Five-MicroRNA Signature: Predicting Outcomes in HPV-Negative Head and Neck Cancer

The prognosis for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma is generally poorer than for those with HPV-positive disease. Dr. Julia Hess, of the German Research Center for Environmental Health GmbH in Neuherberg, and colleagues sought to find prognostic markers to help predict the risk of recurrence in this patient population and thus create personalized treatments with radiation, targeted drugs, and immune checkpoint inhibitors. They may have succeeded: By retrospectively performing microRNA (miRNA) expression profiling, they discovered a “five-miRNA signature [that] is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative head and neck squamous cell carcinoma,” the authors reported. Of note, added Dr. Hess in Clinical Cancer Research, “its prognostic significance is independent from known clinical parameters.”

The five-miRNA signature, when combined with established risk factors, allowed four prognostically distinct groups to be defined. Recursive-partitioning analysis classified 162 patients into being at low (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P < .001).

“[The five-miRNA signature] represents the basis for a more focused search for molecular therapeutic targets,” which would potentially improve “therapy success for appropriate patients,” the researchers stated. Currently, even when given state-of-the-art, standard-of-care therapy, patients with HPV-negative head and neck squamous cell carcinoma cancer have an overall survival rate of only about 50%.

Scientists Are Getting Closer to a Pill That Can Mimic The Effects of Exercise

But it’s not for lazy people.

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Not everyone can exercise. People with muscle-wasting diseases and movement disorders, the frail, the very obese and post-surgical patients are among those who face a significant challenge when it comes to working out.

This can be frustrating, considering the well-established benefits of exercise.

But what if a drug could stimulate the body into producing some of the same effects of exercise – more endurance and weight control, for example – without the need to run a single step?

Such a pill may be on the way. Several scientists are testing compounds that apparently can do this – and people wouldn’t even have to move at all to benefit.

“Our goal is to understand these circuits,” says Ronald Evans, director of the gene expression laboratory at the Salk Institute for Biological Studies in La Jolla, California.

“We are taking this concept and trying to develop a drug that can help us game the system that is naturally activated during exercise.”

Salk scientists have been working since 2007 on a chemical compound, known as 516, that mimics the effects produced by exercise by triggering a specific genetic circuit, “a back door into the exercise genetic network,” Evans says.

The researchers built upon earlier work that identified a gene mechanism that encourages the muscles to burn fat, rather than carbohydrates, much as highly trained elite athletes do.

“There are many reasons why people cannot run or walk or exercise,” Evans says. “If you can bring them a small molecule that can convey the benefits of training, you can really help a lot of people.”

Several other scientists are studying compounds that work differently from 516, but with the same aim: to give the benefits of exercise to people who aren’t able to do it.

Ali Tavassoli, a professor of chemical biology at Britain’s University of Southampton, has discovered a drug known as compound 14 that works “by fooling cells into thinking they have run out of energy,” Tavassoli says.

It does this through a series of molecular actions that spur cells into metabolizing sugar, which produces energy, he says.

(Harvard cell biologist Bruce Spiegelman, who is working on an approach using exercise hormones, declined an interview, saying it wouldn’t be “wise” when “this area has been hyped so much.”)

Any such drug would require licensing by the Food and Drug Administration, yet the FDA doesn’t recognize “the inability to exercise” as an illness in need of a drug.

So Evans has targeted 516 for young people with Duchenne muscular dystrophy, an approach that he believes offers the best chance for FDA approval.

“This [disease] afflicts kids who can’t exercise and ultimately die of muscle wasting, often at a relatively early age, at 15 or 16,” Evans says. “It’s a disease with a large unmet medical need.”

But the drug, now undergoing a small human safety study, has “a potentially wide application,” he says, including for amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease, and for “people in wheelchairs.”

He says he also thinks it could be a lifesaver for those rare individuals who develop acute kidney injury, or AKI, a potentially fatal side effect of cardio-bypass surgery that results in often irreversible organ damage.

“The organ or tissue changes its metabolic properties and begins to burn sugar, and because it happens quickly, it’s very hard to stop,” Evans says.

“Our drug helps to draw the tissue back to a more healthy state, returning it from a chronic inflammatory damaged state. It soaks up sugar. If you do this carefully and quickly, you can override the damage response.”

Because Tavassoli’s compound breaks down sugar, he says he sees it as a potential treatment for diabetes or metabolic syndrome, a cluster of conditions that include obesity, hypertension, high blood sugar, high triglycerides and elevated LDL, the “bad” cholesterol.

“The most startling results have been the effect of the molecule on glucose tolerance and body weight in a mouse model of diet-induced obesity,” he says.

“It improves glucose tolerance and reduces body mass.”

Compound 14 has not yet been tested in humans. “While our results are promising, we are quite a way from anything going into the clinic,” Tavassoli says.

Any of these drugs would have the potential for abuse. Amateur athletes might want them to get faster or stronger. Elite athletes might seek them out to cheat the system.

Even the sedentary might look for an easy way to “exercise” without having to really do it. The experimental 516 already is banned by the World Anti-Doping Agency, according to Evans, and “I’m sure any [future] version of it will be, too.”

Evans acknowledges that once a drug is licensed, “people who aren’t sick will want it,” he says.

“Everyone knows that whatever exercise they get probably isn’t enough. But we are not developing a drug like this to make someone run faster.”

Tavassoli agrees. “Unfortunately, as with all other pharmaceuticals, there is no way to prevent abuse, but the potential benefit to millions of people suffering from disease outweighs any concern about abuse by athletes,” he says.

Evans – who hikes and plays tennis – has never taken 516. “I like exercising, and that’s good enough for me,” he says, adding: “People are designed to move.”

“But if they can’t, it’s not healthy to be sedentary. That’s why we are developing this drug. We are trying to take science out of the laboratory and bring it into the clinic in a way that can change people’s lives. If we can do that, it would be a game-changer.”

6 Mistakes You Might Be Making With The Pill

Like not actually taking it when you should.

The Pill is one of the best medical inventions to date. It’s mind-blowing to think that one little tablet has the potential to improve your life in such a huge way, whether it’s by helping you avoid pregnancy or wrangling a beastly period. But in order to reap the Pill’s benefits, taking it properly is non-negotiable.

When taken perfectly—that’s the key word—the Pill is over 99 percent effective. But when you factor in typical use, that number drops to around 91 percent. Beyond boosting your risk of accidental pregnancy, taking your pill improperly can make your life harder by inducing random spotting. Here, ob/gyns explain the birth control pill mistakes they see most frequently, plus how to avoid them so you can live your best life.

Mistake 1: Not taking your pill every day in the first place.

This is a no-no, whether it happens because you simply forgot or because the pharmacy closed before you could grab a new pill pack. Even if it seems like NBD to miss a pill, each time chips away at your perfect record, making you more likely to get pregnant.

That’s not to say missing one pill definitely means you’ll conceive the next time you have sex. But it’s not a good habit to get into, especially if you’re skipping more than one pill at a time. “Once you go those extra couple of days, you put yourself at a higher risk of failure,” Mary Jane Minkin, M.D., a clinical professor of obstetrics and gynecology at Yale Medical School, tells SELF.

If you find yourself continuously forgetting to take the Pill or consistently taking it late, talk to your doctor about other options, like the NuvaRing, Nexplanon implant, or an IUD. “There are other products out there that don’t require patients to take a pill every day,” board-certified ob/gyn Antonio Pizarro, M.D., tells SELF.

Mistake 2: Not knowing what to do when you miss a pill.

It depends on how many you’ve skipped. “If you miss one pill, you should basically catch up and take it as soon as you remember,” Pizarro says. For example, if you missed a pill last night, take it in the morning when the realization strikes you out of nowhere (because isn’t that usually how it goes?). Then take the next one at your regularly scheduled time. If you don’t remember until your regularly scheduled time, take both at once. Doing this might cause spotting, but you can still think of yourself as protected from pregnancy, Pizarro explains.

But if you miss two or more pills, Pizarro recommends using a backup method of contraception, like condoms, until you start your next pack and also seeking out emergency contraception if you’ve recently had unprotected sex.

Mistake 3: Taking a progestin-only pill at the wrong time.

“For the most part, patients I see tend to do really well with their birth control,” Pizarro says. But the most common issue he notices is patients taking their pills at the wrong time. If you’re taking progestin-only pills, taking your pill outside of the same three-hour window each day can raise your risk of pregnancy. Combination pills, on the other hand, have much more wiggle room and are effective as long as you take them every day.

But no matter what kind of pill you take, regularly taking your pill at wildly varied times could lead to irregular bleeding, Pizarro explains.

Mistake 4: Ditching placebo weeks for months on end.

Using the Pill to skip your period—whether because you have a big event coming up or just because you’re tired of bleeding from your vagina every month—is perfectly fine. “The only thing that can happen is if you take birth control pills consecutively for over six to eight weeks, you can get breakthrough bleeding,” Minkin says. “There’s nothing evil or dangerous about it, but it can be annoying.” If you’re not a fan of this side effect, she suggests going through with the placebo week every so often to get your uterus off your back.

Mistake 5: Not filling your doctor in on key parts of your medical history before deciding to take the Pill.

Although the Pill is great, it’s not right for everyone. For example, if you have a history of blood clots (either you’ve had them yourself or someone in your family has), it’s necessary to tell your doctor. The Pill’s pregnancy-prevention hormones can boost your risk of blood clots, which can lead to a stroke. (But the risks are still small overall, with 1 in 1,000 women per year taking birth control pills developing a blood clot.) Being over 35 and smoking raises that risk, as does having migraines with aura, Minkin explains.

Also, certain medications might make your BC less effective. Those include St. John’s Wort, which people sometimes take for mood disorders, and some antibiotics. “Don’t hesitate to talk to doctor or nurse practitioner about these issues,” Minkin says. Depending on your situation, you might need a specific type of pill, or you and a medical professional can discuss whether a different contraceptive option might be best for you.

Mistake 6: Not fully understanding what the Pill can and can’t do.

“One misconception about the Pill I hear routinely is that it might harm pregnancy,” Pizarro says. But if you get pregnant while taking the Pill, it’s extremely unlikely for it to negatively affect the fetus, he explains.

He also sees people thinking taking birth control pills as instructed can end a pregnancy. False. In a pinch, you can take extra birth control pills as emergency contraception, but regularly taking the Pill every day isn’t the same thing as taking the morning after or abortion pills. “Birth control pills do not end pregnancy or destroy pregnancy—they prevent pregnancy,” Pizarro says.

Natural Herbal HPV “Cure” Discovered

Natural Herbal HPV "Cure" Discovered

Despite the widespread belief that HPV infection is a singularly lethal force against which we only have vaccination defend ourselves, both ancient herbal medicine and our body’s inherent immune defenses have newly been confirmed to have significant power against it.

A groundbreaking study published in the Asian Pacific Journal of Cancer Prevention, titled, “Clearance of Cervical Human Papillomavirus Infection by Topical Application of Curcumin and Curcumin Containing Polyherbal Cream: A Phase II Randomized Controlled Study,” reveals that vaccination and watchful waiting are not the only recourse against HPV infection.

The study is believed to be the first of its kind to find an effective and safe therapeutic intervention for the clearance of established cervical human papillomavirus (HPV) infection. Moreover, the study confirmed that HPV infection is self-limiting and clears on its own in 73.3% of the untreated placebo group within 37 days. 

The researchers evaluated the effectiveness of two herbal interventions in eliminating HPV infection from the cervix of women who were determined to have HPV infection through Pap smear and HPV DNA tests (PCR), but whose condition had not yet progressed to high grade cervical neoplasias (i.e. cervical pre-cancer).

The first intervention used was a polyherbal vaginal cream containing containing extracts of curcumin, reetha, amla and aloe vera, known by the trade name Basant. The second intervention was a curcumin vaginal capsule. The other two placebo groups received either a vaginal placebo cream or a placebo vaginal capsule.

All 287 subjects were instructed to use one application of the assigned formulation daily for 30 consecutive days except during menstruation. Seven days after the last application they were recalled for repeat HPV test, cytology and colposcopy.

The results were reported as follows:

“HPV clearance rate in Basant arm (87.7%) was significantly higher than the combined placebo arms (73.3%). Curcumin caused higher rate of clearance (81.3%) than placebo though the difference was not statistically significant.”

Vaginal irritation and itching, mostly mild to moderate, was significantly higher after Basant application. No serious adverse events were noted.

While both of the herbal formulations clearly increased the rate of HPV clearance, it is noteworthy that the placebo group also experienced a 73.3% clearance rate, as it confirms that majority of HPV infections will clear from the body as a result of the immune system doing its job correctly. The researchers acknowledged that this is not a novel finding:

“It is already documented that the majority of HPV infections are self-limiting and cell-mediated immunity is responsible for spontaneous clearance.”

Indeed, we addressed this under appreciated fact in a previous article titled, The HPV Vaccine Debate: Don’t Ask, Don’t Tell:

[I]n 2004, Lancet published a study which found that low-grade squamous intra-epithelial cervical lesions (LSIL) commonly associated with HPV infection spontaneously regress in 61% of females within 12 months and 91% within 36 months.[i] LSIL is considered a mild form of cervical dysplasia (CIN), but is nonetheless often subject to more aggressive measures such as a colposcopy with biopsy,[ii] which sometimes leads to surgical treatment.

Another 2010 study published in the European Journal of Obstetrics, Gynecology and Reproductive Biology found that at the end of 12 months of follow-up, the CIN 2 regression rate was 74% (31/42), progression rate to CIN 3 was 24% (10/42) and in one case CIN 2 persisted (2%).  Finally, a 2011 study in the Journal of Lower Genital Tract Diseases found At 12 months, 70% of CIN 1 and 54% of CIN 2 lesions spontaneously regressed (p<.001).[iii]

The odds therefore are clearly in the favor of HPV-associated abnormal cell changes (so-called ‘precancerous’ lesions) regressing naturally like most self-limiting viral infections. Vaccines are clearly not responsible for the ‘protection’ conferred by our inbuilt immunity; nor is the HPV virus some inevitable force of lethality that only universal HPV vaccination campaigns can effectively countermand.

Given the widespread belief that HPV infection is a lethal force against which we have only vaccination and watchful waiting to defend ourselves, this latest encourages us to recognize both the power of the human body and natural plant allies to help us maintain our health, despite the constant threat of infection.

In actuality, the results of the intervention are not surprising, given the established body of research indicating curcumin’s value as an anti-cancer agent. Not only has this powerful turmeric polyphenol been extensively researched for its anti-cancer properties in over 100 difference cancer cell types, the GreeMedInfo database contains 11 studies specifically on curcumin’s anti-cervical cancer properties, which can be viewed here.

The Human Papillomavirus Vaccine: Current Perspective and Future Role in Prevention and Treatment of Anal Intraepithelial Neoplasia and Anal Cancer

 The incidences of human papillomavirus (HPV)-related anal cancer and its precursor lesion, anal intraepithelial neoplasia, are rising in the U.S. and globally. Five-year survival rates with current modalities of treatment for anal cancer are generally favorable for localized and regional disease. For metastatic disease, the relative survival rate is poor. Major contributing factors for the increase in anal cancer incidence include increasing receptive anal intercourse (hetero- and homosexual), increasing HPV infections, and longer life expectancy of treated people who are seropositive for human immunodeficiency virus. Because treatment outcomes with systemic therapy in patients with advanced disease are so poor, prevention may be the best approach for reducing disease burden. The association of a major causative agent with anal cancer provides an excellent opportunity for prevention and treatment. The advent of the HPV vaccine for anal cancer prevention and treatment is a significant milestone and has the potential to greatly impact these cancers. The data regarding potential use of the HPV vaccine in anal cancer prevention and treatment are reviewed.

Implications for Practice:

The incidences of human papillomavirus (HPV)-related anal cancer and its precursor lesion, anal intraepithelial neoplasia, are on the rise in the U.S. and globally. Based on recent studies, the HPV vaccine is approved for prevention of the infection and development of HPV-related anal cancer. In addition, several small studies have shown that the vaccine may be useful as adjuvant therapy for anal cancer. There is a need for public health strategies aimed at education of both patients and practitioners to improve the use of the vaccine for prevention of HPV-related anal cancer. The development of a therapeutic vaccine is a work in progress.

HPV Vaccine Effective at Multiple Anatomic Sites

Vaccination against high-risk types of human papillomavirus (HPV) protected young women from infection with these HPV types at the cervix, anus, and mouth—the three primary anatomic sites where persistent HPV infections can cause cancer. The multi-site protection also was observed, though at lower levels, in women previously exposed to the virus. NCI researchers reported this finding last week at the 2015 annual meeting Exit Disclaimer of the American Association for Cancer Research (AACR) in Philadelphia.

The findings Exit Disclaimer are among the latest to emerge from theHPV Vaccine Trial in Costa Rica, which was launched a decade ago by NCI, in collaboration with researchers in Costa Rica, to test the efficacy of the bivalent HPV vaccine Cervarix in preventing cervical HPV and pre-cancer in women vaccinated between the ages of 18 to 25.

Previous reports from the trial have demonstrated that the vaccine is highly effective in preventing HPV infections in the cervix, anus, or mouth—especially among women not infected prior to vaccination—when these sites were looked at separately.

“This is the first study to analyze multi-site protection,” explained the lead author on the study, Daniel C. Beachler, Ph.D., a postdoctoral fellow in NCI’s Division of Cancer Epidemiology and Genetics.

The findings presented at the AACR meeting—which involved analysis of samples from all three anatomic sites obtained from nearly 4,200 women—showed that 4 years after the initial vaccination, there was a 65 percent reduction in HPV at any of the three sites.

Women without evidence of prior HPV 16 or 18 exposure—defined as the absence of HPV 16 or 18 antibodies in blood, and no DNA evidence of cervical HPV 16 or 18 infection at time of first vaccination—experienced the greatest protection, with an efficacy of approximately 84 percent at any site, Dr. Beachler reported.

High-risk HPV types can cause several cancers, including oropharyngeal cancer

The vaccine efficacy was lower but still present among women who had evidence of prior exposure to HPV 16 or 18. Overall, the efficacy increased to 91 percent against HPV infection at two or three anatomical sites.

The HPV vaccine, Dr. Beachler stressed, cannot help clear current infections. “But it may provide some protection at one or more sites in women exposed to HPV prior to vaccination.”

The results, he added, support current recommendations for routine HPV vaccination starting at age 11 or 12, and vaccination through age 26 for those not vaccinated previously.

In addition to Cervarix, two other HPV vaccines are available in the United States: the quadrivalent vaccine Gardasil and the recently approved Gardasil9, which protects against seven cancer-causing types of HPV.

Vaccines Do Not Cover Most Common HPV Types in Black Women.

The HPV subtypes that are most common in black women in the United States are not targeted by the currently available vaccinesGardasil and Cervarix, according to new research.

The findings suggest that current HPV vaccination will be less beneficial for black women in the US than for their white counterparts, said study coauthor Catherine Hoyo, PhD, MPH, of Duke University, in Durham, North Carolina.

She spoke at a press briefing today at the annual International Conference on Frontiers in Cancer Prevention Research, in National Harbor, Maryland. The meeting is sponsored by the American Association for Cancer Research.

“The approved cervical cancer vaccines are effective but may not be effective for everyone,” said Paul Limburg, MD, from the Mayo Clinic, in Rochester, Minnesota, who moderated the press briefing. He was not involved with the study.

Persistent infection with HPV 16 and/or HPV 18 accounts for about 70% of all cervical cancers, said Dr. Hoyo. These are the subtypes targeted by Gardasil and Cervarix. Gardasil also targets HPV 6 and HPV 11.

Some black women in the new study did, in fact, have infections with HPV 16 and/or HPV 18. But much less often — their rate was about half of that of white women.

“Since African-American women don’t seem to be getting the same subtypes of HPV with the same frequency, the vaccines aren’t helping all women equally,” said study coauthor Adriana Vidal, PhD, in a press statement. She is also from Duke University.

The investigators prospectively looked at 572 women at 10 Duke-affiliated clinics with abnormal Pap tests who then underwent colposcopy; the group was about evenly divided among blacks (n = 280) and whites (n = 292). And just about even numbers of the respective racial groups subsequently had evidence of cervical intraepithelial neoplasia 1 (CIN1; 112 vs 118).

For whites with CIN1, the most frequent HPV subtypes were 16, 18, 56, 39, and 66.

But for blacks with CIN1, the most frequent HPV subtypes were 33, 35, 58, and 68.

Thus, in blacks, the most common genotypes were not HPV 16 and 18, which defies conventional wisdom about HPV infection.

There were no data on Hispanics in the new presentation because their numbers were too small at this point to be included, said Dr. Hoyo.

Without HPV 16/18, Are Some Black Women “Getting Dropped”?

The study findings may help explain why black women in the US are harder hit by cervical cancer than white women, said Dr. Hoyo.

She pointed out that both the incidence of invasive cervical cancer and related mortality rates are higher in blacks than in whites.

“We don’t know what is causing the disparity,” Dr. Hoyo told Medscape Medical News in a phone interview after the press conference.

“The problem is not likely detection,” she said, explaining that screening rates for precancerous lesions are comparable for black and white women.

The new data, however, suggest that, if clinicians are strongly focusing on HPV 16 and 18 for more careful follow-up in their black patients, then they may be missing some eventual cervical cancers, Dr. Hoyo said.

“Somewhere along the line, some black women may be getting dropped because they don’t have the HPV subtypes that are considered to be most aggressive,” she summarized.

Her advice to clinicians with black females who HPV infection and CIN is: “Broaden the subtypes that you look at.”

Currently, there is a vaccine in phase 3 clinical trials that targets 9 HPV subtypes (6, 11, 16, 18, 31, 45, 52, and 58). That means that 2 of the 4 most common subtypes in blacks are targeted by the experimental vaccine. “We need more African American women to enroll in trials like this to see how beneficial this new vaccine will be for them,” Dr. Hoyo said.

The new study is not the first to indicate that black women have lower rates of HPV 16 and 18.

A recent report found that black race was a predictor of lower HPV 16 and 18 positivity among women with high-grade cervical lesions (Cancer. 2013;119(16):3052-3058).

However, the new study from the Duke team is the first to indicate that this race-influenced distribution of HPV subtypes also occurs in lower-grade cervical lesions.

The Duke investigators also looked at high-grade lesions (CIN2/3).

In CIN2/3, HPV 16, 18, 33, 39, and 59 were the most common genotypes detected in white women, whereas HPV 31, 35, 45, 56, 58, 66, and 68 were the most prevalent in African American women.

Salvage surgery for recurrent oropharyngeal cancer after chemoradiotherapy.



The current study aimed to assess the role of salvage surgery for failure cases of oropharyngeal cancer (OPC) undergoing initial chemoradiotherapy (CRT).


The data for 523 patients with previously untreated OPC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in Japan Clinical Oncology Group (JCOG).


Of the 170 patients who received CRT, 35 patients (21 %) had local recurrence or residual disease. Only 11 patients underwent further salvage surgery, and 24 patients received nonsurgical treatment. There were statistically significant differences between the two groups in terms of patient age and the presence of a simultaneous regional recurrence. The 5-year overall survival rates for the patients who underwent salvage surgery were 49.1 %, whereas those for the patients who received nonsurgical treatment were 16.3 %.


The initial treatment method for OPC should be decided carefully and the limitations of salvage surgery should be fully considered.

Source: International Journal of Clinical Oncology

Safety of the quadrivalent human papillomavirus vaccine.

The prophylactic human papillomavirus (HPV) vaccines are remarkable both for their efficacy against HPV infection and related diseases,1 and for their potential to prevent cervical cancer. Cervical cancer, which is caused by persistent infection with oncogenic HPV types, remains a cause of premature death in women around the world, most of whom have no access to secondary prevention through organised cervical screening programmes.2 The linked study by Arnheim-Dahlström and colleagues (doi:10.1136/bmj.f5906) provides a timely and important contribution to the evidence base on the safety of the quadrivalent HPV vaccine,3 which prevents HPV infection and disease due to the oncogenic types HPV-16 and HPV-18 and types HPV-6 and HPV-11, which cause genital warts.

This population based cohort analysis provides strong evidence that autoimmune conditions, neurological diseases, and thromboembolic disease are not triggered by quadrivalent HPV vaccination. Serious sudden onset conditions such as these, which are largely of undetermined cause, are sometimes falsely attributed to vaccination when population based vaccination programmes are implemented.4 It is crucial that surveillance systems can rule out false associations and identify rare but real adverse effects in the post-vaccine licensure period.5

Although vaccines are subject to rigorous pre-licensure evaluations, with many thousands of subjects in clinical trials, these trials are never powerful enough to detect rare adverse events, such as those that occur in less than one in several thousand vaccinated people. Systematic whole of population analyses, such as the current one, overcome the inherent limitations of passive surveillance systems for assessing adverse events after immunisation. In a passive surveillance system, it is up to individuals or their healthcare providers to report details of adverse health events that occur in the period after vaccination. Reporting can be haphazard and evaluable information is not guaranteed. Such reporting forms the basis for evaluating cases with similar diagnoses and assessing whether there is any indication that such cases are occurring at higher than background rates. Formal epidemiological assessment then follows using a rigorous systematic approach.

Instead, Arnheim-Dahlström and colleagues took a systematic approach from the outset, which removes reporting bias (both under-reporting and over-reporting) from the initial assessment of risk. They used the enviable registry systems available in Sweden and Denmark to identify girls aged 10-17 years who were vaccinated in both countries between 2006 and 2010 (nearly 700 000 doses). Once vaccination status and timing were defined for each girl, the authors calculated the rates of 53 outcomes of interest over the 180 days after vaccination using international classification of diseases codes in hospital records (inpatient and outpatient).

Among the 29 outcomes of interest with five or more vaccinated cases, only three conditions had a significantly increased relative risk—Behçet’s syndrome, type 1 diabetes, and Raynaud’s disease. However, they each fulfilled only one of three criteria examining the strength, consistency, and reliability of the association. Particularly reassuring is the lack of any consistency in the timing of disease onset after vaccination, as visually summarised in the accompanying figures. It is reasonable to assume that these associations were chance findings, given the multiple comparisons made and lack of consistency with risk estimates for these conditions from previous studies.6

The paper lays to rest earlier concerns about an association between vaccination and venous thromboembolism that emerged from a previous analysis of US data from passive surveillance.7 With more than 116 million doses distributed globally, our experience with HPV vaccines is now considerable. The World Health Organization global advisory committee on vaccine safety has reviewed HPV vaccines four times, most recently in June 2013, and each time agreed that the available data suggest these vaccines are safe.8 Although there are published case reports of rare illnesses coincident with HPV vaccination,9 this is the weakest form of evidence, and it is only through more sophisticated studies that such hypotheses can be tested.

The major strength of Arnheim-Dahlström and colleagues’ study is its size and the assessment of a whole population. Its main weakness is that vaccination coverage in the countries under study was still relatively low during the study period and early adopters may be different from non-vaccinees. The authors adjusted for potential confounders, such as socioeconomic status and ethnicity, to control for these differences as far as possible. But ongoing monitoring remains important to provide cumulative evidence of safety, particularly as vaccines are rolled out to new population groups such as boys.

The type of evidence reported by Arnheim-Dahlström and colleagues will help secure continuing confidence in both HPV vaccination and immunisation programmes more generally. The global immunisation environment is now one in which anti-vaccination misinformation about coincidental temporal associations can readily be promulgated through websites and social media. Clear and honest communication about vaccine safety, and rapid high level response and reassurance when the safety of a vaccine comes into question, are the best ways to prevent the erosion of public confidence in immunisation. This new evidence about the quadrivalent HPV vaccine firmly indicates that concern about vaccine related adverse events is not a rational reason to forgo this potentially lifesaving vaccine. This reassurance is particularly important as the vaccine is rapidly being made available to those girls in developing countries who need it most.


Anti-cancer vaccine for Laos.

Khonekham with health card with health card
Khonekham holds her health card showing she has received her first dose of the HPV vaccine

A programme to vaccinate girls against the virus that causes cervical cancer has begun in Laos, South East Asia.

It’s one of nearly a dozen developing nations where the HPV vaccine is being introduced in the coming year as part of a scheme to enable poorer countries to benefit from the newest vaccines.

It is five years since the jab was first offered to girls in the UK.

The project is being organised with the support of the Global Alliance for Vaccines and Immunisation (Gavi).

“Start Quote

The HPV vaccine represents a very significant commitment to women’s health in the coming decades.”

Helen Evans GAVI Alliance

The vaccine protects against the sexually transmitted human papillomavirus – preventing the infections that cause 70% of cases of cervical cancer.

‘Proud’ to be immunised

Khonekham Sirivong, 13, stood patiently in the queue of girls waiting for the HPV vaccine.

This was a poignant moment for her and Somsouk, her aunt, one of the nurses, under the shelter of trees in the school grounds.

Somsouk’s mother – Khonekham’s grandmother – died from cervical cancer. The two helped nurse her through years of illness.

“I remember she was in a lot of pain,” said Khonekham. “The family did everything it could, but she died. I am very proud to be immunised – and to have the HPV vaccine free of charge.”

Vaccine ‘crucial’

Cervical cancer is a far bigger cancer killer in developing countries because most lack a national screening programme, which can detect pre-cancerous changes in the cervix, enabling timely early treatment.

In Laos, most cases are discovered too late. Cancer treatment in the world’s poorest nations is also limited. Laos has no radiotherapy. Patients who can afford it are sent to Thailand.

“Approximately 275,000 women die every year from cervical cancer and over 85% of those deaths are in the developing world,” said Helen Evans, Gavi deputy chief executive.

“The number of deaths is projected to rise dramatically, so that’s why it is absolutely crucial that this vaccine is introduced.

“The HPV vaccine represents a very significant commitment to women’s health in the coming decades.”

survivor of cervical cancer
“I feel lucky to be alive,” said Sommay Khamkeomany

I have visited a lot of hospitals, in many of the world’s poorest countries – from Sierra Leone to Malawi and Bangladesh. But they have rarely been as crowded at Setthathirath hospital in Vientiane.

A senior oncologist, Dr Keokedthong Phongsavan, showed me round one of the wards, where the beds had spilled out into the corridor and were squeezed next to each other to accommodate more patients.

Sent home to die

However, it was not the overcrowding, but the limited treatment options that presented the biggest problem.

“I feel helpless,” said Dr Phongsavan. “Patients are often diagnosed very late, and then there is often very little I can do to help them. I have to send them home to die.”

The mortality rate for cervical cancer in Laos is six times that of the UK. But there are some success stories. Sommay Khamkeomany was diagnosed with cervical cancer last year when she was just 32.

She had surgery and has now been told she has a 95% chance that her cancer will not recur.

“I have two girls aged five and three,” said Mrs Khamkeomany. “When they are old enough I will ensure they have the HPV vaccine – and fortunately I should still be here to see that happen. I feel lucky to be alive.”


The HPV jab is the most expensive of all childhood vaccines. A course of three injections can cost more than £200 privately in the UK and other wealthy countries. It was well beyond the reach of most developing nations until Gavi negotiated a price of less than £10.

Like other Gavi-supported countries, Laos has to make a token financial contribution, but also has to supply the nurses and organise distribution of the vaccine.

The two-year pilot project in Laos involves about 20,000 girls being immunised. If successful, it will lead to a national roll-out of the jab.

By 2020, Gavi hopes to have supported HPV immunisation of more 30 million girls in over 40 countries.

The benefits, in terms of lives saved, won’t be felt for decades, but it represents a milestone in the promotion of women’s health.

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