uploaded by Nancy for Jerome Belinson.

As a bit of an “elder” let me begin with a little history.

Twenty-seven years ago, my colleagues and I entered China with a goal to blend humanitarian care with good science. Our focus was cervical cancer prevention, and my colleague Jerry Pretorius and I were fortunate to begin a series of wonderful collaborations, first with our friend Youlin Qiao in Beijing and beginning in 2008 with Professor Ruifang Wu in Shenzhen.  We were guided to unique populations and locations in China, such as in Shanxi, that made providing needed care and doing statistically significant studies easier due to their high prevalence of disease.

In SPOCCS I, published in 2001, we screened 1997 women with multiple screening technologies, and using our special small biopsy instrument, took a minimum of 5 biopsies including an ECC from every patient in the study. This unique study gave us a clear understanding how well various technologies actually worked, and led to a series of investigations over the following 2 decades. It became very clear, to reach hundreds of millions of women in China with a traditional Pap screening system was impossible. Molecular (HPV) testing which was demonstrably more sensitive needed to be used, and for the first time a screening method allowed the possibility of self-collection.

There were problems to solve:

1.      It took us 5-6 years to understand the secret to make a self-collected specimen equal in sensitivity to a direct collected sample.

a. It was not patient acceptance or patients’ ability to learn to take the sample. Both were easy!

b. It was not the type of sampler used (it just needed to be acceptable to patients).

c. The key was the assay used to analyze the sample. It had to amplify the specimen, like a PCR based assay. (this was SPOCCS III, conducted 2004-6)

At that time PCR assays were impractical laboratory tests not suitable for clinical use. However, four years later, in collaboration with BGI Shenzhen, we did SHENCCAST II. This 10,000 patient randomized clinical trial, defined the effectiveness of self-collection, confirmed the role of a PCR based assay, and demonstrated sampling device design was not important in regards to viral detection. SHENCCAST II also introduced rapid processing, using the PCR based MALDI-TOF. We imagined models with self-collection where we could easily screen more people than any current laboratory test could handle. So then in 2011 with BGI we collaborated to develop and test SEQHPV, the first PCR based assay that used next generation genomic sequencing. SEQHPV not only provided very high throughput, but uniquely maintained high sensitivity with increased specificity due to type specific differential analytical sensitivity.

Over the years that followed we sought or developed technologies that would enhance this centralized laboratory concept which could manage massive screening programs. We studied patient acceptance of self-collection and developed very simple collection kits. We focused on dry specimen transport first with solid media transport cards, then cards that could automatically punch rapidly into PCR solution, and most recently simple dry brushes.  

Understanding that systems solve population problems not isolated technologies, we realized the need to further refine our methodology and focus on healthcare delivery systems that could reach the people most in need. Therefore, using Community Based Participatory modeling we first designed and then conducted a series of trials: first in Peru and then China all with central processing at BGI Shenzhen. Then our colleagues in China, special recognition to Steve Qu, adapted our community based self-collection modeling to an internet-based system. Several years ago in the initial trial using that system, more than 272,000 people were registered in 33 days, and almost 189,000 women were screened in 29 days.

In actual fact, due to the unique processing capacity at BGI for their Next Gen Assay, it becomes easy to implement a massive expansion of this work however many important obstacles become clear. Diagnostic skills in China, and virtually everywhere else in the world are not uniform, and they range from spectacular to non-existent. The same knowledge and skill gaps apply to risk assessment and treatment. We as well as others had solved sensitivity, but the glaring obstacle was specificity.

Though secondary screening tests including cervical cytology, genotyping for hrHPV, viral titers, dual staining for p16/Ki67, and others have been studied, none have yet been effective, affordable, and applicable to populations without advanced health-care infrastructure.  Likewise, though ablation of the cervical transformation zone with hot or cold cautery has been suggested for all women with hrhPV in self-collected vaginal specimens, there has been a lack of enthusiasm for such plan.

So where does this “elder” think we are today?  I still believe there may be some countries that can create country-wide policies and mandates. They have the potential to implement massive screening programs with centralized processing, and then dictate the application of diagnostic and management algorithms tailored to regional human and financial resources. However, it is extremely difficult to duplicate what an organization like BGI can do “in house” in the areas of the world where today the greatest needs exit.

Many of us work in two distant worlds. Remember private / one-on-one care will always be simple. Patients return and time is invariably on our side to get the answer right. We will follow complex algorithms, and then employ the latest and greatest technologies to provide our individual patients with the best we can provide. This however has very little impact on world-wide cervical cancer control. For the millions of women without access to care we need thousands of providers/programs, receiving the results of inexpensive self-collected rapidly processed specimens, and all armed with a simple risk-based diagnostic algorithm and inexpensive, easily transportable treatment technologies. Recently a collaboration between the NIH and Atila Biosystems, updated the AmpFire HPV Assay to ScreenFire, which through simple quick methodology reports in 4 risk-based channels.

Therefore, we have self-collection, we have fast simple point-of-care assays that are risk stratified, we have risk-based diagnostic algorithms, and there are treatment options. Collectively, as is always the case, they seek a system. Our job is to design, study, and implement. Of course vaccination can, and eventually will, have a massive influence. This is already becoming evident in the few areas of the world with high vaccine penetration. But we are decades away from the kind of coverage needed to truly eliminate a disease.

If I were to project further, I now wonder if our specificity targets are reasonable. Are there ways to make screening specificity less important? What it there were effective treatments so benign as to carry with them non-significant risk. And what if these future targeted therapies could be self-administered, which would further simplify the triage step of delineating risk. The current trials of topical Artesunate, from Frantz Viral Therapeutics, fall into this category.

Many of you, like Preventive Oncology International, are intimately involved with studies designed to solve many of the aforementioned concepts and technologies. Our collective efforts promise to save millions of lives world-wide. And remember, Cervical HPV related disease is only one part of the constellation of HPV related neoplasia, which impacts the lives of both men and women. A common etiology may begin as a curse, but ultimately can provide the roadmap to control cancers and their pre-cancers for multiple disease sites.

Jerome L. Belinson, MD

Preventive Oncology International, Inc.