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Cancer, Emergency Medicine, Research, Science, Stanford News

Small molecule may protect against radiation exposure, say Stanford scientists

Small molecule may protect against radiation exposure, say Stanford scientists

P1060359No one wants to imagine a nuclear accident. But, as Fukushima and Chernobyl showed, they do happen. Unfortunately there’s no truly effective way to protect people who have been exposed to large amounts of radiation (more than 10 gray, for those of you wondering; for you overachievers out there, 1 gray is the absorption of 1 joule of radiation energy per kilogram of matter).

Many of these people will die from what’s known as radiation-induced gastrointestinal syndrome when the rapidly dividing cells in their intestinal lining begin to die. As a result, the intestine loses its ability to regulate fluid loss and prevent the entry of pathogens into the body, causing severe diarrhea, electrolyte imbalance and sepsis.

Stanford radiation oncologist Amato Giaccia, PhD, and his colleagues wondered whether a cellular pathway that controls how cells respond to stress could be involved in the intestine’s response to radiation. Their study was featured today on the cover of Science Translational Medicine. As I explain in our release:

The researchers were studying a molecular pathway involved in the response of cells to conditions of low oxygen called hypoxia. Hypoxic cells produce proteins known as hypoxia-inducible factors, which help the cells survive the stressful conditions. (The HIF proteins – HIF1 and HIF2 – are normally degraded quickly when oxygen levels are normal.)

Hypoxia often occurs in fast-growing solid tumors as cells find themselves far from oxygen-delivering blood vessels, but it can also occur during times of inflammation, or in tissues like the intestine that experience natural gradations in oxygen levels. HIF proteins help the intestine absorb needed nutrients while blocking the entry of pathogens and maintaining healthy fluid exchange.

Giaacia and lead study author Cullen Taniguchi, MD, PhD, a postdoctoral scholar, wondered if increasing the levels of HIF proteins in intestinal epithelial cells could help the them survive damaging amounts of radiation. To test their theory, they used a small molecule called DMOG to block the naturally occurring degradation of HIF proteins in laboratory mice exposed to radiation. They found that administering DMOG to the mice significantly increased their survival – even when the molecule was given 24 hours after initial exposure.

The study suggests it may one day be possible to prevent or reduce the incidence of  radiation-induced gastrointestinal syndrome in humans.  It also provides an intriguing hint that it may be possible to mitigate some of the gastrointestinal side effects experienced by patients undergoing radiation therapy for cancer.

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Cancer

Breast cancer awareness: Beneath the pink packaging

We’ve partnered with Inspire, a company that builds and manages online support communities for patients and caregivers, to launch a patient-focused series here on Scope. Once a month, patients affected by serious and often chronic diseases share their unique stories. Our latest comes from a breast cancer patient from Salt Lake City.

Over the years, you may have participated in pink-themed races and donned pink shoe laces in an effort to demonstrate solidarity and support regarding breast cancer awareness.

Good intentions notwithstanding, let’s pause for a moment to consider what has truly been accomplished since National Breast Cancer Awareness Month was launched in 1985. Have fewer people gotten the disease? Have survival rates improved? The answers are disconcerting:

  • Mortality rates remain depressingly flat. In 1988 approximately 40,000 women perished annually from breast cancer; in 2013 39,620 women and 410 men will have died from the disease.
  • Today, approximately 162,000 women and men are living with metastatic breast cancer in the U.S. Some of them developed metastatic disease five, 10, 15, or even 20 or more years after their initial diagnosis. Many are relatively young – in their 20s and 30 – with growing families.
  • A diagnosis of early stage breast cancer provides no reassurance because the disease will eventually spread or “metastasize” to other organs in an astounding 30 percent of these patients.
  • Median survival after a metastatic diagnosis is only three years – with no statistically significant improvement over the past 20 years.

Imagine for a moment that you’ve been diagnosed with early stage breast cancer. You have confidence that if you follow your doctor’s recommendations, you’ll live a normal life – after all, you have been made “aware” of breast cancer! But that doesn’t always happen. Take my case: I was diagnosed with early stage breast cancer at age 39 after 4 years of misdiagnosis. I experienced a double mastectomy, six cycles of the most toxic chemotherapy available at the time, followed by five years of Tamoxifen, a hormonal therapy. I became increasingly convinced that my experience with breast cancer was safely behind me each time I underwent annual cancer checkups with normal results.

Fourteen years after my initial diagnosis, I developed a dry, persistent cough that three doctors misdiagnosed as asthma, GERD, or post-nasal drip. After four years of chronic coughing I became hoarse. Finally a doctor recognized that my vocal cord was paralyzed. He ordered a scan that revealed a tumor pressing on the laryngeal nerve, which in turn caused paralysis.

A biopsy revealed metastatic breast cancer that was hormonally receptive. By then I had developed multiple lung tumors, a liter of malignant pleural effusion and pericardial effusion. A catheter was inserted in my chest to drain the fluid until it disappeared several weeks later. Weak, ill, and terrified, I didn’t know whether I would live for another year and was determined to be as active as possible to enhance my odds of survival.

Although my oncologist recommended chemotherapy, I sought a second opinion from an oncologist who suggested hormonal treatment that has thankfully allowed me to enjoy a better quality of life. I also consult with a naturopathic oncologist regarding supplements and complementary therapies, and I’ve adjusted my diet to exclude sugar and processed foods.

My medical team is rounded out by a wonderful acupuncturist whose skills have enabled me to avoid anti-depressants. For emotional support, I exchange encouragement and information with people online who are coping with metastatic disease, and my husband has retired early so that we can enjoy time together while I am still well enough to do so.

After eight years of misdiagnosis, I’m left with little faith in the diagnostic capabilities of the medical establishment and have no illusions about living a normal life. Yet I’m one of the lucky ones: relatively old (age 60), not on chemotherapy, able to participate in daily activities, and currently pain-free. Conversely, most patients I know suffer terrible side effects from both their cancer and its treatment, such as fatigue, nausea, blistering skin, neuropathy, and excruciating bone pain.

In retrospect, I wouldn’t change any decisions regarding my disease and its treatment. But I have to realize that “early stage” breast cancer, with which I was initially diagnosed, is significantly more lethal than the media conveys – given that nearly one of three early-stage patients will eventually succumb to their disease.

It’s obvious that the battle against breast cancer, with incessant emphasis on “awareness” and early detection, has been watermarked upon the canvas of failure. Increasing awareness – especially when it’s been heavily sugarcoated – will never alter the course of this disease or reduce the victim count. Only by deriving a mechanism to irrefutably prevent breast cancer and effectively treat those who already have it will we forever close the book on stories such as mine.

Anne Loeser is a retired software project manager who was diagnosed with metastatic breast cancer 18 years after developing “early stage” disease. A passionate researcher, she continuously shares information and support on multiple forums with others who are dealing with terminal breast cancer.  Anne currently resides in Salt Lake City, Utah with her husband and parrot.

Related: Pink Think/The hitch with the breast cancer marketing pitch

Cancer, Medicine and Society

A doctor recounts his wife’s battle with cancer: “My knowledge was too clear-eyed”

We’ve written before about doctors becoming patients – but what happens when it’s the physician’s partner who becomes seriously ill? Over the weekend I came across a beautifully written, raw New York piece in which Memorial Sloan Kettering physician Peter Bach, MD, describes his late wife’s fight with cancer. He writes:

When Ruth was first diagnosed with breast cancer, friends would routinely comment to us along the lines of “It’s so good Peter knows so much about this disease.” But others disagreed, imagining I suffered more from my knowledge. Whether I was better or worse off I kept filing away as a pointless academic debate, like wondering if Edna Pontellier’s death in The Awakening was a resignation or a liberation, or whether Batman would ever just get over it. But in the lobby of my hospital, I knew the answer: My knowledge was too clear-eyed. I couldn’t pretend for another day or hour or minute that there were good days ahead.

Bach later describes the moment he knew the end was near:

We were sitting at a coffee shop when the light caught her just right and I saw it. I tried for a few moments to keep talking about whatever topic we had landed on, but I discreetly texted a friend of mine from college, also a doctor, in medicalspeak to share the terrible news—“scleral icterus.”

I couldn’t hold it in anyway. “Your eyes are yellow,” I blurted out.

She was stunned, and slightly panicked. “Why?” she asked. And then something totally unexpected—“What do they do about it?” I seized on this, my escape hatch from having to talk about her liver failing. I said I didn’t know, we’d have to ask. Another lie.

The yellowing, first of the whites of the eyes, later of the skin, is like the check-engine light turning on. The yellowing itself is irrelevant; it means bad things are happening inside. It meant her brain would soon become addled with toxins that at one time her liver could have cleared easily. She was near the end.

My phone pinged. My doctor friend, holding the medical jargon: “Oh [f**k].”

The full piece is worth a read.

Previously: A Stanford physician’s take on cancer prognoses, Both a doctor and a patient: Stanford physician talks about his hemophilia and Red Sunshine: One doctor’s journey surviving stage 3 breast cancer

Cancer, Genetics, Public Health, Research, Stanford News, Technology

Odd couples: Resemblances at molecular level connect diseases to unexpected, predictive traits

Odd couples: Resemblances at molecular level connect diseases to unexpected, predictive traits

odd coupleStanford big-data king Atul Butte, MD, PhD, has made a career out of mining publicly available databases to unearth novel and frequently surprising relationships between, for example, diseases and drugs, nature and nurture, and pain and sexual status.

In his latest Big Dig, Butte (along with his colleagues) has combed through mountains of electronically available data to identify molecular idiosyncrasies linking specific diseases to easily observed traits that on first glance wouldn’t be thought to have any such connection. The results, written up in a study published in Science Translational Medicine, may allow relatively non-invasive predictions of impending disorders.

For example, who would think that magnesium levels in the blood might be an early-warning marker for gastric cancer? Or that platelet counts in a blood sample would predict a coming diagnosis of alcohol dependency? Or that a high PSA reading, typically associated with potential prostate cancer, would turn out to be predictive of lung cancer? Or that a high red-blood-cell count might presage the development of actute lymphoblastic leukemia?

Answer: No one. That’s the beauty of Big Data. You find out stuff you were never specifically looking for in the first place. It just pops out at you in the form of a high, if initially inexplicable, statistical correlation.

But by cross-referencing voluminous genetic data implicating particular gene variants in particular diseases with equally voluminous data associating the same gene variants with other, easily measured traits typically considered harmless, Butte and his associates were able to pick out a number of such connections, which they then explored further by accessing anonymized electronic medical records from Stanford Hospital and Clinics, Columbia University, and Mount Sinai School of Medicine. “We indeed found that some of these interesting genetic-based predictions actually held up,” Butte told me.

Because checking blood levels of one or another substance is far simpler and less invasive than doing a biopsy, and because altered levels of the substance may appear well before observable disease symptoms, this approach may lead to early, more inclusive and less expensive diagnostic procedures.

Butte is one of the speakers at Stanford’s upcoming Big Data in Biomedicine conference. Registration for the May 21-24 event is open on the conference website.

Previously: Nature/nurture study of type 2 diabetes risk unearths carrots as potential risk reducers, Mining medical discoveries from a mountain of ones and zeroes, Newly identified type-2 diabetes gene’s odds of being a false finding equal one in 1 followed by 19 zeroes, Women report feeling more pain than men, huge EMR analysis shows and Cheap Data! Stanford scientists’ “opposites attract” algorithm plunders public databases, scores surprising drug-disease hook-ups
Photo by cursedthing

Cancer, In the News, Stanford News, Women's Health

Using 3-D technology to screen for breast cancer

Using 3-D technology to screen for breast cancer

Yesterday, KGO-TV aired a story discussing the use of 3-D breast-screening at Stanford Hospital. As described here, the technology has the potential to identify breast cancers more accurately, “with fewer false alarms.” More from the piece:

The technology is known as tomosynthesis. It’s a form of x-ray that produces both two dimensional and three dimensional images in a single session. If doctors notice an area that’s suspicious on the normal image, they can turn to the 3D view to essentially examine it from a different angle. Jafi Lipson, M.D. is Assistant Professor of Radiology at Stanford.

“The benefit of tomosynthesis is that you have multiple images at slightly different angles of the x-ray tube that allows you to resolve a lot of artifacts that we normally see when we take two dimensional images of the breast,” Dr. Lipson explains.

Previously: Ask Stanford Med: Radiologist responds to your questions about breast cancer screening, California’s new law on dense breast notification: What it means for women and Five days instead of five weeks: A less-invasive breast cancer therapy

Cancer, Research, Science, Stanford News, Stem Cells

Cellular culprit identified for invasive bladder cancer, according to Stanford study

Cellular culprit identified for invasive bladder cancer, according to Stanford study

Beachy image resizedInvasive bladder cancer is a grim disease that is expensive to treat and requires ongoing monitoring due to its high probability of recurrence. Stanford developmental biologist Philip Beachy, PhD, and urologist Michael Hsieh, MD, PhD, wanted to know how the cancer starts, and what makes it so intractable. Their research was published yesterday in Nature Cell Biology (subscription required).

As Beachy explained in the release I wrote:

We’ve learned that, at an intermediate stage during cancer progression, a single cancer stem cell and its progeny can quickly and completely replace the entire bladder lining. All of these cells have already taken several steps along the path to becoming an aggressive tumor. Thus, even when invasive carcinomas are successfully removed through surgery, this corrupted lining remains in place and has a high probability of progression.

In the photo above, the blue cells are progeny of just one cancer-initiating cell in the basal cell layer of the bladder lining. They’ve “elbowed out” their neighbors to take over the lining. The cells, and the cancers that arise, have a distinctive gene-expression profile. More from our release:

Although the cancer stem cells, and the precancerous lesions they form in the bladder lining, universally express an important signaling protein called sonic hedgehog, the cells of subsequent invasive cancers invariably do not — a critical switch that appears vital for invasion and metastasis. This switch may explain certain confusing aspects of previous studies on the cellular origins of bladder cancer in humans. It also pinpoints a possible weak link in cancer progression that could be targeted by therapies.

Hsieh, who has treated many patients with this type of bladder cancer, explained to me the significance of the finding:

This could be a game changer in terms of therapeutic and diagnostic approaches. Until now, it’s not been clear whether bladder cancers arise as the result of cancerous mutations in many cells in the bladder lining as the result of ongoing exposure to toxins excreted in the urine, or if it’s due instead to a defect in one cell or cell type. If we can better understand how bladder cancers begin and progress, we may be able to target the cancer stem cell, or to find molecular markers to enable earlier diagnosis and disease monitoring.

Previously: Is the worm turning? Early stages of schistosomiasis bladder infection charted, Mathematical technique used to identify bladder cancer marker and Bladder infections–How does your body repair the damage?
Photo by Kunyoo Shin, PhD

Cancer, In the News, Patient Care

Is cancer too complex for targeted therapies?

Cancer. It’s been called “The Big C,” but the more we study it, the more it resembles hundreds of little c’s, each with its own unique molecular makeup. The differentiation exists both among patients with cancers in the same site (the various sub-types of breast cancer, for example) as well as within a single patient. This latter phenomenon is referred to as “intra-patient tumor heterogeneity,” and it has profound implications for the future of cancer treatment, including the viability of so-called “targeted therapies” receiving so much attention and hope.

Many cancer tumors tend to be chaotic mixes of different cell types, some more aggressive – and therefore more dangerous – than others. Chemotherapy and the emerging category of more specific “targeted therapeutics” work by acting on a known characteristic of a particular cancer cell type, like accelerated replication rates or a specific genetic mutation.  But in a complex tumor, not all cells will exhibit that specific characteristic, or at least not do so at the same time. Also, it is possible for cancer cells to adapt and become resistant to a particular therapy, in a partially analogous way in which evolution works on a macroscopic scale.

A recent opinion piece published online in the journal The Scientist points out that intra-patient heterogeneity can also involve treatment-relevant difference between the primary tumor and metastases, as well as among metastases. Written by Stanford Cancer Institute Director Beverly Mitchell, MD; David Rubenson, associate director for administration and strategic planning; and Daniel S. Kapp, MD, professor emeritus of radiation oncology at Stanford, the article discusses these matters in detail and lays out many of the significant scientific and clinical questions surrounding the potential for treating cancers with targeted therapies. This fall, the Stanford Cancer Institute will convene an international symposium to discuss these questions and a range of related issues.

Information on the symposium, titled “Intra-patient Tumor Heterogeneity: Implications for Targeted Therapy,” will soon be available on the Stanford Cancer Institute website.

Previously: Director of the Stanford Cancer Institute discusses advances in cancer care and research

Cancer, Genetics, Research, Stanford News, Technology

Gene panel screens for dozens of cancer-associated mutations, say Stanford researchers

Gene panel screens for dozens of cancer-associated mutations, say Stanford researchers

Stanford scientists have shown that it’s possible to simultaneously screen for dozens of cancer-associated mutations from a single blood sample using a multiple-gene panel. The research is published today in the Journal of Clinical Oncology (subscription required).

As I describe in my release:

Gene panels allow researchers to learn the sequences of several genes simultaneously from a single blood sample. It stands to reason that screening for mutations in just a few select genes is quicker, easier and cheaper than whole-genome sequencing. The technique usually focuses on fewer than 100 of the approximately 21,000 human genes. But until now, few studies have investigated whether homing in on a pre-determined panel of suspects can actually help people.

The researchers, medical oncologists and geneticists James Ford, MD and Allison Kurian, MD, used a customized 42-gene panel to investigate the presence of cancer-associated mutations in 198 women with a family or personal history of breast or other cancers. The women had been referred to Stanford’s Clinical Cancer Genetics Program between 2002 and 2012 to undergo screening for mutations in their BRCA1 or BRCA2 genes. They found that the panel was  a useful way to quickly screen and identify other cancer-associated mutations in women who did not have a BRCA1/2 mutation. From our release:

Of the 198 women, 57 carried BRCA1/2 mutations. Ford and Kurian found that 14 of the 141 women without a BRCA1/2 mutation had clinically actionable mutations in one of the 42 genes assessed by the panel. (An actionable mutation is a genetic variation correlated strongly enough to an increase in risk that clinicians would recommend a change in routine care — such as increased screening — for carriers.)

Eleven of the 14 women were reachable by telephone, and 10 accepted a follow-up appointment with a genetic counselor and an oncologist to discuss the new findings. The family members of one woman, who had died since giving her blood sample, also accepted counseling. Six participants were advised to schedule annual breast MRIs, and six were advised to have regular screens for gastrointestinal cancers; many patients received more than one new recommendation.

One woman, with a history of both breast and endometrial cancer, learned she had a mutation that causes Lynch syndrome, a condition that increases the risk of many types of cancers. As a result, she had her ovaries removed and underwent a colonoscopy, which identified an early precancerous polyp for removal.

The study shows that gene panels can be a useful tool that can change clinical recommendations for individual patients. It also indicates that patients are willing and eager to receive such information. As Ford explains in the release:

Gene panels offer a middle ground between sequencing just a single gene like BRCA1 that we are certain is involved in disease risk, and sequencing every gene in the genome. It’s a focused approach that should allow us to capture the most relevant information.

Previously: Whole genome sequencing: the known knowns and the unknown unknowns,  Assessing the challenges and opportunities when bringing whole-genome sequencing to the bedside and Blood will tell: In Stanford study tiny bits of circulating tumor DNA betray hidden cancers.

Cancer, Genetics, Patient Care, Research, Science, Stanford News

Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

5507073256_36387f3df9_zBlood is a remarkable liquid. Not only does it carry red blood cells to deliver oxygen, it also transports cells of the immune system to protect us from infection. But there’s another, hidden payload: bits of genetic material derived from dying cells throughout the body. In a patient with cancer, a tiny fraction of this circulating DNA comes from tumor cells.

Now researchers in the laboratories of Stanford radiation oncologist Maximilian Diehn, MD, PhD, and hematologist and oncologist Ash Alizadeh, MD, PhD, have found a way to read these genetic messages and use them to diagnose lung tumors and monitor how they respond (or don’t) to treatment. The technique is highly sensitive and should be broadly applicable to many types of solid tumors. It also bypasses some of the more fussy patient-optimization steps that have previously been required.

From our release:

“We set out to develop a method that overcomes two major hurdles in the circulating tumor DNA field,” said [Diehn]. “First, the technique needs to be very sensitive to detect the very small amounts of tumor DNA present in the blood. Second, to be clinically useful it’s necessary to have a test that works off the shelf for the majority of patients with a given cancer.”

“We’re trying to develop a general method to detect and measure disease burden,” said Alizadeh, a hematologist and oncologist. “Blood cancers like leukemias can be easier to monitor than solid tumors through ease of access to the blood. By developing a general method for monitoring circulating tumor DNA, we’re in effect trying to transform solid tumors into liquid tumors that can be detected and tracked more easily.”

Using their technique, the researchers were able to identify 50 percent of patients with Stage I cancers, and all patients with more advanced disease. The research was published Sunday in Nature Medicine.

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Cancer, Global Health, Stanford News, Women's Health

Stanford fellow addresses burden of cervical cancer in Mongolia

Stanford fellow addresses burden of cervical cancer in Mongolia

Mongolian clinic - smallCervical cancer is the third most common cancer among women worldwide, and Mongolia has one of the highest incidence rates in Eastern Asia. Prevention and early detection programs are essential to counteract its prevalence, especially in developing countries.

However, women encounter barriers to knowledge and access to cervical cancer screening services in Mongolia – a country with low population density. The urban–rural divide, lagging healthcare reform, and cultural differences are cited as core factors leading to lack of awareness and treatment.

To address the rising burden, a national cervical cancer screening program was implemented in August 2012 by Mongolia’s Ministry of Health (MOH) facilitated by a grant from the Millennium Challenge Corporation.

Gendengarjaa Baigalimaa, MD, the 2013-14 Developing Asia Health Policy Fellow at Stanford’s Walter H. Shorenstein Asia-Pacific Research Center in the Freeman Spogli Institute, has been evaluating the effects of that program. She serves as a gynecological oncologist at the Mongolian National Cancer Center (NCC). Her early findings show that awareness of cervical cancer has increased, and more women and girls are now getting screened. Gendengarjaa recently talked about her research.

What does your “typical” patient look like at the NCC and how has your work informed your research?

Patients typically arrive at the NCC with an advanced stage of disease – 70 percent of these women have progressive forms of cervical cancer. Of course it is not easy to work with patients who are this far along, especially if we are unable to offer full palliative services. As the only cancer center in the nation, just 10 gynecological oncologists are available to take on the high demand for treatment services. Healthcare providers and policymakers designed the Mongolian Cervical Cancer Program to address the alarming incidence rate. My research analyzes behavioral change before and after the introduction of the national screening program, bearing in mind my experiences with my own patients.

What does the national cervical cancer screening program facilitate?

Before the program was implemented, regular cervical cancer screening did not exist in Mongolia. The program diffused and strengthened primary care screening services (Pap test) as well as prevention programs. Gynecological doctors from the NCC were systematically dispatched to the 338 soums or districts throughout the nation. They trained local doctors and midwives on how to administer the Pap test. The program coordinated two initiatives: a pilot HPV vaccination program for girls aged 11-15 years from four select areas and a Pap test program for women aged 30-60 years. The women and girls who participated are urged to get screened every three years thereafter. Health education campaigns were also broadcast on select television and radio programs targeted at women and girls.

Comparing a survey taken at the program’s outset in 2010 to your survey at the program’s conclusion in 2013, what behavioral changes have been observed?

Our preliminary results have shown increased knowledge about risk factors and screening services. Women in both rural and urban areas are now more informed about cervical cancer risk factors. Awareness of the need for a Pap test increased from 15.3 percent in 2010 to 45.3 percent in 2013. The respondents also reported being more educated about the suggested frequency of visiting a doctor, and the availability of services outside of Ulaanbaatar. Due to increased knowledge, 54.2 percent of the women surveyed confirmed that they had attended cervical screening services.

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