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FDA approves Gardasil 9, the HPV vaccine, to prevent head-and-neck cancer

For the past decade, evidence has suggested that Gardasil, the HPV vaccine, could stem an epidemic of throat cancer. But it has also never received approval from the Food and Drug Administration for that use — and it was unclear if it ever would.

On Friday, the agency granted that approval, clearing the latest version of the vaccine, Gardasil 9, to prevent a cancer that affects 13,500 Americans annually. The decision was announced by Gardasil’s maker, Merck.

The decision doesn’t change recommendations about who should get the vaccine, which is already recommended for females and males ages 9 through 45 to prevent cervical, vulvar, vaginal, and anal cancer as well as genital warts. But cancers of the head and neck — mainly those of the tonsils and throat — have been left off the list.

It’s a striking omission, because head and neck cancer, mostly cancer of the throat, is the most common malignancy caused by HPV, the human papilloma virus, in the U.S. According to the Centers for Disease Control and Prevention, there are 35,000 cases of HPV-related cancer in the U.S. annually. On top of the 13,500 cases in the throat, 10,900 are cases of cervical cancer.

“That’s excellent news,” said Stewart Lyman, a pharmaceutical consultant whose doctors discovered a tumor in his throat in 2016. It was removed surgically, and was caused by HPV. “To have this extended to head and neck cancer is really very helpful for helping to inform the public that this serious disease, which has significant morbidity and mortality associated with it, can be prevented with the vaccine,” Lyman said.

Marshall Posner, the director of head and neck medical oncology at the Tisch Cancer Institute, said the approval is “a good thing for the FDA to do” and that he would be “thrilled” if head and neck cancer cases could be reduced through vaccination in coming decades. He said he has “every expectation” that an HPV vaccine would reduce cancer rates.

The original version of the Gardasil vaccine was approved in 2006 for girls and women between the ages of 9 and 26 based on data from clinical trials showing that the vaccine, by preventing HPV infection, could also prevent precancerous cervical lesions. But such lesions don’t exist in head and neck cancer, and it was not clear how to prove the vaccine’s efficacy.

Maura Gillison, now a professor at M.D. Anderson Cancer Center, first connected a subset of head-and-neck cancers to HPV in 1999. But then she and other epidemiologists noticed something: The number of head and neck cancers was rising rapidly, and HPV seemed to be a culprit. What’s more, these sexually transmitted cases seemed different — and somewhat easier to treat. The most common victims were middle-aged men who had contracted the virus decades before.

The FDA is granting what’s known as an accelerated approval, meaning that the decision is contingent on the production of more data and is based on what’s known as a “surrogate endpoint” — an indication that a medicine works that is not foolproof. In this case, the FDA is approving the drug based on data on preventing anogenital infection. In February, Merck began a study of  6,000 men that will test whether patients who receive the vaccine are less likely to get persistent HPV infections in their throats.

Adding another disease to the approval does impact what Merck can say to doctors and patients about HPV and head and neck cancer. “It’s something that was missing in the label,” said Alain Luxembourg, director, clinical research, Merck Research Laboratories. “It is something missing in the conversation between patients and doctors.”

Otis Brawley, an oncology and epidemiology professor at Johns Hopkins University, said that while he is usually opposed to surrogate endpoints, in this case he is comfortable with the decision. “There’s already enough reasons to vaccinate for HPV in men,” he said, adding that doing so broadly might make it possible to eradicate the virus, and the cancers it causes.

For Gillison, who spotted the emergence of HPV throat cancer, it came too late. She pushed Merck to do a study, and said that the one that started in February is coming “10 years plus after when it would have really mattered.” She also thinks that the real reason for the decision is the weight of epidemiologic evidence that she and others produced.

“The fact of the matter is that this approval probably has little whatsoever to do with the anal data per se,” Gillison wrote via text message. “It is because the FDA is made more comfortable with inference because of all the data that has been generated regarding the relationship between oral HPV infection and HPV vaccination outside of vaccine trials in the last 10 years.”

June, 2020|Oral Cancer News|

Deintensification of Treatment in HPV-Associated Cancers Holds Promise, But With Caveats

Source: Targeted Oncology
Date: May 17th, 2020
Author: Tony Berberabe

 

De-escalating therapy has the potential to dramatically reshape the treatment of patients with HPV-associated oropharyngeal cancers, but only if a number of key trials come back with positive long-term data with 3 cycles of cisplatin at 100 mg/m2 times 3, given every 3 weeks, Sue Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology-Head and Neck Surgery atthe University of California, San Francisco, said in an interview with Targeted Therapies in Oncology (TTO).

Sure, there were some minor variations over the years, small alterations made on a case-by-case basis. “But long story short, that’s fundamentally what was happening: 70 Gy with 3 cycles of high-dose cisplatin,” Yom said. The story began to change a little over a decade ago, with the introduction of a variable that could potentially change the course of therapy for a large percentage of patients with head and neck cancers. Today, the operative word remains potentially.

In 2008, Maura L. Gillison, MD, PhD, of Johns Hopkins University, and colleagues found that whether head and neck squamous cell carcinoma tumors were associated with the human papillomavirus (HPV) turned out to be a major prognostic indicator.1

“When that finally came to be reported, there was a very, very striking result,” said Barbara Burtness, MD, a professor of medicine (medical oncology), Disease-Aligned Research Team leader of the Head and Neck Cancers Program, and coleader of Developmental Therapeutics at Yale Cancer Center in New Haven, Connecticut Patients with HPV-associated stage III or IV head and neck squamous cell carcinoma of the oropharynx or larynx had a 2-year overall survival (OS) rate of 95% versus 62% for patients with HPV-negative tumors.

Two years later, Gillison collaborated with K. Kian Ang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston and published the results of a study in oropharyngeal cancer (NCT00047008), which again found that HPV made a difference in terms of survival.2

Patients with HPV-positive tumors had better OS and progression-free survival (PFS) than patients who were HPV negative (P<.001 for both comparisons). Ang and colleagues reported that the 3-year OS rate was 82.4% (95% CI, 77.2%-87.6%) in patients who were HPV positive compared with 57.1% (95% CI, 48.1%-66.1%) in those who were HPV negative. Similarly, the 3-year PFS rate favored the HPV-positive group, at 73.7% (95% CI, 67.7%-79.8%) versus 43.4% (95% CI, 34.4%-52.4%) for the HPV-negative group (TABLE 1).2

The 3-year absolute benefit of HPV-positive status for OS was 25% (95% CI, 11%-40%), and the absolute benefit for PFS was 30% (95% CI, 15%-45%).

The results were similar with stratification according to p16 expression status. The 3-year rates of OS were 83.6% (95%CI,78.7%-88.6%) in the subgroup that was positive for p16 expression and 51.3% (95% CI, 41.5%-61.0%) in the subgroup that was negative (P<.001). Three-year PFS rates were 74.4% (95% CI, 68.5%-80.2%) and 38.4% (95% CI, 28.9%-47.9%), respectively (P<.001) (TABLE 2).

The study also found that the number of pack-years an individual smoked had a substantialnegative impact on prognosis.

These findings raised serious questions because the current standard of care, unchanged from that described by Yom, can have a profound effect on the life of a patient who survives the cancer. “The after- effects of that dose of radiation are quite real, and they include chronic pain, chronic swallowing difficulties, dry mouth, and dental complications,” Burtness said.

“We are concerned that these patients may be at higher risk for death from the late effects of the treatment.”

Moreover, patients with HPV-associated cancers tended to be younger at diagnosis than those with non-HPV cancers. Patients who develop the cancer in their 50s might have decades of life left—plenty of time for the long-term adverse effects (AEs) of aggressive treatment to show up.

The issue is pressing because HPV-associated cancers represent about 7 in 10 cases of oropharyngeal cancer.3 The most recent statistics from the Centers for Diseases Control & Prevention suggests that 3500 new cases of HPV-associated oropharyngeal cancers are diagnosed in women versus 15,500 diagnosed in men (FIGURE 1).4

Cherie-Ann O. Nathan, MD, chairman of the Department of Otolaryngology–Head and Neck Surgeryat Louisiana State University Health Shreveport, said the new findings underscored the need for more research. “We need to start to look at de-escalating for that low-risk group,” she said.

De-escalation Strategies

Deciding that different strategies might be warranted and choosingwhich approaches make the most sense are 2 different considerations, and both come with difficult questions. Burtness said it can be a challenge just to figure out how to tackle the question.

I think, first of all, it’s challenging to do deintensification trials because they require very large sample sizes, and you want to be sure you’re not deintensifying [treatment in] somebody who would be cured by the full treatment and wouldn’t be cured by the reduced regimen,” Burtness said.

For the most fortunate patients, the OS rate with the current standard of care is in the range of 90% to 95%, setting a high bar for its replacement, Yom said. “It’s a huge ethical and practical situation where you’re actually having to estimate: ‘What would it take to prove that this less intense alternative was as good?’” Yom said.

“Patients do get better with time,” Yom said. “After a year or 2, they can live very normal lives.It’s actually a great treatment in some ways, and 1 question is if we should even be messing with it.”

Another strategy is to reduce the dose or field of radiation. In Yom’s much-anticipated trial, NRG-HN002 (NCT02254278), 306 patients with p16-positive, non–smoking-associated, locoregionally advanced oropharyngeal cancer were stratified by unilateral or bilateral radiation and randomized into 2 groups.4 One group received 60 Gy of intensity-modulated radiation therapy (IMRT) for 6 weeks plus cisplatin (IMRT + C) at 40 mg/m2 weekly. The other group received 60 Gy of modestly accelerated IMRT alone for 5 weeks. The goal was to compare the arms in terms of 2-year PFS rates without unacceptable swallowing difficulty at 1 year. The IMRT + C group met the desired benchmarks; the IMRT alone group did not.

Although the study was just a phase II trial, Yom said the results were encouraging and will lead to further study.

Another strategy is to perform surgery up front, Nathan said. If the margins are negative and there is not a significant number of metastatic lymph nodes or significant extranodal extension, chemotherapy might be avoided. She said transoral surgery has become much more effective and precise in the age of robotics. A common site of lymph node involvement is the retropharyngeal region, shown in FIGURE 2.5

“When robotic surgery became popular and we were able to get margins on these tumors at the base of [the] tongue and tonsils, people started saying [that] for the HPV-associated [tumors], you don’t need the typical wide margins of 5 mm; you could get away with 3 mm,” she said.“ So, the whole purpose of transoral surgery was that after removing the tumor, you could de-escalate.”

Other research has tested the replacement of cisplatin with cetuximab (Erbitux), though one study found that the latter resulted in inferior OS.6

With the exception of the cetuximab strategy, the novel approaches have shown promise. However, Nathan said, clinicians should realize that these are all still hypotheses; there is much that is not yet known.

“Unfortunately, people look at all [these] retrospective data and small institutional trials and make [treatment] decisions, not realizing that it’s still not standard of care,” Nathan said. “It’s fine to de-escalate, but always de-escalate if you can on a clinical trial.”

Ongoing Research

A number of important ongoing trials have the potential to add significant scientific rigor to the debate. Among them is Eastern Cooperative Oncology Group’s ECOG-E3311 trial (NCT01898494), which is examining transoral surgery followed by low- or standard-dose radiation therapy with or without chemotherapy. Initial findings are expected to be presented at the 2020 American Society of Clinical Oncology Annual Meeting and the trial is expected to be completed in 2023. The PATHOS trial (NCT02215265), which is evaluating transoral resection followed by reduced-intensity radiotherapy with or without cisplatin, is expected to be completed in 2026.

Yom and colleagues are working on NRGHN005 (NCT03952585), a phase II/III study in which patients will undergo deintensified radiation therapy with cisplatin or the PD-1 inhibitor nivolumab (Opdivo) versus standard-of-care chemoradiation. The investigators used an innovative design so that the study will produce scientifically rigorous results for the 70 Gy versus 60 Gy question at the phase III level, even if the nivolumab phase II investigation does not meet its targeted end points, Yom told TTO.

In the meantime, Burtness said, the data are beginning tosuggest, if not conclusively, which types of patients might be a good fit for deintensification. “The omission of chemotherapyin the postoperative setting after transoral resection is probably better for patients with smaller nodes, maybe only 1 or 2 nodes,” she said. “The use of more induction chemotherapy and a lesser dose of radiation is better, obviously,for patients who are going to tolerate chemotherapy well. The omission of systemic chemotherapy and the use of immunotherapy may eventually [lead to the development of] a biomarker signature.”

She cautioned that it is not clear that all HPV-associated cancers should be treated the same way. Certain other factors appear to affect the opportunity for deintensification. “Repeatedly, we’ve seen [that] patients with T4 cancers don’t do well with deintensification,” she said. “Patients who’ve smoked more than 10 pack-years won’t do well.”

Burtness added that there is a good chance the end result of all the research will simply be that certain deintensification strategies are better for certain patient populations. Yom agreed. “One of our goals is to make deintensification acceptable within the standard of care,” she said. “But I’m not sure there’s going to be just 1 standard of care going forward.”

Even if these new strategies show equal or better success rates compared with the current standard ofcare, patients who undergo deintensified therapy might avoid the toxicities of more intense therapy at the cost of unexpected long-term AEs.

The 2 key takeaways from the study we put together are that, 1, there are a lot of different deintensification strategies, and in the short term, a lot of these different strategies don’t show any differences in outcomes or toxicity,” Patel said. “But the second point that is crucial is that longer-term follow-up is necessary for making judgments as to whether or not to do deintensified treatments.”

Nathan said 1 major concern is that patients with deintensified treatment regimens might facea higher risk of a subsequent cancer diagnosis. “HPV- associated cancers still have the same distant metastasis rate as HPV-negative cancers,” she said. “And the distant metastasis is occurring years later and sometimes in unusual locations.”

For example, lack of systemic therapy might not affect the current oropharyngeal tumor, but years later, could it lead to a cancer that might have been prevented? That type of question is impossible to answer at thispoint, andNathan says it is problematic to assume the answer is no.

Nathan also raised concerns about changes to the American Joint Commission on Cancer (AJCC) staging system. In the eighth edition of the AJCC Cancer Staging Manual, HPV-associated cancers were restaged because staging is generally meant to match prognoses, and HPV-associated cancers had been shown to have better prognoses, she said.The end result of the restaging, she said, is that some cancers previously deemed stage IV might now be reclassified as stage I or II. Nathan worries that the lower staging will result in even more deintensification because clinicians will not consider cases as serious as they once did, which would be a mistake, she said. “All the patients who did so well and have such good survival [in the existing de-escalation literature] were being treated like they were stage III or IV,” she said. “So, until you have the results of [ongoing clinical trials], you shouldn’t be doing it.”

Deintensification Today

Clearly, some level of deintensification is occurring withinclinics inthe United States.If itturnsout that 1 or more of the new, lower-intensity strategies is effective, the treatment paradigm for patients will be drastically different, Yom said:“To start talking about things like patient preferences and quality of life is foreign and different in oropharyngeal cancer.”

Patient preference is a key consideration,Patel said: “That’s why the data and being able to share with patients that these outcomes aren’t different at longer-term follow-ups is important.”

Different types of patients will likely favor different approaches, even if de-escalation is validated as a standard option, according to Yom. “I have patients who come to my clinic, and they’re like, ‘I have 2 kids. I’m staying alive. Hit me with everything you have,’” she said.

A large spectrum of Yom’s patient population is very highly educated about their cancers, she said, and that knowledge can inform the strategies they prefer. In many cases, education leads patients to be less concerned about mortality and more concerned about the impact of therapy on quality of life.

“There’s a large proportion of that population where their driving concern is this fear of long-term consequences,” she said.

Yom said radiation oncologists will need to better help patients, who until now had few treatment choices, think through their options. “We don’t have good structures and instruments to help people sort through the decision-making process ina way that makes sense to them,” she said. “I don’t think anybody does.”

Even if the data from the current trialsare positive, Nathan cautioned, the time horizon to evaluate outcomes must be longer than a few years. “Most of these trials are looking good, but follow-up is only about 3 to 4 years, she said. “A lot of our toxicities [that we have seen] have occurred 5 and 8 years later.”

That will require oncologists to be involved in decisions that might be thornier than those patients previously faced. “You’re going to have to be a much better oncologist,” Yom said.

Still, she and others say the challenge will be well worth it, but only if the ongoing scientific study findings support the optimism now shared by many in the field. “This deintensification movement will have huge implications [for] how the majority of patients with head and neck cancers will be treated in this country going forward,” Yom said.

May, 2020|Oral Cancer News|

An Occult HPV-Driven Oropharyngeal Squamous Cell Carcinoma Discovered Through a Saliva Test

Source: Frontiers in Oncology
Date: March 31st, 2020
Authors: Kai Dun Tang, Sarju Vasani, Touraj Taheri, Laurence J. Walsh, Brett G. M. Hughes, Lizbeth Kenny, and Chamindie Punyadeera

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.

Introduction

The incidence of high-risk human papillomavirus (HR-HPV−16,-18,-33) driven oropharyngeal cancer (OPC) is rapidly increasing in developed countries (13). HPV-driven OPCs have surpassed cervical cancer as the most common HPV-driven cancer in the USA. The prevalence of HR-HPV has been reported as 3.7% of the USA population, with a bimodal age distribution of incidence (4). It remains unclear why some individuals go on to develop OPC, while others clear the initial HPV infection (5). The strong association between HR-HPV infection and cervical cancer has led to screening programmes in primary healthcare settings, resulting in earlier diagnosis and a reduction in cancer deaths (6). Unlike cervical cancer, no screening test is available for OPC and current HPV vaccines have yet to demonstrate any reduction in future OPC development (7). Here, we report the first ever case of occult OPC detected as a direct result of a theoretical screening test—in this case HPV-16 DNA analysis in salivary oral rinse samples. Our clinical and pathological findings increase our understanding of both the natural history of the disease and the potential for wider screening to identify early stage OPC, facilitating less morbid treatments.

Cases Presentation

An ongoing HPV-16 DNA prevalence study was approved by institutional ethics committees from the University of Queensland; Queensland University of Technology and the Royal Brisbane and Women’s Hospital. A total of 665 cancer-free healthy individuals from Queensland Region, Australia between May 2016 and October 2017 were recruited. All participants gave written informed consent prior to sample collection.

Six hundred and fifty cancer-free healthy individuals with sufficient amount of DNA were tested for oral HPV-16 DNA. Of these 3 have been identified to have persistent oral HPV-16 DNA infection. Following discussion with our ethics team we have approached these three participants and offered them consultation with an Ear, Nose, and Throat (ENT) surgeon. A 63-year-old caucasian male was assessed as part of this consultation process. He had consistently been HPV-16 DNA positive for a period of 36 months, with a steadily rising HPV-16 viral load in his salivary oral rinse samples (Figure 1A). He was invited to attend the ENT clinic for assessment and discussion.

FIGURE 1
www.frontiersin.orgFigure 1. Occult oropharyngeal microcarcinoma detected based on a screening test through the serial measurements of salivary HPV-16 DNA. (A) HPV-16 DNA viral load in salivary oral rinse samples over time. B (Baseline); F1 (6 month follow-up); F2 (12 month follow-up); F3 (36 month follow-up); PT (2-week post-tonsillectomy). (B) Sections of the left tonsillar tissue found a 2 mm non-keratinising squamous cell carcinoma, with focal stromal invasion <1 mm, excised with clear margins. The remainder of the left tonsil showed follicular lymphoid hyperplasia. Hematoxylin-eosin (H&E x200) (C) HPV-16 DNA was only positive in left tonsillar tissue. (D) p16INK4a immunohistochemistry staining (IHC) x20: Diffuse positive brown staining for p16INK4a in tumor region comparing non-affected area in the left tonsil.

He is an ex-smoker, having quit 15 years ago, with a 45 pack year history of smoking. He drinks two standard drinks (2.5 units of alcohol) per day. He is heterosexual, and his social history includes multiple oral sex partners in the past (>5), followed by a long term monogamous relationship. Initial clinical examination of the oropharynx including palpation and white light revealed no significant abnormalities. Both tonsils were irregular due to mucous retention cysts and there was slight tonsillar asymmetry (Left < Right) but no evidence of any malignant lesions. Narrow band imaging (NBI) showed some mild vascular changes at the left glosso-tonsillar sulcus. There were no palpable lymph nodes in the neck. An MRI examination of the oropharynx and neck demonstrated no occult lesions of the tonsils or the base of tongue and no cervical lymphadenopathy.

He was offered continued surveillance, or a biopsy of the area of NBI change with bilateral tonsillectomy. The patient elected for bilateral tonsillectomy and biopsy of the base of tongue with NBI guidance under general anesthetic and informed consent was obtained. The surgical specimens were sent for histology and tissue HPV-16 DNA testing. The patient was discharged from hospital the same day. He had a routine postoperative course with a sore throat for 1 week and recovered fully. An ultrasound scan of his neck was performed 2 months post-surgery which showed no cervical lymphadenopathy. He is currently under routine oncological surveillance. The patient has a very high likelihood of cure with minimal morbidity from single modality treatment.

Clinical Specimens’ Collection and Processing

Salivary oral rinse samples of this individual were collected at baseline, 6, 12, 36 month, and 2 weeks after his bilateral tonsillectomy using previously published method (810). Briefly, participants were asked to swish and gargle for 1–2 min with 2 × 10 mL volumes of 0.9% saline, prior to expectorating the rinse sample into a 50 mL falcon tube. Tissue biopsies from the tonsil and base of tongue were obtained after surgical resection. All samples were immediately frozen on dry ice upon collection and transported back to the laboratory for subsequent processing.

HPV-16 DNA QPCR Analysis

Total DNA was extracted from salivary oral rinse and tonsillar tissue samples using the QIAmp DNA Mini Kit (Qiagen, Germantown, MD, USA) as per manufacturer’s protocol. For detection of HPV-16 genotyping, the qPCR assay targeting the opening reading frame (ORF) region of HPV16 E6/7 was carried out with the QuantStudio™ 7 Flex Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) as described previously (11, 12). For quantification of HPV-16 DNA viral copies in salivary oral rinse and tissue samples, a standard calibration curve was generated using qPCR by plotting threshold cycle (Ct values) against the logarithm of the copy number of 8-fold serially diluted (1 × 101-1 × 108 copies) of pHPV-16 plasmid DNA [American Type Culture Collection (ATCC)® 45113™].

Immunohistochemistry

H&E (Haemotoxylin and Eosin stains) staining on formalin-fixed paraffin-embedded (FFPE) slide was performed to investigate the cellular and tissue structure/morphology. HPV status was evaluated using CINtec® p16INK4a Histology Kit (E6H4 clone) (Roche MTM Laboratories, Heidelberg, Germany) according to manufacturer’s instructions. p16INK4a was considered positive by two independent pathologists when there was a strong, diffuse nuclear and cytoplasmic staining pattern in the majority (>70%) of tumor cells.

Salivary HPV-16 DNA as a Biomarker-Based Tool for HPV-Driven OPC Screening

Salivary oral rinse samples from this individual had been collected at baseline, 6, 12, and 36 month follow-up as well as 2 weeks after his bilateral tonsillectomy. HPV-16 DNA genotyping and viral loads in all samples were analyzed using an in-house developed qPCR assay. HPV-16 DNA viral load in saliva increased exponentially across the 36 month follow-up period (from 3.43 to 1,281.69 copies/50 ng) and subsequently declined to undetectable levels post-tonsillectomy (Figure 1A).

Histologically Confirmed Diagnosis of an Occult P16INK4A Positive OPC

This individual was diagnosed as having a 2 mm squamous cell carcinoma (T1N0M0) in the left tonsil (Figure 1B) using Haemotoxylin and Eosin (H&E) staining. He had only foci of stromal invasion with a depth of <1 mm. The remainder of the left tonsil showed follicular lymphoid hyperplasia. Further, HPV-16 DNA was only positive in left tonsillar tissue (Figure 1C). Immunohistochemistry (IHC) staining for p16INK4a demonstrated diffuse and strong staining in more than 70% of tumor cells (Figure 1D). However, the non-affected remainder of the left tonsil as well as the right tonsil were negative for p16INK4a with usual mosaic pattern of staining. The excision margins of the left tonsillar malignancy were widely clear. No atypia or malignancy could be identified in the right tonsil and bilateral tongue base specimens all of which were negative for HPV-16 DNA.

Discussion

Long-term persistence of HPV-16 infection is likely to be a prerequisite for the development of malignancy (13, 14). Women with persistent HPV-16 infection in the cervix for <1 year have a 40% risk of developing cervical intraepithelial neoplasia grade 2 or more within 3 years (13). Indeed, the natural history of HPV in the oropharynx from initial infection to carcinogenesis is not known with many questions remaining unanswered. Several studies have evaluated the prevalence of HPV-16 DNA in saliva (1518) without clinical assessment of positive individuals. Studies aimed at clinical assessment of those with persistence for premalignancy or microscopic carcinoma have failed to detect significant abnormalities (19). This has led to the assertion that screening for early occult or premalignant oropharyngeal lesions is not feasible. Here, we report the first ever histologically confirmed diagnosis of an asymptomatic occult OPC (T1N0M0) discovered by a theoretical screening test through the serial measurements of HPV-16 DNA in salivary oral rinse samples.

The impact of the pattern of salivary HPV persistence including changes in the absolute HPV viral DNA copies over time has never been investigated. The pattern of salivary HPV-DNA detection in this case demonstrates an exponential upward trend with the titer at first sample being 3.43 copies per 50 ng and the final titer before surgery of 1281.7 viral copies per 50 ng. This may represent progression of the lesion with subsequent shedding of increasing levels of HPV-16 DNA into the saliva. In future cases the presence of this pattern should be evaluated, as it may provide a critical marker for the progression of disease and hence a signal for intervention; indeed the pattern of viral copies in serial measurement may have more importance than the persistence itself.

This case also has important implications with regards to the natural history of the disease. The left tonsil was strongly positive for HPV 16 DNA outside the region of malignancy and as anticipated was p16INK4a positive only within carcinoma. This implies that the malignancy is likely to have developed in a wider field of HPV infection with only a component undergoing malignant change. The existence of a precursor lesion to OPC has long been doubted and is cited as one of the obstacles to OPC screening (16). This case demonstrates that very early lesions can be found in asymptomatic individual, and that they can potentially be eradicated with minimal morbidity.

The quest for a sensitive and specific screening test for HPV-driven OPC is of great importance. The uptake of HPV immunization in developed countries is variable and the developing world remains largely unimmunised. As sexual habits change in the developing world (20, 21) there is likely to be the same rapid expansion in this disease that we have witnessed in the United States and Europe and global burden will continue to rise. As the first singular case, this report does not act as direct evidence of the value of screening in a general population, however, it demonstrates a possible salivary screening test and pathway for the detection of microscopic OPC. It demonstrates that a screened individual can receive significantly less morbid treatment than would be required for the standard presentation at a more advanced stage. This report and previous studies (8, 11, 12, 22), support the value of a salivary oral rinse test as a potential screening tool. Unlike previously published work, our study is the first to demonstrate that continuous monitoring of HPV-16 DNA in salivary oral rinse samples can detect occult OPC.

Data Availability Statement

All datasets generated for this study are included in the article.

Ethics Statement

This study was approved by institutional ethics committees from the University of Queensland (UQ) [HREC No: 2014000679 and 2014000862]; Queensland University of Technology [HREC No: 1400000617 and 1400000641]; and the Royal Brisbane and Women’s Hospital (RBWH) [HREC/16/QRBW/447]. Written informed consent was obtained from this participant for publication of this case report.

Author Contributions

All authors have read and agree to the published version of the manuscript. KT and CP: conceptualization. All authors: methodology, validation, formal analysis, data curation, investigation, and writing—review and editing. KT, SV, and CP: writing—original draft preparation. CP: funding acquisition.

Funding

The prevalence study was funded by Janssen Biotech Inc.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We thank Dr. Gert Scheper from Janssen Vaccines & Prevention B.V. We would also like to thank Lilian Menezes for her assistance in the recruitment of study patient and collection of clinical samples.

 

May, 2020|Oral Cancer News|

John Prine, Who Chronicled the Human Condition in Song, Dies at 73

Source: The New York Times
Date: April 7th, 2020
Author: William Grimes

 

John Prine, the raspy-voiced country-folk singer whose ingenious lyrics to songs by turns poignant, angry and comic made him a favorite of Bob Dylan, Kris Kristofferson and others, died on Tuesday in Nashville. He was 73.

The cause was complications of the coronavirus, his family said.

Mr. Prine underwent cancer surgery in 1998 to remove a tumor in his neck identified as squamous cell cancer, which had damaged his vocal cords. In 2013, he had part of one lung removed to treat lung cancer. He had been hospitalized since late last month.

Mr. Prine was a relative unknown in 1970 when Mr. Kristofferson heard him play one night at a small Chicago club called the Fifth Peg, dragged there by the singer-songwriter Steve Goodman. Mr. Kristofferson was performing in Chicago at the time at the Quiet Knight. At the Fifth Peg, Mr. Prine treated him to a brief after-hours performance of material that, Mr. Kristofferson later wrote, “was unlike anything I’d heard before.”

A few weeks later, when Mr. Prine was in New York, Mr. Kristofferson invited him onstage at the Bitter End in Greenwich Village, where he was appearing with Carly Simon, and introduced him to the audience.

“No way somebody this young can be writing so heavy,” he said. “John Prine is so good, we may have to break his thumbs.”

The record executive Jerry Wexler, who was in the audience, signed Mr. Prine to a contract with Atlantic Records the next day.

Music writers at the time were eager to crown a successor to Mr. Dylan, and Mr. Prine, with his nasal, sandpapery voice and literate way with a song, came ready to order. His debut album, called simply “John Prine” and released in 1971, included songs that became his signatures. Some gained wider fame after being recorded by other artists.

They included “Sam Stone,” about a drug-addicted war veteran (with the unforgettable refrain “There’s a hole in Daddy’s arm where all the money goes”); “Hello in There,” a heart-rending evocation of old age and loneliness; and “Angel From Montgomery,” the hard-luck lament of a middle-aged woman dreaming about a better life, later made famous by Bonnie Raitt.

“He’s a true folk singer in the best folk tradition, cutting right to the heart of things, as pure and simple as rain,” Ms. Raitt told Rolling Stone in 1992.

Mr. Dylan, listing his favorite songwriters in a 2009 interview, put Mr. Prine front and center. “Prine’s stuff is pure Proustian existentialism,” he said. “Midwestern mind trips to the nth degree. And he writes beautiful songs.”

John Prine was born on Oct. 10, 1946, in Maywood, Ill., a working-class suburb of Chicago, to William and Verna (Hamm) Prine. His father, a tool-and-die maker at the American Can Company, and his mother had moved from the coal town of Paradise, Ky., in the 1930s.

Mr. Prine later wrote a ruefully bitter song titled “Paradise,” in which he sang:

The coal company came with the world’s largest shovel
And they tortured the timber and stripped all the land
Well, they dug for their coal till the land was forsaken
Then they wrote it all down as the progress of man

John grew up in a country music-loving family. He learned guitar as a young teenager from his grandfather and brother and began writing songs.

After graduating from high school, he worked for the Post Office for two years before being drafted into the Army, which sent him to West Germany in charge of the motor pool at his base. After being discharged, he resumed his mail route, in and around his hometown, composing songs in his head.

“I always likened the mail route to a library with no books,” he wrote on his website. “I passed the time each day making up these little ditties.”

Reluctantly, he took the stage for the first time at an open-mic night at the Fifth Peg, where his performance of “Hello in There” and “Angel From Montgomery” met with profound silence from the audience. “They just sat there,” Mr. Prine wrote. “They didn’t even applaud, they just looked at me.”

Then the clapping began. “It was like I found out all of a sudden that I could communicate deep feelings and emotions,” he wrote. “And to find that out all at once was amazing.”

Not long after, Roger Ebert, the film critic for The Chicago Sun-Times, wandered into the club while Mr. Prine was performing. He liked what he heard and wrote Mr. Prine’s first review, under the headline “Singing Mailman Who Delivers a Powerful Message in a Few Words.”

“He appears onstage with such modesty he almost seems to be backing into the spotlight,” Mr. Ebert wrote. “He sings rather quietly, and his guitar work is good, but he doesn’t show off. He starts slow. But after a song or two, even the drunks in the room begin to listen to his lyrics. And then he has you.”

Mr. Prine had a particular gift for offbeat humor, reflected in songs like “Jesus, the Missing Years,” “Some Humans Ain’t Human,” “Sabu Visits the Twin Cities Alone” and the antiwar screed “Your Flag Decal Won’t Get You Into Heaven Anymore.”

“I guess what I always found funny was the human condition,” he told the British newspaper The Daily Telegraph in 2013. “There is a certain comedy and pathos to trouble and accidents.”

After recording several albums for Atlantic and Asylum, he started his own label, Oh Boy Records, in 1984. He never had a hit record, but he commanded a loyal audience that ensured steady if modest sales for his albums and a durable concert career.

In 1992, his album “The Missing Years,” with guest appearances by Bruce Springsteen, Tom Petty and other artists, won a Grammy Award for best contemporary folk recording. He received a second Grammy in the same category in 2006 for the album “Fair and Square.”

Mr. Prine, who lived in Nashville, was divorced twice. He is survived by his wife, Fiona Whelan Prine, a native of Ireland whom he married in 1996; three sons, Jody, Jack and Tommy; two brothers, Dave and Billy; and three grandchildren. In 2017, Mr. Prine published “John Prine Beyond Words,” a collection of lyrics, guitar chords, commentary and photographs from his own archive.

In 2019, he was inducted into the Songwriters Hall of Fame, and his album “Tree of Forgiveness” was nominated for a Grammy, for best Americana album. It was his 19th album and his first of original material in more than a decade. (The award went to Brandi Carlile, for “By the Way, I Forgive You.”)

Mr. Prine went on tour in 2018 to promote “Tree of Forgiveness,” and after a two-night stand at the Ryman Auditorium in Nashville — known there as the mother church of country music — Margaret Renkl, a contributing opinion writer for The New York Times, wrote, under the headline “American Oracle”:

“The mother church of country music, where the seats are scratched-up pews and the windows are stained glass, is the place where the new John Prine — older now, scarred by cancer surgeries, his voice deeper and full of gravel — is most clearly still the old John Prine: mischievous, delighting in tomfoolery, but also worried about the world.”

In December, he was chosen to receive a 2020 Grammy for lifetime achievement.

As a songwriter, Mr. Prine was prolific and quick. In the early days, he would sometimes dash off a song while driving to a club.

“Sometimes, the best ones come together at the exact same time, and it takes about as long to write it as it does to sing it,” he told the poet Ted Kooser in an interview at the Library of Congress in 2005. “They come along like a dream or something, and you just got to hurry up and respond to it, because if you mess around, the song is liable to pass you by.”

Featured Image by Chad Batka of the New York Times

April, 2020|Oral Cancer News|

Blood Test Spot On for HPV Cancer Recurrence

Source: MedPage Today
Date: April 1st, 2020
Author: Charles Bankhead

 

A blood test for tumor-associated human papillomavirus (HPV)-DNA had near-perfect accuracy for identifying oropharyngeal cancer patients at high risk of recurrence after treatment, a prospective study showed.

Overall, 28 patients tested positive for circulating tumor (ct) HPV-DNA, including 16 patients who had two consecutive positive tests. All but one of the 16 patients subsequently had biopsy-proven disease recurrence. No patient who had only negative tests developed recurrent disease.

The findings have clear and immediate implications for clinical practice, including earlier initiation of salvage therapy for patients with recurrent disease, reported Bhisham S. Chera, MD, of the UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, and colleagues in the Journal of Clinical Oncology.

“With regard to how this is applicable to clinical practice, I think it improves the effectiveness, it improves the efficiency, and it reduces the cost and financial toxicity to patients,” Chera told MedPage Today. “This blood test’s performance is really good: Negative predictive value (NPV) 100%, two consecutive positive tests, 94% positive predictive value (PPV). This performs better than any physical examination, PET/CT, or fiberoptic re-examination in identifying cancer recurrence. Right now, I think this is the best surveillance tool we have.”

The findings extended those of a previous report, which showed that a persistently negative ctHPV-DNA test ruled out disease recurrence.

HPV infection accounts for a majority of new cases of oropharyngeal cancer in the U.S. After years of rapid increases in prevalence and incidence, oropharyngeal squamous cell carcinoma (OPSCC) has become the most common HPV-associated cancer, surpassing HPV-associated cervical cancer.

In general, HPV-positive OPSCC has a favorable prognosis as compared with HPV-negative disease, which has supported efforts to de-intensify treatment regimens to reduce exposure to potentially toxic therapies. Nonetheless, as many as a fourth of patiens will develop recurrences, the authors noted.

Most recurrences occur within the first 2 years after treatment, but some patients remain at risk of recurrence for as long as 5 years, or even longer in rare cases. Salvage therapy for recurrent HPV-positive OPSCC leads to better outcomes as compared with salvage therapy for recurrent HPV-negative disease.

PET/CT imaging 3 months after definitive treatment is standard for response assessment in many cases, the authors continued. National Comprehensive Cancer Network guidelines recommend surveillance visits at increasing time intervals through 5 years. During the visits, patients often undergo fiberoptic nasopharyngolaryngoscopy, although a recent report showed that routine surveillance rarely identifies recurrent disease.

A blood-based surveillance test based on detection of ctHPV-DNA offers potential for early detection of recurrent disease and has precedents in bladder, breast, and colorectal cancer. Chera and colleagues prospectively evaluated a ctHPV-DNA liquid biopsy in 115 patients who had completed definitive chemoradiotherapy for HPV-positive OPSCC. Each patient had PET/CT imaging 3 months after finishing treatment. Investigators tested patients for ctHPV-DNA at 6- to 9-month intervals.

During a median follow-up of 23 months, 28 patients tested positive for ctHPV-DNA, including 16 patients who had two consecutive positive tests. Also during follow-up, 15 patients developed biopsy-proven recurrence of OPSCC; all 15 had two consecutive positive tests for ctHPV-DNA. The median time from ctHPV-DNA positivity to recurrence was 3.9 months.

Consecutive positive tests had a PPV of 94%. The previous report from the study showed that a negative test had a NPV of 100%.

“The way I see this working in the clinic is that if you have a negative test, we don’t do a fiberoptic exam, we don’t order any imaging,” said Chera. “If you have a patient whose surveillance test is positive, we would bring the patient back 2 or 3 months later and repeat the blood test. If it’s positive again, then we would do an in-depth physical examination; we would do a fiberoptic exam and order a total-body PET/CT scan. This test can help us better identify which patients we can omit imaging in and those patients we can do imaging in.”

The test very well could have value in the management of patients with other types of HPV-related cancers, he said. Investigators have already examined the rate of ctHPV-DNA clearance as a biomarker for response to treatment and a possible decision-making tool for treatment de-escalation.

The testing technology has been licensed to Naveris for commercial development, and multiple medical centers have already partnered with the company to conduct studies across a variety of HPV-related diseases, said Chera.

April, 2020|Oral Cancer News|

How Can Dental Practitioners Join the Fight Against HPV-Associated Oropharyngeal Cancer?

Source: Aegis Dental Network
Date: February 2020, Volume 41, Issue 2
Authors: Jack Dillenberg, DDS, MPH; A. Ross Kerr, DDS, MSD; Alexis Koskan, PhD; Seena Patel, DMD, MPH; Mai-Ly Duong, DMD, MPH, MAEdAeg

Dr. Dillenberg

The entire dental team has the responsibility of impacting the overall health of their patients. This becomes even more relevant with the realization that up to 27 million people each year visit a dentist and not a physician, thus providing a special opportunity for primary care issues to be addressed in the dental setting.

One such opportunity is oropharyngeal cancer (OPC) prevention and control. An estimated 51,540 new cases of oral and pharyngeal cancer occurred in 2019, with a 5-year relative survival rate of 65%.1 Of these, it is estimated that 19,000 are human papilloma virus (HPV)-associated OPC, which is the only cancer that has increased in prevalence in the past 5 years, and that these numbers will continue to rise.1

Whereas the use of alcohol and tobacco were once the leading causes of OPC, the emergence of HPV infection as the main cause of OPC has changed everything. Infection with HPV (particularly HPV type 16) is transmitted primarily through sexual contact and is a vaccine-preventable virus. HPV is the most common sexually transmitted disease and can be spread even when someone infected with this virus has no signs or symptoms. Therefore, the dental team should be aware of this serious emerging cancer, be able to educate patients about risk factors, and engage in preventive activities, such as opportunistic screening and detection, and the promotion of vaccination.

Dr. Kerr

Dental clinicians should be able to recognize the presenting signs and symptoms of HPV-associated OPC (HPV-OPC). The oropharynx encompasses the soft palate, fauces, tonsillar fossae and palatine tonsils, posterior pharyngeal wall, and the base of tongue/lingual tonsils. The most common presenting symptom of a patient who may have a HPV-OPC is a non-painful neck mass.2,3 This occurs in approximately 50% to 70% of patients with OPC, and it corresponds to the spread of the cancer from the primary oropharyngeal site to the regional lymph nodes of the neck. In patients without a neck mass, other symptoms include one or more of the following: sore throat, visible oropharyngeal mass, dysphagia or odynophagia, globus sensation, or otalgia.4

There is insufficient evidence for the US Preventive Services Task Force to recommend specific screening guidelines for the early detection of HPV-OPC. However, standard dental practice dictates that at new patient and recall visits, patients are asked about current symptoms as well as receive a visual and tactile head and neck soft-tissue examination. Palpation with detection of lymphadenopathy that cannot be attributed to a benign cause (such as inflammatory lymph nodes secondary to an odontogenic infection) and/or visualization/palpation of accessible oropharyngeal structures with detection of abnormal lesions or gross asymmetry of tonsillar structures should all raise suspicion for malignancy. Abnormal signs and symptoms should trigger a referral to an expert, ideally an otolaryngologist/head and neck oncologic surgeon.

There is no evidence to support the use of salivary or serum-based screening tests to detect oncogenic HPV genotypes in the general population. Large cohort studies where subjects submit mouthrinse samples demonstrate an approximate prevalence of 1% patients testing positive for HPV 16 infection, the most cancerous of the HPV strains.5 Yet, few of these infections represent persistent infection, and even fewer lead to malignant transformation. Research suggests testing patients who are at higher risk for acquiring persistent HPV 16 infection as a feasible OPC screening strategy in a dental setting.6

Benign HPV-associated lesions (ie, viral papilloma, verruca vulgaris, condyloma acuminatum) involving the oral cavity (and oropharynx) may be detected during examination. Such lesions are typically solitary, exophytic, often pedunculated, pink to white in color, and with a variable surface ranging from papillary (ie, fingerlike projections) to flat. These lesions have no malignant potential, are associated with non-oncogenic HPV genotypes,7 and should be excised.

Dr. Koskan

What is the HPV vaccine? Vaccines that protect against HPV, and therefore HPV-OPC, have been commercially available in the United States since 2006. Currently, healthcare providers administer Gardasil® 9, a vaccine series that protects against nine different HPV genotypes, seven which cause the majority of HPV-related cancers (including OPC) and two that cause genital warts and recurrent respiratory papillomatosis. More specifically, the vaccine protects against HPV type 16, the strain most commonly associated with OPC. Therefore, vaccine uptake and completion is believed to help prevent HPV-OPC.

Whereas the HPV vaccine was once marketed for women, all individuals aged 9 to 26 years should receive the vaccine. Individuals aged 9 to 14 years with healthy immune systems need two doses to complete the series, and persons over age 15 and/or who are immunosuppressed should receive three doses.8 The vaccine is most effective prior to sexual debut. However, even among those previously exposed to HPV strains, the vaccine can protect from future infection from strains in which the individual has not been exposed and from future re-infection from previously exposed HPV strains, thus reducing cancer risk.9

Insurance provides coverage for this otherwise prohibitively expensive vaccine (roughly $230 per dose) series. Some plans provide coverage for adults up to age 45. For this reason, the Centers for Disease Control and Prevention (CDC) recommends shared decision-making with a primary care provider to discuss the vaccine benefits.

The HPV vaccine is safe and effective.10 The most common side effects include mild pain, redness, and, less common, slight swelling at the site of vaccine injection.11 The vaccine is effective in preventing genital warts and infection with the most common cancerous HPV strains.

Drs. Patel and Duong

Oral healthcare providers should be proactive in educating their patients in HPV-OPC prevention, promoting the HPV vaccine, and learning more to reduce the disease’s incidence, as provider recommendation is a vital predictor of HPV vaccine uptake and completion.

First, improving HPV-related health literacy is necessary among dental providers.12-17 Specifically, dental providers having a sound understanding of HPV, its pathophysiology, and its cancer-causing potential is key to educating patients and parents. Second, dental providers need to be well-versed in HPV-associated OPC preventive methods, specifically the HPV vaccine. Most oral health providers still do not know enough about the vaccine, and hence, do not feel comfortable recommending it.18

When discussing the HPV vaccine, it is important to promote it as a cancer prevention tool. It can be likened to other vaccines that have a similar purpose, such as the hepatitis B vaccine, which prevents viral hepatitis and hepatocellular carcinoma. The provider should give a strong recommendation for the vaccine and emphasize that HPV-OPC is a public health epidemic. Communicating the rise in incidence of this disease and the fact that it is caused by a very common infection may help parents understand how critical HPV vaccination is. Alleviating concerns about common myths is also important, such as the vaccine is not only for girls, it does not encourage early sexual debut, and it is not associated with any serious health risks or mortality.

Most practitioners do not feel confident answering patients’ questions about HPV vaccination.19 However, if a trustworthy standard set of talking points were made available, providers are willing to educate their patients about the importance of HPV vaccination and refer patients to medical providers to receive the vaccine.18,19 Further, providers were willing to participate in training programs to promote and administer the HPV vaccine.

Tools are available to improve communication practices about HPV in the dental setting, such as the #HowIRecommend videos posted on the CDC website (cdc.gov). Keeping brochures and educational videos about HPV, HPV-OPC, and the HPV vaccine in the office lobby and patient rooms can help increase knowledge and awareness. Additionally, adding a question on patient intake forms about whether the patient has received HPV vaccine doses allows the provider to more easily start this conversation. Another prime time to recommend this cancer prevention vaccine is during an oral cancer screening.

Conclusion

Dental providers have the unique opportunity to help reduce the incidence of oropharyngeal cancer. Two critical steps can be taken. First, they can work with state and local dental associations to pass regulatory legislation that would allow dentists to administer the HPV vaccine to their patients, as needed. Second, they can educate their patients and patients’ parents that the HPV vaccine is a cancer prevention resource. Enacting these steps may lead to increased HPV vaccine uptake and, in turn, reduced cases of HPV-related oropharyngeal cancer.

About the Authors

Jack Dillenberg, DDS, MPH
Dean Emeritus, Arizona School of Dentistry & Oral Health, A.T. Still University, Mesa, Arizona; The ATSU Center for the Future of the Health Professions

A. Ross Kerr, DDS, MSD
Clinical Professor, Oral and Maxillofacial Pathology, Radiology and Medicine, New York University College of Dentistry, New York, New York

Alexis Koskan, PhD
Assistant Professor, College of Health Solutions, Arizona State University, Phoenix, Arizona

Seena Patel, DMD, MPH
Associate Professor and Associate Director of Oral Medicine, Arizona School of Dentistry & Oral Health, A.T. Still University, Mesa, Arizona; Private Practice, Phoenix, Arizona

Mai-Ly Duong, DMD, MPH, MAEd
Associate Professor and Associate Director of Special Care Dentistry, Arizona School of Dentistry & Oral Health, A.T. Still University, Mesa, Arizona; Private Practice, Phoenix, Arizona

February, 2020|Oral Cancer News|

Cancers Caused by HPV Respond Better to Treatment — a New Study Helps Explain Why

Source: Memorial Sloan Kettering Cancer Center
Date: January 20th, 2020
Author: Matthew Tontonoz

Human papillomavirus (HPV) causes several types of cancer, including cervical, anal, and head and neck cancers. People with these tumors are more easily cured with radiation and chemotherapy than people with tumors not caused by HPV. Scientists at Memorial Sloan Kettering now think they understand why.

“We’ve known that HPV-associated cancers respond much better to radiation therapy, but it hasn’t been clear why that is,” says Daniel Higginson, a physician-scientist at MSK. “Our research shows that it’s likely because the virus alters the cells’ normal DNA repair machinery.”

Radiation therapy damages DNA. Cancers caused by HPV are less able to repair this damage and so they die.

The difference in cure rates between HPV-caused and non-HPV-caused cancers is stark: 85% to 90% of patients with HPV-associated oropharyngeal cancer (which affects the middle part of the throat), for example, are cured by radiation and chemotherapy, compared with about 60% of people with non-HPV-caused oropharyngeal cancer.

“We don’t have many biomarkers that predict response to radiation therapy,” says Dr. Higginson. “But HPV is a very good one and is consistent across multiple malignancies.”

What the Virus Does

HPV promotes cancer by inserting pieces of its own DNA into a person’s cells. The DNA pieces trick the human cells into making two distinct proteins that cooperate to turn normal cells cancerous. These proteins (called E6 and E7) disrupt the cells’ machinery for stopping unwanted growth (specifically, two proteins called p53 and Rb).

When this machinery is disabled, the cells begin to divide without restraint. They also tend to accumulate mutations because DNA damage goes unrepaired. Eventually, the cells have enough additional mutations to turn cancerous.

Tricking the cells into dividing repeatedly is advantageous to the virus because this is how HPV reproduces itself; each time a host cell divides it makes more of the virus.

Previous research had pointed to faulty DNA repair as a possible reason why HPV-caused cancers are more sensitive to radiation. But there are several types of DNA repair — which one might be involved was an open question.

Homing in on DNA Repair

To get to the bottom of these questions, the researchers first looked for evidence of different types of DNA repair in more than 10,000 tumors across 32 cancer types in data sets from The Cancer Genome Atlas. They discovered that HPV-caused cancers have DNA changes more characteristic of a repair process called microhomology-mediated end joining (MMEJ). This form of DNA repair is a backup system that comes into play when other repair systems fail, but it is prone to making errors.

The researchers then turned to laboratory experiments. By introducing DNA breaks into HPV-infected cancer cells and measuring how these breaks were repaired, the MSK scientists confirmed that HPV (specifically the E7 protein) suppresses a form of DNA repair called canonical nonhomologous end joining. As a result, the cells become more dependent on MMEJ.

Why might HPV prefer this form of less-than-accurate repair? Some evidence suggests that MMEJ helps the virus integrate its DNA into the host cell’s DNA.

Dr. Higginson says that looking for biomarkers of MMEJ dependence in cancers may help doctors tailor treatments to those who may benefit from them the most. In addition, the findings provide a rationale for exploring ways to block MMEJ factors with drugs in HPV-caused cancers. These results were published October 7, 2019 in the journal Proceedings of the National Academy of Sciences.

Cancers caused by HPV constitute about 4.5% of all solid tumors. A vaccine to prevent infection with the most dangerous HPV strains is available.

February, 2020|Oral Cancer News|

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|

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|

New cancer treatment delivers weeks of radiation therapy in a second

Source: New Atlas
Date: January 9th, 2020
Author: Michel Irving

Radiation therapy is currently our best shot at treating cancer, but it’s far from a perfect solution. It takes a course of weeks or even months, during which time healthy cells often become unfortunate collateral damage. But what if the whole course of treatment could be over in under a second? Researchers at the University of Pennsylvania have now shown just how this might be feasible.

With the right tools, cancer cells on their own aren’t all that difficult to kill. Radiation or drugs can be administered to kill them off relatively easily – the problem is tumors like to hide in crowds, and whatever weapons we fire at them also tend to hit healthy cells around them. Because radiation therapy takes weeks, there are more opportunities for those healthy cells to be affected, leading to all kinds of health problems even if the cancer is destroyed.

That’s where FLASH radiotherapy comes in. This emerging form of treatment involves giving a patient in one second a similar amount of radiation as they would normally receive over weeks. Previous experiments have shown that the effect on the cancer itself is basically the same, but the collateral damage to healthy tissue is drastically reduced.

For the new study, researchers at Pennsylvania University found that by changing the type of fundamental particle used, they could make FLASH radiotherapy far more effective. Normally, electrons are the particles of choice for this method, but they don’t penetrate very deep into the body. That means they’re only really useful for shallower cancer types such as skin cancer.

In this case the researchers used protons, and showed that linear accelerators already in use in hospitals could be adapted to produce these particles. Since they can pass deeper into the body, they should be more useful against a wider range of tumor types.

The team tested it out on mice with pancreatic flank tumors, and found that the method did inhibit the growth of the cancers with roughly the same effectiveness as regular radiation therapy. Importantly though, the proton FLASH therapy reduced healthy cell loss and didn’t cause intestinal fibrosis, a common side effect of radiation therapy.

“This is the first time anyone has published findings that demonstrate the feasibility of using protons – rather than electrons – to generate FLASH doses, with an accelerator currently used for clinical treatments,” says James M. Metz, co-senior author of the study.

The researchers are currently working on how to translate the treatment to clinical trials. This includes designing a system that can deliver the proton radiation to humans.

January, 2020|Oral Cancer News|