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

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Learning quackery for Continuing Medical Education credit

accme-screenshot

 

The Integrative Addiction Conference 2015 (“A New Era in Natural Treatment”) starts tomorrow in Myrtle Beach, SC. Medical doctors, doctors of osteopathy, naturopaths and other health care providers will hear lectures on such subjects as “IV Therapies and Addiction Solutions,” given by Kenneth Proefrock, a naturopath whose Arizona Stem Cell Center specializes in autologous stem cell transplants derived from adipose tissue. Proefrock, who was disciplined for using prolotherapy in the cervical spine without proper credentialing in 2008, claims that stem cells treatments are an “incredibly versatile therapy” and uses them for variety of conditions, such as MS and viral diseases. At the same time, he admits that they are not FDA approved and he is not claiming they are effective for anything (and he’s right), which leads one to wonder why he employs them.

Proefrock also offers a typical naturopathic mish-mash of services, from oncology to urology to “naturopathic endocrinology,” and claims he specializes in treating influenza, high blood pressure and kidney stones, as well as addiction. In other words, he doesn’t seem to be the sort of expert you’d find speaking at a science-based conference on addiction medicine.

You’ll find similarly troubling bios of some of the other speakers, as well as dubious treatments for addiction, on the conference website. Here, for example, are speaker Giordano’s and Eidelman’s websites.

Dalal Akoury, MD, is the “Title Sponsor” of the conference and appears to be running the show. Although she is listed by the S.C. Board of Medicine as board certified in pediatrics, she is the founder of the “Integrative Addiction Institute” and runs the “AwareMed Health and Wellness Resource Center” in Myrtle Beach. Like the Arizona Stem Cell Center, it offers a range of treatments that defy categorization as any particular specialty: addiction recovery, “adrenal fatigue” treatment, stem cells, “anti-aging,” weight loss, “functional medicine” and “integrative cancer care“. Yet, only Akoury and one licensed practical nurse are on the staff of the Center. Again, it is questionable whether she is has sufficient qualifications in addiction medicine to run a conference on the subject. (more…)

Posted in: Acupuncture, Cancer, Chiropractic, Dentistry, Diagnostic tests & procedures, Energy Medicine, Homeopathy, Medical Academia, Medical Ethics, Naturopathy

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The uncertainty surrounding mammography continues

Screening mammography

Mammography is a topic that, as a breast surgeon, I can’t get away from. It’s a tool that those of us who treat breast cancer patients have used for over 30 years to detect breast cancer earlier in asymptomatic women and thus decrease their risk of dying of breast cancer through early intervention. We have always known, however, that mammography is an imperfect tool. Oddly enough, its imperfections come from two different directions. On the one hand, in women with dense breasts its sensitivity can be maddeningly low, leading it to miss breast cancers camouflaged by the surrounding dense breast tissue. On the other hand, it can be “too good” in that it can diagnose cancers at a very early stage.

Early detection isn’t always better

While intuitively such early detection would seem to be an unalloyed Good Thing, it isn’t always. Although screening for early cancers appears to improve survival, the phenomenon of lead time bias can mean that detecting a disease early only appears to improve survival even if earlier treatment has no impact whatsoever on the progression of the disease. Teasing out a true improvement in treatment outcomes from lead time bias is not trivial. Part of the reason why early detection might not always lead to improvements in outcome is because of a phenomenon called overdiagnosis. Basically, overdiagnosis is the diagnosis of disease (in this case breast cancer but it is also an issue for other cancers) that would, if left untreated, never endanger the health or life of a patient, either because it never progresses or because it progresses so slowly that the patient will die of something else (old age, even) before the disease ever becomes symptomatic. Estimates of overdiagnosis due to mammography have been reported to be as high as one in five or even one in three. (Remember, the patients in these studies are not patients with a lump or other symptoms, but women whose cancer was detected only through mammography!) Part of the evidence for overdiagnosis includes a 16-fold increase in incidence since 1975 of a breast cancer precursor known as ductal carcinoma in situ, which is almost certainly not due to biology but to the introduction of mass screening programs in the 1980s.

As a result of studies published over the last few years, the efficacy of screening mammography in decreasing breast cancer mortality has been called into question. For instance, in 2012 a study in the New England Journal of Medicine (NEJM) by Archie Bleyer and H. Gilbert Welch found that, while there had been a doubling in the number of cases of early stage breast cancer in the 30 years since mass mammographic screening programs had been instituted, this increase wasn’t associated with a comparable decrease in diagnoses of late stage cancers, as one would expect if early detection was taking early stage cancers out of the “cancer pool” by preventing their progression. That’s not to say that Bleyer and Welch didn’t find that late stage cancer diagnoses decreased, only that they didn’t decrease nearly as much as the diagnosis of early stage cancers increased, and they estimated the rate of overdiagnosis to be 31%. These results are in marked contrast to the promotion of mammography sometimes used by advocacy groups. Last year, the 25 year followup for the Canadian National Breast Screening Study (CNBSS) was published. The CNBSS is a large, randomized clinical trial started in the 1980s to examine the effect of mammographic screening on mortality. The conclusion thus far? That screening with mammography is not associated with a decrease in mortality from breast cancer. Naturally, there was pushback by radiology groups, but their arguments were, in general, not convincing. In any case, mammographic screening resulted in decreases in breast cancer mortality in randomized studies, but those studies were done decades ago, and treatments have improved markedly since, leaving open the question of whether it was the mammographic screening or better adjuvant treatments that caused the decrease in mortality from breast cancer that we have observed over the last 20 years.

Given that it’s been a while since I’ve looked at the topic (other than a dissection of well-meaning but misguided mandatory breast density reporting laws a month ago), I thought now would be a good time to look at some newer evidence in light of the publication of a new study that’s producing familiar headlines, such as “Mammograms may not reduce breast cancer deaths“.

Here we go again.
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Posted in: Cancer, Public Health

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Mandatory breast density reporting legislation: The law outpaces science, and not in a good way

Over the years, our bloggers here at Science-Based Medicine have written time and time again about the intersection of law and science in medicine. Sometimes, we support a particular bill or law, such as laws to protect children against religion-inspired medical neglect; laws making it harder for manufacturers of homeopathic “medicines” to deceive the public; or California Bill AB 2109, a bill whose intent was to make it more difficult for parents to obtain nonmedical exemptions to vaccine mandates but whose implementation after being passed into law was profoundly sabotaged by Governor Jerry Brown. or, more recently, California SB 277, a bill currently wending its way through the California legislature that would eliminate nonmedical exemptions to school vaccine mandates and has, not surprisingly, engendered extreme resistance from the antivaccine crowd, including by Robert F. Kennedy, Jr. In the vast majority of cases we explain how the law lets us down when it comes to science in medicine, and, unfortunately, examples are many: Naturopathic licensing laws; supplement regulation (or, more appropriately, lack of regulation); misguided, deceptive, and patient-hostile “right-to-try” laws; state laws regulating medical practice that allow quackery to flourish unchecked; laws regulating pharmaceutical cost transparency that ask the wrong question.

The case I will discuss here is unusual in that it is a case of the law getting ahead of what the science says in a manner that will likely do little, if any, good for patients, cause a lot of confusion until the science is worked out better, and end up costing patients money for little or no benefit. I am referring to laws mandating the reporting of high-breast-density to women with dense breasts undergoing mammography. These laws are sweeping the country (albeit not as rapidly as “right-to-try” laws), with a total of 22 states having passed them as of today since Connecticut became the first to do so in 2009. The most recent of these laws went into effect in my own state of Michigan exactly one week ago:

Women with dense breast tissue — the sort that can hide potentially deadly tumors from routine mammograms — must be notified in writing and encouraged to consider additional tests under a new state law that is effective Monday.

While mammograms remain the gold standard for detecting breast tumors, they’re less reliable in almost half of women with dense breast tissue. Dense or fibrous tissue shows up as splotches of white on a mammogram — so do tumors.

That will likely surprise many of the millions of women who rely on mammography for catching the earliest signs of cancer, said Nancy Cappello. The Connecticut woman was shocked in 2004, when her gynecologist found a lump — advanced cancer that had already spread to her lymph nodes — just months after a mammogram deemed her cancer-free.

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Posted in: Cancer, Politics and Regulation, Public Health

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Let food be thy medicine and medicine be thy food? The obsessive worship of “medicinal foods”

Let food be thy medicine and medicine be thy food? The obsessive worship of “medicinal foods”

Let food be thy medicine and medicine be thy food.

– attributed to Hippocrates

Who said anything about medicine? Let’s eat!

– attributed to one of Hippocrates forgotten (and skeptical) students

 

Who hasn’t seen or heard Hippocrates’ famous quote about letting food be your medicine and your medicine your food? If you have Facebook friends who are the least bit into “natural” medicine or living, you’ve almost certainly come across it in your feed, and if you’re a skeptic who pays the least bit of attention to what’s going on in the quackosphere you will almost certainly have seen it plastered on a picture as a meme, either using a picture of Hippocrates or pictures of plates of green, leafy vegetables, or both. I like to view the fetishization of “food as medicine,” to cite Hippocrates, as one of the best examples out there of the logical fallacy known as the appeal to antiquity; in other words, the claim that if something is ancient and still around it must be correct (or at least there must be something to it worth considering).

Of course, just because an idea is old doesn’t mean it’s good, any more than just because Hippocrates said it means it must be true. Hippocrates was an important figure in the history of medicine because he was among the earliest to assert that diseases were caused by natural processes rather than the gods and because of his emphasis on the careful observation and documentation of patient history and physical findings, which led to the discovery of physical signs associated with diseases of specific organs. However, let’s not also forget that Hippocrates and his followers also believed in humoral theory, the idea that all disease results from an imbalance of the “four humors.” It’s also amusing to note that this quote by Hippocrates is thought to be a misquote, as it is nowhere to be found in the more than 60 texts known as The Hippocratic Corpus (Corpus Hippocraticum).

As Diana Cardenes argues:

But Hippocratic doctors clearly saw a difference between food and medicines. In fact, food was considered as a material that could be assimilated after digestion (e.g. the air was also food) and converted into the substance of the body. For example, food was converted into the different parts of the body such as muscles, nerves, etc. By contrast, the concept of medicines at the time was a product which was able to change the body’s own nature (in terms of humor quality or quantity) but not be converted into the body’s own substance. Thus a food wasn’t considered a medicine. A possible root of the food-medicine confusion is the following cryptic phrase found in the work On Aliment: “In food excellent medication, in food bad medication, bad and good relatively”.3 This text is nowadays attributed to the Hellenistic period, but was considered to be Hippocratic in Antiquity by Galenus in particular.

Now, it is certainly true that Hippocrates and his followers used diet to treat many illnesses, it’s not really clear what sort of success they had. However, this ancient idea that virtually all disease could be treated with diet, however much or little it was embraced by Hippocrates, has become an idée fixe in alternative medicine, so much so that it leads its proponents twist new science (like epigenetics) to try to fit it into a framework where diet rules all, often coupled with the idea that doctors don’t understand or care about nutrition and it’s big pharma that’s preventing the acceptance of dietary interventions. That thinking also permeates popular culture, fitting in very nicely with an equally ancient phenomenon, the moralization of food choices (discussed ably by Dr. Jones a month ago).
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Posted in: Cancer, Nutrition

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Florida strikes out against Brian Clement

CBC interview with Brian Clement.

CBC interview with Brian Clement.

Brian Clement is a charlatan. Unfortunately, that doesn’t seem to be a problem for the State of Florida. I made two (which turned into three) attempts to get the state to take action against Clement or the Hippocrates Health Institute, where he serves with his wife Anna Maria Gahns-Clement as co-director. All of them failed. Brian Clement slithered through the cracks in Florida law each time.

Before we get into the details of Florida’s failure to act, a bit of history (and there is plenty of it) is in order.

In recent months, Clement’s sordid cancer quackery has been well-documented in the media as well as in the science “blogosphere”. (I’ve listed what I hope is a — but almost certainly isn’t — complete blog archive at the end of this post. Many of the Canadian Broadcasting Corporation [CBC] and other news reports are linked in these posts.) Most of the coverage has centered on two Canadian girls suffering from lymphoblastic leukemia whose parents pulled them from conventional cancer therapies, which gave them an excellent chance of survival, in favor of treatment at the Hippocrates Health Institute (HHI), a sprawling spa in West Palm Beach, Florida, licensed as a massage establishment by the state.

Clement gave a talk in Canada, in 2014, claiming “we’ve had more people reverse cancer than any institute in the history of health care.” (“We” is the operative word here, because it later served as Clement’s ticket to avoid prosecution by the Florida Board of Medicine, as you shall soon find out.) The girls’ families were impressed.

Sadly, one of the girls, Makayla Sault, died earlier this year. The other, identified only as “JJ” in the media because of a publication ban, has returned to conventional treatment. However, her mother apparently remains under the influence of Clement: JJ is restricted to a raw foods diet and is still being followed, if that is the right word, by HHI. (more…)

Posted in: Cancer, Health Fraud, Legal, Nutrition, Politics and Regulation, Science and the Media

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Escharotic Treatment for Cervical Dysplasia: A New Incarnation of Black Salve?

Flowers of the bloodroot plant, Sanguinaria canadensis.  You're welcome, I could have used a very different image (warning: gross bordering on horrifying).

Flowers of the bloodroot plant, Sanguinaria canadensis. You’re welcome, I could have used a very different image (warning: gross bordering on horrifying; click on image to see it).

Cervical dysplasia is a precancerous condition picked up by Pap smears. It is most often caused by human papillomavirus (HPV) infection. Mild cases may resolve spontaneously and can be followed by observation with frequent Pap smears, but cervical dysplasia can progress to cancer. The standard treatment is to remove the abnormal cells with a cone biopsy (using a knife) or a Loop Electrosurgical Excision Procedure (LEEP) using a wire loop heated by electricity. Those procedures not only treat the disease, but they provide a pathology specimen that can be examined to rule out more serious or invasive disease. Both LEEP and cone biopsy are 85-90% effective in removing all the abnormal cells. If cancer is suspected, a cone biopsy is preferable because LEEP may damage the edges of the specimen and make it more difficult to interpret. Otherwise, LEEP is often preferred because it is less expensive and doesn’t require anesthesia or an operating room. I have discussed misguided attempts by alternative medicine practitioners to treat cervical dysplasia before.

Surgery is often perceived as scary and not “natural,” so it’s not surprising that a “natural” treatment has been devised to replace surgery. Escharotics are corrosive salves that get their name from the thick dry scab that they can produce called an eschar. The “natural” escharotic treatment alternative for cervical dysplasia involves applying a solution of bloodroot (Sanguinaria canadensis) and zinc chloride. They claim that the solution selectively kills abnormal cells of the cervix while leaving healthy cells unaffected. That claim is almost certainly false, and the efficacy and safety of escharotic treatment has not been properly tested or compared to conventional treatment. (more…)

Posted in: Cancer, Herbs & Supplements, Naturopathy, Obstetrics & gynecology

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Cancer Centers and Advertising Practices

Video advertisement for the Cancer Treatment Centers of America, hosted on their website. Note at the bottom the statement “No case is typical. You should not expect to experience these results” (click to embiggen).

You have probably seen the TV commercials or other ads for Cancer Treatment Centers of America. They make it sound like “the place to go” if you have cancer. They claim to be “different,” to combine the best cancer technologies with natural therapies in a humane, patient-centered approach that helps you fight the disease and maintain your quality of life. They offer a kinder, gentler, more effective oncology. Those ads are misleading.

Dr. Gorski has written about the practices of Cancer Treatment Centers of America here and here. He has shown how they “integrate” real medicine with nonsense like homeopathy and how they misrepresent components of science-based medicine like exercise and diet, re-branding them as “alternative.”

A recent study by Vater et al. published in the Annals of Internal Medicine asked “What are cancer centers advertising to the public?” They found that the ads appealed to emotion, failed to provide important information, falsely portrayed testimonials as typical, and should be viewed as critically as any other advertising. (more…)

Posted in: Cancer, Medical Ethics, Science and the Media

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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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