Clinical Therapeutics/Volume 37, Number 1, 2015
Editor-in-Chief’s Note The PAP Test and the Pap Smear The PAP test and the Pap smear are two tests with similar names, both indicated for cancers of the reproductive organs and both developed in the first half of the 20th century. The “PAP” in the test name is an acronym for prostatic acid phosphatase. Kutcher and Wolberg discovered PAP in 1935.1 A nonspecific phosphodiesterase or ectonucleotidase, PAP is synthesized in the prostate gland and secreted into seminal fluid. Its synthesis is under androgenic control, and levels can increase markedly after prostatic massage. Although used as a test for prostate cancer, PAP is less sensitive than testing for prostate-specific antigen. Unfortunately, neither test is specific enough to serve as a pathognomonic biomarker for prostate cancer. Introduced as a test in the 1940s, PAP was nonetheless the first practical serum tumor biomarker. Several authors have provided additional clarifying information on this topic.2–4 Richard I. Shader, MD Currently, testing for PAP on surfaces is sometimes used in forensics to identify the presence of semen. A rapidly appearing purplish blue color develops when the PAP in semen reacts with the reagent sodium alphanapthylphosphate.5 The Pap smear was introduced in the 1940s, when George Papanicolaou and his associate Herbert Traut published an article on the detection of vaginal cancer.6 Both worked at Cornell University Medical College. Dr. Pap, as colleagues called him, was in the Department of Anatomy, and Dr. Traut was a gynecologic pathologist at New York Hospital where vaginal smears were routinely collected. Dr. Pap had been studying vaginal cytology via microscopy since 1914, the year he joined the Cornell faculty; there he discovered that he could obtain smears from female guinea pigs and determine at what point they were in the estrous cycle. When the Pap smear was introduced in the 1940s, cervical cancer was the leading cause of death in women. As a screening test, the smears were used to detect both precancerous and cancerous changes in the endocervical canal of the uterus. The test has also been used to reveal cancers in the endometrium, vagina, and fallopian tubes. Pap smears identify atypical squamous cell or intraepithelial neoplastic lesions in the cervix. Today, additional tests are used to further identify and characterize these lesions, including DNA in situ hybridization and polymerase chain reaction. These newer methods detect the presence of high-risk human papillomavirus (HPV). Cervical pathology is categorized as atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, atypical squamous cells that cannot exclude high-grade lesions, and high-grade squamous intraepithelial lesions. In recent years, immunostaining for the tumor suppressor gene p16 (cyclin-dependent kinase inhibitor 2A) and Ki67 (MK167), a nuclear protein and cellular marker for proliferation, have been used to supplement Pap smears and high-risk HPV typing. Kileen et al7 and Gustinucci et al8 provide additional useful information on these new combined strategies that improve the overall accuracy of screening for HPV-related cervical pathology. The best approach to dealing with cervical cancer is prevention. Our January 2014 issue of Clinical Therapeutics contained six articles pertaining to HPV.9–14 The thrust of those articles was elucidating the importance of early vaccination for both girls and boys as an effective prevention strategy. In the present issue, Dr. Linda Duska, our Guest Editor for the HPV vaccine issue and our former Topic Editor for Women’s Health and now serving as a Guest Editor, provides us with 5 articles discussing cervical cancer.15–19 In addition to Duska’s overview,15 2 articles discuss immunotherapy and other new therapies.16,17 One such advance has been the approval of bevacizumab* for use in aggressive, late-stage cervical cancer. Bevacizumab is a
January 2015
1
Clinical Therapeutics recombinant humanized monoclonal immunoglobulin G1 antibody originally approved in 2004 for the treatment of other cancers.18 The drug’s effects on quality of life and unwanted treatment outcomes are discussed in 2 additional articles.19,20 Finally, I wish to welcome 3 new members to our Clinical Therapeutics editorial team. Dr. Marjorie Jenkins, MD, Executive Director of the Laura W. Bush Institute for Women's Health at Texas Tech University of Health Science Center, is our new Topic Editor for Women’s Health & Gender Medicine. Dr. Ravi Jhaveri, Associate Professor of Pediatrics, Division of Infectious Diseases at the University of North Carolina at Chapel Hill School of Medicine, is our new Topic Editor for Infectious Disease. Dr. Jill Maron, MD, MPH, Associate Professor of Pediatrics at Tufts University School of Medicine, is our new Topic Editor for Youth and Children. Richard I. Shader, MD Editor-in-Chief
REFERENCES 1. Human prostatic acid phosphatase. http://www.chem.sc.edu/faculty/lebioda/projects/hpap.htm. Accessed December 15, 2014. 2. Ostrowski WS, Kuciel R. Human prostatic phosphatase: selected properties and practical applications. Clin Chim Acta. 1994; 226:121–129. 3. Zimmermann H. Prostatic acid phosphatase, a neglected ectonucleotidase. Purinergic Signal. 2009;5:273–275. 4. Taira A, Merrick G, Wallner K, et al. Reviving the acid phosphatase test for prostate cancer. Oncology. 2007;21:1003–1010. 5. Screening and identification tests. http://www.nfstc.org/pdi/Subject02/pdi_s02_m02_04_a.htm. Accessed December 15, 2014. 6. Shepard EM. George Papanicolaou: development of the Pap smear. http://weill.cornell.edu/archives/blog/2011/06/georgepapanicolaou-development-of-the-pap-smear.html. Accessed December 15, 2014. 7. Kileen JL, Dye T, Grace C, et al. Improved abnormal Pap smear triage using cervical cancer biomarkers. J Low Genit Tract Dis. 2014;18:1–7. 8. Gustinucci D, Passamonti B, Cesarini E, et al. Role of p16(INK4a) cytology testing as an adjunct to enhance the diagnostic specificity and accuracy in human papillomavirus-positive women within an organized cervical cancer screening program. Acta Cytol. 2012;56:506–514. 9. Shader RI. Human papilloma virus infections, more on colchicine, and some farewells and welcomes. Clin Ther. 2014;36:1–2. 10. Duska LR. Safety and success of the human papilloma vaccine: time for a robust vaccination program in the United States and worldwide. Clin Ther. 2014;36:4–7. 11. Erickson BK, Landers EE, Huh WK. Update on vaccination clinical trials for HPV related disease. Clin Ther. 2014;36:8–16. 12. Garland SM. The Australian experience with the human papillomavirus (HPV) vaccine. Clin Ther. 2014;36:17–23. 13. Jeudin P, Liveright E, del Carmen MG, Perkins RB. Review of factors associated with race, ethnicity and income impacting HPV vaccination rates. Clin Ther. 2014;36:24–37. 14. Lazenby GB, Taylor PT, Badman BS, et al. An association between Trichomonas vaginalis 1 and high risk human papillomavirus 2 in rural Tanzanian women undergoing cervical cancer screening. Clin Ther. 2014;36:38–45. 15. Duska LR. Cervical cancer 2015 and beyond: a focus on innovative treatments and attention to survivorship. Clin Ther. 2015;37: 6–8. 16. Krill LS, Tewari K. Exploring the therapeutic rationale for angiogenesis blockade in cervical cancer. Clin Ther. 2015;37:9–19. 17. Eskander RN, Tewari K. Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer. Clin Ther. 2015;37: 20–38. 18. Food and Drug Administration. FDA approves Avastin to treat patients with aggressive and late-stage cervical cancer. http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410121.htm. Accessed December 15, 2014. 19. Pfaendler KS, Wenzel L, Mechanic MB, Penner KR. Cervical cancer survivorship: long-term quality of life and social support. Clin Ther. 2015;37:38–47. 20. Trifiletti DM, Watkins WT, Duska L, et al. Severe gastrointestinal complications in the era of image-guided high dose-rate intracavitary brachytherapy for cervical cancer. Clin Ther. 2015;37:49–60.
http://dx.doi.org/10.1016/j.clinthera.2014.12.002
Trademark: Avastins (Genentech, South San Francisco, California).
*
2
Volume 37 Number 1
Editor-in-Chief’s Note
Women’s Health Specialty Updates This month’s Cervical Cancer Update is a special feature that is relevant to Women’s Health. Women’s Health Updates are published annually available as FREE ACCESS content on the journal’s website. The previous Women’s Health Update, entitled “Helping Physicians Vaccinate: Making a Case for the HPV Vaccine,” was published in Volume 36, Number 1 of Clinical Therapeutics. To view the previous Women’s Health Update, see the articles below: 1. Duska L. Safety and Success of the Human Papillomavirus Vaccine: Time for a Robust Vaccination Program in the United States and Worldwide. 2. Erickson BK, et al. Update on Vaccination Clinical Trials for HPV-Related Disease. 3. Garland SM. The Australian Experience With the Human Papillomavirus Vaccine. 4. Jeudin P, et al. Race, Ethnicity, and Income Factors Impacting Human Papillomavirus Vaccination rates. 5. Lazenby GB, et al. An Association Between Trichomonas vaginalis and High-Risk Human Papillomavirus in Rural Tanzanian Women Undergoing Cervical Cancer Screening.
January 2015
3
Editor-in-Chief’s Note The PAP Test and the Pap Smear The PAP test and the Pap smear are two tests with similar names, both indicated for cancers of the reproductive organs and both developed in the first half of the 20th century. The “PAP” in the test name is an acronym for prostatic acid phosphatase. Kutcher and Wolberg discovered PAP in 1935.1 A nonspecific phosphodiesterase or ectonucleotidase, PAP is synthesized in the prostate gland and secreted into seminal fluid. Its synthesis is under androgenic control, and levels can increase markedly after prostatic massage. Although used as a test for prostate cancer, PAP is less sensitive than testing for prostate-specific antigen. Unfortunately, neither test is specific enough to serve as a pathognomonic biomarker for prostate cancer. Introduced as a test in the 1940s, PAP was nonetheless the first practical serum tumor biomarker. Several authors have provided additional clarifying information on this topic.2–4 Richard I. Shader, MD Currently, testing for PAP on surfaces is sometimes used in forensics to identify the presence of semen. A rapidly appearing purplish blue color develops when the PAP in semen reacts with the reagent sodium alphanapthylphosphate.5 The Pap smear was introduced in the 1940s, when George Papanicolaou and his associate Herbert Traut published an article on the detection of vaginal cancer.6 Both worked at Cornell University Medical College. Dr. Pap, as colleagues called him, was in the Department of Anatomy, and Dr. Traut was a gynecologic pathologist at New York Hospital where vaginal smears were routinely collected. Dr. Pap had been studying vaginal cytology via microscopy since 1914, the year he joined the Cornell faculty; there he discovered that he could obtain smears from female guinea pigs and determine at what point they were in the estrous cycle. When the Pap smear was introduced in the 1940s, cervical cancer was the leading cause of death in women. As a screening test, the smears were used to detect both precancerous and cancerous changes in the endocervical canal of the uterus. The test has also been used to reveal cancers in the endometrium, vagina, and fallopian tubes. Pap smears identify atypical squamous cell or intraepithelial neoplastic lesions in the cervix. Today, additional tests are used to further identify and characterize these lesions, including DNA in situ hybridization and polymerase chain reaction. These newer methods detect the presence of high-risk human papillomavirus (HPV). Cervical pathology is categorized as atypical squamous cells of undetermined significance, low-grade squamous intraepithelial lesions, atypical squamous cells that cannot exclude high-grade lesions, and high-grade squamous intraepithelial lesions. In recent years, immunostaining for the tumor suppressor gene p16 (cyclin-dependent kinase inhibitor 2A) and Ki67 (MK167), a nuclear protein and cellular marker for proliferation, have been used to supplement Pap smears and high-risk HPV typing. Kileen et al7 and Gustinucci et al8 provide additional useful information on these new combined strategies that improve the overall accuracy of screening for HPV-related cervical pathology. The best approach to dealing with cervical cancer is prevention. Our January 2014 issue of Clinical Therapeutics contained six articles pertaining to HPV.9–14 The thrust of those articles was elucidating the importance of early vaccination for both girls and boys as an effective prevention strategy. In the present issue, Dr. Linda Duska, our Guest Editor for the HPV vaccine issue and our former Topic Editor for Women’s Health and now serving as a Guest Editor, provides us with 5 articles discussing cervical cancer.15–19 In addition to Duska’s overview,15 2 articles discuss immunotherapy and other new therapies.16,17 One such advance has been the approval of bevacizumab* for use in aggressive, late-stage cervical cancer. Bevacizumab is a
January 2015
1
Clinical Therapeutics recombinant humanized monoclonal immunoglobulin G1 antibody originally approved in 2004 for the treatment of other cancers.18 The drug’s effects on quality of life and unwanted treatment outcomes are discussed in 2 additional articles.19,20 Finally, I wish to welcome 3 new members to our Clinical Therapeutics editorial team. Dr. Marjorie Jenkins, MD, Executive Director of the Laura W. Bush Institute for Women's Health at Texas Tech University of Health Science Center, is our new Topic Editor for Women’s Health & Gender Medicine. Dr. Ravi Jhaveri, Associate Professor of Pediatrics, Division of Infectious Diseases at the University of North Carolina at Chapel Hill School of Medicine, is our new Topic Editor for Infectious Disease. Dr. Jill Maron, MD, MPH, Associate Professor of Pediatrics at Tufts University School of Medicine, is our new Topic Editor for Youth and Children. Richard I. Shader, MD Editor-in-Chief
REFERENCES 1. Human prostatic acid phosphatase. http://www.chem.sc.edu/faculty/lebioda/projects/hpap.htm. Accessed December 15, 2014. 2. Ostrowski WS, Kuciel R. Human prostatic phosphatase: selected properties and practical applications. Clin Chim Acta. 1994; 226:121–129. 3. Zimmermann H. Prostatic acid phosphatase, a neglected ectonucleotidase. Purinergic Signal. 2009;5:273–275. 4. Taira A, Merrick G, Wallner K, et al. Reviving the acid phosphatase test for prostate cancer. Oncology. 2007;21:1003–1010. 5. Screening and identification tests. http://www.nfstc.org/pdi/Subject02/pdi_s02_m02_04_a.htm. Accessed December 15, 2014. 6. Shepard EM. George Papanicolaou: development of the Pap smear. http://weill.cornell.edu/archives/blog/2011/06/georgepapanicolaou-development-of-the-pap-smear.html. Accessed December 15, 2014. 7. Kileen JL, Dye T, Grace C, et al. Improved abnormal Pap smear triage using cervical cancer biomarkers. J Low Genit Tract Dis. 2014;18:1–7. 8. Gustinucci D, Passamonti B, Cesarini E, et al. Role of p16(INK4a) cytology testing as an adjunct to enhance the diagnostic specificity and accuracy in human papillomavirus-positive women within an organized cervical cancer screening program. Acta Cytol. 2012;56:506–514. 9. Shader RI. Human papilloma virus infections, more on colchicine, and some farewells and welcomes. Clin Ther. 2014;36:1–2. 10. Duska LR. Safety and success of the human papilloma vaccine: time for a robust vaccination program in the United States and worldwide. Clin Ther. 2014;36:4–7. 11. Erickson BK, Landers EE, Huh WK. Update on vaccination clinical trials for HPV related disease. Clin Ther. 2014;36:8–16. 12. Garland SM. The Australian experience with the human papillomavirus (HPV) vaccine. Clin Ther. 2014;36:17–23. 13. Jeudin P, Liveright E, del Carmen MG, Perkins RB. Review of factors associated with race, ethnicity and income impacting HPV vaccination rates. Clin Ther. 2014;36:24–37. 14. Lazenby GB, Taylor PT, Badman BS, et al. An association between Trichomonas vaginalis 1 and high risk human papillomavirus 2 in rural Tanzanian women undergoing cervical cancer screening. Clin Ther. 2014;36:38–45. 15. Duska LR. Cervical cancer 2015 and beyond: a focus on innovative treatments and attention to survivorship. Clin Ther. 2015;37: 6–8. 16. Krill LS, Tewari K. Exploring the therapeutic rationale for angiogenesis blockade in cervical cancer. Clin Ther. 2015;37:9–19. 17. Eskander RN, Tewari K. Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer. Clin Ther. 2015;37: 20–38. 18. Food and Drug Administration. FDA approves Avastin to treat patients with aggressive and late-stage cervical cancer. http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm410121.htm. Accessed December 15, 2014. 19. Pfaendler KS, Wenzel L, Mechanic MB, Penner KR. Cervical cancer survivorship: long-term quality of life and social support. Clin Ther. 2015;37:38–47. 20. Trifiletti DM, Watkins WT, Duska L, et al. Severe gastrointestinal complications in the era of image-guided high dose-rate intracavitary brachytherapy for cervical cancer. Clin Ther. 2015;37:49–60.
http://dx.doi.org/10.1016/j.clinthera.2014.12.002
Trademark: Avastins (Genentech, South San Francisco, California).
*
2
Volume 37 Number 1
Editor-in-Chief’s Note
Women’s Health Specialty Updates This month’s Cervical Cancer Update is a special feature that is relevant to Women’s Health. Women’s Health Updates are published annually available as FREE ACCESS content on the journal’s website. The previous Women’s Health Update, entitled “Helping Physicians Vaccinate: Making a Case for the HPV Vaccine,” was published in Volume 36, Number 1 of Clinical Therapeutics. To view the previous Women’s Health Update, see the articles below: 1. Duska L. Safety and Success of the Human Papillomavirus Vaccine: Time for a Robust Vaccination Program in the United States and Worldwide. 2. Erickson BK, et al. Update on Vaccination Clinical Trials for HPV-Related Disease. 3. Garland SM. The Australian Experience With the Human Papillomavirus Vaccine. 4. Jeudin P, et al. Race, Ethnicity, and Income Factors Impacting Human Papillomavirus Vaccination rates. 5. Lazenby GB, et al. An Association Between Trichomonas vaginalis and High-Risk Human Papillomavirus in Rural Tanzanian Women Undergoing Cervical Cancer Screening.
January 2015
3
