Journal of Clinical Medicine

Review

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Open AccessReview

Cutaneous Squamous Cell Carcinomas in Organ Transplant Recipients

by Ramya Chockalingam, Christopher Downing and Stephen K. Tyring

J. Clin. Med. 2015, 4(6), 1229-1239; https://doi.org/10.3390/jcm4061229 - 3 Jun 2015

Cited by 92 | Viewed by 8681

Non-melanoma skin cancers represent a major cause of morbidity after organ transplantation. Squamous cell carcinomas (SCC) are the most common cutaneous malignancies seen in this population, with a 65–100 fold greater incidence in organ transplant recipients compared to the general population. In recent [...] Read more.

Non-melanoma skin cancers represent a major cause of morbidity after organ transplantation. Squamous cell carcinomas (SCC) are the most common cutaneous malignancies seen in this population, with a 65–100 fold greater incidence in organ transplant recipients compared to the general population. In recent years, human papillomaviruses (HPV) of the beta genus have been implicated in the pathogenesis of post-transplant SCCs. The underlying mechanism of carcinogenesis has been attributed to the E6 and E7 proteins of HPV. Specific immunosuppressive medications, such as the calcineurin inhibitors and azathioprine, are associated with a higher incidence of post-transplant SCCs compared to other immunosuppressive agents. Compared to other immunosuppressives, mTOR inhibitors and mycophenolate mofetil have been associated with a decreased risk of developing post-transplant non-melanoma skin cancers. As a result, they may represent ideal immunosuppressive medications in organ transplant recipients. Treatment options for post-transplant SCCs include surgical excision, Mohs micrographic surgery, systemic retinoid therapy, adjunct topical therapy, electrodessication and curettage, and radiation therapy. This review will discuss the epidemiology, risk factors, and management options of post-transplant SCCs. In addition, the underlying mechanisms of beta-HPV mediated carcinogenesis will be discussed. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Human Papillomavirus: Current and Future RNAi Therapeutic Strategies for Cervical Cancer

by Hun Soon Jung, Nirmal Rajasekaran, Woong Ju and Young Kee Shin

J. Clin. Med. 2015, 4(5), 1126-1155; https://doi.org/10.3390/jcm4051126 - 21 May 2015

Cited by 40 | Viewed by 15424

Abstract

Human papillomaviruses (HPVs) are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi) based cancer therapies, because the viral oncogenes E6 and E7 that cause [...] Read more.

Human papillomaviruses (HPVs) are small DNA viruses; some oncogenic ones can cause different types of cancer, in particular cervical cancer. HPV-associated carcinogenesis provides a classical model system for RNA interference (RNAi) based cancer therapies, because the viral oncogenes E6 and E7 that cause cervical cancer are expressed only in cancerous cells. Previous studies on the development of therapeutic RNAi facilitated the advancement of therapeutic siRNAs and demonstrated its versatility by siRNA-mediated depletion of single or multiple cellular/viral targets. Sequence-specific gene silencing using RNAi shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, siRNA-based targeting requires further validation of its efficacy in vitro and in vivo, for its potential off-target effects, and of the design of conventional therapies to be used in combination with siRNAs and their drug delivery vehicles. In this review we discuss what is currently known about HPV-associated carcinogenesis and the potential for combining siRNA with other treatment strategies for the development of future therapies. Finally, we present our assessment of the most promising path to the development of RNAi therapeutic strategies for clinical settings. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Open AccessReview

Current Cervical Carcinoma Screening Guidelines

by Megan J. Schlichte and Jacqueline Guidry

J. Clin. Med. 2015, 4(5), 918-932; https://doi.org/10.3390/jcm4050918 - 7 May 2015

Cited by 36 | Viewed by 7650

Abstract

A formidable threat to the health of women, cervical carcinoma can be prevented in many cases with adequate screening. The current guidelines for cervical carcinoma screening were created as joint recommendations of the American Cancer Society (ACS), the American Society for Colposcopy and [...] Read more.

A formidable threat to the health of women, cervical carcinoma can be prevented in many cases with adequate screening. The current guidelines for cervical carcinoma screening were created as joint recommendations of the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP) and the American Society for Clinical Pathology (ASCP) in 2012, and later accepted and promoted by the American Congress of Obstetricians and Gynecologists (ACOG). The 2012 recommendations underscore the utility of molecular testing as an adjunct to cytology screening for certain women and provide guidance to clinicians based on different risk-benefit considerations for different ages. This manuscript will review screening techniques and current recommendations for cervical cancer screening and human papilloma virus (HPV) testing, as well as possible future screening strategies. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Advancements in Pharmacotherapy for Noncancerous Manifestations of HPV

by Ramya Kollipara, Erfon Ekhlassi, Christopher Downing, Jacqueline Guidry, Michael Lee and Stephen K. Tyring

J. Clin. Med. 2015, 4(5), 832-846; https://doi.org/10.3390/jcm4050832 - 24 Apr 2015

Cited by 39 | Viewed by 9644

Abstract

Human papillomavirus (HPV) is the most common sexually transmitted disease. Via infection of the basal epithelial cells, HPV causes numerous malignancies and noncancerous cutaneous manifestations. Noncancerous cutaneous manifestations of HPV, including common, plantar, plane, and anogenital warts, are among the most common reasons [...] Read more.

Human papillomavirus (HPV) is the most common sexually transmitted disease. Via infection of the basal epithelial cells, HPV causes numerous malignancies and noncancerous cutaneous manifestations. Noncancerous cutaneous manifestations of HPV, including common, plantar, plane, and anogenital warts, are among the most common reasons for an office visit. Although there are various therapies available, they are notoriously difficult to treat. HPV treatments can be grouped into destructive (cantharidin, salicylic acid), virucidal (cidofovir, interferon-α), antimitotic (bleomycin, podophyllotoxin, 5-fluorouracil), immunotherapy (Candida antigen, contact allergen immunotherapy, imiquimod) or miscellaneous (trichloroacetic acid, polyphenon E). The mechanism of action, recent efficacy data, safety profile and recommended regimen for each of these treatment modalities is discussed. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Advancements in the Management of HPV-Associated Head and Neck Squamous Cell Carcinoma

by Ross Zeitlin, Harrison P. Nguyen, David Rafferty and Stephen Tyring

J. Clin. Med. 2015, 4(5), 822-831; https://doi.org/10.3390/jcm4050822 - 24 Apr 2015

Cited by 1 | Viewed by 5709

Abstract

Head and neck carcinomas have long been linked to alcohol and tobacco abuse; however, within the last two decades, the human papillomavirus (HPV) has emerged as a third etiology and is specifically associated with head and neck squamous cell carcinomas (HNSCC). In this [...] Read more.

Head and neck carcinomas have long been linked to alcohol and tobacco abuse; however, within the last two decades, the human papillomavirus (HPV) has emerged as a third etiology and is specifically associated with head and neck squamous cell carcinomas (HNSCC). In this anatomical region, the oncogenic HPV-16 mediates transformation and immortalization of epithelium, most commonly in the oropharynx. Nevertheless, the recent identification of novel HPV mechanisms thought to be specific to oropharyngeal carcinogenesis has coincided with observations that HPV-associated HNSCC has differing clinical behavior—in terms of natural history, therapeutic response, and prognosis—than HPV-negative head and neck tumors. Taken together with the growing incidence of HPV transmission in younger populations, these discoveries have sparked a rapid expansion in both laboratory and clinical studies on the infection and disease. Herein, we review the clinical characteristics of HPV-associated HNSCC, with particular emphasis on recent advancements in our understanding of the management of this infectious malignancy. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Safety and Efficacy Data on Vaccines and Immunization to Human Papillomavirus

by Natalie Kash, Michael A. Lee, Ramya Kollipara, Christopher Downing, Jacqueline Guidry and Stephen K. Tyring

J. Clin. Med. 2015, 4(4), 614-633; https://doi.org/10.3390/jcm4040614 - 3 Apr 2015

Cited by 78 | Viewed by 12730

Abstract

Since the discovery of the causal association between human papillomavirus (HPV) and cervical cancer, efforts to develop an effective prophylactic vaccine to prevent high-risk HPV infections have been at the forefront of modern medical research. HPV causes 530,000 cervical cancer cases worldwide, which [...] Read more.

Since the discovery of the causal association between human papillomavirus (HPV) and cervical cancer, efforts to develop an effective prophylactic vaccine to prevent high-risk HPV infections have been at the forefront of modern medical research. HPV causes 530,000 cervical cancer cases worldwide, which is the second most common cause of cancer deaths in women; a worldwide collaboration among epidemiologists, molecular biologists, vaccinologists, virologists, and clinicians helped lead to the development of two highly effective prophylactive HPV vaccines. The first, Gardasil, is a quadrivalent vaccine made up of recombinant HPV L1 capsid proteins from the two high-risk HPV types (16/18) responsible for 70% of cervical cancer cases as well as two low-risk HPV types (6/11) which are the causative agent for genital warts. The second, Cervarix, is a bivalent vaccine that was FDA approved three years after Gardasil and is also composed of L1 capsid proteins from HPV types 16/18. This review article focuses on the safety and efficacy data of both FDA-approved vaccines, as well as highlighting a few advances in future HPV vaccines that show promise in becoming additional treatment options for this worldwide disease. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Open AccessReview

The Interaction between Human Immunodeficiency Virus and Human Papillomaviruses in Heterosexuals in Africa

by Anna-Lise Williamson

J. Clin. Med. 2015, 4(4), 579-592; https://doi.org/10.3390/jcm4040579 - 2 Apr 2015

Cited by 52 | Viewed by 7466

Abstract

Sub-Saharan Africa has the highest incidence of human papillomavirus (HPV) and cervical cancer in the world, which is further aggravated by the burden of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) disease with invasive cervical cancer being an AIDS-defining cancer. The prevalence of HPV [...] Read more.

Sub-Saharan Africa has the highest incidence of human papillomavirus (HPV) and cervical cancer in the world, which is further aggravated by the burden of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) disease with invasive cervical cancer being an AIDS-defining cancer. The prevalence of HPV infection and associated disease is very high in HIV-infected people and continues to be a problem even after anti-retroviral therapy. In the genital tract, the interaction between HPV and HIV is complex, with infection with multiple HPV types reported to make both women and men more susceptible to HIV infection. Besides the national programmes to vaccinate girls against HPV and screen women for cervical cancer, there should be targeted cervical cancer screening, treatment and prevention programmes introduced into HIV treatment centres. There is evidence that in high HIV prevalence areas, HIV-positive women could cause increases in the prevalence of genital HPV infection in HIV-negative men and so increase the HPV circulating in the community. Condom use and circumcision reduce the acquisition of HIV-1, and also to some extent of HPV. This review will highlight what is known about the interaction of HIV and HPV, with an emphasis on research in Africa. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Open AccessReview

Immune Dysregulation in Patients Persistently Infected with Human Papillomaviruses 6 and 11

by Alexandra V. Lucs, James A. DeVoti, Lynda Hatam, Ali Afzal, Allan L. Abramson, Bettie M. Steinberg and Vincent R. Bonagura

J. Clin. Med. 2015, 4(3), 375-388; https://doi.org/10.3390/jcm4030375 - 3 Mar 2015

Cited by 17 | Viewed by 10749

Abstract

Human Papillomaviruses (HPVs) 6 and 11 are part of a large family of small DNA viruses, some of which are commensal. Although much of the population can contain or clear infection with these viruses, there is a subset of individuals who develop persistent [...] Read more.

Human Papillomaviruses (HPVs) 6 and 11 are part of a large family of small DNA viruses, some of which are commensal. Although much of the population can contain or clear infection with these viruses, there is a subset of individuals who develop persistent infection that can cause significant morbidity and on occasion mortality. Depending on the site of infection, patients chronically infected with these viruses develop either recurrent, and on occasion, severe genital warts or recurrent respiratory papillomas that can obstruct the upper airway. The HPV-induced diseases described are likely the result of a complex and localized immune suppressive milieu that is characteristic of patients with persistent HPV infection. We review data that documents impaired Langerhans cell responses and maturation, describes the polarized adaptive T-cell immune responses made to these viruses, and the expression of class select II MHC and KIR genes that associate with severe HPV6 and 11 induced disease. Finally, we review evidence that documents the polarization of functional T_H2 and T-regulatory T-cells in tissues persistently infected with HPV6 and 11, and we review evidence that there is suppression of natural killer cell function. Together, these altered innate and adaptive immune responses contribute to the cellular and humoral microenvironment that supports HPV 6 and 11-induced disease. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Open AccessReview

HPV Carcinomas in Immunocompromised Patients

by Nicole M. Reusser, Christopher Downing, Jacqueline Guidry and Stephen K. Tyring

J. Clin. Med. 2015, 4(2), 260-281; https://doi.org/10.3390/jcm4020260 - 29 Jan 2015

Cited by 96 | Viewed by 10391

Abstract

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide and can result in pre-malignancies or overt malignancies of the skin and mucosal surfaces. HPV-related illnesses are an important personal and public health problem causing physical, mental, sexual and financial detriments. [...] Read more.

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide and can result in pre-malignancies or overt malignancies of the skin and mucosal surfaces. HPV-related illnesses are an important personal and public health problem causing physical, mental, sexual and financial detriments. Moreover, this set of malignancies severely affects the immunosuppressed population, particularly HIV-positive patients and organ-transplant recipients. There is growing incidence of HPV-associated anogenital malignancies as well as a decrease in the average age of affected patients, likely related to the rising number of high-risk individuals. Squamous cell carcinoma is the most common type of HPV-related malignancy. Current treatment options for HPV infection and subsequent disease manifestations include imiquimod, retinoids, intralesional bleomycin, and cidofovir; however, primary prevention with HPV vaccination remains the most effective strategy. This review will discuss anogenital lesions in immunocompromised patients, cutaneous warts at nongenital sites, the association of HPV with skin cancer in immunocompromised patients, warts and carcinomas in organ-transplant patients, HIV-positive patients with HPV infections, and the management of cutaneous disease in the immunocompromised patient. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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Recent Insights into the Control of Human Papillomavirus (HPV) Genome Stability, Loss, and Degradation

by Chris Fisher

J. Clin. Med. 2015, 4(2), 204-230; https://doi.org/10.3390/jcm4020204 - 27 Jan 2015

Cited by 19 | Viewed by 10036

Abstract

Most human papillomavirus (HPV) antiviral strategies have focused upon inhibiting viral DNA replication, but it is increasingly apparent that viral DNA levels can be chemically controlled by approaches that promote its instability. HPVs and other DNA viruses have a tenuous relationship with their [...] Read more.

Most human papillomavirus (HPV) antiviral strategies have focused upon inhibiting viral DNA replication, but it is increasingly apparent that viral DNA levels can be chemically controlled by approaches that promote its instability. HPVs and other DNA viruses have a tenuous relationship with their hosts. They must replicate and hide from the DNA damage response (DDR) and innate immune systems, which serve to protect cells from foreign or "non-self" DNA, and yet they draft these same systems to support their life cycles. DNA binding antiviral agents promoting massive viral DNA instability and elimination are reviewed. Mechanistic studies of these agents have identified genetic antiviral enhancers and repressors, antiviral sensitizers, and host cell elements that protect and stabilize HPV genomes. Viral DNA degradation appears to be an important means of controlling HPV DNA levels in some cases, but the underlying mechanisms remain poorly understood. These findings may prove useful not only for understanding viral DNA persistence but also in devising future antiviral strategies. Full article

(This article belongs to the Special Issue Clinical Advances of Human Papillomaviruses)

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