JAMA Study Shows Stroke Risk and Death Rates Falling in Last 2 Decades

Fewer Americans are having strokes and those who do have a lower risk of dying from them finds a new study led by Johns Hopkins Bloomberg School of Public Health researchers.

The study found a 24 percent overall decline in first-time strokes in each of the last two decades and a 20 percent overall drop per decade in deaths after stroke. However, the decline in stroke risk was concentrated mainly in the over-65 set, with little progress in reducing the risk of strokes among young people. In contrast, the drop in stroke-related deaths each decade was primarily found among those under age 65, with mortality rates holding firm in older people.

A report on the results was published in a recent issue of the Journal of the American Medical Association (JAMA).

Journal of the American Medical Association - Archives of Dermatology

JAMA

“We can congratulate ourselves that we are doing well, but stroke is still the No. 4 cause of death in the United States,” says study co-author Josef Coresh, MD, PhD, a professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. “This research points out the areas that need improvement. It also reminds us that there are many forces threatening to push stroke rates back up and if we don’t address them head-on, our gains may be lost.”

Coresh says he worries what the future of stroke will look like as the obesity epidemic, which began in the 90s, matures. As millions more are diagnosed with hypertension and diabetes – which often go hand-in-hand with obesity — they will face increased risk for stroke.

For their analysis, researchers used results from the Atherosclerosis Risk in Communities (ARIC) study, a prospective study of 15,792 residents of four U.S. communities who were between the ages of 45 and 64 when the study began in the late 1980s. In this analysis, they followed 14,357 participants who were free of stroke in 1987, looking specifically for all stroke hospitalizations and deaths between then and the end of 2011.

Seven percent of the study sample (1,051) had a stroke over that period. Of those, 10 percent died within 30 days, and 21 percent, 40 percent and 58 percent died within one year, five years and by the end of the study in 2011. Each decade, the number of deaths occurring within 10 years of a stroke was reduced by roughly eight deaths per 100 cases. The decrease was not across the board. Instead it was primarily the result of stroke victims under the age of 65 surviving longer. While they varied by age, the results were similar across race and gender, a finding that researchers were heartened to discover since a previous study suggested African-American stroke rates were not improving.

The researchers found that the decrease in stroke incidence and mortality is partly due to more successful control of risk factors such as blood pressure, smoking cessation and the wide use of statin medications for controlling cholesterol. However, an increase in diabetes likely acted in the opposite direction, pushing up stroke rates, though to a lesser extent. Stroke severity and improvements in treatment likely also impacted the data, though the study could not measure the exact role they played.

The age disparities in outcomes suggest areas where physicians and researchers may want to focus in the future to prevent strokes in those under 65 and reduce deaths in those over 65.

Nearly 800,000 Americans suffer strokes each year; of those, about 600,000 are first-time strokes. “Stroke is not only one of the main causes of death, but a leading cause of long-term disability in adults. Therefore, prevention is the best strategy,” says study leader Silvia Koton, PhD, MOccH, a visiting faculty member at the Bloomberg School and incoming nursing department chair at Tel Aviv University.

National data show that the number of death certificates listing stroke as the underlying cause of death has decreased for a long time. However, only research studies such as this one can distinguish whether the decline is due to a reduction in the number of strokes or whether people are just living longer after having them, researchers say. In this study, researchers also confirmed the occurrence of each stroke by reviewing each medical chart using uniform criteria. Researchers focused on deaths from all causes because following a stroke, many patients die from other causes including heart disease and pneumonia.

“Since rates are not equally falling across the board, physicians and policymakers need to pay closer attention to specific subgroups,” Koton says. “These data are also helpful in monitoring the results of how we care for people of all ages, hopefully helping them even before they have a stroke.”

- MFP News Services
- 9/2/14

Variation of Glaucoma Discovered To Be an Inflammatory Disease

Researchers at the University of California, San Diego School of Medicine and Sun Yat-sen University in China have shown that acute glaucoma in mice is largely an inflammatory disease and that high pressure in the eye causes vision loss by setting in motion an inflammatory response similar to that evoked by bacterial infections.

University of California - San Diego - School of Medicine

The study, published in this week’s issue of the Proceedings of the National Academy of Sciences, has immediate clinical relevance in treating the tens of millions of people worldwide from what is known as acute closed-angle glaucoma.

“Our research is the first to show an inflammatory mechanism by which high ocular pressure causes vision loss in acute glaucoma patients,” said co-senior author Kang Zhang, MD, PhD and professor of ophthalmology.

The second leading cause of irreversible blindness globally, glaucoma refers to a group of eye diseases associated with elevated intraocular pressure broadly classified as either open-angle or closed-angle. Open-angle is sometimes called the silent thief of sight because of its slow, often overlooked progression. By contrast, acute closed-angle glaucoma often is a painful ophthalmologic emergency in which there is a sudden rise in eye pressure and immediate damage to eyesight.

Less than 10 percent of glaucoma patients in America have the closed-angle form, but in parts of Asia it accounts for almost half of all cases. The higher prevalence of closed-angle glaucoma in Asians and women is believed to be due to a shallower anterior (frontal) eye chamber.

In the study, researchers showed that a rapid, sustained large increase in eye pressure in mice turns on a gene (TLR4) that activates a protein known as caspase-8. This signaling protein in turn triggers the production of inflammatory proteins that normally help mammals fight microbial infections.

“This immune response is a double-edge sword because, while these proteins protect us from infection in a normal situation, they stimulate apoptosis (programmed cell death) in retinal cells in cases of acute glaucoma,” said Zhang, who is also a staff physician at the Veterans Affairs San Diego Healthcare System.

To further confirm the mechanism linking high eye pressure to retinal damage, researchers showed that they could slow retinal cell death in mice with acute glaucoma by suppressing either the TLR4 gene or caspace-8 protein.

The latter is particularly significant because caspace-8 inhibitors are currently in clinical trials for treating cancer and stroke. “By injecting these inhibitors into the eyes of acute glaucoma patients, it may be possible to evaluate and bring them vision-sparing treatments more quickly,” said co-author Robert N. Weinreb, MD, chairman and Distinguished Professor of Ophthalmology.

- MFP News Services
- 9/1/14

Researchers Discover New Route For the Spread of Ovarian Cancer

Circulating tumor cells spread ovarian cancer through the bloodstream, homing in on a sheath of abdominal fatty tissue where it can grow and metastasize to other organs, scientists at The University of Texas MD Anderson Cancer Center report in Cancer Cell.

University of Texas - M. D. Anderson Cancer Center

“This completely new way of thinking about ovarian cancer metastasis provides new potential avenues to predict and prevent recurrence or metastasis,” said senior author Anil Sood, M.D., professor of Gynecologic Oncology and Reproductive Medicine and Cancer Biology.

The researchers found the circulating tumor cells (CTCs) rely on HER3, a less-famous sibling of the HER2 receptor protein prominent in some breast cancers, to find their way to the omentum, a sheet of tissue that covers and supports abdominal organs.

HER3′s heavy presence on these cells makes it a biomarker candidate and suggests possible therapeutic options to thwart ovarian cancer progression, the researchers noted. “The CTCs are not just a correlation, they seem to have a functionally important role in metastasis,” Sood said.

High expression of HER3 in ovarian cancer tumors is associated with shorter survival, the team found.

Ovarian cancer has been thought mainly to spread via direct surface contact with neighboring organs in the abdominal cavity. “However, it also metastasizes to more distant organs such as the liver and spleen, which seems to indicate arrival through the bloodstream,” Sood said.

Ovarian tumor cells are found abundantly in the blood vessels of the omentum and CTCs are present in ovarian cancer patients. However the importance of CTCs was not well understood.

Two mice, one blood supply

The researchers used a parabiosis mouse model, in which two mice are joined at the skin from hip to shoulder. They share blood supply but not lymphatic vessels. “This was the most convincing way to prove that CTCs play a role in metastasis,” said first author Sunila Pradeep, Ph.D., instructor of Gynecologic Oncology and Reproductive Medicine.

When the host mouse of each pair was injected with ovarian cancer cells, a primary tumor developed and metastases were found in the omenta of all of the host mice. In the guest mice, metastatic cells and tumors appeared first in the omentum before spreading to other organs.

The team compared gene expression in tumors between the original ovarian cancer cell line and its metastatic version found in the omentum.

Expression of HER3, also known as ERBB3, was highly elevated and activated. The binding protein, or ligand, most likely to cause that activation is NRG1, which was found abundantly on the metastatic cells.

More than 95 percent of CTCs collected from mice with the metastatic version of ovarian cancer were HER3-positive. The more HER3-positive cells the mice had, the greater the tumor burden.

HER3 expression reduces human survival

In tumor samples from 11 ovarian cancer patients, 90 percent of cells were HER3-positive. Tumor cells found in the omental blood vessels of five patients analyzed also had strong HER3 expression.

In a cohort of 217 advanced-stage patients, lower HER3 expression correlated with improved overall survival of 4.9 years compared to 3.15 years for high-HER3 tumors.

Analyzed by itself, HER3 expression was significantly associated with advanced-stage disease at diagnosis. When other variables such as the patient’s age, disease stage and tumor grade were controlled for, HER3 expression remained an independent factor for patient survival. They also found:

HER3 expression to be significantly higher in human stage 3 and 4 tumors compared to stage 1 and 2 tumors.
Blocking HER3 with siRNA significantly lowered expression of the protein, decreased tumor growth and reduced metastasis in mice.
Plugging HER3 with the antibody MM-121 reduced the size and number of tumors and frequency of metastasis in treated mice to a tiny fraction of that found in control mice.
Results were repeated with additional high-grade serous ovarian cancer and colon cancer models.
NRG1 in omentum draws in circulating tumor cells
Experiments showed knocking down HER3 in cancer cell lines in the lab did not have the same effect as it did in the mice. This led the researchers to suspect something present in the omentum microenvironment caused the cancer’s dependency on HER3.

The binding ligand NRG1 is more abundant in the omentum than in other tissues. The team found:

Colonies of cancer cells treated with NRG1 were triple the size of untreated tumor cell colonies.
Analysis of 11 human tumors found NRG1 evident both in the tumors and the microenvironment.
Blocking NRG1 with siRNA in mice with ovarian cancer significantly reduced metastasis.
“The NRG1 ligand expressed in the omentum attracts HER3-positive CTCs,” Sood said.

The next steps for the team are to further flesh out the details and understand opportunities to intervene in this cancer-spreading process. The findings provide a rational route to develop new drugs, Sood noted.

Potential uses include using HER3-positive cells as a biomarker for recurrence for patients or for occurrence in women at high-risk for developing ovarian cancer. Maintenance anti-HER3 therapy after treatment could prevent metastasis to the omentum.

Clinical trials are under way for pertuzumab, an antibody that blocks HER2, to explore whether it might thwart both proteins in ovarian and breast cancer. HER2 and HER3 are members of the epidermal growth factor receptor family of receptor tyrosine kinase proteins.

- MFP News Services
- 8/27/14