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PET may artificially boost HNC survival rates

Tue, Aug 12, 2014


Author: Donna Domino, Features Editor

The use of positron emission tomography (PET) is associated with a stage migration phenomenon in locally advanced head and neck cancer (HNC) patients, according to a recent report in JAMA Otolaryngology — Head & Neck Surgery.

Multiple studies have shown the increased sensitivity of fluorodeoxyglucose (FDG)-PET over computed tomography (CT) for detecting primary tumors, regional nodal disease, and distant metastases. Because of potential treatment changes and prognostic information, as well as patient and physician preference, FDG-PET has been rapidly adopted for managing head and neck cancers.

Because FDG-PET is more sensitive than CT, it often leads to patients being assigned a higher stage than if they were staged with CT alone, the study authors noted.

In this retrospective study, the researchers sought to confirm whether the increased use of FDG-PET over time is associated with the appearance of improved stage-specific survival due to stage migration (JAMA Otolaryngol Head Neck Surg, July 1, 2014, Vol. 140:7, pp. 654-661).

In the study’s model of clinically important variables, PET scan use was associated with a higher stage of disease. In addition, oropharyngeal cancers were more likely to be assigned a higher stage than oral cavity cancers.

Within the PET era, no statistically significant survival difference was found between those who underwent FDG-PET and those who did not. However, a significant increase in stage-specific survival was detected for patients with locally advanced disease. No stage-specific survival differences were found in patients with local disease or metastatic disease.

Two-year survival for all patients, no PET versus PET, was 55.5% versus 53.2%. Two-year survival for locally advanced disease, no PET versus PET, was 32.1% versus 52.2%.

Recently, a large Medicare claims-based study demonstrated a similar up-staging phenomenon with the increased use of FDG PET scans in non-small cell lung cancers, the study authors noted (Journal of Clinical Oncology, August 1, 2012, Vol. 30:22, pp. 2725-2730)

Lead author Noam VanderWalde, MD, now an assistant professor of radiation oncology at the University of Tennessee West Cancer Center, said this study’s findings reflected the same phenomenon.

“In general, that’s what you tend to see when you have newer diagnostic tools: You get a stage migration,” Dr. VanderWalde told “You get patients put into different stages that artificially looks like there’s a survival benefit, but it’s not a real survival benefit for that individual patient. It’s just places patients better into different stages.”

The researchers found an increase in the number of PET patients who received chemotherapy (43.1% versus 17.5%). However, they also noted that patients who underwent FDG-PET were less likely to receive no treatment compared with patients who did not undergo FDG-PET.

The study was conducted within four large, nonprofit, integrated health systems: Group Health Cooperative (Seattle), Health Alliance Plan — Henry Ford Health System (Detroit), Kaiser Permanente Colorado (Denver), and Kaiser Permanente Northwest (Portland, OR). The study group included patients older than 18 years who were diagnosed as having head and neck cancer between 2000 and 2008.

Disease stages were classified into three clinically relevant groups: localized (stages I and II), locally advanced (stages III, IVA, and IVB), and metastatic (stage IVC).

The PET era was defined as the period from 2005 through 2008; the pre-PET era as 2000 through 2004. The survival comparison for the PET era versus pre-PET era was limited to patients in the PET era diagnosed in 2005 and 2006 and having at least two years of follow-up.

The study included 958 patients, with 46% treated in the PET era. The oral cavity was the most common primary tumor site, and most patients were diagnosed as having localized disease.

Median patient age was 66 years; median follow-up for all patients was 31 months. The median follow-up for patients in the pre-PET era was 56 months. For surviving patients in the PET era, the median follow-up for those who underwent PET was 22 months, and the median follow-up for those who did not undergo PET was 27 months.

Pre-PET era versus PET era
The researchers found no statistically significant differences in the primary tumor sites, stage, age, sex, or comorbidities between patients in the pre-PET and PET eras. However, a significant difference in the type of treatments patients received was detected: less use of surgery (pre-PET era, 66.9% versus PET era, 53.7%) (p < 0.001) and a trend toward increasing use of chemotherapy during the PET era (pre-PET era, 20.5% versus PET era, 25.9%) (p = 0.05). No difference in two-year overall survival rates was found (pre-PET era, 75.5% versus PET era, 74.0%) (p = 0.34).

In the PET era, tumor site was significantly associated with use of PET for staging (p < 0.001). Younger patients and those with later years of diagnosis were more likely to have undergone FDG-PET scans (p < 0.001). The use of FDG-PET for staging purposes has been increasing since 2005 among this group, the study authors noted.

In 2005, about 12.5% of patients received pretreatment FDG-PET scans. By 2008, the percentage more than doubled to 34%. Compared with patients who did not undergo PET, those who underwent PET were more likely to receive radiation treatment (no PET, 48.3% versus PET, 83.3%), more likely to receive chemotherapy (no PET, 17.5% versus PET, 43.1%) and less likely to receive no treatment (no PET, 18.8% versus PET, 0%).

Within the PET-era group, the researchers noted a statistically significant increase in the number of patients staged as having locally advanced disease. In oral cavity and larynx and/or hypopharynx disease, most patients who underwent PET scans were staged as having locally advanced disease, while those without PET were mostly staged as having local disease.

The upstaging of patients with nodal disease identified only by FDG PET improved the survival of all patients with nodal disease, compared with those with obviously identified (no FDG-PET) locally advanced disease, the researchers found.

A difference in staging and survival was not found between the pre-PET and PET eras.

“This is interesting given the increasing incidence of human papillomavirus (HPV)-related oropharyngeal cancers over this period and their associated higher stages and improved prognoses,” the study authors wrote.

One of the potential benefits of a staging FDG-PET scan is the identification of previously unknown metastatic disease, they noted.

“FDG-PET use appeared to be associated with upstaging at diagnosis and improved survival in patients with locally advanced disease but no difference in overall survival for the entire cohort,” the researchers concluded. “The improved stage-specific survival is likely a reflection of stage migration. The ability of FDG-PET to affect patient management for individual patients remains an important area of future research.”

“The real question for clinicians is, ‘Should we routinely be using PET scans to diagnose head and neck cancer patients?’ ” Dr. VanderWalde said. “Unfortunately, the study doesn’t really answer that question. It does say there’s probably not a survival benefit, and that would be the only reason to use PET scans.”

A diagnostic tool’s value lies in helping clinicians determine the best course of treatment, he noted.

“Other studies show PET is more sensitive, but, in general, I think it’s best for clinicians, especially those treating cancer, even if the test is a lot more accurate, is it going to change how they treat a patient?” Dr. VanderWalde said. “If you’re going to be spending a lot of money on a specific type of test, you want it to actually change what you might do.”

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Colgate Total ingredient linked to hormones, cancer spotlights FDA Process

Tue, Aug 12, 2014


Author: Tiffany Kary

The chemical triclosan has been linked to cancer-cell growth and disrupted development in animals. Regulators are reviewing whether it’s safe to put in soap, cutting boards and toys. Consumer companies are phasing it out. Minnesota voted in May to ban it in many products.

At the same time, millions of Americans are putting it in their mouths every day, by way of a top-selling toothpaste that uses the antibacterial chemical to head off gum disease – Colgate-Palmolive Co.’s Total.

Total is safe, Colgate says, citing the rigorous Food and Drug Administration process that led to the toothpaste’s 1997 approval as an over-the-counter drug. A closer look at that application process, however, reveals that some of the scientific findings Colgate put forward to establish triclosan’s safety in toothpaste weren’t black and white — and weren’t, until this year, available to the public.

Colgate’s Total application included 35 pages summarizing toxicology studies on triclosan, which the FDA withheld from view. The agency released the pages earlier this year in response to a lawsuit over a Freedom of Information Act request. Later, following inquiries from Bloomberg News, the FDA put the pages on its website.

The pages show how even with one of the U.S.’s most stringent regulatory processes — FDA approval of a new drug — the government relies on company-backed science to show products are safe and effective. The recently released pages, taken alongside new research on triclosan, raise questions about whether the agency did appropriate due diligence in approving Total 17 years ago, and whether its approval should stand in light of new research, said three scientists who reviewed the pages at Bloomberg News’s request.

Rodent Bones
Among the pages were studies showing fetal bone malformations in mice and rats. Colgate said the findings weren’t relevant. Viewed through the prism of today’s science, such malformations look more like a signal that triclosan is disrupting the endocrine system and throwing off hormonal functioning, according to the three scientists.

Colgate’s application materials also show that the FDA asked questions about the thoroughness of cancer studies, which are partly addressed in recently released documents.

Some questions about triclosan’s potential impact on people are, by nature, unanswerable. Humans are exposed to dozens of chemicals that may interact in the body, making it almost impossible to link one substance to one disease, said Thomas Zoeller, a biology professor at the University of Massachusetts Amherst, who specializes in how chemicals affect the endocrine system.

The chemical triclosan has been linked to cancer-cell growth and disrupted development in animals. Regulators are reviewing whether it’s safe to put in soap, cutting boards and toys. Consumer companies are phasing it out. Minnesota voted in May to ban it in many products.

‘Huge Risk’
“We have created a system where we are testing these chemicals out on the human population. I love the idea they are all safe,” Zoeller said. “But when we have studies on animals that suggest otherwise, I think we’re taking a huge risk.”

New York-based Colgate isn’t accused of wrongdoing, and the 35 pages don’t prove triclosan is harmful. It was the FDA’s decision to keep the documents off of its website, Colgate said.

The FDA followed standard procedure by redacting information that had come from a third party, said spokeswoman Andrea Fischer. Some studies were done in the labs of Ciba-Geigy, the first triclosan maker and a predecessor to its current primary maker, BASF SE, according to the documents. The pages didn’t denote which studies were done by an outside party, or who the party was. Fischer declined to identify them.

Fights Gingivitis
Colgate said Total’s effectiveness and safety are supported by more than 80 clinical studies involving 19,000 people, and that it gave the FDA 98 volumes, numbering hundreds of pages each, in support of Total. Colgate submits annual reports to the FDA reviewing new science and safety findings, said Colgate spokesman Thomas DiPiazza.

“In the nearly 18 years that Colgate Total has been on the market in the U.S., there has been no signal of a safety issue from adverse-event reports,” DiPiazza said. Colgate also pointed to an independent 2013 review by the Cochrane Oral Health Group, a network of doctors, researchers and health advocates, which found no evidence of harmful effects associated with using Colgate Total.

Total has an important health benefit because it fights plaque and gingivitis, DiPiazza said. Gingivitis can progress to periodontal disease, which affects almost half of Americans 30 and over, according to a 2012 study by the Centers for Disease Control and Prevention.

Soap Review
The FDA reviews all new safety information on ingredients to determine whether a reassessment is necessary, said Jeff Ventura, a spokesman. The agency is revisiting triclosan in hand soaps though not in Total, said Sandra Kweder, deputy director of the agency’s Office of New Drugs. That’s because while triclosan hasn’t been proven superior to soap and water at washing hands, she said, its benefit as an active ingredient in toothpaste was made clear through its FDA approval process.

Colgate removed triclosan from its Softsoap liquid handsoaps and Palmolive antibacterial dish liquid in 2011, citing changing consumer preferences and superior formulations. It said it has no plans to reformulate Total, which is the only triclosan toothpaste approved for U.S. sale.

This article is based on interviews with Colgate, former and current FDA staff and oral biology experts, transcripts of FDA meetings, as well as on the 35 pages, which the FDA shared in January with the Natural Resources Defense Council, a public-health advocate that sued for them. The scientists who examined the pages included Zoeller, a second university-affiliated endocrine specialist, and an environmental toxicologist affiliated with the Environmental Working Group, a public health advocacy.

Pet-Food Dispensers
Of the more than 84,000 chemicals sold in the U.S., few are attracting more scrutiny than triclosan. Used for decades in handsoaps, it is now part of almost 200 products including rugs and pet-food dispensers. Companies including Johnson & Johnson and Procter & Gamble Co. have vowed to remove it from their lineups. In May, Avon Products Inc. announced its plans to go triclosan-free.

Those moves are coming in part as consumers, armed with toxicity ranking systems such as the Environmental Working Group’s Skin Deep Database, have turned away from chemicals including Bisphenol A and phthalates, even in the absence of firm scientific or regulatory conclusions.

Wariness is mounting as factors from environment to diet are blamed for a global rise in endocrine-related diseases. Breast, ovarian, prostate and testicular cancer rates have increased over the past 40 to 50 years, according to a 2012 report from the World Health Organization and the United Nations Environment Programme. A rise in preterm and low birthweight babies, early breast development in girls and undescended testicles in boys may be linked to endocrine-disrupting chemicals, the report says.

Regular Exposure
Zoeller, the endocrine specialist, said that while an estimated 800 to 1,000 chemicals are believed to disrupt the endocrine system, triclosan is one of about 10 to which people are regularly exposed. “We may not have to change very much to have a big impact,” he said.

Total, the No. 3 selling brand in the U.S., lost 2 percent of its market share last year, with $189.8 million in sales for the year that ended on Jan. 26, according to market research firm Mintel Group Ltd. Colgate’s Tom’s of Maine line grew 14 percent, to $38.9 million, suggesting shoppers are gravitating toward more natural options, the report said.

Procter & Gamble, which makes Crest 3D White and Crest Pro-Health — the top two U.S. toothpastes according to Mintel — has sought to capitalize. A Google search for “triclosan” and “toothpaste” brings up an advertisement linked to a Procter & Gamble site touting Crest products as “100% triclosan free.”

P&G’s oral-care products have been triclosan-free in the U.S. and several other markets “for a number of years,” said Kristopher Parlett, a spokesman for the Cincinnati-based company. P&G doesn’t produce or market triclosan-containing oral care products anywhere, he added.

GlaxoSmithKline Plc, which once had triclosan in some Aquafresh and Sensodyne toothpastes, has reformulated all of its oral care products that previously contained it, said spokeswoman Joanmarie Goddard. She couldn’t say what year they had been reformulated or whether triclosan versions had been sold in the U.S. The decision was a response to consumer concern that triclosan across a range of products “may have a negative environmental impact in the future,” she said.

Hand Scrubs
From its beginnings as an ingredient in surgical hand scrubs, triclosan — also identified as 5-Chloro-2-(2,4-dichlorophenoxy)phenol — has grown to a $100 million a year chemical globally, according to statistics from the Kline Group. BASF, based in Ludwigshafen, Germany, sells it under the trade names Irgasan and Irgacare. India-based Kumar Organic Products Ltd. and Vivimed Labs Ltd. also make it.

BASF says that 40 years of global studies and publications prove triclosan’s efficacy in oral care and cosmetic products, as well as in hand disinfectants and other health-care applications, according to Thomas Nonnast, a spokesman. Klaus Nussbaum, a spokesman for Kumar, said studies have established triclosan’s safety. Vivimed didn’t respond to requests for comment.

While company-sponsored safety tests on triclosan that would become part of Colgate’s FDA application for Total began as early as 1968, U.S. agencies have yet to comprehensively review it for other uses.

Safety Tests
In 1974, the FDA proposed issuing a so-called monograph that would determine whether antibacterial ingredients such as triclosan were considered safe and effective for hand soaps. Two years later, the U.S. Toxic Substances Control Act of 1976, which aimed to comprehensively regulate chemicals, grandfathered in existing substances with no safety testing.

The law gave the EPA — which oversees triclosan’s use in durable goods including fabrics and sealants — the power to restrict or test substances. It excluded food, drugs and cosmetics, which fall under the FDA’s mandate. The FDA, four decades after its first promise, has yet to issue a ruling on whether triclosan is safe or effective in soaps.

In the meantime, triclosan made its way into toothpaste.

Colgate spent 10 years and $38 million developing Colgate Total, according to Mintel. Introduced in 1992, it was marketed in almost 100 countries before gaining U.S. approval, according to transcripts of FDA meetings.

Four Applications
Colgate applied to the U.S. four times starting in 1992, according to FDA records, before gaining the FDA’s blessing on July 11, 1997. In a statement at the time, Colgate called Total “the most significant advancement in home dental care since the introduction of fluoride.”

In the early 2000’s, Caren Helbing, a professor at the University of Victoria in Canada, noticed the SARS outbreak in China had led to a germ-killing frenzy. Seeing triclosan listed as an active ingredient in many antibacterial products, she looked up its chemical structure. It was similar to both thyroid hormones and to polychlorinated biphenyls, or PCBs, she said. Such a structure, she and other scientists have said, allow the chemicals to become active on hormone receptors.

Helbing, who has a Ph.D. in biochemistry and microbiology, found that tadpoles exposed to triclosan developed into smaller froglets and had malformed legs — results that she and other scientists published in the peer-reviewed Aquatic Toxicology journal in 2006.

Thyroid Function
Other studies found no such links between the chemical and hormone function. A 2011 paper published in Science of the Total Environment found that over four years, the use of triclosan toothpaste had no detectable effect on thyroid function in humans. Three of that study’s five authors received a grant from Colgate. One, Greg Seymour, a professor at the School of Medicine at the University of Queensland, said Colgate requested the analysis of thyroid hormones after it granted them money for a separate study on gingivitis. Colgate had no input on data collection or analysis, he said.

The Cochrane paper, which Colgate cited in its favor, comes to a more complex conclusion. The review of more than 30 studies published from 1990 to 2012 found “moderate quality evidence” that Total is more effective than other toothpastes at fighting gum bleeding and inflammation. On the topic of safety, authors Philip Riley and Thomas Lamont, speaking about the review in a podcast, said the studies didn’t cover enough years to allow them to investigate any long-term ill effects.

Long-Term Exposure
“What I would be concerned about is the amount people are exposed to over time,” said William Bowen, a professor emeritus at the University of Rochester Medical Center, who specializes in oral biology and also served on a subcommittee at the FDA that evaluated dental products in the 1990s.

Meanwhile, triclosan is showing up in humans and the environment. It was found in the urine of 75 percent of 2,517 Americans tested, including children, according to a 2003 study by the Centers for Disease Control and Prevention. It and a related chemical, triclocarban, were detected in 90 percent of surface water samples from the Great Lakes and in many fish species, according to a July 2014 study by the Canadian Environmental Law Association.

Scientific studies that have raised health concerns include one 2012 study linking triclosan to reduced fertility in mice, and another that year suggesting it could impair muscle function. A study last year linked it to lowered sperm production and changed sperm shape in rats. Triclosan’s core credentials have also come under scrutiny: While some studies have supported its benefit in killing bacteria, others have found it no more effective than soap and water — and in some cases suggested it could support growth of bacteria including the type that causes staph infections.

EU Ban
In 2010, the European Union banned triclosan in materials that come into contact with food. Three years later, the EPA, which reviewed the chemical in 2008, began another review, 10 years earlier than planned. It cited the “rapidly developing scientific database” on the chemical, which includes studies on thyroid effects, according to its website.

Amid these debates, the Natural Resources Defense Council turned its attention to one of triclosan’s main regulators. In 2013, it sued the FDA for the toxicology data the agency had relied on in approving Colgate Total. In January, the FDA handed the NRDC the 35 pages and later put them online along with a previously unreleased cancer study and other information.

The pages included a summary of a 1992 study showing that pregnant mice receiving higher doses of triclosan had lower-weight fetuses and increased incidence of irregular bone formation in their skulls and paw bones. Five of the 120 mice delivered prematurely. A study on pregnant rats the same year found that at higher doses, rat litters had increased incidence of delayed bone formation in areas including the skull, vertebrae and pelvis.

The application dismissed both results — saying the premature births weren’t dose related and were therefore “incidental.” The bone-formation issues were due to toxic effects on the mother, not the fetus, the summary said.

Not Enough Detail
The summaries didn’t provide enough detail to justify those dismissals, according to the scientists reviewing them.

“Wow. They kept that private?” said Zoeller of the University of Massachusetts. “The distinction between maternal and fetal toxicity is an excuse to do nothing. And it’s not scientifically justifiable.”

Such results could have served as clues for later scientists if they had been made public, said the third reviewer, Johanna Congleton, a scientist at the EWG who has a PhD in Environmental Toxicology from Cornell University.

Amplified Effect
Since Total’s approval, researchers have gained new insights into chemicals that disrupt the endocrine system. The Total studies focused on whether triclosan had an amplified effect as exposure levels rose — a model consistent with a longstanding belief that the bigger the dose, the greater the poison.

Newer science has shown that even small doses of certain chemicals can significantly affect hormone functions, if they are delivered at the wrong moment — and that rising doses may cause new unpredictable effects, rather than a rising incidence of the same issue. Some of the data Colgate dismissed in the non-public pages are “almost a hallmark of endocrine disruption,” said Helbing, who conducted the study on frogs.

The effects Helbing had documented — smaller froglets and malformed legs — could be seen with doses equivalent to 1/10 of what a person would use in squeezing a pea-sized amount of Total onto a toothbrush twice a day, Helbing said.

The 35 pages of recently released documents also include a cancer study in which triclosan was fed to rats for as long as two years. FDA reviewers deemed the study inadequate, according to the recently released document, and called for another.

Industry Alliance
Shortly after, in February 1996, an FDA dental-products panel said the agency was working closely on a new cancer study with the Triclosan Industry Alliance — a trade group whose members, according to documents on the FDA’s website, included Colgate, Procter & Gamble and Ciba Specialty Chemicals. Colgate said it believes the alliance no longer exists.

According to the minutes of the meeting obtained through a Freedom of Information Act request, the study was expected in 18 months. Total was approved 17 months later. An industry group’s study was submitted to the FDA in 1999, said Colgate’s DiPiazza. Both Colgate and the FDA declined to make that study available.

Carcinogenicity Concerns
The FDA, in response to a Bloomberg News inquiry, said the agency’s concerns about carcinogenicity had been resolved by a cancer study that was submitted in January 1997. The study, which the FDA put on its website following a Bloomberg News inquiry, “supports the FDA’s conclusion that triclosan does not pose a cancer risk for humans,” DiPiazza said.

David Kessler, a former commissioner of the FDA from 1990 to 1997, just prior to when Colgate Total was approved, said he couldn’t comment on the thoroughness of the agency’s review. Typically, he said, only confidential commercial information is redacted from public documents. It’s the manufacturer’s responsibility, he said, to assure its product is safe and that relevant information is made public.

“The real question is did Colgate do a good job,” Kessler said.

Colgate continues to reference its FDA bona fides. This spring, Minnesota became the first state to pass a triclosan ban. Effective 2017, the state will prohibit the sale of triclosan-based cleaning products for the hands and body — except those with FDA approval, such as Total.

Colgate Lobbied

“Colgate came in and lobbied, and said it’s a good product,” said John Marty, a state senator who sponsored the bill.

The FDA, meanwhile, has vowed to deliver the monograph covering triclosan in handsoaps — the one it promised for the first time four decades ago — by 2016.

As part of that review, the agency will look at recent safety data on triclosan, said Kweder, the deputy director of the new drugs office. Kweder said the FDA doesn’t plan to revisit its Total decision but that if it finds concern in its broader review, it could look back into Total’s 1997 approval.

“But we would have to have a good reason to do that,” Kweder said.

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New cancer classification system might boost patient outcomes

Sun, Aug 10, 2014


Author: Robert Preidt, HealthDay Reporter

Changes to the way cancers are classified could lead to more accurate diagnoses and perhaps more effective treatments in about one in 10 cancer patients, new research suggests.

Typically, cancers are categorized according to the tissue in which they originated, such as breast, bladder or kidney cancer. But tissues are composed of different types of cells.

In this study, researchers who analyzed more than 3,500 tumor samples of 12 different cancer types concluded that defining tumors by their cellular and molecular features, rather than by the tissues in which they originated, would improve diagnoses in about 10 percent of cancer cases.

“This genomic study not only challenges our existing system of classifying cancers based on tissue type, but also provides a massive new data resource for further exploration, as well as a comprehensive list of the molecular features distinguishing each of the newly described cancer classes,” study co-senior author Dr. Christopher Benz, professor at the Buck Institute for Research on Aging at the University of California, San Francisco, said in a university news release.

The study, published online Aug. 7 in the journal Cell, is part of The Cancer Genome Atlas initiative, which is led by the U.S. National Cancer Institute and U.S. National Human Genome Research Institute.

The researchers report particularly significant findings in bladder and breast cancers. They identified at least three different subtypes of bladder cancer, including one that was nearly identical to a form of non-small cell lung cancer called lung adenocarcinoma, and another most similar to squamous-cell cancers of the head and neck and of the lungs.

The findings may explain why bladder cancer patients “often respond very differently when treated with the same systemic therapy for their seemingly identical cancer type,” Benz said.

The researchers confirmed known differences between two forms of breast cancers called basal-like and luminal. But they also discovered that these differences are significant and that basal-like breast cancers — commonly referred to as triple-negative — are a distinct class of tumor.

“What’s amazing is that basal breast cancer is as different from luminal breast cancer as it is from, say, kidney cancer,” study co-lead author Denise Wolf, a research scientist based in UCSF’s Department of Laboratory Medicine, said in the news release.

Basal-like cancers are highly aggressive and more common among black and younger women.

“Even though these basal-like cancers arise in the breast, on the molecular level they have more in common with ovarian cancers and cancers of squamous-cell origin than with other subtypes of breast cancer,” explained study co-lead author Christina Yau, a staff scientist at the Buck Institute and assistant professor of surgery at UCSF.

“This is the first time ever you’ve been able to point to important molecular features shared by basal breast cancer, and by squamous head-and-neck cancer and lung cancer,” Wolf said.

“And the same is true of immune activation — we found that different cancer types have very similar immune signatures, a factor that may be relevant clinically with the rise of new immune therapies,” she added.

Further research could reveal that as many as 30 to 50 percent of cancers need to be reclassified, according to Benz.

“Although follow-up studies are needed to validate and refine this newly proposed cancer classification system, it will ultimately provide the biologic foundation for that era of personalized cancer treatment that patients and clinicians eagerly await,” Benz believes.

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Tumour Suppressor Mutations Alone Cannot Explain Deadly Cancer

Fri, Aug 8, 2014


Author: Staff

Although mutations in a gene dubbed ”the guardian of the genome” are widely recognized as being associated with more aggressive forms of cancer, researchers at the University of California, San Diego School of Medicine, have found evidence suggesting that the deleterious health effects of the mutated gene may in large part be due to other genetic abnormalities, at least in squamous cell head and neck cancers.

The study, published online 3 August in the journal Nature Genetics, shows that high mortality rates among head and neck cancer patients tend to occur only when mutations in the tumour suppressor gene coincide with missing segments of genetic material on the cancer genome’s third chromosome.

The link between the two had not been observed before because the mutations co-occur in about 70 per cent of head and neck tumours and because full genetic fingerprints of large numbers of cancer tumours have become available only recently.

”These two genetic malfunctions are not two separate stab wounds to the body,” says co-senior author Trey Ideker, PhD, chief of the division of genetics. ”One exposes the Achilles tendon and the other is a direct blow to it.”

To patients with these cancers, the study’s results mean that there may be therapeutic value in testing tumours for the two genetic identifiers, known as a TP53 mutation (short for tumour protein 53) and a 3p deletion (short for deletions of genetic information on the short arm ”p” of the third chromosome).

TP53 plays a key role in regulating cell growth, detecting and fixing DNA, and directing cell apoptosis (death) if the DNA damage is irreparable. Because of this, the TP53 protein is sometimes called the ”guardian of the genome.”

The study’s findings suggest that if both markers are present, treatment should be intensified. If only one mutation is present, treatment might be de-intensified because the TP53 mutation alone is less deadly than previously thought. The latter would have immediate benefits in reducing deaths caused by complications related to medical care.

”We are in the early stages of being able to personalize head and neck cancer treatments based on the tumor’s actual biology, the same as what’s done with breast cancers,” says co-senior author Quyen Nguyen, MD, PhD, associate professor of otolaryngology-head and neck surgery. ”In the past, treatments have been based largely on the size and location of the tumor. Now, we know that some large tumors may respond to less aggressive treatment while some small tumors may need intensified treatment. This will have a huge impact for patients.”

The study analysed the complete genomic signatures of 250 cases of squamous cell head and neck cancer extracted from The Cancer Genome Atlas, a repository of sequenced cancer genomes for more than 20 different types of human cancers maintained by the National Institutes of Cancer. All of the tumors were from patients younger than 85 years of age.

Of these, 179 had both mutations; 50 had one of the two mutations; and 22 had neither mutation. Comparisons with patient outcome data showed that half of patients with both mutations were likely to die of cancer within two years, while 66 per cent of patients with one or neither mutation would be expected to live five years or more. These survival statistics were independent of the patients’ clinical cancer stage.

Besides causing cervical cancer, the human papilloma virus (HPV) is implicated in the growing epidemic of head and neck cancers in otherwise healthy adults. It is believed that the virus can co-opt the activity of TP53, affecting cells in much the same way as a TP53 mutation but without causing a mutation. For this reason, the analysis examined HPV-positive and HPV-negative tumours separately.

One of the study’s more compelling discoveries is that among HPV-positive tumours, the most aggressive cancer cases were also highly linked to the presence of 3p deletions.

”Our findings raise fundamental questions about the role of TP53 in cancer and suggest that some of the deleterious health effects of TP53 mutations might actually be due to something else going on in the third chromosome,” said lead author Andrew Gross, a graduate student in the Bioinformatics and Systems Biology Program.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

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Cowboy Cody Kiser Joins Anti-Tobacco Campaign to Help Educate Young Consumers

Fri, Aug 8, 2014


Author: Lindsay Lowe


The campaign to educate consumers about the dangers of tobacco has a new all-American hero: rodeo cowboy Cody Kiser, who’s partnering with the Oral Cancer Foundation (OCF) to educate parents and kids about the health risks associated with smokeless tobacco.

While chewing tobacco has long been popular among rodeo cowboys, Kiser, 23, says the drug never appealed to him, and says he hopes to serve as a positive example in an industry with traditionally strong sponsorship ties to the tobacco industry.

“My dad was a cowboy, so I know what it’s like looking up to cowboys as heroes for my whole life,” he said in a release. “Health and fitness have always been incredibly important to my family. My dad was a positive role model in my life growing up in that regard, and the idea of using spit tobacco never appealed to me.”

Tobacco and rodeo have a long intertwining history; the Professional Rodeo Cowboys Association was sponsored by the U.S. Smokeless Tobacco Company from 1986 to 2009, when the Cowboys Association decided to end its relationship with tobacco advertisers.

One can of spit tobacco has the equivalent nicotine of 40 cigarettes, and a “30-minute chew” is the equivalent of smoking three cigarettes, according to the OCF, meaning that an addiction to smokeless tobacco “can be one of the hardest to break.”

Spit tobacco (which can refer to smokeless tobacco, dip, snuff, chew, and chewing tobacco) can cause gum disease, tooth decay, and “white patches and oral lesion that can lead to oral cancer.”

An alarming “15 percent of high school boys, and 9 percent of all high school students, are already using spit tobacco,” the foundation says, while 3.5 percent of adults use the drug. An estimated 43,000 people will be diagnosed with some form of oral cancer in 2014, and the “fastest-growing segment” of that group are “young non-smokers,” says the OCF.

Kiser says he hopes to serve as a role model for young people who idolize rodeo heroes and prevent them from becoming another oral cancer statistic.



*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.


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Study Finds a ‘Fat Burning Process’ Termed ‘Cachexia’ Kills about One Third Cancer Patients

Thu, Aug 7, 2014


Author: Staff

Madrid, Spain (Scicasts) — Most cancer researchers are working on the biology of the tumour. However, Michele Petruzzelli, a member of Erwin Wagner’s group at the Spanish National Cancer Research Centre (CNIO), has been looking for ways to attack the disease indirectly. 

He focused on the effects of tumours on the rest of the body, and not on the tumour itself. His work on the body’s response to a tumour has uncovered that cachexia—the extreme thinness and weakness eventually being the real cause of death in one third of patients with cancer—is triggered by a process that is heavily studied not to fight cancer, but to fight obesity: the conversion of white fat tissue into brown fat tissue.

“It is the first time that this phenomenon we might call burning fat has been associated with a negative effect”, says Erwin Wagner, the Director of the BBVA Foundation-CNIO Cancer Cell Biology Programme. “What we observe is that the transformation of white fat into brown fat, currently one of the most researched subjects because of its potential effects on obesity and diabetes, has very severe consequences in the context of cancer”. The study is published in Cell Metabolism.

The researchers also argue that if it is possible to reduce the transformation of fat tissue, the symptoms of cachexia will improve, although they do not completely disappear. The authors demonstrate this by blocking mediators of inflammation, a process linked to cachexia, specifically, to the expression of the pro-inflammatory cytokine IL-6.

“Inhibiting the conversion of white fat into brown fat is therefore a promising way of improving cachexia for cancer patients”, the authors state in their article.

The CNIO has a large variety of animal (mouse) models for different types of cancer. The starting point for this study, says Petruzzelli, was to choose a dozen of these mouse models to investigate the changes that develop in their bodies as the tumour progresses. The researchers observed several changes in different organ systems, which varied depending on the animal model used as well as the tumour type. Nevertheless, a consistent white fat to brown fat transformation was observed in all organ systems very early, before any sign of cachexia became apparent.

‘Good’ Fat and ‘Bad’ Fat

There is a growing interest in this study because of its significance in two ways. It relates to the transformation of white fat into brown fat, which is beneficial to fight obesity and diabetes, but has a huge disadvantage in cancer-associated cachexia (CAC), which for different reasons has not been studied very much in the past. In recent years both approaches have become hot topics for researchers around the world.

The importance of the transformation process of white fat into brown fat in humans was only discovered a couple of years ago. Most fat in adult humans is white—white adipose tissue—and we know that its main function, but not its only function, is to store energy (those love handles). Brown fat, however, is burned to produce heat; baby fat and the fat of hibernating animals is like that. In the context of the current obesity epidemic, white fat has been labelled bad fat, while brown fat is the good one.

The discovery that adult humans can turn white/bad fat into brown/good fat via exercise or exposure to low temperatures has opened a new line of attack on obesity, and in fact the active search for pharmacological tools to induce the transformation of fat is well underway.

The work of Wagner’s group in the article in Cell Metabolism does not discuss the advantages or disadvantages of each type of fat, it rather highlights that a process that could be strengthened to fight obesity must be fought against in cancer patients.

As for cachexia, it is a less-studied phenomenon despite that doctors have known for a long time that the treatment is difficult and the prognosis negative. Next to patients with cancer, it also affects patients in advanced phases of many illnesses, including infectious diseases, such as AIDS or tuberculosis, and chronic illnesses, such as multiple sclerosis.

It Is Not ‘Self-Cannibalism’

CAC has until recently been interpreted as a kind of self-cannibalism: the body ‘consumes’ itself while trying to supply the energy needs of the constantly growing tumour. Today we know that tumours of any size can cause cachexia, including very small ones, and even at very early stages of tumour development, which does not fit with the idea of self-cannibalism.

Researchers have observed that the process does not respond either to the body’s greater need to generate heat.

These new data, and the often ignored fact that it is the cachexia associated with the tumour—and not the tumour itself—that causes the death of one third of cancer patients, has encouraged the study of this syndrome in recent years. It is now known that this process is tightly associated with inflammation, a hallmark of many cancer types.

This is why in their study Wagner and his group explore the link between inflammation, cachexia and the process of transforming white fat tissue into brown fat tissue. Their results indicate that if the activity of one of the agents that promotes inflammation—cytokine IL-6—is blocked, the fat transformation process is substantially reduced and, as a consequence, the cachexia. The researchers do point out that it is not a cure: IL-6 is just one of several cytokines involved in the process and blocking it is not enough.

A Way To Prevent Cachexia

These novel results suggest that anti-inflammatory drugs could help fight cachexia, but there is a problem: the lack of knowledge about this syndrome is such that for now it is not possible to predict which cancer patient will develop cachexia. Furthermore, anti-inflammatory drugs have often side effects, and therefore these treatments cannot be used to prevent the appearance of cachexia in all cancer patients.

The current study in Cell Metabolism could open up a new way of discovering processes, e.g. the transformation of fat in the initial stages of cachexia. “It allows one to think of the possibility to identify biomarkers that would help to predict which patients are going to develop cachexia in a way we can treat them preventively”, says Petruzzelli.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
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Scientists Discover Genetic Mutations Linked to Salivary Gland Tumours

Wed, Aug 6, 2014


Author: Staff

Juniper, FL — Research conducted at the Florida campus of The Scripps Research Institute (TSRI) has discovered links between a set of genes known to promote tumour growth and mucoepidermoid carcinoma, an oral cancer that affects the salivary glands.

The discovery could help physicians develop new treatments that target the cancer’s underlying genetic causes.

The research, recently published online ahead of print by the Proceedings of the National Academy of Sciences, shows that a pair of proteins joined together by a genetic mutation—known as CRTC1/MAML2 (C1/M2)—work with MYC, a protein commonly associated with other cancers, to promote the oral cancer’s growth and spread.

“This research provides new insights into the molecular mechanisms of these malignances and points to a new direction for potential therapies,” says TSRI biologist Dr. Michael Conkright, who led the study.

The C1/M2 protein is created when the genes encoding CRTC1 and MAML2 mutate into a single gene through a process known as chromosomal translocation. Such mutant “chimera” genes are linked to the formation of several forms of cancer. The team discovered that the C1/M2 protein further activates genetic pathways regulated by MYC, in addition to CREB, to begin a series of cellular changes leading to the development of mucoepidermoid carcinoma.

“The identification of unique interactions between C1/M2 and MYC suggests that drugs capable of disrupting these interactions may have therapeutic potential in the treatment of mucoepidermoid carcinomas, ” said Dr. Antonio L. Amelio, first author of the study who is now assistant professor with the University of North Carolina (UNC) School of Dentistry and member of the UNC Lineberger Comprehensive Cancer Center.

Researchers have known about the role of C1/M2 and its interactions with another protein, CREB, in the development of mucoepidermoid carcinoma, and physicians screen patients for the presence of the C1/M2 protein when testing for this cancer. These new findings deepen the understanding of C1/M2’s role by revealing that it works with a family of cancer-associated genes known as the MYC family to drive the cellular changes necessary for a tumour to develop.

The discovery of these new protein interactions may also reveal insights into the mechanisms behind other cancers that arise due to other genetic mutations involving the CREB and MYC pathways.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

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Quick, low-cost blood test detects early signs of oral cancer

Sat, Aug 2, 2014


Author: DrBicuspid Staff

Australian researchers have developed a quick, low-cost blood test to detect the early signs of oral cancer. The diagnostic test examines the profile of small molecules called microRNA in the blood and can be done at the same time as other routine checks, such as for cholesterol.

At present, no routine screening tests for oral cancer are on the market. The researchers hope that a simple blood test could change that and, in doing so, help stem the global increase of various oral cancers.

About 300,000 new cases of oral cancer were reported globally in 2012, according to the researchers. The main barriers to treatment remain late detection and low disease awareness. Warning symptoms include pain, swelling, a hoarse voice, and difficulty swallowing — symptoms that are often dismissed or misdiagnosed as a common cold.

The test, called miLIFE, was developed by researchers Nham Tran, PhD, and doctoral candidate Samantha Khoury from the University of Technology, Sydney (UTS) Centre for Health Technologies. The blood-based test can be administered by healthcare providers to screen microRNA to reveal the oral cancer’s early warning signs. The turnaround time for the test is about 48 hours at present.

The levels of five specific microRNA molecules are detected with miLIFE and compared with those of healthy, noncancerous individuals. An overabundance or expression of these specific microRNAs would designate people at high risk for oral cancer. These patients would then be referred to a specialist for further examination.

“You don’t need a specialist to administer the test,” Khoury noted. “When you visit your GP [general practitioner] for routine checks of cholesterol, vitamin D, hemoglobin, and so on, the same blood sample can be used to check for the presence of microRNA biomarkers.”

The majority of oral cancer patients who go to the doctor have already developed an advanced lesion, but by then it is too late, Tran stated.

“At this stage, their diagnosis option is to undergo a tumor biopsy or a fine-needle aspiration, both highly invasive and painful procedures,” he noted. “We hope that through miLIFE we can provide early intervention to decrease the number who are diagnosed with oral cancer each year.”

The test is being filed under a UTS provisional patent, and Tran hopes it will be available within two to three years.

The technology, in development since 2006, has evolved via an ongoing collection of consenting cancer patient samples from surgeons based at several Sydney hospitals. The researchers collaborated with the Sydney Head and Neck Cancer Institute, the Cancer Council Australia, and Mount Sinai Hospital in New York.

Next the researchers plan to expand the project with the Vellore Christian Medical College Foundation in India. They targeted India because that country has the world’s highest rates of oral cancer, with 40,000 cases diagnosed annually.

“The introduction of a robust cancer screen will provide a platform for effective cancer management in low-resourced countries,” Tran noted.

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Blood test could predict oral cancer recurrence

Sat, Aug 2, 2014


Author: Rachael Rettner, Senior Writer

A new blood and saliva test that looks for traces of the human papillomavirus (HPV) can predict whether some people with oral cancers will have their cancer come back, early research suggests.

It helps to know as soon as possible that cancer has returned, because tumors that are caught early are easier to treat.

In the study, the researchers analyzed blood and saliva samples from 93 people with head and neck cancers; about 80 percent of these patients had cancers that tested positive for HPV. All of their cancers had previously been treated with surgery, radiation or chemotherapy.

The researchers looked for fragments of DNA from HPV-16, a strain of the virus that is strongly linked with head and neck cancer. The virus may be found in cancer cells that linger in the body after treatment, the researchers said.

Among people with HPV-positive tumors, the new test identified 70 percent of those whose cancer returned within three years, the researchers said.

“Until now, there has been no reliable biological way to identify which patients are at higher risk for recurrence, so these tests should greatly help [to] do so,” study researcher Dr. Joseph Califano, professor of otolaryngology at Johns Hopkins School of Medicine, said in a statement.

Patients with head and neck cancer typically visit the doctor every one to three months during the first year after their diagnoses to check for cancer recurrence. But new tumors in the tonsils, throat and base of the tongue can be difficult to spot, and are often not detected early, the researchers said.

Still, more research is needed to confirm the findings, Califano said. Because HPV infection is common, the test may identify HPV infections that are not related to the cancer. “We can’t be sure our test results are cancer-specific, and not due to other forms of HPV infection or exposure,” Califano said.

The researchers are now looking for additional genetic markers that would increase the accuracy of their test.

The study is published today in the journal JAMA Otolaryngology–Head & Neck Surgery.

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University of Michigan researchers find protein that fuels repair of treatment-resistant cancer cells

Sat, Aug 2, 2014


Author: DentistryIQ Editors

Imagine that you’re fighting for your life, but no matter how hard you hit, your opponent won’t go down.

The same can be said of highly treatment-resistant cancers, such as head and neck cancer. During radiation and chemotherapy, some cancer cells repair themselves to survive and thrive. Head and neck cancer is the sixth most common cancer in the world, but the late detection and treatment resistance result in a high mortality rate.

Now, University of Michigan researchers have found that a particular protein – TRIP13 – encourages those cancer cells to repair themselves, and they have identified an existing chemical that blocks this mechanism for cell repair.


Left: Untreated head and neck cancer cells are tagged fluorescent green. Right: Shows cells treated with the chemical inhibitor that blocks TRIP13, which results in a dramatically smaller tumor.

“This is a very significant advance because identifying the function of the protein that fuels the repair of cancer cells and having an existing chemical that blocks the process could speed the process of moving to clinical trials,” said principal investigator Nisha D’Silva, University of Michigan professor of dentistry and associate professor of pathology.

Typically, if scientists discover a promising drug therapy target, it takes years to develop drug compounds from scratch and move these into clinical trials.


Top: Cancer cells with TRIP13, the protein that encourages cancer cells to repair themselves. Bottom: Cancer cells in which researchers have removed or decreased TRIP13, which results in fewer cells due to cell death.

If cell DNA is damaged, and the cell cannot repair the damage, the cell dies. In head and neck cancers, D’Silva and colleagues showed how cancer cells that overexpress TRIP13 were able to repair their DNA enough to survive and continue to grow as cancer.

“Targeting this repair mechanism with specific drugs could increase effectiveness of treatment and improve survival of cancer patients,” D’Silva said. “And given the overexpression of TRIP13 in several treatment-resistant cancers, this strategy will likely be important for multiple cancers.”

Rajat Banerjee of the University of Michigan School of Dentistry is the first author of the study, “TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer,” which appeared online on July 31 in Nature Communications.

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