Dr. Kenneth Hatch on the History of Cervical Cancer Diagnosis

Interview conducted and documented by Hunter Ackerley

I had the pleasure of interviewing Dr. Kenneth Hatch, Professor of Gynecologic Oncology and Director of Female Pelvic Medicine and Reconstructive Surgery at the University Of Arizona on January 12, 2018 in his office. This experience was rewarding in many ways, as Dr. Hatch provided a detailed history of diagnosing Cervical Cancer through the reading of pap smears and explained his contributions to this process.

In 1988, the false negative reading rate of pap smears was significant enough to warrant regulatory action from Congress (around 50%). This meant the presence of cancer causing human papillomavirus (HPV) DNA would go undetected. A woman would have to have an unlikely amount of six pap smears read before their chance of a false negative reading was reduced to 1.5%. According to Dr. Hatch, pap smear readings had been conducted on dry slides in a select few laboratories across the country. The accuracy of the reading really depended on the person examining the slide’s ability to prep the slide and the quality of the sample they were given to read. Not only were pap smear readings significantly unreliable and inconsistently prepared at the time, but there was a large requirement of manpower necessary to read all of the pap smears across the country on those individual dry slides that was not effectively being met. The Clinical Laboratory Improvement Amendments (CLIA) were enacted in 1988, thereby extending the regulations on readings beyond independent entities. As each pap smear sample provided its on unique complexities, CLIA outlined how tests should be read based on their individual complexity.

As society approached the 1990s, liquid based cytology (LBC) was introduced into the realm of diagnosing cervical cancer. LBC is a method used to prep samples that are to be read by  storing the sample in a preservative liquid that filters out biological elements such as mucus before the sample is spread onto a slide. Before LBC was approved, trials were conducted at 10 clinical locations across the country, of which Dr. Hatch was a major player in organizing. The goal was to test the accuracy of LBC compared to the traditional dry slide method. LBC was approved in 1996 and shown to have an initial false negative rate of 5% rather than 50%. This meant that women had to have significantly less readings in their lifetime in order to reduce the chance of a false negative to a reasonable rate.

Following this development, Polymerase chain reaction (PCR) techniques to read samples sponsored by the company, Roche as well as Hybrid Captures to determine the presence of target HPV DNA sponsored by Digene hit the scene. The PCR technique tests for HPV DNA by first amplifying the DNA in the sample. The amplified samples are then read for the presence of the cancer causing HPV DNA. The amplification of the DNA by the PCR technique allowed for more accuracy in reading a slide due to the abundance of the DNA in the sample. The Hybrid Capture II technology expanded upon this method. The technology operates such that DNA is once again amplified. After this amplification, one then uses microplate chemiluminescent detection (essentially, light detection) to determine the presence of the cancer causing HPV DNA. The final step of this process allows emitted light from the sample to be read by which the intensity of the light determines the presences of the HPV DNA in the sample.

According to Dr. Hatch, people are more susceptible to HPV at a younger age and by having multiple sexual partners. The distribution of likelihood of people carrying HPV shows a much higher rate in the young adult years than at any other time. HPV types 16 and 18 are the most the most prevalent cervical cancer causing versions of the HPV virus. Dr. Hatch says that in any community, more education about the potential harms of HPV is required to continue to reduce the number of cases of cervical cancer. There is a window of optimal time to receive the HPV vaccination, starting as a youth and going through age 26 for woman and age 21 for men. The HPV vaccination can be administered at most any time in one’s lifetime, however, it makes the most sense to get the vaccination at a time when susceptibility to HPV is highest in order to prevent its contraction. Especially since it can cost woman over 26 $600 to get vaccinated.

Society continues to makes improvements in the process of preventing, diagnosing, and treating cervical cancer. We can look to the most modern classifications of dysplastic cells to see just how far we have come in our capability of identifying cervical cancer. The Cervical Intra-epithelial Neoplasia (CIN) classification system identifies abnormal squamous cells found on the surface of the cervix. CIN is divided into three sections (or grades) that indicate the depth of the abnormal cells relative to the surface of the cervix. Upon identifying any level of classification of abnormal cells, repeat screenings are necessary to ensure a woman’s health. The higher the number of classification, the more of the cervix is affected by the abnormal cells. Treatment is then given to remove the abnormal cells classified at CIN2 or CIN3. If untreated, these abnormal cells have the potential to develop into cervical cancer (carcinoma in situ).

Another type of cell exists with the glandular cells that show up first as cancer due to the fact that there is no easily identifiable pre-cancerous phase with these cells. The ratio of cancer cases between squamous versus glandular cells leans more towards the glandular (adenocarcinomas) now at a 34% prevalence rate up from a 3% rate in the recent past. As technology continues to improve, the next step seems to be working on better identifying the adenocarcinoma cells spawned from the glandular cells.

The University of Arizona was one of the first six institutions doing Gardasil (a HPV vaccination) testing. Dr. Hatch has worked his career through all of these developments in diagnosing cervical cancer and preventing the contraction of HPV. In his experience, the main problems that people run into when it comes to dealing with the issues that HPV and cervical cancer present come when people do not take the steps necessary to take care of themselves. He lists the common misconceptions of being too old for a pap smear and not needing them after childbirth (despite being more susceptible to HPV as the area heals after childbirth) as the main reasons that vulnerable people fail to get the treatment they need to stay healthy. Looking cross-culturally, barriers exists especially in the Southern Arizona community where undocumented immigrants fail to come in for screenings due to fear from retaliation due to their status. When it comes to getting vaccinations, diagnoses, and treatment, often times people shy away from these practices due to beliefs about the cost being too great and a lack of education on the prevalence of HPV in society. Even being with just one sexual partner your entire life still leaves you vulnerable to HPV.

To conclude, Dr. Hatch was an informative source on the development of diagnosis and history of HPV and cervical cancer in our society. He believes the most important development was when screening was improved in the 90s such that the incidence of cervical cancer was greatly reduced. Dr. Hatch outlines the necessity of education and communication across barriers and borders to continue to improve our treatment success rates. Looking to the future, he believes that medicine and treatment will become even more personalized as we look toward genetic technology and biomarker identification. The future certainly holds more possibility for successful diagnosis and treatment.

Dr. Anderson and Dr. Blain Christen on HPV Diagnostic Implementation in India

Interview conducted and documented by Jill Leaver

I recently had the opportunity to sit down with Jennifer Blain Christen and Karen Anderson to discuss their work in HPV diagnostic implementation in India. Jennifer Blain Christen received her masters and Ph.D from Johns Hopkins in Electrical Engineering in 2001 and 2006, respectively. She has research expertise in bio-compatible integration techniques for CMOS electronics, microfluidics, and mixed-mode circuits for biomedical/analytical instrumentation. She is also an associate professor at Arizona State University. Karen Anderson is a medical oncologist and an associate professor of medicine at Mayo Clinic Arizona. She is also a professor at the Biodesign Institute for ASU’s center Personalized Diagnostics and ASU’s School of Life Sciences. Her research expertise is centered around understanding the mechanistic underpinnings of immune regulation and immunotherapy. In short, it was a privilege to sit down with both of these highly qualified women to discuss their ground-breaking work.

I first began with discussing the biological applications of Micro Total Analysis Systems with Dr. Blain Christen. These systems eliminate intermediate steps, and automate the necessary steps for chemical analysis. This subsequently increases the efficiency of the process, and eliminates the ineffective underpinnings of a stratified system. These systems are currently being developed for DNA analysis systems, including 23andMe, which is a company that offers personal wellness and genetic risk reports. They are also being developed in tools for personalized medicine, including over the counter pregnancy tests and blood glucose monitors. There is great prospect in these systems for further research concerning cancer biodiagnostics, such that the chemical analysis process can be quicker, cheaper, and subsequently more accessible to under-resourced countries.

CCAP Across The Map has a focus on providing Pap smears to under-resourced countries, so I of course inquired whether or not these systems could be applied to these diagnostics. Since Pap smears are multiplexed testing, meaning they look for multiple biomarkers, it is going to take more time to implement these systems in such a multifaceted test. A pregnancy test only searches for one thing, which is why it was simpler to integrate this testing with the microsystem. Although we are still in the process of integrating these things, progress is being done, such that someday, Pap smears can become more efficient.

I next spoke with both Dr. Blain Christen and Dr. Anderson about Point-of-Care Diagnostics. These types of diagnostics are more accessible to under-resourced countries since they are cheaper. However, with increased price efficiency, we sacrifice a degree of accuracy. We then discussed these low cost point-of-care diagnostics in relation to their work for HPV diagnostics. They first tested to see which biomarkers most frequently indicate cervical cancer, since not all strains of HPV cause it. Then, they determined which strains they want their HPV diagnostic to cover. This project is specifically being implemented in India, which means their diagnostic needs to be cheap, otherwise it is not feasible for these communities to use it.

I next discussed the behind the scenes, bureaucratic element of their operation. They are working with All India Institutes of Medical Sciences (AIMS) in India. They will first conduct a two year pilot study with them, which will be done in a controlled environment. The Center for Disease Control (CDC) is involved to help move things along. Dr. Blain Christen stated that the current most difficult logistic struggle has been obtaining samples. We have strict FDA regulations here in the states that prevent samples of being with invasive cervical cancer just being thrown around. Having those samples is imperative to determining which biomarker to use in their diagnostic.

I also discussed the prospect of bluetooth communication with Dr. Blain Christen. In India, there are currently more cell phones than toilets. This is a supreme advantage when creating medical technology. A patient can receive data for testing done via a “cloud”, which saves a trip to the doctor to just obtain results, which is especially beneficial in these type of areas, since many are not within a proximal distance to a hospital. This also allows medical scientists to obtain this data and study demographics, such that more devices can be made that have a direct impact on these communities. It is the perfect way to combine engineering requirements with customer needs. For their specific project, Bluetooth centralizes the data at AIMS, and will be able to access computers in rural areas and in the back of medical vans, and then all of this information is sent to a localized location, where we can use it here in the states for data analysis.

All of this research has great implications for CCAP Across The Map. Using a bluetooth system for communicating lab results, learning how to work within cultural parameters and how to collaborate with local healthcare communities, and utilizing different diagnostic systems is vital to the future success and efficacy of our non-profit. The research that Dr. Blain Christen and Dr. Anderson are conducting is taking the global healthcare community by force. It was truly inspiring to sit down with both of them to discuss their work, as many of their goals are similar to those of CCAP Across The Map. The next step is to continue these projects in order to provide healthcare to women around the world.

Dr. Uma Goyal on Specialized Brachytherapy Treatment of Cervical Cancer

Interview conducted and documented by Hunter Ackerley

I had the pleasure of conducting an email interview with Uma Goyal, MD and Shona Dougherty, MB, ChB, PhD about their experience with specialized brachytherapy treatments for cervical cancer. Below are my questions and their joint answers. Please enjoy this next interview from our interview series.

Q: What has been your experience with cervical cancer patients and what got you interested in working with them?

A: Our experience with cervical cancer patients has been with those requiring definitive treatment with radiation and chemotherapy or patients who have had surgery and need postoperative radiation with or without chemotherapy. Cervical cancer is one area of oncology that we have vaccines and an effective screening modality that have reduced the incidence within the US. However, in under-developed areas of the world this disease continues to affect a significant number of women and is a major killer of young women.

Q: Can you describe the general process of how specialized brachytherapy treatments have been used to treat cervical cancer patients in your work?

A: Brachytherapy is one of the main modalities of treatment for cervical cancer. Not all women will need it, but it does allow a high radiation dose to be localized to a relatively small region of the body containing tumor. This technique provides effective treatment of the tumor while minimizing side effects. The more common form of brachytherapy that we work with includes an apparatus called “tandem and ovoids.” The process includes the patient having undergone radiation to the whole pelvis and chemotherapy prior to brachytherapy. The patient is then brought to the operating room to be put under anesthesia. We then insert the “tandem” into the uterus and the 2 “ovoids” sit in the upper vagina on either side of the cervix. The apparatus is held in place by balloons which also help to push the healthy bladder and rectum away from the intense radiation. Once placed, we do a CT scan of the patient to make sure the placement of the apparatus is acceptable and we then design our radiation brachytherapy plan. The patient will have the apparatus in place during this time until completion of the brachytherapy treatment at which time the “tandem and ovoids” are removed (same day as the apparatus was placed or the following day in which case the patient stays in the hospital overnight). We then repeat the process to complete the total amount of treatments recommended to adequately treat the tumor based on data from prior studies.

Q: What kind of results did you find when working with this technique as treatment?

A: The technique we use here is the “tandem and ovoids” which deliver the radiation and vaginal balloons that are placed with the “tandem and ovoids” to push the bladder and rectum away from where the radiation will be given. The more we push the bladder and rectum away from where the radiation is delivered then the less side effects we anticipate the patient to have from these organs. Other institutions use gauze that is packed in the vagina to achieve the same thing, but we found that using balloons seems to be significantly more comfortable for our patients. Our results using the balloons instead of the gauze packing have found that treatment is just as effective but much easier for the patient.

Q: How do you see specialized brachytherapy treatments factoring into the future of cervical cancer treatment?

A: Tandem and ovoids brachytherapy will always be a part of cervical cancer treatment. Studies that have omitted it have shown inferior results. Our goal is to make the process as easy as we can for our patients and hence our interest in using the vaginal balloons. We are looking into the reproducibility of the balloons staying in place during the day and overnight if needed. Anecdotally, we find our patients tolerate removing the tandem and ovoids better with balloons than gauze packing. However, we are evaluating the doses to the bladder, rectum, and cervical cancer with the use of balloons. We hope that if the data shows equivalent outcomes as gauze packing, that balloons may be another option for radiation oncologists to use for cervical cancer patients particularly those who have to stay overnight with the tandem and ovoids in place.

Q: What do you think is the most important thing for community members to keep and mind/do in order to help with successful treatment of cervical cancer?

A: For community members, we recommend first thinking about prevention and getting the vaccine and pap smears regularly as advised by a physician. For those diagnosed with cervical cancer, successful treatment is best achieved with the multidisciplinary team involving the gynecology oncologists and radiation oncologists. Cancer treatment is a difficult journey and it’s important to keep in mind that you have many people including your doctors, nurses, radiation therapists, chemotherapy nurses, and social workers to name a few, who are in your corner and there to support you through it.

Rebecca Ewald on HPV Primary Screening

Interview conducted and documented by Jill Leaver

I recently had the opportunity to sit down with Rebecca Ewald, an international business leader with Roche Diagnostics, to discuss HPV-related cancer prevention on a global scale. Mrs. Ewald and I had an in depth discussion regarding HPV Primary Screening and how this diagnostic works in comparison to the Pap smear test. In addition to discussing the technological underpinnings of this diagnostic, we also compared and contrasted cervical cancer screening policies between different countries. Both the scientific and the policy components of this discussion were in accordance with the goals of CCAP Across The Map, so this was an incredibly valuable experience.

The conversation began with discourse concerning the disparity of resource access between different countries. Cervical cancer disproportionately affects socioeconomically disadvantaged women who don’t have access to preventative measures or screening technology. As such, thousands of lives are lost every year to a largely preventable and treatable disease. A key component to solving this issue is improving the technology for cervical cancer detection, such that it strikes a balance between efficiency and affordability. In order to to improve this technology, it is first necessary to pinpoint and improve issues with the current existing technology, which is the Pap smear test.

While the Pap smear test was a pivotal point in diagnostic medicine for its time, there are blatant issues with it that need to be improved in the trek towards cervical cancer eradication. The Pap smear test works by obtaining a swab of cervical cells, and then using cytology, the branch of biology concerned with the structure of cells, to detect abnormalities among the sample. The entire process is performed by a person, the cytopathologist, which lends the diagnosis to subjective interpretation that is dependent on the cytopathologist performing the test. This lends the test to generally less accurate results, and requires training of the personnel using it, which is an issue in under-resourced countries.

Moreover, the sensitivity of the Pap smear test drastically varies based on the cytopathologist who is reading the sample, which is why the test needs to be performed annually. This is a large issue for countries with limited resources, as performing the test at this frequency becomes costly, and many women in under-resourced countries do not live near a clinic or hospital, and are such prevented from getting screened as often as they need to be.

HPV Primary Screening addresses these aforementioned issues. It does this by automating the process, which makes the diagnostic both more accurate and efficient than the Pap smear test. This automation eliminates the need for training, and lends the diagnostic to having a higher sensitivity, which translates to more accurate results, and as a consequence of these more accurate results, a lower frequency in which the test needs to be administered. In addition, it allows women to send in their own samples to be tested, including hair and saliva. These are all huge benefits for those who do not have immediate access to a clinic.

HPV Primary Screening also allows women to be sent home with nearly 100% confidence that they do not have cervical cancer if their results come back negative. Conversely, with Pap smear tests, there is a larger degree of uncertainty involved since this diagnostic process is done by a person. This is one of the major downfalls of using visual assessment treatment (VAT). Patients who have cells the cytopathologist determines are abnormal, but not quite cancerous, are placed in a group called “ASCUS”.

http://www.obgyn.net/gynecological-oncology/national-hpv-cervical-cancer-campaign-you-need-know

As depicted in the image above, the protocol for women placed in this category is to repeat the Pap test three times, then perform an HPV test, and then a colposcopy for further evaluation. Performing the HPV test to begin with alleviates the need to perform the Pap test multiple times, which yields not only more accurate results, but also more cost-efficient ones from a health economics perspective. Moreover, studies found that 57% of cytopathologists disagreed about women placed in the ASCUS group, and 53% of women in this category were misdiagnosed. HPV Primary Screening creates a paradigm of science that creates certainty and alleviates the current wait and worry paradigm of women placed in this category.

Currently in the United States, the balance between using the Pap smear test and HPV primary screening is at the discretion of the physician, which is why the intervals between when a woman is tested have changed from annually to every 3-5 years, depending on the institution administering the test. Sometimes, these tests are done in tandem with the same sample. Although this may seem like a fair compromise to utilize both the Pap smear test and HPV Primary Screening, the difference between cotesting and solely using HPV Primary screening is marginal, so switching to HPV primary screening can further extend intervals between testing periods, is good for health economics, and utilizes new technology for better outcomes for patients.

In addition to discussing rising technological advancements, solving the issue of cervical cancer also requires discussion concerning healthcare policy. As such, Mrs. Ewald and I also discussed global policies that have paved the way for cervical cancer eradication in certain countries. Australia for example, has a national cancer registry for HPV primary screening and a school immunization program that has led it to be the first projected country to eradicate cervical cancer. In the Netherlands, screening is well organized and free of charge. Approximately 800,000 Dutch women receive invitations to receive a screening each year. Because of this policy, only 200-250 women die from cervical cancer every year in The Netherlands, which is a much lower mortality rate compared to the rest of Europe. Countries like these are leading the way to eradicate cervical cancer, and we can all learn from them and work together to prevent and diagnose cervical cancer early. CCAP Across The Map is working to continue the fight on the global stage, and you can too through supporting all organizations involved in the global ambition to eradicate this preventable and treatable disease.   

Dr. Melissa Herbst-Kralovetz on the Vaginal Microbiome

Interview conducted and documented by Hunter Ackerley

I had the pleasure of conducting an email interview with Dr. Melissa Herbst-Kralovetz, Associate Professor at the University of Arizona College of Medicine-Phoenix and Director of the Women’s Health Microbiome Initiative. Dr. Herbst-Kralovetz led a research team to evaluate how cervical cancer and vaginal bacteria are related. We discussed her team’s findings and the implications of these findings on a broader social scale. Continue reading for the full interview!

Q: What were the main findings of your research surrounding vaginal bacteria and cervical cancer?

A: Our study revealed that vaginal microbiome, a community of bacteria that resides in the vagina of women with cervical cancer and precancerous lesions, differs from the microbiome of healthy women. In cancer and pre-cancer patients “good” bacteria, that are lactobacilli, are diminished and replaced by mixture of “bad” bacteria associated with vaginal infections. In our study we also revealed some differences in the microbiome between Arizona Latinas and women of non-Hispanic origin. We also identified new bacteria, which may contribute to development and progression of cervical cancer. We linked the presence of Sneathia, a microbe commonly found in the female reproductive tract, with human papillomavirus (HPV) infection, which is a primary cause of cervical cancer, as well as with cervical cancer and precancerous lesions. We also showed that women with cervical cancer, but not with precancerous lesions or women infected with HPV exhibit inflammation, which is a response of our immune system to fight infections or foreign bodies. Our study also revealed unique proteins, produced by our immune system, to be associated with cervical cancer and vaginal bacteria. Overall, our study revealed unique microbes living in, and proteins produced by our body, to be connected with cervical cancer progression and development.

Q: What implications do you believe these findings have for society at large?

A: Our ultimate goal is to integrate the clinical and molecular data to optimize therapy and deliver superior outcomes to future patients by identifying/targeting the vaginal microbiota for therapeutic modulation of carcinogenesis. Such knowledge would be useful for developing new treatments to aid in prevention of cervical cancer by allowing physicians to identify individuals with particular vaginal microbiota who are at high risk of developing cancer and ultimately reduce mortality rates.

Q: How did your research findings extend beyond your initial inquiries?

A: Now that we have identified Sneathia and other organisms to be associated with cervical carcinogenesis, we can begin to study these bacteria and the mechanisms that they employ that may contribute to cancer.

Q: What do you believe is(are) the next important step(s) to take with continued research, in regards to cervical cancer and/or gynecological health?

A: Our study provides an initial step to understand a complex relationship between HPV persistence, vaginal microbiota and the mucosal inflammation in the local microenvironment during cervical carcinogenesis. Our study provides a foundation for larger clinical studies with longitudinal design, as well as, in vitro studies to assess the functional impact of the vaginal microbiota in cervical carcinogenesis. There is a lot still to learn in terms of vaginal bacteria and their role in women’s health. For example, how do some bacteria contribute to health and other contribute to disease?

Q: What possible steps can society members take with the knowledge that your research provides in order to work to prevent cervical cancer?

A: With regard to our research, more work needs to be conducted and our studies need to be extended to determine women at highest risk. In terms of society, we can promote HPV vaccination and ensure that adolescent girls and women get vaccinated against HPV, which is a very effective means of preventing cervical cancer. In addition, women can make sure that they are going to their routine well woman exams and being screened for cervical cancer.