Advancing the Science

Mayo Clinic Medical Science Blog – an eclectic collection of research- and research education-related stories: feature stories, mini news bites, learning opportunities, profiles and more from Mayo Clinic.

About

Member has chosen to not make this information public.

Posts (23)

2 days ago · Research suggests genetics are key in treating night sweats

This post originally was published on the Center for Individualized Medicine blog on June 25, 2018

Article by Heather Carlson

Women going through menopause know all too well the discomfort associated with night sweats.

Hormone therapy is often used to prevent night sweats. But finding the right dose of estrogen can be tricky, with some women needing more estrogen than others to get relief. Why the difference in how women respond to hormone therapy? The answer may be found in a woman’s genes.

A new Mayo Clinic study published in Menopause: The Journal of the North American Menopause Society found that genetic differences appear to play a role in the effectiveness of hormonal treatment for menopausal women.

Ann Moyer, M.D., Ph.D.

“In this study, we explored how a genetic variant in a gene that regulates how estrogen is cleared from the blood alters estrogen levels and relief of night sweats in menopausal women. We hope that this study will generate interest in the potential use of genetics to individualize hormone therapy dosage and formulation,” says Ann Moyer, M.D., Ph.D., co-director of the Mayo Clinic Personalized Genomics Laboratory.

The four-year study involved 100 women enrolled in Mayo Clinic’s Kronos Early Estrogen Prevention Study. As part of the study, 33 women were given oral estrogen, 33 received an estrogen patch and the remainder was given a placebo pill or patch. At the time of enrollment, the age of women ranged from 42 to 58 and they were on average 1.4 years past menopause.

Researchers zeroed in on one specific gene — SLCO1B1. That gene provides instructions for making a protein found in liver cells. That protein transports estrogen from the blood into the liver so that it can be broken down and cleared from the body.

The study showed a significant association between differences in the SLCO1B1 gene and the amount of estrogen in a woman’s system. Genetic differences also helped determine how well a woman responded to hormone therapy. For example, women given an estrogen patch who have a genetic variation that leads to a decreased movement of estrogen from the blood into the liver saw a significantly greater drop in night sweats compared to other women.

Richard Weinshilboum, M.D.

“In this study, researchers have demonstrated that pharmacogenomics— differences in the DNA sequences in a woman’s genome — can influence the ability of her body to clear estrogen when it is used to treat her for menopausal symptoms, raising the possibility of more highly individualized dosing of estrogen in that setting,” says Richard Weinshilboum, M.D., co-director of the Mayo Clinic Center for Individualized Medicine Pharmacogenomics Program and a co-author of the study. Pharmacogenomics is the study of how your genes affect the way your body processes and responds to medications.

Virginia Miller, Ph.D.

The hope is that one day, physicians can use a woman’s genetic information to determine the right amount of hormone therapy needed to treat night sweats and other menopause-related conditions, according to Virginia Miller, Ph.D., director of the Mayo Clinic Women’s Health Research Center and the study’s senior author.

 

“What we would ultimately like to be able to do is get the genetic profile for women so if they are experiencing these conditions of menopause, we can better target the treatment,” says Dr. Miller.

 

###

Related Resources

Join the conversation

For more information on the Mayo Clinic Center for Individualized Medicine, visit our blogFacebookLinkedIn or Twitter at @MayoClinicCIM.

Register to attend this year’s Individualizing Medicine Conference. It will be held in Rochester, Minnesota, on Sept. 12-13, 2018.

 

 

3 days ago · Tune in during August to -- "Incredible Aging: Adding Life to Your Years"

By Julie Sokoloski

Research developments in aging, including research done here at Mayo Clinic, will be highlighted throughout late August in a PBS special, “Incredible Aging: Adding Life to Your Years.”

Hosted by 14-time Emmy Award-winner, executive producer, and anchor Meredith Vieira, the program provides a blueprint for healthy aging.

A preview of the program can be found on PBS Presents. The documentary will be aired locally on the Twin Cities PBS station (TPT) on several dates in August:

  • Saturday, Aug. 18 at 7:30 p.m. TPT LIFE
  • Wednesday, Aug. 22 at 7 p.m. TPT 2
  • Thursday, Aug. 23 at 1 a.m. TPT 2
  • Saturday, Aug. 25 at 1 p.m. TPT 2
  • Sunday, Aug. 26 at 12:01 a.m. TPT LIFE

The program features Mayo Clinic’s Nathan LeBrasseur, Ph.D., and James Kirkland, M.D., Ph.D.; as well as other experts in aging.

Nathan LeBrasseur, Ph.D., directs the Healthy Aging and Independent Living Program, which seeks to translate discoveries in the biology of aging from the laboratory to the bedside and back.

“We are at the most exciting time in science and medicine, where if we understand this very basic process of aging and develop ways to intervene, we can potentially delay the onset of age related diseases as a group – and that’s going to have a remarkable impact on society and public health without question,” says Dr. LeBrasseur, director of Healthy Aging and Independent Living Program in the Mayo Clinic Robert and Arlene Kogod Center on Aging. “Our hope is that individuals … will take on the responsibility to have healthy dietary choices, to have active lifestyles, to find meaning and purpose, to be socially engaged, so we ensure a long healthspan.”

The documentary also showcases senescence research by Dr. Kirkland, who in addition to being the Kogod Center director, is president-elect for the American Federation for Aging Research.

All the experts featured in the PBS special are members of the federation, both from its community of grantees as well as its board of directors. We invite you to tune in during August to learn their blueprint for healthy aging and what you can do now to increase your healthspan!

###

Related resources:

Tue, Aug 7 6:00am · Senescent cells and aging: Following up on the unexpected pays off

Starting at age 8, Jan van Deursen, Ph.D., helped his carpenter father on the weekends when he built custom staircases, windows and doors for people in their village in the Netherlands.

“My father had a fast pace, and I had to keep up with him,” says Dr. van Deursen. “I didn’t realize it at the time, but he was very creative in solving problems in his craft, which involved significant improvisation. I give him a lot of credit for the influence he had on me.”

That childhood wasn’t idyllic, however. When Dr. van Deursen was 10, his mother started to develop symptoms of pulmonary fibrosis. She died during his last year of high school, after several years in and out of the hospital.

“I had to take care of my dad and do things that most kids of that age didn’t do,” he says. “It wasn’t a good period for me. I’d always been a good student until things became difficult at home. Then I had a hard time just passing my classes so I could go to university. I knew what I wanted to do — pursue biology — but other things were going on in my life that occupied my attention. At university, I set a goal of just making it year to year.

“By my third of five years, I’d passed the hurdle, becoming exceptionally interested in my studies and doing well. I was hooked on learning about all aspects of cells, organisms and molecular mechanisms that drive everything. I won some awards, which set me apart from others and helped me land a job after college in a good Dutch Ph.D. program.”

A niche with mice

In the late 1980s Dr. van Deursen began working with mice to recreate genetic mutations of diseases found in humans — work that wasn’t being done to a great degree at that time.

“My work was at the forefront of that development,” he says. “The senior scientists in the U.S. and Britain, who at the time were ahead of me, received the Nobel prize in 2007 for their groundbreaking work.”

On completion of his Ph.D., he accepted a position with St. Jude Children’s Research Hospital in Memphis, Tennessee, where he spent two years building a transgenic mouse facility. He then became an independent investigator, soon armed with a Research Program Project Grant (R01) from the National Institutes of Health.

“I didn’t know the extent of it beforehand, but very successful researchers wanted animal models for their genes of interest, so I spent two years making animal models,” he says.

From his research came watershed papers in Nature, Science and Cell. Seeking an ideal environment for raising his family, Dr. van Deursen moved to Rochester, Minnesota, with his wife and two daughters in 1999.

He accepted a position at Mayo Clinic.

A new home at Mayo

“Dr. Bill Crist, the former head of hematology/ oncology at St. Jude’s, had gone to Mayo and recruited Rick Bram,(M.D., Ph.D., now chair of the Department of Pediatrics at Mayo Clinic) and me,” says Dr. van Deursen. “The environment at Mayo was extremely collegial.

Physicians at Mayo know a lot about physiology and diseases, are open to interacting with basic science labs and are genuinely interested in collaborating.

A basic research lab can benefit greatly from having clinical colleagues around, as is evidenced by the publications originating from my lab over the last 18 years.

“At some institutions, you are required to be loyal and exclusive to your department. At Mayo, you just find your way — whatever collaboration makes sense. I’ve never found it difficult to identify good collaborators. I really like Mayo’s loose, fluid departmental structure.”

At Mayo, Dr. van Deursen developed a facility to create mouse models of human disease. He unexpectedly hit upon a major breakthrough — one that researchers had been trying to figure out for 50 years. It was the effect of senescent cells on aging. Senescent cells accumulate with age, lose their original function but fail to die.

An accidental discovery

“I was trying to be a cancer biologist,” he says. “In my attempts to make cancer models in 2001, I made a number of interesting discoveries that had nothing to do with cancer. When I see something unexpected, I get more interested in it. I don’t abandon a finding just because it doesn’t fit where I intended to go.

So I followed up on this finding. I’d been trying to make an animal model for aneuploidy — a universal hallmark of cancer cells that rearranges the DNA  and chromosomes. In making the model for that chromosomal instability, we found that the mice didn’t get cancer but developed an aging process that was accelerated by six times.”

Follow-up studies resulted in several high-profile papers, one of which was in Nature in 2011 and also chosen by Science magazine as one of the top 10 scientific breakthroughs of the year.

The mice had a cell type that accumulated at a high rate — a cell type that young mice don’t have. The cells were senescent. No one had yet determined whether senescent cells were neutral, beneficial or detrimental.

“We started to make the connection,” says Dr. van Deursen. “If mice have accelerated aging and accumulate these cells at a young age, maybe the senescent cells actually accelerate aging. In 2008 we published the first link between senescent cells and features of aging including muscle wasting, cataracts and lipodystrophy. This was done in collaboration with Dr. Andre Terzic, a long-term collaborator at Mayo.”

A spin-off

Mayo Clinic spun off Dr. van Deursen’s discovery  to Unity Biotechnology, a company looking to make an impact on aging and diseases of aging. Dr. van Deursen is co-founder of the company, which is focused on determining if senescent cells can be removed in humans and developing therapeutics. The company is gearing up for clinical trials on osteoarthritis and glaucoma in humans.

“I started the basic science groundwork for this about 15 years ago, which led to interesting discoveries in 2011. Now we’re exploring therapeutic applications in human trials,” says Dr. van Deursen. “If these trials are successful, they will open the door for us to explore other diseases.”

Osteoarthritis and glaucoma were chosen for  the first trials because they can be treated with  local administration of the drug — a joint or ocular injection — instead of systemically. This helps to avoid the need to control potential side effects in an early-stage drug.

An encore

In 2016 Dr. van Deursen and colleague Darren Baker, Ph.D., published further research, which showed two major findings:

  1. Mice that were genetically modified to have self-destructing senescent cells were healthier. They had better kidney function, their hearts were more resilient to stress, they developed cancers at a later age, they explored their cages more, and they had an increased lifespan of 25 to 30 percent compared to other mice.
  2. Mice that were genetically engineered to have their senescent cells killed with a drug who were fed a fat-rich diet for three months had 60 percent less plaque (fatty buildup) in a major artery than did the other mice.

“It’s a good reminder to do curiosity-driven research and follow up on unexpected observations.”

“My lab built a program at Mayo from what was basically a failed cancer study, which turned out to be really important for understanding a number of diseases and presented opportunities for future treatment of disease, including Alzheimer’s disease, osteoarthritis, atherosclerosis, heart disease and cancer,” says Dr. van Deursen. “It’s a good reminder to do curiosity-driven research and follow up on unexpected observations. Sometimes that’s a challenge because our clinical colleagues want to make a difference in patients’ lives very quickly. For transformative impact, one really needs to understand the molecular and cellular aspects of a disease.”

Results of the most recent research were published in Nature and Science in 2016 and, again, named by Science as one of the top 10 scientific breakthroughs — the first time a researcher’s work had been ranked more than once. Dr. van Deursen’s research placed fifth.

“The breadth of studies in the top 5 is mind-boggling,” he says. “It’s a great honor to be included.”

By the end of 2016, the research published in Nature already was the 10th most frequently downloaded paper in any scientific journal.

“Understanding the biology of a disease can lead to transformative discovery that may change the treatment of diseases that are chronic and currently impossible to treat,” says Dr. van Deursen.

###

This article was originally published in Mayo Clinic Alumni magazine, Issue 1, 2018.

Related resources:

Stories and news releases

Tue, Jul 31 6:00am · Banking on improved health

This article originally appeared on the Center for Individualized Medicine blog on June 4, 2018.

Article by Barbara Toman

Just as money in the bank boosts your financial well-being, biobanks have the power to impact your health. Think of biobank samples as assets that researchers can draw upon to improve disease treatments.

One such withdrawal from the Mayo Clinic Biobank yielded a key breakthrough in diabetes research. Adrian Vella, M.D., an endocrinologist at Mayo Clinic in Rochester, Minnesota, used blood samples from the biobank — which is operated by Mayo’s Center for Individualized Medicine — to pinpoint an under-investigated factor in diabetes. While most studies focus on insulin — a hormone that moves sugar from the blood into the body’s cells — Dr. Vella’s work implicated an additional hormone, glucagon, in the development of the disease.

Adrian Vella, M.D.

“What we discovered was eye-opening. It completely changed our research focus,” Dr. Vella says.

Dr. Vella has spent nearly two decades investigating the genetic risks that can predispose people to developing diabetes. The work requires collecting DNA samples from people who have certain genetic profiles. In this case, Dr. Vella and his colleagues wanted to study people who don’t have diabetes but who have two copies of a genetic variant that is the strongest known genetic risk factor for developing the disease.

The challenge is that only 10 to 15 percent of people have two copies of this variant, which occurs on a gene known as TCF7L2. Recruiting enough study participants who fit the criteria would require enormous effort.

“We would have to have 100 people come through the door for genetic analysis to perhaps find 10 that fit our criteria. That isn’t a good use of time or resources,” Dr. Vella says. “But that’s where the biobank came in.”

With more than 20,000 patient specimens, the biobank allowed Dr. Vella and his colleagues to assemble relatively quickly the samples they needed for a valid study. The Mayo researchers randomly selected 4,000 DNA samples donated to the biobank by people who didn’t have diabetes. Genetic testing was done to identify donors with two copies of the diabetes-associated TCF7L2 variant as well as donors with a TCF7L2 variant that protects against the development of diabetes.

The donors were then invited to participate in a study that involved metabolic tests. Ultimately, 120 people participated in the testing aimed at determining how these genetic variants affect blood-sugar regulation.

The results upset the conventional wisdom about the diabetes-associated TCF7L2 mutation — that it acts primarily to decrease the secretion of insulin. The Mayo study did detect some defects in insulin secretion in people with the diabetes-associated variants. “But the effects of glucagon were far more prominent than defects in insulin secretion,” Dr. Vella says. “The biobank is a great help for this type of research, which benefits patients.”

Stephen Thibodeau, Ph.D.

Mayo Clinic’s biobanking expertise will now also benefit researchers nationwide. The 35 million biosamples collected through the National Institutes of Health All of Us Research Program will be processed, stored and distributed at Mayo Clinic.

“A detailed analysis of biospecimens can often provide the necessary information to answer questions about how diseases originate and why they affect some individuals but not others,” says Stephen N. Thibodeau, Ph.D., director of the Mayo Clinic Biobank. “As part of our mission to support Mayo investigators, we have built a state-of-the-art biospecimen processing laboratory. Our experience in biobanking, automation and quality systems will serve us well in being the nation’s biobank.”

###

Learn more

Join the conversation

For more information on the Mayo Clinic Center for Individualized Medicine, visit our blogFacebookLinkedIn or Twitter at @MayoClinicCIM.

Learn more about the latest clinical applications of precision medicine at this year’s Individualizing Medicine Conference. It will be held Sept. 12-13, 2018, in Rochester, Minnesota.

###

Wed, Jul 25 6:00am · Advances in lung cancer immunotherapy and management of immune-mediated adverse events

Malignancies before and after immunotherapy (click image for comparison)

Over the last few years, immunotherapy using immune checkpoint inhibitors targeting programmed cell death receptor 1 (PD-1) or programmed cell death receptor ligand 1 (PD-L1) has revolutionized the therapeutic approach to advanced-stage non-small cell lung cancer and numerous other malignancies.

Monotherapy, using the anti-PD-1 antibody pembrolizumab, is now Food and Drug Administration (FDA) approved for patients with stage IV non-small cell lung cancer without a driver mutation and 50 percent or greater tumor cell PD-L1 expression by immunohistochemistry staining. Moreover, the combination of systemic platinum-based chemotherapy and pembrolizumab was also recently approved for first line therapy of metastatic nonsquamous non-small cell lung cancer independent of PD-L1 status.

Nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1) also are FDA approved for second line therapy of stage IV lung cancer. For this indication, with the exception of pembrolizumab, which requires 1 percent or greater PD-L1 expression, no PD-L1 expression level is required to initiate therapy.

On average, objective response rates to immunotherapy range around 20 to 30 percent and sustained long-term responses have been observed. However, since the majority of patients do not benefit from second line immunotherapy, many efforts are being made to improve durable responses. The newest addition is a Mayo Clinic investigator-initiated study, the Trial of Measles Virotherapy in Combination With Atezolizumab in Patients With Metastatic Non-Small Cell Lung Cancer, which explores the combination of the intratumoral administration of the measles virus with systemic PD-L1 targeted immunotherapy using atezolizumab for second line therapy of non-small cell lung cancer.

Immune-mediated adverse events

PD-1/PD-L1 targeted immunotherapy is generally well-tolerated and has fewer acute side effects compared with standard cytotoxic chemotherapies. However, these new therapeutic agents have been linked to a growing number of immune-mediated adverse events (imAEs).

Immune-mediated adverse events (click image for examples)

ImAEs are observed in 70 percent of patients and include autoimmune colitis, thyroiditis, hypophysitis, dermatitis and pneumonitis. The severity of imAEs ranges from asymptomatic to life-threatening presentations, while the time course can be either transient or chronic and relapsing.

Mayo Clinic’s true multidisciplinary team approach includes experts in medical oncology, rheumatology, pulmonary medicine, gastroenterology, endocrinology and neurology to optimally manage patients with imAEs. Besides stopping immunotherapy, patients are most commonly treated with immunosuppression (most commonly corticosteroids).

The pathogenesis, risk factors, diagnostic criteria and individualized management of patients experiencing immunotherapy-related imAEs outside of controlled clinical trials, however, remains unclear. A diagnosis of an imAE, published in Melanoma Research in 2016, represents a diagnosis of exclusion and depends on the active elimination of alternative diagnosis.

For more information

Vyriad. Trial of Measles Virotherapy in Combination With Atezolizumab in Patients With Metastatic Non-Small Cell Lung Cancer. ClinicalTrials.gov.

Kottschade L, et al. A multidisciplinary approach to toxicity management of modern immune checkpoint inhibitors in cancer therapy. Melanoma Research. 2016;26:469.

This article was originally published in Mayo Clinic’s Clinical Updates for Medical Professionals newsletter.

Related links:

Mon, Jul 2 6:00am · A revolution in pancreatic cancer treatment

Mark Truty, M.D., during his first year of college, with his father, Kazimierz, shortly before he was diagnosed with pancreatic cancer.

Mark Truty, M.D., has dedicated his career to giving patients with pancreatic cancer more quality time with their loved ones. Much more time. The mission is personal for him. His own father, Kazimierz Truty, a Polish immigrant and mechanic at a meatpacking plant near Chicago, died 20 years ago from pancreatic cancer at age 58.

“My dad had typical symptoms of back pain, weight loss and diarrhea,” says Dr. Truty, a surgeon in Mayo Clinic’s Division of Hepatobiliary & Pancreatic Surgery. “His symptoms continued, and he developed jaundice and was admitted to a community hospital. A general surgeon who wasn’t experienced with pancreatic cancer operated on the tumor, which was wrapped around blood vessels, and cut through the tumor in trying to remove it. My dad was in the hospital for 89 days, had two more emergency operations and eventually went home, too ill for chemotherapy. He died in my arms after weeks of suffering.

“I was 19 years old, so it was a while ago, but scenarios exactly like this still happen across the country every day,” he says. “When I got into medicine, I knew we had to advance the science and treatment for this disease. Pancreatic cancer treatment hadn’t evolved in three decades. Doctors did the same thing — performed inadequate operations on those whom surgery was unlikely to benefit and avoided surgery in many patients who would potentially benefit from an operation — and expected different results. This approach has been a miserable failure. I applied the surgical skills I learned from my mentors at Mayo Clinic during my training and collaborated with colleagues in other disciplines to break away from that traditional dogma.

“Patients want to know there’s hope. They want another holiday with their loved ones. After they’re diagnosed, they ask me if they’ll live to see another Christmas. Now I get to tell many of them yes.”

Upending traditional treatment

How are Dr. Truty and his Mayo Clinic surgical colleagues so confident in their ability to help patients see another holiday? They’ve upended traditional treatment for pancreatic cancer by introducing a sequenced treatment strategy that’s being mimicked at other leading medical centers around the world.

The multidisciplinary approach includes boosting patients’ health to endure treatment, providing neoadjuvant chemotherapy and radiation, and performing aggressive operations.

The numbers don’t lie. Patients with stage III pancreatic cancer (traditionally inoperable) have had eye-popping improvement in their outcomes. And they show no signs of cancer recurrence in follow up.

Realizing surgery alone isn’t enough

The three-decades-old practice Dr. Truty describes involved a standard approach to surgery — operating on only very localized tumors that account for 15 percent of patients, followed by chemotherapy (proven to improve survival) if the patient could tolerate it. There was a glitch, however: many patients didn’t receive the recommended chemotherapy due  to challenges recovering from surgery or a belief that they didn’t need it.

Despite significant technical improvements in the operation and advances in perioperative patient care, long-term outcomes and average length of survival didn’t budge, averaging only 20 to 24 months. One reason for that may be that tumors thought to be localized had actually spread, reinforcing the concept that although surgery is necessary for long-term survival, it is not sufficient and alone is of minimal benefit. Dr. Truty says all patients with pancreatic cancer need chemotherapy to treat micrometastases.

“It was great that we learned how to safely perform these complex surgeries and decrease complications, but that alone wasn’t going to affect longevity,” says Dr. Truty. “Technical advances cannot defeat biological limitations.”

Wish list

Dr. Truty describes what’s still needed to more effectively identify and treat pancreatic cancer.

Diagnosis prior to development of metastatic disease:

Researchers at Mayo Clinic are working on a more effective, noninvasive screening tool, but it is probably five to 10 years away, he says.

Type 2 diabetes is now considered a risk factor for pancreatic cancer, along with smoking and family history of the disease. Scientists aren’t sure if pancreatic cancer causes diabetes or if diabetes increases the risk of pancreatic cancer.

But most people diagnosed with pancreatic cancer have had a new diagnosis of diabetes within two years or had longstanding diabetes that worsened.

Better chemotherapy drugs:

Dr. Truty’s lab removes pancreatic tumors from patients and grows them in special mice. The tumors are genetically sequenced by investigators in the Mayo Clinic Center for Individualized Medicine to find possible drug targets in the mice. “We have hundreds of identical mice with a single patient’s tumor in them, which enables us to screen a large number of available and new drugs with no risk to the patient,” he says. “If we find a drug
that works in a mouse, it’s predictive of it working in the patient. We look for a biomarker that predicts the drug’s response so we can use the same drug in other patients with that biomarker in a clinical trial.

“This is true individualized oncology, and it’s happening at Mayo Clinic. This work is especially important for rare tumors for which there is no data.”

Dr. Truty says not many medical centers are very successful in growing pancreatic cancer in xenografts. Mayo Clinic succeeds in this effort because of the collaboration between surgeons and pathologists. They can transfer tumor tissue to mice within 30 minutes — “from warm patient to warm mouse.”

“Testing drugs in mice helps us shorten the time normally required to develop clinical trials,” says Dr. Truty. “Most pancreatic cancer patients don’t have the luxury of time to wait five to 10 years for a traditional trial.”

The lab also is transplanting tissue into mice from patients who have had chemotherapy, radiation and surgery to determine if the cancer is completely killed or likely to return. If the cancer cells grow in the mice, it gives Dr. Truty a heads-up to intervene with the patient while the tumor is still small.

Introducing new, ordered components

Not content with the status quo, Dr. Truty and his colleagues explored ways to further improve outcomes. In examining national data of pancreatic cancer patients, they found that surgical patients with elevated levels of the tumor marker CA 19-9 fared significantly worse than those without CA 19-9 elevations, even if their surgery was followed by chemotherapy. The only treatment sequence that provided good long-term outcomes was chemotherapy before surgery. (Read related story).

As a result of that finding, all Mayo Clinic pancreatic cancer patients now have a CA 19-9 blood test at diagnosis to guide treatment. CA 19-9 elevation indicates patients may have metastatic disease, and such patients may benefit from chemotherapy before surgery even if their tumor is otherwise surgically resectable. Pancreatic cancer can spread without it being detectable on scans — the aforementioned micrometastasis — according to Dr. Truty.

“We believe obtaining CA 19-9 levels at diagnosis provides an opportunity to clinically assess tumor aggressiveness,” says Dr. Truty. “The test is widely available, inexpensive and a good predictor of how the patient will fare.”

Armed with this revelation, pancreatic cancer specialists at Mayo Clinic have flipped the script and introduced neoadjuvant chemotherapy for many patients to improve survival and ensure that an operation will be of significant benefit.

There is, however, a larger fraction (35 percent) of patients whose tumors were traditionally considered too high risk for surgery due to growth outside of the pancreas and involvement of critical veins and arteries. Today more than 50 percent of these patients are having operations preceded by chemotherapy, using more effective drug combinations. Neoadjuvant radiation also has been added to the mix. Dr. Truty and other surgeons in his division were instrumental in turning those formerly “unresectable” cases into successful curative cancer surgeries.

Dr. Truty says having these three tools — chemotherapy, radiation and surgery — in the toolbox isn’t the key. Rather, how they’re used and in what sequence is key.

“I compare it to making my wife’s chocolate chip cookies,” he says. “I used the same ingredients, but my cookies didn’t turn out as well. Why? She knows how use all the ingredients in the right amounts and in the right order to get the optimal final product.

“What is the optimal final product for patients with pancreatic cancer? It is not the operation. Our goal is to extend quantity and maintain or improve quality of life. Surgery may be a critical component, or it can worsen both of these goals. We don’t have any secret ingredient. We tailor treatment to each patient and use the available tools in the right order and right amounts to accomplish our goals.”

Although other centers have now adopted this approach, Dr. Truty and his Mayo Clinic colleagues are leading the way in defining how to use this strategy most effectively.

Using more sensitive scanning

The treatment sequencing developed at Mayo Clinic includes looking at the entire patient and addressing their weight loss, malnourishment, jaundice, depression and other medical problems at diagnosis. Mayo Clinic’s multidisciplinary approach involves helping patients get in the best mental and physical shape to battle cancer treatment. After patients are stabilized, they receive modern combinatorial chemotherapy administered by Mayo Clinic medical oncologists specializing in pancreatic cancer.

“Traditionally, we looked at CT scans to see if chemotherapy had successfully reduced tumors,” says Dr. Truty. “But our experience reveals that only 25 percent of tumors show shrinkage on CT scans. That doesn’t mean the therapy wasn’t effective. A  PET MRI scanner is much more sensitive and a better indicator of whether chemotherapy is killing cancer elsewhere in the body. If there is evidence of response with PET MRI, we’re confident the therapy also is treating the cancer ‘seeds.’ Most patients don’t die from their primary tumors; they die from metastases.”

There are fewer than 50 PET MRI scanners in the world. Mayo Clinic has two of them — in Minnesota and Arizona — and the Florida campus is getting one soon. Dr. Truty says the scanner has revolutionized Mayo Clinic’s practice and is an example of how a significant advance in one field — radiology — has allowed evolution in another — oncology.

“PET MRI helps us determine if the chemotherapy is working,” he says. “If it is, we continue chemo- therapy until there is no more viable cancer or until the patient can no longer tolerate the side effects. If scans indicate chemotherapy isn’t working, we switch to another drug combination.”

Preparing for surgery

After chemotherapy, Dr. Truty relies on his colleagues in radiation oncology to initiate therapy, including proton beam, instead of going straight to surgery. “Surgery is only beneficial if we can remove tumors with negative margins,” he says. “Our ability to achieve negative-margin operations is markedly improved when patients have had radiation directed toward the intended surgical site.

“If there’s no evidence of metastases after radiation therapy and the patient is in good enough physical condition, we operate. We do operations most surgeons wouldn’t attempt, often with the assistance of our vascular surgery colleagues. We  are aggressive in removing all the surrounding structure where the tumor may have been in contact with vessels, doing a complex vascular resection and reconstruction. We do more of these arterial custom ‘bespoke’ vascular resections than any other center

— some of the operations lasting 14 hours.”

During the operation the surgeons send tumor samples to a pathologist, who quick-freezes the tissue and examines it for cancer — a technique developed at Mayo Clinic — and then reports back about margins and whether any cancer is still present.

After surgery, some patients receive additional chemotherapy.

The preliminary outcomes with this approach, referred to as total neoadjuvant therapy, will be published soon. The survival benefit is significant.

Collaborating is key

Axel Grothey, M.D. (left), and Mark Truty, M.D., each lost a parent to pancreatic cancer, which makes their mission to revolutionize treatment much more personal. Dr. Grothey says this collaboration is one of the most rewarding he’s had at Mayo Clinic.

Axel Grothey, M.D., a Mayo Clinic oncologist, works closely with Dr. Truty and other cancer surgeons. Like Dr. Truty, Dr. Grothey has personal experience with pancreatic cancer.

In 2003 his mother, Inge, was diagnosed with locally advanced pancreatic cancer in Germany. She had surgery, complicated by blood vessel involvement, and died within a week.

“Improving the outcomes and life expectancy for patients with this disease is very dear to me,” he says.

Dr. Grothey reiterates that aggressive surgery makes sense only if the cancer elsewhere in a patient’s body can be controlled. That’s where new chemotherapy agents come in.

“A  cure is only achievable if control of the tumor spread occurs and the primary tumor can be removed,” he says. “It’s not just about surgical skill but, rather, our overall management of each patient with an integrated team approach. Mayo Clinic does teamwork like nowhere else.”

Dr. Grothey cautions that every patient isn’t a candidate for this pancreatic cancer protocol. “Sometimes patients want to be unrealistically aggressive and use every available tool even though that approach may negatively affect their quality of  life without adding to their longevity. We try to rein them in. In the right patients, we’re more than happy to be aggressive, and there’s no better place to be than Mayo Clinic.

“Working with Dr. Truty and our other colleagues to revolutionize pancreatic cancer treatment has been one of the most rewarding collaborations I’ve had in 14 years at Mayo Clinic.”

Shushing the naysayers

Dr. Truty says that while this approach isn’t a cure for every patient, it’s getting close. The protocol has resulted in significant improvement in survival, even for patients whose tumors previously would have been considered inoperable. Data on more than 160 patients with stage III cancer show remarkable success. With conventional treatment, their expected median survival would be less than a year. Their actual median survival is more than 50 months and counting. The majority of these patients show no signs of cancer.

“When I first started, we didn’t use neoadjuvant therapy, and there were a lot of naysayers … until we had data to demonstrate our success,” says Dr. Truty. “Now other medical centers are using this approach, with Mayo Clinic leading the way.

“Pancreatic cancer is stigmatic for its traditionally deadly diagnosis. Patients begin ‘making arrangements’ and talking about hospice. That’s changing. We’re able to help people who have been told their disease is not treatable. I encourage Mayo Clinic alumni to tell their patients to get another opinion. Many community providers aren’t aware of the revolution underway in the treatment of pancreatic cancer. I’ll be happy when pancreatic patients around the world have the hope our patients feel.”

###

This article was originally published in Mayo Clinic Alumni magazine, Issue 1, 2018.

Editor’s note: Since the time of publication, Dr. Grothey has moved on in his career and now holds a leadership position at Sarah Cannon.

Related resources:

Fri, Jun 29 6:00am · New molecular test employs sponge on a string to detect esophageal cancer

Researchers at Mayo Clinic have developed a new, minimally invasive method to detect and help prevent esophageal cancer in patients at risk for Barrett’s esophagus and esophageal cancer. Their study documenting the discovery and validation of novel methylated markers along with results of a pilot study have been published and are available online in the American Journal of Gastroenterology. Results of a larger validation study were presented at Digestive Disease Week 2018 in June.

Esophageal cancer is often diagnosed at an advanced stage when a patient presents after the onset of symptoms, which include difficulty swallowing or having food stick while swallowing,” says Prasad Iyer, M.D., a gastroenterologist at Mayo Clinic. Dr. Iyer says esophageal cancer is associated with poor outcomes with five-year survival of less than 20 percent.

Dr. Iyer says esophageal cancer arises from a precancerous condition called Barrett’s esophagus which can currently only be diagnosed using an endoscope which involves an invasive, expensive procedure that requires the patient to be sedated.

“Sponge-on-a-string” device used in the study.

Dr. Iyer and his team have developed a novel, non-endoscopic method to diagnose Barrett’s esophagus and associated cancer using a compressed sponge on a string, about the size of a multivitamin capsule covered with a dissolvable shell. A patient undergoing the test swallows the capsule with a few sips of water.  Within eight minutes the capsule dissolves releasing the sponge, which is then pulled out using the attached string.  This sponge provides a rich cellular sample of the entire esophagus, which is then tested for biomarkers consistent with cancer or precancer. The whole procedure takes about 10-12 minutes and the patient does not require sedation.

Dr. Iyer says there is great value in increasing the number of people willing to be tested for esophageal cancer. “When esophageal cancers are diagnosed early, outcomes are significantly better with a five- year survival rate of more than 80 percent,”.

He adds that while screening for Barrett’s esophagus is recommended by many professional societies, widespread adoption of this recommendation has been hampered by the lack of a widely applicable and cost-effective method of testing. Dr. Iyer says the capsule sponge test may be well suited for this purpose.

“This test can make widespread screening for Barrett’s esophagus feasible,” says Dr. Iyer.  “In our initial pilot study the test was able to accurately predict the absence or presence of Barrett’s esophagus with 100-percent accuracy.”  He says the sponge device was successfully swallowed by 98 percent of patients with excellent tolerability and safety and more than 80 percent of patients preferred this technique to receiving sedated endoscopy which is the current standard of care.

###

Related resources:

Tue, Jun 26 6:00am · Register for Transform 2018 today! Discounted rates end June 30

Accelerating Health Innovation. Focusing on People. It’s by Design.

Hosted by Mayo Clinic, Transform has been the preeminent health care conference to proactively confront critical issues, share meaningful insights, and catalyze actionable change for more than a decade. Join us at the Mayo Civic Center, Sept. 26-27, as we explore pivotal opportunities to transform health care in the following key areas:

  • Augmented human intelligence
  • Tangible ways to make innovation possible
  • Retail mergers and their impact on health care
  • Helping people live their best lives

Join the movement to Transform health care and register today.

Early registration rates end June 30.

Conference highlights include presentations from bold leaders including Mona Hanna-Attisha, M.D. (Hurley Children’s Hospital), Cyrus Batheja (UnitedHealthcare Community and State), Tom Insel, M.D. (Mindstrong Health) and a lively Intelligence Squared debate that will explore the impact of recent health care retail mergers.

In addition to a robust schedule of speakers, Transform also features extended opportunities to connect during several breakout sessions, an IBM AI Accelerator workshop, a “design your next competitor” activity led by IA Collaborative, and PechaKucha presentations that will inspire discussions and collaborations to continue beyond the conference.

For a complete schedule and listing of speakers, visit the Transform 2018 website.

###

Follow the latest Transform 2018 news on Facebook and Twitter, using the hashtag #TXFM.

Visit the website for more information about the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, which hosts Transform.

Contact Us · Privacy Policy