Scientists have uncovered details of an immune-cell environment conducive to HIV infection that persists at the location of HSV-2 genital skin lesions long after they have been treated with oral doses of the drug acyclovir and have healed and the skin appears normal. These findings are published in the advance online edition of Nature Medicine on Aug. 2.

Led by Lawrence Corey, M.D., and Jia Zhu, Ph.D., of the Fred Hutchinson Cancer Research Center and Anna Wald, M.D., M.P.H., of the University of Washington, both in Seattle, the study was funded mainly by the National Institute of Allergy and Infectious Diseases (NIAID) with support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, both part of the National Institutes of Health.

“The findings of this study mark an important step toward understanding why HSV-2 infection increases the risk of acquiring HIV and why acyclovir treatment does not reduce that risk,” says NIAID Director Anthony S. Fauci, M.D. “Understanding that even treated HSV-2 infections provide a cellular environment conducive to HIV infection suggests new directions for HIV prevention research, including more powerful anti-HSV therapies and ideally an HSV-2 vaccine.”

One of the most common sexually transmitted infections worldwide, HSV-2 is associated with a two- to three-fold increased risk for HIV infection. Some HSV-2-infected people have recurring sores and breaks in genital skin, and it has been hypothesized that these lesions account for the higher risk of HIV acquisition. However, recent clinical trials, including an NIAID-funded study completed last year, demonstrated that successful treatment of such genital herpes lesions with the drug acyclovir does not reduce the risk of HIV infection posed by HSV-2 (http://www3.niaid.nih.gov/news/newsreleases/2008/hptn039.htm). The current study sought to understand why this is so and to test an alternative theory.

“We hypothesized that sores and breaks in the skin from HSV-2 are associated with a long-lasting immune response at those locations, and that the response consists of an influx of cells that are a perfect storm for HIV infection,” says Dr. Corey, co-director of the Vaccine and Infectious Diseases Institute at The Hutchinson Center and head of the Virology Division in the Department of Laboratory Medicine at the University of Washington. “We believe HIV gains access to these cells mainly through microscopic breaks in the skin that occur during sex.”

The research team took biopsies of genital skin tissue from eight HIV-negative men and women who were infected with HSV-2. These biopsies were taken at multiple time points: when the patients had genital herpes sores and breaks in the skin, when these lesions had healed, and at two, four and eight weeks after healing. The researchers also took biopsies from four of the patients when herpes lesions reappeared and the patients underwent treatment with oral acyclovir. The scientists continued to take biopsies at regular intervals for 20 weeks after the lesions had healed. For comparison, the investigators also took biopsies from genital tissue that did not have herpes lesions from the same patients.

Previous research has demonstrated that immune cells involved in the body’s response to infection remain at the site of genital herpes lesions even after they have healed. The scientists conducting the current study made several important findings about the nature of these immune cells. First, they found that CD4+ T cellsthe cells that HIV primarily infectspopulate tissue at the sites of healed genital HSV-2 lesions at concentrations 2 to 37 times greater than in unaffected genital skin. Treatment with acyclovir did not reduce this long-lasting, high concentration of HSV-2-specific CD4+ T cells at the sites of healed herpes lesions.

Second, the scientists discovered that a significant proportion of these CD4+ T cells carried CCR5 or CXCR4, the cell-surface proteins that HIV uses (in addition to CD4) to enter cells. The percentage of CD4+ T cells expressing CCR5 during acute HSV-2 infection and after healing of genital sores was twice as high in biopsies from the sites of these sores as from unaffected control skin. Moreover, the level of CCR5 expression in CD4+ T cells at the sites of healed genital herpes lesions was similar for patients who had been treated with acyclovir as for those who had not.

Third, the scientists found a significantly higher concentration of immune cells called dendritic cells with the surface protein called DC-SIGN at the sites of healed genital herpes lesions than in control tissue, whether or not the patient was treated with acyclovir. Dendritic cells with DC-SIGN ferry HIV particles to CD4+ T cells, which the virus infects. The DC-SIGN cells often were near CD4+ T cells at the sites of healed lesionsan ideal scenario for the rapid spread of HIV infection.

Finally, using biopsies from two study participants, the scientists found laboratory evidence that HIV replicates three to five times as quickly in cultured tissue from the sites of healed HSV-2 lesions than in cultured tissue from control sites.

All four of these findings help explain why people infected with HSV-2 are at greater risk of acquiring HIV than people who are not infected with HSV-2, even after successful acyclovir treatment of genital lesions.

“HSV-2 infection provides a wide surface area and long duration of time for allowing HIV access to more target cells, providing a greater chance for the initial ’spark’ of infection,” the authors write. This spark likely ignites once HIV penetrates tiny breaks in genital skin that commonly occur during sex. “Additionally,” the authors continue, “the close proximity to DC-SIGN-expressing DCs [dendritic cells] is likely to fuel these embers and provide a mechanism for more efficient localized spread of initial infection.” The investigators conclude that reducing the HSV-2-associated risk of HIV infection will require diminishing or eliminating the long-lived immune-cell environment created by HSV-2 infection in the genital tract, ideally through an HSV vaccine. Further, they hypothesize that other sexually transmitted infections (STIs) may create similar cellular environments conducive to HIV infection, explaining why STIs in general are a risk factor for acquiring HIV.

For more information about HIV/AIDS research, go to http://www3.niaid.nih.gov/topics/HIVAIDS/, and for more information about HSV-2 research, go to http://www3.niaid.nih.gov/topics/genitalHerpes/default.htm.

NIAID conducts and supports researchat NIH, throughout the United States, and worldwideto study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH)The Nation’s Medical Research Agencyincludes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

References: J Zhu et al. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nature Medicine DOI: 10.1038/nm2006 (2009).

C Celum et al. Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial. Lancet DOI: 10.1016/S0140-6736(08)60920-4 (2008).

In the last few years, researchers have shown that the severed wires of the spinal cord, called axons, can be induced to regenerate into and beyond sites of experimental spinal cord injury. But a key question has been how these regenerating axons, on reaching the end of an injury site, can be guided to a correct cell target when faced with millions of potential targets. Further, can regenerating axons form functional, electrical connections called synapses?

“The ability to guide regenerating axons to a correct target after spinal cord injury has always been a point of crucial importance in contemplating translation of regeneration therapies to humans,” said senior author Mark Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and neurologist at the Veterans Affairs San Diego Health System. “While our findings are very encouraging in this respect, they also highlight the complexity of restoring function in the injured spinal cord.”

The UC San Diego study looked at regenerating sensory axons in rat models of spinal cord injury. Sensory systems of the body send axons long, slender projections of the neuron into the spinal cord to convey information regarding touch, position, and pain. Many sensory axons are covered by an insulating myelin sheath which helps these impulses travel efficiently to the brain.

In certain spinal cord injuries, the axons are severed and the myelin sheath damaged. Loss of these systems results in an inability to feel or sense the body. The axons can no longer link to their targets in the brain, which blocks the electrical impulses from reaching the central nervous system.

The UC San Diego scientists showed that regenerating axons can be guided to correct targets using a type of chemical hormone called a growth factor. The team utilized a type of chemical hormone, a nervous system growth factor called neurotrophin-3 (NT-3), to guide regenerating sensory axons to the appropriate target and support synapse formation. Regeneration required two other treatments at the same time: placing a cell bridge in the spinal cord injury site to support axon growth, and a “conditioning” stimulus to the injured neuron that turned on regeneration genes for new growth.

When the growth factor was placed in the correct target as a guidance cue, axons regenerated into it and formed synapses. When the growth factor was placed in the wrong target, axons also followed the growth factor and grew into the wrong region.

Using high-resolution imaging systems, the scientists showed that regenerating axons guided to the correct cell formed synapses that were precisely on target. These axons contained rounded vesicles small packets at the end of the axon, packed with the chemical messengers needed to support electrical activity in the newly formed circuit.

Nonetheless, the connections were not electrically active. Additional study revealed the likely reason for this: the regenerating axons were not covered in myelin, the insulating material of the nervous system.

“Restoring axonal circuitry is complex, requiring several concurrent therapies to achieve axonal regeneration into and beyond a spinal cord lesion site,” said Tuszynski. “But, just as an electrical circuit needs insulation so it doesn’t short-circuit, it appears that these regenerating axons require restoration of the myelin sheath to ultimately restore function.” This will be the next step in the team’s research.

In earlier research (reported in PNAS April 6), the UC San Diego team achieved the first corticospinal motor axon regeneration by genetically engineering injured neurons to over-express receptors for another type of nervous system growth factor called brain-derived neurotrophic factor (BDNF). The growth factor was delivered to a brain lesion site in injured rats, where axons responded and regenerated into the injury site.

The lead author of the Nature Neuroscience study is Laura Taylor Alto of UCSD’s Department of Neurosciences. Additional contributors include Leif A. Havton of UCLA, and James M. Conner, Edmund R. Hollis II and Armin Blesch of UCSD Department of Neurosciences. Their work was supported by the National Institutes of Health, the Veterans Administration, the International Spinal Research Trust, Wings for Life, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Bernard and Anne Spitzer Charitable Trust.

University of California - San Diego

Limits in current technology keep doctors from being able to monitor the growth of the placenta, which, like the gas tank of a car, is the source of fuel for the fetus. The placenta can be so small that the fetus literally runs out of food and oxygen and dies, according to lead author Harvey J. Kliman, M.D., a research scientist in the Department of Obstetrics, Gynecology and Reproductive Sciences. He and his colleagues published the results of their findings in the August 3 issue of the American Journal of Perinatology.

Fetal death, or intrauterine fetal demise (IUFD), affects 30,000 women each year in the United States. Until now, there has been no easy way to determine how much gas is left in the placentas tank.

Kliman decided to study this issue after noting that many late-term pregnancy losses were associated with very small placentas. He theorized that in much the same way that an obstetrician uses ultrasounds to follow the growth of the fetus, or a pediatrician weighs and measures children to ensure they are growing normally, the growth of the fetus placenta could be monitored.

When Kliman asked perinatologists (maternal fetal medicine specialists) why they did not look at the placenta when performing routine ultrasounds, the answer was always the same: The placenta is a curved structure and is too difficult to measure. If they had to measure the placental volume they would need a very expensive machine, specialized training and more time.

With the help of his father, Merwin Kliman, a mathematician and electrical engineer, Kliman developed an equation that used the maximal width, height and thickness of the placenta. Kliman and his team at Yale then validated the method by comparing the volume predicted by the Estimated Placenta Volume (EPV) equation taken just before delivery to the actual weight of the placenta at the time of delivery.

In this study, we showed that the equation predicted the actual placental weight with an accuracy of up to 89 percent, said Kliman. The method works best during the second and early third trimesters, just when routine ultrasound screening is done on many women in the U.S.

In addition to validating the equation, the team is also collecting EPV data from centers around the world to create the normative curves that doctors can use to determine if the placenta is normal, too small or even too big. I hope that the EPV test becomes routine for pregnant women, said Kliman.

Other authors on the study include Humberto Azpurua, M.D., Edmund F. Funai, M.D., Luisa M. Coraluzzi, Leo F. Doherty, M.D., Isaac E. Sasson, M.D., and Merwin Kliman.

Citation: American Journal of Perinatology (August 3, 2009)

Yale University

SAN FRANCISCO, August 1, 2009 The world’s top lung cancer specialists, medical professionals and researchers are convening this week in San Francisco, CA for the 13th World Conference on Lung Cancer (WCLC), organized by the International Association for the Study of Lung Cancer (IASLC). According to a series of studies presented today at the WCLC, targeted therapies, as first-line treatment, have the potential to slow cancer growth and improve patient outcomes. Unlike traditional chemotherapy-based treatments, which destroy cancerous and non-cancerous cells alike, targeted therapies are designed to inhibit only cancer cell replication and tumor growth and are generally well tolerated by patients.

“The studies presented at the WCLC confirm that targeted therapies are on the forefront of treatment innovation and show improved efficacy and prolonged progression-free survival time compared to chemotherapy and combination treatments,” said David Gandara, M.D., WCLC program chair. “Moreover, since the medicines are orally administered, patients can receive treatment in-home versus in a hospital setting, easing the burden on patients and caregivers.”

To dial in to press conference:
U.S. Toll-free Dial-In Number: (800) 230-1074
International Dial-In Number: (612) 234-9959
Verbal Passcode: “lung cancer press conference”
To view press conference slides:
http://www.2009worldlungcancer.org
Click on Press and Media link

CLINICAL OUTCOMES OF PATIENTS WITH EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) MUTATIONS IN IPASS (IRESSATM PAN ASIA STUDY) (ABSTRACT # B9.5)

An epidermal growth factor receptor (EGFR) is a protein found on the surface of cells to which an epidermal growth factor (EGF) binds. When an EGF attaches to an EGFR, it activates the enzyme tyrosine kinase, triggering reactions that cause the cells to grow and multiply. An EGFR is found at abnormally high levels on the surface of many types of cancer cells, which may divide excessively in the presence of an EGF. The drug gefitinib is intended to attach to the EGFR and, thereby, inhibit the attachment of EGF and stop cancer cell division.

IPASS is a randomized phase III study that compared oral gefitinib with chemotherapy as first-line therapy and analyzed the treatment efficacy by EGFR mutation status. Of 1,217 enrolled patients in IPASS, 437 samples were available to assess for EGFR mutation, and 261 were found to be EGFR mutation-positive. The study assessed the clinical outcomes of objective response rate and progression-free survival among patients with an EGFR mutation versus those without.

“Our findings show that gefitinib had longer progression-free survival and greater objective response rate compared to chemotherapy in patients with EGFR mutations,” said Tony Mok, M.D., lead author and professor of clinical oncology at the Chinese University of Hong Kong. “Most notably, we found that responses to both gefitinib and chemotherapy were observed in the small group of patients with T790M mutations, which have previously been reported to be associated with resistance to EGFR tyrosine kinase inhibitors.”

Dr. Mok will present this study on Saturday, August 1, 2009 at 3:20 pm PT in Moscone West, Room 2001-2005, Level 2.

EFFICACY AND SAFETY OF ERLOTINIB AS FIRST-LINE MAINTENANCE IN NSCLC FOLLOWING NON-PROGRESSION WITH CHEMOTHERAPY: RESULTS FROM THE PHASE III SATURN STUDY (ABSTRACT # A2.1)

Erlotinib is an effective and well-tolerated treatment for patients with advanced non-small cell lung cancer (NSCLC) whose disease has progressed after chemotherapy, aimed at extending survival. The phase III SATURN study was initiated to evaluate the efficacy and safety of erlotinib as a first-line maintenance therapy following chemotherapy for patients whose cancer had not progressed following initial treatment.

Erlotinib targets a protein called the epidermal growth factor receptor (EGFR). EGFR, which helps cells divide, is found at abnormally high levels on the surface of many types of cancer cells, including many cases of NSCLC.

The study enrolled 1,949 patients, and 889 of which did not have progressive disease following four cycles of chemotherapy and were randomized to 150 mg/day of erlotinib or placebo. Patients who received erlotinib experienced significantly prolonged progression-free survival (PFS) over those on placebo a 29 to 31 percent reduction in risk of progression with erlotinib or an increase of progression-free survival time of 41 to 45 percent. The disease control rate (including patients whose tumors disappeared or reduced in size or did not get larger) was 40.8 percent with erlotinib versus 27.4 percent with placebo. The study also met a key secondary endpoint of extending overall survival in patients who received erlotinib immediately after initial chemotherapy. A statistically significant improvement in overall survival was seen in this pre-planned final analysis of the total patient population.

Further, a PFS benefit was seen with erlotinib regardless of the patient’s gender, smoking history, ethnicity, or whether testing indicated the patient’s tumor expressed the EGFR.

“The results of this study broaden the patient population for whom erlotinib can be effective,” said Federico Cappuzzo, M.D., lead author and professor and vice director of the Department of Medical Oncology at Instituto Clinico Humanitas in Milan, Italy. “Given that lung cancer is the leading cause of cancer deaths worldwide and that NSCLC is the most common and deadly form of lung cancer, the PFS time that erlotinib can offer represents a significant advance in treatment of this disease.”

Dr. Cappuzzo will present this study on Saturday, August 1 at 2:30 pm PT in Moscone West, Room 2001-2005, Level 2.

MOLECULAR MARKERS AND CLINICAL OUTCOME WITH ERLOTINIB: RESULTS FROM THE PHASE III PLACEBO-CONTROLLED SATURN STUDY OF MAINTENANCE THERAPY FOR ADVANCED NSCLC (ABSTRACT # B9.1)

In another segment of the SATURN study, researchers further examined the efficacy of erlotinib as a maintenance therapy in non-progressive disease patients after first-line platinum-containing chemotherapy. Currently the indications for erlotinib are limited to its use as a second- or third-line agent after failure of first-line chemotherapy.

To expand the potential for the use of erlotinib, Wolfram Brugger, M.D., Ph.D., head of the Department of Hematology, Oncology and Immunology at Schwarzwald-Baar Clinic in Germany, and his team of researchers conducted the phase III, placebo-controlled SATURN study to evaluate the efficacy of erlotinib as a maintenance therapy.

Dr. Brugger enrolled a total of 889 non-small cell lung cancer (NSCLC) patients and treated them with either 150mg/day of erlotinib or placebo after four cycles of platinum-based doublet chemotherapy. Researchers evaluated molecular markers including EGFR protein and EGFR gene copy number, EGFR- and KRAS-mutations and EGFR polymorphism in order to potentially identify predictive markers for erlotinib therapy.

Both arms of the trial were well represented in patient and disease characteristics, specifically regarding biomarker status. Dr. Brugger and his team determined that the use of erlotinib provided a clinical benefit in terms of both progression-free and overall survival for all patients, regardless of the status of biomarkers.

“This study demonstrates the tremendous potential for erlotinib and the potential for its expanded use as a maintenance therapy,” says Dr. Brugger. “The addition of an effective tool physicians can use to maintain a cancer-free state in their patients is crucial to prolonged survival.”

Dr. Brugger will present this study on Saturday, August 1 at 2:30 pm PT in Moscone West, Room 2001-2005, Level 2.

VANDETANIB PLUS DOCETAXEL VERSUS DOCETAXEL AS SECOND-LINE TREATMENT FOR PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER: A RANDOMIZED, DOUBLE-BLIND PHASE III TRIAL (ZODIAC) (ABSTRACT # C2.2)

Vandetanib is an orally administered medication that targets two receptors already known to play a role in non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These receptors are targeted separately by other drugs, but vandetanib is the first drug designed to target both.

In previous research, the addition of vandetanib to chemotherapy was shown to prolong the progression-free survival (PFS) and improve response rate in patients with previously treated advanced NSCLC. To expand upon these findings, researchers conducted a phase III study to further evaluate whether vandetanib plus chemotherapy prolonged the PFS of advanced NSCLC patients when compared to chemotherapy alone.

Over two years, 1,391 patients were recruited to participate in the study. Patients were randomized to receive chemotherapy with vandetanib or chemotherapy with the placebo. A statistically significant difference in PFS was seen (HR = 0.79) in favor of vandetanib. The median PFS time was 17.3 weeks in the vandetanib arm versus 14 weeks in the control arm. While there was no statistical difference in overall survival, a significant improvement in objective response rate was observed. Vandetanib treatment was also associated with a statistically significant improvement in symptoms related to the underlying cancer.

“Clearly in a disease as heterogeneous as lung cancer, the need to target multiple pathways has become paramount. This agent, targeting two key pathways critical for non-small cell lung cancer growth and metastasis, is novel and could play a key role,” said Roy S. Herbst, M.D., Ph.D., chief of thoracic medical oncology at the University of Texas M.D. Anderson Cancer Center and the study’s lead author. “The fact that more patients had an improvement in the symptoms from their lung cancer suggests that the drug could be important for the future management of this disease.”

Dr. Herbst will present this study on Saturday, August 1, 2009 at 10:40 am PT in Moscone West, Room 2007-2011, Level 2. Please note that this research was also presented at the 2009 ASCO Annual Meeting.

A RANDOMIZED PHASE III STUDY OF GEFITINIB VERSUS STANDARD CHEMOTHERAPY (GEMCITABINE PLUS CISPLATIN) AS A FIRST-LINE TREATMENT FOR NEVER-SMOKERS WITH ADVANCED OR METASTATIC ADENOCARCINOMA OF THE LUNG (ABSTRACT # PRS.4)

Doctors are constantly on the look out for advancements to better treat and tailor cancer treatment to the individual. Targeted therapies have been introduced that have improved standard chemotherapy approaches. Combining targeted therapies in specific patients with lung cancer may reduce the need for chemotherapy, and increased understanding of the targets involved in the pathogenesis of lung cancer may help to individualize drug therapy. One of these targeted therapies is gefitinib, a tyrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR), a protein that causes cancer cells to divide. Gefitinib has shown high response rate and extended survival in never-smoker lung cancer patients, especially in those with an EGFR mutation.

In this randomized phase III trial, researchers sought to compare the efficacy of gefitinib as a first-line treatment with standard chemotherapy in patients who were never-smokers. Investigators randomized 309 never-smokers living with late-stage lung cancer into two groups. One group received gefitinib and the other group received chemotherapy.

While the gefitinib did not show an improved overall survival, results showed the group receiving gefitinib had a higher response rate and a significantly better progression-free survival (PFS, length of time during and after treatment when a patient’s disease does not worsen) than those receiving chemo. Also, high-grade toxicity was less common in the gefitinib group than in the chemotherapy group.

Additionally, in the gefitinib group, PFS in the mutation-negative subgroup was shorter than that of the mutation-positive group (with a median of 2.1 vs. 8.4 months). There was no difference between these two subgroups in the chemotherapy group.

“Gefitinib did not improve overall survival over the standard chemotherapy,” said Jin S. Lee, M.D. of the National Cancer Center Korea in Goyang, Korea. “However, a promising survival outcome along with high overall response rate and better toxicity profile suggests that gefitinib might be a reasonable first-line therapy for this group of never-smoker lung cancer patients.”

Dr. Lee will present this study on Monday, August 3 at 9:35 am PT in Moscone West, Ballroom, Level 3.

EFFICIENCY OF MAINTENANCE ERLOTINIB VERSUS PLACEBO IN PATIENTS WITH UNRESECTABLE STAGE III NON-SMALL LUNG CANCER (NSCLC) FOLLOWING CONCURRENT CHEMORADIATION (D0410, NCT00153803) (ABSTRACT # C6.1)

Currently, the role of maintenance therapy following concurrent treatment with chemotherapy and radiotherapy (cCRT) in patients with unresectable stage III non-small lung cancer (NSCLC) remains undefined, and concern has been noted with maintenance therapies. To examine alternative treatment options, this trial was designed to evaluate the effectiveness of maintenance erlotinib following cCRT in unresectable stage III NSCLC patients.

In this upfront, randomized, placebo-controlled phase III trial, scientists randomly assigned 243 patients with unresectable stage III NSCLC to receive erlotinib or placebo daily following their cCRT.

In the intent-to-treat analysis, there was no statistically significant difference in the primary endpoint of progression-free survival (PFS). In a retrospective, subset analysis of subjects dispensed erlotinib following cCRT, their median PFS rate was 13.5 months compared to 10.4 months for subjects randomized to placebo. Furthermore, the median overall survival rate was 30.4 months for erlotinib compared to only 25.1 months for the placebo.

Time to disease progression was delayed in the intent-to-treat analysis for participants randomized to erlotinib and significantly delayed in subjects dispensed erlotinib in the retrospective, subset analysis.

“Based on these trends NSCLC patients exposed to maintenance erlotinib after cCRT treatment, we can conclude that this maintenance therapy may prolong disease progression,” says James R. Rigas, M.D., lead author and Director of the Comprehensive Thoracic Oncology Program at Dartmouth-Hitchcock Norris Cotton Cancer Center. “While more research is needed, we are encouraged by these results and believe erlotinib could be a new maintenance therapy for high risk, stage III patients.”

Dr. Rigas will present this study on Monday, August 3 at 10:30 am PT in Moscone West, Room 2002-2004, Level 2.

ABOUT LUNG CANCER

Lung cancer is the uncontrolled growth of abnormal cells in one or both lungs. As they grow, the abnormal cells can form tumors and impede the function of the lung, which is to provide oxygen to the body via the blood. Approximately 1.3 million new cases of lung cancer will be diagnosed this year, and the disease remains the leading cause of cancer deaths worldwide.

Founded in 1972, the International Association for the Study of Lung Cancer (IASLC) is an international organization of 2,000 lung cancer specialists, spanning 53 countries. IASLC members work towards developing and promoting the study of etiology, epidemiology, prevention, diagnosis, treatment and all other aspects of lung cancer. IASLC’s mission is to enhance the understanding and education of lung cancer to scientists, members of the medical community and the public. In addition to the biannual meeting, the IASLC publishes the Journal of Thoracic Oncology, a prized resource for medical specialists and scientists who focus on the detection, prevention, diagnosis and treatment of lung cancer.

Now researchers at Washington University School of Medicine in St. Louis have modeled Parkinson’s-associated dementia for the first time. Scientists showed that a single night of sleep loss in genetically altered fruit flies caused long-lasting disruptions in the flies’ cognitive abilities comparable to aspects of Parkinson’s-associated dementia. They then blocked this effect by feeding the flies large doses of the spice curcumin.

“Clinical trials of curcumin to reduce risk of Parkinson’s disease are a future possibility, but for now we are using the flies to learn how curcumin works,” says author James Galvin, M.D., a Washington University associate professor of neurology who treats patients at Barnes-Jewish Hospital. “This should help us find other compounds that can mimic curcumin’s protective effects but are more specific.”

Galvin and senior author Paul Shaw, Ph.D., assistant professor of neurobiology, publish their results in the journal Sleep on Aug. 1.

Galvin is an expert in cognitive impairments in human Parkinson’s disease; Shaw studies sleep and the brain in fruit flies. The researchers decided collaborate based in part on evidence that increased sleep loss in Parkinson’s patients can precede or coincide with increased severity in other Parkinsonian symptoms.

More than 74 percent of Parkinson’s patients have trouble sleeping, and up to 80 percent of patients 65 and older who have Parkinson’s disease for seven years will develop dementia, according to Galvin.

Shaw’s lab has linked sleep loss to changes in the dopaminergic system of the brain, the part of the brain that produces the neurotransmitter dopamine and is at the center of the damage caused by Parkinson’s.

“In healthy flies, sleep deprivation decreases dopamine receptor production and causes temporary learning impairments that are fully restored after a two-hour nap,” Shaw says.

Shaw and Galvin studied fruit flies genetically modified to make a human protein called alpha-synuclein in their brains. Scientists don’t yet know what alpha-synuclein does, nor have they found a fly counterpart for it. But they have shown that it aggregates in the brains of Parkinson’s disease patients and believe the processes that cause the aggregations are harming dopamine-producing cells.

Prior studies of fruit flies with human alpha-synuclein in their brains showed that the flies, like human Parkinson’s patients, also lose dopamine-producing neurons, have movement-related problems and develop alpha-synuclein aggregations. But scientists had yet to evaluate the flies for signs of dementia.

Lead author Laurent Seugnet, Ph.D., research associate at L’Ecole Suprieure de Physique Chimie Industrielles in France, first tested the flies’ learning ability using a procedure he helped develop in Shaw’s lab. For the test, Seugnet placed flies in a vial with two branches: one lighted branch containing quinine, a bitter-tasting substance flies prefer to avoid; and a darkened but quinine-free branch. After a few trials, normal flies learn to suppress their natural attraction to the light and fly into the darkened vial instead to avoid the quinine.

Flies with alpha-synuclein in their brains could still learn when they were middle-aged, or about 16 to 20 days old. But when Seugnet deprived them of sleep for 12 hours, he found that their ability to remember was more severely impaired than that of young healthy flies that had also been sleep-deprived.

“This was still true even 10 days later, so it seemed to be a lasting effect,” says Seugnet.

Galvin had earlier found that curcumin, a derivative of the spice turmeric, blocks alpha-synuclein aggregation in cell models of Parkinson’s disease. Based on this, Seugnet fed curcumin to a new batch of flies, repeated the tests and found middle-aged flies with alpha-synuclein retained their ability to learn as well as normal young flies.

“Thanks to this model our labs have created, Dr. Galvin and I can not only quickly test potential new treatments for these symptoms of Parkinson’s, we can also move up our treatments in terms of the timeline along which the disorder develops,” says Shaw. “That may give us a real chance to change the course of the disease.”

Seugnet L, Galvin JE, Suzuki Y, Gottschalk L, Shaw PJ. Persistent short-term memory defects following sleep deprivation in a Drosophila model of Parkinson disease. Sleep, Aug. 1, 2009

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

HCC is the fifth most common cancer and the third most frequent cause of cancer death worldwide. Risk factors for HCC include chronic infection with hepatitis B virus, hepatitis C virus (HCV), dietary aflatoxin, excessive alcohol use, cigarette smoking, diabetes and obesity. The overall 5-year survival for HCC patients is less than 10% and the disease rate is expected to rise due to the high prevalence of HCV in many areas of the world.

Shelly Lu, M.D., of the Keck School of Medicine at the University of Southern California, and colleagues studied the effects of SAMe on chemoprevention and treatment of HCC. In the U.S. the incidence of HCC doubled from 1979 to 1995 and the number of HCC cases for the following 20 to 30 years is projected to increase. Given these projections, there is a tremendous interest in developing effective chemoprevention strategies, said Dr. Lu. And an important property of SAMe that makes it an attractive agent for chemoprevention and treatment of HCC is its ability to selectively kill liver cancer cells, she added.

During the study researchers injected H4IIE cells into rats and found a 1cm tumor developed in the liver two weeks after injection. A regimen of IV SAMe was started one day after injecting the cells and continued for ten days. The researchers monitored the animals using MRI, ultrasound, and visual inspection to assess the liver tumors. Treatment with IV SAMe by continuous infusion significantly reduced the tumor size and significantly prevented tumor development after 11 days, researchers discovered.

Researchers found that if SAMe infusion was started after sizable tumors had already formed it failed to reduce the rate of tumor growth after 24 days of treatment. This is because of a compensatory response of the liver to metabolize SAMe and prevent its accumulation. The observation that SAMe failed to exert any therapeutic effect in already established HCC is disappointing, said Dr. Lu. But whether SAMe can be effective in treating HCC in man remains unclear because this compensatory mechanism may not work properly in human HCC. Nevertheless, effectiveness of SAMe in chemoprevention of human HCC deserves study now.

#############################

Article: S-Adenosylmethionine in the Chemoprevention and Treatment of Hepatocellular Carcinoma in a Rat Model, Shelly Lu, Komal Ramani, Xiaopeng Ou, Mark Lin, Victor Yu, Kwangsuk Ko, Ryan Park, Teodoro Bottiglieri, Hidekazu Tsukamoto, Gary Kanel, Samuel French, Jos Mato, Rex Moats, Edward Grant Hepatology, August 2009

http://www3.interscience.wiley.com/journal/122305560/abstract

Everyone knows that vitamins “from A to zinc” are important for good health. Now, a new research study in the August 2009 print issue of the Journal of Leukocyte Biology (http://www.jleukbio.org) suggests that zinc may be pointing the way to new therapeutic targets for fighting infections. Specifically, scientists from Florida found that zinc not only supports healthy immune function, but increases activation of the cells (T cells) responsible for destroying viruses and bacteria.

“It has been shown that zinc supplementation significantly reduces the duration and severity of childhood diarrhea, lower respiratory infections, and incidence of malaria in zinc-deficient children,” said report co-author, Robert Cousins, Ph.D., who also is the director of the Center for Nutritional Sciences within the Food Science and Human Nutrition Department at the University of Florida. “Age-related declines in immune function have also been related to zinc deficiency in the elderly.”

Scientists administered either a zinc supplement or a placebo to healthy volunteers to assess the effects of zinc on T cell activation. After isolating the T cells from the blood, scientists then simulated infection in laboratory conditions. Results showed that T cells taken from the zinc-supplemented group had higher activation than those from the placebo group. Specifically, cell activation stimulated the zinc transporter in T cells called “ZIP8,” which transports stored zinc into the cell cytoplasm where it then alters the expression of a T cell protein in a way needed to fight infections.

“As the debate over zinc supplementation in healthy individuals continues,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, “studies like this help shed light on how zinc may enhance the ability of our immune systems to fight off foreign invaders. Equally important, this work points toward new possible targets for entirely new drugs to help augment immune function and prevent or stop infections that might be resistant to traditional antibiotics.”

The Journal of Leukocyte Biology (http://www.jleukbio.org) publishes peer-reviewed manuscripts on original investigations focusing on the cellular and molecular biology of leukocytes and on the origins, the developmental biology, biochemistry and functions of granulocytes, lymphocytes, mononuclear phagocytes and other cells involved in host defense and inflammation. The Journal of Leukocyte Biology is published by the Society for Leukocyte Biology.

Details: Tolunay B. Aydemir, Juan P. Liuzzi, Steve McClellan, and Robert J. Cousins Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN- expression in activated human T cells. J Leukoc Biol 2009 86: 337. http://www.jleukbio.org/cgi/content/abstract/86/2/337

Federation of American Societies for Experimental Biology

Led by Georg Schett of the University of Erlangen-Nuremberg in Erlangen, Germany, the study involved 912 healthy individuals in Bruneck, Italy, 60 of whom underwent hip or knee replacement surgery due to severe OA in a 15-year follow-up period. Subjects underwent a baseline exam in 1990 and followup exams were performed every five years until 2005. Blood samples were analyzed for VCAM-1, a sialoglycoprotein (a combination sugar and protein) expressed on cells in the cartilage and connective tissue.

The results showed that VCAM-1 levels were substantially elevated in the 60 individuals who underwent joint replacement, with the highest baseline levels seen in those who underwent bilateral joint replacement. “The level of VCAM-1 emerged as a significant predictor of the risk of joint replacement due to severe OA, equaling or even surpassing the effects of age,” the authors state. They also note that inclusion of VCAM-1 levels in risk prediction models resulted in a more accurate classification of individuals.

VCAM-1 promotes leukocyte adhesion and homing to sites of inflammation. In chondrocytes (cartilage cells), VCAM-1 expression is induced by inflammatory cytokines (proteins released by immune system ells). The authors suggest that increased VCAM-1 levels may therefore mirror active cartilage damage or an inflammatory component in OA. Since it mediates the interaction of chondrocytes with immune cells, VCAM-1 may also contribute to immune-mediated cartilage damage.

Establishing laboratory biomarkers of severe OA is important for a number of reasons. The standard risk factors of age and weight are not enough for accurate risk prediction, and since OA is a highly prevalent disease, it would be helpful to accurately identify those at greater risk of developing rapid progression or severe disease. Early diagnosis would also be beneficial because the disease is present before clinical symptoms are present. Finally, improved prediction of severe OA would help identify patients for treatment interventions such as aerobic exercise, strength training and weight loss and might also help tailor therapeutic measures.

“Further clarification of the mechanism underlying the association between VCAM-1 level and OA may well contribute to a better understanding of disease etiology,” the authors conclude, adding that application of their findings in routine clinical practice would require further studies to duplicate the results.

Wiley-Blackwell

Although early stage ovarian cancer can be treated with a combination of surgery followed by chemotherapy, there are currently no effective treatments for advanced ovarian cancer that has recurred after surgery and primary chemotherapy. Therefore, the majority of treated early stage cancers will relapse.

“This report is definitely a reason to hope. We now have a potential new therapy for the treatment of advanced ovarian cancer that has promise for targeting tumor cells and leaving healthy cells healthy,” said lead researcher Janet Sawicki, Ph.D., a professor at the Lankenau Institute for Medical Research.

Sawicki and colleagues at the Massachusetts Institute of Technology evaluated the therapeutic efficacy of a cationic biodegradable beta-amino ester polymer as a vector for the nanoparticle delivery of a DNA encoding diphtheria toxin suicide gene. These nanoparticles were injected into mice with primary or metastatic ovarian tumors.

To test the efficacy of this technique, the researchers measured tumor volume before and after treatment. They found that while treated tumors increased 2-fold, this was significantly less than the between 4.1-fold and 6-fold increase in control mice.

Furthermore, four of the treated tumors failed to grow at all, while all control tumors increased in size. Administration of nanoparticles to three different ovarian cancer mouse models prolonged lifespan by nearly four weeks and suppressed tumor growth more effectively, and with minimal non-specific cytotoxicity, than in mice treated with clinically relevant doses of cisplatin and paclitaxel.

Edward Sausville, M.D., Ph.D., an associate editor of Cancer Research and associate director for clinical research at the Greenebaum Cancer Center at the University of Maryland, said this report illustrates significant progress in targeted therapy.

“In oncology we have been studying ways to kill tumors for a long time, but much of this has run up against the real estate principle of location, location, location,” he said. “In other words, an effective therapy is not effective if it cannot get to the target.”

Sausville said a major accomplishment of this research is the multiple ways it can target ovarian cancer cells, as scientists were able to deliver diphtheria toxin genes, using a nanoparticle, to the actual tumor site (peritoneum) with a basis for selective activity in the cancer cells (how the toxin genes were regulated once inside the cells).

“A real plus of a cancer therapy like this is not just the functionality of the nanoparticle construct molecule, but the ability to deliver the toxin to the tumor cells,” said Sausville, who agrees that inception of clinical trials could be just 18 months away.

Subscribe to the Cancer Research RSS feed: http://cancerres.aacrjournals.org/rss/recent.xml

Learn more about nanotechnology through the following podcast from CR, the AACR’s magazine for patients, survivors and scientists:

http://www.crmagazine.org/archive/Crpodcasts/Pages/CancerNanotechnology.aspx

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 28,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and nearly 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.