Performance of a handheld point of care ultrasonography to assess IUD position compared to conventional transvaginal ultrasonography.

OBJECTIVE: To compare the performance of the abdominal handheld point-of-care ultrasonography (POCUS) Butterfly-iQ to gold standard transvaginal ultrasonography (US) in identifying the position of intrauterine devices (IUDs) in the hands of a medical doctor specialised in ultrasonography. METHODS: In this diagnostic accuracy study, a single operator conducted abdominal POCUS followed by conventional transvaginal US. Seventy patients utilising copper or hormonal IUDs were assessed between June 2021 and October 2022. IUDs were categorised as entirely within the uterine cavity or malpositioned. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for detecting malpositioned IUDs, with conventional US results serving as the reference standard. Concordance rate and Kappa coefficient were computed to assess the agreement between the two ultrasound modalities. RESULTS: Among the 70 patients, 46 (65.7%) used copper IUDs, and 24 (34.3%) used hormonal IUDs. Conventional transvaginal US showed IUDs entirely within the uterine cavity in 56 (80%) patients and 14 (20%) IUDs were malpositioned. Of the 14 malpositioned IUDs seen by conventional US, POCUS identified 13 demonstrating a sensitivity of 92.9% (66.1-99.8). Of the 56 IUDs entirely within the uterine cavity shown by conventional US, only two cases were considered malpositioned by POCUS demonstrating a specificity of 96.4% (87.7-99.6). The concordance rate was 95.7%, and the Kappa value was 0.87 in differentiating between IUDs entirely within the uterine cavity and those that were malpositioned. CONCLUSION: Abdominal POCUS using Butterfly-iQ, when administered by an imaging specialist, exhibited excellent performance in confirming IUDs entirely within the uterine cavity.

Through a smartphone-based handheld point-of-care ultrasonography it was possible to correctly evaluate the position of intrauterine devices (IUDs) in a sample of 70 patients (46 using copper and 24 using hormonal IUDs).

Prescribing errors intercepted by pharmacist intervention in care of patients hospitalised with breast and gynaecological cancer at a Brazilian teaching hospital.

Oncologic inpatients often require multiple drug therapy. They may be at higher risk of experiencing prescribing errors, which pharmacist interventions may help to avoid. This study aimed to evaluate the types of prescribing errors, pharmaceutical interventions and differences in clinical significance, in prescriptions for hospitalised patients with breast and gynaecological cancer. A cross-sectional, prospective study was conducted at the oncology ward of a clinic specialised in breast and gynaecology cancer. A clinical pharmacist analysed prescriptions, identified errors, performed interventions and classified clinical significance. A total of 1,874 prescriptions of 248 patients were evaluated; 11.5% prescriptions were involved at least in one prescribing error, totalising 283 errors. The most common error was unsafe medication due to drug interaction (89[31.4%]). Drugs for the alimentary tract and metabolism, and nervous system were the most involved in errors with statistical association (p = .0246 and p = .0002 respectively). Of the 294 interventions, 73.5% were accepted. The clinical significance of prescribing errors and interventions were classified as significant and very significant respectively. The pharmacist interventions obtained a good acceptance rate and impact significantly, avoiding prescribing errors classified as significant.

Performance of the IOTA ADNEX model in preoperative discrimination of adnexal masses in a gynecological oncology center.

OBJECTIVE: To evaluate the performance of the International Ovarian Tumor Analysis (IOTA) ADNEX model in the preoperative discrimination between benign ovarian (including tubal and para-ovarian) tumors, borderline ovarian tumors (BOT), Stage I ovarian cancer (OC), Stage II-IV OC and ovarian metastasis in a gynecological oncology center in Brazil. METHODS: This was a diagnostic accuracy study including 131 women with an adnexal mass invited to participate between February 2014 and November 2015. Before surgery, pelvic ultrasound examination was performed and serum levels of tumor marker CA 125 were measured in all women. Adnexal masses were classified according to the IOTA ADNEX model. Histopathological diagnosis was the gold standard. Receiver-operating characteristics (ROC) curve analysis was used to determine the diagnostic accuracy of the model to classify tumors into different histological types. RESULTS: Of 131 women, 63 (48.1%) had a benign ovarian tumor, 16 (12.2%) had a BOT, 17 (13.0%) had Stage I OC, 24 (18.3%) had Stage II-IV OC and 11 (8.4%) had ovarian metastasis. The area under the ROC curve (AUC) was 0.92 (95% CI, 0.88-0.97) for the basic discrimination between benign vs malignant tumors using the IOTA ADNEX model. Performance was high for the discrimination between benign vs Stage II-IV OC, BOT vs Stage II-IV OC and Stage I OC vs Stage II-IV OC, with AUCs of 0.99, 0.97 and 0.94, respectively. Performance was poor for the differentiation between BOT vs Stage I OC and between Stage I OC vs ovarian metastasis with AUCs of 0.64. CONCLUSION: The majority of adnexal masses in our study were classified correctly using the IOTA ADNEX model. On the basis of our findings, we would expect the model to aid in the management of women with an adnexal mass presenting to a gynecological oncology center. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal outcomes of high-risk human papillomavirus (HPV) infections as competing-risks events following cervical HPV test at baseline visit in the NIS-LAMS cohort.

BACKGROUND: The complex natural history of human papillomavirus (HPV) infections following a single HPV test can be modeled as competing-risks events (i.e., no-, transient- or persistent infection) in a longitudinal setting. The covariates associated with these competing events have not been previously assessed using competing-risks regression models. OBJECTIVES: To gain further insights in the outcomes of cervical HPV infections, we used univariate- and multivariate competing-risks regression models to assess the covariates associated with these competing events. STUDY DESIGN AND METHODS: Covariates associated with three competing outcomes (no-, transient- or persistent HR-HPV infection) were analysed in a sub-cohort of 1,865 women prospectively followed-up in the NIS (n = 3,187) and LAMS Study (n = 12,114). RESULTS: In multivariate competing-risks models (with two other outcomes as competing events), permanently HR-HPV negative outcome was significantly predicted only by the clearance ofASCUS+ Pap during FU, while three independent covariates predicted transient HR-HPV infections: i) number of recent (< 12 months) sexual partners (risk increased), ii) previous Pap screening history (protective), and history of previous CIN (increased risk). The two most powerful predictors of persistent HR-HPV infections were persistent ASCUS+ Pap (risk increased), and previous Pap screening history (protective). In pair-wise comparisons, number of recent sexual partners and previous CIN history increase the probability of transient HR-HPV infection against the HR-HPV negative competing event, while previous Pap screening history is protective. Persistent ASCUS+ Pap during FU and no previous Pap screening history are significantly associated with the persistent HR-HPV outcome (compared both with i) always negative, and ii) transient events), whereas multiparity is protective. CONCLUSIONS: Different covariates are associated with the three main outcomes of cervical HPV infections. The most significant covariates of each competing events are probably distinct enough to enable constructing of a risk-profile for each main outcome.

Ultrasound criteria and CA 125 as predictive variables of ovarian cancer in women with adnexal tumors.

OBJECTIVES: To evaluate the capacity to predict malignancy in women with adnexal tumors using CA 125 measurement and ultrasound criteria. METHODS: This was a cross-sectional study including 103 women with a total of 110 adnexal tumors. CA 125 level was measured in a sample of peripheral blood. Lesions were classified by ultrasound, using standardized predetermined criteria, as benign (B) or malignant (M). Those that could not be classified by these criteria were assessed subjectively. Histopathologic examination of surgical specimens was used as the gold standard. RESULTS: Of 110 tumors, 79 (71.8%) were benign and 31 (28.2%) were malignant on histopathology. Ultrasound criteria could be applied to 91 (82.7%) tumors, resulting in a sensitivity of 90%, specificity of 87%, positive predictive value (PPV) of 69% and negative predictive value (NPV) of 97%. In tumors not classifiable according to ultrasound criteria, subjective sonographic assessment gave a sensitivity of 67%, specificity of 80%, PPV of 75% and NPV of 73%. At a cut-off point of 37.4 U/mL, CA 125 had a sensitivity of 69%, a specificity of 87.8%, a PPV of 69% and a NPV of 88% for detection of malignancy. When CA 125 was associated with age and ultrasound criteria in a logistic regression model, the sensitivity and specificity increased in the subset of sonographically malignant tumors. CONCLUSION: The majority of tumors were correctly classified using ultrasound criteria. CA 125 alone performed worse than did ultrasound in discriminating malignant from benign adnexal tumors. CA 125 measurement contributed to the diagnosis of malignancy, improving overall specificity, only in sonographically malignant tumors.

Covariates of high-risk human papillomavirus (HPV) infections are distinct for incident CIN1, CIN2 and CIN3 as disclosed by competing-risks regression models.

BACKGROUND: In addition to the oncogenic human papillomavirus (HPV), several cofactors are needed in cervical carcinogenesis, but whether the HPV covariates associated with incident (i) CIN1 are different from those of incident (ii) CIN2 and (iii) CIN3 needs further assessment. OBJECTIVES: To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV covariates associated with incident CIN1, CIN2, and CIN3. STUDY DESIGN AND METHODS: HPV covariates associated with progression to CIN1, CIN2 and CIN3 were analysed in the combined cohort of the NIS (n = 3187) and LAMS study (n = 12,114), using competing-risks regression models (in panel data) for baseline HR-HPV-positive women (n = 1105), who represent a sub-cohort of all 1865 women prospectively followed-up in these two studies. RESULTS: Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2, and CIN3, respectively. Among these baseline HR-HPV-positive women, the risk profiles of incident CIN1, CIN2 and CIN3 were unique in that completely different HPV covariates were associated with progression to CIN1, CIN2 and CIN3, irrespective which categories (non-progression, CIN1, CIN2, CIN3 or all) were used as competing-risks events in univariate and multivariate models. CONCLUSIONS: These data confirm our previous analysis based on multinomial regression models implicating that distinct covariates of HR-HPV are associated with progression to CIN1, CIN2 and CIN3. This emphasises true biological differences between the three grades of CIN, which revisits the concept of combining CIN2 with CIN3 or with CIN1 in histological classification or used as a common endpoint, e.g., in HPV vaccine trials.

Risk estimates for persistent high-risk human papillomavirus infections as surrogate endpoints of progressive cervical disease critically depend on reference category: analysis of the combined prospective cohort of the New Independent States of the Former Soviet Union and Latin American Screening studies.

To make feasible future clinical trials with new-generation human papillomavirus (HPV) vaccines, novel virological surrogate endpoints of progressive disease have been proposed, including high-risk HPV (HR-HPV) persistence for six months (6M+) or 12 months (12M+). The risk estimates (relative risks [RRs]) of these 'virological endpoints' are influenced by several variables, not yet validated adequately. We compared the impact of three referent groups: (i) HPV-negative, (ii) HPV-transient, (iii) HPV-mixed outcome on the risk estimates for 6M+ or 12M+ HR-HPV persistence as predictors of progressive disease. Generalized estimating equation models were used to estimate the strength of 6M+ and 12M+ HR-HPV persistence with disease progression to squamous intraepithelial lesions (SILs), cervical intraepithelial neoplasia (CIN) grade 1+, CIN2+, CIN/SIL endpoints, comparing three optional reference categories (i)-(iii) in a prospective sub-cohort of 1865 women from the combined New Independent States of the Former Soviet Union (NIS) and Latin American Screening (LAMS) studies cohort (n = 15,301). The RRs of these viral endpoints as predictors of progressive disease are affected by the length of viral persistence (6M+ or 12M+) and the surrogate endpoint (SIL, CIN1, CIN2, CIN/SIL). Most dramatic is the effect of the referent group used in risk estimates, with the HPV-negative referent group giving the highest and most consistent RRs for both 6M+ and 12M+ viral persistence, irrespective of which surrogate is used. In addition to deciding on whether to use 6M+ or 12M+ persistence criteria, and cytological, histological or combined surrogate endpoints, one should adopt the HPV-negative referent group as the gold standard in all future studies using viral persistence as the surrogate endpoint of progressive disease.

Co-factors of high-risk human papillomavirus infections display unique profiles in incident CIN1, CIN2 and CIN3.

In addition to oncogenic 'high-risk' human papillomaviruses (HR-HPV), several co-factors are needed in cervical carcinogenesis, but it is poorly understood whether these HPV co-factors associated with incident cervical intraepithelial neoplasia (CIN) grade 1 are different from those required for progression to CIN2 and CIN3. To gain further insights into the true biological differences between CIN1, CIN2 and CIN3, we assessed HPV co-factors increasing the risk of incident CIN1, CIN2 and CIN3. Data from the New Independent States of the Former Soviet Union (NIS) Cohort (n = 3187) and the Latin American Screening (LAMS) Study (n = 12,114) were combined, and co-factors associated with progression to CIN1, CIN2 and CIN3 were analysed using multinomial logistic regression models with all covariates recorded at baseline. HR-HPV-positive women (n = 1105) represented a subcohort of all 1865 women prospectively followed up in both studies. Altogether, 90 (4.8%), 39 (2.1%) and 14 (1.4%) cases progressed to CIN1, CIN2 and CIN3, respectively. Baseline HR-HPV was the single most powerful predictor of incident CIN1, CIN2 and CIN3. When controlled for residual HPV confounding by analysing HR-HPV-positive women only, the risk profiles of incident CIN1, CIN2 and CIN3 were unique. Completely different HPV co-factors were associated with progression to CIN1, CIN2 and CIN3 in univariate and multivariate analyses, irrespective of whether non-progression, CIN1 or CIN2 was used as the reference outcome. HPV co-factors associated with progression to CIN1, CIN2 and CIN3 display unique profiles, implicating genuine biological differences between the three CIN grades, which prompts us to re-visit the concept of combining CIN2 with CIN3 or CIN1.

Ex vivo expansion of CD56+ NK and NKT-like lymphocytes from peripheral blood mononuclear cells of patients with ovarian neoplasia.

Methods for ex vivo expansion of natural killer (NK) cells have allowed obtaining enough numbers of human NK cells for clinical trials. However, the evaluation of these methods has been mostly limited to haematological malignancies. This study aimed at evaluating a method for selective expansion of NK cells when applied in peripheral blood mononuclear cells (PBMC) of patients with ovarian neoplasia. PBMC from 13 volunteer patients with ovarian neoplasia, seven benign and six malignant tumours, were cultured in CellGro medium supplemented with anti-CD3 (9-10 initial days), IL-2 and foetal bovine serum for 21 days. The resulting effector cells were evaluated for their phenotype, cytotoxicity and cytokine secretion. PBMC cultures resulted in multiple populations (NK, NKT and T) of effector cells, enriched with CD56(+) lymphocytes. NK cells from patients with benign and malignant ovarian neoplasia were expanded 139.6 ± 63.4 and 82.7 ± 25.3-fold, respectively, being the largest lymphocyte subtype among CD56(+) population. Effector cells expanded from patients with malignant ovarian neoplasia had higher proportion of T lymphocytes and altered cytokine production patterns, characterized by lower INF-γ, TNF-α and higher IL-4, compared with patients with benign ovarian neoplasia. Effector cells were cytotoxic against K562 and OVCAR3 cell lines. Cytotoxicity was significantly higher (P < 0.05) using magnetically separated CD56(+) effector cell fractions compared with CD56-deprived ones. The present study demonstrates the feasibility of the culture system employed to generate effector cells, enriched with CD56(+) lymphocytes, from PBMC of patients with ovarian neoplasia. NK cells were the largest lymphocyte subtype among the CD56(+) population and the main variable among the final effector cell preparation affecting target cell killing.

Self-sampling for human papillomavirus (HPV) testing as cervical cancer screening option. Experience from the LAMS study.

PURPOSE: To compare Hybrid Capture II (HC2) in detecting high-risk (HR) HPV in patient-collected vaginal samples with those obtained using gynaecologist collected samples. METHODS: Patients were submitted to Pap smears, visual inspection with acetic acid (VIA) and HC2 for hr-HPV. RESULTS: A total of 1,081 HC2 tests for HR-HPV were performed: 770 (71.2%) samples were collected by a physician and 311 (28.8%) were self-collected by the patients. In detecting any cervical lesion, the sensitivity of HC2 collected by a physician was higher (92.86%) than that (37.5%) in the self-sampling group. Negative predictive value (NPV) was high for both, 99.69% and 93.75%, respectively. Using the CIN2 cutoff, performance of HC2 was significantly improved: 92.9% and 62.5%, respectively. HC2 specificity for any cervical lesion and for CIN2 or higher were close to 90% in both groups. CONCLUSIONS: Self-sampled HPV testing is a powerful option to increase the detection of cervical lesions in women segregated from prevention programs.

Safety of screening with Human papillomavirus testing for cervical cancer at three-year intervals in a high-risk population: experience from the LAMS study.

OBJECTIVES: To assess whether human papillomavirus (HPV) testing is a safe enough approach to warrant extension of the screening intervals of baseline Papanicolaou (Pap)-/HPV- women in low-income settings. METHODS: Of the >1000 women prospectively followed up as part of the Latin American Screening (LAMS) Study in São Paulo, Campinas, Porto Alegre) and Buenos Aires, 470 women with both baseline cytology and Hybrid Capture 2 (HC2) results available were included in this analysis. These baseline Pap-negative and HC2- or HC2+ women were controlled at six-month intervals with colposcopy, HC2 and Pap to assess the cumulative risk of incident Pap smear abnormalities and their predictive factors. RESULTS: Of the 470 women, 324 (68.9%) were high-risk HPV (hrHPV) positive and 146 (31.1%) were negative. Having two or more lifetime sex partners (odds ratio [OR] = 2.63; 95% CI 1.70-3.51) and women using hormonal contraception (OR = 2.21; 95% CI 1.40-3.51) were at increased risk for baseline hrHPV infection. Baseline hrHPV+ women had a significantly increased risk of incident abnormal Pap smears during the follow-up. Survival curves deviate from each other starting at month 24 onwards, when hrHPV+ women start rapidly accumulating incident Pap smear abnormalities, including atypical squamous cells (ASC) or worse (log-rank; P < 0.001), low-grade squamous intraepithelial lesions (LSIL) or worse (P < 0.001) and high-grade squamous intraepithelial lesions (HSIL) (P = 0.03). Among the baseline hrHPV- women, the acquisition of incident hrHPV during the follow-up period significantly increased the risk of incident cytological abnormalities (hazard ratio = 3.5; 95% CI 1.1-11.7). CONCLUSION: These data implicate that HPV testing for hrHPV types might be a safe enough approach to warrant extension of the screening interval of hrHPV-/Pap-women even in low-resource settings. Although some women will inevitably contract hrHPV, the process to develop HSIL will be long enough to enable their detection at the next screening round (e.g. after three years).

Rastreamento anterior para câncer de colo uterino em mulheres com alterações citológicas ou histológicas / Previous screening for cervical cancer among women with cytological and histological abnormalities

OBJETIVO: Analisar a história de rastreamento citológico anterior em mulheres que apresentaram alterações citológicas e confirmação histológica para câncer cervical. MÉTODOS: Estudo transversal com 5.485 mulheres (15-65 anos) que se submeteram a rastreamento para o câncer cervical entre fevereiro de 2002 a março de 2003, em São Paulo e Campinas, SP. Aplicou-se questionário comportamental e foi feita a coleta da citologia oncológica convencional ou em base líquida. Para as participantes com alterações citológicas indicou-se colposcopia e, nos casos anormais, procedeu-se à biópsia cervical. Para investigar a associação entre as variáveis qualitativas e o resultado da citologia, utilizou-se o teste de qui-quadrado de Pearson com nível de significância de 5 por cento. RESULTADOS: Dentre os resultados citológicos, 354 (6,4 por cento) foram anormais, detectando-se 41 lesões intra-epitelial escamosa de alto grau e três carcinomas; em 92,6 por cento revelaram-se normais. De 289 colposcopias realizadas, 145 (50,2 por cento) apresentaram alterações. Dentre as biópsias cervicais foram encontrados 14 casos de neoplasia intra-epitelial cervical grau 3 e quatro carcinomas. Referiram ter realizado exame citológico prévio: 100 por cento das mulheres com citologia compatível com carcinoma, 97,6 por cento das que apresentaram lesões intra-epiteliais de alto grau, 100 por cento daquelas com confirmação histológica de carcinoma cervical, e 92,9 por cento das mulheres com neoplasia intra-epitelial cervical grau 3. A realização de citologia anterior em período inferior a três anos foi referida, respectivamente, por 86,5 por cento e 92,8 por cento dessas participantes com alterações citológicas e histológicas. CONCLUSÕES: Entre as mulheres que apresentaram confirmação histológica de neoplasia intra-epitelial cervical grau 3 ou carcinoma e aquelas que não apresentaram alterações histológicas não houve diferença estatisticamente significante do número de exames...

OBJECTIVE: To examine previous Pap smear history in women screened for cervical cancer with cytological or histological abnormalities. METHODS: Cross-sectional study in a sample of 5,485 women (15-65 years old) who self-referred to cervical cancer screening in Sao Paulo and Campinas, Southeastern Brazil, between February 2002 and March 2003. A behavioral questionnaire was applied and cervical specimens were obtained for testing by Pap smears or liquid-based cytology. Women who had abnormal cytology were referred for colposcopic examination and, if abnormal, for cervical punch biopsy. To explore factors associated to cervical abnormalities Pearson's chi-was conduted square test at a 5 percent significance level. RESULTS: Cytological abnormalities were found in 354 women (6.4 percent) and included 41 high-grade squamous intra-epithelial lesions and 3 carcinomas; 92.7 percent were normal results. Colposcopy was performed in 289 women, and 145 (50.2 percent) showed abnormal results. Punch biopsies showed 14 cervical intraepithelial neoplasias grade 3 and 4 carcinomas. Previous Pap smears were reported in all women who had cytology suspected of carcinoma, 97.6 percent of those with high-grade squamous intra-epithelial lesions, all women with histological diagnosis of carcinoma and 92.9 percent of those who had cervical intraepithelial neoplasias grade 3 histologically. Previous Pap smear in the last tree years was reported by 86.5 percent and 92.8 percent of women with abnormal cytology and biopsy, respectively. CONCLUSIONS: There was no statistically significant difference regarding the number of Pap tests and time since their last test between women with histologically diagnosed carcinoma and cervical intraepithelial neoplasia grade 3 compared with those with normal cytology.

Drug addiction is not an independent risk factor for oncogenic human papillomavirus infections or high-grade cervical intraepithelial neoplasia: case-control study nested within the Latin American Screening study cohort.

Drug abuse (addiction) has been listed among the risk factors for human papillomavirus (HPV) infections, but no case-control studies exist to rule out sexual behaviour and other potential confounders. The aim of this study is to evaluate the role of drug addiction as an independent predictor of HR-HPV infections and (cervical intraepithelial neoplasia) CIN2+ in an age-matched case-control (1:4) study nested within the prospective Latin American Screening (LAMS) study cohort. All 109 women in the LAMS cohort (n=12,114) reporting drug abuse/addiction were matched with four controls (n = 436) of non-abusers strictly by age. Conditional logistic regression analysis was used to estimate the co-variates of drug abuse, and the whole series (n=545) was analysed for predictors of HR-HPV and CIN2+ using univariate and multivariate regression models. Oncogenic HPV infections were significantly (P=0.019) more prevalent among abusers (37.7%) than in controls (21.9%), but there was no difference in high-grade squamous intraepithelial lesions (P=0.180) or CIN2+ lesions (P=0.201). In multivariate conditional logistic regression, number of lifetime sexual partners (P=0.0001), ever smokers (P=0.0001), non-use of OCs (P=0.013), ever having sexually transmitted diseases (STD) (P=0.041) and no previous Pap smear (P=0.027) were independent co-variates of drug addiction. Drug abuse was not an independent risk factor of high-risk (HR)-HPV infection, which was significantly predicted by (1) age below 30 years (P=0.045), (2) more than five lifetime sexual partners (P=0.046) and (3) being current smoker (P=0.0001). In multivariate model, only HR-HPV infection was an independent risk factor of CIN2+ (P=0.031), with adjusted OR=11.33 (95% CI 1.25-102.50). These data indicate that drug addiction is not an independent risk factor of either HR-HPV infections or CIN2+, but the increased prevalence of HR-HPV infections is explained by the high-risk sexual behaviour and smoking habits of these women.

[Previous screening for cervical cancer among women with cytological and histological abnormalities]. / Rastreamento anterior para câncer de colo uterino em mulheres com alterações citológicas ou histológicas.

OBJECTIVE: To examine previous Pap smear history in women screened for cervical cancer with cytological or histological abnormalities. METHODS: Cross-sectional study in a sample of 5,485 women (15-65 years old) who self-referred to cervical cancer screening in Sao Paulo and Campinas, Southeastern Brazil, between February 2002 and March 2003. A behavioral questionnaire was applied and cervical specimens were obtained for testing by Pap smears or liquid-based cytology. Women who had abnormal cytology were referred for colposcopic examination and, if abnormal, for cervical punch biopsy. To explore factors associated to cervical abnormalities Pearson's chi-square test was conducted at a 5% significance level. RESULTS: Cytological abnormalities were found in 354 women (6.4%) and included 41 high-grade squamous intra-epithelial lesions and 3 carcinomas; 92.7% were normal results. Colposcopy was performed in 289 women, and 145 (50.2%) showed abnormal results. Punch biopsies showed 14 cervical intraepithelial neoplasias grade 3 and 4 carcinomas. Previous Pap smears were reported in all women who had cytology suspected of carcinoma, 97.6% of those with high-grade squamous intra-epithelial lesions, all women with histological diagnosis of carcinoma and 92.9% of those who had cervical intraepithelial neoplasias grade 3 histologically. Previous Pap smear in the last tree years was reported by 86.5% and 92.8% of women with abnormal cytology and biopsy, respectively. CONCLUSIONS: There was no statistically significant difference regarding the number of Pap tests and time since their last test between women with histologically diagnosed carcinoma and cervical intraepithelial neoplasia grade 3 compared with those with normal cytology.

Endocervical glandular cell abnormalities in conventional cervical smears: evaluation of the performance of cytomorphological criteria and HPV testing in predicting neoplasia.

OBJECTIVE: To analyse the correlation between cytomorphological criteria in smears with atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) and human papillomavirus (HPV) reflex test results with different neoplastic histological diagnoses, particularly to distinguish between glandular and squamous neoplasia. METHODS: A series of 155 women with glandular abnormalities in their conventional cervical smears was included: 106 with AGC, 35 with AGC associated with high-grade squamous intraepithelial lesion (HSIL) and 14 with AIS. Two reviewers evaluated 35 cytomorphological criteria and hybrid capture II (HCII) was performed in all cases. Colposcopy was carried out in all cases and biopsy in 126/155. For statistical purposes, predictive values and odds ratio (OR) were calculated, followed by chi-square automatic interaction detection. RESULTS: Histology detected 56 cases of squamous and 17 of glandular intraepithelial or invasive neoplasia. Predictive values of the papillary groups and feathering criteria for glandular neoplasia were, respectively, 80.0% and 73.3%. Feathering was the criterion with the highest OR for distinguishing glandular from squamous neoplasia and also for distinguishing between glandular and non-neoplastic diagnosis. Rosettes and pseudostratified strips did not perform as well. Multivariant Classification and Regression Trees analysis identified feathering as the best criterion for distinguishing between glandular, squamous and non-neoplastic diagnoses regardless of HPV status. CONCLUSIONS: Feathering was the best criterion for predicting glandular neoplasia.

Expression of p16 and cervical infection with high-risk human papillomavirus are not related to p53 activity in cervical intraepithelial neoplasia.

The objective of the study was to investigate the expression of p53 and p16(INK4a) in cervical intraepithelial neoplasia (CIN) and their relation with disease severity and high-risk human papillomavirus (HR-HPV) status. A series of 125 women with previous positive Pap smear were selected for this cross-sectional study. All patients underwent gynecological examination, including colposcopy. Specimens for Pap smears, Hybrid Capture 2 (HC2) test, and pathologic analysis were obtained. After evaluation of CIN grade, immunohistochemical detection of proteins p53 and p16(INK4a) was performed on paraffin-embedded sections. The extent of immunoexpression of both proteins was analyzed in relation to CIN grade and HR-HPV status. CIN was graded as 1 in 21, 2 in 17, and 3 in 87 specimens. p16(INK4a) positivity (at least 5% of epithelial cells stained) was found in 99 of 125 cases (79.2%) and was significantly higher in high-grade lesions as compared to low-grade CIN (P < 0.001). The expression of p53 did not differ across histologic strata. Protein expression neither of p16(INK4a) nor of p53 correlated with HR-HPV status. Expression of p16(INK4a) was not related with that of p53. Our study gives further support to previous findings of strong association of p16(INK4a) immunostaining with severity of epithelial atypia, but this protein may not be considered a predictor of HR-HPV status determined with HC2. By contrast, immunoexpression of p53 was related neither to CIN grade nor to HR-HPV status.

Cell proliferation activity unrelated to COX-2 expression in ovarian tumors.

The objective of this study was to assess the expression of Cyclooxygenase-2 (COX-2) and cell proliferation activity (Ki67 expression) in benign, borderline, and malignant serous and mucinous ovarian tumors. Expression of COX-2 and Ki67 proteins were evaluated by immunohistochemistry, in paraffin-embedded sections of ovarian epithelial tumors. The study included 113 serous (67 benign, 15 borderline, and 31 malignant) and 85 mucinous (48 benign, 28 borderline, and 9 malignant) tumors, removed from women who underwent laparotomy between January 1997 and December 2003. From benign to malignant tumors, there was a progressive positive trend in COX-2 expression in both serous and mucinous tumors, more evident in mucinous ones (P < 0.001). Comparing histologic types, COX-2 expression was more prominent in serous than in mucinous benign tumors (P < 0.01), but this difference was not significant in the borderline (P= 0.11) or malignant categories (P= 0.71). There was a progressive Ki67 positivity in line with the tumor histologic gradient for both serous (P < 0.01) and mucinous lesions (P < 0.01), but this increasing expression did not correlate with COX-2 expression in the present series (P= 0.78). There was a higher COX-2 expression in serous ovarian adenomas than in mucinous ones. COX-2 positivity increases in line with the morphologic gradient, from benign to malignant in both histologic types, but it was more prominent in mucinous lesions, pointing to different oncogenic pathways related to different histologic types. A correlation between the expression of COX-2 and Ki67 was not found, suggesting that COX-2 may be required for carcinogenesis, but this pathway is not responsible for cell proliferation in ovarian tumors.

Human papillomavirus testing as an optional screening tool in low-resource settings of Latin America: experience from the Latin American Screening study.

Hybrid capture II (HC II) test for oncogenic human papillomaviruses (HPV) was carried out in a cohort of 4284 women at their first clinical visit. Overall prevalence of HPV was 17.1%, decreasing with age from 33.9% among women below 20 years to only 11.0% among those older than 41 years. HPV prevalence was significantly higher among current smokers (odds ratio [OR] = 1.31; 95% CI 1.1-1.6), in women with two or more lifetime sexual partners (OR = 1.9; 95% CI 1.6-2.4), and those women with two or more sexual partners during the past 12 months prior to examination (OR = 1.6; 95% CI 1.2-2.2). HPV detection increased in parallel with increasing cytologic abnormality, being highest in women with high-grade squamous intraepithelial lesion (P= 0.001). Specificity of the HPV test in detecting histologically confirmed cervical disease was 85% (95% CI 83.9-86.1). Sensitivity of the HPV test in detecting histologic abnormalities increased in parallel with disease severity, ranging from 51.5% for cervical intraepithelial neoplasia (CIN) 1 to 96.5% for CIN 3 and 100.0% for cancer, with respective decline of positive predictive value. These data suggest that HPV testing with HC II assay might be a viable screening tool among this population with relatively high prevalence of cervical disease.

Prediction of high-grade cervical disease with human papillomavirus detection in women with glandular and squamous cytologic abnormalities.

The objective of this study was to assess whether human papillomavirus (HPV) detection with hybrid capture II (HC II) can help predict the presence and the nature, glandular or squamous, of histologic cervical lesions in women referred due to atypical glandular cells (AGC) or high-grade squamous intraepithelial lesion (HSIL). A total of 247 women were included. Referral Pap smears comprised AGC (51 cases), AGC plus HSIL (28 cases), adenocarcinoma in situ (10 cases), and HSIL (158 cases). All patients were tested for high-risk HPV with HC II and had a histologic assessment of their cervix. Histologic analysis showed 38 women with (15.3%) cervicitis, 194 with (75.5%) squamous lesions, and 15 with (9.2%) glandular neoplasia. The overall rate of high-risk HPV detection was 77%. Almost 70% of AGC-HPV-negative patients did not have a pathologically proven cervical neoplasia, whereas 76% of women with AGC-HPV-positive result were diagnosed with a squamous or glandular neoplasia. Most (95%) of the lesions in patients with AGC-HSIL were of squamous nature, and HPV detection did not contribute to their differentiation from glandular lesions. We conclude that in women with AGC, HPV positivity strongly correlated with the presence of glandular or squamous cervical lesion but did not help distinguishing women with squamous from those with glandular neoplasia.

Atypical glandular cells: criteria to discriminate benign from neoplastic lesions and squamous from glandular neoplasia.

OBJECTIVE: To evaluate the presence of some criteria in cervical smears with atypical glandular cells and their correlation with histological patterns to identify pre-neoplastic and neoplastic lesions. METHODS: Seventy-three women referred with an atypical glandular cell smear, who had undergone conization or hysterectomy, were included in this study. Referral Pap smears were reviewed using the set of 27 cyto-morphological criteria that was correlated with the histological diagnosis. RESULTS: Histological results showed intraepithelial or invasive neoplasia in 35 (48%) cases and benign lesions in 38 (52%) cases. After logistic regression and decision tree analysis an increased nuclear/cytoplasmic ratio and the presence of dyskeratotic cells were strongly associated with intraepithelial or invasive neoplasia and the differential cyto-morphological criteria for glandular lesions were decreased cytoplasm, irregular nuclear membranes and the presence of nucleoli. CONCLUSION: The analysis of individual cyto-morphological criteria can better predict intraepithelial or invasive neoplasia and differentiate glandular from squamous lesions.