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Read the latest articles relevant to your clinical practice, including exclusive insights from Healthed surveys and polls.

By reading selected clinical articles, you earn CPD in the Educational Activities (EA) category whenever you click the “Claim CPD” button and follow the prompts. 

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Dr Cameron Webb
  • Clinical Articles

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.The Conversation

- 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.
By Dr Cameron Webb, Ana Ramírez, Andrew Francis van den Hurk, Scott Ritchie, Dr Nicholas J Clark
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Dr Linda Calabresi
  • Clinical Articles

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
By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

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.
By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Stop drinking and lose weight to prevent breast cancer

The spectre of breast cancer looms large for the majority of Australian women. But now researchers say if we tackle obesity and overweight as well as cutting out regular alcohol consumption we can prevent thousands of cases of this disease which is our most common cancer in women and second leading cause of cancer death. A new study has quantified how much these modifiable risk factors contribute to the incidence of breast cancer and predicts how many future cases they will cause. And it’s a bit frightening. According to this large Australian collaborative study, published in the international Journal of Cancer, if all Australian women maintained a healthy weight we could prevent 17,500 breast cancers in the next 10 years. And if women stopped drinking alcohol regularly (even one drink a day) it was estimated 11,600 future breast cancers could be avoided over the next decade. The researchers from University of NSW’s Centre for Big Data Research in Health were able to quantify the burden of these two risk factors after pooling six Australian cohort studies that included over 200,000 women. They were also able to differentiate the contribution of the various factors in premenopausal as opposed to postmenopausal breast cancers. “Regular alcohol consumption is the potentially modifiable risk factor responsible for the largest burden of breast cancer for premenopausal women in Australia, accounting for 12.6% of the burden and 2,600 cases of breast cancer over the next 10 years,” the study authors said. Body weight, or more accurately ‘body fatness’ was not a major factor for developing breast cancer before menopause. Apparently, this is the first time that regular alcohol consumption has been shown to be the leading modifiable contributing factor to breast cancer risk in this age group. And even though the finding would suggest that reducing the number of drinks per day would lessen the risk, the researchers found that the increased risk held true even with an average of one drink a day. Certainly bad news for more than half of Australian women who currently report drinking alcohol regularly, even if they are keeping to the current Australian recommendation not to drink more than two drinks a day on average. Among postmenopausal women, body fatness represents the biggest danger, accounting for 12.8% of the burden (17,500 breast cancer cases) over a decade. Given that three in five postmenopausal women in Australia are currently estimated to be overweight or obese this represents a key target for intervention. And alcohol consumption too, still made a substantial contribution to the risk in this cohort (6.6% or 9,000 breast cancer cases). Other modifiable risk factors included taking the oral contraceptive pill premenopause, and, among postmenopausal women taking menopausal hormone therapy (MHT). As the researchers point out, the issue of oral contraceptives as a breast cancer risk is a little complicated as it has to be weighed up against the protective effect these medications have against endometrial, ovarian and colorectal cancers as well as their reproductive health benefits. And as for MHT, the major breast cancer risk was for women taking MHT for five years or more. “Our findings thus support the current Australian and international recommendations of using MHT for the shortest duration possible, and only to alleviate menopausal symptoms, not for the prevention of chronic disease,” they said. Interestingly, for postmenopausal women at least, being physically active or having a history of breast feeding didn’t seem to alter the risk of developing breast cancer in the future. However, what the study has highlighted is the importance of targeting weight and alcohol as the most effective means to reduce the incidence of breast cancer. “The findings provide evidence to support targeted and population-level cancer control activities in Australia and beyond,” the study authors said.  

Reference

Arriaga ME, Vajdic CM, Canfell K, MacInnis RJ, Banks E, Byles JE, et al. The preventable burden of breast cancers for premenopausal and postmenopausal women in Australia: A pooled cohort study. Int. J. Cancer. 2019 Feb 25. DOI: 10.1002/ijc.32231
By Dr Linda Calabresi
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Dr Linda Calabresi
  • Clinical Articles

Offer Q fever vaccine to all rural Australians

Anyone living in country Australia should consider being vaccinated against Q fever, according to researchers. The recommendation was made on the basis of their study, published in the Medical Journal of Australia which showed that living in a rural area for more than three months was associated with an increased risk of contracting Q fever even if there was little contact with farm animals, the traditional reservoir of the infection. In fact, the risk among country dwellers was 2.5 times higher than among people who had never lived rurally, according to the study which looked for evidence of past infection among 2740 blood donors in Queensland and NSW. “The prevalence of Q fever, caused by Coxiella burnetii, is substantial in Australia despite the availability of a safe and effective vaccine,” the study authors wrote. They point to stats that show that between 2013 and 2017 there were more 2500 notifications of Q fever in this country. They say this is very likely to be an underestimate, as most infections (up to 80%) are asymptomatic and sometimes they may have non-specific symptoms. But what we do know is that when Q fever does cause significant symptoms the morbidity can be substantial - pneumonia, hepatitis, endocarditis, and osteomyelitis. In addition, 10-15% of symptomatic patients will develop a protracted post-Q fever fatigue syndrome. To check just how many people have or have had the condition, researchers assessed blood donors from metropolitan Sydney and Brisbane, as well as blood donors in rural areas, namely the Hunter New England region of NSW and Toowoomba in Queensland. As well as collecting data on exposure, occupation and vaccination, the sera of the subjects was tested for both the C. burnetii antibody (as a measure of past exposure) and C. burnetii DNA (measuring current infection). No patient in the study was found to be currently infected with Q fever. Overall, 3.6% of the participants had evidence of past infection. And even though seroprevalence was higher in the rural areas compared to metropolitan areas, a significant proportion of those people from the city who tested positive for past Q fever had a history of living in the country at some time in the past. As you would expect, people working with sheep, cattle or goats, abattoir workers and people who had assisted at an animal birth were at highest risk. Vaccination of these people is already recommended. Non-farming people who just lived in rural areas were found to be at risk. “Having lived in a rural area, but with no or rare contact with sheep, cattle or goats, was itself an independent predictor of antibody seropositivity after accounting for the effects of other exposures”, the study authors said. Hence the recommendation we vaccinate everyone living in the country. But, as an accompanying editorial points out, expanding the current vaccination program is not without its challenges. Screening for humoral antibody and cell-mediated skin testing is required prior to vaccination so the need for at least two GP visits, access to intradermal skin testing and the cost are all potential barriers, the editorial authors said. There is also an issue with a lack of evidence about the safety and effectiveness of the Q fever vaccine in children. Nonetheless, all the experts agree: if we want to reduce the burden of Q fever in Australia, we will need to look beyond the select populations we are currently targeting for vaccination because there are obviously risk factors other than sheep, cattle and goats, at play.

References

Gidding HF, Faddy HM, Durrheim DN, Graves SR, Nguyen C, Hutchinson P, Massey P, Wood N. Seroprevalence of Q fever among metropolitan and non‐metropolitan blood donors in New South Wales and Queensland, 2014–2015. Med J Aust. 2019 Apr; 210(7): 309-15. DOI: 10.5694/mja2.13004 Francis JR, Robson JM. Q fever: more common than we think, and what this means for prevention. Med J Aust. 2019 Apr; 210(7): 305-6. DOI: 10.5694/mja2.50024
By Dr Linda Calabresi
measles
Dr Linda Calabresi
  • Clinical Articles

Diagnosing Measles

The Department of Health requires suspected cases of measles to be notified immediately without waiting for laboratory confirmation. Measles is an urgent, highly contagious, notifiable disease. Secondary infections occur in 75-90% of susceptible household contacts Transmission of the measles virus is by respiratory droplets and direct contact with respiratory secretions
  • Serological testing and PCR are the mainstays of laboratory diagnosis

    • Background

    Measles is a highly contagious disease with secondary infections occurring in 75 – 90% of susceptible household contacts.1 With suboptimal vaccination coverage in some areas, measles outbreaks remain an unfortunate reality in Australia.2 A single case therefore has significant public health implications.

    Clinical features

    Transmission of measles virus is by respiratory droplets and direct contact with respiratory secretions. The virus can also survive on inanimate objects in the patient’s environment for at least 30 minutes. After an incubation period of 10 days (range 7 – 18 days) patients develop a prodrome consisting of fever, malaise, cough, coryza and non-purulent conjunctivitis. Koplik’s spots may develop during this time. These are whitish spots on an erythematous background on the buccal mucosa classically arising opposite the molar teeth. After about four days, a morbilliform rash appears, initially on the face and head, then extending to the trunk and limbs (Figure 1). The rash lasts 3 – 7 days. Patients usually make a full recovery, but complications including otitis media, pneumonia, seizures, and rarely encephalitis (subacute sclerosing panencephalitis) can occur. The case fatality rate in stable populations is estimated at around 2%, but rates up to 32% have been seen in refugee and displaced populations.4

    Laboratory testing

    Serological testing and PCR are the mainstays of laboratory diagnosis. In the early stages of infection, a single serology result demonstrating negative measles IgG and positive IgM in the context of the clinical picture outlined above provides strong evidence for a case of measles. It is important to note that serology can be negative in the early stages of infection. In a minority of patients, IgM may not be detected up to four days after the rash onset.5 Definitive serological diagnosis can be established with acute and convalescent sera, usually taken 10 – 14 days apart. A diagnostic rise in measles-specific IgG is a reliable indicator of recent infection. In early infection, PCR is performed on nose and throat swabs. Nose and throat swabs are usually pooled and analysed together in the testing laboratory. Swabs sent in viral or universal transport media are acceptable for testing, as are ‘dry’ swabs (no transport media). Swabs using bacterial transport media should be avoided as rates of viral detection may be lower. Other specimens that can be used for PCR are first pass urine and anticoagulated blood. When positive, PCR provides rapid confirmation of the clinical picture.

    Case definition for measles

    Initial investigation of suspected Measles
     
    ▪ Generalised maculopapular rash usually lasting three or more days and ▪ Fever (at least 38° if measured) present at the time of rash onset and ▪ Cough, coryza, conjunctivitis and Koplik’s spots
    Notify immediately.
    Laboratory Testing – Serology (IgG & IgM) and PCR.
     

    Treatment and prevention

    Treatment of measles remains supportive only. Infection control measures are important in order to avoid secondary cases. In the clinic;
    • The receptionist receiving patients should be alert to possible measles cases.
    • Those presenting with fever and rash should be given a single use mask and isolated from other patients
    • Consultation rooms used for assessment of suspected measles cases should be left vacant for at least 30 minutes after the consultation.3
    Measles vaccination as part of the routine immunisation schedule for clinic patients is of the utmost importance. It is also important is ensuring that clinic staff vaccinations are kept up-to-date.

    Notification

    Due to its public health importance, the Department of Health requires all suspected cases of measles to be notified immediately without waiting for laboratory confirmation. This will help facilitate timely follow-up of the contacts, vaccination where required and will help prevent further transmission of the virus.

    References

    1. Perry RT, Halsey NA. The Clinical Significance of Measles: A Review. J Infect Dis. 2004 May 1; 189(S1): S4-16. DOI: 10.1086/377712
    2. Victorian Department of Health, Blue Book, Infectious Diseases Epidemiology and Surveillance, Measles. [Accessed 8.9.2014] Available at: https://www2.health.vic.gov.au/public-health/infectious-diseases/disease-information-advice/measles
    3. Kouadio IK, Kamigaki T, Oshitani H. Measles outbreaks in displaced populations: a review of transmission, morbidity and mortality associated factors. BMC Int Health Hum Rights. 2010 Mar 19; 10: 5 [Accessed 8.9.2014]. DOI: 10.1186/1472-698X-10-5
    - 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.
    By Dr Linda Calabresi
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    Dr Linda Calabresi
    • Clinical Articles

    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    
    By Dr Linda Calabresi
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    Dr Linda Calabresi
    • Clinical Articles

    Dysplastic naevi: the controversy continues

    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.  
    By Dr Linda Calabresi
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    Dr Linda Calabresi
    • Clinical Articles

    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 

    By Dr Linda Calabresi
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    Dr Linda Calabresi
    • Clinical Articles

    Anorexia and cancer risk

    You’d think having anorexia nervosa was bad enough. But among all the negative effects it can have on your body, could it also increase your risk of cancer? Or does the condition perversely mimic the caloric restriction and fasting that have been demonstrated to benefit the prevention of some malignancies - meaning could it protect against cancer? That's what European oncology researchers wanted to find out through their systematic review and meta-analysis of a series of studies involving more than 42,000 people with the eating disorder. The result was both encouraging and intriguing. It appears that overall there was no association of anorexia nervosa with risk of cancer. But that’s not the whole story. On further analysis it appears anorexia nervosa was associated with some cancers and not others. In some cases the condition increased the risk and in others it appeared protective, hence the balancing out effect of no association overall. “Findings from our meta-analysis suggest that anorexia nervosa was associated with decreased breast cancer incidence compared with the general female population, with high confidence,” said the study authors in JAMA Network Open. And on the down side, the researchers found anorexia nervosa appeared to be associated with an increased risk of developing lung and oesophageal cancer, although the evidence was less compelling than that for breast cancer. As the authors point out, the breast cancer protection makes sense in terms of physiology. Anorexia notoriously interferes with a woman’s hormones, reducing her levels of oestradiol as well as insulin-like growth factor 1. Women with anorexia often have delayed puberty, early menopause and an overall decreased lifetime exposure to oestrogen so it stands to reason that a hormone-sensitive cancer, such as breast cancer is less likely to develop. But the increased risk of lung and oesophageal cancer is harder to explain. One might think, given the types of cancer we’re talking about that perhaps there was a greater prevalence of smoking among people with anorexia nervosa. But no. “[T]he increased risk of developing lung or oesophageal cancer does not seem to be attributable to a higher prevalence of smoking among women with anorexia nervosa,” they said. Interestingly the authors refer to a 2016 meta-analysis that determined smoking prevalence was much higher among people with bulimia nervosa than the general population, but not anorexia nervosa. The researchers offer no explanation for the association between anorexia and lung and oesophageal cancer, conceding the evidence isn’t strong. However they do warn that the findings suggest perhaps a need for greater vigilance in investigating symptoms suggestive of cancers of either the respiratory tract or the GIT in anorexia nervosa patients. As with most studies, the study authors call for further research to confirm or refute these associations, suggesting that the findings have possibly important implications. “Understanding the mechanisms underlying these associations could have important preventive potential,” they concluded.  

    Reference:

    Catalá-López F1, Forés-Martos J, Driver JA, Page MJ, Hutton B, Ridao M, et al. Association of Anorexia Nervosa With Risk of Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019; 2(6): e195313. DOI: 10:1001/jamanetworkopen.2019.5313
    By Dr Linda Calabresi
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    Dr Linda Calabresi
    • Clinical Articles

    Quality improvement in aged care

    If you look after patients in an aged care facility you should really have a look at this resource. It’s from the Australian Government’s Department of Health and it basically gives you all you need to know about the most recent initiative to ensure high standard of care in these facilities. From July 1, all aged care facilities that receive government subsidies for the services they provide will need to collect and provide data on three specific adverse outcomes that residents might experience. Specifically the government is asking these facilities to record information on pressure injuries, use of physical restraint and unplanned weight loss because these are indicators of clinical quality, or more exactly indicators of poor clinical quality. Every three months residential facilities will need to submit this Quality Indicator (QI) data to the Department of Health which will generate a report. So where do GPs fit in? According to the resource information, GPs will need to get involved in making sure facilities proactively respond to this QI information. The actions GPs are being asked to take are mainly about getting engaged in the programme – ask questions, ask to see the 3-monthly QI reports and help with the interpretation of the information from these reports. It will also be important that GPs contribute ideas on how to improve care. Even though this new initiative is only looking at three indicators, and there are many more that could be considered such as pain and falls, these three were chosen because they each have a broad impact across a number of other care areas – these are the canaries in the mine so to speak. Improve these and a whole lot of other areas of care improve as well. It’s not our usual type of recommended resource but if you’re a GP looking after patients in aged care you will recognise how this initiative could be very important to the health of our elderly patients. Check it out.   >> Access the resource here

    By Dr Linda Calabresi
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    Dr Bruce Baer Arnold
    • Clinical Articles

    Assassination by pacemaker: Australia needs to do more to regulate internet-connected medical devices

    In the future, people are going to be just a little bit cyborg. We’ve accepted hearing aids, nicotine patches and spectacles, but implanted medical devices that are internet-connected present new safety challenges. Are Australian regulators keeping up? A global recall of pacemakers has sparked new fears and splashy headlines about hacked medical devices. But the next 20 years of medicine will normalise the use of intelligent implants to control pain, provide data for diagnostic purposes and supplement ailing organs, which means we need proper security as well as access in case of emergency.
    Read More: Three reasons why pacemakers are vulnerable to hacking
    Pharmaceuticals and medical devices in Australia are regulated by the Therapeutic Goods Administration (TGA), an arm of the national Health Department. Can we rely on Australia’s medical devices regime? Recurrent criticisms by parliamentary committees and government inquiries suggest the regulator may be struggling.

    The job of the TGA

    The TGA regulates medical devices such as stents, pacemakers, joint implants, breast implants, and the controversial vaginal mesh that has featured recently in the media (and a Senate inquiry) over claims it seriously injured patients. The role of the TGA is vital, because defective devices can result in injury or death. They have a major cost for the public health system and affect patient quality of life. They often result in litigation, sometimes with billion-dollar settlements. In undertaking its mission, the TGA looks to information from manufacturers and distributors, from overseas regulators and its own staff. Like counterparts such as the US Food and Drug Administration, TGA staff are under pressure to get products into the marketplace and reduce “red tape”.

    The TGA and cybersecurity

    Wireless medical devices need greater security than, say, an internet-connected fridge. It is axiomatic that they must work. We need to ensure that information provided by the devices is safeguarded and that control of the devices – implantable or otherwise – is not compromised. To do that, we can use existing tools such as robust passwords, encryption and systems design. It also requires product vendors and practitioners to avoid negligence. Regulators must proactively foster and enforce standards. Put simply, bodies like the TGA need to deal with software rather than simply bits of metal and plastic. It is unclear whether the TGA has the expertise or means to do so.

    Solutions, not panic

    The past decade has seen a succession of inquiries into the TGA, including the 2015 Sansom Review and 2012 Senate PIP Inquiry. Each has demonstrated that the TGA is not always keeping up with its task. Problems are ongoing: think defective joint implants, breast implants and vaginal mesh. But there are some potential paths towards improvement. Accountability One solution is to ensure the TGA is more accountable. Currently, if someone wishes to bring a claim alleging a device was improperly permitted, the TGA has immunity from civil litigation about regulatory failure. Removal of immunity will force it to focus on outcomes. That can be reinforced by giving it independence from the Department of Health, making it report direct to Parliament and ensuring the openness emphasised by the Pearce Inquiry. Regulatory capture Medical products regulation in Australia has been a matter of penny wise, pound poor. The TGA is funded by fees from the manufacturers and distributors that it regulates, in addition to some government funding. It needs a discrete budget that recoups costs but is not dependent on companies that complain regulation is expensive. It needs enough resources to do its job well in the emerging age of the internet of things, including access to independent expertise regarding cybersecurity and devices. A device register How many devices have been implanted and how many removed? The lack of data about medical devices is a problem. The government has so far not embraced recommendations for a comprehensive device register, one allowing timely identification of what was implanted and by whom.
    Read More: Vaginal mesh controversy shows collective failure of the TGA and Australia’s specialists
    Such a register would provide a means for determining problems with devices or medical practice. We need timely, consistent reporting of problems on a mandatory basis, as well as recall and transparent investigation of what went wrong. Disclosure of interests The inquiry into vaginal mesh revealed the WA Branch of Australian Medical Association had a financial interest in a device that may have seriously affected numerous women. There must be full disclosure of such interests, with meaningful sanctions where disclosure has not been made. This requires action by the TGA, professional bodies and the government.

    So, what about assassination by wireless pacemaker?

    The cybersecurity of medical devices is a matter for everyone. We need the TGA to work with manufacturers, distributors and health professionals to mandate best practice. Should, for example, manufacturers and practitioners ensure that implants do not rely on default passwords that are easily crackable? What about access by emergency services? The ConversationThere is a fundamental need to develop and enforce a national safety standard regarding all wireless implants. For that we need thoughtful policy, not just headlines. Bruce Baer Arnold, Assistant Professor, School of Law, University of Canberra This article was originally published on The Conversation. Read the original article.
    By Dr Bruce Baer Arnold

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