Exam Tips, Certification Exam Guides, Microsoft Exam Tips, CISCO Exam Tips: 06/20/13

Thursday 20 June 2013

Clues Found to Prostate Cancer Upgrading

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By Charles Bankhead, Staff Writer, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San FranciscoNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.Almost a third of men on active surveillance for prostate cancer had an upgrade in Gleason pathology grade during follow-up, biopsy results for almost 600 patients showed.Point out that clinical stage at diagnosis, PSA velocity, number of involved biopsy cores, and the interval to follow-up biopsy predicted an increased likelihood of Gleason upgrading.

ORLANDO -- Almost a third of men on active surveillance for prostate cancer had an upgrade in Gleason pathology grade during follow-up, biopsy results for almost 600 patients showed.

During median follow-up of 6.4 years, 31.3% of the localized cancers were upgraded. The proportion of men with upgraded tumors increased over time, D. Andrew Loblaw, MD, reported here at the Genitourinary Cancers Symposium. "This increase over time was not statistically significant, but it allows for some hypothesis generation."

Clinical stage at diagnosis, PSA velocity, number of involved biopsy cores, and the interval to follow-up biopsy predicted an increased likelihood of Gleason upgrading, according to Loblaw, who practices at Sunnybrook Health Sciences Center in Toronto.

Intermediate-risk tumors had an upgrade probability more than double that of low-risk tumors -- 1.9% per year compared with 0.75%, although the difference did not achieve statistical significance.

"Gleason upgrading increases with time from diagnostic biopsies and might be higher in patients with initial Gleason 7 disease as opposed to Gleason 6," Loblaw said.

Men with localized prostate cancer have a 10-year disease-specific survival exceeding 97%, making active surveillance a reasonable option for many patients. Considerable research has focused on factors that can identify men who have an increased risk of progression, but pathologic upgrading has received little attention, said Loblaw.

In the largest published study to date, investigators at the University of California San Francisco found that a third of 377 patients in surveillance had pathologic upgrading of their tumors during 4 years of follow-up (J Clin Oncol 2011; 9: 2185-2190).

However, studies have produced little information about factors associated with upgrading, said Loblaw. In an effort to gain some insight into those factors, he and his colleagues analyzed a prospective database of patients entered into active surveillance at Sunnybrook Health Sciences Center

Eligibility for active surveillance required a biopsy Gleason score =6 and a PSA level =10 ng/mL. For patients older than 70, the criteria consisted of a Gleason score =3+4 and a PSA level =15 ng/mL.

Patients had repeat PSA testing every 3 months for 2 years and then every 6 months thereafter. Scheduled follow-up biopsies occurred after 1 year and then every 3 years until age 80.

Patients and physicians considered active treatment in the event of a PSA doubling time <3 years, histologic upgrading, and clinical progression, as well as patient preference.

As of August 2012, the database included 862 patients, including 592 who had at least one repeat biopsy. The subgroup of re-biopsied patients had a median age of 68 and a median baseline PSA of 5.5 ng/mL.

Loblaw reported that 83% of the patients had T1 disease and 17% had T2. Additionally, 20.2% of patients had intermediate-risk disease, 0.3% had high-risk prostate cancer, and 79.4% had low-risk cancer.

Multivariate analysis of baseline and dynamic factors associated with upgrading identified clinical stage at diagnosis (OR 2.301, P=0.0028), percentage of involved prostate biopsy cores at diagnosis (OR 1.768, P=0.0007), PSA velocity >2 (3.274, P<0.0001), and interval to re biopsy (OR 1.437, P=0.0102).

Subsequently, 114 (62%) of men whose tumors were upgraded chose to undergo treatment. The investigators found that a higher proportion of treated patients had a Gleason score of 8 (22% versus 2.9% of untreated patients), and treated patients had a significantly higher PSA velocity (1.2 versus 0.42 ng/mL/y, P=0.01).

The likelihood of upgrading increased over time, including 18.4% of patients followed for up to a year to 36% of patients followed for 7 to 8 years, 36% of patients followed for 8 to 9 years, and 26% of patients followed for more than 9 years.

In the discussion that followed the presentation, a panel of prostate cancer specialists and the audience engaged in a prolonged discussion about the future of surveillance for localized prostate cancer. Eric Klein, MD, of the Cleveland Clinic, suggested the time has come to reconsider the focus of surveillance.

"We have all patted ourselves on the back that we can identify patients who aren't going to die of their prostate cancer, with appropriate surveillance criteria," said Klein. "Shouldn't we raise the bar now?

"Given the cost and morbidity of metastatic disease [should we be asking] how much longer patients with metastatic disease are living? Should we say the goal of therapy or surveillance ought to be to avoid metastatic disease, rather than simply avoid death?"

The Genitourinary Cancers Symposium is co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Loblaw and co-investigators had no relevant disclosures.

Primary source: Genitourinary Cancers Symposium
Source reference:
Jain S, et al "Gleason upgrading with time in a large, active surveillance cohort with long-term follow-up" GuCS 2013; Abstract 1.

Charles Bankhead

Staff Writer

Working from Houston, home to one of the world's largest medical complexes, Charles Bankhead has more than 20 years of experience as a medical writer and editor. His career began as a science and medical writer at an academic medical center. He later spent almost a decade as a writer and editor for Medical World News, one of the leading medical trade magazines of its era. His byline has appeared in medical publications that have included Cardio, Cosmetic Surgery Times, Dermatology Times, Diagnostic Imaging, Family Practice, Journal of the National Cancer Institute, Medscape, Oncology News International, Oncology Times, Ophthalmology Times, Patient Care, Renal and Urology News, The Medical Post, Urology Times, and the International Medical News Group newspapers. He has a BA in journalism and MA in mass communications, both from Texas Tech University.

NFL: PET Scan IDs Brain Damage in Players (CME/CE)

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By Nancy Walsh, Staff Writer, MedPage Today Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this case-control study of concussed football players with mood and cognitive symptomatology showed higher uptake of a tau-specific tracer in MRI scans compared with healthy controls.Be aware that, as the burden of depression was lower in the control group, the findings of increased tau-protein among cases may be due to depression or cognitive impairment and independent of head injury history.

A new imaging technique has allowed detection of tau protein abnormalities in the concussed brains of living retired football players that are identical to the autopsy findings of chronic traumatic encephalopathy (CTE) in deceased athletes, researchers reported.

Positron emission tomography (PET) scanning using a tracer for tau protein known as FDDNP found significantly higher binding values among retired players than in controls in several regions of the brain, including the amygdala (1.30 versus 1.14, P=0.03) and caudate (1.48 versus 1.23, P=0.03), according to Gary W. Small, MD, of the University of California Los Angeles, and colleagues.

In addition, the tau binding values were highest in the players who had experienced the most concussions during their careers, which "suggests a link between the players' history of head injury and FDDNP binding," the researchers wrote in the February American Journal of Geriatric Psychiatry.

"If this research continues in the direction we expect, it would have a big impact on the early detection of this condition, helping us to develop interventions that could delay the onset of symptoms," Small told MedPage Today.

But it will be important to replicate these findings in larger studies, experts cautioned.

"If indeed it is sensitive and specific enough for tau, it would be extremely exciting and hugely important, but this was only five players," said Robert Cantu, MD, of Emerson Hospital in Concord, Mass., and co-director of Boston University's Center for the Study of Traumatic Encephalopathy.

The list of athletes who experience multiple concussions during routine play and then develop cognitive, behavioral, and mood disturbances, which in some cases lead to suicide, continues to grow, and some 4,000 former National Football League players are suing the league, claiming that the risks of repetitive head injury were long downplayed.

Autopsy findings in players who died have included deposits of phosphorylated tau in neurofibrillary tangles, as well as diffuse injury to axons and abnormalities of white matter.

Despite the increasingly widespread recognition that players with multiple concussions are experiencing severe consequences, research into the resulting condition has been hindered by the fact that no diagnostic test has been available that could identify changes before death.

Small and his colleagues developed the tau tracer FDDNP (2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile) with the goal of detecting the presence of tau tangles and amyloid plaque in the living brains of Alzheimer's disease patients.

They found that with this PET technique they could differentiate Alzheimer's patients from those with milder forms of cognitive impairment or normal changes of aging.

In the current study, they performed neuropsychiatric evaluations of five former players who exhibited mood or cognitive symptoms clinically, and then used PET scanning with FDDNP to examine their brains.

The players had played various positions, including quarterback, center, and defensive lineman, with careers ranging from 10 to 16 years.

The researchers also assessed five controls who were matched for age, body mass index, family history of dementia, and educational attainment.

Cases and controls were both about 60 years of age. The affected players had significantly higher scores on the Hamilton Rating Scale for Depression (8 versus 0) than controls, and also showed a trend toward lower scores on the Mini-Mental State Examination, which evaluates cognitive impairment.

Higher signals for tau binding were seen in a number of subcortical regions in cases compared with controls, including: Putamen, 1.47 versus 1.20 (P=0.05)Thalamus, 1.48 versus 1.29 (P=0.03)Subthalamus, 1.45 versus 1.25 (P=0.03)Midbrain, 1.31 versus 1.14 (P=0.03)Cerebellar white matter, 1.15 versus 1.09 (P=0.05)

The researchers explained that this pattern of findings was different from that seen in patients with cognitive difficulties but no history of head trauma, in elderly depressed patients, and in those with Alzheimer's disease.

While FDDNP can bind to both tau and amyloid in Alzheimer's patients, only a minority of CTE autopsies have identified amyloid plaques, suggesting that in these players, the high levels of binding signals are specific for tau.

"Using a tau marker for detection and tracking of neurodegenerative disease is critically important because severity of tau load, rather than amyloid burden, correlates with rates of neuronal loss," the researchers explained.

They noted that their findings should be interpreted with caution because of the limited number of players and the possibility that other factors such as genetics and overall cerebrovascular health might influence outcomes.

Small expressed hope that, if this diagnostic approach proves accurate in larger numbers, it may open the way to possible treatments.

"We know that inflammation is important both in Alzheimer's disease and traumatic brain injury, and in Alzheimer's we're testing anti-inflammatory and anti-tau treatments," he said.

"We also know that lifestyle choices and everyday health habits including diet, exercise, and stress management are important in protecting our brains," he added.

The study was supported by the Brain Injury Research Institute, the Fran and Ray Stark Foundation Fund for Alzheimer's Disease Research, the Ahmanson Foundation, and the Parlow-Solomon Professorship.

Two of the authors are among the inventors of a technique for labeling beta-amyloid plaques and neurofibrillary tangles and have received royalties. They also have received fees from several companies, including Janssen, Lilly, Novartis, Pfizer, Bristol-Myers Squibb, and Siemens.

Primary source: American Journal of Geriatric Psychiatry
Source reference:
Small G, et al "PET scanning of brain tau in retired National Football League players: Preliminary findings" Am J Geriatr Psychiatry 2013; 21: 138-144.

Nancy Walsh

Staff Writer

Nancy Walsh has written for various medical publications in the United States and England, including Patient Care, The Practitioner, and the Journal of Respiratory Diseases. She also has contributed numerous essays to several books on history and culture, most recently to The Book of Firsts (Anchor Books, 2010).

Heart Disease Death Not as Pervasive as Reported (CME/CE)

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By Chris Kaiser, Cardiology Editor, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerHeart disease deaths are over-reported in the U.S.A hospital-level intervention to reduce heart disease over-reporting led to substantial changes in other leading causes of death, changing the leading cause of premature death.

Hospitals in the U.S. tend to over-report death from heart disease, researchers found, but a simple intervention can improve the quality of cause-of-death reporting.

Hospitals involved in the intervention reduced their reports of heart disease as the leading underlying cause of death from 69% before the intervention to 32% afterwards -- a relative decline of 54%, according to Teeb Al-Samarrai, MD, of the Santa Clara County Department of Public Health in San Jose, Calif., and colleagues.

As reports of heart disease deaths declined, there were increases in four other conditions as leading underlying causes of death, the most dramatic being a 252% relative increase for reported deaths from chronic lower respiratory disease (absolute increase from 2% to 5%), they reported in the latest issue of the CDC's Preventing Chronic Disease.

The other three causes of death that spiked after the intervention were: Influenza and pneumonia -- 193% relative increase, going from 4% to 11% Cerebrovascular disease -- 115% relative increase, going from 2% to 4%Malignant neoplasms -- 48% relative increase, going from 11% to 16%

However, the hospitals not involved in the intervention saw minimal relative changes in leading causes of death -- all 6% or less.

The investigators also determined that the postintervention changes were not an effect of a trend that might have begun before the intervention. A secondary analysis revealed that between 2000 and 2009 (pre-intervention), deaths from heart disease at the hospitals that subsequently were involved in the intervention remained steady -- around 60% to 71%.

Al-Samarrai, who was formerly with the CDC, and colleagues noted that they took on this study because the quality of the information on death certificates "affects the usefulness of vital statistics for public health action."

Lack of physician training serves as the greatest contributor of poor quality of mortality data, they wrote, adding that "Cause-of-death assignment practices also appear to vary by region."

One group for which determining the cause of death is particularly difficult is patients of advanced ages, the researchers noted. "This suggests that inaccurate reporting of cause of death for patients aged 85 or older reflects not only lack of training but also the complexity and challenge of identifying a single underlying condition or clear sequence of events leading to death. Death certificates force physicians to simplify what might be a complex medical situation."

"As the population lives longer and multiple chronic medical conditions become more common, documenting which disease is the underlying cause of death will become more challenging," they continued. "Therefore, using the current 1-cause-to-1-death model for cause-of-death coding might not be appropriate when describing mortality among persons ages 85 or older."

To assess whether the situation could be improved, the investigators performed an intervention consisting of training and communication with staff at eight hospitals in New York City. The pre-intervention period was from July though December 2009. Postintervention spanned January to June 2010.

The total number of deaths at the intervention hospitals was similar in the pre- and postintervention periods (2,120 and 2,069, respectively).

In the pre-intervention period, the total number of deaths attributed to heart disease in the intervention hospitals ranged from 58% to 80%. This dropped in the postintervention period by 28 to 53 percentage points -- to a range of 26% to 44%, researchers noted.

In a subgroup analyses, researchers found that sex and race/ethnicity had no impact on the ranking of leading cause of death.

When researchers restricted for cause of premature death (ages 35 to 74), however, malignant neoplasm took the lead over heart disease (26% versus 25%). No such change was seen in the nonintervention hospitals.

After the intervention, influenza and pneumonia as a leading cause of death moved from third to second; no change occurred in the nonintervention hospitals. Importantly, the largest increase in influenza and pneumonia deaths occurred among those 85 years or older.

When Al-Samarrai and colleagues controlled for age, heart disease as the leading cause of death declined in the intervention group from 36% to 17%. In the nonintervention hospitals, however, this number increased from 16% to 18%.

"To our knowledge, this is the first study to investigate the impact of reducing heart disease over-reporting on other leading causes of death," Al-Samarrai and colleagues wrote. No prior study had demonstrated a reduction in heart disease death concomitant with an increase in other leading causes of death, they added.

The intervention in this study has been expanded to more New York City hospitals, "with preliminarily positive results."

The limitations of the study include the fact that death certificates were not validated, individual physician understanding of death certificates was not evaluated, standardizing for race/ethnicity could have hidden reporting differences, and results may not apply to other settings.

Preventing Chronic Disease is a publication of the CDC.

The authors had no financial or conflicts of interest to disclose.

From the American Heart Association:

Chris Kaiser

Cardiology Editor

Chris has written and edited for medical publications for more than 15 years. As the news editor for a United Business Media journal, he was awarded Best News Section. He has a B.A. from La Salle University and an M.A. from Villanova University. Chris is based outside of Philadelphia and is also involved with the theater as a writer, director, and occasional actor.

Junior Seau Had CTE, NIH Says

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By Nancy Walsh, Staff Writer, MedPage Today

An autopsy examination has determined that football star Junior Seau had chronic traumatic encephalopathy (CTE), the National Institutes of Health announced today. CTE has been linked to repetitive concussions suffered by boxers, football players, and other professional athletes.

Five neuropathologists all found that microscopic examination of Seau's brain revealed "multifocal tauopathy consistent with a diagnosis of chronic traumatic encephalopathy," the NIH explained.

Seau died of a self-inflicted gunshot wound in May 2012; he'd racked up some 1,850 tackles over 2 decades as a linebacker in the National Football League. His family donated his brain to the NIH for study.

In a blinded examination of three brains, the neuropathologists identified tissue samples from Seau's brain as containing abnormal clusters of the protein tau, which folds into tangles in the brains of patients with Alzheimer's disease and other brain diseases. The location of the abnormal tau clusters is distinct in CTE.

The pathology report states: "There are clusters of tau immunoreactive neurofibrillary tangles (NFTs) and neuropil threads in the neocortex, as well as occasional tangles in the subcortical gray matter and brainstem. The superficial location of the NFTs, the perivascular foci, and the tendency for cortical lesions to be at the depths of sulci are consistent with a diagnosis of chronic traumatic encephalopathy."

The consequences of repetitive brain injury were initially noted in boxers, who developed "dementia pugilistica," and emerged as a concern for football players after the suicide of Dave Duerson in 2011.

Duerson had experienced severe depression and personality changes that he attributed to multiple concussions he had experienced during his years on the gridiron, and asked that his brain be examined for signs of chronic injury.

This was done at the Boston University Center for the Study of Traumatic Encephalopathy, where a brain bank has now been established and contains specimens from at least 60 other athletes.

In many cases, family members and friends had noticed behavioral and cognitive changes in the former players.

More than 4,000 members of the National Football League have filed a lawsuit claiming that the league misled the players and public about the dangers of repetitive concussion.

Today's statement from the NIH acknowledges that research into CTE is in early stages, noting that currently the condition can be diagnosed only after death. In addition, much remains to be learned about why certain individuals appear susceptible to these types of injury.

Similar symptoms also have been reported in increasing numbers among members of the U.S. military exposed to concussive events during deployment.

NIH investigators are conducting further research into the pathologic processes resulting from repetitive brain injury, examining tissue samples with high resolution MRI scans.

This week also saw the publication of a neuroimaging study of 26 former football players, which showed pronounced lesions in the white matter and changes in cerebral blood flow.

"Only research will reveal answers to the vexing problems that this condition presents," the NIH statement concluded.

Nancy Walsh

Staff Writer

Infection Site Predicts Death in Septic Shock (CME/CE)

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By Ed Susman, Contributing Writer, MedPage Today Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse PlannerNote that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.Note that this large retrospective study documented higher mortality rates among patients admitted to the ICU with septic shock based upon source of the infection.

PHILADELPHIA -- The anatomic site where an infection originates seems to predict mortality among patients diagnosed with septic shock, researchers reported at the American Thoracic Society conference.

In scouring a database that includes 8,000 septic shock patients in the U.S., Canada, and Saudi Arabia, those ICU patients with hydronephrosis, for instance, had a mortality of 21.1%, said Peter Dodek, MD, MHSc, professor of medicine at the University of British Columbia in Vancouver. But patients with ischemic bowel-caused infections experienced a mortality of 77.8%, he said.

"As many people realize, septic shock is a big issue in critical care medicine," Dodek said at a press conference sponsored by ATS. "Septic shock is associated with a high mortality -- in this study overall mortality was 52.4%."

He said that recently the mortality is decreasing, but "there are a lot of concerns because we haven't found a silver bullet to help treat septic shock."

A major problem in finding a suitable treatment is the heterogeneity of patients, which prevents researchers from focusing on a particular set of patients for clinical trials. With that in mind, Dodek said he and his colleagues asked the question: Are there meaningful differences in hospital mortality among patients who have septic shock, stratified by the location of the original infection?

The answer turns out to be Yes. Their research revealed the following sources and mortality rates: Disseminated infections, 84.5%Spontaneous bacterial peritonitis, 76%Toxic megacolon, 68.3%Other abdominal infections, 66.7%Pulmonary infections, 54%Pyelonephritis, 34.5%Enterocolitis/diverticulosis, 28%

Dodek's study used a dataset that was established to examine patients who have septic shock over the past 20 years, beginning in 1989. Even after using multiple regression analysis and adjusting for age, degree of illness at admission and multiple other factors, Dodek said the differences in infection sites still remained.

"There are meaningful differences in hospital mortality by source of infection," he told MedPage Today. "This may help us to stratify patients into groups for clinical trials of sepsis. Those with the highest risk may be the ones we want to try these disease-modifying agents on." But he suggested that it may be wise to think about scaling back on antibiotics for those who have a lower mortality.

"At the moment the tools we have to treat septic shock are early detection, early use of antibiotics which had been shown in some observational studies to make a difference and there have been a variety of drugs and other agents that have been tested but it is still a big conundrum," he said.

Gary Martin, MD, associate professor of medicine at Emory University in Atlanta, who served as the press conference moderator at which Dodek presented his work, told MedPage Today, "Septic shock is a condition that is difficult to study. You want to be able to target a population where you will have the best chance for intervention. This study may help us understand the mechanism and risk of septic shock."

"Heterogeneity is a major problem," he said. "Some of these patients have cancer, some do not; some are older, some are younger. All these patients are in an intensive care unit. They are all critically ill."

Dodek and Martin had no relevant disclosures.

Primary source: American Thoracic Society
Source reference:
Leligdowicz A, et al "Association between source of infection and hospital mortality in patients admitted to the intensive care unit because of septic shock" ATS 2013.