The first probe of a FLASH proton beam by PET.

The recently observed FLASH effect related to high doses delivered with high rates has the potential to revolutionize radiation cancer therapy if promising results are confirmed and an underlying mechanism understood. Comprehensive measurements are essential to elucidate the phenomenon. We report the first-ever demonstration of measurements of successive in-spill and post-spill emissions of gammas arising from irradiations by a FLASH proton beam. A small positron emission tomography (PET) system was exposed in an ocular beam of the Proton Therapy Center at MD Anderson Cancer Center to view phantoms irradiated by 3.5 × 1010protons with a kinetic energy of 75.8 MeV delivered in 101.5 ms-long spills yielding a dose rate of 164 Gy s-1. Most in-spill events were due to prompt gammas. Reconstructed post-spill tomographic events, recorded for up to 20 min, yielded quantitative imaging and dosimetric information. These findings open a new and novel modality for imaging and monitoring of FLASH proton therapy exploiting in-spill prompt gamma imaging followed by post-spill PET imaging.

The first PET glimpse of a proton FLASH beam.

We demonstrate the first ever recorded positron-emission tomography (PET) imaging and dosimetry of a FLASH proton beam at the Proton Center of the MD Anderson Cancer Center. Two scintillating LYSO crystal arrays, read out by silicon photomultipliers, were configured with a partial field of view of a cylindrical poly-methyl methacrylate (PMMA) phantom irradiated by a FLASH proton beam. The proton beam had a kinetic energy of 75.8 MeV and an intensity of about 3.5 × 1010protons that were extracted over 101.5 ms-long spills. The radiation environment was characterized by cadmium-zinc-telluride and plastic scintillator counters. Preliminary results indicate that the PET technology used in our tests can efficiently record FLASH beam events. The instrument yielded informative and quantitative imaging and dosimetry of beam-activated isotopes in a PMMA phantom, as supported by Monte Carlo simulations. These studies open a new PET modality that can lead to improved imaging and monitoring of FLASH proton therapy.

Evaluation of selected IL6/STAT3 pathway molecules and miRNA expression in chronic obstructive pulmonary disease.

COPD has been regarded as a global epidemic due to an increase in pollution and tobacco exposure. Therefore, the study of molecular mechanism as the basis for modern therapy is important. The aim of the study was the assessment of gene expression levels, IL-6, IL-6ST, PIAS3, STAT3, and miRNAs, miRNA-1, miRNA-106b, miRNA-155, in patients with COPD. Induced sputum as well as PBMC were collected from 40 patients clinically verified according to the GOLD 2021 (A-D) classification and from the control group (n = 20). The levels of gene and miRNA expression were analysed by qPCR. In induced sputum IL6 was significantly down-regulated in COPD group compared with control (p = 0.0008), while IL6ST were up-regulated (p = 0.05). The results were also statistically significant for STAT3 (p = 0.04) and miRNA-155 (p = 0.03) with higher expression in the current smokers compared to ex-smokers. Higher expression levels for IL6ST (p = 0.03) in COPD patients with the exacerbation history compared to COPD patients without the exacerbation history were noted. Compared induced sputum and PB lymphocytes we observed higher expression of IL6 (p = 0.0003), STAT3 (p = 0.000001) miRNA-106b (p = 0.000069 and miRNA-155 (p = 0.000016) in induced sputum with lower expression of PIAS3 (p = 0.006), IL6ST (p = 0.002) and miRNA-1 (p = 0.001). Differences in gene expression levels of the IL-6/IL6ST/STAT3 pathway and miRNA depending on the smoking status and classification of patients according to GOLD suggest the importance of these genes in the pathogenesis of COPD and may indicate their potential utility in monitoring the course of the disease.

Transplantation of a New Biological Product in Rare Diseases, Such as Epidermolysis Bullosa: Response and Clinical Outcome.

BACKGROUND: Epidermolysis bullosa (EB) is a phenotypically diverse group of hereditary blistering disorders involving mutations in 20 different genes. Those debilitating disorders are currently incurable; however, there are a number of promising preclinical trials, where some treatments already approach the stage of early clinical trial. In this paper we introduce a novel surgical approach to the treatment of EB-induced ulcerations. The purpose of our study was to evaluate the safety and efficacy of a new biological dressing in the form of an allogenic human skin equivalent graft before using multipotent stem cells, classified as an advanced therapy medicinal product. METHODS: Implanted human acellular dermal matrices were prepared from the superficial layers of donated human skin. Scaffold sterilization was conducted via irradiation with the use of a linear electron accelerator. Following water-knife debridement, wounds were surgically covered with accordingly prepared grafts and dressed in burn-injury fashion. Subsequently, the wounds were monitored for infection and viability. RESULTS: Our data indicate that grafting as a potential new medicinal product was safe and effective in patients with rare diseases, such as EB, and may be used for stem cells to create new Advanced Therapy Medicinal Products. During a 200-day follow-up, we proved the safety of using human scaffolds (allogeneic graft) by observing no apparent infection or necrosis. Instead, we noted fewer required dressing changes, promoted wound healing, pain reduction, and an overall improvement in the quality of life in patients with EB. CONCLUSION: The protocol for grafting allogenic acellular epidermal sheets is the most promising treatment for severely affected skin areas in EB patients to date.

New Treatment of Wound Healing With Allogenic Acellular Human Skin Graft: Preclinical Assessment and In Vitro Study.

BACKGROUND: Nonhealing wounds can be a major clinical problem. Impaired wound healing is often related to massive tissue injury, concomitant wound healing deficiencies (chronic wounds), burn injury, or congenital conditions. We propose a novel biological dressing as an alternative surgical approach. The dressing is a form of an allogenic human skin graft equivalent with further use of allogeneic stem cells classified as an advanced therapy medicinal product. This new allogenic acellular human skin graft has been specifically developed to address the clinical indications for dressing wound lesions and promoting tissue repair in specific rare genetic diseases. METHODS: This case report illustrates the use of an acellular human skin allograft seeded with multipotent stem cells in the treatment of tissue injuries (burns), congenital conditions, and chronic wounds. Donor-tissue processing yields an acellular dermal matrix with integral collagen bundling and organization, as well as an intact basement membrane complex. RESULTS: Preclinical observations show prolonged viability of acellular human skin grafts with multipotent stem cells. This was confirmed with histological and electron-microscopic evaluation of biopsies, which demonstrated host-cell infiltration and neovascularization of the biological dressing. Moreover, the dressings were characterized by low immunogenicity, as confirmed by histology exam and T-cell proliferation assays in vitro. CONCLUSION: Our data confirmed the safety and efficacy of the evaluated acellular human skin grafts, which may be used in patients with rare diseases, such as epidermolysis bullosa, burn injuries, and chronic wounds.

Position statement for the diagnosis and management of anogenital warts.

BACKGROUND: Anogenital warts (AGW) can cause economic burden on healthcare systems and are associated with emotional, psychological and physical issues. OBJECTIVE: To provide guidance to physicians on the diagnosis and management of AGW. METHODS: Fourteen global experts on AGW developed guidance on the diagnosis and management of AGW in an effort to unify international recommendations. Guidance was developed based on published international and national AGW guidelines and an evaluation of relevant literature published up to August 2016. Authors provided expert opinion based on their clinical experiences. RESULTS: A checklist for a patient's initial consultation is provided to help physicians when diagnosing AGW to get the relevant information from the patient in order to manage and treat the AGW effectively. A number of frequently asked questions are also provided to aid physicians when communicating with patients about AGW. Treatment of AGW should be individualized and selected based on the number, size, morphology, location, and keratinization of warts, and whether they are new or recurrent. Different techniques can be used to treat AGW including ablation, immunotherapy and other topical therapies. Combinations of these techniques are thought to be more effective at reducing AGW recurrence than monotherapy. A simplified algorithm was created suggesting patients with 1-5 warts should be treated with ablation followed by immunotherapy. Patients with >5 warts should use immunotherapy for 2 months followed by ablation and a second 2-month course of immunotherapy. Guidance for daily practice situations and the subsequent action that can be taken, as well as an algorithm for treatment of large warts, were also created. CONCLUSION: The guidance provided will help physicians with the diagnosis and management of AGW in order to improve the health and quality of life of patients with AGW.

Evaluation of Hamamatsu PET imaging modules for dedicated TOF-capable scanners.

Time-of-flight (TOF) capability is becoming an important capability offered in both commercial and research PET scanners. Often commercial vendors and laboratory researchers develop and utilize proprietary electronics for their devices. Consequently, it is challenging for independent research groups to develop their own TOF-PET scanners. In this investigation, we tested a prototype scanner consisting of commercially available TOF-capable modules from Hamamatsu Photonics that can be used as building blocks for PET scanners. The scanner consists of a ring of 16 modules, for a total diameter of 26.7 cm. Testing demonstrated that the scanner is capable of sustaining ~1 MHz single counting rate with a peak noise equivalent count rate (NECR) of 117.5 kHz at 75.25 MBq measured with NEMA NU-4 "rat" phantom. Spatial resolution of 2.3 mm 5 mm from the center of the scanner was measured. Energy resolution of 17.2% at 511 keV was measured. Peak sensitivity of 1.28% is reported. All the measurements were performed with energy cuts from 350 to 700 keV Finally, scanner timing resolution was found to be 462 ps. Results from testing of a prototype scanner constructed using newly released TOF-capable detector modules produced by Hamamatsu demonstrated the promise for these devices to create high performance PET system with TOF capabilities.

Inverse association for diagnosis of Alzheimer's disease subsequent to both melanoma and non-melanoma skin cancers in a large, urban, single-centre, Midwestern US patient population.

BACKGROUND: Although literature demonstrates a decreased risk of Alzheimer's disease (AD) in individuals with various cancers, including squamous cell cancers (SCC) and basal cell cancers (BCC) comprising non-melanoma skin cancers (NMSC), there is a paucity of literature to substantiate an association between malignant melanoma (MM) and AD. OBJECTIVE: The aim of this study was to determine whether an association exists between MM and AD as well as for NMSC and AD. METHODS: A large urban, Midwestern, US, single-centre, medical record (EMR) data repository was searched between January 2001 and December 2015, to identify all patients at age ≥60 and <89 years with a clinic follow-up of at least 1 year and no diagnosis for AD, MM or NMSC at the time of the study entry. Data collected included age, gender, race and duration of follow-up. MM and NMSC were detected by ICD-9 codes and ICD-10 codes. Incident diagnosis of AD was also detected by ICD-9 and ICD-10 codes. Logistic regression analysis was utilized to obtain crude and adjusted odds ratios (ORs). RESULTS: Data for a total of 82 925 patients with known race and gender and were detected. After adjusting for confounding factors (race, gender, age, cerebrovascular disease, peripheral vascular disease and diabetes), there was a significant decreased risk of subsequent AD in patients with MM (OR: 0.39; 95% CI: 0.16-0.96; P = 0.042) as well as in patients with BCC (OR: 0.18; 95% CI: 0.08-0.45; P < 0.0001) and for patients with SCC (OR: 0.08; 95% CI: 0.01-0.56; P = 0.013). CONCLUSION: These findings add to the growing body of evidence for a decreased risk of AD in patients with various cancers and highlight the need for ongoing research to elucidate both neurologic and biologic mechanisms that may underlie this apparent inverse association.

Skin cancer risk in outdoor workers: a European multicenter case-control study.

BACKGROUND: Exposure to ultraviolet radiation (UVR) is the most important external risk factor for skin cancer. Outdoor workers, who are exposed to high ambient UVR levels are at increased risk. OBJECTIVE: To compare outdoor with indoor workers in terms of: (i) skin cancer risk factors, and (ii) risk of developing skin cancer. METHODS: Using descriptive methods and a large multicenter European case-control study, we compared risk factor patterns between outdoor (N = 1416) and indoor workers (N = 1863). Risk of developing basal cell carcinoma (BCC), squamous cell carcinoma (SCC), melanoma and actinic keratosis (AK) were analysed by type of work using multivariate logistic regression models, for three categories of work: indoor; farming/construction; other outdoor work. RESULTS: Although skin phototype was equally distributed by type of work, significantly less outdoor than indoor workers used sunscreen in their own country (44.3% vs. 60.2%), but had more outdoor hobbies (66.2% vs. 58.2%). Outdoor workers had lower educational levels, and felt less confident in understanding medical information and filling medical forms (all P < 0.001). Outdoor workers had more signs of photodamage (78.1% vs. 65.5%) and among the skin cancer patients, 37.7% of outdoor workers vs. 28.6% of indoor workers had ≥2 skin cancers diagnosed during their lifetime. Multivariate logistic regression models showed significantly increased risk of outdoor vs. indoor work for AK (ORother outdoor = 1.55, ORfarming/construction = 2.58), SCC (ORother outdoor = 1.32, ORfarming/construction = 2.77) and BCC (ORother outdoor = 1.53, ORfarming/construction = 1.83). No significant associations were found for melanoma. The risk of all types of skin cancer and AK was significantly increased for workers with ≥5 years of outdoor work. CONCLUSIONS: Outdoor workers had more risk behaviour with similar constitutional skin cancer risk factors: more UV exposure (both occupational and leisure) and less sunscreen use and lower health literacy. This results in higher exposure, more photodamage and an increased risk of developing AK, BCC and SCC.

Possible association between actinic keratosis and the rs7208422 (c.917A→T, p.N306l) polymorphism of the EVER2 gene in patients without epidermodysplasia verruciformis.

BACKGROUND: Mutations of the EVER1 and EVER2 genes cause epidermodysplasia verruciformis (EV), a genodermatosis associated with squamous cell carcinoma (SCC). Recently, it has been found that the rs7208422 (c.917A→T, p.N306l) polymorphism in the EVER2 gene is related to an increased risk of SCC in patients with conditions other than EV. We hypothesized that this polymorphism might be also associated with actinic keratoses (AK). AIM: To determine whether the rs7208422 polymorphism of the EVER2 gene is associated with AK in non-EV patients. METHODS: We genotyped rs7208422 in 65 patients with AK and 274 controls, using reverse transcription PCR. RESULTS: We detected a trend towards an association between AK and the TT genotype of rs7208422; the frequency of this genotype was 38.5% in patients with AK and 26.3% in controls (OR  = â€Š1.75, P  < â€Š0.06 for recessive model of inheritance). We also found an association between rs7208422 TT and both the age at which AK appeared and the extent of the AK. This variant was more frequent in patients who had AK onset before the age of 70 years compared with those whose age of onset was above 70 years (OR = 3.14, P = 0.03 for the recessive model; OR = 2.05, P = 0.04 for allelic comparison) and more frequent in AK involving > 3 body areas (OR = 3.14, P = 0.03 for the recessive model; OR = 2.34, P = 0.01 for allelic comparison). These associations remained significant in a multivariate regression analysis, showing that both parameters were independently associated with the TT genotype (P = 0.031). CONCLUSIONS: This study indicates a potential role of the rs7208422 (c.917A→T, P.N306l) polymorphism of the EVER2 gene in AK.

A large area, silicon photomultiplier-based PET detector module.

The introduction of silicon photomultipliers (SiPM) has facilitated construction of compact, efficient and magnetic field-hardened positron emission tomography (PET) scanners. To take full advantage of these devices, methods for using them to produce large field-of-view PET scanners are needed. In this investigation, we explored techniques to combine two SiPM arrays to form the building block for a small animal PET scanner. The module consists of a 26 × 58 array of 1.5 × 1.5mm2 LYSO elements (spanning 41 × 91mm2) coupled to two SensL SiPM arrays. The SiPMs were read out with new multiplexing electronics developed for this project. To facilitate calculation of event position with multiple SiPM arrays it was necessary to spread scintillation light amongst a number of elements with a small light guide. This method was successful in permitting identification of all detector elements, even at the seam between two SiPM arrays. Since the performance of SiPMs is enhanced by cooling, the detector module was fitted with a cooling jacket, which allowed the temperature of the device and electronics to be controlled. Testing demonstrated that the peak-to-valley contrast ratio of the light detected from the scintillation array was increased by ∼45% when the temperature was reduced from 28 °C to 16 °C. Energy resolution for 511 keV photons improved slightly from 18.8% at 28 °C to 17.8% at 16 °C. Finally, the coincidence timing resolution of the module was found to be insufficient for time-of-flight applications (∼2100 ps at 14 °C). The first use of these new modules will be in the construction of a small animal PET scanner to be integrated with a 3T clinical magnetic resonance imaging scanner.

Artificial membranes as models in penetration investigations.

BACKGROUND/AIMS: In vitro methods used in the research of transepidermal transport of active substances generally rely on the penetration rate of test compounds through standard membranes. Models typically used in penetration experiments are specially prepared human or animal skin samples or synthetic membranes. The objective of this study was to establish if the test results for an artificial liposome membrane can be extrapolated to determine the actual bioavailability of active substances. METHODS: Tests were conducted in a side-by-side diffusion cell. As model membranes, a liquid-crystal lipid membrane (LM), phospholipid membrane (PM) and pig skin sample were used. The test compounds were eight synthetic dyes used in hair colouring products. RESULTS/CONCLUSION: Research findings reveal that membranes composed of lipids, identical to those present in the epidermis and forming analogical liquid-crystal structures provide a close approximation of the actual bioavailability of active substances (correlation between the results obtained for pig skin and LM was significant: R = 0.95 and R = 0.93 in the presence of a 1% Sodium dodecyl sulphate in donor system). Unlike biological membranes, intercellular cement does not contain phospholipids. The observed correlation between penetration coefficients through the PM and pig skin was not significant (R = 0.82). The experiments confirm that the PM constitutes a less credible model for the studies of transepidermal transport in real life conditions.

Known and potential new risk factors for skin cancer in European populations: a multicentre case-control study.

BACKGROUND: During recent years numerous studies have suggested that personal and environmental factors might influence cancer development. OBJECTIVES: To investigate environmental and personal characteristics associated with skin cancer risk. METHODS: A multicentre hospital-based case-control study was performed in Finland, Germany, Greece, Italy, Malta, Poland, Scotland and Spain, including 409 patients with squamous cell carcinoma (SCC), 602 with basal cell carcinoma (BCC) and 360 with cutaneous malignant melanoma (CMM) and 1550 control persons. Exposures were assessed by questionnaires that were partly self-administered, partly completed by dermatologists. Unconditional logistic regression modelling was used to assess associations including the influence of certain drugs and food items on skin cancer risk. RESULTS: The usual associations were observed for sun exposure and pigmentation characteristics, with chronic sun exposure being most strongly associated with SCC risk, and naevi and atypical naevi with CMM risk. Use of ciprofloxacin was associated with a decreased risk of BCC [odds ratio (OR) 0·33] and use of thiazide diuretics was associated with an increased risk of SCC (OR 1·66). Ciprofloxacin was also associated with SCC (OR 0·34) and thiazines with BCC (OR 2·04), but these associations lost significance after correction for multiple testing. Consumption of pomegranate, rich in antioxidants, was associated with decreased BCC and SCC risk, also after correcting for multiple testing. Recent experience of stressful events was associated with increased risk, particularly of CMM. CONCLUSIONS: In this large case-control study from across Europe the expected associations were observed for known risk factors. Some new potential protective factors and potential risk factors were identified for consumption of certain food items, medication use and stress, which deserve further investigation in future studies.

Assessing physicians' preferences on skin cancer treatment in Europe.

BACKGROUND: A wide variety of both surgical and nonsurgical therapies is currently available for patients with skin cancer. OBJECTIVES: This part of the EPIDERM (European Prevention Initiative for Dermatological Malignancies) project is aimed at the evaluation of the treatment preferences for skin cancer in eight countries of the European Union. METHODS: A multicentre hospital-based case-control study was carried out at dermatology departments in Finland, Germany, Greece, Italy, Malta, Poland, Scotland and Spain. Patients with skin cancer (basal cell carcinoma, actinic keratosis, squamous cell carcinoma, cutaneous malignant melanoma and Bowen disease) were consecutively enrolled between July 2008 and July 2010. Information on the study variables (sex, age, country, tumour type, anatomical location and treatment) was obtained from questionnaires designed by the EPIDERM project. RESULTS: In total, 1708 patients with skin cancer were included. Surgery was the first treatment option in 76·5% of the patients (P = 0·001). Actinic keratosis was the only tumour type in which nonsurgical treatment was more frequent than surgery (91·4%). Tumours on the head were less likely to be surgically excised than those at other locations (odds ratio 0·25, P = 0·001). Simple excision or curettage was the most common surgical procedure (65·4%), followed by graft and flaps (22·4%). Cryotherapy was the most common nonsurgical option (52·4%), followed by imiquimod (18·0%), photodynamic therapy (PDT; 12·0%), 5-fluorouracil (5-FU; 5·7%), and diclofenac with hyaluronic acid (4·0%). CONCLUSIONS: Surgery remains the first-choice treatment of skin cancer. Regarding nonsurgical treatments, the conservative treatments available (imiquimod, 5-FU, PDT and diclofenac gel) have not yet exceeded the use of ablative options such as cryotherapy despite their accepted benefit of treating field cancerization.

Risk factors for actinic keratosis in eight European centres: a case-control study.

BACKGROUND: There are limited data regarding the association of actinic keratosis (AK) and other types of nonmelanoma skin cancer (NMSC); studies investigating possible correlation of AK with melanocytic naevi are even scarcer. To our knowledge, there are no data examining the risk of AK in people using specific medications. OBJECTIVE: To investigate constitutional and exposure risk factors leading to AK and the coexistence of AK with NMSC and melanoma. METHODS: A multicentre hospital-based case-control study was performed in Finland, Germany, Greece, Italy, Malta, Poland, Scotland and Spain, including 343 patients with actinic keratosis (AK), 409 with squamous cell carcinoma (SCC), 602 with basal cell carcinoma (BCC), 360 with invasive melanoma and 119 with in situ melanoma, and 686 control subjects. Exposures were assessed by questionnaires that were partly self-administered and partly filled out by dermatologists. Unconditional logistic regression modelling was used to assess associations including the influence of phenotypic characteristics, presence of naevi, sun-exposure habits and certain drugs on AK risk. RESULTS: Differences in hair and eye coloration variably influenced the risk for AK, with red hair signifying a seven times higher risk [odds ratio (OR) 6·9, 95% confidence interval (CI) 4·34-11·00), and brown - compared with blue - eyes, about a 40% reduced risk (OR 0·61, 95% CI 0·13-0·92). The darker the skin phototype, the lower the risk for AK, with phototype IV exhibiting nine times less risk of developing AK. Some and many freckles on the arms were associated with an OR of 1·8 (95% CI 1·08-2·81) and 3·0 (95% CI 1·10-3·54), respectively, while overall number of naevi and high educational level were inversely associated with AK. Sun exposure, thiazide diuretics and cardiac drugs had a higher risk for AK. SCC was the most frequent (58%) skin neoplasm coexisting with AKs, followed by BCC (30%), melanoma in situ (12%) and invasive melanoma (6%). CONCLUSION: In this large case-control study from across Europe the expected associations were confirmed for known risk factors. Some possible new risk factors, including cardiac and diuretic drugs, were identified, creating a new field for further investigation in future studies.

The patient journey: a report of skin cancer care across Europe.

BACKGROUND: There are poorly documented variations in the journey a skin cancer patient will follow from diagnosis to treatment in the European Union. OBJECTIVES: To investigate the possible difficulties or obstacles that a person with a skin malignancy in the European Union may have to overcome in order to receive adequate medical screening and care for his/her condition. In addition, we wished to explore differences in European health systems, which may lead to health inequalities and health inequities within Europe. METHODS: Ten European countries took part in this investigation (in alphabetical order): Finland, Germany, Greece, Italy, Malta, Poland, Romania, Spain, the Netherlands and the U.K. The individual participants undertook local and national enquiries within their own country and completed a questionnaire. RESULTS: This exercise has identified important differences in the management of a skin cancer patient, reflecting major disparities in health care between European countries. CONCLUSIONS: Further investigation of health disparities and efforts to address health inequalities should lead to improvements in European health care quality and reduction in morbidity from skin cancer.

Mechanisms of resistance to antimicrobial drugs in pathogenic Gram-positive cocci.

Many species of Gram-positive cocci are pathogenic. The most important are staphylococci, streptococci, and enterococci. Widespread usage of antibiotics was the main cause for the appearance and spread of resistance to almost all antimicrobials. The occurrence, mechanisms, and genetic background of resistance to antimicrobial drugs other than beta-lactams and glycopeptides among pathogenic staphylococci, streptococci, and enterococci are discussed in the text. Well-established agents (such as macrolides, lincosamides, streptogramins, aminoglycosides, quinolones, mupirocin, chloramphenicol) as well as new agents (linezolid, daptomycin, quinupristine/dalfopristine, ratapamulin, tigecycline, iclaprim and new generations of quinolones) are considered.

The impact of a quadrivalent human papillomavirus (types 6, 11, 16, 18) virus-like particle vaccine in European women aged 16 to 24.

BACKGROUND: Quadrivalent human papillomavirus (HPV types 6/11/16/18) L1 VLP vaccine is highly effective in preventing HPV 6/11/16/18-related cervical and external genital disease. Herein, we evaluated the impact of the quadrivalent HPV 6/11/16/18 L1 VLP vaccine on prevention of HPV-associated cervico-genital lesions in a broad population of sexually active European women. METHODS: Female subjects (N = 9265) aged 16-24 with four or fewer lifetime sexual partners were enrolled and randomized to quadrivalent HPV vaccine or placebo. Subjects underwent cervicovaginal sampling for HPV DNA detection. Papanicolaou testing and anti-HPV 6/11/16/18 serology testing was also performed. RESULTS: Vaccine efficacy against lesions representing immediate cervical cancer precursors (cervical intraepithelial neoplasia grade 2/3 or adenocarcinoma in situ) related to HPV 6/11/16/18 in the per-protocol population was 100.0%[95% confidence interval (95% CI), 89.8-100.0]. Efficacy against external genital lesions (vulvar or vaginal intraepithelial neoplasia, condyloma, vulvar or vaginal cancer) related to vaccine HPV types in the per-protocol European population was 99.0% (95% CI, 94.4-100.0). CONCLUSION: These data demonstrate that quadrivalent HPV 6/11/16/18 vaccination programs in 16- to 24-year-old European women can be beneficial. NCT0009252, NCT00092534, NCT00092495.