Category: Technology Transfer

Technology Transfer

Test Shown to Improve Accuracy in Identifying Precancerous Pancreatic…

Test Shown to Improve Accuracy in Identifying Precancerous Pancreatic Cysts

Aug. 5, 2019

The following was originally published in Johns Hopkins Medicine’s Newsroom.

In a proof-of-concept study, an international scientific team led by Johns Hopkins Kimmel Cancer Center researchers has shown that a laboratory test using artificial intelligence tools has the potential to more accurately sort out which people with pancreatic cysts will go on to develop pancreatic cancers.

The test, dubbed CompCyst (for comprehensive cyst analysis), incorporates measures of molecular and clinical markers in cyst fluids, and appears to be on track to significantly improve on conventional clinical and imaging tests, the research team says. Using information from more than 800 patients with pancreatic cysts who had cyst fluid analysis and cyst removal surgery at The Johns Hopkins Hospital and 15 other medical centers around the world, investigators say CompCyst more often than standard current methods correctly identified which patients needed and likely had a chance to benefit from surgery, and which were unlikely to benefit from surgery or needed further monitoring only. Specifically, they found that using the test would have spared from surgery more than half of patients who underwent cyst removal later deemed unnecessary because the cysts were unlikely to have caused cancer.

CT image of pancreatic cyst (Courtesy of Johns Hopkins Kimmel Cancer Center)

A description of the work is published in the July 17 issue of Science Translational Medicine. Most of the technologies related to CompCyst have been licensed to Thrive Earlier Detection Corp.

“Our study demonstrates the potential role of CompCyst as a complement to existing clinical and imaging criteria when evaluating pancreatic cysts,” says Anne Marie Lennon, M.B.B.Ch., Ph.D., professor of medicine and director of the Johns Hopkins multidisciplinary pancreatic cyst clinic. “It could provide a greater degree of confidence for physicians when they advise patients that they do not require follow-up and can be discharged from surveillance.”

“Although we still need to prospectively validate this test, our results are exciting because they document a new and more objective way to manage the many patients with this disease,” she adds. Plans are underway to begin a prospective validation study in the next year.

Pancreatic cysts are common. They are found in 4% of people in their 60s and 8% of people over age 70, according to other published research. That means some 800,000 people with a pancreatic cyst are identified each year in the U.S. alone. By contrast, only a small fraction of cysts progress to cancer.

“The dilemma facing patients and their physicians is the ability to distinguish precancerous cysts from cysts that will not progress to cancer,” says Lennon.

“Currently available clinical and imaging tests often fail to distinguish precancerous cysts from cysts that have little or no potential to turn cancerous, which makes it difficult to determine which patients will not require follow-up and which patients will need long-term follow-up or immediate surgical resection,” says study investigator Christopher Wolfgang, M.D., Ph.D., M.S., John L. Cameron Professor of Surgery, director of surgical oncology at the Johns Hopkins Kimmel Cancer Center and co-director of the Johns Hopkins Precision Medicine Center of Excellence for Pancreatic Cancer. “As a result, essentially all people diagnosed with a cyst are followed long-term. Surgeons are faced with making recommendations to patients based on the risks and benefits of surgery with limited information. We seldom miss a cancer, but it is at the expense of performing an operation that in hindsight may not have been necessary.  This study directly addresses these fundamental problems in management of pancreatic cysts.”

In the study, the precise nature of the cysts examined was confirmed through histopathological analysis of resected surgical specimens. The cysts were then classified into three groups: those with no potential to turn cancerous, for which patients would not require periodic monitoring; mucin-producing cysts that have a small risk of progressing to cancer, for which patients can receive periodic monitoring for progression to possible cancer; and cysts for which surgery is recommended because there is a high likelihood of progression to cancer.

The CompCyst test, developed by the Johns Hopkins Kimmel Cancer Center-led investigators, was created with patient data including clinical impressions and symptoms, images from CT scans and molecular features such as DNA alterations within cyst fluid.

In the study, the researchers evaluated the molecular profiles, including DNA mutations and chromosome changes, of a large number (862) of pancreatic cysts. They then fed the molecular information, along with clinical and radiologic data, into a computer-based program that used artificial intelligence to classify patients into the three groups noted previously.

Based on histopathological analysis of the surgically resected cysts, the researchers found that surgery was not needed for 45% of the patients that underwent surgery for their cysts. This unnecessary surgery was performed because the clinicians could not determine if the cysts were dangerous. In these patients, if CompCyst had been used, the researchers estimated that 60% to 74% of the patients (depending on the cyst type) could have been spared these unnecessary surgeries.

The study had several limitations, the researchers note, including that pancreatic cyst fluid was obtained at the time of surgery, and that the cysts evaluated are more atypical than those seen in routine clinical practice.

“We think CompCyst has the capacity to substantially reduce unnecessary surgeries for pancreatic cysts. Over the next five years, we hope to use CompCyst in many more patients with cysts in an effort to guide surgical treatment — to determine when surgery is needed and when it is not needed — and evaluate how well the test performs,” says Bert Vogelstein, M.D., Clayton Professor of Oncology, co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center and a Howard Hughes Medical Institute investigator.

Additional study coauthors include David Masica, Christopher Douville, Christopher Thoburn, Bahman Afsari, Lu Li, Joshua Cohen, Elizabeth Thompson, Jin He, Matthew Weiss, Richard Burkhart, Martin Makary, Marcia Canto, Michael Goggins, Janine Ptak, Lisa Dobbyn, Joy Schaefer, Natalie Silliman, Maria Popoli, Alison Klein, Cristian Tomasetti, Rachel Karchin, Nickolas Papadopoulos, Kenneth Kinzler and Ralph Hruban of Johns Hopkins. Other investigators contributing to the study were from Memorial Sloan Kettering Cancer Center, New York; Indiana University School of Medicine, Indianapolis; Massachusetts General Hospital, Boston; University of Pittsburgh; Applied Research on Cancer-Net Research Centre and the University and Hospital Trust of Verona, Italy; Ospedale Sacro Cuore Don Calabria, Negrar, Italy; Asan Medical Center, Seoul, Korea; Seoul National University College of Medicine; St. Vincent’s University Hospital, Dublin; IRCCS San Raffaele Scientific Institute, Milan, Italy; Hospital Curry Cabral, Lisbon, Portugal; University of Colorado, Aurora; Stanford University Medical Center, Palo Alto, Calif.; National Cancer Center Hospital and National Cancer Center Research Institute, Tokyo; Aichi Cancer Center Hospital, Nagoya, Japan; and Amsterdam Medical Center.

The work was supported by the Lustgarten Foundation — Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, the Sol Goldman Pancreatic Cancer Research Center, the Rolfe Pancreatic Cancer Foundation, the Benjamin Baker Scholarship and National Institutes of Health grants P50-CA062924, CA176828 and CA 210170.

Papadopoulos, Kinzler and Vogelstein are founders of Personal Genome Diagnostics and Thrive Earlier Detection Corp. Vogelstein is a member of the scientific advisory boards of Eisai-Morphotek, Sysmex Inostics, Nexus Strategy (Camden Partners), NeoPhore and CAGE. Some of these companies, as well as others, have licensed technologies from Johns Hopkins, and Papadopoulos, Kinzler, Lennon, Springer, Douville, Dal Molin and Vogelstein may receive equity or royalties from these licenses. The terms of these arrangements are managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Technology Transfer

Loose RNA Molecules Rejuvenate Skin, Researchers Discover

Loose RNA Molecules Rejuvenate Skin, Researchers Discover

July 26, 2019

The following was originally published in Johns Hopkins Medicine’s Newsroom.

Want to smooth out your wrinkles, erase scars and sunspots, and look years younger? Millions of Americans a year turn to lasers and prescription drugs to rejuvenate their skin, but exactly how that rejuvenation works has never been fully explained. Now, Johns Hopkins researchers have discovered that laser treatments and the drug retinoic acid share a common molecular pathway. Moreover, that pathway — which lets skin cells sense loose RNA molecules — is also turned up in mice when they regenerate hair follicles. Results are described in the June 26 issue of Nature Communications.

“Understanding the biology behind how cellular damage can lead to this type of regeneration can harness a new generation of therapeutics,” says Luis Garza, M.D., Ph.D., associate professor of dermatology at the Johns Hopkins University School of Medicine.

Technologies related to the discovery are available for licensing through Johns Hopkins Technology Ventures.

(Getty Images)

Researchers have known for decades that mice — unlike humans — can regenerate hair follicles after a deep wound. Recent studies by Garza and others found that loose pieces of RNA, called self-noncoding double-stranded RNA (dsRNA) can spur this regeneration. They hypothesize that this may be because dsRNA is released by damaged cells at the site of a wound. Garza and his colleagues were curious whether dsRNA also played a role in skin rejuvenation treatments such as laser therapy, microneedling and facial abrasion, which all involve temporary damage to skin cells. Although these treatments are well-established among dermatologists, researchers haven’t been clear why they work. The team collected biopsies from 17 patients being treated at The Johns Hopkins Hospital with conventional laser skin rejuvenation to electively erase sunspots and wrinkles. All patients were Caucasian women with an average age of 55, and treatments were performed on their faces and arms. Skin biopsies were collected before the laser treatment and one week after the procedure.

Garza and his colleagues analyzed the expression levels of genes in each sample and discovered that genes involved in sensing dsRNA as well as genes involved in producing the skin’s natural retinoic acid were all expressed at higher levels after the laser treatment. Next, the researchers treated isolated human skin cells with loose dsRNA — mimicking the effect of the laser treatment. The amount of retinoic acid inside the cells increased by more than tenfold. Commercially produced retinoic acid is already used to treat acne, wrinkles and sunspots.

“It’s not an accident that laser rejuvenation and retinoic acid have both been successful treatments for premature aging of the skin from sun damage and other forms of exposure,” says Garza. “They’re actually working in the same molecular pathways and nobody knew that until now.”

To further strengthen and understand the connection, the researchers turned back to mice. They knew that in both mice and humans, a protein called toll-like receptor 3 (TLR3) senses dsRNA. When Garza’s group engineered mice to lack TLR3, the animals could no longer regenerate hair follicles after a wound. But when the researchers gave these mice retinoic acid, they regained the ability to regenerate the follicles. The results point toward a pathway involving TLR3 that senses double-stranded RNA and turns up the synthesis of retinoic acid.

“In retrospect, it makes a lot of sense because retinoic acid is already a mainstay of wrinkle reduction and nobody knew what turned it on,” says Garza. “Now we know that damage leads to dsRNA, which leads to TLR3 activation and retinoic acid synthesis.”

The findings could lead to novel strategies to reduce wrinkles and sunspots by combining retinoic acid and laser treatments in new ways, Garza says. And they could also lead to ways to regenerate hair follicles, as mice do when there’s an increase in dsRNA after a wound.

“After a burn, humans don’t regenerate structures like hair follicles and sweat glands that used to be there,” says Garza. “It’s possible in light of these new findings that double-stranded RNA may be able to improve the appearance of burn scars.”

In addition to Luis Garza, other authors on the Nature Communications paper are Dongwon Kim, Ruosi Chen, Mary Sheu, Noori Kim, Sooah Kim, Nasif Islam, Eric M. Wier, Gaofeng Wang, Ang Li, Angela Park, Wooyang Son, Benjamin Evans, Victoria Yu, Vicky P. Prizmic, Eugene Oh, Zixiao Wang, Nathan K. Archer, Nashay Clemetson, Anna Chien, Ginette A. Okoye, Lloyd S. Miller, Gabriel Ghiaur and Sewon Kang of the Johns Hopkins University School of Medicine; Zhiqi Hu of Nanfang Hospital of Southern Medical University; Jace W. Jones, Maureen A. Kane, Jianshi Yu and Weiliang Huang of University of Maryland; and Amanda M. Nelson of The Pennsylvania State University.

The work and researchers involved were supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR064297 and AR068280), the Department of Defense (AFIRM2-ER11 and CDMRPR W81XWH-16-C-0167), Northrup Grumman Electronic Systems, Maryland Stem Cell Research Fund (2017-MSCRFF-3905), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD077260), and the University of Maryland School of Pharmacy Mass Spectrometry Center (SOP1841-IQB2014).

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