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The YAP signal plays a crucial role in head-and-neck cancer onset

Source: www.eurekalert.org
Author: press release, Kobe University

Joint research between Kobe University and National Hospital Organization Kyushu Cancer Center has revealed that mice with mutations in the YAP signal pathway develop head-and-neck cancer over an extremely short period of time (world’s fastest cancer onset mouse model), indicating that this pathway plays a crucial role in the onset of these cancers. This discovery may shed light on the development of new drugs for head-and-neck cancer.

This research resulted from a collaboration between a research group led by Professor SUZUKI Akira and Associate Professor MAEHAMA Tomohiko at Kobe University Graduate School of Medicine, and Dr. MASUDA Muneyuki’s team at Kyushu Cancer Center.

These results were published in the American scientific journal ‘Science Advances‘ on March 18.

Main Points:
>Deletion of MOB1 (*1, which represses YAP) in mouse tongues causes strong activation of YAP (*2), leading to the early onset of cancer (in about 1 week).

>In humans, the expression of YAP increases during the development of dysplasia (pre-cancerous lesions), prior to the onset of head-and-neck cancer. YAP continues to increase with the development and progression of cancer. This high YAP activation is linked to poor patient prognosis.

>The onset and progression of head-and-neck cancer in the mice in this study, and the proliferation of stem cells in this cancer in humans, are dependent on YAP.

>These results suggest that cancer develops when the YAP activation exceeds a threshold. YAP may play a fundamental role in head-and-neck cancer onset and progression. These conclusions represent a paradigm shift in the understanding of these cancers.

>The mouse model developed in this study can be used in research to develop new drugs for head-and-neck cancer and, in addition, provides a beneficial resource for cancer research in general.

>By inhibiting YAP, the development and progression of head-and-neck cancer can be suppressed. Thus, the YAP pathway provides a good target for head-and-neck cancer treatments.

Research Background

Head-and-neck cancer in humans
Head-and-neck cancer is the sixth most common type of cancer in the world, affecting 600,000 people annually. In Japan there are around 22,500 new cases every year. This ‘head and neck’ includes the oral cavity and areas of the throat (pharynx and larynx). Among these, mouth cancers (especially tongue cancer) are the most prevalent.

It is understood that exposure to carcinogens, such as those found in cigarettes and alcohol, as well as mechanical irritation of the mucous membranes in the mouth, tooth decay and improperly fitted dentures, are risk factors for the development of head-and-neck cancer.

In addition, 15% of head-and-neck cancer is caused by Human Papillomavirus (HPV), which in particular causes oropharynx cancer.

The prognosis for patients who are HPV-positive is relatively good. Conversely, prognosis is poor for HPV negative patients and in most cases, mutations are found in the tumor suppressor gene TP53 (p53). However, mutations in this gene alone are not sufficient to cause head-and-neck cancer. It has been thought that changes in other molecules are also necessary for cancer development, however these causes remain elusive.

From comprehensive cancer genome analyses, it is known that PTEN/P13K (46%), FAT1 (32%), EGFR (15%) gene mutations are also found in HPV-negative head-and-neck cancer. However, the genetic pathway of these molecules in relation to head-and-neck cancer development has not been sufficiently understood.

Mouse models of cancer
Up until now, research using mouse models of head-and-neck cancer has discovered that if both the p53 and Akt genes are mutated, 50% of mice will develop this type of cancer about 9 months after the mutation (the average mouse lifespan is 2 years).

The onset of cancer begins after many genetic mutations have accumulated (multistep carcinogenesis). Mice with a mutation in one important molecule usually develop cancer within 4 to 24 months (with the majority showing signs between 6 to 12 months).

The YAP pathway
The function of the transcriptional co-activator YAP is to turn ‘on’ the transcription of gene clusters related to cell growth. The LATS/MOB1 complex phosphorylates YAP, thereby excluding YAP from the nucleus, leading to the subsequent degradation of YAP proteins. In other words, MOB1 and LATS act as a ‘brake’ (tumor suppressor) to inhibit cell proliferation facilitated by YAP. It has been reported that in 8% of human head-and-neck cancer cases, the YAP gene is amplified and there is a connection between YAP activation, cancer progression and poor prognosis.

This research group produced mice with MOB1 deletion in their tongues (so that YAP would be intrinsically activated) in order to perform a detailed analysis in vivo of the role that the YAP pathway plays in head-and-neck cancer.

Research Methodology

Mice with MOB1 deletion exhibit rapid onset tongue cancer
This research group developed mice with MOB1 deletion in their tongues by applying the drug tamoxifen to their tongues and then modifying them genetically using the Cre-loxP system (*4).

Three days after applying tamoxifen, the amount of MOB1 had barely decreased, however by day 7, the vast majority of these proteins had disappeared. At this point, a third of the mice demonstrated rapid onset head-and-neck cancer (intraepithelial tongue cancer), with all mice developing the disease by day 14. The cancer had progressed in all mice by day 28 (invasive tongue cancer). The team succeeded in developing the world’s fastest mouse model of cancer onset. Both domestic and international patents for this model have been applied for.

This mouse model showed that head-and-neck cancer develops quickly (within a week) when the YAP pathway is strongly activated, suggesting that this pathway plays an extremely important role in head-and-neck cancer onset.

YAP activation and tumorigenic properties of the tongue epithelium in MOB1 deletion mice.
The epithelial cells (on the surface of the tongues) of MOB1 deletion mice exhibited the following properties characteristic of tumor development: increased cell proliferation and cell saturation density, impaired cell polarity, low levels of apoptosis (cell death), increase in undifferentiated cells, and chromosomal instability (characterized by increases in aneuploid cells (*5)), multipolar spindles (*6) and micronucleated cells). On a biochemical level, activation of YAP and a decrease in LATS proteins was evident due to MOB1 deletion.

The epithelial cells acquired the characteristics of tumor cells due to the YAP activation caused by the deletion of MOB1.

YAP activation in the stages of tongue cancer in humans
The development of human tongue cancer can be divided to the following stages; the normal stage, the dysplasia stage, the intraepithelial cancer stage (*8) and the invasive cancer stage (*9).

If we look at YAP activation across all these stages, we can see that YAP is enhanced in the dysplasia stage which proceeds the onset of cancer. YAP activation shows continued increase during the subsequent stages of cancer progression. In cases where YAP is highly activated, overall survival is decreased and the likelihood of cancer relapse is high.

In other words, YAP increases before the onset of cancer and continues to increase as the cancer develops and progresses. Accumulation of YAP is linked to poor patient prognosis.

Cancer formation is dependent on YAP when MOB1 is deleted
Invasive cancer occurred in MOB1 deletion mice. However, when both YAP and MOB1 are deleted from mice, cancer onset is halted at the dysplasia stage, showing that the onset of head-and-neck cancer is dependent on YAP (Figure 2).

Among current YAP pathway inhibitors, the SRC inhibitor Dasatinib (*10) was shown to be the most effective (SRC has been previously shown to activate YAP both directly and indirectly). Dasatinib was shown to prevent the onset of intraepithelial head-and-neck cancer in the MOB1 deletion mice. It also suppressed the development of invasive cancer in MOB1 deletion mice that had reached the intraepithelial head-and-neck cancer stage.

In human head-and-neck cancer stem cells, it is possible to suppress cell proliferation either by inhibiting YAP gene expression or by adding YAP inhibitors. Cisplatin, which is commonly used to treat head-and-neck cancer, is augmented when YAP is suppressed.

In mice, head-and-neck cancer onset and progression was suppressed when YAP was inhibited. In the same way, it was shown that in human tongue cancer stem cells, cell proliferation was also suppressed when YAP was inhibited.

Known genetic mutations in human head-and-neck cancer and YAP activation
Genetic mutations in p53, PTEN/PI3K, FAT1, and EGFR have been identified in HPV-negative head-and-neck cancer.

This research group showed that EGF signal activation and mutations in p53, PTEN and FAT1 each play a role in YAP activation. Furthermore, YAP activation gradually increases as these genetic mutations accumulate.

Normally, cancer takes time to develop as it is a multistep process. However, in this study, intraepithelial head-and-neck cancer rapidly developed just from highly strengthening YAP activation.

In conclusion, this study raises the possibility that the following process for head-and-neck cancer development takes place: A. Cancer develops when the YAP activation exceeds a threshold due to the accumulation of genetic mutations in p53, PTEN/PI3K, FAT1 and EGFR (Figure 3). B. Subsequently, YAP continues to accumulate after cancer has developed, resulting in cancer progression.

Conclusion and Further Developments
YAP is frequently activated in cancer cells although genetic mutations in the YAP pathway are not frequently found. It is thought that this is why the importance of the YAP pathway in the onset of head-and-neck cancer was unclear until now.

1. YAP activation levels are high before the onset of head-and-neck cancer in humans.
2. YAP is further activated as the cancer progresses.
3. The high frequency of mutations in p53, PTEN/PI3K, FAT1 and EGFR all activate YAP.
4. The accumulation of these molecular mutations gradually leads to high YAP activation:
4a. The accumulation of genetic mutations in p53, PTEN/PI3K, FAT1 and EGFR cause YAP to reach its threshold, culminating the onset of cancer.
4b. YAP continues to accumulate after the cancer onset, resulting in further cancer progression.

It is necessary to consider YAP as a basis for head-and-neck cancer onset and progression. This represents a paradigm shift in our understanding of these cancers.

In addition, it has also been shown that risk factors for head-and-neck cancer, such as cigarette smoking, mechanical irritation of mucous membranes and HPV infection, also play a part in YAP activation.

The mouse model in this study: 1. Is the fastest mouse model in the world for showing the natural onset of cancer. 2. Can be used to visualize cancer onset and progression. 3. Allows cancers to be developed naturally at the same time. 4. Allows cancer onset and progression to be analyzed in mice immediately after birth, allowing drug tests to be conducted in a shorter period of time and in small quantities. The results suggest that this mouse model would be ideal, not only for research into developing new treatments for head-and-neck cancer, but also for cancer research in general.

It is expected that the YAP pathway will provide a good target for drugs used in the treatment of head-and-neck cancer because inhibiting YAP not only suppresses the cancer onset but can also prevent its progression.

Researchers from all over the world, including this research group, are currently trying to find new drugs that target the YAP pathway. We have shown one factor that is effective against head-and-neck cancer. It is also expected that the mouse model will become an indispensable tool for evaluating their results and for head-and-neck cancer research.

Glossary
1. MOB1 (Mps One Binder 1): MOB1 is necessary for activating the LATS kinase and acts as a brake (tumor suppressor) on downstream, negatively-controlled YAP. Deletion of MOB1 exacerbates cell proliferation and leads to cancer.
2. YAP (Yes-associated Protein): YAP is a transcriptional coactivator. It forms a complex with multiple transcription factors inside the nucleus to control the expression of various genes. YAP is phosphorylated by the LATS kinase, causing YAP to be excluded from the nucleus and inactivated.
3. Human Papillomavirus (HPV): A type of papillomavirus, there are over a hundred genotypes or varieties of HPV. The virus is linked to genital warts, head-and-neck cancer and cervical cancer.
4. Cre-loxP system: A genetic modification system using Cre recombinase, which catalyze DNA recombination between two loxP sites (a 34-base pair nucleotide sequence). If Cre is expressed in a cell where chromosomal DNA has been artificially inserted into two loxP sites, the intervening DNA segment is deleted.
5. Aneuploid Cells: contain an abnormal number of individual chromosomes. This does not include a difference of one or more complete sets of chromosomes.
6. Multipolar Spindle: Spindles are formed during cell division to separate chromosomes between daughter cells. In normal cells, a pair of centrosomes forms prior to cell division to organize proteins called microtubules into a spindle between the two centrosomes. However, in cancer cells there are more than two centrosomes, and so-called multipolar spindles form. This can cause chromosomal instability and lead to the formation of aneuploid cells because the chromosomes were not correctly allocated at the time of cell division.
7. Dysplasia: The presence of cells of an abnormal type within a tissue. In medical diagnosis, the presence of abnormal-looking cells (dysplasia) observed under a microscope can signify an increased chance of a patient developing cancer (pre-cancerous symptoms).
8. Intraepithelial cancer: This is where cancer cells are found within the intraepithelial layer of cells which form on an organ’s surface. At this point, cancer cells have not been able to penetrate the basement membrane and have not spread deeply. Related terms include Carcinoma in Situ (CIS), intraepithelial tumor and intraepithelial neoplasia.
9. Invasive cancer: is where cancer cells penetrate the basement membrane, a thin membrane separating them from other tissues. From there, cancer can spread to the surrounding area.
10. Dasatinib: a chemotherapy drug that inhibits the SRC kinase family, which can cause malignant transformation in cells. SRC is both directly and indirectly connected to YAP activation, so dasatinib can also inhibit YAP. It is currently used to treat leukemia but is not prescribed for head-and-neck cancer treatment.

Acknowledgements:
This research was made possible primarily through funding to the project ‘The development of cancer treatment methods targeting cancer suppression genes.’ (Lead researcher: Suzuki Akira) as part of the Japanese Agency for Medical Research and Development’s Project for Cancer Research and Therapeutic Evolution (AMED P-CREATE).

March, 2020|Oral Cancer News|
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Surveillance of ctDNA in HPV-positive head and neck cancers may predict recurrence

Source: www.targetedonc.com
Author: Nichole Tucker

The detection of circulating tumor DNA (ctDNA) in human papillomavirus (HPV) with an experimental blood test has been associated with high positive predictive value (PPV) and negative predictive value (NPV) for identifying disease recurrence in HPV-positive oropharyngeal cancer, according to a press release from the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center.1

“The major utility of this test is it’s going to improve our ability to monitor patients after they complete treatment,” said Bhisham Chera, MD, associate professor in the UNC School of Medicine Department of Radiation Oncology. “Currently, our methods to assess whether the cancer has recurred are invasive, expensive and not always accurate.”

In a prospective biomarker clinical trial published in the Journal of Clinical Oncology, investigators obtained 1006 blood samples for their analysis, 999 of which were evaluable for plasma circulating tumor human papillomavirus DNA (ctHPVDNA). The goal was to determine if surveillance of ctHPVDNA can facilitate earlier detection of recurrence compared with normal clinical follow-up.2

Patients were followed for a median of 23.7 months (range, 6.1-54.7 months), and out of 115 patients, 13% developed disease recurrence (n = 15). Of these recurrences, 1 was local only, 1 was regional only, 10 were distant only, 1 was local and distant, and the remaining 2 were regional and distant. Following treatment, 87 patients had undetectable ctHPVDNA, and none developed recurrence (95% CI, 96%-100%). The development of a positive ctHPVDNA occurred in 28 patients during post-treatment surveillance.

The median time to abnormal ctHPVDNA signal was 12.3 months after complete chemoradiotherapy (CRT; range, 2.6-29.1 months). Sixteen patients had 2 consecutive positive ctHPVDNA results, and 15 of those patients developed biopsy-proven recurrence. The 2 ctHPVDNA blood tests that were consecutively positive had a PPV of 54% (95% CI, 0.339-0.725). A 3.9-month median lead time between ctHPVDNA positivity and biopsy-proven recurrence was observed (range, 0.37-12.9). the actuarial 2-year response-free survival (RFS) rate was 30% in patients who had an abnormal blood test during post-treatment surveillance compared with 100% among the remaining participants (P <.001).

In the study, CRT included cetuximab 250 mg/m2, carboplatin AUC 1.5, and paclitaxel 45 mg/m2. Patients received intravenous chemotherapy during intensity-modulated radiotherapy treatment, which was given weekly. There were 6 doses of chemotherapy in total.

The secondary end points of the study were local control rate, regional control rate, local-regional control rate, distant metastasis-free survival, OS, head and neck quality of life assessments, and speech and swallowing function.

Patients aged 18 years and older were eligible to enroll if they had T0-3, N0 to N2c, M0 squamous head and neck cancer, HPV and p16 positivity, radiologically confirmed hematogenous metastasis within 12 weeks before treatment, and ECOG performance status of 0 to 1, and adequate bone marrow, renal, and hepatic function. Individuals with prior history of radiation to the head and neck, head and neck cancer, those with unresectable disease, severe comorbidity, or known human immunodeficiency virus, or those taking disease-modifying rheumatoid drugs were excluded from the study.

Based on this research the investigators reported a 99% accuracy in confirming whether or not patients remained recurrence-free with their screening method, compared with other methods. For patients who had 2 HPV-positive blood tests, the accuracy was said to be 94%.1

“With this new technology, it offers a noninvasive way to accurately monitor patients for cancer recurrence,” Chera said. “In the long run, blood-based surveillance could be more effective, and possibly help us to detect cancer sooner.”

References
1. Study finds blood test accurately tracks HPV-linked head and neck cancer [news release]. Chapel Hill, North Carolina: University of North Carolina Lineberger Comprehensive Cancer Center; February 4, 2020. https://bit.ly/2tzlw7x. Accessed February 6, 2020.
2. Chera BS, Kumar S, Shen C, et al. Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer. J Clin Oncol. doi: 10.1200/JCO.19.01598.

February, 2020|Oral Cancer News|
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National Vaccination Program Leads To Marked Reduction In HPV Infections

Source: Forbes
Date: January 28th, 2020
Author: Nina Shapiro

While widespread vaccination continues to be a source of contention in this country and others, one of the newer vaccines has begun to demonstrate remarkable positive impact, which will hopefully become harder and harder to dispute. The HPV vaccine, with trade name GardasilR, is recommended for both boys and girls, ideally sometime between ages 11 and 12 years, given in two doses at a six month interval. It can be given as early as age 9, and as late as age 26. Older adults, even up to age 45, can receive the vaccine, although it is more likely that these adults have already been exposed to the virus, and are less likely to be protected by the vaccine.

The vaccine prevents infection with the human papillomavirus (HPV), which can cause health problems ranging from nuisance-causing warts to cancer-causing lesions of the cervix, throat, and anorectal area. When HPV-related cancers hit Hollywood, with Michael Douglas publicly attributing his throat cancer to HPV, it became clear that this disease can no doubt affect both men and women. When Marcia Cross announced that her anal cancer was due to HPV infection, it raised yet another red flag that HPV can affect the lower gastrointestinal tract, not just the female reproductive tract. Indeed, HPV can affect any of us, at any age, from stem to stern. As I wrote in an earlier Forbes piece, the vaccine to prevent HPV can prevent not only sexually transmitted infections (STI’s) causing genital warts, but it can also prevent cancer.

A lesser known impact of active HPV infection is that the virus can be transmitted from pregnant mother to her fetus via amniotic fluid. The child can later (usually as a toddler) develop warts on the vocal cords, known as recurrent respiratory papillomatosis, or RRP. These warts lead to progressively worsening airway blockage, and even death. And while there are treatments for RRP, there is no cure; only prevention. In another Forbes article, I explain how reduction of HPV infections, thanks to vaccine programs, can reduce the incidence of RRP in the next generation.

A report released this week by Public Health England, published in Health Protection Report, reviewed surveillance data from outcomes of a national HPV vaccination program, which began in 2008. The vaccine is offered to 12-13 year-old males and females, and the report then looked at incidence of HPV infection of the reproductive tract in sexually active 16-24 year-old females. As is the case with many viruses, HPV has many subtypes, some of which are more likely to be associated with aggressive cancers (subtypes 16 and 18 as well as 31, 33, and 45) and others are more likely to be associated with RRP infections and genital warts (subtypes 6 and 11). Until 2012, the bivalent (HPV 16/18) vaccine (CervarixR) was administered as a three-dose regimen. In years since then, the quadrivalent (HPV 16/18/6/11) (GardasilR) has been the standard vaccine administered in the U.K. as well as the U.S. as a two-dose regimen. Cervical cancer is due to HPV 16 or HPV 18 in up to 80% of cancers.

The recent report out of the U.K. analyzed results of over 18,000 vulvovaginal culture specimens obtained from sexually active 16-24-year-old females, collected between 2010 and 2018. There was significant decline in HPV infection rates in all subtypes in all age groups. Those who had been vaccinated more recently showed more reduction in HPV 6/11 than those who did not receive coverage for these strains in the earlier years of vaccination. Most notable was that the prevalence of HPV 16/18 in the 16-18-year-old cohort declined from 8.2% in 2010 to 0.0% in 2018. In the older groups, there was less decline (from 14% to 0.7% in 19-21-year-olds and 16.4% to 2.6% in 22-24-year-olds), but all reductions were statistically significant.

There was no evidence of increase in the HPV subtypes which were not included in the vaccine. Some have raised concern that vaccinating against specific HPV subtypes would increase growth of subtypes not included in the vaccine, but this was not found to be the case. While there are several limitations to this report, including the fact that each individual sample was not identified as being from a vaccinated or non-vaccinated individual, this marked reduction of all HPV subtype growth in a population which demonstrated a vaccination rate of 86% for both males and females ages 12-13 years is promising. While not all cervical cancers, throat cancers, or anal cancers are directly caused by HPV infection, the high rates of HPV-related cancers due to known HPV subtypes underscores the potential widespread benefits of this vaccine in the decades ahead.

January, 2020|Oral Cancer News|
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What parents need to know about the HPV vaccine

Source: www.news-medical.net
Author: University of Chicago Medical Center, reviewed by Kate Anderton, B.Sc. (Editor)

The vaccine that prevents infection from human papillomavirus (HPV) is nothing short of a medical marvel. “It’s one of the most effective vaccines we have against any disease or infection. And it prevents cancer,” said Andrea Loberg, MD, clinical associate of obstetrics and gynecology.

Pre-teens and teens who are vaccinated against HPV can be spared some of the deadliest, most disfiguring and hard-to-treat cancers-;those of the cervix, vagina, vulva, penis, anus, mouth and throat. Over 90% of cancers caused by HPV can be prevented-;29,000 cases of cancer per year-;with the HPV vaccine.

Concerns about sexual promiscuity
To some parents, however, the HPV vaccine may be an uncomfortable reminder that their child will be moving into adulthood and may choose to express his or her sexuality. HPV is transmitted by oral, vaginal and anal sex and other intimate skin-to-skin contact, and it is extremely prevalent; about 80% of people will be exposed to the virus in their lifetime.

Condoms reduce but don’t eliminate the risk of HPV infections because the virus lives in both oral and genital tissues. Condoms do not cover the entire genital area of either gender. Nor are same-sex female partners protected from contracting the virus, which often causes no symptoms until precancerous lesions or cancer show up years later. “It’s hard for parents to think about our kids becoming sexually active, but we also want them to have fulfilling lives,” said Truehart, whose own two teenagers have received the HPV vaccine. “We want to make sure they are protected before they start having sex.”

The recommended age for receiving the HPV vaccine is 11 or 12, when children are also scheduled to receive the Tdap vaccine (tetanus, diphtheria and pertussis) and the meningitis vaccine. But the two-dose vaccine-;the second dose is given six to 12 months after the first-;can be given to children as young as nine. Teens older than 15 and men and women need three doses of the vaccine to develop an immunity against HPV.

“Pre-teens have a more robust response to the vaccine and generate enough antibodies to protect against HPV after two immunizations, whereas older kids and adults need three doses to get the same immune response,” said Truehart. Another reason not to delay getting the HPV vaccine: an older teen may not want to wait six months or more to be fully immunized against HPV once he or she is on the verge of becoming sexually active. “It’s important for kids to be immunized before they are exposed to HPV,” Truehart said.

Not just for girls
When the U.S. Food and Drug Administration approved the HPV vaccine in 2006, it was recommended for girls and women to protect against cervical cancer. Three years later, the vaccine was approved for boys and men, based on evidence that males are also susceptible to HPV-related cancers. “Cancers caused by HPV affect women and men in equal numbers,” said Loberg. “Each year, there are approximately 10,800 cases of cervical cancer diagnosed in women, and 9,600 cases of head and neck cancer diagnosed in men.” And while there is a screening test for cervical cancer to catch and treat it early, there are no such screening tests for any of the other HPV-related cancers. And because most HPV infections are asymptomatic, people may be unwittingly transmitting the infection to their sexual partners.

HPV also causes genital warts which, although not harmful in most people, can be embarrassing and unsightly. In some cases, however, genital warts can be extremely painful and may even require surgery to remove them. For people with autoimmune disorders or who take medications that compromise their immune system, genital warts can be very difficult to manage, said Loberg. Out of more than 150 strains of HPV, the vaccine targets the most prevalent and harmful ones: two strains that cause genital warts and seven strains that cause various types of cancer.

No serious side effects
Despite HPV being the most common sexually transmitted infection, HPV-related cancers are relatively uncommon because in about 90% of people exposed to HPV, their immune systems clear the virus from their bodies before it causes cancer or precancer. “But we don’t know which individuals will develop a persistent infection, so why take that gamble when cancer can be the consequence?” said Loberg.

When parents ask whether the HPV vaccine is safe, Loberg’s ready answer is that “it’s incredibly safe.” More than 270 million doses of the HPV vaccine have been distributed worldwide since 2006, and there have been no serious side effects. One study that examined data from more than 56 million doses of HPV vaccine administered in the U.S. found that some girls became dizzy or fainted 15 minutes after receiving the vaccine. “That is the only side effect that we see,” other than mild side effects typical of other vaccines, such as fever, headache, and pain and redness at the injection site, said Loberg.

Pediatricians and primary care providers should be recommending the HPV vaccine for children, but if not, parents should bring it up.

“There is absolutely no downside to getting the HPV vaccine, and the upside is preventing your child from getting a deadly or disfiguring cancer,” she said.

January, 2020|Oral Cancer News|
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How Marijuana Accelerates Growth of HPV-related Head and Neck Cancer Identified

University of California San Diego School of Medicine researchers have identified the molecular mechanism activated by the presence of tetrahydrocannabinol (THC) — the ingredient that causes people to feel the euphoria or “high” associated with cannabis — in the bloodstream that accelerates cancer growth in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma.

“HPV-related head and neck cancer is one of the fastest growing cancers in the United States. While at the same time, exposure to marijuana is accelerating. This is a huge public health problem,” said Joseph A. Califano III, MD, senior author and professor and vice chief of the Division of Otolaryngology in the Department of Surgery at UC San Diego School of Medicine.

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide. These cancers begin in the cells that line the mucous membranes inside the mouth, nose and throat. Approximately 30 percent of cases of this disease are related to HPV infection, and it is these cases, in particular that are on the rise. Califano suggested increased marijuana use may be a driving factor.

Previous studies have linked daily marijuana exposure to an increased prevalence of HPV-related throat cancer. However, a mechanism linking cannabis exposure to increased growth of the cancer was unknown.

Reporting in the January 13, 2020 online edition of Clinical Cancer Research, a journal of the American Association for Cancer Research, researchers outline how the presence of THC in the bloodstream activates the p38 MAPK pathway, which controls programed cell death called apoptosis. When activated, p38 MAPK prevents apoptosis from occurring, thus allowing cancer cells to grow uncontrollably.

Working with Chao Liu, MD, visiting scientist at UC San Diego and a physician at China’s Central South University, and other colleagues, Califano and team used animal and human cell lines to show that THC turns p38 MAPK on and were able to stop the growth of HPV-positive head and neck cancer by turning off the pathway.

The team then analyzed blood samples from patients with HPV-related throat cancer who had their genomes comprehensively mapped to define activated gene pathways. Similar to the cell lines, the blood samples showed p38 MAPK activation and loss of apoptosis in tumors from patients with THC in their blood.

The authors said studies and public opinion suggestions that THC and other cannabis products have cancer-fighting properties need additional, more critical evaluation. Past studies showing anticancer effects of THC and other cannabinoids often used levels of THC higher than those found with recreational use, but doses used recreationally clearly activate a cancer-causing pathway, said Califano.

“We now have convincing scientific evidence that daily marijuana use can drive tumor growth in HPV-related head and neck cancer,” said Califano. “Marijuana and other cannabis products are often considered benign, but it is important to note that all drugs that have benefits can also have drawbacks. This is a cautionary tale.”

According to the Centers for Disease Control and Prevention (CDC), HPV infections are responsible for approximately 35,000 new cancer diagnoses each year in the United States. Infection is so common that nearly all men and women will get at least one type of HPV at some point in their lives. Most clear up on their own, without the person ever knowing they’ve had it.

Several vaccines are available that can prevent the majority of HPV-related cancers. The vaccines work best when they are given before a person is exposed to the virus. The CDC recommends vaccinating boys and girls age 11 to 12 years old but it can be administered as early as age 9.

According to the National Institute on Drug Abuse, 15 percent of youth 12 to 17 years old and 47 percent of adults age 26 and older have used or tried marijuana.

Together, a low HPV vaccination rate and an increase in marijuana use among youth has the makings of a storm, said Califano, physician-in-chief and director of the Head and Neck Cancer Center at Moores Cancer Center at UC San Diego Health.

Moores Cancer Center is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers in the country and the only such center in San Diego County.

Treatment options for patients with early- or late-stage head and neck cancers include minimally invasive surgery, reconstruction and rehabilitation, proton therapy and other radiation therapy, innovative clinical trials and targeted therapy, including immunotherapy.

The Head and Neck Cancer Center provides comprehensive care that includes counseling, education and support groups, nutrition, dental rehabilitation, speech and language therapy and social workers to help patients through every step of the process beginning with diagnosis to support lifelong wellness.

Califano and team are now looking at whether cannabidiol, or CBD, has a similar effect to THC. CBD is another major chemical compound found in marijuana, but does not produce the “high” and is now commonly used in various over-the-counter products, such as lotions, ointments and edibles.

In addition, the team is investigating whether p38 MAPK can be targeted with drugs to stop HPV-related head and neck cancer from growing.

Co-authors include: Chao Liu, Sayed Sadat, Koji Ebisumoto, Akihiro Sakai, Bharat Panuganti, Shuling Ren, Yusuke Goto, Sunny Haft, Takahito Fukusumi, Mizuo Ando, Yuki Saito, Pablo Tamayo, Huwate Yeerna, William Kim, Jacqueline Hubbard, Andrew Sharabi and J. Silvio Gutkind from UC San Diego; and Theresa Guo from Johns Hopkins Medical Institutions.

Funding for this research came, in part, from the National Institute of Dental and Craniofacial Research and National Institute of Health (R01 DE023347, U01CA217885, R01HG009285, R01CA121941 and P30CA023100).

January, 2020|Oral Cancer News|
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Cervical pre-cancer rates down 88% in decade since HPV vaccinations began – first findings

Source: The Conversation
Date: April 19, 2019
Author: Kevin Polluck

Cervical cancer is the third most common cancer among women in the UK under the age of 35 after breast and skin cancer. In the majority of cases, the cancer only develops if the patient is infected with human papillomavirus (HPV) types 16 or 18. This virus is mainly transmitted between people having vaginal, anal or oral sex. At some point in their lives, four in five people will be infected by HPV strains – as many as 14 can cause cancer in total. According to recent studies, other cancers heavily linked to HPV infections include head-and-neck, vulvo-vaginal and anal.

In an effort to reduce rates of cervical cancer, a number of countries launched immunisation programmes in the late 2000s, starting with Australia in 2006. The UK and its devolved governments launched a school immunisation programme in 2008 to vaccinate all girls aged 12-13. To speed up the time lag associated with achieving the benefits of vaccination, they also kicked off a three-year catch-up programme for girls aged up to 18 years.

A decade on, we are finally able to publish the first results. The data relates to Scotland, since it was cervically screening women from the age of 20 until 2016 – before falling into line with the minimum age of 25 used in the rest of the UK. This meant that Scotland obtained screening data for the 2008-09 cohort before the change in screening age. Scotland also has very detailed information about take-up rates, which have been very high: running to approximately 90% in Scotland for the routinely vaccinated girls and 65% for the older girls vaccinated as part of the catch-up programme.

For the first time, we can now confirm that the vaccination programme has begun to profoundly alter the prevalence of HPV 16 and 18 among Scottish women – and presumably elsewhere as well.

The study

My team performed an eight-year study of the women eligible for the Scottish national vaccination and cervical screening programmes. We looked at their vaccination status, year of birth, indicators of deprivation and whether they lived in urban or rural areas. Using complex statistical modelling, we were able to calculate the effect of vaccination on cervical pre-cancer. Though not all pre-cancer becomes cancer, all cancer requires pre-cancer. Cervical pre-cancer occurs quicker than cancer and therefore this focus has allowed us to see the impact of the vaccine earlier.

Among women born in 1995-96 – the first group to go through the regular vaccination programme in 2008/09 – there has been an 88% reduction in rates of cervical pre-cancer. This is a fall in incidence from 1.44% to 0.17%.

Not only that, women born in these years who had not received the vaccine were also less likely to develop cervical pre-cancer. This was because the high vaccine uptake meant that HPV incidence was much lower in their age group, thanks to a phenomenon known as “herd protection”. This is particularly good news, since this group is also less likely to attend cervical screenings.

The findings clearly show that the routine HPV vaccination programme for girls aged 12 to 13 has been a resounding success. This is consistent with the fact that we have also seen a big fall in high-risk HPV infection in Scotland in recent years. The obvious conclusion is that we are going to see far fewer cases of cervical cancer in years to come.

From September, the UK is going to extend the vaccination programme to boys – becoming one of numerous countries to do so. This is in response to the fact that rates of head and neck cancer are rising in men: approximately 60% of head and neck cancer is associated with HPV16 infection, and should therefore be mostly preventable through vaccination. This programme should also mean that high-risk HPV infections among the population should be eliminated more quickly, which should have knock-on benefits for rates of HPV-driven cancers.

Meanwhile, in parts of Canada, HPV vaccinations are now being offered to uninfected women as part of the cervical screening process. This may protect older women from developing cervical cancer. This process may be adopted internationally, including the UK. When we look at the picture as a whole, eliminating the HPV virus, and making huge inroads into the various cancers that it helps develop, is now becoming a realistic possibility.

 

 

January, 2020|Oral Cancer News|
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Single dose of HPV vaccine may be as effective as three

Source: www.laboratoryequipment.com
Author: Michelle Taylor, Editor-in-Chief

More than a decade after the introduction of a vaccine that has been proven to stave off 90 percent of human papillomavirus-caused cancers, only half of U.S. adolescents have completed the 3-shot series. While part of that can be attributed to adolescents and adults who question the validity of the vaccine, the majority is due to unawareness of or forgetting the need for additional doses, lack of insurance and non-frequent contact with the medical system.

But, a new study from researchers at the University of Texas Health Science Center at Houston, has revealed a single-dose regimen may be equally as effective as the current 2- to 3-dose system.

“Ensuring boys and girls receive their first dose is a big challenge in several countries and a majority of adolescents are not able to complete the recommended series due to a lack of intensive infrastructure needed to administer two or three doses,” said the paper’s senior author Ashish Deshmukh, assistant professor at UTHealth School of Public Health. “If ongoing clinical trials provide evidence regarding sustained benefits of a one-dose regimen, then implications of single-dose strategy could be substantial for reducing the burden of these cancers globally.”

Deshmukh’s study examined the difference in the prevalence of HPV infection in a total of 1620 women aged 18 to 26 of whom 1,004 were unvaccinated, 616 received at least 1 dose of HPV vaccine 106 received just 1 dose, 126 received 2 doses and 384 received 3 doses.

Compared with unvaccinated women who had a HPV infection (4-valent vaccine types [6,11,16 and 18]) prevalence of 12.5%, women who received at least one dose showed significantly less prevalence—2.4% for women with 1 dose, 5.1% for those with 2 doses and 3.1% for those who received all 3 doses.

According to the paper recently published in JAMA Network Open, there was no significant difference in prevalence for 1 dose versus 2 doses or 1 dose versus 3 doses. Additionally, differences were not statistically significant for cross protection (HPV types 31, 33, and 45), and other high-risk HPV types (HPV types 35, 39, 51, 52, 56, 58, 59, and 68).

Using a multivariable logistic regression model, the authors predicted the probability of HPV infection (types 6, 11, 16, 18) to be higher in unvaccinated women (7.4%) compared with women who received 1 dose (2.3%), 2 doses (5.7), or 3 doses (3.1%).

According to the CDC, 34,800 new cancer diagnoses are linked to human papillomavirus (HPV) annually. The virus is thought to account for more than 90% of all cervical and anal cancers, more than 60% of all penile cancers, and approximately 70% of all oral cancers. While the study authors stressed it is too early for people to rely on a single dose for protection against these cancers, they are encouraged by the results of their research.

“The current HPV vaccine dosing regimen can be cumbersome for people to understand. If one dose is proven effective in trials, the vaccine regimen will be simplified,” said lead author Kalyani Sonawane, also an assistant professor at UTHealth School of Public Health. “This will help improve the coverage rate among adolescents that are currently below the Healthy People 2020 goal and possibly will also increase the momentum of uptake in the newly approved age group.”

January, 2020|Oral Cancer News|
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Test that looks at your spit to tell if you have mouth or throat cancer caused by HPV ‘could save thousands of lives if rolled out for doctors to use’

Source: www.dailymail.co.uk
Author: Connor Boyd, Health Reporter

A saliva test that diagnoses mouth and throat cancer caused by HPV could save thousands of lives each year, a study suggests. Scientists at Duke University in North Carolina discovered the test was 80 per cent accurate at spotting the killer diseases.

Doctors say it is able to detect the cancers early on, giving patients much higher hopes of surviving their battle. Before it can be used in hospitals around the world, further trials will be needed to confirm the technology works. But the researchers are hopeful, claiming the cheaper test – which gives results in as little as 10 minutes – has significant ‘potential’.

Rates of oral cancers are soaring in the Western world, with the number of patients diagnosed in the UK having doubled in a generation. US doctors have also seen a similar spike in the diseases, which can be caused by human papilloma virus (HPV).

The infection – spread through oral sex, as well as anal and vaginal intercourse – is thought to cause around 70 per cent of all cases. Other risk factors include drinking excessive amounts of alcohol over long periods of time and smoking cigarettes.

Professor Tony Jun Huang, study co-author, said there are around 115,000 cases of oropharyngeal cancers each year across the world. He said it is ‘one of the fastest-rising cancers in Western countries due to increasing HPV-related incidence, especially in younger patients’.

Orophayngeal cancer starts in the oropharynx, the back of the throat which includes the base of the tongue and tonsils. It sits under the branch of head and neck cancers, which also includes mouth cancer – another type that can be caused by HPV. Detecting the disease early can boost survival odds from 50 per cent to 90 per cent, according to the NHS. But patients are often not diagnosed until they become advanced, partly because their location makes them difficult to see during routine clinical exams.

The new test uses a chip developed to isolate tiny micro-particles, known as exosomes, in saliva.These particles are secreted into body fluids and several types of cancers are known to multiply their numbers. Exosomes are responsible for transferring molecules between cancer and various cells.

The new test isolates them by filtering out larger particles in the saliva and probing the exosomes for DNA shed by tumours. It also scans fluid in the mouth for HPV-16, one strain of the STI that can put people at risk of oropharyngeal cancer. The test takes five minutes to conduct and a further five to process the results. Experts also said it is cheap – but did not elaborate on the cost. In comparison, current biopsies take around eight hours because they need to be sent away to be assessed by a surgeon.

Professor Huang said: ‘It is paramount that surveillance methods are developed to improve early detection and outcomes.’ He added the successful detection of HPV from saliva ‘offers advantages including early detection, risk assessment, and screening’.

The test was a collaboration between Duke University, the University of California and University of Birmingham in Britain.

Orophayngeal cancer killed 2,722 Britons last year and took the lives of 9,750 people in the US, figures show. New cases of the disease in the UK have risen to 8,302 a year, a jump of 135 per cent compared with 20 years’ ago.

According to the researchers, this technology can also be used to analyse blood, urine, and plasma. The findings were published in the Journal of Molecular Diagnostics.

The Oral Health Foundation last month urged people to wise up to the causes of the ‘devastating’ disease, mainly HPV and alcohol. Dr Nigel Carter OBE, chief executive of the OHF, said: ‘While most cancers are on the decrease, cases of mouth cancer continue to rise at an alarming rate.

‘Traditional causes like smoking and drinking alcohol to excess are quickly being caught by emerging risk factors like the human papillomavirus (HPV).

‘We have seen first-hand the devastating affect mouth cancer can have on a person’s life.’

December, 2019|Oral Cancer News|
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How the ADA Oral Cancer Policy Amendment Will Affect Your Practice

Source: Dentistry Today
Date: November 29th, 2019
Author: Jo-Anne Jones

The ADA recently announced an expansion to its policy on oral cancer detection recommending that dentists and dental hygienists perform routine examinations for oral cancer includingoropharyngeal cancer for all patients.

Passed by the ADA House of Delegates in September, this change was brought about to align with concerns from the Centers for Disease Control and Prevention (CDC) over the escalating numbers of diagnosed cases of oropharyngeal cancer linked to the human papillomavirus (HPV).

While HPV-related oropharyngeal cancer has risen by 225% over the past two decades, oral cancer linked to the historical etiologic pathways of tobacco and alcohol use has declined by 50%. The ADA’s policy also aligns with support for the HPV vaccine, as 70% of oropharyngeal cancers in the United States are related to HPV, according to the CDC.

Dentists and dental hygienists play a critical role in opportunistic screening on all adult patients despite whether they possess the historical risk factors of using tobacco products or alcohol. There is a distinct knowledge gap in today’s population to fully understand that a non-smoker and non-drinker may in fact be at risk for oral and oropharyngeal cancer due to HPV.

It is our responsibility to educate our dental patients about all of the risk factors that exist for both oral and oropharyngeal cancer. Now more than ever, it is critically important to extend our screening practices, both visual and tactile, to every adult in the practice on an annual basis.

Only about a third of adults in the United States report being screened for oral cancer, representing a strong disconnect in our ability to improve earlier discovery rates and improve treatment outcomes.

As dental professionals, it is critical that we elevate our understanding of the escalating profile of HPV-related oropharyngeal cancer. Researchers once predicted that cases of HPV-related oropharyngeal cancer would surpass the leading HPV-related cervical cancer by 2020. Yet recent data from national registries has now confirmed that HPV-related oropharyngeal cancer became the leading HPV-associated cancer in 2015.

How common is HPV-related oropharyngeal cancer? About 53,000 Americans will be diagnosed with oral and oropharyngeal cancer this year. Close to 20,000 of those cases will occur in the oropharyngeal area, with 70% related to HPV.

The CDC also reports that HPV is so common that almost all sexually active adults will have an infection in their lifetimes, with most of the population clearing the infection with no repercussions. In contrast, a persistent infection with a high-risk strain such as HPV-16 can transform into oral or oropharyngeal cancer.

This transformation may take anywhere between 15 and 30 years. It seems to be targeting a much younger profile of white, non-smoking males age 35 to 55 with a four-to-one incidence of gender predisposition of males over females.

HPV has an affinity for lymphoid tissues and occurs most commonly in the tonsillar areas and the base of the tongue, with a smaller percentage occurring anteriorly in the oral cavity. Due to limited visual acuity, it is important to know and recognize the subtle symptoms that may accompany a posteriorly positioned tumor of HPV origin.

The following symptoms may be among the first distinguishable signs of the presence of oropharyngeal cancer:

  • Bleeding in the mouth or throat
  • Hoarseness or a change in the voice
  • A lump in the throat or the feeling that something is stuck in the throat
  • Continual lymphadenopathy or persistent neck masses despite antibiotic therapy
  • Slurred speech or difficulty articulating certain sounds
  • A tongue that tracks to one side when stuck out
  • Asymmetry in the tonsillar area
  • A persistent or recurring throat infection that doesn’t fully resolve with antibiotics
  • Unilateral earache
  • A persistent cough

Oral cancer can be very subtle, so it is extremely important to use magnification such as loupes and a dedicated light source or headlight to be able to discern early visible changes. The paradox that exists is that abnormal cellular differentiation typically starts at the basement membrane. By the time it becomes visible, it has progressed to a later stage of development.

Tactile palpation is paramount in uncovering any areas of hardness or induration possibly suggesting a mass or a tumor that is not yet clinically visible.

Enhanced oral cancer screening with a device such as the VELscope Vx from Apteryx Imaging may reveal what is not visible to the naked eye. It employs direct fluorescence visualization, which has been used successfully in the cervix, lungs, and colon. Using a proprietary wavelength, it gives clinicians the opportunity to visually penetrate the tissue surface to reveal the basement membrane.

The VELscope Vx is an assessment tool, however, and it does not convey a diagnosis. The golden rule always applies. Any oral abnormality that exists beyond 14 days is suspect and requires referral for further evaluation.

The Oral Cancer Foundation offers comprehensive information to help healthcare professionals and the general public to learn more about HPV’s connection with oral and oropharyngeal cancer. In April of 2019, the group launched the “Check Your Mouth” campaign to educate the public about the importance of self-examination of the oral cavity between dental appointments.

The impetus behind this project was to improve earlier discovery rates by having the public self-refer should they find anything new or abnormal that persists beyond 14 days. Cards may be ordered free of charge from the Oral Cancer Foundation store for distribution to dental patients.

Lastly, sharing information regarding the HPV vaccine is one of the strongest prevention methods we have today to make positive inroads in minimizing this type of cancer. The Food and Drug Administration has approved the HPV vaccine for both boys and girls and expanded the use of Gardasil 9 to include individuals age 27 through 45.

Together, we can have an impact on the earlier discovery of oral and oropharyngeal cancer.

Disclosure: Jo-Anne Jones is a KOL and consultant with Apteryx Imaging.

Ms. Jones is the president of RDH Connection, an educational and clinical training company dedicated to quality education and team training. In the midst of preparing to present her extensive research on HPV-related oropharyngeal cancer to her national association, a loved one was diagnosed with late stage HPV-positive tonsillar cancer and lost her life 16 months later. Jo-Anne proudly partners with the Oral Cancer Foundation in conveying the urgent need for changing the way in which we screen for oral cancer to meet the needs of today’s population. She can be reached at jjones@jo-annejones.com.

December, 2019|OCF In The News, Oral Cancer News|
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Late stage head and neck cancer in the U.S. sees increasing incidence

Source: www.cancernetwork.com
Author: Hannah Slater

A study released in Cancer indicates that there is an increasing incidence of late stage head and neck cancer (HNC) in the U.S., mostly due to an increasing incidence of oropharyngeal cancer, most likely due to HPV-related disease in patients diagnosed at stage IVC.1

Blacks, males, those who are underinsured or uninsured, and those who are unmarried tend to fare worse than others. The presented research highlights the need for continuous public health efforts toward the early detection of HNC.

In this cohort of 57,118 patients with stage IV HNC, the age-adjusted rates for stage IV HNC significantly increased by 26.1% (6.11 per 100,000 person-years in 2004 to 7.70 per 100,000 person-years in 2015). Despite a decreasing overall incidence of stage IV HNC in black patients (adjusted OR, 1.28; 95% CI, 1.22-1.34), they along with males (adjusted OR, 3.95; 95% CI, 3.80-4.11) had significantly increased risks of being diagnosed with late-stage HNC.

“In the absence of a mortality benefit for asymptomatic mass screenings, as per the U.S. Preventive Services Task Force oral cancer screening guideline, it is critical that there is sustained public awareness and education regarding the early detection of HNC, and prevention through cancer risk mitigation practices,” the researchers wrote.

Although black males had the highest risk of being diagnosed, the most significant change in annual incidence patterns was driven by white males (annual percent changes, 3.13; P < .01). A significant increase in incidence occurred in the population >50 years, with males tending to be younger at the time of diagnosis than females.

Of all primary tumor sites, the oropharynx was the most likely site for a late-stage diagnosis. The incidence of oropharyngeal cancer has increased dramatically in the U.S. within the last 40 years and is predominantly experienced by white males. Approximately 75% of cases of oropharyngeal cancer are associated with human papillomavirus (HPV), and these tumors often present with small primary tumors and larger cystic regional lymph node metastases as the first notable symptom.

Although patients with oropharyngeal cancer typically have a better prognosis, they also remain at risk of having positive lymph nodes and developing distant metastasis. Research indicated that the oropharynx, an HPV-related site, was the only site to experience a significant increase in the incidence of metastatic stage IV disease.

“If rates of true late-stage HNC continue to rise, it remains paramount to identify those patients who are at risk of potentially worse prognoses when HPV status is unknown,” the researchers wrote.

Stage IV was defined using the American Joint Committee on Cancer (AJCC) sixth edition stage classification as stages IVA, IVB, IVC, and IV not otherwise specified. With recent changes in AJCC staging, future studies are warranted to describe incidence trends based on new staging guidelines.

According to the CDC, HPV is so common that nearly all sexually active men and women get the virus at some point in their lives. Oropharyngeal cancers have traditionally been caused by tobacco and alcohol; however recent studies have suggested that about 70% of cancers of the oropharynx may be linked to HPV.2

References:
1. Thompson-Harvey A, Yetukuri M, Hansen AR, et al. Rising Incidence of Late-Stage Head and Neck Cancer in the United States. Cancer. doi:10.1002/cncr.32583.
2. CDC. Human Papillomavirus (HPV) Statistics. CDC website. cdc.gov/std/hpv/stats.htm. Published January 4, 2017. Accessed November 21, 2019.

November, 2019|Oral Cancer News|
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