2019

Pancreatic cancer support

It’s still probably one of medicine’s most devastating diagnoses – pancreatic cancer.

Despite all the scientific advances that have been made in treating so many malignancies, the prognosis for pancreatic cancer is most often pretty bleak. Consequently, patients presented with this diagnosis are most likely to be in need of significant support.

PanSupport (pansupport.org.au) is a newly-developed site, produced by the University of Melbourne that is likely to prove incredibly valuable to patients battling this condition, and their families.
This resource not only provides valuable information about pancreatic cancer and its treatment, but it also gives practical advice with regard aspects of management such as diet and exercise. Importantly it also directs patients to any potential clinical trials for which they may be eligible.

In keeping with the very practical and realistic approach of the entire site, Pansupport also includes information about palliative care and Advanced Care directives, allowing patients to access what they need to know in their own time frame.

The PanSupport website has been developed in collaboration with the Pancare Foundation, RMIT University and the Peter MacCallum Cancer Centre. It has been funded with a Cancer Grant Initiative funded by the Australian Government.

>> Find out more about PanSuport here 

Dysplastic naevi: the controversy continues

Key Points

• The entity ‘mildly dysplastic naevus’ has been removed from the World Health Organisation’s classification of dysplastic naevi.
• Dysplastic naevi are now to be graded as ‘low grade dysplastic naevus’ (previous moderately dysplastic naevus) or ‘high grade dysplastic naevus’ (previous severely dysplastic naevus).
• Current data suggest no further treatment is necessary for lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia (previous mildly dysplastic and moderately dysplastic naevi) with clear histologic margins and no pigment evident clinically, unless there was a high level of prebiopsy clinical concern.
• Re-excision with a 2-5mm clinical clearance is recommended for high grade dysplastic naevi (previous severely dysplastic naevi) with involved histologic margins.
• There is growing evidence that observation may be reasonable for low grade dysplastic naevi (previous moderately dysplastic naevus) if they were excised with clinically clear margins/ no residual clinical pigment is observed, despite histologically involved margins. More data may be required before this is accepted into clinical practice.
• There does not appear to be a clear consensus regarding whether high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm.

Dysplastic naevus: the controversy since the 1970s

The entity of dysplastic naevus has been shrouded in controversy since first described in the 1970s.¹ This appears to be due to:

1. Interobserver differences between histopathologists in applying the previous three tier grading system for dysplasia
2. Perceived risk of progression to melanoma, and
3. The possibility of benign entities simulating melanoma, all of which contribute to uncertainty and variability in management.^2,3

Dysplastic naevi are benign neoplasms of melanocytes.³

Dysplasia in melanocytes may occur de novo or in association with either congenital dermal naevi or common dermal naevi. It is probable that dysplasia arising in pre-existing naevi results from successive acquisition of genetic abnormalities^.3 Both common naevi and dysplastic naevi demonstrate BRAF or NRAS mutations.³

It was at one time proposed that there is a step-wise model of tumour progression from dysplastic naevi through mild, to moderate, then severe dysplasia, and finally melanoma.⁴ However, there is no evidence that dysplastic naevi are, in fact, common precursors of melanoma.⁴ In actuality, the most common naevus remnant found in association with melanoma is the common acquired naevus.⁴

Given the large number of dysplastic naevi, compared with the comparatively small number of melanomas arising in association with dysplastic naevi, it seems that the rate of progression from dysplastic naevus to melanoma is extremely low.⁴ Dysplastic naevi seen associated with melanomas have an increased incidence of TERT promoter mutations, a common early genetic event in the evolution of melanoma in situ.³ This suggests that some dysplastic naevi are an intermediate entity between benign naevus and melanoma.³

There is a lack of data examining the frequency of similar genetic alterations in non-melanoma associated dysplastic naevi; thus, although the risk of progression is very low, it is suggested that naevi with high grade dysplasia or added genetic events (e.g. TERT promoter mutation) are considered for complete excision.³

It has been suggested that dysplastic naevi represent a marker of increased risk for an individual developing melanoma.⁵

It is difficult to establish the risk of melanoma at a separate site in patients with dysplastic naevi, as the reported incidence of dysplastic naevi in fair-skinned individuals varies widely (between 2% and 50%).⁴

One study has demonstrated that only the diameter of the dysplastic naevus had a significant association with a personal history of melanoma,⁶ whilst another study has shown that individuals with many naevi, whether common or dysplastic, have an increased risk of developing melanoma.⁷ Thus it would seem that two factors are associated with an individual’s risk of developing melanoma: a large number of common or dysplastic naevi (>100) and the larger size of the naevi (>4.4mm).⁶

It is generally agreed that there is low interobserver agreement between pathologists when grading dysplastic naevi, particularly in those lesions exhibiting moderate atypia to early in situ melanoma.^8,9 This leads to uncertainty with regard to management of these lesions, especially if there is margin involvement.

In 2017, Wall et al.2 conducted a survey investigating the management of dysplastic naevi by Australian dermatologists. This survey demonstrated that, similarly to comparable studies reported within the USA and Canada, most dermatologists would re-excise a moderately or severely dysplastic naevus with involved margins.²

There is, however, variability in Australian dermatologists’ approaches to severely dysplastic naevi (clinically concerning for melanoma) which are completely excised on biopsy, with 44% re-excising with a 5mm margin, and the remainder considering no further treatment necessary.² In addition, whilst between 5-12% of US and Canadian dermatologists re-excise mildly dysplastic naevi involving margins, that rate in Australian dermatologists is 49%.²

A consensus statement released by Kim et al.¹⁰ in 2015 identified a critical gap in knowledge with regard to management of dysplastic naevi with involved margins. This consensus statement recommended that mildly to moderately dysplastic naevi with clear histologic margins need no re-excision.

If a biopsy report reveals severe dysplasia with positive margins, re-excision to achieve a 2-5mm clinical margin is recommended. The statement suggested that mildly dysplastic naevi with positive histologic margins after biopsy (and no residual pigment) may be observed, and while observation may be a reasonable option for moderately dysplastic naevi with positive histologic margins (and no clinical pigment), more data are required to make a definitive recommendation.¹⁰

A further multi-centre retrospective cohort study in 2018 by Kim et al.¹¹ suggests that close observation is a reasonable management approach for moderately dysplastic naevi with positive histologic margins. No specific recommendations are made regarding a severely dysplastic naevus with clear margins on biopsy.

WHO redefines melanocytic naevi

The World Health Organisation (WHO) released their new Classification of Skin Tumours in 2018.³ They define dysplastic naevus as ‘a subset of melanocytic naevi that are clinically atypical and characterized histologically by architectural disorder and cytological atypia, always involving their junctional component.¹⁰

Diagnostic criteria for dysplastic naevi traditionally include a division of cytoarchitectural atypia into mild, moderate and severe categories.³ Pathologists often further subdivide these categories into ‘mild to moderate’ and ‘moderate to severe’ to reflect the histological field effect often perceived in these lesions.

Lentiginous junctional or compound naevi (previously labelled mildly dysplastic naevi) are not associated with increased melanoma risk/progression to melanoma, and are also common within the population.³ The WHO consensus meeting working group recommends against the continued use of the term ‘mildly dysplastic naevus’ and instead recommends the use of low grade and high grade dysplasia.

So, where are we now with these new recommendations regarding the grading of dysplastic naevi, and what are the management implications? It seems that the new WHO recommendations support the view that biopsies of the previously known mildly dysplastic naevi need no further treatment, having removed the entity from their classification.

It would appear that there is agreement that dysplastic naevi with high grade dysplasia (previous severely dysplastic naevi) with involved margins requires re-excision to achieve a 2-5mm clinical margin of clearance.

However, there appears to be no recommendations or clear consensus regarding whether these high grade dysplastic (previous severely dysplastic) naevi require re-excision, if initially excised with clear margins, albeit less than 2mm.

With regard to dysplastic naevi with low grade dysplasia (previous moderately dysplastic naevi), there is a slowly growing body of evidence to suggest that it may be reasonable for these cases to be observed if they were excised with clinically clear margins/no residual clinical pigment is observed, despite histologically involved margins.

Given the current variation in clinical management of these lesions, as well as the continued lack of interobserver agreement between histopathologists when diagnosing these lesions, more data may be required before this recommendation is accepted.

In conclusion, as the consensus statement by Kim et al.¹⁰ recommends, the decision to re-excise dysplastic naevi should be based on both the clinical and histologic findings.

If the prebiopsy level of clinical concern is high, re-excision should be considered if the biopsy reveals positive margins, even if the level of histopathological dysplasia is low.

In addition, there may be clinical scenarios warranting re-excision of a mildly, mildly-moderately/moderately dysplastic lesion (now known as lentiginous junctional/compound naevi and dysplastic naevus with low grade dysplasia respectively), including patient preference.¹⁰

References:

1. Duffy K, Grossman D. The dysplastic nevus: from historical perspective to management in the modern era. J Am Acad Dermatol. 2012;67 (1): 1. E1-18. DOI: 10.1016/j.jaad.2012.03.013
2. Wall N, De’Ambrosis B, Muir J. The management of dysplastic naevi: a survey of Australian dermatologists. Australasian Journal of Dermatology. 2017;58:304-307. DOI: 10.1111/ajd.12720
3. Elder DE, Massi D, Scolyer RA, Willemze R, editors (2018). WHO classification of skin tumours. 4th Ed. Lyon: IARC.
4. Busam KJ, Gerami P, Scolyer RA (2019). Pathology of Melanocytic Tumors. 1st Ed. Philadelphia: Elsevier.
5. Elder DE. Dysplastic naevi: an update. Pathology. 2010;56(1):112-120.
6. Xiong M, Rabkin M, Piepkorn M, Barnhill R, Argenyi Z, et al. Diameter of dysplastic naevi is a more robust bio marker of increased melanoma risk than degree of histologic dysplasia: a case-controlled study. J Am Acad Dermatol. 2014;71(6):12578.e4. DOI: https://doi.org/10.1016/j.jaad.2014.07.030
7. Holly EA, Kelly JW, et al. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol. 1987;17:459-468. DOI: https://doi.org/10.1016/S0190-9622(87)70230-8
8. Hiscox B, Hardin MR, Orengo IF, Rosen T, Mir M, Diwan AH: Recurrence of moderately dysplastic nevi with positive histological margins. J Am Acad Dermatol . 2017;76:527530.  DOI: 10.1016/j.jaad.2016.09.009
9. Stefanato C. The “Dysplastic Nevus” Conundrum: A look back, a peek forward. Dermatopathology. 2018;5:53-57. DOl: https://doi.org/10.1159/000487924 
10. Kim C, Swetter S, Curiel-Lewandrowski C, Grichnik J, Grossman D, et al. Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi. JAMA Dermatol. 2015;151(2):212218. DOI: 10.1001/jamadermatol.2014.2694
11. Kim C, Berry E, Marchetti M, Swetter S, Liam G, et al. Risk of subsequent cutaneous melanoma in moderately dysplastic nevi excisional biopsies but with positive histologic margins. JAMA Dermatology. 2018;154(12):1401-1408 DOI: 10.1001/jamadermatol.2018.3359

– General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.

Reproductive carrier screening

Have you seen this? This little print-out could save you a good 30 minutes in valuable consulting time.

It’s the information from Sonic for couples who are planning a family about the potential value for testing their carrier status for conditions such as cystic fibrosis and fragile X.

Even though the information is coming from an organisation with a vested interest in promoting the testing, there is not even a suggestion of bias. It is all straight down the line – here are the risks – this is what is available for testing should you choose to pursue it.

There’s no denying it is worth considering. RANZCOG recommends that information about reproductive carrier screening be offered to every woman either prior to conception (preferred) or in early pregnancy.

Having this site bookmarked and ready to print off ensures your advice when advising women pre-conception is in keeping with best practice.

>> Click here for resource

Fluoroquinolones and neuropathy, is that a thing?

How big is the risk of peripheral neuropathy with fluoroquinolones?

That’s the question UK researchers were looking to answer with their large case-controlled study recently published in JAMA Neurology.

And – cutting to the chase – what’s the answer? Well, the risk isn’t huge but there is certainly a risk. And the association is worth bearing in mind if a patient develops peripheral neuropathy because the timing of this side-effect can be unpredictable, making the link less obvious.

According to the study which analysed details from a large UK primary care population database involving almost 1.4 million patients over seven years, taking oral fluoroquinolone increased the relative risk of developing peripheral neuropathy by 47% compared to not taking the drug.

“The absolute risk with current oral fluoroquinolone exposure was 2.4 per 10,000 patients per year of current use,” the study authors wrote.

And just to be sure the association wasn’t simply related to having an infection that needed antibiotics, the researchers also looked at all those patients who had received a different antibiotic, namely amoxicillin-clavulanate, to see if there was a similar association with this particular side-effect. But no – the problem just seemed to occur with the fluoroquinolones.

“No significant increased risk was observed with observed with oral amoxicillin-clavulanate exposure,” they found.

Aside from quantifying the risk of peripheral neuropathy with fluoroquinolones, which was the main aim of the study, researchers also found that the relative risk remained significantly increased up to 180 days after taking the drug. So, if a doctor is investigating the cause of a patient’s newly-developed peripheral neuropathy, they need to ask about fluoroquinolone use in the previous six months.

The study findings also suggested certain patients might be more at risk of developing this adverse effect than others. The risk appeared to be greater among men and those aged older than 60 years. The risk also seemed to increase the longer a person took the drug.

The findings seem to suggest increased caution needs to be taken when prescribing fluoroquinolones, especially given that they have other known potential side-effects such as tendon rupture and aortic aneurysm.

“Health care professionals should consider these potential risks when prescribing fluoroquinolone antibiotic,” the study authors concluded.

But, an accompanying editorial warns against getting the risk out of perspective.

The editorial authors from the Mayo Clinic in the US point out that when a side-effect is very rare, it can be challenging to determine predisposing factors or potential confounders. There is also a lack of a strong hypothesis on the mechanism underlying fluoroquinolone-induced neuropathy.

“It is clearly a rare event in a sea of fluoroquinolone use, and no clear pattern has been defined that differentiates it from other causes of peripheral neuropathies,” they wrote.

However, they support the findings of the original study that there is an association, but suggest further research is needed before doctors start avoiding using these drugs.

Reference

Morales D, Pacurariu A, Slattery J, Pinheiro L, McGettigan P, Kurz X. Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy. JAMA Neurol. Published online April 29, 2019. doi:10.1001/jamaneurol.2019.0887

Staff NP, Dyck PJB. On the Association Between Fluoroquinolones and Neuropathy. JAMA Neurol. Published online April 29, 2019. doi:10.1001/jamaneurol.2019.0886

Proof – food is medicine

A decent eating program can keep you out of hospital, according to US research into the value of providing ready-to-consume meals to a select adult population.

The retrospective cohort study involved just over 1000 participants, average age 53, almost 500 of whom were allocated to receive 10 meals a week, tailored to a recipient’s specific medical needs, for a period of just over two years. This group was then compared to a control group who had been matched for age and area of residence etc.

Overall the study found the medically tailored meal delivery program was associated with approximately half the number of inpatient admissions over the duration of the study. Similarly, receiving the set meals was associated with significantly fewer admissions to skilled nursing facilities and a substantial reduction in health care costs.

A pretty impressive result, yes? But before we go demanding an MBS item number for Meals on Wheels, even the researchers themselves advise caution in interpreting these results. Firstly, the study was not randomised. People who were allocated to receive the meal delivery intervention were generally more ill than the control patients – they were significantly more likely to have HIV, cancer and diabetes.

“It is unlikely that similar results would be seen were the intervention applied to a healthier population, as the risk of admission or high health care costs, even in the absence of intervention would be substantially lower,” the study authors said in The Journal of the American Medical Association (JAMA) Internal Medicine. 

And we don’t know whether it was the actual healthy food that made the difference, or whether it was the fact that they were getting their food for free thereby enabling the recipients to have more money for other things such as medications (remembering we are talking about the US health system here).

Nonetheless, the study raises some valuable points.

It is well-recognised that ‘following an appropriate diet is a cornerstone of maintaining health and managing illness.’ But this is often difficult for patients with complex medical conditions, especially if they are socioeconomically disadvantaged.

As an accompanying editorial points out, much of the more recent focus has been on diet-related diseases and the health and economic burden they increasingly represent. Diseases such as diabetes, cardiovascular disease and obesity-related cancers have claimed much of the spotlight.

But nutrition as a solution, and how we can use specific nutritional interventions to effectively manage a patient’s health care has been less well defined.

“One obstacle has been demonstrating the efficacy and cost implications of specific nutritional interventions,” the editorial authors said.

This JAMA study does that. Specifically, the researchers have shown that the provision of free, medically tailored meals at home is associated with reduced health care use and net cost savings.

More importantly for Australians, the study supports the incorporation of nutrition into health care to improve patient health outcomes and keep vulnerable patients out of tertiary care.

“Given their potential for significant health benefits and cost-savings, [medically tailored meals] may represent the tip of the spear for a national evolution toward such food-is-medicine approaches,” the editorial concludes.

Reference

Berkowitz SA, Terranova J, Randall L, Cranston K, Waters DB, Hsu J. Association Between Receipt of a Medically Tailored Meal Program and Health Care Use. JAMA Intern Med. Published online April 22, 2019. doi:10.1001/jamainternmed.2019.0198

Mozaffarian D, Mande J, Micha R. Food Is Medicine—The Promise and Challenges of Integrating Food and Nutrition Into Health Care. JAMA Intern Med. Published online April 22, 2019. doi:10.1001/jamainternmed.2019.0184

How much do sedentary people really need to move? It’s less than you think

As little as 20 minutes of exercise a day can offset a sedentary lifestyle. And that exercise can include walking the dog.

People who spend much of their day sitting may need to move around less than we thought to counteract their sedentary lifestyle, new research shows.

Our research, published today in the Journal of the American College of Cardiology, found about 20-40 minutes of physical activity a day seems to eliminate most health risks associated with sitting.

That’s substantially lower than the one hour a day a previous study has found.

We spend almost all our waking day sitting, standing, or moving. The health impact of each one of these can be complex.

For example, too much standing can lead to lower back problems and even a higher risk of heart disease. But sitting for too long and not moving enough can harm our health.

Then there are people who sit for many hours and also get in reasonable amounts of physical activity. For example, someone who has an office job but walks to and from work for 20 minutes each way and runs two to three times a week easily meets the recommended level of physical activity.

While we know moving is better than sitting, what is far less clear is how much of a good thing (moving) can offset the harms of a bad thing (sitting).

That’s what we wanted to find out in our study of almost 150,000 Australian middle-aged and older adults.

We followed people enrolled in the 45 and Up Study for nearly nine years. We looked at links between sitting and physical activity with deaths from any cause, and deaths from cardiovascular disease such as heart disease and stroke, over that time. We then estimated what level of moderate-to-vigorous physical activity might offset the health risks of sitting.

This kind of activity is strenuous enough to get you at least slightly out of breath if sustained for a few minutes. It includes brisk walking, cycling, playing sports or running.

What we found

People who did no physical activity and sat for more than eight hours a day had more than twice (107%) the risk of dying from cardiovascular disease compared to people who did at least one hour of physical activity and sat less than four hours a day (the “optimal group”).

But it wasn’t enough just to sit less. People who did less than 150 minutes of physical activity a week and sat less than four hours a day still had a 44-60% higher risk of dying from cardiovascular disease than the optimal group.

We also calculated the effect of replacing one hour of sitting with standing, walking, and moderate and vigorous physical activity.

Among people who sit a lot (more than six hours a day) replacing one hour of sitting with equal amounts of moderate physical activity like strenuous gardening and housework, but not standing, was associated with a 20% reduction in dying from cardiovascular disease.

Replacing one hour of sitting with one hour of vigorous activity such as swimming, aerobics and tennis, the benefits were much greater, with a 64% reduction in the risk of dying from cardiovascular disease.

What does it all mean?

The great news for people who sit a lot, including sedentary office workers, is that the amount of physical activity needed to offset the health risks of sitting risks was substantially lower than the one hour a day a previous study found.

Even around 20-40 minutes of physical activity a day – the equivalent of meeting the physical activity guidelines of 150 to 300 minutes a week – seemed to eliminate most risks associated with sitting.

For people who sat a lot, replacing sitting with vigorous physical activity was better than replacing it with moderate activity; and replacing sitting with moderate activity or walking was better than replacing it with standing.

What’s the take-home message?

Our study supports the idea that sitting and exercise are two sides of the same health “coin”. In other words, enough physical activity can offset the health risks of sitting.

Should we worry about sitting too much? Yes, because sitting takes up valuable time we could spend moving. So too much sitting is an important part of the physical inactivity problem.

We also know only a minority of adults get enough physical activity to offset the risks of sitting.

For those who sit a lot, finding ways to reduce sitting would be a good start but it is not enough. The most important lifestyle change would be to look for or create opportunities to include physical activity into our daily routine whenever possible.

How to widen our activity ‘menu’

Not everyone has a supportive environment and the capacity to create opportunities to be active. For example, lack of time and physical activity being low on people’s list of priorities are the main reasons why inactive adults don’t exercise. Also, many do not have the motivation to power through a strenuous workout when they are juggling many other life challenges.

There are no known remedies to a lack of time or low motivation. So, perhaps we need to add new approaches, beyond exercising and playing sport for leisure, to the “menu” of physical activity options.

Incidental physical activity like active transportation – think walking fast or cycling part or all of the way to work – or taking stairs are great ways to become or stay active without taking much extra time.

Emmanuel Stamatakis, Professor of Physical Activity, Lifestyle, and Population Health, University of Sydney; Joanne Gale, Research Fellow Biostatistician, University of Sydney, and Melody Ding, Senior Research Fellow of Public Health, University of Sydney

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Don’t kiss your kids? Questioning the recent advice about CMV in pregnancy

These days, guilt seems intrinsic to parenthood. And as many mothers will know, health professionals seem ever ready to stoke up guilt with their advice. Don’t smoke. Don’t drink. Have your vaccines. Take your folate tablets. Eat a nutritious diet, but avoid soft cheese, cured meat, food that’s been long in a fridge, or (the list goes on). Avoid cats. Don’t co-sleep. Breast is best. And if other women can manage all this, why can’t you?

As reported this week, Australia’s college of obstetricians (RANZCOG) has just added another task to the burgeoning to-do lists of doctors and midwives. We’re now to tell women to try to avoid cytomegalovirus (CMV).

They have reasons for doing so, but as a GP and academic, I find myself sceptical.

What is CMV, and why does it matter in pregnancy?

CMV is a widespread virus which often causes only a mild illness. Most adults have been infected with it in the past, and are immune.

But it’s different in pregnancy. If a pregnant woman is not already immune to CMV, and if she catches the virus, it can sometimes infect her fetus. And when it does, sometimes this causes problems such as hearing loss, epilepsy or developmental delay.

Though previously thought to be rare, researchers now think congenital CMV is under-recognised. They estimate that one or two in every 1,000 infants may develop symptoms from being born with CMV – not rare, but uncommon.

The virus is spread through fluids such as saliva, snot and urine. Child-rearing is messy; if toddlers catch CMV, it’s easy for them to pass it on to non-immune parents.

The new guideline

So what are women now urged to do to avoid CMV? To quote from the new RANZCOG guideline:

• Do not share food, drinks, or utensils used by children (under the age of three years)
• Do not put a child’s dummy/soother in your mouth
• Avoid contact with saliva when kissing a child (“kiss on the forehead not on the lips”)
• Thoroughly wash your hands with soap and water for 15-20 seconds especially after changing nappies or feeding a young child or wiping a young child’s nose or saliva
• Clean toys, countertops and other surfaces that come into contact with children’s urine or saliva.

Does that sound easy? If you think so, perhaps double-check with a friend who has young children. From my spot poll of parents, many feel that careful adherence to these rules would be unmanageable. Homes are not hospitals; interacting with our loved ones is not a sterile procedure.

I can’t help but feel that we are setting mothers up to fail by introducing these standards, and thereby compounding the guilt they carry. Early parenthood is a risky time of life for mental health issues like depression.

If we are to make new mothers feel guilty about such fundamental human interactions as sharing meals and kissing, won’t we intensify their stress at this vulnerable time?

If mothers feel they must respond to a joyful kiss from their toddler not with reciprocation, but with admonishment – “not on the lips, darling, only the cheek” – mightn’t this affect their bonding with their child?

What about the evidence?

The stresses above might be worth enduring if there was good evidence that these behavioural changes made a difference. But I’m unconvinced.

According to researchers who recently reviewed the world evidence, there are only three studies looking at whether hygiene and behaviour recommendations can prevent congenital CMV.

The largest was a study comparing how often women in a maternity hospital picked up CMV before and after hygiene advice. Infected proportions changed from 0.42% before the advice to 0.19% afterwards.

But “before-after” studies aren’t a reliable guide to cause-and-effect. The most susceptible women may just have caught CMV earlier, leaving only women at less risk left for the second phase of the study.

The best study design to establish cause-and-effect is a “randomised controlled trial”, in which women are randomly allocated to receive hygiene advice or not. There are two such trials.

One was tiny, and found no significant difference between the non-pregnant women it randomised to hygiene advice. Separately, they followed 14 pregnant women who were given hygiene advice, who all remained uninfected, but they weren’t randomised – there was no group of pregnant women without such advice to compare to.

The bigger trial randomised 166 non-immune mothers of young children to either receive hygiene advice or not. Despite providing free soap and gloves to the hygiene group, and visiting these women every three months to monitor their behaviour, exactly 7.8% of women in each group caught CMV – no difference.

Pregnant women who knew from special tests that their child was shedding CMV had a low infection rate – presumably this test result was a motivator for behaviour change. But this is evidence for the effect of testing, not of giving hygiene advice.

So I can’t see convincing evidence that routine hygiene advice works – not without the addition of tests of mothers’ immunity and children’s viral status. And doing such tests is not part of the new RANZCOG guideline – indeed, it explicitly advises against routine testing.

So what should we do?

I’m really torn on this issue. My heart aches for the families of children severely affected by congenital CMV. They must carry a heavy burden of guilt, wondering if they could have prevented the infection. I understand their motivation to prevent further harms. I share their desire for more research on CMV prevention.

But I am saddened, too, by the prospect of a generation of women taught to see their toddlers as dangerous, all in the name of preventive measures which remain unproven.

What do you think? Perhaps we need a community conversation about balancing the trade-offs here: the uncertain prevention of serious but uncommon outcomes versus widespread anxiety about normal family behaviours.

Meanwhile, it’s time for me to close my laptop, share a meal with my family, and, later, kiss my kids goodnight.

Brett Montgomery, Senior Lecturer in General Practice, University of Western Australia

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Anal cancer and HPV infection

Anal cancer is a neglected disease.

Whether through shame and embarrassment, or self-diagnosis of a haemorrhoid, late presentations are not uncommon and have an overall five-year survival of only 65%. It is an important disease which is potentially preventable but, whether the measure is research time and money, media coverage or the allocation of a coloured ribbon, anal cancer has not received the attention it deserves.

Before discussing who gets anal cancer, why they get it, how we might prevent it and the efforts being taken to do so, the anatomy and terminology need to be established and understood.

• Gentle traction placed on the buttocks will reveal perianal lesions (those falling within 5 cm of the anal opening) however anal canal lesions will be visualised incompletely or not at all by means of this manoeuvre. This is vitally important to appreciate because accurate description of location has direct clinical relevance. Anal canal cancers are more aggressive and require chemoradiation, while perianal cancers behave more like skin cancers and wide excision is usually appropriate.
• The anal canal has three zones – colorectal, transformation and lower canal. The transformation zone, centred on the dentate line, is where the glandular epithelium of the rectum meets the squamous epithelium of the lower canal, and is analogous to that in the cervix. It may encompass several centimetres, have poorly demarcated margins and is characterised by ongoing squamous metaplasia and constant replacement of glandular epithelium.

The transformation zone is where most anal canal cancers arise.

Who gets anal cancer?

While it is a rare disease in the general community (1–1.5/100,000), several sub-populations have very high rates of anal cancer:

• HIV-positive men who have sex with men
• Other HIV-positive individuals (male and female)
• HIV-negative men who have sex with men
• Organ transplant recipients
• Women with a history of HPV-related vulval/vaginal/ cervical cancer or pre-cancer

About 95% of anal cancers are caused by HPV and the great majority of these are caused by HPV 16. HPV is a sexually transmitted infection and anal intercourse an efficient means of HPV transmission; however, anal intercourse is not a prerequisite for anal HPV infection.

Anal HPV infection is common in both sexes (whether or not anal intercourse is reported) but most anal infections are transient.

Anal cancer is a rare outcome associated with persistence of the virus and with other co-factors, such as smoking and immunosuppression.

Is prevention of anal cancer possible?

Vaccination

Australia was the first country in the world to commence an organised HPV vaccination program, starting with girls and young women in 2007 and extending to school-aged boys in 2013.

While vaccine efficacy for the prevention of anal cancer is anticipated to be similar to that for cervical cancer, proof of it will take longer to demonstrate. Unlike cervical cancer, the incidence of anal cancer continues to increase into old age and therefore the benefits of vaccination may take decades to become apparent.

Screening for pre-cancer

Digital anorectal examination (DARE) is currently recommended to detect the earliest anal cancers. In addition, some centres screen for anal pre-cancer using a model based on the multiple similarities which exist between cervical and anal cancer, namely the same virus infecting the same type of transformation zone, leading to development of the same precancerous, high-grade squamous intraepithelial lesion (HSIL) which can be detected cytologically.

These commonalities translate, in the setting of anal cancer screening, to a process involving anal cytology, possibly anal HPV testing and high-resolution anoscopy (akin to colposcopy), followed by biopsy.

Despite these correlations between cervical and anal HPV infection and the plausibility of similar screening protocols being applicable in both settings, a screening program for anal cancer has not been as widely implemented as may have been expected.

Why is this?

-Near-universality of HPV infection in men who have sex with men limits the effectiveness of HPV testing in triage.

-Not enough is known about the natural history of anal HSIL and it is likely to differ in significant ways from cervical cancer. In gay men, for example, high-grade lesions appear to be quite common and a proportion may regress without treatment.

-There is no accepted treatment for patients with biopsy-diagnosed anal HSIL. While the entire transformation zone of the cervix can be excised with few sequelae, this is not possible in the anal canal and there is no reliable evidence for any other interventions currently used.

Summary

At this stage neither HPV testing or anal cytology can be recommended as routine screening procedures for anal cancer and pre-cancer.

Until certain key questions are answered, at-risk patients should be identified, reviewed annually by DARE and managed accordingly.

Vaccination is worth offering to those in at-risk groups and is safe and effective in the immunosuppressed.

– General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.

Is catheter ablation for AF worthwhile?

To ablate, or not to ablate? That is the question.

That’s what international researchers were investigating in two studies just published in The Journal of the American Medical Association.

And the answer? As so often happens in medicine, the answer is: it depends.

Looking at the two studies, patients with symptomatic atrial fibrillation had a greater improvement in their quality of life at the one year mark if they had undergone catheter ablation than if they had been treated with medical treatment alone.

But not to diminish the importance of quality of life as a measure of success, other findings from the latest research are also worth noting.

In the larger of the two studies, a randomised controlled controlled trial of over 2200  patients presenting with symptomatic AF, researchers found after four years of follow-up that there was no significant difference in mortality between the group who had received catheter ablation and those who were treated with drug therapy alone. Similarly, the rate of disabling stroke, serious bleeding and cardiac arrest were the same between the two groups.

As one would expect there was a higher rate of AF recurrence among the drug therapy group as compared with the catheter ablation group (70% vs 50%), however that 50% recurrence rate among those who’d undergone the ablation procedure is still pretty high and overall among that intervention group 19.4% underwent a repeat procedure.

But the study authors who came from 10 different countries did not seem too deflated by the result. While their study failed to show benefit for catheter ablation in any of the primary outcomes such as death or stroke they did find some advantage in terms of secondary outcomes, including quality of life. They also point to a trend toward benefit of the procedure even if that benefit wasn’t large enough to reach clinical significance.

The other JAMA study involved just 155 patients who had symptomatic paroxysmal or persistent AF and who were randomised to receive either catheter ablation or drug therapy. The Scandinavian researchers were particularly assessing their symptoms and their quality of life.

After four years, the catheter ablation group ‘produced 14% more patients who achieved complete or near complete relief from their AF symptoms.’

What’s more the quality of life improved for patients in both groups. However, the improvement was greater in the ablation group.

So, what does it all mean?

Firstly, it needs to be pointed out that, in keeping with the guidelines the majority of patients included in these trials were symptomatic – only 10% were asymptomatic. In other words, there have to be symptoms or another very good reason to consider ablation in a patient with AF.

Secondly, overall, the ablation group was more successful than the drug therapy group in relieving those symptoms.

As an accompanying editorial puts it:

“For patients with symptoms, in whom quality of life is impaired by AF, catheter ablation can improve quality of life to a greater extent than drug therapy.

However, patients who choose drug therapy will also likely experience significant improvements in quality of life and have no worse risk for the most concerning complications of AF, stroke and death. Thus, there is no mandate for these patients to undergo catheter ablation at this time.”

And that’s where we’re at.

Reference:

Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019 Mar 15. DOI: 10.1001/jama.2019.0693 [Epub ahead of print]

Mark DB, Anstrom KJ, Sheng S, Piccini JP, Baloch KN, Monahan KH, et al. Effect of Catheter Ablation vs Medical Therapy on Quality of Life Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019 Mar 15. DOI: 10.1001/jama.2019.0692 [Epub ahead of print]

Albert CM, Bhatt DL. Catheter Ablation for Atrial Fibrillation: Lessons Learned From CABANA. JAMA. 2019 Mar 15. DOI: 10.1001/jama.2018.17478 [Epub ahead of print]

Blomström-Lundqvist C, Gizurarson S, Schwieler J, Jensen SM, Bergfeldt L, Kennebäck G, et al. Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial. JAMA. 2019 Mar 19; 321(11): 1059-68. DOI: 10.1001/jama.2019.0335

Efudix wins over other AK treatments

Got a patient with multiple sun spots on their head that need treatment?

Well it looks like the old, tried and true 5FU cream is still the way to go, according to a randomised trial just published in the New England Journal of Medicine.

Among more than 600 randomly assigned patients, Dutch researchers compared the effectiveness of four topical treatments commonly used to treat multiple actinic keratoses as part of a ‘field treatment’.

In addition to the 5% fluorouracil cream (Efudix), the study looked at the effectiveness of 5% imiquimod cream (Aldara), methyl aminolevulinate photodynamic therapy (MAL PDT or Metvix PDT) and 0.015% ingenol mebutate gel (Picato gel).

After 12 months, the study showed that the Efudix was the most effective in terms of maintaining a reduction of at least 75% of actinic keratoses from the baseline. In other words, this cream was the best of the four therapies, at getting rid of these sun spots completely.

“And the differences between fluorouracil cream and imiquimod, PDT and ingenol mebutate were significant,” the study authors said.

They found the likelihood of success for those patients using fluorouracil was almost 75%, compared with only 54% for imiquimod, 38% for PDT and 29% for those using ingenol mebutate.

And this independent study didn’t do anything tricky with the dosing regimen either.

“In our trial, we used the most commonly prescribed dosing regimens of the therapies studied,” they said.

In terms of sticking to the dosing regimen, patients were much better adhering to the schedule when they were taking ingenol mubutate (99% adherence) or PDT (97%) rather than the fluorouracil (89%) or the imiquimod (88%), but this appeared to directly correlate with how often they had to take the therapy and for how long.

Overall, however this adherence rate did not reflect treatment satisfaction rate.

“Satisfaction with treatment and improvement in health-related quality of life at 12 months after the end of treatment were highest in the fluorouracil,” the study authors reported. Nothing like a treatment actually working to make a patient feel happy about having had it.

A bonus of this study, according to the researchers was the inclusion of patients with the more severe actinic keratosis lesions (Grade III lesions), patients who have been commonly excluded from previous similar trials of topical treatments.

“[Including these patients] is more representative of patients seen in daily practice,” they said.

In addition to effectiveness, cost is another appealing factor for fluorouracil over the other treatments.

This study has the capacity to change practice.

The study authors quote the prevalence actinic keratoses among whites aged 50 and over as being at 37.5%.

While cryotherapy remains the treatment of choice for single lesions, where there are multiple lesions present field treatment should be considered.

Currently the guidelines for this field treatment don’t advocate one treatment over any other, more or less suggesting all four of the treatments in this study as being efficacious.

However, as these Dutch researchers say “our results could affect treatment choices in both dermatology and primary care.”

Reference

Jansen MHE, Kessels JPHM, Nelemans PJ, Kouloubis N, Arits AHMM, van Pelt HPA, et al. Randomized Trial of Four Treatment Approaches for Actinic Keratosis. N Engl J Med. 2019 Mar 7; 380(10): 935-46.  DOI: 10.1056/NEJMoa1811850

Cutaneous Biopsies in General Practice

Introduction

Cutaneous disorders are among the most common conditions presented to primary care doctors. Many are easily identifiable and may be dealt with effectively without the need for cutaneous biopsy. Nevertheless, in many instances the diagnosis is not obvious on clinical grounds. The rash may display atypical features or may not respond to therapy as predicted.

In these cases, and when dealing with cutaneous tumours or worrying pigmented lesions, cutaneous biopsy with histological assessment becomes necessary.

The art of cutaneous biopsy is to derive the maximum amount of information from the minimum amount of tissue, causing least discomfort to the patient. This will be achieved if due regard is given to the advantages and shortcomings of the various techniques available for biopsying cutaneous tissue, and if the pathologist is supplied with a good clinical history.

Clinical History

For several reasons, clinical history assists greatly in the interpretation of skin biopsies. Clinicopathological correlation is particularly important in many inflammatory cutaneous disorders. As the histological features can be very similar, clinical notes may help us to arrange a list of provisional diagnoses in order of likelihood.

The key features to discuss with regard to cutaneous rashes include:

• duration
• distribution
• description (macular, papular, vasculitic or vesicular)
• drugs or other possible aetiological agents
• provisional clinical diagnosis.

As there is wide variation in the normal microscopic picture from different sites, the area biopsied should also be stated.

For biopsies performed to distinguish between squamous cell carcinoma and keratoacanthoma, the rate of growth of the lesion is important.

When sending specimens of pigmented lesions, the degree of clinical suspicion should be stated, together with any history of melanoma within the individual or within the individual’s family. Any condition associated with cutaneous disorders, such as systemic lupus erythematosus, pregnancy or bone marrow transplant, should be mentioned in the clinical notes. The clinical history should also include the type of biopsy procedure used (see below) as this determines the way we handle the specimen in the laboratory. For example, the whole of an incisional biopsy will be blocked in order to gain the maximum amount of information, whereas an excisional biopsy will be transversely sectioned in order to fully assess the lateral excision margins in the case of a tumour biopsy.

Excision Biopsy

This is the best technique to use for pigmented lesions and cutaneous tumours.

It allows for histological assessment and diagnosis of the lesion, and assessment of surgical excision margins. If appropriate, an orientation suture can be placed at one end of the excision, e.g. the superior end of the specimen, so that if the excision is inadequate, the margin involved can be indicated on an accompanying diagram.

Occasionally, excision biopsy is appropriate for inflammatory cutaneous disorders where the condition is characterised by the formation of vesicles. The best chance of removing an intact vesicle (which greatly aids diagnosis) may be through excision.

Incision Biopsy

With incision biopsy, a thin elliptical biopsy is taken radially through the edge of the tumour or through the edge of a macular or annular rash.

Incision biopsy is superior to punch biopsy for diagnosing rashes, more tissue is displayed on histological section and scarring is often reduced. A typical incision biopsy is 5-6 mm in length and about 2 mm in width. It should be deep enough to extend into the subcutaneous adipose tissue. The biopsy should run radially from the centre or central areas of the lesion to include approximately 1 mm of normal cutaneous tissue surrounding the lesion.

Punch Biopsy

Punch biopsies are easier to perform and, in general, are more convenient. Nevertheless, they nearly always yield less information than an incision biopsy.

For tumours, the biopsy should be taken centrally.

For cutaneous eruptions, the biopsy should be taken from an area typical of the rash. In some cases, multiple biopsies may increase the amount of information. In this procedure, it is best not to include normal skin.

Punch biopsies come in various sizes. As 2 mm punches often yield inadequate information for diagnosis, a 3 mm punch biopsy is the smallest that should be used.

Shave Biopsy/Curettage

This technique is suitable for superficially-located lesions with plaque-like clinical features, e.g. seborrhoeic keratoses.

It is not an appropriate technique for nodular lesions, cutaneous rashes or melanocytic lesions.

General comments concerning cutaneous biopsies

Preparation of the skin surface:

Be gentle when cleaning the skin surface prior to biopsy; try not to disturb any overlying scale as the keratin layers sometimes contain diagnostic information (e.g. this is where dermatophytic fungi may be seen).

Let any alcohol preparation dry before collecting specimens for immunofluorescence.

Local anaesthesia:

Only a small amount of local anaesthetic is required for punch biopsy procedures (0.5 mL maximum). Too much local anaesthetic within the tissues can distort the histological appearances and simulate dermal oedema.

Marking the lesion:

It is often prudent to mark the target area for biopsy with an ink marker, as some lesions can blanch following introduction of local anaesthetic. The erythema in many lesions is due to vascular dilatation occurring as part of the inflammatory disorder. Local anaesthetic can cause vasoconstriction and diminish the erythema clinically. This may result in a poorly targeted biopsy yielding subdiagnostic histology.

Depth of biopsy:

It is best to continue into the subcutaneous adipose tissue so that the entire dermis is represented on histological section. This helps greatly with the categorisation of many inflammatory skin disorders and also demonstrates the deep border of any cutaneous tumour. When performing a punch biopsy, the biopsy instrument appears to ‘give’ when it penetrates the dermal connective tissue into subcutaneous adipose tissue. A similar sensation will be noticed when dissecting free an incision biopsy.

Care with biopsy tissue:

All too often, after biopsy tissue has been retrieved from the patient, crush artefact occurs during its transfer into formalin. Crush artefact greatly distorts the histological appearance and repeat biopsy may become necessary.

Rather than grasping the biopsy tissue with non-tooth forceps, it should be transferred to the specimen container using needle tips, a skin hook or fine forceps, delicately grasping one edge of the biopsy.

Fixative:

Ordinary blue, 10% buffered formalin supplied with the specimen jars is suitable for nearly all cutaneous biopsies, except those submitted for microbiological culture or immunofluorescent examination.

Labelling:

Please label all specimen containers with the patient’s name and details, which should match those stated on the request slip. Unlabelled specimens can still be processed and interpreted if they arrive with labelled paperwork; however, the medico-legal status of any generated report is doubtful. The report will usually be generated with a ‘specimen received unlabelled’ comment attached.

Conclusion

Diagnosing cutaneous conditions can be challenging. The chances of success are improved when the clinician, is armed with a variety of biopsy techniques for use in the correct clinical setting, and when the pathologist is supplied with an adequate clinical history.

– General Practice Pathology is a regular column each authored by an Australian expert pathologist on a topic of particular relevance and interest to practising GPs. The authors provide this editorial free of charge as part of an educational initiative developed and coordinated by Sonic Pathology.

Explainer: What is Murray Valley Encephalitis Virus?

Western Australian health authorities recently issued warnings about Murray Valley encephalitis, a serious disease that can spread by the bite of an infected mosquito and cause inflammation of the brain.

Thankfully, no human cases have been reported this wet season. The virus that causes the disease was detected in chickens in the Kimberley region. These “sentinel chickens” act as an early warning system for potential disease outbreaks.

What is Murray Valley encephalitis virus?

Murray Valley encephalitis virus is named after the Murray Valley in southeastern Australia. The virus was first isolated from patients who died from encephalitis during an outbreak there in 1951.

The virus is a member of the Flavivirus family and is closely related to Japanese encephalitis virus, a major cause of encephalitis in Asia.

Murray Valley encephalitis virus is found in northern Australia circulating between mosquitoes, especially Culex annulirostris, and water birds. Occasionally the virus spreads to southern regions, as mosquitoes come into contact with infected birds that have migrated from northern regions.

How serious is the illness?

After being transmitted by an infected mosquito, the virus incubates for around two weeks.

Most people infected don’t develop symptoms. But, if you’re unlucky, you could develop symptoms ranging from fever and headache to paralysis, encephalitis and coma.

Around 40% of people who develop symptoms won’t fully recover and about 25% die. Generally, one or two human cases are reported in Australia per year.

Since the 1950s, there have been sporadic outbreaks of Murray Valley encephalitis, most notably in 1974 and 2011. The 1974 outbreak was Australia-wide, resulting in 58 cases and 12 deaths.

It’s likely the virus has been causing disease since at least the early 1900s when epidemics of encephalitis were attributed to a mysterious illness called Australian X disease.

Early warning system

Given the severity of Murray Valley encephalitis, health authorities rely on early warning systems to guide their responses.

One of the most valuable surveillance tools to date have been chooks because the virus circulates between birds and mosquitoes. Flocks of chickens are placed in areas with past evidence of virus circulation and where mosquitoes are buzzing about.

Chickens are highly susceptible to infection so blood samples are routinely taken and analysed to determine evidence of virus infection. If a chicken tests positive, the virus has been active in an area.

The good news is that even if the chickens have been bitten, they don’t get sick.

Mosquitoes can also be collected in the field using a variety of traps. Captured mosquitoes are counted, grouped by species and tested to see if they’re carrying the virus.

This method is very sensitive: it can identify as little as one infected mosquito in a group of 1,000. But processing is labour-intensive.

How can technology help track the virus?

Novel approaches are allowing scientists to more effectively detect viruses in mosquito populations.

Mosquitoes feed on more than just blood. They also need a sugar fix from time to time, usually plant nectar. When they feed on sugary substances, they eject small amounts of virus in their saliva.

This led researchers to develop traps that contain special cards coated in honey. When the mosquitoes feed on the cards, they spit out virus, which specific tests can then detect.

We are also investigating whether mosquito poo could be used to enhance the sugar-based surveillance system. Mosquitoes spit only tiny amounts of virus, whereas they poo a lot (300 times more than they spit).

This mosquito poo can contain a treasure trove of genetic material, including viruses. But we’re still working out the best way to collect the poo.

Staying safe from Murray Valley encephalitis

There is no vaccine or specific treatment for the virus. Avoiding mosquito bites is the only way to protect yourself from the virus. You can do this by:

• wearing protective clothing when outdoors
• avoiding being outdoors when the mosquitoes that transmit the virus are most active (dawn and dusk)
• using repellents, mosquito coils, insect screens and mosquito nets
• following public health advisories for your area.

The virus is very rare and your chances of contracting the disease are extremely low, but not being bitten is the best defence.

– Ana Ramírez, PhD candidate, James Cook University; Andrew Francis van den Hurk, Medical Entomologist, The University of Queensland; Cameron Webb, Clinical Lecturer and Principal Hospital Scientist, University of Sydney, and Scott Ritchie, Professorial Research Fellow, James Cook University

This article is republished from The Conversation under a Creative Commons license. Read the original article.