Very unusual and interesting case, so thank you for presenting it. Can everyone see my slides? Yes. Yes. Okay. Yes. So I'm just gonna talk quickly a little bit about some of the projects that we're doing with the bioengineering group here at Rice University, looking at innovative technologies for cervical cancer prevention and treatment. As all of you know, there's a lot of inequity with cervical cancer. When you look at this map of the world, the countries in the darker red and brown have the highest incidence of cervical cancer and highest death rates, so primarily in Sub-Saharan Africa, but also in Latin America and Southeast Asia. What we do know is that 85 to 90% of cervical cancers occur in low and middle-income countries. Also, I think everyone on this call knows that cervical cancer is completely preventable, thanks to the great work by Harald Zurhausen and others. We know that cervical cancer is caused by the HPV virus. We have excellent preventive vaccines. We have very good screening with VIA, visual inspection with acetic acid. Pap testing, HPV DNA testing are a combination of any of those. And most importantly is that we have a treatable pre-invasive phase where we can diagnose CIN2, CIN3, and treat it with a cervical cone, a leap, cryotherapy, or now thermal ablation. And most importantly is that it takes about 10 years to progress from pre-invasive disease to cancer, so we have a long time to intervene for these women. So really, no woman should be dying of cervical cancer, yet in all our clinics every day, all of us are seeing women with advanced cervical cancer and often incurable disease. I think everyone's aware that in May of 2018, the director general of the WHO put out a call to action to eliminate cervical cancer as a public health problem. This call to action has been adopted by all the member states of the WHO, and now there are many, many projects around the world to meet the goals, very, very aggressive goals set out by the WHO. One country that is really doing an amazing job is Australia. This is a picture of Professor Ian Fraser, who is one of the co-creators of the HPV vaccine. And I think we have seen that Australia has really led the world along with Rwanda and a few other places in having very, very high vaccination rates, but then also very high screening rates and management of women with pre-invasive disease. The problem we have with our current system to prevent cervical cancer is that it's not very user-friendly. So we really need three visits, at least that's what we do for the most part in the US and in other high resource settings where women come for screening. We do a pap test and or HPV testing, depending on their age. If that's abnormal, we call them, we bring them back for a second visit where we do colposcopy with cervical biopsies. And then if we find high-grade dysplasia or CIN2,3, we call them and we bring them back a third time and we do a leap or a cone or ablation of the precancerous lesions. The system has worked very, very well. We've decreased our cervical cancer rates by 70% in the US over the last 60 years. So the system works, but it doesn't work for everybody. And why I say that is that each of these steps, you need pathology and lab services. So somewhere like MD Anderson, we have those, it's covered, we can get a very good read, but in many places around the world and in many places in the US, we don't have pathology services readily available. The other thing is that the woman has to come back three times and it has to be called given the results and be able to return, have transportation, have childcare, all those many, many barriers. So in lower resource settings, a lot of times they don't come back. And I tell people all the time, when I see someone in my clinics in Houston and ask them if they've ever had, when they come with advanced cervix cancer and I ask them if they've ever had a pap test or any screening, almost always they have, but it was abnormal. And just for whatever reason, they couldn't get colposcopy, they couldn't get a leap, they couldn't get a biopsy. And usually in the US it's because they don't have insurance or they lost their insurance or a lot of times they were scared and didn't understand, they didn't have symptoms, so they didn't feel the need to come back in. But there are many, many barriers and it's not just in LMICs, it's also in the US and in other high resource settings as well, where we don't have good systems and good safety nets for women. So back, you need pathology at each step. So when you look at the pathologists of the world, we're fortunate to have some with us tonight or in the morning for those of you in Nepal. But when you look at how many pathologists there are per population, in the UK it's about one per 15,000, in the US it's about one per 19,000. But when you look at many countries in Africa, there are very, very few pathologists. So in South Africa and Botswana, some of the most developed countries in Africa, there's one pathologist per 200 to 500,000 people. In Mozambique, where we do a lot of work, there's one pathologist per 2.5 to 5 million people. And these pathologists have to do all the autopsies, they have to look at all the colon, resected specimens, they have a lot, a lot of things to do. So to look at cervical biopsies or set up a cytology lab, just isn't feasible in many, many places of the world. So our system that works well, where you have to have three visits with pathology at each step, this isn't feasible in many, many places. So we've been really fortunate in Houston to work with this woman. Her name is Rebecca Richards-Cordom. She is a professor of bioengineering at Rice University, which is a university here in Houston. And she runs a program called Rice 360 for Global Health. And she has an army of faculties, graduate students, undergraduate students, whose mission is to try and develop affordable technologies for lower resource settings related to health. So she does a lot of work in Malawi with newborn technologies. So point of care, bilirubin tests, baby warmers, CPAP machines. And then she works with our group at MD Anderson on developing technologies for cancer screening, cancer diagnosis for the most part, but also for cancer screening. So one of the most exciting things that her team is working on is a paper-based HPV DNA test. I think many of you know that most of the HPV tests we do, we send off to a lab. It takes a couple of weeks to come back. It costs a couple of hundred dollars. So very expensive and not user-friendly. And then some of the point of care ones, such as CareHPV or GeneXpert, have the problem that with CareHPV that you have to run many samples at the same time to make it affordable. And with GeneXpert, it's still expensive at about $15 a test and requires a complicated machine that needs to be in an air conditioned lab with technicians who are trained. So although HPV is very exciting, it's very hard to use in a lower resource setting. So Rebecca and her team developed this lateral flow test, very cheap, less than $2. You don't need a complicated lab or very highly trained personnel. It takes less than an hour and you can do one at a time. So it's very nice. A woman could come to the clinic, get an HPV test, wait for a little bit, and then figure out if it's positive or negative and then be able to either go home or come in and get VIA with cryotherapy or some sort of see and treat or screen and treat visit. Rebecca and her team have tested it, have compared it to some of the hybrid capture assays with very, very similar results. The other thing we've done is sort of look at the usability of it. So we did some tests both by nurses, lab technicians and community health workers in both Mozambique and El Salvador. And many people were able to do it without too much trouble after some training. And so the idea is it will be a test like we do a pregnancy test in our clinics where it will give you two lines if it's positive and one line if it's negative. So these studies are ongoing and I'm hopeful that we will have a good point of care test soon that we can use in Nepal, India, and even here in Houston in our own clinics. So stay tuned. The other great tool that Rebecca's team has developed is called the HRME or the high resolution micro endoscope. And this is a small probe that we put on the cervix and it tells us in real time, so in vivo, whether or not the morphologic features of the cells look like high grade dysplasia. So this looks at things like the nuclear to cytoplasmic ratio, the nuclear size, atypia. So most of the, you know, some of the things that our pathologists look at for us, but it does this without taking a biopsy. So the goal of the HRME is sort of to perform a visual biopsy where we can replace colposcopy and cervical biopsies to diagnose precancerous or cancerous lesions. So this is really important in parts of the world that don't have colposcopists or gynecologists or pathologists that can read all the biopsies. If there's even a gynecologist to do them who actually has biopsy forceps and formalin is able to send it somewhere. So how this works is we put proflavin on the cervix. Proflavin is a topical contrast agent. It's yellow in color and it stains the nuclei. And proflavin is part of triple dye, which is an aseptic agent that we put on the umbilical cords of newborn babies. So after we put the proflavin on, we do it just like we would put acetic acid on. Then we put a small probe on the cervix and then it gives you an image back to a tablet or a smartphone. And you can see here how it looks. So the first image shows a normal cervix where the cells, all the white dots are the nuclei. And so they're well-spaced and on higher power view that you can see that they're normal in size and shape. And then the next one you see inflammation where you have a lot of cells, but they're all normal size and shape. And then it sort of progresses from SYN1 to SYN2 to SYN3 and then to cancer. And you can see here in that patient with cancer that we actually see vessels and neovascularization. And that's not something we could see with a colposcope or with the naked eye. That's something that we've seen just with this probe. So we have done a few studies trying this HRME in Houston and then we just finished a very large study in Brazil. So Brazil cervical cancer is the second most common cancer after breast cancer. We work with a hospital there called Barretos Cancer Hospital. And they actually have mobile vans that go out to screen in the rural areas and in the community. Prior to this study, they were doing pap tests. They would go screen women all over the province and then bring the paps back to Barretos. And then if they were abnormal, they would call the women and invite them to travel to Barretos. But 40 to 50% didn't come because it was far away. And for all the reasons we all see that women won't follow up for abnormal results. So this really led to a lot of the interest in having a point of care diagnostic screening test and diagnostic that you could do in the field instead of making the women travel to the central hospital. So we were able to get a grant from the NCI several years ago to actually try this HRME in a mobile unit. So essentially the screening unit went out, screened everybody. And then those that were positive, the standard of care was to call them and bring them back to the main hospital. But we did a pilot study where we actually compared that standard of care to actually bringing another mobile van to the women to their town so that they could have what would be colposcopy, but an HRME and ablation done right there in their town. So we did this as a cluster randomization. And the reason we did that is that if there were two women in the same village that had abnormal PEPs, we didn't want one to have to travel 500 miles and the other woman to have the van come to them. So we did it by region. And you can see here, this is the van traveling around Brazil to rural areas, hard to reach areas. And inside was a examination table, a colposcope and the HRME device, as well as a cryotherapy machine. So this van traveled all over Brazil, 23,000 kilometers to see all the women with abnormal results. And what we found, not surprising, is that if you bring the diagnosis and treatment to the women, far more will get it than if they have to travel. So 87% for the women where the van came to them versus 64% where they had to travel to a facility. And then more importantly, for all these women, when we did the HRME, we also did a biopsy. So we would do the HRME, collect the images and at the exact same spot, we would do a biopsy and have it read by two different pathologists to see, does the image that we get really give us the answer? And the sensitivity and specificity was very, very similar. And we're not trying to do better with this than a biopsy and pathology, which is the gold standard. But the idea is, can we find something that's good enough for regions of the world where we don't have colposcopy, biopsy and pathology services? And so in the study in Brazil, a small study, we were able to show some preliminary data. And then just actually in the last month, we've published a large study, a much larger study from Brazil and one from El Salvador, where we show that these tools are comparable to colposcopy and biopsy. Not perfect, not quite as good, but maybe good enough to be able to make a diagnosis and then treat in an area where we don't have pathology services. And the other thing is, this is sort of the precursor of the startup, a lot of the ABE work or automated visual assessment, which you may have heard a lot about. Mark Shiffman at the NCI has done a lot of work, but the idea of we could just take a picture with a smartphone and be able to do the automated algorithms to see is there dysplasia there or not. So I think that's the future and that's what's coming. And we're very fortunate to work with this team at Rice, where we have a whole bunch of very, very smart engineers working on all these algorithms. And as I said, we have studies in Brazil and El Salvador. And then we actually did a study on the border of Texas and Mexico. So this is about six hours from Houston, a region called the Rio Grande Valley, where we have very, very high rates of cervical cancer. This is in the US. It's a very underserved, medically underserved community, even though it's not so far, it's driving distance from MD Anderson. But we have very, very high cervical cancer rates there, similar to Latin America and Africa. This is just showing the region we work in, the Rio Grande Valley. You can see it's one of the places we work is a mobile van that provides care to women who don't have insurance or don't have access to healthcare. And the picture on the right is Paul Toscano, who's a physician assistant who runs this van. And he does everything. He takes care of kids, women, men, you name it. And he was doing PAPs for women, but if they had abnormal PAPs, he had nowhere to send them. So he came and spent some time with us to learn colposcopy and biopsy. And so now he's able to do that in the van. And he did one of the studies for us with the HRME so that he could then have the opportunity to treat women at the same time, because again, the same problems of them not being able to come back. We're now doing a large study in Mozambique. It's been put on hold a little bit due to COVID, but we are testing some of these new technologies among women in Mozambique, Africa. This was actually a slide I had from when I was gonna give the talk a month ago, but we are very, very excited and proud of all our colleagues in Nepal for publishing this paper in the Journal of Global Oncology, which is one of the ASCO journals. And this was a paper related to the cervical cancer prevention course that we did in Nepal in November of 2019. So just before the pandemic. So this was recently published and you can see many friends in the pictures, but really it was a great course and it was really nice to see these results in JGO last month. And with that, I will end. Again, some pictures of our team in when we had the good fortune to visit Nepal a little more than a year ago now, and we're hopeful that we'll be able to come back again soon. And with that, I'd be happy to take any questions at all.

cervical cancer prevention

bioengineering group

Rice University

HPV DNA testing

high-resolution micro endoscope

low-resource settings