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Jumat, 29 September 2017

Radiation Therapy for Cancer: Feared, Misunderstood

SAN DIEGO — “Radiation” is not a word obviously associated with healing and medicine but instead often raises specters of nuclear weapons, power plant disasters, and human injury, according to experts who spoke with Medscape Medical News here at the American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting.

As a result, the specialty of radiation oncology needs to step into this information breach and educate patients, the public, and, in a different way, other medical specialties, said commentators.

Patients’ attitudes were a focus at a meeting press conference this week, where Narek Shaverdian, MD, from the University of California Los Angeles presented the results of a survey of 327 patients with breast cancer at their center who received radiation therapy.

Little is known about what patients think about the radiation therapy experience, he said.

The survey revealed that nearly all (94%) of the women were initially fearful of receiving radiation and half (47%) had heard or read frightening stories of serious side effects from the treatment, reported Dr Shaverdian.

The most common initial fears related to damage to internal organs (40%), skin burning (24%), and becoming radioactive (7%).

David Beyer, MD, board chair of ASTRO, who attended the press conference as an observer, was not surprised.

“Most cancer patients have three thoughts in mind when you say radiation: Chernobyl; they think it causes cancer; and they remember an elderly aunt who had horrible radiation burns decades ago,” Dr Beyer told Medscape Medical News.

Patients with cancer are mostly an “older population” and thus can recall a previous era in radiation oncology when adverse events were more common, explained Dr Beyer, who is from the Cancer Centers of Northern Arizona in Sedona. He was not asked for comment but approached Medscape Medical News because he feels so strongly about the subject.

In breast cancer, the evolution of treatment technology and provider skill means that 90% to 95% of patients now report a “good” cosmetic outcome, he said, not citing any statistical source.

“It’s not uncommon to see a woman on follow-up [for breast cancer] and have to consult my notes to see which side was treated,” said Dr Beyer.

Paul Harari, MD, from the Carbone Cancer Center at the University of Wisconsin, Madison, and president-elect of ASTRO, echoed some of these comments.

“The word ‘radiation’ can invoke fear among patients and providers based on misconceptions about toxicity,” he told Medscape Medical News. He also acknowledged that the term “may conjure up worrisome images,” including terrorism.

The specialty needs to get the word out about sophistication of contemporary radiation oncology practice, said Dr Harari.

“A very important effort for the field of radiation oncology is to highlight the tremendous power and precision of radiation in modern cancer treatment,” he said.

To that end, ASTRO’s Board of Directors has recently endorsed an “elevate the profile” initiative. However, “we are only just beginning to develop tactics and tangibles,” said Dr Harari.

A higher profile might help with patients. The breast cancer patient survey from Dr Shaverdian revealed that 68% of respondents had, at the time of diagnosis, “little or no prior knowledge of radiation therapy.”

Doctors also need education, said Dr Shaverdian.

“Breast surgeons are influenced by fears and misconceptions of radiation therapy,” he said while discussing why radiation therapy is not more widely used in high-risk patients with breast cancer after mastectomy, despite recommendations to do so.

Dr Harari hinted at an underlying problem. “Beyond our specialty, there is a relatively limited understanding and appreciation of this remarkably effective modality of cancer treatment,” he said.

The new survey indicated that patients were not scarred by the experience. They completed the survey a median of 31 months (range, 6 to 61 months) after completing radiation therapy

Only eight women (3%) found the negative stories they previously read about radiation therapy to be true, and six women (2%) found the negative stories from family and friends to be true.

On the other hand, 90% reported that the actual experience to be “less scary” than anticipated.

With regard to short-term side effects, 83% reported the overall events to be better than or as expected. And 75%, 61%, and 78% of patients reported pain, skin changes, and fatigue, respectively, to be less than or as expected.

With regard to long-term side effects, 84% reported that these were better than or as expected. And 79%, 73%, and 70% found breast-related pain, size changes, and textural changes, respectively, to be less than or as expected.

In terms of patients’ disease stage, 18% had ductal carcinoma in situ; 38% had stage I; 34%, stage II; and 9%, stage III. Most (82%) underwent breast-conserving surgery. Among the survey respondents, radiation therapy was delivered as standard whole-breast (with or without regional nodal coverage), hypofractionated whole-breast, postmastectomy, and partial breast.

Brian Kavanagh, MD, MPH, from the University of Colorado, Denver, and the outgoing ASTRO president, wondered whether the study results about patients’ fears reflected the fact that any cancer diagnosis is a “frightening prospect.”

Dr Kavanagh moderated the press conference at which Dr Shaverdian spoke.

“It’s always a part of the conversation,” said Dr Kavanagh, who was referring to patient fear and anxiety expressed during an office/clinic visit.

He believes that patients who are not tech savvy (and cannot access online breast cancer information) or who lack financial resources are probably more likely to be fearful.

“I hope most are not incapacitated by fear. I don’t see that personally,” he said about patients in general.

Dr Kavanagh said the important thing is for radiation oncologists to address fears and misconceptions. There is also a built-in tool that enable clinicians to do so. The informed consent process before treatment covers potential side effects, he said, which will address many patients’ lingering and perhaps unspoken concerns.

Study author Dr Shaverdian offered one other insight. “We tried to be proactive in our clinic. We try to explain radiation therapy in simple terms — ‘It’s like an x-ray, but not to take a picture, but to actually treat.'”

One study author disclosed a financial relationship with Accuray. Dr Beyer and Dr Harari have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2017 Annual Meeting. Abstract 85. Presented September 25, 2017.

Follow Medscape senior journalist Nick Mulcahy on Twitter: @MulcahyNick

For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc

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Woman Who Faked Cancer and Cure Is Fined $320,000 Over Hoax

An Australian woman who falsely claimed not only to have had cancer but to have cured it using natural remedies and nutrition has now been fined $322,000 ($420,000 Australian) for misleading the public.

Belle Gibson, a 25-year-old entrepreneur who created a small health and wellness empire after claiming that she had had brain cancer and had cured it herself with the use of natural remedies, fabricated the entire scenario, according to an investigation conducted in 2015 by the Australian newspaper.

As previously reported byMedscape Medical News, an investigation conducted in 2015 by the Australian revealed multiple public contradictions since 2009 about nearly everything – including Gibson’s supposed age, illnesses, treatments, and miraculous recoveries.

In addition, she held fundraisers for charities, but the promised money was never donated.

Last year, Consumer Affairs Victoria launched legal action against her for false and misleading conduct in relation to her health and for unlawful fundraising appeals in 2013 and 2014. She was subsequently ordered to pay $30,000 toward the legal costs of Consumer Affairs Victoria.

Earlier this year, Gibson was found guilty of breaching sections of the Australian consumer law that states “a person must not engage in trade or commerce likely to mislead or deceive.”

She has now been issued a hefty fine by Debra Mortimer, a federal court justice.

Gibson had initially been facing $1.1 million in fines, but the court ordered that she instead pay $420,000 (Australian) because they did not see the point in issuing such a large fine, since she did not have the ability to pay it. As she had done during her trial, Gibson stayed away from court.

A Long, Strange Trip

Little is known about her life prior to 2009, or how much of it is factual. As reported in news.com.au, Gibson described her childhood and adolescence as being filled with extreme distress. She claims to have taken responsibility for an autistic younger brother and a mother with multiple sclerosis by 6 years of age and that she had suffered from severe obesity by age 11. By the time she was 12 years old, she moved out of her home and moved in with a classmate and then with a family friend. She says she never knew her father and became estranged from her mother.

Gibson claims that when she was 20 years old, her current health problems began, and she blames it on a reaction to a vaccine against human papillomavirus. She claims that she experienced vision, memory, and walking problems and that she subsequently suffered a stroke. Not long afterward, she claims she was diagnosed with a malignant brain tumor and that she was given 4 months to live.

After receiving chemotherapy and radiotherapy for 2 months, she passed out on the lawn of a Melbourne hospital. When she awakened, . Gibson says that she “had an epiphany.” The epiphany was that if she only had a few weeks left to live, this was not the way she wanted to live them. And although her physicians thought “she was mad” to refuse further treatment, she embarked on a healing program of natural remedies.

Contrary to predictions by her physicians, Gibson did not die.

In 2010, she gave birth to a healthy son, even though she had been told she could never have children. Two years later, she underwent a miscarriage at 5 months’ pregnancy.

In addition to her brain cancer, she claimed that a German magnetic therapist had diagnosed her with several other malignancies, including cancers of the blood, spleen, uterus, and liver.

Gibson then turned into something of a guru for natural healing. She developed a product called the Whole Pantry, which consisted of a website, a mobile phone app, and a recipe book.

Her $35 cookbook was published by Penguin Books in Australia and had been scheduled to be distributed in the United Kingdom and United States before it was cancelled by the publisher following reports that Gibson’s illness was all a hoax.

Gibson’s $3.79 app had been downloaded at least 300,000 times and was voted Apple’s Best Food and Drink App of 2013. The app was at one time supposed to be part of the recently launched Apple Watch.

She also reportedly ran two fundraising campaigns for various charities, but the bulk of money was never distributed. When questions arose concerning her fundraising activities in 2015, Gibson promised that she would make donations to the organizations which had never been paid after a fundraiser in 2013. She blamed “cash flow” problems for the delay.

Gibson also publicly claimed that she donated 25% of her company’s profits to various causes and reported that $300,000 had already been given to charity. But she soon backtracked on that, claiming that the contributions were in fact never made, because sales of her app were not as robust as she had anticipated. Gibson has been unable to provide a list of any charities that she made donations to, nor has she disclosed how much money the charities have been given.

Guilty as Charged

In 2015, Gibson confessed that “none of it was true.”

She earned a total of $322,00 during the course of her “career”; the court has found that just over $10,000 was made in donations, which was far less than what she claimed.

Gibson never showed up in court during her trial. She was found guilty in March of “most but not all” of the allegations that were levied against her by Consumer Affairs Victoria.

The fine that has now been issued to Gibson was for a variety of infractions, including failing to donate money from the proceeds of her wellness app and failing to fulfill a promise to pay $150,000 to a young boy named Joshua Schwartz who had an inoperable brain tumor.

“Ms Gibson expressly compared the terrible circumstances of young Joshua to her own, asserting she had the same kind of tumor as he did; a statement which was completely false,” Judge Mortimer stated in her ruling.

The infractions and amounts are as follows:

$90,000 for failing to donate proceeds from the sale of The Whole Pantry app, as she had stated she would do
$50,000 for failing to donate proceeds from the launch of The Whole Pantry app
$30,000 for failing to donate proceeds from an event held in 2014 honoring Mothers Day
$90,000 for failing to donate other company profits
$150,000 for failing to donate 100% of 1 week’s app sales to the family of Joshua Schwarz

Physicians ― Get on the Ball

The case of Bell Gibson was highlighted in a Medscape commentary entitled “Are Evil People Influencing Your patients?,” by Art Caplan, PhD, from the Division of Medical Ethics, New York University Langone Medical Center, New York City. He said this case is an example of social media being used to disseminate health information by people who lack ethics and/or knowledge.

“Physicians need to know where to send patients for reliable information. Know the websites, find out about social media so that you can say, ‘Here is a vetted source from the American Cancer Society or the American Medical Association (or other expert professional groups) to help you deal with diseases,’ ” said Dr Caplan. “Do not leave your patients hanging, relying on whatever it is that pops up in the top 10 Google searches.”

The Internet is a powerful tool, he emphasized. “We are not going to censor it. We are not going to shut it down,” said Dr Caplan. “But I believe that medicine has to adapt to and address it. The case of Belle Gibson shows that if we do not do that, a lot of harm may come of it.”

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Brain Inflammation Tied to Depression, Suicidal Thoughts

On individuals with major depressive disorder (MDD), particularly those who experience suicidal thinking, levels of translocator protein (TSPO), a marker of microglial inflammation, are increased, new research shows.

Investigators from the University of Manchester, United Kingdom, found significantly higher levels of TSPO in patients with MDD than in healthy control persons. Levels were particularly high in the anterior cingulate cortex (ACC), which suggests microglial activation. TSPO was also particularly elevated in the insula in patients with depressed and suicidal thoughts compared with those who did not have suicidal thoughts.

“The evidence for a link between depression and inflammation is quite compelling now, and there is also mounting evidence for a link between suicide and inflammation across a range of mental disorders,” lead investigator Peter S. Talbot, MD, told Medscape Medical News.

“If we can learn more about these links, it may lead to more effective prevention or treatments of depression and suicidal thinking by targeting specific aspects of the inflammatory process,” he added.

The study was published online August 12 in Biological Psychiatry.

The Living Brain

Inflammation in depression is a “promising avenue of research for new treatment strategies, based on evidence that at least a subset of individuals with MDD have higher levels of peripheral proinflammatory cytokines,” the authors write.

Previous research has found a high prevalence of depression in patients with inflammatory medical disorders, and there is evidence that inflammation may be associated with lack of response to antidepressants.

Peripheral inflammation can cause an inflammatory response in the brain in which the metabolism of tryptophan “is diverted from the production of serotonin to kynurenine, which is subsequently converted into the neurotoxic quinolinic acid by activated microglia and infiltrating macrophages and monocytes,” they note.

Research on animal models has supported this understanding of the neuroinflammatory pathway. Postmortem studies have found increased levels of quinolinic acid in the ACC of individuals with depression who had died by suicide. In addition, microglial and astrocytic activation has been found in the ACC, the thalamus, and the frontal cortex of patients with depression.

Evidence of an association between neuroinflammation ― specifically, microglial activation ― and suicidality has been based on postmortem studies. No previous research has specifically investigated the association between neuroinflammation and suicidality in living patients.

Positron-emission tomography (PET) scans and radioligands specific for the 18-kDa TSPO, a mitochondrial protein that is upregulated in activated glial cells, provide a useful index for measuring neuroinflammation in living patients.

The researchers set out “to investigate brain TSPO availability in MDD and to explore factors that might be associated with heightened inflammation” using the “prototypical” TSPO radioligand [¹¹C] (R )-PK11195 to measure brain TSPO availability in nonsmoking, medically healthy, and antidepressant-naive or antidepressant-free patients with moderate to severe depression.

Three areas of the brain were chosen as the focus of the study: the ACC, the prefrontal cortex (PFC), and the insula. These areas were chosen because in a previous study, TSPO levels in these areas were to be significantly elevated in patients with depression. These areas also play a role in mood regulation, and previous research has found that the ACC has a role in the association between inflammation and depression.

Markers of Inflammation

A secondary aim of the study was to explore the associations between brain TSPO levels, symptom severity, suicidal ideation, exercise levels, childhood adversity, and peripheral markers of inflammation.

“Most of the previous evidence is based on blood tests and postmortem brain samples, and relatively little has been known so far about what is going on in the living brain during a major depressive episode or suicidal thinking,” said Dr Talbot.

“PET is such an important imaging technique because it allows us to measure levels of a range of chemicals in the living brain and can provide evidence for microglial activation, which is, in turn, evidence for the presence of an inflammatory process in the brain,” he said.

To investigate these associations, the researchers compared 14 patients with moderate to severe MDD with 13 sex- and age-matched health control persons. The patients were 15 to 55 years old and had been diagnosed on the basis of DSM-IV criteria as having moderate to severe MDD. Depression was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) (mean score ± SD = 31 ± 4) and the Hamilton Depression Rating Scale (HDRS) (mean score ± SD = 20 ± 3). Seven of the 13 control persons were men (mean age of control persons ± SD = 33 ± 11 years).

Patients were required to be either antidepressant-naive or to have been free of antidepressant use for at least 8 months. All participants were required to be nonsmokers and to be medically healthy, as determined on the basis of on clinical history, physical examination, routine blood tests, and urine toxicology.

The researchers measured the participants’ body mass index (BMI), degree of childhood adversity (assessed using the Childhood Adversity Questionnaire), physical exercise (measured by the Godin Leisure-Time Exercise Questionnaire), and the levels of several inflammatory markers of inflammation in plasma (tumor necrosis factor–α [TNF-α], interleukin-6 [IL-6], IL-8, IL-1β, and C-reactive protein [CRP]).

TSPO availability ([¹¹C] (R)-PK11195 binding potential [BP_ND]) across the hypothesized regions (ACC, PFC, and insula) was higher by a mean of 39% in the patients with MDD than in the control persons. The finding was statistically significant (MANOVA, main effect of group: F _3,23 = 5.63, P = .005).

The highest increase was found in the ACC (67%); smaller elevations were found in the PFC (29%) and the insula (24%).

Univariate tests conducted on individual regions found that the elevation in ACC was of large effect size and was statistically significant (F _1,25 = 5.99, P = .022; partial η ² = 0.193; Cohen’s d = 0.95). The elevations in the PFC and the insula had small effect sizes and did not reach statistical significance.

“Surprising” Difference in Suicidal Patients

To analyze the effects of suicidal ideation on TSPO availability, the researchers stratified patients into those with and those without current suicidal thoughts (n = 9 and n = 5, respectively).

There were no significant difference in age, sex, BMI, or injected mass of radiotracer between the two MDD subgroups, and they were well matched for overall disease severity with respect to scores on the MADRS and HDRS.

The researchers found significant differences in TSPO availability among the groups (control persons, patients with suicidal thinking, and patients without suicidal thinking) across all three regions (MANOVA, main effect of group: F _6,46 = 4.22, P = .002).

Univariate tests on the individual regions found statistical significance and large effect size in the ACC (F _2,24 = 9.91, P = .001; partial η ² = 0.452) and the insula (F _2,24 = 4.59, P = .021; partial η ² = 0.277) and trend significance in the PFC (F _2,24 = 3.15, P = .061; partial η ² = 0.208).

Pairwise comparisons showed that TSPO availability in the ACC and the insula was significantly higher in patients with suicidal thinking than in those without suicidal thinking and that availability trended higher in the PFC. In addition, TSPO availability in the ACC was also significantly higher in patients with suicidal thinking than healthy control subjects.

The researchers found no significant correlations between BP_ND in any of the regions and symptom severity, illness duration, BMI, childhood adversity, or any of the peripheral inflammatory markers.

Likewise, there were no differences in concentration of peripheral inflammatory markers between patients with and those without suicidal thoughts. However, there was a negative correlation in patients with MDD between BP_ND in the ACC and their degree of physical exercise that reached trend significance (r = −0.47, P = .07).

“One surprising aspect of the results was the size of the difference in microglial activation between the suicidal and nonsuicidal depressed patients,” Dr Talbot commented.

“In one way, it’s not surprising, because it fits with the previous nonimaging literature. But I was surprised that the effect was so large that we could identify it so clearly in such relatively small subgroups,” he said.

He cautioned that because the groups were relatively small, the findings should be regarded as “preliminary and in need of confirmation in a larger study, but they are an important first step in helping us learn more about the links between suicidality and inflammation in the living brain.”

Future Targets

Commenting on the study for Medscape Medical News, Jonathan P. Godbout, PhD, professor in the Neuroscience Institute for Behavioral Medicine Research, Ohio State Wexner Medical Center, Columbus, described the study as “a good starting point to say inflammation in depression is real and is a target for inflammation” because “we need ways to determine neuroinflammation in living, breathing human beings instead of relying on postmortem studies.”

He cautioned that although TSPO is a well-validated, established marker of microglial activation, it is only one inflammatory marker among many, and “there is a lot more to microglial activation than change in a single marker.”

Nevertheless, “it is nice to have imaging techniques that can detect inflammation in humans,” said Dr Godbout, who was not involved in the study.

The research has important clinical implications, he stated. “I think scans like this can one day be used diagnostically, although they are expensive, because if you can identify the cell type generating inflammation in the brain, you have a target for intervention.”

Dr Talbot added that there are some take-home messages for practicing clinicians even now.

“Although PET scans for microglial activation are not yet at a point where they can be used diagnostically or to help guide treatment, there are lifestyle changes that patients with depression could take immediately that are broadly anti-inflammatory and may be helpful in reducing the intensity of their depression over time.”

These include smoking cessation; reducing weight, cholesterol, and blood pressure if they are elevated; and increasing physical exercise, since “our findings showed a trend for those depressed patients who had the highest levels of physical exercise to have the lowest levels of brain microglial activation.”

He noted that there are important implications for future research.

“The link between suicidality and microglial activation is intriguing and needs to be confirmed in a larger study with depressed patients and also investigated in a range of other disorders in which the risk of suicide is increased, such as bipolar disorder and schizophrenia,” he said.

If anti-inflammatory drugs prove effective in treating depression and suicidality, “it is likely that their effectiveness will be in particular subgroups of patients rather than all patients.” Research would be needed to identify those patients most likely to benefit from them.

Lastly, “it will be important to investigate whether nonmedication treatments for depression, such as CBT and lifestyle changes, can have anti-inflammatory effects in the brain as part of their mechanism of effectiveness.”

Financial support for the study was provided by Karl Herholz and the University of Manchester’s Magnetic Resonance Imaging Facility. The authors have disclosed no relevant financial relationships.

Biol Psychiatry. Published online August 12, 2017. Abstract

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Cognitive Dysfunction Linked to Increased Parkinson's Risk

Early cognitive dysfunction may be a significant risk factor for future risk for parkinsonian disorders, including Parkinson’s disease (PD), new research suggests.

Among more than 7300 study participants, those with low overall cognitive scores at baseline were at significantly greater risk for incident parkinsonism and for probable PD 8 years later than those with higher baseline scores.

Risk for parkinsonism was also increased for those with poor scores on a range of different types of tests, including letter-digit substitution and verbal fluency.

“The findings suggest that cognitive dysfunction can be considered a sign of prodromal PD,” the investigators, led by Sirwin K.L. Darweesh, MD, Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands, write.

Dr Darweesh told Medscape Medical News that although the investigators were not surprised to see the association between poor cognitive function and “short-term risk” of parkinsonism, it was interesting to see that the risk went beyond an 8-year interval.

“Furthermore, our observation that diverse domains of cognition, including executive, attention, cognitive speed, and memory, are already implicated in prodromal parkinsonism patients extends prior observations” in those with clinical parkinsonism, he said.

The findings were published online September 25 in JAMA Neurology.

“Growing Urgency”

Although previous research has shown that patients with PD often have cognitive dysfunction, “there is a scarcity of data on cognitive functioning before parkinsonism diagnosis,” the authors write.

“In clinical parkinsonism patients, most notably those with Parkinson’s disease, damage to the brain is already quite advanced at the time of diagnosis, rendering them less susceptible to putative disease-modifying interventions,” added Dr Darweesh.

“As a consequence, there is a growing sense of urgency to unravel the prodromal phase of common parkinsonism diseases.”

For the current analysis, the investigators assessed 7386 participants in the prospective, population-based Rotterdam Study (57.4% women; mean age, 65.3 years). Baseline cognition was assessed between January 2002 and December 2008 by using a battery of tests.

In the study cohort, 1.1% developed incident parkinsonism during a mean follow-up of 8.3 years. Of these participants, 72.2% were diagnosed with probable PD, and 30.4% had comorbid dementia.

In the 24 patients who had comorbid dementia, 10 developed it before onset of parkinsonism, while the others developed it afterwards.

Results showed that the participants who had low global cognition scores at baseline were more likely to have incident probable PD than those with higher scores at baseline (adjusted hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.11 – 2.08). Changes in semantic fluency were also associated with probable PD (HR, 1.35).

The following table shows that low scores on several cognitive tests were significantly associated with increased risk for parkinsonism.

Table. Risk Factors for Incident Parkinsonism

Low Baseline Scores for:	HR (95% CI)
Global cognition	1.79 (1.37 – 2.33)
Letter-digit substitution	1.59 (1.22 – 2.04)
Verbal fluency	1.61 (1.23 – 2.08)
Inverted interference task on Stroop color word test	1.56 (1.25 – 1.96)

The association between poor baseline global cognition scores and incident parkinsonism remained significant past 8 years (HR, 1.59; 95% CI, 1.01 – 2.59). Even after exclusion of the participants who developed dementia, the HR was still a significant 1.72.

The likelihood ratio for parkinsonism development was 2.66 for those who had both cognitive impairment and “subtle motor signs” at baseline (95% CI, 1.64 – 4.32).

“Our data provide important insight” into the link between cognitive dysfunction and risk of parkinsonism within the general population, “especially given the fact that, to our knowledge, only 2 community-based studies have previously published data on this topic,” write the investigators.

Changing the Disease Course

In an accompanying editorial, Ethan G. Brown, MD, and Caroline M. Tanner, MD, PhD, both from the Movement Disorders and Neuromodulation Center at the University of California, San Francisco, write that the Rotterdam Study “provides an excellent setting” for looking into these issues.

“Because this is a large, community-wide cohort with low attrition, the results are broadly applicable,” the editorialists write.

However, noted limitations include the following: “the neuropsychological assessment was not as thorough as currently recommended” for assessing cognition in PD; the primary outcome was development of parkinsonism, including vascular and medication-induced versions, instead of development of PD; and “the study design precluded specialist adjudication of all PD diagnoses.”

Still, “these findings have numerous implications,” Dr Brown and Dr Tanner write.

They note that the association between changes in semantic fluency and probable PD echoes previous results and underlines the importance of giving this type of test early on. Another key finding was that patients with mild cognitive impairment, especially those with subtle motor signs, may have prodomal PD.

“This recognition can allow physicians to screen for falls or other nonmotor aspects of PD in these cases and provide early treatment for these symptoms,” they write.

“Intervening at the earliest stage of PD may provide the best chance for slowing disease progression and maintaining function. Clarification of the early course of PD with studies such as this may allow identification in time to change the course of disease.”

The analysis was supported by Stichting ParkinsonFonds. The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission; the Netherlands Genomics Initiative; and the Municipality of Rotterdam. The study authors have disclosed no relevant financial relationships. Dr Brown receives compensation for serving on the Fellowship Advisory Board for AbbVie Inc. Dr Tanner reports receiving grants from the Michael J Fox Foundation, the Parkinson’s Disease Foundation, the Department of Defense, Sage Bionetworks, and the National Institutes of Health; compensation for serving on Data Monitoring Committees for Biotie Therapeutics, Voyager Therapeutics; and Intec Pharma; and consulting fees from Neurocrine Biosciences, Adamas Therapeutics, and PhotoPharmics.

JAMA Neurol. Published online September 25, 2017. Abstract, Editorial

Follow Deborah Brauser on Twitter: @MedscapeDeb

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All Opioids Now Subject to REMS, FDA Says

The US Food and Drug Administration (FDA) has made good on its promise to require that immediate-release (IR) opioids be subject to the same set of prescribing rules as extended-release formulations of the drugs.

In July, FDA Commissioner Scott Gottlieb, MD, put the public and manufacturers on notice that the agency would soon be putting all opioids on a level playing field. On September 28, Dr Gottlieb said the agency had now taken action and that 277 IR opioids would be subject to Risk Evaluation and Mitigation Strategy (REMS) requirements.

“This week, we issued letters notifying 74 manufacturers of IR opioid analgesics intended for use in the outpatient setting that their drugs will now be subject to a more stringent set of requirements under a Risk Evaluation and Mitigation Strategy,” said the FDA Commissioner in a blog post. “The REMS requires that training be made available to health care providers who prescribe IR opioids, including training on safe prescribing practices and consideration of nonopioid alternatives,” said Dr Gottlieb.

The FDA has asked manufacturers to extend the training offer to pharmacists, nurses, and any providers involved in pain management.

To offer the training, manufacturers have provided unrestricted grants to accredited continuing education providers for courses that have content that has been “outlined” by the FDA, said Dr Gottlieb. That “blueprint” of training content is being updated to cover principles on acute and chronic pain management; nonpharmacologic, opioid, and nonopioid pharmacologic pain therapies; information about the safe use of opioids; and basic information about addiction medicine and opioid use disorders.

The FDA said it is also seeking public comment on whether such training should be mandatory for prescribers.

Interested parties have until December 29 to submit comments to the agency.

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Medullary Thyroid Cancer Surgical Recommendations Often Ignored

Only about a third of patients with medullary thyroid carcinoma (MTC) receive the recommended initial treatment of a total thyroidectomy in addition to central neck lymph-node dissection, despite recommendations in guidelines to combine the two to decrease the possibility of reoperative surgery.

“The low rate of adherence to American Thyroid Association (ATA) guidelines was one of the more puzzling findings of our study,” senior author Masha J Livhits, MD, of the section of endocrine surgery in the department of surgery at the University of California, Los Angeles (UCLA) David Geffen School of Medicine, told Medscape Medical News.

The results of the new study are published this week in JAMA Surgery by Eric J Kuo, MD, also of the department of surgery at UCLA David Geffen School of Medicine, and colleagues.

“The evidence for performance of central neck dissection is robust, [and] prior studies have shown that even in small medullary thyroid cancers less than 1 cm in size, the rate of lymph node metastasis is nearly 40%,” Dr Livhits noted.

“Therefore, the performance of [central neck] nodal dissection in medullary thyroid carcinoma is justified,” she stressed.

Dr Livhits ventured a couple of explanations for the low rates of adherence to the guidelines — one could simply be lack of awareness of the recommendations, she said. Or in some cases, it may be that the surgeon didn’t know the diagnosis was MTC until after the operation, because no preoperative biopsy was performed.

In an invited commentary accompanying the new study, Jessica E Gosnell, MD, and Quan-Yang Duh, MD, of the University of California, San Francisco department of surgery, noted that this latest work underscores the low adherence to ATA guidelines, as well as providing some key insights regarding reoperations.

Only 35% of Patients Had Central Neck Node Dissection at Time of Surgery

Even though only about 5% of thyroid cancer is medullary, this type is more aggressive; it also differs from other thyroid cancers in that patients have elevated calcitonin, for example.

The ATA guidelines for medullary thyroid carcinoma, first published in 2015, support the long-held recommendation of prophylactic central neck dissection with total thyroidectomy as standard treatment; however, population-level data on the practice has been lacking.

For the new research, Dr Kuo and colleagues conducted a retrospective analysis of data from the California Cancer Registry (CCR) and the Office of Statewide Health Planning and Development (OSHPD), identifying 609 patients with medullary thyroid carcinoma who were treated between January 1999 and December 2012 and had a minimum of 2 years postoperative follow-up.

The patients had a mean age at the time of diagnosis of 52.6 years and the mean tumor size was 2.8 cm, with extrathyroidal extension in 18.7% of patients.

Despite the ATA recommendation, only 35.5% (216 patients) had undergone central neck dissection at the time of their initial thyroidectomy.

Of the entire cohort, 99 required reoperation (16.3%), which is consistent with rates reported in the literature. The median time to reoperation was 6.4 months.

After adjustment for multiple factors, a leading risk factor for reoperation was the presence of lymph-node metastasis (hazard ratio [HR], 3.43).

Meanwhile, central as well as lateral neck dissection — which is indicated in the presence of lymph-node metastasis, was protective of the risk of reoperation (HR, 0.53).

“The performance of central and lateral neck dissection was associated with a decreased risk of reoperation, particularly for patients who were initially seen with regional disease,” the authors note.

But of interest, the ATA recommendation of central neck dissection, alone, with thyroidectomy was not significantly associated with a reduced risk of reoperation. However, Dr Livhits underscored the fact that this finding may have been the result of the study design.

“Our finding that central neck dissection alone was not protective of reoperation is likely a limitation of our data source,” she said. “We used an administrative data set that relies on procedure codes being accurately recorded. Codes for central neck dissection are less precise and prone to errors, which likely contributed to our inability to observe an effect in this group.”

Avoid Reoperation Due to Possibility of Complications

The 5-year disease-specific mortality rate for the entire cohort of patients was 13.5% (82 patients), and the strongest factors associated with this were: metastatic disease (HR, 21.08), regional disease (HR, 4.77), larger tumor size (HR, 2.83 for >2 cm to 4 cm and HR, 2.89 for >4 cm), and older age (HR, 1.36 per decade).

There was no significant association between reoperation and an increased risk of mortality; among the 99 patients who underwent reoperation, fewer than half, 45.5% (45), were disease-free at a median follow-up of 7.7 years.

The lack of an association between reoperation and mortality likely represents the selection of appropriate patients, Dr Livhits said.

“In our opinion, this finding indicates that selected patients who have recurrent medullary thyroid cancer, which is amenable to reoperation, still do well following a second surgery,” she noted.

“This supports reoperation when necessary in appropriately selected patients.”

She added that “prior studies have reported that patients whose calcitonin level (a tumor marker for medullary thyroid cancer) is not too high prior to reoperation and who did not have extensive lymph-node dissection during the initial surgery can be cured following reoperation.”

Nevertheless, measures to avoid reoperation in the first place are considered necessary out of concern for the array of potentially serious complications that can arise in a reoperation, particularly relating to the development of scar tissue in a site previously operated on, Dr Livhits explained.

“This makes dissection and identification of important structures more difficult.”

In such situations, the recurrent laryngeal nerve can be placed at risk, which can result in temporary or permanent vocal-cord paralysis, for example.

Also at risk are the parathyroid glands, which, if injured could compromise calcium levels, subsequently resulting in various cardiac, neurologic, and musculoskeletal symptoms.

Adherence to ATA Guidelines for Surgery for MTC Will Reduce Reoperations

Reasons for the relatively low rates of adherence to the ATA guidelines regarding central neck dissection could vary, Dr Livhits speculated.

“In some cases, the surgeon may have not known that the patient had medullary thyroid cancer until after the surgery — [for instance], if the diagnosis was not made on preoperative biopsy, but only made on examination of pathology following surgery,” she said.

“In other cases, it may be due to a lack of awareness of guidelines.”

Evidence in support of the ATA guidelines includes studies showing that central neck metastases are frequently present in medullary thyroid cancer even when not identifiable pre- or intra-operatively.

“It follows that not doing central neck dissection in these patients would leave residual micrometastases that would eventually become clinically significant,” Dr Livhits said.

In addition, other previous research, including a recent study (Ann Surg Oncol. 2015;22:1207–1213), meanwhile have shown fewer reoperations in association with adherence to the ATA guidelines.

In terms of the inclusion of lateral neck dissection, the ATA guidelines indicate that, in addition to the presence of lymph-node metastasis, if patients have very high calcitonin levels, “the likelihood of lateral neck metastasis is high enough to consider lateral neck dissection at the outset as well,” Dr Livhits explained.

“However, to say that lateral neck dissection should be performed routinely in the absence of abnormal lymph nodes seen on preoperative imaging is likely overreaching.”

Study Provides Several Important Lessons

In their commentary, Drs Gosnell and Duh say: “There are several important lessons from this population study of patients with medullary thyroid cancer.

“First, despite the recommendation for total thyroidectomy and bilateral central neck dissection in patients with clinically diagnosed medullary thyroid cancer, a fair proportion of affected patients are not getting these operations.

“Second, neck dissection performed at the initial operation may be protective, [and] third, while many patients with medullary thyroid cancer develop recurrent disease, reoperations are not associated with increased mortality.

“The potential benefits of proactive surgical treatment appear clear,” they state.

The overall message is that “even patients with recurrent and metastatic medullary thyroid cancer can be treated with repeated reoperations and still live full and active lives.” Because of this, it “is therefore critically important to minimize complications along their sometimes decades-long disease course.”
The study received partial support from the H & H Lee Research Program. The authors of the study and editorial had no relevant financial relationships.

JAMA Surgery. Published September 27, 2017. Abstract, Editorial

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Majority of Clinicians Experience Verbal Abuse, Intimidation

The workplace appears to be an occasionally toxic environment for healthcare providers, as a majority of those responding to a recent Medscape Medical News poll said they had been victims of a range of verbal and physical violence at the hands of patients, and, often, colleagues.

Another large majority said they had witnessed violence, and most respondents said they had been given only minimal training to respond to the onslaught, and that there were insufficient protocols in place to protect them.

The poll was conducted in late July, in the wake of the shooting death of Tracy Sin-Yee Tam, DO, a 32-year-old family physician at the Bronx-Lebanon Hospital Center in New York City. A disgruntled ex-employee — a physician — murdered Dr Tam and wounded a patient, two medical students, two residents, and a gastroenterology fellow, before killing himself.

Overall, 88% of the 2389 respondents to the poll — who included nurses, advanced practice nurses, physicians, pharmacists, and other providers — said they’d personally experienced verbal abuse, and 76% said they’d experienced intimidation. About two-fifths said they’d been victims of physical assault, and 30% had experienced sexual harassment. Respondents also reported having been stalked.

Ninety-two percent said they’d witnessed verbal abuse and 81% said they’d witnessed intimidation, while 55% said they’d seen a physical assault.

Most often, the perpetrator acted out because of altered mental state from a mental illness or substance abuse, said poll respondents. Sorina Simion-Rodgers, MD, a psychiatrist, said, “The assaults (both physical and verbal) as well as intimidation and threats that I experienced were not from severely ill mental patients or dementia patients, but rather from malingerers, personality disorders, substance abusers and families.” She added, “We are told by administration that being abused, hurt or even disabled by an attack is ‘part of our job.'”

Susan Hicks, a pharmacist, said that “a patient who demanded a controlled drug” tried to harm her with a box cutter, but, “luckily, I was able to move fast enough to get away from the patient.” Hicks said she “also experienced verbal abuse from drug seekers and pseudoephedrine seekers.”

Some commenters said they had experienced or witnessed violence from patients — or families — who were just plain unhappy with the response they got from health providers. Overall, for instance, 38% said people were irked at long wait times, and 26% said the acting out was in response to receiving bad news.

“Some patients and/or their families become verbally abusive when they don’t agree with your diagnostic impressions and/or treatment plans, leading to a difficult situation,” said Emilio Gonzalez, MD, a rheumatologist.

Seventeen percent said what they witnessed or experienced was a reaction to overcrowding, and a quarter said it was from a disgruntled employee. Overall, 29% of respondents cited “other” as the reason for the violence, which some commenters suggested was a stand-in category for employee-on-employee violence.

“I had to meet with the chief of police regarding threats of physical violence made against me by faculty in my own institution,” said Edward Klatt, MD, a pathologist. The administration “did nothing,” said Dr Klatt, adding, “Incivility sucks the life out of an institution. Everyone is adversely affected in some way.”

Nursing, Emergency Medicine Most Under Fire

Nurses and advanced practice nurses reported personally experiencing or witnessing physical assault more than physicians, pharmacists, or other healthcare providers. Half of all nurses said they were victims of an assault compared with 36% of physicians, 18% of pharmacists, and 24% of other providers. Nurses in emergency medicine settings reported the highest rates of assault — 77% said they’d experienced physical violence — followed closely by those in psychiatric settings.

Verbal abuse and intimidation of nurses was also higher in emergency medicine than in family medicine. Nurses in emergency medicine, psychiatry, and family medicine also reported much higher rates of sexual harassment — both experiencing it and witnessing it — than physician colleagues. Some 42% of psychiatrists, however, said they’d experienced sexual harassment — compared with 28% of emergency medicine doctors, for instance.

Emergency physicians and psychiatrists also experienced and witnessed more physical assault than colleagues in family medicine (25%) or internal medicine (29%). Some 68% of emergency physicians said they’d experienced an assault, and 99% said they’d witnessed violence.

Psychiatrists were more likely to report they’d been victims of stalking — 23%, compared with 13% of emergency medicine doctors and 9% of internists.

Sadly — but perhaps not surprisingly — the violence seems kept under wraps by victims.

About a third of psychiatrists and psychiatry nurses said they always reported violence they had experienced, but they seem to be the exception. Overall, only 18% of emergency nurses and 11% of emergency physicians said they always reported being victims of violence. Nearly 60% of emergency room nurses sometimes, rarely, or never filed a report.

Hospitals Cited as Unsupportive

Overall, the hospital was reported most often as the environment where violence was experienced or witnessed, cited by 85% of respondents. Physicians also reported violence in office and outpatient settings.

Almost 70% of the total respondents said they’d received no or minimal training in how to cope with workplace violence. Many commenters said they blamed administrators for not taking workplace violence — and bullying — seriously.

“I was violently physical[ly] assaulted in an outpatient mental health facility on March 16, 1998,” said Debra Riggs, RN, who added, “I have had severe and chronic [post-traumatic stress disorder] since that time.” Riggs said the facility’s CEO contacted her after her treatment, and that “he thought it funny that my colleagues wanted security in the workplace.” The nurse said that friends and coworkers ostracized her and that she received no support from colleagues or administrators.

Another RN, Denise Bleak, said she had experienced bullying. “I’ve been kicked in the chest, slugged in the mouth, hit on the head by an administrator (she stopped when I told her she was on camera), had a doctor throw a chart at me as a new RN in ICU.”

“My message to all is always speak up, report, and learn to say loudly if it is a coworker, ‘stop it. I don’t like that.’ Being loud made me unpopular and kept me safe.”

Bleak said she believed that “there is no administrative safety culture (it is often fakery) and little peer support for square pegs in round holes.”

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