Posts Tagged ‘Cancer research’

New Type of Killer T-Cell

Reporter: Irina Robu, PhD

Scientists at Cardiff University have revealed a new type of killer T-cell which offers hope of a “one-size-fits-all” cancer therapy. Cancer-targeting via MR1-restricted T-cells is a thrilling new frontier, it increases the prospect of a ‘one-size-fits-all’ cancer treatment; a single type of T-cell that could be proficient of destroying numerous different types of cancers across the population.

T-cell therapies for cancer anywhere immune cells are removed, modified and returned to the patient’s blood to seek and destroy cancer cells – are the latest paradigm in cancer treatments. The most extensively-used therapy, known as CAR-T (Chimeric Antigen Receptor T-cell therapy) encompasses genetic modification of patient’s autologous T-cells to express a CAR specific for a tumor antigen, subsequent by ex vivo cell expansion and re-infusion back to the patient. The therapy is personalized to each patient, but targets only a few types of cancers.

Currently, Cardiff academics discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognizes and kills most human cancer types, while ignoring healthy cells. This new TCR distinguishes when a molecule is present on the surface of a wide range of cancer cells and is able to distinguish between cancerous and healthy cells. Normal T-cells scans the surface of other cells to find anomalies and eliminate cancerous cells, yet ignores cells that contain only normal proteins.

The researchers at Cardiff was published in Nature Immunology, labels a unique TCR that can identify various types of cancer via a single HLA-like molecule called MR1 which varies in the human population. HLA differs extensively between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people. To investigate the therapeutic potential of these cells in vivo, the investigators injected T-cells able to identify MR1 into mice bearing human cancer and with a human immune system.

The Cardiff group were able to demonstrate that T-cells of melanoma patients modified to express this new TCR could destroy not only the patient’s own cancer cells, but also other patients’ cancer cells in the laboratory, irrespective of the patient’s HLA type. Experiments are under way to regulate the exact molecular mechanism by which the new TCR differentiates between healthy cells and cancer.




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#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

Reporter: Gail S. Thornton


News announced during the 37th J.P. Morgan Healthcare Conference (#JPM19): Drugmaker Eli Lilly and Company announced its plans to acquire Loxo for $8 billion, as part of its oncology strategy, which focuses  “opportunities for first-in-class and best-in-class therapies.”   


Please read their press release below.

INDIANAPOLIS and STAMFORD, Conn.Jan. 7, 2019 /PRNewswire/ —

  • Acquisition will broaden the scope of Lilly’s oncology portfolio into precision medicines through the addition of a marketed therapy and a pipeline of highly selective potential medicines for patients with genomically defined cancers.
  • Loxo Oncology’s pipeline includes LOXO-292, an oral RET inhibitor being studied across multiple tumor types, which recently was granted Breakthrough Therapy designation by the FDA and could launch in 2020.
  • Loxo Oncology’s Vitrakvi® (larotrectinib) is an oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the FDA.
  • Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of$235.00 per share in cash, or approximately $8.0 billion.
  • Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST.

Eli Lilly and Company (NYSE: LLY) and Loxo Oncology, Inc. (NASDAQ: LOXO) today announced a definitive agreement for Lilly to acquire Loxo Oncology for $235.00 per share in cash, or approximately $8.0 billion. Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers.

The acquisition would be the largest and latest in a series of transactions Lilly has conducted to broaden its cancer treatment efforts with externally sourced opportunities for first-in-class and best-in-class therapies. Loxo Oncology is developing a pipeline of targeted medicines focused on cancers that are uniquely dependent on single gene abnormalities that can be detected by genomic testing.  For patients with cancers that harbor these genomic alterations, a targeted medicine could have the potential to treat the cancer with dramatic effect.

Loxo Oncology has a promising portfolio of approved and investigational medicines, including:

  • LOXO-292, a first-in-class oral RET inhibitor that has been granted Breakthrough Therapy designation by the FDA for three indications, with an initial potential launch in 2020.  LOXO-292 targets cancers with alterations to the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types, including certain lung and thyroid cancers as well as a subset of other cancers.
  • LOXO-305, an oral BTK inhibitor currently in Phase 1/2. LOXO-305 targets cancers with alterations to the Bruton’s tyrosine kinase (BTK), and is designed to address acquired resistance to currently available BTK inhibitors. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas.
  • Vitrakvi, a first-in-class oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the U.S. Food and Drug Administration (FDA). Vitrakvi is the first treatment that targets a specific genetic abnormality to receive a tumor-agnostic indication at the time of initial FDA approval.
  • LOXO-195, a follow-on TRK inhibitor also being studied by Loxo Oncology and Bayer for acquired resistance to TRK inhibition, with a potential launch in 2022.

“Using tailored medicines to target key tumor dependencies offers an increasingly robust approach to cancer treatment,” said Daniel Skovronsky, M.D., Ph.D., Lilly’s chief scientific officer and president of Lilly Research Laboratories. “Loxo Oncology’s portfolio of RET, BTK and TRK inhibitors targeted specifically to patients with mutations or fusions in these genes, in combination with advanced diagnostics that allow us to know exactly which patients may benefit, creates new opportunities to improve the lives of people with advanced cancer.”

“We are gratified that Lilly has recognized our contributions to the field of precision medicine and are excited to see our pipeline benefit from the resources and global reach of the Lilly organization,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “Tumor genomic profiling is becoming standard-of-care, and it will be critical to continue innovating against new targets, while anticipating mechanisms of resistance to available therapies, so that patients with advanced cancer have the chance to live longer and better lives.”

“Lilly Oncology is committed to developing innovative, breakthrough medicines that will make a meaningful difference for people with cancer and help them live longer, healthier lives,” said Anne White, president of Lilly Oncology. “The acquisition of Loxo Oncology represents an exciting and immediate opportunity to expand the breadth of our portfolio into precision medicines and target cancers that are caused by specific gene abnormalities. The ability to target tumor dependencies in these populations is a key part of our Lilly Oncology strategy. We look forward to continuing to advance the pioneering scientific innovation begun by Loxo Oncology.”

“We are excited to have reached this agreement with a team that shares our commitment to ensuring that emerging translational science reaches patients in need,” said Jacob Van Naarden, chief operating officer of Loxo Oncology. “We are confident that the work we have started, which includes an FDA approved drug, and a pipeline spanning from Phase 2 to discovery, will continue to thrive in Lilly’s hands.”

Under the terms of the agreement, Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of $235.00 per share in cash, or approximately $8.0 billion. The transaction is not subject to any financing condition and is expected to close by the end of the first quarter of 2019, subject to customary closing conditions, including receipt of required regulatory approvals and the tender of a majority of the outstanding shares of Loxo Oncology’s common stock. Following the successful closing of the tender offer, Lilly will acquire any shares of Loxo Oncology that are not tendered into the tender offer through a second-step merger at the tender offer price.

The tender offer represents a premium of approximately 68 percent to Loxo Oncology’s closing stock price on January 4, 2019, the last trading day before the announcement of the transaction. Loxo Oncology’s board recommends that Loxo Oncology’s shareholders tender their shares in the tender offer.  Additionally, a Loxo Oncology shareholder, beneficially owning approximately 6.6 percent of Loxo Oncology’s outstanding common stock, has agreed to tender its shares in the tender offer.

This transaction will be reflected in Lilly’s financial results and financial guidance according to Generally Accepted Accounting Principles (GAAP). Lilly will provide an update to its 2019 financial guidance, including the expected impact from the acquisition of Loxo Oncology, as part of its fourth-quarter and full-year 2018 financial results announcement on February 13, 2019.

For Lilly, Deutsche Bank is acting as the exclusive financial advisor and Weil, Gotshal & Manges LLP is acting as legal advisor in this transaction. For Loxo Oncology, Goldman Sachs & Co. LLC is acting as exclusive financial advisor and Fenwick & West LLP is acting as legal advisor.

Conference Call and Webcast
Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST to discuss the acquisition of Loxo Oncology.  Investors, media and the general public can access a live webcast of the conference call through the Webcasts & Presentations link that will be posted on Lilly’s website at www.lilly.com.  The webcast of the conference call will be available for replay through February 7, 2019.

About LOXO-292
LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. LOXO-292 has been granted Breakthrough Therapy Designation by the U.S. FDA for three indications, and could launch as early as 2020.

About LOXO-305
LOXO-305 is an investigational, highly selective non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma.

About Vitrakvi® (larotrectinib)
Vitrakvi is an oral TRK inhibitor for the treatment of adult and pediatric patients with solid tumors with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

About LOXO-195
LOXO-195 is a selective TRK inhibitor that is being investigated to address potential mechanisms of acquired resistance that may emerge in patients receiving Vitrakvi® (larotrectinib) or other multikinase inhibitors with anti-TRK activity.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and www.lilly.com/newsroom/social-channels. C-LLY

About Loxo Oncology
Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers. Our pipeline focuses on cancers that are uniquely dependent on single gene abnormalities, such that a single drug has the potential to treat the cancer with dramatic effect. We believe that the most selective, purpose-built medicines have the highest probability of maximally inhibiting the intended target, with the intention of delivering best-in-class disease control and safety. Our management team seeks out experienced industry partners, world-class scientific advisors and innovative clinical-regulatory approaches to deliver new cancer therapies to patients as quickly and efficiently as possible. For more information, please visit the company’s website at http://www.loxooncology.com.

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements about the benefits of Lilly’s acquisition of Loxo Oncology, Inc. (“Loxo Oncology”). It reflects Lillys current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in implementing the transaction and in drug developmentAmong other things, there can be no guarantee that the transaction will be completed in the anticipated timeframe, or at all, or that the conditions required to complete the transaction will be met, that Lilly will realize the expected benefits of the transaction, that the molecules will be approved on the anticipated timeline or at all, or that the potential products will be commercially successful. For further discussion of these and other risks and uncertainties, see Lillys most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission (“the SEC”). Lilly will provide an update to certain elements of its 2019 financial guidance as part of its fourth quarter and full-year 2018 financial results announcement. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

Loxo Oncology Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” relating to the acquisition of Loxo Oncology by Lilly. Such forward-looking statements include the ability of Loxo Oncology and Lilly to complete the transactions contemplated by the merger agreement, including the parties’ ability to satisfy the conditions to the consummation of the offer and the other conditions set forth in the merger agreement and the possibility of any termination of the merger agreement, as well as the role of targeted genomics and diagnostics in oncology treatment and acceleration of our work in developing medicines. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. Actual results may differ materially from current expectations because of risks associated with uncertainties as to the timing of the offer and the subsequent merger; uncertainties as to how many of Loxo Oncology’s stockholders will tender their shares in the offer; the risk that competing offers or acquisition proposals will be made; the possibility that various conditions to the consummation of the offer or the merger may not be satisfied or waived; the effects of disruption from the transactions contemplated by the merger agreement on Loxo Oncology’s business and the fact that the announcement and pendency of the transactions may make it more difficult to establish or maintain relationships with employees, suppliers and other business partners; the risk that stockholder litigation in connection with the offer or the merger may result in significant costs of defense, indemnification and liability; other uncertainties pertaining to the business of Loxo Oncology, including those set forth in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of Loxo Oncology’s Annual Report on Form 10-K for the year ended December 31, 2017, which is on file with the SEC and available on the SEC’s website at www.sec.gov. Additional factors may be set forth in those sections of Loxo Oncology’s Quarterly Report on Form 10-Q for the quarter endedSeptember 30, 2018, filed with the SEC in the fourth quarter of 2018.  In addition to the risks described above and in Loxo Oncology’s other filings with the SEC, other unknown or unpredictable factors could also affect Loxo Oncology’s results. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. The information contained in this press release is provided only as of the date of this report, and Loxo Oncology undertakes no obligation to update any forward-looking statements either contained in or incorporated by reference into this report on account of new information, future events, or otherwise, except as required by law.

Additional Information about the Acquisition and Where to Find It

The tender offer for the outstanding shares of Loxo Oncology referenced in this communication has not yet commenced. This announcement is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell shares of Loxo Oncology, nor is it a substitute for the tender offer materials that Lilly and its acquisition subsidiary will file with the SEC upon commencement of the tender offer. At the time the tender offer is commenced, Lilly and its acquisition subsidiary will file tender offer materials on Schedule TO, and Loxo Oncology will file a Solicitation/Recommendation Statement on Schedule 14D-9 with the SEC with respect to the tender offer. THE TENDER OFFER MATERIALS (INCLUDING AN OFFER TO PURCHASE, A RELATED LETTER OF TRANSMITTAL AND CERTAIN OTHER TENDER OFFER DOCUMENTS) AND THE SOLICITATION/RECOMMENDATION STATEMENT WILL CONTAIN IMPORTANT INFORMATION. HOLDERS OF SHARES OF LOXO ONCOLOGY ARE URGED TO READ THESE DOCUMENTS CAREFULLY WHEN THEY BECOME AVAILABLE (AS EACH MAY BE AMENDED OR SUPPLEMENTED FROM TIME TO TIME) BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION THAT HOLDERS OF LOXO ONCOLOGY SECURITIES SHOULD CONSIDER BEFORE MAKING ANY DECISION REGARDING TENDERING THEIR SECURITIES. The Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, will be made available to all holders of shares of Loxo Oncology at no expense to them. The tender offer materials and the Solicitation/Recommendation Statement will be made available for free at the SEC’s web site at www.sec.gov

In addition to the Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, Lilly and Loxo Oncology file annual, quarterly and special reports and other information with the SEC.  You may read and copy any reports or other information filed by Lilly or Loxo Oncology at the SEC public reference room at 100 F Street, N.E., Washington, D.C. 20549. Please call the Commission at 1-800-SEC-0330 for further information on the public reference room.  Lilly’s and Loxo Oncology’s filings with the SEC are also available to the public from commercial document-retrieval services and at the website maintained by the SEC at www.sec.gov.


Eli Lilly and Company – https://www.lilly.com

Other related articles published in this Open Access Online Scientific Journal include the following:


FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)



Pioneers of Cancer Cell Therapy:  Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors



Personalized Medicine – The California Initiative



Volume One: Genomics Orientations for Personalized Medicine


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Innovation + Technology = Good Patient Experience

Reporter: Gail S. Thornton


Following are a sampling of several relevant articles comprising health innovation and technology, which may ultimately lead to a good patient experience. 

When a health journalist found out her 4-year-old son had a brain tumor, her family faced an urgent choice: proven but punishing rounds of chemotherapy, or a twice-a-day pill of a new “targeted” therapy with a scant track record.




Paying for Tumor Testing

A recent U.S. government decision about coverage of tumor sequencing could affect cancer patients.




Dr. Elaine Schattner has authored numerous articles on cancer — as a doctor and patient. She is a freelance journalist and former oncologist who lives in New York City. She is writing a book about public attitudes toward cancer.

A life-long patient with scoliosis and other chronic medical conditions, and a history of breast cancer, Elaine’s current interests include physicians’ health, cancer, and medical journalism.




Speaking Up for Patient Preferences in Cancer Treatment Decisions.

Informed consent should include your input.




Breast Cancer, Risk And Women’s Imperfect Choices




A cancer researchers takes cancer personally: Dr. Tony Blau, who started All4Cure, an online platform for myeloma clinicians and researchers to interact directly with patients to come up with a customer treatment plan.



Julia Louis-Dreyfus Acts Out: The actress on challenging comedy’s sexism, fighting cancer, and becoming the star of her own show.




Thanks to Wendy Lund, CEO of GCI Health (gcihealth.com)  and her team for compiling part of this list. 

Interoperability, patient matching could be fixed by smartphone apps, RAND says: Patients need quality information. A physician at George Washington University School of Medicine and Health Sciences believes that the healthcare community must improve reports by making them more accessible to patients.




Sometimes Patients Simply Need Other Patients: Finding a support community is also getting easier, through resources like the Database of Patients’ Experiences, which houses videos of patients speaking about their experiences



At These Hotels and Spas, Cancer is No Obstacle to Quality Care: A trend among spas and wellness resorts shows the increasing integration of safe wellness treatment options for cancer patients.





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The National Cancer Research Institute (NCRI) identified top 10 research priorities for people living with cancer to consider to improve treatment and quality of life. 

Reporter: Gail S. Thornton

By 2030 four million people in the UK will be living with the long-term consequences of cancer, but currently there is very little research on the problems they face and how these can be tackled. To help them live better lives, more focused research is needed.

To determine priorities for research that will help people live better with and beyond cancer, NCRI partnered with the James Lind Alliance on a Priority Setting Partnership. The two-year project involved two UK-wide surveys which attracted more than 3500 responses from patients, carers, and health and social care professionals. From these, we identified 26 key questions and distilled these down to 10 top research priorities.

This is the first time that clear research priorities have been identified in this area.

Questions 1 – 10 Questions 11 – 26




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GE Healthcare has acquired Biosafe Group SA, a supplier of Integrated Cell Bioprocessing Systems for Cell Therapy and Regenerative Medicine Industry

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Researchers of University of Texas at San Antonio, USA, have developed a new, non-invasive method which can kill cancer cells in two hours, an advance that may significantly help people with inoperable or hard-to-reach tumours, as well as young children stricken with the deadly disease.


The method involves injecting a chemical compound, nitrobenzaldehyde, into the tumour and allowing it to diffuse into the tissue. A beam of light is then aimed at the tissue, causing the cells to become very acidic inside and, essentially, commit suicide. Within two hours, up to 95 per cent of the targeted cancer cells are estimated to be dead.


The method was tested against triple negative breast cancer, one of the most aggressive types of cancer and one of the hardest to treat. The prognosis for triple negative breast cancer is usually very poor. One treatment in the laboratory was able to stop the tumour from growing and doubled the chances of survival in the mice.


According to the researchers all forms of cancer attempt to make cells acidic on the outside and attract the attention of blood vessels as an attempt to get rid of the acid. But, instead, the cancer cells latches onto the blood vessel and uses it to make the tumour grow bigger.


Chemotherapy treatments target all cells in the body, and certain chemotherapeutics try to keep cancer cells acidic as a way to kill the cancer. This is what causes many cancer patients to lose their hair and become weak. This method however, is more precise and can target just the tumour.


This research is presently extended on drug-resistant cancer cells to make this therapy as strong as possible. The researchers also started to develop a nanoparticle that can be injected into the body to target metastasised cancer cells. The nanoparticle is activated with a wavelength of light which can pass harmlessly through skin, flesh and bone and still activate the nanoparticle.


This non-invasive method will help cancer patients with tumours in areas that have proven problematic for surgeons, such as the brain stem, aorta or spine. It could also help people who have received the maximum amount of radiation treatment and can no longer cope with the scarring and pain that goes along with it, or children who are at risk of developing mutations from radiation as they grow older.



































Nuha Buchanan Kadri, Matthew Gdovin, Nizar Alyassin, Justin Avila, Aryana Cruz, Louis Cruz, Steve Holliday, Zachary Jordan, Cameron Ruiz and Jennifer Watts. Photodynamic acidification therapy to reduce triple negative breast cancer growth in vivo. Journal of Clinical Oncology, Vol 34, No 15_suppl (May 20 Supplement), 2016: e12574.


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Cancer initiatives

Larry H. Bernstein, MD, FCAP, Curator



Updated 4/12/2019

AACR 2016: Biden Calls for Overhauling Cancer Research Incentives



The first priority cited by the vice president was data sharing. Biden defended the concept as essential to advancing the process of cancer research and countered a January 21 New England Journal of Medicine editorial in which editor-in-chief Jeffrey Drazen, M.D., contended that data sharing could breed data “parasites.”

Four days later, Dr. Drazen clarified NEJM’s position by adding that with “appropriate systems” in place, “we will require a commitment from authors to make available the data that underlie the reported results of their work within 6 months after we publish them.”

Other priorities Biden said should serve as the basis of new incentives:

  • Involve patients in clinical trial design—Raising awareness of trials, and allowing patients to participate in how they are designed and conducted, could help address the difficulty of recruiting patients for studies. Only 4% of cancer patients are involved in a trial, he said.
  • “Let scientists do science”—Biden contrasted unfavorably NIH’s roughly 1-year process for decisions on grants to that of the Prostate Cancer Foundation, which limits grant applications to 10 pages and decides on those funding requests within 30 days: “Why is it that it takes multiple submissions and more than a year to get an answer from us?” Biden said.
  • Encourage grants from younger researchers—Biden decried the current professional system under which younger researchers are sidetracked for years doing administrative work in labs before they can pursue their own research grants: “It’s like asking Derek Jeter to take several years off to sell bonds to build Yankee Stadium,” the VP quipped.
  • Measure progress by outcomes—Rather than the quantity of research papers generated by grants, Biden said, “what you propose and how it affects patients, it seems to me, should be the basis of whether you continue to get the grant.”
  • Promote open-access publication of results—Biden criticized academic publishing’s reliance on paid-subscription journals that block content behind paywalls and which own data for up to a year. He contrasted that system with the Bill and Melinda Gates Foundation’s stipulation that the research it funds be published in an open-access journal and be freely available once published.
  • Reward verification—Research that verifies results through replication should be encouraged, Biden said, which acknowledging that few people now get such funding.

Biden recalled how following Beau’s diagnosis with cancer, he and his wife Jill Biden, Ed.D., who introduced the VP at the AACR event, “had access to the best doctors in the world.”

“The more we talked to them, the more we understood that we are on the cusp of a real inflection point in the fight against cancer.”

Updated 4/12/2019

Pediatric Cancer Initiatives

Data Sharing for Pediatric Cancers: President Trump Announces Pledge to Fight Childhood Cancer Will Involve Genomic Data Sharing Effort

In the journal Science, Drs. Olena Morozova Vaske ( and David Haussler University of California, Santa Cruz) recently wrote an editorial entitled “Data Sharing for Pediatric Cancers“, in which they discuss the implications of President Trump’s intentions to increase funding for pediatric cancers with a corresponding effort for genomic data sharing.  Also discussed is the current efforts on pediatric genomic data sharing as well as some opinions on coordinating these efforts on a world-wide scale to benefit the patients, researchers, and clinicians.

The article is found below as it is a very good read on the state of data sharing in the pediatric cancer field and offers some very good insights in designing such a worldwide system to handle this data sharing, including allowing patients governance over their own data.

Last month, in a conference call held by the U.S. Department of Health and Human Services and National Institutes of Health (NIH), it was revealed that a large focus of President Trump’s pledge to fund childhood cancer research will be genomic data sharing. Although the United States has only 5% of the world’s pediatric cancer cases, it has disproportionately more resources and access to genomic information compared to low-income countries. We hope that the spotlight on genomic data sharing in the United States will galvanize the world’s pediatric cancer community to elevate genomic data sharing to a level where its full potential can finally be realized.

Pediatric cancers are rare, affecting 50 to 200 children per million a year worldwide. Thus, with 16 different major types and many subtypes, no cancer center encounters large cohorts of patients with the same diagnosis. To advance their understanding of particular cancer subtypes, pediatric oncologists must have access to data from similar cases at other centers. Because subtypes of pediatric cancer are rare, assembling large cohorts is a limiting factor in clinical trials as well. Here, too, data sharing is the first critical step.

Typically, pediatric cancers don’t have the number of mutations that make immunotherapies effective, and only a few subtypes have recurrent mutations that can be used to develop gene-targeted therapies. However, the abnormal expression level of genes gives a vivid picture of genetic misregulation, and just sharing this information would be a huge step forward. Using gene expression and mutation data, analysis of genetic misregulation in different pediatric cancer subtypes could point the way to new treatments.

A major challenge in genomic data sharing is the patient’s young age, which frequently precludes an opportunity for informed consent. Compounding this, the rarity of subtypes requires the aggregation of patients from multiple jurisdictions, raising barriers to assembling large representative data sets. A greater percentage of children than adults with cancer participate in research studies, and children often participate in multiple studies. However, this means that data collected on individual children may be found at multiple institutions, creating difficulties if there are no standards for data sharing.

To enable effective sharing of genomic and clinical data, the Global Alliance for Genomics and Health has developed the Key Implications for Data Sharing (KIDS) framework for pediatric genomics. The recommendations include involving children in the data-sharing decision-making process and imposing an ethical obligation on data generators to provide children and parents with the opportunity to share genomic and clinical information with researchers. Although KIDS guidelines are not legally binding, they could inform policy development worldwide.

To advance the sharing culture, along with the NIH, pediatric cancer foundations such as the St. Baldrick’s Foundation and Alex’s Lemonade Stand Foundation have incorporated genomic data-sharing requirements into their grants processes. Researchers and clinicians around the world have created dozens of pediatric cancer genomic databases and portals, but pulling these together into a larger network is problematic, especially for patients with data at more than one institution, as patient identifiers are stripped from shared data. However, initiatives like the Children’s Oncology Group’s Project Every Child and the European Network for Cancer Research in Children and Adolescents’ Unified Patient Identity may resolve this issue.

We urge the creators of pediatric cancer genomic resources to collaborate and build a real-time federated data-sharing system, and hope that the new U.S. initiative will inspire other countries to link databases rather than just create new siloed regional resources. The great advances in information technology and life sciences in the last decades have given us a new opportunity to save our children from the scourge of cancer. We must resolve to use them.

Source: Olena Morozova Vaske and David Haussler.  Science; 363(6432): 1125 (2019). Data sharing for pediatric cancers. 

NIH-NCI Initiative: International collaboration to create new cancer models to accelerate research

LIVE 1:45 pm – 3:10 pm 4/25/2016 Forum Opening, A War or Moonshot: Where Do We Stand? Creating a Disruptive Cancer Pipeline @2016 World Medical Innovation Forum: CANCER, April 25-27, 2016, Westin Hotel, Boston

Will President Obama’ s Cancer Immunotherapy Colloquium (dubbed Moonshot) mean Government is Fully Behind the War on Cancer or have we heard this before?

Exome Aggregation Consortium (ExAC), generated the largest catalogue so far of variation in human protein-coding regions: Sequence data of 60,000 people, NOW is a publicly accessible database

Healthcare conglomeration to access Big Data and lower costs


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Observations on Human Papilloma Virus and Cancer

Curator: Demet Sag, PhD, CRA, GCP 


What is Human Papilloma Virus?

 HPV 220px-HPV-16_genome_organization

Human papillomavirus

Taxonomy ID: 10566
Inherited blast name: viruses
Rank: species
Genetic code: Translation table 1 (Standard)
Host: vertebrates| human
Other names:

synonym: human papillomavirus HPV
synonym: Human Papilloma Virus

Lineage( full )

VirusesdsDNA viruses, no RNA stagePapillomaviridaeunclassified PapillomaviridaeHuman papillomavirus types

   Entrez records   
Database name Subtree links Direct links
Nucleotide 7,782 7,775
Protein 2,611 2,604
Structure 3 3
Genome 1 1
Popset 34 34
PubMed Central 4,742 4,742
Gene 21 21
SRA Experiments 43 43
Probe 12 12
Assembly 1 1
Bio Project 6 6
Bio Sample 53 53
PubChem BioAssay 5 5
Taxonomy 8 1
Human papillomavirus
Specialty Infectious diseasegynecologyHPV_

WHO_RHR_08.14_eng-Cervical cancer, human papillomavirus (HPV), and HPV vaccinesWHO= papilloma virus info

ICD10 B97.7
ICD9-CM 078.1 079.4
DiseasesDB 6032
eMedicine med/1037
MeSH D030361

ICTV homepage

WHO= papilloma virus info

WHO_RHR_08.14_eng-Cervical cancer, human papillomavirus (HPV), and HPV vaccines

Why is it related to Human Cancer?

 Since its first presumed diagnosis in women by an Italian Physician back in 1800s many developments took place to identify the real causative agents (PMID:19135222). Especially in 1970s the full discovery and relation between HPV and cancer established. Human papilloma virus (HPV)  is the second common cancer death in women, although HPV vaccines helped to decrease the morbidity rate there are complications due to vaccines.  Still there is an increase with cervical cancer estimated to be  490,000.

CDC also provided simple information for public on HPV since there is a misunderstanding that some people think it is like herpes or HIV viruses.  Yet, pathology is much different and changes based on age since younger women or girls can fight off but after age 30 predisposition of HPV as a cancer increases. (http://www.cdc.gov/cancer/hpv/pdf/HPV_Testing_2012_English.pdf)

Cervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide1,2. The etiological role of infection with high-risk human papilloma viruses (HPV) in cervical carcinomas is well established.


  Relationship of mutational spectrum and rates with clinicopathological characteristics in cervical carcinoma presented 



Relationship of mutational spectrum and rates with clinicopathological characteristics in cervical carcinoma presented at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161954/bin/nihms610939f1.jpg

All panels are aligned with vertical tracks representing 115 individuals. The data is sorted in order by histology (middle panel) and total mutational rate (top panel). The relative frequencies of nucleotide mutations occurring at cytosines preceeded by thymines (Tp*C) or at cytosines followed by guanines (*CpG) sites are depicted in red and orange respectively, on the second panel. The bottom heatmap shows the distribution of mutations in significantly mutated genes (q<0.1) in squamous cell carcinomas and adenocarcinomas in the order listed in the following Table, TP53ERBB2 and KRAS were significant recurrence (q<0.1) among cancer driver genes reported in COSMIC.

Nature. Author manuscript; available in PMC 2014 Sep 12.  Published in final edited form as: Nature. 2014 Feb 20; 506(7488): 371–375.

Genes with Significantly Recurrent Somatic Mutations in Cervical Carcinomas

Gene Description Nonsilent mutations Relative frequency Patients Unique sites Silent mutations Indel + null q
FBXW7** F-box and WD repeat domain containing 7 12 15% 12 8 0 2 4.03E-12
PIK3CA phosphoinositide-3-kinase, catalytic, alpha polypeptide 11 14% 10 5 0 1 <9.08e-12
MAPK1** mitogen-activated protein kinase 1 6 8% 6 3 0 0 0.000671
HLA-B+ major histocompatibility complex, class I, B 7 9% 6 7 1 3 0.00169
STK11 serine/threonine kinase 11 3 4% 2 2 0 1 0.012
EP300+ E1A binding protein p300 13 16% 12 13 1 4 0.0354
NFE2L2+ nuclear factor (erythroid-derived 2)-like 2 3 4% 3 2 0 0 0.0597
PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1) 5 6% 5 5 0 3 0.0693
ELF3* E74-like factor 3 (ets domain transcription factor, epithelial-specific) 3 13% 3 3 0 3 0.03
CBFB* core-binding factor, beta subunit 2 8% 2 2 0 1 0.0342

Indel: insertions or deletions;

Null: nonsense, frameshft or splice-site mutations;

q: q value, false discovery rate (Benjamini-Hochberg procedure).

**Genes with mutations observed in only squamous cell carcinomas

*Genes with mutations observed in only adenocarcinomas

+Genes with a majority of mutations occurring in squamous cell carcinomas.

Following figure (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161954/bin/nihms610939f2.jpg)

  Novel recurrent somatic mutations in cervical carcinoma

Novel recurrent somatic mutations in cervical carcinoma

The locations of somatic mutations in novel significantly mutated genes in 115 cervical carcinoma, FBXW7, MAPK1HLA-BEP300NFE2L2 and ELF3 are shown in the context of protein domain models derived from UniProt and Pfam annotations. Numbers refer to amino acid residues. Each filled circle represents an individual mutated tumor sample: missense and silent mutations are represented by filled black and grey circles, respectively while nonsense, frameshift, and splice site mutations are represented by filled red circles and red text. Domains are depicted with various colors with an appropriate key located on the right hand of each domain model.

 Relationships between HPV integration, copy number amplifications and gene expression in cervical carcinoma


Relationships between HPV integration, copy number amplifications and gene expression in cervical carcinoma

Panel (a) shows comparative histograms of true and simulated genomic distances between HPV integration sites and the nearest copy number amplification (log segmean difference >0.5). Panel (b) shows boxplots of gene expression levels across 79 cervical tumors for 41 genes with chimeric human-HPV read pairs. The expression levels for tumors with HPV integration in the respective genes are highlighted in red circles. Panel (c) shows scatter plots comparing copy number alterations and gene expression levels across 79 tumors in selected integration site genes. The red circles represent data for the tumors with HPV integration events involving the respective genes.


Table. Diseases Associated With Specific HPV Types (e-Medicine)

Nongenital Cutaneous Disease HPV Type
Common warts (verrucae vulgaris) 1, 2, 4, 26, 27, 29, 41, 57, 65, 75-78
Plantar warts (myrmecias) 1, 2, 4, 60, 63
Flat warts (verrucae planae) 3, 10, 27, 28, 38, 41, 49
Butcher’s warts (common warts of people who handle meat, poultry, and fish) 1-4, 7, 10, 28
Mosaic warts 2, 27, 57
Ungual squamous cell carcinoma 16
Epidermodysplasia verruciformis (benign) 2, 3, 10, 12, 15, 19, 36, 46, 47, 50
Epidermodysplasia verruciformis (malignant or benign) 5, 8-10, 14, 17, 20-25, 37, 38
Nonwarty skin lesions 37, 38
Nongenital Mucosal Disease HPV Type
Respiratory papillomatosis 6, 11
Squamous cell carcinoma of the lung 6, 11, 16, 18
Laryngeal papilloma (recurrent respiratory papillomatosis)[17] 2, 6, 11, 16, 30, 40, 57
Laryngeal carcinoma 6, 11
Maxillary sinus papilloma 57
Squamous cell carcinoma of the sinuses 16, 18
Conjunctival papillomas 6, 11
Conjunctival carcinoma 16
Oral focal epithelial hyperplasia (Heck disease) 13, 32
Oral carcinoma 16, 18
Oral leukoplakia 16, 18
Squamous cell carcinoma of the esophagus 16, 18
Anogenital Disease HPV Type
Condylomata acuminata 1-6, 10, 11, 16, 18, 30, 31, 33, 35, 39-45, 51-59, 70, 83
Bowenoid papulosis 16, 18, 34, 39, 40, 42, 45
Bowen disease 16, 18, 31, 34
Giant condylomata (Buschke-Löwenstein tumors) 6, 11, 57, 72, 73
Unspecified intraepithelial neoplasia 30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66-69
Low-grade squamous intraepithelial lesions (LGSIL) 6, 11, 16, 18, 26, 27, 30, 31, 33-35, 40, 42-45, 51-58, 61, 62, 67-69, 71-74, 79, 81-84
High-grade squamous intraepithelial lesions (HGSIL) 6, 11, 16, 18, 31, 33, 35, 39, 42, 44, 45, 51, 52, 56, 58, 59, 61, 64, 66, 68, 82
Carcinoma of vulva 6, 11, 16, 18
Carcinoma of vagina 16
Carcinoma of cervix[18, 19] 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 70, 73, 82
Carcinoma of anus 16, 31, 32, 33
Carcinoma in situ of penis (erythroplasia of Queyrat) 16
Carcinoma of penis 16, 18


 epidemiology of HPV in the world

“Human papillomavirus (HPV) has become synonymous with cervical cancer, but its actual footprint is much bigger” said James Mitchell Crow. (PMID: 229324377  James Mitchell Crow. “HPV: The global burden”. Nature 488 S2–S3 (30 August 2012) doi:10.1038/488S2a Published online  29 August 2012).

Every year, over 27,000 women and men are affected by a cancer caused by HPV— that’s a new case every 20 minutes.

Persistent HPV infection can cause cervical and other cancers including:


Virus Diseases [C02]
   DNA Virus Infections [C02.256]

Papillomavirus Infections [C02.256.650]

Warts [C02.256.650.810]  +
Virus Diseases [C02]
   Tumor Virus Infections [C02.928]

Papillomavirus Infections [C02.928.725]



(PMID: 229324377)





In the lab few places propagating HPV. There are measures that need to be taken by the laboratory personnel. CDC as well as WHO published various articles to inform public.

Sensitivity and testing for Pap smear and HPV DNA testing in the detection of CIN2+

Test Sensitivity Specificity
Pap smear 53-55.4% 96.3-96.8%
High-risk HPV DNA testing 94.6-96.1% 90.7-94.1%
Pap smear + high-risk HPV testing 100% 92.5%

Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, Szarewski A, Birembaut P, Kulasingam S, Sasieni P, Iftner T. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer. 2006; 119(5):1095.

Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, Ratnam S, Coutlée F, Franco EL, Canadian Cervical Cancer Screening Trial Study Group.

Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer N Engl J Med. 2007;357(16):1579.

Best Pract Res Clin Obstet Gynaecol. Author manuscript; available in PMC 2013 Apr 22. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632360/)

HPV Genotyping tests1

HPV genotyping test HPV types detected
Cervista® HPV 16/18 (Hologic, Inc;
Marlborough, MA)a
HR HPV types 16 and 18
Digene HPV Genotyping PS Test (Qiagen;
Hilden, Germany)
HR HPV types 16, 18, and 45
Roche LINEAR ARRAY HPV Genotyping
Test (Roche; Basel, Switzerland)
37 LR and HR HPV types
Innogenetics INNO-LiPA HPV Genotyping
Extra (Innogenetics; Gent, Belgium)
28 LR and HR HPV types
SPF10 Line Probe Assay HPV-typing System
(Roche; Basel,
Recognizes most genital
tract HPV types
Papillocheck1 (Greiner Bio-One;
Frickenhausen Germany)
18 HR and 6 LR HPV types
RealTime High Risk HPV Assay (Abbott
Laboratories;Abbott Park, IL)
HPV types 16 and 18
HPV Genotyping LQ Test (Qiagen Inc;
Valencia, CA)
18 HR HPV types
Seeplex HPV4A ACE (Seegene; Rockville,
HPV types 16 and 18
CLART HPV 2 (Genomica; Madrid, Spain) 35 LR and HR HPV types
GenoFlow HPV Array (DiagCor; North Point,
Hong Kong)
33 LR and HR HPV types
fHPV Typing (molGENTIX; Barcelona, Spain) 15 LR and HR HPV types

HPV, human papillomavirus; HR, high-risk; LR, low-risk.

aFDA-approved test.

1Schutzbank TE, Ginocchio CC. Assessment of clinical and analytical performance characteristics of an HPV genotyping test. Diagn Cytopathol. 2011 Apr 6. doi:10.1002/dc.21661.

Most papillomas are sufficiently distinct to be clinically recognizable. Bowenoid papulosis may be mistaken for lichen planus, psoriasis, seborrheic keratoses, or condylomata acuminata.

In additions to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Acanthosis nigricans
  • Acrochordon
  • Actinic keratoses
  • Anogenital malignancy
  • Anogenital warts in children
  • Bowenoid papulosis
  • Carbon dioxide laser surgery for intraepithelial cervical neoplasms
  • Cervical polyp
  • Condyloma latum
  • Corns and calluses
  • Dermatitis papillaris
  • Endoscopic gynecologic surgery
  • Epidermodysplasia verruciformis
  • Fordyce spots
  • Hymenal remnants
  • Hypopigmentation
  • Keloid and hypertrophic scar
  • Keratoacanthoma
  • Laryngeal papillomatosis of neonates and infants
  • Malignant tumors of the mobile tongue
  • Micropapillomatosis labialis
  • Nevi
  • Pap test
  • Pityriasis versicolor
  • Psoriasis (plaque)
  • Recurrent respiratory papillomatosis
  • Seborrheic keratosis
  • Sinonasal papillomas, treatment
  • Skin tags (fibroepithelial polyps)
  • Verrucous carcinoma
  • Vestibular papillomatosis

Differential Diagnoses




1.       Immunomodulators

Class Summary

Immune response modifiers have immunomodulatory effects and are used for treatment of external anogenital warts (EGWs) or condylomata acuminata. Interferon alfa, beta, and gamma may be administered topically, systemically, and intralesionally. They stimulate production of cytokines and demonstrate strong antiviral activity.

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Imiquimod (Aldara, Zyclara)

Imiquimod is an imidazoquinolinamine derivative that has no in vitro antiviral activity but does induce macrophages to secrete cytokines such as interleukin (IL)-2 and interferon alfa and gamma. Its mechanisms of action are unknown. Imiquimod has been studied extensively and is a new therapy relative to other EGW treatments. It may be more effective in women than in men.

Imiquimod is dispensed as an individual dose. Patients are advised to wash the affected area with mild soap and water upon awakening and to remove residual drug.

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Interferon alfa-n3 (Alferon N)

Interferon alfa is a protein product either manufactured from a single-species recombinant DNA process or obtained from pooled units of donated human leukocytes that have been induced by incomplete infection with a murine virus.

The mechanisms by which interferon alfa exerts antiviral activity are not understood clearly. However, modulation of the host immune response may play an important role. This agent is indicated for intralesional treatment of refractory or recurring external condyloma acuminatum and is particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin, surgical excision, laser therapy, or cryotherapy).

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Interferon alfa-2b (Intron A)

This is a protein product manufactured by recombinant DNA technology. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.

This agent is indicated for intralesional treatment of refractory or recurring external condyloma acuminatum and is particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin, surgical excision, laser therapy, or cryotherapy).

2.       Keratolytic Agents

Class Summary

Antimitotic drugs arrest dividing cells in mitosis, resulting in the death of proliferating cells. They cause cornified epithelium to swell, soften, macerate, and then desquamate. Many of them are chemotherapeutic agents. The drugs listed below are used specifically for treatment of EGWs or condylomata acuminata.

Keratolytic agents are used to aid in removal of keratin in hyperkeratotic skin disorders, including corns, ichthyoses, common warts, flat warts, and other benign verrucae.

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Podofilox (Condylox)

Podofilox is a topical antimitotic that can be synthesized chemically or purified from the plant families Coniferae and Berberidaceae (eg, species of Juniperus and Podophyllum). It is the active agent of podophyllin resin and is available as a 0.5% solution. Treatment results in necrosis of visible wart tissue; the exact mechanism of action is unknown. Treatment should be limited to no more than 10 cm2 of wart tissue, and no more than 0.5 mL/day of solution should be given. This is a patient-applied therapy.

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Podophyllum resin (Podocon-25)

Podophyllin is derived from May apple (Podophyllum peltatum Linné) and contains the active agent podophyllotoxin, a cytotoxic substance that arrests mitosis in metaphase. American podophyllum contains one fourth the amount of podophyllotoxin that Indian podophyllum does. The potency of podophyllin varies considerably between batches. The exact mechanism of action is unknown.

Podophyllin is used as a topical treatment for benign growths, including external genital and perianal warts, papillomas, and fibroids. It results in necrosis when applied to anogenital warts. Only a trained medical professional can apply it, and it cannot be dispensed to a patient.

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Trichloroacetic acid 85% (Tri-Chlor)

Trichloroacetic acid (TCA) is a highly corrosive desiccating agent that cauterizes skin, keratin, and other tissues and is used to burn lesions. Although it is caustic, it causes less local irritation and systemic toxicity than other agents in the same class. However, response often is incomplete, and recurrence is common.

Most clinicians use 25-50% TCA, although some use concentrations as high as 85% and then neutralize with either water or bicarbonate. Tissue sloughs and subsequently heals in 7-10 days. TCA therapy is less destructive than laser surgery, electrocautery, or cryotherapy.

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Salicylic acid (Compound W, Dr. Scholl’s Clear Away Warts, Freezone)

By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin without affecting the structure of viable epidermis. It is used for removal of nongenital cutaneous warts, particularly common or plantar warts. Before application, wash the affected area. The wart may be soaked in warm water for 5 minutes. Dry the area thoroughly.

3.       Antineoplastics, Antimetabolite

Class Summary

Antimetabolites interfere with nucleic acid synthesis and inhibit cell growth and proliferation. These are topical preparations that contain the fluorinated pyrimidine 5-fluorouracil (5-FU). Although these chemotherapeutic agents are not formally approved for use against warts, some studies have demonstrated a benefit against EGWs or condylomata acuminata.

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Fluorouracil topical (Efudex, Carac, Fluoroplex)

Topical 5-FU interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid and inhibits thymidylate synthetase, which subsequently reduces cell proliferation. Its primary indication is for topical treatment of actinic keratoses. Although it is not approved by the US Food and Drug Administration (FDA) for the treatment of warts, it has been used in adults, particularly for warts resistant to other forms of treatment. It is used for management of superficial basal cell carcinomas.

The solution contains either 2% or 5% 5-FU in propylene glycol, tris (hydroxymethyl) aminomethane, hydroxypropyl cellulose, paraben, and disodium edetate. The cream contains 5% 5-FU in white petrolatum, stearyl alcohol, propylene glycol, polysorbate 60, and paraben. When topical 5-FU is applied to the lesion, the area undergoes a sequence of erythema, vesiculation, desquamation, erosion, and reepithelialization.

4.       Topical Skin Products

Class Summary

Sinecatechins is another topical product that has gained FDA approval for genital warts.

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Sinecatechins (Veregen)

Sinecatechins ointment is a botanical drug product for topical use that consists of extract from green tea leaves. It contains 15% sinecatechins and is available in 15- and 30-g tubes. Its mode of action is unknown, but it does elicit antioxidant activity in vitro. Sinecatechins ointment is indicated for topical treatment of external genital and perianal warts (condylomata acuminata) in immunocompetent patients.

5.       Vaccines, Inactivated, Viral

Class Summary

Three vaccines are available for the prevention of HPV-associated dysplasias and neoplasia, including cervical, vulvar, vaginal, and anal cancer; genital warts (condylomata acuminata); and precancerous genital lesions.

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Human papillomavirus vaccine, nonavalent (Gardasil 9)

Recombinant vaccine that targets 9 HPV types (6, 11, 16, 18, 31, 33, 45, 52, and 58). It is indicated for females aged 9-26 years to prevent cervical, vulvar, vaginal, and anal cancer. It is also indicated to prevent genital warts and dysplastic lesions (eg, cervical, vulvar, vaginal, anal).

It is also indicated for boys aged 9-15 years for prevention of anal cancer, genital warts, and anal intraepithelial neoplasia. In addition to the approved indications, the CDC recommends vaccinating males aged 16 through 21 years not previously vaccinated. CDC recommendations also include men through age 26 years not previously vaccinated. Vaccination is also recommended by the CDC among men who have sex with men and among immunocompromised persons (including those with HIV infection) if not vaccinated previously through age 26 years.

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Human papillomavirus vaccine, quadrivalent (Gardasil)

The quadrivalent HPV recombinant vaccine was the first vaccine indicated to prevent cervical cancer, genital warts (condylomata acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades I-III; vulvar intraepithelial neoplasia grades II and III; and vaginal intraepithelial neoplasia grades II and III) due to HPV types 6, 11, 16, and 18. Its efficacy is mediated by humoral immune responses following immunization series.

The quadrivalent vaccine is FDA-approved for females aged 9-26 years and is under FDA priority review to evaluate efficacy in women aged 27-45 years. It is indicated for boys and men aged 11-26 years for prevention of condylomata acuminata caused by HPV types 6 and 11. It is also indicated in people aged 9-26 years for prevention of anal cancer and associated precancerous lesions.

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Human papillomavirus vaccine, bivalent (Cervarix)

The bivalent HPV vaccine is a recombinant vaccine prepared from the L1 protein of HPV types 16 and 18. It is indicated in girls and women aged 10-25 years for the prevention of diseases caused by oncogenic HPV types 16 and 18 (eg, cervical cancer, cervical intraepithelial neoplasia grade II or higher, adenocarcinoma in situ, and cervical intraepithelial neoplasia grade I).


HPV Vaccines: Indications Approved and HPV Types by Specific Vaccines

Indicated to Prevent HPV 9-valent* HPV 4-valent HPV 2-valent
Girls and Women
Approved ages 9-26 y 9-26 y 9-25 y
Cervical cancer HPV types 16, 18, 31, 33, 45, 52, and 58 HPV types 16 and 18 HPV types 16 and 18
Vulvar cancer HPV types 16, 18, 31, 33, 45, 52, and 58 HPV types 16 and 18 Not approved
Vaginal cancer HPV types 16, 18, 31, 33, 45, 52, and 58 HPV types 16 and 18 Not approved
Anal cancer HPV types 16, 18, 31, 33, 45, 52, and 58 HPV types 16 and 18 Not approved
Genital warts (condyloma acuminata) HPV types 6 and 11 HPV types 6 and 11 Not approved
Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical adenocarcinoma in situ (AIS) HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 HPV types 6, 11, 16, and 18 HPV types 16 and 18
Cervical intraepithelial neoplasia (CIN) grade 1 HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 HPV types 6, 11, 16, and 18 HPV types 16 and 18
Vulvar intraepithelial neoplasia (VIN) grades 2 and 3 HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 HPV types 6, 11, 16, and 18 Not approved
Vaginal intraepithelial neoplasia (VaIN) grades 2 and 3 HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 HPV types 6, 11, 16, and 18 Not approved
Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 HPV types 6, 11, 16, and 18 Not approved
Boys and Men
Approved ages 9-15 y* 9-26 y Not approved
Anal cancer HPV types 16, 18, 31, 33, 45, 52, and 58 HPV types 16 and 18 Not approved
Genital warts (condyloma acuminata) HPV types 6 and 11 HPV types 6 and 11 Not approved
Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 HPV types 6, 11, 16, and 18 Not approved
*The CDC recommends vaccinating males 16-21 y not previously vaccinated, and through age 26 y among men who have sex with men and among immunocompromised persons (including those with HIV infection) if not vaccinated previously



Clinical Trials:


Two trials of clinically approved human papillomavirus (HPV) vaccines, Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE I/II) and the Papilloma Trial Against Cancer in Young Adults (PATRICIA), reported a 22% difference in vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 2 or worse in HPV-naïve subcohorts; however, serological testing methods and the HPV DNA criteria used to define HPV-unexposed women differed between the studies.

The risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681).

The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults,NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants.


PMID: 25139208  PMCID: PMC4157699

Lang Kuhs KAPorras CSchiller JTRodriguez ACSchiffman MGonzalez PWacholder SGhosh ALi Y,Lowy DRKreimer ARPoncelet SSchussler JQuint Wvan Doorn LJSherman MESidawy MHerrero R,Hildesheim ASafaeian MCosta Rica Vaccine Trial Group. “Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates”. Am J Epidemiol. 2014 Sep 15;180(6):599-607. doi: 10.1093/aje/kwu168. Epub 2014 Aug 19.

PMID: 24610876-PMCID: PMC4111909

Castellsagué X1Naud P2Chow SN3Wheeler CM4Germar MJ5Lehtinen M6Paavonen J7Jaisamrarn U8,Garland SM9Salmerón J10Apter D11Kitchener H12Teixeira JC13Skinner SR14Limson G15Szarewski A16Romanowski B17Aoki FY18Schwarz TF19Poppe WA20Bosch FX21de Carvalho NS22Peters K23,Tjalma WA24Safaeian M25Raillard A26Descamps D27Struyf F27Dubin G28Rosillon D27Baril L27.”Risk of newly detected infections and cervical abnormalities in women seropositive for naturally acquired human papillomavirus type 16/18 antibodies: analysis of the control arm of PATRICIA”.  J Infect Dis. 2014 Aug 15;210(4):517-34. doi: 10.1093/infdis/jiu139. Epub 2014 Mar 8.  Comment in Naturally acquired immunity against human papillomavirus (HPV): why it matters in the HPV vaccine era. [J Infect Dis. 2014]

PMID: 25313727

Khode SR1Dwivedi RCRhys-Evans PKazi R.  Exploring the link between human papilloma virus and oral and oropharyngeal cancers. J Cancer Res Ther. 2014 Jul-Sep;10(3):492-8. doi: 10.4103/0973-1482.138213.


PMID: 24970795 PMCID: PMC4147298

Zaravinos A1. An updated overview of HPV-associated head and neck carcinomas.

Oncotarget. 2014 Jun 30;5(12):3956-69.

PMID: 24568473

Hamzi Abdul Raub S1Isa NMZailani HAOmar BAbdullah MFMohd Amin WANoor RMAyub MCAbidin ZKassim FVicknesh VZakaria ZKamaluddin MATan GCSyed Husain SN.  Distribution of HPV genotypes in cervical cancer in multi- ethnic Malaysia.  Asian Pac J Cancer Prev. 2014;15(2):651-6.


PMID: 24204068

de la Cruz MS1Young APRuffin MT 4thHuman papillomavirus (HPV) testing for normal cervical cytology in low-risk women aged 30-65 years by family physicians. J Am Board Fam Med. 2013 Nov-Dec;26(6):720-7. doi: 10.3122/jabfm.2013.06.120260.

PMID: 24127500

van der Zee RP1Richel Ode Vries HJPrins JM. The increasing incidence of anal cancer: can it be explained by trends in risk groups?  Neth J Med. 2013 Oct;71(8):401-11.


PMID: 23557172-PMCID: PMC3623745

van Poelgeest MI1Welters MJvan Esch EMStynenbosch LFKerpershoek Gvan Persijn van Meerten EL,van den Hende MLöwik MJBerends-van der Meer DMFathers LMValentijn AROostendorp JFleuren GJ,Melief CJKenter GGvan der Burg SH. HPV16 synthetic long peptide (HPV16-SLP) vaccination therapy of patients with advanced or recurrent HPV16-induced gynecological carcinoma, a phase II trial.  J Transl Med. 2013 Apr 4;11:88. doi: 10.1186/1479-5876-11-88.


PMID: 23441786

Prabhu SR1Wilson DF. Human papillomavirus and oral disease – emerging evidence: a review. Aust Dent J. 2013 Mar;58(1):2-10; quiz 125. doi: 10.1111/adj.12020. Epub 2013 Jan 31.


PMID: 24260180-PMCID:  PMC3834039

Jaisamrarn UCastellsagué XGarland SMNaud PPalmroth JDel Rosario-Raymundo MRWheeler CM,Salmerón JChow SNApter DTeixeira JCSkinner SRHedrick JSzarewski ARomanowski BAoki FY,Schwarz TFPoppe WABosch FXde Carvalho NSGermar MJPeters KPaavonen JBozonnat MC,Descamps DStruyf FDubin GORosillon DBaril LHPV PATRICIA Study GroupNatural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study.  PLoS One. 2013 Nov 19;8(11):e79260. doi: 10.1371/journal.pone.0079260. eCollection 2013.

Collaborators (124) Erratum in PLoS One. 2013;8(12). doi:10.1371/annotation/cea59317-929c-464a-b3f7-e095248f229a.


PMID: 22940493

Roset Bahmanyar EPaavonen JNaud PSalmerón JChow SNApter DKitchener HCastellsagué X,Teixeira JCSkinner SRJaisamrarn ULimson GAGarland SMSzarewski ARomanowski BAoki F,Schwarz TFPoppe WADe Carvalho NSHarper DMBosch FXRaillard ADescamps DStruyf FLehtinen MDubin GHPV PATRICIA Study Group.

Collaborators (151) Gynecol Oncol.

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Sylla BS1Wild CP. “A million africans a year dying from cancer by 2030: what can cancer research and control offer to the continent?Int J Cancer. 2012 Jan 15;130(2):245-50. doi: 10.1002/ijc.26333. Epub 2011 Aug 30.


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Herrero R, Quint W, Hildesheim A, Gonzalez P, Struijk L, Katki HA, Porras C, Schiffman M, Rodriguez AC, Solomon D, Jimenez S, Schiller JT, Lowy DR, van Doorn LJ, Wacholder S, Kreimer AR. CVT Vaccine Group. Reduced Prevalence of Oral Human Papillomavirus (HPV) 4 Years after Bivalent HPV Vaccination in a Randomized Clinical Trial in Costa Rica. PLoS One. 2013 Jul 17;8(7):e68329. ClinicalTrials.gov, Registry number NCT00128661.

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Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Jimenez SE, Lowy DR. Costa Rican HPV Vaccine Trial Group. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007;298(7):743–753. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00128661.

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Clinical Trials Publications:

Kreimer AR, Rodriguez AC, Hildesheim A, Herrero R, Porras C, Schiffman M, González P, Solomon D, Jiménez S, Schiller JT, Lowy DR, Quint W, Sherman ME, Schussler J, Wacholder S; CVT Vaccine Group. Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine. J Natl Cancer Inst. 2011 Oct 5;103(19):1444-51. doi: 10.1093/jnci/djr319. Epub 2011 Sep 9.

Kemp TJ, Hildesheim A, Safaeian M, Dauner JG, Pan Y, Porras C, Schiller JT, Lowy DR, Herrero R, Pinto LA. HPV16/18 L1 VLP vaccine induces cross-neutralizing antibodies that may mediate cross-protection. Vaccine. 2011 Mar 3;29(11):2011-4. doi: 10.1016/j.vaccine.2011.01.001. Epub 2011 Jan 15.
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kreimer AR, Struyf F, Del Rosario-Raymundo MR, Hildesheim A, Skinner SR, Wacholder S, Garland SM, Herrero R, David MP, Wheeler CM; Costa Rica Vaccine Trial and PATRICIA study groups. Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA trials. Lancet Oncol. 2015 Jul;16(7):775-86. doi: 10.1016/S1470-2045(15)00047-9. Epub 2015 Jun 9.

Gonzalez P, Hildesheim A, Herrero R, Katki H, Wacholder S, Porras C, Safaeian M, Jimenez S, Darragh TM, Cortes B, Befano B, Schiffman M, Carvajal L, Palefsky J, Schiller J, Ocampo R, Schussler J, Lowy D, Guillen D, Stoler MH, Quint W, Morales J, Avila C, Rodriguez AC, Kreimer AR; Costa Rica HPV Vaccine Trial (CVT) Group. Rationale and design of a long term follow-up study of women who did and did not receive HPV 16/18 vaccination in Guanacaste, Costa Rica. Vaccine. 2015 Apr 27;33(18):2141-51. doi: 10.1016/j.vaccine.2015.03.015. Epub 2015 Mar 18.

Lang Kuhs KA, Porras C, Schiller JT, Rodriguez AC, Schiffman M, Gonzalez P, Wacholder S, Ghosh A, Li Y, Lowy DR, Kreimer AR, Poncelet S, Schussler J, Quint W, van Doorn LJ, Sherman ME, Sidawy M, Herrero R, Hildesheim A, Safaeian M; Costa Rica Vaccine Trial Group. Effect of different human papillomavirus serological and DNA criteria on vaccine efficacy estimates. Am J Epidemiol. 2014 Sep 15;180(6):599-607. doi: 10.1093/aje/kwu168. Epub 2014 Aug 19.

Hildesheim A, Wacholder S, Catteau G, Struyf F, Dubin G, Herrero R; CVT Group. Efficacy of the HPV-16/18 vaccine: final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial. Vaccine. 2014 Sep 3;32(39):5087-97. doi: 10.1016/j.vaccine.2014.06.038. Epub 2014 Jul 10.

Lang Kuhs KA, Gonzalez P, Rodriguez AC, van Doorn LJ, Schiffman M, Struijk L, Chen S, Quint W, Lowy DR, Porras C, DelVecchio C, Jimenez S, Safaeian M, Schiller JT, Wacholder S, Herrero R, Hildesheim A, Kreimer AR; Costa Rica Vaccine Trial Group. Reduced prevalence of vulvar HPV16/18 infection among women who received the HPV16/18 bivalent vaccine: a nested analysis within the Costa Rica Vaccine Trial. J Infect Dis. 2014 Dec 15;210(12):1890-9. doi: 10.1093/infdis/jiu357. Epub 2014 Jun 23.

Lang Kuhs KA, Gonzalez P, Struijk L, Castro F, Hildesheim A, van Doorn LJ, Rodriguez AC, Schiffman M, Quint W, Lowy DR, Porras C, Delvecchio C, Katki HA, Jimenez S, Safaeian M, Schiller J, Solomon D, Wacholder S, Herrero R, Kreimer AR; Costa Rica Vaccine Trial Group. Prevalence of and risk factors for oral human papillomavirus among young women in Costa Rica. J Infect Dis. 2013 Nov 15;208(10):1643-52. doi: 10.1093/infdis/jit369. Epub 2013 Sep 6.

Herrero R, Quint W, Hildesheim A, Gonzalez P, Struijk L, Katki HA, Porras C, Schiffman M, Rodriguez AC, Solomon D, Jimenez S, Schiller JT, Lowy DR, van Doorn LJ, Wacholder S, Kreimer AR; CVT Vaccine Group. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One. 2013 Jul 17;8(7):e68329. doi: 10.1371/journal.pone.0068329. Print 2013.

Clarke M, Schiffman M, Wacholder S, Rodriguez AC, Hildesheim A, Quint W; Costa Rican Vaccine Trial Group. A prospective study of absolute risk and determinants of human papillomavirus incidence among young women in Costa Rica. BMC Infect Dis. 2013 Jul 8;13:308. doi: 10.1186/1471-2334-13-308.

Castro FA, Quint W, Gonzalez P, Katki HA, Herrero R, van Doorn LJ, Schiffman M, Struijk L, Rodriguez AC, DelVecchio C, Lowy DR, Porras C, Jimenez S, Schiller J, Solomon D, Wacholder S, Hildesheim A, Kreimer AR; Costa Rica Vaccine Trial Group. Prevalence of and risk factors for anal human papillomavirus infection among young healthy women in Costa Rica. J Infect Dis. 2012 Oct 1;206(7):1103-10. Epub 2012 Jul 30.

Kreimer AR, González P, Katki HA, Porras C, Schiffman M, Rodriguez AC, Solomon D, Jiménez S, Schiller JT, Lowy DR, van Doorn LJ, Struijk L, Quint W, Chen S, Wacholder S, Hildesheim A, Herrero R; CVT Vaccine Group. Efficacy of a bivalent HPV 16/18 vaccine against anal HPV 16/18 infection among young women: a nested analysis within the Costa Rica Vaccine Trial. Lancet Oncol. 2011 Sep;12(9):862-70. doi: 10.1016/S1470-2045(11)70213-3. Epub 2011 Aug 22. Erratum in: Lancet Oncol. 2011 Nov;12(12):1096.

Wacholder S, Chen BE, Wilcox A, Macones G, Gonzalez P, Befano B, Hildesheim A, Rodríguez AC, Solomon D, Herrero R, Schiffman M; CVT group. Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials. BMJ. 2010 Mar 2;340:c712. doi: 10.1136/bmj.c712.

Dessy FJ, Giannini SL, Bougelet CA, Kemp TJ, David MP, Poncelet SM, Pinto LA, Wettendorff MA. Correlation between direct ELISA, single epitope-based inhibition ELISA and pseudovirion-based neutralization assay for measuring anti-HPV-16 and anti-HPV-18 antibody response after vaccination with the AS04-adjuvanted HPV-16/18 cervical cancer vaccine. Hum Vaccin. 2008 Nov-Dec;4(6):425-34. Epub 2008 Nov 11.

Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, Schiller JT, Gonzalez P, Dubin G, Porras C, Jimenez SE, Lowy DR; Costa Rican HPV Vaccine Trial Group. Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA. 2007 Aug 15;298(7):743-53.

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Reporter: Aviva Lev-Ari, PhD, RN Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing September 18, 2012 By a GenomeWeb staff reporter NEW YORK (GenomeWeb News) – The presence or absence of human papillomavirus DNA on its own in an individual’s head or neck cancer does not provide enough information […]

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Papilloma viruses for cervical cancer

Larry H. Bernstein, MD, FCAP, Curator


Practice Bulletin No. 131: Screening for Cervical Cancer

Obstetrics & Gynecology:

The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening with cervical cytology. In 1975, the rate was 14.8 per 100,000 women. By 2008, it had been reduced to 6.6 per 100,000 women. Mortality from the disease has undergone a similar decrease from 5.55 per 100,000 women in 1975 to 2.38 per 100,000 women in 2008 (1). The American Cancer Society (ACS) estimates that there will be 12,170 new cases of cervical cancer in the United States in 2012, with 4,220 deaths from the disease (2). Cervical cancer is much more common worldwide, particularly in countries without screening programs, with an estimated 530,000 new cases of the disease and 275,000 resultant deaths each year (3, 4). When cervical cancer screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (5, 6).

New technologies for cervical cancer screening continue to evolve as do recommendations for managing the results. In addition, there are different risk-benefit considerations for women at different ages, as reflected in age-specific screening recommendations. The ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) have recently updated their joint guidelines for cervical cancer screening (7), and an update to the U.S. Preventive Services Task Force recommendations also has been issued (8). The purpose of this document is to provide a review of the best available evidence regarding screening for cervical cancer.

Study Backs Co-Testing for Cervical Cancer

A positive co-test result was more sensitive than either a positive HPV-only test or a positive Pap-only test.


Charles Bankhead

Cervical cancer screening with a test for human papillomavirus (HPV) resulted in a 50% higher rate of false-negative results versus Pap testing and three times greater versus co-testing, a large retrospective study showed.

Data encompassing more than 250,000 women showed a false-negative rate of 18.6% compared with 12.2% for Pap testing. With a false-negative rate of 5.5%, screening women with the HPV test and Pap test missed the fewest cancers.

The results support clinical guidelines that recommend co-testing, according to authors of a report in Cancer Cytopathology. The results differ dramatically, however, from those of previous studies that have consistently shown greater diagnostic accuracy for the HPV test compared with the Pap test.

“The reason that women are screened is that they want to be protected from cervical cancer,” study author R. Marshall Austin, MD, PhD, of Magee-Women’s Hospital and the University of Pittsburgh, told MedPage Today. “The previous trials have generally focused on cervical intraepithelial neoplasia 2 or 3, so-called precancer. The difference is that most of what we call precancer will actually never develop into cancer.

“The unique thing about this study, and what makes it so important, is that we looked at over 500 invasive cervical cancers, which are what women want to be protected against, and looked at the effectiveness of the methods of testing.”

A year ago, the FDA approved Roche’s cobas assay for HPV DNA as a first-line test for cervical cancer screening, following a unanimous vote for approval by an FDA advisory committee.

The approval was based primarily on a pivotal trial involving 47,200 women at high risk for cervical cancer. The primary endpoint was the proportion of patients who developed grade ≥3 cervical intraepithelial neoplasia (≥CIN3). The results showed a greater than 50% reduction in the incidence of ≥CIN3 with the DNA test versus Pap testing.

Austin and colleagues retrospectively analyzed clinical records for 256,648 average-risk women, ages 30 to 65, all of whom underwent co-testing as a screen for cervical cancer and subsequently had a cervical biopsy within a year of co-testing. The primary objective was to determine the sensitivity of the three screening methods for detection of biopsy-proven ≥CIN3 and invasive cancer.

The results showed that 74.7% of the women had a positive HPV test, 73.8% had an abnormal Pap test (atypical squamous cells of undetermined significance or worse), 89.2% had a positive co-test, and 1.6% had ≥CIN3.

Biopsy results showed that co-testing had the highest sensitivity for ≥CIN3 (98.8% versus 94% for HPV test only and 91.3% for Pap testing alone, P<0.0001). The Pap test had greater specificity versus HPV testing alone or co-testing (26.3% versus 25.6% versus 10.9%, P<0.0001).

Investigators identified 526 patients who developed biopsy-proven invasive cervical cancer. Of those patients, 98 tested negative by HPV assay only, 64 by Pap test only, and 29 by co-testing.

Given the average risk of the patient population included in the study, the results are broadly applicable to women in the age range studied, regardless of baseline risk for cervical cancer, Austin said.

The results are clearly at odds with previously reported comparative data showing superiority for the HPV assay versus Pap testing as a standalone screening test, but the reasons for the inconsistency aren’t clear, said Debbie Saslow, PhD, of the American Cancer Society (ACS) in Atlanta.

The data also show that co-testing is better than either test alone, which supports current ACS recommendations for cervical cancer screening.

“The current approach, according to the American Cancer Society and 25 other organizations that worked with us on our last guideline, co-testing is the preferred strategy,” Saslow told MedPage Today. “This paper completely backs that up. Even though a Pap alone is acceptable, clearly, co-testing is the best way to go.”

Noting that only half of women in the U.S. do not under go co-testing despite clinical guidelines recommending it for more than a decade, Saslow asked, “What’s taking so long?”

Earlier this year, several organizations released joint “interim guidance” regarding cervical cancer screening. Described as an aid to clinical decision-making until existing guidelines are updated, the interim guidance characterized the HPV-DNA test as an acceptable alternative to Pap testing as a primary screening test.

Acknowledging that the guidance focused on use of the HPV assay as a single test, interim guidance lead author Warner Huh, MD, of the University of Alabama at Birmingham, noted that “Every single study worldwide that has looked at this issue shows the same result: HPV testing outperforms Pap testing.”

In their article, Austin and colleagues argued that the HPV assay should be evaluated in comparison with the Pap test but as an alternative to co-testing.

“HPV-only primary screening for cervical cancer presents many challenges for clinicians,” the authors said. “Questions arise regarding its effectiveness, its long-term risk, and when it is the best option for a particular patient.

“Clinicians had similar questions when co-testing was first recommended for women 30 and older in 2006,” they added. “Since then the adoption of co-testing has steadily increased, with approximately 50% of physicians co-testing women 30 and older, but it is still not done at the recommended level.”

The study had some limitations. The authors could not confirm that the cervical biopsy results were from women who did not have an intervening screening test or treatment with a different provider during the study period.

Also, the authors were unable to draw conclusions based on the overall population of women who were screened for cervical cancer because the dataset consisted of screening results of women who underwent biopsies.


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