squamous cell carcinoma

Expert says Nivolumab Poised to Change Standard of Care in SCCHN

Source: www.onclive.com
Author: Laura Panjwani


Nivolumab (Opdivo) is a game-changing agent for the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN), according to Robert L. Ferris, MD, PhD.

“Recent findings have shown us that this agent is really the new standard-of-care option for all platinum-refractory patients with head and neck cancer,” says Ferris, vice chair for Clinical Operations, associate director for Translational Research, and co-leader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute. “This is regardless of whether patients are PD-L1–positive or negative or whether they are HPV-positive or negative.”

The PD-L1 inhibitor received a priority review designation by the FDA in July 2016 based on the CheckMate-141 study, which demonstrated a median overall survival (OS) with nivolumab of 7.5 months compared with 5.1 months with investigator’s choice of therapy (HR, 0.70; 95% CI, 0.51-0.96; P = .0101) in patients with recurrent or metastatic SCCHN.

The objective response rate (ORR) was 13.3% with nivolumab and 5.8% for investigator’s choice. The FDA is scheduled to make a decision on the application for the PD-1 inhibitor by November 11, 2016, as part of the Prescription Drug User Fee Act.

Ferris was the lead author on an analysis that further evaluated preliminary data from CheckMate-141, which was presented at the 2016 ASCO Annual Meeting. In an interview with OncLive, he discusses the findings of this study, potential biomarkers for nivolumab, and questions that remain regarding the use of the immunotherapy in SCCHN.

OncLive: What were the updated findings from CheckMate-141 presented at ASCO?

Ferris: The data that were presented at the 2016 ASCO Annual Meeting were further evaluations and follow-up on some preliminary data—originally presented at the 2016 AACR Annual Meeting—that listed the OS results.

At ASCO, we recapped the primary endpoint of OS as an important endpoint for immunotherapies because response rate and progression-free survival may not be as accurate. Ultimately, the FDA and people at large want OS. In this study, OS was 36% at 1 year in the nivolumab-treated arm and 16.6% in the comparator arm, which was investigator’s choice of single-agent chemotherapy, consisting of methotrexate, docetaxel, or cetuximab. In this phase III randomized trial, nivolumab was given in a 2:1 randomization: 240 patients received nivolumab and 120 received investigator’s choice.

Also at ASCO, we presented further evaluations consisting of what the regimens are in the comparator arm. There was about 20% each of docetaxel and methotrexate and 12% of cetuximab. Approximately 60% of the patients had prior cetuximab exposure and we stratified by cetuximab as a prior therapy. We also demonstrated the ORR, which was 13.3% in the nivolumab-treated arm versus 5.8% in the investigator’s choice arm.

Therefore, there was an improvement in overall response, but the difference seemed more modest than the OS benefit—which was a doubling—with 20% more patients alive at 1 year. This reinforces the concept that perhaps response rate may not be the best endpoint. Progression-free survival (PFS) was double at 6 months, with about 20% in the nivolumab arm versus about 9.9% in the investigator’s choice arm. The median PFS was not different, but the 6-month PFS was twice as high. The time to response was about 2 months in each arm at the first assessment.

Your analysis also looked at biomarkers. Can you discuss these findings and their significance?

The p16 or HPV-positive group had a better hazard ratio for OS than the overall study population. The hazard ratio was .73 for the overall population, using a preplanned interim analysis. With the HPV-positive group, we had a hazard ratio of .55 and the HPV-negative group had a hazard ratio of .99. It is still favoring the nivolumab-treated patients but, with the curves separated earlier in the HPV-positive group, one could see the improvement with nivolumab at about 1 to 2 months. It took 7 or 8 months with the HPV-negative group to show a separation of the curves in favor of nivolumab.

We looked at PD-L1 levels, and PD-L1—using a 1% or above level—had an improvement in the PD-L1–positive patients in favor of nivolumab in terms of OS and ORR. When we looked at 5% and 10% thresholds of PD-L1, the OS did not seem to improve. Therefore, in all levels above 1%, the OS was similarly beneficial over the PD-L1 less-than-1% group. However, essentially all levels of PD-L1–positivity and PD-L1–negativity still favored nivolumab, but the benefit was more when its levels were greater than 1%.

We could combine HPV status with PD-L1 status and look at subsets; however, essentially every subset benefited, whether it was PD-L1–negative or positive. This indicates that, in this group of patients, who progress within 6 months of platinum-based therapy, that no current systemic therapeutic options benefit patients as well as nivolumab.

With regard to these findings, what are you most excited about?

Head and neck cancer is a difficult disease. Until recently, we didn’t know the impact of this enrichment for HPV-positive virus-induced subsets and we didn’t know if this was an immune responsive cancer. Clearly, it is. We have all of the hallmarks that we have seen for a bright future—based on the melanoma data—and a series of other cancers indicating response rates in the 15% to 20% range, suggesting that we now have a platform of the PD-1 pathway to combine with other checkpoints and to integrate earlier in disease with radiation and chemotherapy.

We have a demonstration of head and neck cancer as an immune-responsive cancer. We are beginning to get an idea of the biomarkers and starting to be able to segment patients who will benefit. Now, we have a large comparative trial with an OS endpoint and tissue to look at biomarkers to try and understand what the best future combinations will be.

What are some questions that you still hope to answer regarding nivolumab in head and neck cancer?

We have to get down deeper into the nonresponders. We should acknowledge that the majority of patients neither had a response nor benefited. Understanding who is more likely to benefit is useful, but we also need to understand the levels of alternative checkpoint receptors or other biomarkers of resistance.

We have sequential lymphocyte specimens from the peripheral blood, tissues, and serum so those are intensively under evaluation. There are interferon gamma signatures that have risen from the melanoma checkpoint field that will certainty be applied, as well.

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

August, 2016|Oral Cancer News|

Nivolumab Could Change Head and Neck Cancer Treatment Paradigm

Source: www.Targetedonc.com
Author: Laura Panjwani

“To have an anti–PD-1 agent be proven to improve survival in head and neck cancer in a randomized phase III trial, and the potential for a new FDA approval in the near future is a game changer.” – Robert Ferris, MD, PhD

With the phase III CheckMate-141 trial being stopped early due to the anti–PD-1 agent nivolumab having met its primary endpoint of overall survival improvement in head and neck cancer, Robert Ferris, MD, PhD, couldn’t be more elated.

“This is what I’ve devoted my career to, and it is gratifying to see that really come to pass,” said Ferris, professor and chief, Division of Head and Neck Surgery, vice chair for Clinical Operations, associate director for Translational Research, and coleader of the Cancer Immunology Program at the University of Pittsburgh Cancer Institute, in an exclusive interview with Targeted Oncology.

“To have an anti–PD-1 agent be proven to improve survival in head and neck cancer in a randomized phase III trial, and the potential for a new FDA approval in the near future is a game changer. There is now hope for a lot of patients and physicians who have been frustrated by this difficult-to-treat disease. This opens up a whole new class of therapies for this population.”

Ferris, who acted as cochair/coprimary investigator for the trial alongside Maura Gillison, MD, PhD, Ohio State University, said the trial pitted nivolumab against the investigator’s choice of cetuximab (Erbitux), methotrexate, or docetaxel in patients with platinum-refractory squamous cell carcinoma of the head and neck (SCCHN).

Eligible patients who are still enrolled in the study are now able to continue their current treatment regimen, or switch over to nivolumab. Ferris says the prospect of having a new drug available for SCCHN is exciting, especially considering the last FDA approval for the disease type came in 2006.

“It was 2006 when cetuximab was approved and that was a relatively modest advance, although it was the first targeted therapy. We have a population without any other therapeutic options and a very rapid progression,” he said.

“Anti–PD-1 agents have had promising data in melanoma and squamous non–small cell lung cancer (NSCLC). Squamous NSCLC genomically resembles HPV-negative head and neck cancer in its behavior regarding carcinogen exposure. Therefore, we felt it might respond well to anti–PD-1 agents, too. We designed the study to hopefully create something new and effective for an essentially hopeless palliative group of patients.”

The phase III data have not yet been released from the trial, though early discontinuation has generated significant excitement in the field. The trial was scheduled to run until October 2016, has generated significant excitement in the field, says Ferris, who is a primary author on the abstract submitted for presentation at the ASCO Annual Meeting.

Ferris says the study was designed reflect the idea that there are different standards of care for SCCHN throughout the world, which is why cetuximab, methotrexate, or docetaxel were chosen for the control arms.

“We still don’t have public data for what all of the standard of care selections were, but we do know that cetuximab tends to be used more in North America. Meanwhile, the other 2 agents are more likely to be used in Europe and other countries because cetuximab is not approved there,” he said.

“The benefits are really very modest with those single-agent treatments and they are toxic. There is very much a need for a new treatment. We are very interested in the toxicity profile of nivolumab, as it has proven to be well tolerated in other cancers.”

Ferris adds that the excitement generated in the field stems from the revelation of efficacy for pembrolizumab (Keytruda) at the 2015 ASCO Annual Meeting, saying the data from both pembrolizumab and nivolumab “appear to be very similar.”

“There was a suspicion that nivolumab would be promising in head and neck cancer, as well. There is a great deal of buzz from medical oncology leaders all over the country regarding this. People have really been waiting with bated breath for something for our patients. This is a real win for the community and for a population of patients with a devastating disease in a very important area of the body,” he said.

“This disease can disrupt speaking, drinking, swallowing, and has catastrophic consequences. I expect enthusiasm and support from the community regarding this.”

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

February, 2016|Oral Cancer News|

HPV Persistence Predicts Poor Prognosis in Head/Neck Cancer

Source: www.medscape.com
Author: Roxanne Nelson, RN, BSN

Among patients with human papillomavirus–positive oropharyngeal cancer (HPV-OPC), persistence of HPV following treatment is associated with a poorer prognosis.

Results of a new study show that the persistence of HPV16 DNA, detected in oral rinses after treatment has ended, may be predictive of disease recurrence.

In a cohort of 124 patients with HPV-OPC, HPV16 DNA was detected in oral rinses from 54% (n = 67) of patients at the time of their diagnosis. Following treatment, it was detected in only six patients after treatment, including five patients with persistent oral HPV16 DNA that was also detected at diagnosis.

All five patients with persistent HPV16 experienced disease recurrence, with three eventually dying of their cancer. Conversely, only nine of 119 patients without persistent oral HPV16 DNA developed recurrent disease.

“Our findings indicate that persistent HPV16 DNA in oral rinses may be a useful early marker of disease that has either recurred or never fully responded to treatment,” said first author Eleni Rettig, MD, of the Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.

“In the clinical setting, this could one day be a part of routine surveillance after treatment for HPV-positive oropharyngeal cancers, in addition to clinical examination and imaging,” she told Medscape Medical News.

The study was published online July 30 in JAMA Oncology.

Biomarker Potential?

In an accompanying editorial, Julie E. Bauman, MD, MPH, and Robert L. Ferris, MD, PhD, both of the University of Pittsburgh, in Pennsylvania, point out that HPV-specific biomarkers in oropharyngeal squamous cell carcinoma (OSCC) may be used to improve clinical outcomes, and “this pioneering study demonstrates an association between persistent oral HPV16 DNA detection and recurrence.”

But an ideal biomarker for recurrence, they say, should have a number of characteristics, including high sensitivity to identify the population with salvageable locoregional recurrence, a high positive predictive value (PPV) so as to avoid the economic, physical, and emotional costs of false-positive evaluations, and accuracy for detecting subclinical locoregional recurrence.

The prevalence of a positive oral rinse at diagnosis, however, was only 54%, and so the “low sensitivity of the assay, even with gross disease present, raises legitimate questions regarding its utility for diagnosing subclinical disease,” they say.

Of the six cases in which posttreatment HPV16 DNA was detected, five patients developed recurrent disease, representing a PPV of 83%, the editorialists write. When restricted to the five cases with persistent HPV16 DNA, the PPV then becomes 100%.

Although this looks impressive, they point out that “persistence can only occur in those who initially test positive — making this recurrence biomarker irrelevant for half of patients with HPV-positive” disease.

In addition, they add, the PPV can apply to any recurrence, including presentation with distant metastases, and “unfortunately, early diagnosis of disseminated OPSCC [oropharyneal squamous cell carcinoma] has not been associated with improved survival.”

“Operating characteristics, including low sensitivity, low confidence in the PPV, and high NNT [number needed to treat], preclude immediate clinical adoption,” say Dr Bauman and Dr Ferris. They add that incorporating an HPV-specific biomarker in future surveillance guidelines will require some refinement, including improved sensitivity and perhaps combining it with other serologic markers, such as HPV16 DNA or E6 antibodies.

“Meanwhile, the high negative predictive value of oral rinse HPV16 DNA detection raises the promise of deintensifying surveillance visits and/or costly imaging, particularly if on a prospective trial,” they conclude.

Dr Rettig agrees that more studies are needed before this test can be recommended. “For example, we need to understand when and how frequently to administer the test, what exactly we should do with a positive result, and what the cost-effectiveness would be, given the small number of individuals who actually have persistent oral HPV16 ― only five of 124 people in our study,” she said.

“We also can’t say for sure that all of the HPV16 DNA comes from tumor cells, and in some cases, it might just come from an oral HPV16 infection,” Dr Rettig explained. “For all of these reasons, right now, this test should only be used in the research setting until we have more information from additional studies.”

Associated With Recurrence

In this study, Dr D’Souza and colleagues examined HPV DNA detection in oral rinses after treatment for HPV-OPC and how it related to disease recurrence and survival.

This prospective cohort study included HPV-OPC patients diagnosed from 2009 to 2013 at four centers. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis) and were evaluated for HPV DNA. One or more posttreatment oral rinses were available for the 124 patients included in the study.

The median follow-up time was 33 (24-41) months, during which there were 14 recurrences and six deaths — all due to recurrent disease.

Two years after diagnosis, disease-free survival (DFS) was 92% (95% confidence interval [CI], 94% – 100%), and overall survival was 98% (95% CI, 93% – 99%).

The presence of HPV16 DNA in oral rinses at the time of diagnosis was not associated with either DFS (P = .15) or overall survival (P = .14), but on univariate analysis, persistent HPV16 DNA detection in oral rinses (eg, both at diagnosis and any time after treatment) was associated with a greater than 20-fold increased risk for recurrence (hazard ratio [HR], 29.7; 95% CI, 9.0 – 98.2) and death (HR, 23.5; 95% CI, 4.7 – 116.9).

It still remained associated with both DFS (adjusted HR [aHR], 35.8; 95% CI, 8.6 – 149.1) and overall survival (aHR, 16.1; 95% CI, 2.8 – 92.7) after adjusting for pack-years of smoking and tumor stage.

This research was supported financially by the Johns Hopkins Richard Gelb Cancer Prevention Award (Dr D’Souza), the Oral Cancer Foundation (Dr D’Souza), the National Institute of Dental and Craniofacial Research, and the National Institutes of Health Training in Otolaryngology grant (Dr Rettig). Several of the authors report relationships with industry, as noted in the article. The editorialists report no relevant financial relationships.

JAMA Oncol. Published online July 30, 2015. Abstract, Editorial

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


Proteomic analysis of oral/head and neck cancer

Source: http://cancerres.aacrjournals.org
Author: Shen Hu, Lifeng Zhang, Jiang Jiang, Martha Arellano-Garcia, and David Wong

Abstract: The stagnant survival rates over the past few decades for patients with oral/head and neck squamous cell carcinoma (OSCC/HNSCC) emphasize the need for identifying novel diagnostic and therapeutic targets based on molecular profiling of the tumor. In this study, we have conducted patient-based proteomic analysis towards the discovery of potential serum and tissue protein targets associated with OSCC/HNSCC. First, we have utilized quantitative proteomics based on gel electrophoresis and stable isotope labeling/tandem mass spectrometry (MS/MS) to identify differentially expressed serum proteins between lymph-node metastatic and non-metastatic OSCCs. Proteins in PAGE gel bands were digested and the resulting peptides were labeled with iTRAQ reagents and subsequently quantified with liquid chromatography (LC) with quadrupole time-of-flight MS or linear ion trap MS (LTQ). The differentially expressed proteins included transthyretin, alpha-fibrinogen, tetranectin, hemopexin, ficolin, HGF activator, plasminogen, clusterin, etc. Second, we have performed comparative proteomic analysis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs because HPV has been recognized as an important risk factor for a subset of OSCC/HNSCC. Differentially expressed proteins were revealed by 2-D gel electrophoresis and then identified using in-gel tryptic digestion followed by LC-MS/MS (linear ion trap). Interesting targets associated with HPV-positive HNSCC included NHEJ1, PARK7 (oncogene DJ-1), superoxide dismutase, heat shock protein beta-1, fatty acid-binding protein, etc. NHEJ1 is a DNA repair protein involved in DNA nonhomologous end joining whereas PARK7 acts as a positive regulator of androgen receptor-dependent transcription and has cell-growth promoting and transforming activities. In addition, we have profiled the E6- and E7-binding proteins within HPV-positive and HPV-negative HNSCC tissues using immunoprecipitation and LC-MS/MS. Apart from helping us to understand the molecular mechanism of the cancer diseases, these protein targets may also have potential clinical applications such as biomarkers if further validated.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
October, 2014|Oral Cancer News|

Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling

Source: http://cancerres.aacrjournals.org

Authors: Faina Linkov, Alex Lisovich, Zoya Yurkovetsky, Adele Marrangoni, Lyudmila Velikokhatnaya, Brian Nolen, Matthew Winans, William Bigbee, Jill Siegfried, Anna Lokshin, and Robert Ferris

Abstract: Squamous cell carcinoma of the head and neck cancer (SCCHN) is an aggressive disease which has been linked to altered immune, inflammatory, and angiogenesis responses. A better understanding of these aberrant responses might improve early detection and prognosis of SCCHN and provide novel therapeutic targets. Previous studies examined the role of multiplexed serum biomarkers in small cohorts or SCCHN sera. We hypothesized that an expanded panel comprised of multiple cytokines, chemokines, growth factors, and other tumor markers, which individually may show some promising correlation with disease status, might provide higher diagnostic power if used in combination. Thus, we evaluated a novel multi-analyte LabMAP profiling technology that allows simultaneous measurement of multiple serum biomarkers. Concentrations of 60 cytokines, growth factors, and tumor antigens were measured in the sera of 116 SCCHN patients prior to treatment (active disease group), 103 patients who were successfully treated (no evidence of disease, NED, group), and 117 smoker controls without evidence of cancer. The multi-marker panel offering the highest diagnostic power was comprised of 25 biomarkers, including EGF, EGFR, IL-8, tPAI-1, AFP, MMP-2, MMP-3, IFN-α, IFN-γ, IP-10, RANTES, MIP-1α, IL-7, IL-17, IL-1Rα, IL-2R, G-CSF, mesothelin, IGFBP-1, E-selectin, cytokeratin (CK)19, V-CAM, and CA-125. Statistical analysis using an ADE algorithm resulted in a sensitivity of 84.5%, specificity of 98%, and 92% of patients in the active disease group correctly classified from a cross-validation serum set. The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
October, 2014|Oral Cancer News|

AACR says that new drug may assist therapy for Head and Neck Cancer

Source: hcplive.com

THURSDAY, Sept. 18, 2014 (HealthDay News) — The investigational drug alpelisib (previously known as BYL719) appears to inhibit activation of the pathway that leads to resistance to cetuximab, an anti-epidermal growth factor receptor agent used in the treatment of head and neck cancer. These findings were presented at the American Association for Cancer Research’s special conference “Targeting the PI3K-mTOR Network in Cancer,” held from Sept. 14 to 17 in Philadelphia.

Pamela Munster, MD, of the University of California in San Francisco, and colleagues tested the combination of BYL719 and cetuximab in vivo in a cetuximab-sensitive and a cetuximab-resistant xenograft model of esophageal squamous cell carcinoma. In a phase Ib study, BYL719 was administered in combination with cetuximab in adults with recurrent or metastatic squamous cell carcinoma of the head and neck that was resistant or intolerant to platinum-based chemotherapy; prior cetuximab therapy was allowed.

The researchers found that the addition of BYL719 to cetuximab showed an additive effect in the cetuximab-sensitive model. BYL719 restored sensitivity to cetuximab in the cetuximab-resistant model. In the phase Ib study, as of March 10, 2014, 37 patients have received BYL719 and cetuximab, and the overall response rate is 11%. Based on the data from preclinical studies and the phase Ib study, the combination of alpelisib and cetuximab for squamous cell carcinoma of the head and neck is being explored in a phase II study.

“Treatment resistance is often conveyed through activation of the PI3K/AKT/mTOR pathway, and alpelisib is an inhibitor of this pathway,” Munster said in a statement.

The study was funded by Novartis, the developer of alpelisib (BYL719).

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
September, 2014|Oral Cancer News|

Curt Schilling Reveals his Diagnosis of Oral Cancer and Believes Chewing Tobacco was the Cause

Source: boston.com
Author: Steve Silva

Curt Schilling, the former Red Sox pitcher and ESPN analyst, announced today during the WEEI/NESN Jimmy Fund Radio Telethon that he was diagnosed with squamous cell carcinoma — which is cancer in the mouth — in February.

“This all came about from a dog bite,” Schilling said. “I got bitten by a dog and I had some damage to my finger and I went to see a doctor, and the day that I went to see the doctor, I was driving and I went to rub my neck and I felt a lump on the left side of my neck. And I knew immediately it wasn’t normal. So there happened to be an ENT [Ear, Nose, and Throat] right next door to the hand doctor, and I thought what the heck, let me just stop in and see and so I waited in the office and went in there and they did the biopsy, and two days later, they diagnosed me with squamous cell carcinoma.

“You know what the amazing thing was? And I was just dumbfounded by it. You’ve just been told you have cancer and you walk out into the public and the world’s still going on and it was really a challenge to wrap my head around that. My second thought was, ‘Yeah, really, you think I can handle this too?’ So after a couple of tests, I got sent over to Brigham and Women’s and Dana-Farber and that’s where I met Dr. Haddad and the amazing team of people that got me through my treatment.”

Dr. Robert Haddad, from the Dana-Farber Cancer Institute, described Schilling’s cancer.

“Commonly this is known as mouth cancer,” Dr. Haddad said. “This is the type of the cancer we call the squamous cell carcinoma. It’s cancer of the lining of the mouth and the lump in the neck is why most patients go to the doctor first, because they feel the lump in the neck so that’s the lymph node that’s enlarged and that’s the most common presentation for these cancers. It often presents as a lump in the neck that drives the patient to go see the doctor, and then the biopsy is done and then that shows squamous cell carcinoma, and that’s the type of the cancer.”

The 47-year-old Schilling — who weighed just over 200 pounds prior to his cancer diagnosis — lost 75 pounds during his treatment. Most of the weight loss was due to the fact that he was unable to swallow. He also has lost his ability to taste and smell.

The former Red Sox righthander stressed the importance of getting in for treatment early.

“One of the amazing things was early on when I was talking to [Dr. Haddad] about this, I literally went to see a doctor like five days after I felt the lump, he said the average time for a patient is 10 months,” Schilling said. “Ten months from the time they notice something to the time they say something. I can’t believe… people need to be more self-aware.

“I didn’t talk about it for two reasons. No. 1, I didn’t want to get into the chewing tobacco debate, which I knew was going to come about, which to me, I’ll go to my grave believing that was why I got what I got… absolutely, no question in my mind about that. And the second thing was I didn’t want people to feel sorry for me. I didn’t want the pity or any of that stuff because early on… I ended up spending about six months in the hospital because I had a bad reaction. I had a staph infection. I had what’s called C. diff. I had a couple different problems and there was a week there, there’s a week of my life I don’t remember while I was in the hospital going through this.

“The second or third day — I got chemo and radiation for seven weeks — and I came back to the room and my family was sitting there and I thought, ‘You know what, this could be so much worse. It could be one of my kids, it’s not. I’m the one guy in my family that can handle this,’ and so from that perspective it never, ever said ‘Why me? And I never will. I do believe without a doubt, unquestionably that chewing is what gave me cancer and I’m not going to sit up here from the pedestal and preach about chewing. I will say this: I did for about 30 years. It was an addictive habit. I can think of so many times in my life when it was so relaxing to just sit back and have a dip and do whatever, and I lost my sense of smell, my taste buds for the most part. I had gum issues, they bled, all this other stuff. None of it was enough to ever make me quit. The pain that I was in going through this treatment, the second or third day it was the only thing in my life that had that I wish I could go back and never have dipped. Not once. It was so painful.”

According to Schilling, the most painful part of the treatment was the radiation, which he received five days a week over seven weeks. Schilling’s doctors created a pliable mask to protect his face. Schilling called it “the straitjacket for when they are giving you radiation.”

“The first day I went in, they clamped [the mask] down, they do the radiation into the tumors,” Schilling said. “The second day they did it. And about the third day I started developing almost a phobia and I literally had to be medicated for the seven weeks to go and do that. I couldn’t control myself under the mask… If this happened again, I’m not sure if I would go through the treatment again, it was that painful.”

Dr. Haddad concurred that chewing tobacco leads to the mouth cancer Schilling was diagnosed with.

“One of the directs for oral cancer is smokeless tobacco, just what we’re talking about here,” Dr. Haddad said. “So it is not a question mark. This is shown repeatedly and the National Cancer Institute clearly makes the case that any form of tobacco is harmful and should not be used.”

Schilling spoke about the day he found out about Tony Gwynn’s death. Gwynn – a Hall of Famer — died of salivary gland cancer on June 16 at the age of 54. Gwynn blamed his mouth cancer on his habit of dipping smokeless tobacco during his 20-year career with the San Diego Padres.

“I knew a while ago that things were not going well just because he went radio silent after everything that happened,” Schilling said. “From the people I talked to, he was in very, very bad shape at the end. Again, I got lucky. There’s so may other places this could have come up and they could have had to take half my jaw. I met a guy — so I was Brigham and Women’s palliative care floor, the fifth floor, which is kind of a new thing and an amazing thing — who had, smoker, who had cancer of the mouth and they had to cut off half of his tongue and they went down and grafted from his forearm and rebuilt it back. Just the stuff was mind boggling…

“I’ve seen Dana-Farber from the other side. As someone who’s been around spring training with the kids. I’ve been over there and visited a couple of times, but being on this side of it was mind boggling.”

Schilling spoke about what lies ahead for him from hereon out.

“I’m in remission,” he said. “Doc and I are going to be meeting each other on and off for the next five years. It’s the recovery that’s a challenge because there are so many things that are damaged during the process. I don’t have any salivary glands so I can’t taste anything and I can’t smell anything right now so and there’s no guarantee they’ll come back.”

Dr. Haddad stressed that these types of cancers are treatable and that his sense of taste and smell should come back.

“Without discussing this specific case, in head and neck cancers or cancers of the mouth, these are treatable cancers, these are curable cancers in a large percentage of patients,” Dr. Haddad said. “But the treatment is very tough, it’s very grueling, a lot of side effects. Those side effects are acute, meaning they happen [during] the first year of treatment like we’re seeing now with Curt: the dry mouth and the trouble swallowing and eating, the infections, and there’s the long-term side effects, So that is the recovery process that can take up to five years but these cancers are treatable, are curable, they do require a lot of specialties coming together.”

Clay Buchholz and Dustin Pedroia, two Red Sox stars with young children, addressed their chewing habit at Fenway Park in June.

“Cancer runs in my family,” said Buchholz, as he sat in front of his locker with a wad of smokeless tobacco wedged between his lower lip and gums. “There’s been people that have never smoked a cigarette or had a dip or chew and they’ve died of lung cancer.

“Everybody here is a grown man, and I think that’s how everybody views it. I don’t dip during the offseason, it’s only during baseball. It’s more of a stress-reliever type of thing for me.”

I’m trying to stop,” said Pedroia. “It’s not a good habit. It’s one of those things, you try like heck. I wish I had never started.

“Everyone crushes me about it. You don’t want any kid to start doing it. Obviously, it’s addicting. It’s not good for you and can cause a lot of problems.

“You try the best you can to stop or not start it. It’s like any bad habit. People do things that aren’t good for you. A lot of things can hurt yourself, whether its drinking or tobacco. It’s hard to stop. I’ve stopped a few times and started back up. But I’ve cut back a lot.”

“I’m addicted to it, former Sox pitcher Josh Beckett told the Los Angeles Times after Gwynn’s death. “It’s more than just the nicotine. Its the oral fixation. I don’t think anyone does it just for the nicotine thing, or wed probably all be on the patch.”

The 2011 labor agreement between the players’ union and Major League Baseball included certain limits on the use of smokeless tobacco, but did not ban its use entirely. Players are not allowed to carry tobacco packages in their uniform pockets, and tobacco use during televised interviews and non-game functions is prohibited. Also, teams cannot provide tobacco for players.

In June, nine major medical and public health organizations have written to MLB and the players’ union urging them to agree to a complete prohibition on tobacco use at ballparks and on camera.

In April, Schilling’s wife Shonda, herself a melanoma survivor, tweeted that Schilling had finished radiation.

On Facebook that month, Schilling wrote, To the many, many amazing folks at Dana Farber, [Brigham and Women’s Hospital] and [Massachusetts General Hospital], thank you and to the amazing team these last 5 months. I’ve been told my cancer is in remission, start the 5-year clock.

In May, a weakened Schilling took the field at Fenway as part of the 10th anniversary celebration of the 2004 championship team. Schilling was aided onto the field by his son Gehrig and said he was back in the hospital two days later.

“I was in the hospital at the time, and they wouldn’t let me come over here and go back,” Schilling said. “So I had to determine if I was OK and ready to be discharged and I said ‘yeah, yeah, yeah, OK,’ and two days later I was back in the hospital. That’s why Gehrig walked out with me because I was afraid I was going to fall on the way in because I was so discombobulated. But it was nice. It was good to see the guys.”

On June 25, Schilling tweeted: “As of yesterday I am in remission. Start the 5 year clock!”

Schilling, who spent four seasons of his 20-year major league career with the Red Sox and was instrumental in their World Series victories in 2004 and ’07, joined ESPN as a studio analyst for ESPN’s “Baseball Tonight” in 2010.

In December, he was chosen to replace Orel Hershiser for the high-profile role as a color analyst on ESPN’s “Sunday Night Baseball” broadcasts alongside Dan Shulman and John Kruk.

Schilling pitched for five teams during his major league career, winning 216 games and compiling 3,116 strikeouts. He made six All-Star teams, won at least 21 games in a season three times — including in 2004 with the Red Sox. He won his first of three World Series titles with the 2001 Diamondbacks.

Schilling had found his niche as an analyst after enduring some difficult times in recent years. A video game business suffered a prominent and costly failure in Rhode Island, one that cost the state tens of millions of dollars and Schilling the bulk of his baseball fortune. He revealed to the Globe’s Stan Grossfeld in an August 2013 story that he suffered a heart attack in November 2011 that required surgery to implant a stent in an artery.

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.
August, 2014|Oral Cancer News|

Nutritional and Zinc Status of Head and Neck Cancer Patients: An Interpretive Review

Source: Journal of the American College of Nutrition
Authors: Ananda S. Prasad, MD, PhD, MACN, Frances W.J. Beck, PhD, Timothy D. Doerr, MD, Falah H. Shamsa, PhD, Hayward S. Penny, MS, RD, Steven C. Marks, MD, Joseph Kaplan, MD, Omer Kucuk, MD and Robert H. Mathog, MD



In this review, we provide evidence based on our studies, for zinc deficiency and cell mediated immune disorders, and the effects of protein and zinc status on clinical morbidities in patients with head and neck cancer. We investigated subjects with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. Patients with metastatic disease and with severe co-morbidity were excluded. Nutritional assessment included dietary history, body composition, and prognostic nutritional index (PNI) determination. Zinc status was determined by zinc assay in plasma, lymphocytes, and granulocytes. Pretreatment zinc status and nutritional status were correlated with clinical outcomes in 47 patients. Assessment of immune functions included production of TH1 and TH2 cytokines, T cell subpopulations and cutaneous delayed hypersensitivity reaction to common antigens.

At baseline approximately 50% of our subjects were zinc-deficient based on cellular zinc criteria and had decreased production of TH1 cytokines but not TH2 cytokines, decreased NK cell lytic activity and decreased proportion of CD4+ CD45RA+ cells in the peripheral blood. The tumor size and overall stage of the disease correlated with baseline zinc status but not with PNI, alcohol intake, or smoking. Zinc deficiency was associated with increased unplanned hospitalizations. The disease-free interval was highest for the group which had both zinc sufficient and nutrition sufficient status.

Zinc deficiency and cell mediated immune dysfunctions were frequently present in patients with head and neck cancer when seen initially. Zinc deficiency resulted in an imbalance of TH1 and TH2 functions. Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations. These observations have broad implications in the management of patients with head and neck cancer.

The following news story is scientifically tied together with the study above; one explains the other. Please follow this link to read the study titled: 
Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFκB, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line



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


July, 2013|Oral Cancer News|

The New Face of Oral Cancer

Source: nursing.advanceweb.com
By Jonathan Bassett
Posted on: April 22, 2013

For decades tobacco was the primary cause of oral cancer but a more insidious culprit has emerged. 

Jerry Wilck had no reason to suspect anything. Why would he? He only smoked for a couple of years and gave it up more than 40 years ago. He didn’t drink excessively, didn’t have a family history of cancer, and took good care of himself.

In fact, maybe the only reason the 59-year-old consulted an oral surgeon about the small sore on his tongue – the result of a habit of running this particular spot along his teeth – was that there happened to be such a specialist right there in his office.
Wilck was a general practice dentist in Langhorne, Pa., and particularly attuned to anomalies of the soft tissues of the mouth. His oral surgeon took no chances and ordered a biopsy.

Wilck was “floored” the night in March 2005 when the lab report arrived by fax from the oral pathology department at Temple University in Philadelphia – squamous cell carcinoma.

Wilck immediately consulted with John Ridge, MD, PhD, FACS, chief of head and neck surgery at Temple’s Fox Chase Cancer Center. After surgical removal of part of his tongue and lymph nodes from his neck, along with a round of physical and speech therapy, Wilck is now cancer free and has full use of his jaw, throat and voice.

“I was lucky,” confessed Wilck, who retired from practice in 2009 and now spends a large part of his time speaking to dental students, advocacy groups and the media about the dangers of oral cancers. “The surgery was successful and I didn’t need radiation or chemotherapy. A lot of people in other lines of work might have ignored the symptoms. My story could have ended very differently.”


Under the Radar

Wilck was one of the fortunate cases caught early and treated effectively.

Oral cancer, along with cancers of the head and neck, respond well to treatment when detected early in their development, explained Dong Moon Shin, MD, FACP, Frances Kelly Blomeyer Chair in Cancer Research and professor of hematology, medical oncology and otolaryngology at Emory University School of Medicine in Atlanta.

A leading researcher in the field of oral cancer, Shin has authored more than 220 peer-reviewed articles and is principal investigator of Emory’s National Cancer Institute-funded Head and Neck Cancer Specialized Program of Research Excellence (SPORE), an interdisciplinary research collaborative on the forefront of discovering treatments and preventive measures for these cancers, along with other NCI-funded research programs.

Shin’s current research directions center on prevention with natural compounds (including green tea and cancer-fighting agents found naturally in vegetables), along with anti-cancer drug delivery with nanotechnology – using nanometer-sized particles with novel properties engineered for the targeted delivery of anticancer drugs into cancer cells, while sparing healthy cells. Such “smartly” formulated nanoparticles carrying anti-cancer drugs can be specifically delivered to the cancer cells, thus minimizing side effects and maximizing the anti-cancer activity of the drugs, explained Shin. “Nanotechnology has the potential to revolutionize cancer care.”

Despite these encouraging research avenues, oral cancer is a specialty area deserving of more physicians and scientists such as Shin devoted to it, said Terry Day, MD, FACS, director of the division of head and neck oncologic surgery and the Head and Neck Tumor Center at Hollings Cancer Center at the Medical University of South Carolina in Charleston.


What You Need to Know about Oral Cancer: 

Christine Brader an oral cancer activist who has survived three bouts with the disease.

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While oral cancer kills almost three times as many people as cervical cancer – one person dies every hour of every day from the disease, according to the Oral Cancer Foundation – it often receives less attention than more recognizable forms such as cancer of the skin or lungs.

“During my medical school training I began to see that these patients often had nowhere to turn,” said Day of the dearth of qualified specialists. He decided to make it his career’s mission to treat this complex, disabling, and potentially deadly subgroup of oncology.

“To look in the mirror and not recognize the person looking back at you – it’s shocking,” said Christine Brader, 49, an oral cancer activist who has survived three bouts with the disease. “I couldn’t believe it was me. Children would be scared of me out in public. I looked like a monster.”


Complex Complications

After “too many surgeries to count,” including the removal of her teeth and half of her jaw, implantation of a titanium plate (which her body rejected), and radiation and chemotherapy, Brader is now cancer free and maintains the use of her voice.

But it wasn’t an easy road. Oral cancer affects everything, said Brader – the way you look, the way you speak, your ability to eat and swallow. She spent two weeks in a medically induced coma, months in the hospital, and a grueling year-long recovery to get where she is today. She had to give up her job, her dogs, and her beloved home in Lehighton, Pa. The single mother of two had no caregiver to depend on, making the treatments even harder to get through.

“This is different than breast cancer and [cancer of] the internal organs,” said Brader, who is now independent but lives with many aftereffects and tires easily. “There’s no hiding it with clothing.”

She spends much of her time volunteering for the Oral Cancer Foundation’s public forum, helping new members and speaking at awareness events. She speaks to young people and the media regarding the dangers of smoking and chewing tobacco. She shares her story freely with the media, attends oral cancer screening events and volunteers for anti-smoking groups. She appeared in a TV commercial for Truth, a national anti-smoking prevention campaign, and the CDC’s Tips From Former Smokers Campaign.

“I try to make a difference,” Brader said. “I tell young people, ‘if someone you know starts smoking, be a friend and try to help them quit.’ It could save their life. By never starting to smoke, you never have to quit.”


Emergence of HPV

Brader began smoking as a teenager as a result of peer pressure, and continued the habit throughout her life. Her journey with oral cancer represents the traditional path – for decades, oral cancer was a disease of lifelong tobacco users that showed up later in life.

Fortunately, patient education regarding the riskiness of smoking, chewing tobacco and alcohol abuse has lowered the incidence of oral cancers from those origins, said Day.

However, a new contributing factor has moved into its place – human papilloma virus number 16 (HPV16). HPV16 is a common sexually transferred virus that is also responsible for the majority of cervical cancers in women. It’s now responsible for about 52% of newly diagnosed patients with oral and oropharyngeal cancer, according to the Oral Cancer Foundation.

The emergence of HPV16 as a risk factor has changed the demographic of oral cancers in the U.S. The disease is trending younger; the fastest growing segment of the oropharyngeal cancer population is those between the ages of 25 and 50, said Day. This is primarily due to HPV16, and cancers from this origin typically occur in the area of the throat behind the mouth, in the oropharynx, tonsils, and at the base of the tongue.

It also means oral and oropharyngeal cancers can strike in subtle silence; when in years past, a history of smoking or using chewing tobacco might prompt primary care physicians and their patients to be more diligent in screenings, HPV is a silent invader that can display little or no symptoms until it’s too late.

“HPV is definitely the coming epidemic in oral cancer,” said Brian Hill, a stage four oral cancer survivor and founder of the Oral Cancer Foundation. Hill had never used tobacco and his cancer – of an HPV16 etiology – was detected after bilaterally metastasizing and progressing into his cervical lymph nodes.

“My own journey included radiation and surgery, back in the days before IMRT [intensity modulated radiation therapy], and a very difficult and protracted recovery with significant quality of life issues, now a decade out,” Hill said.


Partners in Prevention

For Day, the ideal strategy to get a handle on the disconcerting mortality rates associated with oral cancer arises from a partnership between primary care physicians and dental professionals providing routine screenings for early-stage symptoms and swiftly referring to specialists.

Survival rates after early detection (stages 1 and 2) can be 80%-90%, while survival rates of late-stage detections (after the disease has advanced to stage 3 and 4) fall to 40%-50%, said Shin.

Head and neck screenings for cancer are relatively simple, painless, two- to three-minute visual and tactile exams performed in the dentist’s office, said Seung-Hee Rhee, DDS, FAGD, a general practice and cosmetic dentist in New York City, and spokesperson for the Academy of General Dentistry.

“You’re looking for any asymmetries, sores that don’t heal, abnormal lesions that seem suspect,” said Rhee, who makes these screenings part of her regular dental exams along with obtaining a thorough patient history to uncover potential signs and risk factors before they become major problems.

And new technology is making these screenings even easier for dentists, explained Rhee. Handheld blue-spectrum light emitters such as the Velscope shined inside the mouth will illuminate soft tissue abnormalities in different patterns than healthy tissue. This can aid dentists in detecting cancers even before they can be picked up by the unassisted eye.

“Early detection is where we’ll make a difference,” said Rhee. “[Dentists] are often the first line of defense.” She adds that HPV vaccinations for cervical cancer administered in the pre-teen years are another potential course of action being studied to help prevent these diseases. The Oral Cancer Foundation supports the use of the HPV vaccine for its potential in reducing the incidence of oral cancer, though the FDA currently prohibits drug manufacturers from making this specific claim.

“We highly encourage people who have precancerous lesions in the oral cavity or voice box [to] participate in clinical trials of chemoprevention to block the progression to invasive cancer,” said Shin.


Spreading the Word

While dental professionals work on the front lines to detect cases early, and researchers work tirelessly to unearth promising new treatments,

Wilck, Brader and a small army of former patients and activists travel the country speaking to schools, community groups and media outlets to underscore the importance of avoiding risk factors and receiving periodic screenings.

To mark Oral Cancer Awareness Month, the Oral Cancer Foundation is teaming with dental offices nationwide to offer free oral cancer screenings throughout April. Over 1200 free screening events are taking place in dental offices across America. A list is viewable at www.oralcancer-screening.org/events/.

The Head and Neck Cancer Alliance this year sponsored the 16th annual Oral Head and Neck Cancer Awareness Week April 14-20, said Day, who serves as president of the HNCA. This weeklong series of events promotes awareness and offers free screenings. Details are at http://www.ohancaw.com/.

“Reducing the high death rate associated with oral cancer is a tangible opportunity today,” said Hill. “We do need increased public awareness, coupled with an engaged professional dental and medical community doing opportunistic screenings.”

“My role these days is to keep people from taking the same path I did,” said Wilck. “If I reach just one person, it’s been worth it.”



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


Genes May Link Disparate Diseases

Source: The Wall Street Journal

Diseases that strike different parts of the body—and that don’t seem to resemble each other at all—may actually have a lot in common.

Scientists have identified the genetic basis for many separate diseases. Now, some researchers are looking at how the genes interact with each other. They are finding that a genetic abnormality behind one illness may also cause other, seemingly unrelated disorders. Sometimes diseases are tangentially linked, having just one gene in common. But the greater the number of shared genetic underpinnings a group of diseases has, the greater the likelihood a patient with one of the illnesses will contract another.

Researchers have found evidence, for example, that there is a close genetic relationship between Crohn’s disease, a gastrointestinal condition, and Type 2 diabetes, despite the fact the two conditions affect the body in very distinct ways. Other illnesses with apparently close genetic links are rheumatoid arthritis and Type 1 diabetes, the form of the disease that usually starts in childhood, says Joseph Loscalzo, chairman of the department of medicine at Brigham and Women’s Hospital in Boston.

This network approach, known among scientists as systems biology, could change the way medical specialists view and treat disease, according to some researchers. Rather than only looking to repair the parts of the body that are directly affected by illness, “we should be looking at what the wiring diagram [inside of cells] looks like,” says Albert-László Barabási, a physicist at Northeastern University’s Center for Complex Network Research in Boston.

Research work in the field is being done by geneticists, biologists and physicists at several universities and drug makers. The aim is to map how genes and the proteins they produce interact within cells in order to gain a better understanding of what goes wrong in the body to cause disease.

The information could help better predict a person’s risk of developing diseases, researchers say. It also could aid drug development. By figuring out which proteins are most critical to the normal functioning of the body, pharmaceutical companies could target those key proteins to treat disease. In some cases, drug companies may want to avoid interfering with key proteins to avoid too many unintended side effects, says Marc Vidal, director of the Center for Cancer Systems Biology at Dana-Farber Cancer Institute in Boston.

Since all the DNA in the human body was first sequenced in 2000, some 4,000 diseases with a known genetic basis have been identified, according to the National Institutes of Health. But only about 250 of those diseases have treatments, leaving many genetic puzzles left to untangle.

Scientists have long known that proteins and other molecules in the body don’t act alone. In order for the body to operate efficiently, biological substances must bind to or pass chemical messages to each other to start and stop working. The system is complex: Each gene is thought to produce, on average, five separate substances, mostly proteins, and these products interact with each other. When a protein, or group of proteins, malfunctions, it appears to give rise to a variety of distinct illnesses.

Dr. Barabási and his colleagues set out to see which diseases shared genetic underpinnings. They used information from a vast database at Johns Hopkins University in Baltimore that pulled together research from around the world on diseases and genes they were linked to. The scientists then mapped out a network indicating which diseases were seemingly connected to each other through common genes.

Of the 1,284 diseases mapped, nearly 900 had genetic links to at least one other disease. And 516 of these formed a so-called disease cluster, in which illnesses, mainly cancers, were linked to each other through multiple genetic connections.

Among the findings: Deafness shared at least one of 41 genes with over 20 other diseases, suggesting that it sits centrally in a cluster of other diseases. These include cardiomyopathy, a condition in which the heart muscle deteriorates; and ectodermal dysplasia, an abnormal development of the skin, hair, nails or teeth. Colon cancer shared at least one of 34 genes with 50 other diseases. Also in the cancer cluster were squamous cell carcinoma, a type of skin cancer, and throat cancer, but these had fewer genetic links between them. The work was published in the Proceedings of the National Academy of Sciences in 2007.

Because the diseases in the cluster were linked at the level of the cellular network, “the breakdown of one gene can lead to many apparently unrelated diseases,” says Dr. Barabási.

Another study by Dr. Barabási’s team aimed to see if their database analysis of genetically linked diseases was borne out in real life. The researchers analyzed more than 32 million Medicare hospital claims.

When patients developed multiple conditions, they were more likely to get illnesses that had close genetic links to their original disease than they were to get other disorders.

The study, published in 2009 in one of the journals of the Public Library of Science, PLoS Computational Biology, also showed that patients who developed diseases that tend to coincide with many others were more likely to die sooner than people whose diseases were more tangentially connected.

Using the data, the researchers estimated people’s likelihood of getting a second disease. A patient with ischemic heart disease, for example, has a 60% greater risk of getting Type 2 diabetes than an average healthy person.

Other biological processes also link seemingly unrelated diseases. In work published in 2008 in the Proceedings of the National Academy of Sciences, Dr. Barabási’s team identified a cluster of diseases, including diabetes and anemia, or coronary heart disease and hypertension, that appear to share common metabolic pathways, such as how chemicals are broken down or used in the body.

Dr. Vidal is currently working with Dr. Barabási and other researchers to map out all the possible protein interactions within a human cell. Dr. Vidal says about 20% of the project is finished, making it already the most complete map of the human protein network. The researchers also are developing protein-network maps for other organisms, including a yeast cell and Caenorhabditis elegans, a tiny worm with some 19,000 genes, about the same number as humans.

To test the role played by key proteins, or hubs, the researchers selectively deleted proteins or genes in the organisms and observed what happened. In the yeast cell, they found only about a quarter of the genes and proteins appeared to be essential, in that they connected to large numbers of other proteins and substances. The organism died when these hubs were removed, Dr. Vidal says.

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

May, 2012|Oral Cancer News|