Could modified PapTest help detect endometrial and ovarian malignancy?

A new multiplex PCR-based test called PapSEEK was able to detect endometrial and ovarian malignancy from fluid samples collected during routine Pap test, reported Yuxuan Wang, MD, of Johns Hopkins University School of Medicine in Baltimore.

The authors also used a longer sampling brush that sweeps cells from the lining of the uterus called Tao brush, to further increase the sensitivity of detection for the less accessible tumors.

The paper was published in Journal Science Translational Medicine on March 21, 2018, and the study identified endometrial cancer with high sensitivity from samples collected by Pap test and Tao brush, while sensitivity for reporting ovarian cancer was low, but increased when it was combined with DNA testing in the blood samples.

Pap test has been instrumental in bringing down the incidence of cervical cancer by about 60% since its introduction in 1940 but it is not able to detect endometrial and cervical cancers. The researchers at John Hopkins University based this test on the evidence put forth by the previous study published in Journal Science Translational Medicine that both endometrial cancer and ovarian cancer shed cells that collect at the cervix. These cells can be identified by looking for ‘Tumor DNA’ in the samples.

It is to be noted that DNA mutations have already been identified for specific cancers. In the study, the researchers tested for 18 genes common to endometrial and cervical cancer.

The researchers looked at 1915 samples from 1658 individuals, including 656 patients with endometrial or ovarian cancers and 1002 healthy controls.

PapSEEK was used on Pap test samples of 382 women with endometrial cancer, 245 women with ovarian cancer, and 714 women without cancer.

PapSEEK gave a positive result in 81% of endometrial cancer patients, which included 78% of patients with stage I or stage II disease, and 92% of patients with stage III or stage IV disease.

While 33% of Pap test samples were PapSEEK-positive in ovarian cancer patients, including 34% of patients with stage I or stage II disease and 33% of patients with stage III or stage IV disease.

When samples collected by Tao brush was examined, they tested positive in 93% of cases endometrial cancer and 45% cases of ovarian cancer.

The researchers then tested plasma samples from 83 ovarian cancer patients and found that 43% of these patients had detectable circulating tumor DNA. On applying the papSEEK test to the Pap test samples from this group, it was seen that positive results were obtained in 63% of patients.

Currently, there are no screening tests for both endometrial and ovarian cancer and incidence of both is on the rise.  

More than 63,000 women are diagnosed with endometrial cancer in the U.S. each year, and more than 11,000 die each year from the disease. Ovarian cancer is less common but more lethal, affecting more than 22,000 women and killing about 14,000 in the U.S. each year.

Yuxuan Wang, first author on the study said, “Our study demonstrates the ability to detect endometrial and ovarian cancer using cervical fluids obtained using two different methods.”

Full text

Media Courtesy: John Hopkins University 

In case you missed it: Here are the top 5 posts this month

September was a very busy month with lots of good research papers and systematic reviews published on various topics. We also saw many guidelines and recommendations updates from ACOG, ASRM and USPSTF. Here are the top 5 most read posts for the month of September.

USPSTF simplifies cervical cancer screening recommendations: Dual testing no longer advised

The US Preventive Services Task Force (USPSTF) has issued new draft recommendations for cervical cancer screening with a major change that it recommends either cervical cytology (CC) or high-risk HPV (hrHPV) test as a screening procedure every 3 years for women aged 30-65 years, and not both ( Grade A)  

https://obgynupdated.blogspot.com/2017/09/uspstf-simplifies-cervical-cancer.html

ACOG issues clinical practice guidelines for Gestational Diabetes Mellitus

The American College of Obstetricians and Gynecologists (ACOG) has issued clinical practice guidelines for the diagnosis and treatment of gestational diabetes mellitus (GDM).

Although prevalence of GDM is directly proportional to prevalence of type 2 DM in a given population, it is estimated that GDM accounts for 90% of cases diabetes in pregnancy. The prevalence of DM in pregnancy is around 6-9%.

https://obgynupdated.blogspot.com/2017/09/acog-issues-clinical-practice.html

ASRM guidelines update: Metformin alone is not the first line of treatment for ovulation induction in women with PCOS

Practice Committee of the American Society for Reproductive Medicine does not recommend Metformin alone for ovulation induction as a first line therapy in women with PCOS. The guidelines were published in Journal Fertility and Sterility Epub ahead of print.

Metformin is a biguanide used as an oral insulin lowering agent in type2 diabetes, but also used enthusiastically in women with PCOS because of shared pathophysiology of insulin resistance in both.

https://obgynupdated.blogspot.com/2017/09/asrm-guidelines-update-metformin-alone.html

Oral Nifedipine parallels IV hydralazine in lowering down BP in acute hypertensive emergency in pregnancy

Intravenous hydralazine and oral nifedipine both exhibit the same efficacy in lowering the blood pressure in acute hypertensive emergency of pregnancy reports the results of small randomized trial published online in journal American Journal of Obstetrics and Gynecology.

https://obgynupdated.blogspot.com/2017/09/oral-nifedipine-parallels-iv.html

Oral diclofenac potassium plus cervical lidocaine cream eases the pain during hysterosalpingography

Oral diclofenac potassium tab 30 minutes before hysterosalpingography (HSG) and cervical lidocaine cream 5% significantly relieves pain and eases patient anxiety during the procedure and for half an hour after reports the results of a randomized trial published in September issue of journal Fertility and Sterility.

https://obgynupdated.blogspot.com/2017/09/oral-diclofenac-potassium-plus-cervical.html 

Today is World Cancer Research Day: A call to action by ASCO- Don’t Stand Still. We Won’t

September 24th is  World Cancer Research Day. American Society of Clinical Oncology (ASCO)calls upon to continue and heighten research in areas of cancer prevention and treatment, along with discovering new drugs. World Cancer Research Day is a global initiative that aims to raise awareness about the critical importance of cancer research.

It is estimated that by 2030 cancer will be the leading cause of death worldwide with new cases expected to increase to 21.6 million each year. According to the GLOBOCAN report, in 2012 there were 14 million new cases diagnosed and 8.2 million cancer-related deaths worldwide.

Life years and productivity loss, together with disabilities resulting from cancer account for the largest economic cost on a global scale, compared to other causes of death including infectious diseases.

One of the most important areas is to support and promote research on the causes, prevention and early detection of cancer as a key element in controlling the disease. This will lead us towards the discovery of a cure for cancer or transforming the disease into a chronic illness, both approaches translating into higher survival rates.

Some of the important research paper on Obstetrics and Gynecological cancer published recently are:

USPSTF simplifies cervical cancer screening recommendations: Dual testing no longer advised

The US Preventive Services Task Force (USPSTF) has issued new draft recommendations for cervical cancer screening with a major change that it recommends either cervical cytology (CC) or high-risk HPV (hrHPV) test as a screening procedure every 3 years for women aged 30-65 years, and not both ( Grade A)  

https://obgynupdated.blogspot.com/2017/09/uspstf-simplifies-cervical-cancer.html

Magseed, a minimally invasive breast marker for cancer localization during surgery receives clearance in Europe

Endomag, a surgical guidance company received CE clearance for Sentimag+Magseed breast cancer diagnostic system, that guides surgeon for precise location of impalpable tumor during breast lumpectomy. It improves outcome and reduces the amount of radioactive exposure for patients.

https://obgynupdated.blogspot.com/2017/09/magseed-minimally-invasive-breast.html

FDA clears first 2D digital mammography system that allows patients to control the compression

GE Healthcare announced today FDA 510(k) clearance of an industry-first, patient-assisted mammography system, Senographe Pristina Duetathat makes mammography experience more comfortable by putting the control in patients’ own hands.

https://obgynupdated.blogspot.com/2017/09/fda-clears-first-2d-digital-mammography.html

FDA approves world’s first pioneering gene therapy for cancer

The U.S.Food and Drug Administration in its landmark and historic action today approved the world’s first gene therapy, Novartis' Kymriah (tisagenlecleucel) for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL).

This opens a new frontier in treatment of cancer and other serious and life-threatening diseases.

https://obgynupdated.blogspot.com/2017/09/fda-approves-worlds-first-pioneering.html

Are you dense? What every woman and her healthcare provider needs to know.

Nearly 20 plus years of research have provided sufficient evidence to link dense breast tissue and increased risk of missing cancer diagnosis by screening mammography. As the breast density increases, the reliability of mammogram as a screening tool for picking up breast malignancy decreases.

What is meant by “being dense”? Breast density does not correlate with physically palpated firmness of breast, it is a radiologic finding and cannot be predicted without obtaining a mammogram. 

https://obgynupdated.blogspot.com/2017/08/are-you-dense-what-every-woman-and-her.html

Now Ovarian Tissue paper to support normal hormonal production: Breakthrough in Regenerative Medicine

An accidental Spill has sparked a breakthrough in the field of regenerative medidicne. Scientists and engineers at the Northwestern Medicine have invented a range of bioactive “tissue papers” made from organs combined with a polymer to make them so pliable.

These new “tissue papers” are so thin and pliable that they can be folded into an origami bird. Their clinical application is for wound healing and aid in natural hormone production in young cancer patients.

https://obgynupdated.blogspot.com/2017/08/now-ovarian-tissue-paper-to-support.html

Adjunct Metformin helps reversal of atypical endometrial hyperplasia

Adjunct metformin treatment help reversal of atypical endometrial hyperplasia (AEH) and improves overall survival in endometrial cancer reports the result of a systematic review and meta-analysis published ahead of print in Journal of Gynecologic Oncology.

https://obgynupdated.blogspot.com/2017/08/adjunct-metformin-helps-reversal-of.html

FDA Approves PARP inhibitor Zejula for treatment of recurrent ovarian cancer.

The U.S.Food and Drug Administration today approved Zejula (niraparib) for the maintenance treatment of epithelial ovarian, fallopian tube or primary peritoneal cancer in adult patients who have already responded well to platinum-based chemotherapy.

https://obgynupdated.blogspot.com/2017/03/fda-approves-parp-inhibitor-zejula-for.html

Here is an interesting video about importance of research on World Cancer Research Day 2017

USPSTF simplifies cervical cancer screening recommendations: Dual testing no longer advised

The US Preventive Services Task Force (USPSTF) has issued new draft recommendations for cervical cancer screening with a major change that it recommends either cervical cytology (CC) or high-risk HPV (hrHPV) test as a screening procedure every 3 years for women aged 30-65 years, and not both ( Grade A)  

It still continues to recommend Pap screening every 3 years for women aged 21- 29 years in line with 2012 recommendations (Grade A).

Screening is not recommended in women younger than 21 years because despite their being sexually active, screening in this population subgroup does not reduce cervical cancer incidence or mortality (Grade D).

It also continues to recommend against routine screening for women aged 65 and above who had regularly undergone screening earlier and are not at high risk for cervical cancer and in women who have had a total hysterectomy with no history of cervical intraepithelial neoplasia [CIN] grade 2/3 or cervical cancer (Grade D).

These recommendations do not apply to women with in utero exposure to diethylstilbestrol, or a compromised immune system (living with HIV).

“Cervical cancer is highly curable when found and treated early,” says USPSTF member Carol Mangione, MD, MSPH. “Most cases of cervical cancer occur in women who have not been regularly screened or treated. Therefore, making sure all women are adequately screened and treated is critical to reducing deaths from cervical cancer.”

“The Task Force looked at the evidence on the effectiveness of different screening tests and intervals based on age, and found that after age 30, the Pap test and hrHPV tests are both effective for cervical cancer screening,” says Task Force member Maureen G. Phipps, MD, MPH. “Women ages 30 to 65, therefore, have a choice between the Pap test every three years or hrHPV test every five years.”

The Task Force’s draft recommendation statement and draft evidence review have been posted for public comment on the Task Force website. It is open for public comments from September 12 through October 9, 2017.

 The American Cancer Society (ACS), American Academy of Family Physicians (AAFP), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) recommends similar screening strategy for women aged 21-29 years. 

They defer with USPSTF for age group 30-65 years of age in whom dual screening with cytology and HPV testing is advised every 5 years or cytology alone every 3 years.

ACOG also prefers cotesting with cytology and HPV testing every 5 years but  only cytology every 3 years is acceptable according to a 2016 statement.

USPSTF Draft Recommendation Statement Full Text 

HPV testing vs Pap test in cancer screening: Cochrane Systematic review

A negative HPV test is more reassuring than a negative Pap test, as the cytology screening has a higher chance of being false negative thereby missing some women with precancerous lesions and delaying treatment says the result of a Cochrane Systematic review published ahead of print.

Since decades the usual method of screening for cervical cancer is based on cell cytology, but since the etiological relationship between cervical cancer and HPV infection was confirmed along with advent of HPV testing in 1999, the supremacy of these two tests is debated.

Some physician advice Pap and HPV both, especially for women over 30 years old, who are most at risk of cervical cancer, getting both tests provides the best assurance of finding cervical disease before it becomes cancer.

Younger women (20-30) are advised to get HPV test only if their Pap smear looks "inconclusive" or "borderline.”

This systematic review by Cochrane was aimed at determining efficacy of the two tests in detecting precancerous lesions (CIN 2+ and CIN 3+). Literature search for relevant studies till November 2015 identified about 40 studies amounting to a total of 140,000 women between 20 to 70 years old who underwent cervical cancer screening.

Data analysis identified true positives (TP), false positives (FP), true negatives (TN), and false negatives for each screening test (HPV test and cytology) used in each study.

It was seen that HPV test was more sensitive than conventional Pap test and liquid based test in identifying CIN 2+ and CIN 3+, but less specific than Pap test in detecting precancerous lesion.

Data analysis showed that for every 1000 women screened, around 20 women will have precancerous lesions. If HPV test is used, it will correctly identify 16 of the 20 women to be positive for the lesions (but will miss 4 women who have the lesions). The Pap test will correctly identify 12 of the 20 women (but will miss 8 women).

Similarly, for every 1000 women screened, there will be 980 women who will not have precancerous changes. The HPV test will correctly identify 879 women as disease free (but 101 women will be incorrectly told that they have a lesion). The Pap test will correctly identify 951 women (but 29 will be incorrectly told that they have a lesion).

This high false positive rate of HPV testing will lead to high unnecessary referrals and further tests like colposcopy, biopsy and surgery but at the same time it will also identify 50% more women with precancerous changes as compared to conventional cytology.  

The authors concluded that,” Whilst HPV tests are less likely to miss cases of CIN 2+ and CIN 3+, these tests do lead to more unnecessary referrals. However, a negative HPV test is more reassuring than a negative cytological test, as the cytological test has a greater chance of being falsely negative, which could lead to delays in receiving the appropriate treatment.”

Source: Koliopoulos G, Nyaga VN, Santesso N, Bryant A, Martin-Hirsch PP, Mustafa RA, Schünemann H, Paraskevaidis E, Arbyn M. Cytology versus HPV testing for cervical cancer screening in the general population. Cochrane Database Syst Rev. 2017;8:CD008587. doi: 10.1002/14651858.CD008587.pub2. PMID: 28796882

Access the abstract here.

New slender hand-held pocket colposcope will make cervical cancer screening comfortable and accessible for more women.

courtesy:Duke University 

Uncomfortable speculums and high cost colposcopes can soon be replaced by a simple hand-held device for cervical cancer screening say researchers at Duke University.

Invasive cervical cancer (ICC) affects the lives of 500,000 women worldwide each year, and results in more than 270,000 deaths.Many deaths can be prevented by addressing the barriers to cervical cancer screening which also includes travel distance to the provider, comfort during the procedure  and  adequate assessment of risk.

The “pocket colposcope” is a slender wand that can connect to many devices, including laptops or cell phones. It can be used by woman for self-screening in low resource settings, including some areas in US.

The paper was published on May 31 in the Journal Plos One.

“The mortality rate of cervical cancer should absolutely be zero percent because we have all the tools to see and treat it,” said Nimmi Ramanujam, the Robert W. Carr, Jr., Professor of Biomedical Engineering at Duke. “But it isn’t. That is in part because women do not receive screening or do not follow up on a positive screening to have colposcopy performed at a referral clinic. We need to bring colposcopy to women so that we can reduce this complicated string of actions into a single touch point.”

courtesy: Plos One 

The device has a slender, tubular body just like a tampon with a funnel-like curved tip measuring approximately 2.5 cm in diameter. The inserter has a side channel which a 2 megapixel (MP) mini camera with LED illumination to enable image capture.

The device also includes a channel through which contrast agents used for the cervical cancer screening procedure can be applied. The researchers recruited a group of volunteers to try the new device and  92.3%  said that they would prefer it over a traditional speculum. 80% women got good image and the rest said that they can do it with a better practice.

Dr. Ramanujam and Asiedu, a graduate student in Duke’s Global Women’s Health Technologies Center are working on clinical trials to compare it with traditional speculum and coloscopes.

Asiedu is also working to teach the computer to spot precancerous and cancerous lesions. This involves machine learning so that the screening can be performed by midwives, community health workers and even the women themselves.

Test strips for point of care detection of cervical cancer: Reality in near future.

A prototype of  test strip that could be used for the early detection of cervical cancer.
(Credit: Purdue Research Foundation photo/Curt Slyder)

Researchers at Purdue are developing technology that could enable us to detect cervical cancer with low-cost, easy-to-use, lateral flow test strips that are very similar to home pregnancy tests.

Joseph Irudayaraj, professor of biological engineering in Purdue’s School of Agricultural and Biological Engineering “This field really needs an additional way to test for cervical cancer. A test that can report cervical cancer right away is very instrumental in a lot of low- and middle-income countries where women often get HPV tests and then never come back. In higher-income countries, it’s important that anything beyond HPV tests have the ability to complement those tests.”

The technology developed by Purdue researchers works on the basis of color change of the strip that is visible to naked eye within 15-20 minutes because of reaction with proteins that are specific for cervical cancer.

Using proteomics and bioinformatics, researchers have identified valosin-containing protein (VCP) that are expressed differentially between normal specimens and those with cervical intra-epithelial neoplasia grade 2/3 (CIN2/CIN3+) or worse.

VCP-specific immunohistochemical staining (validated by a point-of-care technology) provided sensitive (93%) and specific (88%) identification of CIN2/CIN3+ and may serve as a critical biomarker for cervical-cancer screening.

The paper was published earlier in April 2016 in Journal of Oncotarget .

Combining proteomics and lateral-flow immunochromatography (LFIC) technology the researchers have formulated a simple point of care test for cervical cancer screening that can be used in low- and middle-income countries (LMICs).

Pap cytology followed by further evaluation using HPV DNA/ colposcopy and biopsy for abnormal cytology test is the current screening test for detecting cervical cancer. This multistep process that depends on recall system is not sustainable in LMICs.

About 84% of cervical cancer cases occur in low- and middle-income countries, where it is still diagnosed at very late stage leading to high morbidity and mortality according to the World Cancer Research Fund International.

Researchers have already documented the proof of concept are working on the early prototype for the technology, and improving sensitivity and specificity.

“We’re working to greatly improve the detection limit of our testing,” said Wen Ren, a Purdue postdoctoral researcher working with Irudayaraj. “That will make it much easier to detect cervical cancer based on a very low amount of markers in smaller samples.”

Additional work is also underway to develop the test for additional samples like cervical lavage specimens, PreservCyt specimens and cervical swabs.

Larger studies are needed for robust clinical validation and commercialization of the test.

The technology could be of use to detect other diseases in future including pathogens of infectious disease.

FDA approves Roche’s COBAS HPV Test for use with SurePath Preservative Fluid.

  

The SurePath kit for collecting and transporting the cervical specimens.  

Clinical pearls:

• HPV testing can now be performed on samples collected for liquid based pap test in the BD SurePath preservation fluid using the SurePath vial. 
• Before the approval, healthcare providers have to collect two different samples in two different collecting fluids according to the specification of the testing labs.
• It is not approved as a first line primary screening test.

The U.S. FDA today approved the Roche COBAS test as the first test for Human Papilloma Virus(HPV) from cervical samples collected for Pap Test in BD SurePath Preservative fluid.[1]

COBAS HPV test is a qualitative in vitro test for the detection of Human Papillomavirus in patient specimens. The test utilizes amplification of target DNA by the Polymerase Chain Reaction (PCR) and nucleic acid hybridization for the detection of 14 high-risk (HR) HPV types in a single analysis.

BD SurePath is a liquid based pap test and the test pack includes collection kit, along with storage and transportation components with a vial of preservative liquid.

Some other properties of BD SurePath liquid-based Pap test are ease of transportation, have less than 24% Ethanol which results in immediate and complete cell fixation, preserving the morphology. It also has the ability to preserve the sample for 4 weeks at room temperature, 6 weeks refrigerated.[2]    

The kit comes with specific instructions on how to collect samples to minimize the risks of false negative results.

Till date FDA has not approved any HPV test that can be used with the preservation liquids. Healthcare providers have to collect two different samples, in two different collecting fluids before the announcement was made.

Now, a single sample collected can be used for carrying out both the tests. The test has been approved in women 21 years and more, and helps to determine additional follow-up and diagnostic procedures after ASC-US (Atypical Squamous Cells of Undetermined Significance) Pap cytology results. It has also been approved for use is patients 30 years and older as a primary screening test for HPV along with pap cytology. It detects 14 high-risk HPV types, including HPV 16 and 18, which are responsible for causing 70% of cervical cancer worldwide.

According to the National Cancer Institute, there will be an estimated 12,990 new cases and 4,120 deaths from cervical cancer in the United States during 2016.[3]

"Many labs have a preference in how samples are collected for processing, and this additional approval gives them another clinically validated option for the Cobas HPV test," Uwe Oberlaender, head of Roche Molecular Diagnostics, said in a statement.

---

[1] http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm510251.htm

[2] http://www.bd.com/tripath/products/outside_us/outside_us_sp.asp

[3] http://www.cancer.gov/types/cervical/hp