Hybrid PET and MRI imaging on the horizon: Shows promise for the detection of cancerous tumors

ScienceDaily (June 6, 2011) — Preliminary research presented at SNM's 58th Annual Meeting is breaking new ground for the development of a brand new hybrid molecular imaging system. Simultaneous positron emission tomography (PET) and magnetic resonance imaging (MRI) is providing important diagnostic information about soft tissues and physiological functions throughout the body. Scans focused on screening suspicious lesions for cancer are already comparable to more conventional molecular imaging methods. Further research could lead to the clinical use of PET/MRI as an additional tool for detecting cancer and other diseases.

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"Combining MRI technology with PET in a single integrated system adds the advantages of the extremely broad spectrum of diagnostic MRI procedures to the arsenal of available PET procedures," said Alexander Drzezga, MD, TU Muenchen, Munich, Germany, lead author of the study. "This could potentially result in the development of new imaging agents that bring together specific diagnostic strengths of PET and MRI. It offers exciting scientific options to image physiologic and pathophysiologic processes at the same time and to improve our understanding of both. This and further studies could potentially open a whole new hybrid imaging discipline within the field of nuclear medicine."

The most commonly used hybrid molecular imaging technology is the PET/CT system. MRI shows some advantages for combination with PET when compared to computed tomography (CT), which uses X-ray technology to capture structural information but it is not as sensitive as MRI data in terms of soft tissue contrast. CT images of certain areas of the body -- including the brain, head and neck, and pelvis -- provide restricted resolution of anatomical structures. MRI technology is excellent for imaging these complex areas of soft tissue and may provide answers to unresolved musculoskeletal questions. In combination with PET, MRI may also have value for imaging liver and breast tissues and would provide a useful tool for imaging children due to its reduced radiation dose.

Simultaneous PET and MRI imaging has been a tricky business, as the magnetic field of MRI technology has limited PET imaging in the past, specifically the photomultipliers needed for data acquisition. Previous prototypes have been simply side-by-side designs or were solely for imaging the brain. The advent of "avalanche photodiodes" and their introduction to the new, fully integrated and whole-body PET/MRI prototype used in the current study is a leap forward for this technology. A number of these integrated scanners are available for research purposes worldwide. It is speculated that these systems will grow rapidly in number if clear clinical benefit continues to be demonstrated.

For this study, eleven patients with cancer diagnoses underwent dual-imaging single-injection PET/CT imaging followed by PET/MRI imaging. Simultaneous PET/MRI acquisition was feasible and offered good-quality PET and MRI diagnostic data. Tracer-uptake was similar in relation to lung, liver, spleen and bone scanning, all acquired within a short examination timeframe. Results already indicate that combined PET/MRI shows comparable performance in the detection, diagnosis and allocation of suspected tumors in patients with oncological diagnoses as compared to conventional PET/CT.

The next step for PET/MRI is studying the added benefit of introducing sophisticated MRI sequences to the diagnostic imaging protocol. This and other related studies may lead to the establishment of hybrid PET/MRI imaging as a new diagnostic imaging system similar to PET/CT for its effectiveness and ability to provide a wealth of both functional and anatomical information about the body.

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New molecular imaging agent targets cornerstone of cancerous tumors

ScienceDaily (June 13, 2011) — A study introduced at SNM's 58th Annual Meeting may lead to the next wave of cancer imaging by helping to develop a molecular imaging agent that detects many malignant cancers' incessant development of blood vessels -- a process called angiogenesis. A protein biomarker known as CD105 has been shown to indicate tumor angiogenesis in cancer patients.

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"Non-invasive molecular imaging is a critical component of 21st century personalized medicine, and one of the hallmarks of cancer is angiogenesis," says Weibo Cai, PhD, assistant professor of radiology, medical physics and biomedical engineering at the University of Wisconsin-Madison's School of Medicine and Public Health. "CD105 is considered by many to be the best biomarker for evaluating tumor angiogenesis. Non-invasive imaging of this protein's expression could potentially play a variety of roles in the future of cancer patient management. CD105-targeted imaging agents also represent a new paradigm for the assessment of cancer therapies that target tumor angiogenesis. Applications for this agent could reach far beyond cancer and open many new avenues for future research."

Malignant cancers are defined by their ability to grow like weeds, forming fast and strong networks of blood vessels that carry oxygen and nutrients to the cancer's insatiable cellular structure. Endoglin, or CD105, is a naturally occurring protein that resides on the cell's surface. Above-normal expression of this protein is associated with poor cancer prognosis in more than 10 solid tumor types. The clinical standard for evaluating tumor angiogenesis is microvessel density (MVD) analysis, which is conducted by staining CD105 in tumor tissues that have been obtained by either surgical removal or biopsy. This study represents the first of its kind to report preliminary data on the non-invasive imaging of CD105 expression with positron emission tomography (PET), which provides a reliable measure of angiogenesis in the tumor.

Researchers used the medical isotope Copper-64 (64Cu) to label an antibody called TRC105, which binds to CD105. The full name of the agent is (64)Cu-DOTA-TRC105. The TRC105 antibody is currently being studied in a U.S. multicenter phase 1 human trial and multiple phase 2 therapy trials are planned or already underway for a range of cancer types. The current study specifically marks the effectiveness of using 64Cu-DOTA-TRC105 to gauge tumor angiogenesis. Results of the study showed this PET imaging agent to be highly effective, with rapid and persistent CD105-targeted uptake by tumors in mice.

Not only could this potentially be a turning point for cancer imaging and therapy, but some other major causes of death like heart attack, stroke and atherosclerosis also actively demonstrate the over-expression of CD105. Molecular imaging of this protein could one day lead to expanded tools for the detection and treatment of any number of diseases characterized by enhanced angiogenesis.

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Cancer protein discovery may aid radiation therapy: Blocking cyclin D1 might help sensitize tumors to radiation

ScienceDaily (June 9, 2011) — Scientists at Dana-Farber Cancer Institute have uncovered a new role for a key cancer protein, a finding that could pave the way for more-effective radiation treatment of a variety of tumors.

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Many cancers are driven in part by elevated levels of cyclin D1, which allow the cells to escape growth controls and proliferate abnormally. In the new research, reported in the June 9 issue of Nature, researchers discovered that cyclin D1 also helps cancer cells to quickly repair DNA damage caused by radiation treatments, making the tumors resistant to the therapy.

Based on this finding, the researchers made cancer cells more sensitive to several cancer drugs and to radiation by using a molecular tool to lower the cancer cells' cyclin D1 levels, said Peter Sicinski, MD, PhD, senior author of the report and a professor of genetics at Dana-Farber.

"This is the first time a cell cycle protein has been shown to be directly involved in DNA repair," said Siwanon Jirawatnotai, PhD, the lead author of the paper. "If we could come up with a strategy to inhibit cyclin D1, it might be very useful in treating a variety of cancers."

The gene for cyclin D1 is the second most-overexpressed gene found in human cancers, including breast cancer, colon cancer, lymphoma, melanoma, and prostate cancer. Cyclin D1's normal function in cellular growth control is to temporarily remove a molecular brake, allowing the cell to manufacture more DNA in preparation for cell division. When cyclin D1 is mutated or is overactivated by external growth signals, the cell may run out of control and proliferate in a malignant fashion.

The findings came in a series of experiments by Jirawatnotai, a post-doctoral fellow in the Sicinski lab. With the goal of uncovering details of cyclin D1's function in human cancer cells, Jirawatnotai broke open four types of cancer cells, isolated the cyclin D1 protein, and searched for other proteins with which it interacted.

The experiment netted more than 132 partner proteins, most of them part of the cell cycle protein mechanism in which cyclin D1 is a major player. But unexpectedly, the scientists also observed that the cyclin D1 protein was binding to a cluster of DNA repair proteins, most importantly RAD51. The RAD51 protein is an enzyme that rushes to broken parts of the cancer cell's DNA instructions and repairs the damage, including damage caused by radiation therapy administered to stop cancer cells' division and growth. In another experiment, it was observed that cyclin D1 was recruited along with RAD51 to the DNA damage site.

"This was a surprise," said Jirawatnotai. "This finding showed that cyclin D1 has an unexpected function in repairing broken DNA." In additional experiments, he used a molecular tool, RNA interference (RNAi) to drastically reduce the level of cyclin D1 in the cancer cells. "When you lower D1 levels, you get poorer repair," he said.

When cancer cells with reduced cyclin D1 protein levels were administered to mice, the resulting tumor proved to be more sensitive to radiation than those grown from cells with overexpressed cyclin D1.

Currently, cyclin D1 is thought to be responsible for driving cancer cell proliferation. Agents that target cyclin D1 are currently in clinical trials, with the goal of reducing cancer cell growth. The new findings strongly suggest that targeting cyclin D1 may increase susceptibility of human cancers to radiation, said the scientists, and this discovery may encourage targeting cyclin D1 even in these cancers whose cells do not depend on cyclin D1 for proliferation.

"Our results potentially change the way we think about cyclin D1 and cancer and may encourage targeting cyclin D1 in a very large pool of human cancers which do not need cyclin D1 for proliferation, but may still depend on cyclin D1 for DNA repair," said Jirawatnotai, who also holds a faculty position at the Mahidol University in Bangkok, Thailand.

In addition to Sicinski and Jirawatnotai, the paper's other authors include Wojciech Michowski, PhD, Yiduo Hu, PhD, Lisa Becks, Yaoyu Wang, PhD, John Quackenbush, PhD, Mick Correll, and David Livingston, MD, Dana-Farber; and Steven Gygi, PhD, Harvard Medical School.

The research was supported by grants from the National Institutes of Health.

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Mushroom compound suppresses prostate tumors

ScienceDaily (May 24, 2011) — A mushroom used in Asia for its medicinal benefits has been found to be 100 per cent effective in suppressing prostate tumour development in mice during early trials, new Queensland University of Technology (QUT) research shows.

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The compound, polysaccharopeptide (PSP), which is extracted from the 'turkey tail' mushroom, was found to target prostate cancer stem cells and suppress tumour formation in mice, according to an article written by senior research fellow Dr Patrick Ling in the online journal PLoS ONE, published by the Public Library of Science.

Dr Ling, from the Australian Prostate Cancer Research Centre-Queensland and Institute for Biomedical Health & Innovation (IHBI) at QUT, said the results could be an important step towards fighting a disease that kills 3,000 Australian men a year.

"The findings are quite significant," Dr Ling said.

"What we wanted to demonstrate was whether that compound could stop the development of prostate tumours in the first place.

"In the past, other inhibitors tested in research trials have been shown to be up to 70 per cent effective, but we're seeing 100 per cent of this tumour prevented from developing with PSP.

"Importantly, we did not see any side effects from the treatment."

Dr Ling said conventional therapies were only effective in targeting certain cancer cells, not cancer stem cells, which initiated cancer and caused the disease to progress.

During the research trial, which was done in collaboration with The University of Hong Kong and Provital Pty Ltd, transgenic mice that developed prostate tumours were fed PSP for 20 weeks.

Dr Ling said no tumours were found in any of the mice fed PSP, whereas mice not given the treatment developed prostate tumours. He said the research suggested that PSP treatment could completely inhibit prostate tumour formation.

"Our findings support that PSP may be a potent preventative agent against prostate cancer, possibly through targeting of the prostate cancer stem cell population," he said.

He said PSP had been previously shown to possess anti-cancer properties, and 'turkey tail' mushrooms (known as Coriolus versicolor or Yun-zhi) had been widely used in Asia for medicinal benefits.

However, Dr Ling said it was the first time it had been demonstrated that PSP had anti-cancer stem cell effects.

Although 'turkey tail' mushrooms had valuable health properties, Dr Ling said it would not be possible to get the same benefit his research showed from simply eating them.

A fundraiser has been organised in September to support further tests for the therapeutic potential of PSP against prostate tumours either alone or in combination with other anti-cancer compounds.

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Surgeon caseload, practice setting affect treatment of small kidney tumors

ScienceDaily (May 14, 2011) — Patients with small kidney tumors are more likely to be offered treatment options based on surgeons' case volume and type of practice than on tumor characteristics, a Mayo Clinic study has found. Fellowship-trained surgeons who practice in academic medical centers with high volumes of patients with kidney tumors were 70 to 80 percent more likely to follow American Urological Association (AUA) guidelines by recommending partial nephrectomy. Surgeons in private practice who see few patients with kidney tumors more often offered radical nephrectomy: removal of the entire kidney.

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Mayo Clinic researchers presented their findings during the AUA Annual Meeting in Washington.

"There is wide variability in how renal masses are managed. We must recognize these discrepancies may be due to different perceptions of technical feasibility in performing a partial nephrectomy," says Christopher Weight, M.D., of Mayo Clinic's Department of Urology. "What we're encouraging is a discussion between physicians and patients about all options available. Some patients may benefit from a referral to surgeons with more experience with renal tumors."

The study shows that as kidney tumors get larger and more complex, all surgeons tend to offer a radical nephrectomy. However, the tumor complexity that may result in one surgeon recommending total removal of the kidney may be well below a more experienced surgeon's threshold. Approximately 45,000 Americans require radical or partial nephrectomy each year.

Other study investigators include Simon Kim, M.D., Christine Lohse, Stephen Boorjian, M.D., R. Houston Thompson, M.D., and Bradley Leibovich, M.D., all of Mayo Clinic; and Rodney Breau, M.D., and Paul Cripsen, M.D., formerly of Mayo Clinic.

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Recurring cancers in women with a history of breast cancer differ from the original tumors

ScienceDaily (May 18, 2011) — When women with a history of breast cancer learn they have breast cancer again, one of the first questions they and their doctors ask is: Has my cancer come back, or is this a new case? Now, new data from Fox Chase Cancer Center suggest that both new and recurring cancers will differ significantly from the original tumors, regardless of how many months or years women spent cancer-free, and doctors should tailor treatment to the specific qualities of the second tumor, regardless of whether it's old or new.

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Anita Patt, MD, surgical oncology fellow at Fox Chase and lead author on the study, will be presenting the findings at the 2011 Annual Meeting of the American Society of Clinical Oncology on Monday, June 6.

"There tends to be a stigma and a lot of anxiety about the word 'recurrence,'" says Richard J. Bleicher, MD, FACS, attending surgeon at Fox Chase and senior author on the study. "Sometimes women will worry more if they believe their original cancer is back, meaning they didn't 'beat it' the first time around. These findings suggest they should not get hung up on that idea, because any subsequent diagnosis -- whether it's a recurrence or a new tumor -- will look significantly different from their first cancer."

In women with a history of breast cancer, doctors often approach new tumors differently depending on whether they believe it's a recurrence of the first tumor, or a totally new one, Bleicher explains. But there are no official ways to distinguish between the two types, so doctors typically rely on a few criteria, then form their own opinion based on an "overall gestalt," he says.

One of the criteria doctors have used to distinguish between new and recurring cancers is the amount of time women spent cancer-free, reasoning that the longer the time between the two tumors, the more likely the second one is to be an entirely new case.

To investigate if this and other criteria indeed distinguish new and recurring tumors, Bleicher, Patt, and their colleagues looked at data collected from 4,420 women with a history of breast cancer. Two-hundred and thirty five women were eventually diagnosed with another tumor in the same breast, suggesting it could be a recurrence.

However, when the researchers compared the first and second tumors, they saw that 89% differed in at least one key characteristic that could potentially affect treatment or prognosis, regardless of whether the second tumors were new cases or a recurrence of the original cancer. Sixty percent of the second tumors differed from the first by at least 2 or more criteria, including whether or not it would respond to hormones, how it was diagnosed, and whether at least 25 percent of the tumor was confined to the ducts, and therefore less able to spread throughout the body.

Half of the women experienced a second tumor within 60.5 months of their first. And, importantly, the amount of time they spent cancer-free appeared to have no bearing on whether the two tumors differed in any key characteristics.

The findings suggest that patients and doctors shouldn't spend much time determining if the second tumor is a recurrence of the first, or a totally new entity, says Bleicher, and should instead tailor treatment to the specific qualities of the second tumor, regardless of whether it's old or new.

"When a patient comes back with a relapse, whether it's a new tumor or a recurrence, it really doesn't make a difference," he says. "We treat them both as potentially curable."

Co-authors on the study include Tianyu Li, Massimo Cristofanilli, and Elin Sigurdson, from Fox Chase and Gary Freedman from the Hospital of the University of Pennsylvania.

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Results of international Phase III clinical trial for newly diagnosed brain tumors announced

ScienceDaily (May 18, 2011) — RTOG reports on the largest trial to-date for patients with newly diagnosed glioblastoma demonstrating the importance and feasibility of prospective molecular analysis of tumor tissue although finding that patients received no additional benefit from dose-intensive temozolomide as compared to standard adjuvant temozolomide after combined temozolomide and radiotherapy. The integration of tumor analysis with the clinical trial and international collaboration, major components of this unprecedented study, will significantly impact future trial design, ultimately leading to advances in patient care.

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In the randomized trial, RTOG 0525 Phase III Trial Comparing Conventional Adjuvant Temozolomide with Dose-Intensive Temozolomide in Patients with Newly Diagnosed Glioblastoma, no significant improvement in overall patient survival or disease progression was observed for patients who received the dose-intensive (dose-dense) TMZ plus radiotherapy as compared to patients who received standard-dose TMZ plus radiotherapy. The trial did however prove the feasibility of collecting and analyzing tumor tissue prospectively in a multi-center setting.. The international trial was led by RTOG principal investigator Mark R. Gilbert, MD (University of Texas M. D. Anderson Cancer Center, Houston) and conducted in concert with the European Organization for Research and Treatment of Cancer (EORTC) and the North Central Cancer Treatment Group (NCCTG).

Four presentations will report study results at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, June 3-7.

"Given the promising preliminary data of improved patient outcomes using an adjuvant dose-intensive schedule of temozolomide, the trial allowed us to robustly test whether this treatment strategy provides a significant benefit over standard-dose temozolomide treatment," says Gilbert. "While dose-dense temozolomide did not demonstrate improved efficacy for patients newly diagnosed with a glioblastoma, the study results confirmed the prognostic significance of MGMT gene methylation and demonstrated the feasibility of prospective tumor tissue collection, molecular stratification and collection of patient outcomes in a large transatlantic intergroup trial."

One hundred and eighty-five facilities in North America and 24 facilities in Europe enrolled 1173 study participants. Key study eligibility criteria required that tumor tissue, obtained at the time of biopsy or surgery and with patient consent, be sent for central pathology review to confirm the tumor as a glioblastoma and as adequate to perform MGMT gene methylation analysis and molecular risk classification (to assess whether a correlation exists between these biomarkers and study participant outcomes).

Upon pathology confirmation, eligible patients were enrolled in the trial and randomized into one of two adjuvant treatment arms: Arm 1 (standard arm: TMZ days 1-5 every 28 days for up to 12 cycles/months) or Arm 2 (experimental arm: TMZ days 1-21 every 28 days for up to 12 cycles/months).

Study participants were stratified to assess correlation of their outcome with three major criteria: (1) prognostic recursive partitioning (based upon age, performance status, extent of pretreatment surgery, neurologic function and mental status), (2) MGMT status (methylated, unmethylated, or indeterminate) and (3) radiation therapy treatment (US standard vs European).

Trial co-chair for neuropathology and correlative biology Kenneth D. Aldape, MD (M.D. Anderson Cancer Center, Houston), comments, "In this trial we've demonstrated the positive correlation between clinical outcomes and molecular classification of glioblastoma, which will enable improved future prognostic prediction, spur the development of specific therapies based on tumor biology, and ultimately lead to individualization of treatment." Aldape will present findings of the tumor tissue profiling at the 2011 ASCO Annual Meeting.

"This trial was a tremendous undertaking with the complexities of confirming the presence of the MGMT gene as an eligibility criteria -- the first time a molecular marker has been used in this manner -- and of conducting the trial internationally," says RTOG Group Chair Walter J. Curran, MD, FACR,(Winship Cancer Institute of Emory University, Atlanta). "The collaboration with EORTC and NCCTG significantly helped to expedite trial enrollment and consequentially to expediently report trial results."

The clinical trial also included longitudinal data collection to measure neurocognitive function, symptom burden and health-related quality of life, collectively called net clinical benefits. The important correlations of these measures with outcomes shown by the trial will also be reported at the ASCO meeting, along with seven presentations regarding other RTOG trials.

RTOG 0525 was supported by Award Number U10CA021661 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. RTOG also received support from Merck to conduct this trial.

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