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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    Medicalxpress.com/news 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    www.medscape.com        

 

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)  www.medscape.com 

 

Doctors' assumptions on sex heighten lesbians' cervical cancer risk: study
25 February 2015

Lesbians may be at higher risk of cervical cancer because they get fewer screenings than heterosexual women, due partly to doctors' sometimes incorrect assumptions about their sexual history

Although nearly all cases of cervical cancer are attributable to a human papillomavirus, or HPV, infection, healthcare providers often do not encourage lesbian patients to get regular HPV screenings, the researchers found.

That is because the disease is most commonly transmitted during heterosexual sex and doctors may wrongly assume lesbians have only had sex with other women, despite studies that have found most lesbians and their partners have had sex with men, researchers said.

A lack of testing can also occur at times because lesbians lack insurance or do not always have a need for pregnancy prevention checkups, or may not want to share their sexual orientation with doctors, the researchers said.

"If we are serious about reducing the rates of cervical cancer in lesbians, an unbiased health assessment by a provider must ask the question: 'Do you have sex with men, women or both?'" University of Washington School of Nursing professor Joachim Voss said in a statement.

Voss and Lindsay Waterman, an adult nurse practitioner at the Seattle-based university, analyzed medical literature and studies, including Pap screen rates, between 2000 and 2013, published in last month's Nurse Practitioner journal.

"Ob-gyns should provide the same comprehensive gynecologic health care to lesbians and bisexual women as they do to heterosexual women, including Pap tests," the American College of Obstetricians and Gynecologists has said.

Researchers were unable to quantify the overall rates of cervical cancer among lesbians compared with heterosexual women because cancer patients are not typically asked their sexual orientation, Voss said.

Screening every three years can detect abnormal cervical cells and pre-cancerous lesions in women ages 21 to 65, but lesbians are screened at rates 5 percent to 18 percent lower than heterosexual women because of the perceived lack of risk exposure, the researchers said.

HPV can be transmitted between women partners through both skin-to-skin contact and contact with sex toys.

Nearly eight of every 100,000 U.S. women are diagnosed with cervical cancer annually, the researchers said.

 

Reuters 10th Feb 2015 -Seattle

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

Urine-based HPV test 'feasible alternative for cervical cancer screening'
25 September 2014

A new study published in The BMJ claims that a simple urine test for human papillomavirus could increase screening uptake among women by offering them a non-invasive option.

According to the researchers of this latest study - including Dr. Neha Pathak of the Women's Health Research Unit at the Blizard Institute of Barts and the London School of Medicine and Dentistry in the UK - past studies have indicated that an alternative to Pap testing could be to test urine for signs of HPV. But they note the accuracy of such testing has been unclear. Dr. Pathak and colleagues set out to compare the accuracy of urine HPV testing against the collection of cervical samples.They have analyzed the results of 14 studies that looked at both forms of testing, involving a total of 1,443 women who were sexually active.They found that on average, the sensitivity of urine HPV testing - the proportion of positive results correctly identified - was 87%, while specificity - the proportion of negative results correctly identified - stood at 94%, compared with collection of cervical samples. When using urine HPV testing to identify HPV types 16 and 18 - the primary causes of cervical cancer - sensitivity was 73% and specificity was 98%.Accuracy of the urine HPV test increased when the first urine sample of the day, referred to as the "first-void," was used.

They note, however, that their results should be "interpreted with caution" because of the variation found between individual studies, which could lead to overestimation or underestimation of results.

"The consequences of overestimation are especially important as they can lead to unacceptable morbidity and mortality," say the researchers. "False negative results would lead to missing cases of precancerous or cancerous lesions, and false positive results would lead to overinvestigation and anxiety Both scenarios could easily result in a lack of trust in HPV testing."

The team believes more studies are warranted to further investigate the accuracy on urine HPV testing, and to look at the feasibility and costs of this method in a clinical setting.

In an editorial linked to the study, Harry C. Kitchener and Gemma L. Owens, of the University of Manchester in the UK, say urine HPV testing could be an achievable and beneficial alternative to HPV testing of cervical samples.

"In well-resourced health systems, self-sampling could be used for women who are reluctant to attend for regular cervical screening," they note. "In lower income countries that lack infrastructure, self-sampling might even be beneficial and cost-effective for all women who are eligible for screening. More research is now required to identify the true clinical performance and acceptability of urine testing for HPV in both settings."

 

Accuracy of urinary human papillomavirus testing for presence of cervical HPV: systematic review and meta-analysis Neha Pathak et al., published in The BMJ, 16 September 2014.

Editorial: Urine testing for HPV, Harry C. Kitchener, Gemma L. Owens, published in The BMJ, 16 September 2014

Finding better ways to treat, prevent HPV
12 September 2014

Gathering of the brightest minds to discuss new advances in HPV research – and what’s still needed

Twenty-nine years ago, scientists didn’t know what caused many of the genital-tract cancers they studied, much less how to stop them.

Today, not only has human papillomavirus been pinpointed as  the viral perpetrator behind nearly all genital-tract and some head and neck cancers, there’s now an incredibly effective vaccine that can prevent high-risk HPV infections from ever developing into cancer.

“You can almost say on the street, ‘I’m doing HPV research’ and ordinary people will know what that is,” said Aaro Turunen, an HPV researcher from the University of Turku in Finland.  “It’s a sexy subject, especially for the media.”

While scientific advancements, public awareness and yes, media coverage, have grown exponentially in the last three decades, there is still much to learn and do – particularly with regard to getting the vaccine to the people who most need it, both here in the U.S. and around the world.

That’s where the International Papillomavirus Conference, currently in its twenty-ninth year, comes in.

The HPV2014 conference, now underway at the Washington State Convention Center in Seattle, has drawn the brightest minds in HPV research, including nearly 1,300 basic scientists, public health researchers, physicians, providers and others dedicated to eliminating the suffering caused by the human papillomavirus. The goal of the conference is to share cutting-edge scientific advances in the field of HPV infection and disease and come up with new ways to collaborate to advance science and public health.

The conference officially began today but kicked off early Wednesday with two days of clinical and public health pre-conference workshops covering everything from HPV infection and disease in HIV-infected men to implementing and evaluating two-dose vaccine schedules to a peek at the next generation of HPV vaccines coming down the pike.

Conference chair Dr. Denise Galloway, who holds a joint appointment with Fred Hutch’s Human Biology and Public Health Sciences divisions, said she was thrilled the conference was taking place in the Hutch’s back yard.

“I’m excited that the HPV meeting will be here as it recognizes the strength and breadth we have in HPV research in Seattle,” she said. “Our main goal was to provide a setting where people from all over the world who study various aspects of papillomavirus biology, disease and prevention could come together to share their data and ideas.”

Galloway, who has been investigating the link between cancer and viruses since 1978, was instrumental in both discovering HPV’s association with many cancers and paving the way for a vaccine able to check cervical cancer before it starts in hundreds of thousands of women worldwide.

These days, she’s researching B cell memory in order to determine how effective the HPV vaccine is over a person’s lifetime.

“If a vaccine is going to work, it’s not just important how well this will stimulate the immune system, which you can measure within a couple of months after you get the vaccine,” she said. “You also want to know, is it going to be durable? Are you going to have a response 10 years, 20 years or 30 years from now? We’re trying to figure that out by looking at the cells that are there and available to make the responses in 10 and 15 years.”

Long-term efficacy is just one of many topics covered at the conference, which boasts an ambitious lineup of over 700 abstract presentations, nine satellite sessions, four symposia and four plenary sessions, all highlighting basic, clinical and public health science topics ranging from molecular virology to novel cancer screening and treatment strategies to global public health.

Also represented at the conference are pharmaceutical companies such as Merck, producer of the HPV vaccine Gardasil, and Roche, developer of the cobas HPV test. Also present are medical device manufacturers such as QIAGEN, which along with support from Seattle’s PATH, developed the careHPV test, a field-friendly and inexpensive test that allows women, particularly in developing countries, to gather screening samples themselves.

On Friday morning, Dr. Freddie Bray of the International Agency for Research on Cancer talked about the need for quality data and cancer registries, especially in developing countries and and Dr. Scott Ramsey of Fred Hutch’s HICOR division spoke about the value of prevention-based studies and interventions.

“There was a nice study done by the CDC a few years ago that looked at the cost effectiveness of HPV vaccination of young girls in the U.S.,” he said. “This is a slide I wish I could produce as a health economist more often. HPV vaccines in this population are among the most cost effective interventions we have in the U.S.“

Despite the efficacy and overall cost effectiveness of the vaccine, however, delivery and implementation of the vaccine remain a problem, said Galloway.

“We need to find better strategies to get girls and boys to take the vaccine,” she said. “In other countries, where they have school-based programs, they’re doing much better than in the U.S.”

Saturday’s plenary will feature talks on the natural history of HPV infection and cervical cancer, the natural history of oral HPV and its progression of oropharyngeal cancer and the “genetic arms race” between host and viral genomes, presented by Fred Hutch’s Dr. Harmit Malik. Vaccines will be covered in the Sunday plenary session with talks on Merkel cell carcinoma by Fred Hutch’s Dr. Paul Nghiem, an update on Australia’s HPV vaccination program and a presentation on vaccine dosage.

“There is a growing consensus of switching from three doses to two and it will be exciting to hear more about that,” said Galloway.

Finnish researcher Turunen, whose research focuses on the relationship between HPV and the Epstein-Barr virus, said he was amazed at how much the field – and the International Papillomavirus Conference -- had grown, adding that a much smaller HPV conference took place in Seattle 20 years ago.

Ref Fred Hutch Research Centre News 22.8.14

“Both HPV researchers were there,” he quipped.

Startup’s antiviral drug combats HPV, new study shows
12 September 2014

San Diego startup Hera Therapeutics is developing a topical antiviral drug that attacks human papillomavirus -

The drug candidate, HTI-1968, blocked the replication of HPV-16, HPV-18 and HPV-11 cells, according to the NIAID-sponsored study. The work was conducted primarily by University of Alabama researchers Louise T. Chow and Thomas Broker. The drug could be effective against more, CEO Karl Hostetler said, but these are the only three HPV strains available for screening through the NIH.

“We believe it’s possible the drug’s pangenotypic – that is, active against all strains – but can’t prove that because these are the only three strains available right now for testing,” Hostetler said.

Hera Therapeutics doesn’t yet know the exact steps the antiviral takes, but it essentially blocks the pathway that allows the virus to make its DNA using cellular enzymes, Hostetler said.

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“It’s a nucleoside analog, and that’s all we’re wiling to say about it right now,” Hostetler said.

The nascent company has started safety testing for the drug, and hopes to file an IND by late next year. It is working with a contractor to develop a prototype to combat the sexually transmitted infection, Hostetler said.

Hostetler, a professor emeritus at University of California, San Diego, previously founded three other companies - Vical, Chimerix and Triangle Pharmaceuticals. He founded Hera Therapeutics in late 2012. It has received $2.4 million in funding to date, including $1.3 million last month.The startup is housed in the Janssen Labs accelerator in San Diego.

HPV is painfully common, with 6.2 million Americans getting newly infected each year, according to the CDC. Nearly 4,000 women die each year from invasive cervical cancer, which is largely a result of an undetected case of the virus. However, outside of the Gardasil vaccinethat’s not really available to women older than 26, or those who have already contracted it, there isn’t much in the way of HPV prevention or treatment. Hostetler expounds on why there’s been a dearth of HPV antivirals on the market:

“Over the years, there haven’t really been many antiviral drugs developed for HPV, probably because the screening process is so difficult.

Most antivirals interfere with the viral polymerase that makes the DNA or RNA. The thing about HPV is that if it does not have its own polymerase enzyme, it hijacks some of the human cell DNA synthesizing pathways to make it viral DNA, and that’s led a lot of people to believe that you couldn’t develop a nucleoside that would be selective for the virus.

HIV, for instance, has a retroviral polymerase, and AZT and tenofivir and lots of other drugs inhibit that. That’s great. But here’s a virus that doesn’t have a polymerase, so it’s been very difficult historically to find things that will selectively block it.”

However, a number of immunotherapy candidates are in clinical testing to treat HPV, so it’ll be worth watching to see which therapies shake out as medically – and commercially – viable

Ref Medcity News by Meghana Keshavan  August 25, 2014

 

Small study: Text message-based cancer screening education may help at-risk minority groups
12 September 2014

In a recent JMIR study, a team of researchers in Minnesota explored the potential of mobile health to reach people who sometimes fall through the cracks of the healthcare system.

They found that a text message intervention could help Korean American women, a group that has one of the highest cervical cancer mortality rates in the United States, seek preventative screenings (Pap tests).

“A variety of structural and cultural factors act as barriers to screening for Korean American women,” the authors write. “Structural obstacles include health access due to inadequate health insurance, expense, time constraints, and language limitations. Cultural barriers to cervical cancer screening encompass lack of knowledge regarding cervical cancer and cervical cancer screening, a wrongly held belief that screening is unnecessary in the absence of symptoms or at young ages, cultural modesty or embarrassment, lack of culturally appropriate health care providers, and fear of receiving negative screening results.”

Researchers designed a text message based intervention for a study group of 30 Korean American women, 90 percent of whom had been living in the United States for less than 9 years and nearly two-thirds of whom had a family history of cancer. Based on a screening conducted ahead of time, women received messages tailored to their specific needs; for instance, a woman who had scored high on a pre-test scale for cultural embarrassment might receive the message “We understand it is a bit embarrassing to get it done. But do it for you! Your happy cervix will appreciate it!” in addition to the other messaging. Participants received messages for seven days, and many of them were interactive, prompting responses from the participants.

Results were mixed. A week after the intervention, participants were generally more knowledgable about cervical cancer and the importance of screening. Significant differences were observed in general knowledge, knowledge of risk factors, and knowledge about and attitudes toward the Pap test. But when asked whether they planned to get a screening in 1 year, 3 months, 1 month, or not at all, the increase wasn’t statistically significant, though this could be owing partly to the small sample size. At a three month follow-up, just seven of the 30 women had actually gone in to get screened for cervical cancer.

Nonetheless, researchers are hoping to follow up the study with a larger RCT, possibly modifying the experiment design to deliver the messages over a shorter time or to incorporate a smartphone app.

“Given the widespread use of mobile phones (98 percent) and smartphones (83 percent) among young adults, a mobile phone-based health intervention could be a cost-effective method of reaching hard-to-reach populations with tailored, individual messages that cover broad content areas and overcome restrictions to place and time of delivery,” they wrote. “Our developed model could be expanded for delivery to different age groups of Korean American women to promote additional types of cancer screening, such as colonoscopy or mammogram. It could also be used with other underserved minority groups. Vietnamese, Hmong, and Laotian American women face similar barriers to cancer screening and report high cervical cancer incidence and mortality. It is likely that these populations may also benefit from a similarly tailored intervention approach.”

Ref: MobiHealth News By: Jonah Comstock  Aug 28, 2014

 

HPV vaccination programme schedule changing from 3 to 2 doses
16 May 2014

Change follows on from advice from the Joint Committee on Vaccination and Immunisation (JCVI).

A letter from Public Health England, the Department of Health and NHS England was disseminated today detailing changes to the human papillomavirus (HPV) vaccination programme. From September 2014, the schedule will change from 3 to 2 doses. The HPV vaccine is currently routinely offered to girls aged 12 to 13 in school year 8.

This follows a recommendation from the Joint Committee on Vaccination and Immunisation (JCVI) this March. Recent research shows that antibody response to the 2 dose schedule in adolescent girls is equivalent to the response that correlated with protection against persistent infection and precancerous lesions in the initial vaccine trials. Both Gardasil and Cervarix have been approved for use in a 2 dose schedule.

Since 2008, the first year of the routine vaccination programme for 12 to 13 year old girls, acceptance of the vaccine has been consistently high. In the school year starting September 2012, 89.6% of girls received at least 2 doses of vaccine, and 86.1% completed the 3 dose course. Recent data indicate that the HPV vaccination programme has successfully reduced vaccine-type HPV infections in sexually active young women in England[1]. It is hoped the new dosage schedule will build upon this success.

Unlike the current schedule, the 2 doses of the new schedule must be given at least 6 months and not more than 24 months apart. Consult the complete letter for detailed guidance on the recommended gaps between the 2 doses.

Importantly, girls who have received 2 HPV vaccine doses under the 2013 to 2014 programme should still receive their third dose, to complete their course. An updated Q & A for health professionals and revised information leaflet will be available from mid-June.

For further information, please read the full letter outlining programme changes

Enquiries: immunisation@phe.gov.uk

  1. Mesher D, Soldan K, Howell-Jones R, Panwar K, Manyenga P, Jit M, Beddows S, Gill ON. Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England. Vaccine 2013; 32(1):26-32.

DNA or Pap?
17 April 2014

Some women's health advocacy groups are pushing the US Food and Drug Administration to not approve Roche's cobas HPV test to replace the Pap test as a first-line choice for cervical cancer screening, the AP reports.

FDA is considering making the move, as its Microbiology Devices Panel of the Medical Devices Advisory Committee just last month recommended using the cobas, which tests for HPV DNA, as a first-line option for assessing cervical cancer risk in women 25 years and older.

Groups like the American Medical Women's Association and Our Bodies Ourselves say that moving away from the well-tested Pap test would be "a radical shift" that could lead to higher medical costs, over treatment, and confusion.

"It replaces a safe and effective well-established screening tool and regimen that has prevented cervical cancer successfully in the US with a new tool and regimen not proven to work in a large US population," the groups say in a letter to FDA commissioner Margaret Hamburg.

They worry that the DNA test will lead to overtreatment of younger women who carry the HPV virus, but who have little risk of developing cervical cancer. They also say the test is not very useful by itself because "so many women have HPV that will disappear without any treatment," Diane Zuckerman of the Cancer Prevention and Treatment Fund tells the AP.

"Having an HPV test without also getting a Pap smear to check for problems is going to scare a lot of women who are not developing cervical cancer," she adds.

Although Pap testing has contributed significantly to a 50 percent decrease in cervical cancer in the US over the past 30 years, an estimated 12,000 cases of the cancer are expected to be diagnosed this year. The latest guidelines from the American Cancer Society recommend a Pap and HPV test every five years or a Pap alone every three years in women over the age of 30, but it does not recommend the HPV test in women under 30 because it would increase the odds of more invasive testing that can be harmful to the cervix and could affect pregnancies.

Roche wants FDA to clear the company to market its test to women ages 25 and up, and the FDA's microbiology devices panel recommended unanimously that the cobas test is safe and effective as a first-line screening tool.

But the cost is a concern, AP reports. The HPV test costs between $80 and $100, more than twice the $40 Pap, and Roche has proposed that women who test positive for HPV be referred for colposcopy, which can cost up to $500.

 

Genomeweb The Daily Scan April 16 2014 by Jian Sun

FDA Panel: Roche's DNA Test Can Replace Pap Smear
18 March 2014

An FDA advisory committee voted unanimously Wednesday to recommend that the Pap smear be replaced with a human papillomavirus (HPV) test as the first-line standard of care for cancer screening.

The FDA's Medical Devices Advisory Committee Microbiology Panel agreed by a vote of 13-0 in each of three successive votes that the cobas viral DNA test for HPV -- made by Roche Molecular Systems -- was safe and effective for cervical cancer screening, and that the benefits of the tests outweighed the risks.

The cobas test currently has approval as a follow-up assessment for women 21 and older who have abnormal Pap tests, and as a co-test with the Pap smear to screen for the high-risk p16 and p18 HPV strains in women 30 to 65. The test comprises genotyping for HPV16 and 18 and pooled assessment of 12 additional high-risk HPV strains.

According to the proposal submitted by Roche, women 25 and older who test positive for HPV16 or 18 would proceed directly to colposcopy for further assessment.

Patients who test negative for HPV16 or 18 but positive for the other high-risk strains would have a Pap test to determine the need for colposcopy. Women who have a completely negative test would be followed at their physician's discretion.

Panelists did express some concerns about dropping the age at which women should have the test from 30 to 25. The ATHENA study used as the basis for the application found that about 11% of women ages 25 to 29 tested positive for HPV16 or 18 with the cobas test, compared with 7.28% among women 25 to 29 who had cytology alone as their first-line screening. Panel member Paula Hillard, MD of Stanford University in California, said that would mean more patients in that age group "who will be anxious about potentially having cancer."

In addition, Hillard expressed concern about off-label use. "I'm concerned that all those women potentially with other high-risk positivity won't go to Paps next but go [straight] to colposcopy. That's not what's proposed here, but what control does FDA have once it's out there?"

Panelist Kenneth Noller, MD of the American Board of Obstetrics and Gynecology, in Dallas, agreed that real-world use could differ from the protocol proposed by Roche. "I've been watching how people practice; if you're high-risk HPV positive you're going to get colposcopy," he said. "That doesn't necessarily mean it's bad -- it's what you do with the colposcopy."

Noller added that although he was "somewhat biased against dropping the age to 25 before I came here ... I find the data presented today somewhat compelling to drop it to 25."

Panel member Kimberly Hanson, MD, MHS of the University of Utah and ARUP Laboratories, both in Salt Lake City, agreed. "Now we have the opportunity to identify women earlier, and to me that's compelling," she said. "Although colposcopy is invasive and can be anxiety-provoking, it's really very safe, so I think I'm leaning toward earlier screening."

The committee members were not concerned about losing other diagnostic benefits of the Pap smear -- such as finding trichomonas and abnormal endometrial cells -- that would be lost if Pap smears were no longer the first-line screening method. "If this is how you're diagnosing trichomonas and [other diseases], there are much more effective ways of doing it," said panel chair Angela Caliendo, MD, PhD, of Rhode Island Hospital in Providence.

The presentations by FDA staff and Roche relied on long-term follow-up data from ATHENA, a 47,208-patient cohort study that was conducted in the U.S.

According to the summary submitted by FDA staff members, "The data show that the proposed primary screening indication for the cobas HPV test detects more women with disease and requires fewer women without disease to go to colposcopy than cytology alone."

The staff summary included the following performance characteristics of the cobas test versus cytology in the prospective cohort study:

By Joyce Frieden News Editor, MedPage Today  12.3.14

 

  • Sensitivity for ≥cervical intraepithelial neoplasia (CIN3) -58.26% versus 42.63%
  • Positive predictive value -12.25% versus 6.47%
  • Negative predictive value -0.42% versus 0.59%
  • False-positive rate -4.09% versus 6.04%

 

Benefit-risk analyses favored the HPV DNA test whether expressed in terms of number of cases of high-grade cervical disease per 10,000 women screened or per 100 colposcopy procedures.

The FDA is not bound to follow its advisory committees' recommendations, but does so in most cases.

A Power Surge for Cancer Immunotherapy
12 February 2014

Antibodies,vaccines,and engineered T cells fuel new optimism

The field of cancer immunotherapy,which explores how a patient's own immune system can be coaxed into fighting tumours is suddenly booming.The pharmaceutical industry is investing heavily in a braod range of strategies.

Many tumours are inherently resistant to the body's immune response.Because they develop from our own cells,they usually do not contain anything that the immune system would recognise as foreign and thus view as a potental threat.Researchers believe that many cancers can dodge our defences by exploiting regulatory pathways that the immune system normally uses to prevent overactivity and autoimmunity.

However many researchers are now unveiling multiple strategies to kee the immune system active ,identifying and targeting cancers as threats , and then eliminating them.Dr Butterfield the Professor of Medicine,Surgery and immunology at the University of Pittsburgh Cancer Institute Immunlogic Monitoring and Cellular Products Laboratory syas " the punchline of the lecture is no longer limited to "my therapy was safe and well-tolerated by the patient".Now you hear "This is the high percantage of overall clinical responses of patient's tumours melting away,and these are the breadth of tumour types that repsonded ,and the duration of patient's surviving" she says.

Releasing the Blockades

So far, a theurapeutic intervention that relies on T-cell checkpoint inhibitors or bockades has captured much of the early excitement.When repsnding to infections, the immune system normally tamps down its own activity after it has cleared the pathogen.This response ,prompted by inhibitory signals,can be mediated by suppressor cells and by surface molecules on T-cells themselves."we try to release those blockades, get rid of the suppressor cells,remove these checkpoints where the T-cells tell themsleves ,'I have been for a while I should turn myself off ' Dr Butterfield says.

In 2011 , the US FDA approved a monoclonal antibody ipilimumab for the treatment of metastatic melanoma. One of the first immunotherapy drugs on the market,ipilimumab allows T-cells to remain active by blocking an inhibitory signal emitted by a surface protein called cytotoxic T-lymphocyte antigen 4 (CTLA-4).Although the drug's overal repsonse rate of approximately 11% is relatively modest, the response in many patients has been durable. This success comes with a caveat ,however by ramping up T-cell activity,checkpoint inhibitors can cause autoimmune-based side effects.As the immune therapies move forward in clinical trials, researchers conceded that a major challenge will be boosting an antitumour T-cell repsonse while minimising autoimmunity.

The next generation strategy,researchers are designing monoclonal antibodies that bind to proteins in a similar signalling pathway named programmed death 1 (PD-1).Whereas  the PD-1 protein appears on the outer surface of T-cells, a binding partner called prommed death ligand (PDL-1) studs the surface of tumour cells.When the T-cells arrive at the tumour site,crosstalk between the two proteins  instructs the T-cells to shut down.More than six companies are now developing antibodies against either PD-1 or PDL-1, to block these T-cells inactivating signals.

In phase 1 clinical trials the best response rate has been closer to 30%, with less toxicity than ipilimumb.

With the growing body of molecular and cellular knowledge researchers can start to take more precisely targeted and personilased approaches to induce effective tumour immunity.

 

 by Bryn  Nelson editorial CytoSource in the  Cancer Cytopathology Journal January 2014 Vol 122 Issue 1

 

 

Precancerous Cells on Cervix Tied to Higher Risk of Disease, Death
22 January 2014

Women who have been diagnosed with and treated for precancerous cells on the cervix may be at increased risk for developing and dying from cervical or vaginal cancer, new research suggests.

The study authors analyzed data from more than 150,000 Swedish women who were treated for abnormal cells on the cervix. Of those, nearly 1,100 were later diagnosed with invasive cervical cancer and about 150 were diagnosed with invasive vaginal cancer. There were more than 300 deaths from cervical cancer and about 50 deaths from vaginal cancer.

As women who had been treated for precancerous cells on the cervix grew older, their risk of cervical or vaginal cancer increased. The risk accelerated after age 60 and again after age 75, according to the study. The researchers found that incidence rates of cervical and vaginal cancer in the oldest group of women exceeded 100 per 100,000 women.

 

The more recently women had been treated for abnormal cells on the cervix -- and the older they were at the time of treatment -- the greater their risk of cancer. Those who were treated at ages 60 to 69 had a five times higher risk than those treated at ages 30 to 39, according to the study.

The findings were published online Jan. 14 in the journal BMJ.

The risk of death from cervical or vaginal cancer also increased with age among women who had been treated for abnormal cells on the cervix, according to a journal news release. Thirty years after treatment, these women were more than twice as likely to die from cervical or vaginal cancer than those in the general population. At age 72, death rates from these cancers increased to 50 per 100,000 women, the study found.

The older a woman was when she was treated for precancerous cells on the cervix, the greater her risk of death from cervical or vaginal cancer, according to the news release.

The findings show that women who have been treated for abnormal cells on the cervix "should be followed up in old age," said researcher Bjorn Strander, from the University of Gothenburg, and colleagues at the Karolinska Institute, both in Sweden.

It is worrying that the study found that women who received treatment more recently were at greater risk of developing cervical and vaginal cancer, Dr. Marc Arbyn, from the unit of cancer epidemiology of the Scientific Institute of Public Health, in Brussels, Belgium, said in an accompanying editorial.

Arbyn called for research to identify signs that predict a woman's future risk of cervical and vaginal cancer.

"Measures should be taken to assure full compliance with follow-up after treatment of cervical pre-cancer,"

 

SOURCE: BMJ.com, news release, Jan. 14, 2014

 

 

 

Cervical Cancer Screening Tests in Older Women
22 January 2014

Researchers say their results support screening women up to age 65 and beyond

Cervical cancer screening beyond age 50 saves lives and remains beneficial to women up to age 69, a new British study suggests.

Both the U.S. Centers for Disease Control and Prevention and the U.S. Preventive Services Task Force recommend that cervical cancer screening end at age 65.

In this new study, researchers examined data from all 1,341 women aged 65 to 83 in England and Wales who were diagnosed with cervical cancer between 2007 and 2012, and compared them to women in the same age group who did not have cervical cancer.

The results showed that women who did not undergo cervical cancer screening after age 50 were six times more likely to be diagnosed with cervical cancer than those who had regular screenings between ages 50 to 64 and had no abnormalities. There were 49 cancers in the first group versus eight cancers in the second group per 10,000 women over 20 years, found the study in the journal PLoS Medicine

Continue reading below...

The rate of cervical cancer was 86 per 10,000 over 20 years among women who were screened regularly between ages 50 to 64 and found to have abnormalities, according to a journal new release.

The findings suggest that cervical cancer screening in older women has a substantial impact in reducing cervical cancer risk, said researchers Peter Sasieni and colleagues from Queen Mary University of London.

"Screening up to age 65 years greatly reduces the risk of cervical cancer in the following decade, but the protection weakens with time and is substantially less 15 years after the last screen. In the light of increasing life expectancy, it would seem inappropriate for countries that currently stop screening between the ages 60 and 69 years to consider reducing the age at which screening ceases," the researchers concluded.

This type of new data from older women can help experts determine whether current guidelines that recommend a halt to cervical cancer screening at age 65 meet all women's needs, Anne Rositch, from the University of Maryland School of Medicine, and colleagues wrote in an accompanying editorial.

Here are the cervical cancer screening guidelines from the U.S. Centers for Disease Control and Prevention:

  • Start getting regular Pap tests at age 21. The Pap test is one of the most reliable and effective cervical cancer screening tests. If your Pap test results are normal, your doctor may tell you that you can wait three years until your next Pap test.
  • If you are 30 years old or older, you may want to have a human papillomavirus (HPV) test along with the Pap test. Both tests can be performed by your doctor at the same time. If your test results are normal, your chance of getting cervical cancer in the next few years is very low. Your doctor may then tell you that you can wait as long as five years for your next screening. But you should still go to the doctor regularly for a checkup.
  • If you are 21 to 65 years old, it is important for you to continue getting a Pap test as directed by your doctor, even if you think you are too old to have a child or are not having sex anymore. If you are older than 65 and have had normal Pap test results for several years, or if you have had your cervix removed as part of a total hysterectomy for non-cancerous conditions, like fibroids, your doctor may tell you that you do not need to have a Pap test anymore.

Here are the cervical cancer screening guidelines from the U.S. Preventive Services Task Force:

  • Women aged 21 to 65 years should have a Pap test every three years. Women aged 30 to 65 who want to lengthen the screening interval can undergo screening with a combination of Pap and HPV testing every five years.
  • Screening is not recommended for women younger than 21, or for women older that 65 "who have had adequate prior screening and are not otherwise at high risk for cervical cancer."
  • Screening is not recommended for women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion or cervical cancer.
  • HPV testing, alone or in combination with a Pap test, should not be used for cervical cancer screening in women younger than 30.

 

PLoS Medicine, news release, Jan. 14, 2014

HPV Vaccine: The Earlier, the Better
08 January 2014

Women who were 18 and up or had abnormal cervical cytology when vaccinated against human papillomavirus (HPV) subsequently had rates of cervical dysplasia similar to those of unvaccinated women

Women ≥18 without cervical abnormalities at vaccination had a 23% reduction in the risk of high-grade squamous intraepithelial lesions (HSIL) as compared with unvaccinated women. The quadrivalent vaccine did not appear to protect against HSIL among women who had abnormal cytology at the time they were vaccinated, they reported online in the Journal of Clinical Oncology.

"A significant percentage of vaccinated women may not be protected against HSIL or lesser dysplasia especially if they were vaccinated at older age or had abnormal cytology before vaccination," Salaheddin M. Mahmud,MD, PhD, of the University of Manitoba in Winnipeg, and colleagues concluded.

"These findings affirm the importance of vaccination before any significant exposure to HPV occurs and underscore the need for screening programs that cover all sexually active women, even if they were vaccinated," they wrote.

The quadrivalent HPV vaccine has been shown to reduce the risk of cervical cancer, which evolves from infection with HPV 16 and 18 in 70% of cases worldwide. Whether the vaccine protects against cervical dysplasia had been been studied by use of population-based individual-level data, the authors noted in their introduction.

To examine HPV vaccine effectiveness against cervical dysplasia, Mahmud and colleagues reviewed records for 3,541 females vaccinated at age ≥15 in Manitoba from September 2006 to April 2010. Each vaccinated patient was matched with three unvaccinated patients.

Investigators calculated hazard ratios for three outcomes: atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), and HSIL.

During a median follow-up of 3.1 years, vaccinated patients had LSIL and HSIL rates of 3.3% and 2.3%, respectively, compared with 3.7% and 2.6% for unvaccinated patients. No patient (vaccinated or not) developed cervical cancer during follow-up, but 12 vaccinated patients (0.3%) and 22 unvaccinated patients (0.2%) developed carcinoma in situ.

Investigators analyzed the data by age group and history of abnormal cervical cytology. Vaccine effectiveness varied by both factors.

Among girls ages 15 to 17 at enrollment, vaccine effectiveness estimates were 35% against HSIL, 21% for LSIL, and -1% for ASCUS. Exclusion of girls who did not have at least one Pap test after enrollment resulted in higher estimated effectiveness: 46% against HSIL, 35% against LSIL, and 23% for ASCUS.

For patients who were ≥18 and had no history of abnormal cytology before enrollment, estimated effectiveness rates were 23% of HSIL, -18% for LSIL, and -20% for ASCUS. A history of abnormal cytology reduced the estimates to -8% for HSIL, 37% for LSIL, and 56% for ASCUS but with wide confidence intervals.

Exclusion of women ≥18 who did not have at least one Pap test after enrollment resulted in estimated vaccine effectiveness rates of 35% for HSIL, 2% for LSIL, and -5% for ASCUS in the subgroup who had no history of abnormal cytology before enrollment and rates of -33%, 25%, and 53% for those with a history of abnormal cervical cytology.

"Postmarketing epidemiological studies are needed to evaluate the real-life effectiveness of the HPV vaccines and to monitor their impact on other preventive measures such as screening and sexually transmitted infection control programs," the authors concluded.

The findings confirm data from previous studies showing that HPV vaccine is less effective in older teens and young women, said Ronald Alvarez, MD, PhD, of the University of Alabama at Birmingham.

"We know that this group of women is more likely to have had exposure to human papillomavirus and perhaps even had some disease," Alvarez told MedPage Today. "In that setting, we know that the HPV vaccine is less likely to be effective."

HPV vaccine will be most effective when three criteria are met, said Krishnansu Tewari, MD, of the University of California Irvine.

  • No high-risk vaccine-specific HPV DNA on the cervix at the time of vaccination
  • No antibodies against the high-risk vaccine-specific HPVs in the serum of the patient at the time of vaccination
  • The patient’s cervical cytology is, and has been normal at the time of vaccination

“It is so important that males and females are vaccinated as early as possible, before the so-called sexual debut -- before they start having sex,”

Primary source: Journal of Clinical Oncology
Source reference: Mahmud SH, et al "Effectiveness of the quadrivalent human papillomavirus vaccine against cervical dysplasia in Manitoba, Canada" J Clin Oncol 2013; DOI: 10.1200/JCO.2013.52.464.

HPV: Sex, cancer and a virus
03 December 2013

Human papillomavirus is causing a new form of head and neck cancer— leaving researchers scrambling to understand risk factors, tests and treatments

On a sunny day in 1998, Maura Gillison was walking across the campus of Johns Hopkins University in Baltimore, Maryland, thinking about a virus. The young oncologist bumped into the director of the university's cancer centre, who asked politely about her work. Gillison described her discovery of early evidence that human papillomavirus (HPV) — a ubiquitous pathogen that infects nearly every human at some point in their lives — could be causing tens of thousands of cases of throat cancer each year in the United States. The senior doctor stared down at Gillison, not saying a word. “That was the first clue that what I was doing was interesting to others and had potential significance,” recalls Gillison.

 

 

She knew that such a claim had a high burden of proof. HPV was known to cause cervical cancer and small numbers of genital cancers, but no other forms. So Gillison started a careful population study comparing people with cancer to healthy individuals. Over seven years, she recruited 300 participants, collected tissue samples, and never once looked at the data. “My policy, when doing a study, is that we wait until all the data are in, and do all the analyses at once,” says Gillison, who is as careful as she is blunt. “I don't know anything until the data tell me.”

Only in 2005 did Gillison finally sit down with a doctoral student to analyse the data. Within an hour, the fruits of those years of labour popped up on the computer screen: people with head and neck cancer were 15 times more likely to be infected with HPV in their mouths or throats than those without1. The association backed up some of Gillison's earlier work, which showed2 how HPV DNA integrates itself into the nuclei of throat cells and produces cancer-causing proteins. Gillison leapt from her chair and began jumping up and down. “The association was so incredibly strong, it made me realize this was absolutely irrefutable evidence,” she says.

Since then, she and a network of other researchers have amassed a mountain of evidence that HPV causes a large proportion of head and neck cancers, and that these HPV-positive cancers are on the rise. The finding has been “a paradigm-shifting realization in the field”, says Robert Ferris, chief of the division of head and neck surgery at the University of Pittsburgh Cancer Institute in Pennsylvania.

The medical community is struggling to come to grips with the implications. There is currently no good screening method for HPV-caused cancer in the head and neck, and commercially available HPV vaccines are still prescribed only to people under the age of 26, despite evidence that they could prevent head and neck cancer in all adults. Plus, if HPV can get into the mucous membranes of the mouth and throat, where does it stop? There are hints that HPV is a risk factor for other, even more common, types of cancer, including lung cancer.

For now, researchers and doctors need to learn more about how HPV causes cancer, and how best to prevent and treat it, says Gillison. “Our clinics are flooded” with head and neck cancers triggered by HPV, she says, vexation clear in her voice. “But though I talk about it constantly in public settings and the lay press, it amazes me that it's often as if no one has heard of it.”

New threat

James Rocco, director of head and neck molecular oncology research at Massachusetts General Hospital in Boston, remembers the first signs that something was changing. Until the late 1990s, most cases of cancer in the back of the throat (the oropharynx) could be blamed on alcohol and tobacco use: the majority of Rocco's patients were men around 50 years old, who had been smoking and drinking for 30 years. But then 40-year-old marathon runners and people in otherwise good health began to trickle — then stream — into his office. And when treated with chemotherapy and radiation, these people seemed to have better survival rates than the other head and neck cancer patients.

There were also irregularities in the laboratory. When biopsied, the site of the cancer was slightly different in this healthier cohort: instead of beginning on the surface of the tonsil as normal, tumours seemed to start deep in tonsil crevices. And more and more of the tumours lacked mutations in a protein called p53 — then considered a hallmark of oropharyngeal cancer. “We kind of knew we were dealing with something different,” recalls Rocco.

Gillison started pursuing the issue in 1996, after a passing comment by a colleague. Keerti Shah, a molecular microbiologist at the Johns Hopkins Bloomberg School of Public Health, had mentioned research in Finland that had identified HPV in a cell line developed from an oropharyngeal tumour3. As Shah and Gillison walked around campus one day, they talked about the finding. Was it an isolated case? Had HPV contaminated the sample? Or, as Shah suspected, could HPV cause some cases of head and neck cancer?

Gillison went straight to her office to do a literature search. She began analysing tumour samples from the Head and Neck Cancer Center at Hopkins and found HPV in about 25% of them. She used multiple techniques to be sure that positive results were not attributable to laboratory contamination. She looked for the virus in early, middle and late stage tumours. HPV was not just present; she found that its DNA had infiltrated the tumours and was producing two potent oncoproteins, an indication it was the cause of the cancer. Gillison also profiled people with HPV to learn about the cancer's clinical characteristics, and identified molecular biomarkers that were absent in tumours without HPV. She worked on the project for 18 months, without taking a day off.

She, Shah and their colleagues published their results in 2000 (ref. 2), demonstrating that HPV-positive oropharyngeal cancer is a distinct type of cancer that starts deep in the tonsils, has HPV DNA present in the tumour-cell nuclei but not neighbouring cells, has fewer p53 mutations than HPV-negative cancer, has less association with smoking and alcohol consumption and has better survival rates. But many oncologists were sceptical: some suspected that HPV was just a passenger virus, or that its presence was the result of contamination. Others thought that HPV might be just a risk factor, rather than a cause, for head and neck cancer — one of several ingredients, including drinking and smoking, that when combined together congealed into a cancerous stew.

In 2007, Gillison published her seven-year population study showing the link between oral HPV infection and oropharyngeal cancer1; the next year, she released a study4 showing that HPV-positive and HPV-negative oropharyngeal cancers had completely different risk profiles. People with HPV-positive cancer tended to have had many oral-sex partners, but there was no statistical association with tobacco smoking or drinking; those with HPV-negative cancers were heavy drinkers and cigarette smokers but there was no association with sexual activity. “These were two completely different diseases,” says Gillison. “They might superficially look similar — a patient comes in with a neck mass and their throat hurts — but I realized what drove the pathogenesis was completely different in the two cases.”

By then, all doubts had faded. In 2007, the World Health Organization's International Agency for Research on Cancer in Lyons, France, declared that there was sufficient evidence to conclude that HPV causes a subset of oropharyngeal cancers. Gillison's research has been “definitive”, says Jeffrey Myers, director of head and neck surgery research at the University of Texas MD Anderson Cancer Center in Houston.

Community acceptance came not a moment too soon. The number of oropharyngeal cancers has been growing over the past 30 years: there are now 10,000 cases in the United States each year, a number that is likely to climb to 16,000 by 2030 (see 'Emerging threat'). An overwhelming majority are caused by HPV. Worldwide, cancer centres report that the virus is responsible for between 45% and 90% of oropharyngeal cancers . “In Europe, HPV-positive oropharyngeal cancers have almost quadrupled in number over a period of 10 to 15 years,” says Hisham Mehanna, director of the Institute of Head and Neck Studies and Education at the University of Birmingham, UK, who has published a meta-analysis5 of more than 250 papers on prevalence rates. “Our projection suggests that it's going to continue to increase significantly.” Why rates are escalating is unknown, although one suggestion points to increasing numbers of sexual partners.

Problem proteins

It turns out that HPV causes throat cancer in much the same ways as it causes cancer in the cervix. The virus's DNA integrates into human DNA in the nuclei of healthy cells, and uses the cells' machinery to produce two harmful proteins, E6 and E7. These bind to, and shut down, two important tumour-suppressor proteins, p53 and pRb. Active pRb prevents excessive cell growth; without it, cells proliferate unchecked. Active p53 arrests the cell-division cycle when DNA is damaged, and then either activates DNA repair or initiates cell death. Without p53, a cell replicates wildly even if it has DNA damage.

“If HPV can get into the mucous membranes of the mouth and throat, where does it stop?”

In cancers caused by HPV, the virus silences p53 but leaves the gene that produces it intact; by contrast, in HPV-negative cancers, the gene is mutated, probably through exposure to carcinogens, and produces an ineffective version of the protein. This may explain why people with HPV-positive oropharyngeal cancer respond better to treatment: early evidence suggests6 that chemotherapy or radiation may somehow reactivate p53 in HPV-positive cancers, turning the powerful protein back on to fight the tumour.

There are other possibilities. It could be that people with HPV-positive cancer are generally healthier than their HPV-negative counterparts: they tend to be younger, generally don't smoke and are more likely to comply with treatment regimes. Another possibility, supported by a study7 using sequencing data from 74 head and neck cancers, is that HPV-negative tumours are more heterogeneous than HPV-positive tumours. The cells have many more mutations, and a wider range of them. In an HPV-negative tumour, therefore, “there's more likely to be something in there that will resist therapy”, says Rocco, a co-author of the study.

Toxic treatment

The fact that people with HPV-positive cancer have better outcomes has caused many clinicians, including Gillison and Ferris, to wonder whether these patients should get different treatments. The current standard therapy for oropharyngeal cancer is a combination of cisplatin — a toxic, potent chemotherapy drug — and radiation. This has many potential side effects, including damage to the voice box and throat, which can hinder the ability to speak and swallow. With the younger, healthier HPV-positive patients, who are 58% less likely to die within three years of treatment than HPV-negative patients, clinicians worry about the long-term effects of the treatment, and are exploring techniques including less-toxic chemotherapy regimens.

Researchers are also looking at ways to prevent the disease in the first place. More than 90% of HPV-related oropharyngeal cancers are caused by HPV-16, a particularly dangerous strain and the main cause of cervical cancer. The two vaccines approved to prevent cervical cancer, Merck's Gardasil and GlaxoSmithKline's Cervarix, both protect against HPV-16. In theory, therefore, protection against HPV-positive oropharyngeal cancer is already in doctors' cabinets. A clinical trial of 5,840 women, published this year by researchers at the US National Cancer Institute8, showed that Cervarix is 93% effective at preventing oral HPV infection in both women with pre-existing cervical infections and those without, none of whom had been previously vaccinated.

A major barrier stands in the way of official approval for using the vaccine to protect against oropharyngeal cancer: there is not yet a way to prove that it would work. For cervical cancer, doctors test cells taken from the cervix during routine screening, looking for changes that precede the emergence of cancer. Because HPV-positive oropharyngeal cancer arises deep in the tonsil, checks would have to be much more invasive. “In theory, we could detect it, but we would need to do a tonsillectomy on everyone in the vaccine trial,” says Gillison. “That's never going to happen.”

There may be another way. Mehanna and his colleagues are in the process of analysing the tonsils of 1,250 people who underwent tonsillectomies for non-cancerous reasons. The researchers have identified what they think are pre-malignant lesions in some HPV-positive samples that may represent the earliest stages of the cancer, and could serve as a biomarker. “We're now testing to make sure this pre-malignancy is driven by HPV and is not just random,” says Mehanna.

Other concerns and questions linger. For example, scientists have yet to determine whether oral HPV infection comes only from sexual acts that involve contact between the mouth and genitals, or also from other acts including deep kissing. And most people who develop an HPV infection do not get oropharyngeal cancer: about 90% of those who become infected orally clear the infection within two years. No one is sure why.

Researchers are also investigating whether HPV causes other types of cancer. There have been studies of the relationship between the virus and oesophageal cancer, but findings have been inconclusive. Another area of interest is the lung. There, too, tobacco has been the primary culprit for decades, but some 15–20% of lung-cancer cases in men and 50% in women are in people who have never smoked. Doctors have theorized that a virus lies behind them.

The available data are conflicting. One paper9 in 2001 identified HPV DNA in 55% of 141 lung tumours, compared with 27% of 60 non-cancer control samples. And in 2009, researchers led by Iver Petersen, director of the Institute for Pathology at Jena University Hospital in Germany, conducted a meta-analysis10 of 53 publications examining 4,508 cases of lung cancer, and concluded that “HPV is the second most important cause of lung cancer after cigarette smoking”. They encouraged more research. But many other studies have refuted those observations, including one from Gillison and her colleagues, in which they used sensitive DNA assays to study the lung cancers of 450 patients, and found no HPV (ref. 11).

With head and neck cancer, however, Gillison is optimistic that new knowledge about HPV as a cause of the disease will help physicians to treat it — and eventually to prevent it with a vaccine. “In terms of cancer,” she says, “there aren't many populations where we've identified the necessary cause and have a potential solution on the shelf.”

Journal name:

Nature Volume:503, Pages:330–333 Date published:(21 November 2013)

doi:10.1038/503330a

 

 

HPV vaccine could be given to boys as well as girls in UK
29 November 2013

Government advisers consider whether vaccine should be used to protect men who have sex with men from some cancers

Government advisers are to consider whether the HPV vaccine, routinely offered to girls at the ages of 12 and 13 since 2008 to help protect them against cervical cancer, should also be offered to boys and some men.

They are to review "all the issues" on HPV, including whether targeted vaccination would help cut the risk of anal and throat cancers among men who have sex with men as well as the wider question over whether a universal male vaccination programme given to pre-teen or teenage boys is necessary as well, an idea that has previously been rejected.

The review is revealed in draft minutes of the Joint Committee on Vaccination and Immunisation (JCVI), the UK-wide advisory body.

A decision from the government advisers on what to recommend is unlikely to be quick since JCVI has yet to establish a sub-committee to examine the arguments in detail.

There will be doubts that a UK-wide programme for boys is necessary since take-up of the HPV programme for girls is so good that experts could consider it is enough to protect the general heterosexual population.

The issue of boys getting the vaccine has already been raised in the UK and Scottish parliaments and by the UK charity Throat Cancer Foundation, which believes a UK-wide programme is needed. Supporters believe the present programmes for girls are not offering the same sort of protection for boys as there would be if both sexes were inoculated. The JCVI subcommittee is also to look at whether the programme for girls might soon need to be modified since there is a possibility manufacturers could try to get licences for two-dose courses.

The vaccination, now given in three doses over a year, has already been given to millions of girls – usually in secondary schools – to combat a family of viruses which can also cause warts and verrucas. They are very common and the vaccine, first under the Cervarix brand and now Gardasil, licensed for both boys and girls, is introduced before most girls are sexually active.

Half the population will have some form of HPV at some time in their life and in most cases they suffer no ill effects. The vaccine is known to be effective for eight years. It is unknown how much longer it is effective

John Ashton, president of the Faculty of Public Health, the professional body, said: "This is to be welcomed. We have to seriously consider this measure in the light of the recent increase in oral cancer. The original decision to vaccinate girls was based on the need to prevent cervical cancer."

The US Centres for Disease Control already recommends boys have it too – and both sexes have it in America when 11 or 12. Australia too offers the vaccine free in schools for both sexes.

The Department of Health said: "There are currently no plans to extend HPV vaccination to males, based on an assessment of currently available scientific evidence." It added: "Vaccination of boys was not recommended by the JCVI because once 80% coverage among girls has been achieved, there is little benefit in vaccinating boys to prevent cervical cancer in girls. 80% coverage for the full course of three doses of the vaccine was achieved in the first year of the HPV vaccination programme in 2008-09, and has since exceeded that level."

It has been estimated that 400 lives a year could be saved in the UK as a result of vaccinating girls before they are infected. At the moment 2,900 women are diagnosed each year with cervical cancer.

Although most girls don't start having sex until after they are 16, the NHS says getting the vaccine as early as possible will protect them in the future.

In 2010, around 4,300 men and 2,200 women were diagnosed with oral cancer, according to Cancer Research UK, a rise of a third in the last decade.

 

James Meikle The Guardian Thursday 28th November

The review is revealed in draft minutes of the Joint Committee on Vaccination and Immunisation (JCVI), the UK-wide advisory body.

Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England
20 November 2013

Reduction in the prevalence of vaccine type HPV infection in young women is an early indication of the impact of the HPV immunisation programme and a necessary outcome if the subsequent impact on cervical cancer is to be realised.

METHODS:

Residual vulva-vaginal swab (VVS) specimens from young women aged 16-24 years undergoing chlamydia screening in community sexual health services (formerly known as family planning clinics), general practice (GP), and youth clinics in 2010-2012 were submitted from 10 laboratories in seven regions around England. These specimens were linked to demographic and sexual behaviour data reported with the chlamydia test, anonymised, and tested for type-specific HPV DNA using a multiplex PCR and Luminex-based genotyping test. Estimated immunisation coverage was calculated and findings were compared to a baseline survey conducted prior to the introduction of HPV immunisation in 2008.

RESULTS:

A total of 4664 eligible specimens were collected and 4178 had a valid test result. The post-immunisation prevalence of HPV 16/18 infection was lowest in this youngest age group (16-18 years) and increased with age. This increase with age was a reversal of the pattern seen prior to immunisation and was inversely associated with estimates of age-specific immunisation coverage (65% for 16-18 year olds). The prevalence of HPV 16/18 infection in the post-immunisation survey was 6.6% amongst 16-18 year olds, compared to 17.6% in the similar survey conducted prior to the introduction of HPV immunisation.

CONCLUSIONS:

These findings are the first indication that the national HPV immunisation programme is successfully preventing HPV 16/18 infection in sexually active young women in England. The reductions seen suggest, for the estimated coverage, high vaccine effectiveness and some herd-protection benefits. Continued surveillance is needed to determine the effects of immunisation on non-vaccine HPV types.

Vaccine. 2013 Nov 5. pii: S0264-410X(13)01492-8. doi: 10.1016/j.vaccine.2013.10.085. [

Mesher D, Soldan K, Howell-Jones R, Panwar K, Manyenga P, Jit M, Beddows S, Gill ON.

Source

Public Health England, HIV & STI Department, 61 Colindale Avenue, London NW9 5EQ, UK. Electronic address: david.mesher@phe.gov.uk.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genomic differences in types of cervical cancer may affect treatment choices
26 September 2013

Marked differences in the genomic terrain of the two most common types of cervical cancer suggest that patients might benefit from therapies geared to each type's molecular idiosyncrasies, according to a new study

The new study, conducted by researchers at Dana-Farber Cancer Institute and Brigham and Women's Hospital, is the first to compare the spectrum of cancer-related gene mutations in the two main subtypes of cervical cancer, adenocarcinoma and squamous cell carcinoma. In tests on 80 cervical tumor samples, the investigators found high rates of mutations in two genes: PIK3CA and KRAS. While PIK3CA mutations appeared in both subtypes, KRAS mutations were found only in adenocarcinomas.

By linking their findings to data on the patients' treatment and survival, the research team found the PIK3CA mutations are associated with a shorter survival period. The patients whose tumors carried these mutations lived a median of 67 months after diagnosis compared with 90 months for patients whose tumors lacked the mutations.

“We have historically treated cervical cancers as one disease,” said the study's lead author, Alexi Wright, MD, MPH, of the Susan F. Smith Center for Women's Cancers at Dana-Farber. “However, our findings suggest that some patients may be at higher risk of dying from their disease and might benefit from a more tailored treatment approach.”

The discovery of high rates of PIK3CA mutations in the cervical tumor samples suggests that many patients could benefit from drugs known as PI3-kinase inhibitors, which target the family of proteins associated with the gene, the authors say. Patients with the adenocarcinoma subtype of cervical cancer may benefit from targeted agents known as MEK inhibitors, which have shown some success in clinical trials.

Cervical cancer is the second leading cause of cancer deaths among women worldwide, responsible for 275,000 deaths annually. While Pap tests have helped decrease the incidence of squamous cell cervical cancer, adenocarcinomas now account for nearly a quarter of all cervical cancers, up from 5% 20 years ago.

In the study, investigators probed the DNA of 80 cervical cancer tumors—40 adenocarcinomas and 40 squamous cell carcinomas—for 1,200 mutations in hundreds of genes linked to cancer. The probe was done with OncoMap, a system developed at Dana-Farber to test large numbers of tumor samples for cancer-related genes. They found that 31% of the samples had PIK3CA mutations; 17.5% of the adenocarcinomas (and none of the squamous cell carcinomas) had KRAS mutations; and 7.5% of the squamous cell carcinomas (but none of the adenocarcinomas) had a rare mutation in the gene EGFR.

“While current treatment strategies don't take into account whether cervical tumors are adenocarcinomas or squamous cell carcinomas, our study suggests that identifying and targeting distinct subsets of patients may improve outcomes for women with early or late-stage disease,” Wright commented.

Publication: Oncology Nurse Advisor - Kathy Boltz, 18th September 2013

Researchers use Pap test to detect ovarian and endometrial cancers.
26 September 2013

Using a highly accepted and widely used Pap test for more than HPV screening may be the diagnostic equivalent of "more bang for the buck."

That sort of helpful screening blast may be what researchers at Johns Hopkins Kimmel Cancer Center discovered when they used cervical fluid obtained during routine Pap tests to run a parallel test for ovarian and endometrial cancers.

According to background information provided from Johns Hopkins, cervical fluid of patients with gynecological cancer carries normal cellular DNA mixed with DNA from cancer cells, so the researchers were charged with determining normal cellular DNA from cancerous DNA with the help of genomic sequencing. First they identified the most common genetic changes in ovarian and endometrial cancers in order to prioritize which genomic regions to include in their test. Then, building on the strength of information gleaned from former genome studies, as well as conducting genome-wide sequencing on 22 endometrial cancers, the team identified 12 of the most frequently mutated genes in both cancers. Their new PapGene assay was born of that Herculean effort.

Dovetailing Assays

Johns Hopkins graduate student Yuxuan Wang explained that one of the focuses of the effort was to develop a sensitive assay using local secretions paired with a specific test to find cancer-specific mutations. "The actual procedure really is not any different from the current HPV test in terms of DNA collection and purification. We would just add primers to find mutations common in ovarian and endometrial cancers, in parallel to the standard HPV testing. There's no need for different or additional samples; there is already plenty."

In addition, Wang noted that the PapGene test added a barcode to one of the primers in the primer pair, as a way to determine if a mutation is preexisting (and seen in the parent and all daughter amplicons), an amplification artifact (present only in some daughter amplicons), or absent altogether. "This is how we distinguish any error that occurred in the amplification process from any true mutation, leading to higher sensitivity and specificity."

After the test was developed, the investigators applied the new assay to Pap samples from known ovarian and endometrial cancer patients at Johns Hopkins, Memorial Sloan-Kettering Cancer Center, University of Sao Paulo in Brazil, and ILSbio, a tissue bank. PapGene was able to detect both early- and late-stage ovarian and endometrial cancers. No healthy women in the control group were misclassified as having cancer, according to Johns Hopkins literature.

Research Findings

"That there was DNA sent from these ovarian and endometrial cancers that we could detect in Pap smears was of itself an intriguing and exciting finding for us," said Chetan Bettegowda, MD, PhD, assistant professor of neurosurgery and oncology at Johns Hopkins. "That there was enough there to allow us to actually form the basis of a test was our next important finding. But most exciting was the realization that we were able to detect sufficient quantities of cancerous DNA to theoretically be able to assist in diagnosis of ovarian and endometrial cancers."

Throughout the research process, the investigators continued to fine-tune the testing procedure on samples, working to  increase the test's sensitivity in detecting ovarian cancer. "Performing the test at different times during the menstrual cycle, inserting the cervical brush deeper into the cervical canal, and assessing more regions of the genome may boost the sensitivity," said Bettegowda.

An extreme optimism flows from the researchers' efforts, as PapGene's specific stats are revealed. The assay was able to correctly identify 100% of endometrial cancers, and 41% of ovarian cancers among patients known to have the disease, and delivered no false positives among healthy women.

"With ovarian cancer detection, 41% is certainly a great place to start, considering that existing technology detects close to 0% of a tumor that is often diagnosed in advanced stages and has a relatively high mortality rate for women. That is certainly exciting," said Bettegowda. But he admits that commercialization of PapGene is still a few years away. "This is the first iteration of our attempts and we hope future versions will enhance our ability to detect these ovarian tumors. This research is more a proof of concept; still a lot of work needs to be done to validate this work in larger cohort studies that are randomized and well-controlled, and to show the utility of the test. We are working along those progressive lines now, but we are still years away."

The Road Ahead

Could this PapGene assay turn out to be a pioneer of genomic-based cancer screening tests for these and other cancers? Mark H. Einstein, MD, MS, spokesperson for the Society of Gynecologic Oncology (SGO) and Gynecologic Oncologist at Montefiore Medical Center, Bronx, NY, thinks so, though he says the society remains neutral in terms of endorsing or rejecting the study's finding.

"It is incredibly early and preliminary research," said Einstein, "yet it is indeed proof of principle. In the last 20 years we've had an explosion in molecular technologies that have allowed us to take away the subjective, human element in diagnostics and make them much more objective, sensitive and, to some extent, more high-throughput and cost effective. Now we are seeing that perhaps we can use the testing we are already doing now for other things as well. We can mine a lot more information out of the samples we collect."

A gynecological oncologist, Einstein commented, "There have been only limited improvements in screening for ovarian cancer to date. So any screening technologies that are new and different from what has already been tested are something we take up with great enthusiasm." Yet he reminded that new tests also demand a healthy dose of skepticism that can only be cured with further research, development, and testing.

"As a clinician taking care of cancer patients, I could only hope this could someday become the magic bullet to finding ovarian cancer, a very tough cancer, when it is in the earliest stages. We need a new technology in this space," said Einstein. "I would be very happy to never have to take care of a patient suffering from ovarian cancer again."

Valerie Neff Newitt is on staff at ADVANCE. Contact: vnewitt@advanceweb.com

 
 

 

 

DNA Double Take
26 September 2013

From biology class to “C.S.I.,” we are told again and again that our genome is at the heart of our identity

Read the sequences in the chromosomes of a single cell, and learn everything about a person’s genetic information — or, as 23andme, a prominent genetic testing company, says on its Web site, “The more you know about your DNA, the more you know about yourself.”

But scientists are discovering that — to a surprising degree — we contain genetic multitudes. Not long ago, researchers had thought it was rare for the cells in a single healthy person to differ genetically in a significant way. But scientists are finding that it’s quite common for an individual to have multiple genomes. Some people, for example, have groups of cells with mutations that are not found in the rest of the body. Some have genomes that came from other people.

“There have been whispers in the matrix about this for years, even decades, but only in a very hypothetical sense,” said Alexander Urban, a geneticist at Stanford University. Even three years ago, suggesting that there was widespread genetic variation in a single body would have been met with skepticism, he said. “You would have just run against the wall.”

But a series of recent papers by Dr. Urban and others has demonstrated that those whispers were not just hypothetical. The variation in the genomes found in a single person is too large to be ignored. “We now know it’s there,” Dr. Urban said. “Now we’re mapping this new continent.”

Dr. James R. Lupski, a leading expert on the human genome at Baylor College of Medicine, wrote in a recent review in the journal Science that the existence of multiple genomes in an individual could have a tremendous impact on the practice of medicine. “It’s changed the way I think,” he said in an interview.

Scientists are finding links from multiple genomes to certain rare diseases, and now they’re beginning to investigate genetic variations to shed light on more common disorders.

Science’s changing view is also raising questions about how forensic scientists should use DNA evidence to identify people. It’s also posing challenges for genetic counselors, who can’t assume that the genetic information from one cell can tell them about the DNA throughout a person’s body.

Human Blueprint

When an egg and sperm combine their DNA, the genome they produce contains all the necessary information for building a new human. As the egg divides to form an embryo, it produces new copies of that original genome.

For decades, geneticists have explored how an embryo can use the instructions in a single genome to develop muscles, nerves and the many other parts of the human body. They also use sequencing to understand genetic variations that can raise the risk of certain diseases. Genetic counselors can look at the results of genetic screenings to help patients and their families cope with these diseases — altering their diet, for example, if they lack a gene for a crucial enzyme.

The cost of sequencing an entire genome has fallen so drastically in the past 20 years — now a few thousand dollars, down from an estimated $3 billion for the public-private partnership that sequenced the first human genome — that doctors are beginning to sequence the entire genomes of some patients. (Sequencing can be done in as little as 50 hours.) And they’re identifying links between mutations and diseases that have never been seen before.

Yet all these powerful tests are based on the assumption that, inside our body, a genome is a genome is a genome. Scientists believed that they could look at the genome from cells taken in a cheek swab and be able to learn about the genomes of cells in the brain or the liver or anywhere else in the body.

In the mid-1900s, scientists began to get clues that this was not always true. In 1953, for example, a British woman donated a pint of blood. It turned out that some of her blood was Type O and some was Type A. The scientists who studied her concluded that she had acquired some of her blood from her twin brother in the womb, including his genomes in his blood cells.

Chimerism, as such conditions came to be known, seemed for many years to be a rarity. But “it can be commoner than we realized,” said Dr. Linda Randolph, a pediatrician at Children’s Hospital in Los Angeles who is an author of a review of chimerism published in The American Journal of Medical Genetics in July.

Twins can end up with a mixed supply of blood when they get nutrients in the womb through the same set of blood vessels. In other cases, two fertilized eggs may fuse together. These so-called embryonic chimeras may go through life blissfully unaware of their origins.

One woman discovered she was a chimera as late as age 52. In need of a kidney transplant, she was tested so that she might find a match. The results indicated that she was not the mother of two of her three biological children. It turned out that she had originated from two genomes. One genome gave rise to her blood and some of her eggs; other eggs carried a separate genome.

Women can also gain genomes from their children. After a baby is born, it may leave some fetal cells behind in its mother’s body, where they can travel to different organs and be absorbed into those tissues. “It’s pretty likely that any woman who has been pregnant is a chimera,” Dr. Randolph said.

Everywhere You Look

As scientists begin to search for chimeras systematically — rather than waiting for them to turn up in puzzling medical tests — they’re finding them in a remarkably high fraction of people. In 2012, Canadian scientists performed autopsies on the brains of 59 women. They found neurons with Y chromosomes in 63 percent of them. The neurons likely developed from cells originating in their sons.

In The International Journal of Cancer in August, Eugen Dhimolea of the Dana-Farber Cancer Institute in Boston and colleagues reported that male cells can also infiltrate breast tissue. When they looked for Y chromosomes in samples of breast tissue, they found it in 56 percent of the women they investigated.

A century ago, geneticists discovered one way in which people might acquire new genomes. They were studying “mosaic animals,” rare creatures with oddly-colored patches of fur. The animals didn’t inherit the genes for these patches from their parents. Instead, while embryos, they acquired a mutation in a skin cell that divided to produce a colored patch.

Mosaicism, as this condition came to be known, was difficult to study in humans before the age of DNA sequencing. Scientists could only discover instances in which the mutations and the effects were big.

In 1960, researchers found that a form of leukemia is a result of mosaicism. A blood cell spontaneously mutates as it divides, moving a big chunk of one chromosome to another.

Later studies added support to the idea that cancer is a result of mutations in specific cells. But scientists had little idea of how common cases of mosaicism were beyond cancer.

“We didn’t have the technology to systematically think about them,” said Dr. Christopher Walsh, a geneticist at Children’s Hospital in Boston who recently published a review on mosaicism and disease in Science. “Now we’re in the midst of a revolution.”

Benign Differences

The latest findings make it clear that mosaicism is quite common — even in healthy cells.

Dr. Urban and his colleagues, for example, investigated mutations in cells called fibroblasts, which are found in connective tissue. They searched in particular for cases in which a segment of DNA was accidentally duplicated or deleted. As they reported last year, 30 percent of the fibroblasts carried at least one such mutation.

Michael Snyder of Stanford University and his colleagues searched for mosaicism by performing autopsies on six people who had died of causes other than cancer. In five of the six people they autopsied, the scientists reported last October, they found cells in different organs with stretches of DNA that had accidentally been duplicated or deleted.

Now that scientists are beginning to appreciate how common chimerism and mosaicism are, they’re investigating the effects of these conditions on our health. “That’s still open really, because these are still early days,” Dr. Urban said.

Nevertheless, said Dr. Walsh, “it’s safe to say that a large proportion of those mutations will be benign.” Recent studies on chimeras suggest that these extra genomes can even be beneficial. Chimeric cells from fetuses appear to seek out damaged tissue and help heal it, for example.

But scientists are also starting to find cases in which mutations in specific cells help give rise to diseases other than cancer. Dr. Walsh, for example, studies a childhood disorder of the brain called hemimegalencephaly, in which one side of the brain grows larger than the other, leading to devastating seizures.

“The kids have no chance for a normal life without desperate surgery to take out half of their brain,” he said.

Dr. Walsh has studied the genomes of neurons removed during those surgeries. He and his colleagues discovered that some neurons in the overgrown hemisphere have mutations to one gene. Two other teams of scientists have identified mutations on other genes, all of which help to control the growth of neurons. “We can get our hands on the mechanism of the disease,” said Dr. Walsh.

Other researchers are now investigating whether mosaicism is a factor in more common diseases, like schizophrenia. “This will play itself out over the next 5 or 10 years,” said Dr. Urban, who with his colleagues is studying it.

Moving Cautiously

Medical researchers aren’t the only scientists interested in our multitudes of personal genomes. So are forensic scientists. When they attempt to identify criminals or murder victims by matching DNA, they want to avoid being misled by the variety of genomes inside a single person.

Last year, for example, forensic scientists at the Washington State Patrol Crime Laboratory Division described how a saliva sample and a sperm sample from the same suspect in a sexual assault case didn’t match.

Bone marrow transplants can also confound forensic scientists. Researchers at Innsbruck Medical University in Austria took cheek swabs from 77 people who had received transplants up to nine years earlier. In 74 percent of the samples, they found a mix of genomes — both their own and those from the marrow donors, the scientists reported this year. The transplanted stem cells hadn’t just replaced blood cells, but had also become cells lining the cheek.

While the risk of confusion is real, it is manageable, experts said. “This should not be much of a concern for forensics,” said Manfred Kayser, a professor of Forensic Molecular Biology at Erasmus University in Rotterdam. In the cases where mosaicism or chimerism causes confusion, forensic scientists can clear it up by other means. In the Austrian study, for example, the scientists found no marrow donor genomes in the hair of the recipients.

For genetic counselors helping clients make sense of DNA tests, our many genomes pose more serious challenges. A DNA test that uses blood cells may miss disease-causing mutations in the cells of other organs. “We can’t tell you what else is going on,” said Nancy B. Spinner, a geneticist at the University of Pennsylvania, who published a review about the implications of mosaicism for genetic counseling in the May issue of Nature Reviews Genetics.

That may change as scientists develop more powerful ways to investigate our different genomes and learn more about their links to diseases. “It’s not tomorrow that you’re going to walk into your doctor’s office and they’re going to think this way,” said Dr. Lupski. “It’s going to take time.

Publication: DNA Doubletake September 17,2013 Carl Zimmer, New York edition page D1

 

 

 

 

 

 

 

 

 

Agreement on Use of Genetic Information from 61 year old Cervical Cancer Cells Set New Ehical Privacy Standards for Clinical Pathology Labs
25 September 2013

Family of Henrietta Lacks, who died in 1951, will have a say in the research use of the HeLA cancer

Patient privacy rights involving genetic information has gone to a new level. Pathologists and clinical laboratory managers will want to understand the legal precedents and new standards established in an unprecedented agreement between the family of a woman who died in 1951 and the growing research establishment studying her cervical cancer cells following her death.

It is a human interest story that attracted global media attention this summer. The immortal cancer cells of Henrietta Lacks—known in research laboratories as “HeLA” cells—are finally coming under legal protection after more than 60 years of travelling the globe.

It was 1951 when Lacks died of an aggressive form of cervical cancer, but her cancer cells were grown without consent of relatives and have been used worldwide in cancer research since her death. Lacks’ living relatives sought and recently obtained a legal agreement with the National Institutes of Health (NIH) to protect their DNA privacy, according to a story published in USA Today.

Agreement Gives Lacks Family a Say in Use of HeLA Cells

Obviously, Henrietta’s genes could reveal information about the health of her offspring and close relatives. Not surprisingly, those individuals wanted restrictions on who has access to this information and how it is used.

This historic agreement allows HeLA cells to continue to be used in research, but calls for involvement by the Lacks family. The agreement requires NIH-funded researchers to use a “controlled-access” database of the HeLA cell genome. Access and use of this database will be governed by a panel that includes living members of Lacks’ family. The agency also is requesting that non-NIH cancer researchers honor the agreement.

This issue came to the attention of the Lacks family because Henrietta was the subject of a best-selling book, The Immortal Life of Henrietta Lacks. The book was written by Rebecca Skloot and Oprah Winfrey is planning to make a movie about this story.

Story of Henrietta’s Cancer Cells Is Remarkable

What made Lacks’ cells unique is that—instead of dying quickly as previous cell lines had—they kept replicating at an astonishing rate. This was a first for science back in 1951 and earned these cells the label “immortal.” It also made them immensely valuable to any scientist who wanted a stable base for experiments. Since 1951, HeLA cancer cells have been used in 74,000 cancer studies and have saved countless lives.

As was common practice in those days, researchers at Johns Hopkins took samples of Lacks’ cancer cells without her knowledge. Now, six decades later and in the era of gene mapping, these cells became the center of debate over genetic privacy. This issue surfaced after a German research team published the gene map, or genome, of the HeLA cells in March 2013.

Privacy Breech by German Researchers Instigated NIH Agreement

This privacy breech sparked a protest by the Lacks family and Skloot over the invasion of privacy. That caused the German scientists to quickly withdraw the HeLA gene map from public view. It also sparked a collaborative effort by NIH head Francis Collins, who formerly led the public Human Genome Project that initiated the human gene mapping era, and the Lacks’ family to protect the privacy rights of genetic sample donors. This collaboration was announced in August 7, 2013 issue of the journal Nature.

“The main issue was the privacy concern,” explained Lacks’ grandson, David Lacks Jr. in the USA Today article. “Right now we are in the early stages of genomic science or genomic medicine, and we don’t know what is going to come down the road in the future.”

NIH Leader Calls for Protecting Privacy of All Future Tissue Donors

Collins has used HeLA cells in his own research. He believes additional steps must be taken to protect DNA privacy of all donor families in the future—not just those made famous by the media. “Frankly, the science has moved faster than the consent process, and maybe it is time to catch up,” Collins told USA Today reporter Dan Vergano in a phone interview.

Collins also stressed the important role HeLA cells have played in understanding what made these cancer cells so deadly to Lacks and so resilient in the research lab. He cited a related study by Andrew Adey, of the University of Washington, which was also published in Nature. Adey’s article reported on the identification and location of the human papilloma virus genes inserted into the HeLA cell gene map that caused them to become cancerous.

Meetings With Lacks Family

Collins personally met with the Lacks family in Baltimore to discuss the agreement, noted Skloot, who assisted in setting up meeting with the NIH. “That wasn’t lost on the family,” she said. “This was the first time in history that scientists really took this kind of time with the [Lacks] family in a really open and transparent way.”

The story of Henrietta Lacks and her cervical cancer cells illustrates how quickly whole human gene sequencing, combined with the increased crunch-power of computers to translate raw data of the human genome, can create information which is instantly accessible via the Internet. In turn, these changes pose medical ethics considerations for society at large.

Reminder that Clinical Laboratories Must Maintain Confidentiality

At the advent of personalized medicine, this agreement is likely to have significance for clinical laboratories and pathology groups. It signals a new level of medical ethics and is a reminder that labs should be vigilent about patient privacy when handling patient specimens and/or when involved in tissue banking activities.

—By Patricia Kirk



Read more: Agreement on Use of Genetic Information from 61-Year-Old Cervical Cancer Cells of Henrietta Lacks Sets New Ethical Standards for Clinical Pathology Laboratories | Dark Daily http://www.darkdaily.com/agreement-on-use-of-genetic-information-from-61-year-old-cervical-cancer-cells-sets-new-ethical-privacy-standards-for-clinical-pathology-laboratories#ixzz2fv5gB4mR


 

Genetic process that promotes cervical cancer warns about anti-viral therapies in certain cases
26 June 2013

The use of anti-viral therapies in certain cases could actually trigger the cancer they are trying to cure.

A new understanding of the genetic process that can lead to cervical cancer may help improve diagnosis of potentially dangerous lesions for some women, and also raises a warning flag about the use of anti-viral therapies in certain cases - suggesting they could actually trigger the cancer they are trying to cure.

The analysis provides a clearer picture of the chromosomal and genetic changes that take place as the human papillomavirus sometimes leads to chronic infection and, in less than 1 percent of cases, to cervical cancer. It is the first to identify specific genes that are keys to this process.

Researchers say they want to emphasize, however, that the HPV vaccine commonly used by millions of women around the world is perfectly safe if done prior to infection with the virus. The concerns raised by this study relate only to viral therapies or possible use of a therapeutic vaccine after the virus has already been integrated into human cells.

"It's been known for decades that only women with prior infection with HPV get cervical cancer," said Andrey Morgun, an assistant professor and a leader of the study in the OSU College of Pharmacy. "In about 90 percent of cases it's naturally eliminated, often without any symptoms. But in a small fraction of cases it can eventually lead to cancer, in ways that have not been fully understood."

These findings were published recently in Nature Communications by researchers from Oregon State University and a number of other universities or agencies in the United States, Norway and Brazil. Collaborators at OSU included Natalia Shulzhenko, an assistant professor in the OSU College of Veterinary Medicine.

The study found that some pre-cancerous lesions can acquire a higher level of chromosomal imbalances in just a small number of cells. These new features appear to do two things at the same time - finally eliminate the lingering virus that may have been present for many years, and set the stage for the beginning of invasive cancer.

So long as the virus is not eliminated, it helps to keep under control viral oncogenes that have been integrated into the patient's genome, researchers said.

"Some of what's taking place here was surprising," Morgun said. "But with continued work it should help us improve diagnosis and early monitoring, to tell which lesions may turn into cancer and which will not."

The study also concludes it could be dangerous to use antiviral treatments or therapeutic vaccines with women whose lesions already show signs of HPV integration.

This may help explain why use of the antiviral drug interferon had inconclusive results in the past, in some studies of its value in treating cervical cancer. Patients with existing HPV lesions may wish to discuss findings of this study with their physicians before starting such treatments, researchers said.

Nature Communications by researchers from Oregon State University and a number of other universities or agencies in the United States, Norway and Brazil. Collaborators at OSU included Natalia Shulzhenko, an assistant professor in the OSU College of Veterinary Medicine.

 

ASCO: Vinegar Test May Reduce Cervical Ca Deaths
04 June 2013

Vinegar may reduce cervical cancer deaths as well, researchers reported here.

CHICAGO -- Vinegar has been used for everything from cleaning refrigerators to taming foot odors, and now this common kitchen staple may reduce cervical cancer deaths as well, researchers reported here.

In a 12-year randomized study of 150,000 women in India, biennial visual inspection with vinegar(acetic acid) reduced cervical cancer mortality by 31%, compared with no screening, reported Surendra Srinivas Shastri, MD, from the Tata Memorial Hospital in Mumbai, and colleagues at the American Society of Clinical Oncology annual meeting.

"We now have a method which could in a very simple way reduce cervical cancer mortality in low-resource countries like India," Shastri said.

Cervical cancer is the leading cause of cancer death in Indian women, and India accounts for 30% of the global burden of cervical cancer deaths, he said.

Pap smear screening isn't feasible because the country doesn't have the necessary health-care infrastructure, such as diagnostic laboratories and trained health care workers, said Shastri.

There's a cost issue, too. The vinegar screening test costs less than $1 per patient, while Pap smear or HPV DNA testing run about $15 per test, he said.

Looking for a simpler alternative, the researchers randomly assigned women, ages 35 to 64 years, with no prior history of cancer to biennial screening with vinegar (75,360 women) or no screening (76,178 women), which is the current standard of care in India. The study was conducted from 1998 to 2002 with 12 years of follow-up.

The vinegar used in the test is a sterilized combination of acetic acid with water -- not your regular off-the-shelf household vinegar.

Trained personnel -- 10th graders were used in the study -- used a cotton swab to apply the solution to the cervix. Cancerous and precancerous cells have more proteins in the nucleus than healthy cervical cells, and they aggregate into a whitish mass within a minute, Shastri said.

The incidence of invasive cervical cancer was similar between the two groups: 26.74 per 100,000 (95% CI 23.41-30.74) in the screening group versus 27.49 per 100,000 (95%CI 23.66-32.09) in the control group. This suggests that screening didn't lead to overdiagnosis, he said.

The researchers estimated this strategy could prevent 22,000 cervical cancer deaths every year in India and close to 73,000 in resource-poor countries worldwide.

The trial was supposed to continue until 2016, but was halted last year at the recommendation of an independent oversight committee due to the overwhelming benefits in the screening group, Shastri said. The government has already started rolling out the program nationally, a process that will take at least 2 years, he said.

The fact that the screening results were known immediately and women treated promptly is a real plus in rural areas where women might otherwise have to travel for hours to see a doctor, commented Carol Aghajanian, MD, of Memorial Sloan-Kettering Cancer Center and a member of the ASCO Communications Committee, Electra Paskett, PhD, of The Ohio State University in Columbus, told MedPage Today that the test will save lives.

"Showing that a screening test reduces mortality is the gold standard, and that had not been done before. Now we have a large randomized trial in a low-resource country showing the vinegar test meets that standard," said Paskett, who was the discussant for the study.

It could also be used in low-resource pockets in the U.S. that don't have access to or can't afford Pap smears or HPV DNA tests, she said.

Previous studies have shown that Pap smears and vinegar screens are comparable in accuracy, Paskett added.

The U.S. National Institutes of Health and Women's Cancer Initiative, an Indian nonprofit group, helped fund the study.

Primary source: American Society of Clinical Oncology
Source reference:
Shastri, SS, et al. "Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality" ASCO 2013; Abstract 2.

Institute for Cancer Research, Royal Marsden Program to Expand Cancer Predisposition Testing
31 May 2013

A new program launched by the Institute of Cancer Research in the UK and the Royal Marsden NHS Foundation Trust, a London-based cancer center, aims to bring cancer predisposition gene testing to all cancer patients in the UK.

Funded with £2.7 million ($4.1 million) from the Wellcome Trust, the three-year program, called Mainstreaming Cancer Genetics, will use a 97-gene panel developed in collaboration with Illumina and will start offering diagnostic testing for subsets of genes next year. Illumina commercialized the panel as a research-use-only capture product called TruSight Cancer last year (CSN 9/12/2013). ICR scientists are also working with scientists at the Wellcome Trust Centre for Human Genetics at the University of Oxford, who are developing data analysis methods for the test.

According to Clare Turnbull, head of ICR's predisposition and translational genetics team and one of the leaders of the program, the goal is to provide cancer predisposition testing to a larger number of cancer patients and their families by "lowering the thresholds by which we offer genetic tests."

One way to achieve this is to offer cancer patients the test through their oncologists as part of their routine appointments, rather than via referral to a clinical geneticist as is currently done. "The change will be the setting in which they're having their genetic testing," she said.

The 97 genes on the panel confer a "significant risk" for cancer and were selected for "clinical utility and management implications," she said. Ninety-four of the genes are sequenced in full, while the remaining are analyzed in part. In addition, the panel includes common cancer predisposition SNPs from genome-wide association studies, she said.

For more than half the genes on the panel, no genetic tests exist in the UK today because mutations in those genes are rare, so "it's really not worth the while of any lab to develop these tests in isolation," Turnbull explained. In a large multi-gene panel, those genes can be included without significantly increasing the test's complexity.

Clinical testing will start sometime next year and will be performed in ICR's translational genetics laboratory, an existing diagnostic lab, using the Illumina HiSeq 2500. The instrument can be run in slow mode with higher throughput, which takes about 11 days, or in fast mode with lower throughput, which takes 27 hours. "In terms of turnaround time, the slow mode is entirely acceptable," Turnbull said, but if samples fail and need to be repeated, or if a treatment decision is contingent on the test result, the lab may opt for the fast mode.

At the moment, the lab is testing how many samples it can multiplex in one run while maintaining the sequence quality and coverage necessary for a diagnostic-grade test. It is also validating the panel with a number of positive controls and continues to improve it, having recently added genes and changed the probe density and layout.

Initially, testing will only be available for certain types of cancer – starting with breast and ovarian – and will report on a subset of genes from the panel, in the first instance the BRCA1 and BRCA2 genes. "We will be running the full panel technically and reporting on parts of it as appropriate as we roll out," Turnbull said.

Next, testing will be expanded to larger numbers of genes and more cancer types, she said, until the full panel is eventually offered. "There are a number of structures that need to be explored and developed in terms of the consent and clinical processes for testing a patient for 97 genes," she said.

The cost for the full panel will be "a few hundred pounds," which she said is low, given that a number of single-gene tests offered through the UK's National Health Service currently cost more than £1,000 ($1,512).

The results go back to the oncologist who ordered the test and are expected to be negative in about 90 percent of cases. If the result is positive, the patient is referred to a clinical geneticist. The ICR is currently developing materials for communicating cancer risk to mutation carriers, but "we still envisage these being managed by specialists and experts in management of genetic conditions," rather than oncologists, Turnbull said.

It is unclear whether the Mainstreaming Cancer Genetics program will be the first effort to implement Illumina's TruSight Cancer panel in the clinic. According to Matt Posard, senior vice president and general manager of Illumina's translational and consumer genomics business, interest in Illumina's TruSight content sets "has been tremendous" and "multiple institutions" are evaluating them. Among them is Kindstar Global in China, which is using TruSight assays – including the cancer panel – as part of a strategic collaboration with Illumina to validate and implement molecular assays in its laboratories. The collaboration, he said, allows Kindstar "to expand its esoteric and specialty testing services offerings within its network of more than 3,300 hospitals across China."

However, Illumina isn't the only firm that has developed or is developing a panel for cancer predisposition testing. GeneDx, for example, is developing its own hereditary cancer panel. "We use our expertise to choose the most important clinically relevant genes for our tests, where the results will be meaningful in the care of the patients," said Sherri Bale, the firm's managing director. GeneDx will fully sequence all the genes on its panel, "thus providing higher sensitivity in a clinical setting," she added.

Myriad Genetics is also developing a multi-gene hereditary cancer panel, called MyRisk Hereditary Cancer, which will initially include 25 genes. The company said recently that it holds IP rights to several genes on its panel, which could potentially prevent competitors from including these in their products (CSN 5/15/2013). GeneDx, Illumina, and ICR all declined to comment on Myriad's patents, and how they might affect their tests. "Their IP position is not known to us at the moment," Turnbull said.

 

GenomeWeb's In Sequence and Clinical Sequencing News. 29.5.13 Julia Karow

 

Exploring Trends in Cytology
28 May 2013

For those laboratory technicians who enjoy helping many different patients in many different ways, cytology is the place to go. And with new technology constantly emerging, the time to act is now.

Bolstering Education
"I believe there is a certain type of dedication for a person to do cytology work," Nelson Barayuga, MBA, MT (ASCP), CT(ASCP), clinical laboratory supervisor, Syosset Hospital, N.Y., and cytotechnologist at LabCorp said. "The desire to make a difference for patients is important, but the interest in microscopic work should also be there."

As listed by the Commission on Accreditation of Allied Health Education Programs, there are currently 30 accredited cytotechnology programs in the nation, down from 39 in 2009 and 32 in 2011.

"In our program, we have seen an overall decline in the number of students enrolling in our programs, which mirrors the general decline of cytology programs across the country," Smith said. "The state of the economy right now makes it very hard for students in states that don't have cytology programs to take the time to leave for another state, learn cytology, then go back to their home state where there might be good jobs," she said.

Smith said that in her home state of Wisconsin, it's a difficult but necessary part of her job to tell students not to expect to work in the state after graduation. "We have three schools in Wisconsin, so our graduates are competing with those from two other in-state schools, and two other nearby schools in Minnesota," she said. "Meanwhile, there are no schools in the Chicago area, for example, and only two in California. It is very challenging for students from other states to come to Wisconsin, and most students within the state don't want to leave."

To combat the challenging logistics of cytology education, Smith said some programs are exploring distance learning education.

"I think the public needs a better understanding of the profession and an adaptation of the curriculum for those students who want to become a cytologist," Barayuga said. "I personally believe that a strictly traditional cytology program will be a challenge, so we need to mirror our academic programs with the changing times." 

Both Smith and Barayuga agreed that it is important to continue outreach to students on the high school level, teaching about the importance of laboratory work and what exactly it entails. If more students knew the role laboratorians play in healthcare, enrollment levels would increase.

Multitasking Masters

Those who do pursue cytology education and make it into the field are something to marvel. Smith says that cytotechnologists aren't your average laboratorian - they are the type of professionals who like to be responsible for many different areas of the lab.

"We are responsible for partnering with many types of clinicians, including radiologists, pulmonologists, general practitioners and obstetricians and gynecologists," she said. "We have the opportunity to work with many different patients in many different ways."

From the bench to education and more unconventional avenues, those trained in cytology have a unique skill set that is unmatched by other specialties in the lab profession. "Cytologists can apply their skills to many jobs," Smith said. "Quality assurance would be a great job for cytologists - identifying issues in quality checks is just like screening slides and finding abnormalities," she said.

Smith also mentioned risk management, coding and billing, anatomy, physiology, pathology, management and supervisory roles, pharmaceuticals and laboratory test development as potential job avenues for graduating cytologists. "Cytology is also an excellent way to get your feet wet in medicine, when the goal is to eventually pursue graduate school, medical school, nursing or physician assistant studies," she said.

Evolving Technology

As cytology and its laboratorians evolve, so does the technology that drives it. "We are faced with finding a way between what we have been doing and what we will be doing," Smith said. "Right now, we're in a place of the past versus the future. It's a little bit scary not knowing what our roles as cytologists in healthcare will be, but that gives us an interesting and fun opportunity to help drive where the future will go."

Smith said that emerging molecular technology will involve cytotechnologists in testing that is not interested solely in throughput, but methodology, analysis and the chemistry behind it. "We will soon be asking, 'How did the chemistry in the body react to make this molecular DNA change that results in a particular disease process?'" Smith said.

Barayuga added, "Image guided screening, molecular diagnostics, the HPV vaccination and newer regulations regarding slide limits have all affected the profession. We see changes each day in the way we screen, the type of smears we deal with, and a decrease in the frequency of Pap smear examinations."

As the availability of molecular diagnostic procedures increases, he said, so will the methods that supplement traditional screening procedures and the way that cytologists view cells.

"There are changes and challenges of molecular testing that are evolving right now," Smith said. "We can either be a part of it and participate in an active way, or wait for it to happen to us. Personally, I want to be a part of the change."

Growing the Field

Despite the decreasing number of cytology programs across the nation, the demand for cytologists is growing. "With the emergence of the Affordable Care Act, there are expected to

 

Kelly Wolfgang is assistant editor for ADVANCE. She can be reached at kwolfgang@advanceweb.com.

TCGA Study Shows Molecular Subtypes May Better Stratify Endometrial Cancer Patients than Histology
08 May 2013

Results from The Cancer Genome Atlas' (TCGA) analysis of several hundred endometrial cancers have classified the disease into four molecularly defined groups with differing prognoses.

According to the study, some endometrial tumors with similar histologic features actually differ in their molecular profile and might benefit from different treatments.

While the new classification does align in some ways with earlier histological categories, some patients that would have been classified in a lower-risk histological category according to current subtypes would now be grouped in the category with the worst prognosis according to the molecular results from TCGA's study published today in Nature. For patients that fall in this molecular subtype, this finding could mean that they should receive alternative treatments.

"One of the problems is that, especially for higher-grade tumors, it is difficult for pathologists to classify them. There can be disagreement among pathologists and those have important ramifications on what treatments we recommend," the study's lead author, Douglas Levine from Memorial Sloan-Kettering Cancer Center, told PGx Reporter this week. "There are cases that are just difficult and this is where molecular information can help to add another layer of clarity."

The latest study also separated a small group of subjects into a new category that looks to have extremely good prognosis. If the results hold over time, it could mean these patients, if identified based on their molecular signature, would require less or even no treatment compared to the other subtypes.

Current methods of histologic assessment classify an endometrial carcinoma as one of two types — either endometrioid tumors, with relatively better prognoses, or serous tumors, with relatively worse prognoses. Endometrioid cancers are most often treated with radiation, while serous tumors are treated with chemotherapy.

TCGA's new genomic data breaks these cancers instead into four groups: a new subgroup categorized by mutations in the gene POLE and an overall-high mutation rate; a group with high mutation rate and high microsatellite instability, but without POLE mutations; a group with high microsatellite instability but low rates of copy number alterations; and a group with high copy number alterations.

Overall, the study profiled 373 tumor samples using whole-exome sequencing, microarrays, RNA-seq, and other methods.

The POLE group, with 17 tumors, or less than 10 percent of the cohort, was associated with the best prognosis in the study, while those in the copy number-high group had the worst outcomes. The other two subgroups fell in the middle.

According to Levine, the fact that the fourth subgroup had much worse prognosis was not surprising. "The unique thing, he said, "is that we put some of the endometrioid cases with the serous cases based on the molecular features, suggesting that we can identify a subset of endometrioid cases that may have a poorer outcome."

Currently, known-serous cases frequently get treated with chemotherapy, but those classified as endometrioid, "depending what stage they are, they could get anything from nothing to radiation to chemotherapy and radiation," he said. "The suggestion from the molecular data is that maybe they should just get chemo like the serous group."

However, the molecular subgroups identified in this study must first hold up in terms of their association to cancer prognoses in follow-up investigations. "Once we do that we can then design trials that stratify based on these types."

He said researchers behind the study are planning to validate the findings in an upcoming prospective trial of chemotherapy and alternative treatments in endometrial cancer patients by measuring a variety of molecular targets to classify patients in the trial into the same four subtypes. They will evaluate whether the four subtypes hold true, that is, whether patients with the copy number-high subtype really do have worse outcomes than those in the other groups.

If so, it would suggest that some patients with these copy number-high or "serous-like" endometriod tumors might benefit from more aggressive treatment, as do those with clearly serous tumors.

The study authors suggested the results could provide a map for future clinical trials of targeted therapy. "Each tumor subtype might warrant dedicated clinical trials because of the marked genomic differences between them that are indicative of different drivers of cancer … and developing therapies for each subtype independent of the other may improve outcomes, as has been shown in breast cancer," said study co-leader Elaine Mardis of Washington University School of Medicine in a statement.

The new four-tier categorization of endometrial carcinoma is a highlight of the TCGA results, but the researchers also found other data that could potentially impact how physicians treat these tumors in the future.

Cancers in the copy number-high group — serous and serous-like endometrioid tumors — shared a number of molecular similarities with both serous ovarian tumors and basal-like, or triple-negative, breast cancers. For example, the cancers share a high frequency of TP53 mutations — between 84 and 96 percent — and a low frequency — 1 to 2 percent — of PTEN mutations.

"For ovarian serous tumors, the standard treatment is combination chemotherapy, which works very well," Levine said. "We use that same regimen for uterine serous tumors now. But in basal-like breast cancer, treatments are often different and some investigators want to test these in other groups. But it’s a question whether it will work as well in all these tumor types, because they do have all these similarities, but they also have lots of differences."

Additionally, Levine said, the study results shore up previous observations that the PI3K – AKT pathway is highly active in endometrial cancers. They also showed that the pathway is activated to a different extent in serous and in non-serous cases — significantly more so in non-serous tumors.

 

"Lots of drug companies [working on PI3 kinase inhibitors] are interested in studying endometrial cancer because they know this pathway has a lot of activation in this tumor type," he said. From the results, he said, "the pathway seems in fact to be so active in the non-serous cases that it might be hard to suppress it with only one of the targeted drugs available." That, he said, may be important information for these companies to use going forward.

In the group's upcoming validation study, Levine said he and his colleagues are prospectively collecting tumor samples in a three-arm trial involving just over 300 patients and testing various treatment methods and doing a "cadre of molecular tests" to reproduce these subtypes identified by the recent TCGA study. "We are screening for P53 mutations, POLE, PIK3CA, MSI — and we should be able to reproduce the four subsets within the context of this trial," he said.

"Then we can ask the question, do these endometrioid cases that have this molecular feature of being serous-like actually [do] worse— does that affect [their] response to treatment?"

If Levine and his colleagues are able to reproduce the findings, "the next trial will be to see if we give chemo to these patients who would normally get radiation or no treatment, does that actually make a difference? That would be step two of the validation process."

Nature; D. Levine,  Memorial Sloane-Kettering Cancer Centre –Genome Web Daily News

 

Genital Wart Decline Tracked to HPV Vaccine
19 April 2013

The incidence of genital warts declined by more than 90% in adolescent and teenage girls in the first 4 to 5 years after introduction of the human papillomavirus (HPV) vaccine in Australia, investigators reported.

Genital warts occurred more than 70% less often among women 21 to 30, as compared with the 3 to 4 years before the vaccine became available. The reductions in wart incidence among girls and women were accompanied by 50% to 80% decreases in the incidence of genital warts among heterosexual boys and young men.

No decline in wart frequency was seen in heterosexual women or men older than 30, Basil Donovan, MD, of the University of New South Wales in Sydney, and co-authors reported online in BMJ.

"In 2011 no genital wart diagnoses were made among 235 women under 21 years of age who reported prior human papillomavirus vaccination," the authors noted. "The significant declines in the proportion of young women found to have genital warts and the absence of genital warts in vaccinated women in 2011 suggests that the human papillomavirus vaccine has high efficacy outside the trial setting. Large declines indiagnoses of genital warts in heterosexual men are probably due to herd immunity."

The study provided a glimpse of the impact of HPV vaccination in a real-world community setting as opposed to a clinical trial.

"It actually generated data consistent with what we hoped and predicted would happen," said Greg Poland, MD, of Mayo Clinic in Rochester, Minn. "It showed in a large study that [the vaccine] worked and it worked fabulously."

It is probable that the results are readily applicable to the U.S. and other countries that have introduced HPV vaccination, he added. In particular, the results should reassure girls, young women, and parents that the vaccine is safe, effective, and does not promote promiscuity, which has been a concern to some people.

In 2007 Australia implemented one of the first nationwide HPV vaccination programs for girls and young women. The nationally funded program provides free vaccination to girls 12 to 13 in schools, and a vaccination "catch-up" program from 2007 to 2009 offered vaccinations to girls 13 to 18 and women 18 to 26.

The vaccination program included a surveillance network to monitor the effect of the vaccine on the incidence of genital warts in patients seen at sexual health services clinics. The first report from the program, 2 years after its implementation, showed a 59% reduction in wart incidence among vaccine-eligible women 12 to 26 and a 39% decrease in heterosexual men of the same age.

Donovan and colleagues updated the population effects of the vaccination program for 2007 to 2011.

From 2004 to 2011, 85,770 native-born Australians made initial visits to eight sexual health services. Evaluations showed that 7,686 (9.0%) of the patients had new diagnoses of genital warts (2,394 women and 5,292 men). From 2004 to 2007 the proportion of women with genital warts increased from 8.9% to 9.6% and then decreased to 2.7% by 2011. Among men, the rate declined from 12.8% to 11.7% during the first years, followed by a decrease to 7.4% by 2011.

The largest decline in genital-wart incidence occurred among women younger than 21. From a peak of 11.5% in 2007, the incidence of genital warts decreased to 0.85% by 2011, representing a reduction of 92.6% (P<0.001). Among women 21 to 30, the incidence of genital warts declined slightly from 12.5% in 2004 to 11.3% in 2007 before falling to 3.1% by 2011, a 72.6% decrease (P<0.001). The incidence did not decline significantly among women older than 30.

Rates of genital warts among heterosexual men seen at the sexual health services facilities increased by 68% (7.2% to 12.1%) from 2004 to 2007 (P<0.01) but declined by 82.8% to a low of 2.2% in 2011 (P<0.001). The incidence not changed significantly over time among men 21 to 30 or those older than 30.

Authors of a related editorial said the study showed a "remarkable reduction" in genital warts among women younger than 21 and predicted that "near eradication of genital warts in young Australian women will probably have a major impact on the costs of sexual healthcare."

"It remains to be seen whether we will see similar dramatic reductions in HPV-16 and HPV-18 associated diseases, such as cervical cancer, vulval cancer, other anogenital cancers, and head and neck tumors as a result of national vaccination programs," wrote Simon Barton, MD, of the Chelsea and Westminster Foundation Trust in London, and Colm O'Mahony, MD, of the Countess of Chester Trust in Chester, England.

"This is likely given the reported evidence of the vaccines. It is hoped that future vaccines will protect against other HPV types, such as types 31 and 45, which are also involved in the genesis of genital cancer. Countries should carefully explore whether it is economically feasible to vaccinate young men."

Source reference:
Ali H, et al "Genital warts in young Australians five years into national human papillomavirus vaccination program: National surveillance data" BMJ 2013; DOI: 10.1136/bjm.f2032.

 

Genome-wide siRNA screen for HPV 16
11 April 2013

Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus

Despite major advances in our understanding of many aspects of human papillomavirus (HPV) biology, HPV entry is poorly understood. To identify cellular genes required for HPV entry, we conducted a genome-wide screen for siRNAs that inhibited infection of HeLa cells by HPV16 pseudovirus. Many retrograde transport factors were required for efficient infection, including multiple subunits of the retromer, which initiates retrograde transport from the endosome to the trans-Golgi network (TGN). The retromer has not been previously implicated in virus entry. Furthermore, HPV16 capsid proteins arrive in the TGN/Golgi in a retromer-dependent fashion during entry, and incoming HPV proteins form a stable complex with retromer subunits. We propose that HPV16 directly engages the retromer at the early or late endosome and traffics to the TGN/Golgi via the retrograde pathway during cell entry. These results provide important insights into HPV entry, identify numerous potential antiviral targets, and suggest that the role of the retromer in infection by other viruses should be assessed.

Alex Lipovsky et al Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520-8011;

March 12 2013- Proceedings of the National Academy of Sciences of the United States of America

 

HPV vaccination effectiveness 'reduced in over-20s'
22 March 2013

Immunising women aged 20 years or older against HPV infection is too late to offer adequate protection against genital warts, say researchers.

The study

Researchers in Sweden followed 2,209,263 females aged 10 to 44 years and collected information on HPV vaccinations from vaccination registers. Vaccine effectiveness was calculated using incident rate ratios of genital warts, which used a time to first event of genital warts as part of the analysis.

The findings

Vaccine effectiveness was highest in girls vaccinated before the age of 14, with an effectiveness of 93%. This dropped to 80% for girls vaccinated aged 14 to 16 years, 71% for girls vaccinated at 17 to 19 years and 48% for women vaccinated aged 20 to 22 years.

What does it mean for GPs?

The authors concluded that among women vaccinated at 20 years or older ‘there was low to immeasurable effectiveness and suggestive evidence that vaccinations tended to reach women at high genital warts risk.’ They added that it suggested ‘that vaccinations in this age group were not adequate for achieving the intended health benefit.’

Journal of the National Cancer Institute, online 13 March

Personalized Medicine Experts Call on Pathology Profession to Create a New Breed of Pathologist
13 March 2013

‘National Agenda’ seeks to marshal efforts to sharpen the clinical impact of pathology in the genomics era

Pathologists are being urged to seize the high ground as the unfolding revolutions in genomics and bioinformatics create unprecedented capabilities to more accurately diagnose patients and guide the selection of appropriate therapies.

Two experts in these fields have come together to issue a call to action for the pathology profession, stating that pathologists need to be prepared for the sequencing revolution. “Revolution is not too strong a word; this is not incremental change,” declared Dennis P. Wall, Ph.D. and Peter J. Tonellato, Ph.D. in a recent story published in The Scientist “The use of whole-genome analysis (WGA) can, should, and will replace many current standard pathology practices of diagnosis and prognosis on which proper therapy and disease management rely,” the co-authors asserted.

Wall is an associate professor and director of Computational Biology at Harvard Medical School (HMS). Tonellato is a professor and director of the Laboratory for Personalized Medicine at HMS.



Read more: Personalized Medicine Experts Call on Pathology Profession to Create a New Breed of Pathologist | Dark Daily http://darkdaily.com/personalized-medicine-experts-call-on-pathology-profession-to-create-a-new-breed-of-pathologist-22513#ixzz2NQcQZDcA

Less frequent Pap smears may miss cancer precursors
13 March 2013

Certain types of cervical abnormalities that can lead to cancer may be missed when young women go years between Pap smears, a new study suggests.

Last year, the government-backed U.S. Preventive Services Task Force said women under 21 don't need to be screened for cervical cancer and Pap smears can be done once every three years after that.

Those guidelines broadly agreed with others released by the American Cancer Society, the American Society for Colposcopy and Cervical Pathology and the American Society for Clinical Pathology.

The new study's lead author, Dr. Lisa Barroilhet, said she agrees with those recommendations and that her findings are "absolutely" not a reason to change them.

"Any time you have new guidelines, you just want to make sure you're not assuming this is going to be the right thing long term for every patient," Barroilhet, from the University of Wisconsin Hospital in Madison, told Reuters Health.

She and her colleagues reviewed the records of 242 women with adenocarcinoma in situ, or AIS - cervical abnormalities that can lead to adenocarcinoma, one form of cervical cancer.

Those cancers occur further up the cervix than the squamous cell carcinomas typically caught by Pap smears, Barroilhet explained - so they're not the focus of Pap-related guidelines.

However, she and her colleagues found most young women in their study were diagnosed with AIS because of other abnormal lesions picked up on Pap smears that led to more testing and biopsies.

That was the case for 16 of the 17 women diagnosed with AIS before age 21, they wrote Thursday in Obstetrics & Gynecology.

Even though Pap smears weren't designed to catch adenocarcinoma precursors, the findings mean less-frequent Paps could lead to more of those full-on cancers developing, Barroilhet told Reuters Health. That's especially a concern because adenocarcinomas can be faster growing than squamous cell carcinomas, she said.

But Rebecca Horvat, a pathologist from the University of Kansas Medical Center representing the American Society for Clinical Pathology, said most abnormal lesions still take years to develop into adenocarcinoma.

"It doesn't go, as soon as you get it, you get a cancer," Horvat, who wasn't involved in the new study, told Reuters Health. "It can easily be picked up every three years."

She said the main challenge with moving to screening every three years may be a psychological one for women who have spent years getting their annual Pap.

The American Cancer Society estimates 12,340 U.S. women will be diagnosed with cervical cancer in 2013. Up to four times as many may develop AIS.

Because both adenocarcinomas and squamous cell carcinomas can be caused by human papillomavirus, or HPV, Barroilhet said preventing the sexually transmitted infection remains a public health priority.

The best way to prevent any of this is HPV vaccination," she said

Read more: http://www.foxnews.com/health/2013/03/08/less-frequent-pap-smears-may-miss-cancer-precursors/#ixzz2NQdlEFyE

 

Video created by UK researchers helps increase numbers being vaccinated for HPV
13 March 2013

Cervical cancer mortality rates are 45 percent higher in Eastern and southeastern Kentucky than in the rest of the country, according to statistics from the Centers for Disease Control.

One in five women in Eastern and southeastern Kentucky has not had a Pap test during the past three years, and Pap tests are key to revealing cervical changes that can lead to cancer.

For those women, the three-shot HPV vaccine Gardasil, which became available several years ago and fights the virus linked with cervical cancer, should have been sending young women flocking to health care providers.So why didn't it?

University of Kentucky health behavior researchers Elisia Cohen, an associate professor of communication, and Robin C. Vanderpool, an assistant professor in the department of public health, decided to look in to why women 18-26 weren't getting the full series of shots.

Their findings were included in an article in the academic publication Journal of Communication in February. When the vaccine was introduced in 2006, it was targeted at younger teens, who often would be brought to physicians and clinics by their parents.

The researchers asked themselves: What kind of incentive would it take to get young women older than 18 to commit to getting three shots within six months, knowing it could save their lives?

They knew that simply providing the full series of three shots at no cost did not work. They recruited 246 women in 2010-11 from rural health clinics with vouchers for the full series of shots. Only 45 percent took the first shot; 14 percent of those who took the first shot returned for the second, and only 5 percent received the third.

So researchers tried again: They gave the first dose of medication free to 344 young women at health departments, medical clinics, community colleges, outdoor festivals, Wal-Mart stores, businesses and homes.Then, they asked those women if they'd like to take part in a study. This time, though, they'd make it personal: Women getting their first shot would watch a video in which area medical providers and women who had received the shots would talk about the importance of taking charge of their health. The video team used interviews and focus groups to design the DVD.

It was theorized that women who saw other young women like themselves talking positively about the vaccine's effect would be more willing to get all the shots."Really, half the battle is getting them in for dose one," Vanderpool said. "But there's also getting them in for dose two or three."One of the young women in the video talked about losing her grandmother to cervical cancer. Another addressed questions young women have about why they should get the shots when they're in a monogamous relationship, and whether young men should feel threatened by having a girlfriend who takes care of her body and health."The (video) messages were more salient," Vanderpool said. "People look like them, talk like them ... so it resonates with the young women. ... It was also about changing social norms, how people talk about this — that it's OK to get the HPV vaccine."

Plans are being made for videos to urge younger teenagers to be vaccinated — and young men as well. And while the videos are helping, legislation might, too. A bill sponsored by Rep. David Watkins, D-Henderson, requiring that young boys and girls be immunized against HPV was approved 54-40 by the House on Feb. 26. The bill, now in the Senate, would provide the ability to opt out for parents who do not want their children — girls 9-16 and boys 10-16 — immunized.

Vanderpool, assistant professor in the Department of Health Behavior in the UK College of Public Health, led the study about how the DVD helped increase the number of women who took the entire course of shots.She called it "one part research, one part community outreach.""Now that we have the vaccine and regular Pap testing, we have two ways that we can fight this cancer," she said. Cheryl Truman: (859)231-3202. Twitter: @CherylTruman.

Read more here: http://www.kentucky.com/2013/03/03/2540803/video-created-by-uk-researchers.html#storylink=cpy

Targeting Cancer With New Microscopy Technique
13 March 2013

For scientists to improve cancer treatments with targeted therapeutic drugs, they need to be able to see proteins prevalent in the cancer cells

This has been impossible, until now. Thanks to a new microscopy technique, University of Akron researcher Dr. Adam Smith, assistant professor of chemistry, has observed how clusters of epidermal growth factor receptor (EGFR) — a protein abundant in lung and colon cancers, glioblastoma and others — malfunctions in cancer cells.

“We can directly observe protein clusters, in a living cell membrane, that are invisible to traditional methods. This opens up the possibility to directly measure the effect of drugs on the target proteins,” Smith says.

Smith’s work lies at the heart of current-day cancer research, which focuses on developing targeted drugs that kill cancer cells without the collateral damage associated with traditional treatments like chemotherapy.

Specifically, Smith used a cutting-edge photon-counting technique, which enables scientists to measure the cluster size of EGFR proteins. The technique represents a significant advancement from studying the cultures with a traditional microscope, which cannot visually capture objects as small as the EGFR clusters, according to Smith, a lead author of “Conformational Coupling across the Plasma Membrane in Activation of the EGF Receptor,” published in the Jan. 31 issue of the journal Cell, which highlights the technique.

“Another difficulty with studying EGFR is that it’s located in the cell membrane, which can be thought of as a fence line that defines the cell boundary, but in reality it is more like an untamed hedge row,” says Smith, explaining how the new laser-based microscope technique overcomes that obstacle and allows scientists to study, in real time, how EGFR works in healthy cells and also how it malfunctions in cancer cells.

Smith’s subsequent work studying the interaction of drugs with the targeted EGFR “will significantly improve drug discovery, which too often relies on indirect measure of efficacy,” he says.

Partners in Smith’s research include scientists from the University of California, Berkeley, and Columbia University. The National Cancer Institute, Howard Hughes Medical Institute and the U.S. Department of Energy provided funding for this research.

On The Net:


 

Age 25 is too late to start testing for cervical cancer say Canadian's
27 February 2013

In a newly released position paper, the SOGC, the Society of Gynecologic Oncology and the Society of Canadian Colposcopists say age 25 is too late to begin Pap testing because precancerous and cancerous lesions may have developed earlier in some women.

The Canadian Task Force on Preventive Health Care, which issued national guidelines in early January, advises that women wait three years between screenings, which should continue to age 69. For years, women were told to get annual Pap smears, though that interval has been stretched in recent years in a number of countries.

Dr. Jennifer Blake, CEO of SOGC, said the task force was correct in saying that waiting until 25 would have little effect on the number of women under 25 who die from cervical cancer, which usually is a relatively slow-growing cancer.

But we do think that you can find -- and we do find -- advanced lesions in young girls or even if we find early lesions in young girls, just by doing very minor things, removing those abnormal cells even in the process of a biopsy, you impact the natural history of the disease," Blake said Thursday from Ottawa.

"And what can happen then is if you do end up needing to treat, treatment is less destructive," she said, explaining that having to remove a larger part of an otherwise healthy cervix can affect a woman's fertility.

That was a major concern of the task force, which suggested that Pap smears that turn up abnormal tissue can lead to overly aggressive treatment in young women that can affect future fertility. Treatment can result in an inability to carry a pregnancy to term.

"That doesn't mean you don't start screening," said Blake. "That means you don't over treat."

"So we now say that if you are seeing problems in younger women, you can safely watch them with conservative treatment, just doing a biopsy and watching."

But Dr. James Dickinson, chair of the task force, said age 25 was recommended because evidence shows that cervical cancer is rare in young women, even up to age 30, and "vigorous screening has not reduced cancer much at these young ages."

Dickinson, a professor of family medicine at the University of Calgary, said 10 per cent of Pap smears are positive in women up to age 30 and require at least one cervical biopsy and possible treatment that can lead for some to miscarriage or premature labour.

"Those women, those young women, have a risk that this can cause trouble because the cervix has a function -- it holds babies in. And part of that function may be lost," Dickinson said from Gold Coast, Australia, where he is on sabbatical at Bond University's Centre for Research in Evidence-Based Practice..

Women can also suffer psychological harm, worrying about whether they have cancer as they wait for biopsy results, he said.

Dr. Betsy Brydon, president of the Society of Canadian Colposcopists -- the doctors who perform cervical biopsies -- said new guidelines were issued in December aimed at reducing potential harm from diagnostic and treatment procedures, and discouraging aggressive treatment unless clearly warranted.

"So we try not to treat when we don't need to treat, and when we do treat, we try to limit the amount of skin that we remove (from the) cervix," she said from Regina.

Dickinson said the task force, which bases its recommendations on international studies and epidemiological evidence, attempts to balance potential benefits against potential harms.

Much of the data comes from other countries, and the three medical organizations called that evidence "weak."

Blake said there is no data on Canada's female population that would show it is safe to wait until age 25 to start screening or for waiting three years between tests -- an interval she suggested women would find difficult to remember.

"We should not be interpreting evidence from other countries and applying it to our own young women unless we really have very good certainty that it's a safe thing to do," she said.

"We're saying let's err on the side of being conservative ... because (cervical cancer) remains the second most common cancer in young women (aged 20 to 44) and it still has a significant impact on mortality and loss of fertility and sexual function."

Dickinson said citing the 20-44 figure is misleading because cervical cancer is still relatively rare: without screening, a woman's lifetime risk of developing cervical cancer is 1.5 per cent.

The Pap smear is one of the most effective screening procedures that doctors have, he said, and it's reduced the incidence of cervical cancer by 80 per cent.

"That's really great. But we've got to balance that against the fact that for 98 per cent of women who are never going to get it, having Pap smears is just a thorough nuisance and causes some harm."

The Canadian Cancer Society estimated that in 2012, 1,350 Canadian women were diagnosed with cervical cancer and 390 died from the disease.

Research shows most of the benefit of cervical cancer screening occurs for women in their 40s and older, the point at which most cervical cancer cases are diagnosed.

However, abnormal test results are not uncommon in younger women because the Pap smears pick up lesions caused by infections with the human papillomaviruses (HPV), which can cause cervical cancer.

Many of those lesions would heal on their own and would not go on to become cancer. But once they are found, women often need additional testing and treatments, some of which can make it hard for a woman to later carry a pregnancy to term.

As vaccines to prevent HPV infection become more widely used -- they are now recommended for females age nine to 49 and males nine to 26 -- screening guidelines will likely change.

Meanwhile, screening with the Pap smear and expanding HPV testing across Canada remain critical for preventing cases of cervical cancer and cervical cancer deaths, she said.

Blake said the emphasis needs to be put on getting females to have regular Pap smears: more than half of Canadian women diagnosed with cervical cancer had never been screened, while the rest of those diagnosed could have had a Pap test, but it either was not done recently or there had been a false negative.

As well, a recent Toronto study showed one-quarter of women who had an abnormal Pap smear did not have follow-up tests or treatment.

"The biggest problem with cervical cancer in Canada isn't the frequency of screening, it's not the age of initiation of screening, it's not whether or not we do HPV co-testing," said Brydon. "The problem is that women don't go for testing."

That's one thing Dickinson agrees with -- a push is needed to identify groups of women who are not getting tested, possibly because of living in rural or isolated communities with poor access to services or for socioeconomic reasons.

Blake conceded that young women may be confused by the conflicting advice being given by two groups of credible medical professionals, making them unsure when they should start being tested or how often.

"I think the message is that there's a difference of opinion and you may want to talk to your doctor and make a decision yourselves," she said.

Brydon suggested women go online to check screening guidelines being used by their individual province or territory or ask their doctors.

Study Suggests DNA from Pap Test Samples Can Be Used to Detect Ovarian, Endometrial Cancers
10 January 2013

The same liquid samples collected during many modern-day Papanicolaou, or "Pap," tests for cervical abnormalities and human papillomavirus infection may serve as a resource for finding genetic changes linked to endometrial and ovarian cancers,

"Although improvements need to be made before applying this test in a routine clinical manner," the study authors argued, "it represents a promising step toward a broadly applicable screening methodology for the early detection of gynecologic malignancies."

Using existing genetic data on ovarian tumors and newly generated exome sequences for nearly two-dozen endometrial tumors, investigators from Johns Hopkins University and elsewhere in the US and Brazil started by sussing out which genes are most frequently mutated in the gynecological cancers.

From there, the team went on to show that mutations found in ovarian or endometrial tumors often tended to turn up in sequences from matching Pap test fluid samples, particularly in individuals with endometrial cancer.

And by bringing such findings together, the investigators narrowed in on a panel of oft-mutated genes, which dubbed "PapGene," that appears to show promise for finding endometrial or ovarian cancer-related mutations in fluid collected during Pap tests.

Though more research is needed to assess the potential genetic test and its utility in the clinic, they said, results so far hint that sequencing the PapGene panel may broaden the information that can be obtained from the sorts of patient samples already being collected routinely in the clinic.

"Our genomic sequencing approach may offer the potential to detect these cancer cells in a scalable and cost-effective way," co-senior author Luis Diaz, Jr., a researcher with the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University and director of the institute's Swim Across America Laboratory, said in a statement.

Pap tests involve the collection of cervical cells to look for signs of cervical cancer or pre-cancerous lesions. For liquid-based versions of the test, which are often used today, study authors said, clinicians preserve some of the sample in a liquid form. That sample can then be used to test for the presence of DNA from HPV, a virus that sometimes leads to cervical cancer.

But Diaz and his colleagues suspected that cervical fluid might contain other informative genetic material as well. In particular, they speculated that cancers occurring in nearby endometrial or ovarian tissues might slough off mutation-containing DNA that would make its way to the cervix and get caught up in the Pap sample.

To begin testing that theory, the researchers started by trying to take stock of the most common mutations in some gynecological cancers.

Along with analyses of existing ovarian and endometrial tumor data, the team performed exome sequencing on matched tumor and normal samples from 22 individuals with endometrioid cancer, the most common endometrial cancer subtype.

After capturing protein-coding regions in the tumor and normal samples with an Agilent SureSelect Human Exome kit, the team used Illumina's GAIIx instrument to sequence each of the exomes to an average depth of around 149-fold over more than 88 percent of the bases targeted.

Within the 22 tumors tested, mutation profiles clustered in two broad groups, the researchers noted. A dozen tumors harbored more than 100 predicted somatic coding mutations (perhaps owing to alterations affecting DNA repair pathways), while the remaining 10 tumors had fewer than 100 somatic mutations apiece.

By folding in existing data on ovarian cancers and endometrial tumors from other subtypes, the investigators came up with a list of the top mutation-containing candidate genes across the gynecological cancer types.

Analyses of targeted or whole-genome sequence data on another 24 endometrial tumor samples and 22 ovarian tumor samples verified the notion that the team's gene list contained authentic cancer players: Each of the 46 tumors tested harbored a mutation within at least one of the genes.

And that prompted researchers to go a step further, testing for DNA alterations in Pap test fluid samples collected from the same 46 women whose tumors had been tested directly. There, researchers found tumor-related mutations in cervical fluid samples from all 24 women with endometrial cancer and in nine of the 22 women with ovarian cancer.

Similarly, investigators found mutations in genes from their PapGene panel through targeted sequencing on Pap test samples from two more women with ovarian cancer and another 12 women with endometrial cancer. In contrast, such alterations did not turn up in Pap test samples from 14 unaffected women.

Moreover, the sequencing-based method uncovered mutations in the PapGene panel in individuals with both early stage cancers and those whose cancers had progressed to later stages.

In an effort to ward off false-positive PapGene tests caused by amplification, sequencing, or other errors, the researchers used the so-called "Safe-SeqS" method to sequence the targeted genes in each of the cervical fluid samples.

That involves slapping 14-base DNA barcodes onto DNA fragments in samples prior to amplification and analyses so that the team can check back to see if apparent mutations in the cancer genes are present in all amplicons from the same stretch of sequence.

Going forward, the group hopes to make additional improvements to the PapGene test and to further explore its utility.

"Performing the test at different times during the menstrual cycle, inserting the cervical brush deeper into the cervical canal, and assessing more regions of the genome may boost the sensitivity," said JHU neurosurgery researcher Chetan Bettegowda, one of the first authors on the study, in a statement.

In an accompanying perspectives article in the same issue of Science Translational Medicine, researchers from the University of Texas' MD Anderson Cancer Center and the Dana-Farber Cancer Institute discussed the PapGene sequencing strategy within the context of past and current schemes for diagnosing such gynecological diseases.

They also touched on some of the issues that would need to be addressed before the test enters the clinic and noted that a similar approach may eventually offer clues about the biological processes involved in the development of such cancers.

For instance, along with the sensitivity and specificity of the genetic test, they said that it will likely be important to consider its ease and affordability. They also noted that the advent of screening strategies for ovarian and endometrial cancers based on Pap test samples may prompt changes to the frequency with which the tests are administered and/or the age of the patient groups targeted.

Ovarian Cancer

Evaluation of DNA from the Papanicolaou Test to Detect Ovarian and Endometrial Cancers

Isaac Kinde et al

Sci Transl Med
Vol. 5, Issue 167, p. 167ra4
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004952

 

Sexual revolution effect maybe hiding true extent of HPV prevalence
10 January 2013

Human papillomavirus (HPV) infection in older women is commonly due to reactivation of latent disease rather than new infection, research indicates.

The study, published in The Journal of Infectious Diseases, showed that the age-specific prevalence of HPV rose with the number of sexual partners, a finding of particular relevance to women who became sexually active during the sexual revolution of the 1960s and 1970s, say the researchers.

"Our historical experience with HPV and cervical neoplasia in postmenopausal women may not be very predictive of the experience of the baby boomer generation of women who are now entering the menopausal transition at a higher risk than their mothers," remarked study co-author Patti Gravitt (Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA) in an accompanying press statement.

Gravitt and colleagues explored age-related fluctuations in HPV infection in the USA, where the prevalence peaks among younger women around the age of sexual debut. In other geographic regions there is a second attenuated peak around the age of menopause but this bimodal distribution is not seen in the US.

"Explanations for this variability include differences in relative prevalence of new partnerships at older ages, risk of HPV reactivation at older ages, and cohort effects," writes the team.

They enrolled 843 women aged 35-60 years and tested them for HPV DNA. The women's mean age was 46.6 years, 74.3% were White, and 19.0% were Black.

The prevalence of HPV - whether all types combined or just high-risk strains - decreased with age and increased with the number of lifetime sexual partners, with a threshold observed between four and five such partners. HPV prevalence was also higher among women with a recent new sexual partner.

Interestingly, the prevalence of HPV declined with increasing age among women with fewer than five lifetime sex partners. However, among women reporting five or more lifetime partners, the prevalence of any HPV and high-risk HPV declined between ages 35-40 years, increased again during ages 40-54 years, and then decreased at ages 55-60 years.

The interaction between age and lifetime number of sex partners was modest for any HPV and statistically significant for high-risk HPV, after adjustment for recent sexual behavior, marital status, history of colposcopy, and current cytologic abnormality.

This finding is consistent with an age-associated increased risk of HPV reactivation, say the authors. The older women in this study, who experienced sexual debut at the beginning of the US sexual revolution of the 1960s and 1970s, had a lower lifetime risk for HPV infection as demonstrated by a lower self-reported lifetime number of sex partners, they note.

Gravitt and co-authors conclude: "We propose that the cohort effect of the sexual revolution in the USA is masking an increase in HPV prevalence at older ages, which may be secondary to reactivation of 'latent' infection. Further follow-up of the HPV in perimenopause cohort and national surveillance data will be required to confirm this hypothesis."

 

The Journal of Infectious Diseases Jan 2013

 

Knowing How Cells Know They Aren't Upside Down May Help Fight Cancer
10 January 2013

The tops and bottoms of cells do different jobs, and healthy organs and tissue contain well-organized cells that are the right way up. One of the first signs of cancer is when cells become disorganized and can end up upside down

The Extracellular Matrix

The extracellular matrix is a protein-rich "scaffolding" that holds cells in place to form three-dimensional tissue. It is essential to the design and shape of organs.

However, unlike the inert scaffolding used on building sites, the extracellular matrix interacts with the cells that it holds in place.

For instance, in a recently published study led by the Massachusetts Institute of Technology, scientists uncovered a clue to an important question in  cancer research: how do cancer cells spread? They found molecular interactions with tumor cells alter the stickiness of the matrix so the cells become unstuck and travel to other parts of the body to start new tumors.

Other studies have shown that the extracellular matrix not only sticks to the cells but also guides them into the right positions.

But what Streuli and Akhtar wanted to explore was an area that was still a mystery: how does the extracellular matrix communicate the guiding messages to the cells so they assume the correct position, the right way up?

For their study, they decided to look at epithelial cells, which make up the majority of body tissue. The particular epithelial cells they studied were the ones in the milk-producing glandular tissue of the breast. These cells also line the mammary ducts that carry milk to the nipple.

If these cells aren't organized correctly, the breast can't send milk to the nipple when a baby is suckling. And one of the first signs of cancer is that the epithelial cells become disorganized.

Lack of Integrin Disorients Cells

One of the ways the extracellular matrix connects with breast epithelial cells is via receptors called integrins. These receptors tell cells about their environment, and also send messages from within cells to their environment.

Streuli and Akhtar conducted experiments with the integrins in breast epithelial cells to see how they affected cell behavior.

In one experiment, they found cells that lacked the gene for integrins ended up the wrong way up in the extracellular matrix and also in the wrong place.

In another experiment, they discovered that removal of integrins in cultured breast cells led to the same disordered effect.

Integrins Linked to Microtubules Is the Key to Cell Orientation

A further experiment helped the researchers understand how cells know they are the right way up.

They discovered that inside cells, the integrin receptors connect to a protein called ILK that in turn links to microtubules, a protein transport network inside cells.

They found it is the combination of integrins and microtubules within a cell that makes sure the correct proteins are sent to the top and the bottom of the cell to ensure the cell goes into position the right way up.

Streuli says in a statement that they discovered "a vital interplay between the transport machinery and the integrin receptors which makes sure that proteins are transported to the correct area of the cell."

"Without this interplay the proteins end up in the wrong place, and this can lead to cells becoming disorganized," says Streuli.

He goes on to explain that when they compared breast tissue from their experiments with that of patients in early stages of breast cancerthey appeared very similar:

"The cells were upside down and disorganized so they couldn't carry out their functions."

"We hope that our work to better understand cell polarity could ultimately lead to better diagnosis for cancer patients," he adds.

The Work Is Relevant to Other Organs

Although they only experimented with breast epithelial cells, Streuli and Akhtar believe epithelial cells from other organs would behave in the same way.

An important aspect of their work is the use of special 3D cultures to grow the cells, where they formed tiny organs that looked remarkably similar to breast tissue.

"Growing the breast cells so that they can form 3D structures rather than on hard petri dishes means they develop in a way that is much more akin to how they grow in the body," says Akhtar.

"Over 90% of cancers come from epithelial cells, which is why we chose to study them," she adds.

Streuli and Akhtar now plan to test whether changing levels of integrin leads to the disorganization of cells that is seen in the early stages of cancer.

On line published in Nature Cell Biology on 23 December.  Charles Streuli and Nasreen Akhtar of the Wellcome Trust Centre for Cell-Matrix Research, an interdisciplinary unit in the Faculty of Life Sciences at the University of Manchester



 

HPV Vaccine No 'License for Sex' in Girls
15 October 2012

There did not appear to be any difference in the sexual behaviors of adolescent girls who received the human papillomavirus (HPV) vaccine and their unvaccinated peers, researchers found.

Among girls ages 11 and 12 enrolled in a large, managed-care organization, there were no between-group differences in the rate of pregnancy, testing for or diagnosis of a sexually transmitted infection, or receipt of contraceptive counseling by a physician, according to Robert Bednarczyk, PhD, of Kaiser Permanente Center for Health Research-Southeast in Atlanta, and colleagues.

In addition, the average age at the first composite outcome was no different between vaccinated and unvaccinated girls (14.4 versus 14.6, P=0.325), which indicates "that there may not be any earlier onset of sexual activity after HPV vaccination," the researchers reported online in Pediatrics.

"It is likely that any disinhibition or risk compensation would occur closer to the time of vaccination (i.e., within 18 months) rather than much later," they wrote. "If HPV vaccination was 'a license for sex,' we would have expected to see more adverse outcomes shortly after vaccination, when the girls were more aware of their recent vaccination status."

The Advisory Committee on Immunization practices recommended in 2006 that all girls ages 11 to 12 receive the HPV vaccine, with the idea that immunity to the sexually transmitted disease will develop before sexual activity begins.

Uptake of the vaccine, however, has trailed that of other recommended adolescent vaccines, including tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine and the quadrivalent meningococcal conjugate vaccine (MCV4).

One concern raised about HPV vaccination is that immunized girls will increase their sexual activity because of less fear of disease. Surveys based on self-reported data have shown that girls do not plan on changing their sexual behaviors after vaccination, but no studies had examined the issue using clinical outcomes free from the bias of self-report.

Bednarczyk and colleagues did such a study using electronic data from Kaiser Permanente Georgia. Their analysis included 1,398 girls ages 11 or 12 who were enrolled in the health plan from July 2006 through December 2007 -- 35% received at least one dose of HPV vaccine in addition to other vaccines and the rest received Tdap, MCV4, or both, but not HPV vaccine.

Through 3 years of follow-up, the rate of pregnancy, testing for or diagnosis of a sexually transmitted infection, and receipt of contraceptive counseling was 5.5 per 100 person-years in the vaccinated group and 3.9 per 100 person-years in the control group, a difference that was not statistically significant after adjustment for healthcare-seeking behavior, age at vaccination, race, and socioeconomic status (incidence rate ratio 1.29, 95% CI 0.92 to 1.80).

There were no between-group differences in rates of secondary outcomes either, although the rate of receiving contraceptive counseling came close to being higher in the vaccinated group (1.39 versus 0.50 per 100 person-years; IRR 2.31, 95% CI 0.99 to 5.38).

"The administrative data used for this study did not provide an opportunity to do a detailed examination of the reasons for this counseling or of the extent of hormonal contraceptive use among girls in this cohort," the authors wrote.

They acknowledged some additional limitations, including the possibility that differences remain between the vaccinated and unvaccinated girls despite adjustment for some confounders, the use of administrative data, the possibility that some of the girls received vaccines or reproductive healthcare at outside clinics, the limited ability to generalize the findings to other age groups, and possible confounding by physician behavior.

 

 

Primary source: Pediatrics
Source reference:
Bednarczyk R, et al "Sexual activity-related outcomes after human papillomavirus vaccination" Pediatrics 2012; DOI: 10.1542/peds.2012-1516.