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
- Staining and Labeling MeSH
- Early Detection of Cancer MeSH
- DNA MeSH
- Adult MeSH
- Uterine Cervical Dysplasia * diagnosis MeSH
- Papillomavirus Infections * MeSH
- Humans MeSH
- Human papillomavirus 16 genetics MeSH
- Human papillomavirus 18 genetics MeSH
- Uterine Cervical Neoplasms * MeSH
- Papanicolaou Test MeSH
- Mass Screening MeSH
- Triage MeSH
- Vaginal Smears MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: A population-based cervical cancer screening programme is implemented in the Czech Republic. However, participation is insufficient among women over 50 years. This study aimed to estimate the potential improvement in participation through directly mailed HPV self-sampling kits (HPVssk) compared with standard invitation letters in women aged 50-65 non-participating in screening. METHODS: The study recruited 1564 eligible women (no cervical cancer screening in the last 3 years or more, no previous treatment associated with cervical lesions or cervical cancer). Eight hundred women were mailed with an HPVssk (HPVssk group), and 764 women were sent a standard invitation letter (control group) inviting them to a routine screening (Pap test). The primary outcome was a comparison of the overall participation rate between study groups using a binominal regression model. RESULTS: The participation rate in the HPVssk group was 13.4% [95% confidence interval (CI) 11.2-15.9%; 7.4% of women returned the HPVssk and 6.0% attended gynaecological examination] and 5.0% (95% CI 3.6-6.8%) in the control group. Using the binominal regression model, the difference between the groups was estimated as 7.6% (95% CI 5.0-10.2%; P < 0.001). In the HPVssk group, 22% of women who returned HPVssk had a positive result and 70% of them underwent a follow-up examination. CONCLUSIONS: Compared with traditional invitation letters, the direct mailing of the HPVssk achieved a significantly higher participation rate, along with a notable HPV positivity rate among HPVssk responders. This approach offers a potentially viable method for engaging women who have not yet attended a cervical screening programme.
- MeSH
- Early Detection of Cancer methods MeSH
- Papillomavirus Infections * diagnosis MeSH
- Humans MeSH
- Uterine Cervical Neoplasms * diagnosis prevention & control MeSH
- Mass Screening methods MeSH
- Vaginal Smears MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
Cauda equina neuroendocrine tumors (CENETs) are neoplasms of uncertain histogenesis with overlapping features between those of paragangliomas (PGs) and visceral neuroendocrine tumors (NETs). We have explored their biological relationship to both subsets of neuroendocrine neoplasms. The clinical and radiological features of a cohort of 23 CENETs were analyzed. A total of 21 cases were included in tissue microarrays, along with a control group of 38 PGs and 83 NETs. An extensive panel of antibodies was used to assess epithelial phenotype (cytokeratins, E-cadherin, EpCAM, Claudin-4, EMA, CD138), neuronal and neuroendocrine features (synaptophysin, chromogranin A, INSM1, neurofilaments, NeuN, internexin-α, calretinin), chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase), and possible histogenesis (Sox2, T-brachyury, Oct3/4, Sox10). The cohort included 5 women (22%) and 18 men (78%). The average age at the time of surgery was 48.3 years (range from 21 to 80 years). The average diameter of the tumors was 39.27 mm, and invasion of surrounding structures was observed in 6/21 (29%) tumors. Follow-up was available in 16 patients (median 46.5 months). One tumor recurred after 19 months. No metastatic behavior and no endocrine activity were observed. Compared to control groups, CENETs lacked expression of epithelial adhesion molecules (EpCAM, CD138, E-cadherin, Claudin-4), and at the same time, they lacked features of chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase). We observed no loss of SDHB. Cytokeratin expression was present in all CENETs. All the CENETs showed variable cytoplasmic expression of T-brachyury and limited nuclear expression of Sox2. These findings support the unique nature of the neoplasm with respect to NETs and PGs.
- MeSH
- Epithelial Cell Adhesion Molecule MeSH
- Cauda Equina * metabolism pathology surgery MeSH
- Claudin-4 MeSH
- Humans MeSH
- Neoplasm Recurrence, Local pathology MeSH
- Central Nervous System Neoplasms * pathology MeSH
- Neuroendocrine Tumors * pathology MeSH
- Paraganglioma * MeSH
- Repressor Proteins MeSH
- Transcription Factors MeSH
- Tyrosine 3-Monooxygenase MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N = 162 in total) with early-stage estrogen-receptor-positive luminal BC-high-coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro-RNA (miRNA) transcriptome microarrays-we describe complex oxysterol-related interaction (correlation) networks, with validation in public datasets (n = 538) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, interconnected through miR-125b-5p, miR-99a-5p, miR-100-5p, miR-143-3p, miR-199b-5p, miR-376a-3p, and miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol-related genes. STARD5 was upregulated in patients with positive lymph node status. High expression of hsa-miR-19b-3p was weakly associated with poor survival. This is the first study of oxysterol-related genes in BC that combines DNA, mRNA, and miRNA multiomics with detailed clinical data. Future studies should provide links between intratumoral oxysterol signaling depicted here, circulating oxysterol levels, and therapy outcomes, enabling eventual clinical exploitation of present findings.
- MeSH
- Humans MeSH
- RNA, Messenger genetics MeSH
- MicroRNAs * genetics metabolism MeSH
- Breast Neoplasms * pathology MeSH
- Oxysterols * MeSH
- Transcriptome genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Diagnostic Imaging methods MeSH
- Adult MeSH
- Granulomatous Mastitis * diagnosis pathology therapy MeSH
- Humans MeSH
- Prednisone pharmacology therapeutic use MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Biopsy methods MeSH
- Adult MeSH
- Granulomatous Mastitis * diagnosis pathology therapy MeSH
- Histological Techniques MeSH
- Humans MeSH
- Mammography methods MeSH
- Prednisone administration & dosage adverse effects therapeutic use MeSH
- Ultrasonography methods MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Oxysterols, oxidized derivatives of cholesterol, have been implicated in multiple pathologies, including cancer. In breast cancer, the link is especially strong due to interactions between oxysterols and estrogen receptor activity. Here, we provide the first dedicated study of 113 oxysterol-related genes in breast cancer patients of the luminal subtype, in terms of both their somatic and germline variability, using targeted high-throughput DNA sequencing of 100 normal-tumor pairs with very high coverage. In the full cohort, or subsets of patients stratified by therapy, we found 12 germline variants in ABCA1, ABCA8, ABCC1, GPR183, LDLR, MBTPS1, NR1I2, OSBPL2, OSBPL3, and OSBPL5 to associate with poor survival of patients and variants in ABCA8, ABCG2, and HSD3B7 (three in total) associated with better survival. However, no associations remained significant after correction for multiple tests. Analysis of somatic variants revealed significantly (after FDR correction) poorer survival in patients mutated in CYP46A1 and 9 interacting (according to STRING analysis) genes, as well as in OSBPL3 and a set of 20 genes that collectively associated with the progesterone receptor status of patients. We propose further exploration of these genes in an integrative manner together with gene expression and epigenomic data.
- MeSH
- Anastrozole therapeutic use MeSH
- Antineoplastic Agents, Hormonal therapeutic use MeSH
- Hysterectomy MeSH
- Carcinoid Tumor surgery diagnostic imaging MeSH
- Humans MeSH
- Breast Neoplasms surgery pathology MeSH
- Ovarian Neoplasms surgery diagnostic imaging pathology MeSH
- Ovariectomy MeSH
- Neoplasms, Second Primary * MeSH
- Aged MeSH
- Neoplasm Grading MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- Keywords
- EQUITAMP,
- MeSH
- Carcinoma, Ductal, Breast nursing MeSH
- Hemostatic Techniques MeSH
- Wound Healing MeSH
- Amoxicillin-Potassium Clavulanate Combination administration & dosage MeSH
- Skin Ulcer etiology drug therapy nursing MeSH
- Hemorrhage therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Metastasis diagnostic imaging MeSH
- Breast Neoplasms * nursing pathology MeSH
- Tampons, Surgical MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Cíl studie: Práce hodnotí výsledky dvouletého sledování kohorty žen ve věku 35–36 a 45–46 let, které se účastní projektu LIBUŠE, jehož cílem je ověřit účinnost společného vyšetření HPV DNA testu, cytologického stěru a cytologického barvení p16/Ki67 v národním cervikálním screeningu. Typ studie: Prospektivní observační studie. Název a sídlo pracoviště: Gynekologicko-porodnická klinika VFN a 1. LF UK, Praha. Materiál a metodika: Ze všech žen zařazených do studie LIBUŠE byly vybrány pouze ty, kterým bylo při vstupu do studie 35–36 a 45–46 let. Pacientkám byl odebrán konvenční cytologický stěr a HPV DNA test (Cobas 4800, Roche Diagnostics). Ženy byly podle vstupních výsledků stratifikovány do tří úrovní rizika: 1. nerizikové, 2. vysoce rizikové a 3. se střední mírou rizika, které byly tříděny pomocí imunocytochemického barvení p16/Ki67. Vysoce rizikové pacientky a pacientky s pozitivitou duálního barvení byly referovány k expertnímu kolposkopickému vyšetření. Případy s biopticky verifikovanou prekancerózou nebo karcinomem byly považovány za „pozitivní nálezy“. Výsledky: Věkové kritérium splnilo 352 žen. U 26 (7,4 %) žen byla zjištěna HPV DNA pozitivita, z toho u devíti pozitivita HPV 16/18. Závažná cytologická abnormita byly zjištěna pouze u jedné pacientky (0,3 %), která byla současně HPV pozitivní. K expertní kolposkopii bylo primárně referováno deset (2,8 %) žen splňujících kritérium vysokého rizika. U dalších 18 pacientek bylo doplněno barvení p16/Ki67 a čtyři pozitivně testované byly rovněž referovány k expertní kolposkopii. Při kontrole po roce bylo identifikováno devět pacientek středního rizika, při druhé kontrole po dalším roce bylo identifikováno dalších šest pacientek středního rizika. Během dvouletého sledování bylo ke kolposkopii referováno dalších devět pacientek. Za dobu sledování byla zjištěna prekanceróza u deseti pacientek a u žádné pacientky nebyl zjištěn invazivní karcinom. Závěr: Doplnění stávajícího cytologického screeningu o HPV DNA test se selektivní genotypizací HPV 16/18 umožňuje významně zvýšit citlivost a bezpečnost našeho cervikálního screeningového programu.
Objective: The study evaluates results of 2-years follow-up of patients in ages 35–36 and 45–46, who are participating in the project LIBUSE, that deals with efficacy of HPV DNA and Pap smear co-testing and p16/Ki67 dual staining in the Czech national cervical screening. Design: Prospective observational study. Setting: Department of Obstetrics and Gynecology, General University Hospital and 1st Medical Faculty, Charles University, Prague. Materials and methods: Out of all women enrolled in the project LIBUSE only those who were at the beginning of the study 35–36 and 45–46 years old were sellected. Conventional Pap smear and HPV DNA test (Cobas 4800, Roche Diagnostics) had been collected at the baseline. Women were stratified according to their results in the three risk groups: 1. low-risk, 2. high-risk and 3. intermediate risk, who subsequently underwent p16/Ki67 dual staining. All high-risk patients and those with positive result of dual staing were refered to the expert colposcopy. The cases with biopsy proven precancers or cancers were considered as „positive findings“. Results: Altogether 352 women meet the age requirements. In 26 (7.6%) women had been proven HPV DNA positivity and out of the them 9 cases were HPV 16/18 positive. Severe cytological abnormality was found only in one patient (0.3%), who was simultaneously HPV positive. Ten women (2.8%) were classified as high-risk and directly refered to colposcopy. Another 18 patients underwent p16/Ki67 dual staining and 4 positive cases were refered to colposcopy too. After one year further 9 patients were classified as intermediate risk and 6 more were identified after two years of follow-up. Within two years 9 more patient were refered to colposcopy. After the entire period of follow-up in 10 patients biopsy confirmed precancer lesions, none of them had invasive cancer. Conclusions: Addition of HPV DNA testing with selective HPV 16/18 genotyping to the cytology based screening significantly increases sensitivity and safety of our cervical screening program.
- Keywords
- studie LIBUŠE, p16/Ki67,
- MeSH
- Cytological Techniques MeSH
- Human Papillomavirus DNA Tests methods MeSH
- Adult MeSH
- Carcinoma diagnosis MeSH
- Clinical Studies as Topic MeSH
- Humans MeSH
- Uterine Cervical Neoplasms * diagnosis MeSH
- Papanicolaou Test MeSH
- Papillomaviridae * isolation & purification MeSH
- Mass Screening MeSH
- Precancerous Conditions diagnosis MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
