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OBJECTIVE: To identify predictive clinico-pathologic factors for concurrent endometrial carcinoma (EC) among patients with endometrial intraepithelial neoplasia (EIN) using machine learning. METHODS: a retrospective analysis of 160 patients with a biopsy proven EIN. We analyzed the performance of multiple machine learning models (n = 48) with different parameters to predict the diagnosis of postoperative EC. The prediction variables included: parity, gestations, sampling method, endometrial thickness, age, body mass index, diabetes, hypertension, serum CA-125, preoperative histology and preoperative hormonal therapy. Python 'sklearn' library was used to train and test the models. The model performance was evaluated by sensitivity, specificity, PPV, NPV and AUC. Five iterations of internal cross-validation were performed, and the mean values were used to compare between the models. RESULTS: Of the 160 women with a preoperative diagnosis of EIN, 37.5% (60) had a post-op diagnosis of EC. In univariable analysis, there were no significant predictors of EIN. For the five best machine learning models, all the models had a high specificity (71%-88%) and a low sensitivity (23%-51%). Logistic regression model had the highest specificity 88%, XG Boost had the highest sensitivity 51%, and the highest positive predictive value 62% and negative predictive value 73%. The highest area under the curve was achieved by the random forest model 0.646. CONCLUSIONS: Even using the most elaborate AI algorithms, it is not possible currently to predict concurrent EC in women with a preoperative diagnosis of EIN. As women with EIN have a high risk of concurrent EC, there may be a value of surgical staging including sentinel lymph node evaluation, to more precisely direct adjuvant treatment in the event EC is identified on final pathology.
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Hiperplasia Endometrial , Neoplasias do Endométrio , Gravidez , Humanos , Feminino , Estudos Retrospectivos , Neoplasias do Endométrio/patologia , Biópsia , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/patologia , Hiperplasia Endometrial/cirurgiaRESUMO
BACKGROUND AND OBJECTIVES: The 9-valent human papillomavirus (9vHPV) vaccine Phase III immunogenicity study in 9- to 15-year-old boys and girls was extended to assess immunogenicity and effectiveness through 10 years after the last vaccine dose (NCT00943722). METHODS: Boys (n = 301) and girls (n = 971) who received three 9vHPV vaccine doses in the base study (day 1, months 2 and 6) enrolled in the extension. Serum was collected through month 126 for antibody assessments by competitive Luminex immunoassay and immunoglobulin G-Luminex immunoassay. For effectiveness analysis starting at age 16 years, genital swabs were collected (to assess HPV DNA by polymerase chain reaction) and external genital examinations conducted every 6 months. Primary analyses were conducted in per-protocol populations. RESULTS: Geometric mean antibody titers peaked around month 7, decreased sharply between months 7 and 12, then gradually through month 126. Seropositivity rates remained ≥81% by competitive Luminex immunoassay and ≥95% by immunoglobin G-Luminex immunoassay at month 126 for each 9vHPV vaccine type. After up to 11.0 (median 10.0) years of follow-up postdose 3, there were no cases of HPV6/11/16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or condyloma in males or females. Incidence rates of HPV6/11/16/18/31/33/45/52/58-related 6-month persistent infection in males and females were low (54.6 and 52.4 per 10000 person-years, respectively) and within ranges expected in vaccinated cohorts, based on previous human papillomavirus vaccine efficacy trials. CONCLUSIONS: The 9vHPV vaccine demonstrated sustained immunogenicity and effectiveness through â¼10 years post 3 doses of 9vHPV vaccination of boys and girls aged 9 to 15 years.
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IMPORTANCE: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA). OBJECTIVE: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe. EVIDENCE REVIEW: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or nonrandomized controlled trials targeting postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness and involving ospemifene or at least one VVA local treatment were considered. Efficacy data included changes from baseline in superficial and parabasal cells, vaginal pH, and the most bothersome symptom of vaginal dryness or dyspareunia, as required for regulatory approval. Endometrial outcomes were endometrial thickness and histologic classifications, including endometrial polyp, hyperplasia, and cancer. For efficacy and safety outcomes, a Bayesian NMA was performed. Endometrial outcomes were compared in descriptive analyses. FINDINGS: A total of 44 controlled trials met the eligibility criteria ( N = 12,637 participants). Network meta-analysis results showed that ospemifene was not statistically different from other active therapies in most efficacy and safety results. For all treatments, including ospemifene, the posttreatment endometrial thickness values (up to 52 wk of treatment) were under the recognized clinical threshold value of 4 mm for significant risk of endometrial pathology. Specifically, for women treated with ospemifene, endometrial thickness ranged between 2.1 and 2.3 mm at baseline and 2.5 and 3.2 mm after treatment. No cases of endometrial carcinoma or hyperplasia were observed in ospemifene trials, nor polyps with atypical hyperplasia or cancer after up to 52 weeks of treatment. CONCLUSIONS AND RELEVANCE: Ospemifene is an efficacious, well-tolerated, and safe therapeutic option for postmenopausal women with moderate to severe symptoms of VVA. Efficacy and safety outcomes with ospemifene are similar to other VVA therapies in North America and Europe.
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Dispareunia , Neoplasias do Endométrio , Doenças Vaginais , Feminino , Humanos , Dispareunia/tratamento farmacológico , Dispareunia/patologia , Vagina/patologia , Hiperplasia/tratamento farmacológico , Hiperplasia/patologia , Teorema de Bayes , Metanálise em Rede , Vulva/patologia , Atrofia/tratamento farmacológico , Atrofia/patologia , Tamoxifeno/efeitos adversos , Moduladores Seletivos de Receptor Estrogênico/efeitos adversos , Doenças Vaginais/tratamento farmacológico , Doenças Vaginais/patologia , Neoplasias do Endométrio/patologiaRESUMO
OBJECTIVE: To determine the prevalence of underlying high-intermediate (high-IM) and high-risk endometrial cancer (EC) in patients with preoperative diagnosis of Endometrial intraepithelial neoplasia (EIN) and to assess the impact of the information retrieved from the sentinel lymph node (SLN) on adjuvant therapy. METHODS: Retrospective cohort study of women undergoing hysterectomy, optional bilateral salpingo-oophorectomy (BSO) and lymph nodes assessment for EIN between December 2007 and August 2021. RESULTS: One hundred and sixty two (162) eligible patients were included, of whom 101 (62.3%) had a final diagnosis of EIN, while 61 (37.7%) were ultimately diagnosed with carcinoma. Out of 15 patients with high-IM to high-risk disease (9.25% of all EIN), 12 had grade 2-3 EC including 8 with >50% myometrial invasion, 2 with serous subtype, 1 with cervical invasion and 2 with pelvic lymph nodes involvement. Of the 3 patients with grade 1 EC, one patient had disease involving the adnexa and 2 patients had tumor invading >50% of the myometrium and with lymphovascular space invasion (LVSI). Ten patients received vaginal brachytherapy after surgery, 3 patients with extrauterine spread were treated with systemic chemotherapy followed by vaginal brachytherapy and pelvic external-beam radiotherapy and 2 patients with early-stage serous carcinoma received chemotherapy followed by vaginal brachytherapy. CONCLUSIONS: Information from SLN, even when negative, can be helpful in the management of patients with EC after preoperative EIN, as some patients are found to have high-IM to high-risk disease on final pathology. These patients would require either re-staging surgery or adjuvant external beam radiotherapy, both could be avoided by proper staging.
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Carcinoma , Neoplasias do Endométrio , Linfadenopatia , Linfonodo Sentinela , Humanos , Feminino , Linfonodo Sentinela/patologia , Excisão de Linfonodo , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/cirurgia , Estudos Retrospectivos , Estadiamento de Neoplasias , Linfonodos/patologia , Biópsia de Linfonodo Sentinela , Linfadenopatia/patologia , Carcinoma/patologiaRESUMO
OBJECTIVE: A demonstration project of primary human papillomavirus (HPV) testing was initiated in 2011 among more than 23,000 women attending routine cervical cancer screening. We examined the additional diagnostic performance of HPV genotyping for detecting disease in women with abnormal cytology. METHODS: Women aged 30 to 65 years were originally screened for HPV using Hybrid Capture II test. Women with positive results were triaged using conventional cytology, and those with atypical squamous cells of undetermined significance or worse (≥ASC-US) were referred to colposcopy. We retrospectively genotyped (Roche cobas 4800 HPV system [Roche Molecular Systems Inc, Pleasanton, CA]) cervical specimens that were HPV + with Hybrid Capture II test and extracted women's medical history postbaseline screening. We calculated positive predictive values (PPVs) and 95% confidence intervals (CIs) of triage tests to detect histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2 + ) within the first year of follow-up among women positive for HPV16, HPV18, and HPV16 and/or HPV18 as well as among those negative for HPVs 16 and 18. RESULTS: Of 1,396 HPV-positive women, 1,092 (78%) were classified as normal, 136 (10%) had CIN1, 80 (6%) had CIN2, 81 (6%) had CIN3, and 7 women had cancer throughout the entire follow-up period. Seventy CIN2 + cases were detected within the first year of follow-up. The PPV for detecting CIN2 + was 20.9% (63/239; 95% CI = 16.4-25.9) for ASC-US + cytology. In women with ASC-US + , PPVs were 31.2% (24/77; 95% CI = 21.1-42.7) for HPV16 + , 27.8% (5/18; 95% CI = 9.7-53.5) for HPV18 + , 30.8% (28/91; 95% CI = 21.5-41.3) for HPV16 + and/or HPV18 + women, and 16.6% (35/211; 95% CI = 11.8-22.3) in women testing negative for HPVs 16 and 18. CONCLUSION: Partial genotyping as an additional triage strategy to cytology can markedly improve clinical diagnostic performance.
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Células Escamosas Atípicas do Colo do Útero , Infecções por Papillomavirus , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Gravidez , Feminino , Humanos , Neoplasias do Colo do Útero/patologia , Genótipo , Triagem , Detecção Precoce de Câncer/métodos , Estudos Retrospectivos , Displasia do Colo do Útero/patologia , Colposcopia , DNA Viral/genética , Papillomaviridae/genéticaRESUMO
Among women aged 27-45 years, the quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was generally well tolerated, efficacious, and immunogenic in the placebo-controlled FUTURE III study (NCT00090220; n = 3253). The qHPV vaccine was also generally well tolerated and highly immunogenic in men aged 27-45 years who participated in the single-cohort mid-adult male (MAM) study (NCT01432574; n = 150). Here, we report results of a long-term follow up (LTFU) extension of FUTURE III with up to 10 years follow-up. To understand the relevance of the mid-adult women LTFU study in the context of mid-adult men vaccination, we report results from post-hoc, cross-study immunogenicity analyses conducted to compare immunogenicity (geometric mean titers; GMTs) at 1-month post-qHPV vaccine dose 3 in women and men aged 27-45 years versus women and men aged 16-26 years from prior efficacy studies. The qHPV vaccine demonstrated durable protection against the combined endpoint of HPV6/11/16/18-related high-grade cervical dysplasia and genital warts up to 10 years (median 8.9) post-dose 3 and sustained HPV6/11/16/18 antibody responses through approximately 10 years in women aged 27-45 years. Efficacy of qHPV vaccine in men aged 27-45 years was inferred based on the cross-study analysis of qHPV vaccine immunogenicity demonstrating non-inferior HPV6/11/16/18 antibody responses in men aged 27-45 years versus 16-26 years. In conclusion, durable effectiveness of the qHPV vaccine was demonstrated in women 27-45 years of age, and vaccine efficacy was inferred in men 27-45 years of age based on the serological results.
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Infecções por Papillomavirus , Vacinas contra Papillomavirus , Adulto , Anticorpos Antivirais , Estudos Clínicos como Assunto , Feminino , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18 , Humanos , Imunogenicidade da Vacina , Masculino , Pessoa de Meia-Idade , Papillomaviridae , Infecções por Papillomavirus/prevenção & controle , Vacinas CombinadasRESUMO
BACKGROUND: The quadrivalent human papillomavirus (HPV) vaccine was shown to prevent infections and lesions related to HPV6, 11, 16, and 18 in a randomised, placebo-controlled study in men aged 16-26 years. We assessed the incidences of external genital warts related to HPV6 or 11, and external genital lesions and anal dysplasia related to HPV6, 11, 16, or 18, over 10 years of follow-up. METHODS: The 3-year base study was an international, multicentre, double-blind, randomised, placebo-controlled trial done at 71 sites in 18 countries. Eligible participants were heterosexual men (aged 16-23 years) or men who have sex with men (MSM; aged 16-26 years). Men who had clinically detectable anogenital warts or genital lesions at screening that were suggestive of infection with non-HPV sexually transmitted diseases, or who had a history of such findings, were excluded. Eligible participants were randomly assigned (1:1) to receive three doses of either quadrivalent HPV vaccine or placebo on day 1, month 2, and month 6, administered as a 0·5-mL injection into the deltoid muscle. The 7-year, open-label, long-term follow-up extension study was done at 46 centres in 16 countries. Participants who received one or more doses of the quadrivalent HPV vaccine in the base study were eligible for enrolment into the long-term follow-up study (early vaccination group). Placebo recipients were offered the three-dose quadrivalent HPV vaccine at the end of the base study; those who received one or more quadrivalent HPV vaccine doses were eligible for enrolment into the long-term follow-up study (catch-up vaccination group). The primary efficacy endpoints were the incidence of external genital warts related to HPV6 or 11 and the incidence of external genital lesions related to HPV6, 11, 16, or 18 in all participants and the incidence of anal intraepithelial neoplasia (including anal warts and flat lesions) or anal cancer related to HPV6, 11, 16, or 18 in MSM only. The primary efficacy analysis was done in the per-protocol population for the early vaccination group, which included participants who received all three vaccine doses, were seronegative at day 1 and PCR-negative from day 1 through month 7 of the base study for the HPV type being analysed, had no protocol violations that could affect evaluation of vaccine efficacy, and had attended at least one visit during the long-term follow-up study. For the catch-up vaccination group, efficacy was assessed in the modified intention-to-treat population, which included participants who had received at least one vaccine dose, were seronegative and PCR-negative for HPV types analysed from day 1 of the base study to the final follow-up visit before receiving the quadrivalent HPV vaccine, and had at least one long-term follow-up visit. Safety was assessed in all randomised participants who received at least one vaccine dose. This study is registered with ClinicalTrials.gov, NCT00090285. FINDINGS: Between Aug 10, 2010, and April 3, 2017, 1803 participants were enrolled in the long-term follow-up study, of whom 936 (827 heterosexual men and 109 MSM) were included in the early vaccination group and 867 (739 heterosexual men and 128 MSM) were included in the catch-up vaccination group. Participants in the early vaccination group were followed up for a median of 9·5 years (range 0·1-11·5) after receiving the third dose of the quadrivalent HPV vaccine, and participants in the catch-up vaccination group were followed up for a median of 4·7 years (0·0-6·6) after receiving the third dose. In early vaccine group participants during long-term follow-up compared with the placebo group in the base study, the incidence per 10â000 person-years of external genital warts related to HPV6 or 11 was 0·0 (95% CI 0·0-8·7) versus 137·3 (83·9-212·1), of external genital lesions related to HPV6, 11, 16, or 18 was 0·0 (0·0-7·7) versus 140·4 (89·0-210·7), and of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 in MSM only was 20·5 (0·5-114·4) versus 906·2 (553·5-1399·5). Compared with during the base study (ie, before quadrivalent HPV vaccine administration), during the long-term follow-up period, participants in the catch-up vaccination group had no new reported cases of external genital warts related to HPV6 or 11 (149·6 cases per 10â000 person-years [95% CI 101·6-212·3] vs 0 cases per 10â000 person-years [0·0-13·5]) or external genital lesions related to HPV6, 11, 16, or 18 (155·1 cases per 10â000 person-years [108·0-215·7] vs 0 cases per 10â000 person-years [0·0-10·2]), and a lower incidence of anal intraepithelial neoplasia or anal cancer related to HPV6, 11, 16, or 18 (886·0 cases per 10â000 person-years [583·9-1289·1] vs 101·3 cases per 10â000 person-years [32·9-236·3]). No vaccine-related serious adverse events were reported. INTERPRETATION: The quadrivalent HPV vaccine provides durable protection against anogenital disease related to HPV6, 11, 16, and 18. The results support quadrivalent HPV vaccination in men, including catch-up vaccination. FUNDING: Merck Sharp & Dohme.
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Neoplasias do Ânus , Condiloma Acuminado , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Minorias Sexuais e de Gênero , Condiloma Acuminado/epidemiologia , Condiloma Acuminado/prevenção & controle , Método Duplo-Cego , Seguimentos , Homossexualidade Masculina , Humanos , Imunogenicidade da Vacina , Masculino , Papillomaviridae , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/prevenção & controleRESUMO
The Lower Anogenital Squamous Terminology (LAST) Project recommends the use of p16 immunohistochemistry as an adjunct to morphologic assessment of cervical biopsies according to a specific set of criteria. We analyzed the effect of adjunctive p16 according to LAST criteria in a US-based diagnostic utility study involving 70 surgical pathologists providing a total of 38,500 reads on cervical biopsies. Compared with the results obtained using hematoxylin and eosin-stained slides only, including p16-stained slides per LAST criteria increased sensitivity and specificity for diagnosing histologic high-grade squamous intraepithelial lesions across all cases by 8.1% (95% confidence interval [95% CI], 6.5-9.7; P<0.0001) and 3.5% (95% CI, 2.8-4.2; P<0.0001), respectively, using expert consensus diagnoses on hematoxylin and eosin+p16 as reference. Within the subset of cases classified by the pathologists as fulfilling the LAST criteria, adding p16 significantly increased both sensitivity (+11.8%; 95% CI, 9.5-14.0; P<0.0001) and specificity (+9.7%; 95% CI, 7.8-11.5; P<0.0001). However, a comparable improvement in sensitivity (+11.0%; 95% CI, 7.8-14.1; P<0.0001) was found when p16 was used in cases for which p16 staining was not ordered per LAST by the pathologists, whereas specificity decreased by -0.8% (95% CI, -1.1 to -0.5; P<0.0001). The study demonstrates a clinically and statistically significant increase in sensitivity and specificity for high-grade squamous intraepithelial lesion when p16 is used according to LAST criteria. Expanding the use of p16 into non-LAST cases would lead to a comparable improvement in sensitivity within this subgroup of biopsies, at the cost of a minimal, but statistically significant difference in specificity.
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Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Lesões Intraepiteliais Escamosas Cervicais/metabolismo , Neoplasias do Colo do Útero/química , Biópsia , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Lesões Intraepiteliais Escamosas Cervicais/patologia , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVE: To evaluate if the prognostic value of lymphovascular space invasion (LVSI) is different in endometrial cancer patients with negative lymph nodes following sentinel lymph node (SLN) mapping or lymph node dissection (LND) as staging procedure. MATERIAL AND METHODS: A retrospective study of 510 patients diagnosed with endometrial carcinoma in our institution between 2007 and 2014. We excluded patients that were diagnosed with positive nodes (Stage IIIc). We compared patients' characteristics and survival outcomes as function of their LVSI status (positive LVSI vs negative LVSI subgroups) in each cohort separately. RESULTS: 413 patients met the inclusion criteria, out of whom 239 underwent SLN and 174 patients underwent LND only. In the SLN group, life table analysis showed 5-year OS and PFS of 80% and 72% in patients with LVSI compared to 96%, and 93% without LVSI. Same trend was observed among patients with LND with 5-year OS and PFS of 74% and 64% in patients with LVSI compared to 97%, and 90% without LVSI. On multivariable analysis, adjusted for age, FIGO stage, grade and maximal tumor size, the favorable survival of negative LVSI remained only in the LND cohort (SLN cohort: HR 1.2, CI [0.3-4.0], P = 0.8 and HR 1.7, CI [0.7-4.3], p = 0.2 for OS and PFS, respectively; LND cohort: HR 3.1, CI [1.4-6.5], p < 0.001 and HR 2.5, CI [1.2-4.9], p = 0.01 for OS and PFS, respectively). CONCLUSIONS: The prognostic value of LVSI disappears when patients undergo staging with SLN and are found to have negative nodes in contrast to those who have undergone LND. Future studies should confirm our observation on patients with negative sentinel nodes, and plan on tailoring adjuvant treatment to this specific subgroup.
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Vasos Sanguíneos/patologia , Neoplasias do Endométrio/mortalidade , Vasos Linfáticos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Seguimentos , Humanos , Histerectomia , Excisão de Linfonodo , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Salpingo-Ooforectomia , Linfonodo Sentinela/patologia , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo Sentinela/estatística & dados numéricosRESUMO
The aim of this study was to evaluate the impact of discordant endometrial sampling on the prognosis of patients finally diagnosed with uterine papillary serous carcinoma (UPSC) and to analyze UPSC mutational profile. Retrospective cohort study comparing outcomes of patients post-operatively diagnosed with UPSC and preoperatively diagnosed with endometrioid endometrial cancer (EEC) or UPSC. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 40 patients post-operatively diagnosed with UPSC, using next generation sequencing. 61 patients with UPSC on post-surgical, final pathology were included in the study. Prior to surgery, 15 were diagnosed with EEC (discordant) and 46 were correctly diagnosed with UPSC (concordant). After a median follow-up of 41.6 months [5.4-106.7], a preoperative diagnosis of EEC was associated with better 3-year progression-free survival (100% vs. 60.9%, P = 0.003) and longer disease free interval (63.5 versus 15 months, P = 0.026) compared to patients with an initial diagnosis of UPSC. Patients with a concordant diagnosis of UPSC were 5 times more likely to progress or die compared to those with a discordant EEC diagnosis (P = 0.02, P = 0.03, respectively), and their tumors were associated with higher rates of TP53 (88.9% vs. 61.5%, P = 0.04), and a lower rate of PTEN (14.8% vs. 38.5%, P = 0.09) and ARID1A (3.7% vs. 23.1%, P = 0.05) mutations. A pre-surgical diagnosis of EEC is associated with improved prognosis in patients with UPSC. Some histologically defined UPSC tumors contain endometrioid-like molecular characteristics that may confer a survival advantage, suggesting a possible need for molecular approaches to better stratify patients into risk groups.
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Large-scale genomic studies have detailed the molecular landscape of tumors from patients with high-grade serous ovarian cancers (HGSC) who underwent primary debulking surgery and correlated the identified subgroups to survival. In recent years, there is increased use of neoadjuvant chemotherapy (NACT) for patients with HGSC and while abundant data exist for patients who underwent primary debulking, little data are available on the cancer cells remaining after NACT that could lead to recurrences. We aimed to analyze gene expression profiles of NACT-treated HGSC tumor samples, and correlate them to treatment response and outcome. Tumor samples were collected from patients with stage III or IV HGSC (NACT cohort, N = 57) at the time of surgery and diagnosis (biopsy samples N = 8). Tumor content was validated by histologic examination and bioinformatics. Gene expression analysis was performed using a tailored NanoString-based assay, while sequencing was performed using MiSeq. A cross-validated survival classifier revealed patient clusters with either a "Better" or "Worse" prognostic outcome. The association with overall survival remained significant after controlling for clinical variables, and differential gene expression, gene set enrichment analyses, and the appropriate survival models were used to assess the associations between alterations in gene expression in cancer cells remaining after NACT and outcome. Pathway-based analysis of the differentially expressed genes revealed comparatively high levels of cell cycle and DNA repair gene expression in the poor outcome group. IMPLICATIONS: Our work suggests mRNA expression patterns in key genes following NACT may reflect response to treatment and outcome in patient with HGSC.
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Cistadenoma Seroso/tratamento farmacológico , Terapia Neoadjuvante , Neoplasias Ovarianas/tratamento farmacológico , Transcriptoma/genética , Cistadenoma Seroso/genética , Cistadenoma Seroso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , Resultado do TratamentoRESUMO
OBJECTIVE: Nine-valent human papillomavirus (9vHPV) vaccine efficacy against disease and cervical surgeries related to all nine vaccine components was assessed compared with a historic placebo population. This was not assessed in the 9vHPV vaccine efficacy trial since the trial was quadrivalent HPV (qHPV) vaccine-controlled, efficacy was measured for the five HPV types covered only by 9vHPV vaccine (HPV31/33/45/52/58), but not the four types covered by both vaccines (HPV6/11/16/18). METHODS: Three international, randomized, double-blind studies were conducted using the same methodology. In the 9vHPV vaccine study (NCT00543543), 7106 and 7109 women received 9vHPV or qHPV vaccine, respectively. In the historic qHPV vaccine studies (FUTURE I [NCT00092521] and II [NCT00092534]), 8810 and 8812 women received qHPV vaccine or placebo, respectively, based on the same eligibility criteria. Cervical cytological testing was performed regularly. Biopsy or definitive therapy specimens were assessed for HPV DNA. RESULTS: Among women negative for 14 HPV types prior to vaccination, incidence of high-grade cervical disease (9vHPV, nâ¯=â¯2 cases; placebo, nâ¯=â¯141 cases) and cervical surgery (9vHPV, nâ¯=â¯3 cases; placebo, nâ¯=â¯170 cases) related to the nine HPV types was reduced by 98.2% (95% confidence interval [CI], 93.6-99.7) and 97.8% (95% CI, 93.4-99.4), respectively. The 9vHPV vaccine did not prevent disease related to vaccine HPV types detected at baseline, but significantly reduced cervical, vulvar, and vaginal diseases related to other vaccine HPV types. CONCLUSIONS: Effective implementation of the 9vHPV vaccine may substantially reduce the burden of HPV-related diseases and related medical procedures. TRIAL REGISTRATIONS: clinicaltrials.gov: NCT00543543, NCT00092521, NCT00092534.
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Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/administração & dosagem , Displasia do Colo do Útero/prevenção & controle , Doenças Vaginais/prevenção & controle , Doenças da Vulva/prevenção & controle , Adulto , DNA Viral/isolamento & purificação , Método Duplo-Cego , Feminino , Humanos , Papillomaviridae/genética , Papillomaviridae/imunologia , Infecções por Papillomavirus/patologia , Vacinas contra Papillomavirus/efeitos adversos , Vacinas contra Papillomavirus/imunologia , Displasia do Colo do Útero/patologia , Displasia do Colo do Útero/cirurgia , Displasia do Colo do Útero/virologia , Doenças Vaginais/patologia , Doenças Vaginais/virologia , Doenças da Vulva/patologia , Doenças da Vulva/virologia , Adulto JovemRESUMO
OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.
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Carcinoma in Situ/virologia , Genótipo , Papillomaviridae/genética , Infecções por Papillomavirus/virologia , Neoplasias Vaginais/virologia , Neoplasias Vulvares/virologia , Adolescente , Adulto , Carcinoma in Situ/epidemiologia , Feminino , Humanos , Papillomaviridae/classificação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus , Placebos , Neoplasias do Colo do Útero/virologia , Neoplasias Vaginais/epidemiologia , Neoplasias Vulvares/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Evaluation of the impact of lower uterine segment involvement (LUSI) in type II endometrial cancer, and mutational profile of uterine papillary serous carcinomas (UPSC). METHODS: Retrospective cohort study comparing patients with type II endometrial cancer with LUSI to patients without LUSI. Genes commonly implicated in carcinogenesis were analyzed in a subgroup of 42 patients with UPSC using next generation sequencing. RESULTS: 83 patients with type II endometrial cancer were included in the study, of these, LUSI was diagnosed in 31.3%. During a median follow-up of 45.5â¯months, patients with LUSI developed more local and distant recurrences (local: 19.2% vs. 3.5%, Pâ¯=â¯.03; distant: 50% vs. 17.5%, Pâ¯=â¯.004) and progression events (73.1% vs. 26.3%, Pâ¯<â¯.001), with shorter mean progression-free survival (16â¯months compared to 26.5â¯months, Pâ¯<â¯.01). In a multivariate analysis, LUSI was the only significant pathological factor, associated with a 2.9-fold increase in the risk of progression (Pâ¯=â¯.007), and a 2.6-fold increase in the risk of death (Pâ¯=â¯.02). In the subgroup of patients with UPSC, mutations were identified in 54 genes, including TP53 (80%), PPP2R1A (40%), and PTEN (22.5%). Frequent mutations in the PTEN-PI3K-AKT signaling pathway were found in patients with tumor in the upper uterine segment only (Pâ¯=â¯.04), with PTEN being mutated in 29% of the samples (Pâ¯=â¯.07). CONCLUSION: Type II endometrial cancers presenting in the LUS have a significantly worse prognosis and this might be associated with a unique mutational profile.
RESUMO
The diagnosis of squamous intraepithelial lesions in cervical tissue specimens is subject to substantial variability. Adjunctive immunohistochemical (IHC) staining for p16 has been shown to add objective biomarker information to morphologic interpretation of hematoxylin and eosin (H&E)-stained tissues. In the CERvical Tissue AdjunctIve aNalysis (CERTAIN) study, we systematically analyzed the impact of adjunctive p16 IHC on the accuracy (agreement with reference pathology results) of diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) in the United States. Eleven hundred cervical biopsies were divided into 4 sets of 275 cases by stratified randomization. All H&E slides from each set were interpreted by 17 to 18 individual surgical pathologists, for a total of 19,250 reads by 70 surgical pathologists. After a wash-out period and blinding to original results, cases were re-read by the same pathologists using H&E+p16-stained slides. Using expert consensus diagnoses on H&E+p16 as reference, adjunctive p16 IHC use significantly improved diagnostic agreement of surgical pathologists by 4.7% (95% confidence interval [CI], 3.9, 5.4; P<0.0001). This improvement was driven by an increase of 11.5% (95% CI, 9.3, 13.5; P<0.0001) in sensitivity and an increase of 3.0% (95% CI, 2.2, 3.7; P<0.0001) in specificity. Diagnostic performance was significantly increased as well when expert consensus diagnoses established on H&E only was used as reference. Furthermore, interobserver reliability improved significantly from moderate (H&E: κ=0.58) to substantial (H&E+p16: κ=0.73; P<0.0001). Adjunctive use of p16 IHC provides more accurate and reproducible diagnostic results in the interpretation of cervical biopsies, ensuring that more patients are treated correctly without treating more patients.
Assuntos
Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Imuno-Histoquímica , Lesões Intraepiteliais Escamosas Cervicais/metabolismo , Neoplasias do Colo do Útero/química , Adulto , Biópsia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Lesões Intraepiteliais Escamosas Cervicais/patologia , Coloração e Rotulagem , Estados Unidos , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
BACKGROUND: Primary analyses of a study in young women aged 16-26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years. METHODS: We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16-26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor's study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov, number NCT00543543. FINDINGS: Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14â215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10â000 person-years in the 9vHPV and 19·0 cases per 10â000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0-99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related. INTERPRETATION: The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide. FUNDING: Merck & Co, Inc.
Assuntos
Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/administração & dosagem , Papillomavirus Humano 6/imunologia , Imunogenicidade da Vacina/imunologia , Infecções por Papillomavirus/prevenção & controle , Neoplasias do Colo do Útero/prevenção & controle , Vacinação/métodos , Adolescente , Adulto , Anticorpos Antivirais/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/imunologia , Humanos , Imunoensaio , Injeções Intramusculares , Infecções por Papillomavirus/epidemiologia , Cooperação do Paciente/estatística & dados numéricos , Segurança do Paciente , Prevenção Primária/métodos , Resultado do Tratamento , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/virologia , Adulto JovemRESUMO
Substantial evidence exists to support the introduction of molecular testing for human papillomavirus (HPV) as the primary technology in cervical cancer screening. While HPV testing is much more sensitive than cytology for detection of high-grade precancerous lesions, it is less specific. To improve efficiency, it is therefore recommended that a specific test (like cytology) be used in triaging HPV positive women to colposcopy. A number of studies have been conducted that support the use of cytology alone or in conjunction with HPV genotyping for triage. The decision to incorporate genotyping also depends on the commercial HPV test that is selected since not all tests provide results for certain individual high-risk types. Regardless of whether policy officials decide to adopt a triage approach that incorporates genotyping, the use of liquid based cytology (LBC) may also improve screening performance by reducing diagnostic delays. With LBC, the same cell suspension from a single collection may be used for HPV testing and a smear can be immediately prepared if HPV status is positive. This was a critical lesson from a community based demonstration project in Montreal (VASCAR study), where conventional cytology exists and specimen co-collection was not permitted for ethical reasons, requiring HPV positive women to return for an additional screening visit prior to colposcopy.
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Detecção Precoce de Câncer/métodos , Papillomaviridae/isolamento & purificação , Encaminhamento e Consulta , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Colposcopia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Since being introduced in the 1940s, cervical cytology - despite its limitations - has had unequivocal success in reducing cervical cancer burden in many countries. However, we now know that infection with human papillomavirus (HPV) is a necessary cause of cervical cancer and there is overwhelming evidence from large-scale clinical trials, feasibility studies and real-world experience that supports the introduction of molecular testing for HPV as the primary technology in cervical cancer screening (i.e., "HPV primary screening"). While questions remain about the most appropriate age groups for screening, screening interval and triage approach, these should not be considered barriers to implementation. Many countries are in various stages of adopting HPV primary screening, whereas others have not taken any major steps towards introduction of this approach. As a group of clinical experts and researchers in cervical cancer prevention from across Canada, we have jointly authored this comprehensive examination of the evidence to implement HPV primary screening. Our intention is to create a common understanding among policy makers, agencies, clinicians, researchers and other stakeholders about the evidence concerning HPV primary screening to catalyze the adoption of this improved approach to cervical cancer prevention. With the first cohort of vaccinated girls now turning 21, the age when routine screening typically begins, there is increased urgency to introduce HPV primary screening, whose performance may be less adversely affected compared with cervical cytology as a consequence of reduced lesion prevalence post-vaccination.
Assuntos
Testes Diagnósticos de Rotina/métodos , Detecção Precoce de Câncer/métodos , Papillomaviridae/isolamento & purificação , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/prevenção & controle , Canadá , Feminino , Humanos , Neoplasias do Colo do Útero/virologiaRESUMO
Background: High-risk human papillomavirus (HR-HPV) testing has become a preferred cervical cancer screening strategy in some countries due to its superior sensitivity over cytology-based methods for identifying cervical intraepithelial neoplasia of grade 2 or worse (CIN2+). Improved sensitivity has been accompanied by reductions in specificity and concerns regarding overscreening and overtreatment of women with transient or nonprogressing HR-HPV infections. Triage of HR-HPV+ women to colposcopy is, thus, warranted for appropriate management and treatment.Methods: Using data from the Canadian Cervical Cancer Screening Trial (CCCaST), we compared the performance of cytology and HR-HPV strategies to detect CIN2+ among HR-HPV+ women (age, 30-69 years). Colposcopy referral rates and performance gains from adding other HR-HPV genotypes to HPV16/18+ triage were also evaluated.Results: A strategy referring all women HPV16/18+ and HPV16/18-, but with atypical squamous cells of undetermined significance or worse cytology (ASC-US+) had the highest sensitivity [82.5%; 95% confidence interval (CI), 70.9%-91.0%] but yielded the highest colposcopy referral rate. HPV16/18+ triage was the next most sensitive strategy (64.1%; 95% CI, 51.1%-75.7%). Low-grade squamous intraepithelial lesion or worse cytology (LSIL+) triage yielded a low sensitivity (32.8%; 95% CI, 21.9%-45.4%) but had the most favorable specificity (93.6%; 95% CI, 91.0%-95.6%), positive predictive value (41.5%; 95% CI, 28.1%-55.9%), and colposcopy referral rate of strategies examined. HPV viral load triage strategies did not perform optimally overall. Inclusion of HR-HPV genotypes 31 and 52 to HPV16/18+ triage provided the highest sensitivities.Conclusion: Concerns surrounding HPV-based screening can be effectively mitigated via triage.Impact: Balancing the benefits of HPV-based primary cervical screening with informed management recommendations for HR-HPV+ women may decide the success of its widening utilization. Cancer Epidemiol Biomarkers Prev; 26(6); 923-9. ©2017 AACR.
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Programas de Rastreamento/métodos , Papillomaviridae/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Adulto , Idoso , Canadá , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: Sentinel lymph node (SLN) mapping has emerged as a promising solution to the ongoing debate regarding lymphadenectomy in the initial surgical management of endometrial cancer. Currently, little is known about its possible impact on location of disease recurrence compared to systematic lymphadenectomy. METHODS: In this retrospective study, 472 consecutive patients with endometrial cancer who underwent either SLN mapping (SLN cohort, n=275) or systematic lymphadenectomy (LND cohort, n=197) from sequential, non-overlapping historical time points were compared. Clinical characteristics were extracted from a prospectively gathered electronic database. Both overall and pelvic sidewall recurrence free survival (RFS) were evaluated at 48-month post-operative follow-up. RESULTS: No significant difference in overall RFS could be identified between the cohorts at 48months (HR 0.74, 95% CI 0.43-1.28, p=0.29). However, the SLN cohort had improved pelvic sidewall RFS compared to the LND cohort (HR 0.32, 95% CI 0.14-0.74, p=0.007). The pelvic sidewall recurrences accounted for 30% of recurrences in the SLN cohort (8 out of 26 recurrences) compared to 71.4% in the LND cohort (20 out of 28 recurrences). CONCLUSIONS: SLN mapping may enable more efficient detection of the LNs at greatest risk of metastasis and help to guide adjuvant therapy, which in turn seems to decrease the risk of pelvic sidewall recurrences.