Origin of Intelligence and Mental Illness Linked to Ancient Genetic Accident.


Scientists have discovered for the first time how humans — and other mammals — have evolved to have intelligence.

 

Researchers have identified the moment in history when the genes that enabled us to think and reason evolved.

This point 500 million years ago provided our ability to learn complex skills, analyse situations and have flexibility in the way in which we think.

Professor Seth Grant, of the University of Edinburgh, who led the research, said: “One of the greatest scientific problems is to explain how intelligence and complex behaviours arose during evolution.”

The research, which is detailed in two papers in Nature Neuroscience, also shows a direct link between the evolution of behaviour and the origins of brain diseases.

Scientists believe that the same genes that improved our mental capacity are also responsible for a number of brain disorders.

“This ground breaking work has implications for how we understanbraind the emergence of psychiatric disorders and will offer new avenues for the development of new treatments,” said John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, one of the study funders.

The study shows that intelligence in humans developed as the result of an increase in the number of brain genes in our evolutionary ancestors.

The researchers suggest that a simple invertebrate animal living in the sea 500 million years ago experienced a ‘genetic accident’, which resulted in extra copies of these genes being made.

This animal’s descendants benefited from these extra genes, leading to behaviourally sophisticated vertebrates — including humans.

The research team studied the mental abilities of mice and humans, using comparative tasks that involved identifying objects on touch-screen computers.

Researchers then combined results of these behavioural tests with information from the genetic codes of various species to work out when different behaviours evolved.

They found that higher mental functions in humans and mice were controlled by the same genes.

The study also showed that when these genes were mutated or damaged, they impaired higher mental functions.

“Our work shows that the price of higher intelligence and more complex behaviours is more mental illness,” said Professor Grant.

The researchers had previously shown that more than 100 childhood and adult brain diseases are caused by gene mutations.

“We can now apply genetics and behavioural testing to help patients with these diseases,” said Dr Tim Bussey from Cambridge University, which was also involved in the study.

 

Source: sciencedaily.com

Take Action: Add Your Voice to Keep the Internet free and open.


A free and open world depends on a free and open web.

The Internet has connected more than two billion people around the world.

Some governments want to use a closed-door meeting in December to increase censorship and regulate the Internet.

Join together to keep the Internet free and open.

Add your voice. URL: https://www.google.com/takeaction/?utm_source=social&utm_medium=facebook&utm_campaign=freeandopenoa

wath the video on youtube:

Source: google.com

Fight against Female Genital Mutilation wins UN backing.


The adoption today of a resolution against female genital mutilation (FGM) in the UN General Assembly’s human rights committee is a major boost to civil society organizations fighting for an end to the abusive practice, Amnesty International said.

This is the first time the Assembly’s Third Committee, which addresses social, humanitarian and human rights issues, has adopted a resolution on FGM – the cutting of a girl’s genitalia often without anaesthetic in conditions that risk potentially fatal infection.

“FGM is an indictment of us all – that a girl or young woman can be held down and mutilated is a violation of her human rights and – shockingly – an estimated three million girls are at risk each year,” said José Luis Díaz, Amnesty International’s UN representative in New York.

“Vitally, this UN resolution places FGM in a human rights framework and calls for a holistic approach, stressing as it does the importance of empowerment of women, promotion and protection of sexual and reproductive health and breaking the cycle of discrimination and violence.”

FGM is commonplace in 28 countries in Africa as well as in Yemen, Iraq, Malaysia, Indonesia and in certain ethnic groups in South America.

However it is an issue of worldwide concern. Women and girls in diaspora communities can be at risk of being subjected to FGM.

Amnesty International sees the UN resolution as a reminder to governments that they need to develop national action plans, beyond laws, and ensure that they are well-resourced and monitored, in order to raise awareness.

The resolution makes clear too that this is something that must involve all those affected – including men and boys – if we are to finally end this practice.

“It is important to highlight that FGM is a gender-based and child-specific persecution and the UNHCR – the UN refugee agency – has established that a girl or woman seeking asylum because she has been compelled to undergo, or is likely to be subjected to FGM, can qualify for refugee status,” said Díaz. Protection of refugee women at risk of having undergone FGM must be integrated into the overall strategy for protection.

The resolution makes concrete recommendations for prevention of FGM, for protecting girls at risk, ending impunity and provision of support services to those suffering from the lifelong consequences. Amnesty International urges governments to implement these recommendations urgently.

The resolution on FGM adopted by the Assembly’s Third Committee is expected to be endorsed by the General Assembly Plenary in December.  Although not legally binding, UN General Assembly resolutions carry considerable moral and political weight.

Source: Amnesty International.

All That Glitters: A Glimpse into the Future of Cancer Screening.


Ask experts to predict the future of cancer screening, and you’ll get a range of answers. But all would agree that we need better ways to detect cancers early in the course of disease, and these new tools should improve on the benefits of screening while limiting the harms.

“There have been some improvements in triaging patients with new molecular approaches, but with the possible exception of spiral CT screening for lung cancer, we haven’t had any major breakthroughs in early detection” for more than two decades, noted Dr. David Sidransky, director of head and neck cancer research at the Johns Hopkins University School of Medicine.

The dearth of such advances is not for lack of trying. Developing new screening approaches and rigorously establishing their validity is challenging, however, and there are many potential stumbling blocks along the way.

“The bar for ‘proof’ that a particular screening strategy is clinically effective is very high,” noted Dr. Mark Greene, chief of the Clinical Genetics Branch in NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “A screening test must be shown to reduce the death rate from the disease for which screening is being done.”

Much of the search for new screening tests focuses on biomarkers—proteins, DNA, RNA, or other molecules that can signal the presence of cancer and be detected noninvasively in blood, urine, or other readily obtained patient samples or tissues. Researchers are also developing new imaging methods that could be used for early detection, either alone or in concert with biomarkers.

Whatever the approach, “screening is moving away from detecting an advanced consequence of cancer, which is the formation of a mass [or tumor], toward detecting the very earliest changes in the cancer process,” said Dr. Larry Norton, deputy physician-in-chief for breast cancer programs at Memorial Sloan-Kettering Cancer Center.

Dr. Norton chairs the external consulting team for the Early Detection Research Network (EDRN), an initiative of NCI’s Division of Cancer Prevention that supports efforts to discover and validate new cancer biomarkers and technologies.

“Molecular detection of cancer is possible only through evidence-based strategies and implementation,” commented Dr. Sudhir Srivastava, who directs the EDRN. “It takes a village to meet the challenges of early-detection research.”

The Post-PSA Era

In the case of some cancers, researchers are developing new screening tests because the value of existing tests for those cancers has been called into question, perhaps most notably in the case of prostate specific antigen (PSA) testing for prostate cancer. (See “Benefits and Harms of PSA Screening for Prostate Cancer.”)

“The idea that one biomarker such as PSA is going to be useful for all settings has evolved. We now believe that we’ll need panels of biomarkers,” said Dr. Mark Rubin, a professor of pathology at Weill Cornell Medical College. To identify those biomarkers, researchers are using methods such as microarrays and whole-genome sequencing, which rapidly yield a wealth of information, to profile changes that occur in cancer.

Using such an approach, Dr. Rubin, Dr. Arul Chinnaiyan of the University of Michigan, and their colleagues discovered the fusion gene TMPRSS2-ERG, which is found in about half of all prostate cancers. “That fusion gene is seen only in cancer, and, in particular, only in prostate cancer,” said Dr. Rubin, whose team has developed a test to assess the levels of this fusion gene in urine samples. “Our approach now is to try to explain the other 50 percent of prostate cancers with other cancer-specific molecular events” that could eventually form a screening test based on a panel of genetic markers.

For example, Dr. Rubin co-led a recent study that identified a gene called SPOP that is mutated in about 10 percent of prostate cancers. “We can add that gene mutation to the gene fusion to improve on the test,” he explained. “This is the sort of approach we think will be useful for prostate cancer, as well as other cancers in the future.”

Applying Lessons Learned

To avoid unnecessary biopsies or treatment of prostate and other screen-detected cancers, researchers are trying to find biomarkers that better identify which cancers are likely to progress, noted Dr. Joshua LaBaer, director of the Center for Personalized Diagnostics at the Biodesign Institute at Arizona State University and co-chair of EDRN’s steering committee. Whereas some cancers detected by screening will progress and metastasize, others may never cause illness during a person’s lifetime.

“What we’ve learned from PSA is that if we’re going to come up with new screening tools, we also have to develop tools that give us a better idea of disease prognosis,” said Dr. James Brooks, a professor of urology at Stanford University.

Dr. Brooks and Dr. Sanjiv Gambhir, chair of the department of radiology at Stanford, lead a project to deploy new technologies that could form the basis for the next generation of prostate cancer screening tests.

To pave the way for tests that rely on panels of blood-based diagnostic or prognostic protein biomarkers, they are starting to test the performance of a magneto-nanosensor chip technology developed at Stanford. The sensor, which detects proteins tagged with magnetic particles, can measure the levels of up to 64 different proteins simultaneously, in very small sample volumes.

The Stanford team also hopes to adapt an imaging technology being studied in Dr. Gambhir’s lab to improve the accuracy of prostate cancer detection by transrectal ultrasound. The method uses gas “microbubbles” that are encased in a lipid shell to which specific antibodies are attached as a contrast material for ultrasound imaging. The antibodies target a receptor for vascular endothelial growth factor, which is a protein found in newly formed tumor blood vessels. The patented antibody-labeled microbubbles are awaiting Food and Drug Administration approval for human testing.

The Stanford team’s long-term goal is to combine their blood-based biomarker and imaging methods to improve early detection and prognostic assessment of prostate cancer and eventually other cancers. Combining molecular biomarkers and imaging for cancer screening “is a very powerful approach,” commented Dr. Sidransky. “We used to believe in the power of a marker to do everything,” he added. “We now know that’s not true.”

A Sense of Urgency

Researchers have long sought an effective screening strategy for ovarian cancer, and numerous candidate biomarkers for the disease have fallen short of expectations.

“Ovarian cancer is the paradigm for why we need early detection,” said Dr. Michael Birrer, a professor of medicine at Harvard Medical School. The disease can be cured by surgery if discovered early. But “75 percent of tumors are detected at the advanced stage, and those patients are hard to cure,” said Dr. Birrer.

Dr. Birrer and Dr. Steven Skates, an associate professor of medicine at Harvard, are leading a two-pronged effort to discover new biomarker candidates that may ultimately lead to a blood test for the early detection of ovarian cancer.

The first strategy will use extensive proteomic profiling of fluids from benign and malignant tissues, such as ovarian cysts, “to find candidate biomarkers that are systematically different between the two,” Dr. Skates explained.

We used to believe in the power of a marker to do everything. We now know that’s not true.

—Dr. David Sidransky

The second strategy involves genomic analyses to identify genes that are expressed differently in ovarian cancer tissue samples than they are in normal tissues that may give rise to ovarian cancer, and then bioinformatic analyses to look for genes whose protein products are also likely to be secreted into the bloodstream.

Using either the proteomic or genomic approach, or a combination of both, the researchers hope to come up with a short list of candidate biomarkers for further testing and refinement. “We may be lucky to find that some of those candidates are actually early-detection biomarkers that can be measured in blood,” Dr. Skates said.

Those biomarkers could form the basis of a blood test to screen postmenopausal women, and other women at increased risk of ovarian cancer, at regular intervals. For women who test positive on the blood test, a follow-up test, such as transvaginal ultrasound or newer imaging methods, might be used as part of an overall screening approach in the future, Drs. Birrer and Skates suggested.

Gazing into the Crystal Ball

No one can predict with certainty which types of tests will be most effective for screening for particular cancers. However, “if you want to prognosticate the future of cancer screening, my guess is that nucleotide [RNA or DNA]-based tests are going to be the most promising, at least in the short term,” Dr. Brooks said. “The power of nucleic acids is that you can amplify them to an extraordinary degree, which you can’t do with proteins,” Dr. LaBaer added.

Future DNA-based screening tests might detect methylation or other epigenetic modifications of DNA that occur specifically in cancer. “For example, we published a paper last year showing widespread and reproducible changes in DNA methylation in prostate cancer,” Dr. Brooks said.

And future screening tests may detect biomarkers in patient samples other than blood or urine. “One area where I think you’re going to see a change is in…tumors that affect the gastrointestinal tract” or other parts of the digestive system, Dr. LaBaer predicted. “You can look in stool for aberrant nucleic acids [from cells shed by tumors].” Researchers are also investigating sputum-based tests to detect lung cancer early.

“A possibility for the future is that we may stop thinking about cancers in terms of organ sites and may think more in terms of disrupted pathways or molecular variants of cancer,” Dr. LaBaer continued. In that case, “the biomarker people are going to have to work closely with the imaging people to very quickly turn a biomarker discovery into identifying where the tumor is.”

“We’re rapidly changing our concept of what cancer is,” noted Dr. Norton. “You can’t separate screening from understanding biology, from therapy, from prevention. The biggest challenge is weaving it all together [into] the big picture.”

Furthermore, he added, “we may find out that early detection is not helpful in certain situations, and that’s also important. We may not want to screen for certain cancers if we find out that prevention may be a better place to put our resources.”

“Mortality rates for some cancers have remained constant for the past 40 years, and in some of these cancers, new therapies have extended life for a few years but are not increasing the cure rates,” Dr. Skates noted. “Improved early detection for these cancers could shift that number so that more people are cured…. The payoff could be so big.”

Source:NCI.

 

 

Alternative Type of Brachytherapy Proves Effective in Mice.


An injectable genetically engineered peptide polymer may one day offer an alternative to conventional brachytherapy, a commonly used radiation therapy technique, according to the results of a new study in mice. The treatment could eliminate some of the difficulties associated with brachytherapy, the researchers believe, and could be used to treat more cancer types than brachytherapy. The study results were published November 15 in Cancer Research.

Using mouse models of two different cancer types, the researchers showed that their alternative brachytherapy approach—directly injecting tumors with a biodegradable elastin-like polypeptide (ELP) that is “labeled” with radioactive iodine—effectively shrank tumors and, in many cases, eliminated them completely.

In conventional brachytherapy, radioactive seeds are implanted in tumors and later removed. This type of internal radiation therapy is used frequently to treat localized prostate cancer and, to a lesser extent, to treat breast cancer. The seeds must be implanted and removed surgically, however. Another disadvantage is that implanted seeds can travel to other, healthy tissues, explained the study’s lead investigator, Dr. Wenge Liu of Duke University, and his colleagues.

By contrast, ELPs are liquid at room temperature and can be injected into tumors. Once inside tumors, they assemble into small seeds, or depots. In the study, the researchers tested ELP formulations that varied in their amino acid composition, size, and concentration to determine which one developed the most stable depots and was retained longest in the tumor before breaking down.

The researchers identified the ELP that had demonstrated the best tumor retention, and they tested three variations in mouse models of prostate and head and neck cancers. After only a single administration, the most effective variation shrank tumors in all of the mice regardless of tumor type. It also completely eliminated tumors in two-thirds of the mice with head-and-neck tumors and all of the mice with prostate tumors.

A potential advantage of the ELP is that it eventually breaks down into nontoxic forms that are naturally excreted by the body, Dr. Liu and his colleagues wrote. They reported no clinical signs of side effects in the treated mice, and additional examinations showed that the radioactive iodine was concentrated at the tumor site, with very little accumulation in healthy tissues.

In addition to treating several types of localized tumors, an ELP has other potential uses, the researchers wrote, including shrinking (debulking) tumors considered to be inoperable so that they can be removed surgically.

The researchers are continuing to refine the approach, Dr. Liu said in an e-mail message, including investigating whether the radioactive iodine dose can be lowered without sacrificing efficacy and working to improve delivery of the ELP “to solid tumors located deep in the body, such as in the esophagus, bronchus, stomach, and colon or abdominal cavity.”

Source:NCI.

Fusion Gene Linked to Rare Form of Childhood Leukemia.


Researchers have identified a fusion gene that may drive some rare and difficult-to-treat cancers in children called acute megakaryoblastic leukemias (AMKL). The investigators have also developed a test that can detect this genetic change in children at the time of diagnosis, which will help doctors identify candidates for future clinical trials of much-needed new therapies.

The findings, published November 13 in Cancer Cell, are from the Pediatric Cancer Genome Project. Led by St. Jude Children’s Research Hospital in Memphis and Washington University in St. Louis, the project is analyzing the normal and cancer genomes of hundreds of children and adolescents with a variety of cancers.

This particular study focused on AMKL that develops in children without Down syndrome, an aggressive form of the disease whose biology is poorly understood. (Children with Down syndrome who develop AMKL have excellent prognoses.)

The researchers initially found the fusion gene in 7 of the first 14 patients whose RNA they analyzed, which was an unexpectedly high frequency. After finding the fusion gene in a substantial fraction of another, larger group of patients, the researchers estimated that 27 percent of children with AMKL have the fusion gene.

When the investigators looked at survival statistics, the results were striking. At St. Jude, only 34 percent of children with the fusion gene were alive 5 years after diagnosis, compared with nearly 89 percent of those who lacked the fusion gene. AMKL in children without Down syndrome “is very rare, but the outcomes are very poor,” noted Dr. Tanja Gruber of St. Jude, the study’s first author.

The fusion gene codes for a chimeric protein that includes part of CBFA2T3, a protein that helps immature blood cells continue to divide (proliferate), and GLIS2, a transcription factor that is expressed in the kidneys and that had not been associated previously with cancer. Studies in mice suggested that the fusion protein helps immature blood cells proliferate for longer than normal cells.

In further experiments, the authors traced this effect to a signaling pathway known as BMP, which was much more active in cells with the fusion gene than in cells without it. The fusion protein is likely to affect other signaling pathways as well, the researchers said.

No drugs are currently available to block the effects of the fusion protein. But a diagnostic test based on a laboratory technique called PCR will enable clinical trials to begin as promising treatments emerge, Dr. Gruber noted. For now, the fusion gene could be a marker of poor prognosis.

The researchers also found that patients with the fusion gene had, on average, seven other genetic changes, whereas patients without the fusion had 17 other genetic changes. “This tells us that while you do need additional mutations beyond the fusion gene to cause the disease, you need very few of them,” said Dr. Gruber. Which of these lesions are important in the disease still needs to be determined in future studies, she added.

Source:NCI.

 

After Negative Colonoscopy, Rescreening with Other Tests May Be Effective.


According to a new modeling study, people who have a colonoscopy that finds no precancerous polyps (a negative colonoscopy) at age 50 can be rescreened beginning at age 60 with one of three alternative methods rather than having colonoscopies every 10 years, without affecting their life expectancy. Rescreening with one of the alternative methods—highly sensitive fecal occult blood testing (HSFOBT), fecal immunochemical testing (FIT), or computed tomographic colonography (CTC or “virtual colonoscopy”)—would also cause fewer complications and cost less.

These results, from the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) team from the University of Minnesota School of Public Health and their colleagues, were published November 6 in the Annals of Internal Medicine.

Most current guidelines recommend rescreening with colonoscopy 10 years after an initial negative colonoscopy. However, these recommendations are not based on results from randomized trials. “There are ongoing trials of colonoscopy, but none of them have reported results yet,” said lead author Dr. Amy Knudsen.

The researchers used a model called SimCRC, which was used to inform the 2008 update of the United States Preventive Services Task Force guidelines on colorectal cancer screening . Dr. Knudsen and her colleagues used the model to simulate five different rescreening strategies: no further screening, colonoscopy every 10 years, HSFOBT every year, FIT every year, or CTC every 5 years.

Two adherence scenarios were evaluated: one in which people received the tests as scheduled (perfect adherence) and one that mimicked real-life adherence, as recorded in several published studies (imperfect adherence).

The results were the same in both scenarios: all four rescreening methods reduced the number of deaths from colorectal cancer compared with no rescreening, and the difference among the four methods was small. For example, the imperfect-adherence scenario yielded between 6.1 and 6.7 deaths per 1,000 persons for all four screening methods. (See the table.)

Rescreening with colonoscopy not only produced the highest rates of perforation (tears in the colon) and other complications, but it was the most expensive strategy. Rescreening with one of the other three screening methods produced lifetime savings of up to $495 per person, compared with imperfect adherence with colonoscopy. (See the table.) At a population level, these savings could add up to nearly $3 billion for HSFOBT or FIT, and $0.6 billion for CTC, over the lifetimes of the estimated 6.5 million people who had negative colonoscopy results in 2008.

“Models can be helpful to inform [population] guidelines overall. On an individual level, decisions should be made in consultation with one’s doctor,” concluded Dr. Knudsen.

Screening Methods Compared (Imperfect Adherence)
Screening Method Deaths per 1,000 People Estimated Lifetime Savings Per Person, Compared with Colonoscopy
Colonoscopy 6.4 n/a
Fecal immunochemical testing 6.4 $450
Computed tomographic colonography 6.1 $91
Highly sensitive fecal occult blood test 6.7 $495

Source:NCI.

 

 

Fusion Gene Linked to Rare Form of Childhood Leukemia

Researchers have identified a fusion gene that may drive some rare and difficult-to-treat cancers in children called acute megakaryoblastic leukemias (AMKL). The investigators have also developed a test that can detect this genetic change in children at the time of diagnosis, which will help doctors identify candidates for future clinical trials of much-needed new therapies.

The findings, published November 13 in Cancer Cell, are from the Pediatric Cancer Genome Project. Led by St. Jude Children’s Research Hospital in Memphis and Washington University in St. Louis, the project is analyzing the normal and cancer genomes of hundreds of children and adolescents with a variety of cancers.

This particular study focused on AMKL that develops in children without Down syndrome, an aggressive form of the disease whose biology is poorly understood. (Children with Down syndrome who develop AMKL have excellent prognoses.)

The researchers initially found the fusion gene in 7 of the first 14 patients whose RNA they analyzed, which was an unexpectedly high frequency. After finding the fusion gene in a substantial fraction of another, larger group of patients, the researchers estimated that 27 percent of children with AMKL have the fusion gene.

When the investigators looked at survival statistics, the results were striking. At St. Jude, only 34 percent of children with the fusion gene were alive 5 years after diagnosis, compared with nearly 89 percent of those who lacked the fusion gene. AMKL in children without Down syndrome “is very rare, but the outcomes are very poor,” noted Dr. Tanja Gruber of St. Jude, the study’s first author.

The fusion gene codes for a chimeric protein that includes part of CBFA2T3, a protein that helps immature blood cells continue to divide (proliferate), and GLIS2, a transcription factor that is expressed in the kidneys and that had not been associated previously with cancer. Studies in mice suggested that the fusion protein helps immature blood cells proliferate for longer than normal cells.

In further experiments, the authors traced this effect to a signaling pathway known as BMP, which was much more active in cells with the fusion gene than in cells without it. The fusion protein is likely to affect other signaling pathways as well, the researchers said.

No drugs are currently available to block the effects of the fusion protein. But a diagnostic test based on a laboratory technique called PCR will enable clinical trials to begin as promising treatments emerge, Dr. Gruber noted. For now, the fusion gene could be a marker of poor prognosis.

The researchers also found that patients with the fusion gene had, on average, seven other genetic changes, whereas patients without the fusion had 17 other genetic changes. “This tells us that while you do need additional mutations beyond the fusion gene to cause the disease, you need very few of them,” said Dr. Gruber. Which of these lesions are important in the disease still needs to be determined in future studies, she added.

Source:NCI.

 

 

Decades of Data Point to Overdiagnosis from Breast Cancer Screening.


Since breast cancer screening came into widespread use in the United States in the 1970s, more than 1 million women may have been diagnosed with cancers that never would have caused them harm or required treatment, a new study suggests. These women may have been exposed unnecessarily to the adverse effects of treatment, the authors reported in the November 22 New England Journal of Medicine.

The detection of cancers that do not grow or grow so slowly that they would never cause illness is known as overdiagnosis. Previous studies have shown that screening mammography, which looks for breast cancer in the absence of symptoms, can lead to overdiagnosis.

Overdiagnosis may account for nearly one-third of newly diagnosed breast cancers among women aged 40 and older in the United States, the authors of the new study estimated. In 2008, for example, more than 70,000 women may have received an unnecessary diagnosis, they noted.

“This is a significant public health concern,” said co-author Dr. Archie Bleyer of St. Charles Health System in Bend, OR. “Women need to be aware of the potential benefits of screening, as well as the downsides—including being diagnosed with cancers that [are not life-threatening].”

To look for evidence of overdiagnosis, Dr. Bleyer and Dr. H. Gilbert Welch of Dartmouth Medical School in Hanover, NH, used NCI’s Surveillance, Epidemiology, and End Results (SEER) database to analyze trends in breast cancer incidence between 1976 and 2008.

The authors reasoned that if screening leads to the earlier detection of cancers that are destined to become lethal, detecting more breast cancers at an earlier stage—when they tend to be curable—should lead to a corresponding drop in late-stage cancers. But the SEER data did not show this to be true: The rise in early-stage breast cancers over three decades (an absolute increase of 122 cases per 100,000 women) was not matched by an equivalent drop in late-stage cancers. Instead, there was an absolute decrease of 8 cases per 100,000 women. This imbalance, the authors concluded, must be due to overdiagnosis.

This estimate of overdiagnosis is generally consistent with estimates from other countries. A recent Norwegian study found that as many as 1 in 4 invasive breast cancers diagnosed in that country through its population-based mammography screening program never would have caused harm.

Nonetheless, comparing studies can be a challenge because of differences in study design. For instance, Drs. Bleyer and Welch counted noninvasive tumors known as ductal carcinomas in situ among the early-stage breast cancers, whereas the Norwegian researchers did not.

A limitation of the current study was the fact that the authors had to infer overdiagnosis from incidence statistics in the population, because overdiagnosis cannot be directly observed at the individual patient level.

The study does not clarify whether an individual woman should be screened for breast cancer, the authors acknowledged. But they noted that the potential harms of unnecessary diagnoses are clear: emotional stress and anxiety, surgery, radiation therapy, hormonal therapy, chemotherapy, or, as is often the case, a combination of these treatments—all for abnormalities that would not have caused illness.

“Women need to understand that screening has positive and negative consequences,” said Dr. Stephen Taplin of NCI’s Division of Cancer Control and Population Sciences, who has studied screening for 25 years but was not involved in this study. “But they also need to know that a decision about screening is not a forever choice. A woman can choose to be screened later, or not at all.”

He added, “This is one of many studies that is expanding the discussion about screening. It demonstrates that women need to make decisions based on their circumstances, not just based on recommendations.”

Source:NCI.

 

 

Using an Ocean of Data, Researchers Model Real-Life Benefits of Cancer Screening.


Randomized clinical trials are widely acknowledged as the best way to determine whether a cancer screening test saves lives. But even when trial results indicate that a particular screening method has a clear benefit, the findings may not be easily translated into recommendations for the public. The results of a screening trial may apply only to certain people, and the findings can change as the study period lengthens—all of which means that the results may not apply to the general population.

For example, the National Lung Screening Trial (NLST) showed that screening of current or former heavy smokers with three annual low-dose spiral CT scans can reduce their risk of dying from lung cancer. But NLST enrolled only people aged 55 to 74 who had smoked for 30 pack years and had quit less than 15 years previously.

“Would a similar screening regimen also benefit younger or older smokers? Would lighter smokers benefit equally? And when should they start and stop screening?” asked Dr. Eric “Rocky” Feuer, scientific coordinator of NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET). Patients and doctors alike will almost certainly ask these questions.

CISNET’s five research teams use modeling to try to answer these types of questions for several different cancer types. Using the results of screening trials, the teams are trying to estimate the true benefit of screening in the general population and to identify the optimal way to implement screening within the health care system.

The teams’ extremely complex computer programs, which for some cancer types (such as breast and colorectal) have been used and constantly refined for over a decade, incorporate a wide variety of information. This information includes not only trial data but observational data, epidemiologic data, and information on the natural history of each cancer type.

One of CISNET’s original mandates was to tease out the role that screening has played in the observed decline in deaths from some cancer types over the last few decades. In a landmark 2005 paper in the New England Journal of Medicine, CISNET researchers determined that screening mammography likely accounted for half of the 24 percent decrease in breast cancer mortality that was observed between 1989 and 2000.

From there, the teams moved to providing data that inform screening guidelines, said Dr. Feuer. In 2008, the United States Preventive Services Task Force (USPSTF) used a CISNET modeling study as part of the evidence behind the update of its screening recommendations for colorectal cancer. In 2009 a similar modeling study was used to update the USPSTF mammography screening recommendations. Now, CISNET teams are trying to help resolve some of the questions emerging from screening trials in lung, prostate, and esophageal cancer.

Matching the Population Experience

A major goal of the CISNET lung cancer team is to “integrate the NLST results into general practice,” said Dr. Pamela McMahon of Massachusetts General Hospital, the principal investigator of the lung cancer team, which also includes researchers from five other universities. “We have to extrapolate from the limited scenario of the NLST, because that [trial] doesn’t match the population experience.” (See “After Landmark Study, Exploring Questions about Lung Cancer Screening.”)

“We’re looking at every permutation you can think of: ages to start screening, ages to stop screening, how many pack years [smoked], how many years since quitting, how frequently to do the screens,” said Dr. McMahon.

The team is aided by access to data on every single patient enrolled in NLST as well as every patient in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), also funded by NCI.

Once the results are complete, the researchers hope to use them to create an interactive projection tool that will let policy makers see how implementations of different lung cancer screening programs in their community would alter lung cancer mortality, similar to the mortality projection tool produced by the CISNET colorectal cancer team.

Two Enormous Trials, Two Different Results

The three research groups in the CISNET prostate cancer team are tackling an equally ambitious, although entirely different problem. Two large randomized clinical trials of prostate cancer screening—one in the United States and one in Europe—have generated long-term data on how screening may affect prostate cancer mortality. And the two trials had different results.

In the European Randomized Study of Screening for Prostate Cancer (ERSPC), men who were screened for prostate cancer were less likely to die from prostate cancer than men who were not screened. That was not the case in the PLCO trial, which found that men who were screened did not have a lower risk of dying from prostate cancer than unscreened men. The trials were conducted very differently, and each had limitations, including a large number of unscheduled screenings (referred to as “contamination”) in the control group of the PLCO trial and a lack of standardized cancer treatment in ERSPC.

“So the question that we’re trying to answer is whether there is a range of screening benefits that is consistent with the results of both trials,” said Dr. Ruth Etzioni of the Fred Hutchinson Cancer Research Center, principal investigator of the CISNET prostate team. Researchers from both trials have allowed the CISNET team access to all of their data, down to the level of each individual patient, to resolve whether screening reduces prostate cancer deaths.

The CISNET team has spent years modeling the natural history of prostate cancer. “We can’t see when a person’s cancer begins…but we can see how disease is diagnosed in the population, at what ages people get diagnosed, and at what stages they get diagnosed. All of that informs us about what’s happening at a somewhat-below-the-surface level,” explained Dr. Etzioni.

The prostate modeling groups will use their knowledge of the natural history of prostate cancer and overall health and life histories of men in the United States “to ‘replicate’ what happened in ERSPC and PLCO on top of those life histories and disease histories,” Dr. Etzioni elaborated. “And when we replicate the two trials we’ll see if there is a range of true benefit, where we get something reasonably close to what was observed in both trials.”

The team is also beginning to look at how immediate versus delayed treatment may change the benefit/harm ratio of prostate cancer screening and at how the prevention of endpoints other than mortality—such as metastatic disease—may also alter that ratio. (See “Benefits and Harms of Prostate Cancer Screening.”)

Modeling Targeted Screening

For the first 10 years of the program, CISNET focused on four of the most common cancers in the United States: breast, prostate, lung, and colorectal. In 2010, it added a less common cancer—esophageal—which presents a different set of issues: determining how to screen for a cancer in a subpopulation of people with well-known risk factors for the disease.

“Esophageal cancer is not common enough to do population-based screening, but [doctors do] targeted screening based on individual risk,” explained Dr. Chin Hur of Massachusetts General Hospital, principal investigator of the esophageal cancer team.

“We chose a less common cancer [to include in CISNET] because the effort that we go through to find a relatively few esophageal cancers is incredibly inefficient,” commented Dr. Feuer. Although gastroesophageal reflux disease and a related condition called Barrett esophagus are known risk factors for esophageal cancer, relatively few people with either problem will develop the disease.

But doctors do not yet know how to identify which people with these conditions are most likely to develop esophageal cancer and may, therefore, benefit from targeted screening. “There’s huge potential to do things better,” said Dr. Feuer. The goal for the CISNET team is “to come up with cost-effective strategies to diminish the morbidity and mortality from esophageal cancer,” added Dr. Hur.

The esophageal team is developing three models using existing clinical trial data and is collaborating with modelers working at the molecular level of cancer. This so-called “multiscale modeling” will let the team build a more accurate representation of the natural history of esophageal cancer into their models. Once the models have been finalized, the researchers will use them to virtually “re-run” and analyze trials not only of endoscopic monitoring and radiofrequency ablation in people with Barrett esophagus but also other emerging strategies for preventing the progression of esophageal cancer.

Although endoscopic screening and radiofrequency ablation of Barrett esophagus have been tested in many smaller clinical studies, these trials have nowhere near the numbers of patients—or, therefore, the statistical power or general applicability—that large screening trials for breast, prostate, lung, and colorectal cancer have.

This poses a paradox for the modelers and for the esophageal cancer research community in general: “Where there is less clinical trial data available, there’s more uncertainty about the projections. At the same time, there is less data around to inform both clinical decision making and policy, so our results are more important. So, although there’s more uncertainty about [modeling], there’s also more need for it,” summarized Dr. Hur.

“We need to be very open and transparent about the limitations, explore those fully, and be careful about the conclusions of our analyses,” he said. “But [modeling] is better than someone just taking a best guess. It’s a systematic approach, with intense peer review and multiple modeling groups, that tries to distill the evidence that is out there.”

Source:NCI.

 

 

 

Crunching Numbers: What Cancer Screening Statistics Really Tell Us.


Over the past several years, the conversation about cancer screening has started to change within the medical community. Be it breast, prostate, or ovarian cancer, the trend is to recommend less routine screening, not more. These recommendations are based on an emerging—if counterintuitive—understanding that more screening does not necessarily translate into fewer cancer deaths and that some screening may actually do more harm than good.

Much of the confusion surrounding the benefits of screening comes from interpreting the statistics that are often used to describe the results of screening studies. An improvement in survival—how long a person lives after a cancer diagnosis—among people who have undergone a cancer screening test is often taken to imply that the test saves lives.

But survival cannot be used accurately for this purpose because of several sources of bias.

Sources of Bias

A graphic illustrating lead-time bias. Click to enlarge the image and to read the full caption. (Image from O. Wegwarth et al., Ann Intern Med, March 6, 2012:156)

Lead-time bias occurs when screening finds a cancer earlier than that cancer would have been diagnosed because of symptoms, but the earlier diagnosis does nothing to change the course of the disease. (See the graphic on the right for further explanation.)

Lead-time bias is inherent in any analysis comparing survival after detection. It makes 5-year survival after screen detection—and, by extension, earlier cancer diagnosis—an inherently inaccurate measure of whether screening saves lives. Unfortunately, the perception of longer life after detection can be very powerful for doctors, noted Dr. Donald Berry, professor of biostatistics at the University of Texas MD Anderson Cancer Center.

“I had a brilliant oncologist say to me, ‘Don, you have to understand: 20 years ago, before mammography, I’d see a patient with breast cancer, and 5 years later she was dead. Now, I see breast cancer patients, and 15 years later they’re still coming back, they haven’t recurred; it’s obvious that screening has done wonders,'” he recounted. “And I had to say no—that biases could completely explain the difference between the two [groups of patients].”

Another confounding phenomenon in screening studies is length-biased sampling (or “length bias”). Length bias refers to the fact that screening is more likely to pick up slower-growing, less aggressive cancers, which can exist in the body longer than fast-growing cancers before symptoms develop.

A graphic illustrating overdiagnosis bias. Click to enlarge the image and to read the full caption. (Image from O. Wegwarth et al., Ann Intern Med, March 6, 2012:156)

Dr. Berry likens screening to reaching into a bag of potato chips—you’re more likely to pick a larger chip because it’s easier for your hand to find, he explained. Similarly, with a screening test “you’re going to pick up the slower-growing cancers disproportionately, because the preclinical period when they can be detected by screening—the so-called sojourn time—is longer.”

The extreme example of length bias is overdiagnosis, where a slow-growing cancer found by screening never would have caused harm or required treatment during a patient’s lifetime. Because of overdiagnosis, the number of cancers found at an earlier stage is also an inaccurate measure of whether a screening test can save lives. (See the graphic on the left for further explanation.)

The effects of overdiagnosis are usually not as extreme in real life as in the worst-case scenario shown in the graphic; many cancers detected by screening tests do need to be treated. But some do not. For example, recent studies have estimated that 15 to 25 percent of screen-detected breast cancers and 20 to 70 percent of screen-detected prostate cancers are overdiagnosed.

How to Measure Lives Saved

Because of these biases, the only reliable way to know if a screening test saves lives is through a randomized trial that shows a reduction in cancer deaths in people assigned to screening compared with people assigned to a control (usual care) group. In the NCI-sponsored randomized National Lung Screening Trial (NLST), for example, screening with low-dose spiral CT scans reduced lung cancer deaths by 20 percent relative to chest x-rays in heavy smokers. (Previous studies had shown that screening with chest x-rays does not reduce lung cancer mortality.)

However, improvements in mortality caused by screening often look small—and they are small—because the chance of a person dying from a given cancer is, fortunately, also small. “If the chance of dying from a cancer is small to begin with, there isn’t that much risk to reduce. So the effect of even a good screening test has to be small in absolute terms,” said Dr. Lisa Schwartz, professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice and co-director of the Veterans Affairs Outcomes Group in White River Junction, VT.

For example, in the case of NLST, a 20 percent decrease in the relative risk of dying of lung cancer translated to an approximately 0.4 percentage point reduction in lung cancer mortality (from 1.7 percent in the chest x-ray group to 1.3 percent in the CT scan group) after about 6.5 years of follow-up, explained Dr. Barry Kramer, director of NCI’s Division of Cancer Prevention.

A recent study published March 6 in the Annals of Internal Medicine by Dr. Schwartz and her colleagues showed how these relatively small—but real—reductions in mortality from screening can confuse even experienced doctors when pitted against large—but potentially misleading—improvements in survival.

Tricky Even for Experienced Doctors

To test community physicians’ understanding of screening statistics, Dr. Schwartz, Dr. Steven Woloshin (also of Dartmouth and co-director of the Veterans Affairs Outcomes Group), and their collaborators from the Max Planck Institute for Human Development in Germany developed an online questionnaire based on two hypothetical screening tests. They then administered the questionnaire to 412 doctors specializing in family medicine, internal medicine, or general medicine who had been recruited from the Harris Interactive Physician Panel .

The effects of the two hypothetical tests were described to the participants in two different ways: in terms of 5-year survival and in terms of mortality reduction. The participants also received additional information about the tests, such as the number of cancers detected and the proportion of cancer cases detected at an early stage.

The results of the survey showed widespread misunderstanding. Almost as many doctors (76 percent of those surveyed) believed—incorrectly—that an improvement in 5-year survival shows that a test saves lives as believed—correctly—that mortality data provides that evidence (81 percent of those surveyed).

Recent Screening Recommendation Changes

About half of the doctors erroneously thought that simply finding more cases of cancer in a group of people who underwent screening compared with an unscreened group showed that the test saved lives. (In fact, a screening test can only save lives if it advances the time of diagnosis and earlier treatment is more effective than later treatment.) And 68 percent of doctors surveyed said they were even more likely to recommend the test if evidence showed that it detected more cancers at an early stage.

Doctors were three times more likely to say they would recommend the test supported by irrelevant survival data than the test supported by relevant mortality data.

In short, “the majority of primary care physicians did not know which screening statistics provide reliable evidence on whether screening works,” Dr. Schwartz and her colleagues wrote. “They were more likely to recommend a screening test supported by irrelevant evidence…than one supported by the relevant evidence: reduction in cancer mortality with screening.”

Teaching the Testers

“In some ways these results weren’t surprising, because I don’t think [these statistics] are part of the standard medical school curriculum,” said Dr. Schwartz.

“When we were in medical school and in residency, this wasn’t part of the training,” Dr. Woloshin agreed.

“We should be teaching residents and medical students how to correctly interpret these statistics and how to see through exaggeration,” added Dr. Schwartz.

Some schools have begun to do this. The University of North Carolina (UNC) School of Medicine has introduced a course called the Science of Testing, explained Dr. Russell Harris, professor of medicine at UNC. The course includes modules on 5-year survival and mortality outcomes.

The UNC team also recently received a research grant to form a Research Center for Excellence in Clinical Preventive Services from the Agency for Healthcare Research and Quality. “Part of our mandate is to talk not only to medical students but also to community physicians, to help them begin to understand the pros and cons of screening,” said Dr. Harris.

Drs. Schwartz and Woloshin also think that better training for reporters, advocates, and anyone who disseminates the results of screening studies is essential. “A lot of people see those [news] stories and messages, so people writing them need to understand,” said Dr. Woloshin.

Patients also need to know the right questions to ask their doctors. “Always ask for the right numbers,” he recommended. “You see these ads with numbers like ‘5-year survival changes from 10 percent to 90 percent if you’re screened.’ But what you always want to ask is: ‘What’s my chance of dying [from the disease] if I’m screened or if I’m not screened?'”

Sharon Reynolds

Source:NCI.