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.

Print Friendly, PDF & Email
April, 2020|Oral Cancer News|

Guidelines developed for head and neck care during COVID-19

Source: www.physiciansweekly.com
Author: posted by Physicians Weekly

In a special article published online March 31 in JAMA Otolaryngology-Head & Neck Surgery, guidelines are presented for head and neck physical examination and associated procedures during the coronavirus disease 2019 (COVID-19) pandemic.

Since head and neck examinations are considered high risk in patients with suspected or confirmed COVID-19, Babak Givi, M.D., from NYU Langone Health in New York City, and colleagues developed recommendations for health care workers based on review of the literature and communication with physicians with firsthand knowledge of safety procedures during the COVID-19 pandemic.

The authors note that nonurgent appointments should be postponed to limit infection of patients or health care workers. This may include postponing appointments for patients with benign disease and for those undergoing routine surveillance after treatment for head and neck cancer. Patients should be queried by telephone about new or concerning signs or symptoms that may indicate recurrence and/or pending issues, as well as symptoms suggestive of COVID-19. In-person clinic visits should be offered to those at risk for significant negative outcomes without evaluation. To maintain relationships with patients and support assessments that can be made without in-person examinations, the use of telephone, video, or telemedicine visits should be considered. In-person examinations should be limited to patients who need a thorough head and neck examination. Detailed guidelines are provided for physical examinations and associated procedures.

“By following carefully planned routines and procedures, we will be able to provide excellent care and help protect the safety and health of our colleagues,” the authors write.

Print Friendly, PDF & Email
April, 2020|Oral Cancer News|

New blood test can detect wide range of cancers, now available to at risk individuals in clinical study at Dana-Farber

Source: www.dana-farber.org
Author: news release

In a study involving thousands of participants, a new blood test detected more than 50 types of cancer as well as their location within the body with a high degree of accuracy, according to an international team of researchers led by Dana-Farber Cancer Institute and the Mayo Clinic.

The results, published online today by the Annals of Oncology, indicate that the test – which identified some particularly dangerous cancers that lack standard approaches to screening – can play a key role in early detection of cancer. Early detection can often be critical to successful treatment.

Developed by GRAIL, Inc., of Menlo Park, Calif., the test uses next-generation sequencing to analyze the arrangement of chemical units called methyl groups on the DNA of cancer cells. Adhering to specific sections of DNA, methyl groups help control whether genes are active or inactive. In cancer cells, the placement of methyl groups, or methylation pattern, is often markedly different from that of normal cells – to the extent that abnormal methylation patterns are even more characteristic of cancer cells than genetic mutations are. When tumor cells die, their DNA, with methyl groups firmly attached, empties into the blood, where it can be analyzed by the new test.

“Our previous work indicated that methylation-based tests outperform traditional DNA-sequencing approaches to detecting multiple forms of cancer in blood samples,” said Dana-Farber’s Geoffrey Oxnard, MD, co-lead author of the study with Minetta Liu, MD, of the Mayo Clinic. “The results of this study suggest that such assays could be a feasible way of screening people for a wide variety of cancers.”

In the study, investigators used the test to analyze cell-free DNA (DNA from normal and cancerous cells that had entered the bloodstream upon the cells’ death) in 6,689 blood samples, including 2,482 from people diagnosed with cancer and 4,207 from people without cancer. The samples from patients with cancer represented more than 50 cancer types, including breast, colorectal, esophageal, gallbladder, bladder, gastric, ovarian, head and neck, lung, lymphoid leukemia, multiple myeloma, and pancreatic cancer.

The overall specificity of the test was 99.3%, meaning that only 0.7% of the results incorrectly indicated that cancer was present. The sensitivity of the assay for 12 cancers that account for nearly two-thirds of U.S. cancer deaths was 67.3%, meaning the test could find the cancer two-thirds of the time but a third of the time the test returned a negative result. Within this group, the sensitivity was 39% for patients with stage I cancer, 69% for those with stage II, 83% for those with stage III, and 92% for those with stage IV. The stage I-III sensitivity across all 50 cancer types was 43.9%. When cancer was detected, the test correctly identified the organ or tissue where the cancer originated in more than 90% of cases – critical information for determining how the disease is diagnosed and managed.

“Our results show that this approach to testing cell-free DNA in blood can detect a broad range of cancer types at virtually any stage of the disease, with specificity and sensitivity approaching the level needed for population-level screening,” Oxnard observed. “The test can be an important part of clinical trials for early cancer detection.”

The study was funded by GRAIL, Inc. As part of further validation research, Dana-Farber has joined a multi-center clinical trial of the test. The PATHFINDER study intends to enroll about 6,200 participants across the U.S. Participants in the study will have the results of the test communicated to them.

Dana-Farber researchers are aiming to enroll hundreds of individuals, mainly cancer survivors and other people who are at elevated cancer risk. Enrollment is limited to individuals who receive care through the Partners HealthCare system.

Print Friendly, PDF & Email
April, 2020|Oral Cancer News|

Insurance coverage key to timely care in head and neck cancer cases

Source: www.eurekalert.org
Author: Medical University of South Carolina

A study published in the JAMA Otolaryngology-Head & Neck Surgery examines the effect of Medicaid expansion on head and neck cancer patients, finding that the expansions under the Affordable Care Act (ACA) were associated with improved access to care for these patients and selective Medicaid expansion may worsen existing regional disparities in terms of access to care and outcomes.

Medicaid expansion refers to a provision in the ACA that called for expansion of Medicaid eligibility to cover more low-income Americans. It was determined that each state would decide whether to participate in the expansion – accept federal funds – or not. As of 2020, 37 states including the District of Columbia accepted Medicaid expansion. South Carolina is one of 14 states that has not. As a result, there are gaps in coverage for adults who have incomes above Medicaid eligibility limits yet still below the poverty level, exacerbating challenges with access to care, which is vital in the early detection of cancer.

“We performed the study because delivering timely head and neck cancer care is critical for optimal outcomes,” said Evan Graboyes, M.D., a researcher at Hollings Cancer Center at the Medical University of South Carolina and senior author on the study. The surgeon at MUSC Health specializes in the treatment of head and neck cancers.

The team analyzed data from a national sample of nearly 91,000 adults with newly diagnosed head and neck cancer who were identified from the National Cancer Database. In this observational study, researchers examined the effect that Medicaid expansion, as part of the ACA, had on the patients’ stages of cancer at the time of diagnosis as well as treatment delays for these patients.

Medicaid expansions are known to increase the percentage of patients getting treatment who have localized (stages I or II) cancer at diagnosis for cancers such as colon and breast cancer that have screening tests. Graboyes said the researchers wanted to know the effect of Medicaid expansions on head and neck cancer, which lacks a screening test, he said.

The study showed in states that expanded Medicaid as part of the ACA, patients with head and neck cancer were more likely to be diagnosed with localized (stages I to II) cancer and initiate treatment in a timelier fashion than patients in nonexpansion states. Because of the strong association with a particular stage at diagnosis and the timely treatment that leads to survival for head and neck cancer, the study suggests that Medicaid expansion that offers insurance coverage may help to improve outcomes for these patients.

“I hope that the data we produce gets referenced and is used by policy makers in the future,” Graboyes said.

Helmneh Sineshaw, M.D., lead author on the study and a principal scientist at the American Cancer Society, said the study found that Medicaid expansion provided a huge benefit to those who didn’t have access to insurance, leading to earlier diagnosis and timely treatment.

“What we find is that patients, in states that expanded Medicaid, had a greater chance of being diagnosed early, whereas patients living in nonexpansion states were likely to be diagnosed in a more advanced stage,” Sineshaw said.

Graboyes said delays in the delivery of head and neck cancers are a key driver of suboptimal survival for patients with head and neck cancers and contribute to racial disparities in mortality. Head and neck cancers are rising in number and carry a high mortality rate, with black patients even more likely to die from it.

This study adds to a growing portfolio of other health disparity studies by Graboyes and colleagues, including:

A 5-year $1.2 million grant from the National Cancer Institute awarded in 2019 to decrease mortality and racial disparities in survival for head and neck cancer patients by developing innovative interventions to improve the timeliness, equity and quality of care delivery.

A 2018 study in JAMA Otolaryngology-Head & Neck Surgery that found that ensuring head and neck cancer patients receive postoperative radiotherapy within six weeks of their surgical procedure maximizes their chances of a cure.

Graboyes said more research is needed to understand more fully how changes in insurance coverage affects patients with head and neck cancer. Although there is a strong relationship between the patient’s stage at diagnosis and timely treatment, the current study does not address whether Medicaid expansion is associated with fewer recurrences or better survival since there has not been enough time since the implementation of Medicaid expansion to answer this question.

Another limitation of the current study is that it did not analyze how Medicaid expansion was associated with changes in the cost of treatment for head and neck cancer patients. More research is needed to understand the relative costs of expansion of Medicaid provisions as compared to the assumed cost savings of catching and treating head and neck cancers in a more localized stage (I to II) versus advanced stages (III to IV), he said.

“The study is an important first step in understanding how insurance coverage affects health care delivery for patients with head and neck cancer, particularly those who, due to lack of insurance coverage, are more likely to present with advanced disease and experience treatment delays.”

Print Friendly, PDF & Email
April, 2020|Oral Cancer News|

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

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

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

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

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

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

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

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

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

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

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

Research Background

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

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

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

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

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

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

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

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

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

Research Methodology

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Print Friendly, PDF & Email
March, 2020|Oral Cancer News|

Okayama University Research: disrupting blood supply to tumors as a new strategy to treat oral cancer

Source: www.prnewswire.com
Author: press release provided by Okayama University

Researchers at Okayama University have recently published a study in Cells in which they reduced the size of oral cancer tumors by damaging the blood vessels surrounding the tumor cells.

Cancer cells have ingenious mechanisms of survival within the body. One strategy they adopt is developing a network of blood vessels around themselves as a source of blood supply. Scientists have long been investigating ways to prevent this blood flow to cancer cells. CXCR4 is a protein known to be closely involved with tumor growth. However, its exact role in tumor progression is unclear. A research team led by Assistant Professor KAWAI Hotaka and YOSHIDA Saori (graduate student, D.D.S.), Assistant Professor EGUCHI Takanori at Okayama University has now shown that CXCR4 is the main culprit maintaining the arrangement of tumor blood vessels.

Firstly they found, immunohistochemistry on human clinical specimens revealed that tumor vessels expressed CXCR4 in human oral cancer specimens. The next question to arise was whether the CXCR4-rich blood vessels were promoting tumor growth. In order to investigate this further, the oral cancer cells were transplanted into mice. Once the tumor grew in mice body, they were given AMD3100—a drug that antagonises CXCR4. When the tumors were subsequently observed under a microscope, several areas were found to necrotic. A characteristic pattern of necrosis was observed in which the tumor tissue that were at a distance away from the blood vessel was necrotic, leaving the tumor tissue close to the periphery of the blood vessel. This randomized pattern of tumor cell death was termed ‘tumor angiogenic inhibition triggered necrosis’ (TAITN) by the researchers. The wide area of tumor tissue also showed a severe lack of oxygen which was accompanied by an impairment of angiogenesis. CXCR4 inhibition thus seemed to induce tumor necrosis by damaging the blood vessels and preventing the cells of a healthy oxygen supply.

This study is the first to show the role of CXCR4 in promoting tumor growth by supplying cancer cells with a healthy, organized network of blood vessels. Strategies that can disrupt this network can be explored further as anti-cancer therapies. “CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment,” concludes the team.

Background

CXCR4: CXCR4 is a protein vital in maintaining and growing the cells that produce blood within our body. In fetuses, CXCR4 is also responsible for the formation of certain blood vessels. Incidentally, CXCR4 is also present in various forms of cancers such as breast, liver, and oral cancer. Often, tumors which show the presence of CXCR4 tend to grow faster that those without. Given its link with blood vessels and cancer progression, the research team from Okayama University sought out to investigate whether CXCR4 directly promotes cancer growth by supplying tumors with blood.

Reference

Saori Yoshida, Hotaka Kawai*, Takanori Eguchi*, Shintaro Sukegawa, May Wathone Oo, Chang Anqi, Kiyofumi Takabatake, Keisuke Nakano, Kuniaki Okamoto, Hitoshi Nagatsuka. Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer. Cell, 2019, 8(7), 761.

Print Friendly, PDF & Email
March, 2020|Oral Cancer News|

Identified: 15 genes that trigger rapid growth of head and neck squamous cell carcinoma

Source: medicalxpress.com
Author: Bob Yirka , Medical Xpress

A team of researchers affiliated with several institutions in Canada has identified 15 tumor suppressor genes that can trigger rapid growth of human head and neck squamous cell carcinoma (HNSCC) when they mutate. In their paper published in the journal Science, the group describes their reverse genetic CRISPR screen, which allowed them to analyze almost 500 long-tail genetic mutations that lead to HNSCC.

HNSCC is the sixth-most common type of human cancer, and sadly, has a low survival rate. As the researchers note, to date, most studies looking into a cure have focused on the few genes that mutate at a very high rate. This has given them a high profile. But there is another class of slower mutating gene that can lead to tumors in low numbers of patients. Prior research has shown that there are hundreds of these so called “long tail” genes, many of which have not been identified. In this new effort, the researchers used a reverse genetic CRISPR screen that allowed them to identify 15 of them.

The work focused on tumor suppressor genes that regulate cell division. When something goes wrong with them, such as a mutation, they lose their function and thus cannot prevent the cells they were regulating from mutating out of control. More specifically, the team focused their attention on the genes in cells that are part of the notch signaling pathway—in particular, those cells that develop into HNSCC tumors. All mammals have four kinds of notch receptors, which are used for communications between cells. The team carried out in vivo CRISPR screening on 484 long-tail gene mutations that had triggered the development of tumors in mice and identified 15 tumor suppressor genes. They then looked for the same types of mutations in human long-tail mutations and were able to calculate percentages for each.

The researchers conclude that 67 percent of human HNSCC cases occur along the notch signaling pathway, which suggests notch inactivation is a distinguishing characteristic of HNSCC.

Print Friendly, PDF & Email
March, 2020|Oral Cancer News|

Gabapentin shows efficacy as opioid alternative for patients with head and neck cancer

Source: www.healio.com
Author: Jennifer Byrne

For many patients with head and neck cancer, treatment-associated oral mucositis is a source of severe pain. Managing this pain is a priority for physicians and interdisciplinary care teams.

Although opioid painkillers historically have been used for this purpose, researchers at Roswell Park Comprehensive Cancer Center investigated the use of gabapentin, a drug used to alleviate nerve pain, as an alternative to narcotics for this patient population.

“Virtually all patients will require some type of pain relief or analgesic medication during the course of chemotherapy and radiation,” study author Anurag K. Singh, MD, professor of oncology and director of radiation research at Roswell Park, told Healio. “We’ve been studying better ways to improve pain control in this population because standard narcotics just don’t work that well. Patients tend to use a lot and they still experience pain, but they are sleepier.”

A dose-dependent effect
In their study, published in Cancer, Singh and colleagues randomly assigned 60 patients with head and neck squamous cell carcinoma to one of two treatment regimens: high-dose gabapentin (2,700 mg daily), progressing sequentially to hydrocodone-acetaminophen and fentanyl when needed (n = 31), or low-dose gabapentin (900 mg daily) progressing to methadone as needed (n = 29).

Safety and toxicity served as the study’s primary endpoints. Pain, opioid requirement and quality of life served as secondary endpoints.

Results showed no difference in pain between the treatment groups, but more patients in the high-dose gabapentin group did not need an opioid while receiving treatment (42% vs. 7%; P = .002). Patients whose treatment progressed to methadone rather than hydrocodone and fentanyl had significantly better quality-of-life outcomes in terms of general health (P = .05), physical functioning (P = .04) role functioning (P = .01) and social functioning (P = .01).

“The bottom line is there was a dose-dependent effect of gabapentin,” Singh told Healio. “When you go from 7% in the lower-dose arm, or 0% if you weren’t giving gabapentin at all, to 42% in the higher-dose arm, that’s a really obvious difference.”

‘Potential arrow in our quiver’
The team at Roswell Park has begun using gabapentin as a first-line approach to pain for patients with head and neck cancer, Singh said.

“We use even higher-dose gabapentin now. We go up to 3,600 mg and follow it with methadone when needed,” he told Healio. “We’re having excellent results. Currently, we’re studying whether we can add something to the gabapentin to get narcotics even further out of the equation.”

Singh and study first author Gregory Hermann, MD, MPH, resident physician in radiation medicine at Roswell Park, have started to evaluate use of the antidepressant venlafaxine (Effexor, Pfizer), which was shown in a study conducted in Europe to enhance the effects of gabapentin.

“Venlafaxine is an SNRI [serotonin-norepinephrine reuptake inhibitor] that is similar to other drugs like duloxetine (Cymbalta, Eli Lilly) that have been used for neuropathic pain in diabetes. It’s a very common medication that is used in primary care,” Hermann told Healio. “At the end of the study, we’ll be able to say whether 3,600 mg is more effective than 2,700 mg and whether venlafaxine adds anything.”

Although opioid painkillers are known for their addictive potential, opioid abuse is less likely among patients with head and neck cancer, provided they are used properly, according to Heath Skinner, MD, PhD, associate professor of radiation oncology at UPMC Hillman Cancer Center. improve significantly within a few weeks of treatment completion,” Skinner told Healio. “In that situation, the goal is to manage pain to allow for eating and drinking as much as possible. Once the acute event leading to the pain is at least partially resolved, we start to wean those medications down. So, in the acute setting, I think these medications have a very limited addiction potential.”

However, if improperly prescribed for long-term use, opioid painkillers could become addictive, Skinner said. Moreover, narcotic painkillers are associated with significant toxicities for an already sick population.

“Constipation is a common effect with opioids and can be particularly challenging for [patients with head and neck cancer] because they’re not drinking a lot of fluids or eating much food,” Skinner told Healio. “That could exacerbate a problem known to happen with narcotic-based pain medications.”

Skinner said gabapentin is a promising alternative to opioids that is readily accessible to clinicians.

“It’s available in the setting of pain control and easily prescribed,” he said. “It’s not something that’s proprietary that a clinician couldn’t acquire. It’s nice to have another potential arrow in our quiver.” – by Jennifer Byrne

Reference:
Hermann GM, et al. Cancer. 2020;doi:10.1002/cncr.32676,

Print Friendly, PDF & Email
March, 2020|Oral Cancer News|

Increasing ion channel function in cancer T cells could be new immunotherapy

Source: www.drugtargetreview.com
Author: Ameet Chimote et al.

A previously unknown T cell mechanism that could explain the reason behind decreased immune function in cancer patients has been discovered. According to the researchers, their finding may present a new immunotherapeutic target for patients with head and neck cancers.

The study, conducted at the University of Cincinnati (UC), US, revealed that a reduced interaction between a molecule called calmodulin and the ion channel KCa3.1 in the immune cells of cancer patients plays an important role in the limited function of these cells. The team performed experiments on cytotoxic T cells taken from the blood of patients with head and neck cancer.

“Cytotoxic T cells are like the soldiers of our immune system and are our body’s first line of defence against cancerous tumours,” said first author Ameet Chimote. “These cytotoxic T cells are expected to penetrate the solid tumours by migrating within the tumour mass and then secreting chemicals called cytokines to kill these tumour cells. Sadly, for some reason, these cells do not function properly in patients with cancer and they do not penetrate the tumours and attack the tumour cells, causing the cancerous tumours to grow uncontrollably.”

Lead researcher Professor Laura Conforti, explained: “Identifying the mechanism of this underlying dysfunction can help us identify molecules that we can target with drugs and ultimately restore the ability of these cells to enter and kill the tumours.” Molecules, known as ion channels, are present in the T-cell membranes and are essential for their function.

“In this study, we were able to show that the function of these channels in cells from cancer patients is decreased which results in a decreased T-cell accumulation in solid tumours,” Conforti said.

These types of channels require the signalling molecule calmodulin to bind to them in order to function to their full capacity; this is needed even more in cancer T cells. Using several intricate microscopy imaging techniques on cells isolated from the blood of cancer patients, the team found out that, when compared to T cells from healthy individuals, the cancer T cells have fewer calmodulin molecules in their membranes.

“This would mean that there is less calmodulin binding to the channels in the T cells from cancer patients,” Conforti said. “As previously stated, the channels do not function if the calmodulin does not bind to them. Thus, the decreased calmodulin binding in T cells from cancer patients results in decreased function and leads to reduced tumour infiltration and killing of the cancer cells.”

“We observed that if we increase the function of these channels by drugs that enhance their activity, the cancer patients’ T cells can penetrate the tumours better and also produce increased cytokines which can kill tumour cells,” Chimote explained. “These are exciting findings that could lead to additional treatments for patients with cancer.”

“These findings strengthen the therapeutic potentials of [these] activators, which could restore cytotoxic T-cell functionality and can ultimately lead to additional immunotherapeutic options for patients with cancer,” Conforti conlcuded.

The study was published in Frontiers in Pharmacology.

Print Friendly, PDF & Email
March, 2020|Oral Cancer News|

Another vaping hazard: less-healthy mouths

Source: www.usnews.com/
Author: Serena Gordon, HealthDay Reporter

Your lungs might not be your only concern if you’re trying electronic cigarettes — your mouth may pay the price, too. Vaping alters the natural bacteria found in the mouth, leaving you more vulnerable to oral infections and inflammation, a new study reports.

The researchers said this study is the first to show that vaping can alter the natural balance of beneficial bacteria (microbiome) in the mouth, adding to the list of potential health effects associated with e-cigarette use.

“Cells that are exposed to e-cigarettes are more susceptible to infections,” said the study’s senior author, Deepak Saxena. He’s a professor of basic science and craniofacial biology at NYU College of Dentistry in New York City.

Saxena said that e-cigarettes also lead to increased inflammation, which harms oral health. And once someone develops inflammation, it’s possible to develop white patches in the mouth called leukoplakia that sometimes develop into cancer. However, this study doesn’t have enough long-term evidence to show whether or not these changes could lead to oral cancers in the future, Saxena said.

“Our study is just one piece of this big puzzle on e-cigarettes, and I would advise people to not use them. If you have not started, don’t start. Nicotine is highly addictive,” he said.

A U.S. Centers for Disease Control and Prevention report from November suggested that as many as one out of every five U.S. high school students had vaped in the last month. That’s especially concerning since more than 2,500 Americans have been hospitalized with lung injuries traced back to e-cigarette use. An additive sometimes used when people vape is suspected as a trigger for these injuries. Fifty-four people have died as a result.

People who smoke traditional tobacco cigarettes are known to have a higher risk of gum disease and oral infections. Tobacco causes changes in the mouth’s usual environment that dampen the immune system response and let bad bacteria flourish, the researchers explained.

E-cigarettes have been considered less harmful, but there hasn’t been a lot of research, particularly long-term studies on the new devices.

For the new study, the research team recruited 119 participants, including roughly equal numbers of people who didn’t smoke or vape, people who smoked tobacco cigarettes, and those who had only used e-cigarettes. The researchers performed oral exams and collected saliva samples to test for the bacteria living in the participants’ mouths.

Almost three-quarters of tobacco smokers showed signs of gum disease or infection. Forty-three percent of e-cigarettes users also showed signs of these problems. Only 28% of the nonsmokers had signs of gum disease or infection.

When they tested for bacteria, the researchers found different types of predominant bacteria in the three groups.

“We found there is a shift in the microbiome of e-cigarette users, making it much closer to that of regular cigarette smokers,” Saxena said.

Co-author Xin Li, an associate professor at NYU College of Dentistry, noted that the researchers can’t say if e-cigarettes are more dangerous for oral health than traditional tobacco cigarettes.

“We saw a similar trend to inflammation and periodontitis (a serious gum infection), but I don’t think we can draw any conclusions about whether e-cigarettes are more harmful,” she said.

If you vape and have concerns about these potential changes, Saxena suggested taking greater care with your oral health and perhaps seeing your dentist more frequently. Li said maybe probiotics can help restore the microbiome in the mouth. But both noted these steps haven’t been studied yet.

Li said if you are using e-cigarettes to help with quitting traditional tobacco cigarettes, try to use e-cigarettes for the shortest time you can. Plan on how you’ll cut back. Don’t plan to use e-cigarettes indefinitely, she advised.

Ronald Burakoff is chairman of dental medicine at Long Island Jewish Medical Center and North Shore University Hospital in New York. He said the study’s findings make sense.

“This article describes in detail some of the adverse outcomes associated with [e-cigarette] usage. Firstly, it increases the amount of bacteria in the mouth; secondly, it promotes inflammation of the gums,” Burakoff said. He added that these changes could lead to an increased risk of infection.

Note: The study was published online Feb. 26 in iScience.

Print Friendly, PDF & Email
February, 2020|Oral Cancer News|