Forefront is a complimentary magazine from the Mayo Clinic Cancer Center, a National Cancer Institute-designated cancer center located in Arizona, Florida and Minnesota. The Cancer Center specializes in translational research and the effort to discover better ways to prevent, detect and treat cancer. It serves diverse patient populations across a broad geographic area and collaborates across the full spectrum of cancer research, from basic biology to treatment.
Email edition available Forefront articles highlight Mayo Clinic’s cancer research and its translation into clinical advances. Forefront is published in print and online annually, but beginning in summer 2012 a complimentary quarterly email edition will also be available. Subscribers to the email version receive:
Gerardo Colon-Otero, M.D., with the Department of Hematology/Oncology at Mayo Clinic in Florida, discusses results of a randomized pilot study that show that an intervention that explains the benefits of hospice and addresses advanced directives early in the course of treatment leads to measurable improvement in the patient’s emotional and mental quality of life (QoL).
There is a paucity of randomized studies evaluating the value of palliative interventions on a prospective basis in newly diagnosed oncology patients. We sought to prospectively evaluate quality of life (QoL) outcomes in advanced cancer patients who received discussion-based palliative care interventions from an advanced registered nurse practitioner (ARNP) integrated into the oncology team, and compare these outcomes with a control population.
Patients with metastatic cancer were randomized to standard care or an ARNP-directed intervention that included discussions of the benefits of hospice, discussions on living wills and advanced directives (Five Wishes document) along with an assessment of QoL. Relevant endpoints included change from baseline QoL and improvement in hospice knowledge.
From Nov. 13, 2008, through July 28, 2009, 26 patients were accrued at the Mayo Clinic in Jacksonville, Fla. The study closed early due to published data demonstrating the benefits of early palliative care interventions in the management of metastatic cancer patients. Statistically significant improvements from baseline were noted in emotional and mental QoL assessments in the intervention group that were not seen in the control group. Patients found it useful to have the living will and Five Wishes documents offered as part of the ARNP intervention.
An ARNP-directed intervention that explains the benefits of hospice and addresses advanced directives early in the course of metastatic cancer patients’ treatment is well-received by the patients and their relatives and leads to measurable improvement in the patient’s emotional and mental QoL.
Jayant A. Talwalkar, M.D., a hepatologist with the Department of Gastroenterology and Hepatology and the Mayo Clinic Transplant Center in Rochester, Minn., discusses diagnosis, complications, liver transplantation, and Mayo’s role in the development of new diagnostic tests and effective therapies for patients with primary sclerosing cholangitis (PSC).
Dr. Talwalkar notes that PSC is the last major liver disease without effective treatment. There is currently no effective medical therapy to halt disease progression and so avoid complications such as liver failure or bile duct cancer for patients with PSC. PCS is considered an autoimmune condition. It develops silently, most often in patients 40-50 years.
Dr. Talwalkar’s team focuses on clinical trials for the development of diagnostic tests and effective drug therapies for PSC, before transplant is needed. Mayo specialists see several hundred patients with PSC each year.
Steven R. Ytterberg, M.D., with the Department of Rheumatology at Mayo Clinic in Rochester, Minn., discusses a study that examined similarities and differences between two forms of vasculitis: giant cell arteritis and Takayasu’s arteritis. Findings suggest that TAK and GCA may exist on a spectrum within the same disease. The study was published online on Feb. 10, 2012 in the Annals of the Rheumatic Diseases.
To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu’s arteritis (TAK) and giant cell arteritis (GCA).
Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorized by age at disease onset.
Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification.
Results Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset.
Computer-derived classification models distinguished TAK from GCA in two subgroups, defining 26 percent and 18 percent of the study sample; however, 56 percent of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA.
Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.
Authors Peter C. Grayson, Kathleen Maksimowicz-McKinnon,Tiffany M. Clark, Gunnar Tomasson, David Cuthbertson, Simon Carette, Nader A .Khalidi, Carol A. Langford, Paul A. Monach, Philip Seo, Kenneth J. Warrington, M.D., Steven R. Ytterberg, M.D., Gary S. Hoffman, and Peter A. Merkel, for the Vasculitis Clinical Research Consortium
C. Daniel Smith, M.D. , chair of the Department of Surgery at Mayo Clinic in Florida, discusses minimally invasive surgical options for patients with gastroesophageal reflux disease (GERD). A novel device, a ring of tiny magnetic titanium beads that acts to keep stomach acid from leaking into the esophagus, is now offered at Mayo Clinic in Florida. Read more about the LINX Reflux Management System in the April 11, 2012, edition of MedCity News.
Mayo Clinic in Florida is one of the first health care institutions in the U.S. to offer a newly approved device to treat GERD. Mayo Clinic in Florida helped test the device in patients. The U.S. Food and Drug Administration (FDA) approved the device and treatment procedure on March 22, 2012, for patients with GERD who continue to have chronic reflux symptoms despite taking medication. Mayo Clinic in Florida was one of 14 centers nationally that participated in a clinical trial that led to the FDA’s approval of the device.
About GERD In patients with gastroesophageal reflux disease, liquid or food in the stomach flow back up into the esophagus due to the inability of a ring of muscle between the lower esophagus and the top of the stomach to close properly. If drugs aimed at neutralizing the acid in the stomach fails to prevent GERD, an operation designed to correct the mechanical defect is considered. Nearly 2 million patients of those patients could benefit from this treatment, which is much less complex than current surgical options, says Dr. Smith.
The results of the clinical study that led to approval of the device have not yet been published. “The data presented to the FDA, however, revealed striking results when compared to other GERD treatments that have been investigated over the past 20 years,” says Dr. Smith. “The system offers effective control of GERD with limited side effects and thus far an excellent safety record.”
The implanted device is a ring of tiny magnetic titanium beads that is wrapped around the junction between the stomach and esophagus, serving as a mechanical augmentation of the lower esophageal sphincter (the ring of muscle). The magnetic attraction between the beads is strong enough to keep the sphincter closed to refluxing acid, but weak enough so that food can pass through it into the stomach. The device can be implanted using minimally invasive surgery methods.
“I expect this device to be a game changer for the treatment of GERD in select patients who have failed management with drugs,” says Dr. Smith.
Kenneth R. DeVault, M.D. , chair of the Department of Internal Medicine at Mayo Clinic in Florida, also participated in the studies. “I have many patients who are searching for something more than medication for their reflux, but have been hesitant to undergo a traditional reflux surgery,” he says. “I think this procedure may well be a very attractive option for that group.”
Drs. Smith and DeVault were consultants to the company that developed the device and participated in the research study. Mayo Clinic licensed related technology to the company in exchange for equity.
Randal J. Thomas, M.D., director of Mayo Clinic’s Cardiovascular Health Clinic, and colleagues found that patients who participate in cardiac rehabilitation after having heart interventions such as angioplasty, stents and clot-busting drugs have a 45 percent lower mortality rate.
The research team studied data from more than 2,300 patients between 1994 and 2008, and recently published the results inCirculation.
Only about 40 percent of patients in the study participated in cardiac rehabilitation. These findings are particularly important for interventional cardiologists, Dr. Thomas says, because encouraging patients to pursue cardiac rehab after their procedure can potentially save more lives than previously thought.
Mayo Clinic researchers have found that cardiac patients who have skin allergies to metals commonly found in jewelry, such as nickel, are at no higher risk for complications if they receive a stent containing these metal components.
Mayo Clinic cardiologist Rajiv Gulati, M.D., Ph.D., and colleagues studied a total of 29 patients with a history of skin allergies to stent metal components who subsequently underwent coronary stent implantation. The research team compared clinical outcomes with a matched control group of 250 non- metal allergic patients who received similar stents. In addition to following the study patients’ outcomes in the long term, the team reviewed blood to look for signs of allergic reactions.
Vanda A. Lennon, M.D., Ph.D., with the Departments of Laboratory Medicine and Pathology and Neurology, discusses research that identifies critical properties of neuromyelitis optica, a potentially debilitating neurological disease that is often misdiagnosed as multiple sclerosis (MS).
Dr. Lennon’s team isolated and identified an antibody unique to NMO that may interfere with the transport of the water. In some areas of autopsied brain tissue studied, there was an accumulation of water in the myelin itself that the team believes may lead to the secondary destruction of the myelin in NMO and potential misdiagnosis of NMO as MS.
ABSTRACT The astrocytic aquaporin-4 (AQP4) water channel is the target of pathogenic antibodies in a spectrum of relapsing autoimmune inflammatory central nervous system disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG. Neuromyelitis optica is the most severe of these disorders. The two major AQP4 isoforms, M1 and M23, have identical extracellular residues.
This report identifies two novel properties of NMO-IgG as determinants of pathogenicity:
The binding of NMO-IgG to the ectodomain of astrocytic AQP4 has isoform-specific outcomes. M1 is completely internalized, but M23 resists internalization and is aggregated into larger-order orthogonal arrays of particles that activate complement more effectively than M1 when bound by NMO-IgG.
NMO-IgG binding to either isoform impairs water flux directly, independently of antigen down-regulation.
We identified, in nondestructive central nervous system lesions of two NMO patients, two previously unappreciated histopathological correlates supporting the clinical relevance of our in vitro findings:
Reactive astrocytes with persistent foci of surface AQP4
Vacuolation in adjacent myelin consistent with edema
The multiple molecular outcomes identified as a consequence of NMO-IgG interaction with AQP4 plausibly account for the diverse pathological features of NMO: edema, iflammation, demyelination and necrosis.
Differences in the nature and anatomical distribution of NMO lesions, and in the clinical and imaging manifestations of disease documented in pediatric and adult patients, may be influenced by regional and maturational differences in the ratio of M1 to M23 proteins in astrocytic membranes.
Ayalew Tefferi, M.D., with the Department of Hematology at Mayo Clinic in Rochester, Minn., discusses the results of a study of 1,000 patients who have primary myelofibrosis.
Key findings Researchers found that when patients with myelofibrosis present, their clinical features are not at a steady state and usually progress within the first few months of the diagnosis. It is best to wait a several months before providing a prognostic score.
Many patients with primary myelofibrosis can live a long life (exceeding 15 years) and patients who won’t live that long can be identified.
The most recent version of DIPSS-plus scoring system performed much better than prior versions, helping researchers to determine what proportion of patients with myelofibrosis are suitable for therapies. More than 50 percent of patients require observation alone.
ABSTRACT Objective To share our decades of experience with primary myelofibrosis and underscore the importance of outcomes research studies in designing clinical trials and interpreting their results.
Patients and methods One thousand consecutive patients with primary myelofibrosis seen at Mayo Clinic between Nov. 4, 1977, and Sept. 1, 2011, were considered.
The International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus were applied for risk stratification. Separate analyses were included for patients seen at time of referral (N=1000), at initial diagnosis (N=340), and within or after 1 year of diagnosis (N=660).
To date, 592 deaths and 68 leukemic transformations have been documented. Parameters at initial diagnosis vs time of referral included:
Median age (66 vs 65 years)
Male sex (61% vs 62%)
Red cell transfusion need (24% vs 38%)
Hemoglobin level less than 10 g/dL (38% vs 54%)
Platelet count less than 100 × 109/L (18% vs 26%)
Leukocyte count more than 25 × 109/L (13% vs 16%)
Marked splenomegaly (21% vs 31%)
Constitutional symptoms (29% vs 34%)
Abnormal karyotype (31% vs 41%)
Mutational frequencies were 61% for JAK2V617F, 8% for MPLW515, and 4% for IDH1/2.
DIPSS-plus risk distributions at time of referral were 10% low, 15% intermediate-1, 37% intermediate-2, and 37% high. The corresponding median survivals were 17.5, 7.8, 3.6, and 1.8 years vs 20.0, 14.3, 5.3, and 1.7 years for patients younger than 60 years of age.
Compared with both DIPSS and IPSS, DIPSS-plus showed better discrimination among risk groups. Five-year leukemic transformation rates were 6% and 21% in low- and high-risk patients, respectively.
Conclusion The current document should serve as a valuable resource for patients and physicians and provides context for the design and interpretation of clinical trials.
Rosebud O. Roberts, M.B.Ch.B. with the Division of Epidemiology, discusses a study that measured the incidence of MCI and its subtypes using published criteria. Results showed a statistically significant difference between incidence rates among men and women. The study also found that individuals with only a high school education developed either aMCI or naMCI at a higher rate than those with some higher education.
The study was published in the Jan. 25, 2012, issue of Neurology.
Although incidence rates for mild cognitive impairment (MCI) have been reported, few studies were specifically designed to measure the incidence of MCI and its subtypes using published criteria. This study estimates the incidence of amnestic MCI (aMCI) and nonamnestic MCI (naMCI) in men and women separately.
A population-based prospective cohort of Olmsted County, Minn., residents age 70 to 89 on Oct. 1, 2004, underwent baseline and 15-month interval evaluations that included:
The Clinical Dementia Rating scale
A neurologic evaluation
A panel of examiners blinded to previous diagnoses reviewed data at each serial evaluation to assess cognitive status according to published criteria.
Results Among 1,450 subjects who were cognitively normal at baseline, 296 developed MCI.
The age- and sex-standardized incidence rate of MCI was 63.6 (per 1,000 person-years) overall, and was higher in men (72.4) than women (57.3) and for aMCI (37.7) than naMCI (14.7).
The incidence rate of aMCI was higher for men (43.9) than women (33.3), and for subjects with ≤12 years of education (42.6) than higher education (32.5).
The risk of naMCI was also higher for men (20.0) than women (10.9) and for subjects with ≤12 years of education (20.3) than higher education (10.2).
Conclusions The incidence rates for MCI are substantial. Differences in incidence rates by clinical subtype and by sex suggest that risk factors for MCI should be investigated separately for aMCI and naMCI, and in men and women.