Archive for Basic Science

“Liquid biopsies” for cancer screening: Life-saving tests, or overdiagnosis and overtreatment taken to a new level?

Could a blood draw be all you need to diagnose cancer and identify the best treatment for it? Not so fast...

Could a blood draw be all you need to diagnose cancer and identify the best treatment for it? Not so fast…

I’ve written many times about how the relationship between the early detection of cancer and decreased mortality from cancer is not nearly as straightforward as the average person—even the average doctor—thinks, the first time being in the very first year of this blog’s existence. Since then, the complexities and overpromising of various screening modalities designed to detect disease at an early, asymptomatic phase have become a relatively frequent topic on this blog. Before that, on my not-so-super-secret other blog, I noted that screening MRI for breast cancer and whole body CT scans intended to detect other cancers early were not scientifically supported and thus were far more likely to cause harm than good. That was well over ten years ago. Now we have a company offering what it refers to as a “liquid biopsy” for the early detection of cancer. I fear that this is the recipe for the ultimate in overdiagnosis. I will explain.

The problem, of course, is that disease progression, including cancer progression, is not always a linear process, in which the disease progresses relentlessly through its preclinical, asymptomatic phase to symptoms to complications to (depending on the disease) death. There is such a thing as disease that remains asymptomatic and never progresses (at which point it’s hard to justify actually calling it a disease). As I pointed out in my first SBM post on the topic, at least three-quarters of men over 80 have evidence of prostate cancer in autopsy series. Yet nowhere near three-quarters of men in their 80s die of prostate cancer—or ever manifest symptoms from it. This is what is meant by overdiagnosis, the diagnosis of disease that doesn’t need to be treated, that would never cause a patient problems.

When teaching medical students and residents, I frequently emphasize that overdiagnosis is different from a false positive because overdiagnosis does diagnose an actual abnormality or disease. For example, ductal carcinoma in situ (DCIS) diagnosed by mammography leading to a biopsy is a real pathological abnormality; it is not a false positive. We just do not know which cases of DCIS will progress to cancer and which will not, leading to a question of how DCIS should be treated or at the very least whether we should treat it as aggressively as we do now, particularly given that the apparent incidence of DCIS has increased 16-fold since the 1970s, all of it due to mammographic screening programs and the increased diagnosis of DCIS and early stage breast cancer has not resulted in nearly as much of a decrease in the diagnosis of advanced stage breast cancer as one would expect if early diagnosis were having an impact in reducing the diagnosis of late stage disease.

Overdiagnosis would not be such an issue if it didn’t inevitably lead to overtreatment. DCIS, for instance, is treated with surgery, radiation, and anti-estrogen drugs. Early stage prostate cancer used to be treated with radical prostatectomy, but now more frequently with radiation. Many of these men and women didn’t actually need treatment. We just don’t know which ones. This is why over the last six or seven years a significant rethinking of screening for breast and prostate cancer has occurred. There has been a backlash, of course, but the rethinking seems to have taken hold.

Not everywhere, of course. (more…)

Posted in: Basic Science, Cancer, Diagnostic tests & procedures, Public Health

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“Precision medicine”: Hope, hype, or both?

The cost to sequence a whole genome has been plummeting impressively since 2007.

The cost to sequence a whole genome has been plummeting impressively since 2007.

I am fortunate to have become a physician in a time of great scientific progress. Back when I was in college and medical school, the thought that we would one day be able to sequence the human genome (and now sequence hundreds of cancer genomes), to measure the expression of every gene in the genome simultaneously on a single “gene chip,” and to assess the relative abundance of every RNA transcript, coding and noncoding (such as microRNAs) simultaneously through next generation sequencing (NGS) techniques was considered, if not science fiction, so far off in the future as to be unlikely to impact medicine in my career. Yet here I am, mid-career, and all of these are a reality. The cost of rapidly sequencing a genome has plummeted. Basically, the first human genome cost nearly $3 billion to sequence, while recent developments in sequencing technology have brought that cost down to the point where the “$1,000 genome” is within sight, if not already here, as illustrated in the graph above published by the National Human Genome Research Institute. Whether the “$1,000 genome” is truly here or not, the price is down to a few thousand dollars. Compare that to the cost of, for instance, the OncoType DX 21-gene assay for estrogen receptor-positive breast cancer, which costs nearly $4,000 and is paid for by insurance because its results can spare many women from even more expensive chemotherapy.

So, ready or not, genomic medicine is here, whether we know enough or not to interpret the results in individual patients and use it to benefit them, so much so that President Obama announced a $215 million plan for research in genomic mapping and precision medicine known as the Precision Medicine Initiative. Meanwhile, the deeply flawed yet popular 21st Century Cures bill, which passed the House of Representatives, bets heavily on genomic research and precision medicine. As I mentioned when I discussed the bill, it’s not so much the genomic medicine funding that is the major flaw in the bill but rather its underlying assumption that encouraging the FDA to decrease the burden of evidence to approve new drugs and devices will magically lead to an explosion in “21st century cures,” the same old antiregulatory wine in a slightly new bottle. Be that as it may, one way or the other, the federal government is poised to spend lots of money on precision medicine.

Because I’m a cancer doctor, and, if there’s one area in medicine in which precision medicine is being hyped the hardest, it’s hard for me not to think that the sea change that is going on in medicine really hit the national consciousness four years ago. That was when Walter Isaacson’s biography of Steve Jobs revealed that after his cancer had recurred as metastatic disease in 2010. Jobs had consulted with research teams at Stanford, Johns Hopkins, and the Broad Institute to have the genome of his cancer and normal tissue sequenced, one of the first twenty people in the world to have this information. At the time (2010-2011), each genome sequence cost $100,000, which Jobs could easily afford. Scientists and oncologists looked at this information and used it to choose various targeted therapies for Jobs throughout the remainder of his life, and Jobs met with all his doctors and researchers from the three institutions working on the DNA from his cancer at the Four Seasons Hotel in Palo Alto to discuss the genetic signatures found in Jobs’ cancer and how best to target them. Jobs’ case, as we now know, was a failure. However much Jobs’ team tried to stay one step ahead of his cancer, the cancer caught up and passed whatever they could do. (more…)

Posted in: Basic Science, Cancer, Clinical Trials, Science and the Media

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How should we treat DCIS?

How should we treat DCIS?

I’ve written more times than I can remember about the phenomenon of overdiagnosis and the phenomenon that is linked at the hip with it, overtreatment. Overdiagnosis is a problem that arises when large populations of asymptomatic, apparently healthy people are screened for a disease or a condition, the idea being that catching the disease at an earlier stage in its progression will allow for more successful treatment. Two prominent examples include—of course—screening for breast cancer with mammography and screening for prostate cancer with prostate-specific antigen (PSA) testing, and I’ve written about the problem of overdiagnosis with each of them on many occasions. Basically, overdiagnosis occurs when the screening test picks up what we call “preclinical” disease (i.e., disease that hasn’t become symptomatic) that, if left untreated, would never become symptomatic or endanger the health or life of the patient). Although intuitively, it seems to the lay public (and, truth be told, most doctors) that detecting cancer earlier must be inherently better, it turns out that it’s way more complicated than you think. There is a price to be paid for early diagnosis in the form of overtreatment of disease that doesn’t need treatment and for disease that is destined to threaten the life of the patient earlier treatment doesn’t always result in better outcomes. Also, whenever you screen for a condition in asymptomatic people, you will always—always—find much more of it, and the significance of those added diagnoses is not always clear, as a new study in JAMA Oncology shows.

DCIS and mammography: Some background

Before I get to the meat of the study, from my perspective, nowhere is the problem of overdiagnosis and overtreatment in cancer screening as pronounced than in the condition known as ductal carcinoma in situ (DCIS). DCIS is commonly referred to as “stage 0″ breast cancer and is characterized by milk duct cells that appear malignant but remain confined to the milk ducts. In other words, they haven’t invaded the tissue surrounding the ducts. In general, DCIS is treated similarly to breast cancer, with surgical excision, either by mastectomy or breast-conserving surgery, followed by radiation therapy if breast conserving surgery is used. Then, depending on its hormone receptor status, adjuvant treatment consists of blocking estrogen for five years. The rationale for this treatment is the view of DCIS as being a precursor to fully invasive breast cancer and that treating the DCIS will prevent the development of breast cancer. Over the last couple of decades, however, it has become clear that not all DCIS is created equal. Much of it will never progress to breast cancer in the lifetime of the woman (particularly if the woman is older, which means less time for fully malignant transformation to occur). Evidence suggesting this includes studies showing an increase in DCIS incidence by 16-fold since the 1970s, when mammography started to be introduced on a large scale, with little change in the incidence of invasive cancer. Today, 20-25% of mammography-detected breast cancer diagnoses are DCIS; forty years ago, DCIS was an uncommon diagnosis, except associated with an invasive cancer.

Posted in: Basic Science, Cancer, Clinical Trials, Science and the Media

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“Aborted fetal tissue” and vaccines: Combining pseudoscience and religion to demonize vaccines

Yes, there are antivaccinationists who actually believe this.

Yes, there are antivaccinationists who actually believe this.

As hard as it is to believe after seven and a half years of existence and nearly 2,400 posts on SBM, every so often, something reminds me that we here at SBM haven’t discussed a topic that should be discussed. So it was a couple of weeks ago, when I saw a familiar name in a news story that wasn’t about vaccines. You might recall a news story last month when a shadowy group with ties to radical antiabortion groups, the Center for Medical Progress, led by a man named David Daleiden, ran a highly questionable “sting” operation (complete with fake IDs) to “prove” that Planned Parenthood was selling aborted fetuses for medical research.

While reading news stories about Daleiden and CMP, I came across a familiar name, a name that many of us who discuss antivaccine misinformation are familiar with. I’m referring to Theresa Deisher, founder of the Sound Choice Pharmaceutical Institute. It turns out that Deisher helped to prepare Daleiden for his role as a biomedical representative that he assumed in order to deceive representatives of Planned Parenthood. She taught him how to talk the talk and walk the walk, so to speak, so that he was convincing as a representative of a biomedical research firm.

I can hear you asking: So what? What do Daleiden and CMP have to do with vaccines? It’s not CMP per se, but Deisher who is relevant. The reason that Deisher is so relevant to Science-Based Medicine (SBM) is because she is one of the foremost promoters of a particularly pernicious form of antivaccine misinformation that tries desperately to create a religious basis to oppose vaccines with antivaccine activism. It is a form of misinformation designed to deceive those who believe abortion is a moral wrong into thinking that vaccines, too, are a moral wrong because some of the viruses used to make specific vaccines are grown during the manufacturing process in cell lines derived from human fetuses decades ago. But Deisher goes one huge step beyond just guilt by association for vaccines. She is, as the news story cited above notes, the foremost promoter of a related and equally pernicious form of antivaccine information that claims that DNA from the fetal cell lines used to grow vaccine strains of viruses is a cause of autism. The truly depressing thing about Deisher is that she is, in fact, a real scientist (or at least was).

In any event, it occurred to me that, although I’ve mentioned Deisher briefly before in the context of the Disneyland measles outbreak, I’ve never deconstructed her antivaccine misinformation in detail here. Yet, her work is often cited by antivaccine activists to persuade those whose religion tells them abortion is morally wrong that they shouldn’t vaccinate their children by adding to the false claim that somehow “fetal parts” are used in the making of vaccines the even more false claim that fetal DNA somehow gets into the brain, recombines with the DNA in neurons, and causes autism. She’s also just released what appears to be a new paper claiming to show how fetal DNA causes autism. The confluence of her name coming up in stories about CMP and Planned Parenthood and her release of this new “paper” makes this a perfect time to write about Deisher.

Posted in: Basic Science, Critical Thinking, Religion, Vaccines

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The 21st Century Cures Act: The (Somewhat) Good, The (Mostly) Bad, and The (Very) Ugly

The 21st Century Cures Act: Unnecessary and misguided.

The 21st Century Cures Act: Unnecessary and misguided.

The approval of new drugs and medical devices is a process fraught with scientific, political, and ethical landmines. Inherent in any such process is an unavoidable conflict between rigorous science and safety on the one side, which tend to slow the process down by requiring large randomized clinical trials that can take years, versus forces that demand faster approval. For example, patients suffering from deadly diseases demand faster approval of drugs that might give them the hope of surviving their disease, or at least of surviving considerably longer. This is a powerful force for reform, as evidenced by HIV/AIDS activism in the 1980s and 1990s that led to the development of fast-track approval mechanisms for drugs for life-threatening conditions, a change whose effects have been mixed. It’s also a powerful force potentially for ill, as I’ve documented in my posts about the understandable but misguided “right-to-try” movement. After all, what politician can say no to a constituency representing desperately ill people who only want a shot at survival? It’s not all desperate patients, however. Also wanting more rapid drug approval are powerful business interests in the form of the pharmaceutical and medical device industries, for whom the time and expense of prolonged clinical trials eat into profits and make some drugs not worth developing from a business standpoint.

In 1962, after Frances O. Kelsey, MD, PhD (who died on Friday at the age of 101) successfully prevented the approval of the drug thalidomide in the US, a drug found to cause serious birth defects, Congress passed the Kefauver-Harris Drug Amendments to the Federal Food, Drug, and Cosmetic Act. These amendments required that drug companies not just show safety before their drugs could be FDA-approved, as had been the case prior to the amendments, but also to provide substantial evidence of effectiveness for the product’s intended use. That evidence had to be in the form of adequate and well-controlled clinical trials, which at the time was considered a revolutionary requirement. (Believe it or not, no requirement for high quality clinical trials existed before 1962.) This led to the current system of phase I, II, III, and IV clinical trials in force in the United States today. The amendments also included a requirement for informed consent of study subjects and codified good manufacturing processes, as well as the requirement that adverse events be reported. This has been, with some tweaking over the years, the law of the land regarding how the FDA approves drugs for specific indications

Medicine is a lot more complex now than it was in the 1960s however, and there has been a growing sentiment that the system is, if not broken, at least functioning in a way that is behind the times, a manner that was acceptable and appropriate 40 years ago but is no longer so in this era of genomics, precision medicine (formerly known as “personalized medicine”), and targeted therapies. The new drug approval process, which can take up to a decade and cost a billion dollars, it is argued, is too rigid, cumbersome, and slow for the 21st century. (Why it wasn’t too rigid, cumbersome, and slow in the 20th century, no one seems to say. I guess that “21st century” sounds way cooler.)

Into this ongoing controversy have marched Rep. Fred Upton (R-Mich.) and Rep. Diana DeGette (D-Colo.), who have sponsored a bill passed by the House of Representatives in a rare display of bipartisanship in July. The bill, H.R.6, is entitled the “21st Century Cures Act“. Given how it passed the House by a vote of 344-77, one would think that it should glide through the Senate easily. Certainly, its sponsors and supporters have mounted a mighty PR effort. That might not be the case, given that in the Senate a single senator can hold up or even kill a bill through a filibuster, and to shut down a filibuster or prevent a threatened filibuster requires 60 votes. Be that as it may, I’m not so much interested in the politics of this bill, which, if it survives the Senate, will almost certainly be significantly amended, but rather what the bill does.

Posted in: Basic Science, Clinical Trials, Politics and Regulation

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ASEA, ORMUS, and Alchemy

Ormus powder. “Ormus could be the source of all metals. Therefore, we identify the Ormes elements in relationship to the metal they can unfold into (e.g. Ormus copper, Ormus gold, Ormus rhodium, etc.)”

An example of Ormus powder. “Ormus could be the source of all metals. Therefore, we identify the Ormus elements in relationship to the metal they can unfold into (e.g. Ormus copper, Ormus gold, Ormus rhodium, etc.)”

I got an e-mail from a woman who had read my article on ASEA, a multilevel marketing diet supplement that I characterized as an expensive way to buy water.  She had not tried ASEA products but was applying for a position as an accountant with the company, and she chastised me for not doing my due diligence and researching the new science of ORMUS.

First she dismissed science, saying “science as we know it is no longer valid and quantum physics clearly shows this.” Then she claimed there was valid science that would support ASEA’s claims. She had personally done a sea salt cleanse with good results. If ASEA is only salt water, that doesn’t negate its validity, since ORMUS material is from sea salt and when minerals are rearranged they no longer register as the original element. Alchemy is not a myth, and the “quantum non-mainstream sciences” prove it is real. Quantum physics “explains that particles can interact without actually being on contact, this is a form or property of superconductivity.” She thinks ORMUS material is superconductive and constitutes a percentage of the human brain mass, allowing transmission of thoughts to others who tune in to these superconductive energy transmissions.

But wait, there’s more! She went on to tell me about an experiment where a dog’s entire blood volume was replaced by seawater. She shared her belief that the power of the mind can heal all disease, and she explained that she relies on a natural knowing within herself and only uses outside evidence to confirm her beliefs. She has been studying subjects like sacred geometry, Vedic mathematics, the golden ratio, quantum physics, and extraterrestrials.

Orbitally Rearranged Monoatomic Elements

This woman is obviously misguided and misinformed, but what is this ORMUS she’s talking about? I’d never heard of it, so I started with Rational Wiki:

ORMUS, also called ORMEs (Orbitally Rearranged Monoatomic Elements) and m-state materials, is a fictitious group of substances exhibiting many miraculous properties, such as healing powers and superconductivity at room temperature. They were supposedly discovered in 1975 by David Hudson, a cotton farmer from Arizona.


Posted in: Basic Science, Energy Medicine, Herbs & Supplements

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Bastions of quackademic medicine: Georgetown University

The cover of Georgetown Medicine Spring/Summer 2015 issue. This image will drive Mark Crislip crazy, as it features yet another acupuncturist not using gloves while sticking needles into people. Dr. Gorski loves watching Dr. Crislip's reactions to such photos.

The cover of Georgetown Medicine Spring/Summer 2015 issue. This image will drive Mark Crislip crazy, as it features yet another acupuncturist not using gloves while sticking needles into people. Dr. Gorski loves watching Dr. Crislip’s reactions to such photos.

We frequently discuss a disturbing phenomenon known as quackademic medicine. Basically, quackademic medicine is a phenomenon that has taken hold over the last two decades in medical academia in which once ostensibly science-based medical schools and academic medical centers embrace quackery. This embrace was once called “complementary and alternative medicine” (CAM) but among quackademics the preferred term is now “integrative medicine.” Of course, when looked at objectively, integrative medicine is far more a brand than a specialty. Specifically, it’s a combination of rebranding some science-based modalities, such as nutrition and exercise, as somehow being “alternative” or “integrative” with the integration of outright quackery, such as reiki and “energy healing,” acupuncture, and naturopathy, into conventional medicine. As my good bud and fellow Science-Based Medicine (SBM) blogger Mark Crislip put it, mixing cow pie with apple pie does not make the cow pie better, but we seem to be “integrating” the cow pie of quackery with the apple pie of science-based medicine thinking that somehow it will improve the smell, taste, and texture of the cow pie.

I remember how, when I first discovered how prevalent outright pseudoscience and quackery had become in medical academia (which was before I became one of the founding SBM bloggers), I was in denial. I couldn’t believe it. Then I tracked this phenomenon with something I called the Academic Woo Aggregator. It turned out to be a hopeless endeavor because, as I soon discovered, the phenomenon was so pervasive that it was really hard to keep the Aggregator up to date. Since then, I’ve generally only focused on particularly egregious examples, naming names when institutions like my alma mater embrace anthroposophic medicine; “respectable” journals publish “integrative medicine” guidelines for breast cancer patients; cancer organizations include “integrative oncology” in their professional meetings; NCI-designated comprehensive cancer centers promote reiki to pediatric cancer patients or offer high dose unproven vitamin C treatment to patients; or respected academic institutions embrace traditional Chinese medicine (TCM) and the quackery that is function medicine. You get the idea. It’s depressing just how far medical academia has fallen in terms of being “open-minded” to the point of brains falling out when it comes to medical pseudoscience.

Posted in: Acupuncture, Basic Science, Energy Medicine, Homeopathy, Medical Academia

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Aging and Longevity: Science for Spring Chickens

Spring Chicken

We’re all going to die, but we don’t like to think about it. I’ll reach the proverbial threescore years and ten next month, so I’ve been thinking more about it, wishing I knew some reliable way to ensure that I would live many more years and remain fully functional until I suddenly collapsed like the Deacon’s wonderful one-hoss shay. There are myriad “longevity clinics” and “anti-aging” formulas, and every centenarian has an explanation that is the direct opposite of some other centenarian’s explanation. But what does the scientific evidence say? In his new book Spring Chicken: Stay Young Forever (Or Die Trying), Bill Gifford has done us a great service by investigating the latest scientific evidence about aging and presenting his findings in an engaging narrative form. He interviews some of the major players and introduces us to health fanatics who are convinced they can prolong their lives by doing things like monitoring their own blood cholesterol levels on a weekly basis, exercising obsessively, severely restricting their calorie intake, fasting intermittently, deliberately exposing themselves to stress like swimming in icy water, competing in extreme athletics, taking boatloads of hormones and supplements, experimenting on themselves with investigational drugs, and doing other questionable and sometimes bizarre things.

Are there limits to human life expectancy?

There is no documented case of anyone living longer than Jeanne Calment of France, who died at the age of 122. Jay Olshansky thinks biological forces limit how long we can live. Aubrey de Grey thinks some people alive today will live to be a thousand years old. Gifford explains the controversy and the reasoning behind both sides. Will we someday be able to re-engineer human biology to overcome the limits? The jury is still out. (more…)

Posted in: Basic Science, Book & movie reviews

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The measles vaccine protects against more than just the measles

Vaccines Protect

One of the disadvantages of writing for this blog is that sometimes I feel as though I spend so much time deconstructing bad science and pseudoscience in medicine that I’m rarely left with the time or the opportunity to discuss some interesting science. Of course, even when I do that, usually it’s in the context of that very same bad science or pseudoscience, and this post won’t be different. Still, there was some interesting science with respect to vaccines published last week in Science, and I think it’s worth looking over. The only thing that surprises me is that the antivaccine movement hasn’t jumped all over it yet. On the other hand, its press coverage was relatively minimal, and I didn’t really notice it until an article appeared on (sadly, yes) The Huffington Post entitled “The Measles Vaccine Can Protect Against Much More Than Measles, According To New Study“:

A new study suggests the measles shot comes with a bonus: By preventing that disease, the vaccine may also help your body fight off other illnesses for years.

It’s long been known that contracting measles weakens the immune system for weeks or months, putting people, especially children, at increased risk for potentially fatal infection by a host of germs.

Now, scientists find that this vulnerable period goes on much longer than thought, up to three years. So the benefit of avoiding measles also extends longer than was appreciated. Researchers also found that measles vaccination campaigns were followed by a drop in deaths for other infectious diseases.

Experts said the work is a wake-up call to parents who don’t vaccinate their children out of unfounded fears about a link between vaccines and autism.


Posted in: Basic Science, Vaccines

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Angelina Jolie, surgical strategies for cancer prevention, and genetics denialism (revisited)

Angelina Jolie

Angelina Jolie

Sometimes, weird things happen when I’m at meetings. For example, I just got home from the Society of Surgical Oncology (SSO) meeting in Houston over the weekend. Now, one thing I like about this meeting is that, unlike so many other meetings these days—cough, cough, ASCO, I’m looking at you—at the SSO there wasn’t a single talk I could find about “complementary and alternative medicine” (CAM) or, as its proponents like to call it now, “integrative medicine.” It’s also a great chance to get caught up on new science and clinical guidelines in cancer surgery, as well as to see people I tend only to see at these meetings.

However, I must admit that by the last day I tend to be “meeting-ed” out and sometimes my attention wanders. Unfortunately, there are ample ways to indulge that attention deficit. Actually, it’s my iPhone. And it’s Twitter. So it was an odd coincidence that right after a talk by Dr. Deanna Attai about whether surgical oncologists can or should offer genetic counseling services to their patients, when I somehow let myself get into an exchange with Sayer Ji, the “natural health expert” responsible for GreenMedInfo, over BRCA1 mutations and the risk of breast and ovarian cancer, in other words, exactly the sort of thing that Dr. Attai had just discussed. For example:

After a bit of back-and-forth, I got fed up:

This minor Twitter exchange came about because of Angelina Jolie’s announcement in a New York Times op-ed last week entitled “Diary of a Surgery” that she had had her ovaries removed to prevent ovarian cancer due to her being a carrier of a high-risk mutation in BRCA1. As you might recall, I wrote about Jolie’s case two years ago, when she first announced in a NYT op-ed entitled “My Medical Choice” that she had undergone a bilateral mastectomy with reconstruction to decrease her BRCA1-related risk of breast cancer. Although I had discussed the story before, I thought it worth doing again here in a bit more detail. (more…)

Posted in: Basic Science, Cancer, Surgical Procedures

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