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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Drug shows promise in prostate cancer spread to bone

ScienceDaily (June 8, 2011) — A new drug to treat prostate cancer shows early promise, particularly against tumors that have spread to the bone, a multi-site study shows.

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The drug Cabozantinib is designed to target mainly two important pathways linked to the growth and spread of prostate cancer. The drug had the most effect on tumors that had spread to the bone.

"Not only did three-quarters of bone scans have partial or complete resolution, but this was accompanied by improvement in bone pain and decreased need for narcotic use," says lead study author Maha Hussain, M.D., FACP, professor of internal medicine and urology and associate director of clinical research at the University of Michigan Comprehensive Cancer Center.

Hussain presented the findings at the American Society of Clinical Oncology annual meeting.

The trial enrolled 171 men with metastatic prostate cancer. In more than three-quarters of the men enrolled, cancer had spread to the bone.

Researchers found 76 percent of patients saw some or all of their tumor shrink on bone scans following treatment with Cabozantinib. In addition, among patients who were on narcotics due to bone pain, 67 percent reported less pain and 56 percent either stopped taking narcotics or reduced the dosage. In addition, more than two-thirds of patients had some tumor regressions in areas of spread outside the bone. The treatment effects lasted on average 29 weeks.

The study found moderate side effects from Cabozantinib, including fatigue, gastrointestinal symptoms and high blood pressure.

"What's interesting about this drug is it brings to the table something we haven't seen before. Dramatic improvements in bone scans are unprecedented in this disease. Despite measurable progress, current treatment options for advanced prostate cancer tend to be modest in effect, so adding to and improving these options is a high priority," Hussain says.

Hussain cautions that this is very early data, but it opens a new door for further investigation. The manufacturer, Exelixis, has developed a randomized clinical trial that is currently open at the U-M Comprehensive Cancer Center and other locations. For information, call the U-M Cancer AnswerLine at 800-865-1125.

U-M researchers are also planning a clinical trial with this drug in patients with metastatic prostate cancer who have had no previous chemotherapy. Laboratory research at the University of Michigan will look to better understand Cabozantinib's effects on the bone. Cabozantinib is not approved by the U.S. Food and Drug Administration.

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Cancer drug holds promise as first treatment for common, inherited dementia

ScienceDaily (June 1, 2011) — A drug already approved for people with cancer shows early potential as a therapy for a common form of dementia, UT Southwestern Medical Center researchers report.

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"Suberoylanilide hydroxamic acid (SAHA) holds promise as a first-generation drug for the prevention and treatment of familial frontotemporal dementia (FTD), a progressive, inherited neurodegenerative disease for which there is no treatment," said Dr. Joachim Herz, director of the Center for Alzheimer's and Neurodegenerative Diseases and the study's senior author.

"SAHA is already approved for clinical use in an unrelated condition, which should make it easier to move quickly to human trials," added Dr. Herz, professor of molecular genetics and neuroscience at UT Southwestern.

FTD -- usually diagnosed around age 60 -- trails only Alzheimer's disease among non-elderly dementias. The as-yet untreatable condition is marked by a progressive deterioration in decision-making ability, behavioral control and/or language skills.

In a study available online and in the current issue of the Journal of Biological Chemistry, UT Southwestern researchers from the Alzheimer's Center, the Harold C. Simmons Comprehensive Cancer Center and the Protein Chemistry Technology Center showed that SAHA increased the cell-signalling protein progranulin (GRN) levels in a dose-dependent way in cultured mouse cells and also demonstrated that it restored near-normal GRN production in cells from human subjects with FTD.

Up to 25 percent of patients with FTD have an inherited form of the disease that is thought to be caused by one of several genetic mutations that reduce production of GRN, Dr. Herz said. Because familial FTD patients inherit one working copy of the GRN gene and one mutated one, the researchers wanted to identify a drug that would make the working copy of the gene work harder.

In an attempt to move as quickly as possible from basic science to clinical trials, the team established a method to quickly screen 1,200 drugs that already had Food and Drug Administration approval. SAHA emerged as the most active of the chemicals they screened, said lead author and graduate student Basar Cenik, who works in the laboratories of both Dr. Herz and co-senior author Dr. Gang Yu, associate professor of neuroscience.

SAHA is in a class of drugs called histone deacetylase inhibitors, and is approved for use in a cancer called cutaneous T-cell lymphoma.

"We found a drug that can overcome the chemical deficiency associated with the condition, and we showed that it worked in cells taken from humans with FTD," Dr. Yu said.

It is not yet known if the drug will efficiently cross the blood-brain barrier, a biologically protective system that keeps many chemicals from reaching the brain, Dr. Yu said. The next research step, he said, will be to screen larger chemical libraries in an effort to find other promising GRN-stimulating drugs for human trials.

Drs. Herz and Yu are both investigators for the Consortium for Frontotemporal Dementia Research and are working toward human trials with that national network, which is based at the University of California at San Francisco.

Other UT Southwestern authors are Drs. Chantelle Sephton, Wenze Niu and Daniel R. Dries, all postdoctoral researchers of neuroscience; Colleen Dewey, graduate student in neuroscience; Dr. Xunde Xian, postdoctoral researcher of molecular genetics; Dr. Shuguang Wei, senior research scientist of biochemistry; Dr. Bruce A. Posner, associate professor of biochemistry; and Kimberly Yu, summer high school intern researcher. Researchers from the University of California, Los Angeles, the Gladstone Institute for Cardiovascular Disease, the University of Massachusetts Medical School, and the University of California, San Francisco also participated in the research.

The study received support from the National Institutes of Health, the Consortium for Frontotemporal Dementia Research, the California Institute for Regenerative Medicine, the National Cell Repository for Alzheimer's Disease, the Ted Nash Long Life Foundation, the Welch Foundation, the Humboldt Foundation and the American Health Assistance Foundation.

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Pleural mesothelioma: Combination therapy shows promise for rare, deadly cancer caused by asbestos

ScienceDaily (June 2, 2011) — Pleural mesothelioma patients who undergo lung-sparing surgery in combination with photodynamic therapy (PDT) show superior overall survival than patient treated using the conventional therapy of extrapleural pneumonectomy (EPP) (or en bloc removal of the lung and surrounding tissue) with PDT, indicates new research from the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania. The research is published in the June 2011 issue of the Annals of Thoracic Surgery.

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"Unlike patients who receive traditional lung sacrificing surgery for mesothelioma, the patients in our study who underwent lung sparing surgery and photodynamic therapy, a light-based cancer treatment, have experienced unusually long overall survival rates. The median survival for those patients had not been reached at over two years when the results were analyzed. That's unusual in this field, especially when the majority of those patients are older and have advanced cancer," said Joseph Friedberg, MD, co-director of the Penn Mesothelioma and Pleural Program and the thoracic surgeon who performed the operations cited in the study. "In addition to the overall survival statistics, the difference between having and not having a lung, both with respect to the risk of surgery and the ability to enjoy a normal life after surgery, is crucial for these patients."

Mesothelioma is one of the most aggressive and deadliest forms of cancer and is usually caused by exposure to asbestos. Exposure to asbestos typically precedes development of the cancer by anywhere from 10 -- 50 years, but once it occurs, the average survival rate following diagnosis is often only 9-12 months.

Although mesothelioma can occur in other locations like the abdomen, pleural mesothelioma is the most common form of the disease and accounts for roughly 70 percent of cases. This form originates in the pleura -- the membrane surrounding the lung and lining the chest -- where it starts off as a microscopic sheet of malignant cells that coats the interior of the chest and can grow to be several inches thick. The coating and enveloping nature of the cancer makes it impossible to completely remove it with surgery alone. As a result, the conventional surgery-based approach to treatment involves radical surgery that includes removing the lung, in combination with chemotherapy and whole chest radiation. Even with this aggressive treatment, the disease will recur in almost all patients.

The current study had two goals. The first was to determine if using a new combination of PDT and surgery would allow a less extensive surgical procedure to be used in lieu of an EPP. The second was to determine if, based on previous research from Penn with PDT, the treatment would have any positive effect on survival for patients.

Unlike radiation, which passes through the body, the PDT therapy used in the current study penetrates only a short distance which allows the lung to be preserved. The PDT treatment aims to eradicate the remaining microscopic disease trigger a patient's own immune system to help fight cancer. Penn is one of only two centers in the world where PDT is used to treat pleural mesothelioma.

In the study, 28 patients (19 men, 9 women) underwent surgical resection plus PDT for pleural mesothelioma. Patients were aged from 27 to 81 years. All patients were seen in a multidisciplinary setting and educated about the spectrum of treatment options available, including surgical intervention and its currently investigational status. Of the study group, 14 patients were treated by modified extrapleural pneumonectomy (MEPP) and 14 by radical pleurectomy (RP) and intraoperative PDT. Twenty-two of the 28 patients also received chemotherapy.

Demographics in the MEPP and RP cohorts were similar in age, sex, stage, nodal status, histology, and adjuvant treatments. Stage III/IV disease was present in 12 of 14 patients (86 percent) in both groups. The median overall survival for the patients who received the MEPP treatment was 8.4 months. At a follow-up 2.1 years after the end of treatment, a median survival rate for the patients who received a radical pleurectomy had not yet been reached. The results yielded by the radical pleurectomy and adjuvant PDT were superior to other studies of surgical treatment plans with patients of similar demographics.

"Our primary motivation in attempting the lung sparing surgery was preservation of quality of life, and we were hoping the survival results would at least be similar to the more traditional pneumonectomy approach," said Friedberg. "Although our pneumonectomy results were in line with what is often reported for similar patients having surgery-based treatments, we were completely caught off guard when the analysis revealed a significantly longer survival for the patients who retained both lungs."

Although all patients in the current study received the PDT therapy in combination with a different surgical technique, the researchers further note that the use of intraoperative PDT is the evident difference between the multimodal protocol used in the current study and other standard treatment options presently in use, and it seems worth speculating on any potential direct contributions of the PDT to the overall survival rates.

"Why this is happening is unclear and has emerged as the focus of our continuing research," said Friedberg. The possibility exists that the residual PDT-treated microscopic disease induced an autologous tumor vaccine effect or potentially enhanced the effect of adjuvant treatments.

"This study has limitations, as many mesothelioma studies do, but these results are very encouraging. The findings from our study are particularly notable because many of the patients in this study would often be excluded from surgery-based therapy because of their advanced age or unfavorable oncologic characteristics such as the large bulk of their cancers or the spread to the lymph nodes," said Dr. Friedberg. "Based on these results this lung-sparing technique, combined with photodynamic therapy, has become the backbone of our surgery-based treatment protocols."

A larger study investigating the efficacy of this multimodal approach is currently underway at Penn.

The Penn Mesothelioma and Pleural Program is a unique program that consists of a multidisciplinary team of dedicated specialists with a passion and expertise for treating patients with these difficult cancers. The Penn Program offers a true multidisciplinary approach, presenting patients with essentially all treatment options offered world wide and a number of treatments offered only at Penn.

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Experimental vaccine made from frozen immune cells shows promise for prostate cancer patients

ScienceDaily (June 3, 2011) — Metastatic prostate cancer patients who received an investigational vaccine made from their own frozen immune cells lived 10 months longer than those not treated with it, according to data being presented by researchers from the Kimmel Cancer Center at Jefferson at the 2011 American Society of Clinical Oncology annual meeting in Chicago.

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In an exploratory, multi-institutional analysis, researchers administered the vaccine APC8015F to a group of patients from the control arm of three randomized, Phase 3 clinical trials evaluating sipuleucel-T, a similar, FDA-approved cancer vaccine for metastatic castrate resistant prostate cancer.

APC8015F is made from immune system cells taken from a patient with prostate cancer; however, unlike sipuleucel-T, which is never frozen, APC8015F is cryopreserved at a time before the disease progressed.

Results from the analysis showed that patients treated with APC8015F had improved survival relative to the patients who were not treated in the control arm. Following disease progression, the median survival of patients treated with APC8015F was 20.0 months compared to 9.8 months for control patients.

"The study is important because it suggests that the sipuleucel-T therapy may have extended survival for a longer time than estimated in the clinical trials due to the beneficial effects of the frozen product on some men who initially received the placebo," said Leonard Gomella, M.D., Chair of Urology at Jefferson's Kimmel Cancer Center in Philadelphia. "Further, the clinical activity of the frozen-activated product is maintained."

Post-progression treatment with APC8015F, which is not FDA approved, may have extended survival of subjects, potentially reducing the magnitude of survival difference observed between sipuleucel-T and controls in randomized controlled trials.

Sipuleucel-T is FDA approved under the brand name Provenge to treat men with advanced prostate cancer that is asymptomatic or minimally symptomatic and no longer responding to hormonal therapy.

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Combination antibody therapy shows promise in metastatic melanoma

ScienceDaily (June 3, 2011) — A duo of drugs, each targeting a prime survival strategy of tumors, can be safely administered and are potentially more effective than either drug alone for advanced, inoperable melanomas, according to a phase 1 clinical trial led by Dana-Farber Cancer Institute investigators.

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The findings are being presented in an oral session at the annual meeting of the American Society of Clinical Oncology in Chicago.

The drugs -- ipilimumab and bevacizumab -- are both monoclonal antibodies, intensified formulations of natural disease-fighting proteins. Ipilimumab spurs the immune system to attack diseased cells, including tumor cells. Bevacizumab, also known by the trade name Avastin, blocks the growth of blood vessels that provide tumors with nourishment. Ipilimumab has extended the lives of metastatic melanoma patients in previous clinical trials, and bevacizumab is often used to treat tumors of the colon, lung, and kidney.

The trial involved 22 patients with metatastic melanoma that was not treatable by surgery.

F. Stephen Hodi, MD, the study's lead author and director of the melanoma treatment center at Dana-Farber, said the trial is the first to explore whether the two agents enhance each other's effectiveness. Most of the participants didn't experience serious adverse side effects, although some did experience inflammation of artery walls, the liver, thyroid gland, colon, or uvea (the middle layer of the eye). Five patients required steroid treatment for these problems and were removed the trial.

Positron emission tomography (PET) scans showed a prompt immune system response to many of the melanoma tumors, and computed tomography (CT) scans showed decreased blood flow to the tumors. Eight of the participants had partial responses -- showing some tumor shrinkage -- to the dual treatment, and six had stable disease. All the responses lasted at least six months. Biopsies performed after the treatment showed a more vigorous immune system response than would be expected with ipilimumab alone.

"Our findings indicate that ipilimumab and bevacizumab can be safely administered with careful management of side effects," said Hodi. "The results of lab tests suggest that the two agents may work synergistically, with 14 of 21 evaluable patients experiencing a clinical benefit. This approach merits exploration in further clinical trials."

Funding for the trial was provided by grants from the Melanoma Research Alliance and National Institutes of Health.

The other co-authors of the study are Philip Friedlander, MD, Annick Van Den Abbeele, MD, Nageatte Ibrahim, MD, Xinqi Wu, PhD, Jun Zhou, PhD, Anita Giobbie-Hurder, Travis Hollmann, MD, PhD, Sara Russell, MD, Pamela Dipiro, MD, Jeffrey Yap, PhD, Dana-Farber; George Murphy, MD, David McDermott, MD, Brigham and Women's Hospital; Michael Atkins, MD, Beth Israel Deaconess Medical Center; and Donald Lawrence, MD, Massachusetts General Hospital.

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