ladder are DNA base pairs. The fundamental building blocks of DNA are the four bases adenine (A), cytosine (C), guanine (G) and thymine (T). They are commonly known by their respective letters, A, C, G and T. Three billion of these letters form the complete manual for building and maintaining  your body, but tiny errors can cause disease.  For example, a mutation that turned one specific A into a T results in the most common form of sickle cell disease.
 
The original CRISPR
 
The original CRISPR tool, which is the first and most popular gene editing system, uses a guide RNA (principally a messenger carrying instructions from your DNA for controlling the synthesis of proteins) to locate a mutated gene plus an enzyme, like Cas9, to cut the double-stranded gene helix and create space for functioning genes to be inserted. However, a concern about CRISPR is that the editing could go awry and cause unintended changes in DNA that could trigger health problems. Findings of a study published in the July 2018 edition of  the journal Nature Biotechnology found that such inaccuracies, referred to as off-target effects, were substantially higher than originally reported and some were thought to silence genes that should be active and activate genes that should be silent. These off-target effects, such as random insertions, deletions, translocations, or other base-to-base conversions, pose significant challenges for developing policy associated with the technology.

Subsequently however, the paper was retracted, and an error correction was posted on a scientific website. Contrary to their original findings, the authors of the Nature Biotechnology paper restated that the CRISPR-Cas9 gene editing approach, "can precisely edit the genome at the organismal level and may not introduce numerous, unintended, off-target mutations".

 
Base editing

Notwithstanding, researchers remained concerned about CRISPR’s off target effects and several devised a technique, referred to as base editing, to reduce these. Base editing is described in three research papers published in 2017: one in the November edition of the journalProtein and Cell’, another in the October edition ofSciencethe and a third by researchers from the Broad Institute, in the October edition of the journal Nature’. Base editing takes the original CRISPR-Cas9 and fuses it to proteins that can make four precise DNA changes: it can change the letters C-to-T, T-to-C, A-to-G and G-to-A. The technique genetically transforms base pairs at a target position in the genome of living cells with more than 50% efficiency and virtually no detectable off-target effects. Despite its success, there remained  other types of point mutations that scientists wanted to target for diseases.

 

Prime editing
 
Prime editing is different to previous gene editing systems in that it uses RNA to direct the insertion of new DNA sequences in human cells. According to David Liu,  the senior author of the 2019 Nature paper and a world renowned authority on genetics and next-generation therapeutics, “a major aspiration in the molecular life sciences is the ability to precisely make any change to the genome in any location. We think prime editing brings us closer to that goal”.  Because prime editing provides a means to be more precise and more efficient in editing human cells in a versatile way, which eliminates many of CRISPR’s unintentional errors, it significantly expands the scope of gene editing for biological and therapeutic research.
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There are around 75,000 different mutations that can cause disease in people and prime editing has the potential to correct up to 89% of known disease-causing genetic variations. According to Liu, "Prime editing is the beginning, rather than the end, of a long-standing aspiration in the molecular life-sciences to be able to make any DNA change in any position of a living cell or organism, including potentially human patients with genetic diseases". Liu’s team at the Broad Institute intends to continue optimizing prime editing. In their October 2019 Nature paper researchers reported that they can precisely correct mutant genes, which cause sickle cell anaemia and Tay Sachs disease.
 

Sickle cell anaemia and Tay Sachs
 
Sickle cell anaemia is an inherited form of anaemia. This is when there are not enough healthy red blood cells  (haemoglobin) to carry adequate oxygen throughout your body. The condition is the most common inherited blood disorder in the US, affecting 70,000 to 80,000 and further it is estimated  each year some 300,000 babies are born with the disorder worldwide. Tay-Sachs disease is a rare and fatal nerve condition often caused by the addition of four extra letters of code.  Although anyone can be a carrier of  the disease it is much more common among people of Ashkenazi (Eastern European) Jewish descent. In the Ashkenazi Jewish population, the disease incidence is about 1 in every 3,500 new-borns and the carrier frequency is 1 in every 29 individuals.

 
Some moral and ethical implications of CRISPR
 
Being able to modify your DNA with CRISPR tools has transformed scientific research and is revolutionising medicine although it will be some time before the technology is regularly used in clinics. In addition to its potential benefits there are significant moral and ethical challenges associated with the technology, especially when it is used for germline engineering, which is the process by which your genome is edited in such a way that the change is heritable. Inappropriate use of germline editing could dent the progress of the CRISPR technology.
 
The first CRISPR babies
 
One well publicized  inappropriate use of CRISPR is a team in China, led by He Jiankui of the Southern University of Science and Technology in Shenzhen, which in November 2018 “created” the first gene edited twins, known by their pseudonyms Lulu and Nana. He edited the twins’ cells to be immune to HIV infection when they were embryos, therefore ensuring that every cell in their bodies were changed, including their reproductive ones, which means their edited genomes can be passed on to their children and grandchildren, despite the fact that scientists cannot be sure what the long term effects of such lasting modifications might be. The twins are the first CRISPR babies and the first humans to have every cell in their body genetically modified using the technology.
 
In 2015 Chinese researchers were the first to edit the genes of a human embryo in a laboratory dish. Although the embryos did not go to term, the experiment triggered an international outcry from bioethicists, who argued that CRISPR should not be used to make babies. Notwithstanding, He Jiankui did just this.
 
He  employed CRISPR to alter a gene in IVF embryos to disable the production of an immune cell surface protein, CCR5, which HIV uses to establish an infection before insemination. CCR5 is a well-studied genetic mutation, and there is scientific and medical value in understanding how CRISPR can be used to disable and prevent HIV/AIDS. He believed that the use of CRISPR technology was medically appropriate and expected his experiment, “to produce an IVF baby naturally immunized against AIDS”. But more contentiously, He created twins who could pass the protective mutation to future generations. It is CRISPR’s ability to easily and cheaply edit human embryos, eggs, or sperm in order to create irrevocable changes and the potential for designer babies, which raises concerns.  
 
He defended his work at a Hong Kong genomics conference in late November 2018, but there was immediate and significant international criticism about the scientific and ethical legitimacy of his experiments, which broached China’s guidelines as well as international ethical and regulatory norms. A Chinese government investigation found He to have violated state law in pursuit of “personal fame and fortune”.  His endeavours cost him his university position and the leadership of a biotech company he founded, which had successfully raised US$43m start-up capital and was advised by Craig Melloprofessor  of the University of Massachusetts Medical School and Nobel Laureate for medicine in 2006 for his genetics research.
 
Opacity and scientific competition
 
Some scientists are reluctant to be critical of He and suggest his studies, which resulted in the first CRISPR babies,  simply signal the “next chapter in the technology’s story”. He Jiankui appears to be an ambitious scientist desperate to become the first to conduct the gene editing experiment on humans, but who made some significant errors of judgement by initiating his study prematurely and by withholding information from regulatory authorities and his university. A generous interpretation might suggest that He was motivated by science and humanity. Through a Beijing-based organization, which helps Chinese people with HIV, he recruited couples for his experiment where only the fathers were living with HIV infections, which they managed by antiviral drugs. Eight couples agreed to participate, although one subsequently withdrew.
 
Since He’s statement at the Hong Kong conference he has disappeared, but the background to his studies has been well documented. In late 2017, He, who specialized in sequencing DNA, began his efforts to produce human babies from gene edited embryos and before and during his study it is reported that he sought advice from international experts in the field and communicated openly with international colleagues about his plans. Notwithstanding, it is alleged that He faked a blood test for one of the fathers in the study, aware that in China the HIV status of the father would disqualify him from participating in fertility treatments. Also, He failed to appropriately inform the hospital where the twins were edited and implanted of the status of his experiments.

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Fierce competition among scientists is not uncommon and competition fuels opacity among scientists in their battle to become the first to make a discovery. Indeed, it is not uncommon for scientists to shield their ideas and research. This does not condone He’s actions, but it might help to explain them. Generally speaking, scientific opacity is not created by ambitious scientists alone, but it is partly created by scientific funding bodies and research institutions. Such opacity is a significant obstacle to open collaboration. In addition to wanting to be the first, He’s intentions might also have been an attempt to spare children of parents with HIV/AIDS  from inheriting the disease.
CRISPR is not yet safe
 
Be that as it may, many scientists agree that CRISPR is not yet safe and precise enough to be used in human embryos. In the March 2019 edition of Nature a group of 18 prominent CRISPR scientists and bioethicists from seven countries called for a global moratorium on heritable genome editing until the establishment of an international framework that would compel countries to establish both scientific safety and broad societal agreement before allowing the technology to progress.  "We call for a global moratorium on all clinical uses of human germline editing; that is, changing heritable DNA (in sperm, eggs or embryos) to make genetically modified children" , the scientists wrote.

Opposition to germline editing is mixed
 
However, opposition to germline editing is mixed. In February 2017 the US National Academies of Sciences, Engineering, and Medicine (NASEM) published a report, which did not call for an international ban of germline editing, but instead suggested that it "might be permitted" if strict criteria were met. In July 2018, the UK’s Nuffield Council of Bioethics published a report on heritable genome editing and suggested that under certain circumstances it could be morally permissible, even in cases of human enhancement. 

Given that CRISPR is cheap, easy-to-use and already an effective tool in thousands of laboratories throughout the world, it seems reasonable to assume that standards and laws are unlikely to prevent a determined scientist and desperate patients from using the technology prematurely. Indeed, science and medicine have a history of researchers attracting public criticism for undertaking experiments prematurely only to have those experiments become common medical practices: in-vitro fertilization  (IVF) is one such example. Although IVF has a chequered history today it accounts for millions of births worldwide and  1% to 3% of all births every year in the US and Europe.
 
Germline engineering and somatic genetic modification
 
Here we describe the difference between germline and somatic adjustments. The former uses CRISPR to modify DNA in such a way that the change is heritable. The latter uses CRISPR to modify the DNA of people with incurable diseases in a way that such modifications are limited to the people treated and not passed on to future generations. Broadly speaking, your body has two kinds of cells: somatic and germ cells. The vast majority are somatic. These cells make up your body and are responsible for forming all your familiar structures: such as your skin, blood, muscles and organs etc. Your somatic cells die when you die so there is no chance of them creating a new organism. However, germ cells are different. Early in your development your germ cells  are sequestered: they divide more slowly and under restricted circumstances. Germ cells cannot become a physical feature such as an ear or a finger, but they do make the only bits of you, which can form a new person: your eggs and your sperm. Every cell in your body holds your DNA in an unbroken lineage stretching back millions of years and thousands of generations, but only the germline has a chance to go forward. Human germline modification means deliberately changing the genes passed on to children and future generations and thereby creating genetically modified people. Somatic genetic modification is different. It adds, cuts, or changes the genes in some of your cells, typically to alleviate a medical condition. The use of human genome editing to make edits in somatic cells for purposes of treating genetically inherited diseases is already in clinical studies. If perfected, somatic gene editing (gene therapy) holds promise for helping people who are sick, affecting only an individual consenting patient. With the exception of He’s studies, human clinical studies with CRISPR have been limited to somatic cells. In effect, this renders CRISPR no more consequential than any other experimental drug or treatment. Any CRISPR-made somatic cell changes are a genetic dead-end and are not heritable. However, germline cells have the possibility of immortality, with the potential to affect thousands of people over the course of several generations. Tampering with germline cells is therefore a much more serious proposition.
 
Clinical studies of gene therapies
 
Gene therapy is primarily available in a research setting. The US Food and Drug Administration (FDA) has approved only a limited number of gene therapy products for sale in the US.According to the US National Institutes of Health, which serves as a clearinghouse for biomedical research worldwide, there are over 800 clinical studies currently underway to test gene therapy as a treatment for genetic conditions. The list includes a relatively small number of CRISPR studies as a treatment for cancers of the lung, bladder, cervix and prostate, the majority of which are in China where doctors appear to be leading the race to treat cancer by editing genes. For the past two decades China has been investing heavily in biomedicine. It is one way that China is able to compete with the West and demonstrate its technological prowess in the 21st century. Also, it is important for China to keep its vast population healthy in the 21st century. Given the somewhat ambiguous state of CRISPR technology it seems reasonable to assume that the first therapeutic applications of CRISPR will be in diseases where cells can be taken out of your body, edited, checked to ensure they are safe and then reintroduced. This suggests blood disorders such as sickle cell or thalassemia.
 
Takeaways
 
Bioethicist Henry T (Hank) Greely, professor at Stanford University, California, US, compares CRISPR to the Model T Ford, which was not the first automobile, but because of its simplicity of production, dependability and affordability it transformed society. CRISPR is not the first gene editing technology, but it is cheap and easy to use and is on the cusp of transforming biomedicine. A significant challenge is getting CRISPR tools, which are capable of performing gene edits, into the right place and to ensure they are safe. Prime editing is a smart, innovative and a substantial step forward in achieving this. Indeed, David Liu and his colleagues from the Broad Institute  have expanded the gene editing toolbox to facilitate ever-more precise editing ability and efficiency. Significantly, the overwhelming majority of human genetic disorders are due to the types of mutation that prime editing is able to correct, which stands the technique in good stead to be useful in therapies for intractable diseases. Notwithstanding, it is one thing to cut out sequences of DNA that cause genetic diseases and another to make genetic changes that are passed down to all later generations. Because CRISPR is cheap, easy-to-use, in the hands of scientists throughout the world, and already has been used to create babies with heritable traits, the technology provokes deep ethical and societal debate about what is, and what is not acceptable in efforts to prevent disease. Given that CRISPR has the potential to change the nature of humanity, it is incumbent on all citizens, not just scientists, bioethicists and regulators, to call for open and inclusive processes associated with all aspects of CRISPR.
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  • Diabetic foot ulcers (DFUs) are a result of diabetes complications and can lead to amputations and death
  • Scientists and clinicians struggle to reduce the vast and escalating burden of DFUs
  • In wealthy countries like the UK there are specialist multidisciplinary diabetic foot clinics
  • New and innovative therapies are beginning to emerge, which accelerates the rate of complete wound closure for DFUs
  • Notwithstanding new products coming to market, the best therapy is prevention
  
The vast and rapidly growing burden of diabetic foot ulcers and amniotic tissue
 
This Commentary discusses diabetic foot ulcers (DFUs) within the context of chronic wounds. Although chronic wounds tend to be an overlooked area of medicine and do not feature prominently in the popular media; NHS England, spends £5bn a year treating 2m patients with chronic wounds. The incidence rates of people affected with wounds are rising fast and some experts suggest that nearly 60% of all wounds become chronic. According to Una Adderley, a wound expert and Director of NHS England’s National Wound Care Strategy Programme, therapy in England for chronic wounds is patchy and suboptimal, “leading to non-healing or delayed healing (which) increases the number of people living with chronic wounds. Too many people are receiving care for which there is little evidence that it works and too few are receiving care for which there is strong evidence that it works”.
 
According to a 2019 report by the consulting firm MarketsandMarkets the global wound care market in 2019 is estimated to be US$20bn and projected to reach US$25bn by 2024. Market drivers include the vast and fast-growing incidence rates of hard-to-heal chronic wounds, a large proportion of which are associated with diabetes, increasing R&D spending, technological developments, the growing use of regenerative medicine in wound care, recent advances in molecular data that have contributed to genome sequencing, and the increasing use of AI in the management of wound care solutions. The chronic wound care markets of North America and Europe are expected to grow at a CAGR of ~4.5% for the next 5 years, but the highest CAGR is expected in Asia where the vast pool of patients is increasing significantly, and favourable reimbursement policies are expected to persist in the region for the next decade. 

When accompanied by an underlying condition such as diabetes, chronic wounds in the form of DFUs, are challenging to heal and have a deleterious effect on your quality of life: you experience pain, suffering, disfigurement, anxiety impaired mobility, malodour and social isolation. Because the prevalence of diabetes is increasing worldwide, DFUs have become a large, severe and growing public health issue as described in two research papers published in 2019.
 
One, published in the May 2019 edition of Diabetic Medicine, reports findings of an 18 year study of DFUs, and suggests that although current therapies in the UK result in better than previously reported survival in persons < 65 years (10 year survival is 85%), treatments fail to, “reduce recurrent incidence (of DFUs and) cumulative prevalence of all ulcers continues to increase”; from 20.7 to 33.1 per 1,000 persons between 2003 to 2017. The second paper, published in the January-March 2019 edition of the International Journal of Applied Basic Research, report sfindings of a prospective Indian study of 63 patients >18 with DFUs and shows the increase in the severity of DFUs and the consequent increase in the rate of hospital readmissions, amputations and mortality.
 
In this Commentary
 
This Commentary briefly describes the increasing prevalence of diabetes and its complications, the causes and symptoms of DFUs, which benefit from specialist multidisciplinary clinics and strategies to prevent them deteriorating to the point where the only therapy is amputation. We complete the Commentary by briefly mentioning how human amniotic membrane is being used in the current standard of care as a therapy for DFUs and describe the findings of two amniotic membrane studies. Notwithstanding these and other new product offerings coming to market, which accelerate the closure of DFUs, the most efficacious therapy for DFUs is prevention.
 
Diabetes and DFUs
 
Diabetes is a chronic disease that occurs either when your pancreas does not produce enough insulin or when your body cannot effectively use the insulin it produces. Insulin is a hormone that regulates your blood sugar level. High blood sugar levels (hyperglycaemia) is a common effect of uncontrolled diabetes and can lead to serious complications, which include blindness, kidney failure, heart attacks, stroke, diabetic foot ulcers (DFUs), and lower limb amputations. According to the World Health Organization, the global prevalence of diabetes among people >18 has risen from 4.7% in 1980 to 8.5% in 2014. Today, some 422m people worldwide have diabetes, which has increased from 108m in 1980. There is expected to be some 642m people >18 living with diabetes by 2040.
 
If you have diabetes you are prone to ulcers because your increased blood sugar levels create thick, sticky blood, which can lead to  peripheral artery disease (PAD), neuropathy (a loss of sensation due to nerve damage), and/or problems with circulation due to damage to your small blood vessels, which reduce your body’s ability to heal injuries.
 
Signs and symptoms of DFUs include numbness in your toes and a loss of feeling in your feet, painful tingling sensations, blisters, minor abrasions and cuts without pain that do not heal, skin discoloration and temperature changes  With a loss of sensation, a minor injury to your foot can go unnoticed and untreated, and quickly lead to an ulcer. If you are living with diabetes, ulceration is an ongoing challenge. Only about 66% of DFUs eventually heal without surgery. If you have had a foot ulcer you are at increased risk of further ulceration. Studies suggest that around 25% of people living with diabetes who become ulcer-free have developed new ulcers within 3 months, and 34% to 41% within 12 months. Some foot ulcers are painful, and treatment often requires that you spend a significant amount of time visiting clinics to frequently change your wound dressings. The poor prognosis of DFUs is often attributed to other complications of diabetes such as peripheral neuropathy, peripheral vascular disease and persistent hyperglycaemia. Managing diabetic foot ulcers is a major challenge for healthcare systems globally and the main cause of more than half of nontraumatic lower limb amputations: every 30 seconds in the world, a lower limb is amputated due to diabetes. Amputations have life-altering repercussions for patients and represent a significant burden for the healthcare industry as a whole. Between 0.03% and 1.5% of people with DFUs require an amputation and most amputations start with ulcers.

 
Major amputations and mortality rates
 
For major amputations, the prognosis is poor because your other limb is at risk.  Research suggests that only around 50% of patients survive for two years after major diabetes related amputations. The one-year mortality rate has been estimated at 32.7% after major amputation and 18.3% after minor amputation if you have diabetes. Five-year cumulative mortality for patients with diabetes undergoing a first major amputation has been estimated at 68% to 78.7%. Thus, if you have diabetes and a DFU you have almost a 50% chance of being dead within five years, which is significantly higher than for people with either breast (18%) or prostate (8%) cancers.

 
The UK
 
In the UK some 70,000 to 90,000 people living with diabetes have DFUs at any one time. If you have diabetes you are about 23 times more likely to experience an amputation than someone without diabetes. In England, diabetes leads to more than 9,000 lower limb amputations each year. Each week in England some 169 people undergo an amputation procedure as a result of diabetes. Analysis by the charity Diabetes UK found that between 2014 and 2017, 26,378 people had lower limb amputations linked to diabetes, which represented a 19% rise from 2010 to 2013. Diabetes affects almost 3.7m people in the UK. In 2017 NHS England launched a special transformation fund aimed at improving patients with diabetes access to specialist multidiscipline foot care clinics to help avoid amputations.

 
Specialist multidisciplinary treatment centres
 
In the video below Hisham Rashid, Consultant Vascular Surgeon at King’s College Hospital, London, describes a DFU and explains why they benefit from specialist multidisciplinary treatment centres. “DFUs have similar features to other ulcers, and often present in the toes and heal areas of the foot with the loss of skin and an exposed base with infection and necrosis. The significant difference is that a DFU usually comes with multiple pathologies, which, in addition to infection, include neuropathy and peripheral vascular disease. DFUs do not heal quickly and often require vascular surgeons working closely with radiologists, orthopaedic surgeons to correct any deformity and a microbiology unit to manage infection,” says Rashid.

 
What are diabetic foot ulcers?
 
Why does therapy for diabetic foot ulcers complications require a special center?

Rashid also explains that different therapies are used to heal DFUs. “If the patient has peripheral artery disease (ischaemia) then this has to be treated first with an angioplasty or a bypass or both to improve blood circulation into the foot. Once this is achieved, the ulcer is debrided and dressed. There are different dressings, which include negative pressure dressing, which sucks the blood into the tissues and thereby promotes healing. Sometimes skin graphs are necessary to get the tissue to heal faster. This can be done as a day surgery using local anaesthetic,” says Rashid.
 

How do diabetic foot ulcers heal?

Prevention of DFUs
 
Given the severity of DFUs and their vast and rapidly increasing burden on individuals with diabetes and healthcare systems, increasing attention is being devoted to prevention,  which involves adequate glycaemic control and modification of risk factors. While education is an obligation of healthcare professionals, it is crucial that people living with diabetes themselves increase their awareness and understanding of the condition and integrate regular feet examination and care into their daily lives.  In the video below, Roni Sharvanu Saha, Consultant in Acute Medicine, Diabetes and Endocrinology, St George’s Hospital, London, suggests that, “We’re getting better at understanding why DFUs occur, and better at examining peoples’ feet. In England, if you have diabetes you are entitled to a clinical examination of your feet at least twice a year. Checks include whether you have any minor abrasions, or whether you can distinguish hot and cold water with your feet, and  signs that you might have problems with your circulation and nervous system. Ensuring that people living with diabetes receive regular checks means that if you have reduced or poor circulation, you’re referred to the correct specialty team in order to protect you from developing DFUs. Prevention is better that cure. If we can get better at examining feet, outcomes will improve. If diabetes is not controlled complications will occur”.
 
 
New therapies and amniotic membrane
 
With the well-being of millions of people living with diabetes at stake, there is a pressing need for therapies that bring DFUs to closure as quickly as possible. The current standard of care (SOC) regimen for DFUs involves maintaining a moist wound environment, debriding nonviable tissue, relieving pressure with an offloading boot and preventing or managing wound infection. Even with a good SOC, DFUs are notoriously slow to close, creating a demand for new and innovative medicines and techniques to enhance closure. Increasingly, there are advanced therapies to facilitate healing DFUs when traditional approaches fail.
 
An example of a relatively new product to help close DFUs is human amniotic membrane.  Amniotic membrane has been used for wound healing purposes since the early 20th century, but it represents a relatively recent and promising advanced therapy to accelerate healing in DFUs. Amniotic membrane is derived from the human placental sac that supports the foetus by forming the inner lining of the amniotic cavity. Functions of amniotic membrane include the exchange of water-soluble molecules and the production of cytokines and growth factors  to facilitate the development of the foetes. The anatomic makeup of amniotic membrane dictates its functionality, and a significant characteristic is its ability to produce a wide variety of regenerative growth factors that facilitate foetal development. These growth factors, in combination with various other cytokines, have substantial potential benefits in wound healing, which include creating a structural scaffold for tissue proliferation, modulating the immune response, reducing inflammation, stimulating angiogenesis and facilitating tissue re-modelling.

 
Two studies of human amniotic membrane products used in wound healing

Two small but significant prospective cohort studies on the effectiveness of human amniotic tissue to treat DFUs were reported in the journal Wounds. One in the March 2016 edition and another in the November 2017 edition. The first is a prospective, randomized, multicentre, controlled study and the second a retrospective cohort study of 20 patients. In both studies amniotic membrane is used in combination with SOC, including debridement, well-controlled offloading, management of bacterial burden, and adequate perfusion.
 
Both studies suggested that the use of amniotic membrane is more likely to: (i) lead to complete wound closure, (ii) accelerate the rate of wound closure, and (iii) present no additional safety risks when compared to SOC alone in the treatment of DFUs. The first study demonstrated a statistically significant advantage of an amniotic membrane as compared to SOC in facilitating closure of chronic DFUs. 45% of participants achieved complete wound closure, while 0% of SOC participants alone achieved complete wound closure within 6 weeks. Further, there appears to be no increased rate of adverse events associated with the use of amniotic membrane in these wounds. The second study was a retrospective cohort study using a human amniotic membrane on 20 patients presenting with DFUs and venous leg ulcers. Patients underwent a 2-week ‘run-in’ period with good SOC; and if upon their return the ulcer had closed ≥ 30% in area, the subject was excluded from participation in the study. All wounds were effectively closed in approximately 10 weeks, DFUs in 12 weeks and venous leg ulcers in 9 weeks, and no adverse events were noted, suggesting that the therapy using human amniotic membrane is safe.
 
Discussion
 
The most significant limitation of both studies is their small sample size, which decreases the generalizability of their findings. Notwithstanding, the studies suggest that amniotic tissue products are efficacious options for DFUs when used in conjunction with the current SOC, which includes aggressive sharp debridement, adequate offloading and the application of sterile dressings. Further, amniotic membrane, like most biologic tissue products, requires significant processing and therefore its cost is relatively high: on average between US$500 to US$1,000 per application. Notwithstanding, these costs are significantly less than the average annual therapy cost of US$28,000 per patient for SOC for a DFU. And therefore, using amniotic tissue in the therapy for DFUs could result in significant savings for healthcare systems. Tissue storage as well as the time and skill required to apply amniotic membranes also represent challenges inherent to these products.
 
Takeaways
 
Millions of people are living with diabetes, which, if not managed appropriately can lead to life-changing complications. A DFU is one such complication, which often starts with a minor abrasion on your ankle or toe that you do not feel and therefore tend not to perceive to be important, until that is, it quickly escalates into a chronic wound that does not heal and eventually leads to a lower limb amputation. In most wealthy nations, health providers are aware of the dangers of DFUs and have set up multi-disciplinary diabetic foot clinics to treat and manage the condition. However, access to such clinics is patchy and the prevalence of DFUs continues to increase, and the eye-watering costs of treating and managing DFUs continue to escalate. In recent years, the therapy for DFUs has been improved by technological advances. We describe one of these: the use of amniotic tissue in conjunction with standard of care protocols. Recent research findings suggest that the use of amniotic tissue holds out the possibility not only of significant therapeutic benefits, but also of substantial cost savings for healthcare systems. Notwithstanding, perhaps the most efficacious therapy for DFUs is prevention. This means investing in effective education and awareness programs, good glycaemic control and appropriate footwear; encouraging people living with diabetes to participate in regular foot examinations and screening for peripheral neuropathy and peripheral arterial disease, and insisting that early telltale signs of foot wounds, no matter how minor, should be immediately referred to a specialist clinic.
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In our experience, the vast majority of people are looking for a gentle re-volumisation of lips that may have thinned with the passage of time.


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