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Biomedical subjects

Herbert Pfister

Publications and source records attributed to Herbert Pfister.

At least 19 recordsLinked to original sources
PubMed2006

Reactivation of an occult hepatitis B virus escape mutant in an anti-HBs positive, anti-HBc negative lymphoma patient.

BACKGROUND: Hepatitis B virus (HBV) often persists after resolution, but its replication is suppressed by antiviral T cells. Immunosuppressive treatment may lead to viral reactivation and severe hepatitis. Early antiviral therapy prevents reactivation but some occult HBV infections are not easily detectable. RESULTS: Here we describe a patient with a progressive non-Hodgkin lymphoma who had probably not been vaccinated against HBV and, before immunosuppression, showed antibodies (anti-HBs) against the viral surface antigen (HBsAg) as the only possible marker of occult HBV infection. Under immunosuppression he developed viremia (>10(8)copies/mL). The virus exhibited three S gene mutations (L109R, C137W, G145R) which led to false negative HBsAg results and diminished binding of vaccine-induced anti-HBs. CONCLUSIONS: Reliable screening and monitoring of severely immunosuppressed patients for HBV should include, in addition to anti-HBc and HBsAg, anti-HBs and sensitive HBV DNA assays. Furthermore, active vaccination or hepatitis B immune globulin may not protect against such mutants.

Adult↗
PubMed2006

Children and partners of patients with recurrent respiratory papillomatosis have no evidence of the disease during long-term observation.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm affecting the larynx and upper respiratory tract. The aim of our study was to investigate whether children and partners of patients with RRP develop the same disease and to determine whether there is an impact of pregnancy on the course of RRP. PATIENTS AND METHODS: Thirty-eight of 42 patients with RRP were accepted for a multicenter prospective study in Germany in 21.06.83-12.03.90. Mean follow-up duration was 15.3+/-1.8 years. The data of partners of patients with RRP was collected during the period of observation and then updated via interviews in January 2006. Twenty-nine children and four grandchildren were born to 14 patients with RRP. Fifteen of 448 cases of patients with RRP were treated in Saint Vladimir Moscow Children's Hospital in Russia in 1988-2003 and analyzed retrospectively. Sixteen children and one grandchild were born to 15 patients with RRP from Russia. In both studies, the virus type of patients with RRP was identified by nested PCR or Southern blot hybridization. Statistical analysis was performed using Fisher's exact test (probability value set at p<0.05). RESULTS: All children born to patients with RRP were healthy. RRP was not diagnosed in any of them on the basis of clinical or histological examination. Four of 45 children developed dysphonia, two of them had vocal cord nodules. None of the sexual partners of patients has developed RRP during the follow-up period. Pregnancy was accompanied by excessive growth of papillomas in all women (100%) with RRP associated with HPV type 11, and only in 16.7% of women with RRP associated with HPV type 6 (p=0.001). CONCLUSIONS: Patients with RRP are able to have healthy children regardless of the stage of the disease. Partners of RRP patients do not develop RRP during an observation period of 15 years. Pregnancy has a negative impact on the course of RRP and local laryngeal status in patients; it is more significant in HPV type 11 associated cases as it is manifested by more rapid papillomas growth and more frequent recurrence.

Adolescent↗
PubMed2006

Primary HIV drug resistance and efficacy of first-line antiretroviral therapy guided by resistance testing.

BACKGROUND: Primary HIV drug resistance has been associated with poor treatment outcome of first-line highly active antiretroviral therapy (HAART) in several trials. The aim of the study was to assess the efficacy of first-line HAART guided by resistance testing. METHODS: In a prospective multicenter study in the state of Nordrhein-Westfalen, Germany, chronically HIV-infected patients underwent genotypic resistance testing and were monitored for 48 weeks after initiation of HAART. RESULTS: Primary drug resistance was found in 30 of 269 patients entering the study between January 2001 and December 2003 [11.2%; 95% confidence interval, 7.4-14.9]. In intent-to-treat analysis, the proportion of patients with viral load below 50 copies/mL after 24 and 48 weeks was 70.0% and 66.7%, respectively, in patients with resistance and 74.1% and 73.6%, respectively, in patients without (P = 0.66 and 0.51). In on-treatment analysis, the proportions were 80.8% and 83.3%, respectively, in patients with resistance and 81.9% and 85.0%, respectively, in patients without (P= 0.79 and 0.77). These results were also valid considering a detection limit of 400 copies/mL. CONCLUSIONS: The prevalence of primary drug resistance was 11.2% in chronically HIV-infected patients. HAART guided by resistance testing had similar efficacy in patients with primary drug resistance as compared with patients with wild-type virus. Based on these facts, resistance-adapted first-line HAART is suggested as routine practice.

Adult↗
PubMed2006

Imiquimod treatment of anal intraepithelial neoplasia in HIV-positive men.

OBJECTIVE: To evaluate the treatment of anal intraepithelial neoplasia (AIN) with the local immune response modifier imiquimod in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). DESIGN: Prospective, nonrandomized, open-label pilot study, with a mean follow-up time of 9(1/2) months. SETTING: Dermatology department of a university hospital. Patients Twenty-eight consecutive HIV-positive MSM with histologically confirmed perianal (n = 23) or intra-anal (n = 5) AIN. Intervention Overnight treatment with self-applied imiquimod cream (perianal AIN) or suppositories (intra-anal AIN) 3 times a week for 16 weeks. MAIN OUTCOME MEASURES: Response to treatment was documented using clinical, cytologic, and histologic criteria. Human papillomavirus (HPV) typing and HPV DNA load determination for the high-risk HPV types 16, 18, 31, and 33 were performed. RESULTS: Seventeen (61%) of all 28 patients included in the study and 17 (77%) of the 22 patients with AIN, who applied imiquimod as instructed, showed clinical and histologic clearance at the end of therapy. Four patients had residual AIN and 1 patient did not improve. Clinical response was accompanied by a sharp decline in HPV DNA loads and by a reduction in the number of HPV types, but long-term HPV clearance was rarely achieved. In the follow-up period, AIN cleared in 3 patients with residual AIN. Fourteen (78%) of 18 imiquimod responders with at least 5 five months of follow-up had a normal cytologic and clinical picture at the end of the follow-up period. Three primary responders developed a recurrence. In 6 noncompliant patients, there was no clinical or morphological improvement and the HPV DNA loads remained high. CONCLUSIONS: Imiquimod appears to be a safe and effective treatment option for AIN in HIV-positive MSM. Clinical response is accompanied by a significant decrease in high-risk HPV DNA load. These results should encourage controlled randomized studies of imiquimod treatment of AIN.

Administration, Cutaneous↗
PubMed2006

Expression of matrix metalloproteinase (MMP)-2, MMP-9, MMP-13, and MT1-MMP in skin tumors of human papillomavirus type 8 transgenic mice.

Human papillomaviruses (HPV) are small DNA viruses that induce a wide variety of hyperproliferative lesions in cutaneous and mucosal epithelia. It is proposed that HPV is involved in non-melanoma skin cancer development. We have previously shown that HPV8 transgenic mice spontaneously develop papillomatous skin tumors. Histology revealed epidermal hyperplasia, acanthosis and hypergranulosis and in some cases squamous cell carcinomas (SCC). Zymographic and immunoblot analysis of normal skin extracts identified increased amounts of matrix metalloproteinase (MMP)-9, MMP-13 and MT1-MMP in HPV8-positive mice compared with HPV8-negative animals. In situ gelatin zymography of tumor specimens displayed a strong proteolytic activity in papillomas, and SCC putatively attributed to the increased amounts of activated MMP-9 found in tissue extracts. In addition, immunoblot analysis revealed increased amounts of active MMP-13 and MT1-MMP in tumor extracts as compared with control extracts. Immunohistochemical stainings of SCC specimens depicted MMP-13 to be specifically expressed in stromal fibroblasts neighboring the tumor islands, whereas MT1-MMP was detected both in tumor cells and in stromal cells. Taken together, these results implicate a role for MMPs in the development of HPV8-induced cutaneous tumors.

Animals↗
PubMed2005

Development of skin tumors in mice transgenic for early genes of human papillomavirus type 8.

The cutaneous human papillomavirus (HPV) 8 is clearly involved in skin cancer development in epidermodysplasia verruciformis patients and its early genes E2, E6, and E7 have been implicated in cell transformation in vitro. To examine the functions of these genes in vivo we integrated the complete early region of HPV8 into the genome of DBA/Bl6 mice. To target their expression to the basal layer of the squamous epithelia the transgenes were put under the control of the keratin-14 promoter. Transgenic mice were back-crossed for up to six generations into both FVB/N and Bl6 mouse strains. Whereas none of the HPV8 transgene-negative littermates developed lesions in the skin or any other organ, 91% of HPV8-transgenic mice developed single or multifocal benign tumors, characterized by papillomatosis, acanthosis, hyperkeratosis, and varying degrees of epidermal dysplasia. Squamous cell carcinomas developed in 6% of the transgenic FVB/N mice. Real-time reverse transcription-PCR showed highest expression levels for HPV8-E2, followed by E7 and E6. There was no consistent difference in relative viral RNA levels between healthy or dysplastic skin and malignant skin tumors. Whereas UV-induced mutations in the tumor suppressor gene p53 are frequently detected in human skin carcinomas, mutations in p53 were not observed either in the benign or malignant mouse tumors. Nonmelanoma skin cancer developed in HPV8-transgenic mice without any treatment with physical or chemical carcinogens. This is the first experimental proof of the carcinogenic potential of an epidermodysplasia verruciformis-associated HPV-type in vivo.

Animals↗
PubMed2005

Clinical spectrum and virologic characteristics of anal intraepithelial neoplasia in HIV infection.

BACKGROUND: Anal intraepithelial neoplasia (AIN) represents a precursor lesion of invasive squamous cell carcinoma with a clear association to high-risk human papillomavirus (HPV) types. HIV infection is strongly associated with a higher prevalence of genital HPV infection, a higher incidence of AIN, and, consecutively, an increased risk for anal cancer. OBJECTIVE: The aim of this study was to determine the clinical spectrum of AIN and lesional HPV colonization in a cohort of homosexual men who were HIV positive and had a history of receptive anal intercourse. METHODS: In all, 103 men who were HIV-1 positive were screened by using clinical, proctologic, cytologic, histologic, and HPV DNA testing. RESULTS: Of all patients, 86% had anal HPV infection at their first visit. HPV-16 (53%), HPV-18 (27%), HPV-58 (22%), and HPV-83 (22%) were the most frequently found HPV types. AIN was diagnosed in 20 of the 103 patients (19.4%). High-risk HPV types were present in all AIN cases with up to 7 different high-risk and up to 5 different low-risk types per lesion. Histologically, 7 (35%), 7 (35%), and 6 (30%) of the patients had AIN grade I, II, or III, respectively. Four different types of clinical presentation could be distinguished in the 20 patients with AIN: bowenoid (1 case, 5%); erythroplakic (2 cases, 10%); verrucous (6 cases, 30%); and leukoplakic (11 cases, 55%). All verrucous lesions were graded as high-grade intraepithelial lesions in cytology, whereas 6 of the 11 leukoplakic lesions (55%) were low grade. All verrucous AIN carried at least 4 different HPV types, always including HPV-16, and the mean number of HPV types was higher in verrucous lesions than in leukoplakic lesions (5.5 vs 3.8, respectively). CONCLUSION: These data confirm the high incidence and prevalence of AIN in patients who are HPV positive with HIV infection. Four different clinical types of AIN can be distinguished that might have prognostic implications. Standardized screening programs for anal cancer prevention and treatment protocols for AIN in patients infected with HIV must be implemented.

Adult↗
PubMed2005

Human papillomavirus-DNA loads in actinic keratoses exceed those in non-melanoma skin cancers.

Recent studies suggest a role of cutaneous human papillomaviruses (HPV) in non-melanoma skin cancer (NMSC) development. In this study viral DNA loads of six frequent HPV types were determined by quantitative, type-specific real-time-PCR (Q-PCR) in actinic keratoses (AK, n=26), NMSC (n=31), perilesional tissue (n=22), and metastases of squamous cell carcinomas (SCC) (n=8) which were previously shown to be positive for HPV5, 8, 15, 20, 24, or 36. HPV-DNA loads in AK, (partially microdissected) NMSC, and perilesional skin ranged between one HPV-DNA copy per 0.02 and 14,200 cell equivalents (median: 1 HPV-DNA copy per 344 cell equivalents; n=48). In 32 of the 79 HPV-positive skin biopsies and in seven of the eight metastases viral loads were even below the detection limit of Q-PCR. Low viral loads in NMSC were confirmed by in situ-hybridization showing only a few HPV-DNA-positive nuclei per section. Viral loads in SCC, basal cell carcinomas, and perilesional tissue were similar. But, viral loads found in AK were significantly higher than in SCC (p=0.035). Our data suggest that persistence of HPV is not necessary for the maintenance of the malignant phenotype of individual NMSC cells. Although a passenger state cannot be excluded, the data are compatible with a carcinogenic role of HPV in early steps of tumor development.

Adult↗
PubMed2005

Use of interferon-alpha in recurrent respiratory papillomatosis: 20-year follow-up.

OBJECTIVES: The aim of this study was analysis of the results of use of interferon-alpha (IFN-alpha) in patients with recurrent respiratory papillomatosis (RRP) and correlation of the results with human papillomavirus (HPV) type. METHODS: A multicenter prospective series (42 patients from 22 hospitals) yielded 20 years of follow-up of patients with RRP and HPV typing who were treated with IFN-alpha in doses of 3 MU/m2 3 times per week. RESULTS: During long-term follow-up (mean +/- SD, 172 +/- 36.8 months), the rate of event-free survival evaluated by Kaplan-Meier analysis was 42.8%, and the overall survival rate was 82.6%. The HPV typing revealed an association of HPV 11 with a more aggressive disease course (64% of HPV 11 patients versus 24% of HPV 6 patients), a lower incidence of long-term response to IFN-alpha therapy (14% of HPV 11 patients versus 64% of HPV 6 patients), and a higher incidence of malignant transformation and mortality during follow-up (36% and 24%, respectively, of HPV 11 patients versus 0% of HPV 6 patients). CONCLUSIONS: The obtained results revealed maximal effectiveness of IFN-alpha therapy in RRP patients with HPV 6 as compared with HPV 11. The association of HPV 11 with a worse long-term response to IFN-alpha therapy and a higher incidence of malignant transformation and mortality is clinically important and indicates the necessity of HPV typing in RRP patients after the first biopsy.

Adolescent↗
PubMed2005

Circulating soluble tumour necrosis factor receptors in patients with epidermodysplasia verruciformis as compared to patients with cutaneous tumours in the general population.

Soluble tumour necrosis factor receptors type I and II (sTNF-RI and II) were evaluated in sera from patients with epidermodysplasia verruciformis and patients with cutaneous warts, actinic keratoses, squamous cell carcinomas or basal cell carcinomas by specific enzyme-linked immunobiological assays. In patients with widespread epidermodysplasia verruciformis lesions, the levels of both sTNF-Rs were in normal range. Both types of sTNF-Rs were significantly increased in patients with warts. The levels of sTNF-RI were significantly increased in patients with multiple actinic keratoses, squamous cell carcinoma and basal cell carcinoma. Increased levels of circulating sTNF-Rs may facilitate development of cutaneous tumours. Normal levels of sTNF-Rs in patients with epidermodysplasia verruciformis might, at least partially, contribute to a slow growth and low metastatic potential of cancers in these patients.

Adult↗
PubMed2004

The human papillomavirus type 8 E2 protein suppresses beta4-integrin expression in primary human keratinocytes.

Human papillomaviruses (HPVs) infect keratinocytes of skin and mucosa. Homeostasis of these constantly renewing, stratified epithelia is maintained by balanced keratinocyte proliferation and terminal differentiation. Instructions from the extracellular matrix engaging integrins strongly regulate these keratinocyte functions. The papillomavirus life cycle parallels the differentiation program of stratified epithelia, and viral progeny is produced only in terminally differentiating keratinocytes. Whereas papillomavirus oncoproteins can inhibit keratinocyte differentiation, the viral transcription factor E2 seems to counterbalance the impact of oncoproteins. In this study we show that high expression of HPV type 8 (HPV8) E2 in cultured primary keratinocytes leads to strong down-regulation of beta4-integrin expression levels, partial reduction of beta1-integrin, and detachment of transfected keratinocytes from underlying structures. Unlike HPV18 E2-expressing keratinocytes, HPV8 E2 transfectants did not primarily undergo apoptosis. HPV8 E2 partially suppressed beta4-integrin promoter activity by binding to a specific E2 binding site leading to displacement of at least one cellular DNA binding factor. To our knowledge, we show for the first time that specific E2 binding contributes to regulation of a cellular promoter. In vivo, decreased beta4-integrin expression is associated with detachment of keratinocytes from the underlying basement membrane and their egress from the basal to suprabasal layers. In papillomavirus disease, beta4-integrin down-regulation in keratinocytes with higher E2 expression may push virally infected cells into the transit-amplifying compartment and ensure their commitment to the differentiation process required for virus replication.

Apoptosis↗
PubMed2003

High prevalence of epidermodysplasia verruciformis-associated human papillomavirus DNA in actinic keratoses of the immunocompetent population.

Skin cancers in both immunosuppressed and immunocompetent populations are associated with epidermodysplasia verruciformis human papillomavirus (EV-HPV) DNA. However, little is known about the prevalence of EV-HPVs in actinic keratoses in immunocompetent individuals. Actinic keratoses from 114 patients were classified as low-grade ( n=76) or high-grade ( n=38) according to the extent of histological atypia. HPV DNA was amplified from 54 frozen and 60 paraffin-embedded biopsy specimens by nested polymerase chain reaction (PCR) with several consensus and type-specific primers. PCR products were sequenced for typing. These results were compared with HPV detection in skin cancers ( n=20) and Bowen's disease ( n=18). A broad spectrum of EV-HPV types including oncogenic HPV5 and HPV8 and partially characterized sequences were detected in actinic keratoses and cutaneous cancers. In actinic keratoses a higher prevalence of EV-HPV DNA was found in frozen tissues than in formalin-fixed tissues (85% vs 67%). There was no difference between the low- and high-grade actinic keratoses either in terms of EV-HPV DNA prevalence or the results of serological study using HPV8 virus-like particles. The detection rate of EV-HPVs was lower in skin cancers and Bowen's disease. This would suggest involvement of EV-HPVs in the early stages of cutaneous oncogenesis.

Antibodies, Viral↗
PubMed2003

Chapter 8: Human papillomavirus and skin cancer.

A high prevalence of human papillomavirus (HPV) DNA, particularly in squamous cell skin carcinoma of immunosuppressed but also of immunocompetent patients, has renewed great interest in a possible etiologic role of HPV in nonmelanoma skin cancer. It is difficult, however, to interpret these findings against a background of low-level infections with multiple HPV types from supergroup B (HPV4-related and epidermodysplasia verruciformis [EV] HPV), probably acquired by everyone early in and throughout life. Thus far, no high-risk HPV types have been identified. Because of the low copy numbers of HPV DNA in skin cancers, probably not every tumor cell contains a viral genome, which is compatible with cutaneous HPV being possibly important for tumor initiation and progression, but not for maintenance of the malignant phenotype. The question with regard to high-risk types should, therefore, be readdressed in case-control studies on the basis of serology, which can reveal viral activities over years. The viruses lingering in all people are apparently activated by sunlight (UV) exposure, by immunosuppression, and by hyperproliferation of the epithelium (psoriasis) and/or in the specific genetic background of the host (EV). It is intriguing that most of these factors are established risk factors in skin carcinogenesis. The weak transforming activity of cutaneous HPV in vitro compared with the transforming activity of genital HPV may explain the need for activators and synergistic factors. The antiapoptotic activities of E6 proteins of cutaneous HPV could be relevant to oncogenesis in the interplay with UV exposure. Prospective studies should determine the kinetics of HPV activation relative to tumor development.

Carcinoma, Squamous Cell↗