Day: 09/30/2015

U.S. states urge FDA to ensure warnings on liquid nicotine products

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Attorneys general of 33 U.S. states, including New York’s Eric Schneiderman, urged the Food and Drug Administration to ensure health warning labels on nicotine-containing liquids and other novel tobacco products.

The attorneys general in a letter on Tuesday urged the health regulator to take immediate action to stem the increasing incidence of liquid nicotine poisoning among children.

The news comes more than three months after New York fined four makers of liquid nicotine used in electronic cigarettes over packaging that was too easy for children to open, in violation of a law enacted in 2014.

More than 3,700 children exposed to liquid nicotine were reported at poison control centers in 2014, a sharp increase from previous years, according to the American Association of Poison Control Centers.

The cases reported included half of those related to poisoning of children under the age of five along with an 18-month-old toddler in New York who died after ingesting liquid nicotine.

The letter cited a survey in which 87 percent of adult respondents supported FDA requirements for child-resistant packaging for all e-cigarettes and liquid nicotine refills.

The e-cigarette industry has seen an increase in demand from young people and this increased usage has resulted in accidental poisonings from exposure to liquid nicotine.

Liquid nicotine comprises nicotine, which is extracted from tobacco and added with chemical additives. It is used in electronic cigarettes, which convert the liquid nicotine to a vapor inhaled by the user.

“Given the growing popularity of ‘tank’-style vaping devices, which require periodic refilling with liquid nicotine, public health threats from nicotine exposure will increase in the absence of appropriate FDA regulation,” the letter said.

Hiker Fatality From Severe Hyponatremia in Grand Canyon National Park

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We present the case of a hiker who died of severe hyponatremia at Grand Canyon National Park. The woman collapsed on the rim shortly after finishing a 5-hour hike into the Canyon during which she was reported to have consumed large quantities of water. First responders transported her to the nearest hospital. En route, she became unresponsive, and subsequent treatment included intravenous normal saline. Imaging and laboratory data at the hospital confirmed hypervolemic hyponatremia with encephalopathy. She never regained consciousness and died of severe cerebral edema less than 24 hours later. We believe this is the first report of a fatality due to acute hyponatremia associated with hiking in a wilderness setting. This case demonstrates the typical pathophysiology, which includes overconsumption of fluids, and demonstrates the challenges of diagnosis and the importance of appropriate acute management. Current treatment guidelines indicate that symptomatic exercise-associated hyponatremia should be acutely managed with hypertonic saline and can be done so without concern over central pontine myelinolysis, whereas treatment with high volumes of isotonic fluids may delay recovery and has even resulted in deaths.

Case presentation

On September 3, 2008, a previously healthy 47-year-old woman from London, England, hiked for approximately 10 km on the South Kaibab Trail in Grand Canyon National Park, descending and then ascending roughly 900 m in elevation over a 5-hour period. The day was clear and sunny. Temperatures were near 10°C at the start of the hike at approximately 0800 hours, and 26.6°C at the end of the hike near 1300 hours. During the hike, her husband reported she “drank a large amount of water and ate very little,” but actual amounts are unknown. On arrival at the rim, she took a shuttle bus ride of approximately 15 minutes from the trailhead to Grand Canyon Village. Shortly thereafter, at 1400 hours, she had a syncopal episode, falling face forward onto a concrete sidewalk. According to her husband, she quickly regained consciousness, with no apparent head trauma. Grand Canyon National Park Service emergency medical service (EMS) responders were notified and arrived on the scene within 8 minutes of the call.

The patient was found sitting upright, awake but slow to respond to questions and complaining of a headache. She had no obvious signs of trauma to her head or elsewhere, and other than appearing lethargic, she had an unremarkable examination. An initial Glasgow Coma Score (GCS) was 15. Initial vital signs were stable, with blood pressure of 110/74 mm Hg, pulse of 70 beats/min, and respiratory rate of 16 breaths/min. Pulse oximetry was normal at 96%, and finger stick glucose was 82 mg/dL. An intravenous (IV) line was started, and the patient was placed in cervical spine precautions. At 1430 hours, 30 minutes after her syncopal episode, as ground ambulance transport began to the nearest hospital emergency department (128 km and 1.5 hours away), she abruptly sat upright, pulling out her IV line in the process. She then vomited a large amount of clear fluid (estimated 500 to 1000 mL) and immediately became unresponsive with a GCS of 8. She was noted to have sinus bradycardia immediately after the emesis, with a heart rate of 42 beats/min and blood pressure of 124/75 mm Hg. An electrocardiogram was unremarkable other than the bradycardia. An IV line was reestablished, and she was given 0.5 mg of IV atropine. The decision was made to expedite her transport by changing from ground to air ambulance, with the ground ambulance meeting an EMS helicopter at a highway location 48 km south of Grand Canyon Village where the transfer would be made. Over the next 30 minutes while in route to the transfer location, she received 600 mL IV normal saline. A nasopharyngeal airway was placed, and pulse oximetry was 99% on supplemental oxygen. At approximately 1540 hours, the patient and her care were transferred to the air ambulance EMS team. Her blood pressure and pulse remained stable, but her neurologic status had deteriorated to a GCS of 7. Her nasopharyngeal airway was replaced with an endotracheal tube. At approximately 1600 hours, she was on a life flight to the hospital 80 km away. An additional 400 mL IV normal saline was given before arrival at the hospital. Prehospital serum sodium testing was not done at any point because neither EMS crew was equipped with point-of-care blood analyzers at the time.

On arrival in the hospital emergency department at 1645 hours, the patient’s blood pressure was 161/108 mm Hg, heart rate 76 beats/min, respiratory rate 16 breaths/min, temperature 33.3°C (method not recorded), and oxygen saturation 100% on ventilator. On physical examination, her head was found to be normocephalic and atraumatic. Her eyes showed fixed and dilated pupils at 5 mm. Lungs were clear, heart tones were normal, and no extremity edema was noted. A comprehensive metabolic profile showed the following: low serum sodium at 127 mmol/L (normal range 135–145 mmol/L), low potassium at 2.5 mmol/L, chloride 91 mmol/L, bicarbonate 22 mmol/L, glucose 204 mmol/L, anion gap 17, calcium 8.4 mg/dL, albumin 4.7 g/dL, total bilirubin 0.5 mg/dL, alanine aminotransferase 21 U/L, aspartate aminotransferase 33 U/L, alkaline phosphatase 60 U/L, blood urea nitrogen 13 mg/dL, creatinine 0.6 mg/dL, and slightly low calculated serum osmolality of 275 mOsm/kg. Creatinine kinase was 361 IU/L; complete blood count and cardiac enzymes and coagulation studies were normal. A Foley catheter was placed, and 2000 mL clear urine was obtained with specific gravity of 1.007. Urinalysis and urine toxicology were negative. Urine osmolality was not done. Severe closed head injury was considered part of the differential diagnosis, and a head computed tomography scan was obtained. It showed severe cerebral edema and impending herniation, but no evidence of trauma or intracranial hemorrhage. Cervical spine radiographs were normal.

During the 2 hours of treatment in the emergency department before transfer to the intensive care unit, an intensivist and neurosurgeon were consulted. The patient received 60 g IV mannitol and 40 mg IV furosemide, and was started on a 3% hypertonic saline drip at 40 mL/h. She was also provided IV normal saline at 125 mL/h. She was hyperventilated to a Pco2 of 34 mm Hg, and the head of her bed was elevated to 25 degrees. Her neurologic status never improved. Although her serum sodium eventually corrected to 143 mmol/L a little more than 4 hours after admission, a cerebral flow study obtained early the next morning showed the absence of blood flow to the brain, confirming brain death. She was pronounced dead at 0838 hours from “severe cerebral edema from water intoxication resulting in uncal herniation and brain death,” less than 19 hours after her syncopal episode.

Jump to Section
Introduction
Case presentation
Discussion
References

Discussion

Exercise-associated hyponatremia is a potentially serious condition that is now generally known to be due to overhydration in combination with fluid retention from nonosmotic stimulation of arginine vasopressin (AVP) secretion.25, 26 Nonosmotic stimuli for secretion of AVP include intense exercise, nausea or vomiting, hypoglycemia, and nonspecific stresses such as pain and emotion.27, 28, 29 Excessive losses of urine sodium due to secretion of brain natriuretic peptide may also contribute to the pathophysiology of EAH.14, 30, 31

Early symptoms of EAH include nausea, vomiting and headache, which can rapidly progress to confusion, altered mental status, seizure, and death if untreated.26 Often, there is a delay in the presentation of symptomatic EAH after exercise cessation.1, 17, 32 This delay is thought to be due to absorption of fluid remaining in the gastrointestinal tract once exercise has stopped and blood flow is redistributed away from skeletal muscles. The signs and symptoms of EAH encephalopathy are due to cerebral edema resulting from water following the osmotic gradient from the blood into brain tissue. Typical symptoms of EAH-related cerebral edema include an altered level of consciousness, seizures, coma, and in rare cases, death. In this patient’s case, her syncope and lethargy on presentation were probably related to cerebral edema, and her sudden collapse into an unresponsive state after her emesis was possibly related to a Valsalva-induced exacerbation of already elevated intracranial pressure from the underlying brain swelling.

Symptomatic EAH is known to occur at serum sodium concentrations that some might not consider especially low. For instance, symptomatic EAH has been reported at serum sodium concentrations above 125 mmol/L,17,33, 34 and an EAH-related fatality of a Marine with an admission serum sodium concentration of 128 mmol/L has been reported.2 The admission serum sodium concentration of 127 mmol/L in the present EAH fatality case should serve as further evidence that treatment should be based on the extent of symptoms rather than the absolute sodium concentration. It is likely that symptom severity is related more to the rapidity at which the serum sodium changes than to the absolute value.

Appropriate management of EAH relies on early recognition. Although signs and symptoms of EAH are nonspecific and overlap with other conditions such as heat illness, acute mountain sickness, and hypoglycemia,25 a history of high-volume fluid intake and seizure, or rapid mental status deterioration after exercise, should raise suspicion for EAH. When point-of-care blood sodium analysis is possible, the diagnosis of EAH can be readily confirmed. However, when blood analysis is not available, a presumed diagnosis may be necessary based on the available history, symptoms, and clinical signs.

The recommended current treatment includes fluid restriction to avoid further fluid overload, and oral or IV hypertonic saline.25, 26 Although the typical recommendation has been as much as three 100-mL IV boluses of 3% saline, larger volumes of hypertonic saline have been required.35 Boluses of hypertonic saline are given over 1 minute by IV push. An interval of 10 minutes is recommended between boluses to observe for spontaneous improvement in symptoms. If none are seen, the total 300 mL of 3% saline should be given within 30 minutes. Even in a situation where EAH is a presumed diagnosis, a single bolus of hypertonic saline is thought to offer a favorable risk-to-benefit ratio.25 Furthermore, rapid reversal of the hyponatremia when occurring acutely in EAH has not been associated with any known cases of central pontine myelinolysis.25, 26

Avoiding additional fluid overload in EAH is particularly important.15, 25 Because dehydration is often a reflex diagnosis for a symptomatic exerciser in a hot environment, the usual treatment of oral or IV isotonic or hypotonic fluids needs be resisted if there is a strong likelihood that the underlying condition is EAH. Furthermore, it should be recognized that the presence of oliguria, which would be anticipated with dehydration, may only confound the situation because oliguria is also common with EAH owing to secretion of AVP.25, 26

The case described here of a hiker shows a typical presentation of EAH. She had a suggested history of excessive fluid intake, a known stimuli for AVP secretion, and a delay in the onset of symptoms after exercise cessation followed by rapid deterioration in mental status. Her initial and subsequent treatment, which included isotonic fluids, remains common practice. In fact, there have been continued reports in recent years of EAH cases being managed with isotonic or hypotonic fluids,9, 13, 16, 17, 19, 20, 22, 24, 34, 36 making it evident that there is a need for further education on the proper management of EAH.

Emergency medical practitioners should be aware of current management guidelines for EAH because the persistent common treatment with high volumes of isotonic fluids has been associated with delayed recovery,5,9, 13, 14, 16, 17, 20, 22, 24, 32, 34 and has likely contributed to deaths.34, 36 Conversely, early recognition and treatment of symptomatic EAH with hypertonic saline has been demonstrated to be safe and effective, and is now the mainstay of current management guidelines.25, 26 Additionally, for situations or locales in which EAH is common, such as at endurance athletic events or where desert hiking takes place, it is beneficial for prehospital providers to have point-of-care serum sodium testing and IV hypertonic saline administration capabilities. Grand Canyon National Park has implemented this approach. We hope that this report of a fatal outcome from EAH and the discussion about the importance of rapid recognition and treatment will stimulate others to develop more appropriate systems for the recognition and treatment of EAH.

Sierra Leone starts new countdown to Ebola-free status

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Sierra Leone has released its last two known Ebola patients and begun a new 42-day countdown to a declaration that it is officially free of the virus, officials said on Monday.

More than 11,300 people have died of Ebola in Guinea, Sierra Leone and Liberia in an outbreak that was declared in March 2014 and is rated the world’s worst.

The two women just released from hospital were treated in Kambia district on the Guinea border after being infected by a 67-year-old woman who posthumously tested positive for Ebola.

Her death lead to almost 1,000 people being put in isolation and stopped the previous countdown a week after it began in August. One community is still under quarantine but that should be lifted this week barring any new cases, officials said.

There were only two new cases in Guinea in the week of Sept. 20 and none in either Sierra Leone or Liberia, according to figures from the U.N.’s World Health Organisation (WHO).

A country must record zero new infections in 42 days to be declared Ebola-free, said WHO, which began the count in Sierra Leone on Sunday.

“It’s good news for Sierra Leone and the sub-region. I am hoping that this time we won’t fall off,” Pallo Conteh, who heads the national Ebola Response Centre, said.

“It is difficult to say you are confident because you know with Ebola one mistake might just lead to a spike again,” he said.

Human Brain: Positive Lifestyle, Satisfaction Linked To A Particular Pattern Of Brain Circuitry

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Functional Connectivity
Are some brains wired for a lifestyle that includes education and high levels of satisfaction, while others are wired for anger, rule-breaking, and substance use? Image courtesy M. F. Glasser and S. M. Smith for the WU-Minn HCP consortium

A strong relationship exists between positive behavior traits and the wiring of your brain, anew Oxford University study finds. While some brains appear to be wired for a lifestyle that includes education and high levels of satisfaction, others appear to be wired for anger, rule-breaking, and substance use, the research suggests.

A single positive-negative axis linked “lifestyle, demographic, and psychometric measures to each other and to a specific pattern of brain connectivity,” wrote the study authors.

The Human Connectome Project, a National Institutes of Health-funded venture which will conclude this year, seeks to create comprehensive diagrams of the brain circuitry for 1,200 adults. To conduct this work, scientists use noninvasive neuroimaging equipment, including customized head coils and cutting-edge MRI hardware. The splendid maps that result show the trajectories of fiber bundles coursing through white matter and functional connections between gray matter regions.

Study participants include a high proportion of twins and their non-twin siblings to help the researchers understand whether brain circuits are inherited. At the same time, all participants have had their genomes mapped so genetic influences on brain wiring can be evaluated. The participants also completed questionnaires and tests measuring behavior and demographic traits.

Importantly, the data is made freely available for scientists around the world to use in their own private studies.

Positive-Negative Axis

For one such study, researchers at Oxford University’s Centre for Functional MRI of the Brain accessed completed brain maps from 461 Human Connectome Project participants. Using this data, the team created a general or population-average map of connections among 200 regions of the brain. Then, the team looked at how much, in separate participants, those regions communicated with each other. Essentially, they created a map of the brain’s strongest connections for each participant.

Finally, the team performed a mathematical analysis to compare this imaging data with some old-fashioned facts and figures — specifically, 280 measurements of behavior traits and demographic information. What did this comparison reveal?

Most people fall into one of two groups along an axis created from the two datasets, the scientists discovered. Those with brain wiring patterns at one end of the scale scored highly on measures most people consider “positive,” such as life satisfaction, income, vocabulary, memory, and years of education. Similarly, those with patterns at the other end of the scale had high scores for traits most people view as “negative,” such as anger, rule-breaking, substance use, and poor sleep.

This positive-negative axis, as the scientists refer to it, apparently spells the difference between a happy life and discontent. With additional studies the team may one day discover why most of us can be found at either end of this scale.

This Is Your Brain On Drugs: How Drug Public Service Announcements Have Changed Over The Years

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Anti-drug
The history and effectiveness of anti-drug PSAs. globochem3x1minus1 CC BY 2.0

Public service announcements (PSAs) have been around since World War II, when the Ad Council began creating PSAs to inspire the general public into helping the war effort. Over time, however, PSAs changed by branching out into a myriad of subjects from global awareness and preventing forest fires to drunk driving. Many antidrug PSA’s have also come out over the years, dating back to the late 1930s with the release of the film Reefer Madness,which decried the use of marijuana. Antidrug PSAs have evolved over the years, however, so let’s take a look at what PSAs of the last 80 years have looked like and how effective they’ve been.

A History of Drug PSAs

The 1950s

Aside from the aforementioned Reefer Madness, it wasn’t until 1951 that what is widely recognized as the first antidrug PSA was released. It has the same basic plot as ReeferMadness, telling the story of a good boy named Marty who experiments with marijuana. But then he goes on to use heroin. Eventually he goes to jail. While it may be considered tame by today’s standards, it shows that even back then, people believed marijuana could be agateway drug.

1960s Propaganda

The 1960s found PSAs in a more propaganda-like place, with overbearing narrators and first-person camera angles showing the perils of drug use, and how doing them can essentially ruin the world. Most of these PSAs only warned of the dangers of smoking marijuana — something people might find amusing today, considering marijuana is legal in some form in 23 states .

“The brain, the body, indeed the freedom to do can be so jeopardized by these drugs, that new politics, more realistic values, and a meaningful, less materialistic society may never have the opportunity of becoming a reality,” one PSA narrator said.

The Beginning Of The War on Drugs

The “War on Drugs” was a term first coined in the early 1970s after President Richard Nixon sent a special message to Congress about drug abuse and prevention. In it, he called drugs “public enemy number one,” and went on to say that he would deal with the rampant drug use by asking Congress to provide an additional $155 million for drug-control measures. “This will provide a total of $371 million for programs to control drug abuse in America,” he said. The PSAs of this decade also expanded their reach, going after amphetamines, barbiturates, and sniffing glue in addition to marijuana.

‘This Is Your Brain On Drugs’

During the 1980s, cartoon characters, like He-Man , Sonic the Hedgehog, and the G.I. Joes, were the ones telling young viewers that drugs can ruin lives. Even Michael Jordanparticipated in keeping kids aware of the harm drugs could have on their future. Despite such influential figures advocating for kids to be drug-free, most of the PSAs lasted less than a minute and didn’t show exactly how drugs could cause harm.

It wasn’t until the “This is Your Brain on Drugs” campaign aired in 1987 that PSAs turned to more hard-hitting visuals. In it, an egg representing the brain was thrown into a sizzling hot frying pan, which represented drugs. The PSA ended by saying, “This is your brain on drugs. Any questions?”

The 90s: Building on the Past

PSAs in the early 1990s went back to relying on cartoon characters to spread the message. In one, the Teenage Mutant Ninja Turtles helped a kid who was offered marijuana find his way out of the uncomfortable situation.

The “Your Brain on Drugs” PSA also made a reappearance in 1997 by building on the same premise. Instead of cooking an egg in a frying pan, however, the frying pan was used to smash the egg to pieces. Then, the frying pan was used to destroy the kitchen, which represented the destruction of the user’s life.

The 2000s

As the millennium came and went, PSAs began to get a little smarter with their messaging. They asked people to talk to their friends about their drug problems, and showed just how harmful marijuana and meth could be. In one, a person who was high on weed was shown hitting a child with their car. Meanwhile, PSAs for meth portrayed an addict robbing a store for drug money. These ads also started using statistics to hammer their points home, and some even showed family pets disappointed in their owners’ drug use.

The Present Day

With the modern day rise of social media and other Internet websites facilitating global communication, PSAs have begun to take the form of online trends like memes, gifs, and emojis. A new antidrug campaign by the Partnership for Drug-Free Kids, which created the “Your Brain on Drugs” ad, uses emojis to spread the message.

“It’s not about saying drugs are bad. It’s about saying drugs are not for me,” Kristi Rowe, CMO at the Partnership for Drug-Free Kids, told Adweek. The campaign, which involves outdoor, print, cinema, and mobile platforms, uses emojis to to create a string of words.

Emoji PSAThis emoji translates to “I want to fit in, but I don’t want to smoke.” Photo courtesy of Partnership for Drug-Free Kids

Are PSAs Effective?

So, after 80 years of anti-drug PSAs, how effective have they been?

A study from 2002 found that the effectiveness of PSAs varied. Researchers asked 3,608 adolescent boys and girls about the effectiveness of 30 antidrug PSAs, and found that 16 of the PSAs were perceived as significantly effective in reducing drug use. Meanwhile, six other PSAs were perceived as less effective at teaching the students how to deal with drug situations, or deterring them from using drugs with their friends. The final eight had a reportedly minimal effect on the students.

Another study, published in The Lancet in 2010, found antidrug PSAs don’t work as well as antismoking PSAs. “A PSA campaign can be very good at making people do stuff that doesn’t require that much of a sacrifice, like going and getting a colonoscopy or a mammogram, or waiting to get to your garbage can to throw away your litter,” Robert Thompson, professor of popular culture at Syracuse University, told UPI. “It’s much harder to get people to stop eating fatty foods.” And arguably, fatty foods can be just as addictive as drugs.

As popular as the “Your Brain on Drugs” campaign was — TV Guide and Entertainment Weeklyboth called it one of the best commercials of all time —  a case study from 2000 found that between 1987 and 1992, when the ad was heavily circulated, monthly illicit-drug use in kids aged 12 to 17 dropped from 3.2 million children to 1.3 million. However, come 1994, when the ad got less exposure, drug use jumped back up to 2.1 million children.

While antidrug PSAs may not have been as effective as they sought to be, the message behind them — that drug use can have a lot of negative effects on a person’s life — is still important.

A nurse with fatal breast cancer says end-of-life discussions saved her life

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Amy Berman says discussions with her doctors have been very valuable. 
By Amy Berman September 28
To: Centers for Medicare & Medicaid Services:

News reports say you will soon make a final decision about paying doctors and other providers who talk to their patients about end-of-life planning, I have a fatal form of breast cancer, and I’d like to tell you how such conversations have allowed me to survive, and live well, in the five years since my diagnosis.

I am a nurse, a nationally recognized expert in care of the aged and senior program officer at the John A. Hartford Foundation, which is devoted to improving the care of older people in the United States. Yet my perspective is not simply professional. For, you see, I live with Stage 4 (end-stage) inflammatory breast cancer. And while this metastatic cancer will one day kill me, the advanced-care planning conversations I have had with my health-care team have been lifesaving since my diagnosis.

I use the word “lifesaving” advisedly because that is what these conversations are truly about. When done well, they can shape care in ways that give people with serious illness a chance at getting the best life possible.

This kind of conversation initially helped my care team understand what was important to me and helped clarify my goals of care. Faced with an incurable disease and a prognosis where only 11 to 20 percent survive to five years and there is no statistic for 10-year survival because it so rarely happens, I came to understand that my priority was to seek a “Niagara Falls trajectory” — to feel as well as possible for as long as possible, until I quickly go over the precipice. Quality of life is more important to me than quantity of days, if they are miserable days.

Following a discussion with my oncologist (a conversation that would be reimbursed if you in fact move ahead and change your rules), we initially decided on a palliative regime to slow the cancer’s spread with the least amount of burdensome side effects. We would not impose the most difficult curative treatments on an incurable disease.

This treatment has included a pill I take each evening to hold back the hormones that fuel my cancer, coupled with a monthly infusion to keep my bones strong. I don’t take most difficult treatments, the typical noxious cocktail of two chemotherapy drugs that 90 percent of people with inflammatory breast cancer receive, coupled with surgery to remove my breast, followed by weeks of radiation and more debilitating chemotherapy.

When I suggested a second opinion after I was diagnosed, my oncologist blessed it. Sadly, when I sat down with this esteemed expert, he didn’t ask about my goals or wishes. Instead, he suggested an aggressive, hail-Mary treatment regime — including rounds of chemotherapy, a mastectomy and radiation — that would have compromised the quality of my remaining life without any real benefit. There was no conversation. He was expert in everything but what really mattered to me. I thanked him for his time, and left.

I am pleased to report that the subsequent nearly five years have rewarded my decision to seek palliative rather than more aggressive treatment. The cancer has spread a bit farther from my spine and into a couple of my ribs. But because my treatment focuses on helping me live well and feel well, I haven’t been in the hospital. I feel great. My pain has been minimal so far — with one exception.

Six months ago, the cancer spread to a new spot, my fourth and fifth ribs. It was painful. The standard treatment is 10 to 20 doses of radiation to get rid of the pain. My palliative care provider, an expert in fostering discussions about goals of care, said that a recent recommendation of the Choosing Wisely Campaign, which promotes patient-physician conversations about unnecessary medical tests and procedures, suggested that I could get rid of the pain with a single, larger dose of radiation. It worked like a charm. I felt better, avoided the terrible side effects of repeated radiation, got immediate relief and avoided paying for all the unnecessary doses of radiation.

I estimate I’ve saved about a million dollars by avoiding care I do not want, which includes the cost of chemotherapy, radiation, surgery to remove the breast, at least one hospitalization for that care, and the follow-up care to the surgery. Chemotherapy alone would have cost upward of $500,000. Insurance would have covered much of this, but not all.

 Meanwhile, I continue to work full time and have redoubled my efforts to improve the health-care system for older people. And I live a good life with serious illness. I have climbed the Great Wall of China, ridden a camel in the Jordanian desert and water-skied to the Statue of Liberty, and I continue to enjoy time with my family and friends.

So my original advance-care planning discussion has been lifesaving. It has also saved the health-care system a great deal of money.

All people deserve care that meets their emotional and financial needs. Unfortunately, health-care providers, including those paid by Medicare, have not had the incentives, time or training to sit down with people facing a life-threatening illness and discuss what’s important to us as our health deteriorates, things such as where we want to die (I want to be at home), what’s most important (control my pain) and what treatments we want to avoid (I don’t want to be on life support and don’t want to be resuscitated). As a result, our system provides a lot of expensive crisis care as people reach the end of life — care that people, if asked and engaged, might say they never wanted.

This does not have to happen. High-quality advance-care planning discussions help people like me understand their options and make their wishes known. They can identify a surrogate to make decisions when they are unable to, and they can document their preferences in their medical records. These discussions — which should be ongoing, not just one-time — can revisit decisions in the face of new challenges, and over time they can guide providers to deliver the care that patients and their families want.

The benefits of a rule from Medicare covering such conversations are clear: better health, better care and, in many cases, lower costs. Most important, these conversations will be lifesaving, enabling those of us with serious illness to live the way we want to, fully and deeply for as long as possible.

Thank you for your consideration.

Breast Cancer, Radiation Therapy, and Ischemic Heart Disease

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image

Breast cancer is the leading cause of cancer deaths in women in the U.S. Survival is better when breast cancer is diagnosed while still local, and 60.8% of women in the U.S. are diagnosed at this stage. In this group of patients, 5-year survival is 98.5%, according to data from the Surveillance, Epidemiology, and End Results (SEER) Program.1 In these cases, surgical treatment with lumpectomy or mastectomy is often followed by radiation therapy.

In fact, a recent meta-analysis of 22 randomized trials provided additional support for the use of postmastectomy radiation in decreasing the rate of mortality related to recurrent cancer and breast cancer in women found to have 1 to 3 positive lymph nodes during mastectomy and axillary dissection.2 As a result of this and other studies, the need to understand the long-term effects of radiation therapy has become more urgent. One of the most important questions is: Does radiotherapy to the chest increase the incidence of ischemic heart disease (IHD)?

The dose of radiation to the breast and heart is now considerably lower than it has been in the past.3 Nonetheless, when malignancies of the right breast are treated with radiation, the heart is typically exposed to a dose of approximately 1 to 2 Gy. Heart exposure is higher for disease of the left breast, of course, and may run up to 10 Gy.4

A recent study assessed how the dose of radiation a woman receives during breast cancer treatment affects her subsequent risk of IHD.

Darby and colleagues performed a case-control study of major coronary events in women who received external beam radiotherapy for invasive breast cancer.4 Major coronary events were defined as myocardial infarction, coronary revascularization, and death from IHD. Their study, recently published in the New England Journal of Medicine (NEJM), included 2168 women who received radiotherapy for breast cancer from 1958 to 2001 in Sweden and Denmark. Of these, 963 women had major coronary events, and 1205 did not and served as controls. Radiation doses to the whole heart and to the left anterior descending artery were estimated based on radiotherapy records.

Mean radiation dose to the heart was 4.9 Gy (range, 0.03 to 27.72). The rate of cardiovascular events increased by 7.4% for each increment of 1 Gy (95% CI, 2.9 to 14.5;P<.001), with no threshold below which there was no risk. This deleterious effect on the heart started within the first 5 years after therapy and continued for at least 20 years. The presence of cardiac risk factors increased the absolute rate of cardiac outcomes but didn’t affect the proportional increase in the rate of major coronary events per Gy.

None of the women in the study received the cardiotoxic chemotherapeutic agents taxanes or trastuzumab, and very few received anthracyclines, thus minimizing these confounders for ischemic outcomes.

Though radiation delivery techniques have improved considerably in recent decades, the incidental exposure of radiation to the heart is always of concern, and strategies to minimize radiation should be exercised whenever possible. Despite this, as Fei-Fei Liu, MD, Professor of Radiation Oncology at the University of Toronto, stated in an editorial that accompanied the Darby article, “It is important to reassure women with breast cancer that with the use of current technologies, the cardiac dose can be decreased considerably, and cardiac risk factors can be better managed.”

Investigator Sarah C. Darby, PhD, of the Clinical Trial Service Unit at the University of Oxford, England, says that “One thing that our studies have shown rather clearly is that any radiation-related risk probably multiplies the risk that a woman already has. Therefore, women who are already at increased risk of heart disease are likely to be at the greatest risk.”

Dr. Darby and her colleagues provided an example of this in the NEJM article:

  • In a 50-year-old woman with no cardiac risk factors at baseline, a 3-Gy dose of radiation to the heart would increase her risk of fatal IHD at age 80 from 1.9% to 2.4% (0.5 percentage points) and her risk of having at least 1 acute coronary event from 4.5% to 5.4% (0.9 percentage points).
  • In a 50-year-old woman with at least 1 cardiac risk factor, a 3-Gy dose of radiation would increase her risk of fatal IHD at age 80 from 3.4% to 4.1% (0.7 percentage points) and her risk of having at least 1 acute coronary event by then by 1.7 percentage points.

In their conclusions, Dr. Darby’s team wrote that because the percentage increase in IHD risk per unit increase in the mean radiation dose to the heart was similar in women with and without cardiac risk factors, one could assume that absolute risk increase at a specific dose was larger for women with preexisting cardiac risk factors.

“Therefore, clinicians may wish to consider cardiac dose and cardiac risk factors as well as tumor control when making decisions about the use of radiotherapy for breast cancer,” they wrote.

Significant decreases in the dose exposure to the heart can be achieved by changing the patient’s position (from supine to prone, for example) and the field in which the radiotherapy is delivered.3,5 Silvia C. Formenti, MD, chair of the Department of Radiation Oncology at NYU Langone Medical Center, in New York City, commented, “There are ways to limit dose radiation to the heart beyond what was available in the Darby study.”

Dr. Darby adds, “Published studies of tangential radiation, without irradiation of the internal mammary chain, indicate that for patients treated in the prone position, the heart is usually receiving about 1 to 2 Gy. This is similar to the heart dose delivered to patients treated in the supine position with breathing control. It remains to be seen which of these 2 methods will become more popular with oncologists.”

“Clearly,” she continues, “modern radiotherapy planning systems, including patient-specific CT scans, have the potential to increase the ability of radiation oncologists to control the dose to the heart more precisely than has been possible in the past.”

As these issues are sorted out, Dr. Darby urges clinicians to stay focused: “Remember that the most important thing is to cover the target tissue adequately. Compromising on coverage of the target tissue in order to reduce the dose to the heart is likely to be a risky practice,” she says.

Contralateral Prophylactic Mastectomy: It’s Increasing, But Is Survival Improving?

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The rate of contralateral prophylactic mastectomies (CPMs) in women with unilateral breast cancer in the U.S. increased by a whopping 150% between 1998 and 2003.1 This suggests the widespread adoption of aggressive surgical intervention in an attempt to reduce risk or prevent cancer in the noncancerous breast.

This trend isn’t endorsed by the National Comprehensive Cancer Network’s breast cancer guidelines, however, which discourage prophylactic mastectomy in most women. The removal of a noncancerous breast is recommended only in women who are considered at high risk for contralateral breast cancer.2

CPM is no longer being exclusively performed on high-risk patients, however. More low-risk women are opting for this aggressive approach.3This trend is occurring even in light of a low likelihood of a second primary breast cancer. Data suggest that the 10-year cumulative risk of contralateral breast cancer is approximately 4% to 5%, and possibly lower for women diagnosed in 2014.4

In light of the increasing use of CPM, the obvious question is: Does a double mastectomy improve survival? According to a recent assessment of data obtained for nearly 190,000 women with early-stage, unilateral breast cancer from the California Cancer Registry, the answer is no. Kurian and colleagues found no survival benefit with bilateral mastectomy compared with breast-conserving surgery plus radiation. And consistent with other data showing increasing trends, the authors reported that the rate of bilateral mastectomy increased from 2% in 1998 to 12.3% in 2011, reflecting an annual increase of 14.3%. The rate increase was highest among women younger than 40 years, jumping from 3.6% in 1998 to 33% in 2011, for an annual increase of 17.6%. By comparison, unilateral mastectomy was found to be the least popular option, decreasing in all age groups and yielding a lower survival rate.5 With regard to this last finding, the authors said they agreed with other researchers that patients whose tumors exhibit signs consistent with a poorer prognosis are more likely to have unilateral mastectomy than breast conservation—and are also more likely to have a poorer survival.

In contrast, Kruper and colleagues reported improved disease-specific and overall survival (OS) in women who underwent CPM. In this study, the Surveillance, Epidemiology, and End Results database was used. The researchers identified approximately 27,000 patients with unilateral breast cancer who underwent a mastectomy with or without CPM between 1998 and 2010. Notably, group differences in OS were greater than the group differences for disease-specific survival, a finding reported to be consistent with selection bias. The authors noted that the observed survival benefit may be attributed to healthier women being chosen or recommended for CPM.6

In a small, single-center study, 237 women younger than 40 years who were diagnosed with breast cancer at Mount Sinai Medical Center in Miami Beach, Fla., between 1980 and 2010 were identified. Zeichner and colleagues found that CPM provided an OS advantage after 10 years of follow-up but not after 5 years, regardless of genetics, tumor, and patient characteristics.7

Not surprisingly, women seem to be choosing CPM in hopes of extending survival. According to a survey conducted by Rosenberg and colleagues of women aged 40 or younger, 94% reported that improving survival was an extremely or very important factor in their decision to undergo CPM. Only 18% of respondents, however, believed that women who undergo CPM would live longer than those who do not. So while there’s a clear motivation to undergo CPM to improve survival, the majority of women seem to believe that CPM may not extend their lives. Additionally, women without BRCA mutations tended to overestimate their risk of contralateral breast cancer, while women with a known BRCA mutation more accurately perceived their risk.8

The survey also found that the desire to decrease the risk of contralateral breast cancer and get peace of mind both ranked high in the respondent’s decision to undergo CPM (in 98% and 95% of women, respectively). Overall, the women surveyed were satisfied with their decision, with 80% indicating extreme confidence.8

“There are several potential reasons for this trend,” said Todd M. Tuttle, MD, of the Division of Surgical Oncology, Department of Surgery, at the University of Minnesota in Minneapolis. Among those he cited were:

  • improvement in mastectomy and reconstruction techniques
  • increased awareness of hereditary breast cancer
  • increased use of magnetic resonance imaging, which has raised doubts about the contralateral breast
  • overestimation of the risk of contralateral breast cancer
  • overestimation of the survival outcomes of bilateral mastectomy.

The debate over whether CPM improves survival will likely continue. Despite mixed survival-advantage data, there’s a clear, increasing trend in women diagnosed with unilateral breast cancer to choose this more aggressive surgical intervention, a trend which is particularly high in young Caucasian women.1,5 Understanding what motivates women to make this decision will help guide physicians in how they counsel patients. Women who are accurately informed, and who have a better understanding of risk and overestimation, will be better positioned to make appropriate treatment decisions.

Inhaled p38 inhibitor reduced lung inflammation markers in early-stage study

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The drug in question, still undergoing clinical trials, is known as AZD7624 (or simply 7624), an inhaled p38 inhibitor developed by AstraZeneca. The drug appeared to show promise for its anti-inflammatory properties when it was tested using lung and systemic markers of inflammation following a lipopolysaccharide (LPS) challenge.

“The anti-inflammatory potential indicates 7624 as a novel treatment for COPD,” said lead study author Naimish Patel, MD, PhD, a research scientist at AstraZeneca, the drug’s manufacturer. “We can dampen some of the inflammation of COPD, but more remains to be seen in follow-up studies.”

Patel presented the findings at the European Respiratory Society International Congress.

Patel and colleagues randomized 30 healthy volunteers in a double-blind, placebo-controlled cross-over study. Participants received a single inhaled dose of AZD7624 (1200 micrograms) or placebo 30 minutes prior to undergoing an LPS challenge, a test designed to trigger the body’s inflammatory response mechanisms. Sputum induction followed 6 hours after the LPS challenge, and blood samples were taken at 0.25, 6.5, 12, and 24 hours post-dose in order to measure cell counts and inflammatory biomarkers.

The research team found that inhaled AZD7624 reduced LPS challenge-induced inflammation in both sputum and blood, attenuating a sputum neutrophil differential increase of 56.8% (P<0.001) compared with the placebo. This reduction, Patel noted during his presentation, is more than twice that of other p38 inhibitors. The target is mitogen-activated protein kinase long recognized for its pro-inflammatory properties.

During the study, AZD7624 also mitigated an increase of interleukin-6, an inflammatory cytokine, in the sputum by 76.5%, and led to attenuated differential increases of blood neutrophil counts by 43.5% and blood interleukin-6 by 70%.

Perhaps most tellingly, however, AZD7624 completely inhibited the macrophage inflammatory protein known as MIP-1β or CCL4, in the blood. AZD7624 also attenuated the degree of C-reactive protein increase by 93% in the blood following the LPS challenge.

There also was a significant change in sputum neutrophilia and interleukin 6, correlated with change in blood neutrophilia (R=0.531, P<0.0001) and interleukin-6 (R=0.492,P=0.0003).

As a result of the findings, the study authors concluded, “inhaled AZD7624 significantly inhibits LPS-induced lung and systemic inflammation, and lung inflammation markers correlate with systemic markers indicating a potential for AZD7624 as an inhaled treatment for COPD.”

Though the study was a big first step, Patel said the research team is continuing to work to answer more questions about the drug.

Patel and other AstraZeneca officials are currently recruiting participants for a phase IIa study to investigate the efficacy and safety of AZD7624 in COPD patients who are on standard maintenance therapy.

High-dose vitamin D does not improve outcomes in postmenopausal women

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High-dose vitamin D supplements slightly increase calcium absorption but do not improve bone density, muscle function and mass or fall rates in postmenopausal women, new research has shown.

“We found no data to support experts’ recommendations to maintain serum 25-hydroxyvitamin (OH)D level of 30 ng/mL or higher in postmenopausal women,” said lead author Dr. Karen E. Hansen from the University of Wisconsin School of Medicine and Public Health, Wisconsin, US and colleagues.

The researchers examined the impact of vitamin D supplementation on 230 women who were 5 years past menopause (age 75 years or younger) with 25(OH)D levels of 14 through 27 ng/mL at study entry. Women were randomized to low-dose or high-dose cholecalciferol or placebo. [JAMA Intern Med 2015;doi:10.1001/jamainternmed.2015.3874]

At 1 year of treatment, mean 25 (OH) levels increased in the low-dose and high-dose group (28 and 56 ng/mL, respectively) but decreased in the placebo group (19 ng/mL). Fractional excretion of calcium was slightly better with high-dose cholecalciferol compared with low-dose cholecalciferol or placebo, but these differences are not clinically significant.

Neither dose of cholecalciferol improved bone mineral density or muscle outcomes (function, strength, mass) or the number of falls among the three groups.

Although it is possible that treatment for over a year may result in better outcomes, the findings suggest that vitamin D supplementation may be no better than placebo, said Dr. Deborah Grady from the University of California, San Francisco, US, in an accompanying editorial. “The data provide no support for use of higher-dose cholecalciferol replacement therapy or any dose of cholecalciferol compared with placebo.” [JAMA Intern Med2015; doi:10.1001/jamainternmed.2015.3937]

The low-dose regimen consisted of 800 IU vitamin D daily, and the high-dose regimen 50,000 IU twice monthly administered after a 15-day loading dose. Women in the high-dose group received extra doses as needed to keep their serum 25(OH)D level above 30 ng/mL.