London Regional Cytology Training Centre

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LRCTC News - 2015

Novacyt Validating Cervical Cancer Screening Prep with Abbott HPV test
15 December 2015

European sample prep firm Novacyt has announced it will validate its Novaprep liquid-based cytology platform with an assay for high-risk human papillomavirus from Abbott.

Abbott and Novacyt will collaborate to systematically validate Novaprep's performance compared to storage vials used by competing liquid-based cytology systems for Abbott's RealTime High Risk HPV assay.

In June, Novacyt launched a molecular HPV testing service from its labs in Cambridge, UK, using Abbott's assay.

The firms will now seek to demonstrate whether the quality of cervical cancer sample preparation and preserved cell storage are critical to the performance of HPV testing, and will publish results from the validation in coming months.

Novaprep is part of the Novacyt automated processing system to select cells of interest and display them on glass slides, according to the firm's website.

"There is a critical need for a good quality sample preparation and storage system which can be universally used in the market for HPV testing across multiple HPV testing platforms," Novacyt CEO Graham Mullis said in a statement. The Abbott collaboration is "an example of major expansion opportunities that exist for Novacyt to develop other potential strategic partnerships with HPV platform providers," he added.

Mullis was previously CEO of Lab21 and became head of Novacyt when the two firms merged last year.

The company, which also has headquarters in Paris, recently raised €2 million ($2.2 million) in private financing to further automate the Novaprep system and to support introduction of a reagent rental policy.

Genomeweb Dec 14 2015 

Discovery contributes to future treatment of cervical cancer
09 December 2015

A team of scientists from Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has uncovered new molecular interactions involved in the development of cervical cancer. Proteins EDD1 and TIP60 were found to interact with the Human Papilloma Virus (HPV), which causes cervical cancer.

EDD1 is an E3 ubiquitin ligase involved in degrading cellular proteins, while TIP60 act as a tumor suppressor protein, and can both be found in the human body.

The research team, comprising Assistant Professor Sudhakar Jha, Dr Vanitha K. Subbaiah and Mr Zhang Yanzhou, found that HPV E6 oncogene interacts with EDD1 to destabilise the TIP60 protein, thereby resulting in an increased tumorigenesis. In support of this finding, experiments also revealed that an increase in cellular TIP60 levels could inhibit cancer cell growth.

The findings of the study were first published online in the journal Oncogene on 3 August 2015.

Previous studies have implicated the roles of both EDD1 and TIP60 in cancer progression however their roles in viral-mediated cancers have not been well-explored. Notably, this study is one the few which explores the functional role of TIP60 in viral-mediated cancers. It is also the first to suggest EDD1 as a novel interacting partner of TIP60, a finding which advances the understanding of how this pathway could contribute to cancer progression not only in cervical cancer but also in many other cancer types such as breast and ovarian cancer.

Oncoviruses (cancer-causing viruses) are said to account for about 12% of new cancer cases annually. Cervical cancer, which is the cancer of the cervix, accounts for about 8% of all cancer cases worldwide and is the fourth most common cause of cancer and deaths from cancer in women. Infections with cancer-causing viruses such as HPV are a major health burden worldwide, and contribute significantly to patient mortality. Availability of prophylactic vaccines hold promises in the prevention of the disease, but unfortunately does not help already-infected patients.

Said Asst Prof Jha, "We are excited about this discovery. Understanding how the two proteins interact with HPV E6 oncogene is a critical first step towards developing methods to target HPV-induced cancers as there is no specific treatment available at the moment. Our team is currently developing methods that can be used to screen small molecule inhibitors of EDD1 and also looking into how the regulation of TIP60 levels can be translated into therapeutic advances for the treatment of viral-mediated cancers such as cervical cancer. If successful, this could potentially be a significant breakthrough."

 Explore further: Some types of papilloma virus might prevent cervical cancer

More information: V K Subbaiah et al. E3 ligase EDD1/UBR5 is utilized by the HPV E6 oncogene to destabilize tumor suppressor TIP60, Oncogene (2015). DOI: 10.1038/onc.2015.268 

Study tests method to boost immune system response to inoperable cervical cancer
09 December 2015

A clinical trial to determine whether an investigational DNA cancer vaccine (INO-3112) is safe and can stimulate the immune systems of women with inoperable, recurrent or progressive/persistent cervical cancer to attack malignant cells.

INO-3112 is a DNA immunotherapy. It targets the E6 and E7 proteins of human papillomavirus (HPV) types 16 and 18, a common cause of cervical cancers. It combines two investigational products, VGX-3100 and INO-9012.

VGX-3100 consists of a small piece of DNA that targets HPV. INO-9012 is an immune system activator. It expresses interleukin-12 (IL-12), which can potentially enhance the immune response.

INO-3112 is injected into a muscle followed by electroporation, a technique that uses controlled, millisecond electrical pulses that make it easier for the DNA plasmids to enter muscle cells.

Once the DNA plasmids enter muscle cells, they instruct those cells to produce the E6 and E7 proteins as well as IL-12. These proteins are then presented to the immune system, which alerts the body that an infection and cancer is present. The body, in return, produces an immune response that attacks virally infected cervical cancer cells.

"This one-of-a-kind immunotherapy protocol for cervical cancer subjects, now open to subjects with recurrent or persistent disease, has the potential to have a significant impact," said Yasmin Hasan, MD, assistant professor of radiation and cellular oncology at the University of Chicago and director of the study.

A previous phase II study of VGX-3100 alone to treat women with high-grade cervical cancer showed that 49.5 percent of women who received VGX-3100 had regression to low-grade neoplasia (CIN1) or to no disease. This is almost 20 percentage points higher than women who received only a placebo (30.6%).

Clearance of the HPV in conjunction with regression of cervical lesions occurred in 40.2 percent of women who received VGX-3100, compared to 14.3 percent of women who received the placebo.

The researchers plan to enroll a total of 30 subjects in two study groups. One is for patients with newly diagnosed but inoperable cervical cancer who have completed chemoradiation therapy.

The other is for subjects with recurrent or progressive/persistent cervical cancer. Subjects will receive four doses into a muscle in the arm over the course of three months.

Enrolling in this study is a commitment. Study participants must return to the clinic every two weeks for the first four months, every eight weeks for the next seven months and every three months for follow-up visits. Participation involves study drug administration, scheduled blood tests, biopsies and swabs, and necessary medical imaging—such as PET and CT scans—which are part of standard follow-up. Over the three-and-a-half-year course of the trial, participants will undergo multiple blood draws at specified intervals.

There are potential risks associated with this study. For example, intramuscular injections can cause pain at the site of the shot. The electroporation device, which uses needles and electrical current to increase DNA uptake, also causes temporary discomfort.

To be eligible for the study, participants must have HPV 16 or 18 positive cervical cancer and have completed standard chemoradiation therapy. Subjects with recurrent or persistent cervical cancer will be eligible if they meet the inclusion criteria.

Although an effective vaccine to prevent HPV infection was approved by the United States Food and Drug Administration in 2006, cervical cancer still remains a major problem worldwide. It is the second leading cause of cancer death in women with almost 500,000 new cases each year and nearly 275,000 deaths.

The trial, known as the "Open-Label, Safety, Tolerability, and Immunogenicity Study of VGX- 3100 and INO-9012 Delivered by Electroporation in Women with Cervical Cancer after Chemoradiation," is also open at the University of Michigan, Ann Arbor, and Columbia University in New York City.

 Explore further: FDA clears Avastin for late-stage cervical cancer Novmber 2015

ACOG Updates Recommendations to Include 9-Valent HPV Vaccine
14 July 2015

Gardasil 9 (Merck), the new vaccine protects against the original four strains in the quadrivalent vaccine, as well as five additional strains, all of which are responsible for cervical, vulvar, vaginal, penile, and anal cancers.

The US Food and Drug Administration licensed the new formulation, Gardasil 9 (Merck), in December 2014. The new vaccine protects against the original four strains in the quadrivalent vaccine, as well as five additional strains, all of which are responsible for cervical, vulvar, vaginal, penile, and anal cancers. Another earlier bivalent vaccine protects against strains 16 and 18, which are responsible for the majority of cervical cancers. The 9-strain vaccine is more than 99% effective in reducing HPV disease from strains 6, 11, 16, and 18, and it is 96.7% effective in reducing disease from strains 31, 33, 45, 52, and 58.

Despite existing recommendations for HPV vaccination in adolescents, only about 50% of US girls between the ages 13 and 17 years have received at least one dose, and 33% have received all three doses. The CDC estimates that an immunization rate of at least 80% would prevent an additional 53,000 cases of cervical cancer during the lifetimes of those currently younger than 12 years.

Neither the CDC's Advisory Committee on Immunization Practices nor ACOG routinely recommends anyone receive the 9-strain vaccine if he or she received all three doses of the previous vaccine. However, providers can use the 9-strain vaccine to complete any series for males or females who received one or two doses of the earlier vaccines.

The safety profile of the 9-strain vaccine resembles that of the quadrivalent vaccine, with the exception of greater redness and swelling at the injection site in the newer vaccine. After more than 60 million doses of HPV vaccine administered, "there are no data to suggest that there are any severe adverse effects or adverse reactions linked to vaccination," the committee writes. "Obstetrician–gynecologists or other providers should counsel patients to expect discomfort after vaccination and that such discomfort is not a cause for concern," they write, although anyone with a previous life-threatening reaction to the HPV vaccine or its components, including yeast, should not receive the vaccine.

The committee does not recommend routine pregnancy testing or routine HPV testing before a patient receives the vaccine, and those in the target age range who may already have a positive HPV DNA test should still receive the vaccine. Despite reassuring safety data for HPV vaccination during pregnancy, ACOG recommends that women do not receive the vaccine while pregnant. Lactating women may receive it.

Human Papillomavirus Vaccination." ACOG. Published online June 26, 2015  Tara Haelle June 29, 2015        


HPV Screening Alone May Miss Cervical Cancer
14 July 2015

Human papillomavirus (HPV) screening used on its own can miss cervical cancer.

Human papillomavirus (HPV) screening used on its own can miss cervical cancer, according to a study that found that more cases were detected when it was used in combination with cytology.

The study was published online April 10 in Cancer Cytopathology.

In a "real-world" population of more than 250,000 women, 526 cases of confirmed cervical cancer were detected. HPV results were negative in 18.6% of these women, Pap test results were negative in 12.2%, and both test results were negative in 5.5%.

This translates into an almost three-fold improvement in the rate of cancer detection with cotesting, compared with HPV testing alone, the researchers report. So women who actually have cervical cancer are more likely to have a negative result with HPV testing alone than with cotesting.

In addition, for the detection of grade 3 cervical intraepithelial neoplasia (CIN), a positive Pap test is better than either a positive HPV test alone or positive cotests (26.3% vs 25.6% vs 10.9%; P < .0001).

These data are "a reminder that the limitations of HPV testing are greater than have been advertised, especially in the most important group — the women who are developing cervical cancer," said study author R. Marshall Austin, MD, PhD, medical director of cytopathology and staff pathologist in gynecologic and breast surgical pathology at Magee–Womens Hospital in Pittsburgh.

It well established that persistent carcinogenic HPV infections underlie virtually all cases of cervical cancer, and testing for HPV is an attractive proposition for detecting this cancer.

"But what isn't acknowledged or taken into account in studies is that by the time patients are diagnosed with cancer, they may be HPV-negative because of a low viral load," Dr Austin told Medscape Medical News. In addition, "there are some cancers without underlying HPV, and not all types of HPV are included in the standard test."

What has been misleading in the development of an HPV standalone test is that the clinical trials did not use cancer as an end point. "Instead, they looked at precancerous lesions, most of which will never progress to cancer," Dr Austin pointed out. "This is almost never discussed, but our paper adds evidence as to why it is important to look at women with invasive cancer."

"The recommended strategy is cotesting," he said. "That is the most effective method and gives patients the most protection."

In 2011, the US Food and Drug Administration (FDA) approved the use of HPV testing in conjunction with or as a follow-up to cell cytology for women 30 years and older. It was also approved for use in women 21 years and older as a follow-up if cytology results were abnormal.

In April 2014, the cobas HPV test was approved as a standalone screening test for cervical cancer. The test can recognize DNA from 14 high-risk types of HPV, including types 16 and 18, which are responsible for 70% of cervical cancers. Data from the prospective ATHENA study, which involved 47,208 women 25 years and older who underwent routine cervical exams, supported its approval as a primary screening tool for cervical cancer.

Recent studies have argued that HPV-only screening might be more effective than Pap-only screening for both CIN and cancer, Dr Austin and his colleagues note. However, those prospective trials were conducted in well-defined, controlled circumstances in select populations, and they usually compared HPV-only testing with Pap-only testing, rather than the guideline-recommended cotesting.

In their study, Dr Austin's team reviewed data from 256,648 women who were 30 to 65 years at the time of cotesting and who had a cervical biopsy specimen obtained within 1 year of screening.

In this cohort, 74.7% of the samples were positive for HPV, 73.8% had an abnormal Pap test (atypical squamous cells of undetermined significance or worse), 89.2% had a positive cotest, and 1.6% exhibited CIN of at least grade 3.

Sensitivity was higher for CIN of at least grade 3 in women who had positive cotest results, and specificity was higher in women who had only a positive Pap test.

Table. Accuracy of Testing

Measure                                    Cotesting    Pap Only    HPV Only
Sensitivity, %                              98.80          91.30          94.00
Specificity, %                              10.90          26.30          25.60
Positive predictive value, %           1.76          1.97              2.00
Negative predictive value, %          99.83       99.50             99.6

This study was conducted by Quest Diagnostics Health Trends. Dr Austin has disclosed no relevant financial relationships. Some of his coauthors are employees of Quest Diagnostics.

Cancer Cytopathol. Published online April 10, 2015.        Roxanne Nelson, RN   April 22, 2015 (abstract) 


Despite CDC and doctors' recommendations, parents still wary of HPV vaccine
17 February 2015

Human papillomavirus or HPV is the most common sexually transmitted infection.But almost ten years later, the Centers for Disease Control and Prevention says vaccination rates are still "unacceptably low."

It's a vaccine to help prevent a deadly form of cancer that many parents are hesitant to allow their children to receive. More than 4,000 women die of cervical cancer each year. The American Cancer Societyrecommends women aged 30 to 65 have an HPV test with their pap smear every five years to detect cervical cancer. ACS also recommends that girls receive the HPV vaccine at age 11 or 12.

But almost a decade later, many of the same concerns remain. A July 2014 CDC study found the top five reasons parents did not vaccinate their children against HPV were: A lack of knowledge about the vaccine, feeling that it was not necessary, safety concerns or side effects, their doctor did not recommend it to them and finally, their child was not sexually active. The same study found just 57 percent of girls between 13 and 17 received the first of three doses of the vaccine. In Maryland, that figure was even lower--at 50 percent.

Dr. Steven Adashek, a Baltimore-area OB-GYN said it is up to doctors to explain to parents what the vaccine is and why kids need to be vaccinated as pre-teens.

 "We are under-vaccinating mostly because it is sometimes uncomfortable to have the discussion," he said. "It's how we present it to patients. If we said, this is the time for your vaccine. The parents who want to protect their children say, of course."

 The CDC recommends both girls and boys be vaccinated against HPV at age 11 or 12.

 "It is almost 100 percent effective, if given before exposure," Dr. Adashek said. "Unfortunately, with this vaccine, if you get exposed to HPV and then get the vaccine, it does no good. So waiting until the child is about to have sex, in high school and college, is too late."

 Almost every sexually active person will acquire HPV in their lifetime. For most people, it will clear up on its own. But in the most serious cases, HPV can cause cancers of the cervix, genitals, anus and throat. Each year, almost 18,000 HPV-related cancers occur in women, about 9300 in men. Gardasil 9, just approved by the FDA in December, has the potential to prevent 90 percent of cervical, vulvar, vaginal and anal cancers.

 "I always tell moms, if I had a vaccine that would prevent 90 percent of breast cancer, you would sue me if I did not give it to your daughters," Dr. Adashek said.

 Dr. Adashek hopes that the HPV vaccine will one day become as commonplace as the Hepatitis B vaccine, which many parents don't hesitate to give to their children.

 "We give babies when they're born, Hepatitis B vaccines," he said.  "Hepatitis B is a sexually transmitted disease that causes real life disease and real life deaths in adults. So we give children the vaccine to protect them against it. HPV should be viewed the same way. Because we can prevent 70 and soon 90 percent of cervical cancers, prevent them, that means you don't have to go through treatment, you don't have to get surgery, you don't have to get radiation, you actually don't ever get the disease. It's criminal to die of a disease that's totally preventable."

 Dr. Adashek said we may not see the true effect of the vaccine on the occurrence of HPV-related cancers until several years, even decades down the line, when the generation already vaccinated and getting vaccinated now gets older. Though a recent study found that states with higher cervical cancer rates, tended to have low HPV vaccination rates among young women.

 Doctors say this is a very safe vaccine. Since FDA approval in 2006, health care workers gave more than 67 million doses of the vaccine. People reported some 25,000 adverse effects. The most common side effects are similar to other vaccines and include pain, redness or swelling at injection site, fever, headache and fainting. Ninety-two percent of these reactions are classified as non-serious. 28th Jan 2015

Cervical Cancer Awareness Campaign Uses Smeared Lipstick Selfies To Encourage Pap Smears In UK
17 February 2015

Jo’s Cervical Cancer Trust in the United Kingdom has launched a selfie campaign like none other called #SmearForSmear

The clever campaign title is trying to spread awareness in order to get more women into doctors’ offices for their routine Pap smears.

Throw on some lipstick for the camera, smear it however you like, take a selfie, and post it on social media with the appropriate hashtag. It’s a simple yet effective way of reaching out to younger populations of women who may not be as aware of the importance of getting tested.

"The number of women taking up their cervical screening invitation in the UK is going down year on year and this is extremely worrying," Jo's Cervical Cancer Trust spokeswoman Maddy Durrant told the Huffington Post "Smear tests can prevent women from ever reaching a diagnosis, or can ensure early diagnosis so treatment plans are less extensive and side effects less impactful. Similarly, an early diagnosis means a better chance of survival. Quite simply, a smear test could save a woman’s life."

An alarming 20 percent of women actually think cervical screening is a superfluous health test for women, but little do they know about 4,100 womenwill die from cervical cancer in the United States by the end of 2015. Cervical cancer can be found early, and sometimes prevented entirely, by simply having a regular Pap smear test at your gynecologist’s office. Because of smear tests, cervical cancer is one of the most successfully treated cancers of all. However, if found in its latest stage, there's only a 15 percent chance of survival, according to the American Cancer Society

In the UK, one in three women between the ages of 25 and 29 are skipping testing, which only increases the likelihood of someone with cervical cancer slipping through the cracks. Going untested means choosing risks we can’t afford with our health. Hopefully, a little smudge of rouge for Instagram can boost the numbers to a higher compliance and save some lives along the way. Celebrities, such as Georgia May Jagger and Rita Ora have come onboard to help the campaign grow in popularity by reaching out to their target audiences flooding social media.

"We understand it’s near impossible to replicate a viral campaign like the Ice Bucket Challenge as these campaigns often start organically and require a little bit of magic," Durrant said. "Smearing lipstick was an obvious — and very visual — choice. Using a hashtag that directly links the cause with the image was also key."  Feb 1, 2015 04:32 PM By Samantha Olson