Get Off My Case

In my inbox this morning, via ASCO‘s “Cancer in the News” feed:

The UK’s Telegraph (5/6, Beckford) reported that as “many as 20,000 British women could avoid developing” breast cancer “each year, if they took more exercise, drank less and ate better.” Latest figures “suggest that 47,600 women developed breast cancer in 2008,” and the World Cancer Research Fund estimates that estimates that “42 per cent of these cases…would be preventable if women developed healthier lifestyles.” The WCRF’s “10 Recommendations for Cancer Prevention include being ‘as lean as possible without becoming underweight’; keeping fit; limiting consumption of fatty, salty and sugary food and drink; eating fruit, vegetables and pulses; eating less red meat and processed meat; drinking less and choosing a balanced diet rather than vitamin supplements.”

This follows numerous reports that women may develop breast cancer or suffer recurrences because they eat too much, drink too much, work too much or fret too much. (But don’t relax and put down your vacuums, girls – there’s striking evidence that household chores can reduce your risk!)

Of course it’s wise from a general medical perspective – think in terms of heart disease, osteoarthritis, type 2 diabetes and other ailments prevalent in our too-developed world – to be slender instead of fat, exercise regularly and eat a balanced diet.

I’m tired of the press trumpeting poorly-done trials that feed into a stereotypic conception of how women should behave. Yes, diet and stress could play a role in any hormone-driven disease, but so do a lot of things. As for alcohol, maybe consumption is a surrogate for wealth and living in a place like the U.S. where people drink freely, where breast cancer rates are unseemly.

We should be sure of the facts before pronouncing these fatal flaws in our ways of existence and being. Plenty of women feel badly about their tumors and disfigurement without this added layer of insult.

And what did you eat for dinner last night, big brother?

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New York City Reports Long Delays for Mammograms

A recent audit of nine NYC’s Health and Hospitals Corporation found City Comptroller Liu described as dangerous delays in women’s health care. It takes too long for women to get screening and diagnostic mammograms.

The 2009 audit found women at Elmhurst Hospital had the longest waits – 50 working days (that would be 10 weeks, i.e. 2.5 months) for diagnostic mammograms, on average. You can find more details here.

According to the Times’ coverage:

Ana Marengo, a spokeswoman for the city’s Health and Hospitals Corporation, which runs the public health system, said that the comptroller’s data was outdated…

At Elmhurst, she said, the wait as of December 2010 was 20 days for screening and 23 days for a general diagnostic test, as opposed to an urgent one.

Still, at Queens Hospital Center, the wait for a screening test was 56 days in December <2010>, Ms. Marengo said. “It’s due to volume and higher demand,” she said. “We only have a certain amount of resources.”

From the comptroller’s press release, a statement from Alice Yaker, Executive Director, of SHARE: Self-help for Women with Breast or Ovarian Cancer:

“While controversies about efficacy surround the screening of healthy women, there is no controversy about the need for a diagnostic mammogram in a woman who presents with a lump in her breast, for example. This requires our urgent attention, budget cuts and hospital closings notwithstanding.”

The comptroller’s message says there’s no guideline for how soon a woman with breast cancer symptoms, such as a lump, should receive a diagnostic mammogram. For screening, guidelines suggest the wait be no longer than 14 days for an appointment.

This blogger’s vote: set up a maximum wait time for diagnostic mammography: 10 working days.

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New Findings on Leprosy and Armadillos

A surprise lesson arrived in my snail mailbox today: the April 28 issue of NEJM includes a fascinating research paper on a probable cause of leprosy in the southern U.S. New, detailed genetic studies show that armadillos, long-known to harbor the disease, carry the same strain as occurs in some patients; they’re a likely culprit in some cases.

Dr. Gerhard Henrik Armauer Hansen, who identified the bacteria causing leprosy

Dr. Gerhard Henrik Armauer Hansen, who identified the bacteria causing leprosy

For those who didn’t go to med school: Leprosy is a chronic, infectious disease cause by Mycobacterium leprae. In my second year we were told to refer to the illness as Hansen’s disease. We learned that some people are more susceptible to it than others, possibly due to inherited immunological differences, a point that is reiterated in the current article.

The World Health Organization reports there are under 250,000 cases worldwide every year. Here in the U.S., Hansen’s disease is quite rare, with about 150 new cases reported annually according to the study authors. The condition wasn’t evident in the Americas before Columbus’ travels, but by the mid-18th Century it was affecting some settlers near New Orleans. Today, most cases in the U.S. arise in travelers and others who’ve lived or worked abroad in regions where leprosy is endemic. About a third crop up in people who’ve never left the country, and these cases tend to cluster in the southeastern U.S.

Leprosy tends to affect the skin, and what the NEJM investigators first did was examine skin biopsy specimens from patients who live in the U.S. and hadn’t traveled. It’s been known for decades that armadillos can carry these bacteria, and so the researchers took specimens from wild armadillos in five southern states, and analyzed the M. leprae bacterial genomes. They matched. Then they looked at more patients’ samples, and also analyzed M. leprae sequences from patients in other parts of the world.

The conclusion is that wild armadillos and some leprosy patients in the southern U.S. are infected with an identical strain of the bacteria that causes leprosy. From this information, the authors infer that armadillos are a reservoir for this stigmatizing germ, and that they may be the source of some patients’ infections.

So the news is that leprosy may be a zoonosis.

A personal note –

Only once I saw a patient with Hansen’s disease, at the Bellevue dermatology clinic, when I was a fourth-year student. She was an elderly woman from China. Her face, which I can picture now, had classic leonine features. The resident caring for her,  an intern with a plan to become a dermatologist, prescribed antibiotics.

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Dr. Greenfield is Human

A few days ago I read that Dr. Lazar Greenfield, Professor Emeritus at the University of Michigan, resigned as the president-elect of the American College of Surgeons over flak for authoring a Valentine’s Day-pegged, tacky, tasteless and sexist piece in Surgery News. The February issue is mysteriously absent in the pdf-ied archives. According to the Times coverage: “The editorial cited research that found that female college students who had had unprotected sex were less depressed than those whose partners used condoms.

From Pauline Chen, also in the Times:

It begins with a reference to the mating behaviors of fruit flies, then goes on to discuss studies on the menstrual cycles of heterosexual and lesbian women who live together. Citing the research of evolutionary psychologists at the State University of New York, it describes how female college students who had been exposed to semen were less depressed than their peers who had not, concluding: “So there’s a deeper bond between men and women than St. Valentine would have suspected, and now we know there’s a better gift for that day than chocolates.”

Not that I’m OK with any of this, as I’ve known the ickiness of older male physicians who don’t even realize when they’re being inappropriate.

But this morning I learned from Orac that Dr. Greenfield is the Dr. Greenfield, the one that invented the Greenfield filter. This threw me a bit, because I admire Dr. Greenfield for his work. He’s saved a lot of lives, perhaps tens of thousands. (I’m guessing on this number; it could be more, the point is – a Tsunami’s worth of lives.)

Doctors, including non-surgeons like me, would sometimes advise insertion of Greenfield filters in patients with blood clots and a contraindication to blood thinning. One example of countless I recall in my own experience as an oncologist: an elderly patient with pancreatic cancer and limited mobility who had a DVT in the leg and a brain met. We wouldn’t want to give the patient a standard blood thinner, like heparin or coumadin, because the tumor in the brain might bleed with catastrophic effect.

The common teaching was that a Greenfield filter, inserted through a large thigh vein up to the inferior vena cava, would prevent a blood clot from spreading from a patient’s leg up to the heart’s right chamber and into the lung’s circulation, where it might lodge in the form of a pulmonary embolus, a serious and sometimes lethal condition.

As a patient, I once had a newer-model Greenfield placed on a temporary basis. Because I’d had a major DVT while immobilized after spine surgery for scoliosis as a teenager, and then I had breast cancer – another risk factor for DVT – when I needed spinal repair as an adult in 2003, my orthopedist and hematologist were concerned that my risk for developing another major clot was great. Because they couldn’t put me on an anticoagulant for days after such a big operation, they advised prophylactic insertion of a temporary Greenfield device. I accepted the plan, hesitatingly, as reasonable.

So from both my professional doctor’s and my patient’s perspective, I’ve perceived value in Dr. Greenfield’s contribution and possibly benefited from his work. Then again, a 2000 review in Blood suggests more evidence is needed to support the filters’ widespread use. I agree.

The clearest take, maybe, is that some powerfully driven, innovative and brilliant people make personal mistakes.

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About the Premarin Study and Breast Cancer

This week a paper came out in JAMA showing a surprising reduction in breast cancer cases among women who had hysterectomies and then took Premarin, an estrogen-only remedy compounded from steroids in horses’ urine.

drawing of a horse (Wiki-Commons)

The research merits attention because it’s part of the Women’s Health Initiative and is well-done by several measures: The study is large, placebo-controlled and randomized. The investigators followed 10,739 post-menopausal women ages 50-79, all who previously had surgical removal of the uterus. The women took CEE (conjugated equine estrogens) at a dose of 0.625 mg by mouth per day, or a placebo. The trial was stopped a year early, after an average follow-up of seven years, after the analysts noted that more women taking Premarin had strokes. But I digress…

The main findings were two: 1) Premarin, at the dose prescribed, had no clear effect on cardiovascular disease, overall, either way; and 2) there was a significant reduction in invasive breast cancer among women taking estrogen in this study. More precisely: the incidence of BC was 0.27% in women who took Premarin and 0.35% in the placebo group. For the stats-guys: the relative risk (RR) was 0.77, with 95% confidence intervals of 0.62-0.95.

The findings were covered by major news organizations and other women’s health bloggers. Still you may wonder, what’s ML’s take on this subject?

According to the Times as many as a third of women in the U.S. have had hysterectomies. The CDC says that approximately 600,000 hysterectomies are performed each year in the U.S. No matter what the numbers – which seem to me discordant – my first reaction is to wonder why so many women have their uterus removed.

About the apparently lower incidence of breast cancer, it may be that this particular dose of estrogen in the form of Premarin does tend to reduce or somehow suppress BC in post-menopausal women who’ve had hysterectomies.

But it could just as well be a statistical fluke-

If you examine a sufficient number of outcomes in a research group of thousands of women, you’re likely to find one aberration or another. What we do know is that most breast cancer cells do express receptors for estrogen, which can stimulate those cells’ growth.

Presumably, time and the scientific process will yield the truth about Premarin and other hormones some people take so that they might feel better. Then again

Personally, I wouldn’t go near the stuff.

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Art, Science and Radiation Imagery on a Magazine Cover

This week’s New Yorker cover pretty well sums up my thoughts lately. It’s a bleak, semi-natural image that blends art and science, offers brightness amidst darkness, and reminds us of how little most of us know about physics, nuclear energy and radioactivity.

And it’s a strange, unsettling start for the Spring.

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Bristol-Meyers Says Ipilimumab Prolongs Survival in Metastatic Melanoma

This morning health business mavens are chirping with bright results for ipilimumab, a monoclonal antibody that can extend life in people with metastatic melanoma. If the new data – which I haven’t seen – are true, it’s good news for patients.

In 2010, melanoma affected 68,000 people in the U.S. and led to death in approximately 8,700. The WHO estimates that over 50,000 people die of this disease worldwide annually. For patients with metastatic disease, median survival is less than one year.

Last August, investigators reported in the NEJM that ipilimumab prolonged overall survival in patients with metastatic melanoma from approximately 6 to 10 months. Those findings were based on a randomized, multicenter Phase III study funded by Bristol-Myers Squibb, the drug’s manufacturer. In that trial, the most common serious toxicity of the drug was deemed to be immune-based diarrhea. Now, the drug is up for FDA approval and Bristol-Myers is saying that another study (“024” – presumably that’s short for CA184-024) reveals prolonged survival in patients with advanced melanoma. The findings will be presented at the ASCO meeting in early June.

Ipilimumab binds a molecule called CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) on the surface of T cells. It works as a double negative kind of immune activator: by blocking CTLA-4, which normally clamps down on lymphocyte activity, the drug fosters an anti-melanoma response by the body’s healthy immune cells. Like other monoclonal antibodies, Ipilimumab is given to patients by intravenous infusion. So it’s costly in itself, and because of the need for nurses to administer the drug, IV equipment, etc.

In principle, this drug might be applied to other tumors or infectious diseases to which the immune system doesn’t adequately respond. The NIH Clinical Trials website lists other protocols, including other tumor types, for which this drug is being tried.

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Considering the Coverage of the Earthquake, Tsunami and Nuclear Reactor Breakdowns

Listening to and watching the news, last night and this morning, I’ve heard all kinds of stuff – mainly from reporters who don’t seem to know very much about physics or radiation. (Personal kudos to Anderson Cooper, who seems to have a broader command of the terms and handle on the situation than some of CNN’s designated experts.)

image via multiple sources, originally on NHK world news (link)

In general, my take on the English media coverage so far is that the New York Times is doing a good job with the physics and the unfolding events in themselves (with the exception of an irrelevant, essentially absurd three paragraphs in a strange piece with quotes from a former astronaut on why we should worry about asteroids hitting the earth that fell into the Sunday Week in Review; don’t know how that got through the editor’s non-panic button); Scientific American has some strong coverage on the matter; Slate has its streaming, distinct slant

Here in the U.S., yesterday (and perhaps earlier) some people started worrying how this might affect us, here. Some friends have asked me what I think they should do. Supposedly all companies that manufacture potassium iodide pills have sold out. I don’t offer public health advice here, and I won’t comment on the confusing and contradictory published recommendations and doses for potassium iodide which has, if anything, a limited potential to protect people from thyroid cancer.

The sites below are unfortunately limited in the information they provide, and outdated as I considered last weekend, but the sources are comparatively reliable:

Union of Concerned Scientists

U.S. Nuclear Regulatory Commission

CDC on Radiation Emergencies

EPA on What You Can Do

FEMA on Nuclear Power Plant Emergency

Radiation Effects Research Foundation (a joint project of the Japanese and U.S. Governments; hat tip to Merrill Goozner for cluing me into this agency’s existence)

The bottom line is that there’s no easy fix, or ready protection from most forms of radioactivity. My personal opinion is that the risks here are low, essentially negligible, and that the reason to watch all of this is to learn how we (in the big sense, including them) can build better, safer energy sources in the future.

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Still Thinking About the Earthquake in Japan, and How to Help

Here is a partial list of agencies helping to provide assistance and relief to the people of Japan during this emergency:

Save the Children

Doctors Without Borders

The American Red Cross*

United Jewish Appeal Japan Earthquake Relief Fund

You may have your own favorite charity, which of course may be the best way for you to help.

And then I found Lady Gaga on-line late this evening; she’s lending a hand with proceeds from special Japan prayer bracelets that she’s designed. Based on her website links, it appears the money she raises, promoted via Twitter, will go to the Citizen Effect Japan Earthquake Relief Fund.  Whatever works –

Addendum, 3/16/11 – I read in today’s NY Times that the Japanese Red Cross is not accepting help from the American Red Cross, or from many other (unspecified) charities and international agencies. I cannot verify the goodness or efficiency of any particular charities, except to say that in general it seems from the pictures that the people in northeast Japan need food and clean water, among other things.

I don’t know which are the “best” ways to help, if you can and want to do so, except that money that can be used as needed is generally considered more effective than sending, say, hundreds of thousands of used shoes and blankets and canned vegetables. Or maybe not.

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Searching for Information in Case of a Nuclear Disaster

I find it hard to think much about anything besides the earthquake and devastation in northeast Japan. It’s a place I’ve never been. I don’t speak the language.

In trying to learn something from this, it makes sense to review what to do in case of a nuclear disaster, the kind of thing that should never happen. Today millions of people on the planet are concerned about the radioactivity and what’s happening to the power plants without electricity and the usual cooling systems, with failed backup generators and tons of uncertainty.

Yesterday evening CNN had Bill Nye, the science guy, on TV telling us about nuclear plant meltdowns. This reminded me of my children when they were children and watched his good show. Not helpful, now. (Sorry, Bill.)

The problem is the dearth of reliable information on what to do about nuclear reactors that are or were or are intermittently releasing radiation into the atmosphere. The Times says the Danger Posed by Radioactivity in Japan is Hard to Assess. Scientific American offers expert details on reactors, instructive on the physics but not exactly useful for people wondering what they ought to do in an emergency.

Here is what I could find in the way of practical links in English:

CDC on radiation emergencies and potassium iodide (and Prussian blue, not recommended without a doctor’s supervision; of historical interest to hematologists, for reasons of iron staining in bone marrow specimens, and others);

EPA on Responding to Radiological Emergencies (with subpages, mainly on how the EPA and officials would work) and What You Can Do (clear info on reporting a problem; little advice on what to do in case one happens);

FDA on potassium iodide (w/ info on doses);

FEMA on Nuclear Power Plant Emergency. This site seems to have the most practical advice on what to do during a nuclear event;

Health Physics Society doesn’t seem to cover this topic (please correct me if I’m wrong);

Nuclear Regulatory Commission (NRC) on Preparing for and Responding to a Radiological Emergency (recommendations to check radio or TV for updates seem outdated as they would be problematic in case of widespread power failures).

To be thorough, I searched what some would call the blogosphere –  medical and physics – for updates on this, and found essentially nothing. Weekend effect?

My main observation is that publicly-available information on this topic is woefully inadequate. Surely, health officials around the world are taking notes.

The other main point, as is explained on the CDC’s site, is that potassium iodide (KI) can protect from absorption of radioactive iodine in the thyroid gland. This would reduce the risk of thyroid cancer developing later on, but doesn’t protect from harmful effects of other isotopes.

My thoughts and prayers are with the people of northeastern Japan.

all links accessed 3/13/11

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Benlysta, A New Treatment for Lupus

Lupus, an autoimmune disease, turned up on the front page, right side of today’s Wall Street Journal. It cropped up, also, on the first page of the New York Times business section, and elsewhere. Scientific American published a nice on-line review, just now. The reason is that yesterday the FDA approved a new, monoclonal antibody for treatment of this condition.

The drug, Benlysta (belimumab), targets a molecule called BlyS (B-lymphocyte Stimulator). The newspapers uniformly emphasize that this drug marks some sort of triumph for Human Genome Sciences, a biotech company that first reported on BlyS in the journal Science way back in 1999. BlyS triggers B cells to produce antibodies that, in patients with lupus tend to bind and destroy their own cells’ needed machinery, causing various joint, lung, liver, kidney, brain, blood vessel and other sometimes life-threatening problems. So if and when Benlysta works, it probably does so by blocking aberrant, autoimmune B cell activity.

micrographs of lupus pathology in the kidney, Nephrol Dial Transplant, 25: 153-159 (2010)

The papers don’t give a lot of details on the drug’s effectiveness, except that it appears to help roughly 1 in 11 patients and the main benefit may be that some lupus patients on Benlysta can reduce their use of steroids, which have long-term and toxic effects on many organs. The most recent, major medical publication on a trial on the drug came out in the Lancet, two weeks ago.

Some reported caveats are that the drug has not been adequately tested or approved for patients with severe kidney or neurological manifestations of the disease, and that its activity, marginal as it is, appears to be less in patients of African heritage based on trials completed thus far. Additional trials are in the works.

The drug is expensive, to the updated tune of $35,000 per year. According to the WSJ: “Estimates of how many Americans are affected range from 161,000 to 1.5 million.” (How’s that for a wide ballpark figure? – likely a function of how hard it is to define and establish diagnosis for this disease, which anticipates how hard it will be to measure this drug’s effects, see below.) The same Journal piece says analysts expect the drug to become a blockbuster, with annual sales eventually topping $1 billion.

I’ve been intrigued by lupus ever since I was a second-year medical student, studying pathology before BlyS was discovered and monoclonal antibodies could be bulk-manufactured and tested in clinical trials. The disease’s name – from the Latin term for wolf, refers to the appearance of a facial rash that some patients develop.

Lupus can be scary to treat. One of my clearest late-night memories of my residency was when a 23 year old woman with lupus “rolled in,” as we would say, to the E.R. around 5:30 AM, as I was nearing the end of my then nearly-unrestricted shift. “We’ve got a sickie,” a nurse said as she roused me from my work on a hand-written note about someone else. The patient was dehydrated and gasping for air, and I remember having trouble getting her IV in, but somehow I did and she made it at least to the ICU.

From an immunologist’s perspective, it’s a fascinating condition because it flares and quiets – sometimes on its own – and affects different organs in distinct patterns among patients. The causes of lupus are likely varied. It may be that shutting down BlyS with an antibody is just a fancy and possibly more-targeted, less-toxic way of doing what steroids, like prednisone, do to B lymphocytes.

The problem I’d anticipate with the trials – carried out by my ever-patient, expert rheumatology colleagues – is that it’s sometimes hard to measure disease activity and responsiveness in lupus, apart from the kidney, because so many of the symptoms are subjective. And because the disease can affect so many organs, it’ll be hard to appreciate the drug’s toxicity, as apart from disease in itself.

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New Data for Avastin (Bevacizumab)

A new report was published on-line this afternoon by the Journal of Clinical Oncology (JCO). It covers a Phase III (randomized) clinical trial of Avastin (Bevacizumab) in women with metastatic BC. Over 1200 patients were included in the analysis, all with Her2 negative disease.

The design of the randomized study protocol was a bit unusual, in that the treating physicians could choose among a few, standard chemo options to give their patients – the so-called “backbone” for treatment for each cohort in the trial, along with hormonal treatment and the study drug: Avastin or a placebo. Avastin is a monoclonal antibody that binds to the vascular endothelial growth factor (VEGF). It’s manufactured by Roche and is quite costly.

What the investigators report, now, is that women who received Avastin and any of the chemo regimens did better – in terms of what’s called progression free survival – than did those who received the same chemo and placebo treatment. The difference was a matter of a few months, on average, and there were no measurable change in overall survival. What this means is that in some women with metastatic breast cancer, Avastin appears to help keep the disease in check.

The study is called RIBBON-1, which I learned this evening would be for the first study of Regimens in Bevacizumab for Breast Oncology. Sounds lame, I know, but believe me – it’s hard for oncologists to keep trials straight without acronyms. Even with the acronyms.

It happens I know some women with triple negative BC who have benefited from Avastin. These women may be outliers on the curve, but they are real and they exist and I know them personally, in what should be the middle of their lives.

Maybe we, and the FDA, shouldn’t give up so fast on Avastin.

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Tennis News and Why a Healthy Young Woman Might Get a Pulmonary Embolism

Yesterday I learned that Serena Williams, the tennis pro, has been treated for a pulmonary embolus. My husband found out this morning upon reading the newspaper. He wondered why this would happen to a strong, young, athletic woman.

Without delving into the private or specific aspects of her case:

A pulmonary embolism, or PE in doctor-speak, happens when a blood clot enters or forms in the blood supply to the lungs. It’s a serious condition, because when blood vessels in the lungs are compromised, the lung cells can’t deliver fresh oxygen to hemoglobin that would normally pass through in red blood cells. Symptoms sometimes but not always include shortness of breath, pain in the chest that’s sharp in quality, and fatigue. Usually the diagnosis is made by a scan, such as a VQ or a special kind of (spiral) CT.

tennis racket and ball (Wikimedia Commons)

Treatment includes a blood-thinner, usually for a period of months. At first, and depending on the severity of the circumstances, patients may benefit from oxygen treatment through a light face mask or by nasal prongs. In general, doctors monitor patients for a short time in a hospital, to make sure the clot doesn’t get worse and that they don’t need additional oxygen support, and that the anti-coagulant is working.

When patients get blood clots it’s usually because they have a genetic tendency combined with some situation that aggravates that disposition. For example, if someone is born with a deficiency in a protein – of which there are quite a few – that normally dissolves clots, they might feel fine throughout life and be unaware of their hypercoaguable state. But after a big surgery, or if they were immobilized and dehydrated on a long plane ride, that might lead to a clot formation.

Sometimes surgery or inflammation in an extremity, such as a leg, can dispose to clot formation. When a clot forms there, it’s called a deep venous thrombosis (DVT) and that can, especially if untreated, break off and move through the large veins, to the right side of the heart, and then enter the pulmonary artery and smaller vessel or vessels in the lung. In that case it’s a PE.

Pregnancy, in itself and especially in women with underlying clotting disorders, can dispose young women to a DVT or PE. The same is true for estrogen-containing medications including birth control. Smoking, too –

A short personal perspective is that I once cared for a woman who had a PE who was young and attractive. She had been on a long, international flight a few days before she came to the E.R. It took hours for her to get past triage, and I suspect that was because she looked so healthy. It turned out she had a huge clot in her lungs, and a complex clotting disorder.

If a person with a DVT or PE turns out to have a genetic disposition, it doesn’t mean they need life-long treatment with a blood thinner. Depending on the location, severity of the clot and the circumstances, treatment is given for weeks or months. But it can be helpful to know if you have a clotting disorder. Some patients take prophylactic, low-doses of blood thinners when they travel or after immobilizing surgery, like a hip replacement.

Here are some useful websites that provide information on blood clots:

The American Society of Hematology (which confirms that March is DVT Awareness Month)

PreventDVT.org

Medline Plus

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Breast Cancer Rate in the U.S. is No Longer Declining

A worrisome report on breast cancer trends in the U.S. appeared on-line today, ahead of print in an AACR journal, Cancer Epidemiology, Biomarkers & Prevention.

The analysis, based on the NCI’s SEER data from 2000 – 2007, shows that the incidence of breast cancer in the U.S. is no longer declining. (A drop after 2002 in BC incidence is generally attributed to an abrupt reduction in HRT around that time.)

Since 2003 the overall BC rate has been steady overall, with a few exceptions:

The incidence of BC in non-Hispanic white women ages 60-69 rose by 4.8% in this period. “It remains to be seen if this trend will continue,” according to the study authors.

Among white women ages 40-49 rates of estrogen receptor (ER) positive (ER+) breast cancer significantly increased by an average of 2.7% per year during this period. In contrast, the rate of ER- breast tumors decreased, overall, although the trends were statistically significant only for women ages 40-49 and 60-69.

Apart from women younger than 40, overall BC rates and ER+ case rates were highest among non-Hispanic white women, followed by non-Hispanic black and Hispanic women. Among black women ages 40-49, the incidence of ER+ BC increased (5.2% per year) during 2003-2007, and there were non-significant, recent increases in ER+ BC among older black women.

Of note, in contrast to the pattern for ER+ breast cancer, non-Hispanic black women have the highest rates of ER- breast cancer in every age group. (These ER- cases would include triple negative BC.)

Sorry for the jargon, readers – I hadn’t planned to post now. But I think this information warrants attention.

This matters for a number of reasons. First, it’s bad news in terms of women’s health, plain and simple. Second, these numbers relate to the mammography math, which has been on my mind lately. The point is that if more women between the ages of 40 and 49 are developing ER+ (read: most treatable) tumors, this would influence the net benefit of cancer screening in that age group.

And please don’t misread me here: This is not an academic argument I want to win. Rather, I wish the incidence of breast cancer were declining. And I wish, even more, that so many middle-aged women I know personally weren’t affected by this devastating illness.

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New Numbers Should Factor Into the Mammography Equation

On Friday the New York Times reported that surgeons are performing far too many open breast biopsies to evaluate abnormal mammogram results. A new American Journal of Surgery article analyzed data for 172,342 outpatient breast biopsies in the state of Florida. The main finding is that between 2003 and 2008, surgeons performed open biopsies in an operating room – as opposed to less invasive, safer biopsies with needles – in 30 percent of women with abnormal breast images.

I was truly surprised by this should-be outdated statistic, which further tips the mammography math equation in favor or screening. These numbers matter, and should be based in modern medical practice.

When the Annals of Internal Medicine published the since-adjusted recommendations for breast cancer screening by mammography in November 2009, the stated considerations were not about dollars and cents – which were incalculable – but about the number of women needed to be screened to save one life, and the incidence of false positives which cause harm – worrying, needless biopsies, complications of procedures, overtreatment, etc.

In the context of the health care reform discussion, and considering our country’s out-of-the-sky-and-rising medical bills, some (hopefully) well-intentioned economists heard about those trumped-up mammography papers and concluded that we shouldn’t screen women under 50 for breast cancer because it’s harmful and, what’s more, we can’t keep paying for this sort of care because it’s not evidence-based.

Those conclusions were flawed, though, because the data in those papers were old, as I’ve written previously, and didn’t include studies of digital mammography – which is better for detecting cancer in younger women who tend to have denser breast tissue. In December 2009, I noted that it was unreasonable to consider the costs of open needle biopsies in O.R.’s in any calculation of the harms of mammography, as had the Annals authors, because those kinds of procedures are outdated, or so I thought they were.

It turns out I’ve been living, still, in an academic medical enclave. According to the Timescoverage by Denise Grady:

The reason for the overuse of open biopsies is not known. Researchers say the problem may occur because not all doctors keep up with medical advances and guidelines. But they also say that some surgeons keep doing open biopsies because needle biopsies are usually performed by radiologists. The surgeon would have to refer the patient to a radiologist, and lose the biopsy fee…

The Times article suggests this pattern of over-doing open-biopsies, as documented in Florida, likely reflects national tendencies, including variation among different types of practices – academic, hospital-based, etc.

According to the article published in the American Journal of Surgery, the costs of a core needle biopsy using imaging guidance is around $5,000, or – if a vacuum biopsy device is used, around $6,000; the costs of an open procedure in the O.R. run in the range of $11,000 or more. The Times article indicates that doctors’ fees for a needle procedure range from $750 to $1500, and for an open, surgical biopsy from $1,500 to $2,500. For a ballpark estimate of the cost difference, say a core needle procedure is $5,500 + $1,000 for the doctor’s fees – that’s ~$6,500; a surgical procedure is $11,000 + $2,000 for the surgeon’s fees – that’s $13,000, an easy double.

So let’s say, for the sake of future calculations on mammography, that 10 percent of breast biopsies really do need to take place in the O.R. (which is a generous over-estimate, I think it should be 5 percent or fewer). But if 10 percent need be in the O.R.: then 20 percent of breast biopsies in the U.S. each year – said in the surgery paper to be 1.6 million per year in the U.S. – are being performed through an unnecessary, costlier technique.

An extra $6,500 x 20 percent of 1.6 million procedures = $2.08 billion additional costs, per year.

Let’s call it an even $2.1 billion, or $2 billion, we should shave off the collective amount we spend on mammography and appropriate follow-up. The last digit doesn’t matter; these are huge numbers. No wonder the Times put this story on the front page.

These results should be factored into any proper calculation of costs in breast cancer screening. Now add (or better, subtract) the implications of the findings of two weeks ago – that full lymph node dissection is usually not necessary in women, even if the sentinel node is found to be positive at the time of definitive surgery for what turns out to be a cancer.

What needs be reassessed by public health specialists and economists who weigh in on these issues – and please help me out here, Task Force members and Dartmouth friends, if you would, because your input affects public thinking and, ultimately, policy – are the legitimate costs of screening (every other year, as opposed to annually), doing needle biopsy procedures (instead of open biopsies) and reducing the costs and long-term complications of surgery by eliminating routine lymph node dissection from the equation.

And then we should assess those numbers relative to the costs of treating a woman with metastatic breast cancer, which still has not yet been determined.

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Breast Cancer Study Shows No Benefit In Extensive Lymph Node Removal

Today’s Times leads with a story on surgical removal of lymph nodes in women with breast cancer. The dramatic digital headline, Lymph Node Study Shakes Pillar of Breast Cancer Care, made me tremble at first glance. The article by Denise Grady covers a new report* in the Journal of the American Medical Association (JAMA).

The key finding is that for women with apparently limited disease before surgery who undergo subsequent radiation and chemotherapy, taking out all the cancerous nodes from the axilla (armpit) has no advantage.

I read the original publication and took some notes:

The randomized study, carried out by the American College of Surgeons, involved 891 women with early-stage breast cancer without palpable lymph nodes in the armpit. All underwent lumpectomy and sentinel lymph node examination that was positive – meaning that pathologists observed malignant cells in a sentinel lymph node. Half of the women underwent complete axillary lymph node dissection, by removal of 10 or more lymph nodes, and half did not undergo removal of additional nodes. All of the patients received radiation therapy and the overwhelming majority (>96%) got chemotherapy. The proportions of women treated with endocrine therapy were similar between the two treatment groups.

What the researchers found was that removing additional glands didn’t improve survival in women who had positive (involved) sentinel nodes upon lumpectomy. Survival was measured at 5 years, and the median follow-up was 6.3 years. There was no difference in overall or disease-free survival. This finding supports that for breast cancer patients who will have radiation and chemotherapy, it’s OK for surgeons to leave malignant lymph nodes in place rather than remove those by more aggressive surgery.

Why this matters:

In the majority of BC patients, the lymph nodes in the armpit are not noticeably enlarged at the time of diagnosis. But one in five will have a malignant node detected at surgery. Up until now the standard of care would include a complete axillary lymph node dissection in those women. This procedure can lead to lymphedema, a condition of chronic arm and hand swelling that can be painful and disabling. Lymphedema affects a small but significant fraction of the growing ranks of women – approaching 3 million in the U.S. – who are alive after breast cancer treatment.

According to the Times article, the new research findings could eliminate the need for axillary lymph node dissection in as many as 40,000 women in the U.S. each year: “The discovery turns standard medical practice on its head.”

I’m not so sure I’d go so far as saying that – mainly because I don’t find the results surprising. But I do think it’s a study that matters: The implications bear on costs of breast cancer care (and, yes, on the “costs” of mammography and finding BC) and should have a positive effect on the quality of life for millions of women living after breast cancer treatment. There’s the potential to reduce surgery, and its complications, for the majority of new breast cancer cases.

Why aren’t the results surprising?

Breast cancer treatment, and our understanding of breast cancer biology, has advanced steadily in the past 25 years.

Now it’s routine to give treatments – like chemotherapy, hormone modulators or antibodies like Herceptin – that target breast cancer cells where-ever they reside in the body. The whole point of adjuvant therapy is to destroy malignant cells remaining after surgery. If there are some residual lymph nodes with malignant cells in the armpit region, those would likely be destroyed by chemotherapy and other treatments, combined with radiation to the affected chest and underarm area.

What are the study’s limitations?

What’s not adequately addressed is the situation for women who undergo mastectomy and don’t get radiation, as is standard after lumpectomy.

Another limitation is the study’s relatively short follow-up, of just over 5 years. This is a valid concern in any study of BC survival, but my own opinion is that the axillary node intervention is unlikely to result in a big difference later on. That’s because in 2011 what matters most for treatment decisions, after diagnosis and initial surgery, is the nature – in terms of genetic and molecular features – of the malignant cells.

It happens the NEJM ran a relevant paper on sentinel node dissection last week; we should explore those findings, tomorrow.

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Contemplating Diet and Nutrition: A First Look at the USDA’s New Guidelines

On Sunday afternoons I tend to think about food for my family. Sometimes that’s because we’re having a few more than usual at the dinner table. Also, it’s a time when I order the bulk of fish, meat, produce and other ingredients for the week ahead.

Since I had cancer, I’ve paid much more attention to the food I serve in our home than before. While a balanced diet is no fail-safe for avoiding disease, I do think it’s prudent to be aware of the variety and quantity of food we eat. In medical school we learned surprisingly little about nutrition. Most of what I know I’ve learned from reading books – like Michael Pollen’s In Defense of Food – and reading through detailed reports like the USDA’s new Dietary Guidelines for Americans (7th Edition) issued a few days ago.

From the press USDA and HHS joint press release:

Because more than one-third of children and more than two-thirds of adults in the United States are overweight or obese, the 7th edition of Dietary Guidelines for Americans places stronger emphasis on reducing calorie consumption and increasing physical activity.

The Times summed up the new guidelines nicely in its headline: Government’s Dietary Advice: Eat Less.

But it’s not a trivial report. Rather, it’s a hefty-if-printed (I didn’t) 112-page pdf with some fluff (even blank pages for notes) and some excellent, hard-to-find-elsewhere details on nutrients. Some highlights include Figure 5-1, which demonstrates with abundant clarity that we don’t eat sufficient fruits, vegetables, whole grains or most other recommended foods:

I’m still digesting (sorry, I can’t help myself) detailed chapters and tables in the full report. There’s a lot of useful information to take in. For example, Appendix 11, on p. 85, charts the “Estimated EPA and DHA and Mercury Content in 4 Ounces of Selected Seafood Varieties” – handy if you serve fish for dinner at least twice per week, and like me, figure it’s best to hedge on potential toxic effects by serving a variety of fish.

More from the press release, on tips that will be provided to help consumers translate the Dietary Guidelines into their everyday lives:

• Enjoy your food, but eat less.

• Avoid oversized portions.

• Make half your plate fruits and vegetables.

• Switch to fat-free or low-fat (1%) milk.

• Compare sodium in foods like soup, bread, and frozen meals – and choose the foods with lower numbers.

• Drink water instead of sugary drinks.

All of these seem wise, but obvious. Still, it’s clear that most of us aren’t following the guidelines, or even common sense.

Setting guidelines should help, so teachers in schools and cafeteria-caterers can know what to tell and feed kids, so they develop good eating habits. But really I think that most of the information, if you can call it that – what constitute our dietary habits begun in childhood – has to be cultivated in our homes, the popular culture and community at large. So my plan is to delve further into the USDA report, and elsewhere, and once each week (maybe) post a nutritional ML. I hope it won’t be too simple or boring.

Like a diet, we’ll see how this goes –

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A New Twist on Peanut Allergies and Other Allergic Reactions

The current New Yorker unfolds an engaging story on childhood food allergies. As related by Dr. Jerome Groopman, there’s a shift in how some doctors think about how these conditions  are best managed and, even better – might be prevented. The article feeds into the recent discussion that medical science, and even dogma, too-often turns out to be incorrect.

Groopman interviews Dr. Hugh Sampson, director of the Jae Food Allergy Institute at Mount Sinai Medical Center in New York:

…”This increase in the incidence of food allergy is real,” Sampson said when we spoke recently. He cannot say what is causing the increase, but he now thinks the conventional approach to preventing food allergies is misconceived. For most of his career, he believed, like most allergists, that children are far less likely to become allergic to problematic foods if they are not exposed to them as infants. But now Sampson and other specialists believe that early exposure may actually help prevent food allergies.”

I recommend the full read if you can get it: Groopman probes potential causes of discordant food allergy rates in children of different geographic regions. I learned a number of details on how some doctors in the U.S. use protein-breakdown methods desensitize children to food allergies, how in Israel newly-speaking infants are said to ask eagerly for Bamba, a manufactured, peanut-containing snack (which, for the record, I don’t particularly endorse), and how in some cultures parents chew their young children’s food in a manner that might that might facilitate breakdown of complex proteins by enzymes in saliva.

All interesting –

Of course it’s hard to know exactly what’s true in this, and the causes of allergies are likely to vary among children. There’s a randomized LEAP study (Learning Early About Peanut Allergy) in the U.K. that may provide some hard evidence on this one way, or another.

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An Oncologist Considers Rare Lymphomas in Women With Breast Implants

I have to admit that when I first read about the FDA’s report tying rare cases of anaplastic large cell lymphoma to breast implants, my mind raced with a strange blend of excitement, intense interest and concern. My thoughts shifted from “wow, that’s really interesting” to “exactly what did the FDA find” to “should I be worried?”

So I’ve decided to write this morning’s post from my perspective as an oncologist who spent roughly 15 years of her life studying the causes of lymphomas and related blood malignancies. Some readers of this blog, who fortunately at this point in ML’s slow-but-steady growth are mainly strangers, may be unaware that understanding rare lymphomas was what I lived for in my research work, which occupied the bulk of my time and thought, which I loved very much (as strange as that may seem to some) and which I miss intensely, still, today.

The reality, as very-carefully documented by the FDA in its excellent analysis (which, in my opinion, far surpasses that of most case series reported in the medical literature; I’d give the agency an A+ for detail, thoroughness, clarity and openness about the limitations of the findings thus far), is that these cases of ALCL are few and far between: a total of 60 cases, worldwide, as I reviewed in yesterday’s post. Sometimes just a few cases are indicative of a problem, and I think that is exactly what’s going on with these rare lymphomas.

The pathology is interesting: Essentially all of the ALCL cases are T-cell derived and express CD30. Anaplastic lymphoma kinase (ALK) was negative in each of 26 cases examined for that receptor. The findings are plausible in the context of an aberrant immune response – which can occasionally become malignant – to a foreign body or particular antigen associated with the implants. These oddly uniform characteristics among these rare lymphoma cases support that the FDA’s findings are not random.

Most of the ALCL tumors were limited to the area of the implant capsules, and could – as best I can tell from the few reports – be treated by removal of the implants and affected, adjacent breast tissue. These don’t appear to be aggressive lymphomas, as are some ALCL’s. I would go as far as to speculate that these might indeed be antigen-driven tumors; in this light, it would make sense in principle and in practice to treat these by removal of the implants, at least as a first-line approach.

So if I had a patient with this condition, I’d tell her that these lymphomas are very rare and, when they do arise, can usually be treated by removal of the implant. But I wouldn’t down-play the risk, which is tiny but real.

As an oncologist, I found most of the coverage of the FDA’s alert disappointing, the discussion dominated by plastic surgeons’ reassurances and device makers’ dismissals. Statements like “a woman is more likely to be struck by lightning than get this condition” – proffered by an Allergan spokeswoman as quoted and emphasized in the WSJ Health Blog, Bloomberg News, LA Times and elsewhere – are not helpful to women with implants who are genuinely concerned about their health.

Because I understand that once a woman has had one form of cancer, her risk of developing another tumor is elevated – from whatever genetic, environmental or other disposition she has for malignancy, and from treatment toxicity. Most of the women I’ve seen with implants after mastectomies have some problems considered minor – like thickening of the capsule and dimpling in peri-implant tissue. But these are the exact sort of abnormalities as described in the FDA’s alert, for which there is now a recommendation: evaluate and report cases to the FDA.

Ultimately this is an issue about informed consent – and I don’t mean by this the paperwork, but the reality of women with choosing, or not, to get breast implants. Doctors need more information about these rare lymphomas: how often these arise, why they occur, and how they should be managed so as to cause the least harm when and if treatment is necessary.

The FDA provides a helpful list of sources, from which I’ve selected those that seem most relevant (see reference page). Of historic interest, also, is a NEJM perspective from 15 years ago on the debate about rheumatologic illness, the public’s perception and risks associated with breast implants.

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FDA Reports on Association of Breast Implants and a Rare Form of Lymphoma

Yesterday the FDA issued an alert about a possible link between breast implants – saline or silicone – and a rare form of lymphoma called anaplastic large cell lymphoma (ALCL). These lymphoma cases are exceedingly rare, but the association appears to be significant.

The FDA identified a total of approximately 60 ALCL cases in association with implants, worldwide. Of these, 34 were identified by review of published medical literature from 1997 to May, 2010; the others were reported by implant manufacturers and other sources. The agency estimates the number of women worldwide with breast implants is between 5 and 10 million. These numbers translate to between 6 and 12 ALCL cases in the breast, per million women with breast implants, assessed over 13 years or so.

In women who don’t have implants, ALCL is an infrequent tumor, affecting approximately 1 in 500,000 women is the U.S. per year. This form of lymphoma – a malignancy of lymphocytes, a kind of white blood cell – can arise almost anywhere in the body. But ALCL cases arising in the breast are unusual. The FDA reports that roughly 3 in 100,000,000 women are diagnosed with ALCL in the breast per year in the U.S.

These are very small numbers. Still, the finding of ALCL tumors by the implant capsules is highly suggestive. Almost all of the implant-associated ALCL cases were T-cell type, whereas most breast lymphomas are of B-cell type. The lymphomas arose in women with both silicone and saline-type implants, and in women with implants placed for purposes or augmentation and for reconstruction after mastectomy.

The clinical features varied among the reported cases. From the FDA’s review:

… the median time from breast implant placement to ALCL diagnosis was 8 years, with a range from 1 year to 23 years. Most patients were diagnosed when they sought medical treatment for implant-related symptoms such as persistent seromas, capsular contractures, or peri-implant masses warranting breast implant revision operations. In each case, lymphoma cells were found in the effusion fluid (seroma) surrounding the implant, in the fibrous capsule, or within a peri-implant mass. Typically, there was no invasion beyond the fibrous capsule into the breast parenchyma.

Figure 1 illustrates the location of the reports of ALCL adjacent to the breast implant.

This illustration shows the breast implant placed under the skin and breast tissue. The implant is separated from the breast tissue by a fibrous scar capsule. ALCL lymphoma cells are shown in the effusion fluid between the breast implant and the capsule and attached to the capsule itself.

Figure 1. Presence of ALCL cells in close proximity to a breast implant. In most cases, the ALCL cells were found in the effusion fluid (seroma) surrounding the implant or contained within the fibrous capsule. ALCL is lymphoma, a type of cancer involving cells of the immune system. It is not cancer of the breast tissue, and typically, invasion of the lymphoma beyond the fibrous capsule into the breast parenchyma was not observed. Modified from Thompson et al, (2010).

With such a small number of cases worldwide, it’s hard to draw evidence-based conclusions regarding the appropriate treatment of these rare lymphomas. More from the FDA:

Treatment was reported for 20 patients. Most had the implants removed, and some went on to receive treatment with radiation and/or chemotherapy. Overall, the outcomes appeared to be more favorable than would typically be expected for systemic ALCL. Outcomes were reported for 19 cases. Of these, 14 patients had no evidence of disease at last follow-up. However, most cases were diagnosed with early stage disease, and follow-up on many cases was limited.

At this time, the FDA is advising health care providers to be aware of the possible diagnosis, to carefully evaluate breast implant patients with suspected ALCL, and to report all confirmed cases to the agency.

As for patients, the situation is troubling. The incidence of these tumors is quite low, almost immeasurable, and the prognosis – based on the few treatment reports – seems good. But many women do have some fluid, contractures, thickening and other complications around the implant capsules. Most of those physical aberrations surrounding the implants are not lymphoma.

It’s a Pandora’s box, but one that needs be opened. The problem is that if we biopsy every abnormality – such as a minor thickening or fluid accumulation adjacent to a breast implant – we’ll hike up the costs and, more importantly, the complications associated: With every needle stick there’s a risk of infection, additional scar formation and more. On the other hand, you wouldn’t want to overlook a treatable, early-stage lymphoma. Women need to know of the risks of implants, which can only be determined if doctors thoroughly investigate these sorts of complications.

The LA Times quotes Dr. Phil Haeck, president of the American Society of Plastic Surgeons: “I think there’s reason to be concerned about this, but there shouldn’t be reason for panic,” he said. According to that article: “Signs of ALCL associated with implants ‘are pretty dramatic. There’s a lot of swelling and pain. They won’t miss it,’ Haeck said.”

I’m not so sure. Lymphoma, including ALCL in my experience as an oncologist, can be very subtle.

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