Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Uterine Cervical Dysplasia

Hyperplasia

Precancerous Conditions

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Cervical Intraepithelial Neoplasia

Srinivasan Professor and Chair, MD

Mary R Nittala, DrPH

Uterine cervical dysplasia and other female genital dysplasia continue to be significant health problems despite Cervical Screening Programs and HPV vaccinations being available. These female genital dysplasia \[FGD\] induced by HPV infections affect disadvantaged women in the US and globally more than others: minorities like African Americans \[AA\], rural populations, lower socioeconomic strata of the society and less educated in the US and lower / middle income countries. The reasons are: lack of access to screening and vaccines, lack of infrastructure, fear and shame of getting a pelvic examination and pap's smear and inability to go to the health centers that provide these cares. A simple blood test that can diagnose FGD can help make many of those hurdles go away. This proposal is to utilize the emergence of 'liquid biopsy' concepts using genomic/precision medicine advances of the past decade to have such a blood test to be made available. Collaborating with Naveris, Inc,® the clinical study will use their NavDx® blood test. This is a test for circulating cell-free tumor tissue modified viral (TTMV®)-HPV DNA. TTMV-HPV DNA is a clinically proven and analytically validated highly sensitive and specific biomarker for the identification of post-treatment recurrent and residual Human Papillomavirus (HPV)-driven squamous cell oropharyngeal carcinoma (OPSCC)1,2. Data is accruing for other major HPV-driven cancers including anal cancer and uterine cervical cancer with clinical utility appear similarly promising3. TTMV-HPV DNA is a distinct biomarker for HPV-driven malignancy and can distinguish between HPV-driven malignancy and acute and or chronic HPV infection. In this study, taking advantage of a robust Cervical Dysplasia Clinic in existence at UMMC and a team of multidisciplinary experts focused on this project, the blood levels of TTMV-HPV DNA will be determined through a fully informed IRB approved clinical trial process to correlate with the grades of dysplasia, any increasing values correlating with worsening grade/malignant transformation and other variables. This pilot study is the first of this type of biomarker-based 'screening' study, and if successful, will lead to a more efficient and convenient way to diagnose HPV-induced that will be cost effective and will need minimal infrastructure. Such a test will make remarkable beneficial differences in early diagnosis, early screening compliance, early interventions as well as improving outcomes in FGD patients worldwide. With the available infrastructure and expert team, this project can be successfully completed in a relatively short time.

Hypothesis:

1. The HPV induced dysplasia in cervical and vaginal tissues can lead to a detectable level of TTMV-HPV-DNA in the blood.
2. Those levels will increase when there is progression of the dysplasia from lower grade to a higher grade.
3. The blood levels of TTMV-HPV-DNA can distinguish lower versus higher grades of HPV induced dysplasia.
4. Serial measurements of TTMV-HPV-DNA in the blood can help diagnose progression of dysplasia to a higher grade earlier and in a more efficient and convenient way. This will help improved compliance with screening, early diagnosis, early interventions, and better clinical outcomes.
5. TTMV-HPV-DNA detection is also likely possible with touch preparations on the lesions, thus leading to easier diagnosis of such lesions.

Specific Aims:

1. To collect blood and touch-preparation samples from the dysplasia lesions among patients with HPV induced dysplasia in cervical and vaginal tissues in human subjects with such lesions in a phase I/II clinical trial setting.
2. Measure TTMV-HPV-DNA in those samples.
3. Correlate the detectable levels of TTMV-HPV-DNA with demographics, grades of dysplasia, progression in the grades with serial measurements and HIV status and correlate with biopsy results in terms of progression in PIN grades and malignant transformation.
4. Design future studies from these findings to enable early detection of potential progression to malignancy so that early curative interventions can be instituted.

Objectives:

1. To develop an innovative and pilot clinical trial in HPV related female genital dysplasia that integrates basic science, public health, clinical and translational cutting-edge knowledge and information using 'liquid biopsy' concepts to help prevent progression to malignancy.
2. To collect and analyze data in a prospective manner among a diverse population in terms of ethnic, racial, and socioeconomic variations that could help improve screening acceptance in the most vulnerable women at risk for female genital cancer.
3. To serve as a model for middle and low-income countries as well as resource-scarce, rural and disparity-affected populations in high-income countries in developing a blood-specimen based HPV-related early diagnosis screening tool.

1. Blood collection from the subject vein by UMMC's trained professionals of about four table spoons of blood like for any other blood test.
2. The samples collected will be frozen and stored to be utilized in the future for research studies. These samples will be labeled using a key code instead of the subject name, and no one using these samples for future research will know your name.
3. Touch Preparation from the subject genital lesion being taken by our clinical care providers.

Our research personnel will collect relevant information from your electronic medical records. The samples collected in this study could be used for genetic research studies. However, these results will not be added to your medical records. The samples collected in this study could be used to develop new treatments, drugs, or for other commercial purposes/third party company

Adult women with female genital dysplasia; Non pregnant women; No prisoners; Competent to give informed consent

Clinical, Translational and Biomarker-Based Female Genital HPV Induced Dysplasia and Cancer Screening Study Using Cf-HPV-DNA Blood Tests

Circulating Cell-Free Tumor Tissue Modified Viral (TTMV)-HPV DNA As A Biomarker For Early Cancer Detection Among Human Subjects With HPV-Induced Dysplasia In Female Genital [Uterine Cervix, Vaginal and Vulvar] Organs: A Clinical, Translational and Biomarker-Based Cancer Screening Study

Correlate the detectable levels of TTMV-HPV-DNA with demographics, grades of dysplasia, progression in the grades with serial measurements and HIV status and correlate with biopsy results in terms of progression in PIN grades and malignant transformation.

Given the pilot nature of the proposed study, extensive use of exploratory data analysis will be done. For any analysis of time-to-event data,Kaplan-Meier analyses paired with two-sided log-rank tests will be used. For any necessary modeling, a generalized linear model framework will be employed with appropriate family and link functions, depending on the outcome. Should independence fail between the sampling units (repeated measures, etc.), this will be extended to generalized linear mixed models with random intercepts. All linearity assumptions will be checked and modifications to modeling strategies will be undertaken where necessary."

University of Mississippi Medical Center

Digestive System Diseases

Carcinoma

Carcinoma, Squamous Cell

Uterine Cervical Neoplasms

Vulvar Neoplasms

Anus Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Anus Diseases

Rectal Diseases

Vulvar Diseases

Anal Cancer

Vulvar Cancer

All patients will receive an anal Pap test. 75% of patients with a negative anal Pap will complete study with no further intervention.

All patients will receive an anal Pap test. Remaining 25% of patients will proceed to high-resolution anoscopy (HRA) clinic to assess the negative predictive rate of HRA.

All patients will receive an anal Pap test. Any patient with abnormal cytology on their Pap test will be referred to HRA clinic for management. This includes potential biopsy and treatment.

75% of patients with negative cytology on their anal Pap smear will not receive high-resolution anoscopy

Screening anal Pap smear - No high-resolution anoscopy

25% of patients with negative cytology on their anal Pap smear will receive high-resolution anoscopy. All patients with positive (abnormal) cytology on their anal Pap smear will receive high-resolution anoscopy.

Screening anal Pap smear - High-resolution anoscopy

Nithla Mohanathas, BSc

Anika Mohan, BSc

Dr. Danielle Vicus, MD

Danielle Vicus, MD

Almost half of all women will develop an HPV infection in their lifetime. While most infections are naturally asymptomatic or cleared by the immune system, some persist and can lead to the development of cervical, vulvar, or anal lesions and eventually cancer. Screening regimens for these lesions are currently only in place for the cervix through regular Pap tests. These Pap tests usually involve an examination of the vulva -however, no screening procedures exist for anal cancer for women. Several studies have suggested that women with existing gynecological lesions are more likely to develop anal lesions and anal cancer. Here the investigators propose a multi-center study which seeks to screen for and treat anal cancer in women over the age of 40 with vulvar lesions and a stable immune system. The investigators will achieve this through performing anal Pap smears on eligible women and conducting High Resolution Anoscopy (HRA) and appropriate treatment procedures on those with abnormal anal cells. With enough evidence, there may be an indication to establish regular anal cancer screening measures in this potentially underserved population.

Hypothesis: The investigators hypothesize that at least 40% of women with vulvar cancer or VIN2/3 will have abnormal anal cytology. 35% of the population will be hrHPV DNA positive and 11% will additionally have AIN2/3. This prospective study may lay the groundwork for routine anal screening regimens in Ontario and help shift health policy to treat this population.

Screening for Anal Cancer in Women With High-grade Vulvar Dysplasia or Vulvar Cancer.

Dr. Danielle Vicus

Dr. Danielle Vicus, MD, MSc, FRCSC

Imaging complete cervix from endocervical canal to transformation zone to ectocervix.

Both groups will be imaged with the OCT-AFI device. Imaging will not influence standard of care biospies, treatment and procedures.

OCT-AFI

Calum MacAulay, Ph.D.

The multimodal imaging technology, OCT-AFI, will be used to image sites on the cervix, the endocervical canal and vulva. The imaging probe is small enough, it can be inserted into the endocervical canal for imaging. The probe can also be placed in a conformable holder that can be shaped to conform the the folds of the vulva for vulvar imaging. The resultant images will be compared to histology images.

The objectives are to determine

1. feasibility of the technology in imaging vulva and its capability in detecting vulvar intraepithelial neoplasias
2. feasibility in imaging cervix from endocervical canal to transformation zone to ectocervix
3. if combined OCT with AFI increases the sensitivity of detecting high grade lesions in the cervix compared to just AFI alone (previous work was AFI alone).

The multimodal optical imaging technology, OCT-AFI, has demonstrated the ability to image the small peripheral airways of the lung, allowing for high resolution of structural and functional details of airway tissue and the vasculature. Through the OCT (optical coherence tomography) component, the bronchial epithelium can be visualized and its thickness quantifiable. Micro invasion of the basement membrane can be seen in the acquired images. The AFI (autofluorescence imaging) component showed the vascular network, areas of pulmonary fibrosis and areas with loss of endogenous fluorescence beside pulmonary nodules.

The investigators anticipate OCT-AFI to be able to see subsurface structures in the cervix and vulva as well. Through previous work, the investigators found AFI to be sensitive to detecting high grade cervical lesions but the technology was confounded by normal subsurface tissue structures. By combining OCT with AFI, the investigators anticipate a higher sensitivity to detecting high grade lesions on the cervix than with just AFI. The OCT-AFI imaging probe is also small enough to fit into the endocervical canal and will allow for imaging of neoplasias that originate in the canal. These abnormalities are on the rise. Vulvar neoplasias are also on the rise and visually difficult to identify and determine surgical margins. OCT-AFI may help clinicians locate and determine the extent of vulvar lesions.

The objectives are to determine

1. feasibility of the technology in imaging vulva and its capability in detecting carcinoma and vulvar intraepithelial neoplasias
2. feasibility in imaging complete cervix from endocervical canal to transformation zone to ectocervix
3. if combined OCT with AFI increases the sensitivity of detecting high grade lesions in the cervix compared to just AFI alone (previous work was AFI alone).

This study will image 10 subjects for endocervical canal and ectocervix sites. Another 10 subjects will be imaged for vulvar sites. Imaging will not affect where standard of care biopsies will be taken from. Imaging results will be correlated with histology.

No statistical analysis will be performed. This feasibility study will look at the quality and utility of the acquired image sets. If possible, the investigators will quantify the images in terms of epithelium thickness, basement membrane location, presence of vasculature and sub-epithelial structures.

OCT-AF Imaging of Pre-cancers of Vulva and Cervix

Co-registered Multimodal Optical Imaging for the Early Detection and Management of Cancers of the Vulva and Cervix

The ability to image complete cervix including endocervical canal or vulvar lesions in one continuous imaging run will indicate the device is feasible for use in the clinical setting for cervix and vulva. Note whether a complete image scan was collected or not after each imaging session.

Correlate sub-epithelial structures seen in OCT-AFI with histology images

Measure epithelial thickness along entire scanned image. Units of measure in millimeters.

Locate basement membrane in OCT-AFI images and note presence or absence of invasion. Note presence or absence of fluorescence in epithelial layer in images.

Make notes regarding vasculature patterns seen in the OCT-AFI images.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical, Translational and Biomarker-Based Female Genital HPV Induced Dysplasia and Cancer Screening Study Using Cf-HPV-DNA Blood Tests	NCT05536843	Cervical Dyspla... Vaginal Dysplas... Vulvar Dysplasi...		18 Years - 100 Years	University of Mississippi Medical Center
Screening for Anal Cancer in Women With High-grade Vulvar Dysplasia or Vulvar Cancer.	NCT03061435	Vulvar Cancer Cervical Cancer Vulvar Dysplasi... Cervical Dyspla... Anal Cancer Anal Dysplasia HPV-Related Ana...	Screening anal ... Screening anal ...	40 Years -	Sunnybrook Health Sciences Centre
Clinical, Translational and Biomarker-Based Female Genital HPV Induced Dysplasia and Cancer Screening Study Using Cf-HPV-DNA Blood Tests	NCT05536843	Cervical Dyspla... Vaginal Dysplas... Vulvar Dysplasi...		18 Years - 100 Years	University of Mississippi Medical Center
Screening for Anal Cancer in Women With High-grade Vulvar Dysplasia or Vulvar Cancer.	NCT03061435	Vulvar Cancer Cervical Cancer Vulvar Dysplasi... Cervical Dyspla... Anal Cancer Anal Dysplasia HPV-Related Ana...	Screening anal ... Screening anal ...	40 Years -	Sunnybrook Health Sciences Centre
OCT-AF Imaging of Pre-cancers of Vulva and Cervix	NCT03285841	Cervical Dyspla... Vulvar Dysplasi... Precancerous Le... Vulvar Cancer Cervical Cancer	OCT-AFI	18 Years -	British Columbia Cancer Agency

Spots Global Cancer Trial Database for vulvar dysplasia