Infectious Agents and Cancer - Latest Comments

HPV test is a virology test, not for predicting cancer

Sin Hang Lee — 2009-08-19T16:16:22Z

Since Dr. Castle wrote this Commentary from an office in the authoritative National Cancer Institute of the United States (NCI) and the Commentary was published in a peer-reviewed international scientific journal, his opinions will unfortunately influence many health care policy makers whose decisions will in turn affect the welfare of many women worldwide. The undersigned felt obligated to comment on this Commentary.

Under an academic title, the Commentary promotes a generation of less specific HPV tests which may refer more women to unnecessary colposcopic biopsies than the Digene hc2 HPV test due to cross-reactivity with non-target HPV types. The Commentary endorsed these HPV tests “despite the cross-reactivity to these weakly carcinogenic or non-carcinogenic HPV genotypes”. By its “definition”, cross-reactivity is a good thing because “it may indirectly increase the reassurance following a negative HPV test i.e. the negative predictive value of an HPV test for cervical precancer and cancer”, and the only bad thing is when “the tradeoff of more false positives for greater reassurance may not be acceptable if the local infrastructure cannot manage the screen positives”. The Commentary addressed the issues of clinical sensitivity, specificity and negative predictive value (NPV) of the commercial HPV test kits available now and under development in the pipeline of the manufacturing companies. It justified introduction of “a generation of HPV tests (even some that are not now in clinical trials but too far along in the formulation phase to alter)” that “will be slightly less specific than what might otherwise be achieved.” However, the Commentary did not mention even once the positive predictive value (PPV) of these virology DNA tests, using precancer or cancer histopathology as the endpoint for evaluation in a real-life population, e.g. among women who receive their regular gynecological care rendered by board-certified gynecologists in private practice in the US. The sad truth is that the NCI does not have any HPV testing ppv data on the non-Hispanic white majority living in the US where the cervical cancer prevalence rates range from <1 to 7 per 100,000 women from one local population to another. The data presented in Figure 1 of the Commentary were based on data collected from various parts of the world, including most regions where the cervical cancer prevalence rates are known to be exceedingly high. It is a common knowledge that a laboratory test developed in population with high disease prevalence will lose its acceptable ppv when applied to populations with a low disease prevalence rate.

The undersigned has been practicing diagnostic cancer pathology and clinical microbiology at the hospital laboratory bench for more than 50 years. Since each test result generated at the bench may have serious impacts on the well-being of a patient, the expected ppv of all cancer tests, e.g. an intra-operative frozen section diagnosis, is 100%. The expected ppv for identification of a microbe in clinical specimens as the causative agent of an infection is also 100%. The Commentary endorsed converting a virology test to a cancer test with a >95% false positive rate [1] and a <5% ppv, which is unprecedented in laboratory medicine. It overemphasized the benefit of the high clinical sensitivity of the commercial HPV screen test kits in detecting more precancer or cancer at the expense of specificity, without mentioning the ppv of these tests. Based on this argument, any test, HPV or not, that refers all tested women blindly to colposcopic biopsy will have a 100% clinical sensitivity in detecting biopsy-proven precancer or cancer. However, this is not the traditional way to practice cancer pathology.

The Commentary endorsed a “once-in-a-lifetime low-cost and rapid HPV testing” for low-resource settings of the world while pointing out the fact that this “will need sufficient numbers of highly-trained colposcopists to handle the clinical volume of screen positives, which could approach 10-15% of the population in many location.” Since more than 95% of hc2 HPV test referrals for cervical biopsies are unnecessary [1], if this recommendation were implemented in a low-resource setting like Sichuan, China with a population of about 100 million, there would be 10 million or more women to undergo unnecessary cervical biopsies in that province alone. The downstream unnecessary expenses to cover the colposcopy, histotechnology, and the pathology professional services for 10 million 4-quadrant cervical biopsies resulting from this “low-cost and rapid HPV testing” would be enormous, let alone the cost in human suffering associated with the psychological and physical trauma of an invasive procedure. Previously, Dr. Castle stated on record that “the medical community should emphasize persistence of cervical HPV infection, not single-time detection of HPV, in management strategies and health messages [2].” Unfortunately, this Commentary was not formulated on the basis of the last statement.

Sin Hang Lee, M.D., F.R.C.P.(C)

References
1. Stout NK, Goldhaber-Fiebert JD, Ortendahl JD, Goldie SJ. Trade-offs in cervical cancer prevention: balancing benefits and risks. Arch Intern Med 2008, 168: 1881-1889.
2. Rodríguez AC, Schiffman M, Herrero R, Wacholder S, Hildesheim A, Castle PE, Solomon D, Burk R; Proyecto Epidemiológico Guanacaste Group. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008, 100: 513-517.

Please investigate cytomegalovirus

Carol Thompson — 2009-02-15T12:34:34Z

Please investigate cytomegalovirus before concluding that smoking is the cause. For socioeconomic reasons, smokers are more likely to have been infected by this virus, which is known to have powerful immunosuppressive effects.

Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination--an impact of immunosenescence. P Trzonkowski, J Myśliwska, E Szmit, J Wieckiewicz, K Lukaszuk, LB Brydak, M Machała, A Myśliwski. Vaccine 2003 Sep 8;21(25-26):3826-3836. "Non-responders of both ages we characterised by higher levels of anti-CMV IgG and higher percentages of CD57+CD28- lymphocytes (known to be associated with CMV carrier status) together with increased concentrations of TNFalpha and IL6 and decreased levels of cortisol."

http://www.ncbi.nlm.nih.gov/pubmed/12922116

Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. N Khan, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, AB Rickinson, PA Moss. J Immunol 2004 Dec 15;173(12):7481-7489. "CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status."

http://www.jimmunol.org/cgi/content/full/173/12/7481

Cancer of Uterine Cervix and Oncological Terrain with Inherited Oncological Real Risk.

Sergio Stagnaro — 2009-02-11T12:17:12Z

Editors,

I consider artiche conclusion unfortunately erroneously incomplete: The strong association found between HPV infection, specifically types 16 and 18 and cancer of the uterine cervix in Zaragoza, Spain, stresses the importance of ongoing efforts to institute a vaccine program with recently approved HPV vaccines in order to prevent cervical cancer in this population. As a matter of facts, cervix cancer involves exclusively women with Oncological Terrain “and” Inherited Oncolgical Real Risk of cervix. If we administer anti-HPV Vaccine to women without such as predisposition, we lose money, time and energy uselessly(1-10).

1) Stagnaro-Neri M., Stagnaro S. Introduzione alla Semeiotica Biofisica. Il Terreno Oncologico. Travel Factory, Roma, 2004. http://www.travelfactory.it

1. Stagnaro S. Genes and Cancer: a clinical view-point. The Oncological Terrain. BioMed Central Informatics. http://www.biomedcentral.com/1471-2105/5/21/comments#10454 2004

2. Stagnaro S., Stagnaro-Neri M., Oncological Terrain, conditio sine qua non of Oncogenesis: http://www.gutjnl.com/cgi/eletters?lookup=by_date&days=60 2004

3. . Stagnaro Sergio. "Genes, Oncological Terrain, and Breast Cancer", World Journal of Surgical Oncology. 2005, http://www.wjso.com/content/3/1/45/comments#205475 2005

4. Stagnaro Sergio. Cancer Risk Factors and Oncological Terrain. 2006. http://www.wjso.com/content/4/1/74/comments#247528

5. Stagnaro Sergio. Without Oncological Terrain oncogenesis is not possible. CMAJ. 23 March 2007 http://www.cmaj.ca/cgi/eletters/176/5/646

6. Stagnaro Sergio. GPs , Biophysical Semeiotics, and bedside cancer diagnosis. 08 July 2007, International Seminar of Surgical Oncology, http://www.issoonline.com/content/4/1/11/comments#281539

7. Stagnaro Sergio. Oncological Terrain and Inherited Oncological Real Risk: New Way in Malignancy Primary Prevention and early Diagnosis. International Seminars in Surgical Oncology, 2007. http://www.issoonline.com/content/4/1/25/comments#290565

8) Stagnaro Sergio. Bedside Biophysical-Semeiotic Diagnosis of Breast Cancer, since initial Stage. International Seminars in Surgical Oncology 2007, http://www.issoonline.com/content/4/1/21/comments

9. Stagnaro Sergio. What about Oncological Terrain. www.thescientist.com 2007. http://www.the-scientist.com/article/display/53938/

10. Stagnaro Sergio. Oncogenesis is possible exclusively in individuals Oncological Terrain-positive.

www.thescientist.com 2007. http://www.the-scientist.com/blog/print/53498/

11.Stagnaro Sergio. Overloking Oncological Terrain and oncological Real Risk, no paper is up-dated! 18 January 2008 Ann. Intern Med. http://www.annals.org/cgi/eletters/147/11/775

12. Stagnaro Sergio. Bedside Biophysical-Semeiotic Osteocalcin Test in Diagnosing and Monitoring Diabetes. January 28, 2008, http://www.thelancet.com/journals/lancet/article/PIIS0140673608601014/comments?action=view&totalComments=2

13. Stagnaro Sergio. Biological System Functional Modification parallels Gene Mutation. www.Nature.com,March 13, 2008,

http://blogs.nature.com/nm/spoonful/2008/03/gout_gene.html

14. Stagnaro Sergio. Oncogenesis, Oncological Terrain, and Inherited Oncological Real Risk. www.nature.com, 21 April 2008,

http://blogs.nature.com/nm/spoonful/2008/04/stress_as_a_therapy_1.html

Seeking comments on "Human Mammary Tumor Virus"

Brian Foley — 2006-11-16T12:55:56Z

There are now dozens of GenBank DNA sequence entries for "Human Mammary Tunor Virus", such as the ones with accession numbers DQ910870 and AF248269. There are also many more, identified as "Mouse Mammary Tumor Virus" from human cancer tissue. Also AF513916 "human betaretrovirus". As well as at least one paper linking the geographical distribution of mice to human breast cancers (1).

However, many human cancer researchers doubt that a mammary tumor virus is involved (2,3). If tumor viruses are involved in human cancers, determining the mode of transmission from mice to humans and/or from human to human is important. It is my opinion, that the evidence for a "human mammary tumor virus" should be based on more than PCR amplification of sequences, as that method is too prone to false positive results by contamination of PCR reactions with DNA from positive control reactions. The sequences of putative HMTV are nearly identical to lab strains of MMTV.

REFERENCES:

1: Br J Cancer. 2000 Jan;82(2):446-51.

Comment in:

Br J Cancer. 2000 Jul;83(1):133; author reply 134.

Breast cancer incidence highest in the range of one species of house mouse, Mus domesticus.

Stewart TH, Sage RD, Stewart AF, Cameron DW.

PMID: 10646903

2: Mant C, Gillett C, D'Arrigo C, Cason J. Human murine mammary tumour virus-like agents are genetically distinct from endogenous retroviruses and are not detectable in breast cancer cell lines or biopsies.

Virology. 2004 Jan 5;318(1):393-404.

PMID: 14972564

3: Szabo S, Haislip AM, Garry RF.

Of mice, cats, and men: is human breast cancer a zoonosis?

Microsc Res Tech. 2005 Nov;68(3-4):197-208. Review.

PMID: 16276516