̽��ֱ�� of Cambridge - Evelyn Trust

One in four patients in vegetative or minimally conscious state able to perform cognitive tasks, study finds

cjb250 — Wed, 14 Aug 2024 21:00:11 +0000

Severe brain injury can leave individuals unable to respond to commands physically, but in some cases they are still able to activate areas of the brain that would ordinarily play a role in movement. This phenomenon is known as ‘cognitive motor dissociation’.

To determine what proportion of patients in so-called ‘disorders of consciousness’ experience this phenomenon – and help inform clinical practice – researchers across Europe and North America recruited a total of 353 adults with disorders of consciousness, including the largest cohort of 100 patients studied at Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust.

Participants had mostly sustained brain injury from severe trauma, strokes or interrupted oxygen supply to the brain after heart attacks. Most were living in specialised long-term care facilities and a few were living at home with extensive care packages. ̽��ֱ��median time from injury for the whole group was about eight months.

Researchers assessed patterns of brain activation among these patients using functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). Subjects were asked to repeatedly imagine performing a motor activity (for example, “keep wiggling your toes”, “swinging your arm as if playing tennis”, “walking around your house from room to room”) for periods of 15 to 30 seconds separated by equal periods of rest. To be able to follow such instructions requires not only the understanding of and response to a simple spoken command, but also more complex thought processes including paying attention and remembering the command.

̽��ֱ��results of the study are published today in the New England Journal of Medicine.

Dr Emmanuel Stamatakis from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge said: “When a patient has sustained a severe brain injury, there are very important, and often difficult, decisions to be made by doctors and family members about their care. It’s vitally important that we are able to understand the extent to which their cognitive processes are still functioning by utilising all available technology.”

Among the 241 patients with a prolonged disorder of consciousness, who could not make any visible responses to bedside commands, one in four (25%) was able to perform cognitive tasks, producing the same patterns of brain activity recorded with EEG and/or fMRI that are seen in healthy subjects in response to the same instructions.

In the 112 patients who did demonstrate some motor responses to spoken commands at the bedside, 38% performed these complex cognitive tasks during fMRI or EEG. However, the majority of these patients (62%) did not demonstrate such brain activation. This counter-intuitive finding emphasises that the fMRI and EEG tasks require patients to have complex cognitive abilities such as short-term memory and sustained concentration, which are not required to the same extent for following bedside commands.

These findings are clinically very important for the assessment and management of the estimated 1,000 to 8,000 individuals in the UK in the vegetative state and 20,000 to 50,000 in a minimally conscious state. ̽��ֱ��detection of cognitive motor dissociation has been associated with more rapid recovery and better outcomes one year post injury, although the majority of such patients will remain significantly disabled, albeit with some making remarkable recoveries.

Dr Judith Allanson, Consultant in Neurorehabilitation, said: “A quarter of the patients who have been diagnosed as in a vegetative or minimally conscious state after detailed behavioural assessments by experienced clinicians, have been found to be able to imagine carrying out complex activities when specifically asked to. This sobering fact suggests that some seemingly unconscious patients may be aware and possibly capable of significant participation in rehabilitation and communication with the support of appropriate technology.

“Just knowing that a patient has this ability to respond cognitively is a game changer in terms of the degree of engagement of caregivers and family members, referrals for specialist rehabilitation and best interest discussions about the continuation of life sustaining treatments.”

̽��ֱ��researchers caution that care must be taken to ensure the findings are not misrepresented, pointing out, for example, that a negative fMRI/EEG result does not per se exclude cognitive motor dissociation as even some healthy volunteers do not show these responses.

Professor John Pickard, emeritus professorial Fellow of St Catharine's College, Cambridge, said: “Only positive results – in other words, where patients are able to perform complex cognitive processes – should be used to inform management of patients, which will require meticulous follow up involving specialist rehabilitation services.”

̽��ֱ��team is calling for a network of research platforms to be established in the UK to enable multicentre studies to examine mechanisms of recovery, develop easier methods of assessment than task-based fMRI/EEG, and to design novel interventions to enhance recovery including drugs, brain stimulation and brain-computer interfaces.

̽��ֱ��research reported here was primarily funded by the James S. McDonnell Foundation. ̽��ֱ��work in Cambridge was supported by the National Institute for Health and Care Research UK, MRC, Smith’s Charity, Evelyn Trust, CLAHRC ARC fellowship and the Stephen Erskine Fellowship (Queens’ College).

Reference
Bodien, YG et al. Cognitive Motor Dissociation in Disorders of Consciousness. NEJM; 14 Aug 2024; DOI: 10.1056/NEJMoa2400645

Adapted from a press release from Weill Cornell Medicine

Around one in four patients with severe brain injury who cannot move or speak – because they are in a prolonged coma, vegetative or minimally conscious state – is still able to perform complex mental tasks, a major international study has concluded in confirmation of much smaller previous studies.

When a patient has sustained a severe brain injury, there are very important, and often difficult, decisions to be made by doctors and family members about their care

Emmanuel Stamatakis

Witthaya Prasongsin (Getty Images)

Male patient in a hospital bed - stock image

Acknowledgements

̽��ֱ��multidisciplinary Cambridge Impaired Consciousness Research Group, led by Emeritus Professors John Pickard (Neurosurgery) & David Menon (Anaesthesia) and Drs Judith Allanson & Emmanuel A. Stamatakis (Lead, Cognition and Consciousness Imaging Group), started its research programme in 1997, partly in response to emerging concern over the misdiagnosis of the vegetative state. This pioneering work has only been possible by having access to the world class resources of the Wolfson Brain Imaging Centre, the NIHR/Wellcome Clinical Research Facility at Addenbrooke’s Hospital, the MRC Cognition and Brain Sciences Unit (Professors Barbara Wilson & Adrian Owen), the Royal Hospital for Neuro-disability (Putney) and the Central England Rehabilitation Unit (Royal Leamington Spa).

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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‘Ageing’ immune cell levels could predict how well we respond to vaccines

cjb250 — Tue, 27 Jun 2023 09:00:30 +0000

During the COVID-19 pandemic, it has become clear that some patients are better protected by vaccination than others. Many studies have shown that SARS-CoV-2 vaccines are less effective in people with weakened immune systems, but also that this effect is not uniform.

Vaccination involves priming the immune system to look for – and get rid of – invading pathogens, such as viruses and bacteria. In part, this involves stimulating the production of antibodies uniquely programmed to identify a particular invader. These antibodies are themselves produced by a type of immune cell known as a B cell.

One specific subset of B cells is known as age-associated B cells (ABCs). While, on average, less than one in 20 of a healthy individual’s B cells is an ABC, the proportion gradually increases as we get older. ̽��ֱ��reasons for this increase are not yet fully understood, but may include previous infections. Certain people with weakened immune systems accumulate ABCs still faster.

A team from the Medical Research Council (MRC) Toxicology Unit at the ̽��ֱ�� of Cambridge, led by Dr James Thaventhiran, examined ABCs from two very different patient groups – one comprised of people with an inherited condition that impairs the activity of their immune systems and a second group comprised of cancer patients taking immunotherapy drugs – as well as from healthy individuals.

Emily Horner, from Thaventhiran’s lab, explained the aim of this research: “By looking at patients’ B cells, we hoped to learn how we could stratify vulnerable patients – in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others.”

̽��ֱ��researchers measured the relative proportion of ABCs compared to healthy B cells, and used a technique known as single cell RNA sequencing to look in detail at the activity of cells. They also teamed up with Dr Nicholas Matheson, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease, to test how these factors influenced the ability of a vaccinated individual’s immune system to neutralise live SARS-CoV-2 virus.

Dr Juan Carlos Yam-Puc, also from the MRC Toxicology Unit, said: “What we found, much to our surprise, was that the age-associated B cells in these very different groups looked the same. ̽��ֱ��key difference was in the amount of these cells – the greater the proportion of ABCs in an individual’s blood, the less effective that individual was post-vaccination at neutralising the virus.”

This could help explain the variability seen within particular patient groups in responses to the vaccine: people with fewer ABCs are likely to respond better to vaccines.

Although the researchers examined ABCs in the context of responses to the SARS-CoV-2 vaccine, they believe that this phenomenon will almost certainly apply more widely, for example to the annual influenza vaccine.

Dr Pehuén Pereyra Gerber, who performed the experiments with live SARS-CoV-2 virus in Matheson’s lab, added: “Looking at blood levels of ABCs could tell us that person A should respond well to a vaccine, while person B might need a stronger vaccine or to be prioritised to receive a booster.”

Thaventhiran added: “Ultimately, this research could lead to the development of a clinical test to predict vaccine efficacy for immunodeficient patients, and for the population more generally.”

̽��ֱ��research was funded by the Medical Research Council, the Medical Research Foundation, and ̽��ֱ��Evelyn Trust.

Reference
Yam-Puc, JC et al. Age-Associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade. Nat Comms; 27 June 2023; DOI: 10.1038/s41467-023-38810-0

Cambridge scientists have identified a signature in the blood that could help predict how well an individual will respond to vaccines. ̽��ֱ��discovery, published today in Nature Communications, may explain why, even among vulnerable patient groups, some individuals have better responses to vaccines than others.

By looking at patients’ B cells, we hoped to learn how we could stratify vulnerable patients – in other words, work out whether some patients were at greater risk from infection, even after vaccination, than others

Emily Horner

Ed Us

Vaccination

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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̽��ֱ��off-patent drug that could protect us from future COVID-19 variants

cjb250 — Mon, 05 Dec 2022 16:00:00 +0000

Cambridge scientists have identified a drug that can be repurposed to prevent COVID-19 in research involving a unique mix of ‘mini-organs’, donor organs, animal studies and patients.

Lab-grown ‘mini brains’ hint at treatments for neurodegenerative diseases

cjb250 — Thu, 21 Oct 2021 15:00:41 +0000

A common form of motor neurone disease, amyotrophic lateral sclerosis, often overlaps with frontotemporal dementia (ALS/FTD) and can affect younger people, occurring mostly after the age of 40-45. These conditions cause devastating symptoms of muscle weakness with changes in memory, behaviour and personality. Being able to grow small organ-like models (organoids) of the brain allows the researchers to understand what happens at the earliest stages of ALS/FTD, long before symptoms begin to emerge, and to screen for potential drugs.

In general, organoids, often referred to as ‘mini organs’, are being used increasingly to model human biology and disease. At the ̽��ֱ�� of Cambridge alone, researchers use them to repair damaged livers, study SARS-CoV-2 infection of the lungs and model the early stages of pregnancy, among many other areas of research.

Typically, researchers take cells from a patient’s skin and reprogramme the cells back to their stem cell stage – a very early stage of development at which they have the potential to develop into most types of cell. These can then be grown in culture as 3D clusters that mimic particular elements of an organ. As many diseases are caused in part by defects in our DNA, this technique allows researchers to see how cellular changes – often associated with these genetic mutations – lead to disease.

Scientists at the John van Geest Centre for Brain Repair, ̽��ֱ�� of Cambridge, used stem cells derived from patients suffering from ALS/FTD to grow brain organoids that are roughly the size of a pea. These resemble parts of the human cerebral cortex in terms of their embryonic and fetal developmental milestones, 3D architecture, cell-type diversity and cell-cell interactions.

Although this is not the first time scientists have grown mini brains from patients with neurodegenerative diseases, most efforts have only been able to grow them for a relatively short time frame, representing a limited spectrum of dementia-related disorders. In findings published today in Nature Neuroscience, the Cambridge team reports growing these models for 240 days from stem cells harbouring the commonest genetic mutation in ALS/FTD, which was not previously possible – and in unpublished work the team has grown them for 340 days.

Dr András Lakatos, the senior author who led the research in Cambridge’s Department of Clinical Neurosciences, said: “Neurodegenerative diseases are very complex disorders that can affect many different cell types and how these cells interact at different times as the diseases progress.

“To come close to capturing this complexity, we need models that are more long-lived and replicate the composition of those human brain cell populations in which disturbances typically occur, and this is what our approach offers. Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell.”

While organoids are usually grown as balls of cells, first author Dr Kornélia Szebényi generated patient cell-derived organoid slice cultures in Dr Lakatos’ laboratory. This technique ensured that most cells within the model could receive the nutrients required to keep them alive.

Dr Szebényi said: “When the cells are clustered in larger spheres, those cells at the core may not receive sufficient nutrition, which may explain why previous attempts to grow organoids long term from patients’ cells have been difficult.”

Using this approach, Dr Szebényi and colleagues observed changes occurring in the cells of the organoids at a very early stage, including cell stress, damage to DNA and changes in how the DNA is transcribed into proteins. These changes affected those nerve cells and other brain cells known as astroglia, which orchestrate muscle movements and mental abilities.

“Although these initial disturbances were subtle, we were surprised at just how early changes occurred in our human model of ALS/FTD,” added Dr Lakatos. “This and other recent studies suggest that the damage may begin to accrue as soon as we are born. We will need more research to understand if this is in fact the case, or whether this process is brought forward in organoids by the artificial conditions in the dish.”

As well as being useful for understanding disease development, organoids can be a powerful tool for screening potential drugs to see which can prevent or slow disease progression. This is a crucial advantage of organoids, as animal models often do not show the typical disease-relevant changes, and sampling the human brain for this research would be unfeasible.

̽��ֱ��team showed that a drug, GSK2606414, was effective at relieving common cellular problems in ALS/FTD, including the accumulation of toxic proteins, cell stress and the loss of nerve cells, hence blocking one of the pathways that contributes to disease. Similar drugs that are more suitable as medications and approved for human use are now being tested in clinical trials for neurodegenerative diseases.

Dr Gabriel Balmus from the UK Dementia Research Institute at the ̽��ֱ�� of Cambridge, collaborating senior author, said: “By modelling some of the mechanisms that lead to DNA damage in nerve cells and showing how these can lead to various cell dysfunctions, we may also be able to identify further potential drug targets.”

Dr Lakatos added: “We currently have no very effective options for treating ALS/FTD, and while there is much more work to be done following our discovery, it at least offers hope that it may in time be possible to prevent or to slow down the disease process.

“It may also be possible in future to be able to take skin cells from a patient, reprogramme them to grow their ‘mini brain’ and test which unique combination of drugs best suits their disease.”

̽��ֱ��study was primarily funded by the Medical Research Council UK, Wellcome Trust and the Evelyn Trust.

Reference

Szebényi, K et al. Human ALS/FTD Brain Organoid Slice Cultures Display Distinct Early Astrocyte and Targetable Neuronal Pathology. Nature Neuroscience; 21 Oct 2021; DOI: 10.1038/s41593-021-00923-4

Cambridge researchers have developed ‘mini brains’ that allow them to study a fatal and untreatable neurological disorder causing paralysis and dementia – and for the first time have been able to grow these for almost a year.

Not only can we see what may happen early on in the disease – long before a patient might experience any symptoms – but we can also begin to see how the disturbances change over time in each cell

András Lakatos

Andras Lakatos

Mini brain organoids showing cortical-like structures

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Likelihood of severe and ‘long’ COVID may be established very early on following infection

cjb250 — Mon, 18 Jan 2021 12:39:36 +0000

Among the key findings, which have not yet been peer-reviewed, are:

Individuals who have asymptomatic or mild disease show a robust immune response early on during infection.
Patients requiring admission to hospital have impaired immune responses and systemic inflammation (that is, chronic inflammation that may affect several organs) from the time of symptom onset.
Persistent abnormalities in immune cells and a change in the body’s inflammatory response may contribute to ‘long COVID’.

̽��ֱ��immune response associated with COVID-19 is complex. Most people who get infected by SARS-CoV-2 mount a successful antiviral response, resulting in few if any symptoms. In a minority of patients, however, there is evidence that the immune system over-reacts, leading to a flood of immune cells (a ‘cytokine storm’) and to chronic inflammation and damage to multiple organs, often resulting in death.

To better understand the relationship between the immune response and COVID-19 symptoms, scientists at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, have been recruiting individuals who test positive for SARS-CoV-2 to the COVID-19 cohort of the NIHR BioResource. These individuals range from asymptomatic healthcare workers in whom the virus was detected on routine screening, through to patients requiring assisted ventilation. ̽��ֱ��team take blood samples from patients over several months, as well as continuing to measure their symptoms.

In research published today, the team analysed samples from 207 COVID-19 patients with a range of disease severities taken at regular interviews over three months following the onset of symptoms. They compared the samples against those taken from 45 healthy controls.

Because of the urgent need to share information relating to the pandemic, the researchers have published their report on MedRXiv. It has not yet been peer-reviewed.

Professor Ken Smith, senior co-author and Director of the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), said: “ ̽��ֱ��NIHR BioResource has allowed us to address two important questions regarding SARS-CoV-2. Firstly, how does the very early immune response in patients who recovered from disease with few or no symptoms, compare with those who experienced severe disease? And secondly, for those patients who experience severe disease, how rapidly does their immune system recover and how might this relate to ‘long COVID’?”

Listen to Professor Ken Smith discuss the findings with the Naked Scientists

̽��ֱ��team found evidence of an early, robust adaptive immune response in those infected individuals whose disease was asymptomatic or mildly symptomatic. An adaptive immune response is where the immune system identifies an infection and then produces T cells, B cells and antibodies specific to the virus to fight back. These individuals produced the immune components in larger numbers than patients with more severe COVID-19 managed, and within the first week of infection – after which these numbers rapidly returned to normal. There was no evidence in these individuals of systemic inflammation that can lead to damage in multiple organs.

In patients requiring admission to hospital, the early adaptive immune response was delayed, and profound abnormalities in a number of white cell subsets were present. Also present in the first blood sample taken from these patients was evidence of increased inflammation, something not seen in those with asymptomatic or mild disease. This suggests that an abnormal inflammatory component to the immune response is present even around the time of diagnosis in individuals who progress to severe disease.

̽��ֱ��team found that key molecular signatures produced in response to inflammation were present in patients admitted to hospital. They say that these signatures could potentially be used to predict the severity of a patient’s disease, as well as correlating with their risk of COVID-19 associated death.

Dr Paul Lyons, senior co-author, also from CITIID, said: “Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms. This finding could have major implications as to how the disease needs to be managed, as it suggests we need to begin treatment to stop the immune system causing damage very early on, and perhaps even pre-emptively in high risk groups screened and diagnosed before symptoms develop.”

̽��ֱ��researchers found no evidence of a relationship between viral load and progression to inflammatory disease. However, once inflammatory disease was established, viral load was associated with subsequent outcome.

̽��ֱ��study also provides clues to the biology underlying cases of ‘long COVID’ – where patients report experiencing symptoms of the disease, including fatigue, for several months after infection, even when they no longer test positive for SARS-CoV-2.

̽��ֱ��team found that profound alterations in many immune cell types often persisted for weeks or even months after SARS-CoV-2 infection, and these problems resolved themselves very differently depending on the type of immune cell. Some recover as systemic inflammation itself resolves, while others recover even in the face of persistent systemic inflammation. However, some cell populations remain markedly abnormal, or show only limited recovery, even after systemic inflammation has resolved and patients have been discharged from hospital.

Dr Laura Bergamaschi, the study’s first author, said: “It’s these populations of immune cells that still show abnormalities even when everything else seems to have resolved itself that might be of importance in long COVID. For some cell types, it may be that they are just slow to regenerate, but for others, including some types of T and B cells, it appears something is continuing to drive their activity. ̽��ֱ��more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of COVID-19.”

Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “ ̽��ֱ��NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”

̽��ֱ��research was supported by CVC Capital Partners, the Evelyn Trust, UK Research & Innovation COVID Immunology Consortium, Addenbrooke’s Charitable Trust, the NIHR Cambridge Biomedical Research Centre and Wellcome.

Reference
Bergamaschi, L et al. Early immune pathology and persistent dysregulation characterise severe COVID-19. MedRXiV; 15 Jan 2021; DOI: 10.1101/2021.01.11.20248765

New research provides important insights into the role played by the immune system in preventing – and in some cases increasing the severity of – COVID-19 symptoms in patients. It also finds clues to why some people experience ‘long COVID’.

Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest around the time that they begin to show symptoms

Paul Lyons

NIH Image Gallery

SARS-CoV-2 virus particles are shown emerging from the surface of cells cultured in the lab

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Evidence-based web tool aims to better inform and refine need for treatment in early prostate cancer

cjb250 — Tue, 12 Mar 2019 19:00:20 +0000

̽��ֱ��tool, PREDICT Prostate, launches today to coincide with publication in the journal PLOS Medicine of the research that underpins it. It brings together the latest evidence and mathematical models to give a personalised prognosis, which the researchers say will empower patients as they discuss treatment options with their consultant.

According to Cancer Research UK, there were 47,151 new cases of prostate cancer in 2015. Progression of the disease, which usually presents in later life, is very variable: in most cases, the disease progresses slowly and is not fatal. It is often said that more men die with prostate cancer than from it. However, it is still the case that in a significant number of men, the tumour will metastasise and spread to other organs, threatening their health.

When a patient is diagnosed with prostate cancer, they are currently classified as low, intermediate or high risk. Depending on the patient’s risk group, clinicians will recommend either an ‘active monitoring’ approach or treatment. Treatment options include radiotherapy or surgery and can have potentially significant side-effects, including erectile dysfunction and urinary incontinence.

However, evidence suggests that these classifications, which are in the current guidelines provided by the National Institute for Health and Care Excellence (NICE), are only 60-70% accurate. This means that many men may elect for treatment when it is not necessary. In fact, a recent study carried out in the UK showed that for early prostate cancer (low and intermediate risk), treatment is no more beneficial in terms of ten year survival compared to no treatment.

Cambridge researchers have already shown that it is possible to improve the accuracy of the NICE-endorsed model to more than 80% by stratifying patients into five rather than three groups. Their next challenge was to use this information to give a more individual prediction of outcome to patients at no extra cost. ̽��ֱ��result is PREDICT Prostate.

PREDICT Prostate takes routinely available information including PSA test results, the cancer grade and stage, the proportion of biopsies with cancerous cells, and details about the patient including his age and other illnesses. It then gives a 10-15 year survival estimate. Importantly, the tool also estimates how his chance of survival differs depending on whether he opts for monitoring or treatment, providing context of the likelihood of success of treatment and risk of side effects.

“As far as we are aware, this is the first personalised tool to give an overall survival estimate for men following a prostate cancer diagnosis,” says first author Dr David Thurtle, Academic Clinical Fellow in Urology at the ̽��ֱ�� of Cambridge and Addenbrooke’s Hospital, which is part of Cambridge ̽��ֱ�� Hospital NHS Foundation Trust (CUH).

“PREDICT Prostate is designed for men who are considering whether to choose to monitor or to opt for treatment. This is the choice that faces nearly half of all men who are diagnosed with prostate cancer. We hope it will provide a more accurate and objective estimate to help men reach an informed decision in discussion with their consultant.”

̽��ֱ��research was led by Dr Vincent Gnanapragasam, ̽��ֱ�� Lecturer and Honorary Consultant at CUH, and undertaken by Dr Thurtle, both of the Academic Urology Group in Cambridge, and in collaboration with Professor Paul Pharoah of the Department of Cancer Epidemiology.

“We believe this tool could significantly reduce the number of unnecessary – and potentially harmful – treatments that patients receive and save the NHS millions every year,” says Dr Gnanapragasam.

“This isn’t about rationing treatments – it’s about empowering patients and their clinicians to make decisions based on better evidence. In some cases, treatment will be the right option, but in many others, patients will want to weigh up the treatment benefits versus the risks of side effects. It will also show men who do need treatment a realistic estimate of their survival after treatment.”

Data from the National Prostate Cancer Audit has shown that rates of treatment for low risk prostate cancer vary across different hospitals between 2-25%. ‘Radical’ treatment – surgery or radiotherapy, for example – costs on average around £7,000 per patient and treating these men unnecessarily wastes considerable resources as well as causing significant side-effects.

Dr Thurtle and Dr Gnanapragasam have since carried out a randomised study of almost 200 prostate cancer specialists in which they gave some clinicians access to the tool and a series of patient vignettes, while others received the vignettes only. In most cases, the clinician overestimated the risk of the patient dying from the cancer, compared to the estimate given by PREDICT, going on to recommended treatment in many cases and overestimate how successful this treatment would be. When given access to the tool, the clinicians were less likely to recommend treatment in good prognosis cancers.

Dr Gnanapragasam says that the development of PREDICT Prostate has only been possible because of the intactness of records available through Public Health England – the tool was developed using data from over 10,000 UK men recorded in the East of England. This regional registry, he says, is one of the highest quality and most comprehensive data sets available both in the UK and internationally. ̽��ֱ��data was then validated externally in a sample of 2,500 prostate cancer patients in Singapore. ̽��ֱ��web tool was developed in collaboration with the Winton Centre for Risk and Evidence Communication

̽��ֱ��researchers caution that the tool is strongly recommended for use only in consultation with a clinician. It is also not suitable for men with very aggressive disease or who have evidence of disease spread at the time of diagnosis.

̽��ֱ��research was funded by the Evelyn Trust and the Urology Foundation.

Reference
Thurtle, DR et al. Individual prognosis at diagnosis in non-metastatic prostate cancer: Development and external validation of the PREDICT Prostate multivariable model. PLOS Medicine; 12 March 2019; DOI: 10.1371/journal.pmed.1002758

Making prostate biopsies safer

Dr Gnanapragasam recently announced the start of clinical trials of CamProbe, a device to make prostate biopsies safer.

̽��ֱ��current method to retrieve samples from the prostate uses a transrectal ultrasound probe inserted into the anus to allow the biopsy to be taken. Patients who undergo this procedure are at risk of urinary infections or sepsis as the needle has to pass through the bowel wall to reach the prostate. Around 30-40,000 prostate biopsies are done every year using this method in the UK alone.

̽��ֱ��CamProbe, invented and developed in Cambridge, has been designed so the biopsies can be taken more safely through the skin under the scrotum (transperineal) and avoid the bowel.

“ ̽��ֱ��design of the CamProbe is a needle within a needle and allows us to collect tissue from the prostate through a more sterile part of the body,” says Dr Gnanapragasam, who co-leads the Urological Malignancies Programme at the CRUK Cambridge Centre.

“Most importantly it can be done under local anaesthetic in the out-patient department. Previously this kind of approach was only possible if a general anaesthetic was used with very significant additional costs.”

̽��ֱ��trial for the CamProbe is now underway using funding from the National Institute for Health Research (NIHR). It will run for a year at several hospitals around the UK including at the Cambridge Clinical Research Centre. If the trial is successful, the CamProbe could be adopted into mainstream use within two years.

“Our goal is to show that the CamProbe is a simple alternative for taking prostate biopsies which eliminates infection risks to patients and drastically reduces the need for antibiotics,” added Dr Gnanapragasam. “Its simplicity also means it will be a very low-cost device, and, in addition to reducing infections, the need for antibiotics and sepsis related admissions, could potentially save the NHS an estimated £7-11 million pounds every year.”

A new tool to predict an individual’s prognosis following a prostate cancer diagnosis could help prevent unnecessary treatment and related side effects, say researchers at the ̽��ֱ�� of Cambridge.

We believe this tool could significantly reduce the number of unnecessary – and potentially harmful – treatments that patients receive and save the NHS millions every year

Vincent Gnanapragasam

PREDICT Prostate

Researcher profile: Dr David Thurtle

Dr David Thurtle a clinician at Addenbrooke’s, Cambridge ̽��ֱ�� Hospitals, has spent the past two years pursuing a research doctorate in prostate cancer. As he comes to the end of his studies, he is preparing to return to focusing on his clinical work.

“I never see myself straying far from clinical practice,” he says, “but I hope to maintain research interests throughout my career to challenge and improve upon best practice, stretch myself and ensure I’m always up to date for the sake of my patients.”

It was during his final months at medical school at Nottingham ̽��ֱ�� when he carried out a four week placement in the urology department that David realised he wanted a career in this field. With its mix of medicine and surgery, utilisation of technology such as lasers and robots, and treatment of conditions that have profound impacts on patients’ quality and length of life “Urology has it all!” he says.

Since starting an Academic Clinical Fellowship in Cambridge in 2014, he has worked on a range of clinical prostate cancer related topics, collaborating with radiologists, engineers and epidemiologists amongst many others. “I love the daily interaction and satisfaction of clinical medicine and have always sought out research projects that are ‘close to the coal-face’ of clinical work.”

David’s research sets out to inform both patients and doctors about the long term survival outcomes for men diagnosed with localised prostate cancer.

“Prostate cancer has many different guises – some cases are indolent and may never impact upon a patient’s length of life, while others can rapidly metastasise causing significant problems and shortening life. So, management decisions are not as straight-forward as in some other cancers.”

Although treatments are improving, they each carry risks, so his work seeks to provide patients with as much information as possible about their cancer, and help contextualise it against their age and health otherwise.

“Men may have gross misconceptions about the outcomes from prostate cancer, and clinicians may have understandable biases towards certain treatments,” he says. “Our work seeks to ‘switch on the light’ and provide accurate, unbiased estimates of what benefit treatment might offer so that men can make informed decisions based on their own priorities.”

A strong track-record of prostate cancer research and world-renowned academics in cancer epidemiology make Cambridge the ideal place for David and colleagues to carry out their research. “Cambridge has an openness in collaboration that I have not seen elsewhere, with clinicians and academics from disparate disciplines keen to work together - and easy to work with.”

There is also another, perhaps unexpected, reason to enjoy the Cambridge environment. “Cambridge also has a distinct lack of hills which makes for far more enjoyable running and cycling – so much so that I’ve taken up triathlons!”

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Many cases of dementia may arise from non-inherited DNA ‘spelling mistakes’

cjb250 — Mon, 15 Oct 2018 09:00:25 +0000

̽��ֱ��findings suggest that for many people with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, the roots of their condition will trace back to their time as an embryo developing in the womb.

In common neurodegenerative diseases, toxic proteins build up in the brain, destroying brain cells and damaging brain regions, leading to symptoms including personality changes, memory loss and loss of control. Only around one in twenty patients has a family history, where genetic variants inherited from one or both parents contributes to disease risk. ̽��ֱ��cause of the majority of cases – which are thought to affect as many as one in ten people in the developed world – has remained a mystery.

A team of researchers led by Professor Patrick Chinnery from the Medical Research Council (MRC) Mitochondrial Biology Unit and the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge hypothesised that clusters of brain cells containing spontaneous genetic errors could lead to the production of misfolded proteins with the potential to spread throughout the brain, eventually leading to neurodegenerative disease.

“As the global population ages, we’re seeing increasing numbers of people affected by diseases such as Alzheimer’s, yet we still don’t understand enough about the majority of these cases,” says Professor Chinnery. “Why do some people get these diseases while others don’t? We know genetics plays a part, but why do people with no family history develop the disease?”

To test their hypothesis, the researchers examined 173 tissue samples from the Newcastle Brain Tissue Resource, part of the MRC’s UK Brain Banks Network. ̽��ֱ��samples came from 54 individual brains: 14 healthy individuals, 20 patients with Alzheimer’s and 20 patients with Lewy body dementia, a common type of dementia estimated to affect more than 100,000 people in the UK.

̽��ֱ��team used a new technique that allowed them to sequence 102 genes in the brain cells over 5,000 times. These included genes known to cause or predispose to common neurodegenerative diseases. They found ‘somatic mutations’ (spontaneous, rather than inherited, errors in DNA) in 27 out of the 54 brains, including both healthy and diseased brains.

Together, these findings suggest that the mutations would have arisen during the developmental phase – when the brain is still growing and changing – and the embryo is growing in the womb.

Combining their results with mathematical modelling, their findings suggest that ‘islands’ of brain cells containing these potentially important mutations are likely to be common in the general population.

“These spelling errors arise in our DNA as cells divide, and could explain why so many people develop diseases such as dementia when the individual has no family history,” says Professor Chinnery. “These mutations likely form when our brain develops before birth – in other words, they are sat there waiting to cause problems when we are older.”

“Our discovery may also explain why no two cases of Alzheimer’s or Parkinson’s are the same. Errors in the DNA in different patterns of brain cells may manifest as subtly different symptoms.”

Professor Chinnery says that further research is needed to confirm whether the mutations are more common in patients with dementia. While it is too early to say whether this research will aid diagnosis or treatment this endorses the approach of pharmaceutical companies who are trying to develop new treatments for rare genetic forms of neurodegenerative diseases.

“ ̽��ֱ��question is: how relevant are these treatments going to be for the ‘common-or-garden’ variety without a family history? Our data suggests the same genetic mechanisms could be responsible in non-inherited forms of these diseases, so these patients may benefit from the treatments being developed for the rare genetic forms.”

̽��ֱ��research was funded by Wellcome, the Evelyn Trust, Medical Research Council, and the National Institute for Health Research Cambridge Biomedical Research Centre.

Reference
Keogh, MJ, Wei, W et al. High prevalence of focal and multi-focal somatic genetic variants in the human brain. Nature Comms; 15 Oct 2018; DOI: 10.1038/s41467-018-06331-w

Only a small proportion of cases of dementia are thought to be inherited – the cause of the vast majority is unknown. Now, in a study published today in the journal Nature Communications, a team of scientists led by researchers at the ̽��ֱ�� of Cambridge believe they may have found an explanation: spontaneous errors in our DNA that arise as cells divide and replicate.

Why do some people get these diseases while others don’t? We know genetics plays a part, but why do people with no family history develop the disease?

Patrick Chinnery

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Public Domain

Study in mice suggests personalised stem cell treatment may offer relief for progressive MS

cjb250 — Thu, 22 Feb 2018 17:00:03 +0000

̽��ֱ��study, led by researchers at the ̽��ֱ�� of Cambridge, is a step towards developing personalised treatments based on a patient’s own skin cells for diseases of the central nervous system (CNS).

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord. Symptoms are unpredictable and include problems with mobility and balance, pain, and severe fatigue.

Key immune cells involved in causing this damage are macrophages (literally ‘big eaters’), which ordinarily serve to attack and rid the body of unwanted intruders. A particular type of macrophage known as microglia are found throughout the brain and spinal cord – in progressive forms of MS, they attack the CNS, causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that diseases of the CNS may be improved by the use of stem cell therapies. Stem cells are the body’s ‘master cells’, which can develop into almost any type of cell within the body. Previous work from the Cambridge team has shown that transplanting neural stem cells (NSCs) – stem cells that are part-way to developing into nerve cells – reduces inflammation and can help the injured CNS heal.

However, even if such a therapy could be developed, it would be hindered by the fact that such NSCs are sourced from embryos and therefore cannot be obtained in large enough quantities. Also, there is a risk that the body will see them as an alien invader, triggering an immune response to destroy them.

A possible solution to this problem would be the use of so-called ‘induced neural stem cells (iNSCs)’ – these cells can be generated by taking an adult’s skin cells and ‘re-programming’ them back to become neural stem cells. As these iNSCs would be the patient’s own, they are less likely to trigger an immune response.

Now, in research published in the journal Cell Stem Cell, researchers at the ̽��ֱ�� of Cambridge have shown that iNSCs may be a viable option to repairing some of the damage caused by MS.

Using mice that had been manipulated to develop MS, the researchers discovered that chronic MS leads to significantly increased levels of succinate, a small metabolite that sends signals to macrophages and microglia, tricking them into causing inflammation, but only in cerebrospinal fluid, not in the peripheral blood.

Transplanting NSCs and iNSCs directly into the cerebrospinal fluid reduces the amount of succinate, reprogramming the macrophages and microglia – in essence, turning ‘bad’ immune cells ‘good’. This leads to a decrease in inflammation and subsequent secondary damage to the brain and spinal cord.

“Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS,” says Dr Stefano Pluchino, lead author of the study from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge.

“This is particularly promising as these cells should be more readily obtainable than conventional neural stem cells and would not carry the risk of an adverse immune response.”

̽��ֱ��research team was led by Dr Pluchino, together with Dr Christian Frezza from the MRC Cancer Unit at the ̽��ֱ�� of Cambridge, and brought together researchers from several university departments.

Dr Luca Peruzzotti-Jametti, the first author of the study and a Wellcome Trust Research Training Fellow, says: “We made this discovery by bringing together researchers from diverse fields including regenerative medicine, cancer, mitochondrial biology, inflammation and stroke and cellular reprogramming. Without this multidisciplinary collaboration, many of these insights would not have been possible."

̽��ֱ��research was funded by Wellcome, European Research Council, Medical Research Council, Italian Multiple Sclerosis Association, Congressionally-Directed Medical Research Programs, the Evelyn Trust and the Bascule Charitable Trust.

Reference
Peruzzotti-Jametti, L et al. Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation. Cell Stem Cell; 2018; 22: 1-14; DOI: 10.1016/j.stem.2018.01.20

Scientists have shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, help reduce inflammation and may be able to help repair damage caused by multiple sclerosis (MS).

Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS

Luca Peruzzotti-Jametti

Andrew c

Neuron with oligodendrocyte and myelin sheath (edited)

Researcher profile: Dr Luca Peruzzotti-Jametti

It isn’t every day that you find yourself invited to play croquet with a Nobel laureate, but then Cambridge isn’t every university, as Dr Luca Peruzzotti-Jametti discovered when he was fortunate enough to be invited to the house of Professor Sir John Gurdon.

“It was an honour meet a Nobel laureate who has influenced so much my studies and meet the man behind the science,” he says. “I was moved by how kind he is and extremely impressed by his endless passion for science.”

Dr Peruzzotti-Jametti began his career studying medicine at the ̽��ֱ�� Vita-Salute San Raffaele, Milan. His career took him across Europe, to Switzerland, Denmark, Sweden and now to Cambridge. After completing a PhD in Clinical Neurosciences here he is now a Wellcome Trust Research Training fellow.

His work focuses on multiple sclerosis (MS), an autoimmune disease that affects around 100,000 people in the UK alone. Despite having several therapies to help during the initial (or ‘relapsing remitting’) phase of MS, the majority of people with MS will develop a chronic worsening of disability within 15 years after diagnosis. This late form of MS is called secondary progressive, and differently from relapsing remitting MS, it does not have any effective treatment.

“My research sets out to understand how progression works in MS by studying how inflammation is maintained in the brains of patients, and to develop new treatments aimed at preventing disease progression,” he explains. Among his approaches is the use of neural stem cells and induced neural stem cells, as in the above study. “My hope is that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS.”

Dr Peruzzotti-Jametti is based on the Cambridge Biomedical Campus where he works closely with clinicians at Addenbrooke’s Hospital and with basic scientists, a community he describes as “vibrant”.

“Cambridge has been the best place to do my research due to the incredible concentration of scientists who pursue novel therapeutic approaches using cutting-edge technologies,” he says. “I am very thankful for the support I received in the past years from top notch scientists. Being in Cambridge has also helped me competing for major funding sources and my work could have not been possible without the support of the Wellcome Trust.

“I wish to continue working in this exceptional environment where so many minds and efforts are put together in a joint cause for the benefit of those who suffer.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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