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Under Our Nose: Supplemental Oxygen Can Make Tumors Shrink, Says New Study

PITTSBURGH, March 4, 2015 – A method of profoundly enhancing some cancer treatments could be right under our noses. A study co-authored by a University of Pittsburgh researcher has shown in an animal model that breathing air with a higher than usual concentration of oxygen can alter certain metabolic pathways to allow chemotherapy and immunotherapy to shrink tumors more effectively.

The blood supply of a tumor often does not match the pace of the cancer’s growth, which leads to areas that are ischemic, or oxygen deprived, explained Edwin Jackson, Ph.D., professor of pharmacology and chemical biology, Pitt School of Medicine, and a co-author of a paper published online today in Science Translational Medicine. That causes the tumor cells to make adenosine, a molecule that not only promotes blood flow, but also binds to a receptor on killer T-cells and essentially puts them to sleep. In effect, adenosine acts as a shield against immune system cells that would otherwise attack the cancer.

“We realized if we could find a way to block the increase in adenosine, we might be able to help the immune system respond to the tumor to make anti-cancer therapies more effective,” Dr. Jackson said. “This study shows that simply breathing more oxygen can accomplish that aim, which could lead to an amazing breakthrough in cancer treatment.”

The study team, led by Michail Sitkovsky, Ph.D., director of the New England Inflammation and Tissue Protection Institute at Northeastern University, exposed mice with lung tumors to respiratory hyperoxia at levels of 40 to 60 percent oxygen, comparable to what patients might receive in the hospital. Another group of mice breathed air, which is approximately 21 percent oxygen. Tumors in mice that received supplemental oxygen shrank – some regressed completely – and the animals were more likely to survive than those on room air.

“Supplemental oxygen prevented the tumor from making extra adenosine, so the immune cells could do their job and attack the cancer cells,” Dr. Sitkovsky explained. “But if anti-tumor immune cells aren’t present, oxygen has no effect. We hope we will soon see clinical trials of respiratory hyperoxia in combination with immunotherapies to see whether it can help cancer patients.”

He noted also the effects might be stronger in combination with an agent that he calls “super-caffeine,” which blocks the receptor where adenosine binds to inhibit the immune cells.

For Dr. Jackson, whose lab is thought to be the world’s best in the measurement of adenosine and its metabolites, the breakthrough research is personally deeply rewarding. Fourteen years ago, his older brother, James F. Jackson, died at 57 of renal cell carcinoma. In 1986, Mr. Jackson received the National Science Foundation Presidential Award for Excellence in Science Teaching from Vice President George H.W. Bush.

“Jim was my childhood mentor and the reason I am a scientist today. His three years of treatment was an emotional and frustrating time for me because we didn’t have the right tools to help him,” Dr. Jackson said. “I started doing cancer research because of that experience, and I hope these results will one day prevent suffering and loss by countless other families.”

Other study investigators included researchers from the Dana Farber Cancer Institute, Harvard Medical School and the University of Miami. The project was funded by National Institutes of Health grants CA 112561, CA 111985, AT 002788, and AI 091693; National Cancer Institute grant 5PO1CA109094-03; and Northeastern University.

UPMC CancerCenter First in World to Treat Patient with New Cyberknife MLC that Shapes Radiation to Tumor, Decreases Treatment Time

PITTSBURGH, March 2, 2015UPMC CancerCenter last week became the first center in the world to treat a patient with the CyberKnife® M6™ System’s new multileaf collimator, which enables precise shaping of radiation beams to any irregularly shaped tumor, sparing healthy surrounding tissues and reducing the time patients must undergo treatments.

The CyberKnife® M6™ System with the InCise™ Multileaf Collimator (MLC) was used for the first time on Feb. 26 on a 56-year-old western Pennsylvania woman being treated for a benign brain tumor. UPMC CancerCenter was one of the InCise MLC evaluation sites working in collaboration with Accuray, the device’s manufacturer. The patient’s treatment lasted 22 minutes, about half of the time treatment would have taken without the use of advanced software and novel technologies, said Dwight E. Heron, M.D., FACRO, FACR, director of Radiation Services at UPMC CancerCenter, a partner with the University of Pittsburgh Cancer Institute.

This new technology will be especially useful for tumors in the body that are hard to reach or tend to move, he said. The treatment was administered as a multidisciplinary effort between Steven Burton, M.D., from the department of Radiation Oncology and Johnathan Engh, M.D., from the department of Neurosurgery.

“Our patient was diagnosed with a brain meningioma and was a good candidate for the highly-focused treatment that can be delivered by the CyberKnife,” said Dr. Heron, who oversees the largest system in the U.S. accredited by the American College of Radiation Oncology. “With the addition of the MLC, we were able to precisely target the tumor and spare healthy tissue, and it took us significantly less time to do it. This real-world case is consistent with our InCise MLC technical evaluation experience and exceeded our expectations in its efficiency.”

The M6 Series delivers radiosurgery and stereotactic body radiation therapy, enabling precise, high-quality dose distributions to be administered to patients with extreme accuracy over a minimum number of treatments, reducing side effects and preserving patients’ quality of life. The system is able to adjust and automatically stay on target in real-time, accounting for patient and tumor motion. CyberKnife is the only robotic radiosurgery system available today that delivers such high-precision treatments throughout the body.

“We congratulate Dr. Heron, Dr. Saiful Huq and their team on treating the first patient using the CyberKnife M6 System and InCise MLC,” said Joshua H. Levine, president and chief executive officer of Accuray. “With the addition of the MLC, clinicians can deliver the same precise radiosurgery treatments they have come to expect with the CyberKnife System for a wider range of tumor types, including larger and different kinds of tumors than were previously treated.”

UPMC Whitfield Cancer Centre Receives Joint Commission International Accreditation for 3rd Time; Meets Highest Standards of Safety and Quality

PITTSBURGH, Feb. 19, 2015 – For the third time since 2008, the UPMC Whitfield Cancer Centre, operated by UPMC in Waterford, Ireland, has successfully achieved accreditation from the Joint Commission International (JCI). This recognition is based on an extensive review of the center’s patient safety and quality standards and processes.

The JCI is the recognized leader in international health care accreditation and is considered the gold standard in global health care. Its accreditation process focuses on determining whether a health care facility has the right systems and processes in place to support high-quality and safe patient care, and has the culture and capacity to continuously improve care. JCI’s surveyors examine crucial issues such as patient and family education, access to care and medication management. The process requires hospitals to demonstrate a track record of standards compliance and relies on candid interviews with patients, nurses and physicians about care practices.

“The success of this, our third, accreditation survey reflects the ongoing efforts of the whole Cancer Centre team and their dedication to continuing to provide a quality service to all cancer patients in the southeast region,” said Catriona McDonald, director of operations and radiotherapy services manager.

“Demonstrating compliance with JCI standards serves as validation of an organization’s commitment to an internationally recognized, time-tested and comprehensive level of quality,” explained Cheryl Brill, UPMC’s vice president of international clinical operations and quality. “This outstanding result is a testament to the UPMC Whitfield Cancer Centre staff and to their commitment to excellence in the treatment of patients.”

UPMC Whitfield Cancer Centre offers the most advanced radiation therapy, including intensity-modulated radiation therapy and image-guided radiation therapy, to residents of the southeast region of Ireland. One of only four ambulatory care centers to be JCI-accredited in Ireland, the center is committed to delivering the highest standard of radiation therapy and supportive care for patients with all types of cancer.

Established to respond to a growing demand around the world for standards-based evaluation of quality in health care, JCI today accredits or certifies more than 700 health care organizations and clinical care programs in over 100 countries. JCI is the international arm of the Joint Commission, which has worked for more than 50 years to improve the quality and safety of health care services. As the largest accreditor of health care organizations in the United States, the Joint Commission accredits and certifies more than 20,500 health care organizations through a voluntary process and is recognized as a leader in all aspects of safe, high-quality care.

Statins Inhibit Spread of Some Cancers in Laboratory Tests

PITTSBURGH, January 15, 2015 – Cholesterol-lowering drugs appear to be a promising, cost-effective way to reduce the risk of metastases in some cancers, according to laboratory research led by the University of Pittsburgh School of Medicine. Metastases, rather than the original tumor, are what usually kill people with cancer.

The discovery, published in the open-access journal Scientific Reports, part of the Nature Publishing Group, reveals the mechanism by which statins may impede the process that cancerous tumor cells need in order to split off from the primary tumor and cause cancer elsewhere in the body.

“We didn’t plan to discover this – we were actually modeling metabolism of tumor cells and looking at the response of various tumor cells to existing drugs, including statins,” said senior author Zoltán Oltvai, M.D., associate professor of pathology at Pitt. “But, sure enough, we were able to show that these cholesterol-lowering drugs interrupt the growth of some cancer cell lines that are very similar to those cancer cells that leave the primary tumor and eventually colonize other organs.”

When a tumor metastasizes, it spreads cancer cells through the body using the blood stream. The cells then come to rest at another site in the body, eventually forming new tumors. Sometimes these cells lie dormant, and a person can appear cancer-free after the primary tumor is removed, only to have his or her cancer reappear years later in another organ.

Scientists have known for several years that statins sometimes seem to fight cancer; however, the mechanism wasn’t clear, and previous clinical trials have yielded mixed results regarding statins as anti-cancer drugs.

Cancer cells require the synthesis of cholesterol and cholesterol precursor molecules to reprogram themselves from an adherent, or “epithelial” state, to a mobile, or “mesenchymal” state, in order to leave or “shed” from the primary tumor and recolonize elsewhere in the body. Statins, which are routinely used to lower lipid levels, could potentially block cancer cell spread by inhibiting an enzyme that catalyzes a key step in the cholesterol synthesis process, Dr. Oltvai said.

His team found that slower-growing, mesenchymal-like cancer cell lines that contain the protein vimentin inside the cell, but do not display the protein E-cadherin on their surface, are particularly sensitive to statins. Knowing this, doctors eventually may be able to test biopsies from cancerous tumors for these markers to determine if statins may be effective.

“While statins probably aren’t going to be effective against a patient’s primary tumor, they could work to block the tumor’s ability to metastasize,” said Dr. Oltvai. “And that is very important because most cancer patients die because of the metastases.”

Dr. Oltvai noted that coupling treatment of the primary tumor – which can involve chemotherapy, surgical removal of the tumor and radiation – with statins might be a way to prevent the primary tumor from shedding cells, and also prevent those cells from surviving their journey through the body or reactivating elsewhere in the body later on.

These are preliminary results, and people should not start taking statins as an anti-cancer drug, Dr. Oltvai stressed. His team tested the cancer cells’ reaction to statins in the laboratory, and the process could be different in the human body. The researchers are pursuing funding for additional studies on how exactly statins can interfere with the process that leads to metastases and whether combining statins with other drugs may be even more potent than using statins alone.

Additional researchers on this study are Katsuhiko Warita, Ph.D., Tomoko Warita, Ph.D., Colin Beckwitt, B.S., Mark Schurdak, Ph.D., and Alan Wells, M.D., D.M.S., all of Pitt; and Alexei Vazquez, Ph.D., of Rutgers Cancer Institute of New Jersey. Dr. Wells is also part of the Pittsburgh VA Health System, and Drs. Wells and Schurdak also are affiliated with the University of Pittsburgh Cancer Institute.

This research was supported by a U.S. Department of Veterans Affairs Merit grant, a National Center for Advancing Translational Sciences grant and a grant from the National Science Foundation.

Coupling Head and Neck Cancer Screening and Lung Cancer Scans Could Improve Early Detection, Survival

PITTSBURGH, January 5, 2015 – Adding head and neck cancer screenings to recommended lung cancer screenings would likely improve early detection and survival, according to a multidisciplinary team led by scientists affiliated with the University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter.

In an analysis published in the journal Cancer and funded by the National Institutes of Health (NIH), the team provides a rationale for a national clinical trial to assess the effectiveness of adding examination of the head and neck to lung cancer screening programs. People most at risk for lung cancer are also those most at risk for head and neck cancer.

“When caught early, the five-year survival rate for head and neck cancer is over 83 percent,” said senior author Brenda Diergaarde, Ph.D., assistant professor of epidemiology at Pitt’s Graduate School of Public Health and member of the UPCI. “However, the majority of cases are diagnosed later when survival rates generally shrink below 50 percent. There is a strong need to develop strategies that will result in identification of the cancer when it can still be successfully treated.”

Head and neck cancer is the world’s sixth-most common type of cancer. Worldwide every year, 600,000 people are diagnosed with it and about 350,000 die. Tobacco use and alcohol consumption are the major risk factors for developing the cancer.

The early symptoms are typically a lump or sore in the mouth or throat, trouble swallowing or a voice change, which are often brushed off as a cold or something that will heal. Treatment, particularly in later stages, can be disfiguring and can change the way a person talks or eats.

Dr. Diergaarde and her team analyzed the records of 3,587 people enrolled in the Pittsburgh Lung Screening Study (PLuSS), which consists of current and ex-smokers aged 50 and older, to see if they had a higher chance of developing head and neck cancer.

In the general U.S. population, fewer than 43 per 100,000 people would be expected to develop head and neck cancer annually among those 50 and older. Among the PLuSS participants, the rate was 71.4 cases annually per 100,000 people.

Recently, the U.S. Preventive Services Task Force, as well as the American Cancer Society and several other organizations, recommended annual screening for lung cancer with low-dose computed tomography in people 55 to 74 years old with a smoking history averaging at least a pack a day for a total of 30 years. The recommendation came after a national clinical trial showed that such screening reduces lung cancer mortality.

“Head and neck cancer is relatively rare, and screening the general population would be impractical,” said co-author David O. Wilson, M.D., M.P.H., associate director of UPMC’s Lung Cancer Center. “However, the patients at risk for lung cancer whom we would refer for the newly recommended annual screening are the same patients that our study shows also likely would benefit from regular head and neck cancer screenings. If such screening reduces mortality in these at-risk patients, that would be a convenient way to increase early detection and save lives.”

Dr. Diergaarde’s team is collaborating with otolaryngologists to design a national trial that would determine if regular head and neck cancer screenings for people referred for lung cancer screenings would indeed reduce mortality.

Additional researchers on this study are Ronak Dixit, Joel L. Weissfeld, M.D., M.P.H., Paula Balogh, D.N.P., F.N.P., Pamela Sufka and Jennifer R. Grandis, M.D., F.A.C.S., all of Pitt; and Jill M. Siegfried, Ph.D., of the University of Minnesota.

This research was funded by NIH grants P50 CA097190, P50 CA090440 and P30 CA047904.

Save the Date: Breast Symposium 2015

PITTSBURGH, Dec. 19, 2014 – Breast Symposium 2015: Updates in the Management of Breast Cancer/Breast Disease will be held at the Herberman Conference Center in Pittsburgh, Pa. on Friday, April 24, 2015.

This course is designed to cover the most recent advances in breast health screening and diagnosis including methods of detection, application of new technology, and benign disease and cancer management. Upon completion of the activity, participants should be able to:

  • Discuss the latest breast cancer methods of detection, treatment, surveillance, and research
  • Describe how these advances can be applied to their practice

Who Should Attend
This course is designed for physicians, nurses and other health care professionals practicing in the areas of Primary Care, Gynecology, Radiology, and General Surgery; recommended for any practitioner caring for women.

Location
UPMC Shadyside
Herberman Conference Center
5230 Centre Avenue
Pittsburgh, PA 15232

Course Co-Directors
Marguerite A. Bonaventura, MD
Associate Professor of Surgery
University of Pittsburgh School of Medicine

Gretchen M. Ahrendt, MD
Associate Professor of Surgery
University of Pittsburgh School of Medicine

This activity has been approved for AMA PRA Category 1 Credit.TM

Online registration will be available on the Upcoming Events page at the Center for Continuing Education in the Health Sciences.

Expert in Immune Responses in Stem Cell Transplantation Joins UPCI

PITTSBURGH, Dec. 17, 2014 – Warren Shlomchik, M.D., a leading expert in investigating the immunologic mechanisms underlying graft-versus-host-disease (GVHD), a common complication for some stem cell transplant patients, has been named director of stem cell transplantation and cell therapies for the University of Pittsburgh’s Division of Hematology-Oncology and University of Pittsburgh Cancer Institute (UPCI), a partner with UPMC CancerCenter, and UPCI’s scientific director of hematopoietic malignancies.

Dr. Shlomchik’s appointment is effective March 1, 2015. He will also serve as a professor of medicine and immunology at the University of Pittsburgh School of Medicine. He comes to Pittsburgh from Yale Cancer Center at the Yale University School of Medicine, where he had been on the senior faculty for 16 years.

“Warren’s work has been invaluable in helping researchers understand more about the mechanisms of GVHD. His main priorities here in Pittsburgh will be to continue to conduct innovative, ground-breaking lab-based science and to oversee the translation of that science into investigator-initiated clinical trials, which will be a huge advance for our transplant and hematopoietic malignancies clinical research program,” said Edward Chu, M.D., chief of the Division of Hematology/Oncology and deputy director of UPCI.

Dr. Shlomchik is a leading expert in GVHD, a well-established complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted donor cells attack the transplant recipient’s body. At Pitt, Dr. Shlomchik will continue his research on GVHD mechanisms as well as work to develop novel immunologic-based and cell therapy approaches to circumvent and/or overcome the development of GVHD.

“We’ve been very fortunate at UPCI this year to add several renowned researchers to our ranks, including Dr. Shlomchik,” said Nancy E. Davidson, M.D., director of UPCI and UPMC CancerCenter. “The decision of these researchers to come here shows that we are serious about the work we are doing to unravel the mysteries of cancer and take those findings directly to our patients.”

Dr. Shlomchik earned his bachelor of arts at Harvard University and his medical degree at the University of Pennsylvania. He completed his residency in internal medicine at New York Hospital/Cornell Medical Center and was a fellow at the University of Pennsylvania in hematology-oncology.

Newly-Identified Gene Mutation Could Help Explain How Breast Cancer Spreads

SAN ANTONIO, Dec. 9, 2014 – A newly-identified genetic mutation could increase our understanding of how breast cancer spreads and potentially guide treatment options for women with the disease, according to a study from Magee-Womens Research Institute (MWRI) and the University of Pittsburgh Cancer Institute (UPCI) presented today at the 2014 San Antonio Breast Cancer Symposium.

This research represents the most comprehensive analysis to date of genomic changes that occur in breast cancer progression and indicate the extensive changes that happen during the spread of the disease.

Researchers from MWRI and UPCI sequenced frozen breast tumor samples from six patients, beginning with the primary tumor when the cancer was first diagnosed through the progression of metastatic disease.  Using multiple sequencing techniques, the team identified a new gene created by two separate genes that fused together as a result of unstable DNA.  This fusion gene was identified in a metastatic tumor sample and is believed to play a part in the spread of the original breast cancer.

“We applied all of our sequencing technologies to the tumors in order to understand the changes that occur between the first breast cancer occurrence and late-stage disease,” said Ryan Hartmaier, a research instructor at the University of Pittsburgh and lead author of the study.

Since several types of breast cancer are fueled by the hormone estrogen, estrogen blocking treatment is often recommended to prevent the disease from spreading. However, the fusion gene identified did not  respond to estrogen blocking treatment, contributing to the breast cancer’s spread.

“This research helps us further understand the genomic landscape of metastatic breast cancer,” said Adrian Lee, Ph.D., the study’s senior author, director of the Women’s Cancer Research Center and professor of pharmacology, chemical biology and human genetics Pitt. “The new class of genetic changes identified take us another step further in personalized medicine and could change the way we treat certain patients if we are able to identify who will develop this genetic mutation.”

New Drug Therapy A Safe, Effective Option for Elderly Patients with Acute Myeloid Leukemia

PITTSBURGH, Dec. 8, 2014 – Seventy percent of elderly patients with acute myeloid leukemia (AML) who were treated with a combination of drugs aimed to make chemotherapy treatments effective and less toxic achieved remission or a slowing of disease progression, according to research at the University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter. The findings were presented Sunday at the 56th American Society of Hematology Annual Meeting in San Francisco.

The research is important because most elderly patients diagnosed with AML can’t tolerate the aggressive chemotherapy needed and tend to have more aggressive disease than younger patients, making prognosis poor. So researchers, led by UPCI’s Annie Im, M.D., an assistant professor of medicine in Pitt’s Division of Hematology/Oncology, examined whether an epigenetic strategy using the drugs decitabine followed by cytarabine would help make other treatments more tolerable by reactivating genes that had previously been silenced by the malignancy.

“Outcomes are really poor in elderly patients who have AML because the only therapies we have are often too toxic to offer as treatment options, and the unmet need for novel therapies is dire,” Dr. Im said. “But we have shown that using this therapy in this patient population is safe and effective.”

In the study, 23 patients were evaluated after receiving what’s called an induction therapy of decitabine intravenously for five days followed by a standard dose of cytarabine intravenously for five days. Fourteen patients had complete remission and five patients had a complete remission with delayed bone marrow recovery. All patients except for two received two cycles of induction.

Researchers believe the drugs work because they help reactivate genes that had been silenced by the malignancy. In addition, evidence suggests that epigenetic priming by decitabine enhances the efficacy of cytarabine. The next phase of the trial will examine overall survival and the rate of adverse events, and include epigenetic correlative studies.

NSAIDs Prevent Colon Cancer by Inducing Death of Intestinal Stem Cells That Have Gene Mutation

PITTSBURGH, Nov. 3, 2014 – Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against the development of colorectal cancer by inducing cell suicide pathways in intestinal stem cells that carry a certain mutated and dysfunctional gene, according to a new study led by researchers at the University of Pittsburgh Cancer Institute (UPCI) and the School of Medicine. The findings were published online today in the Proceedings of the National Academy of Sciences.

Scientists have long known from animal studies and clinical trials that use of NSAIDs, such as aspirin and ibuprofen, lowers the risk of developing intestinal polyps, which can transform into colon cancer. But they have not known why, said senior investigator Lin Zhang, Ph.D., associate professor, Department of Pharmacology and Chemical Biology, Pitt School of Medicine, and UPCI, a partner with UPMC CancerCenter.

“Our study identifies a biochemical mechanism that could explain how this preventive effect occurs,” he said. “These findings could help us design new drugs to prevent colorectal cancer, which is the third leading cause of cancer-related deaths in the country.”

The research team performed experiments in animal models and examined tumor samples from patients who had taken NSAIDs and those who hadn’t. They found that NSAIDs activate the so-called death receptor pathway, which selectively triggers a suicide program in intestinal stem cells that have a mutation in the APC gene that renders the cells dysfunctional. Healthy cells lack the mutation, so NSAIDs cause them no harm. In that manner, the drugs instigate the early auto-destruction of cells that could lead to precancerous polyps and tumors.

“We want to use our new understanding of this mechanism as a starting point to design better drugs and effective cancer prevention strategies for those at high risk of colon cancer,” Dr. Zhang said. “Ideally, we could harness the tumor-killing traits of NSAIDs and avoid possible side effects that can occur with their chronic use, such as gastrointestinal bleeding and ulcers.”

The research team included lead author Brian Leibowitz, Ph.D., and Jian Yu, Ph.D., of UPCI and the Pitt’s Department of Pathology, as well as others from UPCI and Pitt School of Medicine; Sichuan University, China; INCELL Corp, San Antonio, Texas; and Indiana University School of Medicine.

The project was funded by National Institutes of Health grants CA106348, CA121105, CA172136, CA129829 and DK085570, and the American Cancer Society.

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