Patients with gout are at increased risk of chronic kidney disease and kidney failure, according to recent University of Limerick-led…
Ms Laura O’Connor, Research Co-ordinator (RLA projects), highlights the work of the Centre for Pain Research, based in NUI Galway…
An overview of emerging strategies and new Irish research on lung cancer treatments
Dr Alex J Eustace gives an overview of the 11th International Symposium on Translational Research in Oncology, which took place in Dublin recently
COPD patients suffered fewer respiratory-related problems when treated with targeted lung denervation, phase 2 study results show
Global prevalence of rosacea higher than previously thought, study finds
An estimated 5.46 per cent of the population worldwide is affected by rosacea, with predominance at the age of 45-to-60 years, according to a new systematic review and meta-analysis of published data.
No significant difference between men and women and no significant association between higher prevalence and latitude were observed in the study, published in the British Journal of Dermatology this summer.
The authors of the study, a group of researchers of the University of Copenhagen, Denmark, selected 32 studies from three databases, namely PubMed, Embase and Web of Sciences, examining 32 studies of 41 populations and a total of 26,519,836 individuals.
Twenty-two populations were from Europe, three from Africa, four from Asia, nine from North America and three from South America. The pooled proportion of individuals with rosacea was 5.46 per cent in the general population and 2.39 per cent among dermatological outpatients.
A substantial difference was observed between self-reported rosacea (9.71 per cent) and dermatologist-diagnosed (5.53 per cent) rosacea, suggesting a low specificity of questionnaires based on symptoms.
Rosacea affected both women (5.41 per cent) and men (3.9 per cent), and mostly those aged 45-to-60 years.
No significant association was observed between higher prevalence of rosacea and latitude.
Presence of Demodex mite higher in people with rosacea
Patients with rosacea were significantly more likely than controls to have Demodex mite infestation, according to findings from a study published in the Journal of the American Academy of Dermatology.
The evidence-based meta-analysis of the prevalence and degrees of Demodex mite infestation in patients with rosacea included 1,513 patients from 23 case-control studies.
Patients in the rosacea group were more than nine times more likely to have Demodex mites than controls. Density of Demodex mites was also significantly greater in the rosacea group compared with controls.
Subtype analysis results indicated that Demodex mite density was significantly greater in both erythematotelangiectatic rosacea (standardised mean difference = 2.686) and papulopustular rosacea (standardised mean difference = 2.804), compared with controls.
Other key findings indicated that Demodex mites occurred in 70.4 per cent (range 33.3-to-100 per cent) of patients with rosacea and 31.8 per cent (range 3.8-96 per cent) of controls.
In the rosacea group, the mean density of mites was 71 mites/ cm2 (range 1.9-376.8 mites/cm2), while the density was 8.7 mites/cm2 (range 0.06-89.6 mites/cm2) among controls.
Limitations of the study included that the inter-study variability was high, and a causal relationship could not be established by case-control studies.
“Patients with rosacea had significantly higher prevalence and degrees of Demodex mite infestation than did control patients. Demodex mites may play a role in both erythematotelangiectatic rosacea and papulopustular rosacea,” the researchers concluded.
Separately, a recent Indian study found that rosacea was found to be a statistically significant risk factor for Demodex infestation in eyelashes, irrespective of age and sex, with a higher prevalence in papulopustular variety.
The comparative, open, observational, and cross-sectional study included 41 patients diagnosed with rosacea and 41 referents without rosacea diagnosis or ophthalmic alterations. The individuals underwent a slit-lamp examination in which two eyelashes per eyelid were removed with fine forceps.
Of the 41 patients with rosacea, 31 had erythematotelangiectatic rosacea and 10 had papulopustular rosacea.
The presence of Demodex was found in 32 patients: 24 patients with rosacea diagnosis (16 of the erythematotelangiectatic subtype and eight of papulopustular subtype); and eight patients without rosacea or ophthalmic alterations (P ≤0.001).
It is now accepted that the presence of Demodex mites plays an important role in rosacea aetiopathogenesis. Demodex mite treatment may reduce the severity of the disease and slow its progressive nature.
Rosacea linked to a slightly increased risk of dementia
A new study has uncovered an increased risk of dementia —in particular, Alzheimer’s disease — in patients with rosacea. Importantly, the risk was highest in older patients and in patients where rosacea was diagnosed by a hospital dermatologist. The findings are published in the Annals of Neurology, a journal of the American Neurological Association and Child Neurology Society.
Rosacea, a common chronic inflammatory skin disorder, is characterised by elevated expression of certain proteins —including matrix metalloproteinases and antimicrobial peptides — that are also involved in various neurodegenerative disorders, such as Alzheimer’s disease and other forms of dementia.
A team led by Dr Alexander Egeberg, University of Copenhagen, investigated the association between rosacea and dementia in Danish registers. There were 5,591,718 Danish citizens aged ≥18 between 1997 to 2012, including 82,439 patients with rosacea. Individuals were followed until December 31, 2012; migration, a diagnosis of dementia, or death from any cause, whichever came first. A total of 99,040 individuals developed dementia, of whom 29,193 were diagnosed with Alzheimer’s disease. After adjustments for potential confounding factors, patients with rosacea had a 7 per cent increased risk of dementia and a 25 per cent increased risk of Alzheimer’s disease compared with individuals without rosacea. Stratified by sex, women had a 28 per cent increased risk of Alzheimer’s disease and men had a 16 per cent increased risk if they had rosacea. When results were stratified by age at study entry, the risk of Alzheimer’s disease was only significantly increased in individuals ≥60 years (who had a 20 per cent increased risk). When analyses were limited to patients with a hospital dermatologist diagnosis of rosacea only, the increased risks of dementia and Alzheimer’s disease were 42 per cent and 92 per cent, respectively.
“A subtype of patients have prominent neurological symptoms, such as burning and stinging pain in the skin, migraines, and neuropsychiatric symptoms, suggesting a link between rosacea and neurological diseases,” explained Dr Egeberg. “Indeed, emerging evidence suggests that rosacea may be linked with neurological disorders, including Parkinson’s disease and now also Alzheimer’s disease. There are certain mechanistic overlaps between rosacea and Alzheimer’s disease that may explain the observed association, albeit the pathogenic links between these conditions are still unclear.”
Further research is warranted to examine whether treating rosacea may also modify patients’ risk of developing dementia, he said.
New standard classification and pathophysiology of rosacea published
A new standard classification and pathophysiology of rosacea has been published in the Journal of the American Academy of Dermatology. Developed by a consensus committee and review panel of 28 rosacea experts worldwide, the updated system is based on the substantial advances in the understanding of rosacea gained through scientific investigations over the last 15 years.
“There has been an explosion of research on rosacea since the first standard classification system appeared in 2002, and that has resulted in a much deeper scientific understanding of this common but once little-known disorder,” said Dr Richard Gallo, Chairman of Dermatology, University of California-San Diego.
“Growing knowledge of rosacea’s pathophysiology has established that a consistent multivariate disease process underlies its various clinical manifestations, which may also potentially be associated with other systemic disorders.”
Although the cause of rosacea remains unknown, researchers have now identified major elements of the disease process that may lead to significant advances in its treatment. Recent studies have shown that the initial redness is likely to be the start of an inflammatory continuum initiated by a combination of neurovascular dysregulation and the innate immune system.
While the original classification system designated the most common groupings of primary and secondary features as subtypes, the committee noted that because rosacea appears to encompass a consistent inflammatory continuum; it now seems appropriate to focus on the individual characteristics (phenotypes) that may result from this disease process.
Observing the respective phenotypes in clinical practice will also encourage consideration of the full range of potential signs and symptoms that may occur in any individual patient, and assessment of severity and the selection of treatment may be more precisely tailored to each individual, the committee believes.
According to the new system, the presence of one of two phenotypes — persistent redness of the facial skin or, less commonly, phymatous changes where the facial skin thickens — is considered diagnostic of rosacea. Additional major cutaneous signs, which often appear with the diagnostic features, include papules and pustules, flushing, telangiectasia and certain ocular manifestations. The presence of two or more major phenotypes independent of the diagnostic features is also considered diagnostic of rosacea. Secondary phenotypes, which must appear with one or more diagnostic or major phenotypes, include burning or stinging, swelling and dry appearance.
Signs suggestive of ocular rosacea include telangiectasias on the eyelid margin and bloodshot eyes, as well as inflammation and growth of fibrous tissue on the eye. Burning, stinging, light sensitivity and the sensation of a foreign object may also occur, as well as conjunctivitis, inflammation of oil glands at the rim of the eyelids (blepharitis) and crusty accumulations at the base of the eyelashes, in addition to others.
“Although rosacea’s various phenotypes may appear in different combinations and at different times, research suggests that all are manifestations of the same underlying disease process, and that rosacea may progress not only in severity but to include additional phenotypes,” Dr Gallo said.
The committee also acknowledged the psychosocial effects of rosacea, noting that multiple patient surveys have documented rosacea’s substantial adverse impact on emotional, social and occupational well-being. They stressed that this should also be an important consideration, and suggested the development of appropriate severity scales to measure this dimension, as well as the need for further research to adequately assess rosacea’s negative effects.
In an accompanying commentary on rosacea comorbidities and future research, the committee summarised the many recent studies that have found associations between rosacea and increased risk for a growing number of potentially serious systemic disorders. These include cardiovascular disease, gastrointestinal disease, neurological and autoimmune diseases and certain cancers. Although causal relationships have not been determined, the committee noted these findings may significantly increase the clinical significance of rosacea as evidence that the disorder may be an outcome of systemic inflammation continues to mount.
In addition to comorbidities, they identified a number of areas where further research may be of particular value. Recent evidence suggests rosacea may appear often in individuals with darker skin types, and the updated standard criteria can be used to determine its prevalence in various ethnicities as well as populations worldwide. In addition, recent studies have found genetic factors that might affect the disease and may also be used to identify potential further comorbidities. Data also suggest that the skin microbiome may play a role.
The committee noted that, as with the original classification of rosacea, the updated standard system is considered provisional and may require modification as the causes and pathogenesis of rosacea become clearer, and its relevance and applicability are tested by investigators and clinicians.
Ketamine has potential therapeutic role in adolescents with treatment-resistant depression…
Time is a concept understood only by humans apparently. Very few creatures in the animal world have much concept of yesterday or tomorrow. In the medical profession, we certainly understand the concept of time. Time heals. Time left. Time in theatre. Time out. The list goes on.
In the field of ophthalmology, time passes more quickly given the pace of innovation.
I want to share the concept of time and how it changes the management of common conditions over a short period, perhaps 15 years or less.
Take the case of a patient with progressive keratoconus (steepening of the cornea resulting in irregular astigmatism and reduced quality of vision) who also has a cataract that requires surgery. Three eras, within the timeframe of less than 15 years, provide fascinatingly different approaches and outcomes.
Keratoconus treatment: pre-2007
Before 2007 there was no treatment for progressive keratoconus in Ireland until corneal cross-linking (CXL) was introduced in January 2007, the same month that CXL was approved in the EU.
The keratoconus aspect was previously managed either by rigid contact lenses and if the steepening progressed, by means of a corneal transplant. The cataract was removed using phaco-emulsification of the cataract (breaking the natural lens up into small pieces that can be aspirated through a tiny, sutureless incision, using ultrasound) and replacing it with an intraocular lens (IOL). A challenge in this case would also be the calculation of the IOL power required. When replacing the natural lens, the surgeon has it within his or her power, to select an IOL of the appropriate power to improve the patient’s vision without the use of spectacles. IOL power calculation is notoriously difficult, even today, in these aberrated corneas and getting the IOL power right was a particularly difficult issue.
Furthermore, the diagnosis was very much a clinical diagnosis and there was not much objective validation of the corneal contribution versus the lens contribution to the reduced vision.
Keratoconus treatment: 2007 to present day
From 2007 to the present day CXL has changed the way that we manage keratoconus completely. Back in 1994, I was doing more than 50 corneal transplants per year, that number now is so small, that I no longer do corneal grafts. I refer them to someone that is still doing a reasonable number. This is all thanks to CXL. This procedure strengthens the cornea and, in some cases, even improves the corneal shape thereby improving the quality of vision. CXL was traditionally performed by removing the corneal epithelium, hence leading to a healing phase of the epithelium. For the past six years we are performing 90 per cent of our CXL procedures without removing the corneal epithelium, making the procedure safer, allowing less time off work with much less morbidity.
Combining the procedure with topography-guided photo-refractive keratectomy (TG-PRK) has also allowed the regularisation of the cornea before the improved corneal shape is stabilised by the CXL. This leads to improved corneal optics and simpler and more accurate IOL power calculations for the IOL to be selected. The only IOL in these aberrated corneas that could be contemplated was a monofocal (single focal power) IOL. More recently, we are implanting pinhole optic IOLs (the IC-8 IOL from AcuFocus) in these eyes and the results are outstanding, with the pinhole reducing much of the corneal higher order aberrations that lead to starburst, halos and glare. The pinhole IOL is also more forgiving in terms of refractive accuracy due to the increased depth of focus provided by the pinhole.
Patient undergoing CXL treatment
The diagnosis has become more objective too with devices like the iTrace and the HD Analyzer being able to illustrate the optical contribution from the cornea and from the cataract, making it simpler to plan surgery. Should the cataract be treated first, or should the cornea be treated first? Could they be treated at the same surgical procedure?
Today and the near future
Corneal regularisation may soon be achieved by tissue addition rather than tissue subtraction as we currently do (excimer laser ablation by means of photo refractive keratectomy (PRK)). Allotex Ltd is a company providing excimer laser shaped human corneal lenticules for refractive use. This allows tissue with 0.25-micron accuracy to be used for corneal addition procedures. Clinical trials, expected to commence in Q3 of this year in eight European sites including the Wellington Eye Clinic in Dublin for presbyopia and hyperopia, are expected to prove the value of this technique for regular corneas and lay the foundation for the use of allograft onlays and inlays for keratoconic corneas. As corneal surgeons, adding thickness to a keratoconic cornea resonates well. With improved corneal regularity, IOL power calculations become more predictable.
However, with keratoconus the posterior corneal surface can also be distorted and current IOL power formulae do not account for this. Refractive surprises are therefore not uncommon. This is where the RxSight Light Adjustable Lens (RxLAL) may play a significant role in improving outcomes. We are currently enrolling eyes in a four-site European study on using this IOL that can be adjusted using UV light after it has been implanted in the eye and allowed time to settle into its final effective lens position (ELP). ELP has always been blamed for missing refractive targets as we have found it challenging to predict the healing and contraction of the capsular bag and its effect on the final IOL position within the eye. With the RxLAL, this no longer matters. Once the IOL has stabilised within the eye, the IOL power is adjusted using a light delivery device (LDD) that can change the power of the IOL to achieve a desired refractive outcome. Incredibly, early results show the accuracy and predictability even supersede that of LASIK. The IOL power can be adjusted up to three times and then ‘locked-in’ with a final treatment after which no further adjustments can occur.
This case study shows how in the relatively short time-frame, that something regarded as radical and innovative only 11 years ago, has evolved in a short time to be potentially replaced by fundamentally different approaches that have led to increased safety, increased predictability and ultimately, increased patient satisfaction.
In the interests of brevity certain further innovations were deliberately omitted, but it is worthwhile mentioning that femtosecond laser innovation is set to further disrupt the current cataract techniques where phaco is used. Within the next 12 months we are commencing a clinical trial where phaco is no longer required following femtosecond laser fragmentation of the cataract.
New drugs are in the pipeline whereby retinal dosages of some pharmacologic agents can be achieved with topical application of drops rather than intravitreal injections.
Innovation is alive and well and ophthalmology has proven to be a fitting partner for our engineering and physics PhD colleagues to apply their considerable talents. It would be wonderful, however, if time could slow down just a tad.
Major study shows prostate MRI reduces cancer over-diagnosis compared to standard biopsy
A large international study has shown that an MRI scan can reduce the number of invasive prostate biopsies by up to 28 per cent. The PRECISION trial shows that using MRI to target prostate biopsies leads to more of the harmful prostate cancers, and fewer harmless cancers, being diagnosed. Given that more than a million men in Europe undergo a prostate biopsy every year, the authors believe that this work could change clinical practice. The results were presented at the 2018 EAU Congress in Copenhagen, with simultaneous publication in the New England Journal of Medicine.
Dr Veeru Kasivisvanathan of University College London, UK, and first author of the study, said: “PRECISION is the first international, multi-centre, randomised trial to show the benefits of using MRI at the start of the prostate cancer diagnosis process.
“In men who need to have investigation for prostate cancer for the first time, PRECISION shows that using an MRI to identify suspected cancer in the prostate and performing a prostate biopsy targeted to the MRI information leads to more cancers being diagnosed than the standard way that we have been performing prostate biopsy for the last 25 years.”
Dr Caroline Moore, Reader in Urology at University College London and senior author of the study, commented: “We compared standard prostate biopsy to the use of MRI, offering targeted biopsies to only those men who had a suspicious MRI. The MRI pathway detected more harmful cancers that needed treatment and it reduced over-diagnosis of harmless cancers, even though fewer men had a biopsy in the MRI arm.”
Under the PRECISION study, researchers from 23 centres randomly allocated 500 men to be examined, either with a standard 10-to-12 core TRUS (TRansrectal UltraSound guided prostate biopsy), or with an initial MRI scan, followed by a targeted biopsy if the MRI showed an abnormality. The main aim was to assess what proportion of men were diagnosed with clinically significant prostate cancer (defined as a Gleason Grade of ≥3+4).
It also aimed to assess the proportion of men who were diagnosed with clinically insignificant cancer (Gleason Grade 3+3).
The researchers found that 71 (28 per cent) of the 252 men in the MRI arm of the study avoided the need for a subsequent biopsy. Of those who needed a biopsy, the researchers detected clinically significant cancer in 95 (38 per cent) of the 252 men, compared with 64 (26 per cent) of the 248 men who received only the TRUS biopsy.
“This shows that a diagnostic pathway with initial MRI assessment, followed by biopsy when required, can not only reduce the overall number of biopsies performed, but can give more accurate results than TRUS-biopsy alone. We also found that patients who had MRI had fewer side-effects than those who just had the standard TRUS biopsy. This is because the MRI allows some men to avoid biopsy and in those who need one, is able to better indicate which area of the prostate needs to be investigated, so you don’t need to randomly sample the whole prostate and can use fewer biopsy cores,” said Dr Kasivisvanathan.
Several elements need to be considered for MRI to be generally adopted in the diagnostic process. As Dr Kasivisvanathan, who was awarded a National Institute for Health and Research Doctoral Fellowship to carry out the study, said: “The ability to perform good-quality MRI and the ability to interpret the MRI information are specialist skills. We will therefore need appropriate training for clinicians to use the technology and changes in health services to increase availability and capacity to perform prostate MRI. In the long term, this new diagnostic pathway can be cost-effective. Costs can be saved by the reduction in the number of men undergoing biopsy in the first place, by the earlier diagnosis of harmful cancers, and in the avoidance of the diagnosis of harmless cancers.”
Prostate cancer is the most common male cancer, with around 400,000 new cases confirmed every year in Europe.
Smart software can diagnose prostate cancer as well as a pathologist
Chinese scientists and clinicians have developed a learning artificial intelligence (AI) system that can diagnose and identify cancerous prostate samples as accurately as any pathologist, the 2018 EAU Congress in Copenhagen heard. In addition, the software can accurately classify the level of malignancy of the cancer, so eliminating the variability that can creep into human diagnosis.
This holds the possibility of streamlining and eliminating variation in the process of cancer diagnosis. It may also help overcome any local shortage of trained pathologists. In the longer term, it may lead to automated or partially-automated prostate cancer diagnosis.
Prostate cancer is the most common male cancer, with around 1.1 million diagnoses every year worldwide.
“This is not going to replace a human pathologist,” cautioned research leader Prof Hongqian Guo (Nanjing, China), “We still need an experienced pathologist to take responsibility for the final diagnosis. What it will do is help pathologists make better, faster diagnosis, as well as eliminating the day-to-day variation in judgement which can creep into human evaluations.”
Prof Guo’s group took 918 prostate whole-mount pathology section samples from 283 patients and ran these through the analysis system, with the software gradually learning and improving diagnosis. These pathology images were subdivided into 40,000 smaller samples; 30,000 of these samples were used to ‘train’ the software, the remaining 10,000 were used to test accuracy – the results showed an accurate diagnosis in 99.38 per cent of cases (using a human pathologist as a ‘gold standard’), which is effectively as accurate as the human pathologist.
They were also able to identify different Gleason Grades in the pathology sections using AI; 10 whole-mount prostate pathology sections have been tested so far, with similar Gleason Grade in the AI and human pathologist’s diagnosis. (The group has not started testing the system with human patients.)
Prof Guo continued: “The system was programmed to learn and gradually improve how it interpreted the samples. Our results show that the diagnosis the AI reported was at a level comparable to that of a pathologist. Furthermore, it could accurately classify the malignant levels of prostate cancer. Until now, automated systems have had limited clinical value, but we believe this is the first automated work to offer an accurate reporting and diagnosis of prostate cancer. In the short-term, this can offer a faster throughput, plus a greater consistency in cancer diagnosis from pathologist-to-pathologist, hospital-to-hospital, country-to-country.
“AI is advancing at an amazing rate — you only need to look at facial recognition on smartphones, or driverless cars. It is important that cancer detection and diagnosis takes advantage of these changes.”
The authors note some limitations to the work. There were more samples of Gleason Grade 3 and 4 than other grade, which may influence the AI calculation to some extent. They are also looking for suitably-objective standards to allow direct comparison of Gleason Grade with the AI.
Researchers discover experimental obesity drug prevents development of kidney stones
Scientists have found that a drug connected with fat regulation prevents the formation of kidney stones in mice. This early work opens the possibility of developing drugs that may help prevent kidney stones in at-risk individuals. The work was presented at the 2018 EAU Congress in Copenhagen in March.
The EAU estimates that around 50-to-60 million Europeans suffer from kidney stones — that is roughly one in 11 Europeans. Incidence has almost doubled over the last 20 years, due to increasing obesity and diet and lifestyle changes.
Now a group of Japanese scientists have discovered that an experimental drug leads to a significantly-reduced number of kidney stones in mice. They gave 20 mice 1mg/kg of the β3-agonist CL316243 for 12 days. The mice, plus 20 controls, were then injected with glyoxylate, which causes the formation of kidney stones.
At various time points, the mice were then checked to see if they had formed stones: The formation of stones decreased to 17 per cent in the experimental group, compared with the controls.
“This is experimental work for now,” said lead researcher Dr Teruaki Sugino, Nagoya City University Graduate School of Medical Sciences, Japan. “But I believe that this may open the way to the development of the new drugs which can stop the development of kidney stones in at-risk people. So far, we have only tested this on mice, but in mice it seems to work.
“We were able to analyse the biochemical differences between the control and experimental group, and discovered that the β3-agonist reduced the expression of adipocytokine molecules, which are associated with inflammation.”
The researchers believe that free fatty acids cause inflammation and cytotoxic effects in kidneys, which promotes stones. β3-agonists are known to cause white fat cells (which are found in excess in overweight and obese persons) into beige fat cells, which burn extra calories, which is why these molecules are also being considered for anti-obesity uses. The researchers suspect that beige cells consume free fatty acids, which may be the cause of inflammation in the kidneys, leading to kidney stones. This means that β3-agonists have the potential to prevent not only obesity, but also kidney stones.
A quarter of penis cancer sufferers do not get recommended treatment
A major international survey has found that around a quarter of penis cancer patients are not receiving the recommended treatment for this rare cancer. It also found that these patients had half the survival rate of those who were treated according to guidelines. The study, presented at the EAU Conference in Copenhagen, found that non-adherence is partly due to patients refusing treatment, or doctors being reluctant to treat appropriately or being unfamiliar with the best procedures.
Around one-in-100,000 men contract penis cancer every year in the Western world, however in recent years this rate has risen by 20-to-25 per cent in many countries, especially in older men.
Cancer of the penis is extremely distressing. Partially or completely removing the penis is often the most effective way to cure penile cancer, but for many men this cure seems worse than the disease.
In this large international survey, researchers found that a significant minority (25 per cent) of patients do not receive the recommended treatment. In part, this is due to patients being reluctant to go ahead with surgery, and in part due to doctors not proceeding with the appropriate surgery to treat this rare cancer.
Researchers from 12 centres in Italy, Spain, the US, Brazil and Hungary looked at adherence to the EAU guidelines on the treatment of penile cancer. They retrospectively examined the records of 425 patients who had been treated in the 2010-2016 period.
Lead author Dr Luca Cindolo, Abruzzo, Italy, said: “We found that most patients were treated in accordance with the gold-standard EAU recommendations, but around 25 per cent of patients had not received appropriate treatment. From our work, we see that around twice as many patients survive if they have been treated according to recommended guidelines. In around half of those patients not treated according to guidelines, the decision was made by the doctor, and we suspect that this is because many doctors are unfamiliar with treating this rare but devastating cancer. In one-in-six cases, the patient, or the patient’s carers, made the decision not to be treated according to guidelines. We often find that patients don’t want to be treated, or that the patients’ carers are unwilling to take the decision to treat.
“These are often difficult treatment decisions to make, and so they need to be arrived at after open discussion between the patient and the medical team. It’s a condition which most urologists don’t see very often, so it’s best if the medical team is experienced in dealing with the condition. This may mean that the treatment in national or international centres of excellence is the best way to proceed.”
Commenting, Dr Vijay Sangar, Director of Surgery, Christie Hospital, Manchester, UK, said: “We often find that patients with rare cancers get short-changed because the cancer is so seldom encountered by doctors. We can suggest that if we treat rare cancers in national or even international centres of excellence, the chances of better management improve. In the UK, for example, we centralised the treatment of penis cancer into just 10 centres of excellence, whereas in some countries, such as Hungary, Spain and Italy, these rare urological cancers are still treated locally, which may reflect the lower survival rates. Generally, the more penile cancer a team sees, the better they become at managing the disease. The recently-established eUROGEN consortium [the European Reference Network for rare and complex urogenital diseases and conditions] will make a huge difference to European patient care; this gives patients with rare urological diseases access to the best management, no matter where they are in Europe.”
Major study shows five times greater suicide rate in patients with urological cancers
A major UK survey has shown that patients with urological cancers, such as prostate, bladder or kidney cancer, are five times more likely to die by suicide than people without cancer. The analysis, presented at the recent 2018 EAU Congress in Copenhagen, also shows that cancer patients generally are around three times more likely to die by suicide than the general population, and that the proportion of attempted suicides which result in a completed suicide was higher in cancer patients, with a higher proportion still in patients with urological cancers.
This is the largest UK study looking at suicide in cancer patients and the research team, led by Mr Prashant Patel at the University of Birmingham, retrospectively examined the records from the England and Wales Hospital Episode Statistics database, from the period 2001 to 2011. They linked this with cause of death statistics from the Office of National Statistics.
This is also the first time that a major study has examined suicidal intent in cancer patients, which they defined as the ratio of completed suicides to the rate of attempted suicides.
They found that this rate was far higher (one-to-seven) in patients with prostate cancer than in the general population (one-to-25), which may show a greater risk of suicide in cancer patients. “This is important,” said study first author Dr Mehran Afshar, St George’s Hospital, London, “as we know that people who attempt suicide are at higher risk of subsequently being successful in completing a suicide, and we have shown this ‘intent’ to commit to be far higher in our cancer population, thus confirming a real need to address psychological issues early on in the management of these patients.”
Dr Afshar continued: “Our data confirms research from other countries that suicide rates are higher in cancer patients and we show this to be higher, particularly in patients with urological cancers. There are particular issues which are specific to this cancer group — for example, men with prostate cancer undergo treatment which can affect their bladder function, their bowel function, erectile function and libido, can result in symptoms similar to the female menopause, and entirely alter their personality, leading to relationship problems, anxiety, depression and post-traumatic stress disorder.
“We know from a 2014 study by Cancer Research UK that the vast majority of cancer patients who have symptoms of depression go untreated. We can see from the results of our study that although all cancers have a higher suicide rate, inferring a higher level of psychological distress, there are disparities between cancers. This needs to be addressed within our healthcare systems and more focus is needed on integrating the robust and specialist assessment and treatment of mental health needs in cancer care.”
The study also showed significant differences between the time to a successful suicide, which means that some cancer patients are more vulnerable in certain periods.
The team noted a limitation of the study: They looked at the general suicide rate, not at the rate of suicides according to age (age-standardised suicide rate), however, a comparison to baseline population suicide rates could only be made using crude suicide rates per 100,000, as this is the population-level data available.
Early HIV treatment key to avoiding neurological damage
Early initiation of HIV treatment is key to avoiding brain atrophy and resulting long-term health consequences like memory loss, dementia and balance issues, new research has found.
While it has been known for some time that HIV-infection causes reduced volume and cortical thickness in some regions of the brain, it was unclear when these changes begin and what role combination antiretroviral therapy (cART) plays in stopping or slowing its progression.
To answer these questions, the study researchers from analysed MRI data from 65 patients at the University of California, San Francisco, US, who had been infected less than one year before and compared it to that of 19 HIV-negative participants and 16 HIV-positive patients who had been infected for at least three years.
The researchers found that the longer the duration of untreated infection, the greater the volume loss and cortical thinning in several brain regions. Once cART treatment began, the volume changes in these regions stopped, and cortical thickness increased slightly in the frontal and temporal lobe.
These results, published in the journal Clinical Infectious Diseases, reinforce the need for early detection of HIV and delivery of cART as soon as possible to avoid neurological damage.
HIV infection can lead to memory loss, dementia later in life, and balance and vision problems, among other symptoms. Early screening and antiretroviral therapy can stop these symptoms before they occur, or stop their progression in patients who haven’t received fast enough treatment. At the end of 2016, there were 36.7 million people living with HIV, and of those, only 53 per cent had access to treatment.
“There have been few longitudinal structural neuroimaging studies in early HIV infection, and none that have used such sensitive analysis methods in a relatively large sample,” noted Mr Ryan Sanford, the study’s first author. “The findings make the neurological case for early treatment initiation and send a hopeful message to people living with HIV that starting and adhering to cART may protect the brain from further injury.”
Study links gut-homing protein levels with HIV infection risk, disease progression
For the first time, scientists have shown a relationship between the proportion of key immune cells that display high levels of a gut-homing protein called alpha-4 beta-7 at the time of HIV infection and health outcomes. Previous research illustrated this relationship in monkeys infected with a simian form of HIV.
The new study found that women who had more CD4+ T cells displaying high levels of alpha-4 beta-7 on their surface were more likely to become infected with HIV, and the virus damaged their immune systems more rapidly than women with fewer such cells.
“Our findings suggest that having a high frequency of alpha-4 beta-7-expressing CD4+ T cells, which HIV preferentially infects, leads to more HIV-infected CD4+ T cells moving to the gut, which in turn leads to extensive damage to gut-based immune cells,” said Dr Anthony S Fauci, co-author of the paper and Chief of the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases (NIAID).
The US National Institutes of Health co-funded the study with the South African Medical Research Council as part of the US-South Africa Programme for Collaborative Biomedical Research. In addition, NIH scientists collaborated on the study.
The research team compared the percentage of CD4+ T cells displaying high levels of alpha-4 beta-7 in blood samples drawn from 59 women shortly before they acquired HIV to the percentage of such cells in 106 women who remained HIV negative.
Aged 18-to-40 years, the women were selected from participants in the CAPRISA 004 study, which evaluated the safety and efficacy of tenofovir gel for HIV prevention in KwaZulu-Natal, South Africa, from 2007 to 2010.
Understanding HIV acquisition and disease progression among African women is especially important because women accounted for nearly 60 per cent of new HIV infections among adults in sub-Saharan Africa in 2016.
The proportion of CD4+ T cells with high levels of alpha-4 beta-7 had an effect, albeit modest, on the risk of acquiring HIV among both the women in the CAPRISA 004 study and a separate cohort of 41 female sex workers in Kenya. The risk of HIV acquisition rose by 18 per cent for each one per cent increase in alpha-4 beta-7 protein. The authors show a similar association in monkeys that were vaginally exposed to a simian form of HIV.
“These findings suggest that interventions in addition to ART may be needed to restore CD4+ T cells in the GI tracts of people living with HIV,” said Dr McKinnon. “One such intervention could be an anti-alpha-4 beta-7 antibody called vedolizumab, which is FDA-approved for the treatment of ulcerative colitis and Crohn’s disease.”
The report is published in the journal Science Translational Medicine.
Rising levels of HIV drug resistance
HIV drug resistance is approaching and exceeding 10 per cent in people living with HIV who are about to initiate or reinitiate first-line antiretroviral therapy, according to the largest meta-analysis to date on HIV drug resistance, led by researchers from UCL, the World Health Organisation (WHO) and part funded by the Bill and Melinda Gates Foundation.
The study, published in The Lancet Infectious Diseases, looked at data for people who were beginning antiretroviral therapy and found that resistance — particularly to one of the main types of first-line drug, non-nucleoside reverse transcriptase inhibitors (NNRTIs) — is increasing and those who exhibited drug resistance were more likely to have previously been exposed to antiretroviral drugs, often during pregnancy.
“Treatments for HIV have improved immensely in recent years, and close to 21 million people worldwide are now being treated with antiretroviral therapy. Yet to end the AIDS epidemic as a public health threat, minimising drug resistance will be one part of the response. Our findings show the importance of improving how we monitor drug resistance, and suggest we should review which drugs are included in first-line therapies,” said the study’s lead author Prof Ravindra Gupta.
The researchers pulled together 358 datasets, including data from 56,044 adults across 63 low- to middle-income countries who were beginning first-line therapy for HIV from 1996 and 2016. The research was conducted by a team of 33 authors on five continents.
Current WHO treatment guidelines for first-line therapy recommend NNRTIs in combination with nucleoside reverse transcription inhibitors (NRTI). The research team focused on studies that included data on the presence of drug-resistant mutations in the virus most commonly resistant to NNRTI drugs.
The research team found that, from 2001-2016, the odds of drug resistance in low- to middle-income countries across Sub-Saharan Africa, Latin America and Asia were increasing. In particular, the yearly incremental increase in NNRTI resistance was greatest in Eastern Africa (29 per cent annual increase) and in Southern Africa (23 per cent annual increase, with an absolute increase of 1.8 percentage points from 2015 to 2016) and was the smallest in Asia (11 per cent annual increase).
The study did not focus on high-income countries, but other studies have found that levels of drug resistance to NNRTIs in high-income countries were either plateauing or declining.
The study authors found drug resistance to be highest in Southern Africa, where 11.1 per cent of people beginning first-line therapy had a virus with NNRTI drug-resistant mutations, compared to 10.1 per cent in Eastern Africa, 7.2 per cent in Western/Central Africa, and 9.4 per cent in Latin America. The study team also found that people starting therapy who self-report previous use of antiretroviral drugs are more likely to carry resistant virus, and are at greater risk of virological failure.
Their data suggests that in some areas, 10-to-30 per cent of people presenting for antiretroviral therapy have previously been exposed to antiretroviral drugs. “Many people develop drug resistance after being treated by antiretroviral drugs if they stop taking their medication — often due to personal reasons, difficulty accessing treatment providers, or drug supply issues that are common in low-income regions. When these individuals restart treatment at a later date, they are less likely to respond to therapy and may pass on the drug-resistant strains to other people,” explained Prof Gupta.
If no action is taken, drug resistance to NNRTIs exceeding 10 per cent in people starting therapy could result in 890,000 more AIDS deaths and 450,000 more infections in Sub-Saharan Africa alone before 2030, as most people whose antiretroviral therapy is unsuccessful have a drug-resistant virus, according to prior research.
“If we are to combat HIV drug resistance, we must ensure countries can do a good job in monitoring and responding to it when needed,” said co-author Dr Silvia Bertagnolio of the WHO. “New WHO guidelines and a global action plan aim to help make this happen.”
WHO’s guidelines on pre-treatment HIV drug resistance recommend that countries switch to more robust first-line treatment when levels of resistance reach 10 per cent.
The five-year Global Action Plan calls on all countries and partners to join efforts to prevent, monitor and respond to HIV drug resistance and to protect the ongoing progress towards the Sustainable Development Goal of ending the AIDS epidemic by 2030.
Irish mums with HIV worried more about impact on their children than themselves — study
The immediate concern of Irish-based mothers upon diagnosis of HIV was for their babies and children, rather than themselves, as many minimise the significant personal impact of the news, according to new research.
In total, 11 women, five from Ireland, five from Africa and one from Europe, were interviewed for the narrative-based research report, ‘Frozen in a Moment of Time: The Experiences of Mothers Being Diagnosed with HIV Infection’.
Author of the report, Dr Denise Proudfoot of Dublin City University’s School of Nursing and Human Sciences, commented: “Few of the participants talked about personal responses following the diagnosis because their immediate worries were that they had infected their children with HIV, demonstrating that their response to a HIV positive diagnosis is strongly associated with maternal responsibilities.”
The variety and depth of testimony provides previously unheard-of accounts of these HIV-positive women with children, as little is known about their lives, she noted. “Upon diagnosis, participants were very much ‘frozen in a moment of time’ which they could not overcome until the HIV status of their children was known,” commented Dr Proudfoot.
The findings highlight that healthcare professionals need to be aware of how mothers-to-be and mothers worry about the possibility of infecting their children, despite the low likelihood of it happening due to HIV prevention interventions during pregnancy.
The study noted that although older children, born before their mothers were diagnosed with HIV, were unlikely to have the infection, “the possibility did concern mothers following diagnosis and most prioritised viral testing of their children”. Most of the study participants’ children were HIV-negative.
For these mothers, personal needs were secondary to those of their children and this indicated that healthcare professionals needed to adopt a “mother-centred” approach when supporting mothers living with HIV, as there is potential that they can neglect their own health, concluded Dr Proudfoot.
Over 8,000 people have been diagnosed with HIV in Ireland since testing began in the early 1980s. According to data from the Health Protection Surveillance Centre (HPSC), 508 people in Ireland were newly diagnosed with HIV in 2016, the majority of whom were gay men. However, approximately a quarter of those were female, mostly aged under 45 years and who may be mothers or pregnant when diagnosed.
Type 1 diabetes is caused by the destruction of the insulin-producing cells in the pancreas and is primarily treated with daily insulin injections.
While incremental improvements in diabetes treatment are continuing, with pancreas and islet cell transplants offering effective options for some complex patients, there have been a number of recent research breakthroughs that point to potential long-term cures or even prevention of the condition.
For example, a preventive vaccine for type 1 diabetes is to be studied in humans for the first time this year after it was tested successfully in mouse models.
The connection between viral infections and type 1 diabetes has been researched for over 25 years at the University of Tampere in Finland.
Type 1 diabetes is becoming more common and cases of it occur in Finland more than elsewhere in the world.
A research group at the University of Tampere led by Prof Heikki Hyöty, Professor of Virology, has long pioneered the development of a vaccine that could prevent type 1 diabetes.
Their research indicates that one virus group, enteroviruses, play a part in developing type 1 diabetes. They can infect the insulin-producing cells in the pancreas and damage them permanently.
It has now been shown that a prototype enterovirus vaccine can protect against virus-induced type 1 diabetes in a mouse model.
“These exciting results showing that the vaccine completely protects against virus-induced diabetes, indicate the potential that such a vaccine has for elucidating the role of enteroviruses in human type 1 diabetes,” says Prof Malin Flodström-Tullberg at the Karolinska Institutet whose group were responsible for the pre-clinical studies.
“Already now it is known that the vaccine is effective and safe on mice. The developing process has now taken a significant leap forward as the next phase is to study the vaccine in humans,” says Prof Hyöty.
In the first clinical phase, the vaccine will be studied in a small group of adults to ensure the safety of the vaccine. In the second phase, the vaccine will be studied in children and the aim is to investigate both the safety of the vaccine and its effectiveness against enteroviruses. In the third phase, the aim is to investigate whether the vaccine could be used to prevent the onset of type 1 diabetes.
However, it can take about eight years in order to certainly know whether the vaccine prevents type 1 diabetes.
“The aim is to develop a vaccine that could prevent a significant number of type 1 diabetes cases. Additionally, the vaccine would protect from infections caused by enteroviruses, such as the common cold, myocarditis, meningitis and ear infections. However, in light of current research, the vaccine could not be used to cure existing diabetes,” explains Prof Hyöty.
The research phase beginning now is the result of a long period of negotiations between several stakeholders interested in the matter.
The research project will be funded by the US-based company Provention Bio. Other partners include the Juvenile Diabetes Research Foundation (JDRF), which is the largest foundation funding research on type 1 diabetes in the world.
Meanwhile, ViaCyte, a privately-held US regenerative medicine company is developing novel cell replacement therapies as potential long-term diabetes treatments to reduce the risk of hypoglycaemia and diabetes-related complications.
ViaCyte’s product candidates are based on the derivation of pancreatic progenitor cells from stem cells, which are then implanted in durable and retrievable cell delivery devices. Once implanted and matured, these cells are designed to secrete insulin and other pancreatic hormones in response to blood glucose levels.
The company has two product candidates in clinical-stage development. The PEC-Direct product candidate delivers the pancreatic progenitor cells in a non-immunoprotective device and is being developed for type 1 diabetes patients who have hypoglycaemia unawareness, extreme glycaemic lability, and/or recurrent severe hypoglycaemic episodes.
“Patients with high-risk type 1 diabetes complications, such as hypoglycaemia unawareness, are at constant risk of life-threatening low blood glucose,” said Dr Jeremy Pettus, investigator in the clinical trial and Assistant Professor of Medicine at UC San Diego, US. “The PEC-Direct islet cell replacement therapy is designed to help patients with the most urgent medical need.”
The PEC-Direct product candidate is currently in a phase 1/2 open-label clinical trial at multiple sites in the US and Canada to evaluate safety and efficacy.
In January the company announced that the first patients have been implanted in cohort two with a potentially efficacious dose of the company’s PEC-Direct islet cell replacement therapy.
Cohort two is expected to enrol up to 40 patients and the primary efficacy measurement will be the clinically relevant production of insulin, as measured by the insulin biomarker C-peptide, in a patient population that has little to no ability to produce endogenous insulin at the time of enrolment. Other important endpoints will be evaluated including injectable insulin usage and the incidence of hypoglycaemic events.
“The implantation of a potentially efficacious dose of PEC-Direct marks an important milestone in the development of a functional cure for diabetes,” said Dr Paul Laikind, PhD, President and CEO of ViaCyte.
The company is also developing the PEC-Encap (also known as VC-01) product candidate, which delivers the same pancreatic progenitor cells in an immunoprotective device and is being developed for all patients with diabetes, type 1 and type 2, who use insulin.
About 10 per cent of type 1 diabetes patients have high-risk type 1 diabetes.
These patients are often eligible for islet transplants in countries that provide them (currently not available in Ireland).
“Islet transplants have been used to successfully treat patients with unstable, high-risk type 1 diabetes, but the procedure has limitations, including a very limited supply of donor organs and challenges in obtaining reliable and consistent islet preparations,” noted trial investigator Dr James Shapiro, Director of the Clinical Islet Transplant Programme, University of Alberta, US. “An effective stem cell-derived islet replacement therapy would solve these issues and has the potential to help a greater number of people.”
The PEC-Direct product candidate could overcome some of the key limitations of islet transplant by providing a virtually unlimited supply of cells manufactured under quality-controlled conditions, with a potentially safer and more optimal route of administration.
The PEC-Direct product candidate delivers stem cell-derived PEC-01 pancreatic progenitor cells in a device designed to allow direct vascularisation of the cells, which is expected to allow for a robust engraftment and cellular performance similar to the anatomy of a normal islet. Given the open nature of the device, patients implanted with PEC-Direct, as with other transplants, will require immune suppression.
Thus, PEC-Direct is being developed to treat patients with the greatest unmet medical need, including type 1 diabetes patients who already require immune suppression following a kidney transplant, as well as type 1 patients who are at high-risk for acute complications, such as hypoglycaemia unawareness, extreme glycaemic lability, and/or severe hypoglycaemic episodes.
ViaCyte recently announced funding from the California Institute for Regenerative Medicine (CIRM) to support yet another potentially transformative cell therapy approach that could be used for the treatment of diabetes. The company plans to engineer its CyT49 pluripotent stem cell line to be immune evasive, which it says, if successful, would open up off-the-shelf therapeutic applications in a number of fields.
ViaCyte is headquartered in San Diego, California, US, and is also funded in part by the JDRF.
Diabetes Ireland seeks parity of access to new blood glucose-monitoring technology for type 1 diabetes patients
Diabetes Ireland is calling on the HSE to reimburse a flash glucose monitoring system that does not require finger blood pricks for all type 1 diabetics.
In January Minister for Health Simon Harris announced that the continuous monitoring technology was being reimbursed only for children and young adults who require multiple dose injections of insulin in the first instance.
Diabetes Ireland said it is extremely disappointed that the Freestyle Libre technology is not being made available for every person with type 1 diabetes based on their clinical need. “We are very much aware of the many disappointed adults, who currently pay up to €120 a month for this device and have seen much improvement in their health and quality-of-life from using the device daily over the past 12 months.
“A lot of these adults were encouraged to get the device by their diabetes team, based on their clinical need, and on the basis that it would eventually be reimbursed by the HSE, as it is in the UK and many other countries.”
Almost 19,000 people have now signed an online petition created by diabetes advocate, Davina Lyon, campaigning for reimbursement of the device for all people with type 1 diabetes.
There are approximately 20,000 people with type 1 diabetes in Ireland, Diabetes Ireland said. According to the 2012 Irish Paediatric Diabetes Audit, there are 2,750 children under 16 years with type 1 diabetes. With the current restrictions on the reimbursement scheme only a small percentage of those children will be included and 17,000 adults with type 1 diabetes completely excluded because of their age, Diabetes Ireland pointed out.
It said that the HSE used the Health Technology Assessment Group (HTAG) advice note to estimate that the “average additional cost per patient per year for using Freestyle Libre is a minimum of €62.60” making the cost of providing the Libre to all people with type 1 diabetes approximately €1.2 million, with an estimated additional saving in the “expected reduction in the need to perform finger prick testing of over 2,000 times per year”.
Diabetes Ireland said this is “an insult to the diabetes community as the HSE has already saved €5 million on blood glucose strips since April 1, 2016, when the rules governing access to blood glucose strips for people with type 2 diabetes were changed”.
Representatives from the diabetes community have requested a meeting with Minister Harris to discuss their concerns and to present the online petition.
Diabetes Ireland reiterated that it is very supportive of the Type 1 Diabetes Community Advocacy Group position and firmly believes that everyone with type 1 diabetes should have access to the technology that bests support them to clinically manage their condition most effectively on a daily basis.
“However, it seems in this instance the HSE decision was based more on a cost basis rather than from the perspective of the patient’s quality-of-life and clinical need.”
Further information from the HSE in a response to a recent Parliamentary Question by Ms Mary Butler, TD, about the patient eligibility criteria for Freestyle Libre, is causing more confusion as it is not made clear whether a person needs to meet just one of the criteria, or all of the criteria to qualify for the technology.
“If it is the case that all of the criteria need to be met, then only a very small group of people will be eligible and this is not acceptable. The HSE will be asked to further clarify and explain its position on this issue,” said Diabetes Ireland.