Strains Of Papillomavirus Research Articles

FDA approves Gardasil 9 to protectagainst five more HPV types

Since 2006, when FDA approved the first vaccine for the preventionof certain strains of human papillomavirus (HPV), CDC’s AdvisoryCommittee on Immunization Practices (ACIP) has recommendedGardasil (Merck) in three doses for routine vaccination of adolescent girlsand boys aged 11–12 years. FDA-approved Cervarix (GlaxoSmithKline)is a similar vaccine recommended for girls this age as well

Detection of human papilloma virus (HPV) and human immunodeficiency virus (HIV) in oral squamous cell carcinoma: A polymerized chain reaction (PCR) study

Aims and Objectives: Certain strains of human papillomavirus (HPV) have been shown to be etiologically related to the development of uterine, cervical, and other genital cancers, but their role in the development of malignancies at other sites is less well established. Previous studies have shown HPV in tumors of the head and neck, but its prevalence has varied depending on the detection methods and the types of tumor and/or tissue examined. This study was undertaken for the detection of high-risk HPV types 16 and 18 and human immunodeficiency virus (HIV) in oral squamous cell carcinoma. Materials and Methods: Twenty-five patients histologically diagnosed with oral squamous cell carcinoma and 10 apparently normal persons as controls were selected for the present study. Two biopsy specimens were removed surgically by incision biopsy for histopathological examination and polymerized chain reaction (PCR) study. Results: Out of 25 oral squamous cell carcinoma subjects, 8 were found to be HPV positive in PCR. Out of these eight subjects, four had HPV 16 and the other four had other genotypes, and one subject was HIV positive. Conclusion: The conclusion drawn from the present study was that well-defined risk factors like HPV may play a prominent role in the development of oral squamous cell carcinomas, in addition to other risk factors. Further studies with a larger sample size are necessary to arrive at conclusions and to explore the relationship of HPV and HIV in oral squamous cell carcinoma.

The High-Risk HPV16 E7 Oncoprotein Mediates Interaction between the Transcriptional Coactivator CBP and the Retinoblastoma Protein pRb

The oncoprotein E7 from human papillomavirus (HPV) strains that confer high cancer risk mediates cell transformation by deregulating host cellular processes and activating viral gene expression through recruitment of cellular proteins such as the retinoblastoma protein (pRb) and the cyclic-AMP response element binding binding protein (CBP) and its paralog p300. Here we show that the intrinsically disordered N-terminal region of E7 from high-risk HPV16 binds the TAZ2 domain of CBP with greater affinity than E7 from low-risk HPV6b. HPV E7 and the tumor suppressor p53 compete for binding to TAZ2. The TAZ2 binding site in E7 overlaps the LxCxE motif that is crucial for interaction with pRb. While TAZ2 and pRb compete for binding to a monomeric E7 polypeptide, the full-length E7 dimer mediates an interaction between TAZ2 and pRb by promoting formation of a ternary complex. Cell-based assays show that expression of full-length HPV16 E7 promotes increased pRb acetylation and that this response depends both on the presence of CBP/p300 and on the ability of E7 to form a dimer. These observations suggest a model for the oncogenic effect of high-risk HPV16 E7. The disordered region of one E7 molecule in the homodimer interacts with the pocket domain of pRb, while the same region of the other E7 molecule binds the TAZ2 domain of CBP/p300. Through its ability to dimerize, E7 recruits CBP/p300 and pRb into a ternary complex, bringing the histone acetyltransferase domain of CBP/p300 into proximity to pRb and promoting acetylation, leading to disruption of cell cycle control.

Cervical cancer incidence in ontario women: differing sociodemographic gradients by morphologic type (adenocarcinoma versus squamous cell).

Identify patterns in cervical cancer incidence in Ontario according to neighborhood sociodemographic characteristics over time and by morphologic type. Incident cases of cervical cancer diagnosed from 1991 to 2009 were obtained from the Ontario Cancer Registry. Population data and data on neighborhood sociodemographic characteristics were obtained from the Canadian Census. Age-standardized incidence rates (ASIR) and rate ratios (RRs) with 95% confidence intervals (CIs) were calculated for each sociodemographic characteristic, stratified by morphologic type (squamous cell carcinoma and adenocarcinoma) and time period of diagnosis. Incidence was 51% higher in the poorest neighborhoods compared with the richest (RR, 1.51; 95% CI, 1.42-1.61) and 7% higher in rural areas compared with urban (RR, 1.07; 95% CI, 1.01-1.13). Incidence of squamous cell carcinoma was significantly higher in the poorest neighborhoods compared with the richest (RR, 1.74; 95% CI, 1.61-1.88), a trend observed for all time periods, and in rural areas compared with urban (RR, 1.10; 95% CI, 1.02-1.18). For adenocarcinoma, ASIRs in the earlier time period (1991-1998) were higher in the poorest neighborhoods compared with richest (RR, 1.26; 95% CI, 1.01-1.57), whereas for the more recent time period (1999-2009), ASIRs were lower for women living in the poorest neighborhoods compared with the richest (RR, 0.82; 95% CI, 0.68-0.99). This study identified significantly higher incidence of cervical cancer in low-income neighborhoods in Ontario. The association was especially pronounced for squamous cell carcinoma and varied by time period for adenocarcinoma. Improvements to screening and prevention efforts against oncogenic human papillomavirus strains would increase the detection of cervical cancer, adenocarcinoma especially, and may further reduce cervical cancer incidence.

HPV vaccine stimulates cytotoxic activity of killer dendritic cells and natural killer cells against HPV-positive tumour cells.

Cervarix™ is approved as a preventive vaccine against infection with the human papillomavirus (HPV) strains 16 and 18, which are causally related to the development of cervical cancer. We are the first to investigate in vitro the effects of this HPV vaccine on interleukin (IL)-15 dendritic cells (DC) as proxy of a naturally occurring subset of blood DC, and natural killer (NK) cells, two innate immune cell types that play an important role in antitumour immunity. Our results show that exposure of IL-15 DC to the HPV vaccine results in increased expression of phenotypic maturation markers, pro-inflammatory cytokine production and cytotoxic activity against HPV-positive tumour cells. These effects are mediated by the vaccine adjuvant, partly through Toll-like receptor 4 activation. Next, we demonstrate that vaccine-exposed IL-15 DC in turn induce phenotypic activation of NK cells, resulting in a synergistic cytotoxic action against HPV-infected tumour cells. Our study thus identifies a novel mode of action of the HPV vaccine in boosting innate immunity, including killing of HPV-infected cells by DC and NK cells.

"If you can't treat HPV, why test for it?" Women's attitudes to the changing face of cervical cancer prevention: a focus group study.

BackgroundThe relationship between infection with high-risk strains of human papillomavirus (HPV) and cervical cancer is transforming prevention through HPV vaccination and HPV oncogenic testing. In Ireland, a national cervical cancer screening programme and HPV vaccination were recently launched; HPV testing is currently being integrated into the screening programme. Women’s views on the transformation of cervical cancer prevention have been relatively little investigated.MethodsUsing qualitative focus groups, we determined women’s knowledge, attitudes towards, and acceptability of cervical cancer screening, HPV oncogenic testing and vaccination of HPV. Fifty nine women, recruited through primary care in Ireland, participated in ten focus groups. A dynamic topic guide was developed from literature reviewed. Women were provided with standardised information about HPV infection, HPV testing. Discussion transcripts were analysed thematically.ResultsThe primary themes that emerged regarding HPV infection were: knowledge, emotional response and societal influences; especially those of healthcare practitioners. Knowledge, logistics, and psychological impact were the primary themes relating to HPV testing. Women’s attitudes towards HPV testing changed during discussion as issues were explored, thus demonstrating the complexity of this issue; lack of existing treatment for HPV infection influenced women’s attitudes, attachment to existing cervical cancer screening also was a significant factor.ConclusionsWomen currently have a strong attachment to cytology and any changes towards HPV primary testing will need to be managed carefully. To ensure that future cervical cancer prevention strategies will be acceptable to women, sufficient thought will have to be given to information provision and education. We identified the importance to women of healthcare practitioners’ opinions regarding HPV. Appropriate and timely information on HPV will be crucial in order to minimise possible psychological effects women may have.

Oncogenic Viral Prevalence in Invasive Vulvar Cancer Specimens From Human Immunodeficiency Virus–Positive and -Negative Women in Botswana

The primary aim of this study was to describe the prevalence of select oncogenic viruses within vulvar squamous cell carcinoma (VSCC) and their association with human immunodeficiency virus (HIV) status in women in Botswana, where the national HIV prevalence is the third highest in the world. A cross-sectional study of biopsy-confirmed VSCC specimens and corresponding clinical data was conducted in Gaborone, Botswana. Polymerase chain reaction (PCR) and immunohistochemistry (IHC) viral testing were done for Epstein-Barr virus, human papillomavirus (HPV) strains, and Kaposi sarcoma herpesvirus, and PCR viral testing alone was done for John Cunningham virus. Human papillomavirus prevalence by PCR was 100% (35/35) among tested samples. Human papillomavirus type 16 was the most prevalent HPV strain (82.9% by PCR, 94.7% by either PCR or IHC). Kaposi sarcoma herpesvirus prevalence by PCR had a significant association with HIV status (P = 0.013), but not by IHC (P = 0.650). The high burden of HPV, specifically HPV16, in vulvar squamous cell cancer in Botswana suggests a distinct HPV profile that differs from other studied populations, which provides increased motivation for HPV vaccination efforts. Oncogenic viruses Kaposi sarcoma herpesvirus and Epstein-Barr virus were also more prevalent in our study population, although their potential role in vulvar squamous cell cancer pathology is unclear.

Robotic Surgery for Oropharyngeal Cancer

Oropharyngeal cancer represents a growing proportion of head and neck malignancies. This has been associated with the increase in infection of the oropharynx by oncogenic strains of human papillomavirus (HPV). Transoral robotic surgery (TORS) has opened the door for minimally invasive surgery for HPV-related and non-HPV-related oropharyngeal cancer. Compared to traditional open surgical approaches, TORS has been shown to improve functional outcomes in speech and swallowing, while maintaining good oncologic outcomes.

Antibody avidity measurements in recipients of Cervarix® vaccine following a two-dose schedule or a three-dose schedule

The HPV-16/18 vaccine (Cervarix®) is a prophylactic vaccine for the prevention of cervical cancer and contains recombinant virus-like particles (VLPs) assembled from the L1 major capsid proteins of human papillomavirus (HPV) strains 16 and 18. Although a correlate of protection has yet to be identified, HPV-specific antibodies are thought to prevent virus infection of the genital mucosa. Therefore, antigen-specific antibodies as assessed by ELISA or pseudovirion-based neutralisation assay are frequently measured in clinical trials to substantiate the immune responses induced by the vaccine. Measuring antigen-antibody binding avidities, which reflects the degree of affinity maturation in the B-cells, is another valuable method to assess the quality of the antibody responses. Here we describe the antigen-specific antibody avidities in samples taken from a clinical trial examining the feasibility of adopting a two-dose (Months 0 and 6) schedule for 9–14 year olds instead of the three-dose schedule (Months 0, 1 and 6). Antibody avidity (i.e. avidity index [AI]) was determined in the ELISA by the ratio of antibody concentrations in serum samples treated or not with the chaotropic agent NaSCN. Importantly, in the comparison between the groups of two-dose and three-dose recipients, no differences in AIs were observed at Months 7, 24 and 48. The results suggest that from Month 7 to 48, the quality of the antibody response in terms of avidity was similar in the two-dose recipients to that in the three-dose recipients. Hence these results support the adoption of a two-dose schedule in 9–14 year-old girls.

Acquired epidermodysplasia verruciformis in a renal transplant recipient - Case report

A 24-year-old male patient, who underwent kidney transplant six years ago due to Lupus nephritis, for the last two years presented asymptomatic erythematous scaly plaques on the abdomen and areas exposed to light. Post-transplantation immunosuppressive medications included prednisone, mycophenolate sodium and sirolimus. The histopathologic features were typical for epidermodysplasia verruciformis. Epidermodysplasia verruciformis is a rare autosomal recessive genodermatosis with increased susceptibility to specific strains of cutaneous human papilloma virus. The term ''acquired epidermodysplasia verruciformis'' was recently introduced to the literature and describes epidermodysplasia verruciformis occurring in patients with impaired cell-mediated immunity. We report an additional case associated to immunosuppression after kidney transplantation.

Self-Construal as a Predictor of Korean American Women's Intention to Vaccinate Daughters against Human Papillomavirus.

Korean Americans represent one of the fastest growing Asian subpopulations in the United States. Despite a dramatic reduction in incidence nationwide, cervical cancer remains a major threat for Korean American women. By preventing the strains of the Human Papillomavirus (HPV) known to cause cervical cancer, the HPV vaccines appear to be a promising solution to reduce the persistent disparities in cervical cancer among not only Korean Americans, but also other racial and ethnic minorities more generally. However, current literature lacks a better understanding of how cultural and behavioral factors influence Korean American women's intention to vaccinate their adolescent daughters against HPV. This manuscript presents the results of testing the mechanisms through which interdependent self-construal (an orientation of self in which individuals define themselves primarily through their relationships with others), attitudes, and subjective norms impact Korean American mothers' intention to vaccinate their daughters. Our findings suggest that self-construal holds promise for health communication research to not only uncover the rich variance of health-related beliefs among individuals of shared cultural descent, but also to understand the context in which these beliefs are embedded.

Identification of a Novel Strain of Human Papillomavirus from Children with Diarrhea in China

A highly divergent human papillomavirus (HPV) strain, HPV-L55, was identified in fecal samples from children hospitalized with diarrhea in China. The L1 gene of HPV-L55 shares <75% identity with previously reported HPVs, indicating that this virus represents a novel type of HPV. Phylogenetic analysis classified this virus as a member of the gammapapillomaviruses.

P2.084 A Case of Rapid Clearance of Penile Bowenoid Papulosis with Imiquimod Cream

Introduction Bowenoid papulosis is a form of penile intraepithelial neoplasia associated with the oncogenic human papilloma virus (HPV) strains 16, 18, 31 and 33. It occurs in young sexually active patients and has a low risk of progressing to invasive squamous cell carcinoma. Case report The patient was a 31 year old chinese male who presented with a 3 month pruritic rash over his glans penis. Previous treatment with hydrocortisone cream had caused more lesions to appear and was stopped. On examination, there were multiple erythematous discrete papules over the glans penis and a cluster of papules at the inner prepuce. A skin biopsy was consistent with bowenoid papulosis showing a thickened epidermis with full thickness atypical keratinocytes with loss of normal polarity. A band like infiltrate of lymphocytes, plasma cells and eosinophils was present within the dermis. The rest of his sexually transmitted infection screen including syphilis serology and human immunodeficiency virus tests were negative. He was started on topical imiquimod three applications per week and noted complete clearance of the prepuce lesions after two weeks, with flattening of the lesions on the glans. All lesions were noted by the patient to have cleared after four weeks of imiquimod use, and only post inflammatory hyperpigmentation was noted at his review after six weeks. Minimal side effects were noted by the patient except for transient itch. Discussion We report our first case of penile bowenoid papulosis responding to imiquimod monotherapy, and is the 5th reported case to date. Our case demonstrates one of the most rapid clinical clearance within six weeks, after only four weeks of imiquimod application. Other treatment modalities like electrocurrettage, 5-fluorouracil or topical interferon have all been associated with recurrence. Immunomodulatory treatment for this condition appears safe and efficacious, with the added convenience of being patient administered.

Current treatment options for management of anal intraepithelial neoplasia.

Anal squamous cell cancer is an uncommon malignancy caused by infection with oncogenic strains of Human papilloma virus. Anal cancer is much more common in immunocompromised persons, including those infected with Human immunodeficiency virus. High-grade anal intraepithelial neoplasia (HGAIN), the precursor of anal cancer, is identified by clinicians providing care for patients with anorectal disease, and is increasingly being identified during screening of immunosuppressed patients for anal dysplasia. The traditional treatment for HGAIN has been excision of macroscopic disease with margins. This approach is effective for patients with small unifocal HGAIN lesions. Patients with extensive multifocal HGAIN frequently have recurrence of HGAIN after excision, and may have postoperative complications of anal stenosis or fecal incontinence. This led to the suggestion by some that treatment for HGAIN should be delayed until patients developed anal cancer. Alternative approaches in identification and treatment have been developed to treat patients with multifocal or extensive HGAIN lesions. High-resolution anoscopy combines magnification with anoscopy and is being used to identify HGAIN and determine treatment margins. HGAIN can then be ablated with a number of modalities, including infrared coagulation, CO2 laser, and electrocautery. These methods for HGAIN ablation can be performed with local anesthesia on outpatients and are relatively well tolerated. High-resolution anoscopy-directed HGAIN ablation is evolving into a standard approach for initial treatment and then subsequent monitoring of a disease which should be expected to be recurrent. Another treatment approach for HGAIN is topical treatment, principally with 5-fluorouracil or imiquimod. Topical therapies have the advantage of being nonsurgical and are well suited for treating widespread multifocal disease. Topical treatments have the disadvantage of requiring extended treatment courses and causing a symptomatic inflammatory response. Successful treatment requires adherence to a regime that is uncomfortable at best and at worst painful. Topical treatments can be successful in motivated adherent patients willing to accept these side effects.

Bovine Papillomavirus Type 13 DNA in Equine Sarcoids

Equine sarcoids are locally aggressive fibroblastic neoplasms considered to be the most common skin tumors of horses worldwide. Bovine papillomavirus types 1 and 2 have typically been associated with sarcoids in equids. Investigations aiming to identify papillomavirus strains, aside from bovine papillomaviruses 1 and 2, which might be associated with sarcoid lesions, have been lacking. The aim of this article is to report the identification of a third bovine papillomavirus type, bovine papillomavirus 13, associated with equine sarcoids. Six sarcoid lesions were collected from diverse anatomical sites on two horses from southern Brazil. To detect a broad spectrum of papillomavirus strains, eight degenerate primer pairs designed to detect conserved regions on the L1 and E1 genes were tested on the DNA samples. Direct sequencing was then performed on the obtained amplicons, and sequence identities were compared with sequences from all bovine papillomavirus types. The FAP59/FAP64, MY09/MY11, and AR-E1F2/AR-E1R4 sequences generated from the sarcoids were shown to present 99 to 100% identity with bovine papillomavirus 13, a new bovine papillomavirus type previously described in cattle. The results from this study suggest that there is a need to identify bovine papillomavirus type 13 and other papillomavirus strains that might be associated with sarcoids in diverse geographical areas; such investigations might establish the frequency of occurrence of this viral type in these common tumors of equids.

Coronary Artery Disease as Clogged Pipes

A recent advertisement on the back cover of a special health issue of the New York Times Magazine section read “Ironic that a plumber came to us to help him remove a clog.”1 The ad referred to doctors in the cardiac catheterization laboratory as “one kind of pipe specialist,” and noted that the patient in the ad returned to work “just 2 days after having his own pipes cleaned out.” Although the image of coronary arteries as kitchen pipes clogged with fat is simple, familiar, and evocative, it is also wrong. Conceptual models help us to make sense of a complex world. In both research and clinical practice, our conceptual models inform our decisions about which outcomes to measure, which confounders to adjust for, and which patients are likely to benefit from a particular treatment. For example, the model of cervical cancer as the consequence of infection with certain strains of human papilloma virus has led to the development of a vaccine to prevent cancer. However, when a conceptual model is flawed, as in the case of the clogged pipes analogy, we are supposed to discard it and replace it with a more accurate one. In Structure of Scientific Revolutions , Kuhn observed that such paradigm shifts do not occur easily.2 Instead, scientists cling tenaciously to the old, accepted model, despite its inability to explain observed phenomena. In medicine, too, misconceptions embedded in an outdated model may linger for years, influencing physicians’ practice and patients’ expectations. Simple models, especially those we have worked for years to get the public to understand, may be the hardest to abandon. The clogged pipe analogy of stable coronary heart disease has been particularly difficult to dislodge. This representation had its origins in the 1970s, when researchers observed that the degree of coronary …

Evolutionary Perspective of Human Papilloma Virus Infection in Humans

The Human Papilloma Virus (HPV) strains (16 and 18 mainly) have been proved to be the major cause of cancers of cervix, vulva, penis, Oropharyngeal tissues and many others. HPV infection spreads mainly through sexual intercourse. There are very limited non-sexual modes of HPV transmission available. Sexual intimacy, which includes kissing, is a major mode of transmission in case of HPV whereas in the case of other sexually transmitted infections like HIV and HBV non-sexual factors like contaminated blood transfusions contribute significantly in the spread of the virus to the other host. According to recent research, the HPV virus has been found to be associated with oral and breast cancers which have been linked with the rampant trend of oral sex among the western youth. The virus has adopted to colonize the oral cavity thus creating a new opportunity to spread through passionate kissing which has been confirmed by genotyping. Intense selection pressure can select virus to manipulate the host sexual behavior in a way that facilitates transmission. The selection pressure for such manipulations is very strong in the countries having conservative societies like India, Srilanka, Nepal, Bangladesh and others where sexuality still remains a taboo. People in these countries generally disapprove love marriage, premarital sex and having multiple sex partners. Majority of the population avoids more than one sex partner post-marriage in their entire lifetime. This is a very serious constraint for the virus to get into new hosts. DNA viruses like high risk HPV strains can produce substantial number of variants owing to factors like large population sizes, long infection time and hypermutation of the epitopes which can lead to significant evolution of virus within the host. Evolutionary Medicine can help us to understand infectious diseases better and thus take a step closure to their cure.

Screening for cervical cancer

Cervical cancer is one of the most common gynecological oncopathology on women. It was shown that cervical cancer can be caused by oncogenic strains of human papillomavirus (HPV). So it is important to timely prevent the disease through regular screening of women (particularly of risk group) and vaccination against HPV. The article contains recommendations Society of Obstetricians and Gynecologists of Canada regarding the regular cytological screening for cervical cancer – its benefits, methods, features and so on.

Transformation of Tobacco cpDNA with Fusion E7GGG/GUS Gene and Homologous Recombination Mediated Elimination of the Marker Gene

ABSTRACTA transformation vector harboring the marker gene aadA conferring spectinomycin resistance and the fusion E7GGG/gus gene of interest was employed for the transformation of tobacco cpDNA via biolistics. The gene of interest consisted of the oncogenic E7GGG gene from human papillomavirus strain 16 fused with the reporter gus gene. Both transgenes were equipped with the same promoter and termination sequences arranged as direct repeats. Biolistics with circular vector yielded 20 shoots rooted in spectinomycin containing medium; with linear vector no rooted plants were obtained. After 4 months of in vitro selection the plants were burst into flower in a greenhouse and pollinated with non-transgenic plant pollen. Seeds were harvested individually from each plant capsule and planted onto selection medium. Rare white seedlings were recovered by transfer onto medium without spectinomycin and self-pollinated. GUS activity of 15 seedlings from each self-pollinated plant was measured and 26 plants with higher activity (and one without any GUS activity) were PCR analyzed for the presence of both the marker gene and the gene of interest. Finally, 8 plants were analyzed in detail by Southern hybridization, RT-PCR, and Western blot. We identified 6 plants harboring the E7GGG/gus gene only, where the marker gene was eliminated by homologous recombination; one plant with both transgenes; and one with the aadA gene only. RT-PCR showed the presence of the respective mRNAs in all 8 plants analyzed but Western blot proved that only the GUS part of the fusion E7GGG/GUS protein was present in all plants harboring the fusion gene. We discuss why E7GGG protein could not be detected.

Basic consideration of research strategies for head and neck cancer

Head and neck cancer (HNC) consists of a group of malignancies affecting closely related anatomical regions of the upper aerodigestive tract (UADT), including the oral cavity, salivary glands, upper and lower jaw bones and facial skin; the nasal cavity, paranasal sinuses, pharynx, larynx and thyroid gland (although the latter is often excluded and considered as part of endocrine neoplasms). Of these, 90% of HNCs are histologically squamous cell carcinomas originating from the mucosal lining. These malignancies are strongly associated with certain environmental and life-style risk factors, principally tobacco in both smoked and smokeless forms, excessive alcohol consumption, diets poor in antioxidants and essential micronutrients, UV light, chemicals used in certain workplaces, and viruses, principally certain strains of human papillomavirus (HPV) and Epstein-Barr virus (EBV). These cancers are frequently aggressive in their biological behaviour with local invasion and metastasis to lymph nodes in the neck. Since most patients are already at late stages of disease at the time of diagnosis, the desirable practice of early diagnosis (first sign of the malignant lesion at an initial stage) and early treatment, a critical priority to save lives and retain quality of life, is difficult to implement. Thus, primary prevention has been set as a key goal. This article aims to reinforce the basic knowledge of aetiology, key risk factors related to the development of head and neck cancer, basic features of clinical appearance of this group of cancers, and strategies for prevention and early detection.We also suggest basic research strategies on the basis of current knowledge, which should ultimately lead to the improvement of clinical management.