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Copyright 2025 - Integrated Care Services Association

The Development of Psychiatric Care - Professor Wendy Burn, President of the Royal College of Psychiatrists

“The added disability from which our health system suffers is the isolation of mental health from the rest of the health services”

This doesn’t sound out of place today. Mental health services are still seen as the poor relation of the NHS and too often continue to be delivered on isolated sites in dilapidated buildings. My clinic room can be a windowless cupboard.

But this was said by Nye Bevan, founder of the NHS, in 1946, two years before the creation of now the world’s largest publicly funded health service. Fast forward to 2018 and we can wish a very happy 70th birthday to the NHS. Will there be cake?

Cake, of sorts, was promised to the NHS by the Prime Minister. Whether this will be enough to go around and, importantly, how it will be divvied up, is being picked over. There is no hyperbole that does justice to the achievements of the NHS. But unfortunately the isolation of mental health services that Bevan spoke of in the 1940s continued.

“As the NHS has grown mental health was not a service that was prioritised”. Prime Minister Theresa May recognised. This is exactly why mental health services are asking for a bigger slice of the cake; why mental health services need a bigger, fairer slice.

The much lauded “cradle to grave” NHS offer really is a source of national pride. The service has retained its founding principles, including “comprehensiveness within available resources”. But, frustratingly, the needs of people with mental illness weren’t truly considered part of a “comprehensive” healthcare offer. There has been progress over the decades. When I started work on NHS mental health wards thirty years ago there were still patients who had been incarcerated for life in an asylum for illnesses that they had long recovered from. This would now, thankfully, be unthinkable.

But some current experiences of patients with mental illness are still unthinkable for those with physical illnesses.

There’s no stronger indictment than the significantly stunted lives of people with serious mental illnesses - these reduce life expectancy by 10 to 20 years. Far too many missed birthdays.

People with mental illnesses use emergency health services far more than other people – 7% of the adult population make use of mental health services but 17% of AE attendances are for patients who also use mental health services. This is a sure sign that the right support really isn’t there.

And this is escalating even further into more people being detained under the Mental Health Act. A sobering irony at a time where we look back with pride on the huge transformation away from a model of institutionalisation that the mental health sector underwent decades ago. Ending this requires a truly comprehensive cradle to grave NHS, which takes mental and physical health fully into account.

What would this look like? Really, this starts before the cradle. A good start in life is inextricably linked with a mother’s health - their physical and their mental health. Until recently, support for the many mothers who suffer from mental illness during pregnancy and immediately after (the perinatal period) was scarce. This meant that not only did suffer without support but their untreated illnesses would often have had a severe impact on their child’s development.

One of the absolute best developments in the NHS in recent years is that 7000 more women now receiving specialist perinatal mental health support, their children benefitting in turn. This is world class stuff, but we can’t forget what a low base we have been working from.

The local investment into these amazing new services needs to be maintained so that their benefit does not fade. A future NHS should provide universal perinatal mental health support, with antenatal classes including mental health advice with support for fathers also available.

Now moving on to children and young people. It certainly doesn’t take a doctor to tell you that there is “something going on” with the mental health of young people. To be brutally honest we just don’t know the scale of mental illness within children or of the extent of unmet need. It’s been 14 years since any proper review of the extent of mental illness within our children.

Simon Stevens, chief executive of the NHS, says that the long awaited figures on children and young people’s mental health, due this year are “bound to show that the level of undiagnosed mental health problems and distress among young people is much higher than has officially previously been recorded.”

Recognition of this is certainly something. In the long term expectations and ambitions need to be raised. We need to aim to treat the majority of young people with a mental illness, rather than the minority, and for services to be commissioned accordingly. After all, is it any help for the Prime Minister herself to talk of prioritising something if your child isn’t getting support? It is essential that local spending on services for child and adolescent services is upheld, including for emerging new services such as Mental Health Support Teams in schools.

And then to adulthood. How does such a gaping void of up to two decades emerge between life expectancies of people with and without some types of serious mental illness? A large part of this answer lies within the care received, or not, during this expanse known as being an adult. Recent focus has been on quite specific areas, rather than on “general” services for people with long term serious mental illness and psychosis.

Services that support these people are being cut back and early intervention services are patchy. The whole country knows when A&E departments see 90% of patients within 4 hours rather than 95%. We have no idea how long people are waiting for mental health crisis treatment.

It’s no coincidence this comes at a time when increasing numbers of people are being detained under the Mental Health Act. “Those with the most severe forms of mental illness have the greatest needs, and continue to be the most neglected and discriminated against” the interim report of the Review of the Act investigating this rise says succinctly.

RCPsych wants to see all areas commission first response services to be able to direct 111 callers to support and for resourcing of community health services and rehabilitations teams to be prioritised in all areas so that fewer people go without support and hit crisis point.

And now to those older generations, who, like the NHS, are looking beyond their 70th Birthday. Whereas in 1948, women could expect to live to 70 and men to 66, today those figures are 83 and 79 respectively. Our ageing population is no secret. Again, no medical degree is needed to guess that this poses a challenge to the whole NHS.

Supply really has not geared up to meet rapidly growing demand on mental health services of a much larger group of older people. Old age mental health has not been prioritised in recent years, which shows through lack of services and staff. As this issue is not going to go away, and the tax payers purse will know all about it, the NHS must start to focus on ensuring that the specialist, complex mental health needs of older adults are catered for, including the implementation of the Dementia Care Pathway by all CCGs

I work with the elderly and our disjointed health and social care system is far from meeting their needs. No one wants to have to repeat their story endlessly or to attend different hospital appointments in separate places thinking about individual problems, especially not an 80 year old with many, interrelated problems.

The progress in recent years both in public attitudes towards mental illness and available services throughout the 70 years of the NHS is invaluable, particularly recent bounds forward. Momentum needs to keep up, a greater number of medical students need to be encouraged to choose psychiatry, and locally commissioners and providers need to work to ensure their own work places are mentally healthy to retain the staff they do have. Otherwise the opportunity to provide comprehensive care and change the lives of the millions in this country living with mental illness will be lost. The NHS and its patients will continue to suffer.

We can’t have our cake and eat it. Mental health services know that any new resources come with new responsibilities to modernise and become more efficient. We are up for that.

By the time the NHS reaches the big 8-0 I want “cradle to grave” to really mean something different. Another slice please.

Content provided by Professor Wendy Burn, President of the Royal College of Psychiatrists.

SANE - a leading UK mental health charity improving quality of life for anyone affected by mental illness - SANE

SANE was founded in 1986 by its Chief Executive, Marjorie Wallace CBE, following her pioneering articles, The Forgotten Illness, in The Times. These exposed the way in which society neglected individuals and families affected by mental illness, and the lack of information, treatments and strategies for prevention.

The charity aims to;

  • raise awareness and understanding of all mental health conditions
  • fight to improve frontline mental health services for individuals and carers
  • provide support, information and guidance through its helpline, SANEline, ongoing support service, Textcare and Online Forum
  • promote and host research into causes, treatments and therapies at the Prince of Wales International Centre for SANE Research in Oxford

Marjorie WallaceSince SANE was founded the mental health landscape has changed dramatically. National programmes and strategies for service development have been established, and public awareness and anti-stigma campaigns have brought mental illness out of the shadows. Yet we still find ourselves fighting on behalf of people for whom services are not available or do not meet need, and who often feel they have nowhere to turn in crisis.

While many important service developments have been introduced, such as the Improving Access to Psychological Therapies programme, the fundamentals of good mental health care are often still lacking. A major concern is the lack of psychiatric beds available locally for those in crisis, or who need longer-term care. We wish to see beds and units provided in sufficient numbers to prevent people being denied treatment or sent hundreds of miles from home for inpatient care. This would also help to relieve the pressure on overstretched community mental health teams.

We wish to see training and recruitment of mental health professionals in all disciplines - psychiatrists, nurses, therapists and counsellors – to make good the serious shortfalls and enable safe and therapeutic inpatient and community care and psychological therapies to be provided.

In order to achieve genuine parity between mental and physical health care, people presenting with a mental health problem should be treated with the same level of response as are those with a physical health problem. Those who are suicidal or self-harming should be assessed and treated, and given appropriate follow-up care.

SANE provides emotional support, guidance and information to anyone affected by mental ill-health through our helpline, SANEline. SANEline remains the only out-of-hours national, specialist mental health helpline, available from 4pm to 10pm 365 days a year to people in crisis, those with enduring and relapsing conditions and those who care for them. Our team of highly-trained volunteers offers listening, understanding, up-to-date information and support to callers in need and distress.

As well as our helpline, SANE provides a range of further support. SANE has retained the Call Back service we first opened during the pandemic, where someone struggling can call and leave a message, providing their name and phone number, and SANE’s team of volunteers will call back within a few days. Through Textcare SANE provides personalised, targeted messages to people at times allocated by them when they feel most lonely and vulnerable, such as on an anniversary or a bereavement, Christmas and other holidays, or when alone in the evenings or at weekends. People can also seek help from our Email Support service, a dedicated email address where individualised replies are sent within 24 hours.

        

The Prince of Wales International Centre for SANE Research hosts teams working across professional disciplines. Current research includes virtual reality therapy, which is being tested in clinical trials with patients with psychosis. The Subramanium Study Centre brings together global experts from a range of fields and industries, across the public and private sector, to advance the study of mental health through original research. A key focus is to support the discovery of new and practical treatments for a variety of disorders, including clinical depression and schizophrenia.

We continue to run our Black Dog Campaign to raise awareness of depression and other mental health conditions and encourage people to seek help. Sculptures of Black Dogs wearing coats designed by artists, celebrities and others are placed in business foyers, public parks and shopping centres in towns and cities throughout the UK, and they also tour workplaces, schools and universities.

The SANE Creative Awards Scheme aims to improve the quality of life for people with mental health problems, their families and carers, by encouraging them to fulfil their creative potential. It provides grants to individuals to cover the cost of materials, specific projects and courses, or towards relief cover for carers. The Charles Bracken Award is a specific award which recognises exceptional talent in communicating the relationship between creative endeavour and mental illness. The award is in honour of Charles Bracken MBE, a founding director and Chairman of SANE, and is supported by his widow, Madeline, and the family.

SANE is working in partnership on the scheme with the Open College of the Arts, which is providing advice, guidance and members of the awards assessment panel.

SANE logo

Content provided by SANE. For more information please visit www.sane.org.uk.

C-Reactive Protein (CRP) and Pro-calcitonin (PCT) Point of Care Testing - J Bolodeoku MBBS MSc MBA DPhil (Oxon) FRCPath

In the United Kingdom, about 79% of the prescribing of antibiotics occurs in community and respiratory tract infections account for about 60% of the diagnosis. With many of these respiratory tract infections, the condition is self-limiting or caused by viruses, and therefore do not warrant the use of antibiotics1. A diagnostic test that could differentiate between a viral and bacterial respiratory tract infection could help inform or guide the healthcare professional as to whether the patient requires antibiotics or not. It can be difficult to predict pneumonia in patients with respiratory tract infections based on their symptoms alone: absence of a runny nose, breathlessness, crackles, diminished breath sounds on auscultation, tachycardia and fever2. CRP is an acute-phase protein produced by the liver following infection or injury. There is usually only a very small amount detectable within the blood and a viral infection would generally give rise to a modest increase in the blood, peaking about day 2 and 4. CRP levels correlate with the degree of severity of the infection3. Measuring CRP in patients presenting with suspected respiratory tract infections can help differentiate between viral and self-limiting infections from more serious bacterial infections that need antibiotics. Therefore, complementing the history, clinical signs and symptoms and measuring the CRP would improve the probability of predicting pneumonia.

There are several studies conducted with CRP point of care testing in adults to guide antibiotic prescribing in respiratory tract infections which we would evaluate. In a general practice study conducted in the Netherlands assessing the effect of general practitioner testing using CRP and training in communication skills on antibiotic use in lower respiratory tract infections, the general practitioners in the CRP test group prescribed antibiotics to 31% of patients compared with 53% in the group of general practitioners who did not test the CRP. The general practitioners trained in the enhanced communication skills prescribed antibiotics to 27% of the patients compared with 54% in the no training group. In this study, 227 patients were allocated to point of care testing, the range determined was <8 to 225 mg/L. Overall, 69% of the patients had CRP levels of less than 2 mg/L, 24% had CRP levels of 20 – 99 mg/L and only 7% had greater than 100 mg/L4. In the United Kingdom, another study of 99 patients presenting with symptoms of respiratory tract infections in a GP surgery between July 2014 and May 2015, CRP levels of 0 - 5, 6 - 13, 31 – 100, > 100 ng/mL, were observed in 48 (48%), 35 (35%), 13 (13%) and 3 (3%) patients, respectively5. Recently, the Scottish Microbial Prescribing Group (SAPG) developed a proposal to evaluate the feasibility of using CRP testing in GP Practices and unscheduled care settings (e.g. out-of-hours service). The objective was primarily to evaluate the qualitative aspect of the implementation, but within the methodological limitations of a pragmatic feasibility study to also assess the perceived impact on antibiotic prescribing behaviour. Ten GP Practices were recruited from four health board areas through direct invitation by SAPG members. The test methodology used the following test result ranges (recommended by NICE) to inform treatment options: Low CRP (<20mg/L) rules out need for antibiotic Intermediate; (CRP 20 – 100mg/L) use clinical judgement to decide need for antibiotics; High CRP (>100mg/L) rules in need for antibiotics. Details of each consultation were collected to provide information on patient demographics, test results and prescribing decisions. CRP test results were documented for 231 patients (94%) with the remaining tests having problems with instrument error messages. For the majority of patients (72%), the CRP test result was <20mg/L and in 74% of cases GPs perceived that the CRP test results did have an influence on prescribing decisions. The outcome of using the test was that no prescription for antibiotics was issued in 64% of cases and a delayed prescription was issued in 14%. About 22% of patients were prescribed antibiotics6.

The current NHS treatment pathway for the management of a suspected respiratory tract infection provides the decision to prescribe antibiotics based on medical history, clinical examination and assessment of risk. The NICE guidelines on the diagnosis and management of pneumonia in adults recommends that point of care CRP testing should be considered for people with symptoms of lower respiratory tract infection if a diagnosis is unclear after clinical assessment, and that antibiotic should be prescribed based on the results. Immediate antibiotic treatment should be offered if the CRP level is more than 100mg/L and delayed prescription should be considered at the levels between 20 and 100 mg/L. It is not recommended for CRP levels less than 20 mg/L7. Currently, CRP levels can be measured using a number of point of care devices. NICE is aware of the following CE marked devices that all quantify CRP levels in the blood: Afinion AS 100 (Alere), AQT90 Flex (Radiometer Medical ApS), iCHROMA (Boditech Med), NycoCard Reader II (Alere), Smart analyser (Eurolyser Diagnostica), Quik Read Go (Orion Diagnostics) and has published innovation briefings on the QuikRead Go (Orion Diagnostics)8 and Afinion (Alere)9.

Inflammatory markers, such as CRP or white blood cells lack specificity for bacterial infections and therefore has led to the investigation of other more specific markers for bacterial infections such as procalcitonin (PCT). PCT is more specific about infections and may also help to distinguish between bacterial infections from viral illnesses, it is seen to increase within 6 to 12 hours. PCT also corresponds with bacterial load and the severity of infection. In addition, it has some prognostic indications in predicting fatal outcome in patients with community-acquired pneumonia. A meta-analysis was performed to evaluate the accuracy of determination of pro-calcitonin (PCT) and CRP levels for the diagnosis of bacterial infection. PCT levels were more sensitive and more specific than CRP levels for differentiating bacteria from non-infective causes of information10. The use of the combination of CRP and PCT in a ‘both positive’ test format, a higher specificity (86%) and higher positive predictive value (PPV) of 90%11. There are several bench top PCT assay methods available but there are is only one point of care device that measures both CRP and PCT, the i-CHROMA (Boditech Med). There was good correlation between POCT system i-CHROMA SMART and traditional laboratory method DxC for CRP and PCT12. The future would probably require a POCT system that is able to measure both CRP and PCT to improve the sensitivity of antibiotic prescription for upper respiratory infection.

References

  1. NICE. Respiratory tract infections - antibiotic prescribing. Prescribing of antibiotics for self limiting respiratory tract infections in adults and children in primary care. NICE clinical guideline 69 www.nice.org.uk/guidance/cg69/evidence/cg69-respiratory-tract-infections-full-guideline3 2008
  2. Hopstaken R, Muris J, Knottnerus J, Kester A, Rinkens P, Dinant G. Contributions of symptoms, signs, erythrocyte sedimentation rate and C-reactive protein to a diagnosis of pneumonia in acute lower respiratory tract infection. Br J Gen Pract 2003; 53 (490): 358 – 364
  3. Melbye H, Hvidsten D, Holm A, Nordbo SA, Brox J. The course of C-reactive protein response in untreated upper respiratory tract infection. Br J Gen Pract 2004; 54 (506): 653 – 658
  4. Cals JWL, Butler CC, Hopstaken RM, Hood K, Dinant G-J. Effect of point of care testing for C reactive protein and training in communication skills on antibiotic use in lower respiratory tract infections: cluster randomised trial. BMJ 2009; 338: b1374
  5. Penney O C-reactive protein point of care testing reduces diagnostic uncertainty and unnecessary antibiotic prescribing for respiratory tract infections in general practice. Poster No 003 presented at the RCGP Annual Meeting, Glasgow, 1-3 October 2015
  6. SAPG Executive summary report on Evaluation of CRP testing in primary care. http://www.scottishmedicines.org.uk/files/sapg1/Executive_summary_Evaluation_of_CRP_testing_in_primary_care_July_2016.pdf
  7. NICE (December 2014). Pneumonia- Diagnosis and management of community- and hospital-acquired pneumonia in adults
  8. QuikRead go for C-reactive protein testing in primary care/Advice/NICE http://www.nice.org.uk/advice/mib78 September 2016
  9. Alere Afinion CRP for C-reactive protein testing in primary care/Advice/NICE http://www.nice.org.uk/advice/mib81 September 2016
  10. Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and c-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2014; 39: 206 – 217
  11. Li H-X, Liu Z-M, Zhao S-J, Zhang D, Wang S-J, Wang Y-S. Measuring both procalcitonin and C-reactive protein for a diagnosis of sepsis in critically ill patients. J Int Med Res 2014 42 (4) 1050 – 1059
  12. Rim JH, Ahn H-J, Yoon KK, Kim HR, Kim Y-A, Lim HS, Yoo JY. Performance evaluation of the ichroma SMART analyzer in measuring c-reactive protein and procalcitonin levels. Lab Med Online 2016 6 (1) 19 -24

Content provided by J Bolodeoku MBBS, MSc, MBA, DPhil (Oxon), FRCPath
Independent Pharmaceutical Physician and Chemical Pathologist, JB Consulting MDP Limited, UK & Honorary Consultant Physician, North Hampshire Hospital, Basingstoke
JB Consulting (MDP) Limited, Cherwell Innovation Centre, 77 Heyford Park, Upper Heyford, Oxfordshire, OX25 5HD, United Kingdom

Development of novel stem cell therapies for chronic diseases - Professor Søren Paludan Sheikh MD PhD

The regenerative capacity of stem cells is widely accepted, however in reality not many stem cell therapies have become standard treatments in the clinic beyond rare diseases including bone marrow transplantation. To address the high expectations of stem cell therapy, it will be necessary to test the safety and efficacy of different types of stem cells to extend the regenerative approach to major diseases and conditions. This is especially important since current medical treatments for many chronic diseases are mainly symptomatic and palliative while stem cell therapy has the potential to be curative by repairing damaged cells. Developing curative therapies for chronic diseases would reduce the burden on the public health system and improve life quality for the patients. Therefore, understanding the underlying cellular mechanisms and molecular circuits in the human regenerative response including stem cell therapy and adopting novel insight into standard patient care is at the core of modern health care.

Stem cells possess a unique dual ability: they can undergo symmetric division (to increase their own numbers) and they can differentiate into multiple other cell types. Stem cells ensures maintenance of homeostasis in our tissues and body. Since approx. 106 cells are lost in our body every second, we would not last long without stem cells. In the adult, especially the so-called mesenchymal stem cells (MSC’s) including progenitor/stem cells isolated from adult adipose tissue, perinatal sources or bone marrow, have attracted attention as a cell source for clinical treatment. Adipose-derived regenerative cells (ADRCs) have strong regenerative capacity and have proven safe for human use1,2. A systematic review of 70 studies including 1474 patients and another review including 600 patients suggest MSC/ADRC treatment2,3 does not give rise to clinically important adverse effects. These cells work as site-regulated ‘drugstores’ in vivo by secreting molecules that facilitate repair. Our goal is to develop and implement novel stem cell therapies, understand the mode of action of stem cells and help to transform modern medicine. For this to happen, the regulatory bodies in different countries would need strong data to approve novel stem cell therapies for public use for the benefit of patients. To this end, it will be necessary to perform clinical trials in several different countries using the same method for stem cell isolation and the same design of the clinical trials. The data from all the trials could be pooled resulting in a higher power. This design can potentially help shape the view on stem cell treatment by reducing the barriers including public skepticism and regulatory approval. We are performing multicenter double-blind randomized, placebo controlled phase 2 clinical trials analyzing safety and efficacy of autologous (the patient’s own cells) ADRCs to correct erectile dysfunction (ED)4,5 and alleviate Breast cancer-related lymphedema (BRCL)6 and treat hip and knee pain (HJP) at key hospitals in multiple countries.

There is a large unmet need for all these three chronic diseases. It is estimated that around 40% of European men between the age of 40 and 79 suffer from ED. Taking into account the limitation and dropout rate of current medical treatment, stem cell treatment is in reality the best treatment option. For breast cancer alone there is app. 4500 new patients pr. year in Denmark alone, and app. 25% of these (=1.214) patients will eventually suffer from BCRL. Current compression treatment and physiotherapy has only marginal effect. Osteoarthritis (OS) is the main reason for chronic pain worldwide. This causes a significant impact to the public health system, since OS affects every eights person. We treat the patients with autologous fat stem cells (cells from the patient him-/her-self) in a one-day procedure, where the patient is first subjected to an abdominal liposuction under anesthesia. Next, we isolate the multipotent ADRC’s using a semi-automatic enzyme-based and GMP-compliant system, followed by injection into the patient. The ADRC’s are used freshly isolated and thus no tissue culture of the stem cells is necessary. Besides these three diseases, different types of mesenchymal stem/progenitor cells are being tested for safety and efficacy in multiple other conditions worldwide including cardiovascular diseases such as heart failure and critical limp ischemia, diabetes, liver and kidney diseases, inflammation and autoimmune conditions, graft-versus-host disease, wound healing, oncology, neurodegenerative diseases and spinal cord injury.

Cell therapy using ADRC’s is currently at the epicenter of regenerative medicine. The multipotent autologous ADRC’s have the ability to differentiate into novel cells belonging to bone, cartilage, skin, blood vessels, lymphatic vessels, neurons, and liver. As opposed to many clinical trials that use cultured cells isolated from bone marrow, we recommend using freshly isolated stem/progenitor cells from adipose tissue. Adipose tissue is so rich in ADRC’s (also called stromal vascular fraction) that we do not need to culture the cells to increase cell number. This reduces the cost of treatment since GMP culturing is expensive, time consuming and requires an advanced laboratory and regulatory permits. It is important to stress that the ARDC’s is a heterogeneous mixture of different cell types including stem cells (mesenchymal stromal cells, hematopoetic stem cells, pericytes and supra-adventicial cells), progenitor cells (endothelial and vascular progenitor cells, preadipocytes and hematopoetic progenitors) and mature cells (adipocytes, fibroblasts, endothelial cells, and blood cells including monocytes and macrophages)7. At this stage of the game, this may be an advantage since more than one cell types likely contribute to the clinical effects in different diseases. However, the heterogeneity also presents a problem since we do not currently understand the mechanism of action. Thus, it is not known which of these cells are responsible for the clinical effect, but it is likely that they are not all involved. It is known that the ADRC’s modulate the immune system to induce a regenerative response in the damaged tissue8,9. In addition, the ADRC’s contain a host of molecules that facilitate repair and reduce inflammation including growth factors, hormones, cytokines and different forms of DNA and RNA molecules. Since transplanted ADRC’s do not remain long in the host organism, it is thought that the therapeutic effects of stem cells are mediated by the aforementioned soluble mediators that change the balance in the immune system and promotes regeneration while reducing inflammatory processes by several mechanisms including inhibition of macrophage activation. The molecules may be delivered to damaged tissues in extracellular vesicles or by transport in microtubules. In addition, cell-to-cell contacts between stem cells and damaged cells may also play a role in the tissue regeneration.

Erectile dysfunction is defined as the inability to attain or maintain a penile erection satisfactory for sexual intercourse10. As mentioned, it is a prevalent disease, and existing treatments have major problems including lack of efficiency, numerous side effects, decreased libido because of ED and the reduced spontaneous element in the sexual behaviour11. In addition, ED is often considered a general indicator of decreased male health. The success rate of current treatment for ED after radical prostatectomy is estimated to be 14-53% for oral PDE-5 inhibitors (such as Cialis), 49-75% for the urethral pellets that delivers prostaglandin E1 (PGE1) also called ‘Medicated System for Erection’ (MUSE), and 47-80% for penile injections with PGE1 (alprostadil) alone or in combination with papaverine and phentolamine. Finally, patients can be treated quite successfully by getting a penile prosthesis implanted. However, this requires a sophisticated operation with placement of three different mechanical parts. The rationale for using ADRC’s to treat ED is based on these progenitors cells ability to stimulate repair of epithelial cells, vascular smooth muscle cells and neurons. The mechanism behind penile erection is that blood fills the penile sinusoids by relaxation of vascular smooth muscle cells induced by release of nitric oxide (NO) from the cavernous nerves and endothelial cells. NO diffuses into the vascular muscle cells, activates guanosine cyclase to produce cGMP, which in turn reduces Ca2+ levels and induces relaxation10. At Odense University Hospital in Denmark, we are currently enrolling 70 patients in a prospective, randomized, placebo-controlled and double-blinded phase 3 clinical trial using autologous ADRC’s for erectile dysfunction after prostate cancer. Accordingly, 35 men receive ADRC’s while 35 men are injected with saline. Prostate cancer is the most common cancer in men, and 16-60% experience ED after radical prostatectomy. The Danish regulatory bodies have approved the current trial based on preliminary data from our phase 1 study that describes a stem cell therapy that appears safe and potentially can correct ED after prostatectomy4. Briefly, we treated 17 men with no recovery using conventional therapy including PDE-5 or PGE-1 analogs. All subjects were sexually active before the operation, and were prostatectomized 5-18 months before stem cell treatment. All men underwent a liposuction performed by a plastic surgeon, followed by ADRC isolation and intracavernous injection of 4 x 1 ml ADRC’s. The men received between 8.4 and 37.2 million ADRC’s immediately after cell isolation. Interestingly, with a one year follow up period, 8 out 11 urinary continent men recovered their erectile function and were able to accomplish sexual intercourse as assessed by extensive self-reporting questionnaires dubbed International Index of Erectile Function (IIEF) and Erection Hardness Score (EHS). In contrast, none of the 6 incontinent men regained erectile function. Importantly, the procedure was safe and well tolerated, since only minor events including tenderness, redness and small bleedings related to the liposuction and injection sites was reported at the one-month evaluation. None of the men contacted a doctor for any side effect. Our study has limitations since we had no control group, it was an un-blinded investigation, we had no objective measurements for ED recovery and we do not know the mode of action of the stem cells. Finally, the treatment did not work in all patients. Nevertheless, we conclude that ADRC treatment is a promising interventional therapy for erectile dysfunction following prostatectomy. By extension, it is likely that the ADRC therapy would also work for other ED due to other common causes including diabetes, age, atherosclerosis and neural diseases. ED after prostatectomy is a severe form due to severed nerves followed by hypoxia and fibrosis in the penile tissue.

Our findings may open a new treatment paradigm in organic male impotence in general and including novel possibilities for a large group of men with ED due to late complication of type 1 and 2 diabetes. In further work, it will be necessary to design experiments to unravel the underlying molecular and cellular mechanisms of ADRC action, establish the optimal delivery mode including stem cell dose number, timing and administration route. It will also be important to lower costs of the treatment and develop methods to identify the patients that will respond to ADRC treatment or recover by standard treatment. In addition, considering the heterogeneous nature of ADRC’s, different methods of isolation and preparation yield different and often inconsistent results regarding relative amounts of stem/progenitor cells and mature cells. On top of that, most researchers employ expanded cells cultured under different conditions including media, addition of growth factors and passage numbers. Therefore, it is important that we develop better markers of the cells that are important for the clinical effect, and use standard methods to characterize the cells. Lastly, we need to increase efficiency of ADRC isolation. In addition, the literature is full of case reports and reports with very small numbers of patients treated with poorly defined stem/progenitor cells. Finally, there have been concerns that these progenitor cells could increase the risk of malignancies. We may never see stem cell therapy reach its full potential unless the field solves these problems and provides compelling evidence from adequately powered and controlled clinical trials that meet regulatory standards. Human regeneration is viewed as the most important biological process for managing repair for the chronic diseases in an ageing population. Thus, regenerative medicine is going to change the way we think about treatments of especially chronic diseases. A vision would be to develop standard stem cell treatments based upon scientific evidence regarding the molecular events underlying regeneration with the goal to offer the treatments as standard ‘packages’ including high technology to hospitals and professional clinics worldwide, thus making stem cell science immediately applicable for the patients.

References

  1. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Molecular biology of the cell 2002; 13(12): 4279-95.
  2. Toyserkani NM, Jorgensen MG, Tabatabaeifar S, Jensen CH, Sheikh SP, Sorensen JA. Concise Review: A Safety Assessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events. Stem cells translational medicine 2017; 6(9): 1786-94.
  3. Casiraghi F, Remuzzi G, Abbate M, Perico N. Multipotent mesenchymal stromal cell therapy and risk of malignancies. Stem Cell Rev 2013; 9(1): 65-79.
  4. Haahr MK, Jensen CH, Toyserkani NM, et al. Safety and Potential Effect of a Single Intracavernous Injection of Autologous Adipose-Derived Regenerative Cells in Patients with Erectile Dysfunction Following Radical Prostatectomy: An Open-Label Phase I Clinical Trial. EBioMedicine 2016; 5: 204-10.
  5. Lin CS, Xin Z, Dai J, Huang YC, Lue TF. Stem-cell therapy for erectile dysfunction. Expert opinion on biological therapy 2013; 13(11): 1585-97.
  6. Toyserkani NM, Jensen CH, Andersen DC, Sheikh SP, Sorensen JA. Treatment of Breast Cancer-Related Lymphedema with Adipose-Derived Regenerative Cells and Fat Grafts: A Feasibility and Safety Study. Stem cells translational medicine 2017; 6(8): 1666-72.
  7. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315-7.
  8. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105(4): 1815-22.
  9. Yagi H, Soto-Gutierrez A, Parekkadan B, et al. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant 2010; 19(6): 667-79.
  10. Reed-Maldonado AB, Lue TF. The Current Status of Stem-Cell Therapy in Erectile Dysfunction: A Review. World J Mens Health 2016; 34(3): 155-64.
  11. Carvalheira AA, Pereira NM, Maroco J, Forjaz V. Dropout in the treatment of erectile dysfunction with PDE5: a study on predictors and a qualitative analysis of reasons for discontinuation. The journal of sexual medicine 2012; 9(9): 2361-9.

Content provided by Professor Søren Paludan Sheikh 
Dept. Head, MD, PhD
Dept. for Clinical Biochemistry & Pharmacology
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Odense Universitetshospital
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