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Brain Cancer News for August 2004
Peregrine Pharmaceuticals Announces Patient Enrollment Completion for Cotara(TM) Phase I Study for Colorectal Cancer
TUSTIN, Calif., Aug. 2 /PRNewswire-FirstCall/ -- Peregrine Pharmaceuticals (Nasdaq: PPHM) announced today that patient enrollment has been completed in its colorectal cancer Phase I clinical trial evaluating Cotara(TM) at Stanford University. The Phase I study was designed to determine the maximum tolerated dose (MTD) and safety profile of intravenously administered Cotara. Cotara is an Iodine-131 radiolabeled Tumor Necrosis Therapy (TNT) monoclonal antibody that may be useful for the treatment and diagnosis of various solid tumor cancers. Interim data from the trial is currently being analyzed as follow-up data on treated patients continues to be collected.
"We have achieved an important milestone in the development of Cotara for treating solid tumors," said Steven King, Peregrine's president and chief executive officer. "The safety and distribution data generated from this study will be used to guide us in the planning of Phase II clinical studies in other solid tumor indications. We will be working closely with our scientific advisors and investigators to explore all development options for Cotara, both as a single agent and in combination with other therapies."
About Tumor Necrosis Therapy (TNT)
Rapidly growing tumors quickly outgrow their blood supply resulting in a region of tumor cells that do not receive adequate oxygen, nutrients and waste removal. The accumulation of dying cells results in the formation of a dead, or necrotic, core present in virtually all solid tumors beyond a very small size. Tumor Necrosis Therapy (TNT)-based products directly target and bind to dead and dying tumor cells found in virtually all solid tumors. Hence, TNT-based therapeutic agents have the potential to deliver therapeutic agents preferentially targeted to virtually all solid tumors.
Peregrine's TNT antibodies bind to universal intracellular antigens, DNA/Histone complexes, exposed in the necrotic core of malignant solid tumors. Since DNA and Histone are not normally accessible in normal tissues, the DNA/Histone complex represents a stable and specific marker of tumors Given TNT's near universal appearance as a tumor marker, TNT antibodies make excellent delivery molecules for a wide variety of anti-cancer killing agents. To date, the TNT technology platform has been used to deliver various killing agents such as radioactive isotopes and cytokines to solid tumors.
About Peregrine Pharmaceuticals
Peregrine's research and development efforts focus on discovering and
developing products that affect blood flow to tumors. Peregrine's vascular research programs fall under several different proprietary platforms including Anti-Phospholipid Therapy (APT), Vascular Targeting Agents (VTAs), Anti-Angiogenesis and Vasopermeation Enhancement Agents (VEAs). The company has research collaborations with pharmaceutical and biotechnology companies to
develop its VTA platform for therapeutic and diagnostic applications and expects to enter its first APT compound into clinical trials for cancer therapy during calendar year 2004. Peregrine's vascular agents may also have applications in other angiogenesis-dependent diseases besides cancer such as diabetes, arthritis, skin disorders and eye diseases. Peregrine currently has exclusive rights to over 190 U.S. and foreign patents and patent applications that broadly cover
its vascular programs. In addition, the company is currently evaluating its proprietary technology for use in treating non-angiogenesis dependent diseases such as viral infections.
The company believes that the pre-clinical data generated by the company and the broad nature of its intellectual property may provide many opportunities for product development, partnering and licensing. Peregrine's most clinically advanced therapeutic program is based on a targeting platform outside vascular biology. This technology platform is known as Tumor Necrosis Therapy (TNT) and targets dead or dying tumor cells that are common to the majority of different tumor types. Cotara(TM), the most clinically advanced TNT program, is currently in a Phase I clinical trial for the treatment of colorectal carcinoma at Stanford University Medical Center. In addition, we received protocol approval from the U.S. Food and Drug Administration ("FDA") to initiate a registration clinical study in February 2003 for the treatment of brain cancer. The company is currently seeking a development or funding partner to move the brain cancer program forward.
The company believes that continuing the clinical development of Cotara(TM) in tumor types other than brain cancer will add significant value to the program. The company has a research collaboration to develop immunocytokines based on the TNT platform and a TNT based agent has been developed and approved for the treatment of lung cancer in China under a licensing agreement. The company also operates a cGMP contract manufacturing facility for monoclonal antibodies and recombinant proteins through its wholly owned
subsidiary Avid Bioservices, Inc. (http://www.avidbio.com). Avid produces clinical trial materials to support Phase I through Phase III clinical trials for biotechnology companies including Peregrine. Copies of Peregrine press releases, SEC filings, current price quotes and other valuable information for investors may be found on the websites http://www.peregrineinc.com,
http://www.hawkassociates.com and http://www.hawkmicrocaps.com.
Safe Harbor Statement: This release may contain certain forward-looking statements that are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Actual events or results may differ from the company's expectations as a result of risk factors discussed in Peregrine's reports on file with the U.S. Securities and Exchange Commission, including, but not limited to, Peregrine's report on Form 10-Q for the quarter ended January 31, 2004 and on Form 10-K for the year ended April 30, 2004.
Peregrine Investor Relations
Frank Hawkins and Julie Marshall, Hawk Associates, Inc.
(800) 987-8256 or info@hawkassociates.com
SOURCE Peregrine Pharmaceuticals, Inc.
Web Site: http://www.peregrineinc.com
http://www.hawkassociates.com http://www.hawkmicrocaps.com
Smart drug that targets cancer cells in the brain following removal of a tumor
Posted By: News-Medical in Medical Research News
Published: Tuesday, 3-Aug-2004
The use of a "smart" drug that targets cancer cells in the brain following removal of a tumor may provide treatment that can extend the survival of people with the most common form of primary malignant brain tumor, glioblastoma multiforme (GBM).
A phase III research study being conducted at Rush University Medical Center by neurosurgeon Dr. Richard Byrne involves the use of convection-enhanced delivery, a novel drug delivery approach, to facilitate infusion of the study drug, IL13-PE38QQR, into the brain. IL13-PE38QQR is designed to attach to specific receptors on tumor cells that are not present on normal brain cells.
The problem with current treatments for brain tumors is that while neurosurgeons can remove as much as 95 percent or more of a tumor, some cancer cells will remain undetectable and scattered throughout the brain tissue adjacent to the tumor site. Current methods to kill the remaining cancer cells with radiation or chemotherapy have resulted in a median survival rate after initial diagnosis of about nine to twelve months, and normal brain cells can be injured in the process.
Patients in the study first will undergo neurosurgery to remove as much of the GBM tumor as possible. Within a week, magnetic resonance imaging (MRI) will be used to scan the brain tissue around the cavity where the tumor has been removed to identify suspicious areas where cancer cells may remain.
With the target areas identified, Byrne and his team will then perform a second surgical procedure using an image guidance technique to pass catheters through the skull into the brain to reach two to four areas of tissue suspected of harboring residual, infiltrating tumor cells. Following catheter placement, the drug is continually infused or delivered through the catheters into the brain. A pump is used to slowly push the drug solution through the catheters. This method of treatment is referred to as convection-enhanced delivery, or CED. The patient is able to walk around during this time.
IL13-PE38QQR is a hybrid protein that contains the cytokine IL13, which allows the drug to specifically attach or bind to tumor cells that have the IL13 receptor. "Like a key to a lock," the cytokine binds to the receptor and allows the study drug to enter and potentially kill the tumor cells. Normal brain cells remain unaffected because they do not appear to have the IL13 receptor and therefore the study drug does not bind to them.
The positive-pressure, convection-enhanced delivery method is used to diffuse the drug throughout the targeted brain tissue. Convection enhanced delivery to brain tissue allows the drug to bypass the blood-brain barrier, which protects the brain by preventing "foreign substances" such as drugs in the blood from reaching brain tissue, which can occur when drugs are administered systemically. "There are countless success stories of treating tumors that work in cell lines that fail when we try them in the brain, in part because of the blood brain barrier," said Byrne, who is a member of the Chicago Institute of Neurosurgery and Neuroresearch medical group (CINN). He is the principal investigator for the study at Rush.
"Previous studies with this drug have shown that it was safe and that there were some very dramatic responses in terms of eliminating residual tumor in the brain and prolonging patient life. We believe this drug can positively improve life span for some GBM brain tumor patients by destroying the cancerous cells we cannot remove through neurosurgery," said Byrne.
One-third of the patients enrolled in the trial will be randomly assigned to receive one treatment currently available. These patients will undergo surgery to remove the tumor and to have FDA approved chemotherapeutic "wafers" placed in the tumor cavity. The wafers slowly dissolve over 2 to 3 weeks, releasing chemotherapeutic drugs to the area. Two-thirds of the study patients will be randomly assigned to receive the IL13-PE38QQR study drug.
GBM is the most common and aggressive form of primary brain tumors, and most cases occur in people between the ages 40 and 60. GBM is a highly malignant tumor and infiltrates the normal brain tissue surrounding the tumor. GBMs may also invade the membranes covering the brain, or spread via the spinal fluid bathing the brain and spinal cord. Most malignant gliomas are known to re-grow in a location close to the resection cavity left by the removal of the tumor.
People with these brain tumors typically suffer from some degree of symptoms that can include headaches, nausea and vomiting, personality changes, seizures, vision loss and slowing of cognitive function.
Individuals interested in participating in this study must have a diagnosis of recurrent glioblastoma multiforme and the tumor must have reoccurred after surgical resection, radiation and chemotherapy were used to treat the initial tumor.
The "PRECISE" (Phase III Randomized Evaluation of Convection IL13) trial is designed to enroll up to 300 patients. A number of the world's leading brain tumor treatment centers, including Rush University Medical Center, have agreed to participate in the PRECISE trial to further the study of treatments for GBM. NeoPharm, Inc., based in Lake Forest, Ill., funds the study and supplies the IL13-PE338, which was developed in the Laboratory of Molecular Tumor Biology of the U.S. Food and Drug Administration.
http://www.rush.edu
4-Aug-2004
Contact: Karen Kreeger
karen.kreeger@uphs.upenn.edu
215-349-5658
University of Pennsylvania Medical Center
Molecular therapeutics advance fight against brain cancer
(Philadelphia, PA) -- An estimated 41,000 new cases of primary brain tumors are expected to be diagnosed in 2004, according to the American Brain Tumor Association. To further narrow the gap between diagnosis and effective therapy, physicians at the University of Pennsylvania Health System now offer several promising approaches to brain tumor treatment, including novel imaging for oncologic neurosurgery and refined genetic testing for tumors to better target treatment.
Through enhanced magnetic resonance imaging (MRI), newer and broader information is helping to better guide tumor removal. MRI is used to measure the anatomy and metabolism of tumors. This informs surgeons pre- and post-operatively with a three-dimensional map of tumor-associated blood flow to more precisely assess the full extent of tumor growth versus conventional imaging methods. "This novel approach helps guide surgery and assessment of treatment response," says Donald M. O'Rourke, M.D., Associate Professor of Neurosurgery. These novel imaging methods are leading to increased patient survival by allowing for greater tumor removal in a safe manner.
Neuroscientists are also ushering in a new era in which genetics will dictate treatment. In the 1990s researchers noted that a more favorable prognosis in patients with certain brain tumors, primarily oligodendrogliomas, was associated with a deletion of genes on chromosomes 1 and 19. This genetic loss translates into a significant life-expectancy gain for some patients and is therefore a robust predictor that post-surgery chemotherapy should be given to such patients.
Patients with the genetic deletion on chromosome 1 have a median survival in certain cases of about 10 years and respond particularly well to chemotherapy given immediately after surgery. Patients with the deletion have slower-growing tumors and show a better response to chemotherapy; whereas, those without the deletion have relatively faster-growing tumors and are less responsive to chemotherapy, so radiation therapy is required sooner. "Given the expected increase in the life-span of patients with this deletion, there is no need to give radiation therapy early in their treatment," explains O'Rourke.
The deletion can only be detected by genetic analysis. "Under the microscope these tumors can look identical, so there's no way of knowing the difference unless a genetic analysis is performed," explains O'Rourke.
Having the ability to provide such genetic testing to determine treatment is of benefit to patients. "The idea of using a genetic test to predict prognosis and select therapy, thereby deferring potentially deleterious treatment is tremendously attractive," says O'Rourke. "Penn's genetic testing is done in-house, so patients don't have to wait for the results." Further, there is no cost to the patient at this point since the tests are performed by the Neuro-oncology Program and supported by the Abramson Cancer Center at Penn. In addition, there is no requirement for additional blood samples, so results will be given more quickly with no need for follow-up visits.
Penn colleagues J. Carl Oberholtzer, MD, PhD, Department of Neuropathology and Myrna Rosenfeld, MD, PhD, Department of Neurology and Director of the Division of Neuro-oncology as well as Jaclyn Biegel, PhD, Director of Cytogenetics, Children's Hospital of Philadelphia, collaborated with O'Rourke on developing the genetic testing program. Dr. Biegel's laboratory performs the genetic test and has significant experience with genetic testing of brain tumors.
O'Rourke is also Director of the Human Brain Tumor Tissue Bank at Penn, one of only a few such dedicated banks in the United States. Tissue banks allow for the direct evaluation of human tumors and are one of the best ways to advance treatment options for gliomas and other human cancers. O'Rourke's basic research interests include finding new treatments for gliomas based on genetic alterations detected in tumors. He is currently investigating a variant of the epidermal growth factor receptor that is present in many primary glioblastomas to better understand the development of malignancy in the brain and how it relates to cancer cell division, survival, and movement.
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O'Rourke and colleagues are now prepared to discuss potential surgical and clinical treatments and genetic evaluation of brain tumor patients. Contact Dr. O'Rourke at 215-662-3490 for more information.
This release can also be found at: www.uphs.upenn.edu/news
PENN Medicine is a $2.5 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation's first integrated academic health system).
Penn's School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
Penn Health System is comprised of: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.
Brain Tumor Risk Higher if Born in Winter
Infections, Diet, Toxins, Weather, Hormones Put Winter Babies at Risk
By Jeanie Lerche Davis
WebMD Medical News Reviewed By Michael Smith, MD
Aug. 3, 2004 -- Winter babies are at higher risk of developing a brain tumor later in life. Summer babies seem to be safest, new research shows.
The study, published in the current issue of Neurology, looks at this phenomenon of birth season and disease. Study after study has pointed to patterns. Epilepsy has consistently been found more frequently in people born from December through March. Schizophrenia, bipolar disorder, Alzheimer's disease, and narcolepsy are all linked with winter births. Leukemia, lymphoma, breast cancer, and testicular cancer have also shown seasonal patterns.
In the uterus and during infancy, a baby's brain and spinal cord are highly sensitive to the environment. That sensitivity, plus the slow development of nervous system disorders, raises the possibility that variations in seasonal exposure may influence the risk of brain tumors in adulthood, writes lead researcher A.V. Brenner, MD, PhD, an epidemiologist with the National Cancer Institute.
Brenner's study involved 686 patients in three large hospitals, all diagnosed with benign brain tumors. When Brenner and his colleagues matched their birth dates with those of 799 patients without brain tumors, they found distinct patterns.
People born in winter -- particularly January and February -- had the highest risk, while those born in August and July had the lowest risk.
Handedness also affected the association between seasons and brain tumor risk. Left-handed and ambidextrous people born in late fall through early spring were at particularly high risk of having brain tumors.
The study builds on evidence that adult disease can have origins very early in life. However, it's not clear what factors -- infections, the mother's diet, environmental toxins, sun exposure, temperature, weather, and hormones -- are triggering brain tumor patterns, Brenner writes.
Five brain cancers linked to single gene
August 05, 2004
Hotspots in two areas of a gene that encodes a specific signaling enzyme, or kinase, are vulnerable to a variety of mutations found in five types of brain cancers, according to a report published in the August 1 issue of the journal Cancer Research. Mutations in the gene PIK3CA occur spontaneously as part of the brain tumor development rather than being passed genetically between generations, said Hai Yan, M.D., Ph.D., the senior scientist of the studies. ''PIK3CA mutations are known to occur in as much as 30 percent of colorectal and gastric cancers and glioblastomas and they are also present, to a lesser extent, in breast and lung cancer,'' Yan noted. ''Our studies defined the association of mutant PIK3CA gene in a wider spectrum of adult and pediatric brain tumors as well.''
From American Association for Cancer Research :
Clusters of Alterations on PIK3CA Gene Found in Brain Cancers
Hotspots in two areas of a gene that encodes a specific signaling enzyme, or kinase, are vulnerable to a variety of mutations found in five types of brain cancers, according to a report published in the August 1 issue of the journal Cancer Research.
Mutations in the gene PIK3CA occur spontaneously as part of the brain tumor development rather than being passed genetically between generations, said Hai Yan, M.D., Ph.D., the senior scientist of the studies conducted by a collaborative research team from Duke University, Johns Hopkins University, and the University of Utah.
''PIK3CA mutations are known to occur in as much as 30 percent of colorectal and gastric cancers and glioblastomas and they are also present, to a lesser extent, in breast and lung cancer,'' Yan noted. ''Our studies defined the association of mutant PIK3CA gene in a wider spectrum of adult and pediatric brain tumors as well.''
PIK3CA is part of a family of genes that encode lipid kinases, enzymes that modify fatty molecules and direct cells to grow, change shape and move. Kinases have been the focus of recent drug development strategies, with some tumor-inhibiting compounds such as Gleevec, which is a protein kinase inhibitor already in use clinically to thwart tumor growth.
Yan and colleagues pinpointed a cluster of 13 mutations on two particular areas of the PIK3CA gene, exons 9 and 20. The mutations were identified in 14 percent of anaplastic oligodendrogliomas, 5 percent of medulloblastomas, 5 percent of glioblastomas and 3 percent of anaplastic astrocytomas. No PIK3CA mutation variants were found in samples of ependymomas or low-grade astrocytomas.
Nine of the eleven PIK3CA mutations were consistent with alterations observed in the colorectal cancers. Two additional, new mutations were also observed.
Identification of PIK3CA as an oncogene associated with brain cancers opens the door to screening processes that can identify patients for treatment strategies, as well as development of targeted molecular therapeutics aimed controlling brain cancer development through regulation of the errant gene, Yan said.
Yan is an assistant professor of pathology, Duke University Medical Center. His colleagues who contributed to this work include Daniel Broderick, Chunhui Di, Timothy Parrett, Roger McLendon, and Darell Bigner, Duke University; and Yardena Samuels, Jordan Cummins and Victor Velculescu, The Johns Hopkins University Medical Institutions; and Daniel Fults, the University of Utah School of Medicine. This work is supported by the National Institute of Health and Pediatric Brain Tumor Foundation.
5-Aug-2004
Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
3-D irradiation of brain cancer in children spares IQ, memory, other cognitive functions
Encouraging results of Phase II conformal radiation trial for ependymoma could resolve the dilemma on whether to withhold therapeutic radiation from children to preserve their cognitive development
A radiation therapy technique that kills brain tumors in children while sparing normal tissue allows young patients to enjoy normal development of memory, reasoning, problem-solving and other cognitive functions, according to investigators at St. Jude Children's Research Hospital. The results of a Phase II clinical trial of this technique, called conformal radiation therapy (CRT), hold promise for sparing cognitive development even in children younger than three years.
This research is published in the August issue of the Journal of Clinical Oncology. The St. Jude study found that about 75 percent of the children treated for ependymoma with CRT did not experience progression of their cancer after three years, and their cognitive development was not significantly impaired by radiation therapy.
Ependymoma is a malignant brain tumor that occurs predominately in children. About 150 cases occur in the United States each year among people younger than 14 years.
The study's findings could offer an answer to a long-standing dilemma facing physicians treating children who have brain tumors, according to Thomas Merchant, D.O., Ph.D., chief of Radiation Oncology at St. Jude. Following surgery to remove as much of the tumor as possible, radiation treatment is more effective than chemotherapy at eradicating the remaining cancer. However, despite its lower rate of treatment success, chemotherapy has been used in the past for young children because of fear among physicians and parents of radiation-related treatment effects.
Merchant is the principal investigator and lead author of the JCO report.
"The long-term problems with cognitive development caused by traditional radiation therapy make this treatment unpopular among both physicians and parents," Merchant said. "However, the improved outcomes we have seen in both disease control and intellectual development using CRT suggest that it might be possible to reintroduce the routine use of radiation therapy as a treatment option even for very young children."
Merchant is currently principal investigator for a national trial of CRT for ependymoma based on the study's findings. The trial is conducted by the Children's Oncology Group.
CRT combines CAT scans and MRI to create pictures of the cancer that a computer then turns into three-dimensional images of the tumor exactly as it appears in the brain. These images are combined with computer-controlled radiation beams and meticulous positioning of the treatment table on which the patient lies. Radiation hits the tumor at precisely calculated angles and depths matching the 3-D image of the tumor, obliterating the cancer and sparing healthy tissue.
The median age of the 88 patients in the St. Jude study was 2.85 years, and 48 patients were younger than three years. According to Merchant, the inclusion of children younger than 3 years at the time of irradiation was unique, since children in this age group are at greatest risk of the effects of irradiation.
Before CRT, all patients underwent surgery to remove as much tumor as possible. Patients underwent testing of their cognitive abilities before CRT and again at six, 12, 24, 36, 48 and 60 months after start of radiation therapy. The tests varied according to age and included assessments of IQ, verbal memory and recall, academic achievement and other developmental skills that could be disrupted by radiation damage to the brain.
Merchant attributes the encouraging results of the study to three factors: 1) the large number of patients that underwent extensive surgery to remove most of the tumor before irradiation therapy; 2) the use of CRT to target tumors; and 3) the relatively high dose of radiation that could be used with CRT without jeopardizing healthy brain tissue.
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Other authors of this study are Raymond K. Mulhern, Matthew J. Krasin, Larry E. Kun, Tani Williams, Chenhong Li, Xiaoping Xiong, Raja B. Khan, Robert H. Lustig, Frederick A. Boop and Robert A. Sanford.
This work was supported in part by a Cancer Center Support grant from the National Cancer Institute, the American Cancer Society and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit http://www.stjude.org.
Scientists encode gene to help fight brain cancer
Washington, August 06, 2004
Scientists from the Duke University, Johns Hopkins University and the University of Utah have reportedly discovered two regions in a gene that encode a specific signaling enzyme or kinase, and are vulnerable to a variety of mutations found in five types of brain cancers.
The findings which appear in the journal Cancer Research, states that mutations in the gene PIK3CA occur spontaneously as part of the brain tumor development rather than being passed genetically between generations.
"PIK3CA mutations are known to occur in as much as 30 percent of colorectal and gastric cancers and glioblastomas and they are also present, to a lesser extent, in breast and lung cancer. Our studies defined the association of mutant PIK3CA gene in a wider spectrum of adult and pediatric brain tumors as well", the journal quoted Dr. Hai Yan, the senior scientist, as saying.
Dr Yan and his team are optimistic that identification of PIK3CA as an oncogene associated with brain cancers will ease up the screening processes required to identify patients for different treatment strategies. (ANI)
Physicians offer several promising and unique approaches to brain tumor treatment
Posted By: News-Medical in Medical Procedure News
Published: Thursday, 5-Aug-2004
An estimated 41,000 new cases of primary brain tumors are expected to be diagnosed in 2004, according to the American Brain Tumor Association. To further narrow the gap between diagnosis and effective therapy, physicians at the Hospital of the University of Pennsylvania now offer several promising -- and unique to the Philadelphia region -- approaches to brain tumor treatment, including novel imaging for oncologic neurosurgery and refined genetic testing for tumors to better target treatment.
Through enhanced magnetic resonance imaging (MRI), newer and broader information is helping to better guide tumor removal. MRI is used to measure the anatomy and metabolism of tumors. This informs surgeons pre- and post-operatively with a three-dimensional map of tumor-associated blood flow to more precisely assess the full extent of tumor growth versus conventional imaging methods. “This novel approach helps guide surgery and assessment of treatment response,” says Donald M. O’Rourke, M.D., Associate Professor of Neurosurgery. These novel imaging methods are leading to increased patient survival by allowing for greater tumor removal in a safe manner.
Neuroscientists are also ushering in a new era in which genetics will dictate treatment. In the 1990s researchers noted that a more favorable prognosis in patients with certain brain tumors, primarily oligodendrogliomas, was associated with a deletion of genes on chromosomes 1 and 19. This genetic loss translates into a significant life-expectancy gain for some patients and is therefore a robust predictor that post-surgery chemotherapy should be given to such patients.
Patients with the genetic deletion on chromosome 1 have a median survival in certain cases of about 10 years and respond particularly well to chemotherapy given immediately after surgery. Patients with the deletion have slower-growing tumors and show a better response to chemotherapy; whereas, those without the deletion have relatively faster-growing tumors and are less responsive to chemotherapy, so radiation therapy is required sooner. “Given the expected increase in the life-span of patients with this deletion, there is no need to give radiation therapy early in their treatment,” explains O’Rourke.
The deletion can only be detected by genetic analysis. “Under the microscope these tumors can look identical, so there’s no way of knowing the difference unless a genetic analysis is performed,” explains O’Rourke.
Having the ability to provide such genetic testing to determine treatment is of benefit to patients. “The idea of using a genetic test to predict prognosis and select therapy, thereby deferring potentially deleterious treatment is tremendously attractive,” says O’Rourke. “Penn’s genetic testing is done in-house, so patients don’t have to wait for the results.” Further, there is no cost to the patient at this point since the tests are performed by the Neuro-oncology Program and supported by the Abramson Cancer Center at Penn. In addition, there is no requirement for additional blood samples, so results will be given more quickly with no need for follow-up visits.
Penn colleagues J. Carl Oberholtzer, MD, PhD, Department of Neuropathology and Myrna Rosenfeld, MD, PhD, Department of Neurology and Director of the Division of Neuro-oncology as well as Jaclyn Biegel, PhD, Director of Cytogenetics, Children’s Hospital of Philadelphia, collaborated with O’Rourke on developing the genetic testing program. Dr. Biegel’s laboratory performs the genetic test and has significant experience with genetic testing of brain tumors.
O’Rourke is also Director of the Human Brain Tumor Tissue Bank at Penn, a unique resource to the region and one of only a few such dedicated banks in the United States. Tissue banks allow for the direct evaluation of human tumors and are one of the best ways to advance treatment options for gliomas and other human cancers. O’Rourke’s basic research interests include finding new treatments for gliomas based on genetic alterations detected in tumors. He is currently investigating a variant of the epidermal growth factor receptor that is present in many primary glioblastomas to better understand the development of malignancy in the brain and how it relates to cancer cell division, survival, and movement.
O’Rourke and colleagues are now prepared to discuss potential surgical and clinical treatments and genetic evaluation of brain tumor patients. Contact Dr. O’Rourke at 215-662-3490 for more information.
http://www.uphs.upenn.edu
New treatment strategy for brain cancer
Posted By: News-Medical in Medical Research News
Monday, 9-Aug-2004
Virginia Commonwealth University Massey Cancer Center researchers have found that combining ionizing radiation with a secreted protein that selectively inhibits tumor cell growth and survival can target cancer cells and leave healthy cells alone, perhaps presenting a new approach for treating the deadliest type of brain tumor.
In a study published in the August 2004 issue of the journal Cancer Biology and Therapy, VCU Massey Cancer Center researchers report that exposing primary human glioma cells to radiation combined with the secreted protein, MDA-7 (IL24), activates the pathways in the cell that are associated with cell death. The study builds upon previous findings that demonstrated MDA-7 could sensitize rat brain tumor cells to the toxic effects of radiation both in vitro and in animals.
About 20,000 people in the United States are diagnosed each year with glioblastoma multiforme, the most common malignant brain tumor in adults and the most resistant to treatment. Typically, radiation therapy and chemotherapy are used in the management of gliomas, either following surgical removal or as primary therapy in patients who are not surgical candidates. But glioma is an invasive tumor and the cells are extremely migratory, so even if the bulk of a tumor mass is surgically removed, the cancer is likely to recur.
Lead investigator, Paul Dent, Ph.D., an associate professor in the department of radiation oncology, and his colleagues treated healthy brain-tissue cells and brain-cancer cells with either purified MDA-7 protein or with a genetically engineered adenovirus to make MDA-7 (Ad.mda-7). By itself, MDA-7 or Ad.mda-7, lowered the rate of growth and cell viability of brain cancer cells, but not of the healthy brain tissue cells. MDA-7 magnified the toxicity of radiation in the brain cancer cells - which did not occur in healthy brain tissue cells - suggesting that MDA-7 selectively targets tumor cells.
Researchers also found that MDA-7 made in healthy brain-tissue cells infected with Ad.mda-7 can be exported out of the normal cell and into the surrounding growth media. When a layer of soft agar containing glioma cells was spread over each plate of infected astrocytes, the growth of glioma cells was suppressed by the exported MDA-7. The exported MDA-7 also sensitized the glioma cells in the agar to the toxic effects of radiation. Thus, infected normal brain tissue cells produced MDA-7 which had a toxic "bystander effect" on the tumor cells - the healthy cell, via MDA-7, kills the bystander tumor cell.
"This data suggests that MDA-7 could have a significant bystander effect in the brain," Dent said. "Normal astrocytes will make MDA-7 and can diffuse readily. MDA-7 would not only suppress the growth of the glioma cells, but it also would make the cells more radiosensitive.
"The findings of this research have implications for the design of a novel therapy for glioma," he said. "Currently, with Ad.mda-7, there is Phase I data in other malignancies such as head and neck, breast, lung and melanoma," he said. "The initial reports indicate that some patients are having significant responses with MDA-7 by itself."
"Unfortunately, treatment strategies for glioma that combine chemotherapy and radiation have failed to produce the effects observed in other tumor cell types," Dent said. "We believe that new strategies that enhance the effectiveness of standard radiotherapy protocols in glioma, such as Ad.mda-7, are needed."
Also participating in the study were: Departments of Neurosurgery, Pathology and Urology, Columbia University Medical Center, College of Physicians and Surgeons, New York, N.Y.; Section of Medical Oncology, Department of Oncology, Mayo Clinic and Foundation, Rochester, Minn.; Department of Neurology, University of Pennsylvania, Philadelphia, Pa.; Gene Therapy Center, University of Alabama at Birmingham, Ala.
www.vcu.edu/uns
Posted on Mon, Aug. 09, 2004
Power line OK expected
By John Woolfolk
Mercury News
As the California Public Utilities Commission prepares to approve a major new power line along the Peninsula, the regulators also will revisit a concern that has bedeviled transmission projects for years: potential health risks from electric field exposure.
Fear of exposure to the invisible electric and magnetic fields surrounding high-voltage wires already has led to numerous alterations of Pacific Gas & Electric's proposed 27-mile Jefferson-Martin power line from Redwood City to Daly City.
Proposed two years ago, the much-needed $207 million line through wealthy Peninsula communities such as Hillsborough and Burlingame will almost certainly be approved in some form at the commission's Aug. 19 meeting. Its expected completion by early 2006 will boost Peninsula transmission capacity 20 percent, easing a notorious bottleneck and allowing an old, polluting power plant in San Francisco to close.
But Commissioner Loretta Lynch, assigned to oversee the project's review, wants to open a proceeding on whether to toughen the rules for reducing exposure to power-line electric fields. She cites a recent state health department study suggesting an exposure link to brain cancer, miscarriage, Lou Gehrig's disease and childhood leukemia.
``I think it's incumbent upon us to revise our rules,'' Lynch said. ``The science has changed dramatically in the last 11 years.''
But the commission's president, Michael Peevey, said there's still too much uncertainty to justify new rules that could bog down power-line projects the state badly needs to avoid electricity problems such as those in 2000 and 2001.
``This is an issue that's been exhaustively looked at throughout the world, without any conclusive evidence that I'm aware of that this has harmful health effects,'' Peevey said. ``Everywhere you go, nobody wants a transmission line, but we continue to have increasing needs for capacity. It makes it tough for the state to meet its electricity needs.''
Few doubt the need for new transmission lines like Jefferson-Martin. Named after the electrical substations it would connect, the line would deliver 345 megawatts of added capacity, about equal the output of a large power plant. A megawatt powers about 750 average homes.
The 230-kilovolt lines running along Interstate 280 near existing 60-kilovolt wires also would provide a backup route in case of problems with the main transmission corridor along Highway 101, improving system reliability. And it would allow PG&E to close a polluting power plant in San Francisco's Hunters Point.
``This is a critical project to keep power flowing to the Bay Area,'' said Stephanie McCorkle, spokeswoman for the California Independent System Operator, which oversees the transmission grid.
PG&E initially proposed Jefferson-Martin as a cheaper $190 million above-ground line. Neighbors concerned about an eyesore along scenic Interstate 280 persuaded the utility to bury the wires along all but three miles of the route in Millbrae and San Bruno.
But concerns about electric-field exposure have driven a host of proposed modifications. Burlingame residents successfully lobbied to reroute the wires away from Trousdale Drive, a thoroughfare lined with homes and schools.
A community group called 280 Corridor Concerned Citizens now wants to move and bury a mile of the line west of Skyline Boulevard near Hillsborough so it runs 50 feet farther from about 400 homes.
But Lynch said the group's proposed modification would require eminent-domain proceedings to secure an easement through private property, something that probably will prove unfeasible.
Commission policy, established in 1993, provides for extra measures to reduce electric-field exposure so long as they don't raise the project cost more than about 4 percent.
Lynch said tougher rules should be considered in light of a 2002 commission-sponsored research survey by three state Department of Health Services scientists. The scientists said they were ``inclined to believe'' that electric and magnetic fields ``can cause some degree of increased risk of childhood leukemia, adult brain cancer, Lou Gehrig's disease and miscarriage.''
But the study also noted that electric-field exposure came from a variety of sources, including household wiring and appliances, and that any effect it might have had on disease risk appeared to be small. PG&E and other utilities worry about setting a standard that would needlessly complicate power-line projects.
``A change in policy, especially one that's not based on any science, could certainly have an impact on how we site power lines,'' PG&E representative Paul Moreno said. Proposed modifications to the Jefferson-Martin line to reduce exposure have been within the 4 percent cost range, he said. Lynch says tougher rules will lessen community opposition, making power lines easier to build.
``That was the argument 11 years ago when we adopted the limited EMF rules we have now, and we've built billions of dollars worth of lines since then,'' Lynch said. Jack Sahl, Southern California Edison's health and safety director who proposed the 4 percent standard, called it a ``precautionary approach'' appropriate for reducing uncertain risks without draining funds needed to address certain dangers such as electrocution. ``It's clear from these reports that there is still uncertainty out there,'' Sahl said.
Marijuana May Stall Brain Tumor Growth
Active Ingredient in Marijuana Inhibits Cancer Growth in Early Study
By Jennifer Warner
WebMD Medical News Reviewed By Michael Smith, MD
Aug. 15, 2004 -- The active ingredient in marijuana may help fight brain tumors, a new study suggests. Researchers say the cannabinoids found in marijuana may aid in brain tumor treatment by targeting the genes needed for the tumors to sprout blood vessels and grow. Their study showed that cannabinoids inhibited genes needed for the production of vascular growth factor (VEGF) in laboratory mice with glioma brain tumors and two patients with late-stage glioblastoma multiforme, a form of brain cancer.
VEGF is a protein that stimulates blood vessels to grow. Tumors need an abundant blood supply because they generally grow rapidly. So when VEGF is blocked, tumors starve from lack of blood supply and nutrients. Blocking of VEGF constitutes one of the most promising tumor-fighting approaches currently available, says researcher Manuel Guzman, professor of biochemistry and molecular biology, at the Complutense University in Madrid, Spain, in a news release.
Guzman says the findings suggest VEGF may be a new target for cannabinoid-based treatments. Previous studies have shown that cannabinoids could inhibit the growth of tumor-associated blood vessels in mice, but until now little was known about how they worked. The results of the study appear in the Aug. 15 issue of the journal Cancer Research.
Cannabinoids May Help Starve Tumors
In the study, researchers looked at the effects of cannabinoid treatment on gliobastoma multiforme, a form of brain cancer that affects about 7,000 Americans each year. It's considered one of the deadliest forms of cancer and usually results in death within one to two years after diagnosis. Treatment typically involves surgery, followed by radiation and/or chemotherapy. But despite these efforts to destroy the tumor, this type of brain tumor often survives and starts growing again, which is why researchers are looking for novel ways to attack it.
In order to grow, all tumors require a network of blood vessels to feed them, and they create this network through a process known as angiogenesis. VEGF is critical to this process. In the first part of the study, researchers induced brain cancer in mice and then treated them with cannabinoids. They then analyzed the genes associated with the growth of blood vessels in the tumor and found that cannabinoids inhibited several of the genes related to VEGF.
In the second part of the study, researchers injected cannabinoids into tumor samples taken from two human glioblastoma patients. "In both patients, VEGF levels in tumor extracts were lower after cannabinoid inoculation," says Guzman. Researchers say more study is needed but the results suggest that cannabinoid-based therapies may offer a new alternative for treatment of these otherwise untreatable brain tumors.
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SOURCES: Blazquez, C. Cancer Research, Aug. 15, 2004; vol 64: pp 5617-5623. News release, American Association for Cancer Research.
August 15, 2004
Contact: Warren R. Froelich
Phone: 215/440-9300 Ext. 198
E-mail: froelich@aacr.org
Marijuana Ingredient Inhibits VEGF Pathway Required for Brain Tumor Blood Vessels
PHILADELPHIA -- Cannabinoids, the active ingredients in marijuana, restrict the sprouting of blood vessels to brain tumors by inhibiting the expression of genes needed for the production of vascular endothelial growth factor (VEGF).
According to a new study published in the August 15, 2004 issue of the journal Cancer Research (click here to read the article as an Adobe Acrobat PDF), administration of cannabinoids significantly lowered VEGF activity in laboratory mice and two patients with late-stage glioblastoma.
“Blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available,” said Manuel Guzmán, professor of biochemistry and molecular biology, with the Complutense University in Madrid, Spain, and the study’s principal investigator.
“The present findings provide a novel pharmacological target for cannabinoid-based therapies.”
Glioblastoma multiforme, the most aggressive form of glioma, strikes more than 7,000 Americans each year and is considered one of the most malignant and deadliest forms of cancer, generally resulting in death within one to two years following diagnosis.
The disease is usually treated with surgery, followed by conventional radiation alone or in combination with chemotherapy. However, the main tumor often evades total destruction, surviving and growing again, eventually killing the patient. For this reason, researchers are actively seeking other therapeutic strategies, some of which might be considered novel.
In this study, the investigators chose to work with cannabinoids which, in previous studies, have been shown to inhibit the growth of blood vessels, or angiogenesis, in laboratory mice. However, little was known about the specific mechanisms by which cannabinoids impair angiogenesis, or whether the chemical might do the same in human tumors.
To answer the first part of the question, the scientists induced gliomas in mice, which were subsequently inoculated with cannabinoids. Using DNA array analysis, the team examined 267 genes associated with the growth of blood vessels in tumors and found that cannabinoids lowered the expression of several genes related to the VEGF pathway, critical for angiogenesis.
The researchers also discovered that cannabinoids apparently worked by increasing the activity of ceramide, a lipid mediator of apoptosis, resulting in the functional inhibition of cells needed for VEGF production. The ability of cannabinoids to alter VEGF production was significantly stifled following the introduction of a ceramide inhibitor.
“As far as we know, this is the first report showing that ceramide depresses VEGF pathway by interfering with VEGF production,” according to Guzmán.
To answer the second part of the question relating to clinical tests, the scientists obtained tumor biopsies from two patients with glioblastomas who had failed standard therapy, including surgery, radiotherapy and chemotherapy. The biopsied tissue was analyzed before and after local injection of a cannabinoid.
“In both patients, VEGF levels in tumor extracts were lower after cannabinoid inoculation,” said Guzmán.
The results, he added, suggest a potential new approach toward the treatment of these otherwise intractable brain tumors.
“It is essential to develop new therapeutic strategies for the management of glioblastoma multiforme,” the scientists wrote, “which will most likely require a combination of therapies to obtain significant clinical results.”
Also participating in the study were Cristina Blázquez and Amador Haro, from Complutense University; Luis González-Feria, from University Hospital, Tenerife, Spain; Luis Álvarez, from La Paz University Hospital in Madrid; and M. Llanos Casanova, from the Project on Cellular and Molecular Biology and Gene Therapy, CIEMAT, also in Madrid.
# # # #
Founded in 1907, the American Association for Cancer Research is a professional society of more than 22,000 laboratory, translational, and clinical scientists engaged in all areas of cancer research in the United States and in more than 60 countries. AACR’s mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. AACR’s Annual Meetings attract more than 15,000 participants who share new and significant discoveries in the cancer field. Specialty meetings, held throughout the year, focus on the latest developments in all areas of cancer research.
Accelerate Brain Cancer Cure and National Brain Tumor Foundation Co-Fund Brain Cancer Genetics Research at UCSF
August 17, 2004
- Leading Researchers to Study Role of Genetics in Patient Survival -
BURLINGAME, Calif. and SAN FRANCISCO, Aug. 17 /PRNewswire/ -- Accelerate Brain Cancer Cure (ABC2) and the National Brain Tumor Foundation (NBTF) announced today that the two non-profit organizations have joined together to fund a population-based study at the University of California, San Francisco, led by Margaret R. Wrensch, MPH, Ph.D. The goals of the study are to gain a better understanding of the development of glioblastoma multiforme (GBM) and variations in survival rates among patients diagnosed with this deadly form of brain cancer. ABC2 is dedicated to accelerating therapies leading to a cure for brain cancer and NBTF is dedicated to serving people whose lives are affected by brain tumors.
Dr. Wrensch is among nine research scientists to receive a 2004 Project Award from ABC2 for her translational research project, a pioneering effort involving very large scale genotyping of constitutive DNA from brain cancer patients. Combining NBTF resources with those from ABC2 enabled the original scope of this project to be broadened, thus enhancing its potential for identifying factors related to disease prognosis and treatment selection.
We are pleased to be collaborating with NBTF to expand the pioneering research being done by Dr. Wrensch and her colleagues," stated John Reher, ABC2 Executive Director. "It is our hope that this study may give us clues as to why some brain cancer patients survive longer than others. With this knowledge, we hope the medical community can ultimately identify effective therapies to prolong survival for brain cancer patients."
"We chose the specific subjects and hypotheses for this project to be the best first step in a multi-stage process aimed at delineating the role of polymorphisms in glioma prognosis and etiology," explained Dr. Wrensch. "The funding we are receiving from ABC2 and NBTF will allow us to generate extremely valuable genetic information about GBM."
"By working together, NBTF and ABC2 can make an even greater impact on brain tumor research," noted Rob Tufel, MSW, MPH, NBTF Executive Director. "This type of research is crucial for the over 100 people diagnosed each day with a benign or malignant brain tumor. By increasing our understanding of survival, we can eventually improve treatments as well."
About ABC2
Accelerate Brain Cancer Cure (ABC2) was founded in May 2001 by Dan and Steve Case and their families, along with leading scientists and entrepreneurs. ABC2 aims to raise awareness about brain cancer and help mobilize critical scientific research through research grants and partnerships. ABC2 funds outstanding and novel translational science that is aimed at the discovery of a cure for brain cancer.
Each year more than 17,000 people in the United States find out that they have a malignant primary brain tumor. An additional 100,000 patients are diagnosed with a brain tumor that has metastasized from another part of the body. The mission of ABC2 is to accelerate a cure for brain cancer by increasing the number of potential therapies discovered and then rapidly moving them into the clinic to help patients. In order to accelerate progress in what has been an under-served field of research, ABC2 provides researchers from all backgrounds with the support they need to make critical breakthroughs in brain cancer research. Further information can be found at www.abc2.org.
About NBTF
The National Brain Tumor Foundation is a nationwide non-profit organization serving people whose lives have been affected by brain tumors. They are dedicated to promoting a cure for brain tumors, improving the quality of life and giving hope to the brain tumor community by funding meaningful research and providing patient resources, timely information and education. For more information please contact NBTF, toll free, at 1-800-934-CURE (2873) or visit www.braintumor.org.
Contacts:
John Reher -------------------Rob Tufel, MSW, MPH
Executive Director, ABC2 ------Executive Director, NBTF
650-685-2200 ----------------415-834-9970 ext.107
john.reher@abc2.org ----------tufel@braintumor.org
Marijuana Extract Fights Brain Cancer in Mice
The current debate over medical marijuana hinges on its use as pain medication. But an extract of the plant could one day form the basis of cancer treatments. New findings indicate that Cannabis extracts can shrink brain tumors by blocking the growth of blood vessels that nourish them.
Manuel Guzman of Complutense University in Spain and his colleagues tested extracts of marijuana known as delta-9-tetrahydrocannabinols in 30 mice that had brain tumors. The researchers analyzed the animals' DNA and identified 267 genes associated with blood vessel growth, or angiogenesis. The cannabinoids inhibited the expression of several genes critical to angiogenesis known as the VEGF (vascular endothelial growth factor) pathway. “Blockade of the VEGF pathway constitutes one of the most promising antitumoral approaches currently available,” Guzman says. The cannabinoids work by increasing the potency of a fat molecule known as ceramide, the team posits. Increased ceramide activity, in turn, inhibits cells that would normally produce VEGF and encourage blood vessel growth.
The scientists also tested the therapy on tumors taken from two patients who had not responded to conventional therapy for their glioblastoma, a deadly form of brain cancer. After the cannabinoid injections, both tumors exhibited decreased VEGF levels. Writing in the current issue of the journal Cancer Research, the team notes, however, that a combination of therapies will most likely be required to obtain significant clinical results. --Sarah Graham
Vaccination and Chemotherapy Appear to Work Together to Increase Survival in Patients with Glioblastoma
According to recent results published in Clinical Cancer Research, patients with glioblastoma who were treated with a combination of vaccination and chemotherapy lived longer and had cancer progression significantly delayed compared to patients treated with either approach alone.
Approximately 17,500 people are diagnosed with primary brain cancer in the United States each year. Primary brain cancer is cancer that originates in the brain and has not spread from cancer already located elsewhere in the body. Glioblastoma is one of the most common, and fatal, types of primary brain cancer. Glioblastoma is cancer of the glial cells, which are the most abundant cells in the nervous system. Glial cells perform many functions in the brain. One important role is providing support for neurons, the cells that transmit impulses between the brain, spinal column and nerves.
Standard treatment options for glioblastoma consist of surgical removal of the cancer if possible, radiation therapy and/or chemotherapy. However, the majority of chemotherapy agents cannot penetrate the blood-brain barrier. The blood-brain barrier is a membrane that surrounds the brain and spinal cord and protects the brain and nervous system by allowing only very select molecules to pass through. Thus, even with the most aggressive treatment available, most patients will survive less than one year after diagnosis.
Because of the difficulties with chemotherapy in the treatment of brain cancers, researchers have turned to vaccines. Cancer vaccines work by mobilizing the patient’s own immune system against the tumor. Unfortunately, researchers have not found a significant clinical benefit with vaccines alone, and they are evaluating vaccines in combination with chemotherapy.
In the recent Cedars-Sinai study, a small group of patients with glioblastoma were treated with vaccine plus chemotherapy (13), vaccine alone (12), or chemotherapy alone (13).
The patients who were treated with the combination lived longer on average (26 months) than those who received vaccine alone (18 months) or chemotherapy alone (16 months). Furthermore, the patients who received the combined treatment experienced a high rate of tumor regression (>50%) that is rarely seen in brain tumors and lived longer than is commonly seen with glioblastoma; 42% of patients lived 2 years and 18% lived 3 years.
Reference: Christopher J. Wheeler, Asha Das, Gentao Liu. Clinical responsiveness of glioblastoma multiforme to chemotherapy after vaccination. Clinical Cancer Research. 2004; 10: 5316 - 5326.
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Financial troubles threaten care at Dallas' only public hospital
LISA FALKENBERG
Associated Press
DALLAS - Paula Holland's brain tumor is a mystery to her. She doesn't know how big it is, how long it's been there or whether it's deadly.
She only knows that she's been waiting for more than a year for doctors at Parkland Memorial Hospital to remove it.
Holland is one of thousands of patients at Dallas County's only public hospital forced to endure long waits because of patient overcrowding, too few doctors and nurses, and a financial crisis that some doctors say erodes patient care and threatens lives.
"It's always something. One thing or another. They keep putting it off," said Holland, a 47-year-old former volunteer firefighter. "It's mentally draining."
Like Parkland, more than 1,100 public hospitals and clinics across the country struggle to provide charity care to a growing number of uninsured patients at a time when state and federal health care dollars are shrinking.
"The situation, which is generally always grim, is even grimmer now," said Rick Wade, a spokesman for the American Hospital Association. "You look at every part of the public health care system and you see enormous strain and you see everybody hollering for help."
Nearly 82 million people - one-third of the U.S. population younger than 65 - lacked health insurance at some point over the past two years, according to study released in June by Families USA, a private consumer group. Texas had the highest rate in the nation, with more than 43 percent of its non-elderly population uninsured.
Those uninsured turn to public hospitals for free or low-cost care at a time when public hospitals are losing money. The National Association of Public Hospitals and Health Systems, which represents over 100 hospitals and health systems, says 52 percent of its members reported financial losses in 2002, the latest data available.
"It's not a pretty picture," said Jonathan Freedman, an analyst with Los Angeles County, which is being sued by patients' rights groups after it cut beds at its largest public hospital and closed a rehabilitation clinic. Even with the cuts, the Los Angeles system, which treats 600,000 uninsured patients annually, projects a $491 million budget deficit for 2007-2008, he said.
Parkland and its clinics reported more than 849,000 patient visits last year. Only 7 percent of those treated had private insurance. Nearly 40 percent couldn't afford to pay, and the rest were Medicare or Medicaid patients.
Nearly $33 million of Parkland's $812 million budget went to covering the unpaid medical bills of patients from surrounding counties without public hospitals, including Collin County, the richest county in Texas.
The Parkland system also lost about $74 million in state and federal funding for 2004-05 due to government budget cuts. To compensate, Parkland has eliminated about 500 jobs as part of a two-year, $70 million cost-cutting effort.
Since Parkland refuses to turn patients away, its burden only grows as its resources wither.
The delivery room is a critical example. Parkland has one of the busiest maternity wards in the country - nearly 16,000 babies were delivered last year. At the current growth rate, Parkland could deliver 22,000 a year by 2011.
Sometimes women give birth in the hallways while waiting for rooms. Others wait hours for painkillers.
"It's kind of uncomfortable and embarrassing," said 19-year-old Araceli Santoyo, who after a car accident laid on a gurney in a hallway, waiting for doctors to examine her 8-month-old fetus.
Next to her, a woman on another gurney covered her head with a sheet. Down the hall, hospital workers setup a privacy screen so a patient could use a bed pan. A janitor with an overflowing trash cart squeezed through the maze.
The environment isn't ideal, especially for a first-time mother, Santoyo said. "You see other patients and if something's wrong with them, it makes you nervous," she said.
In Parkland's emergency room, where President Kennedy was taken after he was shot, patients without life threatening injuries wait, on average, more than seven hours for care. In the pharmacy, they line up before dawn to pick up prescriptions.
Hernia and gall bladder surgeries are often canceled and rescheduled several times over a period of months because surgeons are tied up with emergency operations. A woman with a breast lump may wait up to three months for a biopsy.
Parkland surgeons are on pace to perform about 15,300 surgeries this year, compared with about 13,000 in 2001.
Dr. Ron Anderson, Parkland's CEO for 22 years, said surgeons work night and day to meet the demand, but when they say they're physically exhausted and worried about compromised care, people need to listen.
"Sometimes, the crisis isn't in public view. It's pushed downstream, but nevertheless, it happens and I think it's time to tell people," Anderson said.
Like triage on the battlefield, doctors and nurses prioritize and ration the hospital's resources and space, he said. They take care of people injured in car crashes, the gun shot victims, the patients closest to death and put off the rest.
Anderson notes that Parkland has made U.S. News & World Report's best hospitals list for the past 11 years. In July, the magazine recognized Parkland for excellence in seven categories, including gynecology and heart surgery.
The ranking speaks to the dedication of doctors, nurses and support staff to provide quality care at a time when funding cuts threaten the hospital's future, Anderson said.
"There's a point where it's going to become unsafe," he said. "It already has in some ways."
Over the years, public hospitals have teamed with medical schools to pool resources and offer specialized treatment, which draws paying patients or those with insurance, while helping to educate future doctors. Parkland is the primary teaching hospital of the University of Texas Southwestern Medical Center at Dallas.
In March, UT-Southwestern's executive vice president for clinical affairs wrote Anderson, warning that overcrowding and understaffing threatened patient lives.
"If we fail to act right away, the current level of service deterioration will become irreversible and unacceptable," Dr. Willis Maddrey wrote.
That's what scares Holland, the cancer patient.
Doctors tell her the mass has coiled itself around a band of nerves above her neck, strangling her vocal chords and pinching her voice to a rasp. If it isn't removed soon, doctors say it could affect her hearing and swallowing.
Doctors at a private hospital discovered the tumor and another one behind her eye in October 2002 after she nearly died from a brain aneurism. They referred her to Parkland neurosurgeons, who removed the tumor behind her eye, but haven't gotten to the other one.
A hospital official familiar with Holland's case said doctors would have operated sooner if the tumor were growing rapidly or threatening her sight, but its size hasn't changed much.
Holland said she has seen about 20 doctors in several different Parkland clinics. She waits five, maybe six hours each time to spend 10 minutes with a doctor who always seems rushed.
"It's kind of like cattle. They run you in and run you out, except you wait for hours in between," she said.
She'd like to go somewhere else, but as a Medicaid patient, her options are few.
"They tell you you have a brain tumor and the first thing that enters your brain is 'oh my God, I'm going to die,'" Holland said. "Then they tell you they're going to set a date and then they don't."
Dallas County commissioners have hired consultants to study the problems at Parkland. Some adamantly oppose any additional funding and proposals to build the bigger hospital Anderson says is needed. On Tuesday, commissioners voted not to raise taxes next year to provide more money for Parkland.
Jim Jackson, Dallas County commissioner for 30 years, says Parkland should screen its patients better to make sure it's only serving the neediest ones. And, if necessary, Parkland should start turning people away.
"People can say it's inhumane not to furnish everything everybody needs," Jackson said. "It's inhumane to load the system up so that it collapses under its own weight, and nobody gets care."
ON THE NET
Parkland Memorial Hospital: http://www3.utsouthwestern.edu/parkland/
Fluorescence can distinguish brain tumor from normal tissue
August 01, 2004
When molecules in cells are stimulated by light, they respond by becoming excited and re-emitting light of varying colors (fluorescence) that can be captured and measured by highly sensitive optical equipment. Now, researchers at Cedars-Sinai Medical Center and the University of Southern California are developing miniaturized spectroscopic instruments and computer software to take a real-time look at biochemical, functional and structural changes occurring within the cells and tissue of the brain. If the technology continues to progress as anticipated, neurosurgeons will be able to shine a light during surgery to diagnose brain tumors instantaneously and they will be able to discern the borders of tumors with greater precision than ever. Early studies appear to support these possibilities.
From Cedars-Sinai Medical Center :
Study shows that fluorescence spectroscopy can distinguish brain tumor from normal tissue
When molecules in cells are stimulated by light, they respond by becoming excited and re-emitting light of varying colors (fluorescence) that can be captured and measured by highly sensitive optical equipment.
Now, researchers at Cedars-Sinai Medical Center and the University of Southern California are developing miniaturized spectroscopic instruments and computer software to take a real-time look at biochemical, functional and structural changes occurring within the cells and tissue of the brain. If the technology continues to progress as anticipated, neurosurgeons will be able to shine a light during surgery to diagnose brain tumors instantaneously and they will be able to discern the borders of tumors with greater precision than ever. Early studies appear to support these possibilities. The researchers report in the July/August issue of Photochemistry and Photobiology that the techniques and device they have developed are able to quickly and accurately discriminate between brain tumor and normal tissue.
Glioblastoma multiforme (GBM), the most common and deadly type of brain tumor, was the subject of the study. Because these tumors grow quickly and invade healthy tissue rapidly, patient survival rates usually are measured in weeks or months despite aggressive treatment with traditional surgery, chemotherapy and radiation. When ''image complete'' resection is accomplished -- no remaining tumor is visible with high-resolution imaging techniques -- patients have a median survival of about 70 weeks.
But complete removal is nearly impossible because the tumors aggressively infiltrate neighboring tissue and are irregularly shaped with poorly defined borders. Also, tumor cells tend to migrate away to establish satellites in other parts of the brain. When surgical removal is less than image complete, median survival is less than 19 weeks.
''Although our surgical goal is to remove as much tumor as possible without damaging healthy brain, distinguishing between the two is extremely difficult,'' said Keith L. Black, MD, neurosurgeon, director of the Maxine Dunitz Neurosurgical Institute, the Division of Neurosurgery and the Comprehensive Brain Tumor Program.
''Fluorescence spectroscopy is one of several innovative imaging techniques in development, and I think the evolution of this capability comes at a critical time because we are beginning to see encouraging results in several therapeutic approaches,'' continued Dr. Black, who holds the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai and is one of the journal article's authors. ''The clarity that fluorescence technology appears to offer may provide greater precision in surgery and also help us target cancer cells with a combination of new, highly focused therapies.''
The ability to immediately analyze cells revolves around the fact that different metabolic states and biochemical components emit light differently. Just as a prism splits white light into a full spectrum of color, laser light focused on tissue is re-emitted in colors determined by the properties of the molecules. Analyzing the colors in space and time provides information about the types of molecules present and their conformation.
''With time-resolved laser-induced fluorescence spectroscopy we measure both the wavelength of the emission and the time that molecules stay in the excited state before returning to the ground state. This provides information about the chemical composition of the tissue, about molecular and biochemical changes, as a function of the stages of disease,'' said Laura Marcu, PhD, director of the Biophotonics Research and Technology Development Laboratory at Cedars-Sinai.
A research associate professor of electrical and biomedical engineering at USC's Viterbi School of Engineering, Dr. Marcu is directing several USC graduate students and postdoctoral fellows in the creation of the optical imaging devices, hardware and software. She is working in conjunction with the neurosurgeons and researchers at the Maxine Dunitz Neurosurgical Institute to adapt the system's clinical applications to central nervous system tissue, and is collaborating with cardiologists to pursue spectroscopic detection of atherosclerosis.
According to Dr. Marcu, first author of the article, the researchers found that high-grade gliomas are characterized by fluorescence emissions of longer duration overall, compared to those of normal tissue. Furthermore, gliomas can be distinguished by fluorescence lifetimes that differ at various wavelengths: glioma fluorescence is long-lived at certain short wavelengths but short-lived at some longer wavelengths. Analyzing the tissue in terms of both fluorescence intensity and fluorescence lifetime provides information that translates into a high level of diagnostic specificity.
Currently, the spectroscopic system consists of an optical instrument about the size of a ballpoint pen that is connected by a fiber-optic cable to a computer. Through a lens at the tip, the probe provides light and magnification for surgeons. Light from a nitrogen laser can be used to stimulate the molecules within cells and the light emitted from the cells is sent back to the data processing system.
The equipment is enabling the research teams to acquire accurate, repeatable measurements in living tissue and is serving as a prototype for future diagnostic technology. Dr. Marcu, a biomedical engineer specialized in optical spectroscopy and imaging, said a number of technological challenges are being addressed.
''Most of the earlier investigations were done in my laboratory on the optical table,'' she said. ''Now we're in a new stage in which we have put together optical instrumentation that can go onto a standard endoscopic cart in the operating room.''
Before fluorescence spectroscopy can become routine in the operating room, the equipment must be miniaturized and fine-tuned, and the information displayed must be simplified, said Dr. Marcu. ''At present, we look at a computer screen that contains information about the tissue. But we hope to develop miniature systems that provide yes or no answers -- perhaps a light that changes colors to show which tissue is healthy and which is diseased. It will recognize in real time the characteristics of the tissue.''
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