TAG: "Kidney"

Revealing kidney cancer’s secret


Tumors gain survival advantage by reprogramming their metabolism.

Robert Weiss, UC Davis

By Dorsey Griffith, UC Davis

An international team of scientists, led by UC Davis nephrologist Robert Weiss, have used a sophisticated combination of proteomics and metabolomics to show how renal cell carcinoma (RCC) reprograms its metabolism and evades the immune system. In addition, the study found that cancer grade has a major impact on this reprogramming. These results, published in the journal Cancer Research, point to new therapeutic options for this particularly deadly cancer.

“The mortality for someone with highly metastatic RCC is somewhere in the 90 percent range,” said Weiss, professor of nephrology and internal medicine at UC Davis and chief of nephrology at the VA Northern California Health System in Sacramento. “We now know this cancer is actually reprogramming its environment to minimize the immune response.”

The team used a unique approach to make these discoveries, combining proteomics with metabolomics. The proteomic analyses examined how RCC affects levels of different proteins. Meanwhile, metabolomic studies performed a similar task with metabolites­ – the compounds that remain when larger molecules are broken down or metabolized.

Both proteomic and metabolomic analyses are quite intensive, requiring major computational and statistical firepower. However, combining these two “omics” provided a better view of the mechanisms that govern kidney cancer, like using a wide-angle lens to capture a complete landscape.

“One particular omics technique will tell you part of the story, but it won’t give you the whole thing,” said Weiss, a scientific member of the UC Davis Comprehensive Cancer Center. “We wanted to combine metabolomics and proteomics and come up with a ‘unified field theory’ to look at the metabolites in cancer.”

This more comprehensive approach paid dividends in several ways. For example, the proteomic analysis showed how RCC increases an enzyme that breaks down the amino acid tryptophan. In turn, the metabolomics studies flagged that tryptophan metabolites suppress the immune system.

A similar story unfolded with glutamine, another amino acid. By manipulating glutamine, kidney cancer removes reactive oxygen species, a key immune system weapon that would usually help destroy the cancer.

“Normally, immune surveillance would shut down the cancer, but RCC has evolved to turn off the immune system, giving it a survival advantage,” said Weiss.

The research also uncovered another important story: how cancer grade affects this remodeling. While cancer stage describes how far the disease has progressed through the body – from localized to metastasized – grade describes how abnormal the cancer cells have become. In the case of RCC, higher-grade cancers were remodeling their environments more aggressively.

“We often treat kidney cancers the same, regardless of grade,” noted Weiss. “We should think about grade, and not just stage, when we’re treating patients.”

From a procedural standpoint, the study highlights how combining proteomics and metabolomics can detect cancer mechanisms that either method, by itself, might miss. In addition, this better understanding of how cancer grade affects its ability to alter its surroundings could help oncologists develop more personalize therapies.

But even more importantly, the work points to new therapeutic targets, such as the tryptophan and glutamine pathways, which could help clinicians unleash the immune system against RCC.

“We are going to be testing inhibitors against some of these enzymes so we can stop the tumors from creating these immunosuppressant metabolites,” said Weiss.

Other researchers were Hiromi Wettersten, Josephine Trott and Omran Abu Aboud Dexter Morin at UC Davis; A. Ari Hakimi and James  Hsieh at Memorial Sloan Kettering Cancer Center; Cristina Bianchi and Roberto Perego at the University of Milano-Bicocca; Megan. Johnstone and Dallas Donohoe at the University of Tennessee; Steven Stirdivant, Bruce Neri and Robert Wolfert at Metabolon; and Benjamin Stewart at Lawrence Livermore National Laboratory.

This research was funded by National Institutes of Health grants 5UO1CA86402, 1R01CA135401-01A1 and 1R01DK082690-01A1, the Medical Service of the U.S. Department of Veterans’ Affairs, the LLNL-UCDCC Fitzpatrick Award, and grants from the Paula Moss Trust and the J. Randall & Kathleen L. MacDonald Research Fund in Honor of Louis V. Gerstner.

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Kidney care: A minimally invasive approach


UC Irvine innovative technique offers alternative to surgery.

By Camila Hernandez, UC Irvine

David and Ricki Pearl were meant to be together. They met as children and David proudly remembers it was love at first sight. Circumstances in life separated them for more than 30 years, but eventually they found each other again. Then, at age 70, David found out he had a growth in his kidney.

The specialist who discovered the growth told the Pearls he was certain it was cancerous, and David would need surgery right away. A biopsy would be too complicated, he said, because of the risk of seeding. Seeding is the spread of malignant cancer cells throughout the body.

The Pearls asked for a second opinion and were referred to Dr. Jaime Landman, chair of the Department of Urology at UC Irvine Health. Landman is a pioneer of a revolutionary minimally invasive ultrasound-guided technique that allows urologists to safely perform kidney biopsies with almost no risk of seeding.

Landman developed this innovative technique in collaboration with industry leaders and a team of UC Irvine Health urologists, anesthesiologists, nurses and medical students. After thorough testing in the lab, the team began performing ultrasound-guided kidney biopsies on patients, with excellent results.

The biopsy revealed that David Pearl’s tumor was not cancerous. Like David, many of the patients who undergo these biopsies turn out to have benign tumors and do not need surgery to remove the kidney. Nationally, up to 30 percent of kidney surgeries performed are unnecessary because tumors are later revealed to be benign.

“At UC Irvine Health, we are truly changing the way we diagnose and treat kidney cancer. No other medical center in Orange County is doing this,” Landman said. “I’m surprised we’re not doing this all over the world.”

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Forging ahead in fight against hemochromatosis


Research advances are improving prognosis for hereditary blood-iron overload disorder.

By Tom Vasich, UC Irvine

Since coming to the UC Irvine School of Medicine in 1998, Christine and Gordon McLaren have been leading the way in the research and treatment of hemochromatosis, a hereditary disease that causes the body to absorb too much iron from ingested food.

The excess iron is stored in various organs – especially the liver, heart and pancreas – and can poison them, precipitating such life-threatening conditions as cirrhosis and liver cancer, heart arrhythmias and diabetes. Once considered a rare disease, hemochromatosis is now recognized as one of the most common inherited disorders, affecting as many as 1 million people in the U.S.

Christine McLaren is a professor of epidemiology, and Dr. Gordon McLaren is a professor of medicine specializing in hematology and oncology who practices in the Veterans Affairs Long Beach Healthcare System.

Over the past few months, the wife and husband have made noteworthy strides: Last September, they received a $2 million grant from the National Institute of Diabetes & Digestive & Kidney Diseases to investigate the genetic modifiers of iron status in hemochromatosis. And a study the McLarens presented in December at the annual meeting of the American Society of Hematology was a “Best of ASH” honoree.

Here, they discuss their work:

How did you both acquire an interest in this field?

Christine: We developed a focus on the disorder independently. Early in my career, I provided statistical consulting for hematologists who had research projects involving iron overload and iron deficiency. Meanwhile, Gordon has had a long-standing interest for over 30 years in the area of iron metabolism, with an emphasis on hemochromatosis.

In 2000, after Gordon and I had joined the faculty at UCI, we were fortunate to receive National Institutes of Health funding to work together and to screen more than 20,000 primary care patients for iron overload and hereditary hemochromatosis at UCI ambulatory care clinics.

The primary goal of that research was to contribute to a national epidemiologic study of iron overload and hereditary hemochromatosis in a multicenter, multiethnic, primary care-based sample of over 100,000 people.

How are people susceptible to hemochromatosis?

Gordon: Generally, iron overload occurs only in people with two copies of the hemochromatosis gene (one copy inherited from each parent). The frequency of having two copies in the European-American population is about 5 per 1,000 persons.

However, not all people with two copies of the gene will develop iron overload. Thus, we think there must be other factors – such as mutations in other genes affecting dietary iron absorption – that are required for the disease to become fully manifest, and this is what we’re studying.

If we can identify what causes the difference, we may be able to use this information to predict which patients are at greater risk of developing iron overload and when to begin therapy to remove excess iron before it accumulates to toxic levels.

Interestingly, the frequency of the genetic predisposition to hemochromatosis among European-Americans is the same in men and women, but for reasons that are not completely understood, men are more likely to develop the full-blown syndrome.

What do you plan to accomplish with the $2 million in support from the National Institute of Diabetes & Digestive & Kidney Diseases?

Gordon: We’re leading a multidisciplinary team of investigators at eight research institutions in the U.S., Canada and Australia. To better understand the reasons for this variability in disease expression, our group will examine genetic factors in the susceptibility or resistance to iron overload in patients with a genetic predisposition for hemochromatosis across a wide range of geographic areas.

The purpose of this research is to identify other inherited traits that may interact to cause more severe disease in certain patients. It’s important to identify persons at risk because effective iron removal treatment is available, and beginning such therapy before iron overload becomes advanced can prevent disease complications.

Christine: This work can have important clinical applications, including the ability to identify young hemochromatosis patients at risk for potentially severe iron overload later in life, thereby influencing physicians’ recommendations for iron removal therapy and long-term follow-up. We’re hopeful that our findings will lead to new approaches that will inform the development of innovative prevention and treatment strategies tailored to the individual.

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Three receive kidney transplants in live donor chain at UC Irvine


For one recipient, identifying a suitable kidney ‘like finding a needle in a haystack.’

Three Orange County people have received kidney transplants at UC Irvine Medical Center thanks to the altruism of an anonymous donor.

The donation started a three-way donor chain in which two people who were not tissue-compatible with their loved ones could offer their kidneys to others who suffered from end-stage renal failure and were tissue matches.

“Three people received transplants that would not have happened without the generosity of one altruistic donor,” says Dr. Clarence Foster III, director of the UC Irvine Health Kidney Transplant Program. He said one of the recipients had medical complications that made identifying a suitable kidney “like finding a needle in a haystack.”

Foster says the donors and recipients are doing well several weeks after he and Dr. Hirohito Ichii recovered the organs and transplanted them over two days.

Designated living donors have become more common in recent years as family members or friends who are a tissue match donate organs to loved ones.  More rare are donors with no connection to someone in need of a transplant but who chooses to donate to a stranger. Such unspecified donors, as they are called in the transplant community, can spark a chain that gives the gift of life to many more people.

This month’s set of transplants is Orange County’s second matched donor chain. Last year, Foster transplanted a donated kidney into a woman who had spent eight years on dialysis while waiting for an organ to become available. Her transplant became possible when an anonymous Yorba Linda man donated a kidney that was a match for a Huntington Beach resident. That recipient’s spouse could then donate a kidney that was matched and subsequently transplanted into the long-term dialysis patient.

More than 100,000 people in the U.S. are waiting for a kidney to become available. At UC Irvine Health transplant specialists have been providing kidney transplants to patients with end-stage kidney disease for more than 40 years. A comprehensive range of transplant services is available, including living kidney donations.

For more information or to make an appointment, please call the UC Irvine Health Kidney Transplant program at (714) 456-8441.

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Blood test predicts signs of acute rejection in kidney transplants


UCSF finding could lead to earlier detection, treatment and improved organ survival.

Researchers at UC San Francisco have developed a potential test for diagnosing and predicting acute rejection in kidney transplants, a finding that eventually could replace the need for biopsies and lead to earlier detection and treatment.

The study is in today’s (Nov. 11) issue of PLOS Medicine.

“We have found a set of genes in blood that pick up inflammation and acute rejection in different solid organ transplants and thus can replace the need for an invasive biopsy in the future,” said senior author Minnie Sarwal, M.D., Ph.D., professor of transplant surgery at UCSF. “This assay also predicts the onset of histological rejection by three to four months, meaning graft inflammation can be treated early and proactively, even reversed.”

“This is the first assay of its kind that can provide a sensitive readout of very early rejection and inflammation in the organ, which cannot be picked up by any other blood test on the market,” Sarwal continued. “The result is improved graft function and survival.”

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Bonded by love and life-saving transplant


Lisa Flowers donated a kidney to give her daughter a normal adolescence.

Kaylyn Flowers experienced kidney failure at just 10 years of age, but returned to a fairly normal adolescence after an organ donation from her mother, Lisa.

Lisa Flowers knew her 10-year-old daughter Kaylyn’s fatigue wasn’t normal, but the urgent call from the local doctor still took her aback.

Physicians had been testing the girl to determine if a recent eye problem was due to an autoimmune disease, and they hadn’t given Lisa reason to think anything was seriously wrong. Now they reported that Kaylyn’s kidneys had been failing, quietly but completely, and that she would likely require a transplant.

“It’s one of those moments in your life that you’ll always remember, one of those life-changing phone calls,” Lisa said. “The doctor said, ‘She won’t die from this, and we’ll do everything that we can, but it’s really serious and we need her seen within the hour. Go pack, and I’ll call you back.’ ”

Yet thanks to her mother’s love, Kaylyn would return to a fairly normal adolescence within just five months. Testing revealed that Lisa was a match to donate a kidney to her daughter, a major undertaking but one that would spare the girl years of disruptive dialysis treatments.

UC Davis’ nationally renowned nephrology and transplant programs were available to perform the procedure a short drive from the family’s Roseville home.

“Everything fell in line perfectly for us,” Lisa said. “The transplant team responded right away when we said dialysis was not for us. They came immediately, started the workup and it couldn’t have gone any easier.”

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Potential blood test uncovered for disorder than can accelerate organ failure


Discovery could allow for customized therapies, improved patient selection for transplant.

Researchers at UC San Francisco and Rush University Medical Center, Chicago, may have found a predictor for a disorder affecting kidney transplant recipients that can accelerate organ failure, a discovery that eventually could allow for customized therapies and improved patient selection for transplant.

The study of focal segmental glomerulosclerosis (FSGS), a devastating form of kidney disease, is in today’s (Oct. 1) issue of Science Translational Medicine. Research was conducted by an international study team, with Necker Hospital in Paris and UCSF joint lead authors and Rush University Medical Center and UCSF joint senior authors.

“This is a new blood test to monitor patients before kidney transplant and predict who may have recurrence of FSGS, thereby preventing loss of kidneys,” said co-senior author Minnie Sarwal, M.D., Ph.D., professor of transplant surgery at UCSF.

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Research may lead to cure for deadly kidney disease


Biochemists solve ‘address problem’ in cells that leads to lethal kidney disease.

Carla Koehler, UCLA (Photo by Reed Hutchinson, UCLA)

Research by UCLA biochemists may lead to a new treatment — or even a cure — for PH1, a rare and potentially deadly genetic kidney disease that afflicts children. Their findings also may provide important insights into treatments for Parkinson’s disease, Alzheimer’s disease and other degenerative diseases.

Led by Carla Koehler, a professor of chemistry and biochemistry in the UCLA College, the researchers identified a compound called dequalinium chloride, or DECA, that can prevent a metabolic enzyme from going to the wrong location within a cell. Ensuring that the enzyme — called alanine: glyoxylate aminotransferase, or AGT — goes to the proper “address” in the cell prevents PH1.

The findings were published online in the Proceedings of the National Academy of Sciences and will appear later in the journal’s print edition.

In humans, AGT is supposed to go to an organelle inside the cell called the peroxisome, but for people with a particular genetic mutation, the enzyme mistakenly goes instead to the mitochondria — tiny power generators in cells that burn food and produce most of the cells’ energy — which causes PH1.

Koehler’s team demonstrated that adding small amounts of DECA, which is FDA-approved, to cells in a Petri dish prevents AGT from going to the mitochondria and sends it to its proper destination, the peroxisome.

“In many mutations that cause diseases, the enzyme doesn’t work,” Koehler said. “In PH1 the enzyme does work, but it goes to the wrong part of the cell. We wanted to use DECA in a cell model to block AGT from going to the wrong address and send it back to the right address. DECA blocks the mitochondria ‘mailbox’ and takes it to the peroxisome address instead.”

How often did it work?

“All the time,” said Koehler, a member of UCLA’s Jonsson Comprehensive Cancer Center, Molecular Biology Institute and Brain Research Institute.

For people with the mutation, the correct peroxisome address is present in AGT, but it is ignored because it is accompanied by the address of the mitochondria, which the cell reads first, Koehler said.

Koehler, who also is a member of the scientific and medical advisory board of the United Mitochondrial Disease Foundation, hopes to find out whether a similar “correct address” strategy can slow cancer down. Her laboratory has identified approximately 100 other small molecules, which she calls MitoBloCKs, that she and her colleagues are testing for their ability to combat Parkinson’s, Alzheimer’s and other diseases.

PH1 — short for primary hyperoxaluria 1 — starts at birth and is usually fatal for patients who do not receive both kidney and liver transplants. Approximately half of those with the disease have kidney failure by age 15. Koehler has presented her findings to the Oxalosis and Hyperoxaluria Foundation, which provides support for PH1 patients and their families.

Scientists’ ability to diagnose rare diseases has improved in recent years because technological advances in genomics have made it easier to identify more genetic mutations, Koehler said.

According to Koehler, to treat diseases, scientists must first understand how proteins like AGT move inside the cell. Her research, which encompasses biochemistry, genetics and cell biology, studies how mitochondria are assembled and function, how proteins enter the mitochondria and reach the right location inside cells, and how mitochondria communicate with the rest of the cell.

Her laboratory uses model systems that enable them to study the biochemistry in a way that is not possible with humans. Much of the work is conducted in yeast.

“It’s exciting that our studies in baker’s yeast, a typical laboratory model, might be able to help kids with a complicated disease,” Koehler said.

The lead author of the PNAS research was Non Miyata, a former UCLA postdoctoral fellow in Koehler’s laboratory. Co-authors included Christopher Danpure, emeritus professor at University College London; and Sonia Fargue, a former researcher in Danpure’s laboratory.

Koehler’s research was funded by the National Institutes of Health’s National Institute of General Medical Sciences (grants GM073981 and GM61721).

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CT scan is no better than ultrasound to detect kidney stones


UCSF study leader recommends change in standard practice.

Rebecca Smith-Bindman, UC San Francisco

To diagnose painful kidney stones in hospital emergency rooms, CT scans are no better than less-often-used ultrasound exams, according to a clinical study conducted at 15 medical centers and published in the Sept. 18 issue of the New England Journal of Medicine.

Unlike ultrasound, CT exposes patients to significant amounts of radiation. Although CT scans are favored by emergency-room physicians for kidney stone diagnosis, ultrasound should be used as the first step, according to senior study author Rebecca Smith-Bindman, M.D., a professor in the departments of radiology; epidemiology and biostatistics; and obstetrics, gynecology and reproductive medicine at UC San Francisco.

“Ultrasound is the right place to start,” Smith-Bindman said. “Radiation exposure is avoided, without any increase in any category of adverse events, and with no increase in cost.” Patients in the study who were first examined with ultrasound sometimes received a follow-up CT exam at the physician’s discretion.

“Our results do not suggest that patients should undergo only ultrasound imaging, but rather that ultrasonography should be used as the initial diagnostic imaging test, with further imaging studies performed at the discretion of the physician on the basis of clinical judgment,” the study authors said.

Kidney stone rates are increasing, and in a 2010 National Health and Nutrition Examination Survey, one in 11 people reported having had at least one kidney stone. The use of CT to diagnose kidney stones has risen 10-fold in the last 15 years. CT exams generally are conducted by radiologists, while ultrasound exams may be conducted by emergency room physicians as well as radiologists.

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Innovation Profile: Rebecca Smith-Bindman

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Improving long-term health of kidney transplant recipients


UCSF is lead institution on $17M multicenter study to improve long-term survival.

Flavio Vicenti, UC San Francisco

UC San Francisco is the lead institution on a new seven-year, $17 million multicenter study funded by the National Institutes of Health to determine if certain immune system cells and/or a drug now used for treating rheumatoid arthritis can be effective in improving and maintaining the long-term health of kidney transplant recipients.

The goal of this study is to reduce or eliminate inflammation in kidney transplants and prevent the associated decline in function, thereby maximizing long-term organ survival. It will involve two clinical trials and research in parallel by biologists and by researchers for the mechanistic cores.

Despite advances in transplantation – reducing early acute rejection rates to less than 15 percent and improving one-year graft survival to more than 90 percent – long-term graft success rates have remained unchanged at 4 percent loss annually. A major contributor is progression of interstitial fibrosis and tubular atrophy in the kidney.

The cells that the researchers are focused on are regulatory T cells (Tregs), which are a small population of lymphocytes that suppress the activity of other immune cells. They maintain normal immune system homeostasis and safeguard against autoimmune diseases, and their immunosuppressive properties also can be harnessed to control transplant rejection.

Tregs have the potential to induce long-term donor-specific tolerance without impeding desired immune responses to pathogens and tumors in transplant patients.

The principal investigator of the study is Flavio Vincenti, M.D., UCSF professor of medicine and a kidney and pancreas transplant specialist at UCSF Medical Center. Other participating institutions are the University of Alabama at Birmingham, Emory University and Cedars-Sinai Medical Center.

“This grant allows us to work toward achieving two important advances in the transplant field,” said Vincenti. “We can introduce personalized medicine by treating patients based on molecular profiling of their kidney. We also can allow control of the response to the transplant by the patients’ own immune systems by regulatory T cells, either through infusions or pharmacologically.”

Researchers believe inflammation can be controlled in kidney transplant recipients by increasing the number or activity of Tregs, either by infusing them into the body or by blocking interleukin 6 (IL6) with the drug tocilizumab.

To do so, they will conduct two clinical trials – TASK (Treg Adaptive therapy in Subclinical inflammation in Kidney transplantation) and TRAIL (Therapy to Reduce Allograft Inflammation with IL6 inhibition).

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First-of-its-kind program seeks to encourage kidney donors


UCSF joins with Walgreens in blood pressure testing program for living kidney donors, potential donors.

While recipients of living donor kidney transplants receive steady follow-up care, the living donors themselves also need to be monitored. To make follow-up care more accessible, UC San Francisco and Walgreens are collaborating to launch the first program in the country that provides blood pressure testing at no charge to living kidney donors.

UCSF will provide vouchers for blood pressure tests redeemable at more than 4,500 Walgreens pharmacies and Healthcare Clinic at select Walgreens locations nationwide. Vouchers also are available to potential kidney donors, as blood pressure testing is a part of the initial screening process.

Tests are available daily during pharmacy and clinic hours with no appointment necessary and administered by health care professionals at Walgreens pharmacies and Healthcare Clinic at select Walgreens.

“The use of living donors has revolutionized kidney transplants, and this new program provides the opportunity to monitor their long-term health in a convenient, efficient way,” said John Roberts, M.D., professor of surgery and chief of UCSF Transplant Service and former president of the United Network for Organ Sharing (UNOS). “UCSF performs the most kidney transplant procedures in the United States, and we are pleased to be first to join with Walgreens in this effort that we hope encourages people to donate as there is a critical need.”

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Robot-assisted technique improves surgeons’ ability to remove kidney tumors


UCLA-led study finds the approach may shorten surgeries, could reduce risk of complications.

Schematic showing the robotic device's proper position during surgery. (Image by Eric Treat, UCLA)

Roughly 50,000 Americans are diagnosed with kidney cancer each year. Most of them have small tumors that doctors discover while screening for other health problems.

The surgeries to remove renal tumors can be difficult, particularly if the cancer is on the posterior side of the kidney and if patients have had previous abdominal surgery, because scar tissue from previous operations usually makes it hard for surgeons to distinguish the normal parts of the body from one another.

Now, a study led by Dr. Jim Hu and researchers at UCLA’s Jonsson Comprehensive Cancer Center has shown that a newer surgical technique called robot-assisted retroperitoneoscopic partial nephrectomy is more effective than other current techniques to remove kidney tumors when the masses are located on the back of the kidney or when a patient has had previous abdominal surgery. RARPN is a minimally invasive laparoscopic procedure in which surgeons use precise robotic arms and magnified, high-definition 3-D cameras.

The study, published online in European Urology, was the largest multicenter study to date on this technique. The five-year project reviewed surgeries for 227 patients whose average age was 60, with most between ages 52 and 66.

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