Condylomata acuminata, or genital warts, are proliferative lesions of genital epithelium caused by human papillomavirus (HPV) infection. HPV types 6 and 11 are most often detected in these lesions. Genital lesions consistent with exophytic condylomata acuminata were removed by excision biopsy from 65 patients, 41 of whom were otherwise healthy individuals (control group) and 24 of whom had conditions known to cause immunosuppression. Histologically, the majority of the lesions were typical condylomata acuminata. Three lesions removed from immunosuppressed individuals also contained foci of moderate to severe dysplasia (intraepithelial neoplasia grade II/III). A recently developed PCR and reverse blot strip assay was used to determine the specific HPV types present in the genital lesions. With a set of oligonucleotide primers based on the same primer binding regions used for the MY09 and MY11 primer pair, this PCR assay detects the presence of 27 HPV types known to infect the genital tract. All but two condylomata acuminata contained either HPV type 6 or 11. The predominant type in the lesions from control patients was HPV 6, while lesions from immunosuppressed types most often contained HPV 11. Condylomata acuminata from immunosuppressed patients contained significantly more overall HPV types than lesions from the control group. HPV types associated with an increased risk of dysplasia (high-risk types) were detected in 42 (64.6%) of the total of 65 specimens; 18 (43.9%) specimens were detected in the 41 otherwise healthy individuals, and 24 (100%) specimens were detected in the 24 immunosuppressed patients. HPV 16 was the most common high-risk type detected, found in 21 of 65 (32.3%) specimens. After HPV types 6 and 11, HPV types 53 and 54 were the most frequently detected low-risk HPV types. This study demonstrates that a high percentage of condylomata acuminata lesions contain multiple HPV types, including types associated with a high risk of dysplastic abnormalities. Further studies are needed to determine the influence these additional HPV types have on the epidemiology of genital tract HPV infections and the natural history of condylomata acuminata, especially in immunosuppressed patients.
Exophytic condylomata acuminata of the external genitalia of 40 patients were analyzed for human papillomavirus (HPV) DNA by the Southern blot and hybrid capture methods. All lesions were initially analyzed by the Southern blot method by using a mixture of HPV type 6, 11, 16, and 18 whole genomic probes. Southern blots demonstrated characteristic PstI restriction patterns of HPV type 6, 11, or 16 in all but one lesion. HPV 6 subtypes accounted for 28 of 39 HPV-positive lesions. Twenty-seven of these 28 lesions contained HPV type 6a, and 1 lesion contained HPV type 6c. Eight lesions contained HPV type 11 and three contained HPV type 16. Two of the three condylomata acuminata containing HPV type 16 were obtained from solid-organ transplant recipients receiving immunosuppressive medications. The third lesion containing HPV type 16 was a typical exophytic condyloma acuminatum from a woman with previously resected vulvar carcinoma. The hybrid capture assay detected HPV DNAs in all lesions except the Southern blot-negative lesion. Twenty-five lesions were positive for the A probe only (HPV types 6 and 11 and related types). All of these lesions were found to contain HPV type 6 or 11 sequences in the Southern blot assay. The remaining 14 lesions were positive for both the A probe and the B probe (HPV types 16 and 18 and related types). The strongest signal in these 14 lesions by the hybrid capture assay was consistent with the result of the Southern blot assay in all but one case. We conclude that (i) HPV type 6a is the most common type found in these lesions, (ii) HPV type 16 may be present more often in exophytic condylomata acuminata from immunosuppressed individuals, (iii) hybrid capture is a useful tool for documenting the presence of HPV sequences in DNAs from exophytic condylomata acuminata, and (iv) in samples containing multiple HPV types, hybrid capture allows detection of minority HPV types.
Among 237 cases of condyloma diagnosed in Uganda between 1964 and 1975 seven types of lesions were defined. Three of these were found within a wide age range in both young and elderly people, namely, the common (49.4%) and the flat (2.0%) condyloma acuminatum, and condyloma acuminatum of irregular outline (13.5%). Four variants, on the other hand, fell into different age groups. Condyloma acuminatum, showing marked cell death (5.1%) and observed exclusively among girls in the first decade of life, displayed numerous aciophil bodies, presumably reflecting single cell necroses. Condylomata acuminata showing marked acanthosis (16.9%) were found in patients between 12 and 30 years, dysplastic condylomata acuminata (5.9%) between 20 and 62 years, and proliferative (giant) condylomata acuminata (7.2%) between 31 and 80 years of age. In the latter two groups of lesions, the inflammatory stromal infiltrate was more prominent, but cytoplasmic vacuolation, often believed to be a sign of viral infection, was seen less frequently than in the remaining types. In young people, the features seen resemble, therefore, a cytocidal and/or vacuolating viral infection, whereas the dysplastic and proliferative changes observed in older patients are compatible with malignant transformation being under way.
OBJECTIVES: To evaluate a sustained release chemotherapy for treating condylomata acuminata with an injectable gel containing fluorouracil and adrenaline (5-FU/adrenaline gel). Study 1-- To assess contributions of the components of 5-FU/adrenaline gel to efficacy. Study 2--To assess therapeutic contribution of adrenaline and safety and efficacy of the formulations. DESIGN: Randomised, double blind, placebo controlled studies. SETTING: Private practices and university clinics in the United States. PATIENTS: Men and women with new, recurrent, or refractory external condylomata acuminata. INTERVENTION: Six injections over 8 weeks; follow up visits at weeks 1, 4, 8, and 12. MAIN OUTCOME MEASURES: Efficacy: patient/wart response, times to complete response, recurrence rates. Safety: injection reactions, tissue conditions, other adverse events, laboratory studies. RESULTS: Study 1: 132 evaluable patients. Complete response (CR) rate was highest for the 5-FU/adrenaline gel group, followed by the 5-FU/adrenaline solution group, then the 5-FU gel group. 5-FU, adrenaline, and the collagen gel vehicle (in the presence of 5-FU) significantly affected CR and strongly influenced time to CR. The effects of 5-FU and adrenaline were statistically significant. Cutaneous reactions were mild to moderate. Study 2: 187 evaluable patients. Patients treated with 5-FU/adrenaline gel had a significantly higher CR rate and lower cumulative 90 day recurrence rate than those treated with 5-FU gel without adrenaline. Treatments were generally well tolerated, with only three treatment related, serious adverse events. CONCLUSION: 5-FU/adrenaline gel is safe and efficacious for treatment of condylomata acuminata, and when compared with individual or various combinations of components, this formulation provided the greatest therapeutic advantage.
Uncontrolled trials indicate that treatment of condylomata acuminata with the carbon dioxide laser is effective and probably superior to conventional surgical treatment. We performed a controlled study of refractory condylomata acuminata to clarify whether this is the case. In this randomised trial 21 patients were treated with the carbon dioxide laser and 22 by conventional surgery after having been treated with podophyllin for an average of 33 and 35 weeks respectively. Five and seven patients respectively had previously required additional treatment, such as an operation. The treatment schedule was equally effective for both groups of patients. No difference between the two groups was seen in numbers of recurrences, postoperative pain, healing time, and rate of scar formation (p greater than 0.1-0.2). Treatment of recalcitrant condylomata acuminata with the carbon dioxide laser did not offer any advantages over traditional surgery, including electrocautery.
OBJECTIVE--To determine whether interferon alpha-2a, when utilised as adjuvant chemotherapy following ablation of condylomata acuminata (genital warts) by cryotherapy, is effective in the prevention of recurrences. DESIGN--Randomised, placebo-controlled, double-blind study. Statistical analysis was by 2-tailed Fisher's Exact Test. PATIENTS--97 patients with recurrent condylomata acuminata. INTERVENTION--49 patients were treated with cryotherapy plus subcutaneously administered interferon alpha-2a, and 48 received cryotherapy plus placebo. Of these, 36 and 37 patients, respectively, completed the study and were evaluable. MAIN OUTCOME MEASURE--Clinical eradication of condylomata for six months following adjuvant chemotherapy. RESULTS--By completion of the adjuvant chemotherapy, 10 (28%) interferon recipients and 16 (43%) placebo recipients experienced recurrences. At six months follow-up, 25 (69%) interferon and 27 (73%) placebo recipients experienced recurrences. In the six months following interferon therapy, only 31% of interferon and 27% of placebo recipients remained free of recurrences (p = 0.99). CONCLUSIONS--Interferon alpha-2a administered subcutaneously offers no benefit as a chemotherapeutic adjuvant to cryotherapy when used alone in the therapy of genital warts in this population of patients with recurrent condylomata.
Human papillomaviruses (HPVs) are a diverse family of viruses, of which 30–40 genotypes specifically infect the genital tract. Genital HPVs are largely transmitted sexually, with most infections being asymptomatic and transient. In contrast, persistent infection with oncogenic genotypes in a minority is a strong risk factor, for subsequent development of high grade dysplasia, the precursor lesion to cervical neoplasia, which generally occurs after a long latency period. It is unknown whether there is a disease correlate in children chronically infected with oncogenic HPVs. Low risk HPV genotypes 6 and 11 are the primary cause of condylomata acuminata, although in children non‐genital genotypes are also found in a proportion, with the mode of transmission being either perinatal, horizontal, or sexual. The finding of asymptomatic HPV DNA in children, and correlation with live virus, infectivity, or disease is unclear. Long term follow up for children with anogenital warts is recommended, although there are no longitudinal studies available to clarify whether they are at risk of developing carcinoma in young adulthood.
human papillomaviruses; genital warts; sexual abuse
Four cases of condylomata acuminata in children (two boys, two girls) are reported. Three children had perianal warts and one vulvar warts. One of the four children had been sexually assaulted, but a history of sexual contact was absent in the other three. Surgical excision was undertaken in one case and the others responded well to the local application of 25% podophyllin in benzoin tincture compound. In the absence of sexual contact, a non-coital mode of transmission of infection could be a possibility.
The aim of this study was to test the hypothesis that particular clinical features of foreskin condylomata acuminata in Chinese male patients are associated with diabetes. A prospective study enrolled 126 men presenting with foreskin condylomata acuminata from 2001 to 2006. Mean age was 46 years (age range 25–74 years) and mean duration of disease was 4.8 months (range 1–18 months). Patients were divided into two groups according to clinical features. In group 1, 42 men had distinctive signs such as redundant prepuce, crown warts circling the entire preputial ring, maceration, fissures, phimosis and balanitis, and 37 of 42 (88%) patients were found to have concurrent type 2 diabetes, furthermore 32 of these 37 patients had an insidious onset and were previously undiagnosed. In group 2, 84 male patients did not have those distinctive clinical features and type 2 diabetes was found in only 10 cases (11.9%, p < 0.0001, Fisher's exact test). These clinical features strongly suggest the presence of diabetes. Therapy should address diabetes and condylomata concurrently.
condylomata acuminata; diabetes mellitus; clinical features
Buschke–Löwenstein tumour (BLT) of the anogenitalia is a locally invasive, destructively growing verrucous carcinoma that does not metastasise. Histologically BLT resembles benign condylomata acuminata. Nevertheless, the tumour grows relentlessly and may rarely progress into squamous cell cancer (SCC).
A human immunodeficiency virus (HIV)-infected immunosuppressed patient developed (peri)anal warts accompanied by recurrent abscesses and fistulae. Histology revealed condylomata acuminata, and low-risk genital human papillomavirus (HPV) type 11b was detected. Six months later, the tumour had progressed into an ulcerated SCC that destroyed the rectum and perineum, with metastases to the inguinal lymph nodes. Whereas highly active antiretroviral therapy (HAART) effectively suppressed HIV replication, radiochemotherapy plus anti-EGFR antibody did not halt tumour progression, and the patient died from tumour-cachexia.
As far as is known, this is the first report demonstrating rapid progression of a BLT into a metastasising SCC in an HIV-infected patient.
Saikosaponin-d (Ssd) is a triterpenoid saponin derived from Bupleurum falcatum L., which has been shown to exhibit a variety of pharmacological properties, including anti-inflammatory, antibacterial and antiviral properties. The aim of the present study was to investigate the effect of Ssd on the differentiation, maturation and function of human monocyte-derived dendritic cells (DCs) isolated from condylomata acuminata patients. The results of the present study demonstrated that Ssd reduced the differentiation of DCs, as evidenced by decreased expression levels of cluster of differentiation (CD)1a, CD80 and CD86 molecules and increased CD14 expression. Expression levels of the mannose receptor and CD32 were also significantly elevated, which was associated with enhanced fluorescein isothiocyanate-dextran endocytic activity. Furthermore, Ssd treatment promoted DC maturation by increasing the expression levels of CD40, CD83, CD80 and CD86. In addition, the function of mature DCs, including the secretion of IL-12 and the stimulation of lymphocyte proliferation, was significantly increased following Ssd administration. In conclusion, the present study indicated that Ssd exhibited immunomodulatory effects and may be a novel potent chemopreventive drug candidate for the treatment of condylomata acuminata.
saikosaponin-d; human papillomavirus; dendritic cells; differentiation; maturation
OBJECTIVE--To determine whether patients with condylomata acuminata have an increased risk of developing cancer. DESIGN--Prospective cohort study on patients diagnosed as having condylomata acuminata. The number of malignant tumours in the cohort was compared with national incidences obtained from the Swedish Cancer Registry. SETTING--Dermatology department of the Karolinska Hospital, Stockholm, Sweden. SUBJECTS--3260 patients (2549 males and 711 females, median (range) age 23 (1-80) years) seen during 1969-84, with a mean follow up of 7.8 years. MAIN OUTCOME MEASURES--Number of malignant tumours observed in the cohort during the study period and expected number from national incidence. RESULTS--There were 27 malignancies in the study group. There was no significant increase genital cancer in females compared with the national incidence. Only one patient had invasive cervical cancer (relative risk = 1.8; 95% confidence interval 0 to 10.1). Seventeen women had cervical carcinoma in situ (1.5; 0.9 to 2.5) compared with an expected number of 11.5; this increase was not significant. For males 22 cancers were observed at all sites (1.6; 1.0 to 2.5). The number of genitourinary cancers observed in males was almost three times higher than expected (2.6; 1.2 to 5.0). CONCLUSION--The results indicate that the risk of developing cervical carcinoma in situ or invasive cervical cancer after a genital human papillomavirus infection is less than previously thought. The implications of increase in the genitourinary malignancies in males are uncertain.
A 30 year old man presented with a large, penile, warty growth. The histopathological features were consistent with giant condylomata acuminata. After successful treatment with 5-fluorouracil cream and electrocautery some growth recurred at the excision site. Subtotal amputation of the penis was performed to remove the warty base. Because of the infective component of giant condylomata acuminata patients as well as their wives should be examined regularly.
OBJECTIVE--To determine the adverse psychological implications of referral for colposcopic screening within a genitourinary medicine clinic. DESIGN--Cross sectional survey. SETTING--A colposcopy clinic held within a genitourinary medicine clinic. SUBJECTS--160 consecutive women referred to the clinic were assessed for psychiatric morbidity using the General Health Questionnaire (GHQ-28). Women were referred to the colposcopy clinic because of one or more of the following: abnormal cervical cytology, condylomata acuminata, HIV antibody positivity. A history of prior local ablative therapy to the cervix was also included in the analysis. RESULTS--There was no difference in psychiatric morbidity, as detected by the GHQ-28, in women referred to the clinic because of abnormal cervical cytology or condylomata acuminata. The total GHQ-28 scores indicated a significant increase in psychiatric morbidity, with increased sub-scores indicating social dysfunction, anxiety and somatic symptoms, in women who had had prior laser therapy to the cervix. Women with HIV infection attending the clinic were noted to have an increase in GHQ-28 sub-scores indicating social dysfunction and depression. CONCLUSIONS--Women who have undergone laser therapy to the cervix may benefit from psychological evaluation and supportive measures if they develop further genital lesions which require colposcopic evaluation. Women with HIV infection need further psychological evaluation prior to planning intervention and preventative strategies.
The therapeutic effectiveness of the carbon dioxide laser was evaluated in 55 women with condylomata acuminata, particularly of the vulva but also of the urethral meatus and anal region, and in 11 women with multicentric vulvar intraepidermal neoplasia. The rates of persistence and recurrence were 13% and 5% respectively for condylomata and were both 9% for intraepidermal neoplasia. Perioperative and postoperative complications occurred in 6 of the 66 cases (9%) and all were managed on an outpatient basis. Laser beam therapy is recommended as an effective and safe means of treating extensive condylomata and intraepidermal neoplasia of the external urogenital region and anal mucous membrane.
We have performed the first molecular analysis of a time course of infection by a papillomavirus. The Hershey isolate of the human papillomavirus type 11 was used to infect human foreskin tissues, which were then implanted under the renal capsules of nude mice. The xenografts were recovered every 2 weeks for 14 weeks, fixed in formalin, and embedded in paraffin. Four-micrometer serial sections were examined by light microscopy for morphological changes, by immunocytochemistry for virion antigen production, and by in situ hybridization with 3H-labeled RNA probes for viral DNA replication and expression of the major mRNA species. After a lag period, probes spanning the E4 and E5 open reading frames, which are present in all E region viral mRNAs, generated the first detectable signals at week 4. Signals of other E region probes were minimally detected at week 6. Between weeks 6 and 8, there was an abrupt change in the implant such that cellular proliferation, viral DNA replication, and E and L region mRNA transcription were robust and reached a plateau. By weeks 10 to 12, the experimental condylomata were morphologically and histologically indistinguishable from naturally occurring condylomata acuminata. These findings suggest that cellular hyperproliferation and the morphologic features of condylomata are direct results of viral genetic activities. Unlike other DNA viruses, the E region transcripts increased with cell age and cellular differentiation and persisted throughout the entire experiment. In particular, the mRNA encoding the E1iE4 and perhaps E5 proteins remained overwhelmingly abundant. In contrast, viral DNA replication, L region mRNA synthesis, and virion antigen production were restricted to the most differentiated, superficial cells.
5-Fluorouracil (5-FU) cream was compared with podophyllin 25 percent in alcohol for treating genital and urethral condylomata acuminata. The cure rate after four weeks was found to be 6 of 18 patients treated with 5-FU and 10 of 19 treated with podophyllin. By changing the treatment for those not cured, warts regressed after four weeks in four more patients in each group. Patients were followed up for four to nine months; 10 of 27 treated with 5-FU and 14 of 31 treated with podophyllin remained in remission. It is not possible to support earlier reports on the successful treatment of meatal warts using 5-FU cream. More than half of the patients given 5-FU reported side effects after 10 to 14 days' treatment, which in some cases led them to stop using the cream. Twenty-one men considered to be treatment failures or relapses were examined by urethroscopy. No intraurethral condylomata were found but three cases of warts in the fossa navicularis were doscovered; this prompted us to introduce an instrument to examine the urethral meatus and the fossa navicularis.
The safety and efficacy of intralesionally administered interferon alfa-2b were assessed in 11 patients suffering from condylomata acuminata for four to 10 months for whom application of podophyllum resin had proved unsuccessful. Three warts from each patient were injected with 10(6) IU interferon alfa-2b three times a week for three weeks. Treatment was followed by a 13 week observation period. Interferon alfa-2b treatment resulted in a highly significant (p less than 0.0001) reduction in the mean size of the treated warts, which decreased from an initial size of 29 mm2 to 2-3 mm2 by week 16. In six out of the 10 patients completing the trial, both the test condylomata and adjacent control warts cleared completely; a recurrence was observed in one of these six patients. Influenza like symptoms (headache and myalgia) were the most common side effects reported, though they were mild in nature and not disabling. These results corroborate those of previous trials with interferon preparations and indicate that its antiviral activity makes it a possible treatment for this sexually transmitted disorder.
OBJECTIVE--To evaluate the clinical efficacy of a 0.15% and a 0.3% cream formulation of podophyllotoxin in comparison with the 0.5% solution in the treatment of condylomata acuminata and to compare the treatment modalities regarding side effects. DESIGN--The study was designed as an open randomised trial. Ninety male patients with signs of penile HPV infection, with either acuminate or papular lesions, were randomised into three parallel treatment groups. The study medication comprised 0.15% and 0.3% cream and 0.5% solution of podophyllotoxin. The patients treated themselves twice daily for three consecutive days and if total regression of the warts was not achieved after this first treatment cycle, further treatment cycles at 7-day intervals were to be repeated up to a maximum of four treatments. SETTING--The study was carried out in three outpatient clinics: two STD clinics, Department of Dermatology and Venereology, University Hospital (45 patients) and Institut Antoine Fournier, Paris (30 patients), and one military hospital, S1/FO 47/48, Sjukhusenheten, Enköping (15 patients). RESULTS--Statistical evaluation of the treatment effect was based on a "Response rate" calculation at each visit. The number of completely responding patients after the first, second, third and fourth cycle were 40 (44%), 61 (68%), 67 (74%) and 70 (78%), respectively. There was no statistically significant difference between the three treatments after four treatment cycles. However, the 0.15% cream had a significantly slower onset of efficacy as compared with the 0.3% cream and 0.5% solution. Adverse effects were less severe and less frequent with the 0.15% cream than with the other treatment modalities. Severe adverse effects were reported by 12 patients, of whom two were treated with 0.15% cream, five with 0.3% cream and five with 0.5% solution. Thirty-one patients were completely free from adverse effects. CONCLUSION--In this open randomised study with three parallel treatment groups, two cream formulations of 0.15% and 0.3% podophyllotoxin and a 0.5% solution of the same drug all showed an equally good response rate after four treatment cycles. Reported adverse effects were few and mild. The convenience of having different formulations to offer when prescribing treatment for condylomata must be considered.
OBJECTIVE--To assess prevalence, incidence and potential risk factors of human papillomavirus (HPV) infection among heterosexual men and women with multiple partners and to identify niches of HPV-infection. DESIGN--A prospective study of heterosexual men and women with multiple partners attending an STD clinic as participants in a study on HIV from May 1988 until January 1991. Routine STD examination and physical examination using colposcopy were performed, interviews with standardised questionnaires were administered. Specimens for HPV DNA detection by polymerase chain reaction were collected from multiple sites of the genital, anorectal and oral regions. In women cervical cytology was performed. SETTING--The STD Clinic of the Municipal Health Service of Amsterdam. PARTICIPANTS--162 women and 85 men entered the study, 110 women and 48 men were followed up. RESULTS--At entry of the study 37 (23%) women and 24 (28%) men were found positive for HPV DNA at any site. Only in one woman was oral presence of HPV DNA found during follow-up. Abnormal cervical cytology was observed in four women. In multivariate analysis, diagnosis of condylomata [odds ratio (OR) 5.61, 95% confidence interval (CI) 1.86 to 16.90)], reporting genital dermatological abnormalities (OR 3.72, 95% CI 1.38 to 9.99) and age (OR per year 0.93, 95% CI 0.88 to 0.99) predicted independently the presence of HPV DNA in women at entry of the study. In women 59 of the 99 (60%) HPV infections were observed in the genital region and 40% in the anorectal region: in men these figures were 65% and 35%, respectively. The incidence of HPV infection was 47.1 and 50.5 per 100 person-years for women and men respectively. At least 20/99 (20%) infections in women were intermediate or long persistent and only 3/48 (6%) HPV infections in men (P = 0.03). No risk factor for persistency could be determined, either in women or in men. CONCLUSIONS--HPV infection was found to be a multicentric genital and/or anorectal event both in women and men. The oral presence of HPV DNA was detected only once in one of the participants. In women persistent HPV infection was more common than in men. Independent predictors for presence of HPV DNA in women were diagnosis of condylomata acuminata, reporting genital dermatologic abnormalities and age. Incidence of HPV infection in women turned out to be 47.1 infections per 100 person-years and for men 50.5 per 100 person-years.
OBJECTIVES--to compare the response to treatment and recurrence rate of condylomata accuminata using subcutaneous injection of interferon alfa 2a 1.5 million units three times weekly for four weeks, or podophyllin resin 25% applied to lesions twice weekly for up to six weeks. DESIGN--Randomised open study. SETTING--Multicentre European study in genitourinary medicine, dermatovenereology, and gynaecology departments. PATIENTS--87 males and 67 females with condylomata acuminata for less than six months and no history of previous treatment. MAIN OUTCOME MEASURES--Complete clearance of lesions and evidence of recurrence at three months and nine months after treatment commenced. RESULTS--A complete response was achieved at three months in 15 of 64 (23%) in the interferon treated group, and 31 of 69 (45%) in the podophyllin treated group (p = 0.003). At nine months 10 of 13 patients in the interferon group and 22 of 30 patients in the podophyllin group remained completely clear of lesions.
An immunohistological study of four men whose perianal warts were undergoing spontaneous regression was undertaken, and the results compared with those obtained from non-regressing condylomata from six men. CD4+ and CD8+ cells were noted in the stroma of each wart, but there was no clear difference in the density of the infiltrate between regressing and non-regressing warts. Natural killer cells (CD16+ and CD57+) were only noted in the stroma and epidermis of regressing warts. Possible immunological mechanisms of regression of condylomata acuminata are discussed.
Toll-like receptors (TLRs) have first been characterized for their capacity to detect conserved microbial components like lipopolysaccharide (LPS) and double-stranded RNA, resulting in the elicitation of potent (innate) immune responses against invading pathogens. More recently, TLRs have also been shown to promote the activation of the cognate immune system against cancer cells. Today, only three TLR agonists are approved by FDA for use in humans: the bacillus Calmette-Guérin (BCG), monophosphoryl lipid A (MPL) and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) is mainly used as a vaccine against tuberculosis, but also for the immunotherapy of in situ bladder carcinoma. MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix®, a vaccine against human papillomavirus-16 and -18. Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy.
Coley’s toxin; HPV; MyD88; Mycobacterium bovis; dsRNA; resiquimod
Wolfsburg HPV Epidemiological Study (WOLVES) is a population-based cohort study on HPV infections and associated diseases in the pre-vaccination era in young women in Wolfsburg, Germany.
Women born 1983/84 or 1988/89 were invited to participate. Participants were recruited in gynecology practices, and completed a questionnaire with socioeconomic, sexual and medical data including vaccination status. Pelvic examination with Pap smear and HPV testing (HC2 = Hybrid Capture 2) was obligatory. HC2-positive and 10% of HC2-negative samples were tested for specific HPV types with SPF-10-PCR, and in inconclusive cases with DNA sequencing. Women with genital warts (GW) and those with atypical Pap smears were transferred for colposcopy. GWs were classified as typical condylomata acuminata (TCA), flat condyloma (FC) and seborrheic wart-like (SWL).
In total, 1258 subjects were recruited from the target population of 2850 (44.1%). Overall the prevalence of HC2 low-risk (LR) types was 8.5%. HPV6 was the most frequent LR type (2.1%), followed by HPV42 (1.1%), HPV11 and HPV44 (each 0.4%). LiPA showed a low sensitivity for HPV types 42, 90 and 91, which were detected only by HC2 and HPV sequencing. Nine women (0.7%) were transferred with incident GW: five TCA, two FC and two SWL. All TCA were associated with HPV6 in corresponding cervical swabs and warts. Tissues of SWL contained HPV6 (n = 1) and HPV16 (n = 1). The cumulative life-risk for GW was 1.4% in the 1988/89 and 4.8% in the 1983/84 cohort. Eight of 107 HC2-LR + and five of nine cases of GW had concomitant abnormal Pap smears. All CIN lesions could be linked to high-risk HPV types but borderline and low-grade abnormal smears were explained by vaginal and cervical TCA in four cases.
HC2 was a specific test for the detection of established and potential LR types. In this first WOLVES analysis, HPV6 was the most frequent HPV type and the single LR type linked to disease. The observed GW incidence of 715 per 100,000 fits well with estimates of healthcare providers. Although life risks for GW were lower than in Scandinavian analyses, the societal burden within the WOLVES populations was considerable.
Bacillus Calmette-Guerin (BCG) immunotherapy is established as an effective adjuvant intravesical treatment for non-muscle invasive bladder cancer. BCG is also effective in the treatment of Condylomata acuminata caused by low-risk human papilloma virus (HPV). The aim of this study was to determine the efficacy of BCG for the treatment of cervical cancer or HPV high-risk infections. BCG-activated killer (BAK) cells were incubated with a high-risk HPV18-infected cervical cancer cell line, HeLa. The cell cycle distribution and apoptotic index of the HeLa cells were analyzed by flow cytometry. The alterations of HPV-E7, retinoblastoma (RB) and E2F1 levels were detected at the transcriptional and translational levels. The BAK cell cytotoxicity to HeLa cells was 24.08, 14.74 and 6.8% and the natural killer (NK) cell cytotoxicity was 17.62, 10.78 and 5.8% at the E/T ratios of 40:1, 20:1 and 10:1, respectively. The BAK cells significantly induced the apoptosis of HeLa cells to result in an apoptosis level of 24.2% compared with 13.45% by the NK cell treatment at the ratio of 20:1. BAK cells inhibit the proliferation of HeLa cells by G1/S cell cycle arrest and this may be associated with the RB/E2F1 pathway. However, G1/S arrest and the alteration of RB protein (pRB) and E2F1 levels in the HeLa cells did not show significant differences between the BAK cell- and NK cell-treated groups. HPV-E7 appeared not to be associated with the alteration in cell cycle progression. This study showed that immunotherapy may be a potential treatment for cervical cancer and that BCG immunotherapy may be an alternative and effective method, but further experiments and clinical trials are required to verify this effect.
Bacillus Calmette-Guerin immunotherapy; Bacillus Calmette-Guerin-activated killer cells; peripheral blood mononuclear cells; HeLa cells; human papilloma virus-E7; retinoblastoma/E2F1 pathway