BACKGROUND: Second-line treatment options for persistent, recurrent or metastatic (r/m) cervical cancer are limited. We investigated the safety, efficacy, and immunogenicity of the therapeutic DNA-based vaccine VB10.16 combined with the immune checkpoint inhibitor atezolizumab in patients with human papillomavirus (HPV)16-positive r/m cervical cancer. PATIENTS AND METHODS: This multicenter, single-arm, phase 2a study (NCT04405349, registered 26 May 2020) enrolled adult patients with persistent, r/m HPV16-positive cervical cancer. Patients received 3 mg VB10.16 (every 3 weeks (Q3W) for 12 weeks, hereafter every 6 weeks) combined with 1,200 mg atezolizumab (Q3W) for 48 weeks in total with a 12-month follow-up. The primary endpoints were incidence and severity of adverse events (AEs) and objective response rate (ORR; Response Evaluation Criteria in Solid Tumor V.1.1). ORR was assessed in the efficacy population, being all response-evaluable patients who received any administration of VB10.16 and atezolizumab and had at least one post-baseline imaging assessment. RESULTS: Between June 16, 2020, and January 25, 2022, 52 patients received at least one administration of study treatment. Of these, 47 patients had a minimum of one post-baseline tumor assessment. The median follow-up time for survival was 11.7 months. AEs related to VB10.16 were non-serious and mainly mild injection site reactions (9 of 52 patients). There were no signs of new toxicities other than what was already described with atezolizumab. ORR was 19.1% (95% CI 9.1% to 33.3%). Median duration of response was not reached (n.r.) (95% CI 2.2 to n.r.), median progression-free survival was 4.1 months (95% CI 2.1 to 6.2), and median overall survival was 21.3 months (95% CI 8.5 to n.r.). In programmed death-ligand 1 (PD-L1)-positive patients (n=24), ORR was 29.2% (95% CI 12.6 to 51.1). HPV16-specific T-cell responses were analyzed in 36 of 47 patients with an increase observed in 22/36 (61%). CONCLUSIONS: The therapeutic DNA-based vaccine VB10.16 combined with atezolizumab was safe and well tolerated showing a promising clinically meaningful efficacy with durable responses in patients with persistent, r/m HPV16-positive cervical cancer, especially if PD-L1-positive.

• MeSH
• DNA vakcíny * aplikace a dávkování   terapeutické užití   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• infekce papilomavirem virologie   imunologie   komplikace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidský papilomavirus 16 * imunologie   MeSH
• lokální recidiva nádoru MeSH
• metastázy nádorů MeSH
• nádory děložního čípku * farmakoterapie   virologie   MeSH
• senioři MeSH
• vakcíny proti papilomavirům aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH

High-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications are initiated by interactions with cellular heparan sulphates (HS), however, their molecular nature and functional consequences remain elusive. Combining virological assays with hydrogen/deuterium exchange mass spectrometry, and atomic force microscopy, we investigate the effect of capsid-HS binding and structural activation. We show how HS-induced structural activation requires a minimal HS-chain length and simultaneous engagement of several binding sites by a single HS molecule. This engagement introduces a pincer-like force that stabilizes the capsid in a conformation with extended capsomer linkers. It results in capsid enlargement and softening, thereby likely facilitating L1 proteolytic cleavage and subsequent L2-externalization, as needed for cell entry. Our data supports the further devising of prophylactic strategies against HPV infections.

• MeSH
• heparitinsulfát * metabolismus   chemie   MeSH
• infekce papilomavirem virologie   MeSH
• internalizace viru * MeSH
• kapsida * metabolismus   chemie   MeSH
• lidé MeSH
• lidské papilomaviry MeSH
• lidský papilomavirus 16 metabolismus   fyziologie   MeSH
• mikroskopie atomárních sil * MeSH
• Papillomaviridae fyziologie   MeSH
• polysacharidy metabolismus   chemie   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• virové plášťové proteiny * metabolismus   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: The objective of this study was to evaluate the effectiveness of human papillomavirus HPV test with HPV16/18 genotyping and liquid-based cytology (LBC) triage as a primary screening method for cervical cancer compared to conventional Pap test in women undergoing routine cervical cancer screening in Tbilisi. METHODS: Cross-sectional, prospective study was conducted, where 1,000 enrolled women aged 30-60 years during one visit underwent conventional Pap smear and Hr-HPV testing (Roche Cobas system). Women with any positive screening results were referred for further evaluation and remaining cells from the Cell Collection Medium vial were used for LBC. The study calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for each screening method and receiver-operating characteristic (ROC) curve to evaluate the accuracy of each diagnostic method in identifying people with CIN2+ diseases. RESULTS: The HPV test with HPV16/18 genotyping and LBC triage demonstrated higher sensitivity (76.9%), specificity (71.6%), and PPV (34.5%) compared to conventional Pap tests (p < 0.05). NPV was also high with the HPV test (94.1%). The HPV test alone had the highest sensitivity (92.3%) and NPV (96.7%), but lower specificity (41.4%) and PPV (22.6%) than the HPV test with HPV16/18 genotyping and LBC triage (p < 0.05). Comparing the areas under the curve (AUCs), only the HPV with HPV16/18 genotyping and LBC triage showed a statistically significant difference when compared to conventional Pap (0.71 vs. 0.55, p = 0.03) and high figures of AUC 0.71 (95% CI: 0.58-0.85) suggesting that HPV test with HPV16/18 genotyping and LBC triage is a more reliable screening method for detecting CIN2+ disease and preventing cervical cancer, than other screening modality. CONCLUSION: The results suggest that the HPV test with HPV16/18 genotyping and LBC triage is a more effective primary screening method compared to conventional Pap tests. This information should be the basis for transition from cytological screening to HPV testing in Georgia.

• MeSH
• časná detekce nádoru * metody   MeSH
• dospělí MeSH
• genotyp MeSH
• infekce papilomavirem * diagnóza   virologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidský papilomavirus 16 genetika   izolace a purifikace   MeSH
• lidský papilomavirus 18 genetika   izolace a purifikace   MeSH
• nádory děložního čípku * virologie   diagnóza   MeSH
• Papanicolaouův test * MeSH
• prospektivní studie MeSH
• průřezové studie MeSH
• senzitivita a specificita MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Gruzie MeSH

OBJECTIVE: The substantial material and legislative investments in establishing and maintaining cytological screening in the Czech Republic represent barriers to a direct transition to primary HPV screening. Therefore, the LIBUSE project was implemented to test the efficacy of phasing in HPV DNA testing as a co-test to cytology in routine screening of women >30 years of age. METHODS: Women aged 30 to 60 years who underwent regular annual Pap smears were co-tested for HPV DNA with selective 16/18 genotyping at 3-year intervals. All HPV 16/18-positive cases and/or cases with a severe abnormality in cytology were sent for colposcopy; HPV non-16/18-positive cases and LSILs were graded using p16/Ki67 dual-stain cytology, and positive cases were sent for colposcopy. RESULTS: Overall, 2409 patients were included. After the first combined screening (year 'zero') visit, 7.4% of women were HPV-positive and 2.0% were HPV16/18-positive; only 8 women had severe Pap smear abnormalities. Triage by dual staining was positive in 21.9% of cases (28/128). Biopsy confirmed 34 high-grade precancer lesions. At the second combined visit (year 'three'), the frequency of HPV infection (5.3% vs. 7.4%) frequency of HPV16/18 (1.1% vs. 2.0%), referrals for colposcopy (35 vs. 83), and biopsy verified high-grade lesions (5 vs. 34) were significantly lower (all P ≤ 0.001). CONCLUSION: The addition of HPV DNA testing with selective genotyping of HPV16/18 to existing cytology screening significantly increased the safety of the program. The gradual introduction of HPV testing was well received by healthcare professionals and patients, and can facilitate transformation of the cytology-based screening. ClinicalTrials.gov Identifier: NCT05578833.

• MeSH
• barvení a značení MeSH
• časná detekce nádoru MeSH
• DNA MeSH
• dospělí MeSH
• dysplazie děložního hrdla * diagnóza   MeSH
• infekce papilomavirem * MeSH
• lidé MeSH
• lidský papilomavirus 16 genetika   MeSH
• lidský papilomavirus 18 genetika   MeSH
• nádory děložního čípku * MeSH
• Papanicolaouův test MeSH
• plošný screening MeSH
• třídění pacientů MeSH
• vaginální stěr MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

• MeSH
• infekce papilomavirem * MeSH
• lidé MeSH
• lidské papilomaviry MeSH
• lidský papilomavirus 16 MeSH
• nádory hlavy a krku * diagnóza   MeSH
• nádory orofaryngu * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Human papillomaviruses (HPVs) represent a diverse group of double-stranded DNA viruses associated with various types of cancers, notably cervical cancer. High-risk types of HPVs exhibit their oncogenic potential through the integration of their DNA into the host genome. This integration event contributes significantly to genomic instability and the progression of malignancy. However, traditional detection methods, such as immunohistochemistry or PCR-based assays, face inherent challenges, and thus alternative tools are being developed to fasten and simplify the analysis. Our study introduces an innovative biosensing platform that combines loop-mediated amplification with electrochemical (EC) analysis for the specific detection of HPV16 integration. By targeting key elements like the E7 mRNA, a central player in HPV integration, and the E2 viral gene transcript lost upon integration, we show clear distinction between episomal and integrated forms of HPV16. Our EC data confirmed higher E7 expression in HPV16-positive cell lines having integrated forms of viral genome, while E2 expression was diminished in cells with fully integrated genomes. Moreover, we revealed distinct expression patterns in cervical tissue of patients, correlating well with digital droplet PCR, qRT-PCR, or immunohistochemical staining. Our platform thus offers insights into HPV integration in clinical samples and facilitates further advancements in cervical cancer research and diagnostics.

• MeSH
• biosenzitivní techniky metody   MeSH
• DNA vazebné proteiny genetika   MeSH
• DNA virů genetika   MeSH
• elektrochemické techniky * metody   MeSH
• genom virový MeSH
• infekce papilomavirem * virologie   MeSH
• integrace viru * genetika   MeSH
• lidé MeSH
• lidský papilomavirus 16 * genetika   MeSH
• messenger RNA * genetika   MeSH
• nádory děložního čípku * virologie   MeSH
• onkogenní proteiny virové * genetika   MeSH
• Papillomavirus E7 - proteiny * genetika   MeSH
• progrese nemoci MeSH
• RNA virová genetika   MeSH
• techniky amplifikace nukleových kyselin metody   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Prezentujeme kazuistiku 40letého pacienta s lézí na glans penis, primárně histologicky potvrzena jako penilní intraepiteliální neoplazie (PeIN). V první linii na sektorovém dermatovenerologickém pracovišti byla zvolena lokální terapie 5‐fluorouracilem. Následná opakovaná biopsie glandu histologicky prokazuje perzistenci PeIN. U pacienta byla provedena cirkumcize a parciální resurfacing glandu s použitím bukálního štěpu s dosažením příznivého kosmetického i funkčního efektu.

We present a case report of a 40 year old patient presenting with lession on glans penis. First biopsy histologically confirmed penile intraepithelial neoplasia (PeIN) associated with HPV p16. Local treatment with 5-fluorouracil provided by dermatologist was ineffective and another biopsy of glans penis again confirmed persistence of PeIN. The patient underwent a circumcision and partial glans resufacing using a buccal graft with favourable aesthetical and functional outcome.

• Klíčová slova
• resurfacing glandu,
• MeSH
• dospělí MeSH
• fluoruracil terapeutické užití   MeSH
• infekce papilomavirem diagnóza   terapie   MeSH
• lidé MeSH
• lidský papilomavirus 16 patogenita   MeSH
• nádory penisu * chirurgie   diagnóza   MeSH
• protinádorové antimetabolity MeSH
• transplantace kůže MeSH
• urologické chirurgické výkony u mužů MeSH
• zákroky plastické chirurgie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• práce podpořená grantem MeSH

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

• MeSH
• genetické markery MeSH
• infekce papilomavirem * MeSH
• lidé středního věku MeSH
• lidé MeSH
• lidské papilomaviry MeSH
• lidský papilomavirus 16 genetika   MeSH
• nádory hlavy a krku * MeSH
• nádory orofaryngu * MeSH
• onkogenní proteiny virové * genetika   MeSH
• protilátky virové MeSH
• rizikové faktory MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients. RESULTS: The WIDTM-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case-control) and predictive setting (nested case-control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WIDTM-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WIDTM-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt-) index sample who were diagnosed with CIN3 1-4 years after sample donation. CONCLUSION: We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WIDTM-qCIN, a PCR-based DNAme test. The WIDTM-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case-control settings and future studies will assess performance and generalisability in a randomised controlled trial.

• MeSH
• Alphapapillomavirus * MeSH
• časná detekce nádoru MeSH
• dospělí MeSH
• dysplazie děložního hrdla * diagnóza   genetika   MeSH
• infekce papilomavirem * diagnóza   genetika   MeSH
• lidé MeSH
• metylace DNA MeSH
• nádory děložního čípku * diagnóza   genetika   MeSH
• Papillomaviridae genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• Alphapapillomavirus patogenita   MeSH
• infekce papilomavirem epidemiologie   prevence a kontrola   MeSH
• karcinom MeSH
• kondylomata akuminata epidemiologie   prevence a kontrola   MeSH
• kontrola infekčních nemocí MeSH
• lidé MeSH
• nádory děložního čípku epidemiologie   prevence a kontrola   MeSH
• preexpoziční profylaxe * ekonomika   statistika a číselné údaje   MeSH
• prekancerózy epidemiologie   prevence a kontrola   MeSH
• vakcíny proti papilomavirům * aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• přehledy MeSH