human papillomavirus

The epidemic of throat cancer sweeping the industrialized world

Source: www.mercurynews.com
Author: Dr. Bryan Fong

Tonsils – Angina Pectoris

Over the past three decades, a dramatic increase in a new form of throat cancer has been observed throughout the industrialized world. The good news is that it’s potentially preventable — if parents get their children vaccinated.

The disease shows up primarily in men, typically between the ages of 45 and 70. Those who are affected often lead healthy lifestyles. They do not have extensive histories of smoking tobacco or consuming alcohol, which are risk factors for traditional throat cancers.

The rate of this new cancer has been increasing 5 percent per year and today, it is more than three times as common as in the mid-1980s. If you think this scenario sounds like a slow-moving infectious medical drama (think Contagion or World War Z), you would be right.

The source of this cancer is a virus, the human papillomavirus (HPV) — the same virus that causes most cervical cancer in women. It’s widely known that parents should get their girls vaccinated. Now, with the surge in oral HPV cancers, especially in men, parents should get their boys vaccinated too.

Currently, vaccination against HPV is recommended by the Centers for Disease Control for children and young adults ages 9-26. The vaccination includes a series of two or three injections; the side effects are mild.

Ideally, the vaccinations should be administered before someone becomes sexually active. That’s because HPV is spread via sexual activity. Risk of HPV infection and throat cancer increases with the number of lifetime partners.

Men have a lower immune response to the virus than women, which explains the predilection of this disease for men. It’s difficult to know if someone has an active oral HPV infection because there are no symptoms. Currently, there is no widely accepted test for HPV in men.

Chronic infection leads to cellular changes within the lymphatic tissues in the throat, specifically the tonsils and base of tongue. Over the course of 20-30 years, these changes can result in the formation of cancer.

Throat cancer caused by HPV is insidious. The primary tumor in the tonsil or base of tongue often causes little to no symptoms. Early signs of this cancer may be a mild sore throat, occasional blood-tinged oral saliva, or increased or new snoring.

Often, the first sign of the cancer is a lump in the neck after the cancer has spread into the lymphatic system. The lump may arise quickly and then shrink to varying degrees, lulling one into complacency.

Early stage cancer can be treated with surgery or radiation. More advanced cancers are treated with combined therapy such as surgery followed by radiation therapy, or chemotherapy in conjunction with radiation therapy.

Finally, some good news. Treatment for HPV-related throat cancer is successful in about 90 percent of cases and is significantly more successful than treatment of non-HPV related throat cancer.

But, as successful as medicine has been in treating this cancer, an even better alternative is prevention via vaccination. Initial studies have shown that vaccination produces an immune response to HPV and reduces the rate of HPV infection. Given time and good vaccination coverage, a decline in throat cancer is expected.

In summary, here are a few simple take-home messages: If you have a lump in the neck or a chronic sore throat, don’t procrastinate. Have your doctor check it out. If you are a partner of someone with these symptoms, strongly encourage your partner to see his or her doctor.

If you have children ages 9-17, talk to your pediatrician about HPV vaccination. If you are 18-26 years old, talk to your primary care doctor about vaccination. These simple steps may save your life or the life of your loved one.

Note: Dr. Bryan Fong is the senior practicing head and neck surgical oncologist for Northern California Kaiser Permanente.

February, 2019|Oral Cancer News|

Why salivary diagnostics for dental practices?

Source: www.dentistryiq.com
Author: Barbara Kreuger, MA, RDH

I recently had the opportunity to visit OralDNA Labs and learn more about the process of running salivary diagnostic tests. Admittedly, when I first heard about salivary diagnostics, I didn’t immediately embrace the tests and what they had to offer. I was not convinced that they were necessary, believing they would not change how we treat dental disease.

However, we’ve been fortunate to use salivary diagnostics in practice and see the benefits in our patients firsthand. These tests have proven to be a great addition to our prevention tool box. Salivary diagnostics can play an important role in helping us produce high quality outcomes for patients and create awareness of their oral-systemic risk factors.

Bacterial identification
There are numerous salivary diagnostic tests available. The most widely used test from OralDNA Labs is MyPerioPath, which tests for the 11 pathogens that are known to contribute to periodontal destruction.(1) Once the test reveals which pathogens are contributing to the patient’s periodontal disease, it also offers antibiotic recommendations that target these specific bacteria.

When combined with periodontal maintenance visits and patient homecare, this test can lower a patient’s bacterial load, thus increasing positive outcomes. Retesting has shown that this reduction in bacteria can have a dramatic effect. We’ve seen tough cases—patients who were compliant with homecare but still exhibited clinical signs of periodontal disease—that improved dramatically after being treated with the test’s recommended systemic antibiotic. Periodic monitoring with MyPerioPath combined with periodontal maintenance treatment can help keep patients’ oral health stable.

Genetic predisposition
In addition to bacterial profile testing, various tests from OralDNA labs can tell us a patient’s genetic predisposition toward inflammation. This can reveal one of the reasons why some patients continue to experience periodontal destruction after treatment despite compliance and lower quantities of periodontal pathogens. In addition, much of the research connecting oral health to systemic conditions reveals that it is a patient’s total inflammatory burden that puts someone at risk for a host of health problems.(2,3)

While the patient’s genetic profile cannot be changed, the knowledge that the person has an overactive inflammatory response can help the practitioner and patient understand that there is a need for more frequent continuing care, adjunctive therapies, or treatment with a periodontist. This information can also help patients manage and control their systemic health with the help of their physician.

Caries risk assessment
When we look beyond the patient’s periodontal health, salivary diagnostics can also test for the bacteria that are known to contribute to caries. When we have an objective measure of the quantity and types of cariogenic bacteria in the patient’s mouth, we can once again tailor treatments to reduce his or her caries risk and motivate the patient toward behavioral change. If we then combine the test with a caries risk assessment tool, we can use the test to monitor the effectiveness of these behavior changes. Knowing the patient’s risk allows us to encourage the person to use interventions, such as fluoride to re-mineralize teeth and xylitol to inhibit the bacterial metabolism.

Oral cancer screening
Finally, salivary diagnostics can also test for the presence of various human papillomavirus (HPV) strains that have been shown to cause oral cancer. According to the American Cancer Society, oral cancer will take the lives of 10,860 people this year, and HPV is now seen as the leading cause.(4,5) Early diagnosis is key and increases survival from a dismal 20% when discovered after it has metastasized to distant sites, to 93% when discovered early.(6)

Knowing a patient’s HPV status may prompt us to increase the frequency of someone’s oral cancer screenings, or to use adjunctive diagnostic tools such as oral anomaly detection devices to more closely monitor the patient and potentially catch the cancer at an earlier stage.

More and more research studies are correlating the various bacteria that cause periodontal disease to systemic conditions. The more we understand about a patient’s bacterial load and risk factors, the better equipped we can be to help manage periodontal disease and improve overall health. Salivary diagnostics can help us provide optimal care for patients, increasing our ability to provide them with positive outcomes through tailored treatment and patient education.

Barbara Kreuger, MA, RDH, earned a Bachelor of Science in dental hygiene from the University of Minnesota and holds a Master of Arts in organizational leadership from St. Mary’s University of Minnesota. She spent more than 18 years as a clinical dental hygienist before moving to her current role as dental hygiene senior specialist for Pacific Dental Services. Barbara is currently serving as president of the Minnesota Dental Hygienists’ Association.

References

1. Oral DNA tests. OralDNA website. https://www.oraldna.com/tests.html. Accessed February 1, 2019.
2. Hunter P. The inflammation theory of disease. The growing realization that chronic inflammation is crucial in many diseases opens new avenues for treatment. EMBO Rep. 2012;13(11):968-70.
3. Minihane AM, et al. Low-grade inflammation, diet composition and health: current research evidence and its translation. Brit Jour Nutrition. 2015;114(7):999–1012.
4. Key Statistics for Oral Cavity and Oropharyngeal Cancers. American Cancer Society website. https://www.cancer.org/cancer/oral-cavity-and-oropharyngeal-cancer/about/key-statistics.html. Accessed February 1, 2019.
5. HPV/Oral Cancer Facts. Oral Cancer Foundation website. https://oralcancerfoundation.org/understanding/hpv/hpv-oral-cancer-facts/. Accessed February 1, 2019.
6. Survival Rates for Oral Cavity and Oropharyngeal Cancer. American Cancer Society website. https://www.cancer.org/cancer/oral-cavity-and-oropharyngeal-cancer/detection-diagnosis-staging/survival-rates.html. Accessed February 1, 2019.

February, 2019|Oral Cancer News|

HPV discovery raises hope for new cervical cancer treatments

Source: www.eurekalert.org
Author: press release – University of Virginia Health Syste

Researchers at the University of Virginia School of Medicine have made a discovery about human papillomavirus (HPV) that could lead to new treatments for cervical cancer and other cancers caused by the virus.

HPV is responsible for nearly all cases of cervical cancer and 95 percent of anal cancers. It is the most common sexually transmitted disease, infecting more than 79 million Americans. Most have no idea that are infected or that they could be spreading it.

“Human papillomavirus causes a lot of cancers. Literally thousands upon thousands of people get cervical cancer and die from it all over the world. Cancers of the mouth and anal cancers are also caused by human papillomaviruses,” said UVA researcher Anindya Dutta, PhD, of the UVA Cancer Center. “Now there’s a vaccine for HPV, so we’re hopeful the incidences will decrease. But that vaccine is not available all around the world, and because of religious sensitivity, not everybody is taking it. The vaccine is expensive, so I think the human papillomavirus cancers are here to stay. They’re not going to disappear. So we need new therapies.”

HPV and Cancer
HPV has been a stubborn foe for scientists, even though researchers have a solid grasp of how it causes cancer: by producing proteins that shut down healthy cells’ natural ability to prevent tumors. Blocking one of those proteins, called oncoprotein E6, seemed like an obvious solution, but decades of attempts to do so have proved unsuccessful.

Dutta and his colleagues, however, have found a new way forward. They have determined that the virus takes the help of a protein present in our cells, an enzyme called USP46, which becomes essential for HPV-induced tumor formation and growth. And USP46 enzyme promises to be very susceptible to drugs. Dutta calls it “eminently druggable.”

“It’s an enzyme, and because it’s an enzyme, it has a small pocket essential for its activity, and because drug companies are very good at producing small chemicals that will jam that pocket and make enzymes like USP46 inactive,” said Dutta, chairman of UVA’s Department of Biochemistry and Molecular Genetics. “So we are very excited by this possibility that by inactivating USP46 we’ll have a way to treat HPV-caused cancers.”

Curiously, HPV uses USP46 for an activity that is opposite to what the oncoprotein E6 was known to do. E6 has been known for more than two decades to recruit another cellular enzyme to degrade the cell’s tumor suppressor, while Dutta’s new finding shows that E6 uses USP46 to stabilize other cellular proteins and prevent them from being degraded. Both activities of E6 are critical to the growth of cancer.

The researchers note that enzyme USP46 is specific to HPV strains that cause cancer. It is not used by other strains of HPV that do not cause cancer, they report.

Notes:
(1) The researchers have published their findings in the scientific journal Molecular Cell. The team included Shashi Kiran, Ashraf Dar, Samarendra K. Singh, Kyung Yong Lee and Dutta. All are from UVA’s Department of Biochemistry and Molecular Genetics.

(2)The work was supported by the National Institutes of Health, grant R01 GM084465.

December, 2018|Oral Cancer News|

Standard chemotherapy treatment for HPV-positive throat cancer remains the most effective, study finds

Source: www.eurekalert.org
Author: press release, University of Birmingham

A new study funded by Cancer Research UK and led by the University of Birmingham has found that the standard chemotherapy used to treat a specific type of throat cancer remains the most effective.

The findings of the trial, which aimed to compare for the first time the outcomes of using two different kinds of treatment for patients with Human papillomavirus (HPV)-positive throat cancer, are published today (November 15th) in The Lancet.

Throat cancer is one of the fastest rising cancers in Western countries. In the UK, incidence was unchanged between 1970 and 1995, then doubled between 1996 and 2006, and doubled again between 2006 and 2010. The rise has been attributed to HPV, which is often a sexually transmitted infection. Most throat cancers were previously caused by smoking and alcohol and affected 65 to 70 year old working class men. Today, HPV is the main cause of throat cancer and patients are middle class, working, have young children and are aged around 55.

HPV-positive throat cancer responds well to a combination of cisplatin chemotherapy and radiotherapy, and patients can survive for 30 to 40 years, but the treatment causes lifelong side effects including dry mouth, difficulty swallowing, and loss of taste.

The De-ESCALaTE HPV study, which was sponsored by the University of Warwick, compared the side effects and survival of 164 patients who were treated with radiotherapy and cisplatin, and 162 who were given radiotherapy and cetuximab. The patients were enrolled between 2012 and 2016 at 32 centres in the UK, Ireland, and the Netherlands. Patients were randomly allocated to be treated with radiotherapy and either cisplatin or cetuximab. Eight in ten patients were male and the average age was 57 years.

Importantly, the results found that there was very little difference between the two drugs in terms of toxicity in patients and side effects such as dry mouth, however, there was a significant difference in the survival rates and recurrences of cancer in patients taking part in the trial.

They found that the patients who received the current standard chemotherapy cisplatin had a significantly higher two-year overall survival rate (97.5%) than those on cetuximab (89.4%). During the six-year study, there were 29 recurrences and 20 deaths with cetuximab, compared to 10 recurrences of cancer and six deaths in patients who were treated with the current standard chemotherapy cisplatin.

And cancer was three times more likely to recur in two years following treatment with cetuximab compared to cisplatin, with recurrence rates of 16.1 per cent versus six per cent, respectively.

Study lead Professor Hisham Mehanna, Director of the University of Birmingham’s Institute of Head and Neck Studies and Education, said: “Many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as cisplatin chemotherapy with radiotherapy and caused fewer side effects but there has been no head-to-head comparison of the two treatments.

“Cetuximab did not cause less toxicity and resulted in worse overall survival and more cancer recurrence than cisplatin.

“This was a surprise – we thought it would lead to the same survival rates but better toxicity. Patients with throat cancer who are HPV positive should be given cisplatin, and not cetuximab, where possible.”

Dr Emma King, Cancer Research UK Associate Professor in head and neck surgery at the University of Southampton, said: “Studies like this are essential for us to optimise treatments for patients. We now know that for HPV-positive throat cancer, the standard chemotherapy treatment remains the most effective option.

“However, we must keep testing new alternatives to ensure patients always have access to cutting-edge and kinder treatments. Chemotherapy and radiotherapy can leave head and neck cancer patients with long term pain and difficulties swallowing, so we should always strive to minimise side effects.”

Professor Janet Dunn from the University of Warwick, whose team ran the De-ESCALaTE HPV trial, said: “In the current trend for de-escalation of treatment, the results of the De-ESCALaTE HPV trial are very important as they were not as we expected. They do highlight the need for academic clinical trials and are an acknowledgement of the key role played by Warwick Clinical Trials Unit at the University of Warwick as the co-ordination and analysis centre for this important international trial.”

The patients on the De-ESCALaTE trial Steering Committee endorsed the importance of research findings.

Malcom Babb, who is also President of the National Association of Laryngectomee Clubs, said: “From a patient perspective, De-ESCALaTE has been a success by providing definitive information about the comparative effectiveness of treatment choices.”

November, 2018|Oral Cancer News|

Cultural barriers still stand in the way of HPV vaccine uptake

Source: arstechnica.com
Author: Cathleen O’Grady

Every year, nearly 34,000 cases of cancer in the US can be attributed to HPV, the human papillomavirus . The CDC estimates that vaccination could prevent around 93 percent of those cancers. Yet HPV vaccination rates are abysmal: only half of the teenagers in the US were fully vaccinated in 2017.

Cultural barriers play a role in that low rate. Vaccinating pre-teens against a sexually transmitted infection has had parents concerned that that this would encourage their kids to have sex sooner, with more partners, or without protection or birth control. And vaccine rates vary across different social and cultural groups: for instance, rural teenagers are less likely to be vaccinated than urban ones.

Two recent studies explore different facets of the cultural barriers standing in the way of better HPV vaccine uptake. The first, a paper published last month in the Canadian Medical Association Journal, looks at the data on whether the vaccine encourages riskier sexual behavior and finds no evidence that it does. And the second, an early draft of a paper presented at an American Association for Cancer Research meeting this week, reports the results of a culturally-targeted intervention aiming to increase vaccine uptake among low-income Chinese Americans.

The kids are alright
Although the vaccine is now recommended for both boys and girls, the initial drive was to get teenage girls vaccinated, given the link between HPV and cervical cancer. That’s why girls are the focus of the recent study on risky sexual behavior: the researchers used data from high school girls in Canada, where a huge survey on adolescent health is administered every few years.

A team of researchers was able to use this data to compare results from the survey before and after a large-scale HPV vaccine program was implemented across high schools in Canada in 2008. The researchers compared data from 2003, before the program began, to data from 2008 and 2013. Altogether, nearly 300,000 girls’ survey responses were analyzed.

The researchers found that, on every measure they looked at, risky sexual behaviors either decreased or stayed the same. The number of girls who had ever had sex decreased from 21.3 percent in 2003 to 18.3 percent in 2013. The girls who’d had sex before age 14 decreased from 14.3 percent to 10.2 percent, and girls who’d ever been pregnant went from 5.9 percent to 3.4 percent. The use of condoms increased, as did the use of birth control pills.

The researchers are careful to point out that they don’t think the HPV vaccine caused the increase in safe sex among the teenagers. That shift was already underway, they write, pointing to data showing “a downward trend in risky sexual behaviors since before 2003.” But it does suggest that the introduction of the vaccine in 2008 wasn’t associated with an increase in risky sexual behaviors.

Survey data like this has its problems, especially when the questions involve sex. It’s likely that the girls aren’t telling all, even when the survey is anonymous. But because all three years of the survey are likely to suffer from the same problem, the comparison is still apples with apples. And it’s possible that in a parallel universe without the vaccine, the risky behaviors could have plummeted even further; there’s simply no way to tell.

The researchers plan to explore whether risky behavior looks different in girls who had been vaccinated compared to those who hadn’t. To do this, they will introduce a new question in the survey, which asks girls about their HPV vaccination status. But in the meantime, these results fit in well with a growing body of literature: a study in the US that compared girls who were and weren’t vaccinated found no differences in pregnancy or STD rates between the two groups, while a different Canadian study found similar results.

Some research has even found that girls who’ve had the vaccine have safer sex than those who haven’t. That could be because HPV vaccine programs often go hand-in-hand with sex education, and teasing apart those influences is extremely difficult. But it seems unlikely that a significant change in risky behavior is lurking hidden in the data.

Different tactics for different groups
The obvious benefits of the vaccine make it important for us to understand why its uptake isn’t higher. The rate is even lower among certain groups, says Grace X. Ma, director of the Center for Asian Health in Philadelphia. While Asian American teenagers have rates similar to the average, “there are certain subgroups, such as Chinese Americans whose parents are low-income and have limited English proficiency, for whom uptake is much lower.” According to Ma, different sources placed the rate at between 10 and 30 percent at the time she started her research.

Ma designed a program to reach these parents through doctors, using materials written in their own languages and delivered through a source they were inclined to trust. In a small pilot study, Ma engaged pediatricians working in low-income Asian communities in Philadelphia and New York. By the end of the study, 110 parents had been reached by the materials, while a control group of 70 hadn’t. More than 70 percent of the teenagers of those 110 parents “had at least one dose of the HPV vaccine, compared with 10 percent of adolescents whose parents did not receive the intervention,” Ma reports.

Without a lot more information, it’s difficult to know what was driving this difference: it could be the cultural specificity of the materials, it could simply be access to the information in a language the parents understand, or a longer and more focused conversation with the doctor might drive the change.

But research in this vein, exploring the effects of different kinds of interventions, could give important clues to how vaccine uptake could be improved in a wider range of population groups. The potential barriers could range from cultural attitudes about sex to language issues to financial access to medical care. But clearly, simple access to the vaccine isn’t enough to encourage widespread adoption.

Source: Canadian Medical Association Journal, 2018. DOI: 10.1503/cmaj.180628 (About DOIs).

November, 2018|Oral Cancer News|

Scientists untangle the evolutionary history of the world’s most common STI

Source: www.iflscience.com
Author: Rosie McCall

Scientists have analyzed the genomes of viruses to reveal the surprisingly complex evolutionary past of the human papillomavirus (HPV), exposing the salacious details of our ancestors’ sexual history in the process.

HPV comes in several flavors but HPV16 is the most common subtype worldwide – and it is the one most frequently identified in cervical cancer. Together HPV16 and HPV18 are responsible for 70 percent of all cases, accord to stats from the World Health Organization (WHO).

The problem is, it isn’t exactly clear how HPV strains contribute to cervical cancer (and other types, including cancer of the anus, the throat, the base of the tongue, and the tonsils). Or why the virus naturally clears in some people but not others. Researchers hope that studying the evolution of the virus will expose biological insights and point at mechanisms that might explain how cervical cancer develops.

To try to untangle HPV16’s thorny evolutionary past, scientists led by the Chinese University of Hong Kong isolated and examined oral, perianal, and genital samples in 10 adult female squirrel monkeys (Saimiri sciureus) and eight adult rhesus monkeys (Macaca mulatta), half of whom were male and half of whom were female.

They found that the virus strains with most in common came from the same part of the body – meaning the oral samples from the squirrel monkeys and rhesus monkeys had more in common than oral and genital samples from the same species, for example. This, the authors say, implies the viruses adapted to a specific body part (or niche) where they co-evolved with their host for millions of years before passing to humans.

For the next part of the study, published in the journal PLOS Pathogens, the researchers compared 212 complete HPV16 virus genomes and 3,582 partial sequences to find out when exactly the HPV16 variants A, B, C, and D diverged from one another.

Schematic illustration of HPV16 codivergence with archaic hominins. Chen et al./PLOS Pathogens

Previous studies have shown that one (the HPV16 A variant) was a lover’s gift from our hominid relatives, the Neanderthals, transmitted to modern humans after a few too many nights of interspecies shagging. Now, it looks like this particular variant split from the virus’ “family tree”, setting off its own trajectory, just as modern humans and archaic hominins (Neanderthals and Denisovans) parted ways, evolutionarily speaking, 618,000 or so years ago.

While the HPV16 A variant co-evolved with its Neanderthal and Denisovan hosts, HPV16 B and HPV16 C variants co-evolved with modern humans. The different strains remained in their respective hosts for hundreds of thousands of years, the study authors say. Then, 100,000 years ago or thereabouts, a small band of Homo sapiens ventured outside of Africa and into Eurasia where they met – and intermingled – with other hominin species, contracting certain HPV16 A variants in the process.

The consequences of this can still be seen today and can help explain why certain variants are more commonly seen in certain groups, the HPV16 A variant in Europeans and Asians, for instance. Hopefully, the authors say, this new information will improve our understanding of why some variants of HPV16 may be inherently more carcinogenic than others.

November, 2018|Oral Cancer News|

A Look at Therapy Toxicities & Biology in Head & Neck Cancers

Source: journals.lww.com
Author: Valerie Neff Newitt

A measure of intrigue and discovery pertaining to head and neck cancer, spiked with compassion for patients struggling against treatment toxicities, helps quench the intellectual thirst of Yvonne Mowery, MD, PhD, Butler Harris Assistant Professor of Radiation Oncology at Duke University Medical Center, Durham, N.C.

Splitting time between the clinic and laboratory, Mowery is actively engaged in patient care as well as preclinical, translational, and clinical research. “I hope to get a better understanding of the biology of head and neck cancer and determine pathways that we can target to reduce metastatic spread of the disease and improve responsiveness to available treatments,” she told Oncology Times.

Long before reaching her current status as an award-winning investigator, Mowery grew up in Richmond, Va., in the midst of a “completely non-scientific” family. “I was an oddball,” she joked, while recalling her parents’ patience with her backyard composting experiments that became so foul-smelling that the health department was contacted. As a kid, her idea of a great present was an encyclopedia of science, and the thing that caught her eye at the toy store was a junior chemistry set.

Science was clearly her path when she headed to the University of Virginia. In her sophomore year, Mowery began working in a genetics lab. That’s where the lure of fruit flies took hold. “I looked at the development of their reproductive system and found that very interesting,” she recalled.

Nearing the completion of her undergraduate education, Mowery debated between attending medical school or graduate school. The eventual winner? Both. “I investigated physician-scientist training programs and arrived at Duke in 2004 to do a combined MD/PhD.” Today, Mowery spends 1 day a week in clinic where she sees patients, then moves to the lab for the remainder of the week to find strategies to improve patient care and develop therapies to deliver better outcomes for patients, both present and future.

Clinical Challenges
“I treat cancers primarily of the head and neck—such as oral cavity, larynx, tonsils, base of tongue, sinuses—with radiation therapy. I think of head and neck cancers as being in a ‘very high-stakes real estate’ area,” she said, “because they are often close to saliva glands, vocal cords, etc. This requires intricate planning for radiation treatment. Visualization of the tumor through fiberoptic laryngoscopy allows me to see a tumor responding to radiation and chemotherapy during the weeks of treatment; it is gratifying to watch it happen with your own eyes.”

Mowery said toxicity associated with treatment of this area of the body can be severe, partially due to the fact that it is typically “…one of the longer courses of radiation that we do—about 7 weeks, 5 days a week,” she explained. “Patients typically require pain medicine to eat and drink a soft diet, lose their sense of taste, and experience very dry mouth, sometimes requiring a feeding tube for nutrition. In addition, the skin on their neck often falls off.” Comparing it to severe sunburn, Mowery said skin typically blisters and peels off, leaving behind a neck that is “red, angry, and very uncomfortable. It just comes with the territory.”

In addition to these side effects, Mowery said there is also an unusual biological aspect to head and neck cancers which figures largely in her work. “Something very interesting scientifically drew me to these cancers,” she informed. “There are two main causes of cancer in this area: tobacco use and human papillomavirus (HPV). Outcomes for patients with HPV-positive oropharynx cancers are excellent; even when the cancer is locally advanced about 80-90 percent of patients are cured. But the tobacco-induced cancers, by contrast, do much worse (about 60% or less survival rate for locally advanced disease). Even if the tumor size is the same and the number of involved lymph nodes are the same, the biology is completely different for the HPV-related and the HPV-unrelated disease.”

In fact, the staging system was changed at the beginning of this year so that HPV-related cancers and HPV-negative cancers are staged differently. “HPV-positive cancers that used to be staged at IVA may now be staged at I or II, but they remain at stage IVA if the cancer is HPV-negative,” Mowery detailed.

Asked why tobacco-related cancer behaves so badly, Mowery answered, “We do not have a good understanding of that; it is something I am studying. We do know, however, that HPV-negative tumors exhibit a loss of function of the p53 gene, [which] is really the king of all tumor suppressors. In HPV-related tumors, p53 is usually genetically still intact but its activity is affected by HPV.”

She also commented that people still actively smoking during treatment tend to do much worse, likely due in part to having lower oxygen levels in the tumor, which in turn causes the radiation to work less effectively. “If we can figure out ways to make HPV-negative tumors behave more like HPV-positive tumors, outcomes would improve.”

From Clinic to Research
These realities on the clinical side have informed and inspired some of Mowery’s research efforts. One of her projects aims at reducing the toxicity of treatment while maintaining good outcomes in patients.

“A clinical trial that I am about to start will use PET/CT, a type of metabolic imaging, as an early litmus test to evaluate how patients are responding during treatment. If we find they are responding well, we will de-intensify and back off on the chemotherapy and radiation dose while still trying to achieve good outcomes,” Mowery explained.

She noted that because HPV-positive and HPV-negative cancers are still treated exactly the same way when not on a clinical trial, investigators also hope to find out if treatment can be de-intensified for the HPV-positive patients who tend to have more successful outcomes by virtue of their cancer type, thus allowing them to avoid some of the severe side effects.

“Of course, even in HPV-positive cancers, not every patient is cured,” cautioned Mowery, “so we want to see if we can identify, early on, who is going to do well and who, in contrast, still needs that full 7-week intensive course of radiation therapy and chemotherapy.”

Another clinical trial ongoing at Duke in which Mowery is involved is testing a drug called BMX-001 given to patients through a subcutaneous injection during radiation. “We hope the drug will reduce the—the inflammation and irritation of the lining of the mouth and throat during radiation—and dry mouth,” she said.

Mowery is also busy in lab with intensive work in developing new mouse models of both HPV-related and HPV-unrelated squamous cell carcinoma of the head and neck. “My objective is to develop a platform in which I can develop radiation with immunotherapy, as well as with chemotherapy and various novel systemic agents, to try to improve outcomes particularly for HPV-negative disease,” noted Mowery, also the winner of a 2017 Conquer Cancer Young Investigator Award. “I want to discover if there are ways that we can make our bodies and our immune system realize that these cells are not ‘self’ and activate the immune system to attack and eliminate them.”

Tobacco-related cancer is induced in mice by giving them a carcinogen present in tobacco, “… causing them to become like a tobacco chewer or smoker,” Mowery explained. “Having that exposure causes mutations in cells in the lining of their mouth.”

Mowery further said her research is taking advantage of large sequencing projects in which various head and neck tumors have been sequenced. These data are publicly available and published primarily by The Cancer Genome Atlas organization. “I have been able to see which genes are most commonly mutated and then can genetically engineer mice to have those mutations. In other words, I can specifically knock out certain genes in the head and neck to model the cancer in mice.”

This is extremely important because it allows Mowery and team to interrogate the biology of the mutations, and determine which genetic changes and pathways lead to the cancer spreading from its site of origin to the lymph nodes or the lungs. “It helps us to develop therapies to block the cancer and keep it at bay, and to determine if there are better ways to sensitize the cancer to radiation and chemotherapy,” she detailed. “And we have an opportunity to test drugs that we hope will help with side effects of radiation. We must make sure that drugs protecting normal tissue are not also protecting the tumor. Having great animal models of human cancer is really important to making progress.”

As if her work in head and neck cancer were not enough, Mowery is continuing an earlier effort begun in the lab of her research mentor David G. Kirsch, MD, PhD, by acting as radiation oncology principal investigator for a multi-site, international prospective randomized clinical trial investigating the combination of the immune checkpoint inhibitor pembrolizumab (anti-PD-1 antibody) and radiation therapy for patients with high-risk soft tissue sarcoma of the extremities. The researchers are also examining the biology behind the effects of radiation combined with pembrolizumab in a co-clinical trial using primary mouse models of sarcoma.

“We saw promising results combining them in this model. Our hope is by using this combination during the early stage of disease we may be able to eliminate those cells that have escaped the primary tumor before they cause a problem.”

Who Has Time for Hobbies?
Asked about her life outside of the clinic and lab, Mowery admitted that little time is left for hobbies. “I used to play tennis, but now I just enjoy watching it,” she said through a chuckle. “I splurged on a Labor Day vacation to the U.S. Open in New York. In my off time, I mostly read and spend time with my family. I am married; my wife is a nurse at Duke working in bone marrow transplant. We have no children.”

But the couple does have the patter of little feet in their midst. “We have two small dogs, Heidi and Cassie, a Maltese and a Maltese Shih Tzu mix—both less than 10 lbs.,” Mowery offered. “We live in downtown Durham, N.C., which is a burgeoning area. It’s kind of cool, and a little bit grungy—but in a good way. I love going for walks and checking out new restaurants. And I love food,” she added brightly.

After a brief pause, Mowery turned her thoughts again to patients. “There is one other clinical trial we’ve recently opened in the head and neck space. We are looking at financial toxicity of patients,” she said. “We are very concerned about the bills patients incur for cancer care and how that affects their quality of life.

“Unfortunately, some people just can’t afford to fill their whole prescription. Some take their drugs every other day because they are worried about cost. Some patients just do not follow through on therapy. We need to get a better sense of how much of that is going on and if there are early warning signs we can detect allowing us to intervene.”

Mowery added that better communications between health care providers and patients are needed to help patients better understand costs they face and identify resources that can help them.

“We just opened this survey-based pilot trial in June. We hope to have data next year and be able to develop a follow-up plan to employ the strategies that we find,” said Mowery. “There are a lot of ways we can try to help our patients.”

November, 2018|Oral Cancer News|

HPV blood test shows promise for tracking head and neck cancer after treatment

Source: www.eurekalert.org
Author: from UNC Lineberger Comprehensive Cancer Center

A new blood test developed by University of North Carolina Lineberger Comprehensive Cancer Center researchers shows promise for tracking HPV-linked head and neck cancer patients to ensure they remain cancer-free after treatment.

Researchers will present preliminary findings at the 60th Annual Meeting of the American Society for Radiation Oncology in San Antonio on Tuesday, Oct. 23. Their study evaluated a blood test for HPV-linked oropharyngeal squamous cell carcinoma, which is a cancer of the back of the throat. The findings demonstrated the test could be an effective and less costly alternative for monitoring for cancer recurrence after radiation treatment.

“The goal of this study was to evaluate whether this test can be used to track patients who are completely asymptomatic, and thought to have no active cancer,” said UNC Lineberger’s Gaorav P. Gupta, MD, PhD, assistant professor in the UNC School of Medicine Department of Radiation Oncology. “We already knew that our test was very sensitive and specific, but we did not know the degree to which it would be useful in early detection of disease recurrence in patients who are otherwise thought to be disease-free.”

HPV, or the human papillomavirus, is the most common cause of sexually transmitted infection in the United States, according to the U.S. Centers for Disease Control and Prevention. Infection with certain strains of HPV can cause cervical cancer in women, genital cancers in both men and women, and cancer of the oropharynx, which is the back of the throat, including the base of the tongue and tonsils. The CDC estimates that approximately 70 percent of oropharyngeal cancer cases diagnosed in the United States are probably caused by HPV, which accounts for nearly 13,000 cases per year.

Gupta and his colleagues developed a blood test that can detect fragments of HPV’s genetic material that have been released into the blood by dying cancer cells.

“We realized it is important to distinguish HPV DNA that’s being released by dying tumor cells from the natural HPV DNA that is present during a viral infection,” Gupta said. “Our method accomplishes this feat, thus making it a more sensitive and specific test for cancer.”

For their study, the researchers followed 89 patients with HPV-associated oropharyngeal squamous cell carcinoma who received chemotherapy and radiation treatment. They administered the blood test before and during treatment, and then during follow-up visits. The patients received scans three months after treatment, and then came back for clinical exams every two to four months during the first two years, and then every six months in years three through five. Patients received X-rays or CT scans every six months, and again if they had positive HPV results.

“We are detecting subclinical disease with this blood test, and the imaging patients received confirmed those findings,” said UNC Lineberger’s Bhishamjit S. Chera, MD, associate professor in the UNC School of Medicine Department of Radiation Oncology and the study’s co-corresponding author. Chera presented the findings from the study at the ASTRO meeting.

Of the 70 patients whose blood tests were negative three months after treatment, none developed recurrence. Nineteen patients had positive blood tests, and eight of those patients developed recurrence. Physicians are continuing to monitor the remaining eleven who had positive blood tests but no evidence of recurrence.

“The most striking finding of our study is that of the patients who did not have any signal using our blood test, none of them developed disease recurrence,” Chera said. “That raises the question: Do we need to be scanning these patients? Scans come with a lot of cost, and because of the cost, we’re not able to do it as frequently. Patients end up having a lot of anxiety from one scan to the next, wondering if their cancer has come back. This blood test could spare patients the need for additional imaging and potentially alleviate some anxiety.”

The researchers say the next steps will involve investigating whether the test can be used prospectively to monitor patients and to make decisions that could avoid unnecessary imaging, thereby reducing costs. They also see additional applications for the blood test, including monitoring for other HPV-linked cancers, including cervical cancer.

“We are confident this blood test will be translatable to other cancers driven by HPV, and as a monitoring tool for cancer diagnosis,” Chera said. “We strongly believe that this test may also have a role in screening, not just for oropharyngeal cancer, but also cervical or anal cancers, possibly in a general population setting, or at least in patients who may be at higher risk of developing these conditions.”

In addition to Chera and Gupta, other authors include Sunil Kumar, PhD; Colette Shen, MD, PhD; Robert Amdur, MD; Roi Dagan, MD; Jared Weiss, MD; Juneko Grilley-Olson, MD; Adam Zanation, MD; Trevor Hackman, MD; Jeff Blumberg, MD; Samip Patel, MD; Brian Thorp, MD; Mark Weissler, MD; Nathan Sheets, MD; and William Mendenhall, MD.

The study was supported by the University Cancer Research Fund, Burroughs Wellcome Fund, the University of North Carolina School of Medicine Department of Radiation Oncology, UNC Lineberger and the University of Florida School of Medicine Department of Radiation Oncology.

Intellectual property related to the test and held by the University of North Carolina at Chapel Hill has been licensed to Naveris, a company in which Chera and Gupta hold equity stakes.

October, 2018|Oral Cancer News|

Why oral cancer threatens men

Source: www.scientificamerican.com
Author: Claudia Wallis, Scientific American November 2018 Issue

Back in 2006, when the vaccine for human papillomavirus (HPV) was introduced, I rushed to get my teenage daughters immunized. Here, amazingly, was a vaccine that could actually prevent cancer. By blocking HPV infection, it protects girls from the leading cause of cervical malignancies. I didn’t give much thought to my son, and neither did the medical establishment. It wasn’t until 2011 that health authorities recommended the vaccine for boys.

In hindsight, that delay was a mistake, though perfectly understandable: the vaccine was developed with cervical cancer in mind and initially tested only in girls. Today, however, we see a rising tide of cancers in the back of the throat caused by HPV, especially in men, who are three to five times more vulnerable than women. This surge of oropharyngeal cancers, occurring in many developed nations, took doctors by surprise. Oral cancers were expected to decline as a result of the drop in smoking that began in the 1960s.

Smoking-related oropharyngeal cancers are, in fact, down. But making up the difference, particularly in men, are those related to HPV, which have more than doubled over the past two decades. With cervical cancer waning (thanks to screening and prevention), this oral disease is now the leading HPV-related cancer in the U.S. Nearly 19,000 cases were reported in 2015, according to a recent report by the Centers for Disease Control and Prevention. Roughly nine out of 10 involve a nasty strain called HPV-16.

Researchers link the rise of these cancers to changing sexual practices, perhaps dating back to the 1970s. “People have more partners than they had in the past, and they initiate oral sex at an earlier age than previous generations did,” says Gypsyamber D’Souza, associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health. Greater exposure to oral sex means that the nearly ubiquitous virus gets transferred from the genitals to the mouth.

Studies suggest that most women develop protective antibodies to HPV after having a few sexual partners, but for men, it may take more than 10 partners. A likely reason for the difference, says oncologist Maura Gillison of the University of Texas MD Anderson Cancer Center, is that “in women, the infection is vaginal-mucosal; in men, it’s entirely on the skin,” where it is much less likely to trigger an antibody response. Males can get an active infection again and again, and it lingers longer than in women, making them the “Typhoid Marys of HPV,” as Gillison puts it. The path from infection to cancer may take decades and is not well understood.

Fortunately, the HPV vaccine should prevent these oral cancers, just as it protects against cervical cancer (as well as virus-related cancers of the vulva, labia, penis and anus). After lagging for years, U.S. rates of vaccination of boys are catching up with that of girls. New CDC data show that in 2017, 68.6 percent of girls and 62.6 percent of boys, ages 13 to 17, had received at least one dose of the vaccine—up from 65.1 and 56 percent, respectively, in 2016. If the trend continues, HPV-related cancers will ultimately become a scourge of the past in the U.S.

The tough question is what to do in the meantime for the large number of people, especially at-risk men, who have never been immunized. The CDC recommends the vaccine for children as young as nine and up to age 21 for boys and 26 for girls. Merck, which makes the only HPV vaccine now used in the U.S., is seeking approval to make it available up to age 45, but the $130-a-dose vaccine is less cost-effective in older populations. “It’s best given before people are sexually active,” explains Lauri Markowitz, team lead and associate director of science for HPV at the CDC. “The vaccine is not therapeutic; it’s prophylactic.” A vaccine advisory committee meeting this fall will weigh whether to revise current recommendations. One possibility, she says, is raising the upper age for boys to 26, matching that for girls.

D’Souza, Gillison and others are investigating ways to identify and screen people who may be at an especially high risk for oral HPV cancers—a significant challenge. There is no Pap-smear equivalent for this devastating disease, no reliable way to spot precancerous or early-stage lesions. And research by and her colleague Carole Fakhry shows that even if you focus on a high-risk group such as men in their 50s—8 percent of whom are infected with one of the noxious HPV strains—only 0.7 percent will go on to develop the cancer. There’s little point in terrifying people about the small odds of a bad cancer, D’Souza says, so “we’re working on understanding which tests would be useful.”

October, 2018|Oral Cancer News|

As HPV-related cancer rates climb, experts scrutinize barriers to HPV vaccination

Source: www.cancertherapyadvisor.com
Author: Bryant Furlow

Oropharyngeal squamous cell carcinomas (SCCs) are now the most commonly diagnosed human papillomavirus (HPV)-associated cancers in the United States, with 15,479 men and 3438 women diagnosed in 2015, according to an analysis by the Centers for Disease Control and Prevention (CDC).1

Between 1999 and 2015, cervical cancer and vaginal squamous cell carcinoma (SCC) rates declined, by 1.6% and 0.6% per year, respectively. But rates for vulvar SCC increased by 1.3% annually during the same period. Anal SCC rates also climbed by approximately 2% a year among men and 3% among women.1

Rates of oropharyngeal SCC — cancers of the throat and tongue — climbed as well, particularly among men (2.7% a year vs 0.8% in women).

All told, more than 43,000 Americans were newly diagnosed with HPV-related cancers in 2015, the analysis showed, up from 30,115 in 1999.1 Most people diagnosed with HPV-associated malignancies are older than 49 years.1 Most women diagnosed with cervical cancer are older than 30 years.1

“We don’t actually know what caused the increase in HPV infections but we know now that we have a safe and effective vaccine that can prevent infections,” said Lois Ramondetta, MD, professor of gynecologic oncology and reproductive medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We’re seeing people who were infected decades ago developing these cancers,” Dr Ramondetta said. “We’ll see rates continue to rise over the coming years because the vaccine wasn’t available before 2006.”

HPV vaccination rates are improving, Dr Ramondetta noted.

Overall, approximately half of adolescents in the United States have completed the HPV vaccine dose-series — well shy of the 2020 herd immunity goal of 80%.

“That’s the overall up-to-date vaccination rates for adolescents aged 13 to 17,” Dr Ramondetta explained. “That’s definitely not where we want it to go but it is 5% higher than last year. If you look at the one-completed-dose vaccine initiation rate, that’s 65.5%.”

HPV vaccination rates are improving more rapidly among boys than girls.

“For some reason, safety is not as big a concern for boys and their parents,” Dr Ramondetta said. “It shouldn’t be a concern at all. This vaccine has been studied more than just about any other vaccine. But if you ask parents why girls are not vaccinating, safety seems to be a concern for some.”

There appears to be less stigma among parents about sons becoming sexually active than there is about the sexual activity of daughters, said Debbie Saslow, PhD, senior director of HPV-related and women’s cancers at the American Cancer Society in Atlanta, Georgia.

Vaccination rates vary geographically, both between countries and within the US. Only a handful of states require that public school students receive the HPV vaccine. Vast expanses of the rural US have few or no pediatricians and limited access to the vaccine.

Australia introduced HPV vaccines at the same time as the US, nearly a decade ago, but Australia achieved 80% vaccination rates in just a year, Dr Saslow said. That was largely because the Australian government paid for the vaccines and they were administered in schools. As a result, this year, Australia changed cervical cancer screening recommendations to reflect the reduced risk: at age 25, women start undergoing HPV testing (rather than pap tests) every 5 years.

That will eventually happen in the US as well, Dr Saslow predicted.

“It’s going to happen but the question is when,” she said. “What will happen is we’ll start screening later, at age 25 and maybe eventually 30, and screening will get away from Pap testing, because Pap tests are not as effective in vaccinated people: they’ll detect a bunch of cervical changes unrelated to cancer. It will all be false positives. We’ll need to go to strictly HPV-based testing” or potentially some new type of screening test, according to Dr Saslow.

In the US, there appear to be socioeconomic or class barriers at play regarding HPV vaccination. Completion rates tend to be higher among more affluent groups, meaning that those who get the first vaccine are more likely to complete the series.

But there’s also a “reverse disparity” in initiating HPV vaccination at all Dr Saslow noted. “Poor and minority kids have higher rates of [the] first dose. Providers might be doing their own risk-based recommendations to parents, which they should not be doing, saying these kids are at higher risk.”

In high-socioeconomic-status urban and suburban communities, vaccine hesitance and prevalent “anti-vax” conspiracy theories may be barriers to vaccination. In rural areas, religious conservativism about sex and sexually transmitted disease — as well as the political climate — are likely factors, Dr Ramondetta added. Rates of HPV vaccination are worse than those for, say, polio or measles, suggesting that hesitance is related to the sexual nature of HPV transmission.

“There’s still a stigma about HPV infection, which is crazy, since most people are exposed,” said Dr Ramondetta. “Normalizing HPV is important — it’s just an aspect of the human condition, like flu.”

“There is ample evidence of the efficacy, safety and durability of this vaccine,” Dr Ramondetta said. “We need to find new ways to educate the public. We can talk to one another all we want in journals but meanwhile, social media is filled with [misinformation] … We need to take a larger role in social media, flooding it with accurate information.”

“Most parents just need reassurance,” she added. “Their motivation is to keep their kids safe.”

Doctors should recommend HPV vaccination every time they see adolescent patients and their parents, Dr Saslow emphasized. And, oncologists need to reach out to family physicians and pediatricians, she said.

References
1. Van Dyne EA, Henley SJ, Saraiya M, Thomas CC, Markowitz LE, Benard VB. Trends in human papillomavirus-associated cancers — United States, 1999-2015. MMWR Morb Mortal Wkly Rep. 2018;67(33);918–924.

October, 2018|Oral Cancer News|